1
00:00:04,723 --> 00:00:06,091
HELLO AND GOOD MORNING,

2
00:00:06,091 --> 00:00:06,358
EVERYONE.

3
00:00:06,358 --> 00:00:11,330
HWE WOULD LIKE TO WELCOME YOU TO

4
00:00:11,330 --> 00:00:12,865
THE HEALTH AND AGING

5
00:00:12,865 --> 00:00:14,266
TRAJECTORIES, SHARED AND

6
00:00:14,266 --> 00:00:16,568
COMPETING RISKS AND RESILIENCES

7
00:00:16,568 --> 00:00:18,537
FOR CHRONIC DISEASES ASSOCIATED

8
00:00:18,537 --> 00:00:19,304
WITH AGING.

9
00:00:19,304 --> 00:00:20,606
AGAIN WE WELCOME YOU.

10
00:00:20,606 --> 00:00:22,908
SO GOOD MORNING, MY NAME IS

11
00:00:22,908 --> 00:00:25,978
DEIRDRE O'NEILL, I AM THE NHLBI

12
00:00:25,978 --> 00:00:26,845
WORKSHOP SUPPORT COORDINATOR.

13
00:00:26,845 --> 00:00:30,449
THANKS AGAIN FOR JOINING US

14
00:00:30,449 --> 00:00:32,885
VIRTUALLY.

15
00:00:32,885 --> 00:00:35,587
AS WE WELCOME YOU TODAY, WE JUST

16
00:00:35,587 --> 00:00:36,922
WANT TO SAY THAT WE'RE VERY

17
00:00:36,922 --> 00:00:37,689
EXCITED FOR EVERYTHING THAT WE

18
00:00:37,689 --> 00:00:38,557
HAVE PUT TOGETHER.

19
00:00:38,557 --> 00:00:40,192
AND THEN WE'RE GOING TO HAVE

20
00:00:40,192 --> 00:00:43,262
SOME WELCOME AND OPENING

21
00:00:43,262 --> 00:00:48,834
HOUSEKEEPING SLIDES READ BY

22
00:00:48,834 --> 00:00:49,101
GABRIELA.

23
00:00:49,101 --> 00:00:50,903
>> GOOD MORNING, EVERYONE.

24
00:00:50,903 --> 00:00:53,972
MY NAME IS GABRIELA RISCUTA, AND

25
00:00:53,972 --> 00:00:56,608
I AM A PROGRAM OFFICER IN THE

26
00:00:56,608 --> 00:01:00,012
DIVISION OF CANCER PREVENTION AT

27
00:01:00,012 --> 00:01:00,612
THE NATIONAL CANCER INSTITUTE

28
00:01:00,612 --> 00:01:01,880
AND I'M ONE OF THE CO-CHAIRS OF

29
00:01:01,880 --> 00:01:09,421
THIS WORKSHOP SUPPORTED BY NCI,

30
00:01:09,421 --> 00:01:11,723
NHLBI, ODS AND NIA.

31
00:01:11,723 --> 00:01:15,360
IT IS MY PLEASURE TO WELCOME YOU

32
00:01:15,360 --> 00:01:19,231
ALL TO THIS INFORMATIVE WORKSHOP

33
00:01:19,231 --> 00:01:20,432
AND THANK YOU FOR TAKING TIME

34
00:01:20,432 --> 00:01:23,268
FROM YOUR BUSY SCHEDULE TO

35
00:01:23,268 --> 00:01:26,805
PARTICIPATE AND HELP US IDENTIFY

36
00:01:26,805 --> 00:01:28,073
NEW GAPS IN KNOWLEDGE AND FUTURE

37
00:01:28,073 --> 00:01:29,608
DIRECTIONS OF RESEARCHMENT AS

38
00:01:29,608 --> 00:01:33,211
YOU ALL KNOW, LIFE EXPECTANCY IS

39
00:01:33,211 --> 00:01:36,081
GOING UP, WHICH IS WONDERFUL

40
00:01:36,081 --> 00:01:40,018
NEWS, BUT THE HEALTHY LIFE

41
00:01:40,018 --> 00:01:41,219
EXPECTANCY IS NOT IMPROVING AT

42
00:01:41,219 --> 00:01:41,753
THE SAME SPEED.

43
00:01:41,753 --> 00:01:43,055
SO THE PURPOSE OF THIS WORKSHOP

44
00:01:43,055 --> 00:01:44,289
IS TO INQUIRE IF THERE ARE

45
00:01:44,289 --> 00:01:47,793
CERTAIN PATHWAYS OF AGING

46
00:01:47,793 --> 00:01:49,328
LEADING TO ONE CHRONIC DISEASE

47
00:01:49,328 --> 00:01:51,830
VERSUS ANOTHER, OR THERE ARE

48
00:01:51,830 --> 00:01:53,498
COMPETING RISKS OR EVEN BETTER

49
00:01:53,498 --> 00:01:56,001
IF WE CAN FIND THE PATHWAY

50
00:01:56,001 --> 00:01:56,768
TOWARD RESILIENCE.

51
00:01:56,768 --> 00:02:00,072
SO WE INVITED THE BEST EXPERTS

52
00:02:00,072 --> 00:02:01,039
IN THE WORLD AND THEY ARE HERE

53
00:02:01,039 --> 00:02:04,676
TODAY TO ENLIGHTEN US AND SHARE

54
00:02:04,676 --> 00:02:08,146
WITH US THEIR TREMENDOUS WORK

55
00:02:08,146 --> 00:02:09,881
AND HELP US TO FIND FUTURE

56
00:02:09,881 --> 00:02:11,216
DIRECTION OF RESEARCH AND I ALSO

57
00:02:11,216 --> 00:02:14,252
WANT TO THANK YOU NOT ONLY TO

58
00:02:14,252 --> 00:02:15,587
THE SPEAKERS BUT ALSO TO THE

59
00:02:15,587 --> 00:02:18,090
PLANNING COMMITTEE, WHICH WORK

60
00:02:18,090 --> 00:02:20,959
VERY HARD TO PUT THIS WORKSHOP

61
00:02:20,959 --> 00:02:22,060
TOGETHER, SO I'M GOING TO START

62
00:02:22,060 --> 00:02:32,371
WITH MY CO-CHAIRS.

63
00:02:47,252 --> 00:02:48,220
VERY SPECIAL THANK YOU, SHE DID

64
00:02:48,220 --> 00:02:58,597
A LOT, A LOT OF WORK.

65
00:03:02,167 --> 00:03:06,405
AND OUR WONDERFUL CONTRACTOR

66
00:03:06,405 --> 00:03:11,510
TEAM LED BY DEIRDRE O'NEILL.

67
00:03:11,510 --> 00:03:12,611
WE HOPE EVERYTHING IS GOING TO

68
00:03:12,611 --> 00:03:15,013
GO WELL.

69
00:03:15,013 --> 00:03:18,216
SO I HAVE JUST A VERY FEW

70
00:03:18,216 --> 00:03:19,951
HOUSEKEEPING INFORMATION FOR

71
00:03:19,951 --> 00:03:20,285
YOU.

72
00:03:20,285 --> 00:03:25,290
SO THIS IS AN ENTIRELY VIRTUAL

73
00:03:25,290 --> 00:03:26,425
WORKSHOP AND THIS WORKSHOP IS

74
00:03:26,425 --> 00:03:29,695
BEING RECORDED AND WILL BE

75
00:03:29,695 --> 00:03:32,431
AVAILABLE FOR FUTURE VIEWING AT

76
00:03:32,431 --> 00:03:35,267
NIH VIDEOCAST WEB SIGH.

77
00:03:35,267 --> 00:03:37,002
THE WORKSHOP COMPRISES OF FOUR

78
00:03:37,002 --> 00:03:37,269
SESSIONS.

79
00:03:37,269 --> 00:03:39,571
WE WILL HAVE TWO COFFEE BREAKS

80
00:03:39,571 --> 00:03:44,676
AND A LUNCH BREAK AFTER EACH D 

81
00:03:44,676 --> 00:03:45,110
DAY.

82
00:03:45,110 --> 00:03:47,312
KEYNOTE SPEAKERS WILL PRESENT

83
00:03:47,312 --> 00:03:50,048
FOR 25 MINUTES FOLLOWED BY FIVE

84
00:03:50,048 --> 00:03:52,451
MINUTES Q & A, AND ALL OTHER

85
00:03:52,451 --> 00:03:54,086
SPEAKERS WILL PRESENT 15 MINUTES

86
00:03:54,086 --> 00:03:57,823
FOLLOWED BY 5 MINUTES Q & A.

87
00:03:57,823 --> 00:03:59,124
TO MAKE SURE WE WILL STAY ON

88
00:03:59,124 --> 00:04:03,195
TIME, THERE WILL BE ONE TWO

89
00:04:03,195 --> 00:04:04,463
MINUTES BEFORE THEIR TIME WILL

90
00:04:04,463 --> 00:04:05,030
END.

91
00:04:05,030 --> 00:04:09,401
AND WE HAVE 20 MINUTES MODERATED

92
00:04:09,401 --> 00:04:13,105
PANEL DISCUSSION AFTER EACH

93
00:04:13,105 --> 00:04:13,672
SESSIONS.

94
00:04:13,672 --> 00:04:18,443
THE MODERATORS ALSO WILL KEEP

95
00:04:18,443 --> 00:04:19,244
EVERYONE ON TIME.

96
00:04:19,244 --> 00:04:20,879
WE HOPE THERE WILL BE NO ISSUES,

97
00:04:20,879 --> 00:04:22,748
BUT IN CASE OF SYSTEM-WIDE

98
00:04:22,748 --> 00:04:26,384
TECHNICAL DIFFICULTIES, PLEASE

99
00:04:26,384 --> 00:04:31,289
WAIT A COUPLE OF SECONDS, DO NOT

100
00:04:31,289 --> 00:04:34,359
TURN OFF YOUR ZOOM.

101
00:04:34,359 --> 00:04:35,694
IF THE PROBLEM WILL TAKE TOO

102
00:04:35,694 --> 00:04:36,962
LONG, THEN PLEASE CHECK YOUR

103
00:04:36,962 --> 00:04:41,233
EMAIL AND YOU'LL FIND DIRECTION

104
00:04:41,233 --> 00:04:42,567
OF HOW WE CAN MOVE FORWARD.

105
00:04:42,567 --> 00:04:45,203
AND IF YOU WANT TO ASK, WE

106
00:04:45,203 --> 00:04:48,807
ENCOURAGE YOU TO SEND YOUR

107
00:04:48,807 --> 00:04:50,108
QUESTION THROUGH THE Q & A,

108
00:04:50,108 --> 00:04:52,878
PLEASE MENTION THE SPEAKER NAME

109
00:04:52,878 --> 00:04:54,613
SO WE KNOW TO WHICH SPEAKER YOU

110
00:04:54,613 --> 00:04:58,784
ARE ADDRESSING YOUR QUESTION.

111
00:04:58,784 --> 00:05:00,085
THANK YOU AGAIN AND NOW IT'S MY

112
00:05:00,085 --> 00:05:03,155
PLEASURE TO INTRODUCE MY

113
00:05:03,155 --> 00:05:04,689
CO-CHAIR, DR. ZORINA GALIS.

114
00:05:04,689 --> 00:05:06,224
DO YOU WANT TO SAY A FEW WORDS?

115
00:05:06,224 --> 00:05:06,658
>> SURE.

116
00:05:06,658 --> 00:05:10,595
THANK YOU SO MUCH FOR THE

117
00:05:10,595 --> 00:05:11,329
OPPORTUNITY TO SAY SOMETHING.

118
00:05:11,329 --> 00:05:12,864
THANK YOU, YOU WERE VERY

119
00:05:12,864 --> 00:05:16,067
COMPREHENSIVE IN YOUR REMARKS.

120
00:05:16,067 --> 00:05:19,571
BUT I WOULD LIKE TO ALSO ADD A

121
00:05:19,571 --> 00:05:24,042
VERY BRIEF WELCOME TO ALL OF YOU

122
00:05:24,042 --> 00:05:28,413
AND ALSO SOME THINGS FROM THE

123
00:05:28,413 --> 00:05:31,082
VIEW OF NHLBI.

124
00:05:31,082 --> 00:05:32,717
WE ARE USING ALL THESE ACRONYMS.

125
00:05:32,717 --> 00:05:34,352
I HOPE PEOPLE KNOW THIS IS THE

126
00:05:34,352 --> 00:05:35,453
HEART, LUNG AND BLOOD INSTITUTE

127
00:05:35,453 --> 00:05:37,522
SO I'M REPRESENTING THE HEART,

128
00:05:37,522 --> 00:05:38,957
LUNG AND BLOOD INSTITUTE.

129
00:05:38,957 --> 00:05:40,926
SO FIRST OF ALL, AS GABRIELA

130
00:05:40,926 --> 00:05:44,629
POINTED OUT, THIS WAS THE DREAM

131
00:05:44,629 --> 00:05:46,832
OF A GROUP OF DEDICATED NIH

132
00:05:46,832 --> 00:05:50,235
EMPLOYEES FROM SEVERAL

133
00:05:50,235 --> 00:05:53,505
INSTITUTES THAT INCLUDE AS YOU

134
00:05:53,505 --> 00:05:55,574
HEARD CANCER, NCI, HEART, LUNG

135
00:05:55,574 --> 00:06:00,612
AND BLOOD, NHLBI, NEUROLOGICAL

136
00:06:00,612 --> 00:06:02,480
DISORDER AND STROKE, NINDS, AND

137
00:06:02,480 --> 00:06:04,883
THE AGING INSTITUTE, NIA, AS

138
00:06:04,883 --> 00:06:06,218
WELL AS THE OFFICE OF THE

139
00:06:06,218 --> 00:06:09,688
DIRECTOR.

140
00:06:09,688 --> 00:06:15,060
SO AS OUR NAMES INDICATE BY THE

141
00:06:15,060 --> 00:06:17,596
WISDOM OF THE FOUNDERS, WE ARE

142
00:06:17,596 --> 00:06:19,231
FOCUSING IN VARIOUS INSTITUTES

143
00:06:19,231 --> 00:06:22,734
EITHER ON SPECIFIC BODY PARTS OR

144
00:06:22,734 --> 00:06:27,205
THEIR FUNCTION, THEIR CYST

145
00:06:27,205 --> 00:06:28,406
DYSFUNCTION OR POTENTIALLY ON

146
00:06:28,406 --> 00:06:31,743
SPECIFIC CONDITIONS OR DIFFERENT

147
00:06:31,743 --> 00:06:32,244
LIFE STAGES.

148
00:06:32,244 --> 00:06:35,647
SO WE ARE AWARE OF THAT, AND THE

149
00:06:35,647 --> 00:06:37,716
GROUP THAT YOU ALREADY HEARD

150
00:06:37,716 --> 00:06:40,685
MENTIONED HAS FORMED A GROUP, A

151
00:06:40,685 --> 00:06:45,390
WORKING GROUP THAT IS CALLED THE

152
00:06:45,390 --> 00:06:46,591
SAME, HEALTH AND AGING

153
00:06:46,591 --> 00:06:48,226
TRAJECTORIES, AND WHAT WE ARE

154
00:06:48,226 --> 00:06:52,230
TRY DOGTRYING TO DO IS BASICALLE

155
00:06:52,230 --> 00:06:55,767
OUT HOW WE CAN BRIDGE PERCEIVED

156
00:06:55,767 --> 00:06:57,202
BARRIERS OUTSIDE THE KNOWLEDGE

157
00:06:57,202 --> 00:06:58,403
DOMAIN TO BASICALLY BRING US

158
00:06:58,403 --> 00:07:02,207
BACK TOGETHER INTO ONE BODY,

159
00:07:02,207 --> 00:07:04,075
EXPERIENCING HEALTH OR

160
00:07:04,075 --> 00:07:06,077
POTENTIALLY DISEASE, ESPECIALLY

161
00:07:06,077 --> 00:07:11,983
AS IT MANIFESTS WITH AGING.

162
00:07:11,983 --> 00:07:13,618
AND SO WE STARTED ASKING ALL

163
00:07:13,618 --> 00:07:17,789
KINDS OF INTERESTING QUESTIONS,

164
00:07:17,789 --> 00:07:19,524
COULD OUR INDIVIDUAL HEALTH AND

165
00:07:19,524 --> 00:07:23,128
DISEASE TRAJECTORY BE DEFINED.

166
00:07:23,128 --> 00:07:26,631
PERHAPS CAN THEY BE PREDICTED.

167
00:07:26,631 --> 00:07:28,066
COULD WE ENHANCE RESILIENCE,

168
00:07:28,066 --> 00:07:31,069
COULD YOU PREVENT OR INTERCEPT

169
00:07:31,069 --> 00:07:32,671
THESE DISEASES, AND SPECIFICALLY

170
00:07:32,671 --> 00:07:37,075
ARE THERE SIGNALS THAT WE SHOULD

171
00:07:37,075 --> 00:07:40,979
OR MAYBE WE ARE ALREADY ABLE TO

172
00:07:40,979 --> 00:07:45,350
MEASURE AND TRY TO REA SPOND TO

173
00:07:45,350 --> 00:07:46,785
SOME OF THESE QUESTIONS.

174
00:07:46,785 --> 00:07:48,219
THEN WE ALSO WOULD LIKE TO KNOW

175
00:07:48,219 --> 00:07:50,088
WHETHER THERE ARE SHARED RISK

176
00:07:50,088 --> 00:07:51,656
FACTORS OR RESILIENCE OR

177
00:07:51,656 --> 00:07:55,527
POTENTIALLY TRADEOFFS SPECIFIC

178
00:07:55,527 --> 00:07:58,063
FOR HEALTH AND AGING

179
00:07:58,063 --> 00:07:58,830
TRAJECTORIES.

180
00:07:58,830 --> 00:07:59,898
SO WITH GABRIELA, WE STARTED

181
00:07:59,898 --> 00:08:02,934
FROM THE VERY SORT OF CLEAR FORK

182
00:08:02,934 --> 00:08:04,769
THAT IS BECOMING CLEAR IN THE

183
00:08:04,769 --> 00:08:06,972
PAST FEW YEARS BETWEEN

184
00:08:06,972 --> 00:08:07,839
CARDIOVASCULAR DISEASE AND

185
00:08:07,839 --> 00:08:11,977
CANCER, SO THAT'S KIND OF HOW WE

186
00:08:11,977 --> 00:08:12,644
GOT STARTED.

187
00:08:12,644 --> 00:08:14,179
SO FIRST I WANT TO THANK THIS

188
00:08:14,179 --> 00:08:18,883
DEDICATED GROUP OF PEOPLE WHO

189
00:08:18,883 --> 00:08:22,387
HAASK ALL THESE QUESTIONS BUT

190
00:08:22,387 --> 00:08:24,022
PEOPLE IN VARIOUS DOMAINS TO

191
00:08:24,022 --> 00:08:26,992
ANSWER THEM, AND OF COURSE I

192
00:08:26,992 --> 00:08:28,827
WANT TO THANK OUR DISTINGUISHED

193
00:08:28,827 --> 00:08:31,896
INVITED SPEAKERS, AND I WANT TO

194
00:08:31,896 --> 00:08:36,701
THANK THEM IN ADVANCE FOR

195
00:08:36,701 --> 00:08:40,672
HELPING US ANSWER SUCH QUESTI 

196
00:08:40,672 --> 00:08:40,939
QUESTIONS.

197
00:08:40,939 --> 00:08:41,873
AS YOU PROBABLY ALREADY SAW FROM

198
00:08:41,873 --> 00:08:44,709
THE AGENDA, THERE ARE FOUR

199
00:08:44,709 --> 00:08:46,911
VIRTUAL SESSIONS, BUT EACH OF

200
00:08:46,911 --> 00:08:47,812
THEM HAS BEEN DESIGNED

201
00:08:47,812 --> 00:08:52,150
SPECIFICALLY TO ACTUALLY PRESENT

202
00:08:52,150 --> 00:08:53,685
A VARIETY OF PERSPECTIVES, SO WE

203
00:08:53,685 --> 00:08:54,886
ARE HOPING THAT YOU'LL BE GLUED

204
00:08:54,886 --> 00:08:57,589
TO THE SESSIONS TO THE POINT OF

205
00:08:57,589 --> 00:09:01,326
NOT LEAVING US, ESPECIALLY FOR

206
00:09:01,326 --> 00:09:03,628
THOSE TALKS THAT MAY PRESENT

207
00:09:03,628 --> 00:09:05,030
PERSPECTIVES THAT YOU MIGHT HAVE

208
00:09:05,030 --> 00:09:08,767
NOT CONSIDERED PREVIOUSLY.

209
00:09:08,767 --> 00:09:10,535
AS YOU HEARD, WE ARE ALSO VERY

210
00:09:10,535 --> 00:09:12,070
INTERESTED IN ENGAGING THE

211
00:09:12,070 --> 00:09:14,672
AUDIENCE AND I THANK YOU ALL,

212
00:09:14,672 --> 00:09:15,940
THOSE WHO WERE ABLE TO JOIN US

213
00:09:15,940 --> 00:09:18,176
THIS MORNING.

214
00:09:18,176 --> 00:09:21,346
IF YOU JOINED US ON ZOOM, YOU

215
00:09:21,346 --> 00:09:22,514
CAN PREFERABLY ASK QUESTIONS BY

216
00:09:22,514 --> 00:09:24,649
Q & A, BUT YOU CAN ALSO ASK
BY

217
00:09:24,649 --> 00:09:24,849
CHAT.

218
00:09:24,849 --> 00:09:27,152
WE ALSO HAVE PEOPLE WHO JOIN US

219
00:09:27,152 --> 00:09:31,222
ON VIDEOCAST, ON NIH VIDEOCAST.

220
00:09:31,222 --> 00:09:32,657
THOSE PEOPLE CAN SEND EMAILS AND

221
00:09:32,657 --> 00:09:34,059
WE ARE GOING TO COLLATE ALL

222
00:09:34,059 --> 00:09:35,727
THESE QUESTIONS AND PRESENT THEM

223
00:09:35,727 --> 00:09:37,462
TO THE SPEAKERS AND THE

224
00:09:37,462 --> 00:09:43,802
MODERATORS.

225
00:09:43,802 --> 00:09:45,737
AS EXPECTED, WE ARE NOT PROBABLY

226
00:09:45,737 --> 00:09:46,771
GOING TO HAVE TIME TO ASK ALL

227
00:09:46,771 --> 00:09:47,972
THE QUESTIONS BUT I'M SURE THAT

228
00:09:47,972 --> 00:09:50,942
THE SPEAKERS WILL MAKE EVERY

229
00:09:50,942 --> 00:09:53,545
EFFORT TO ANSWER TO YOU IN Q
& A

230
00:09:53,545 --> 00:09:57,182
AND THE MODERATORS WILL COLLATE

231
00:09:57,182 --> 00:09:58,683
SOME OF THESE QUESTIONS AND

232
00:09:58,683 --> 00:10:01,786
POTENTIALLY ADDRESS THEM DURING

233
00:10:01,786 --> 00:10:05,356
THE PANEL DISCUSSION.

234
00:10:05,356 --> 00:10:07,125
SO WE WELCOME EVERY SINGLE ONE

235
00:10:07,125 --> 00:10:10,929
OF YOU AND FINALLY, WHAT I HAVE

236
00:10:10,929 --> 00:10:16,968
THE PLEASURE OF INTRODUCING

237
00:10:16,968 --> 00:10:18,837
DR. DAVID GOFF, WHO WILL HELP US

238
00:10:18,837 --> 00:10:21,439
KICK OFF THE WORKSHOP.

239
00:10:21,439 --> 00:10:22,674
DR. DAVID GOFF IS DIRECTOR OF

240
00:10:22,674 --> 00:10:24,843
THE DIVISION OF CARDIOVASCULAR

241
00:10:24,843 --> 00:10:26,144
DISEASES AT THE NATIONAL HEART,

242
00:10:26,144 --> 00:10:28,913
LUNG AND BLOOD INSTITUTE WHICH

243
00:10:28,913 --> 00:10:32,383
IS THE HOST OF THIS SEMINAR.

244
00:10:32,383 --> 00:10:35,687
SO I HOPE THAT DR. GOFF WAS ABLE

245
00:10:35,687 --> 00:10:38,423
TO JOIN US MEANWHILE, I KNOW HE

246
00:10:38,423 --> 00:10:41,693
HAD AN IMPORTANT STAFF MEETING

247
00:10:41,693 --> 00:10:42,894
AND WE ARE LOOKING FORWARD TO

248
00:10:42,894 --> 00:10:44,662
YOUR REMARKS, DR. GOFF, IF YOU

249
00:10:44,662 --> 00:10:45,230
ARE ALREADY ONLINE.

250
00:10:45,230 --> 00:10:55,406
THANK YOU.

251
00:10:59,711 --> 00:11:00,712
CAN SOMEBODY LOOK WHETHER

252
00:11:00,712 --> 00:11:01,880
DR. GOFF IS ONLINE?

253
00:11:01,880 --> 00:11:07,285
IF NOT, MAYBE GABRIELA, YOU CAN

254
00:11:07,285 --> 00:11:17,662
INTRODUCE DR. CASTLE.

255
00:11:24,869 --> 00:11:27,539
>> IS DR. CASTLE ONLINE?

256
00:11:27,539 --> 00:11:31,276
I KNOW HE WAS SUPPOSED TO BE 10

257
00:11:31,276 --> 00:11:32,177
MINUTES LATER.

258
00:11:32,177 --> 00:11:35,980
>> I DON'T SEE ANY OF
THEM, I'VE

259
00:11:35,980 --> 00:11:38,483
BEEN IN CONTACT WITH HIS

260
00:11:38,483 --> 00:11:42,086
ASSISTANT AND SENT HIM AN EMAIL.

261
00:11:42,086 --> 00:11:44,822
SHE SAID DR. GOFF SHOULD BE HERE

262
00:11:44,822 --> 00:11:46,257
PROMPTLY.

263
00:11:46,257 --> 00:11:48,660
APOLOGIES FOR THE INCONVENIENCE.

264
00:11:48,660 --> 00:11:49,260
THERE HE IS.

265
00:11:49,260 --> 00:11:50,728
>> DR. GOFF, WELCOME!

266
00:11:50,728 --> 00:11:57,202
WE ARE LOOKING FORWARD TO YOUR

267
00:11:57,202 --> 00:11:58,736
REMARKS KICKING OFF THE

268
00:11:58,736 --> 00:11:59,170
WORKSHOP.

269
00:11:59,170 --> 00:12:03,641
I HOPE YOU CAN CONNECT, IF YOU

270
00:12:03,641 --> 00:12:05,009
HAVE SOME THOUGHTS FLOATING

271
00:12:05,009 --> 00:12:09,681
AROUND.

272
00:12:09,681 --> 00:12:19,991
YES, PLEASE GO ON.

273
00:12:23,027 --> 00:12:23,728
DR. GOFF, PLEASE GO ON IF YOU

274
00:12:23,728 --> 00:12:24,162
ARE ABLE.

275
00:12:24,162 --> 00:12:26,130
CAN YOU DO A SOUND CHECK?

276
00:12:26,130 --> 00:12:27,665
>> OH, HI, ZORINA.

277
00:12:27,665 --> 00:12:28,633
GOOD TO SEE YOU.

278
00:12:28,633 --> 00:12:29,634
JUST GOT HERE.

279
00:12:29,634 --> 00:12:31,369
>> YES, THANK YOU SO MUCH!

280
00:12:31,369 --> 00:12:32,604
I INTRODUCED YOU.

281
00:12:32,604 --> 00:12:34,672
WE'RE WAITING FOR YOU TO KICK

282
00:12:34,672 --> 00:12:35,473
OFF THE WORKSHOP.

283
00:12:35,473 --> 00:12:36,774
THANK YOU SO MUCH.

284
00:12:36,774 --> 00:12:38,176
>> WELL, THANK YOU.

285
00:12:38,176 --> 00:12:39,277
SORRY THAT I'M RUNNING A LITTLE

286
00:12:39,277 --> 00:12:39,477
LATE.

287
00:12:39,477 --> 00:12:40,912
HAD A LEADERSHIP MEETING THIS

288
00:12:40,912 --> 00:12:44,048
MORNING THAT  USUALLY GOES UNTIL

289
00:12:44,048 --> 00:12:44,949
10:00 BUT WE CLOSED IT EARLY SO

290
00:12:44,949 --> 00:12:46,818
I COULD GET HERE TO WELCOME YOU,

291
00:12:46,818 --> 00:12:47,885
BECAUSE THIS IS A REALLY

292
00:12:47,885 --> 00:12:51,489
IMPORTANT WORKSHOP FOR US.

293
00:12:51,489 --> 00:12:53,024
I'M DAVID GOFF, I LEAD THE

294
00:12:53,024 --> 00:12:54,259
DIVISION OF CARDIOVASCULAR

295
00:12:54,259 --> 00:12:56,494
SCIENCES AND IT MY PLEASURE TO

296
00:12:56,494 --> 00:12:57,528
WELCOME YOU AND THANK YOU FOR

297
00:12:57,528 --> 00:13:00,932
BEING HERE.

298
00:13:00,932 --> 00:13:01,933
 HERE TO REALLY HELP US

299
00:13:01,933 --> 00:13:03,368
MOVE FORWARD IN THIS IMPORTANT

300
00:13:03,368 --> 00:13:06,838
AREA OF HEALTH AND AGING AND HOW

301
00:13:06,838 --> 00:13:10,008
WE CAN MAINTAIN AND ENHANCE

302
00:13:10,008 --> 00:13:15,813
RESILIENCE AS WE ALL AGE.

303
00:13:15,813 --> 00:13:16,881
WE KNOW THERE'S A LOT OF

304
00:13:16,881 --> 00:13:17,649
DIFFERENT THINGS YOU CAN BE

305
00:13:17,649 --> 00:13:18,983
DOING WITH YOUR TIME SO THE FACT

306
00:13:18,983 --> 00:13:20,485
THAT YOU CHOSE TO SPEND SOME OF

307
00:13:20,485 --> 00:13:22,153
IT WITH US TO GIVE US YOUR

308
00:13:22,153 --> 00:13:23,154
THOUGHTS AND YOUR INPUT IS

309
00:13:23,154 --> 00:13:24,255
SOMETHING FOR WHICH WE'RE VERY

310
00:13:24,255 --> 00:13:24,589
GRATEFUL.

311
00:13:24,589 --> 00:13:28,393
SO I WANT TO LET YOU KNOW WHAT

312
00:13:28,393 --> 00:13:31,029
OUR EXPECTATIONS ARE FOR ACTING

313
00:13:31,029 --> 00:13:34,098
ON THE INPUT THAT YOU GIVE US.

314
00:13:34,098 --> 00:13:35,500
WE HAVE SEVERAL EXPECTATIONS OF

315
00:13:35,500 --> 00:13:37,235
HOW WE'LL MOVE FORWARD WITH IT.

316
00:13:37,235 --> 00:13:44,042
FIRST IS THAT WE ANTICIPATE

317
00:13:44,042 --> 00:13:45,677
PUTTING A REPORT ON OUR WEBSITE

318
00:13:45,677 --> 00:13:46,344
HOPEFULLY WITHIN ABOUT A MONTH

319
00:13:46,344 --> 00:13:47,545
OF THIS WORKSHOP, SO WE

320
00:13:47,545 --> 00:13:51,082
ENCOURAGE YOU TO GET THE

321
00:13:51,082 --> 00:13:52,083
EXECUTIVE SUMMARY OF YOUR INPUT

322
00:13:52,083 --> 00:13:53,484
TOGETHER IN A TIMELY MANNER SO

323
00:13:53,484 --> 00:13:55,586
IT CAN BE SHARED WITH THE LARGER

324
00:13:55,586 --> 00:13:56,988
BIOMEDICAL RESEARCH COMMUNITY

325
00:13:56,988 --> 00:13:58,089
WHILE IT'S STILL FRESH AND

326
00:13:58,089 --> 00:13:58,523
TIMELY.

327
00:13:58,523 --> 00:14:00,258
SO THE GOAL IS TO GET THAT

328
00:14:00,258 --> 00:14:01,359
EXECUTIVE SUMMARY ON OUR WEBSITE

329
00:14:01,359 --> 00:14:05,430
WITHIN THE NEXT MONTH OR SO.

330
00:14:05,430 --> 00:14:08,499
YOU MAY ALSO D DECIDE THAT YOU

331
00:14:08,499 --> 00:14:10,568
WANT TO WRITE A PAPER FOR

332
00:14:10,568 --> 00:14:13,304
SUBMISSION FOR CONSIDERATION AND

333
00:14:13,304 --> 00:14:14,505
PUBLICATION IN A PEER REVIEWED

334
00:14:14,505 --> 00:14:14,839
JOURNAL.

335
00:14:14,839 --> 00:14:17,141
IF YOU DECIDE TO DO THAT, WE'LL

336
00:14:17,141 --> 00:14:17,775
SUPPORT THAT EFFORT.

337
00:14:17,775 --> 00:14:20,311
OUR TEAM WILL WORK WITH YOU.

338
00:14:20,311 --> 00:14:21,512
AND AGAIN, WE WOULD ENCOURAGE

339
00:14:21,512 --> 00:14:23,014
YOU TO DO THAT IN A TIMELY

340
00:14:23,014 --> 00:14:23,915
MANNER, WITHIN A FEW MONTHS SO

341
00:14:23,915 --> 00:14:27,185
THAT IT GETS OUT WHILE THE

342
00:14:27,185 --> 00:14:29,587
INFORMATION IS STILL FRESH FROM

343
00:14:29,587 --> 00:14:30,722
THE DISCUSSION FOR THE BENEFIT

344
00:14:30,722 --> 00:14:33,224
OF THE LARGER BIOMEDICAL

345
00:14:33,224 --> 00:14:33,925
RESEARCH COMMUNITY.

346
00:14:33,925 --> 00:14:34,926
WE ALSO ANTICIPATE THAT AFTER

347
00:14:34,926 --> 00:14:38,229
THE ROBUST EXCHANGE OF IDEAS

348
00:14:38,229 --> 00:14:39,931
THAT OCCURS DURING THE WORKSHOP

349
00:14:39,931 --> 00:14:41,299
THAT MANY OF YOU WILL GO HOME

350
00:14:41,299 --> 00:14:43,034
AND WRITE COMPELLING

351
00:14:43,034 --> 00:14:45,703
APPLICATIONS THAT WILL COMPETE

352
00:14:45,703 --> 00:14:47,038
WELL IN THE INVESTIGATOR

353
00:14:47,038 --> 00:14:50,608
INITIATED PEER REVIEWED POOL OF

354
00:14:50,608 --> 00:14:52,443
APPLICATIONS.

355
00:14:52,443 --> 00:14:54,078
THE VAST, VAST MAJORITY OF THE

356
00:14:54,078 --> 00:14:58,716
RESOURCES THAT WE AWARD TO

357
00:14:58,716 --> 00:15:00,118
RESEARCHERS EVERY YEAR GOES OUT

358
00:15:00,118 --> 00:15:02,320
TO INVESTIGATOR INITIATED PEER

359
00:15:02,320 --> 00:15:05,623
REVIEWED APPLICATIONS, AND SO WE

360
00:15:05,623 --> 00:15:06,924
WOULD ENCOURAGE YOU TO GO HOME

361
00:15:06,924 --> 00:15:08,359
AND WRITE GREAT APPLICATIONS.

362
00:15:08,359 --> 00:15:10,762
I TELL PEOPLE IT'S SIMPLE,

363
00:15:10,762 --> 00:15:11,896
WRITING A GOOD APPLICATION, GET

364
00:15:11,896 --> 00:15:13,498
A GOOD SCORE, WE LOVE TO GIVE

365
00:15:13,498 --> 00:15:13,931
MONEY AWAY.

366
00:15:13,931 --> 00:15:15,466
I DIDN'T SAY IT WAS EASY, JUST

367
00:15:15,466 --> 00:15:17,535
SIMPLE.

368
00:15:17,535 --> 00:15:19,337
BUT WE MAY ALSO PUT OUT

369
00:15:19,337 --> 00:15:19,971
INITIATIVES AS A RESULT OF THE

370
00:15:19,971 --> 00:15:21,239
INPUT THAT YOU GIVE US.

371
00:15:21,239 --> 00:15:23,474
NOW, WE DON'T DO THAT FOR EVERY

372
00:15:23,474 --> 00:15:25,676
WORKSHOP BECAUSE WE HAVE MORE

373
00:15:25,676 --> 00:15:27,612
WORKSHOPS EACH YEAR THAN WE CAN

374
00:15:27,612 --> 00:15:29,280
PUT OUT, FUNDED INITIATIVES.

375
00:15:29,280 --> 00:15:31,048
BUT WE MAY ALSO PUT OUT A NOTICE

376
00:15:31,048 --> 00:15:33,217
OF SPECIAL INTEREST, WHICH

377
00:15:33,217 --> 00:15:35,186
INDICATES TO THE COMMUNITY OUR

378
00:15:35,186 --> 00:15:40,758
INTEREST IN AN AREA THAT MAY

379
00:15:40,758 --> 00:15:41,859
ALSO INFLUENCE WHAT WE DO WITH

380
00:15:41,859 --> 00:15:43,494
WHAT WE CALL OUR SELECT PAY

381
00:15:43,494 --> 00:15:43,928
RESOURCES.

382
00:15:43,928 --> 00:15:44,762
YOU PROBABLY KNOW THAT IN

383
00:15:44,762 --> 00:15:48,199
ADDITION TO A PAYLINE FOR 

384
00:15:48,199 --> 00:15:49,400
R01s, WE ALSO HAVE A SMALL POT

385
00:15:49,400 --> 00:15:54,238
OF RESOURCES THAT WE CAN USE FOR

386
00:15:54,238 --> 00:15:55,406
WHAT WE CALL SELECT PAY

387
00:15:55,406 --> 00:15:57,275
OPPORTUNITIES, AND THESE ARE

388
00:15:57,275 --> 00:15:58,910
APPLICATIONS THAT ARE JUST ON

389
00:15:58,910 --> 00:15:59,911
THE WRONG SIDE OF THE PAYLINE

390
00:15:59,911 --> 00:16:01,446
BUT ARE STRATEGICALLY ALIGNED

391
00:16:01,446 --> 00:16:05,616
WITH HIGH PRIORITIES, AND SO WE

392
00:16:05,616 --> 00:16:07,018
SOMETIMES USE THE INPUT FROM

393
00:16:07,018 --> 00:16:09,754
WORKSHOPS LIKE THIS TO GUIDE OUR

394
00:16:09,754 --> 00:16:16,093
SELECT PAY OPPORTUNITIES AND KE

395
00:16:16,093 --> 00:16:16,527
DECISIONS AS WELL.

396
00:16:16,527 --> 00:16:17,762
SO I JUST WANTED TO GIVE YOU THE

397
00:16:17,762 --> 00:16:18,930
FULL RANGE OF ACTIONS THAT WE

398
00:16:18,930 --> 00:16:20,665
WOULD EXPECT TO TAKE BASED ON

399
00:16:20,665 --> 00:16:22,533
THE ROBUST DISCUSSION AND INPUT

400
00:16:22,533 --> 00:16:27,839
THAT WE ANTICIPATE GETTING FROM

401
00:16:27,839 --> 00:16:29,140
THIS WORKSHOP SO THAT YOU KNOW

402
00:16:29,140 --> 00:16:30,107
THIS IS REALLY IMPORTANT TO US

403
00:16:30,107 --> 00:16:31,442
AND WE'LL TAKE IT QUITE

404
00:16:31,442 --> 00:16:31,809
SERIOUSLY.

405
00:16:31,809 --> 00:16:34,178
SO I WANT TO END WHERE I

406
00:16:34,178 --> 00:16:35,713
STARTED, THANKING YOU FOR YOUR

407
00:16:35,713 --> 00:16:37,682
CONTRIBUTION OF TIME AND ENERGY

408
00:16:37,682 --> 00:16:40,184
TO THIS EFFORT.

409
00:16:40,184 --> 00:16:42,019
I ESPECIALLY WANT TO THANK

410
00:16:42,019 --> 00:16:45,256
ZORINA GALIS AND GABRIELA

411
00:16:45,256 --> 00:16:48,326
RISCUTA FROM NIH WHO ARE LEADING

412
00:16:48,326 --> 00:16:52,363
THIS, AS WELL AS THE CO-CHAIRS

413
00:16:52,363 --> 00:16:53,598
FOR THE WORKSHOP.

414
00:16:53,598 --> 00:16:56,334
SO WITH THAT, I'LL TURN THE

415
00:16:56,334 --> 00:16:58,970
BATON BACK TO ZORINA OR MAYBE

416
00:16:58,970 --> 00:17:01,906
IT'S GABRIELA WHO IS GOING TO DO

417
00:17:01,906 --> 00:17:02,673
THE WELCOME.

418
00:17:02,673 --> 00:17:03,808
GABRIELA, PLEASE.

419
00:17:03,808 --> 00:17:04,809
>> GABRIELA IS ON.

420
00:17:04,809 --> 00:17:06,310
>> THANK YOU, DR. GOFF.

421
00:17:06,310 --> 00:17:09,280
SO IT IS MY PLEASURE AND HONOR

422
00:17:09,280 --> 00:17:11,682
TO INTRODUCE DR. PHIL CASTLE,

423
00:17:11,682 --> 00:17:14,185
THE DIRECTOR OF THE DIVISION OF

424
00:17:14,185 --> 00:17:15,520
CANCER PREVENTION AT THE

425
00:17:15,520 --> 00:17:16,387
NATIONAL CANCER INSTITUTE.

426
00:17:16,387 --> 00:17:19,323
SO DR. CASTLE, WE ARE ON, SO

427
00:17:19,323 --> 00:17:20,758
PLEASE HELP US START THIS

428
00:17:20,758 --> 00:17:22,193
WORKSHOP.

429
00:17:22,193 --> 00:17:23,928
>> WELL, THANK YOU FOR THE

430
00:17:23,928 --> 00:17:27,331
OPPORTUNITY TO KICK THIS OFF.

431
00:17:27,331 --> 00:17:30,167
IT'S A VERY EXCITING TOPIC,

432
00:17:30,167 --> 00:17:32,236
OBVIOUSLY RELEVANT ACROSS THE

433
00:17:32,236 --> 00:17:33,571
SPECTRUM OF HEALTH.

434
00:17:33,571 --> 00:17:36,173
LET ME GO TO THE FIRST SLIDE,

435
00:17:36,173 --> 00:17:39,343
PLEASE.

436
00:17:39,343 --> 00:17:41,546
SO WE'LL JUST GO BACK ONE SLIDE,

437
00:17:41,546 --> 00:17:42,980
PLEASE.

438
00:17:42,980 --> 00:17:44,382
SO I'M, AS STATED.

439
00:17:44,382 --> 00:17:45,816
THE DIRECTOR OF THE DIVISION OF

440
00:17:45,816 --> 00:17:46,350
CANCER PREVENTION.

441
00:17:46,350 --> 00:17:48,319
I'M ALSO AN INTRAMURAL

442
00:17:48,319 --> 00:17:49,620
INVESTIGATOR, SENIOR

443
00:17:49,620 --> 00:17:50,821
INVESTIGATOR IN THE DIVISION OF

444
00:17:50,821 --> 00:17:55,693
CANCER EPIDEMIOLOGY AND GENET 

445
00:17:55,693 --> 00:17:59,263
GENETICS.

446
00:17:59,263 --> 00:18:00,798
SO JUST SOME DISCLAIMERS.

447
00:18:00,798 --> 00:18:05,069
THESE ARE MY OPINIONS ALONE, MY

448
00:18:05,069 --> 00:18:06,504
COMMENTS ARE INFORMAL AND SHOULD

449
00:18:06,504 --> 00:18:08,005
NOT BE TAKEN AS A SIGNAL, PER

450
00:18:08,005 --> 00:18:10,975
SE, FOR FUNDING PRIORITIES AND

451
00:18:10,975 --> 00:18:13,511
IF I MENTION SPECIFIC COMMENTS,

452
00:18:13,511 --> 00:18:15,446
THEY SHOULD NOT BE TAKEN AS AN

453
00:18:15,446 --> 00:18:17,081
ENDORSEMENT OF SAID PRODUCTS.

454
00:18:17,081 --> 00:18:18,382
SO THE MISSION OF THE DIVISION

455
00:18:18,382 --> 00:18:21,485
OF CANCER PREVENTION IN THE

456
00:18:21,485 --> 00:18:23,654
NATIONAL CANCER INSTITUTE IS AS

457
00:18:23,654 --> 00:18:25,189
FOLLOWS.

458
00:18:25,189 --> 00:18:29,894
LEADS, SUPPORTS AND PROMOTES

459
00:18:29,894 --> 00:18:30,895
RIGOROUS, INNOVATIVE RESEARCH

460
00:18:30,895 --> 00:18:32,763
AND TRAINING TO REDUCE RISKS,

461
00:18:32,763 --> 00:18:33,731
BURDENS AND CONSEQUENCES OF

462
00:18:33,731 --> 00:18:34,832
CANCER TO IMPROVE THE HEALTH OF

463
00:18:34,832 --> 00:18:35,833
ALL PEOPLE.

464
00:18:35,833 --> 00:18:37,768
AS I'M SURE YOU CAN APPRECIATE

465
00:18:37,768 --> 00:18:40,071
AGING INFLUENCES BOTH THE RISK

466
00:18:40,071 --> 00:18:42,073
OF GETTING CANCER, WHAT HAPPENS

467
00:18:42,073 --> 00:18:43,140
AFTER YOU GET CANCER, YOUR

468
00:18:43,140 --> 00:18:44,675
ABILITY TO RESPOND TO CANCER

469
00:18:44,675 --> 00:18:47,078
TREATMENT, AND THE QUALITY OF

470
00:18:47,078 --> 00:18:48,713
LIFE WHILE YOU'RE A CANCER

471
00:18:48,713 --> 00:18:49,180
SURVIVOR.

472
00:18:49,180 --> 00:18:51,449
AND SO WE CAN'T REALLY ESCAPE

473
00:18:51,449 --> 00:18:55,753
THE REALITIES OF AGING, BUT IF

474
00:18:55,753 --> 00:18:57,488
WE COULD UNDERSTAND THEM BETTER,

475
00:18:57,488 --> 00:18:59,123
PERHAPS WE COULD MITIGATE THEM

476
00:18:59,123 --> 00:19:00,992
AND PERHAPS THEY COULD INFORM US

477
00:19:00,992 --> 00:19:04,028
ON PRECISION MEDICINE APPROACHES

478
00:19:04,028 --> 00:19:05,363
TO MITIGATING EACH OF THESE

479
00:19:05,363 --> 00:19:06,564
STEPS IN THE CANCER CARE

480
00:19:06,564 --> 00:19:11,802
CONTINUUM.

481
00:19:11,802 --> 00:19:13,004
I JUST WANT TO HIGHLIGHT THAT

482
00:19:13,004 --> 00:19:15,439
THIS IS THE DIVISION THAT I'M

483
00:19:15,439 --> 00:19:17,842
GREATLY HONORED TO LEAD.

484
00:19:17,842 --> 00:19:19,810
THEY DO ALL THE WORK.

485
00:19:19,810 --> 00:19:24,315
SI JUI JUST GETTO STAND UP HEREW

486
00:19:24,315 --> 00:19:25,082
INTRODUCTORY COMMENTS BUT THIS

487
00:19:25,082 --> 00:19:26,050
IS AN AMAZING GROUP OF PEOPLE

488
00:19:26,050 --> 00:19:28,019
AND I WANT TO ACKNOWLEDGE AND

489
00:19:28,019 --> 00:19:29,353
THANK THEM FOR ALL THE HARD WORK

490
00:19:29,353 --> 00:19:32,623
AND DEDICATION TO THE EXTRAMURAL

491
00:19:32,623 --> 00:19:38,429
COMMUNITY.

492
00:19:38,429 --> 00:19:41,932
ARE SO THISO THIS IS THE AGE CUF

493
00:19:41,932 --> 00:19:45,269
YOU WILL, NORMALIZED INCIDENCE

494
00:19:45,269 --> 00:19:50,508
FOR COLORECTAL, LEUKEMIA, LUNG,

495
00:19:50,508 --> 00:19:52,810
PANCREAS, BREAST, PROSTATE, AND

496
00:19:52,810 --> 00:19:54,311
ALL CANCERS SHOWN AGAINST THE

497
00:19:54,311 --> 00:19:54,979
AXIS OF AGE GROUP.

498
00:19:54,979 --> 00:19:58,015
YOU CAN SEE THAT CANCER BELOW

499
00:19:58,015 --> 00:20:01,318
THE AGES OF ESSENTIALLY 50 ARE

500
00:20:01,318 --> 00:20:02,887
VERY RARE, AND THEN THERE'S A

501
00:20:02,887 --> 00:20:06,824
VERY SHARP INCREASE IN THAT.

502
00:20:06,824 --> 00:20:08,325
THE AGE PEAKS ARE VERY SIMILAR

503
00:20:08,325 --> 00:20:09,560
FOR THESE DIFFERENT CANCERS THAT

504
00:20:09,560 --> 00:20:12,029
HAVE VERY DIFFERENT ETIOLOGIES.

505
00:20:12,029 --> 00:20:13,798
IF WE HAD CERVICAL CANCER ON

506
00:20:13,798 --> 00:20:15,332
HERE, IT WOULD BE A DECADE

507
00:20:15,332 --> 00:20:17,101
EARLIER, BECAUSE THE KEY

508
00:20:17,101 --> 00:20:21,372
EXPOSURE OCCURS AT A MUCH

509
00:20:21,372 --> 00:20:22,473
EARLIER AGE.

510
00:20:22,473 --> 00:20:24,675
IT'S THE SEXUAL TRANSMISSION OF

511
00:20:24,675 --> 00:20:25,543
HUMAN PAPILLOMAVIRUS AND THE

512
00:20:25,543 --> 00:20:26,210
DEVELOPMENT OF CHRONIC

513
00:20:26,210 --> 00:20:26,544
INFECTION.

514
00:20:26,544 --> 00:20:29,580
BUT IT ALL HAS AN AGE COMPONENT,

515
00:20:29,580 --> 00:20:30,648
PARTLY BECAUSE OF THE EFFECTS OF

516
00:20:30,648 --> 00:20:32,216
AGE AND PARTLY BECAUSE IT TAKES

517
00:20:32,216 --> 00:20:35,286
TIME TO GO FROM INITIATION OF

518
00:20:35,286 --> 00:20:37,788
CANCER TO OVERT FRANK INVASIVE

519
00:20:37,788 --> 00:20:41,292
CANCER.

520
00:20:41,292 --> 00:20:42,827
THESE ARE SOME OF THE HALL MARKS

521
00:20:42,827 --> 00:20:46,430
OF CANCER, AND AS YOU'LL SEE IN

522
00:20:46,430 --> 00:20:48,399
THIS SLIDE AND THE NEXT SLIDE ON

523
00:20:48,399 --> 00:20:49,734
AGING MORE GENERALLY, THEY SHARE

524
00:20:49,734 --> 00:20:55,673
A FAIR NUMBER OF CHARACTERI 

525
00:20:55,673 --> 00:20:57,608
CHARACTERISTICS, SUSTAINING

526
00:20:57,608 --> 00:21:00,010
PROLIFERATIVE SIGNALS, INVADING

527
00:21:00,010 --> 00:21:02,513
GROWTH SUPPRESSORS, ACTIVATING

528
00:21:02,513 --> 00:21:04,915
AIMING METASTASIS, INVADING

529
00:21:04,915 --> 00:21:07,351
REPLICATED IMMORTALITY, INDUCING

530
00:21:07,351 --> 00:21:08,519
ANGIOGENESIS AND RESISTING CELL

531
00:21:08,519 --> 00:21:08,853
DEATH.

532
00:21:08,853 --> 00:21:10,921
SOME OF THE EMERGING HALL MARKS

533
00:21:10,921 --> 00:21:13,124
AND CHARACTERISTICS INCLUDE

534
00:21:13,124 --> 00:21:15,659
DEREGULATION OF CELLULAR

535
00:21:15,659 --> 00:21:21,565
ENERGETICS, AVOIDING IMMUNE

536
00:21:21,565 --> 00:21:24,502
DESTRUCTION, TUMOR PROMOTING

537
00:21:24,502 --> 00:21:26,270
INFLAMMATION.

538
00:21:26,270 --> 00:21:27,571
LET'S GO TO THE NEXT SLIDE,

539
00:21:27,571 --> 00:21:27,905
PLEASE.

540
00:21:27,905 --> 00:21:32,309
SO THIS IS MORE GENERAL BUT YOU

541
00:21:32,309 --> 00:21:34,812
CAN SATISFY THINGS LIKE CELLULAR

542
00:21:34,812 --> 00:21:37,982
SENESCENCE AND DYSFUNCTION AND

543
00:21:37,982 --> 00:21:39,717
DYSREGULATION, GENOMIC

544
00:21:39,717 --> 00:21:47,558
INSTABILITY, TE TE SOME OF THE L

545
00:21:47,558 --> 00:21:49,193
HALL MARKS OF AGING APPLY VERY

546
00:21:49,193 --> 00:21:52,897
DIRECTLY TO THE DEVELOPMENT OF

547
00:21:52,897 --> 00:21:56,700
CANCER AND THE MORBIDITY AND

548
00:21:56,700 --> 00:21:57,501
MORTALITY RELATED TO CANCER.

549
00:21:57,501 --> 00:22:01,172
I WILL ALSO SAY THAT MY OWN

550
00:22:01,172 --> 00:22:05,276
THINKING ABOUT THE WORLD IN

551
00:22:05,276 --> 00:22:06,677
IMMUNE SENESCENCE IS EMERGING OR

552
00:22:06,677 --> 00:22:07,978
MY THOUGHTS ABOUT THIS IS AN

553
00:22:07,978 --> 00:22:12,716
IMPORTANT PART THAT WE ARE

554
00:22:12,716 --> 00:22:14,485
CONSTANTLY BOMBARDED WITH

555
00:22:14,485 --> 00:22:17,421
INITIATION EXPOSURES AND

556
00:22:17,421 --> 00:22:19,190
MUTATION AND YET CANCER

557
00:22:19,190 --> 00:22:22,893
RELATIVELY SPEAKING IS RARE, AND

558
00:22:22,893 --> 00:22:24,428
I'M A FIRM BELIEVER THAT THE

559
00:22:24,428 --> 00:22:26,931
IMMUNE SYSTEM PLAYS AN IMPORTANT

560
00:22:26,931 --> 00:22:31,001
ROLE IN SWEEPING THE SYSTEM FOR

561
00:22:31,001 --> 00:22:32,203
EARLY CHANGES AND ELIMINATING

562
00:22:32,203 --> 00:22:33,704
THEM BEFORE THEY BECOME CANCER.

563
00:22:33,704 --> 00:22:38,542
SO CANCE CANCER IS A RARE OUTCOA

564
00:22:38,542 --> 00:22:40,177
LIFETIME OF EXPOSURES, BUT SINCE

565
00:22:40,177 --> 00:22:42,313
EVERYBODY IS EXPOSED TO AGING

566
00:22:42,313 --> 00:22:44,882
AND OTHER FACTORS, THE

567
00:22:44,882 --> 00:22:46,183
CUMULATIVE INCIDENCE OF CANCER

568
00:22:46,183 --> 00:22:48,953
IS PROBABLY ON THE ORDER OF 40%.

569
00:22:48,953 --> 00:22:51,455
THAT IS 40% OF PEOPLE GET CANCER

570
00:22:51,455 --> 00:22:53,557
SOMETIME IN THEIR LIFE.

571
00:22:53,557 --> 00:22:55,626
THE OTHER THING THAT'S

572
00:22:55,626 --> 00:22:56,627
INTERESTED ABOUT THIS AND CANCER

573
00:22:56,627 --> 00:22:58,929
IN GENERAL IS THE ROLE OF

574
00:22:58,929 --> 00:23:00,898
INFLAMMATION.

575
00:23:00,898 --> 00:23:02,099
OBVIOUSLY INFLAMMATION PLAYS AN

576
00:23:02,099 --> 00:23:04,935
IMPORTANT ROLE IN ESTABLISHING

577
00:23:04,935 --> 00:23:07,037
AN EARLY EFFECTOR IMMUNE

578
00:23:07,037 --> 00:23:07,905
RESPONSE, BUT CHRONIC

579
00:23:07,905 --> 00:23:10,441
INFLAMMATION IS AN IMMUNE

580
00:23:10,441 --> 00:23:12,710
SUPPRESSIVE STATE THAT DOES NOT

581
00:23:12,710 --> 00:23:17,314
ALLOW THAT SURVEILLANCE SYSTEM

582
00:23:17,314 --> 00:23:18,849
TO FIND THAT EARLY INITIATION,

583
00:23:18,849 --> 00:23:20,150
AND ALMOST CERTAINLY AS WE

584
00:23:20,150 --> 00:23:23,020
UNDERSTAND WHAT'S NORMAL, WE'LL

585
00:23:23,020 --> 00:23:25,322
FIND OUT, WE'LL HAVE A BETTER

586
00:23:25,322 --> 00:23:27,725
SENSE OF WHAT'S ABNORMAL IN

587
00:23:27,725 --> 00:23:29,693
TERMS OF INFLAMMATION AND IMMUNE

588
00:23:29,693 --> 00:23:32,329
SURVEILLANCE.

589
00:23:32,329 --> 00:23:37,234
THIS AFFECTS ALL STAGES OF LIFE.

590
00:23:37,234 --> 00:23:37,902
INCLUDING THOSE WITH

591
00:23:37,902 --> 00:23:42,039
DISABILITIES.

592
00:23:42,039 --> 00:23:43,040
SO CAN WE DO?

593
00:23:43,040 --> 00:23:44,375
HOW DO WE IMPROVE THE QUALITY OF

594
00:23:44,375 --> 00:23:47,878
LIFE AND THAT INCLUDES BOTH

595
00:23:47,878 --> 00:23:48,846
PREVENTING CANCER, CONTROLLING

596
00:23:48,846 --> 00:23:52,483
CANCER, TREATING CANCER, AND

597
00:23:52,483 --> 00:23:54,018
IMPROVING THE QUALITY OF LIFE OF

598
00:23:54,018 --> 00:23:54,785
CANCER SURVIVORS.

599
00:23:54,785 --> 00:23:56,353
I WOULD SAY THAT FUNDAMENTALLY,

600
00:23:56,353 --> 00:23:57,721
WE DON'T KNOW WHAT NORMAL IS.

601
00:23:57,721 --> 00:23:59,423
WE DON'T KNOW WHAT NORMAL

602
00:23:59,423 --> 00:24:00,491
PHYSIOLOGY IS AND WE CERTAINLY

603
00:24:00,491 --> 00:24:02,526
DON'T KNOW WHAT A NORMAL HEALTHY

604
00:24:02,526 --> 00:24:04,828
IMMUNE SYSTEM IS IN THE GENERAL

605
00:24:04,828 --> 00:24:05,829
POPULATION.

606
00:24:05,829 --> 00:24:09,099
WE LACK UNDERSTANDING OF MUCH OF

607
00:24:09,099 --> 00:24:12,036
THE STEPS IN EARLY

608
00:24:12,036 --> 00:24:12,736
CARCINOGENESIS IN THE NATURAL

609
00:24:12,736 --> 00:24:13,971
HISTORY OF CANCER, AND SO WE

610
00:24:13,971 --> 00:24:15,773
NEED TO UNDERSTAND THE BIOLOGY

611
00:24:15,773 --> 00:24:17,975
OF AGING, THE BU BIOLOGY OF CANR

612
00:24:17,975 --> 00:24:19,143
AND HOW IT INFLUENCES THE

613
00:24:19,143 --> 00:24:20,377
LATTER.

614
00:24:20,377 --> 00:24:22,780
HOW THE FORMER INFLUENCES THE

615
00:24:22,780 --> 00:24:23,113
LATTER.

616
00:24:23,113 --> 00:24:24,515
THAT WILL ALLOW US TO DO A

617
00:24:24,515 --> 00:24:26,483
BETTER JOB OF RISK

618
00:24:26,483 --> 00:24:28,252
STRATIFICATION, DEVELOP

619
00:24:28,252 --> 00:24:29,119
BIOMARKERS OF CLINICAL

620
00:24:29,119 --> 00:24:30,754
SIGNIFICANCE FOR SCREENING BUT

621
00:24:30,754 --> 00:24:32,289
ALSO GUIDING PRECISION

622
00:24:32,289 --> 00:24:33,490
INTERCEPTION AND FOR CANCER

623
00:24:33,490 --> 00:24:35,359
PREVENTION AND INTERCEPTION.

624
00:24:35,359 --> 00:24:36,994
AND WITH THAT, I THINK THAT WAS

625
00:24:36,994 --> 00:24:39,063
THE LAST SLIDE.

626
00:24:39,063 --> 00:24:40,931
YES, THANK YOU SO VERY MUCH.

627
00:24:40,931 --> 00:24:43,100
I WISH YOU A VERY SUCCESSFUL

628
00:24:43,100 --> 00:24:45,302
MEETING AND LOOK FORWARD TO THE

629
00:24:45,302 --> 00:24:46,870
OUTCOMES OF THIS WORKSHOP.

630
00:24:46,870 --> 00:24:48,005
THANK YOU.

631
00:24:48,005 --> 00:24:49,239
>> THANK YOU SO MUCH,

632
00:24:49,239 --> 00:24:51,875
DR. CASTLE.

633
00:24:51,875 --> 00:24:53,610
, FOR YOUR WORDS.

634
00:24:53,610 --> 00:24:57,114
SO IT IS MY HONOR NOW TO

635
00:24:57,114 --> 00:25:02,920
INTRODUCE DR. LUIGI FERRUCCI.

636
00:25:02,920 --> 00:25:04,121
DR. FERRUCCI HAS BEEN THE

637
00:25:04,121 --> 00:25:05,723
SCIENTIFIC DIRECTOR AT THE

638
00:25:05,723 --> 00:25:07,391
NATIONAL INSTITUTE ON AGING

639
00:25:07,391 --> 00:25:09,460
SINCE MAY 2011.

640
00:25:09,460 --> 00:25:20,437
BUT HE JOINED NIA IN SEPTEMBR

641
00:25:23,741 --> 00:25:25,709
SEPTEMBER 2ND.

642
00:25:25,709 --> 00:25:27,111
HE MADE A MAJOR CONTRIBUTION TO

643
00:25:27,111 --> 00:25:30,147
THE LITERATURE ON AGING AND THE

644
00:25:30,147 --> 00:25:31,048
FIELD OF AGING.

645
00:25:31,048 --> 00:25:33,650
SO HE'S ONE OF THE MOST CITED

646
00:25:33,650 --> 00:25:35,519
SCIENTISTS AND OF COURSE HE'S

647
00:25:35,519 --> 00:25:38,155
EXTREMELY BUSY.

648
00:25:38,155 --> 00:25:40,124
EVEN NOW, DR. FERRUCCI IS

649
00:25:40,124 --> 00:25:44,061
TRAVELING, BUT HE KINDLY

650
00:25:44,061 --> 00:25:45,262
ACCEPTED TO BE RECORDED SO WE'RE

651
00:25:45,262 --> 00:25:50,167
GOING TO LISTEN TO HIS RECORD 

652
00:25:50,167 --> 00:25:51,668
RECORDING, AND DR. FERRUCCI IS

653
00:25:51,668 --> 00:25:58,575
ASKING TO EMAIL HIM ONCE AFTER

654
00:25:58,575 --> 00:26:02,079
THE HE IS GOING TO RESPOND TO

655
00:26:02,079 --> 00:26:02,846
YOUR QUESTIONS VIA EMAIL.

656
00:26:02,846 --> 00:26:13,023
THANK YOU.

657
00:26:14,858 --> 00:26:16,427
>> GOOD MORNING OR GOOD

658
00:26:16,427 --> 00:26:17,961
AFTERNOON.

659
00:26:17,961 --> 00:26:19,163
WHENEVER YOU'RE LISTENING TO

660
00:26:19,163 --> 00:26:20,564
THIS PRESENTATION.

661
00:26:20,564 --> 00:26:21,965
THIS IS A VERY EXCITING

662
00:26:21,965 --> 00:26:25,602
OPPORTUNITY TO OPEN THIS TRULY

663
00:26:25,602 --> 00:26:28,372
FANTASTIC SERIES OF CONTRIBUTION

664
00:26:28,372 --> 00:26:32,076
THAT TALKS ABOUT THE INTERFACE

665
00:26:32,076 --> 00:26:35,479
BETWEEN AGING AND CANCER.

666
00:26:35,479 --> 00:26:37,047
MY NAME IS LUIGI FERRUCCI.

667
00:26:37,047 --> 00:26:41,685
I AM THE SCIENTIFIC DIRECTOR OF

668
00:26:41,685 --> 00:26:45,789
THE NATIO NATIONAL INSTITUTE ON.

669
00:26:45,789 --> 00:26:47,357
I AM ENTHUSIASTIC ABOUT THE

670
00:26:47,357 --> 00:26:49,059
STUDY OF AGING, AND I THINK THAT

671
00:26:49,059 --> 00:26:50,928
SO MANY INTERACTION AND

672
00:26:50,928 --> 00:26:52,129
SIMILARITY BETWEEN THE BIOLOGY

673
00:26:52,129 --> 00:26:54,398
OF AGING AND THE BIOLOGY OF

674
00:26:54,398 --> 00:26:59,269
CANCER THAT, YOU KNOW, COMMON

675
00:26:59,269 --> 00:27:00,904
STUDY CAN REALLY OFFER US MORE

676
00:27:00,904 --> 00:27:01,839
AND MORE OPPORTUNITY TO

677
00:27:01,839 --> 00:27:04,708
UNDERSTAND EACH OTHER TOPIC.

678
00:27:04,708 --> 00:27:08,412
I WANT TO START BY TELLING YOU

679
00:27:08,412 --> 00:27:11,515
THAT, YOU KNOW, WHY THIS IS SO

680
00:27:11,515 --> 00:27:12,816
IMPORTANT.

681
00:27:12,816 --> 00:27:14,251
AGING OF THE POPULATION IS

682
00:27:14,251 --> 00:27:16,420
COMPLETELY CHANGING NOW IN THE

683
00:27:16,420 --> 00:27:17,421
FACE OF THE WORLD.

684
00:27:17,421 --> 00:27:21,692
YOU KNOW, AND BEFORE WE DO THAT

685
00:27:21,692 --> 00:27:26,063
BY TAKING A VERY, VERY WIDE

686
00:27:26,063 --> 00:27:29,867
PERSPECTIVE, YOU SEE THAT CHINA

687
00:27:29,867 --> 00:27:34,037
IN 2017 WAS THE MOST POPULOUS

688
00:27:34,037 --> 00:27:35,772
COUNTRY IN THE WORLD.

689
00:27:35,772 --> 00:27:43,614
BELIEVE IT OR NOT, IT'S NOW IN

690
00:27:43,614 --> 00:27:44,214
THIRD PLACE.

691
00:27:44,214 --> 00:27:45,649
FIRST AND SECOND WILL BE INDIA

692
00:27:45,649 --> 00:27:47,284
AND NIGERIA.

693
00:27:47,284 --> 00:27:50,053
NIGERIA CURRENTLY IS NUMBER 7.

694
00:27:50,053 --> 00:27:53,891
AND THAT IS ALSO -- ALL THIS

695
00:27:53,891 --> 00:27:56,160
TRANSFORMATION ARE DIRECTLY OR

696
00:27:56,160 --> 00:27:57,361
INDIRECTLY INDUCED BY THE AGING

697
00:27:57,361 --> 00:28:04,067
OF THE POPULATION.

698
00:28:04,067 --> 00:28:05,402
THIS AGING THAT IS OCCURRING AT

699
00:28:05,402 --> 00:28:10,073
THE POPULATION LEVEL WAS

700
00:28:10,073 --> 00:28:15,445
MEANINGFULLY SUMMARIZED BY JUNE

701
00:28:15,445 --> 00:28:16,747
LAPEL, TO STUDY AGING IN THIS

702
00:28:16,747 --> 00:28:18,515
PAPER THAT WAS PUBLISHED AROUND

703
00:28:18,515 --> 00:28:22,219
THE YEAR 2000.

704
00:28:22,219 --> 00:28:25,622
WHAT JEAN DID WAS TO TAKE THE

705
00:28:25,622 --> 00:28:27,591
COUNTRY THAT WERE THE OLDEST

706
00:28:27,591 --> 00:28:30,661
COUNTRIES IN THE WORLD, AND THEN

707
00:28:30,661 --> 00:28:35,465
PUT THEM -- CREATED A SCATTER

708
00:28:35,465 --> 00:28:38,869
PLOT OF THE TIME AND LIFE

709
00:28:38,869 --> 00:28:39,403
EXPECTANCY.

710
00:28:39,403 --> 00:28:40,871
BELIEVE IT OR NOT, THIS TREND

711
00:28:40,871 --> 00:28:42,839
WAS ENCOURAGING HER.

712
00:28:42,839 --> 00:28:46,009
WHEN WE DO STUDIES, THIS ADDS AN

713
00:28:46,009 --> 00:28:48,178
R SCARE OF 0.99.

714
00:28:48,178 --> 00:28:50,247
WE NEVER SEE THIS TYPE OF

715
00:28:50,247 --> 00:28:51,014
CORRELATION WHEN WE DO OUR

716
00:28:51,014 --> 00:28:52,983
STUDY.

717
00:28:52,983 --> 00:28:53,550
STUDIES.

718
00:28:53,550 --> 00:28:58,255
AND AT THIS POINT, AROUND TH 19,

719
00:28:58,255 --> 00:29:00,490
PEOPLE STARTED LOOKING AT THESE

720
00:29:00,490 --> 00:29:02,092
DATA AND SAID, WELL, OF COURSE

721
00:29:02,092 --> 00:29:06,430
IT'S BEEN INCREASING BUT IT'S

722
00:29:06,430 --> 00:29:07,331
GOING TO SLOW DOWN.

723
00:29:07,331 --> 00:29:10,133
AND SO THEY MADE PROJECTIONS

724
00:29:10,133 --> 00:29:16,073
THAT REALLY SHOW IN THESE D THID

725
00:29:16,073 --> 00:29:17,874
LINE AND, IN FACT, DID NOT.

726
00:29:17,874 --> 00:29:19,276
IN FACT, THE AGING OF THE

727
00:29:19,276 --> 00:29:22,346
POPULATION IS INCREASING.

728
00:29:22,346 --> 00:29:24,314
THEIR DATA ARE LIMITED TO 2018,

729
00:29:24,314 --> 00:29:32,322
BUT I ASSURE YOU THAT THE OLDER

730
00:29:32,322 --> 00:29:36,893
POPULATION IS STILL GROWING.

731
00:29:36,893 --> 00:29:39,863
OF COURSE, THIS IS A MATTER FOR

732
00:29:39,863 --> 00:29:40,364
CELEBRATION.

733
00:29:40,364 --> 00:29:43,567
WE SHOULD BE HAPPY THAT THE

734
00:29:43,567 --> 00:29:45,369
HUMAN BEINGS HAVE BEEN ABLE TO

735
00:29:45,369 --> 00:29:48,105
DO THIS, AND THEN TO GIVE US

736
00:29:48,105 --> 00:29:53,210
MORE OF A HISTORICAL PERSPEC 

737
00:29:53,210 --> 00:29:53,977
PERSPECTIVE, IF YOU LOOK AT THE

738
00:29:53,977 --> 00:29:59,249
LIFE EXPECTANCY I IN 1800, YOU N

739
00:29:59,249 --> 00:30:00,784
SEE MOST OF THE COUNTRIES IN THE

740
00:30:00,784 --> 00:30:04,288
WORLD, THE LIFE EXPECTANCY WAS

741
00:30:04,288 --> 00:30:06,256
BELOW 40 YEARS.

742
00:30:06,256 --> 00:30:09,192
AND WE SWITCHED TO 1950, YOU

743
00:30:09,192 --> 00:30:11,395
KNOW, THERE WAS A SUBSTANTIAL

744
00:30:11,395 --> 00:30:13,463
INCREASE IN LIFE EXPECTANCY,

745
00:30:13,463 --> 00:30:16,400
ALTHOUGH IN AFRICA, STILL, MOST

746
00:30:16,400 --> 00:30:18,935
OF THE COUNTRY HAD THE LIFE

747
00:30:18,935 --> 00:30:21,038
EXPECTANCY BELOW 40 BUT IF WE

748
00:30:21,038 --> 00:30:24,074
LOOK AT 2015, WHICH IS THE MOST

749
00:30:24,074 --> 00:30:27,377
UP TO DATE MAP THAT I COULD FIND

750
00:30:27,377 --> 00:30:28,912
ON THE INTERNET, YOU CAN SEE

751
00:30:28,912 --> 00:30:31,548
THAT THERE IS NO RED AREA,

752
00:30:31,548 --> 00:30:34,484
THERE'S NO EVEN ORANGE AREA.

753
00:30:34,484 --> 00:30:36,586
AND OLDER POPULATIONS HAVE A

754
00:30:36,586 --> 00:30:39,890
LIFE EXPECTANCY THAT IS ABOUT 60

755
00:30:39,890 --> 00:30:41,425
YEARS, WITH, YOU KNOW, MANY OF

756
00:30:41,425 --> 00:30:44,695
THEM IN EUROPE AND NORTH AMERICA

757
00:30:44,695 --> 00:30:50,500
AND IN OCEANA THAT IS ABOUT 80

758
00:30:50,500 --> 00:30:51,268
YEARS OF AGE.

759
00:30:51,268 --> 00:30:52,035
HOWEVER, WHAT IS IMPORTANT TO

760
00:30:52,035 --> 00:30:53,870
CONSIDER IS THAT THIS PHENOMENON

761
00:30:53,870 --> 00:30:55,305
IS RECENT.

762
00:30:55,305 --> 00:31:02,679
LOOK, YOU KNOW, BETWEEN 1770 AND

763
00:31:02,679 --> 00:31:04,314
1870, FOR 100 YEARS, THE LIFE

764
00:31:04,314 --> 00:31:05,282
EXPECTANCY DID NOT CHANGE AT

765
00:31:05,282 --> 00:31:08,685
ALL.

766
00:31:08,685 --> 00:31:10,420
AND THIS LACK OF CHANGE AND THE

767
00:31:10,420 --> 00:31:16,226
CHANGE OCCURRED AROUND 1870, AND

768
00:31:16,226 --> 00:31:19,396
WHEN IT OCCURRED, IT OCCURRED IN

769
00:31:19,396 --> 00:31:20,731
MANY DIFFERENT COUNTRIES A

770
00:31:20,731 --> 00:31:23,767
LITTLE BIT LATER IN ASIA AND IN

771
00:31:23,767 --> 00:31:27,304
AFRICA, WITH A LINEAR PACE.

772
00:31:27,304 --> 00:31:28,472
SO IT'S ALMOST PARALLEL FOR

773
00:31:28,472 --> 00:31:29,239
EVERY COUNTRY.

774
00:31:29,239 --> 00:31:31,875
NOW, THIS IS AN IMPORTANT

775
00:31:31,875 --> 00:31:33,176
CONSIDERATION BECAUSE, YOU KNOW,

776
00:31:33,176 --> 00:31:35,045
A CHANGE IN LIFE EXPECTANCY

777
00:31:35,045 --> 00:31:41,518
OCCURS SO SUDDENLY, AND WE DEEM

778
00:31:41,518 --> 00:31:42,919
THIS RELATIVELY SHORT TIME FRAME

779
00:31:42,919 --> 00:31:44,221
CANNOT BE DUE TO EVOLUTION OR

780
00:31:44,221 --> 00:31:51,027
TO, YOU KNOW, GENETIC CHANGE.

781
00:31:51,027 --> 00:31:53,330
BUT SIMPLY IT DUE TO CHANGE IN

782
00:31:53,330 --> 00:31:54,765
THE ENVIRONMENTAL CONDITION.

783
00:31:54,765 --> 00:32:00,570
YOU KNOW, PROBABLY THE MOST

784
00:32:00,570 --> 00:32:02,739
IMPORTANT CAUSE OF INCREASE IN

785
00:32:02,739 --> 00:32:04,007
LIFE EXPECTANCY WAS THE SUDDEN

786
00:32:04,007 --> 00:32:06,143
AVAILABILITY OF WATER AND FOOD

787
00:32:06,143 --> 00:32:08,879
OR A LARGE PART OF THE

788
00:32:08,879 --> 00:32:14,050
POPULATION, AND THE -- LATER ON

789
00:32:14,050 --> 00:32:15,986
CERTAINLY ALSO THE AVAILABILITY

790
00:32:15,986 --> 00:32:17,854
OF HEALTHCARE AND THE MODERN,

791
00:32:17,854 --> 00:32:21,691
YOU KNOW, PROGRESS OF MEDICINE

792
00:32:21,691 --> 00:32:23,894
HAS CONTRIBUTED TO THIS INCREASE

793
00:32:23,894 --> 00:32:30,333
IN LIFE EXPECTANCY.

794
00:32:30,333 --> 00:32:31,535
OF COURSE THERE'S SOMETHING THAT

795
00:32:31,535 --> 00:32:35,672
IS ALSO NEGATIVE IN THIS PROC 

796
00:32:35,672 --> 00:32:36,339
PROCESS.

797
00:32:36,339 --> 00:32:37,474
AND THE MOST IMPORTANT THING IS

798
00:32:37,474 --> 00:32:42,279
THAT THE INCREASE IN LIFE IS NOT

799
00:32:42,279 --> 00:32:46,016
ALL ACCOUNTED FOR BY THE GOOD

800
00:32:46,016 --> 00:32:46,216
LIFE.

801
00:32:46,216 --> 00:32:48,685
YOU KNOW, LIFE, I BELIEVE,

802
00:32:48,685 --> 00:32:50,954
WITHOUT DISEASE AND DISABILITY.

803
00:32:50,954 --> 00:32:53,890
ALSO THE LIFE THAT IS

804
00:32:53,890 --> 00:32:56,726
CHARACTERIZED BY ILLNESS AND

805
00:32:56,726 --> 00:32:57,727
DISABILITY HAS ALSO EXPANDED.

806
00:32:57,727 --> 00:33:02,999
SO IN A WAY, YOU KNOW, WE HAVE

807
00:33:02,999 --> 00:33:06,169
GAINED GOOD LIFE BUT WE ALSO

808
00:33:06,169 --> 00:33:08,872
GAIN DISEASE AND DISABILITY.

809
00:33:08,872 --> 00:33:13,910
AND ONE VERY DISCONCERTING

810
00:33:13,910 --> 00:33:15,779
PHENOMENON HAS BEEN THE INCREASE

811
00:33:15,779 --> 00:33:19,816
IN UNHEALTHY LIFE EXPECTANCY IS

812
00:33:19,816 --> 00:33:21,585
PROPORTIONAL TO THE HEALTHCARE

813
00:33:21,585 --> 00:33:23,353
EXPENDITURE.

814
00:33:23,353 --> 00:33:25,489
THIS GRAPH JUST SHOWS DIFFERENT

815
00:33:25,489 --> 00:33:29,226
COUNTRIES AND THE RELATIONSHIP

816
00:33:29,226 --> 00:33:30,861
WITH THE CURRENT HEALTH

817
00:33:30,861 --> 00:33:34,231
EXPENDITURE PER CAPITA, AND HERE

818
00:33:34,231 --> 00:33:35,031
WITH SOME DISABILITY.

819
00:33:35,031 --> 00:33:37,000
CAN YOU SEE THE LINEAR

820
00:33:37,000 --> 00:33:38,401
RELATIONSHIP, IT'S VERY, VERY

821
00:33:38,401 --> 00:33:38,768
EVIDENT.

822
00:33:38,768 --> 00:33:40,837
WITH THE UNITED STATES ON TOP OF

823
00:33:40,837 --> 00:33:45,742
EVERY OTHER COUNTRY.

824
00:33:45,742 --> 00:33:47,844
SO HOW COME THE MORE WE SPEND,

825
00:33:47,844 --> 00:33:49,579
THE MORE OUR LIFE WITH

826
00:33:49,579 --> 00:33:53,250
DISABILITY INCREASES?

827
00:33:53,250 --> 00:33:54,084
AND THAT'S A VERY, VERY

828
00:33:54,084 --> 00:33:54,851
IMPORTANT QUESTION THAT I WILL

829
00:33:54,851 --> 00:33:56,953
TRY TO ADDRESS IN MY FOLLOWING

830
00:33:56,953 --> 00:33:58,088
SLIDES.

831
00:33:58,088 --> 00:34:02,259
SO FIRST OF ALL, HOW DO WE GET

832
00:34:02,259 --> 00:34:08,298
TO A DECLINE IN MORTALITY?

833
00:34:08,298 --> 00:34:10,133
AND INCREASE IN LIFE EXPECTANCY?

834
00:34:10,133 --> 00:34:11,468
SO FIRST OF ALL, HEART DISEASE

835
00:34:11,468 --> 00:34:14,304
WAS PROBABLY THE MOST IMPORTANT

836
00:34:14,304 --> 00:34:15,505
CAUSE, THERE WAS A DECLINE IN

837
00:34:15,505 --> 00:34:17,974
HEART DISEASE RELATED MORTALITY,

838
00:34:17,974 --> 00:34:20,544
THERE WAS A DECLINE IN CANCER,

839
00:34:20,544 --> 00:34:23,713
DECLINE IN STROKE, AND DECLINING

840
00:34:23,713 --> 00:34:27,083
CANCER SEEMS TO BE MINIMAL

841
00:34:27,083 --> 00:34:28,618
WHEN -- I'LL SHOW YOU WHEN WE

842
00:34:28,618 --> 00:34:31,054
RELATE THIS TO THE CHANGE IN THE

843
00:34:31,054 --> 00:34:33,089
AGE COMPOSITION OF THE

844
00:34:33,089 --> 00:34:35,525
POPULATION.

845
00:34:35,525 --> 00:34:37,027
IT'S VERY, VERY SIGNIFICANTLY

846
00:34:37,027 --> 00:34:37,494
STRONG.

847
00:34:37,494 --> 00:34:41,531
BUT ON THE OTHER HAND, OTHER

848
00:34:41,531 --> 00:34:43,300
DISEASE THAT ARE TYPICAL OF

849
00:34:43,300 --> 00:34:43,967
INDIVIDUALS WITH MULTIPLE

850
00:34:43,967 --> 00:34:47,137
CHRONIC DISEASE AND DISABILITY

851
00:34:47,137 --> 00:34:51,274
SUCH AS ALZHEIMER'S DISEASE, --

852
00:34:51,274 --> 00:34:53,343
AND DIABETES NOT ONLY DID NOT

853
00:34:53,343 --> 00:34:54,477
DECLINE BUT TEND TO INCREASE

854
00:34:54,477 --> 00:34:55,412
OVER TIME.

855
00:34:55,412 --> 00:34:58,381
AND AS  WAS MENTIONED TO YOU,

856
00:34:58,381 --> 00:35:01,117
WHEN WE LOOK AT THE CANCER

857
00:35:01,117 --> 00:35:03,219
THERE, OF COURSE THERE IS AN

858
00:35:03,219 --> 00:35:04,621
INCREASING CANCER THERE THAT,

859
00:35:04,621 --> 00:35:07,357
YOU KNOW, IS DUE TO THE

860
00:35:07,357 --> 00:35:09,025
INCREASED NUMBER OF PEOPLE IN

861
00:35:09,025 --> 00:35:13,830
THE POPULATION, AND THE FACT

862
00:35:13,830 --> 00:35:16,433
THAT THE OLDEST PEOPLE WITH THE

863
00:35:16,433 --> 00:35:19,936
HIGHEST INCIDENCE OF CANCER ARE

864
00:35:19,936 --> 00:35:21,304
ALSO THOSE THAT HAVE EXPANDED

865
00:35:21,304 --> 00:35:22,238
MORE THAN ANY OTHER PART OF THE

866
00:35:22,238 --> 00:35:22,572
POPULATION.

867
00:35:22,572 --> 00:35:26,710
BUT WHEN WE LOOK AT THE AGE --

868
00:35:26,710 --> 00:35:27,911
CANCER RATE FOR THE ENTIRE

869
00:35:27,911 --> 00:35:29,346
WORLD, THERE'S A SUBSTANTIAL

870
00:35:29,346 --> 00:35:31,681
DECLINE, ESPECIALLY IN EUROPE

871
00:35:31,681 --> 00:35:39,322
AND IN THE UNITED STATES.

872
00:35:39,322 --> 00:35:40,290
THERE'S SOME ACCUMULATION OF

873
00:35:40,290 --> 00:35:41,825
CHRONIC DISEASE WITH AGING.

874
00:35:41,825 --> 00:35:48,064
SO IT IS VERY CLEAR THAT AGING

875
00:35:48,064 --> 00:35:49,165
AFFECT THE -- TO CHRONIC DISEASE

876
00:35:49,165 --> 00:35:50,600
AND IN DIFFERENT ETHNICITY, YOU

877
00:35:50,600 --> 00:35:56,373
SEE THAT THE NUMBER OF CHRONIC

878
00:35:56,373 --> 00:35:57,974
DISEASE, ESTIMATED IN THIS CASE,

879
00:35:57,974 --> 00:36:01,945
THE NUMBER, THE PERCENTAGE OF

880
00:36:01,945 --> 00:36:02,712
INDIVIDUAL THAT HAVE AT THE SAME

881
00:36:02,712 --> 00:36:05,348
TIME TWO OR MORE CHRONIC DISEASE

882
00:36:05,348 --> 00:36:07,217
INCREASED DRAMATICALLY WITH

883
00:36:07,217 --> 00:36:08,852
AGING, AND THIS IS TRUE EITHER

884
00:36:08,852 --> 00:36:11,254
WHEN YOU TAKE ONE CHRONIC

885
00:36:11,254 --> 00:36:12,656
CONDITION, TWO CHRONIC

886
00:36:12,656 --> 00:36:13,556
CONDITIONS, THREE CHRONIC

887
00:36:13,556 --> 00:36:14,524
CONDITIONS OR FOUR CHRONIC

888
00:36:14,524 --> 00:36:18,361
CONDITIONS.

889
00:36:18,361 --> 00:36:20,664
SO THERE'S A PROBLEM THAT WITH

890
00:36:20,664 --> 00:36:22,866
AGING, THE DISEASE PRESENT

891
00:36:22,866 --> 00:36:30,707
THEMSELVES IN CLUSTERS.

892
00:36:30,707 --> 00:36:32,475
AND WE RECENTLY SUBMITTED FOR

893
00:36:32,475 --> 00:36:33,243
PUBLICATION SHOWING THAT THE

894
00:36:33,243 --> 00:36:36,613
MORE DISEASE YOU HAVE, THE

895
00:36:36,613 --> 00:36:37,714
HIGHEST IS THE PROBABILITY THAT

896
00:36:37,714 --> 00:36:41,084
YOU WILL DEVELOP AN ADDITIONAL

897
00:36:41,084 --> 00:36:41,885
DISEASE, INDEPENDENT OF WHAT

898
00:36:41,885 --> 00:36:42,986
KIND OF DISEASE I'M TALKING

899
00:36:42,986 --> 00:36:45,822
ABOUT, WHICH MEANS THAT WHEN YOU

900
00:36:45,822 --> 00:36:48,224
HAVE ONE DISEASE, THE

901
00:36:48,224 --> 00:36:49,325
PROBABILITY OF DEVELOPING

902
00:36:49,325 --> 00:36:53,263
ANOTHER IS HIGHER, AND SO THERE

903
00:36:53,263 --> 00:36:55,765
IS A PRECIPITOUS ACCUMULATION OF

904
00:36:55,765 --> 00:36:58,368
PATHOLOGY WHEN THE HEALTH

905
00:36:58,368 --> 00:37:00,704
EXPECTANCY IS TERMINATED.

906
00:37:00,704 --> 00:37:02,472
I CAN SHOW YOU THIS SAME

907
00:37:02,472 --> 00:37:03,773
PHENOMENON IN ANOTHER WAY.

908
00:37:03,773 --> 00:37:08,478
HERE, FOR AN EXAMPLE, I SHOW YOU

909
00:37:08,478 --> 00:37:12,549
THE LIFE EXPECTANCY THAT IS

910
00:37:12,549 --> 00:37:17,153
INTERRUPTED BY A CLINICAL

911
00:37:17,153 --> 00:37:20,423
THRESHOLD, -- AFFECT THIS

912
00:37:20,423 --> 00:37:21,524
HYPOTHETICAL INDIVIDUAL.

913
00:37:21,524 --> 00:37:23,593
NOW, WE CAN THINK THAT SOMEBODY

914
00:37:23,593 --> 00:37:26,463
ELSE MAY HAVE A LONGER

915
00:37:26,463 --> 00:37:27,530
DISEASE-FREE LIFE EXPECTANCY,

916
00:37:27,530 --> 00:37:31,468
BUT THE SAME CLUSTER OF DISEASE

917
00:37:31,468 --> 00:37:33,336
OCCURS AFTER THIS PERIOD.

918
00:37:33,336 --> 00:37:35,739
AND SOMEBODY HAS A DISEASE-FREE

919
00:37:35,739 --> 00:37:38,241
LIFE EXPECTANCY THAT IS SHORTER,

920
00:37:38,241 --> 00:37:42,212
AGAIN, AFTER THIS DATA, WE SEE

921
00:37:42,212 --> 00:37:44,080
EPIDEMIOLOGICALLY A FIRST DIRECT

922
00:37:44,080 --> 00:37:47,450
RELATION OF CHRONIC DISEASE

923
00:37:47,450 --> 00:37:48,551
DEVELOP CLINICAL IN CLUSTER.

924
00:37:48,551 --> 00:37:50,520
AND THE REAL PROBLEM IS THAT

925
00:37:50,520 --> 00:37:54,557
WHAT WE DO IS THAT WE INTERVENE

926
00:37:54,557 --> 00:37:55,892
ONLY AT THE TIME WHEN DISEASE

927
00:37:55,892 --> 00:37:58,394
BECOMES CLINICALLY EVIDENT.

928
00:37:58,394 --> 00:38:00,130
SO IT DOESN'T REALLY MATTER HOW

929
00:38:00,130 --> 00:38:02,665
GOOD IS OUR MEDICAL CARE,

930
00:38:02,665 --> 00:38:04,200
BECAUSE AT THIS POINT, THE ONLY

931
00:38:04,200 --> 00:38:10,540
THING THAT WE CAN DO IS INCREASE

932
00:38:10,540 --> 00:38:12,742
THE PERIOD -- DISABILITY AND

933
00:38:12,742 --> 00:38:13,710
INTERVENING HERE WILL CERTAINLY

934
00:38:13,710 --> 00:38:15,578
NOT AFFECT THE PART OF LIFE THAT

935
00:38:15,578 --> 00:38:18,414
WE WANT TO EXTEND AND WHERE WE

936
00:38:18,414 --> 00:38:22,218
CAN ENJOY ALL THE OPPORTUNITY

937
00:38:22,218 --> 00:38:25,321
THAT LIFE CAN OFFER.

938
00:38:25,321 --> 00:38:27,290
DO WE HAVE AN ALTERNATIVE HERE?

939
00:38:27,290 --> 00:38:28,691
WELL, THE ALTERNATIVE IS TO

940
00:38:28,691 --> 00:38:32,862
THINK WHY WE DON'T SEE DISEASE

941
00:38:32,862 --> 00:38:33,763
EMERGING UNDERNEATH THE

942
00:38:33,763 --> 00:38:36,499
ACCUMULATION OF PATHOLOGY.

943
00:38:36,499 --> 00:38:38,101
AND IN DISEASE-FREE INDIVIDUAL,

944
00:38:38,101 --> 00:38:40,069
THE ACCUMULATION OF PATHOLOGY

945
00:38:40,069 --> 00:38:42,605
OCCURS AT A DIFFERENT RATE.

946
00:38:42,605 --> 00:38:45,875
THIS INDIVIDUAL, FOR EXAMPLE, IS

947
00:38:45,875 --> 00:38:47,076
FASTER AND SLOWER, IF I COULD

948
00:38:47,076 --> 00:38:49,045
MEASURE THE RATE OF ACCUMULATION

949
00:38:49,045 --> 00:38:53,316
OF PATHOLOGY IN THESE

950
00:38:53,316 --> 00:38:54,717
INDIVIDUALS BEFORE THE EMERGENCE

951
00:38:54,717 --> 00:38:56,386
OF CHRONIC DISEASE, CERTAINLY MY

952
00:38:56,386 --> 00:38:57,687
INTERVENTION COULD BE A LOT MORE

953
00:38:57,687 --> 00:39:01,424
EFFECTIVE.

954
00:39:01,424 --> 00:39:02,959
WELL, IN THE FIELD OF AGING, WE

955
00:39:02,959 --> 00:39:07,130
THINK THESE ACCUMULATIONS,

956
00:39:07,130 --> 00:39:07,997
GREATER ACCUMULATION OF

957
00:39:07,997 --> 00:39:09,065
PATHOLOGY IS REALLY DUE TO THE

958
00:39:09,065 --> 00:39:12,135
PACE OF AGING.

959
00:39:12,135 --> 00:39:13,937
THE GENERAL SCIENCE PARADIGM

960
00:39:13,937 --> 00:39:15,305
POSES THAT THE BIOLOGY OF AGING

961
00:39:15,305 --> 00:39:17,640
AT THE ROOT OF MOST CHRONIC

962
00:39:17,640 --> 00:39:20,043
DISEASE AND DISABILITY OCCUR IN

963
00:39:20,043 --> 00:39:21,578
LATE LIFE.

964
00:39:21,578 --> 00:39:32,121
TO MAKE THIS IN A CONTEXT OF --

965
00:39:33,022 --> 00:39:35,158
WHEN CHRONIC DISEASE OCCUR, WE

966
00:39:35,158 --> 00:39:37,794
HAVE A FANTASTIC ARMAMENTARIUM

967
00:39:37,794 --> 00:39:42,899
OF MEDICAL INTERVENTIONS THAT

968
00:39:42,899 --> 00:39:44,334
CAN REDUCE THE SYMPTOMS AND

969
00:39:44,334 --> 00:39:47,570
INCREASE THE LIFE EXPECTANCY OF

970
00:39:47,570 --> 00:39:50,506
THE INDIVIDUAL THAT SEEK -- I

971
00:39:50,506 --> 00:39:51,908
PUT SOME EXAMPLES HERE.

972
00:39:51,908 --> 00:39:54,210
BUT AN ALTERNATIVE WILL BE TO

973
00:39:54,210 --> 00:39:59,015
SAY CAN I SLOW DOWN THE PACE OF

974
00:39:59,015 --> 00:40:00,216
AGING, AND BY SLOWING DOWN THE

975
00:40:00,216 --> 00:40:02,852
PACE OF AGING, REDUCE THE

976
00:40:02,852 --> 00:40:04,687
INCIDENT OF ALL CHRONIC DISEASE

977
00:40:04,687 --> 00:40:07,891
AND EXPAND THE PERIOD OF HEALTHY

978
00:40:07,891 --> 00:40:09,959
LIFE EXPECTANCY.

979
00:40:09,959 --> 00:40:10,827
WELL, THERE ARE TWO THINGS THAT

980
00:40:10,827 --> 00:40:12,395
I NEED TO DEMONSTRATE FIRST.

981
00:40:12,395 --> 00:40:13,997
FIRST OF ALL, CAN I SLOW DOWN

982
00:40:13,997 --> 00:40:16,032
THE PACE OF AGING?

983
00:40:16,032 --> 00:40:18,401
AND EVEN MORE IMPORTANT, CAN I

984
00:40:18,401 --> 00:40:24,007
MEASURE THE PACE OF AGING TO

985
00:40:24,007 --> 00:40:24,974
DEMONSTRATE THAT SEVERAL

986
00:40:24,974 --> 00:40:26,509
INTERVENTIONS CAN ACTUALLY SLOW

987
00:40:26,509 --> 00:40:28,144
DOWN.

988
00:40:28,144 --> 00:40:30,880
NOW, FIRST OF ALL, IS THAT

989
00:40:30,880 --> 00:40:31,414
POSSIBLE?

990
00:40:31,414 --> 00:40:32,415
AM I TALKING SOMETHING THAT IS A

991
00:40:32,415 --> 00:40:32,749
DREAM?

992
00:40:32,749 --> 00:40:36,686
I THINK THERE ARE MANY EXAMPLES

993
00:40:36,686 --> 00:40:38,554
THAT SUGGEST THAT EXPANDING

994
00:40:38,554 --> 00:40:40,456
HEALTH EXPECTANCY POSSIBLE.

995
00:40:40,456 --> 00:40:43,293
ONE OF THE EXAMPLES IS A STUDY

996
00:40:43,293 --> 00:40:44,193
ON CENTENARIANS.

997
00:40:44,193 --> 00:40:49,766
THIS IS A STUDY FROM TOM PERTS

998
00:40:49,766 --> 00:40:51,067
PUBLISHED AROUND THE YEAR 2000,

999
00:40:51,067 --> 00:40:57,006
AND WHAT HE DID, HE TOOK

1000
00:40:57,006 --> 00:40:57,407
CENTENARIANS.

1001
00:40:57,407 --> 00:40:59,609
AVERAGE AGE 102 YEARS, AND THEN

1002
00:40:59,609 --> 00:41:01,711
HE DID A RETROSPECTIVE ANALYSIS

1003
00:41:01,711 --> 00:41:04,414
OF THEIR FUNCTIONAL STATUS IN

1004
00:41:04,414 --> 00:41:06,049
THE PREVIOUS YEAR.

1005
00:41:06,049 --> 00:41:10,987
YEARS, TWO YEARSBEFORE, THREE YE

1006
00:41:10,987 --> 00:41:11,854
YEARS BEFORE AND 10 YEARS

1007
00:41:11,854 --> 00:41:12,088
BEFORE.

1008
00:41:12,088 --> 00:41:13,289
YOU CAN SEE FOR EXAMPLE THAT

1009
00:41:13,289 --> 00:41:17,226
THREE YEARS BEFORE, ALMOST 55%

1010
00:41:17,226 --> 00:41:19,395
OF THEM, COMPLETE NORMAL

1011
00:41:19,395 --> 00:41:20,396
FUNCTIONAL STATUS.

1012
00:41:20,396 --> 00:41:22,999
YOU HAVE TO COMPARE THIS WITH

1013
00:41:22,999 --> 00:41:26,536
WHAT HAPPENED IN THE GENERAL

1014
00:41:26,536 --> 00:41:28,271
POPULATION, WHERE ONLY 40% OF

1015
00:41:28,271 --> 00:41:33,076
PEOPLE THAT ARE 80 AND OLDER

1016
00:41:33,076 --> 00:41:34,077
HAVE FULL, COMPLETE LACK OF

1017
00:41:34,077 --> 00:41:35,378
DISABILITY.

1018
00:41:35,378 --> 00:41:37,146
SO THAT SUGGESTS THE POTENTIAL

1019
00:41:37,146 --> 00:41:40,416
IN OUR GENOME FOR EXPANSION OF

1020
00:41:40,416 --> 00:41:45,388
HEALTH EXPECTANCY IS THERE.

1021
00:41:45,388 --> 00:41:48,124
IT TURNS OUT MEASURING THE PACE

1022
00:41:48,124 --> 00:41:50,793
OF AGING, THIS IS AN EXPANDING

1023
00:41:50,793 --> 00:41:53,796
LINE OF RESEARCH IN AGING.

1024
00:41:53,796 --> 00:41:56,666
AND THEN THIS IS PROBABLY THE

1025
00:41:56,666 --> 00:41:59,836
MOST IMPORTANT EXAMPLE, THE

1026
00:41:59,836 --> 00:42:02,438
GENETIC CLOCK THAT WAS DEVELOPED

1027
00:42:02,438 --> 00:42:06,709
BY STEVE HORVATH SHOWING THE

1028
00:42:06,709 --> 00:42:10,013
METHYLATION IN -- NUMBER OF

1029
00:42:10,013 --> 00:42:12,181
CBGs IN THE GENOME CAN BE

1030
00:42:12,181 --> 00:42:13,516
SUMMARIZED IN A SCORE, AND THE

1031
00:42:13,516 --> 00:42:15,284
SCORE IS STRONGLY RELATED TO

1032
00:42:15,284 --> 00:42:16,052
CHRONOLOGICAL AGE.

1033
00:42:16,052 --> 00:42:19,989
AND I TELL PEOPLE, IF YOU SEE A

1034
00:42:19,989 --> 00:42:22,191
DROP OF BLOOD IN THE CORRIDOR,

1035
00:42:22,191 --> 00:42:23,526
YOU CAN ANALYZE THAT DROP OF

1036
00:42:23,526 --> 00:42:26,796
BLOOD AND TELL WHAT AGE WAS THE

1037
00:42:26,796 --> 00:42:28,231
PERSON THAT LOST THAT DROP OF

1038
00:42:28,231 --> 00:42:28,865
BLOOD.

1039
00:42:28,865 --> 00:42:31,067
10 YEARS AGO, THIS IDEA WAS

1040
00:42:31,067 --> 00:42:33,936
COMPLETELY PREPOSTEROUS.

1041
00:42:33,936 --> 00:42:36,005
WE HAD ABSOLUTELY NO WAY TO

1042
00:42:36,005 --> 00:42:36,539
ESTIMATE THAT.

1043
00:42:36,539 --> 00:42:39,509
NOT ONLY THIS, WE KNOW THAT WHEN

1044
00:42:39,509 --> 00:42:43,012
WE FACTOR OUT CHRONOLOGICAL AGE,

1045
00:42:43,012 --> 00:42:46,182
BIOLOGICAL AGE CALCULATED WITH

1046
00:42:46,182 --> 00:42:47,717
EPIGENETIC CLOCK IS ASSOCIATED

1047
00:42:47,717 --> 00:42:51,354
WITH THE DIMENSION THAT WE KNOW

1048
00:42:51,354 --> 00:42:52,755
AFFECTING GOOD HEALTH AND BAD

1049
00:42:52,755 --> 00:42:53,089
HEALTH.

1050
00:42:53,089 --> 00:42:56,325
FOR EXAMPLE, SLOWER EPIGENETIC

1051
00:42:56,325 --> 00:42:59,228
AGING IS ASSOCIATED WITH FISH

1052
00:42:59,228 --> 00:43:00,563
CONSUMPTION, FRUITS AND

1053
00:43:00,563 --> 00:43:02,298
VEGETABLE CONSUMPTION, HIGH

1054
00:43:02,298 --> 00:43:07,570
SOCIOECONOMIC STATUS, AND FASTER

1055
00:43:07,570 --> 00:43:13,042
EPIGENETIC AGING IS ASSOCIATED

1056
00:43:13,042 --> 00:43:15,912
WITH OBESITY, HIGH TRIGLYCERIDES

1057
00:43:15,912 --> 00:43:16,846
AND INFLAMMATION.

1058
00:43:16,846 --> 00:43:20,383
IN THIS CASE, WE USE -- TO

1059
00:43:20,383 --> 00:43:21,818
CALCULATE THE CHRONOLOGICAL AGE.

1060
00:43:21,818 --> 00:43:23,186
THE PROBLEM WITH THIS METHOD IS

1061
00:43:23,186 --> 00:43:28,825
THE FACT THAT WE TUNE THIS

1062
00:43:28,825 --> 00:43:31,461
BIOMARKER AGE PREDICTOR BY USING

1063
00:43:31,461 --> 00:43:32,762
CROSS-SECTIONAL STUDIES.

1064
00:43:32,762 --> 00:43:34,497
AND CROSS-SECTIONAL STUDIES ARE

1065
00:43:34,497 --> 00:43:37,066
HIGHLY BIASED.

1066
00:43:37,066 --> 00:43:39,335
SO I WANT TO EXPLAIN TO YOU WHY,

1067
00:43:39,335 --> 00:43:41,771
AND FOR EXAMPLE, IF YOU WANT TO

1068
00:43:41,771 --> 00:43:46,242
COMPARE PEOPLE BETWEEN THE AGE

1069
00:43:46,242 --> 00:43:50,079
OF 20, 100 AND FIVE, YOU CAN

1070
00:43:50,079 --> 00:43:54,450
COMPARE THEM AND SAY THAT THEIR

1071
00:43:54,450 --> 00:43:56,252
DIFFERENCE IN SYSTOLIC BLOOD

1072
00:43:56,252 --> 00:44:00,823
PRESSURE ARE HIGHER THAN THOSE

1073
00:44:00,823 --> 00:44:01,257
AGE 105.

1074
00:44:01,257 --> 00:44:02,225
THE PROBLEM IS THIS INDIVIDUAL

1075
00:44:02,225 --> 00:44:04,861
AT THE AGE OF 20 IS AT THE AGE

1076
00:44:04,861 --> 00:44:07,730
OF 20 IN THE YEAR 2000, WHEN THE

1077
00:44:07,730 --> 00:44:09,165
UNEMPLOYMENT RATE IN THE UNITED

1078
00:44:09,165 --> 00:44:14,737
STATES WAS BELOW 4%, WHICH IS

1079
00:44:14,737 --> 00:44:16,506
NOT ALMOST -- IN THE UNITED

1080
00:44:16,506 --> 00:44:16,906
STATES.

1081
00:44:16,906 --> 00:44:22,178
WHY THIS PERSON THAT IS 90 WAS

1082
00:44:22,178 --> 00:44:24,180
AGE AT THE TIME OF THE GREAT

1083
00:44:24,180 --> 00:44:26,048
DEPRESSION, THERE WAS NO

1084
00:44:26,048 --> 00:44:27,116
PUBLICLY AVAILABLE WATER OR FOOD

1085
00:44:27,116 --> 00:44:27,984
FOR EVERYBODY.

1086
00:44:27,984 --> 00:44:29,218
SO NOT ONLY THESE INDIVIDUALS

1087
00:44:29,218 --> 00:44:30,419
ARE DIFFERENT BECAUSE OF THEIR

1088
00:44:30,419 --> 00:44:31,387
AGE, BUT THEY'RE DIFFERENT

1089
00:44:31,387 --> 00:44:34,457
BECAUSE OF THEIR VERY DIFFERENT

1090
00:44:34,457 --> 00:44:35,558
PAST EXPERIENCE.

1091
00:44:35,558 --> 00:44:38,828
SO THE ONLY WAY TO OVERCOME THIS

1092
00:44:38,828 --> 00:44:42,131
IS TO MEASURE INDIVIDUALS OVER

1093
00:44:42,131 --> 00:44:45,401
TIME, AND THAT IS WHAT THE NEW

1094
00:44:45,401 --> 00:44:51,073
SCIENCE IS DOING, REALLY

1095
00:44:51,073 --> 00:44:52,141
SCRATCHING THE SURFACE OF WHAT

1096
00:44:52,141 --> 00:44:54,544
WAS HAPPENING, THIS IS THE

1097
00:44:54,544 --> 00:44:57,914
ATTEMPT FROM DANIEL BELSKY TO

1098
00:44:57,914 --> 00:45:00,449
SUMMARIZE THE RATE OF AGING BY

1099
00:45:00,449 --> 00:45:03,186
LOOKING AT NUMBER OF PHENOTYPIC

1100
00:45:03,186 --> 00:45:04,086
PARAMETERS, AND THIS IS AN

1101
00:45:04,086 --> 00:45:05,721
EXAMPLE OF THE PARAMETERS THAT

1102
00:45:05,721 --> 00:45:07,990
ARE BEING STUDIED IN THE

1103
00:45:07,990 --> 00:45:09,225
BALTIMORE LONGITUDINAL STUDY OF

1104
00:45:09,225 --> 00:45:09,892
AGING.

1105
00:45:09,892 --> 00:45:12,728
AND ONE OF THE COMPLEXITIES THAT

1106
00:45:12,728 --> 00:45:15,831
WE FACE IN THIS WORK IS THAT,

1107
00:45:15,831 --> 00:45:18,601
YOU KNOW, WHY THERE IS SOME

1108
00:45:18,601 --> 00:45:20,903
PARAMETER THAT ARE DECLINING

1109
00:45:20,903 --> 00:45:21,237
LINEARLY.

1110
00:45:21,237 --> 00:45:26,609
FOR EXAMPLE, YOU KNOW, THERE IS

1111
00:45:26,609 --> 00:45:29,312
INTERLEUKIN 6, CHANGING

1112
00:45:29,312 --> 00:45:30,246
LINEARLY, OTHER PARAMETERS ARE

1113
00:45:30,246 --> 00:45:30,446
NOT.

1114
00:45:30,446 --> 00:45:34,951
YOU KNOW, FOR EXAMPLE, SOME OF

1115
00:45:34,951 --> 00:45:37,987
THE -- RATIOS ARE REALLY

1116
00:45:37,987 --> 00:45:43,292
CHANGING CURVILINEAR WITH AGING,

1117
00:45:43,292 --> 00:45:44,627
SO -- PERSPECTIVE IS QUITE

1118
00:45:44,627 --> 00:45:45,228
COMPLEX.

1119
00:45:45,228 --> 00:45:48,564
I WANT TO FINISH TO YOU BY, YOU

1120
00:45:48,564 --> 00:45:51,634
KNOW, LOOKING AT WHAT IS THE

1121
00:45:51,634 --> 00:45:54,704
UNDERNEATH MODEL FOR THE SCIENCE

1122
00:45:54,704 --> 00:45:58,541
OF AGING, WHY WE HAVE THIS

1123
00:45:58,541 --> 00:46:00,409
INCREASE IN CHRONIC DISEASE.

1124
00:46:00,409 --> 00:46:04,814
IMAGINE THAT AT BIRTH, YOU HAVE

1125
00:46:04,814 --> 00:46:11,254
COMPLETE HOMEOSTATIC EQUILIB 

1126
00:46:11,254 --> 00:46:12,255
EQUILIBRIUM -- THE INTEGRITY OF

1127
00:46:12,255 --> 00:46:15,758
MACRO MOLECULES IN CELLS THAT

1128
00:46:15,758 --> 00:46:20,029
ARE EVOLUTIONARILY PRESERVED TO

1129
00:46:20,029 --> 00:46:21,931
EITHER AVOID, PREVENT OR TO

1130
00:46:21,931 --> 00:46:22,765
COUNTER ACT THIS ACCUMULATION OF

1131
00:46:22,765 --> 00:46:24,900
DAMAGE.

1132
00:46:24,900 --> 00:46:26,202
THE PROBLEM IS THAT THE

1133
00:46:26,202 --> 00:46:28,904
RESILIENCE IS ALSO A BIOLOGICAL

1134
00:46:28,904 --> 00:46:31,574
IPHENOMENON THAT TEND TO DECLINE

1135
00:46:31,574 --> 00:46:38,481
WITH AGING, -- THE DAMAGE

1136
00:46:38,481 --> 00:46:40,483
ACCUMULATION BECOMES FASTER AND

1137
00:46:40,483 --> 00:46:41,117
FASTER WITH AGE.

1138
00:46:41,117 --> 00:46:43,986
AND SO WE DEVELOP CHRONIC

1139
00:46:43,986 --> 00:46:45,154
DISEASE BECAUSE OF LACK OF

1140
00:46:45,154 --> 00:46:46,055
RESILIENCE.

1141
00:46:46,055 --> 00:46:50,226
AND SOME OF THE RESILIENCE

1142
00:46:50,226 --> 00:46:50,960
STRATEGIES, WE'RE STARTING TO BE

1143
00:46:50,960 --> 00:46:52,428
ABLE TO MEASURE, ALTHOUGH WE'RE

1144
00:46:52,428 --> 00:46:54,964
NOT AT THE LEVEL OF CLINICAL

1145
00:46:54,964 --> 00:46:56,165
APPLICATION AND TRANSLATIONAL

1146
00:46:56,165 --> 00:46:57,400
APPLICATION.

1147
00:46:57,400 --> 00:46:59,669
AND THEN IN VERY, VERY OLD AGE,

1148
00:46:59,669 --> 00:47:01,437
WE HAVE THE FRAILTY SITUATION,

1149
00:47:01,437 --> 00:47:03,306
WHERE THE INDIVIDUAL HAS SO

1150
00:47:03,306 --> 00:47:04,840
LITTLE RESILIENCY THAT EVEN THE

1151
00:47:04,840 --> 00:47:08,344
CHALLENGE OF LIVING A NORMAL

1152
00:47:08,344 --> 00:47:14,784
LIFE CAN BE REALLY PROBLEMATIC M

1153
00:47:14,784 --> 00:47:16,218
ONE LAST MESSAGE I WANT TO GIVE

1154
00:47:16,218 --> 00:47:17,987
YOU IS THAT IN THE YOUNGER AGE,

1155
00:47:17,987 --> 00:47:21,924
BEFORE DISEASE ARE ACCUMULATING,

1156
00:47:21,924 --> 00:47:23,559
THERE'S A LOT WE CAN DO TO BRING

1157
00:47:23,559 --> 00:47:24,560
FORTH OUR RESILIENCE.

1158
00:47:24,560 --> 00:47:31,600
WE KNOW, FOR EXAMPLE, STUDY THAT

1159
00:47:31,600 --> 00:47:35,304
GOOD SLEEP, BEHAVIOR MAINTAINING

1160
00:47:35,304 --> 00:47:36,305
HEALTHY WEIGHT AND PHYSICAL

1161
00:47:36,305 --> 00:47:38,274
ACTIVITY INCREASED OUR

1162
00:47:38,274 --> 00:47:40,242
RESILIENCY, THEREFORE,

1163
00:47:40,242 --> 00:47:43,212
COUNTERACT THE EFFECT OF AGING

1164
00:47:43,212 --> 00:47:45,848
ON THE -- FOR CHRONIC DISEASE.

1165
00:47:45,848 --> 00:47:47,817
ON THE OTHER HAND, THE OTHER

1166
00:47:47,817 --> 00:47:50,453
EVENTS OF EXPOSURE THAT

1167
00:47:50,453 --> 00:47:54,190
ACCELERATE AGING, SO INCREASE

1168
00:47:54,190 --> 00:47:56,459
THE -- TO CHRONIC DISEASE, THE

1169
00:47:56,459 --> 00:47:57,893
SCIENCE THAT IS MOVING FAST AND

1170
00:47:57,893 --> 00:47:59,662
MORE AND MORE WILL COME IN THE

1171
00:47:59,662 --> 00:48:02,598
FEWER TOUR.

1172
00:48:02,598 --> 00:48:02,832
FUTURE.

1173
00:48:02,832 --> 00:48:06,001
THANK YOU VERY MUCH FOR YOUR

1174
00:48:06,001 --> 00:48:08,204
ATTENTION, AND SINCE THIS IS

1175
00:48:08,204 --> 00:48:10,406
VIRTUAL, I WILL NOT BE ABLE TO

1176
00:48:10,406 --> 00:48:11,273
RESPOND DIRECTLY TO YOUR

1177
00:48:11,273 --> 00:48:13,709
QUESTION, BUT I INVITE YOU TO

1178
00:48:13,709 --> 00:48:15,244
EMAIL ME, AND I'LL BE HAPPY TO

1179
00:48:15,244 --> 00:48:25,788
ADDRESS ANY QUESTIONS YOU HAVE.

1180
00:48:38,334 --> 00:48:40,236
>> SO WE WANT TO THANK
YOU,

1181
00:48:40,236 --> 00:48:41,537
DR. FERRUCCI.

1182
00:48:41,537 --> 00:48:44,607
I THINK YOU SEE HIS EMAIL IN THE

1183
00:48:44,607 --> 00:48:46,475
CHAT, SO IF THERE ARE QUESTIONS

1184
00:48:46,475 --> 00:48:49,011
FOR HIM, YOU WILL NOT BE ABLE

1185
00:48:49,011 --> 00:48:50,112
TO -- HE WILL NOT BE ABLE TO

1186
00:48:50,112 --> 00:48:52,515
ANSWER LIVE, BUT HE IS --

1187
00:48:52,515 --> 00:48:54,083
>> WE WANT TO THANK YOU,

1188
00:48:54,083 --> 00:48:55,084
DR. FERRUCCI.

1189
00:48:55,084 --> 00:48:56,385
I THINK --

1190
00:48:56,385 --> 00:48:59,655
>> I'M HEARING AN ECHO

1191
00:48:59,655 --> 00:49:05,060
UNFORTUNATELY IN MY ZOOM.

1192
00:49:05,060 --> 00:49:08,597
>> ZORINA, DO YOU HAVE A

1193
00:49:08,597 --> 00:49:12,334
INTERNET WINDOW OPEN?

1194
00:49:12,334 --> 00:49:16,505
>> NO, I ONLY HAVE THIS
ONE.

1195
00:49:16,505 --> 00:49:17,940
>> YOU DON'T HAVE ANY
OTHER

1196
00:49:17,940 --> 00:49:19,375
WINDOWS OPEN?

1197
00:49:19,375 --> 00:49:22,678
>> NO.

1198
00:49:22,678 --> 00:49:26,415
>> OKAY.

1199
00:49:26,415 --> 00:49:28,284
>> IF YOU DO, WHATEVER
ELSE YOU

1200
00:49:28,284 --> 00:49:29,418
HAVE OPEN, YOU HAVE TO CLOSE IT.

1201
00:49:29,418 --> 00:49:30,119
>> OKAY.

1202
00:49:30,119 --> 00:49:30,920
>> OKAY.

1203
00:49:30,920 --> 00:49:31,687
IT WENT AWAY.

1204
00:49:31,687 --> 00:49:32,354
>> ALL RIGHT.

1205
00:49:32,354 --> 00:49:34,957
THANK YOU SO MUCH.

1206
00:49:34,957 --> 00:49:38,394
I HOPE THAT YOU DIDN'T HAVE

1207
00:49:38,394 --> 00:49:40,396
TROUBLE HEARING DR. FERRUCCI'S

1208
00:49:40,396 --> 00:49:41,564
TALK OR ME.

1209
00:49:41,564 --> 00:49:43,098
AND I APOLOGIZE FOR THAT.

1210
00:49:43,098 --> 00:49:47,136
I WOULD LIKE TO INTRODUCE THE

1211
00:49:47,136 --> 00:49:49,205
NEXT DISTINGUISHED KEYNOTE

1212
00:49:49,205 --> 00:49:51,941
SPEAKER WE HAVE TODAY.

1213
00:49:51,941 --> 00:49:54,510
DR. MICHAEL SNYDER, WHO IS TRULY

1214
00:49:54,510 --> 00:49:57,446
MASTERING THE ART OF

1215
00:49:57,446 --> 00:49:58,614
MULTI-OMICS.

1216
00:49:58,614 --> 00:50:02,818
HE IS CURRENTLY AND HAS BEEN

1217
00:50:02,818 --> 00:50:05,554
SINCE 2009, I BELIEVE, THE

1218
00:50:05,554 --> 00:50:06,655
DIRECTOR OF STANFORD DEPARTMENT

1219
00:50:06,655 --> 00:50:08,824
OF GENETICS AND PERSONALIZED

1220
00:50:08,824 --> 00:50:12,361
MEDICINE, AND OF NOTE, SINCE HIS

1221
00:50:12,361 --> 00:50:14,630
LEADERSHIP, STANFORD HAS BEEN

1222
00:50:14,630 --> 00:50:16,932
RANKED AS NUMBER ONE IN

1223
00:50:16,932 --> 00:50:19,235
PERSONALIZED MEDICINE AND

1224
00:50:19,235 --> 00:50:25,374
GENETICS FOR THE PAST DECADE.

1225
00:50:25,374 --> 00:50:28,010
DR. SNYDER IS NOT ONLY A VERY

1226
00:50:28,010 --> 00:50:29,211
TALENTED ACADEMIC RESEARCHER BUT

1227
00:50:29,211 --> 00:50:31,313
ALSO AN ENTREPRENEUR.

1228
00:50:31,313 --> 00:50:35,484
HE HAS SIGNIFICANT CONTRIBUTION

1229
00:50:35,484 --> 00:50:38,654
TO STARTING OR ADVISING A NUMBER

1230
00:50:38,654 --> 00:50:40,222
OF COMPANIES, SO HE CAN REALLY

1231
00:50:40,222 --> 00:50:42,424
GIVE US A VERY INTERESTING

1232
00:50:42,424 --> 00:50:45,828
COMPREHENSIVE VIEW FROM IDEA TO

1233
00:50:45,828 --> 00:50:47,796
POTENTIALLY IMPLEMENTATION OF

1234
00:50:47,796 --> 00:50:48,831
LONGITUDAL STUDIES.

1235
00:50:48,831 --> 00:50:51,033
WE ARE VERY MUCH LOOKING FORWARD

1236
00:50:51,033 --> 00:50:53,402
TO YOUR KEYNOTE AND THANK YOU

1237
00:50:53,402 --> 00:50:56,171
FOR LOGGING IN EARLY IN

1238
00:50:56,171 --> 00:50:56,472
CALIFORNIA.

1239
00:50:56,472 --> 00:51:02,978
THANK YOU.

1240
00:51:02,978 --> 00:51:03,946
>> OKAY, GREAT.

1241
00:51:03,946 --> 00:51:06,682
IT IS A PLEASURE TO BE HERE.

1242
00:51:06,682 --> 00:51:15,357
FLEUR SOMSOMEONE NEEDS TO STOP ,

1243
00:51:15,357 --> 00:51:17,426
ACTUALLY.

1244
00:51:17,426 --> 00:51:18,794
NOW IT'S WORKING.

1245
00:51:18,794 --> 00:51:19,328
GREAT.

1246
00:51:19,328 --> 00:51:22,431
HOPEFULLY YOU CAN SEE THIS.

1247
00:51:22,431 --> 00:51:24,300
SO IT IS A PLEASURE TO BE HERE,

1248
00:51:24,300 --> 00:51:30,005
AND I THINK MY TALK FEEDS NICELY

1249
00:51:30,005 --> 00:51:31,407
FROM WHAT LUIGI JUST PRESENTED.

1250
00:51:31,407 --> 00:51:33,275
SO I WILL TALK ABOUT USING NEW

1251
00:51:33,275 --> 00:51:34,310
DATA AND SOME OF THE NEW

1252
00:51:34,310 --> 00:51:35,511
TECHNOLOGIES WE'RE USING FOR

1253
00:51:35,511 --> 00:51:36,712
MONITORING HEALTH, AND I THINK

1254
00:51:36,712 --> 00:51:38,180
TRYING TO KEEP PEOPLE HEALTHY

1255
00:51:38,180 --> 00:51:42,851
AND EXTENDING THEIR HEALTHSPAN.

1256
00:51:42,851 --> 00:51:44,186
SO I LIKE TO START WITH THE FACT

1257
00:51:44,186 --> 00:51:45,955
THAT OUR HEALTHCARE SYSTEM IS

1258
00:51:45,955 --> 00:51:47,056
BROKEN, AS YOU MAY HAVE SEEN IN

1259
00:51:47,056 --> 00:51:49,258
THE CHAT.

1260
00:51:49,258 --> 00:51:53,162
WE REALLY DO TEND -- AS LUIGI

1261
00:51:53,162 --> 00:51:54,296
SAID, WE TEND TO EXECUTE SICK

1262
00:51:54,296 --> 00:51:55,397
CARE RATHER THAN HEALTHCARE, AND

1263
00:51:55,397 --> 00:51:59,101
EVEN WHEN WE DO TRY TO DO

1264
00:51:59,101 --> 00:52:00,569
HEALTHCARE, IT'S A VERY ARCHAIC

1265
00:52:00,569 --> 00:52:01,570
PROCESS IF YOU THINK ABOUT IT.

1266
00:52:01,570 --> 00:52:04,940
WE TYPICALLY GET IN A CAR, A BUS

1267
00:52:04,940 --> 00:52:06,141
OR SOMETHING AT A VERY

1268
00:52:06,141 --> 00:52:07,376
INCONVENIENT TIME TO TRAVEL TO A

1269
00:52:07,376 --> 00:52:07,710
PHYSICIAN.

1270
00:52:07,710 --> 00:52:09,912
WE ARRIVE AT A DOCTOR'S OFFICE

1271
00:52:09,912 --> 00:52:11,547
THAT PRETTY MUCH LOOKS THE SAME

1272
00:52:11,547 --> 00:52:12,881
AS IT'S LOOKED FOR THE LAST 40

1273
00:52:12,881 --> 00:52:13,082
YEARS.

1274
00:52:13,082 --> 00:52:14,216
WHEN YOU'RE THERE, THEY'LL STICK

1275
00:52:14,216 --> 00:52:16,051
IN A NEEDLE AND PULL OUT A LOT

1276
00:52:16,051 --> 00:52:18,988
OF BLOOD.

1277
00:52:18,988 --> 00:52:21,090
FROM THAT BLOOD AND THE TIME

1278
00:52:21,090 --> 00:52:22,524
YOU'RE THERE, THEY ACTUALLY

1279
00:52:22,524 --> 00:52:24,159
DON'T MAKE VERY MEASUREMENTS,

1280
00:52:24,159 --> 00:52:25,461
AND PERHAPS MOST IMPORTANTLY,

1281
00:52:25,461 --> 00:52:26,495
THEY'LL MAKE DECISIONS ABOUT

1282
00:52:26,495 --> 00:52:29,965
YOUR HEALTH BASED ON POPULATION

1283
00:52:29,965 --> 00:52:32,067
AVERAGES.

1284
00:52:32,067 --> 00:52:33,068
WE BELIEVE EVERY ONE OF THESE

1285
00:52:33,068 --> 00:52:35,037
STEPS CAN BE IMPROVED AND THAT'S

1286
00:52:35,037 --> 00:52:36,572
WHAT WE'VE BEEN WORKING ON AND

1287
00:52:36,572 --> 00:52:38,107
TRYING TO DO A LOT TO KEEP

1288
00:52:38,107 --> 00:52:38,807
PEOPLE HEALTHY.

1289
00:52:38,807 --> 00:52:40,676
WE DO A LOT IN NUTRITION AND

1290
00:52:40,676 --> 00:52:43,078
SUCH AS WELL WHICH I WON'T TALK

1291
00:52:43,078 --> 00:52:44,613
TODAY, AND LIFESTYLE, MAYBE

1292
00:52:44,613 --> 00:52:45,714
WE'LL TOUCH ON THAT.

1293
00:52:45,714 --> 00:52:46,815
BUT ANYWAY JUST TO ILLUSTRATE

1294
00:52:46,815 --> 00:52:48,884
THIS LAST POINT ABOUT POPULATION

1295
00:52:48,884 --> 00:52:49,785
AVERAGES BEING MAYBE NOT THE

1296
00:52:49,785 --> 00:52:52,421
BEST WAY TO THINK ABOUT PEOPLE,

1297
00:52:52,421 --> 00:52:53,756
IS SOMETHING YOU'VE BEEN TOLD

1298
00:52:53,756 --> 00:52:55,391
SINCE YOU'RE LITTLE IS THAT YOUR

1299
00:52:55,391 --> 00:52:56,592
TEMPERATURE WHEN YOU PUT A

1300
00:52:56,592 --> 00:52:58,794
THERMOMETER IN YOUR MOUTH IS

1301
00:52:58,794 --> 00:52:59,228
98.6.

1302
00:52:59,228 --> 00:53:00,896
IF YOU ACTUALLY LOOK AT THE DATA

1303
00:53:00,896 --> 00:53:02,197
THAT ARE OUT THERE, FIRST THAT

1304
00:53:02,197 --> 00:53:03,766
NUMBER IS WRONG, IT TENDS TO BE

1305
00:53:03,766 --> 00:53:05,934
MORE LIKE 97.5.

1306
00:53:05,934 --> 00:53:08,671
ONE BIG, BIG STUDY JUST GOT

1307
00:53:08,671 --> 00:53:11,206
PUBLISHED THAT SAYS IT'S 97.7.

1308
00:53:11,206 --> 00:53:13,308
BUT THE MORE IMPORTANT POINT IS

1309
00:53:13,308 --> 00:53:16,078
THERE'S THAT A SPREAD.

1310
00:53:16,078 --> 00:53:16,845
 A SPREAD.

1311
00:53:16,845 --> 00:53:18,947
WHAT THIS MEANS IN TODAY'S

1312
00:53:18,947 --> 00:53:20,949
WORLD, IF YOUR NORMAL AVERAGE

1313
00:53:20,949 --> 00:53:23,152
HEALTHY BASELINE IS 94.6, YOU GO

1314
00:53:23,152 --> 00:53:24,386
TO A PHYSICIAN TODAY, THEY

1315
00:53:24,386 --> 00:53:26,889
MEASURE YOU AT 98.6, THEY'LL

1316
00:53:26,889 --> 00:53:28,323
TELL YOU, YOU KNOW, YOU'RE

1317
00:53:28,323 --> 00:53:30,025
NORMAL, YOU'RE HEALTHY,

1318
00:53:30,025 --> 00:53:33,162
EVERYTHING IS FINE BUT IF YOU'RE

1319
00:53:33,162 --> 00:53:34,363
4 DEGREES OVER YOUR BASELINE,

1320
00:53:34,363 --> 00:53:35,130
YOU'RE NOT FINE.

1321
00:53:35,130 --> 00:53:37,099
SO WE THINK THIS IS A BIG PART,

1322
00:53:37,099 --> 00:53:38,767
KNOWING WHAT YOUR HEALTHY

1323
00:53:38,767 --> 00:53:40,869
BASELINE IS SO IT CAN DETECT

1324
00:53:40,869 --> 00:53:42,638
SHIFTS FROM THAT AND DETECT

1325
00:53:42,638 --> 00:53:44,506
ILLNESS AT THE EARLIEST POSSIBLE

1326
00:53:44,506 --> 00:53:44,940
TIME.

1327
00:53:44,940 --> 00:53:47,009
SO YOUR HEALTH YOU PROBABLY KNOW

1328
00:53:47,009 --> 00:53:48,444
IS INFLUENCED BY MANY THINGS, BY

1329
00:53:48,444 --> 00:53:50,412
YOUR DNA, YOUR GENOME, BUT WHEN

1330
00:53:50,412 --> 00:53:52,848
IT COMES TO LONGEVITY, YOU MAY

1331
00:53:52,848 --> 00:53:54,149
KNOW THAT THE NUMBERS RANGE

1332
00:53:54,149 --> 00:53:57,319
QUITE A BIT, BUT IT'S ESTIMATED

1333
00:53:57,319 --> 00:54:01,523
ABOUT 16% OF LIFESPAN IS DUE TO

1334
00:54:01,523 --> 00:54:02,624
HERITABILITY, THE REST DUE TO

1335
00:54:02,624 --> 00:54:03,158
GENETICS.

1336
00:54:03,158 --> 00:54:04,493
THE REST IS PROBABLY

1337
00:54:04,493 --> 00:54:05,494
ENVIRONMENTAL FACTORS.

1338
00:54:05,494 --> 00:54:08,597
AND SO EXERCISE, FOOD, STRESS,

1339
00:54:08,597 --> 00:54:09,665
ENVIRONMENTAL EXPOSURES, WE ALL

1340
00:54:09,665 --> 00:54:12,067
KNOW THESE IMPACT YOUR HEALTH,

1341
00:54:12,067 --> 00:54:13,335
BUT WE'RE IN A WORLD NOW WHERE

1342
00:54:13,335 --> 00:54:15,871
WE CAN QUANTIFY SOME PRETTY WELL

1343
00:54:15,871 --> 00:54:19,141
BY ACTIVITY, OTHERS LIKE FOOD,

1344
00:54:19,141 --> 00:54:20,809
WE'RE WORKING A LOT HERE IN THIS

1345
00:54:20,809 --> 00:54:23,145
SPACE, I WON'T SPEND TIME

1346
00:54:23,145 --> 00:54:24,880
TALKING ABOUT THIS, MEASURING

1347
00:54:24,880 --> 00:54:25,614
ENVIRONMENT EXPOSURES.

1348
00:54:25,614 --> 00:54:27,049
SO WE SHOULD BE ABLE TO MEASURE

1349
00:54:27,049 --> 00:54:28,550
THESE THINGS AND ACTUALLY BETTER

1350
00:54:28,550 --> 00:54:29,551
UNDERSTAND HOW THEY IMPACT YOUR

1351
00:54:29,551 --> 00:54:30,018
HEALTH.

1352
00:54:30,018 --> 00:54:31,019
BUT EVEN IF WE DON'T MEASURE

1353
00:54:31,019 --> 00:54:32,855
THEM DIRECTLY, WE CAN MEASURE

1354
00:54:32,855 --> 00:54:35,157
THEIR EFFECTS BY ACTUALLY USING

1355
00:54:35,157 --> 00:54:36,391
DEEP DATA PROFILES ON PEOPLE.

1356
00:54:36,391 --> 00:54:37,726
AND THIS IS SOMETHING WE SET UP

1357
00:54:37,726 --> 00:54:40,462
A NUMBER OF YEARS AGO, WHAT WE

1358
00:54:40,462 --> 00:54:42,030
CALL PERSONAL OMICS PROFILING

1359
00:54:42,030 --> 00:54:45,667
WHERE WE'LL SEE PEOPLE'S GENOME

1360
00:54:45,667 --> 00:54:47,236
AND FROM THEIR BLOOD WE'LL

1361
00:54:47,236 --> 00:54:50,439
MEASURE THEIR METH LOAN,

1362
00:54:50,439 --> 00:54:51,306
TRANSCRIPTOME, PROTEOME OUT OF

1363
00:54:51,306 --> 00:54:52,641
THEIR IMMUNE CELLS, WE'LL ALSO

1364
00:54:52,641 --> 00:54:57,479
MEASURE PLASMA, THEIR PROTEOME

1365
00:54:57,479 --> 00:54:59,248
CYTOKINES, MICROBIOME, WE

1366
00:54:59,248 --> 00:55:00,783
ACTUALLY JUST FINISHED A STUDY

1367
00:55:00,783 --> 00:55:02,084
OF FOUR DIFFERENT MICROBIOMES,

1368
00:55:02,084 --> 00:55:04,219
QUITE INTERESTING.

1369
00:55:04,219 --> 00:55:07,623
THIS IS CLINICAL TESTS,

1370
00:55:07,623 --> 00:55:09,158
QUESTIONNAIRES, STRESS ECHOES,

1371
00:55:09,158 --> 00:55:10,359
GLUCOSE CONTROL, STRESS

1372
00:55:10,359 --> 00:55:15,330
MEASUREMENTS AND ABOUT 10 YEARS

1373
00:55:15,330 --> 00:55:20,002
AGO, FITNESS TRACKERS.

1374
00:55:20,002 --> 00:55:21,570
WE SAMPLE PEOPLE EVERY THREE

1375
00:55:21,570 --> 00:55:22,604
MONTHS WHILE THEY'RE HEALTHY,

1376
00:55:22,604 --> 00:55:25,073
AND IF AN ADVERSE EVENT COMES

1377
00:55:25,073 --> 00:55:26,608
ALONG LIKE VIRAL INFECTION,

1378
00:55:26,608 --> 00:55:27,943
WE'LL TAKE FIVE TO SEVEN

1379
00:55:27,943 --> 00:55:30,913
ADDITIONAL SAMPLINGS.

1380
00:55:30,913 --> 00:55:32,147
WE'VE BEEN RUNNING THIS ON A

1381
00:55:32,147 --> 00:55:33,448
COHORT, IT STARTED OUT AS A

1382
00:55:33,448 --> 00:55:35,684
PILOT GROUP BUT THE DATA GOT

1383
00:55:35,684 --> 00:55:37,619
RICHER AND RICHER, 109 PEOPLE.

1384
00:55:37,619 --> 00:55:39,188
WE'VE BEEN PROFILING THEM FOR

1385
00:55:39,188 --> 00:55:40,389
OVER 10 YEARS NOW, ONE OF THEM,

1386
00:55:40,389 --> 00:55:42,157
WE'VE BEEN DOING ME FOR ABOUT

1387
00:55:42,157 --> 00:55:43,625
13 1/2 YEARS, MOST ABOUT 10 1/2

1388
00:55:43,625 --> 00:55:43,826
YEARS.

1389
00:55:43,826 --> 00:55:46,128
SOME ARE DROPPING OFF OR ADDING

1390
00:55:46,128 --> 00:55:46,428
NEW.

1391
00:55:46,428 --> 00:55:47,896
YOU MIGHT SAY WHY ARE WE DOING

1392
00:55:47,896 --> 00:55:48,664
THIS?

1393
00:55:48,664 --> 00:55:49,464
WE'RE TRYING TO UNDERSTAND WHAT

1394
00:55:49,464 --> 00:55:50,999
IT MEANS TO BE HEALTHY, HOW DOES

1395
00:55:50,999 --> 00:55:52,401
THAT CHANGE OVER TIME, WHICH

1396
00:55:52,401 --> 00:55:53,936
RELATES NICELY TO AGING AND I'LL

1397
00:55:53,936 --> 00:55:54,636
TELL YOU ABOUT THAT A LITTLE

1398
00:55:54,636 --> 00:55:55,604
BIT.

1399
00:55:55,604 --> 00:55:57,706
YOU KNOW, HOW DOES IT VARY, HOW

1400
00:55:57,706 --> 00:55:59,441
DO PEOPLE'S PATTERNS VARY FROM

1401
00:55:59,441 --> 00:56:02,077
ONE PERSON TO THE NEXT.

1402
00:56:02,077 --> 00:56:04,546
WHAT HAPPENS AT THE TIME OF

1403
00:56:04,546 --> 00:56:05,948
ILLNESS LIKE A VIRAL INFECTION,

1404
00:56:05,948 --> 00:56:07,783
AND THEN RELEVANT FOR, I THINK,

1405
00:56:07,783 --> 00:56:09,351
THIS DISCUSSION, CAN WE USE

1406
00:56:09,351 --> 00:56:10,786
THESE ADVANCED TECHNOLOGIES LIKE

1407
00:56:10,786 --> 00:56:12,421
GENOME SEQUENCING, WEARABLES, ET

1408
00:56:12,421 --> 00:56:13,622
CETERA, TO BETTER MANAGE

1409
00:56:13,622 --> 00:56:14,189
PEOPLE'S HEALTH.

1410
00:56:14,189 --> 00:56:15,424
AND I CAN TELL YOU WHEN WE

1411
00:56:15,424 --> 00:56:19,027
STARTED THIS PROJECT, FUZZES IN

1412
00:56:19,027 --> 00:56:23,999
PARTICUPHYSICIANSIN PARTICULAR S

1413
00:56:23,999 --> 00:56:26,835
SEQUENCING PEOPLE'S GENOMES.

1414
00:56:26,835 --> 00:56:27,936
ACTUALLY NOW PEOPLE ARE WARMING

1415
00:56:27,936 --> 00:56:29,404
UP TO IT BETTER, WE'RE STILL NOT

1416
00:56:29,404 --> 00:56:30,272
THERE YET.

1417
00:56:30,272 --> 00:56:31,707
ANYWAY, CAN YOU USE THESE

1418
00:56:31,707 --> 00:56:32,808
ADVANCED TECHNOLOGIES FOR HEALTH

1419
00:56:32,808 --> 00:56:33,141
TRACKING?

1420
00:56:33,141 --> 00:56:34,676
THE ANSWER IS YES.

1421
00:56:34,676 --> 00:56:36,645
JUST FROM THE FIRST 3 1/2 YEARS,

1422
00:56:36,645 --> 00:56:43,018
WE HAD 49 PLAY J 49 MAJOR HEALTH

1423
00:56:43,018 --> 00:56:45,220
DISCOVERIES, AND IT SPANNED A

1424
00:56:45,220 --> 00:56:47,656
WIDE RANGE OF AREAS.

1425
00:56:47,656 --> 00:56:50,158
METABOLIC DISEASE,

1426
00:56:50,158 --> 00:56:51,493
CARDIOVASCULAR DISEASE,

1427
00:56:51,493 --> 00:56:52,327
INFECTIOUS, ET CETERA, ET

1428
00:56:52,327 --> 00:56:52,694
CETERA.

1429
00:56:52,694 --> 00:56:54,363
SO IT'S PRETTY BROAD AND SOME OF

1430
00:56:54,363 --> 00:56:56,431
THESE TURNED OUT TO BE A BIG

1431
00:56:56,431 --> 00:56:56,899
DEAL.

1432
00:56:56,899 --> 00:56:59,868
WE CAUGHT SOME LYMPHOMA, THAT

1433
00:56:59,868 --> 00:57:01,069
CAN CONVERT TO AGGRESSIVE

1434
00:57:01,069 --> 00:57:02,838
CANCERS.

1435
00:57:02,838 --> 00:57:05,007
I SHOULD POINT OUT THESE ARE ALL

1436
00:57:05,007 --> 00:57:06,141
FOUND PRESYMPTOMATICALLY.

1437
00:57:06,141 --> 00:57:10,112
SO NO SYMPTOMS.

1438
00:57:10,112 --> 00:57:12,180
TWO PEOPLE HAD SERIOUS HEART

1439
00:57:12,180 --> 00:57:14,983
ISSUES, ONE PICKED UP BY GENE

1440
00:57:14,983 --> 00:57:16,051
SEQUENCING, ANOTHER BY

1441
00:57:16,051 --> 00:57:16,718
VARIABLES.

1442
00:57:16,718 --> 00:57:17,819
NO ONE TECHNOLOGY FOUND THESE

1443
00:57:17,819 --> 00:57:18,453
THINGS.

1444
00:57:18,453 --> 00:57:19,554
SOMETIMES IT WAS GENOME

1445
00:57:19,554 --> 00:57:20,355
SEQUENCING THAT MADE A

1446
00:57:20,355 --> 00:57:22,224
PREDICTION THAT WE FOUND.

1447
00:57:22,224 --> 00:57:23,959
SOMETIMES WEARABLES.

1448
00:57:23,959 --> 00:57:25,961
LYMPHOMA WAS PICKED UP BY

1449
00:57:25,961 --> 00:57:27,296
IMAGING AND SOME BIOCHEMICAL

1450
00:57:27,296 --> 00:57:29,264
MARKERS THAT WERE OFF.

1451
00:57:29,264 --> 00:57:30,599
THESE ARE BIOCHEMICAL MARKERS.

1452
00:57:30,599 --> 00:57:32,034
SO THE WAY WE LIKE TO THINK

1453
00:57:32,034 --> 00:57:33,669
ABOUT THIS, WE'RE TAKING A

1454
00:57:33,669 --> 00:57:35,337
PRETTY COMPLETE PICTURE ON

1455
00:57:35,337 --> 00:57:37,005
PEOPLE, SO IF YOUR HEALTH IS A

1456
00:57:37,005 --> 00:57:38,407
THOUSAND PIECE JIGSAW PUZZLE,

1457
00:57:38,407 --> 00:57:41,543
WE'RE TRYING TO MEASURE 5- OR

1458
00:57:41,543 --> 00:57:43,612
600 PIECES TO TRY TO GET A

1459
00:57:43,612 --> 00:57:44,780
CLEARER PICTURE VERSUS FIVE OR

1460
00:57:44,780 --> 00:57:46,682
SIX WE MEASURE TODAY.

1461
00:57:46,682 --> 00:57:47,649
AGAIN BECAUSE OF THAT, YOU CAN

1462
00:57:47,649 --> 00:57:49,785
FIND THESE THINGS

1463
00:57:49,785 --> 00:57:50,218
PRESYMPTOMATICALLY.

1464
00:57:50,218 --> 00:57:52,087
ONE OF THE OTHER THINGS WE

1465
00:57:52,087 --> 00:57:52,888
LEARNED WAS THAT AS WE'RE

1466
00:57:52,888 --> 00:57:54,323
TRACKING PEOPLE OVER TIME, WE

1467
00:57:54,323 --> 00:57:56,191
CAN ACTUALLY SEE HOW THEY AGE.

1468
00:57:56,191 --> 00:57:58,393
AND IT TURNS OUT EVERYBODY AGES

1469
00:57:58,393 --> 00:57:59,261
DIFFERENTLY.

1470
00:57:59,261 --> 00:58:01,163
SO FOR EXAMPLE, FROM THIS

1471
00:58:01,163 --> 00:58:03,899
PERSON, JUST BY MEASURING PLASMA

1472
00:58:03,899 --> 00:58:05,300
COMPONENTS, AND MICROBIOME,

1473
00:58:05,300 --> 00:58:07,569
THEIR TOP PATHWAY FOR THIS

1474
00:58:07,569 --> 00:58:11,707
PERSON IS THEIR CARDIAC --

1475
00:58:11,707 --> 00:58:12,808
MEANING THEIR CARDIOAGE.

1476
00:58:12,808 --> 00:58:15,777
WE LATER LEARNED THEY'RE STAGE

1477
00:58:15,777 --> 00:58:17,446
II HYPERTENSIVE, WHICH SORT OF

1478
00:58:17,446 --> 00:58:18,113
MAKES SENSE.

1479
00:58:18,113 --> 00:58:22,951
THIS PERSON, TIP KEL AGER,

1480
00:58:22,951 --> 00:58:24,319
COAGULATION AND -- WE THINK WE

1481
00:58:24,319 --> 00:58:26,154
NEED AS FEW AS FIVE MEASUREMENTS

1482
00:58:26,154 --> 00:58:27,289
WITHIN TWO YEARS WE CAN TELL YOU

1483
00:58:27,289 --> 00:58:27,923
HOW YOU'RE AGING.

1484
00:58:27,923 --> 00:58:29,858
SO WE HAD 43 PEOPLE WITH ENOUGH

1485
00:58:29,858 --> 00:58:32,027
DATA TO ACTUALLY SEE HOW THEY

1486
00:58:32,027 --> 00:58:33,996
WERE AGING, AND AS THEY SAY,

1487
00:58:33,996 --> 00:58:36,231
EVERYBODY AGES DIFFERENTLY, WE

1488
00:58:36,231 --> 00:58:38,433
CLASSIFIED PEOPLE INTO AGER

1489
00:58:38,433 --> 00:58:38,734
TYPES.

1490
00:58:38,734 --> 00:58:41,803
SO THERE'S GOING TO BE MANY AGER

1491
00:58:41,803 --> 00:58:43,171
TYPES, WE ONLY STATISTICALLY

1492
00:58:43,171 --> 00:58:44,706
EMPOWER THE MAIN FOUR, KIDNEY,

1493
00:58:44,706 --> 00:58:46,475
LIVER, METABOLIC AND IMMUNE, SO

1494
00:58:46,475 --> 00:58:48,243
EACH COLUMN IS A DIFFERENT

1495
00:58:48,243 --> 00:58:50,212
PERSON, EACH ROW IS AN AGER TIME

1496
00:58:50,212 --> 00:58:52,180
AND THE PEOPLE HERE ARE AGING IN

1497
00:58:52,180 --> 00:58:52,914
ALL FOUR CATEGORIES.

1498
00:58:52,914 --> 00:58:54,216
THIS PERSON IS AGING IN THREE OF

1499
00:58:54,216 --> 00:58:56,084
THE FOUR, NOT MUCH OF A KIDNEY

1500
00:58:56,084 --> 00:58:58,653
AGER BUT AGING IN THE OTHERS,

1501
00:58:58,653 --> 00:58:59,855
I'M SOMEWHERE IN THE MIDDLE, I'M

1502
00:58:59,855 --> 00:59:02,357
NOT MUCH OF AN IMMUNE AGER BUT I

1503
00:59:02,357 --> 00:59:04,559
AGE IN THE OTHER CATEGORIES.

1504
00:59:04,559 --> 00:59:06,161
MAKES SENSE AS I'M TYPE~2

1505
00:59:06,161 --> 00:59:09,197
DIABETES IK.

1506
00:59:09,197 --> 00:59:10,399
KIDNEY, KIDNEY AND METABOLIC AND

1507
00:59:10,399 --> 00:59:12,834
SO ON, SO WE CAN SEE HOW THEY'RE

1508
00:59:12,834 --> 00:59:13,035
AGING.

1509
00:59:13,035 --> 00:59:15,337
AND THE OTHER THING I'LL TELL

1510
00:59:15,337 --> 00:59:17,205
YOU, AND I DON'T HAVE A SLIDE

1511
00:59:17,205 --> 00:59:19,775
TOGETHER THAT PICKS UP ON

1512
00:59:19,775 --> 00:59:20,776
LUIGI'S POINT, AGE SOMETHING NOT

1513
00:59:20,776 --> 00:59:21,309
LINEAR.

1514
00:59:21,309 --> 00:59:23,612
WE FIND THERE ARE TWO MAJOR

1515
00:59:23,612 --> 00:59:26,715
PERIODS, ONE IN THIS 40, 45

1516
00:59:26,715 --> 00:59:28,683
RANGE WHERE THERE'S BIG

1517
00:59:28,683 --> 00:59:29,684
BIOCHEMICAL SHIFTS.

1518
00:59:29,684 --> 00:59:30,886
AND THE OTHER, KNOWN FROM THE

1519
00:59:30,886 --> 00:59:32,020
DISEASE PLOTS, PEOPLE IN THEIR

1520
00:59:32,020 --> 00:59:33,655
MID 60s, YOU CAN SEE

1521
00:59:33,655 --> 00:59:34,523
BIOCHEMICALLY THEY SHIFT QUITE A

1522
00:59:34,523 --> 00:59:35,657
BIT AS WELL.

1523
00:59:35,657 --> 00:59:37,192
ONE OF THE OTHER THINGS WE FOUND

1524
00:59:37,192 --> 00:59:39,795
IS THAT WE THINK THAT THESE AGER

1525
00:59:39,795 --> 00:59:41,797
TYPES ARE CLINICALLY ACTIONABLE

1526
00:59:41,797 --> 00:59:43,231
BECAUSE THEY'RE ACTUALLY

1527
00:59:43,231 --> 00:59:44,132
MARKERS, CLINICAL MARKERS

1528
00:59:44,132 --> 00:59:45,434
ASSOCIATED WITH THEM.

1529
00:59:45,434 --> 00:59:47,869
SO THIS IS JUST SHOWING

1530
00:59:47,869 --> 00:59:49,638
EXAMPLES, THIS IS, FOR EXAMPLE,

1531
00:59:49,638 --> 00:59:52,140
TRACKING ONE OF THESE MARKERS,

1532
00:59:52,140 --> 00:59:54,209
HEMOGLOBIN A1C, A MARKER OF

1533
00:59:54,209 --> 00:59:55,844
DIABETES, AND WHAT YOU'LL NOTICE

1534
00:59:55,844 --> 00:59:57,245
IS A GROUP AS A WHOLE GOES UP

1535
00:59:57,245 --> 01:00:00,148
OVER TIME, THAT'S EXPECTED.

1536
01:00:00,148 --> 01:00:01,583
EACH BAR IS A DIFFERENT PERSON.

1537
01:00:01,583 --> 01:00:03,652
AND SO MANY DO GO UP.

1538
01:00:03,652 --> 01:00:05,954
DARK BAR MEANS IT'S

1539
01:00:05,954 --> 01:00:06,888
STATISTICALLY SIGNIFICANT BUT

1540
01:00:06,888 --> 01:00:07,923
SOME PEOPLE ACTUALLY REVERSE

1541
01:00:07,923 --> 01:00:08,390
THIS.

1542
01:00:08,390 --> 01:00:10,926
IN THIS CASE, IT'S PRETTY EASY,

1543
01:00:10,926 --> 01:00:12,461
IT'S OBVIOUS WHY.

1544
01:00:12,461 --> 01:00:13,929
TWO PEOPLE WENT ON A DIET, TWO

1545
01:00:13,929 --> 01:00:15,363
PEOPLE LOST WEIGHT, ONE PERSON

1546
01:00:15,363 --> 01:00:18,467
STARTED EXERCISING SO THEY WERE

1547
01:00:18,467 --> 01:00:19,668
ACTUALLY ABLE TO REVERSE THESE

1548
01:00:19,668 --> 01:00:21,536
MARKERS THAT WE THINK ALTER

1549
01:00:21,536 --> 01:00:22,404
THEIR AGER TYPE.

1550
01:00:22,404 --> 01:00:23,972
SO I THINK THIS INFORMATION IS

1551
01:00:23,972 --> 01:00:24,639
ACTIONABLE.

1552
01:00:24,639 --> 01:00:25,640
CREATININE IS ANOTHER

1553
01:00:25,640 --> 01:00:26,942
INTERESTING MARKER.

1554
01:00:26,942 --> 01:00:28,977
THE GROUP AS A WHOLE GOES UP BUT

1555
01:00:28,977 --> 01:00:32,380
MANY PEOPLE WENT DOWN, ACTUALLY

1556
01:00:32,380 --> 01:00:34,549
IMPROVED THEIR KR CREATININE

1557
01:00:34,549 --> 01:00:35,117
LEVELS.

1558
01:00:35,117 --> 01:00:36,551
ONE QUESTION I GET A LOT IS HOW

1559
01:00:36,551 --> 01:00:37,452
ARE YOU GOING TO SCALE THIS.

1560
01:00:37,452 --> 01:00:39,321
WHAT I SHOWED YOU IS A RESEARCH

1561
01:00:39,321 --> 01:00:40,689
STUDY, COST MILLIONS AND

1562
01:00:40,689 --> 01:00:43,625
MILLIONS OF DOLLARS.

1563
01:00:43,625 --> 01:00:45,393
BUT I'M IN SILICON VALLEY SO THE

1564
01:00:45,393 --> 01:00:48,830
WAY WE SCALE THESE THINGS AND

1565
01:00:48,830 --> 01:00:50,465
START UP COMPANIES, ACADEMICS

1566
01:00:50,465 --> 01:00:52,000
ARE PRETTY GOOD AT DISCOVERY AND

1567
01:00:52,000 --> 01:00:55,704
PROOF OF PRINCIPLE, WE'RE NOT

1568
01:00:55,704 --> 01:00:59,040
VERY GOOD AT SCALING.

1569
01:00:59,040 --> 01:01:00,442
SO MEDICAL VERSION, DOESN'T DO

1570
01:01:00,442 --> 01:01:01,776
RNA SEQ AND ALL THE DIFFERENT

1571
01:01:01,776 --> 01:01:03,245
THINGS THEY SHOW BUT DOES A LOT

1572
01:01:03,245 --> 01:01:04,779
OF THE ACTIONABLE INFORMATION.

1573
01:01:04,779 --> 01:01:07,182
AND ON TOP OF THAT, THEY ADDED

1574
01:01:07,182 --> 01:01:08,083
WHOLE BODY MRI.

1575
01:01:08,083 --> 01:01:08,984
ANY PHYSICIAN TODAY WILL TELL

1576
01:01:08,984 --> 01:01:11,920
YOU DON'T DO WHOLE BODY MRI, AND

1577
01:01:11,920 --> 01:01:14,256
THE REASON IS, YOU'LL HAVE

1578
01:01:14,256 --> 01:01:14,623
LESIONS.

1579
01:01:14,623 --> 01:01:16,358
MEN HAVE NODULES IN THEIR

1580
01:01:16,358 --> 01:01:17,893
PROSTATE, WOMEN IN THEIR OVARY.

1581
01:01:17,893 --> 01:01:19,227
100% OF THE TIME.

1582
01:01:19,227 --> 01:01:24,633
JUST DEPENDS HOW FINE YOU LOOK.

1583
01:01:24,633 --> 01:01:26,368
AND MY -- WILL TELL YOU YOU

1584
01:01:26,368 --> 01:01:28,603
ABSOLUTELY SHOULD DO WHOLE BODY

1585
01:01:28,603 --> 01:01:28,770
MRI.

1586
01:01:28,770 --> 01:01:30,372
THE ISSUE ISN'T DO YOU HAVE

1587
01:01:30,372 --> 01:01:31,173
LESIONS, THE ISSUE IS DO YOU

1588
01:01:31,173 --> 01:01:32,474
HAVE ANY GROWING LESIONS.

1589
01:01:32,474 --> 01:01:35,544
THE WAY YOU FIND OUT IS BY THESE

1590
01:01:35,544 --> 01:01:36,545
LONGITUDAL MEASUREMENTS, YOU CAN

1591
01:01:36,545 --> 01:01:37,512
SEE IF THINGS ARE SHIFTING.

1592
01:01:37,512 --> 01:01:40,415
SO IT TURNS OUT, SAME THING FROM

1593
01:01:40,415 --> 01:01:43,818
THE FIRST 100-PLUS PEOPLE.

1594
01:01:43,818 --> 01:01:46,354
THE MEDIAN AGE IS 50, OUR CASE,

1595
01:01:46,354 --> 01:01:47,355
53.4, ALSO IN THE 50s.

1596
01:01:47,355 --> 01:01:54,796
YOU CAN SEE THE Q BIO --

1597
01:01:54,796 --> 01:01:57,465
CARDIOVASCULAR DISEASE, EVEN

1598
01:01:57,465 --> 01:01:59,568
CAUGHT EARLY PANCREATIC CANCER

1599
01:01:59,568 --> 01:02:00,635
THROUGH THE EARLY PROFILING.

1600
01:02:00,635 --> 01:02:02,304
THESE ARE ALL FOUND

1601
01:02:02,304 --> 01:02:02,771
PRESYMPTOMATICALLY.

1602
01:02:02,771 --> 01:02:04,639
THESE DETAILED MEASUREMENTS DO

1603
01:02:04,639 --> 01:02:07,909
REVEAL THINGS EARLY, AND THEY

1604
01:02:07,909 --> 01:02:10,378
DON'T TURN PEOPLE INTO

1605
01:02:10,378 --> 01:02:11,146
HYPOCHONDRIACS SO WE THINK THIS

1606
01:02:11,146 --> 01:02:12,480
KIND OF CLOSE MONITORING IS

1607
01:02:12,480 --> 01:02:13,882
VERY, VERY IMPORTANT.

1608
01:02:13,882 --> 01:02:15,350
NOW, ONE THING THAT WE'VE ALSO

1609
01:02:15,350 --> 01:02:18,086
WORKED HARD ON THESE DAYS IS TO

1610
01:02:18,086 --> 01:02:20,522
TRY TO DO MORE FREQUENT AND

1611
01:02:20,522 --> 01:02:23,158
CONTINUOUS MONITORING, AND SO WE

1612
01:02:23,158 --> 01:02:24,259
ALSO LIKE THE IDEA THAT YOU

1613
01:02:24,259 --> 01:02:26,127
SHOULDN'T ALWAYS HAVE TO GO TO A

1614
01:02:26,127 --> 01:02:27,529
DOCTOR TO GET HEALTH

1615
01:02:27,529 --> 01:02:29,297
MEASUREMENTS.

1616
01:02:29,297 --> 01:02:33,201
SO WE'VE BEEN SO CALLED

1617
01:02:33,201 --> 01:02:35,070
AMAZONNIZEING HEALTHCARE.

1618
01:02:35,070 --> 01:02:37,105
THE REASON -- TWO APPROACHES,

1619
01:02:37,105 --> 01:02:39,908
ONE IS WEARABLES, ONE IS MICRO

1620
01:02:39,908 --> 01:02:41,676
SAMPLES, TAKE A DROP OF BLOOD

1621
01:02:41,676 --> 01:02:43,545
AND MAIL THEM IN.

1622
01:02:43,545 --> 01:02:44,312
OURS DOES WORK.

1623
01:02:44,312 --> 01:02:46,881
SO WEARABLES YOU MAY KNOW ARE

1624
01:02:46,881 --> 01:02:48,817
BECOMING VERY UBIQUITOUS.

1625
01:02:48,817 --> 01:02:51,019
20% OF THE U.S. WEARS THESE AND

1626
01:02:51,019 --> 01:02:52,387
THEY'RE POWERFUL BECAUSE THEY

1627
01:02:52,387 --> 01:02:53,588
MEASURE YOU 24/7.

1628
01:02:53,588 --> 01:02:56,658
WE GOT INVOLVED WHEN THESE FIRST

1629
01:02:56,658 --> 01:02:59,561
CAME OUT AS FITNESS TRACKERS SO

1630
01:02:59,561 --> 01:03:00,862
WE PUT THEM ON OUR COHORT.

1631
01:03:00,862 --> 01:03:02,864
I'M A BIG FAN.

1632
01:03:02,864 --> 01:03:05,100
IF YOU CAN SEE IF YOU LOOK UP,

1633
01:03:05,100 --> 01:03:10,705
I'VE GOT FOUR SMART WATCHES, A

1634
01:03:10,705 --> 01:03:12,274
GLUCOSE RING -- ALMOST RIGHT

1635
01:03:12,274 --> 01:03:13,441
AWAY WE DISCOVER YOU CAN TELL

1636
01:03:13,441 --> 01:03:16,945
PEOPLE ARE GETTING AN INFECTION,

1637
01:03:16,945 --> 01:03:18,280
IF YOU WILL, FROM A SIMPLE SMART

1638
01:03:18,280 --> 01:03:18,580
WATCH.

1639
01:03:18,580 --> 01:03:20,682
IN THIS CASE, SMART WATCH AND

1640
01:03:20,682 --> 01:03:21,082
PULSE OX.

1641
01:03:21,082 --> 01:03:22,717
SO IT ACTUALLY IS WHEN I

1642
01:03:22,717 --> 01:03:24,786
DISCOVERED MY LYME DISEASE OF

1643
01:03:24,786 --> 01:03:27,355
ALL THINGS, WHILE FLYING TO

1644
01:03:27,355 --> 01:03:29,424
NORWAY, BOTTOM LINE IS, MY BLOOD

1645
01:03:29,424 --> 01:03:31,393
OXYGEN DROPPED ABNORMALLY LOW ON

1646
01:03:31,393 --> 01:03:33,094
THIS AIRLINE, NEVER CAME BACK TO

1647
01:03:33,094 --> 01:03:33,528
NORMAL.

1648
01:03:33,528 --> 01:03:35,930
MY HEART RATE ON MY SMART WATCH

1649
01:03:35,930 --> 01:03:40,135
WENT UP, I  LATER LEARNED MY SKN

1650
01:03:40,135 --> 01:03:41,036
TEMPERATURE WENT UP AS WELL.

1651
01:03:41,036 --> 01:03:43,204
THIS IS ALL PRESYMPTOMATICALLY.

1652
01:03:43,204 --> 01:03:44,472
SO THESE THINGS CHANGED, THEN I

1653
01:03:44,472 --> 01:03:46,441
GOT A FEVER OFF AND ON, IT WAS A

1654
01:03:46,441 --> 01:03:46,875
TRICKY.

1655
01:03:46,875 --> 01:03:48,710
I WENT TO A DOCTOR IN NORWAY.

1656
01:03:48,710 --> 01:03:50,011
HE RECOMMENDED PENICILLIN, I

1657
01:03:50,011 --> 01:03:52,614
SAID NO, I NEED DOXYCYCLINE

1658
01:03:52,614 --> 01:03:54,249
WHICH IS WHAT'S USED FOR LYME.

1659
01:03:54,249 --> 01:03:56,117
A LITTLE TENSE, HE GAVE IN, FAVE

1660
01:03:56,117 --> 01:03:57,886
TO ME, CLEARED IT RIGHT UP AND

1661
01:03:57,886 --> 01:03:59,154
THEN TWO WEEKS LATER, SURE

1662
01:03:59,154 --> 01:04:00,588
ENOUGH, I WAS LYME-POSITIVE.

1663
01:04:00,588 --> 01:04:01,656
I THOUGHT IT WAS PROBABLY LYME

1664
01:04:01,656 --> 01:04:02,757
BECAUSE IT WAS TWO WEEKS AFTER.

1665
01:04:02,757 --> 01:04:07,162
I HAD BEEN IN RURAL

1666
01:04:07,162 --> 01:04:09,597
MASSACHUSETTS WHERE 55% OF

1667
01:04:09,597 --> 01:04:11,132
TICKS -- ANYWAY BOTTOM LINE IS

1668
01:04:11,132 --> 01:04:12,434
WE CAN FIRST TELL WHEN I GOT

1669
01:04:12,434 --> 01:04:14,369
LYME FROM A SIMPLE SMART WATCH

1670
01:04:14,369 --> 01:04:17,539
AND PULSE OX, AND THEN WE WENT

1671
01:04:17,539 --> 01:04:19,541
ON TO WRITE ALGORITHM, I WON'T

1672
01:04:19,541 --> 01:04:20,775
SHOW YOU THIS, IT TURNS OUT FOR

1673
01:04:20,775 --> 01:04:22,844
EVERY TIME I HAD A RESPIRATORY

1674
01:04:22,844 --> 01:04:25,413
VIRAL INFECTION, EVEN ONE TIME I

1675
01:04:25,413 --> 01:04:26,748
WAS ASYMPTOMATICALLY -- MY CR

1676
01:04:26,748 --> 01:04:28,283
PSM WAS HIGH, EVERY SINGLE TIME,

1677
01:04:28,283 --> 01:04:29,918
WE CAN PICK IT UP WITH A SMART

1678
01:04:29,918 --> 01:04:31,319
WATCH BECAUSE OF THE RESTING

1679
01:04:31,319 --> 01:04:32,420
HEART RATE JUMPED UP.

1680
01:04:32,420 --> 01:04:34,022
AND WE WROTE ALGORITHMS THAT

1681
01:04:34,022 --> 01:04:36,291
WORKED FOR FINDING ALL THOSE FOR

1682
01:04:36,291 --> 01:04:37,492
ME AND THEN ACTUALLY OTHERS IN

1683
01:04:37,492 --> 01:04:40,562
THE COHORT.

1684
01:04:40,562 --> 01:04:41,229
ALL RETROSPECTIVE.

1685
01:04:41,229 --> 01:04:43,498
WE PUBLISHED THIS IN ABOUT 2017.

1686
01:04:43,498 --> 01:04:46,401
SO THEN ALONG COMES COVID, AND

1687
01:04:46,401 --> 01:04:50,638
OF COURSE IN 2020, WE'RE IN OUR

1688
01:04:50,638 --> 01:04:52,474
NEXT WAVE RIGHT NOW, YOU MAY

1689
01:04:52,474 --> 01:04:55,877
KNOW, SO WE WANTED TO SEE IF

1690
01:04:55,877 --> 01:04:59,214
SMART WATCHES COULD BE USED FOR

1691
01:04:59,214 --> 01:05:01,182
TRACKING THAT, DETECTING COVID.

1692
01:05:01,182 --> 01:05:02,317
SO WHEN THE INFECTION FIRST

1693
01:05:02,317 --> 01:05:03,785
BROKE OUT, WE QUICKLY PARTNERED

1694
01:05:03,785 --> 01:05:06,054
WITH FITBIT, GOT 5300 PEOPLE

1695
01:05:06,054 --> 01:05:06,621
ENROLLED.

1696
01:05:06,621 --> 01:05:08,590
HERE IS RESTING HEART RATE, THIS

1697
01:05:08,590 --> 01:05:10,525
IS OUR VERY, VERY FIRST CASE.

1698
01:05:10,525 --> 01:05:12,794
WE HAD 32 PEOPLE WHO HAD COVID

1699
01:05:12,794 --> 01:05:14,996
WHILE WEARING THEIR FITBIT, AND

1700
01:05:14,996 --> 01:05:16,798
THEY HAD A DIAGNOSIS DAY AND A

1701
01:05:16,798 --> 01:05:17,465
SYMPTOM DAY.

1702
01:05:17,465 --> 01:05:19,100
THIS WAS, AS I SAY, OUR FIRST

1703
01:05:19,100 --> 01:05:19,567
EXAMPLE.

1704
01:05:19,567 --> 01:05:21,903
THIS WAS RESTING HEART RATE, A

1705
01:05:21,903 --> 01:05:23,571
STANDARD DEVIATION PLOT.

1706
01:05:23,571 --> 01:05:25,440
THIS IS BASICALLY THEIR

1707
01:05:25,440 --> 01:05:27,542
DIAGNOSIS DAY IN PURPLE, THEIR

1708
01:05:27,542 --> 01:05:30,178
SYMPTOM DAY IN RED, AND YOU CAN

1709
01:05:30,178 --> 01:05:32,814
SEE THE RESTING HEART RATE

1710
01:05:32,814 --> 01:05:34,949
JUMPED UP 9 1/2 DAYS PRIOR TO

1711
01:05:34,949 --> 01:05:37,051
SYMPTOM ONSET.

1712
01:05:37,051 --> 01:05:38,787
VERY, VERY CLEAR SIGNAL.

1713
01:05:38,787 --> 01:05:42,056
WE WROTE SOME ALGORITHMS THAT

1714
01:05:42,056 --> 01:05:44,192
TRACK YOUR CIRCADIAN RHYTHM AND

1715
01:05:44,192 --> 01:05:46,060
LOOK FOR JUMP UP IN SIGNAL.

1716
01:05:46,060 --> 01:05:47,796
IT WORKED, 80% OF THE TIME WE

1717
01:05:47,796 --> 01:05:49,431
COULD TELL IF PEOPLE WERE

1718
01:05:49,431 --> 01:05:50,331
GETTING COVID AT OR BEFORE

1719
01:05:50,331 --> 01:05:52,767
SYMPTOMS AND THE MEDIAN IS

1720
01:05:52,767 --> 01:05:54,536
4 DAYS, TURNS OUT COVID HAS A

1721
01:05:54,536 --> 01:05:55,403
LONG PRESYMPTOMATIC PERIOD.

1722
01:05:55,403 --> 01:05:57,071
BY THE WAY, YOU CAN SIGN UP FOR

1723
01:05:57,071 --> 01:05:59,307
A STUDY RIGHT HERE.

1724
01:05:59,307 --> 01:06:00,608
WE'RE TRYING TO GET MORE DATA IN

1725
01:06:00,608 --> 01:06:02,043
SO WE CAN GET BETTER

1726
01:06:02,043 --> 01:06:02,744
PREDICTIONS.

1727
01:06:02,744 --> 01:06:05,513
SO THEN WE WENT ON TO BUILD A

1728
01:06:05,513 --> 01:06:07,882
REALTIME DETECTION SYSTEM, A

1729
01:06:07,882 --> 01:06:08,950
CLOUD-BASED SYSTEM THAT CAN

1730
01:06:08,950 --> 01:06:09,918
HANDLE MILLIONS OF PEOPLE.

1731
01:06:09,918 --> 01:06:12,554
NOW, WE HAVE ABOUT -- SOMETHING

1732
01:06:12,554 --> 01:06:15,123
LIKE 10 TO 20,000 PEOPLE

1733
01:06:15,123 --> 01:06:15,790
ENROLLED RIGHT NOW.

1734
01:06:15,790 --> 01:06:18,193
THE WAY THIS WORKS IS IT'S

1735
01:06:18,193 --> 01:06:20,094
TRACKING YOUR RESTING HEART

1736
01:06:20,094 --> 01:06:21,763
RATE, A FEW OTHER THINGS IN

1737
01:06:21,763 --> 01:06:24,399
REALTIME, AND IT HAS A WEIGHTED

1738
01:06:24,399 --> 01:06:25,066
SYSTEM.

1739
01:06:25,066 --> 01:06:27,268
AND IN A CIRCADIAN FASHION SO

1740
01:06:27,268 --> 01:06:28,937
THAT IF YOUR HEART RATE AND

1741
01:06:28,937 --> 01:06:30,805
THESE OTHER PARAMETERS ARE UP

1742
01:06:30,805 --> 01:06:31,806
HIGH ENOUGH FOR A LONG ENOUGH

1743
01:06:31,806 --> 01:06:33,908
PERIOD OF TIME, IT SETS OFF A

1744
01:06:33,908 --> 01:06:34,375
RED ALERT.

1745
01:06:34,375 --> 01:06:35,677
YOU HAVE TO CLICK ON IT, SOON

1746
01:06:35,677 --> 01:06:36,978
YOU WON'T HAVE TO DO THAT.

1747
01:06:36,978 --> 01:06:41,516
AND HERE IS BASICALLY ONE OF OUR

1748
01:06:41,516 --> 01:06:42,283
VERY FIRST CASES.

1749
01:06:42,283 --> 01:06:43,718
AGAIN, THIS IS WHEN THIS

1750
01:06:43,718 --> 01:06:45,887
PERSON'S SYMPTOMS FIRST

1751
01:06:45,887 --> 01:06:46,721
APPEARED, THEY'RE DIAGNOSED THE

1752
01:06:46,721 --> 01:06:47,956
NEXT DAY, BUT THEY WERE GETTING

1753
01:06:47,956 --> 01:06:49,257
RED ALERTS FOR THREE DAYS PRIOR

1754
01:06:49,257 --> 01:06:52,760
TO SYMPTOM ONSET.

1755
01:06:52,760 --> 01:06:54,762
SO THIS WORKS, SAME NUMBER, 80%

1756
01:06:54,762 --> 01:06:58,466
OF THE TIME IT WORKS ON APPLE,

1757
01:06:58,466 --> 01:06:59,968
FITBIT, SHOULD WORK ON ALL

1758
01:06:59,968 --> 01:07:00,502
DEVICES.

1759
01:07:00,502 --> 01:07:03,471
IT EVEN WORKS ON ASYMPTOMATIC

1760
01:07:03,471 --> 01:07:04,005
CASES.

1761
01:07:04,005 --> 01:07:05,039
HERE'S A DIAGNOSIS DAY, BUT YOU

1762
01:07:05,039 --> 01:07:06,140
CAN SEE THIS PERSON IS GETTING

1763
01:07:06,140 --> 01:07:08,977
RED ALERTS FOR ABOUT TWO WEEKS

1764
01:07:08,977 --> 01:07:13,147
PRIOR TO DIAGNOSIS.

1765
01:07:13,147 --> 01:07:14,082
NO SYMPTOMS IN THIS CASE.

1766
01:07:14,082 --> 01:07:18,686
IT ALSO TURNS OUT IT'S MOSTLY A

1767
01:07:18,686 --> 01:07:19,888
STRESS DETECTOR, MEANING IT'S

1768
01:07:19,888 --> 01:07:21,356
NOT SPECIFIC FOR COVID, AND IN

1769
01:07:21,356 --> 01:07:22,790
FACT, THE NUMBER ONE TRIGGER OF

1770
01:07:22,790 --> 01:07:26,261
RED ALERTS WITH PEOPLE WHO

1771
01:07:26,261 --> 01:07:28,396
HAVEN'T HAD COVID TURNS OUT TO

1772
01:07:28,396 --> 01:07:30,265
BE WORKPLACE STRESS SO IT'S ALSO

1773
01:07:30,265 --> 01:07:30,932
MONITORING YOUR MENTAL HEALTH

1774
01:07:30,932 --> 01:07:31,499
STRESS.

1775
01:07:31,499 --> 01:07:33,334
OTHER THINGS WILL TRIGGER THE

1776
01:07:33,334 --> 01:07:34,269
ALERT, INTENSE EXERCISE.

1777
01:07:34,269 --> 01:07:35,837
YOU MAY KNOW IF YOU RUN A

1778
01:07:35,837 --> 01:07:37,038
MARATHON, YOUR HEART RATE WILL

1779
01:07:37,038 --> 01:07:39,607
BE UP FOR A FEW DAYS, SETS OFF

1780
01:07:39,607 --> 01:07:41,142
ALERTS, INFECTIONS, EVEN

1781
01:07:41,142 --> 01:07:42,143
MYCOPLASMA, WE CAN PICK UP AS

1782
01:07:42,143 --> 01:07:43,311
WELL.

1783
01:07:43,311 --> 01:07:45,680
SO WE THINK THIS IS MORE

1784
01:07:45,680 --> 01:07:47,649
SENSITIVE THAN AN ANTIGEN TEST.

1785
01:07:47,649 --> 01:07:49,551
THIS IS DATA FROM MY DATA BUT

1786
01:07:49,551 --> 01:07:51,553
WE'VE SHOWN IT FOR OTHERS NOW

1787
01:07:51,553 --> 01:07:52,954
TOO, WHERE WHEN I FIRST HAD A

1788
01:07:52,954 --> 01:07:54,489
LITTLE BIT OF CONGESTION, WASN'T

1789
01:07:54,489 --> 01:07:55,990
SURE IF IT WAS ALLERGIES OR WHAT

1790
01:07:55,990 --> 01:07:58,293
WAS GOING ON, GOT AN ANTIGEN

1791
01:07:58,293 --> 01:08:06,935
TEST, I WAS NE NEGATIVE BUT MY

1792
01:08:06,935 --> 01:08:08,503
SMART WATCH SAID POSITIVE, SURE

1793
01:08:08,503 --> 01:08:09,871
ENOUGH THE NEXT DAY I CAME UP

1794
01:08:09,871 --> 01:08:10,305
POSITIVE.

1795
01:08:10,305 --> 01:08:12,006
I WAS IN NEW YORK CITY, I HAD TO

1796
01:08:12,006 --> 01:08:14,809
SPEND A WHOLE WEEK IN A HOTEL

1797
01:08:14,809 --> 01:08:16,311
ROOM, ALL BECAUSE I LISTENED TO

1798
01:08:16,311 --> 01:08:17,412
THIS, WHICH I SHOULDN'T HAVE

1799
01:08:17,412 --> 01:08:19,113
DONE, I SHOULD HAVE LISTENED TO

1800
01:08:19,113 --> 01:08:20,748
THIS.

1801
01:08:20,748 --> 01:08:23,151
SO IT CAN GIVE YOU EARLY ALERTS

1802
01:08:23,151 --> 01:08:24,953
AND MAYBE TELL YOU NOT TO GO OUT

1803
01:08:24,953 --> 01:08:29,257
AND PARTY AND THINGS LIKE THAT.

1804
01:08:29,257 --> 01:08:30,992
WE THINK THIS IS THE TIP OF THE

1805
01:08:30,992 --> 01:08:31,426
ICEBERG.

1806
01:08:31,426 --> 01:08:33,595
THESE SMART WATCHES CAN MEASURE

1807
01:08:33,595 --> 01:08:34,696
MANY, MANY THINGS ON YOU AS YOU

1808
01:08:34,696 --> 01:08:35,263
MAY KNOW.

1809
01:08:35,263 --> 01:08:36,431
SO WE'VE WRITTEN MACHINE

1810
01:08:36,431 --> 01:08:37,599
LEARNING ALGORITHMS TO BE ABLE

1811
01:08:37,599 --> 01:08:40,335
TO PICK UP THOSE RED BLOOD CELL

1812
01:08:40,335 --> 01:08:42,103
COUNT, HEMOGLOBIN, ET CETERA.

1813
01:08:42,103 --> 01:08:43,304
THESE AREN'T CLINICAL GRADE

1814
01:08:43,304 --> 01:08:44,439
MEASUREMENTS BUT THEY'RE GOOD

1815
01:08:44,439 --> 01:08:46,841
ENOUGH TO SEE IF THINGS SHIFT.

1816
01:08:46,841 --> 01:08:49,143
EVEN HEMOGLOBIN A1C AND FASTING

1817
01:08:49,143 --> 01:08:51,713
GLUCOSE CAN GET PICKED UP WITH A

1818
01:08:51,713 --> 01:08:53,247
SMART WATCH USING SOME OF THESE

1819
01:08:53,247 --> 01:08:54,115
ADVANCED ALGORITHMS.

1820
01:08:54,115 --> 01:08:55,283
THE OTHER AREA WE'RE PUSHING

1821
01:08:55,283 --> 01:08:56,417
VERY, VERY HARD WHICH I THINK IS

1822
01:08:56,417 --> 01:08:58,987
A BIG DEAL FOR EXTENDING

1823
01:08:58,987 --> 01:08:59,887
HEALTHSPAN IS GLUCOSE

1824
01:08:59,887 --> 01:09:01,589
MONITORING.

1825
01:09:01,589 --> 01:09:03,224
SO THESE ARE BEING USED AT THE

1826
01:09:03,224 --> 01:09:06,260
TIME FOR INSULIN-DEPENDENT TYPE

1827
01:09:06,260 --> 01:09:08,529
1 AND TYPE 2 DIABETICS.

1828
01:09:08,529 --> 01:09:09,864
WE STARTED PUTTING THEM ON

1829
01:09:09,864 --> 01:09:11,299
NORMAL AND PREDIABETICS.

1830
01:09:11,299 --> 01:09:12,600
AND WOULDN'T YOU KNOW THAT SOME

1831
01:09:12,600 --> 01:09:14,302
NORMAL PEOPLE ARE PRETTY NORMAL,

1832
01:09:14,302 --> 01:09:16,270
MEANING THEY DON'T SPIKE THEIR

1833
01:09:16,270 --> 01:09:17,572
GLUCOSE MUCH, BUT THEN A LOT OF

1834
01:09:17,572 --> 01:09:19,073
PEOPLE ARE MODERATE SPIKERS AND

1835
01:09:19,073 --> 01:09:22,043
EVEN A FEW PEOPLE ARE SEVERE

1836
01:09:22,043 --> 01:09:25,246
SPIKERS, WHEN TESTED NORMAL BY

1837
01:09:25,246 --> 01:09:26,047
HEMOGLOBIN A1C AND OTHER

1838
01:09:26,047 --> 01:09:26,447
MEASURES.

1839
01:09:26,447 --> 01:09:28,650
WE THINK THERE'S OTHER FORMS OF

1840
01:09:28,650 --> 01:09:29,617
GLUCODYSREGULATION THAT STANDARD

1841
01:09:29,617 --> 01:09:30,118
MEASURES MISS.

1842
01:09:30,118 --> 01:09:32,320
SO WE WROTE ALGORITHMS THAT

1843
01:09:32,320 --> 01:09:33,287
CLASSIFIED PEOPLE INTO

1844
01:09:33,287 --> 01:09:33,955
GLUCOTYPES.

1845
01:09:33,955 --> 01:09:37,859
LOW MEANS GOOD GLUCOSE CONTROL,

1846
01:09:37,859 --> 01:09:39,827
MODERATE, MODERATE SPIKING

1847
01:09:39,827 --> 01:09:41,029
LEVELS OF GLUCOSE, AND THEN

1848
01:09:41,029 --> 01:09:43,064
THERE'S SEVERE SPIKERS AS WELL.

1849
01:09:43,064 --> 01:09:44,298
AGAIN, NORMAL PEOPLE CAN BE

1850
01:09:44,298 --> 01:09:46,668
SEVERE SPIKERS, SO CALLED

1851
01:09:46,668 --> 01:09:48,503
NORMAL, PROBABLY NOT SO NORMAL

1852
01:09:48,503 --> 01:09:49,137
AFTER ALL.

1853
01:09:49,137 --> 01:09:51,439
SO ONE OF THE THINGS WE

1854
01:09:51,439 --> 01:09:55,910
DISCOVERED AS DID AARON SIEGEL,

1855
01:09:55,910 --> 01:09:57,645
SOME PEOPLE SPIKED AT BANANAS,

1856
01:09:57,645 --> 01:09:59,614
OTHERS TO PASTA, SOME TO POTATO,

1857
01:09:59,614 --> 01:10:01,783
SOME TO WHITE BREAD, SOME TO

1858
01:10:01,783 --> 01:10:02,183
BROWN BREAD.

1859
01:10:02,183 --> 01:10:04,585
SO THIS IS JUST SHOWING TWO

1860
01:10:04,585 --> 01:10:06,120
EXAMPLES FROM AARON'S WORK.

1861
01:10:06,120 --> 01:10:08,623
THIS IS AN INDIVIDUAL TWO SPIKES

1862
01:10:08,623 --> 01:10:10,358
ON BANANA BUT NOT A COOKIE.

1863
01:10:10,358 --> 01:10:11,959
PROBABLY THE ONLY PERSON ON A

1864
01:10:11,959 --> 01:10:13,194
PLANET THAT DOESN'T SPIKE TO A

1865
01:10:13,194 --> 01:10:13,661
COOKIE.

1866
01:10:13,661 --> 01:10:15,663
THIS PERSON, MORE TYPICAL,

1867
01:10:15,663 --> 01:10:17,899
SPIKES AT A COOKIE BUT NOT

1868
01:10:17,899 --> 01:10:18,933
NECESSARILY A BANANA.

1869
01:10:18,933 --> 01:10:20,535
SO AGAIN, AND IT'S THOUGHT FROM

1870
01:10:20,535 --> 01:10:24,906
AARON'S WORK THAT 21% OF THIS IS

1871
01:10:24,906 --> 01:10:26,340
DUE TO YOUR MICROBIOME.

1872
01:10:26,340 --> 01:10:27,809
MOST OF IT'S NOT EXPLAINED, AND

1873
01:10:27,809 --> 01:10:28,609
WE'RE WORKING HARD TO FIGURE

1874
01:10:28,609 --> 01:10:31,379
THIS OUT.

1875
01:10:31,379 --> 01:10:33,047
AND ALSO WHAT FOODS WILL

1876
01:10:33,047 --> 01:10:33,581
SUPPRESS SPIKES.

1877
01:10:33,581 --> 01:10:35,316
THE OTHER AREA WE'VE BEEN

1878
01:10:35,316 --> 01:10:36,384
PUSHING VERY, VERY HARD WHICH I

1879
01:10:36,384 --> 01:10:37,618
THINK IS GOING TO BE VERY

1880
01:10:37,618 --> 01:10:38,619
POWERFUL FOR HEALTH MONITORING,

1881
01:10:38,619 --> 01:10:40,288
THIS IS REMOTE SAMPLING.

1882
01:10:40,288 --> 01:10:43,925
SO WE SENT  SPENT NOW ABOUT 6 12

1883
01:10:43,925 --> 01:10:44,926
YEARS WORKING ON THIS TRYING TO

1884
01:10:44,926 --> 01:10:46,461
FIND THE RIGHT MAY TRUCKS FOR

1885
01:10:46,461 --> 01:10:47,695
COLLECTING ANALYTES AND KEEPING

1886
01:10:47,695 --> 01:10:49,630
THEM STABLE AND GETTING VERY

1887
01:10:49,630 --> 01:10:50,598
REPRODUCIBLE RESULTS.

1888
01:10:50,598 --> 01:10:53,468
WHAT WE ULTIMATELY SETTLED ON

1889
01:10:53,468 --> 01:10:57,672
ARE THESE MITRAs, WHERE YOU

1890
01:10:57,672 --> 01:11:01,275
CAN SAMPLE -- YOU DO LITTLE

1891
01:11:01,275 --> 01:11:03,211
LANCET PRICKS, COLLECT 10 MICRO

1892
01:11:03,211 --> 01:11:10,752
LITERS OF BLOOD IN EACH OF THESE

1893
01:11:10,752 --> 01:11:12,787
PRICKS, FEDEX IT, IN THE END WEE

1894
01:11:12,787 --> 01:11:14,622
MEASURING ABOUT 2200 ANALYTES.

1895
01:11:14,622 --> 01:11:16,491
AND WE'VE GONE ON TO SHOW, I

1896
01:11:16,491 --> 01:11:17,959
DON'T HAVE TIME TO SHOW YOU

1897
01:11:17,959 --> 01:11:19,293
THIS, MOST PROTEINS ARE STABLE,

1898
01:11:19,293 --> 01:11:20,495
MOST METABOLITES ARE STABLE, BUT

1899
01:11:20,495 --> 01:11:22,964
A NUMBER OF THEM ARE OFF BUT WE

1900
01:11:22,964 --> 01:11:24,298
KNOW WHICH WILL GO OFF STABILITY

1901
01:11:24,298 --> 01:11:26,167
WISE, BUT WE KNOW WHICH ONES

1902
01:11:26,167 --> 01:11:27,368
THEY ARE AND CAN CORRECT FOR

1903
01:11:27,368 --> 01:11:27,802
THAT.

1904
01:11:27,802 --> 01:11:29,403
SO THEN WE DID SOME REALLY FUN

1905
01:11:29,403 --> 01:11:30,304
EXPERIMENTS, VERY RELEVANT TO

1906
01:11:30,304 --> 01:11:31,706
THIS MEETING.

1907
01:11:31,706 --> 01:11:35,610
WE HAD 32 PEOPLE DRINK THIS

1908
01:11:35,610 --> 01:11:37,812
ENSURE SHAKE THAT YOU CAN BUY AT

1909
01:11:37,812 --> 01:11:38,346
CVS.

1910
01:11:38,346 --> 01:11:39,781
BASICALLY WE SAMPLED THEM

1911
01:11:39,781 --> 01:11:42,550
BEFORE, 30 MINUTES, 60 MINUTES,

1912
01:11:42,550 --> 01:11:43,017
120, 240 MINUTES.

1913
01:11:43,017 --> 01:11:45,353
SO WE ACTUALLY WERE TRYING TO

1914
01:11:45,353 --> 01:11:46,821
SEAT EFFECT OF DRINKING A SHAKE

1915
01:11:46,821 --> 01:11:48,122
ON PEOPLE'S BIOCHEMISTRY.

1916
01:11:48,122 --> 01:11:50,525
WHAT WE DISCOVERED, THIS PART'S

1917
01:11:50,525 --> 01:11:52,660
NOT A SURPRISE, THEY DO THIS

1918
01:11:52,660 --> 01:11:53,427
AFTER FASTING, YOU KNOW,

1919
01:11:53,427 --> 01:11:54,662
HUNDREDS OF MOLECULES CHANGE,

1920
01:11:54,662 --> 01:11:59,100
BUT WHAT'S NICE IS WE CAN

1921
01:11:59,100 --> 01:12:00,835
QUANTIFY SOME VERY KEY MOLECULES

1922
01:12:00,835 --> 01:12:02,804
LIKE INSULIN, A C PEPTIDE,

1923
01:12:02,804 --> 01:12:04,405
THINGS INVOLVED IN GLUCOSE

1924
01:12:04,405 --> 01:12:05,640
CONTROL, INFLAMMATORY MARKERS

1925
01:12:05,640 --> 01:12:08,376
AND SO ON.

1926
01:12:08,376 --> 01:12:10,044
WHAT WE DISCOVERED MUCH TO OUR

1927
01:12:10,044 --> 01:12:11,212
SURPRISE IS THAT EVERYBODY

1928
01:12:11,212 --> 01:12:12,280
REACTED TO THE SHAKE VERY

1929
01:12:12,280 --> 01:12:13,848
DIFFERENTLY.

1930
01:12:13,848 --> 01:12:17,652
SO EACH BLOCK BOX IS A DIFFERENT

1931
01:12:17,652 --> 01:12:18,719
PERSON, AND WHAT YOU'LL SEE,

1932
01:12:18,719 --> 01:12:23,424
THESE ARE JUST SHOWING THREE

1933
01:12:23,424 --> 01:12:24,091
CARBS.

1934
01:12:24,091 --> 01:12:28,863
THIS PERSON'S CARBS RELATIVELY

1935
01:12:28,863 --> 01:12:30,298
SPEAKING PLUMMETED, THEY WENT

1936
01:12:30,298 --> 01:12:32,066
WAY DOWN, WHEREAS THIS PERSON'S

1937
01:12:32,066 --> 01:12:33,801
WENT WAY UP.

1938
01:12:33,801 --> 01:12:35,837
UP, UP, UP, KIND OF NEUTRAL,

1939
01:12:35,837 --> 01:12:36,170
DOWN, DOWN.

1940
01:12:36,170 --> 01:12:37,538
SO AGAIN, PEOPLE ARE REACTING

1941
01:12:37,538 --> 01:12:38,239
VERY DIFFERENTLY.

1942
01:12:38,239 --> 01:12:41,542
SO SOME PEOPLE, THEIR CARBS WILL

1943
01:12:41,542 --> 01:12:43,778
PLUMMET BUT AMINO ACIDS WILL GO

1944
01:12:43,778 --> 01:12:45,479
UP, FREE FATTY ACIDS MIGHT

1945
01:12:45,479 --> 01:12:45,713
CHANGE.

1946
01:12:45,713 --> 01:12:46,647
SO IT'S VERY, VERY DIFFERENT.

1947
01:12:46,647 --> 01:12:48,549
IN THE END, WE CAN GROUP PEOPLE

1948
01:12:48,549 --> 01:12:49,817
INTO FIVE GROUPS OF PEOPLE.

1949
01:12:49,817 --> 01:12:51,786
ONE OF THE COOL RESULTS IS

1950
01:12:51,786 --> 01:12:53,321
ILLUSTRATED HERE.

1951
01:12:53,321 --> 01:12:54,989
GREY IS THE AVERAGE OF THE

1952
01:12:54,989 --> 01:12:56,924
GROUP, OKAY, THE AVERAGE VALUE,

1953
01:12:56,924 --> 01:13:00,728
IF YOU WILL, ACROSS MULTIPLE

1954
01:13:00,728 --> 01:13:01,195
ANALYTES.

1955
01:13:01,195 --> 01:13:02,296
BROWN ARE THE INFLAMMATION

1956
01:13:02,296 --> 01:13:02,730
MARKERS.

1957
01:13:02,730 --> 01:13:05,967
SO THIS GROUP OF PEOPLE, THE

1958
01:13:05,967 --> 01:13:06,934
INFLAMMATION, INFLAMMATORY

1959
01:13:06,934 --> 01:13:09,604
MARKERS GO DOWN AFTER DRINKING

1960
01:13:09,604 --> 01:13:10,705
THAT SHAKE.

1961
01:13:10,705 --> 01:13:11,772
FOR THIS GROUP OF PEOPLE, THEY

1962
01:13:11,772 --> 01:13:12,740
ACTUALLY GO UP.

1963
01:13:12,740 --> 01:13:15,743
SAME WITH THIS ONE, UP.

1964
01:13:15,743 --> 01:13:17,411
SO FOR SOME PEOPLE, THE SHAKE IS

1965
01:13:17,411 --> 01:13:20,281
PRO INFLAMMATORY, AND FOR

1966
01:13:20,281 --> 01:13:21,782
OTHERS, IT'S ANTI-INFLAMMATORY.

1967
01:13:21,782 --> 01:13:23,885
SO WE'RE ALL REACTING

1968
01:13:23,885 --> 01:13:24,485
DIFFERENTLY TO THE FOOD.

1969
01:13:24,485 --> 01:13:25,786
WE DON'T KNOW THE BASIS OF THIS,

1970
01:13:25,786 --> 01:13:27,121
WE HAVE SOME HYPOTHESES AND

1971
01:13:27,121 --> 01:13:28,389
THAT'S SOMETHING WE'RE SEEING

1972
01:13:28,389 --> 01:13:30,224
NOW, BUT THE IDEA THAT PEOPLE

1973
01:13:30,224 --> 01:13:31,125
RESPOND DIFFERENTLY TO DIFFERENT

1974
01:13:31,125 --> 01:13:32,326
FOODS PROBABLY EXPLAINS WHY

1975
01:13:32,326 --> 01:13:34,462
QUITE A FEW PEOPLE HAVE IBS,

1976
01:13:34,462 --> 01:13:35,730
INFLAMMATORY BOWEL SYNDROME, ET

1977
01:13:35,730 --> 01:13:36,130
CETERA.

1978
01:13:36,130 --> 01:13:37,732
SO WE CAN MEASURE THIS, SO WE

1979
01:13:37,732 --> 01:13:39,600
THINK THIS IS THE WAY OF TEASING

1980
01:13:39,600 --> 01:13:41,435
ALL THIS OUT.

1981
01:13:41,435 --> 01:13:42,436
THE OTHER THING WE'VE DONE IS

1982
01:13:42,436 --> 01:13:43,804
WHAT I CALL THE ULTIMATE

1983
01:13:43,804 --> 01:13:44,272
EXPERIMENT.

1984
01:13:44,272 --> 01:13:47,208
WE HAD ONE PERSON TAKE SAMPLES

1985
01:13:47,208 --> 01:13:49,710
EVERY HOUR DURING WAKING HOURS

1986
01:13:49,710 --> 01:13:52,513
FOR SEVEN STRAIGHT DAYS.

1987
01:13:52,513 --> 01:13:54,715
THEY'RE WEARING A CGM,

1988
01:13:54,715 --> 01:13:55,616
CONTINUOUS GLUCOSE MONITOR, A

1989
01:13:55,616 --> 01:13:56,918
SMART WATCH AND DOING FOOD

1990
01:13:56,918 --> 01:13:57,618
LOGGING.

1991
01:13:57,618 --> 01:13:59,487
SO NOT SURPRISING, THOUSANDS OF

1992
01:13:59,487 --> 01:14:02,123
MOLECULES DID CHANGE, AND THEN

1993
01:14:02,123 --> 01:14:03,991
WE CAN ACTUALLY START

1994
01:14:03,991 --> 01:14:06,260
CORRELATING THESE BIOCHEMICAL

1995
01:14:06,260 --> 01:14:07,228
CHANGES WITH ACTIVITY AND

1996
01:14:07,228 --> 01:14:09,530
LIFESTYLE AND SO ON.

1997
01:14:09,530 --> 01:14:10,731
WHAT WE FIND IS THAT WE'VE

1998
01:14:10,731 --> 01:14:14,335
WRITTEN ALGORITHMS TO FIND TIME

1999
01:14:14,335 --> 01:14:15,303
LAG CORRELATIONS BECAUSE THE

2000
01:14:15,303 --> 01:14:17,505
IDEA IS CAUSATIVE EVENTS WILL BE

2001
01:14:17,505 --> 01:14:19,373
UPSTREAM OF DOWNSTREAM EVENTS SO

2002
01:14:19,373 --> 01:14:20,875
WE CAN SEE POTENTIAL CAUSE OF

2003
01:14:20,875 --> 01:14:23,144
EVENTS BY THIS KIND OF ANALYSIS.

2004
01:14:23,144 --> 01:14:25,947
SO WE FIND THOUSANDS OF

2005
01:14:25,947 --> 01:14:28,149
ASSOCIATIONS OF, SAY,

2006
01:14:28,149 --> 01:14:31,552
METABOLITES WITH STEPS, THESE

2007
01:14:31,552 --> 01:14:34,255
MAGENTA THINGS, PURPLE ONES ARE

2008
01:14:34,255 --> 01:14:38,292
ACTUALLY -- KNOWS  THOSE ARE CY,

2009
01:14:38,292 --> 01:14:40,895
THE BLUE ONES ARE LIPIDS AND THE

2010
01:14:40,895 --> 01:14:43,631
METABOLITES ARE ACTUALLY GREEN.

2011
01:14:43,631 --> 01:14:44,865
WE'LL FIND THOUSANDS OF THESE

2012
01:14:44,865 --> 01:14:45,599
ASSOCIATIONS, THIS IS JUST

2013
01:14:45,599 --> 01:14:46,767
SHOWING SOME OF THE TOP ONES.

2014
01:14:46,767 --> 01:14:47,668
AND THEY'RE PRETTY COOL.

2015
01:14:47,668 --> 01:14:49,737
A LOT OF STUFF IS NEW, WE'LL SEE

2016
01:14:49,737 --> 01:14:51,238
NEW INFLAMMATORY MARKERS COME UP

2017
01:14:51,238 --> 01:14:52,239
AFTER GLUCOSE, FOR EXAMPLE.

2018
01:14:52,239 --> 01:14:54,742
THIS IS SHOWING C PEPTIDE COMES

2019
01:14:54,742 --> 01:14:56,911
UP AFTER GLUCOSE, THAT, WE WOULD

2020
01:14:56,911 --> 01:14:57,578
EXPECT.

2021
01:14:57,578 --> 01:14:58,813
WHAT'S NICE IS WE QUANTIFIED IN

2022
01:14:58,813 --> 01:14:59,981
THIS PERSON, WE KNOW EXACTLY

2023
01:14:59,981 --> 01:15:01,816
WHAT IT IS, 10-MINUTE LAG.

2024
01:15:01,816 --> 01:15:05,319
HERE'S A NEAT RESULT THAT WE

2025
01:15:05,319 --> 01:15:05,853
DIDN'T NECESSARILY EXPECT.

2026
01:15:05,853 --> 01:15:08,489
WE ACTUALLY PICKED UP ALPHA

2027
01:15:08,489 --> 01:15:09,557
SYNUCLEIN, WHICH ALSO SHOWS A

2028
01:15:09,557 --> 01:15:11,525
PRETTY INTERESTING PATTERN.

2029
01:15:11,525 --> 01:15:13,661
WE ACTUALLY THINK -- WE'RE STILL

2030
01:15:13,661 --> 01:15:14,795
ANALYZING THIS BUT WE THINK IT'S

2031
01:15:14,795 --> 01:15:15,896
ASSOCIATED WITH STRESS.

2032
01:15:15,896 --> 01:15:18,332
NOW, ALPHA SYNUCLEIN, YOU MAY

2033
01:15:18,332 --> 01:15:19,433
KNOW IT'S ASSOCIATED WITH

2034
01:15:19,433 --> 01:15:21,535
DEMENTIA, ALSO PARKINSON'S, SO

2035
01:15:21,535 --> 01:15:22,837
IMAGINE IF YOU'RE AT RISK FOR

2036
01:15:22,837 --> 01:15:24,672
THIS, I THINK WHAT YOU'D WANT TO

2037
01:15:24,672 --> 01:15:26,741
DO IS MITIGATE YOUR STRESS SO AS

2038
01:15:26,741 --> 01:15:29,043
TO AVOID SPIKING THIS AND

2039
01:15:29,043 --> 01:15:30,011
PERHAPS THAT WOULD HELP DELAY

2040
01:15:30,011 --> 01:15:33,581
THE ONSET OF DEMENTIA.

2041
01:15:33,581 --> 01:15:35,149
SO THE WAY WE'RE HANDLING THIS

2042
01:15:35,149 --> 01:15:37,184
IS THAT WE CAN PULL ON ALL THESE

2043
01:15:37,184 --> 01:15:38,819
DATA, THE WEARABLE DATA, THE

2044
01:15:38,819 --> 01:15:40,354
OMICS DATA, ALL THESE DIFFERENT

2045
01:15:40,354 --> 01:15:42,189
DATA TYPES AND DISPLAY IT ON A

2046
01:15:42,189 --> 01:15:43,824
DASHBOARD WE BUILT, PERSONAL

2047
01:15:43,824 --> 01:15:46,994
HEALTH DASHBOARD, SO WE THINK

2048
01:15:46,994 --> 01:15:48,195
THIS IS GOING TO EMPOWER

2049
01:15:48,195 --> 01:15:49,463
INDIVIDUALS TO BE ABLE TO BETTER

2050
01:15:49,463 --> 01:15:52,199
TRACK THEIR HEALTH.

2051
01:15:52,199 --> 01:15:53,434
SO WHERE IS ALL THIS GOING?

2052
01:15:53,434 --> 01:15:55,036
WELL, I THINK DEEP DATA IS GOING

2053
01:15:55,036 --> 01:15:56,437
TO BE VERY POWERFUL, JUST LIKE

2054
01:15:56,437 --> 01:15:57,872
IT'S BEEN DOING ALREADY, FOR

2055
01:15:57,872 --> 01:15:59,407
TRACKING PEOPLE'S HEALTH,

2056
01:15:59,407 --> 01:16:00,574
CATCHING DISEASE EARLY, AND

2057
01:16:00,574 --> 01:16:01,809
HAVING HEALTHY DISEASE

2058
01:16:01,809 --> 01:16:02,877
SIGNATURES.

2059
01:16:02,877 --> 01:16:04,278
BUT THERE'S MANY, MANY MORE

2060
01:16:04,278 --> 01:16:05,413
THINGS TO DO, IF YOU THINK ABOUT

2061
01:16:05,413 --> 01:16:06,013
IT.

2062
01:16:06,013 --> 01:16:07,314
THERE'S A LOT WE DON'T KNOW.

2063
01:16:07,314 --> 01:16:09,216
WE DON'T REALLY KNOW WHAT TO

2064
01:16:09,216 --> 01:16:09,617
MEASURE.

2065
01:16:09,617 --> 01:16:11,719
AS I SAY, YOU GO TO A DOCTOR

2066
01:16:11,719 --> 01:16:13,788
TODAY, THEY MEASURE 15 THINGS,

2067
01:16:13,788 --> 01:16:16,290
LIKE RESTING HEART RATE IN

2068
01:16:16,290 --> 01:16:17,558
DOCTOR'S OFFICE, IT'S ALL OVER

2069
01:16:17,558 --> 01:16:19,427
THE MAP, IT'S NOT NECESSARILY

2070
01:16:19,427 --> 01:16:19,960
TERRIBLY ACCURATE.

2071
01:16:19,960 --> 01:16:20,961
WE THINK THERE'S MANY MORE

2072
01:16:20,961 --> 01:16:22,363
THINGS THAT COULD BE MEASURED,

2073
01:16:22,363 --> 01:16:23,998
BUT WE DON'T KNOW THE BEST

2074
01:16:23,998 --> 01:16:26,700
MARKERS, I WOULD ARGUE.

2075
01:16:26,700 --> 01:16:28,269
WE ALSO DON'T REALLY KNOW HOW

2076
01:16:28,269 --> 01:16:29,203
FREQUENTLY YOU SHOULD BE

2077
01:16:29,203 --> 01:16:30,204
MEASURING PEOPLE, LIKE SHOULD

2078
01:16:30,204 --> 01:16:32,073
YOU BE MEASURING THEM EVERY WEEK

2079
01:16:32,073 --> 01:16:33,874
FOR CERTAIN THINGS, MONTHLY,

2080
01:16:33,874 --> 01:16:36,377
YEARLY, WHAT YOU HAVE.

2081
01:16:36,377 --> 01:16:40,548
ABANDONS WHY AND WHY DO WE ALWAE

2082
01:16:40,548 --> 01:16:41,182
AFTER FASTING?

2083
01:16:41,182 --> 01:16:42,183
MAYBE THERE'S OTHER TIMES WE

2084
01:16:42,183 --> 01:16:43,584
SHOULD BE MEASURING PEOPLE, SAY,

2085
01:16:43,584 --> 01:16:45,920
AFTER THEY RUN, THAT'S WHAT

2086
01:16:45,920 --> 01:16:47,388
STRESS ECHOCARDIOGRAMS ARE ALL

2087
01:16:47,388 --> 01:16:48,489
ABOUT, PUTTING PEOPLE THROUGH

2088
01:16:48,489 --> 01:16:50,758
CHALLENGES AND MEASURING THINGS.

2089
01:16:50,758 --> 01:16:52,259
I WOULD ARGUE MECHANISTICALLY,

2090
01:16:52,259 --> 01:16:53,260
WE DON'T KNOW HOW MOST OF THE

2091
01:16:53,260 --> 01:16:55,129
THINGS WE DO REALLY WORK.

2092
01:16:55,129 --> 01:16:58,833
WE DON'T KNOW HOW NUTRITION HAS

2093
01:16:58,833 --> 01:17:01,235
ITS EFFECTS ON PEOPLE AND

2094
01:17:01,235 --> 01:17:02,570
NUTRITION IS SO BROAD THAT WE'VE

2095
01:17:02,570 --> 01:17:03,971
NEVER BROKEN IT DOWN PROPERLY.

2096
01:17:03,971 --> 01:17:05,573
SAME WITH SLEEP, I WOULD ARGUE

2097
01:17:05,573 --> 01:17:07,975
WE DON'T KNOW HOW -- WE HAVE

2098
01:17:07,975 --> 01:17:08,843
ASSUMPTIONS ABOUT HOW IT WORKS

2099
01:17:08,843 --> 01:17:10,611
BUT I DON'T THINK IT'S REAL.

2100
01:17:10,611 --> 01:17:11,579
EXERCISE, BUT THERE IS A PROJECT

2101
01:17:11,579 --> 01:17:13,881
TO GO AFTER THAT.

2102
01:17:13,881 --> 01:17:16,817
AND CERTAINLY WE HAVE MENTAL

2103
01:17:16,817 --> 01:17:19,520
HEALTH, IT'S PRETTY CLEAR,

2104
01:17:19,520 --> 01:17:20,287
SOCIALIZATION IS VERY, VERY

2105
01:17:20,287 --> 01:17:21,622
IMPORTANT FOR THEIR LONGEVITY

2106
01:17:21,622 --> 01:17:22,256
AND HEALTHSPAN.

2107
01:17:22,256 --> 01:17:24,325
SO WE THINK IT WOULD BE NICE TO

2108
01:17:24,325 --> 01:17:26,393
UNDERSTAND HOW ALL THIS WORKS

2109
01:17:26,393 --> 01:17:26,994
MECHANISTICALLY.

2110
01:17:26,994 --> 01:17:28,329
THEN ULTIMATELY, WHAT WE REALLY

2111
01:17:28,329 --> 01:17:30,097
NEED TO DO IS KNOW HOW TO

2112
01:17:30,097 --> 01:17:32,366
OPTIMIZE PEOPLE'S PERSONAL

2113
01:17:32,366 --> 01:17:34,468
LIFESTYLE.

2114
01:17:34,468 --> 01:17:37,738
SO PEOPLE LIKE ME, LUIGI, I TAKE

2115
01:17:37,738 --> 01:17:39,807
MY ANTIOXIDANTS, AND I TRACK

2116
01:17:39,807 --> 01:17:41,108
THIS STUFF, SO MY CASE, I'VE

2117
01:17:41,108 --> 01:17:43,611
BEEN ABLE TO CATCH MY LYME, I

2118
01:17:43,611 --> 01:17:46,981
FIGURED OUT MY DIABETES FROM MY

2119
01:17:46,981 --> 01:17:47,348
GENOME SEQUENCE.

2120
01:17:47,348 --> 01:17:48,749
SO WE THINK THERE'S WAYS OF

2121
01:17:48,749 --> 01:17:51,185
ACTUALLY USING SOME OF THESE

2122
01:17:51,185 --> 01:17:52,520
ADVANCED TECHNOLOGIES TO MAKE

2123
01:17:52,520 --> 01:17:53,687
BETTER PREDICTIONS ABOUT

2124
01:17:53,687 --> 01:17:54,655
PEOPLE'S DISEASE RISK AND HEALTH

2125
01:17:54,655 --> 01:17:56,824
TRACKING.

2126
01:17:56,824 --> 01:17:58,592
SO THIS JUST HAPPENS TO BE MY

2127
01:17:58,592 --> 01:17:59,994
WEARABLES TEAM WHEN IT WAS AT

2128
01:17:59,994 --> 01:18:01,629
ITS PEAK AND THE MICRO SAMPLING

2129
01:18:01,629 --> 01:18:10,504
TEAM WAS LED BY SHAU SHAU RHINE.

2130
01:18:10,504 --> 01:18:11,939
I BELIEVE I'VE SAVED TIME FOR

2131
01:18:11,939 --> 01:18:15,009
SOME QUESTIONS.

2132
01:18:15,009 --> 01:18:16,210
SO IF YOU HAVE QUESTIONS, I'D BE

2133
01:18:16,210 --> 01:18:18,979
HAPPY TO TAKE THEM.

2134
01:18:18,979 --> 01:18:22,683
>> THANK YOU SO MUCH FOR A
VERY

2135
01:18:22,683 --> 01:18:26,620
EXCITING TALK.

2136
01:18:26,620 --> 01:18:28,722
I WOULD LIKE TO START BY KIND OF

2137
01:18:28,722 --> 01:18:29,590
A FUN EXERCISE.

2138
01:18:29,590 --> 01:18:30,891
I MEAN, YOU ARE KNOWN TO BE PART

2139
01:18:30,891 --> 01:18:32,293
OF YOUR OWN STUDIES.

2140
01:18:32,293 --> 01:18:35,763
I THINK YOU PUBLISHED A PAPER IN

2141
01:18:35,763 --> 01:18:38,866
WHICH YOU REPORTED YOUR

2142
01:18:38,866 --> 01:18:41,468
EXPERIENCE WITH A VIRAL

2143
01:18:41,468 --> 01:18:44,104
INFECTION AND EFFECTS ON YOUR

2144
01:18:44,104 --> 01:18:45,639
METABOLISM AND SO FORTH, SO I'D

2145
01:18:45,639 --> 01:18:46,574
LIKE TO ASK YOU IF YOU WOULD

2146
01:18:46,574 --> 01:18:49,543
TELL US RIGHT NOW HOW MANY OF

2147
01:18:49,543 --> 01:18:51,312
THESE WEARABLE DEVICES ARE YOU

2148
01:18:51,312 --> 01:18:52,880
USING?

2149
01:18:52,880 --> 01:18:56,217
>> I NORMALLY USE ABOUT
EIGHT

2150
01:18:56,217 --> 01:18:57,851
EVERY DAY, SO I HAVE MY FOUR

2151
01:18:57,851 --> 01:18:59,220
SMART WATCHES HERE, MY RING.

2152
01:18:59,220 --> 01:19:00,521
RIGHT NOW I DON'T HAVE MY

2153
01:19:00,521 --> 01:19:02,823
GLUCOSE MONITOR ON, JUST SIMPLY

2154
01:19:02,823 --> 01:19:04,258
BECAUSE I HAVEN'T GOT THE NEW

2155
01:19:04,258 --> 01:19:07,394
ONE HOOKED UP YET, SO THAT WOULD

2156
01:19:07,394 --> 01:19:07,928
BE SIX.

2157
01:19:07,928 --> 01:19:12,032
I NORMALLY CARRY AN EXPOSEOMETER

2158
01:19:12,032 --> 01:19:12,633
BECAUSE YOU DON'T KNOW WHAT

2159
01:19:12,633 --> 01:19:13,601
YOU'RE BREATHING RIGHT NOW BUT

2160
01:19:13,601 --> 01:19:14,568
WE CAN MEASURE THAT.

2161
01:19:14,568 --> 01:19:17,371
SOME OF THEM WE GET IN REALTIME

2162
01:19:17,371 --> 01:19:20,241
LIKE PM2.5, PM10, THAT'S WHAT'S

2163
01:19:20,241 --> 01:19:22,009
MEASURED HERE, BUT WE'RE

2164
01:19:22,009 --> 01:19:23,744
COLLECTING SAMPLES TO SEE WHAT

2165
01:19:23,744 --> 01:19:25,746
BIOLOGICALS AND CHEMICALS I'M

2166
01:19:25,746 --> 01:19:26,947
EXPOSED TO, SO THAT'S SEVEN.

2167
01:19:26,947 --> 01:19:28,315
AND THEN MY SMARTPHONE HAS

2168
01:19:28,315 --> 01:19:31,285
SEVERAL THINGS TOO, LIKE MOVES

2169
01:19:31,285 --> 01:19:32,386
APP, STUFF LIKE THAT THAT TRACKS

2170
01:19:32,386 --> 01:19:33,220
THINGS AS WELL.

2171
01:19:33,220 --> 01:19:34,622
SO YEAH, WE TRACK QUITE A FEW

2172
01:19:34,622 --> 01:19:35,089
THINGS.

2173
01:19:35,089 --> 01:19:37,758
OH, I FORGOT TO SAY, EVEN MY

2174
01:19:37,758 --> 01:19:39,526
HEARING AID IS -- IT IS FOR

2175
01:19:39,526 --> 01:19:41,028
HEARING, BY THE WAY, BUT IT ALSO

2176
01:19:41,028 --> 01:19:42,596
IS A TRACKER AS WELL.

2177
01:19:42,596 --> 01:19:44,431
MEASURES MY SOCIAL INTERACTIONS.

2178
01:19:44,431 --> 01:19:47,067
WHICH IS KIND OF INTERESTING.

2179
01:19:47,067 --> 01:19:49,937
AND SO WE THINK -- SO THAT WOULD

2180
01:19:49,937 --> 01:19:52,206
BE NINE IF YOU COUNT ALL THAT

2181
01:19:52,206 --> 01:19:54,408
STUFF.

2182
01:19:54,408 --> 01:19:56,577
>> SO THAT'S AN IMPORTANT

2183
01:19:56,577 --> 01:19:57,878
QUESTION, ESPECIALLY FOR US AS

2184
01:19:57,878 --> 01:19:59,079
WE ARE TRYING TO ENVISION HOW

2185
01:19:59,079 --> 01:20:03,250
WOULD YOU RUN A STUDY OF A

2186
01:20:03,250 --> 01:20:05,886
FAIRLY LARGE SCALE, I WOULD SAY,

2187
01:20:05,886 --> 01:20:07,721
WITH A LOT OF PEOPLE INVOLVED IN

2188
01:20:07,721 --> 01:20:08,155
IT?

2189
01:20:08,155 --> 01:20:09,890
HOW OFTEN, HOW MANY DEVICES, HOW

2190
01:20:09,890 --> 01:20:12,760
MUCH CAN BE SELF-REPORTED, HOW

2191
01:20:12,760 --> 01:20:17,765
MUCH NEEDS TO BE DONE THROUGH A

2192
01:20:17,765 --> 01:20:19,266
LAB AND SO FORTH, SO I KNOW YOU

2193
01:20:19,266 --> 01:20:21,802
ALREADY MENTIONED THAT WE DON'T

2194
01:20:21,802 --> 01:20:24,638
KNOW THAT YET, BUT IF YOU'RE

2195
01:20:24,638 --> 01:20:28,442
GOING TO LOOK INTO YOUR CRYSTAL

2196
01:20:28,442 --> 01:20:29,076
BALL, WHAT WILL YOU SAY?

2197
01:20:29,076 --> 01:20:31,612
>> WELL YOU NEED ONE
TRACKER,

2198
01:20:31,612 --> 01:20:32,579
YOU DON'T NEED ALL FOUR.

2199
01:20:32,579 --> 01:20:34,448
WE DO FOUR BASICALLY BECAUSE I'M

2200
01:20:34,448 --> 01:20:34,848
EVALUATING THINGS.

2201
01:20:34,848 --> 01:20:36,850
SO WHEN I GOT COVID, I HAVEN'T

2202
01:20:36,850 --> 01:20:39,253
FINISHED EVALUATING WHI WHICH DE

2203
01:20:39,253 --> 01:20:40,788
WOULD HAVE BEEN BEST FOR PICKING

2204
01:20:40,788 --> 01:20:42,022
THAT UP AND WHY.

2205
01:20:42,022 --> 01:20:43,924
BECAUSE THEY'VE SAMPLED

2206
01:20:43,924 --> 01:20:45,225
RESOLUTIONS AND THEY MEASURE

2207
01:20:45,225 --> 01:20:46,860
DIFFERENT THINGS.

2208
01:20:46,860 --> 01:20:48,495
BUT I THINK FOR WRITING A STUDY

2209
01:20:48,495 --> 01:20:50,164
THE OBVIOUS THING TO DO IS JUST

2210
01:20:50,164 --> 01:20:51,365
GET ONE SMART WATCH ON PEOPLE.

2211
01:20:51,365 --> 01:20:54,935
I'M A BIG FAN OF TBLEU KOAS GLUE

2212
01:20:54,935 --> 01:20:55,502
MONITORS.

2213
01:20:55,502 --> 01:20:56,537
THEY'RE A LITTLE INCONVENIENT TO

2214
01:20:56,537 --> 01:20:57,905
PUT ON EVERY TWO WEEKS, THAT'S

2215
01:20:57,905 --> 01:20:59,506
HOW LONG THEY LAST, BUT WE

2216
01:20:59,506 --> 01:21:00,507
TYPICALLY RUN -- IT DEPENDS ON

2217
01:21:00,507 --> 01:21:02,142
WHAT THE STUDY DESIGN IS ALL

2218
01:21:02,142 --> 01:21:04,211
ABOUT, WE'LL TYPICALLY USE THEM

2219
01:21:04,211 --> 01:21:05,512
QUARTERLY, FOR EXAMPLE, OR MAYBE

2220
01:21:05,512 --> 01:21:08,482
YEARLY DEPENDING ON THE

2221
01:21:08,482 --> 01:21:09,583
PRINCIPLE OF THE STUDY, SO

2222
01:21:09,583 --> 01:21:10,884
THAT'S A GOOD ONE TO DO.

2223
01:21:10,884 --> 01:21:15,255
I THINK WE DON'T -- WE STILL DO

2224
01:21:15,255 --> 01:21:16,890
BIG BLOOD DRAWS WHEN WE LAUNCH A

2225
01:21:16,890 --> 01:21:18,425
STUDY BUT WE'RE SWITCHING

2226
01:21:18,425 --> 01:21:20,794
EVERYTHING OVER TO MICRO

2227
01:21:20,794 --> 01:21:21,895
SAMPLING, BECAUSE THEN YOU CAN

2228
01:21:21,895 --> 01:21:23,230
SAMPLE PEOPLE AT HOME, WHICH IS

2229
01:21:23,230 --> 01:21:24,732
MORE NATIVE, AND STILL MEASURE

2230
01:21:24,732 --> 01:21:27,735
THOUSANDS OF A ANALYTES.

2231
01:21:27,735 --> 01:21:29,370
SO I THINK THE FUTURE WILL BE TO

2232
01:21:29,370 --> 01:21:31,438
DO THESE MICRO SAMPLE

2233
01:21:31,438 --> 01:21:32,639
COLLECTIONS, SAVES A TON OF

2234
01:21:32,639 --> 01:21:37,211
MONEY, BY THE WAY, AND GETS, WE

2235
01:21:37,211 --> 01:21:37,444
THINK --

2236
01:21:37,444 --> 01:21:40,481
>> AND HOW OFTEN YOU WOULD
SAY,

2237
01:21:40,481 --> 01:21:42,349
ONCE A MONTH WOULD BE --

2238
01:21:42,349 --> 01:21:46,754
>> THAT'S WHAT WE' TRY
WHAT WE'O

2239
01:21:46,754 --> 01:21:46,920
DO.

2240
01:21:46,920 --> 01:21:50,090
WE HAVE A CHRONIC FATIGUE STUDY

2241
01:21:50,090 --> 01:21:51,625
RUNNING, THERE WE SAMPLE PEOPLE

2242
01:21:51,625 --> 01:21:52,826
EVERY TWO WEEKS, THEY GET

2243
01:21:52,826 --> 01:21:54,995
FREQUENT CRASHES, THEN WE SAMPLE

2244
01:21:54,995 --> 01:21:55,896
THEM DURING THE CRASH AND WHAT

2245
01:21:55,896 --> 01:21:57,431
THEY FEEL IS THEIR GOOD DAYS, SO

2246
01:21:57,431 --> 01:21:59,299
WE'LL SAMPLE THEM ON THEIR GOOD

2247
01:21:59,299 --> 01:22:00,167
DAYS AND BAD DAYS.

2248
01:22:00,167 --> 01:22:01,468
SO IT DEPENDS ON THE STUDY.

2249
01:22:01,468 --> 01:22:04,304
FOR THIS STUDY I TOLD YOU ABOUT,

2250
01:22:04,304 --> 01:22:07,474
THE IPOP ONE, WE ARBITRARILY

2251
01:22:07,474 --> 01:22:08,108
PICKED THREE MONTHS BECAUSE WE

2252
01:22:08,108 --> 01:22:10,744
DIDN'T REALLY KNOW WHAT TO DO.

2253
01:22:10,744 --> 01:22:12,379
QBIOWILL TELL PEOPLE TO SAMPLE

2254
01:22:12,379 --> 01:22:16,083
EVERY SIX MONTHS AS A WAY OF

2255
01:22:16,083 --> 01:22:16,417
FOLLOWING.

2256
01:22:16,417 --> 01:22:17,651
NOW, I PERSONALLY THINK THAT IN

2257
01:22:17,651 --> 01:22:18,585
THE LONG RUN, WHAT WE'RE GOING

2258
01:22:18,585 --> 01:22:20,988
TO BE DOING IS SAMPLING CERTAIN

2259
01:22:20,988 --> 01:22:23,490
THINGS LIKE METABOLITES QUITE

2260
01:22:23,490 --> 01:22:24,725
FREQUENTLY AT HOME, LIKE EVERY

2261
01:22:24,725 --> 01:22:25,759
MONTH, SO YOU CAN SEE THINGS

2262
01:22:25,759 --> 01:22:27,995
WHEN THEY GO OFF.

2263
01:22:27,995 --> 01:22:29,196
OTHER THINGS WILL DEPEND ON WHAT

2264
01:22:29,196 --> 01:22:30,631
YOU'RE AT RISK FOR.

2265
01:22:30,631 --> 01:22:33,801
I PERSONALLY THINK WHOLE BODY

2266
01:22:33,801 --> 01:22:35,002
MRIs, THEY TAKE A LONG TIME TO

2267
01:22:35,002 --> 01:22:36,537
RUN BUT THEY WON'T IN THE

2268
01:22:36,537 --> 01:22:36,870
FUTURE.

2269
01:22:36,870 --> 01:22:38,806
THEY'LL BE 15 MINUTES.

2270
01:22:38,806 --> 01:22:40,140
AND YOU'LL BE ABLE TO DO IT

2271
01:22:40,140 --> 01:22:42,609
WHILE YOU'RE AT THE DRUGSTORE,

2272
01:22:42,609 --> 01:22:44,812
AND MAYBE YOU DO THAT ONCE EVERY

2273
01:22:44,812 --> 01:22:45,579
SIX MONTHS.

2274
01:22:45,579 --> 01:22:46,980
I PERSONALLY THINK EVERY FEW

2275
01:22:46,980 --> 01:22:49,049
YEARS IS -- ESPECIALLY US A GET

2276
01:22:49,049 --> 01:22:50,384
OLDER, RIGHT, WHEN YOU HIT YOUR

2277
01:22:50,384 --> 01:22:52,886
50s IS WHEN THINGS HEAD OFF,

2278
01:22:52,886 --> 01:22:53,654
MAYBE EVEN 40s.

2279
01:22:53,654 --> 01:22:55,088
SO YOU'LL MEASURE WITH HIGHER

2280
01:22:55,088 --> 01:22:57,357
FREQUENCY LATER, BUT YOU STILL

2281
01:22:57,357 --> 01:22:59,460
NEED TO MEASURE EARLIER.

2282
01:22:59,460 --> 01:23:00,761
SO AGGRESSIVE CANCERS, THEY CAN

2283
01:23:00,761 --> 01:23:02,629
GO FROM ZERO TO PRETTY BAD

2284
01:23:02,629 --> 01:23:05,566
THINGS IN THREA MONTHS.

2285
01:23:05,566 --> 01:23:07,000
THAT'S PROBABLY A LOT TO DO, BUT

2286
01:23:07,000 --> 01:23:10,604
IT IS DOABLE IF WE CAN DO TEP 10

2287
01:23:10,604 --> 01:23:12,773
MINUTE SCANS ON PEOPLE AND ALSO

2288
01:23:12,773 --> 01:23:16,276
DO SENSITIVE BLOOD TESTS.

2289
01:23:16,276 --> 01:23:19,146
SO I THINK WE CAN INCREASE THE

2290
01:23:19,146 --> 01:23:20,781
FREQUENCIES, REDUCE THE COST AND

2291
01:23:20,781 --> 01:23:21,982
INCREASE OUR SENSITIVITY AND

2292
01:23:21,982 --> 01:23:23,016
SPECIFICITY.

2293
01:23:23,016 --> 01:23:24,151
SO THAT'S HOW I'D LIKE TO SEE

2294
01:23:24,151 --> 01:23:25,953
THINGS GO.

2295
01:23:25,953 --> 01:23:27,554
MY WORLD, THEY'D BE EVERY THREE

2296
01:23:27,554 --> 01:23:28,555
MONTHS ALL THE TIME.

2297
01:23:28,555 --> 01:23:29,756
I THINK RIGHT NOW THAT'S

2298
01:23:29,756 --> 01:23:31,191
PROBABLY NOT PRACTICAL.

2299
01:23:31,191 --> 01:23:33,660
BUT CERTAINLY MORE FREQUENT THAN

2300
01:23:33,660 --> 01:23:34,528
WE'RE DOING IT.

2301
01:23:34,528 --> 01:23:35,729
BUT NOBODY'S RUN THE PROPER

2302
01:23:35,729 --> 01:23:37,664
STUDY TO SAY HOW OFTEN SHOULD

2303
01:23:37,664 --> 01:23:39,399
YOU GET SCREENED FOR CANCER, AT

2304
01:23:39,399 --> 01:23:41,001
A CERTAIN AGE BASED ON CERTAIN

2305
01:23:41,001 --> 01:23:43,070
RISKS THAT YOUR GENOME SEQUENCE,

2306
01:23:43,070 --> 01:23:44,771
OR EVEN FOR RECURRENCE, QUITE

2307
01:23:44,771 --> 01:23:45,138
FRANKLY.

2308
01:23:45,138 --> 01:23:47,841
I DON'T THINK WE HAVE GOOD

2309
01:23:47,841 --> 01:23:49,943
GUIDELINES FOR RECURRENCE.

2310
01:23:49,943 --> 01:23:51,211
IT SHOULD DEPEND ON THE TYPE OF

2311
01:23:51,211 --> 01:23:53,213
CANCER YOU'VE GOT.

2312
01:23:53,213 --> 01:23:54,848
PROBABLY THE TYPE OF GENETIC

2313
01:23:54,848 --> 01:23:55,482
MUTATION YOU'VE GOT.

2314
01:23:55,482 --> 01:23:57,918
SOME ARE MORE AIF THAN OTHERS.

2315
01:23:57,918 --> 01:24:00,120
YOU'RE ASKING A GREAT QUESTION.

2316
01:24:00,120 --> 01:24:01,188
>> THANK YOU SO MUCH.

2317
01:24:01,188 --> 01:24:02,856
YOU ARE GIVING GREAT ANSWERS.

2318
01:24:02,856 --> 01:24:04,791
SO WE DO HAVE SEVERAL QUESTIONS,

2319
01:24:04,791 --> 01:24:06,460
I WANT TO REMIND PEOPLE EVEN IF

2320
01:24:06,460 --> 01:24:08,562
THEY ARE ON VIDEO CHAT, THERE IS

2321
01:24:08,562 --> 01:24:10,831
A BOX YOU CAN SEND A QUESTION,

2322
01:24:10,831 --> 01:24:13,033
THEY WILL COME BY EMAIL.

2323
01:24:13,033 --> 01:24:14,868
PEOPLE WHO ARE IN ZOOM, THEY CAN

2324
01:24:14,868 --> 01:24:18,138
PUT THE QUESTIONS IN Q & A.

2325
01:24:18,138 --> 01:24:19,239
WE ALREADY HAVE SEVERAL LINED

2326
01:24:19,239 --> 01:24:19,573
UP.

2327
01:24:19,573 --> 01:24:20,774
AND I THINK WE'RE ALSO GOING TO

2328
01:24:20,774 --> 01:24:23,710
OPEN THE CHAT IN CASE YOU COULD

2329
01:24:23,710 --> 01:24:26,446
NOT FIND THE Q & A BOX.

2330
01:24:26,446 --> 01:24:27,981
BUT HERE ARE SOME QUESTIONS THAT

2331
01:24:27,981 --> 01:24:32,619
CAME THROUGH Q & A.

2332
01:24:32,619 --> 01:24:37,090
AND IF WE RUN OUT OF TIME,

2333
01:24:37,090 --> 01:24:38,191
PLEASE SEE IF YOU CAN ANSWER

2334
01:24:38,191 --> 01:24:39,059
AFTER THE DISCUSSION.

2335
01:24:39,059 --> 01:24:42,663
HOW DO YOU DIFFERENTIATE TYPE

2336
01:24:42,663 --> 01:24:44,097
2 FROM AUTO ONSET TYPE 1 USING

2337
01:24:44,097 --> 01:24:45,832
THIS APPROACH, OR CAN YOU?

2338
01:24:45,832 --> 01:24:47,568
>> YEAH, I MEAN, WE DON'T
FOR

2339
01:24:47,568 --> 01:24:52,406
OUR GROUP.

2340
01:24:52,406 --> 01:24:53,907
BUT WE DO SUBTYPE PEOPLE WHICH I

2341
01:24:53,907 --> 01:24:55,342
THINK IS A MORE RELEVANT THING.

2342
01:24:55,342 --> 01:24:56,977
ARE THEY HAVING INSULIN

2343
01:24:56,977 --> 01:25:00,380
RESISTANCE VERSUS, SAY, BETA

2344
01:25:00,380 --> 01:25:00,814
CELL EFFECTS.

2345
01:25:00,814 --> 01:25:02,749
SO WE ACTUALLY DEEPLY PHENOTYPE,

2346
01:25:02,749 --> 01:25:04,851
I DIDN'T GET INTO THAT, OUR

2347
01:25:04,851 --> 01:25:05,953
COHORT.

2348
01:25:05,953 --> 01:25:07,154
THESE DAYS WE THINK THAT'S

2349
01:25:07,154 --> 01:25:07,487
IMPORTANT.

2350
01:25:07,487 --> 01:25:08,689
I'M A CLASSIC CASE.

2351
01:25:08,689 --> 01:25:12,326
I'M ACTUALLY INSULIN-SENSITIVE.

2352
01:25:12,326 --> 01:25:14,428
I'M TYPE 2 DIABETIC PREDICTED

2353
01:25:14,428 --> 01:25:15,262
FROM MY GENOME.

2354
01:25:15,262 --> 01:25:17,464
I ACTUALLY MAKE INSULIN, I DON'T

2355
01:25:17,464 --> 01:25:18,999
RELEASE IT FROM THE PANCREAS.

2356
01:25:18,999 --> 01:25:21,068
I'M A METFORMIN NON-RESPONDER AS

2357
01:25:21,068 --> 01:25:22,269
WELL, BUT I RESPOND TO CERTAIN

2358
01:25:22,269 --> 01:25:24,905
DRUGS BUT NOT OTHERS, AGAIN,

2359
01:25:24,905 --> 01:25:25,872
PREDICTED BECAUSE I HAVE THE

2360
01:25:25,872 --> 01:25:26,306
RIGHT DATA.

2361
01:25:26,306 --> 01:25:29,643
SO WE THINK THAT'S MORE

2362
01:25:29,643 --> 01:25:30,944
IMPORTANT THAN CLASSIFYING TYPE

2363
01:25:30,944 --> 01:25:31,378
1, TYPE 2.

2364
01:25:31,378 --> 01:25:32,579
THAT IS IMPORTANT, YOU NEED TO

2365
01:25:32,579 --> 01:25:33,880
KNOW WHETHER YOU'RE MAKING

2366
01:25:33,880 --> 01:25:35,215
INSULIN OR NOT, BUT I THINK THE

2367
01:25:35,215 --> 01:25:36,617
MORE RELEVANT ISSUE IS WHAT'S

2368
01:25:36,617 --> 01:25:39,553
YOUR UNDERLYING DEFECT.

2369
01:25:39,553 --> 01:25:41,088
AND THAT ACCOUNTS FOR -- THAT'S

2370
01:25:41,088 --> 01:25:42,522
BY FAR THE MOST IMPORTANT THING

2371
01:25:42,522 --> 01:25:45,692
FOR CARRYING OUT PRECISION

2372
01:25:45,692 --> 01:25:45,959
DIABETES.

2373
01:25:45,959 --> 01:25:46,360
>> THANK YOU.

2374
01:25:46,360 --> 01:25:48,762
THE OTHER QUESTION IS, SINCE

2375
01:25:48,762 --> 01:25:50,631
THERE COULD BE CONCERN WITH DATA

2376
01:25:50,631 --> 01:25:53,934
PRIVACY, WOU WITH SOME OF THIS

2377
01:25:53,934 --> 01:25:55,102
WEARABLE, AND DO YOU HAVE ANY

2378
01:25:55,102 --> 01:25:57,471
SPECIFIC COMMENTS ABOUT THAT?

2379
01:25:57,471 --> 01:25:59,373
>> PEOPLE DO WORRY ABOUT
THAT.

2380
01:25:59,373 --> 01:26:00,707
WE ARE AS SECURE AS POSSIBLE.

2381
01:26:00,707 --> 01:26:02,009
MY OWN PERSONAL VIEW IS THAT,

2382
01:26:02,009 --> 01:26:03,343
YOU KNOW, GET OVER IT, NOTHING

2383
01:26:03,343 --> 01:26:05,979
IS REALLY PRIVATE.

2384
01:26:05,979 --> 01:26:07,381
SO IF YOU THINK ABOUT WE ALL

2385
01:26:07,381 --> 01:26:11,118
HAVE CREDIT CARDS, WE ALL -- WE

2386
01:26:11,118 --> 01:26:12,552
DO THAT BECAUSE NOBODY WANTS TO

2387
01:26:12,552 --> 01:26:13,987
WALK AROUND WITH BAGS OF CASH.

2388
01:26:13,987 --> 01:26:15,589
CREDIT CARDS HAVE INCREDIBLY

2389
01:26:15,589 --> 01:26:16,056
PERSONAL INFORMATION.

2390
01:26:16,056 --> 01:26:17,257
I WOULD ARGUE MORE PERSONAL THAN

2391
01:26:17,257 --> 01:26:18,458
YOUR HEART RATE.

2392
01:26:18,458 --> 01:26:19,793
HEART RATE VARIABILITY THAT

2393
01:26:19,793 --> 01:26:23,497
PEOPLE CARE ABOUT.

2394
01:26:23,497 --> 01:26:24,798
SO BUT IN SPITE OF MY FLIP

2395
01:26:24,798 --> 01:26:26,066
ANSWER, WE DO TRY TO BE SECURE.

2396
01:26:26,066 --> 01:26:28,869
I DON'T THINK ANYBODY SHOULD BE

2397
01:26:28,869 --> 01:26:30,737
DISCRIMINATED AGAINST ON

2398
01:26:30,737 --> 01:26:31,405
PRE-EXISTING CONDITIONS SO I

2399
01:26:31,405 --> 01:26:32,839
THINK WE NEED A PROPER

2400
01:26:32,839 --> 01:26:33,473
HEALTHCARE SYSTEM THAT TAKES

2401
01:26:33,473 --> 01:26:36,243
CARE OF PEOPLE SO THAT YOU

2402
01:26:36,243 --> 01:26:37,844
AREN'T ABUSED BECAUSE SOME OF

2403
01:26:37,844 --> 01:26:40,147
YOUR DATA DOES GET OUT THERE IF

2404
01:26:40,147 --> 01:26:43,150
SOMEONE WERE TO EVER HACK IT.

2405
01:26:43,150 --> 01:26:44,117
>> OKAY.

2406
01:26:44,117 --> 01:26:47,387
THE OTHER QUESTION IS, IT SAYS

2407
01:26:47,387 --> 01:26:48,722
GREAT TALK WITH SO MUCH DATA,

2408
01:26:48,722 --> 01:26:53,060
DON'T YOU WORRY ABOUT

2409
01:26:53,060 --> 01:26:53,360
OVERFITTING?

2410
01:26:53,360 --> 01:26:54,895
>> WE HAVE TO CORRECT FOR
THAT,

2411
01:26:54,895 --> 01:26:56,697
WE HAVE TO MAKE SURE WE'RE

2412
01:26:56,697 --> 01:26:57,464
STATISTICALLY VALID.

2413
01:26:57,464 --> 01:26:58,331
THAT'S A GOOD QUESTION.

2414
01:26:58,331 --> 01:27:00,300
AND MANY OF OUR STUDIES, AND

2415
01:27:00,300 --> 01:27:02,035
WE'LL ALSO HAVE AN INDEPENDENT

2416
01:27:02,035 --> 01:27:03,570
COHORT, THAT'S HARD TO DO FOR A

2417
01:27:03,570 --> 01:27:06,406
STUDY LIKE THIS WHERE VERY, VERY

2418
01:27:06,406 --> 01:27:07,674
DETAILED MEASUREMENTS ON PEOPLE,

2419
01:27:07,674 --> 01:27:11,244
BUT WE DO TRY TO ALSO FIND

2420
01:27:11,244 --> 01:27:12,612
ORTHOGONAL WAYS OF VALIDATING

2421
01:27:12,612 --> 01:27:14,848
YOUR RESULTS, BUT STATISTICALLY

2422
01:27:14,848 --> 01:27:16,516
SPEAKING, WE'RE VERY CAREFUL.

2423
01:27:16,516 --> 01:27:19,553
THE LONGITUDAL ANALYSES TEND TO

2424
01:27:19,553 --> 01:27:20,654
BE VERY SOPHISTICATED.

2425
01:27:20,654 --> 01:27:23,290
YOU GET A LOT OF POWER OUT OF

2426
01:27:23,290 --> 01:27:23,824
LONGITUDAL.

2427
01:27:23,824 --> 01:27:24,825
PEOPLE DON'T APPRECIATE THAT.

2428
01:27:24,825 --> 01:27:26,893
YOU GET WAY, WAY MORE POWER BY

2429
01:27:26,893 --> 01:27:28,962
TRACKING THE SAME PERSON AND

2430
01:27:28,962 --> 01:27:30,297
SEEING DISEASE SHIFTS THAT WAY

2431
01:27:30,297 --> 01:27:31,832
THAN YOU DO FROM CASE CONTROL

2432
01:27:31,832 --> 01:27:32,699
STUDIES.

2433
01:27:32,699 --> 01:27:34,468
BECAUSE IT'S VERY EASY -- THE

2434
01:27:34,468 --> 01:27:35,769
DIFFERENCES BETWEEN PEOPLE, I

2435
01:27:35,769 --> 01:27:38,305
DIDN'T PRESENT THIS, IS GREATER

2436
01:27:38,305 --> 01:27:40,474
THAN THE DIFFERENCE BETWEEN A

2437
01:27:40,474 --> 01:27:42,442
HEALTHY PERSON AND -- A PERSON

2438
01:27:42,442 --> 01:27:43,543
WHEN THEY'RE HEALTHY AND WHEN

2439
01:27:43,543 --> 01:27:44,411
THEY'RE ILL.

2440
01:27:44,411 --> 01:27:46,613
SO IT'S EASY TO TELL WHEN YOU'RE

2441
01:27:46,613 --> 01:27:47,714
GETTING ILL BY SEEING A SHIFT

2442
01:27:47,714 --> 01:27:49,249
FROM YOUR BASELINE, IT'S HARD TO

2443
01:27:49,249 --> 01:27:51,752
TELL BY COMPARING IT WITH 500

2444
01:27:51,752 --> 01:27:52,619
OTHER HEALTHY PEOPLE.

2445
01:27:52,619 --> 01:27:55,288
SO THIS IDEA OF SEEING SHIFTS,

2446
01:27:55,288 --> 01:27:56,656
THAT'S HUGE, PEOPLE DON'T REALLY

2447
01:27:56,656 --> 01:27:57,224
APPRECIATE THAT.

2448
01:27:57,224 --> 01:27:59,292
YOU CAN GET VERY ROBUST

2449
01:27:59,292 --> 01:28:03,363
STATISTICS ON A SINGLE PERSON.

2450
01:28:03,363 --> 01:28:05,899
>> SO ONE LAST QUESTION,
TWO

2451
01:28:05,899 --> 01:28:06,733
MINUTES, THERE ARE SOME OTHER

2452
01:28:06,733 --> 01:28:07,868
FUN QUESTIONS INCLUDING ABOUT

2453
01:28:07,868 --> 01:28:10,370
BEER.

2454
01:28:10,370 --> 01:28:12,205
SO SOMEBODY ACTUALLY MADE A

2455
01:28:12,205 --> 01:28:17,144
CONNECTION BETWEEN YOUR TALK AND

2456
01:28:17,144 --> 01:28:19,780
DR. FERRUCCI AND THAT WAS THE

2457
01:28:19,780 --> 01:28:20,747
RESILIENCE.

2458
01:28:20,747 --> 01:28:23,383
SO WHAT DO YOU THINK WE COULD

2459
01:28:23,383 --> 01:28:26,119
MEASURE WITH WEARABLES THAT

2460
01:28:26,119 --> 01:28:28,054
COULD REPORT RESILIENCE?

2461
01:28:28,054 --> 01:28:28,655
>> GREAT QUESTION.

2462
01:28:28,655 --> 01:28:30,056
I THINK GLUCOSE IS NUMBER ONE

2463
01:28:30,056 --> 01:28:32,159
THAT WE SHOULD BE MEASURING.

2464
01:28:32,159 --> 01:28:33,960
THAT'S OBVIOUSLY A SPECIAL

2465
01:28:33,960 --> 01:28:34,361
WEARABLE.

2466
01:28:34,361 --> 01:28:37,230
THE SMART WATCH, HEART RATE,

2467
01:28:37,230 --> 01:28:38,598
HEART RATE VARIABILITY EXTREMELY

2468
01:28:38,598 --> 01:28:39,633
ACCURATE OFF A SMART WATCH

2469
01:28:39,633 --> 01:28:39,900
ACTUALLY.

2470
01:28:39,900 --> 01:28:42,469
BUT YOU CAN ALSO GET SOMETHING

2471
01:28:42,469 --> 01:28:47,307
CALLED GALVONIC STRESS RESPONSE

2472
01:28:47,307 --> 01:28:48,809
WHICH IS A BIG DEAL THAT'S

2473
01:28:48,809 --> 01:28:49,910
CONDUCTED ON YOUR SKIN.

2474
01:28:49,910 --> 01:28:51,011
SKIN TEMPERATURE, YOU CAN GET.

2475
01:28:51,011 --> 01:28:53,647
ALL THOSE ARE PRETTY IMPORTANT.

2476
01:28:53,647 --> 01:28:57,217
AND SO PEOPLE HAVE G GOTTEN THER

2477
01:28:57,217 --> 01:28:58,251
AFIB PICKED UP FROM A SMART

2478
01:28:58,251 --> 01:28:58,451
WATCH.

2479
01:28:58,451 --> 01:28:59,886
SO I THINK ALL THOSE THINGS ARE

2480
01:28:59,886 --> 01:29:01,288
PRETTY POWERFUL.

2481
01:29:01,288 --> 01:29:02,389
AS I MENTIONED FROM THE MACHINE

2482
01:29:02,389 --> 01:29:04,157
LEARNING, WE CAN TELL PEOPLE'S

2483
01:29:04,157 --> 01:29:05,926
RED BLOOD CELL COUNTS WHICH IS

2484
01:29:05,926 --> 01:29:07,427
RELEVANT FOR ANEMIA,

2485
01:29:07,427 --> 01:29:08,228
DEHYDRATION, THINGS LIKE THIS,

2486
01:29:08,228 --> 01:29:09,462
SO YOU CAN GET A TON OF STUFF

2487
01:29:09,462 --> 01:29:10,297
FROM A SMART WATCH.

2488
01:29:10,297 --> 01:29:11,198
IT'S A NO-BRAINER.

2489
01:29:11,198 --> 01:29:12,632
ALL STUDIES GOING FORWARD SHOULD

2490
01:29:12,632 --> 01:29:14,601
HAVE A SMART WATCH, OR SMART

2491
01:29:14,601 --> 01:29:16,002
RING, IN MY OPINION.

2492
01:29:16,002 --> 01:29:19,940
AND SLEEP, I THINK IS A BIGGIE.

2493
01:29:19,940 --> 01:29:21,041
SLEEP MEASUREMENTS ARE NOT

2494
01:29:21,041 --> 01:29:21,374
ACCURATE.

2495
01:29:21,374 --> 01:29:22,909
DURATION IS REASONABLE,

2496
01:29:22,909 --> 01:29:24,010
SOMETHING CALLED LATENCY WHEN

2497
01:29:24,010 --> 01:29:27,414
YOU FALL ASLEEP, AN ALSO --

2498
01:29:27,414 --> 01:29:28,715
WHAT'S THE OTHER ONE?

2499
01:29:28,715 --> 01:29:30,350
OH, RESTLESSNESS.

2500
01:29:30,350 --> 01:29:32,018
THOSE ARE ACCURATE.

2501
01:29:32,018 --> 01:29:33,119
REM, DEEP SLEEP, THEY'RE NOT

2502
01:29:33,119 --> 01:29:33,954
VERY ACCURATE FROM A SMART

2503
01:29:33,954 --> 01:29:34,521
WATCH.

2504
01:29:34,521 --> 01:29:36,156
BUT THEY'RE MEASURING SOMETHING,

2505
01:29:36,156 --> 01:29:37,591
IT'S JUST NOT CLEAR WHAT THEY

2506
01:29:37,591 --> 01:29:37,757
ARE.

2507
01:29:37,757 --> 01:29:39,526
BUT THE OTHER THINGS ARE PRETTY

2508
01:29:39,526 --> 01:29:41,862
GOOD, AND I THINK IMPORTANT

2509
01:29:41,862 --> 01:29:42,395
TO -- YEAH.

2510
01:29:42,395 --> 01:29:43,363
>> THANK YOU VERY MUCH.

2511
01:29:43,363 --> 01:29:44,497
YEAH, SLEEP IS ALSO VERY

2512
01:29:44,497 --> 01:29:47,100
IMPORTANT TO OUR INSTITUTE.

2513
01:29:47,100 --> 01:29:52,239
WE HOST THE NATIONAL CE NATIONAR

2514
01:29:52,239 --> 01:29:52,639
SLEEP DISORDERS.

2515
01:29:52,639 --> 01:29:53,773
SO I WOULD ASK YOU TO PLEASE

2516
01:29:53,773 --> 01:29:54,975
ANSWER THE OTHER QUESTIONS IF

2517
01:29:54,975 --> 01:29:56,643
YOU CAN DURING THE BREAK.

2518
01:29:56,643 --> 01:30:00,647
WE ALSO ASK EVERYONE TO STAY ON.

2519
01:30:00,647 --> 01:30:03,083
THERE IS A LITTLE BREAK THAT'S

2520
01:30:03,083 --> 01:30:06,586
COMING UP.

2521
01:30:06,586 --> 01:30:09,456
DR. SNYDER WAS ASKED TO MODERATE

2522
01:30:09,456 --> 01:30:10,824
THE FOLLOWING SESSION.

2523
01:30:10,824 --> 01:30:13,059
THAT WOULD BE A GREAT SESSION,

2524
01:30:13,059 --> 01:30:16,930
AND YOU ALREADY HAVE I THINK THE

2525
01:30:16,930 --> 01:30:17,464
AGENDA.

2526
01:30:17,464 --> 01:30:18,665
SO WE'LL SEE YOU ON THE OTHER

2527
01:30:18,665 --> 01:30:19,099
SIDE.

2528
01:30:19,099 --> 01:30:22,802
I THINK THE BREAK IS UNTIL

2529
01:30:22,802 --> 01:30:24,771
11:10.

2530
01:30:24,771 --> 01:30:27,307
SO PLEASE GO GET A CUP OF COFFEE

2531
01:30:27,307 --> 01:30:31,912
OR A BIO BREAK OR JUST A FEW

2532
01:30:31,912 --> 01:30:33,880
STEPS, DANCING MAYBE.

2533
01:30:33,880 --> 01:30:35,515
DR. SNYDER WILL TELL US TO MOVE.

2534
01:30:35,515 --> 01:30:37,717
THANK YOU SO MUCH.

2535
01:30:37,717 --> 01:30:41,020
COME BACK.

2536
01:30:41,020 --> 01:30:46,159
I'M A PROGRAM DIRECTOR IN THE

2537
01:30:46,159 --> 01:30:46,859
NATIONAL CANCER INSTITUTE IN THE

2538
01:30:46,859 --> 01:30:48,995
DIVISION OF CANCER BIOLOGY.

2539
01:30:48,995 --> 01:30:51,631
I'M CO-CHAIR FOR THE SESSION

2540
01:30:51,631 --> 01:30:58,771
TOGETHER WITH DR. BIRAGYN.

2541
01:30:58,771 --> 01:31:00,440
>> GOOD MORNING, I'M FROM
THE

2542
01:31:00,440 --> 01:31:01,574
NATIONAL INSTITUTE ON AGING, AND

2543
01:31:01,574 --> 01:31:04,777
I'M CO-CHAIR.

2544
01:31:04,777 --> 01:31:07,981
>> IN SESSION 1, WE'LL
DISCUSS

2545
01:31:07,981 --> 01:31:11,050
QUESTIONS LIKE HOW DO WE AGE, DO

2546
01:31:11,050 --> 01:31:12,352
WE AGE DIFFERENTLY AND HOW THE

2547
01:31:12,352 --> 01:31:13,987
AGING PROCESS CAN INCREASE THE

2548
01:31:13,987 --> 01:31:15,755
RISK FOR DISEASES SUCH AS

2549
01:31:15,755 --> 01:31:18,157
CANCER, CARDIOVASCULAR,

2550
01:31:18,157 --> 01:31:22,095
NEURODEGENERATIVE DISEASES CH

2551
01:31:22,095 --> 01:31:23,296
EACH SPEAKER WILL HAVE 15

2552
01:31:23,296 --> 01:31:25,365
MINUTES, THERE WILL BE 2-MINUTE

2553
01:31:25,365 --> 01:31:27,033
MARK, TRY TO STAY IN YOUR TIME.

2554
01:31:27,033 --> 01:31:30,737
AFTER EACH SPEAKER, WE'LL HAVE E

2555
01:31:30,737 --> 01:31:31,938
END OF THE SESSION, THERE WILL

2556
01:31:31,938 --> 01:31:33,306
BE PANEL DISCUSSION WITH ALL THE

2557
01:31:33,306 --> 01:31:34,407
SPEAKERS.

2558
01:31:34,407 --> 01:31:35,708
PLEASE IF YOU WANT TO ASK A

2559
01:31:35,708 --> 01:31:40,413
QUESTION, PLEASE USE THE Q &

2560
01:31:40,413 --> 01:31:42,315
A -- ZOOM Q & A CHAT.

2561
01:31:42,315 --> 01:31:43,750
WITH THAT, I'M GOING TO GO AHEAD

2562
01:31:43,750 --> 01:31:45,685
AND TURN IT OVER TO OUR

2563
01:31:45,685 --> 01:31:47,453
MODERATOR, OUR FANTASTIC KEYNOTE

2564
01:31:47,453 --> 01:31:51,824
SPEAKER, DR. MICHAEL SNYDER.

2565
01:31:51,824 --> 01:31:52,492
>> GREAT.

2566
01:31:52,492 --> 01:31:54,193
WE'RE GOING TO JUMP RIGHT IN.

2567
01:31:54,193 --> 01:31:56,996
OUR FIRST SPEAKER IS PEGGY

2568
01:31:56,996 --> 01:31:58,531
GOODELL WHO WILL TAKE IT AWAY.

2569
01:31:58,531 --> 01:31:59,098
PEGGY.

2570
01:31:59,098 --> 01:32:04,804
>> ALL RIGHT.

2571
01:32:04,804 --> 01:32:05,571
THANK YOU VERY MUCH.

2572
01:32:05,571 --> 01:32:09,308
I'M JUST TRYING TO MAKE SURE

2573
01:32:09,308 --> 01:32:10,276
EVERYTHING IS SET UP FOR ME

2574
01:32:10,276 --> 01:32:10,710
HERE.

2575
01:32:10,710 --> 01:32:11,144
OKAY.

2576
01:32:11,144 --> 01:32:12,578
SLIDES ARE GOOD AND EVERYTHING,

2577
01:32:12,578 --> 01:32:15,114
I HOPE.

2578
01:32:15,114 --> 01:32:15,848
>> YOU'RE GOOD.

2579
01:32:15,848 --> 01:32:16,716
>> GOOD, THANKS.

2580
01:32:16,716 --> 01:32:18,051
IT'S REALLY A PLEASURE TO BE

2581
01:32:18,051 --> 01:32:20,353
HERE AND TO TALK TO YOU ABOUT

2582
01:32:20,353 --> 01:32:21,320
SOME OF THE THINGS THAT WE'RE

2583
01:32:21,320 --> 01:32:22,321
THINKING ABOUT IN THE LAB,

2584
01:32:22,321 --> 01:32:24,624
PARTICULARLY THE RELATIONSHIP

2585
01:32:24,624 --> 01:32:28,828
BETWEEN HEMATOLOGY, AGING AND

2586
01:32:28,828 --> 01:32:30,630
CANCER.

2587
01:32:30,630 --> 01:32:32,165
SO WHAT I REALLY WANT TO FOCUS

2588
01:32:32,165 --> 01:32:37,103
ON TODAY IS CLONAL HEMATOPEE EE

2589
01:32:37,103 --> 01:32:38,738
CYST, REALLY DISCOVERED LESS

2590
01:32:38,738 --> 01:32:39,672
THAN 10 YEARS AGO, SOMETHING

2591
01:32:39,672 --> 01:32:42,375
THAT WE'RE REALLY BEGINNING TO

2592
01:32:42,375 --> 01:32:42,675
UNDERSTAND.

2593
01:32:42,675 --> 01:32:43,943
SO I JUST WANT TO GET EVERYBODY

2594
01:32:43,943 --> 01:32:46,446
ON THE SAME PAGE.

2595
01:32:46,446 --> 01:32:49,348
SO IN YOUR STEM CELLS IN YOUR

2596
01:32:49,348 --> 01:32:50,616
BONE MARROW ARE CONSTANTLY

2597
01:32:50,616 --> 01:32:51,384
REGENERATING ALL THE CELLS OF

2598
01:32:51,384 --> 01:32:52,518
THE BLOOD AND YOU'VE PROBABLY

2599
01:32:52,518 --> 01:32:54,320
GOT A COUPLE HUNDRED THOUSAND

2600
01:32:54,320 --> 01:32:56,122
STEM CELLS THAT ARE REALLY

2601
01:32:56,122 --> 01:32:57,957
RESPONSIBLE THROUGHOUT YOUR

2602
01:32:57,957 --> 01:32:59,158
WHOLE LIFETIME TO GENERATE ALL

2603
01:32:59,158 --> 01:33:00,693
OF THOSE DIFFERENTIATED BLOOD

2604
01:33:00,693 --> 01:33:01,594
CELLS.

2605
01:33:01,594 --> 01:33:03,896
EACH OF THOSE STEM CELLS GAINS

2606
01:33:03,896 --> 01:33:05,765
ABOUT 10 MUTATIONS PER STEM CELL

2607
01:33:05,765 --> 01:33:09,168
PER YEAR.

2608
01:33:09,168 --> 01:33:10,470
ORIGINALLY WE WOULD HAVE THOUGHT

2609
01:33:10,470 --> 01:33:12,472
THAT THE WHOLE HEMATOPOIETIC

2610
01:33:12,472 --> 01:33:14,107
STEM CELL POPULATION WAS FAIRLY

2611
01:33:14,107 --> 01:33:15,208
HOMOGENEOUS BUT WE REALIZED WITH

2612
01:33:15,208 --> 01:33:17,243
THIS MUTATION ACCUMULATION THAT

2613
01:33:17,243 --> 01:33:19,846
THAT ALLOWS REALLY A GENERATION

2614
01:33:19,846 --> 01:33:21,481
OF ENORMOUS DIVERSITY WITHIN

2615
01:33:21,481 --> 01:33:22,448
THAT STEM CELL POOL.

2616
01:33:22,448 --> 01:33:25,585
AND IT TURNS OUT THAT THROUGHOUT

2617
01:33:25,585 --> 01:33:28,221
TIME, NA THOSE STEM CELLS NOW

2618
01:33:28,221 --> 01:33:29,088
SLIGHTLY DIFFERENT BECAUSE

2619
01:33:29,088 --> 01:33:30,423
THEY'VE ACCUMULATED ALL THESE

2620
01:33:30,423 --> 01:33:31,757
MUTATIONS PER YEAR START TO

2621
01:33:31,757 --> 01:33:35,228
COMPETE WITH EACH OTHER SO THAT

2622
01:33:35,228 --> 01:33:37,563
TOWARDS THE END OF LIFE YOU HAVE

2623
01:33:37,563 --> 01:33:38,865
SOME WINNING AND SOME LOSING

2624
01:33:38,865 --> 01:33:39,632
STEM CELLS.

2625
01:33:39,632 --> 01:33:40,733
SO THAT STEM CELL FIELD, IF YOU

2626
01:33:40,733 --> 01:33:42,902
WILL, IS MUCH, MUCH MORE SIMPLE.

2627
01:33:42,902 --> 01:33:46,539
SO A 70-YEAR-OLD HAS ABOUT 7 TO

2628
01:33:46,539 --> 01:33:51,811
10 CODING MUTATIONS PER STEM

2629
01:33:51,811 --> 01:33:54,847
CELL AND THAT CREATES THAT

2630
01:33:54,847 --> 01:33:57,150
SUBSTRATE FOR STEM CELL AND

2631
01:33:57,150 --> 01:33:58,151
COMPETITION AND REALLY IT'S THAT

2632
01:33:58,151 --> 01:33:59,552
OUTCOME OF COLLAPSED DIVERSITY

2633
01:33:59,552 --> 01:34:01,554
OF YOUR STEM CELL POOL THAT WE

2634
01:34:01,554 --> 01:34:05,625
CALL CLONAL HIGH SCHOOL.

2635
01:34:05,625 --> 01:34:06,392
 CLONAL HEMATOPOIESIS.

2636
01:34:06,392 --> 01:34:08,261
SO WHAT ARE THE CONSEQUENCES,

2637
01:34:08,261 --> 01:34:10,429
WHO REALLY CARES?

2638
01:34:10,429 --> 01:34:12,431
IT'S INEVITABLE IN EVERYBODY.

2639
01:34:12,431 --> 01:34:14,300
IF YOU SEQUENCE DEEPLY ENOUGH IN

2640
01:34:14,300 --> 01:34:16,702
YOUNG PEOPLE YOU WILL SEE IT.

2641
01:34:16,702 --> 01:34:18,571
BUT BY THE AGE OF 70 IT'S PRETTY

2642
01:34:18,571 --> 01:34:19,672
EASILY DETECTABLE IN EVERYBODY

2643
01:34:19,672 --> 01:34:21,207
AND BY THE TIME YOU'RE EVEN

2644
01:34:21,207 --> 01:34:22,208
OLDER, IF YOU LIVE LONG ENOUGH,

2645
01:34:22,208 --> 01:34:26,145
YOU WILL HAVE SIGNIFICANT

2646
01:34:26,145 --> 01:34:27,613
CLONES, ONE OR MORE CLONES THAT

2647
01:34:27,613 --> 01:34:28,915
YOU CAN SEE IN EVERYBODY.

2648
01:34:28,915 --> 01:34:30,650
SO THIS STATE OF CLONAL

2649
01:34:30,650 --> 01:34:31,984
HEMATOPOIESIS CONFERS ABOUT A

2650
01:34:31,984 --> 01:34:35,388
TENFOLD INCREASED RISK FOR

2651
01:34:35,388 --> 01:34:36,722
HEMATOLOGIC MALIGNANCY BUT ALSO

2652
01:34:36,722 --> 01:34:37,690
IT BEEN ASSOCIATED WITH ALL

2653
01:34:37,690 --> 01:34:39,225
CAUSE MORTALITY OF A WHOLE

2654
01:34:39,225 --> 01:34:41,227
VARIETY OF AGING ASSOCIATED

2655
01:34:41,227 --> 01:34:42,228
DISEASES, WHICH I'LL TOUCH ON IN

2656
01:34:42,228 --> 01:34:43,429
A MOMENT.

2657
01:34:43,429 --> 01:34:45,831
SO WHAT REALLY DRIVES CLONAL

2658
01:34:45,831 --> 01:34:46,365
HEMATOPOIESIS?

2659
01:34:46,365 --> 01:34:47,800
WELL, THOSE MUTATIONS THAT ARE

2660
01:34:47,800 --> 01:34:49,135
PICKED UP IN THE STEM CELLS,

2661
01:34:49,135 --> 01:34:51,370
SOME OF THEM CONFER A SELECTIVE

2662
01:34:51,370 --> 01:34:53,206
ADVANTAGE TO THE STEM CELL.

2663
01:34:53,206 --> 01:34:54,740
AND THERE'S 20 OR SO GENES THAT

2664
01:34:54,740 --> 01:34:56,809
WE'VE FOUND THAT ARE RECURRENTLY

2665
01:34:56,809 --> 01:34:59,212
MUTATED THAT REALLY PROMOTE THE

2666
01:34:59,212 --> 01:35:00,846
EXPANSION OF SOME OF THOSE STEM

2667
01:35:00,846 --> 01:35:03,416
CELL CLONES, AND SO THOSE 20 OR

2668
01:35:03,416 --> 01:35:06,352
SO MUTANT GENES ACCOUNT FOR MOST

2669
01:35:06,352 --> 01:35:07,253
CLONAL HEMATOPOIESIS, ALSO

2670
01:35:07,253 --> 01:35:08,588
SOMETIMES REFER TO IT AS C.H. IN

2671
01:35:08,588 --> 01:35:09,121
THE TALK.

2672
01:35:09,121 --> 01:35:10,623
AND YOU CAN GROUP THEM IN

2673
01:35:10,623 --> 01:35:11,090
VARIOUS GROUPS.

2674
01:35:11,090 --> 01:35:12,825
WE'RE NOT GOING TO GO INTO THIS

2675
01:35:12,825 --> 01:35:14,794
IN TOO MUCH DETAIL BUT THERE'S

2676
01:35:14,794 --> 01:35:16,229
EPIGENETIC REGULATORS, DNA

2677
01:35:16,229 --> 01:35:18,998
DAMAGE RESPONSE -- FACTORS AND

2678
01:35:18,998 --> 01:35:20,099
SOME OTHER CLASSES.

2679
01:35:20,099 --> 01:35:22,802
THESE ARE SOME OF THE AGING

2680
01:35:22,802 --> 01:35:23,603
ASSOCIATED DISEASES ASSOCIATED

2681
01:35:23,603 --> 01:35:24,203
WITH CLONAL HEMATOPOIESIS.

2682
01:35:24,203 --> 01:35:25,404
THESE ARE ALL PUBLISHED STUDIES

2683
01:35:25,404 --> 01:35:26,839
DONE BY A NUMBER OF GROUPS.

2684
01:35:26,839 --> 01:35:28,074
I HAVEN'T PUT THE CITATIONS ON

2685
01:35:28,074 --> 01:35:30,710
HERE AND HOPEFULLY YOU CAN SEE

2686
01:35:30,710 --> 01:35:32,345
THIS, I'M HAPPY TO SHARE THIS

2687
01:35:32,345 --> 01:35:33,980
SLIDE WITH PEOPLE LATER.

2688
01:35:33,980 --> 01:35:35,648
AND REALLY THERE'S JUST A WHOLE

2689
01:35:35,648 --> 01:35:38,284
SLEW OF THESE STUDIES THAT HAVE

2690
01:35:38,284 --> 01:35:40,920
TRIED TO SHOW THAT CLONAL

2691
01:35:40,920 --> 01:35:43,222
HEMATOPOIESIS CAN BE

2692
01:35:43,222 --> 01:35:46,292
STATISTICALLY LINKED TO THESE

2693
01:35:46,292 --> 01:35:47,026
AGING-ASSOCIATED DISEASES AND IN

2694
01:35:47,026 --> 01:35:48,261
THE MIDDLE, YOU'LL SEE SOME OF

2695
01:35:48,261 --> 01:35:49,929
THE MUTANT GENES THAT ARE

2696
01:35:49,929 --> 01:35:54,066
ASSOCIATED WITH THOSE STATES.

2697
01:35:54,066 --> 01:35:56,269
SO ONE OTHER THING I WANT TO

2698
01:35:56,269 --> 01:35:57,703
EMPHASIZE IS THAT ALTHOUGH I'M

2699
01:35:57,703 --> 01:35:59,905
MOSTLY FOCUSING ON THE BLOOD,

2700
01:35:59,905 --> 01:36:01,874
ALL TISSUES ARE KNOWN TO

2701
01:36:01,874 --> 01:36:03,075
ACCUMULATE THESE SOMATIC

2702
01:36:03,075 --> 01:36:04,176
MUTATIONS AND MOST EXPERIENCE

2703
01:36:04,176 --> 01:36:04,610
CLONAL EVOLUTION.

2704
01:36:04,610 --> 01:36:06,612
AND IT REALLY IS NOT UNDERSTOOD

2705
01:36:06,612 --> 01:36:08,481
AT THIS POINT, THE RELATIONSHIP,

2706
01:36:08,481 --> 01:36:10,783
THE CAUSE VERSUS THE CONSEQUENCE

2707
01:36:10,783 --> 01:36:13,853
OF AGING IS NOT CLEAR.

2708
01:36:13,853 --> 01:36:15,388
CERTAINLY THEY'RE A SUBSTRATE

2709
01:36:15,388 --> 01:36:17,023
FOR CANCER BUT THE DEGREE TO

2710
01:36:17,023 --> 01:36:18,224
WHICH THIS CONTRIBUTES TO AGING

2711
01:36:18,224 --> 01:36:19,325
ITSELF IS NOT YET CLEAR.

2712
01:36:19,325 --> 01:36:21,193
BUT REALLY EXCELLENT STUDIES

2713
01:36:21,193 --> 01:36:24,697
HAVE ALSO BEEN DONE IN THE SKIN,

2714
01:36:24,697 --> 01:36:25,998
ESOPHAGUS, COLON, UTERUS, LIVER

2715
01:36:25,998 --> 01:36:30,836
AND OTH OTHER TISSUES AS WELL.

2716
01:36:30,836 --> 01:36:33,339
THIS IS VERY, VERY NEW, BUT IS

2717
01:36:33,339 --> 01:36:34,307
SOMETHING THAT'S VERY IMPORTANT

2718
01:36:34,307 --> 01:36:35,341
THAT WE SHOULD THINK MORE ABOUT

2719
01:36:35,341 --> 01:36:37,009
IN THE FUTURE.

2720
01:36:37,009 --> 01:36:38,010
OKAY, SO BACK TO CLONAL

2721
01:36:38,010 --> 01:36:39,612
HEMATOPOIESIS.

2722
01:36:39,612 --> 01:36:41,914
SO WHAT ARE THE MECHANISMS

2723
01:36:41,914 --> 01:36:42,948
UNDERLYING CLONAL HEMATOPOIESIS?

2724
01:36:42,948 --> 01:36:44,450
I MENTIONED THESE MUTATIONS THAT

2725
01:36:44,450 --> 01:36:45,017
ACCUMULATE.

2726
01:36:45,017 --> 01:36:47,353
WE WERE INTERESTED IN

2727
01:36:47,353 --> 01:36:48,754
UNDERSTANDING HOW THESE

2728
01:36:48,754 --> 01:36:49,855
MUTATIONS AFFECT STEM CELL

2729
01:36:49,855 --> 01:36:50,423
FUNCTION.

2730
01:36:50,423 --> 01:36:52,391
WE WANTED INSIGHT INTO STEM CELL

2731
01:36:52,391 --> 01:36:53,926
BIOLOGY BUT ALSO UNDERSTANDING

2732
01:36:53,926 --> 01:36:55,761
HOW IT AFFECTS AGING AND CANCER.

2733
01:36:55,761 --> 01:36:58,898
SO WHEN YOU THENG ABOUT IT, THE

2734
01:36:58,898 --> 01:36:59,865
UNDERLYING PRINCIPLE OF CLONAL

2735
01:36:59,865 --> 01:37:01,300
HEMATOPOIESIS IS THIS

2736
01:37:01,300 --> 01:37:01,867
COMPETITION AMONG THE STEM

2737
01:37:01,867 --> 01:37:02,168
CELLS.

2738
01:37:02,168 --> 01:37:05,571
SO WHY DOES A PARTICULAR

2739
01:37:05,571 --> 01:37:06,906
MUTATION MAKE ONE VARIANT STEM

2740
01:37:06,906 --> 01:37:08,841
CELL BETTER THAN ALL THOSE OTHER

2741
01:37:08,841 --> 01:37:09,608
200,000 STEM CELLS IN THE

2742
01:37:09,608 --> 01:37:10,409
INITIAL POOL?

2743
01:37:10,409 --> 01:37:12,278
IT'S ALSO IMPORTANT TO CONSIDER

2744
01:37:12,278 --> 01:37:13,913
THAT ENVIRONMENTAL CONDITIONS

2745
01:37:13,913 --> 01:37:16,215
MATTER AND MUTATION IN ONE

2746
01:37:16,215 --> 01:37:18,184
INDIVIDUAL MAY NOT HAVE THE SAME

2747
01:37:18,184 --> 01:37:19,418
ADVANTAGE AS ANOTHER INDIVIDUAL,

2748
01:37:19,418 --> 01:37:21,053
AND WE REALLY THINK ABOUT THIS

2749
01:37:21,053 --> 01:37:25,124
IN A DARWINIAN SENSE THAT THE

2750
01:37:25,124 --> 01:37:28,194
MUTATIONS MAKE A BIRD SURVIVE

2751
01:37:28,194 --> 01:37:30,062
BETTER UNDER CERTAIN FOOD

2752
01:37:30,062 --> 01:37:31,597
CONDITIONS AND NOT SO MUCH UNDER

2753
01:37:31,597 --> 01:37:33,666
OTHER FOOD CONDITIONS SO THIS IS

2754
01:37:33,666 --> 01:37:34,867
SUSTAINED WITH THESE MUTATIONS

2755
01:37:34,867 --> 01:37:35,434
AND STEM CELLS.

2756
01:37:35,434 --> 01:37:38,270
THESE MUTATIONS, THESE 20 OR SO

2757
01:37:38,270 --> 01:37:40,139
MUTATIONS MIGHT HAVE COMMON

2758
01:37:40,139 --> 01:37:40,906
STRATEGIES FOR MAKING A STEM

2759
01:37:40,906 --> 01:37:41,240
CELL.

2760
01:37:41,240 --> 01:37:43,342
THEY COULD BE BASED ON SURVIVAL

2761
01:37:43,342 --> 01:37:44,443
PROLIFERATION, BUT THE IMPORTANT

2762
01:37:44,443 --> 01:37:46,545
THING IS THIS IS A MARATHON AND

2763
01:37:46,545 --> 01:37:48,080
NOT A SPRINT, SO A SMALL

2764
01:37:48,080 --> 01:37:50,783
ADVANTAGE PAYS OFF.

2765
01:37:50,783 --> 01:37:51,917
WE'RE TALKING ABOUT AGING OVER

2766
01:37:51,917 --> 01:37:53,652
THE LIFESPAN OF AN INDIVIDUAL

2767
01:37:53,652 --> 01:37:55,521
70, 80, NIEP TI YEARS, SO

2768
01:37:55,521 --> 01:37:56,856
ADVANTAGES OF STEM CELLS ARE NOT

2769
01:37:56,856 --> 01:37:59,692
SPRINTING ADVANTAGES, THEY ARE

2770
01:37:59,692 --> 01:38:00,593
REALLY LONG TERM ADVANTAGES THAT

2771
01:38:00,593 --> 01:38:02,228
ALLOW THAT STEM CELL TO WIN OVER

2772
01:38:02,228 --> 01:38:04,563
THAT LONG PERIOD OF TIME.

2773
01:38:04,563 --> 01:38:07,500
SO IN MY LAB, WE'VE STUDIED THE

2774
01:38:07,500 --> 01:38:08,934
WINNING STRATEGIES OF THREE

2775
01:38:08,934 --> 01:38:10,002
VARIANT GENES AND WE DON'T HAVE

2776
01:38:10,002 --> 01:38:12,037
MUCH TIME TODAY SO I'M GOING TO

2777
01:38:12,037 --> 01:38:13,205
JUST EXTREMELY BRIEFLY TOUCH ON

2778
01:38:13,205 --> 01:38:15,741
THREE OF THESE TO SHOW YOU HOW

2779
01:38:15,741 --> 01:38:16,876
THEY'RE SIMILAR AND DIFFERENT

2780
01:38:16,876 --> 01:38:18,110
FROM EACH OTHER AND HOW

2781
01:38:18,110 --> 01:38:20,713
DIFFERENT WINNING STRATEGIES CAN

2782
01:38:20,713 --> 01:38:21,013
PREVAIL.

2783
01:38:21,013 --> 01:38:23,349
SO ONE OF THE FIRST ONES THAT WE

2784
01:38:23,349 --> 01:38:25,317
STUDIED IS CALLED PPM1D.

2785
01:38:25,317 --> 01:38:26,318
IT WAS INTERESTING BECAUSE IT

2786
01:38:26,318 --> 01:38:27,953
REALLY HAD NEVER BEEN STUDIED IN

2787
01:38:27,953 --> 01:38:29,955
THE BLOOD SYSTEM BEFORE.

2788
01:38:29,955 --> 01:38:32,892
SO WE THOUGHT WHAT IS THIS

2789
01:38:32,892 --> 01:38:35,194
INTERESTING GENE DOING?

2790
01:38:35,194 --> 01:38:36,762
PPM1D IS COMMONLY SEEN IN CLONAL

2791
01:38:36,762 --> 01:38:37,096
HEMATOPOIESIS.

2792
01:38:37,096 --> 01:38:38,831
IT COMES UP IN ALL THESE

2793
01:38:38,831 --> 01:38:39,331
STUDIES.

2794
01:38:39,331 --> 01:38:40,699
IT TURNS OUT IT'S A NEGATIVE

2795
01:38:40,699 --> 01:38:43,002
REGULATOR OF P53.

2796
01:38:43,002 --> 01:38:44,403
P53, WE KNOW IS THE MASTER

2797
01:38:44,403 --> 01:38:47,239
REGULATOR OF MANY THINGS, OF

2798
01:38:47,239 --> 01:38:49,475
GENOME STABILITY, MANY ASPECTS

2799
01:38:49,475 --> 01:38:51,243
OF THAT.

2800
01:38:51,243 --> 01:38:54,280
SO PPM1D PARTLY WORKS THROUGH

2801
01:38:54,280 --> 01:38:54,747
P53.

2802
01:38:54,747 --> 01:38:56,415
IT TURNS OUT THAT MOST OF THE

2803
01:38:56,415 --> 01:38:59,151
MUTATIONS IN PPM1D IN CLONAL

2804
01:38:59,151 --> 01:39:00,753
HEMATOPOIESIS ARE THE THREE

2805
01:39:00,753 --> 01:39:02,421
PRIME INTO THE GENE, THEY

2806
01:39:02,421 --> 01:39:03,522
TRUNCATE THE GENE AND YOU END UP

2807
01:39:03,522 --> 01:39:05,191
WITH A TRUNCATED PROTEIN THAT'S

2808
01:39:05,191 --> 01:39:08,360
HIGHLY STABLE.

2809
01:39:08,360 --> 01:39:12,965
SO THAT STABLE PPM1D IS A

2810
01:39:12,965 --> 01:39:14,467
REGULATOR OF P53 SO IT'S

2811
01:39:14,467 --> 01:39:16,168
CONSTANTLY THERE, NOW AT A HIGH

2812
01:39:16,168 --> 01:39:17,036
LEVEL, ALWAYS SUPPRESSING THE

2813
01:39:17,036 --> 01:39:19,238
ACTIVITY OF P53.

2814
01:39:19,238 --> 01:39:21,841
SO IT SORT OF MIMICS A P53

2815
01:39:21,841 --> 01:39:23,709
KNOCKOUT OR KNOCKDOWN, IF YOU

2816
01:39:23,709 --> 01:39:25,144
WILL.

2817
01:39:25,144 --> 01:39:28,881
SO IF YOU STABILIZED PPM1D THIS

2818
01:39:28,881 --> 01:39:30,950
WAY, DO THOSE MUTANT STEM CELLS

2819
01:39:30,950 --> 01:39:32,485
HAVE AN ADVANTAGE IF YOU COMPETE

2820
01:39:32,485 --> 01:39:34,053
THEM HEAD TO HEAD IN A VEL

2821
01:39:34,053 --> 01:39:34,353
COMPETITION?

2822
01:39:34,353 --> 01:39:37,423
CELLCOMPETITION?

2823
01:39:37,423 --> 01:39:39,258
SO WE ESTABLISHED VARIOUS CELL

2824
01:39:39,258 --> 01:39:40,559
MODELS AND MOUSE MODELS TO TEST

2825
01:39:40,559 --> 01:39:41,660
THE COMPETITIVE ADVANTAGE OF

2826
01:39:41,660 --> 01:39:42,862
THESE MUTANT CELLS.

2827
01:39:42,862 --> 01:39:44,563
I'M JUST GOING TO FOCUS ON THE

2828
01:39:44,563 --> 01:39:45,831
IN VIVO DATA FROM THE MOUSE

2829
01:39:45,831 --> 01:39:47,233
MODEL, SO WE TOOK THESE MICE

2830
01:39:47,233 --> 01:39:49,935
THAT HAD OUR PPM1D MUTATION, WE

2831
01:39:49,935 --> 01:39:50,903
TOOK STEM CELLS OUT AND WE

2832
01:39:50,903 --> 01:39:52,905
COMPETED THEM HEAD TO HEAD WITH

2833
01:39:52,905 --> 01:39:55,207
WILD TYPE CELLS FROM ANOTHER

2834
01:39:55,207 --> 01:39:57,610
MOUSE, 20%, 80% RATIO,

2835
01:39:57,610 --> 01:39:58,811
TRANSPLANTED THEM INTO WILD TYPE

2836
01:39:58,811 --> 01:40:01,113
MICE AND WAITED OVER TIME, AND

2837
01:40:01,113 --> 01:40:03,349
WHETHER WE COMPETE WILD TYPE

2838
01:40:03,349 --> 01:40:04,884
VERSUS WILD TYPE OR MUTANT

2839
01:40:04,884 --> 01:40:05,751
VERSUS WILD TYPE, YOU CAN SEE

2840
01:40:05,751 --> 01:40:07,086
THE RED AND THE GREY BARS OVER

2841
01:40:07,086 --> 01:40:08,320
TIME.

2842
01:40:08,320 --> 01:40:10,155
THIS IS WEEKS POST TRANSPLANT.

2843
01:40:10,155 --> 01:40:11,257
THERE'S REALLY NO CHANGE.

2844
01:40:11,257 --> 01:40:13,926
SO UNDER NORMAL CONDITIONS, THE

2845
01:40:13,926 --> 01:40:15,261
PPM1D MUTANT CELLS ARE FINE, BUT

2846
01:40:15,261 --> 01:40:16,195
THEY HAVE NO COMPETITIVE

2847
01:40:16,195 --> 01:40:17,563
ADVANTAGE.

2848
01:40:17,563 --> 01:40:20,332
BUT AS SOON AS WE TREAT THE MICE

2849
01:40:20,332 --> 01:40:22,635
WITH A CHEMOTHERAPEUTIC AGENT,

2850
01:40:22,635 --> 01:40:24,370
IN THIS CASE CISPLATIN, THOSE

2851
01:40:24,370 --> 01:40:25,404
MUTANT CELLS TAKE OFF AND NOW

2852
01:40:25,404 --> 01:40:27,273
THEY HAVE A SPECIFIC SELECTIVE

2853
01:40:27,273 --> 01:40:28,374
ADVANTAGE.

2854
01:40:28,374 --> 01:40:30,676
LIKE THIS DARWINIAN CONTEXT.

2855
01:40:30,676 --> 01:40:32,444
AND WE CAN ALSO SEE THIS IN

2856
01:40:32,444 --> 01:40:34,513
HUMANS THAT HAVE BEEN EXPOSED TO

2857
01:40:34,513 --> 01:40:36,582
CHEMOTHERAPY, THEY TEND TO HAVE

2858
01:40:36,582 --> 01:40:39,785
MANY MORE OF THESE P PM1 DSMGHT

2859
01:40:39,785 --> 01:40:40,452
MU AT THAT PARTICULAR TIME

2860
01:40:40,452 --> 01:40:41,220
CLONES THAN INDIVIDUALS WHO ARE

2861
01:40:41,220 --> 01:40:41,654
NOT.

2862
01:40:41,654 --> 01:40:45,057
SO HOW DOES PPMD CONVEY THIS

2863
01:40:45,057 --> 01:40:47,359
ADVANTAGE IN WE TRY TO FIND A

2864
01:40:47,359 --> 01:40:48,127
PROLIFERATION DIFFERENCE,

2865
01:40:48,127 --> 01:40:49,562
VARIOUS DIFFERENT PARAMETERS.

2866
01:40:49,562 --> 01:40:50,796
THE MAJOR THING WE FOUND WAS A

2867
01:40:50,796 --> 01:40:53,399
TINY DIFFERENCE IN THEIR ABILITY

2868
01:40:53,399 --> 01:40:55,834
TO GO THROUGH CELL DEATH THROUGH

2869
01:40:55,834 --> 01:40:56,168
APOPTOSIS.

2870
01:40:56,168 --> 01:40:58,837
YOU CAN SEE IT WAS A 16%

2871
01:40:58,837 --> 01:40:59,471
DIFFERENCE, WHICH DOESN'T SEEM

2872
01:40:59,471 --> 01:41:01,774
LIKE MUCH BUT OVER YOUR LIFESPAN

2873
01:41:01,774 --> 01:41:03,075
WITH MULTIPLE INSULTS, YOU CAN

2874
01:41:03,075 --> 01:41:04,810
ACTUALLY HAVE A SMALL ADVANTAGE

2875
01:41:04,810 --> 01:41:07,713
AS I WAS REFERRING TO BEFORE AND

2876
01:41:07,713 --> 01:41:09,748
END UP WINNING AMONGST MANY OF

2877
01:41:09,748 --> 01:41:13,953
THE OTHER CELLS OVER TIME.

2878
01:41:13,953 --> 01:41:17,389
SO PPMD MUTANT CLONES THEY WIN

2879
01:41:17,389 --> 01:41:18,490
UNDER ADVERSE CONDITIONS.

2880
01:41:18,490 --> 01:41:20,859
HERE'S A LITTLE MARATHON BEING

2881
01:41:20,859 --> 01:41:23,762
TAKEN IN ANTARCTICA.

2882
01:41:23,762 --> 01:41:27,700
MOST OF THIS WORKS THROUGH P53.

2883
01:41:27,700 --> 01:41:29,668
ANOTHER GENE WE HAVE STUDIED

2884
01:41:29,668 --> 01:41:32,671
THAT WE THOUGHT MIGHT BE SIMILAR

2885
01:41:32,671 --> 01:41:36,709
IS SRCAPMECAP.

2886
01:41:36,709 --> 01:41:38,477
IT BRIDGES EPIGENETICS AND DNA

2887
01:41:38,477 --> 01:41:39,612
REPAIR SO IT WAS INTERESTING TO

2888
01:41:39,612 --> 01:41:41,246
US AS A CHROMATIN REMODELER.

2889
01:41:41,246 --> 01:41:45,117
ALSO HAD NOT BEEN STUDIED IN

2890
01:41:45,117 --> 01:41:45,651
HEMATOPOIETIC SYSTEM.

2891
01:41:45,651 --> 01:41:47,620
SO WE HAD SEEN SOME REPORTED

2892
01:41:47,620 --> 01:41:48,954
MUTATIONS IN THIS AND SO WE SORT

2893
01:41:48,954 --> 01:41:50,589
OF DID THE SAME THING THAT WE

2894
01:41:50,589 --> 01:41:52,157
HAD DONE WITH PPM1D.

2895
01:41:52,157 --> 01:41:54,793
WE MADE MUTANT CELL LINES AND

2896
01:41:54,793 --> 01:41:55,561
MUTANT MICE AND TRIED TO

2897
01:41:55,561 --> 01:42:00,532
UNDERSTAND WHAT THE PECK NISMS D

2898
01:42:00,532 --> 01:42:02,501
CONTEXTS WERE IN WHICH SRCAP

2899
01:42:02,501 --> 01:42:03,268
WOULD SHOW UP.

2900
01:42:03,268 --> 01:42:04,470
THERE'S SOME FLIPS IN THIS

2901
01:42:04,470 --> 01:42:06,372
SLIDE, BUT THE SHORT ANSWER IS

2902
01:42:06,372 --> 01:42:09,441
THAT SRCAP MUTATIONS SEEM TO

2903
01:42:09,441 --> 01:42:12,611
SHOW REDUCED DNA DAMAGE WITH

2904
01:42:12,611 --> 01:42:13,779
STRESS, ACTUALLY IT WAS OPPOSITE

2905
01:42:13,779 --> 01:42:16,448
FROM PPM1D WHICH SHOWED MORE DNA

2906
01:42:16,448 --> 01:42:20,386
DAMAGE AFTER STRESS.

2907
01:42:20,386 --> 01:42:21,387
AGAIN I'M NOT GOING TO GIVE YOU

2908
01:42:21,387 --> 01:42:22,621
THE WHOLE STORY THIS IS REALLY

2909
01:42:22,621 --> 01:42:23,589
JUST THE PUNCH LINE.

2910
01:42:23,589 --> 01:42:25,024
WE ACTUALLY HAVE A PAPER IN

2911
01:42:25,024 --> 01:42:26,558
PRESS ON THIS.

2912
01:42:26,558 --> 01:42:29,862
SRCAP LIKE PPM1D SHOWS THAT

2913
01:42:29,862 --> 01:42:33,565
THESE MUTATIONS ARE ADVANTAGEOUS

2914
01:42:33,565 --> 01:42:34,500
PARTICULARLY IN ADVERSITY, BUT

2915
01:42:34,500 --> 01:42:41,073
IN DIN DIFFERENT CONTEXTS SEEN H

2916
01:42:41,073 --> 01:42:42,508
P PM1D.

2917
01:42:42,508 --> 01:42:44,476
IT'S OTHER KINDS OF STRESSORS,

2918
01:42:44,476 --> 01:42:45,144
OTHERS AGENTS.

2919
01:42:45,144 --> 01:42:46,578
THE NORMAL FUNCTION OF SRCAP

2920
01:42:46,578 --> 01:42:48,647
SEEMS TO BE TO REPRESS THE DNA

2921
01:42:48,647 --> 01:42:49,748
DAMAGE RESPONSE AND THE STEM

2922
01:42:49,748 --> 01:42:51,417
CELL PROGRAM, AND SO WHEN IT'S

2923
01:42:51,417 --> 01:42:52,618
MUTATED, YOU GET BETTER STEM

2924
01:42:52,618 --> 01:42:55,587
CELLS, YOU GET BETTER DNA

2925
01:42:55,587 --> 01:42:56,355
REPAIR.

2926
01:42:56,355 --> 01:42:58,123
AND YOU GET EXPANSION OF STEM

2927
01:42:58,123 --> 01:43:00,259
CELLS AND YOU GET SOME MORE

2928
01:43:00,259 --> 01:43:01,226
LYMPHOID CELLS IN THE MICE AS

2929
01:43:01,226 --> 01:43:05,998
WELL.

2930
01:43:05,998 --> 01:43:13,605
SO ON TO MY FAVORITE GENE, D

2931
01:43:13,605 --> 01:43:14,807
DNMT3A.

2932
01:43:14,807 --> 01:43:17,109
WHAT WAS REMARKABLE TO US WHEN

2933
01:43:17,109 --> 01:43:19,178
CLONAL HEMATOPOIESIS WAS

2934
01:43:19,178 --> 01:43:21,947
DISCOVERED IS THAT DNMT3A WAS

2935
01:43:21,947 --> 01:43:23,582
THE MOST COMMON DRIVER OF CLONAL

2936
01:43:23,582 --> 01:43:24,349
HEMATOPOIESIS.

2937
01:43:24,349 --> 01:43:27,219
SO ABOUT 50% OF INDIVIDUALS IN

2938
01:43:27,219 --> 01:43:28,654
WHICH THERE'S AN IDENTIFIABLE

2939
01:43:28,654 --> 01:43:32,091
DRIVER HAVE CLEAR MUTATIONS IN

2940
01:43:32,091 --> 01:43:32,524
DNMT3A.

2941
01:43:32,524 --> 01:43:34,159
IT'S A DNA METHYL TRANS PHRASE,

2942
01:43:34,159 --> 01:43:37,463
IT CAN CHANGE THE METHYLATION

2943
01:43:37,463 --> 01:43:39,865
STATUS AT THE CPG DIE

2944
01:43:39,865 --> 01:43:40,866
NUCLEOTIDES SO WE'VE ALREADY

2945
01:43:40,866 --> 01:43:43,168
HEARD THAT THERE IS -- THAT DNA

2946
01:43:43,168 --> 01:43:45,270
METHYLATION CAN BE USED TO

2947
01:43:45,270 --> 01:43:48,340
MONITOR BIOLOGICAL AGE AND IT

2948
01:43:48,340 --> 01:43:49,975
COULD BE THAT SOME OF THESE

2949
01:43:49,975 --> 01:43:52,111
EPIGENETIC REGULATORS ARE PARTLY

2950
01:43:52,111 --> 01:43:54,480
UNDERLYING THAT.

2951
01:43:54,480 --> 01:43:56,482
SO HOW DO THESE MUTANT STEM

2952
01:43:56,482 --> 01:43:57,349
CELLS WIN?

2953
01:43:57,349 --> 01:43:58,250
THERE'S STILL A LOT OF WORK TO

2954
01:43:58,250 --> 01:43:59,451
BE DONE ON THAT BUT WE THINK

2955
01:43:59,451 --> 01:44:02,087
THAT THEY LARGELY WIN BECAUSE

2956
01:44:02,087 --> 01:44:03,956
THEY HAVE A BIAS TOWARDS MAKING

2957
01:44:03,956 --> 01:44:04,623
MORE STEM CELLS.

2958
01:44:04,623 --> 01:44:08,193
SO EVERY CELL DIVISION, SOME OF

2959
01:44:08,193 --> 01:44:10,629
THOSE DNMT3A MUTANT CELLS WILL

2960
01:44:10,629 --> 01:44:11,964
MAKE MORE STEM CELLS INSTEAD OF

2961
01:44:11,964 --> 01:44:13,365
GO ON TO DIFFERENTIATE, AND

2962
01:44:13,365 --> 01:44:14,800
AGAIN THAT SLIGHT BIAS, YOU'LL

2963
01:44:14,800 --> 01:44:15,901
END UP WITH MORE STEM CELLS IN

2964
01:44:15,901 --> 01:44:17,903
THE END AND YOU'LL END UP WITH

2965
01:44:17,903 --> 01:44:20,539
MORE DIFFERENTIATED CELLS IN THE

2966
01:44:20,539 --> 01:44:25,577
PERIPHERAL BLOOD.

2967
01:44:25,577 --> 01:44:27,446
WE'VE GONE ON TO STUDY IT IN A

2968
01:44:27,446 --> 01:44:29,848
LOT MORE DETAIL BECAUSE EVERYONE

2969
01:44:29,848 --> 01:44:31,917
ENDS UP WITH MUTANT CLONES, NOW

2970
01:44:31,917 --> 01:44:33,385
THERE'S LOTS AND LOTS OF DATA ON

2971
01:44:33,385 --> 01:44:34,486
THE MUTANT CLONES OUT THERE AND

2972
01:44:34,486 --> 01:44:36,021
THE SIZE OF THOSE CLONES IN

2973
01:44:36,021 --> 01:44:38,390
DIFFERENT INDIVIDUALS.

2974
01:44:38,390 --> 01:44:40,826
SO WE'VE STARTED TO DO

2975
01:44:40,826 --> 01:44:41,727
FUNCTIONAL GENOMICS ON SOME OF

2976
01:44:41,727 --> 01:44:42,694
THOSE MUTATIONS AND SHOWN THAT

2977
01:44:42,694 --> 01:44:43,962
SOME OF THOSE MUTATIONS ARE

2978
01:44:43,962 --> 01:44:44,696
ACTUALLY WORSE THAN OTHERS.

2979
01:44:44,696 --> 01:44:46,265
SO WE FOUND ABOUT A THIRD OF THE

2980
01:44:46,265 --> 01:44:48,534
MUTATIONS THAT MAKE THE PROTEIN

2981
01:44:48,534 --> 01:44:51,904
UNSTABLE, AND SO INDIVIDUALS

2982
01:44:51,904 --> 01:44:53,539
WITH AN UNSTABLE MUTANT

2983
01:44:53,539 --> 01:44:55,307
ESSENTIALLY HAVE SOMETHING LIKE

2984
01:44:55,307 --> 01:44:56,775
A HETEROZYGOUS LOSS OF FUNCTION,

2985
01:44:56,775 --> 01:44:59,611
THEY HAVE HALF THE AMOUNT OF

2986
01:44:59,611 --> 01:45:00,612
DNMT3A PROTEIN AS THEY WOULD

2987
01:45:00,612 --> 01:45:01,146
OTHERWISE.

2988
01:45:01,146 --> 01:45:02,214
THERE'S MANY OTHER MUTATIONS

2989
01:45:02,214 --> 01:45:03,482
THAT ARE STABLE THAT CAN CAUSE

2990
01:45:03,482 --> 01:45:04,583
DIFFERENT KINDS OF EFFECTS, BUT

2991
01:45:04,583 --> 01:45:08,987
YOU CAN CLASSIFY INDIVIDUALS

2992
01:45:08,987 --> 01:45:10,789
TOGETHER WHO HAVE 50% OF THIS

2993
01:45:10,789 --> 01:45:15,060
FUNCTIONAL PROTEIN.

2994
01:45:15,060 --> 01:45:17,796
THE BOTTOM LINE FOR ALL THAT IS

2995
01:45:17,796 --> 01:45:18,664
THAT INDIVIDUALS O.A.R.

2996
01:45:18,664 --> 01:45:19,998
INDIVIDUAL CELLS HAVE DIFFERENT

2997
01:45:19,998 --> 01:45:22,868
AMOUNTS OF DNMT3A ACTIVITY.

2998
01:45:22,868 --> 01:45:24,169
WE THINK THIS ACTIVITY REALLY

2999
01:45:24,169 --> 01:45:25,470
TRACKS VERY CLOSELY WITH THE

3000
01:45:25,470 --> 01:45:26,405
OUTPUT OF THE STEM CELLS AND

3001
01:45:26,405 --> 01:45:28,473
THAT AGAIN BACK TO THIS MARATHON

3002
01:45:28,473 --> 01:45:31,677
OR SPORTS ANALOGY, ANY REDUCTION

3003
01:45:31,677 --> 01:45:33,545
IN DNMT3A IS A PERFORMANCE

3004
01:45:33,545 --> 01:45:35,781
ENHANCER FOR THOSE STEM CELLS.

3005
01:45:35,781 --> 01:45:35,981
SO --

3006
01:45:35,981 --> 01:45:37,583
>> YOU HAVE 2 MINUTES
REMAINING.

3007
01:45:37,583 --> 01:45:39,251
>> THANK YOU.

3008
01:45:39,251 --> 01:45:40,819
DNMT3A IS THE MARATHONER THAT

3009
01:45:40,819 --> 01:45:42,621
ALWAYS WINS, REALLY, IN ALL

3010
01:45:42,621 --> 01:45:44,022
CONTEXTS.

3011
01:45:44,022 --> 01:45:44,356
OKAY.

3012
01:45:44,356 --> 01:45:47,693
SO I'VE TOLD YOU VERY BRIEFLY

3013
01:45:47,693 --> 01:45:48,460
ABOUT THREE DIFFERENT GENES THAT

3014
01:45:48,460 --> 01:45:49,461
ARE INVOLVED IN CLONAL

3015
01:45:49,461 --> 01:45:50,863
HEMATOPOIESIS AND THEY ALL HAVE

3016
01:45:50,863 --> 01:45:53,198
SLIGHTLY DIFFERENT STRATEGIES

3017
01:45:53,198 --> 01:45:53,999
FOR WINNING OVER TIME AND

3018
01:45:53,999 --> 01:45:56,068
PROBABLY ALL HAVE DIFFERENT

3019
01:45:56,068 --> 01:45:56,301
IMPACTS.

3020
01:45:56,301 --> 01:45:57,936
IN THE LAST MINUTE HERE, I JUST

3021
01:45:57,936 --> 01:46:00,939
WANT TO TOUCH ON SOME OF THE

3022
01:46:00,939 --> 01:46:02,341
OTHER REMAINING QUESTIONS FROM

3023
01:46:02,341 --> 01:46:03,909
HERE AND HOW THIS RELATES TO

3024
01:46:03,909 --> 01:46:07,012
AGING MORE BROADLY.

3025
01:46:07,012 --> 01:46:08,447
WE NEED TO CATALOG THE WINNING

3026
01:46:08,447 --> 01:46:10,649
CLONES, WE NEED TO UNDERSTAND

3027
01:46:10,649 --> 01:46:11,450
HOW CLONAL HEMATOPOIESIS

3028
01:46:11,450 --> 01:46:12,751
CONTRIBUTES TO CANCER AND AGING

3029
01:46:12,751 --> 01:46:13,986
AND UNDERSTAND IF THEY'RE ALL

3030
01:46:13,986 --> 01:46:15,187
EQUALLY BAD.

3031
01:46:15,187 --> 01:46:17,789
SO I THINK HOW THESE CONTRIBUTE

3032
01:46:17,789 --> 01:46:20,492
TO AGING IS REALLY THE RESEARCH

3033
01:46:20,492 --> 01:46:20,893
FRONTIER.

3034
01:46:20,893 --> 01:46:22,961
THERE'S BEEN A LOT OF DISCUSSION

3035
01:46:22,961 --> 01:46:25,631
ABOUT IT'S AN INFLAMMATORY

3036
01:46:25,631 --> 01:46:26,565
PROCESS, THE CLONES THEMSELVES

3037
01:46:26,565 --> 01:46:27,833
BECOME MORE INFLAMMATORY BUT

3038
01:46:27,833 --> 01:46:29,701
THEY'RE ALSO MORE SENSITIVE TO

3039
01:46:29,701 --> 01:46:31,703
INFLAMMATION AND THAT MAY

3040
01:46:31,703 --> 01:46:33,906
FURTHER DRIVE THEIR EXPANSION

3041
01:46:33,906 --> 01:46:35,674
AND THE EXPANSION OF THEIR

3042
01:46:35,674 --> 01:46:36,775
DOWNSTREAM CELLS AND THIS MAY BE

3043
01:46:36,775 --> 01:46:37,976
DIFFERENT FOR DIFFERENT CH

3044
01:46:37,976 --> 01:46:38,410
CLONES.

3045
01:46:38,410 --> 01:46:39,878
RECENTLY THERE WAS ONE PAPER

3046
01:46:39,878 --> 01:46:42,414
THAT SHOWED LOSS OF FUNCTION

3047
01:46:42,414 --> 01:46:45,484
MUTATION OF CH WITH DNMT3A

3048
01:46:45,484 --> 01:46:46,952
AND -- 2 ACCELERATED HEART

3049
01:46:46,952 --> 01:46:49,021
DISEASE, AND CONCORDANT WITH

3050
01:46:49,021 --> 01:46:50,122
MACROPHAGE PHENOTYPES, AND THE

3051
01:46:50,122 --> 01:46:53,625
OPPOSITE WAS SHOWN BY THE SAME

3052
01:46:53,625 --> 01:46:54,660
GROUP BUT DIFFERENT COMBINATION

3053
01:46:54,660 --> 01:46:55,627
OF PEOPLE THAT CLONAL

3054
01:46:55,627 --> 01:46:57,062
HEMATOPOIESIS MIGHT PROTECT FOR

3055
01:46:57,062 --> 01:46:59,031
ALZHEIMER'S IN SOME CASES.

3056
01:46:59,031 --> 01:47:00,365
OBVIOUSLY WE NEED ADDITIONAL

3057
01:47:00,365 --> 01:47:01,934
STUDIES AND I WILL JUST SAY THAT

3058
01:47:01,934 --> 01:47:03,335
THERE'S ONE FROM A COLLEAGUE AT

3059
01:47:03,335 --> 01:47:04,303
BAYLOR WHERE THEY'VE BEEN USING

3060
01:47:04,303 --> 01:47:06,271
A MOUSE MODEL TO ALSO LOOK AT

3061
01:47:06,271 --> 01:47:09,007
BOTH TE T2 AND DNMT3A IN AN

3062
01:47:09,007 --> 01:47:10,175
ALZHEIMER'S MODEL, AND THEY

3063
01:47:10,175 --> 01:47:11,410
FOUND OPPOSITE RESULTS FOR THESE

3064
01:47:11,410 --> 01:47:12,644
TWO.

3065
01:47:12,644 --> 01:47:17,449
SO DNMT3A HAD ONE OUTPUT AND TE

3066
01:47:17,449 --> 01:47:19,151
T2 HAD A DIFFERENT OUTPUT IN

3067
01:47:19,151 --> 01:47:20,819
TERMS OF EXACERBATING FEATURES.

3068
01:47:20,819 --> 01:47:23,488
SO CLEARLY THERE'S REALLY A LOT

3069
01:47:23,488 --> 01:47:24,623
MORE TO DO.

3070
01:47:24,623 --> 01:47:25,624
I THINK BECAUSE WE'RE OUT OF

3071
01:47:25,624 --> 01:47:26,692
TIME I REALLY WON'T TOUCH ON

3072
01:47:26,692 --> 01:47:26,925
THESE.

3073
01:47:26,925 --> 01:47:31,029
I CAN LEAVE THIS SLIDE UP AND WE

3074
01:47:31,029 --> 01:47:33,131
CAN TALK ABOUT WHAT THE KEY

3075
01:47:33,131 --> 01:47:33,932
RESEARCH GAPS ARE AND

3076
01:47:33,932 --> 01:47:34,599
OPPORTUNITIES, AND THANK YOU ALL

3077
01:47:34,599 --> 01:47:35,334
AGAIN FOR HAVING ME.

3078
01:47:35,334 --> 01:47:39,438
THANK YOU.

3079
01:47:39,438 --> 01:47:40,772
>> THANKS, PEGGY.

3080
01:47:40,772 --> 01:47:42,207
LET'S SEE WHAT QUESTIONS WE HAVE

3081
01:47:42,207 --> 01:47:45,243
HERE.

3082
01:47:45,243 --> 01:47:47,145
OKAY, LET'S START WITH THE ONE

3083
01:47:47,145 --> 01:47:52,050
IN THE Q & A.

3084
01:47:52,050 --> 01:47:56,355
NEGATIVE REGULATION -- AMPLY

3085
01:47:56,355 --> 01:47:57,956
FAKES FIXES DETECTED IN CH?

3086
01:47:57,956 --> 01:48:02,394
>> THAT'S GREAT QUESTION.

3087
01:48:02,394 --> 01:48:04,930
NOT SO FAR THAT I HAVE SEEN,

3088
01:48:04,930 --> 01:48:06,565
THEY HAVE NOT SHOWN UP YET.

3089
01:48:06,565 --> 01:48:09,568
SO YOU WOULD NEED, THOUGH, AN

3090
01:48:09,568 --> 01:48:10,769
ACTIVATION OF THAT, RIGHT?

3091
01:48:10,769 --> 01:48:13,939
THAT'S ESSENTIALLY WHAT THESE

3092
01:48:13,939 --> 01:48:15,874
PPM1D MUTATIONS DO, THEY

3093
01:48:15,874 --> 01:48:17,309
STABILIZE THE PROTEIN, YOU GET A

3094
01:48:17,309 --> 01:48:20,545
LOT MORE.

3095
01:48:20,545 --> 01:48:22,481
SO IF THERE'S A WAY TO MAKE IT

3096
01:48:22,481 --> 01:48:23,315
HYPERACTIVE, THOSE ARE THE

3097
01:48:23,315 --> 01:48:25,550
MUTATIONS YOU WOULD WANT TO LOOK

3098
01:48:25,550 --> 01:48:25,817
FOR.

3099
01:48:25,817 --> 01:48:26,752
>> GOT IT.

3100
01:48:26,752 --> 01:48:28,653
HOW ABOUT P53 ITSELF, WHILE

3101
01:48:28,653 --> 01:48:29,421
WE'RE ON THAT TOPIC?

3102
01:48:29,421 --> 01:48:30,956
>> THEY ARE QUITE COMMON

3103
01:48:30,956 --> 01:48:34,359
ACTUALLY IN CLONAL HEMATOPOI 

3104
01:48:34,359 --> 01:48:34,693
HEMATOPOIESIS.

3105
01:48:34,693 --> 01:48:34,860
YES.

3106
01:48:34,860 --> 01:48:37,696
AND THEY SHOW UP SORT OF SIDE BY

3107
01:48:37,696 --> 01:48:41,166
SIDE WITH PPM1D AND THEY'RE

3108
01:48:41,166 --> 01:48:42,768
POSITIVELY SELECTED FOR SO

3109
01:48:42,768 --> 01:48:43,468
PROBABLY ALMOST COMPETING WITH

3110
01:48:43,468 --> 01:48:44,636
EACH OTHER IN SOME CASES AS

3111
01:48:44,636 --> 01:48:46,738
WELL.

3112
01:48:46,738 --> 01:48:49,207
>> GOT IT.

3113
01:48:49,207 --> 01:48:50,075
MAYBE ONE MORE QUESTION.

3114
01:48:50,075 --> 01:48:51,176
GO AHEAD, ZORINA.

3115
01:48:51,176 --> 01:48:54,279
>> I WAS GOING TO ASK, WE
WERE

3116
01:48:54,279 --> 01:48:55,614
VERY EXCITED IN THE

3117
01:48:55,614 --> 01:48:57,482
CARDIOVASCULAR FIELD WHEN A FEW

3118
01:48:57,482 --> 01:49:01,553
YEARS BACK, THE DICHOTOMY

3119
01:49:01,553 --> 01:49:02,621
BETWEEN CANCER AND

3120
01:49:02,621 --> 01:49:04,322
CARDIOVASCULAR WAS ACTUALLY

3121
01:49:04,322 --> 01:49:06,291
PINNED ON THIS CLONAL

3122
01:49:06,291 --> 01:49:07,159
HEMATOPOIESIS, SO I WAS

3123
01:49:07,159 --> 01:49:07,926
WONDERING IF YOU HAD SOME

3124
01:49:07,926 --> 01:49:09,127
COMMENTS ABOUT THAT.

3125
01:49:09,127 --> 01:49:11,797
>> WELL, I THINK IT'S A
GREAT

3126
01:49:11,797 --> 01:49:12,064
QUESTION.

3127
01:49:12,064 --> 01:49:14,299
IT'S REALLY ONE OF THE BIG

3128
01:49:14,299 --> 01:49:15,634
FRONTIERS, I THINK, THAT WE NEED

3129
01:49:15,634 --> 01:49:17,536
TO LOOK AT SOME MORE.

3130
01:49:17,536 --> 01:49:19,404
NOW THERE'S BEEN ENOUGH STUDIES

3131
01:49:19,404 --> 01:49:21,907
THAT REALLY VALIDATED THIS

3132
01:49:21,907 --> 01:49:23,809
STATISTICAL LINK IN HUMANS

3133
01:49:23,809 --> 01:49:25,277
BETWEEN CLONAL HEMATOPOIESIS AND

3134
01:49:25,277 --> 01:49:26,111
CARDIOVASCULAR DISEASE.

3135
01:49:26,111 --> 01:49:27,546
BUT WE REALLY DO NOT UNDERSTAND

3136
01:49:27,546 --> 01:49:28,814
THE MECHANISMS.

3137
01:49:28,814 --> 01:49:31,983
WE DO NOT UNDERSTAND IF ALL

3138
01:49:31,983 --> 01:49:33,285
CLONAL HEMATOPOIESIS CLONES ARE

3139
01:49:33,285 --> 01:49:36,254
EQUALLY BAD IN PROMOTING

3140
01:49:36,254 --> 01:49:43,028
CARDIOVASCULAR DISEASE.

3141
01:49:43,028 --> 01:49:46,565
I THIF THINK STUDIES NEED TO BE.

3142
01:49:46,565 --> 01:49:47,899
SOME OF THE NEEDS OVER THE NEXT

3143
01:49:47,899 --> 01:49:49,234
FIVE YEARS WOULD BE LARGE SCALE

3144
01:49:49,234 --> 01:49:52,971
STUDIES OF THE MUTATIONS ACROSS

3145
01:49:52,971 --> 01:49:53,839
INDIVIDUALS AND ACCESSIBLE

3146
01:49:53,839 --> 01:49:56,942
TISSUES EVEN TO LOOK AT SOMATIC

3147
01:49:56,942 --> 01:49:57,209
MOSAICISM.

3148
01:49:57,209 --> 01:49:58,376
SOME OF THIS MIGHT BE ABLE TO BE

3149
01:49:58,376 --> 01:49:59,978
DONE IN EXISTING AGING COHORTS

3150
01:49:59,978 --> 01:50:08,787
TO REALLY LOOK AT THOSE LINKS.

3151
01:50:08,787 --> 01:50:09,521
LINKS.ANOTHER THING I WOULD LIKE

3152
01:50:09,521 --> 01:50:11,123
TO MENTION, IT'S SORT OF TOUCHED

3153
01:50:11,123 --> 01:50:12,124
ON BY HAVING THIS CONFERENCE IN

3154
01:50:12,124 --> 01:50:13,225
THE FIRST PLACE, IS THE CANCER

3155
01:50:13,225 --> 01:50:15,060
AND NON-CANCER RELEVANCE.

3156
01:50:15,060 --> 01:50:17,662
NIH AS WAS MENTIONED IN THE

3157
01:50:17,662 --> 01:50:19,164
BEGINNING LIKES TO BUCKET ALL OF

3158
01:50:19,164 --> 01:50:21,266
THESE DIFFERENT AGING-ASSOCIATED

3159
01:50:21,266 --> 01:50:22,734
DISEASES BUT THEY'RE CLEARLY

3160
01:50:22,734 --> 01:50:23,401
INTERTWINED AND I THINK THIS

3161
01:50:23,401 --> 01:50:25,270
REALLY OFFERS AN OPPORTUNITY TO

3162
01:50:25,270 --> 01:50:28,340
STUDY THEM TOGETHER.

3163
01:50:28,340 --> 01:50:29,608
AND CLONAL HEMATOPOIESIS IS

3164
01:50:29,608 --> 01:50:30,909
IMPLEMENTED IN BOTH.

3165
01:50:30,909 --> 01:50:32,777
>> THANK YOU.

3166
01:50:32,777 --> 01:50:34,513
>> PEGGY, I HAVE A
QUESTION.

3167
01:50:34,513 --> 01:50:36,548
SO YOU SHOWED THIS IMPRESSIVE

3168
01:50:36,548 --> 01:50:39,484
TABLE OF GENES IN CLONAL

3169
01:50:39,484 --> 01:50:40,051
HEMATOPOIESIS LINKED TO

3170
01:50:40,051 --> 01:50:40,685
DIFFERENT DISEASES.

3171
01:50:40,685 --> 01:50:42,454
DO YOU THINK THERE'S GOING TO BE

3172
01:50:42,454 --> 01:50:44,356
LIKE SPECIFIC MUTATION

3173
01:50:44,356 --> 01:50:45,223
SIGNATURES ASSOCIATED WITH

3174
01:50:45,223 --> 01:50:47,125
DISEASE?

3175
01:50:47,125 --> 01:50:50,162
>> WELL, I THINK IT'S
EARLY.

3176
01:50:50,162 --> 01:50:51,863
YOU KNOW, A LOT OF THESE STUDIES

3177
01:50:51,863 --> 01:50:53,832
HAVE NOT BEEN VERY LARGE, AND SO

3178
01:50:53,832 --> 01:50:55,367
IT'S BEEN DIFFICULT TO REALLY

3179
01:50:55,367 --> 01:50:56,134
PINPOINT IT.

3180
01:50:56,134 --> 01:50:57,736
SO FOR EXAMPLE, FOR THE HUMAN

3181
01:50:57,736 --> 01:50:59,171
ALZHEIMER'S STUDY THAT WAS DONE

3182
01:50:59,171 --> 01:51:04,276
THE A STANFORD LED BY SYD

3183
01:51:04,276 --> 01:51:05,243
JASWALL, FANTASTIC STUDY,

3184
01:51:05,243 --> 01:51:06,578
REALLY, REALLY GREAT, BUT THE

3185
01:51:06,578 --> 01:51:08,513
POWER WAS NOT ENOUGH TO REALLY

3186
01:51:08,513 --> 01:51:10,148
SAY WELL, IT WAS LINKED WITH

3187
01:51:10,148 --> 01:51:12,551
DNMT3A AND TET 2 OR A LOT OF

3188
01:51:12,551 --> 01:51:16,488
OTHER DETAILED ASPECTS OF THAT.

3189
01:51:16,488 --> 01:51:19,391
AND HOW THIS RELATES TO THE

3190
01:51:19,391 --> 01:51:20,926
METHYLATION CLOCK THAT HAS BEEN

3191
01:51:20,926 --> 01:51:25,530
DISCUSSED A LOT, YOU KNOW, IS

3192
01:51:25,530 --> 01:51:26,464
CLONAL HEMATOPOIESIS GOING TO BE

3193
01:51:26,464 --> 01:51:28,433
A BETTER OR WORSE MARKER OF

3194
01:51:28,433 --> 01:51:28,967
BIOLOGICAL AGING.

3195
01:51:28,967 --> 01:51:30,669
I THINK IT'S PROBABLY GOING TO

3196
01:51:30,669 --> 01:51:31,536
TRACK VERY CLOSELY WITH IT.

3197
01:51:31,536 --> 01:51:34,539
TALKING ABOUT MONITORING WITH

3198
01:51:34,539 --> 01:51:35,207
DR. SNYDER'S TALK.

3199
01:51:35,207 --> 01:51:36,308
I PERSONALLY THINK WE ALL SHOULD

3200
01:51:36,308 --> 01:51:37,676
BE MONITORED FOR CLONAL

3201
01:51:37,676 --> 01:51:38,643
HEMATOPOIESIS TOO AS WE GET

3202
01:51:38,643 --> 01:51:40,712
ABOVE A CERTAIN AGE BECAUSE WE

3203
01:51:40,712 --> 01:51:42,547
PROBABLY EVENTUALLY WILL

3204
01:51:42,547 --> 01:51:44,516
UNDERSTAND HOW IT TRACKS WITH

3205
01:51:44,516 --> 01:51:46,818
THESE RISKS, ALTHOUGH WE DON'T

3206
01:51:46,818 --> 01:51:47,986
REALLY UNDERSTAND IT RIGHT NOW,

3207
01:51:47,986 --> 01:51:50,689
BUT AS DR. SNYDER SAID, THE

3208
01:51:50,689 --> 01:51:52,557
LONGITUDAL MONITORING HAS

3209
01:51:52,557 --> 01:51:56,094
ENORMOUS VALUE.

3210
01:51:56,094 --> 01:51:58,730
>> PHIL, IF YOU DON'T MIND

3211
01:51:58,730 --> 01:52:00,732
WAITING FOR THE PANEL.

3212
01:52:00,732 --> 01:52:02,133
>> SURE, TO TALK ABOUT ALL
THOSE

3213
01:52:02,133 --> 01:52:02,367
THINGS.

3214
01:52:02,367 --> 01:52:03,368
>> OR POP IT IN THE Q
& A,

3215
01:52:03,368 --> 01:52:04,603
EITHER WAY.

3216
01:52:04,603 --> 01:52:05,870
WE BETTER KEEP MOVING.

3217
01:52:05,870 --> 01:52:06,972
SO THANK YOU FOR THE AWESOME

3218
01:52:06,972 --> 01:52:08,273
TALK THERE, PEGGY.

3219
01:52:08,273 --> 01:52:12,844
AND OUR NEXT SPEAKER IS ASHANI

3220
01:52:12,844 --> 01:52:13,245
WEERARATNA.

3221
01:52:13,245 --> 01:52:14,913
SORRY, I KNEW I'D STUMBLE OVER

3222
01:52:14,913 --> 01:52:15,347
THAT ONE.

3223
01:52:15,347 --> 01:52:17,148
APOLOGIES THERE.

3224
01:52:17,148 --> 01:52:19,784
AGE AGAINST THE MACHINE:  HOW

3225
01:52:19,784 --> 01:52:21,753
THE AGING MICRO ENENVIRONMENT

3226
01:52:21,753 --> 01:52:22,721
DRIVES TUMOR PROGRESSION.

3227
01:52:22,721 --> 01:52:25,056
TAKE IT AWAY, ASHANI.

3228
01:52:25,056 --> 01:52:25,957
>> HI, EVERYONE.

3229
01:52:25,957 --> 01:52:28,793
I HOPE YOU CAN HEAR ME OKAY.

3230
01:52:28,793 --> 01:52:29,261
>> YOU'RE GOOD.

3231
01:52:29,261 --> 01:52:31,196
>> I WILL TRY TO GET
THROUGH

3232
01:52:31,196 --> 01:52:33,565
THIS VERY QUICKLY.

3233
01:52:33,565 --> 01:52:35,700
AND PEGGY SET ME UP VERY NICELY

3234
01:52:35,700 --> 01:52:39,638
SAYING THAT THERE'S A LOT OF

3235
01:52:39,638 --> 01:52:41,206
INTERSECTIONS BETWEEN AGING AND

3236
01:52:41,206 --> 01:52:42,574
CANCER, SO HERE'S A SLIDE I WAS

3237
01:52:42,574 --> 01:52:45,310
ASKED TO PRESENT TO YOU, SO

3238
01:52:45,310 --> 01:52:46,378
HOPEFULLY YOU'LL ALL BE ON THE

3239
01:52:46,378 --> 01:52:47,879
SAME PAGE BY THE END OF THIS

3240
01:52:47,879 --> 01:52:48,747
PRESENTATION, AND UNDERSTAND

3241
01:52:48,747 --> 01:52:51,182
THAT THERE ARE BOTH COMMON ALES

3242
01:52:51,182 --> 01:52:52,584
BETWEEN AGING AND CANCER CELLS

3243
01:52:52,584 --> 01:52:56,154
AND THAT AGE CAN DRIVE TUMOR

3244
01:52:56,154 --> 01:52:57,689
PROGRESSION.

3245
01:52:57,689 --> 01:52:59,090
AS I'VE ALWAYS SAID, CANCER IS A

3246
01:52:59,090 --> 01:53:00,625
DISEASE OF AIMING AND WHEN I

3247
01:53:00,625 --> 01:53:02,460
WORKED AT THE NIA ALMOST A

3248
01:53:02,460 --> 01:53:03,428
DECADE AGO, THAT WAS FROWNED

3249
01:53:03,428 --> 01:53:04,095
UPON.

3250
01:53:04,095 --> 01:53:05,597
HOWEVER, FOR EVERY HUNDRED

3251
01:53:05,597 --> 01:53:06,898
PEOPLE DIAGNOSED WITH CANCER,

3252
01:53:06,898 --> 01:53:07,999
OVER 90% OF THEM ARE OVER THE

3253
01:53:07,999 --> 01:53:09,534
AGE OF 50, AND THIS IS ALSO TRUE

3254
01:53:09,534 --> 01:53:13,305
FOR THOSE WHO DIE OF CANCER FOR

3255
01:53:13,305 --> 01:53:17,342
ALL CANCERS COMBINED GLOBALLY.

3256
01:53:17,342 --> 01:53:19,778
THERE ARE MANY, MANY MOLECULAR

3257
01:53:19,778 --> 01:53:21,146
AND CELLULAR SIMILARITIES

3258
01:53:21,146 --> 01:53:23,048
BETWEEN CELLS THAT ARE AGING AND

3259
01:53:23,048 --> 01:53:24,215
CELLS THAT ARE CANCER CELLS.

3260
01:53:24,215 --> 01:53:25,750
WE HAVE THIS MAP OF THE

3261
01:53:25,750 --> 01:53:28,553
HALLMARKS OF CANCER THAT TALKS

3262
01:53:28,553 --> 01:53:29,521
ABOUT ALL OF THE DIFFERENT

3263
01:53:29,521 --> 01:53:31,523
FEATURES OF CANCER CELLS THAT

3264
01:53:31,523 --> 01:53:32,924
MAKE THEM CANCER CELLS.

3265
01:53:32,924 --> 01:53:34,426
WE SEE THE SAME THING WITH AGING

3266
01:53:34,426 --> 01:53:35,060
CELLS.

3267
01:53:35,060 --> 01:53:37,462
AND WE SEE THAT BETWEEN BOTH

3268
01:53:37,462 --> 01:53:39,130
AGING CELLS AND CANCER CELLS,

3269
01:53:39,130 --> 01:53:41,166
THERE ARE VERY -- THERE ARE LOTS

3270
01:53:41,166 --> 01:53:43,468
OF SIMILARITIES LIKE

3271
01:53:43,468 --> 01:53:44,436
METHYLATION, GENOMIC

3272
01:53:44,436 --> 01:53:45,637
INSTABILITY, CHANGES IN

3273
01:53:45,637 --> 01:53:46,805
METABOLISM, CHANGES IN

3274
01:53:46,805 --> 01:53:47,906
TELOMERES, ALTHOUGH IN THIS CASE

3275
01:53:47,906 --> 01:53:49,874
IN OPPOSITE DIRECTIONS, AS WELL

3276
01:53:49,874 --> 01:53:52,811
AS THE ONSET OF SENESCENCE IN

3277
01:53:52,811 --> 01:53:53,311
BOTH CONDITIONS.

3278
01:53:53,311 --> 01:53:55,180
THERE HAS BEEN SOME BEAUTIFUL

3279
01:53:55,180 --> 01:53:59,784
WORK DONE BY PEOPLE LIKE JOAO

3280
01:53:59,784 --> 01:54:02,854
PEDRO DE IS THE MAGALHAES AT THE

3281
01:54:02,854 --> 01:54:03,922
UNIVERSITY OF LIVERPOOL.

3282
01:54:03,922 --> 01:54:06,358
WHAT HE HAS DONE IS LOOK AT

3283
01:54:06,358 --> 01:54:08,226
MUTATIONS IN CANCER CELLS IN

3284
01:54:08,226 --> 01:54:09,661
MULTIPLE CANCER TYPES OVER THE

3285
01:54:09,661 --> 01:54:13,631
SPECTRUM OF AG AGING AND HE FINS

3286
01:54:13,631 --> 01:54:15,133
AN INCREASE IN GENOMIC STABILITY

3287
01:54:15,133 --> 01:54:18,503
AND THERE'S ALSO CRITICAL

3288
01:54:18,503 --> 01:54:21,573
CHANGES IN THESE SOMATIC COPY

3289
01:54:21,573 --> 01:54:24,609
NUMBER ALTERATIONS, AND THEY

3290
01:54:24,609 --> 01:54:26,578
OCCUR IN CANCER DRIVER GENES.

3291
01:54:26,578 --> 01:54:28,012
AGAIN, THEY INCREASE WITH AGE

3292
01:54:28,012 --> 01:54:30,048
AND THEY OCCUR OVER THE SPECTRUM

3293
01:54:30,048 --> 01:54:33,118
OF AGING AS WELL.

3294
01:54:33,118 --> 01:54:34,853
WE ALL KNEW IT'S NOT JUST AGING

3295
01:54:34,853 --> 01:54:36,821
BUT ALSO -- NOT JUST GENETICS

3296
01:54:36,821 --> 01:54:39,090
BUT ALSO EPIGENETICS.

3297
01:54:39,090 --> 01:54:41,393
PEOPLE LIKE JEAN-PIERRE AND

3298
01:54:41,393 --> 01:54:43,027
SHELLEY BERGER HAVE DONE A BUTTE

3299
01:54:43,027 --> 01:54:45,497
TESTIMONY JOB LOOKING AT

3300
01:54:45,497 --> 01:54:46,831
EPIGENETIC DRIFT WITH AGING AND

3301
01:54:46,831 --> 01:54:48,266
NOT HOW ONLY AGING BUT OTHER

3302
01:54:48,266 --> 01:54:49,768
FACTORS SUCH AS OBESITY AND

3303
01:54:49,768 --> 01:54:51,503
SMOKING CAN COMBINE TO DRIVING

3304
01:54:51,503 --> 01:54:53,471
EPIGENETIC DRIFT THAT LEADS TO

3305
01:54:53,471 --> 01:54:57,475
CHANGES IN CANCER CELLS.

3306
01:54:57,475 --> 01:55:02,614
HARI EASWARAN AT JOHNS HOPKINS

3307
01:55:02,614 --> 01:55:05,316
HAS ALSO MADE ORGANOIDS OUT OF

3308
01:55:05,316 --> 01:55:06,951
COLON CELLS, AND THESE ARE WILD

3309
01:55:06,951 --> 01:55:08,253
TYPE, THEY'RE NOT CANCER, AND HE

3310
01:55:08,253 --> 01:55:11,423
SHOWS THAT IF HE AGES THEM OVER

3311
01:55:11,423 --> 01:55:13,591
A YEAR TO A YEAR AND A HALF, HE

3312
01:55:13,591 --> 01:55:15,994
FINDS EPIGENETIC CHANGES THAT

3313
01:55:15,994 --> 01:55:18,463
OCCUR IN WNT GENES AND THAT

3314
01:55:18,463 --> 01:55:20,331
THESE EPIGENETIC CHANGES DRIVE

3315
01:55:20,331 --> 01:55:22,100
FURTHER MUTATIONS OR FURTHER

3316
01:55:22,100 --> 01:55:25,537
CHANGES, I SHOULD SAY, THAT LEAD

3317
01:55:25,537 --> 01:55:26,871
THESE NORMAL COLON CELLS TO

3318
01:55:26,871 --> 01:55:28,940
BECOME MORE AND MORE PRIMED TO

3319
01:55:28,940 --> 01:55:30,575
BECOME TUMOR CELLS.

3320
01:55:30,575 --> 01:55:33,578
MY GOOD FRIEND JAMES DEGREGORI

3321
01:55:33,578 --> 01:55:34,512
AT THE UNIVERSITY OF COLORADO

3322
01:55:34,512 --> 01:55:36,581
WHO YOU'LL HEAR FROM LATER IN

3323
01:55:36,581 --> 01:55:37,849
THIS SERIES HAS SUMMARIZED ALL

3324
01:55:37,849 --> 01:55:40,485
OF THIS QUITE BEAUTIFULLY INTO

3325
01:55:40,485 --> 01:55:43,455
THIS SPECTRUM OF CHANGES WITH

3326
01:55:43,455 --> 01:55:45,023
AGE, WHERE HE SHOWS THAT THERE

3327
01:55:45,023 --> 01:55:46,891
ARE CHANGES THAT OCCUR WHEN WE

3328
01:55:46,891 --> 01:55:48,560
ARE YOUNG THAT HAVE A

3329
01:55:48,560 --> 01:55:49,828
STABILIZING SELECTION SO, FOR

3330
01:55:49,828 --> 01:55:51,362
EXAMPLE, IF THERE'S GENETIC

3331
01:55:51,362 --> 01:55:52,897
DAMAGE AND MUTATIONS, THOSE STEM

3332
01:55:52,897 --> 01:55:54,065
CELLS ARE QUICKLY PURGED FROM

3333
01:55:54,065 --> 01:55:54,966
THE POOL.

3334
01:55:54,966 --> 01:55:57,769
BUT AS WE AGE, THERE BECOME AS

3335
01:55:57,769 --> 01:55:59,304
CHANGE THAT GOES FROM A

3336
01:55:59,304 --> 01:56:00,405
STABILIZING SELECTION TO A

3337
01:56:00,405 --> 01:56:03,341
POSITIVE SELECTION, POSITIVELY

3338
01:56:03,341 --> 01:56:08,580
EXCELLENTING CSELECTING THAT HAR

3339
01:56:08,580 --> 01:56:09,481
DRIVER MUTATIONS.

3340
01:56:09,481 --> 01:56:11,783
MY LAB HAS FOCUSED ON SOMETHING

3341
01:56:11,783 --> 01:56:12,383
ENTIRELY DIFFERENT.

3342
01:56:12,383 --> 01:56:15,119
WE'VE BEEN LOOKING AT THE TUMOR

3343
01:56:15,119 --> 01:56:15,653
MICROENVIRONMENT AND THE

3344
01:56:15,653 --> 01:56:17,155
QUESTION WE HAVE ASKED OURSELVES

3345
01:56:17,155 --> 01:56:18,823
IS, WHAT IS HAPPENING TO ALL

3346
01:56:18,823 --> 01:56:20,124
THOSE CELLS THAT ARE NOT CANCER

3347
01:56:20,124 --> 01:56:20,992
CELLS?

3348
01:56:20,992 --> 01:56:21,893
AS WE AGE.

3349
01:56:21,893 --> 01:56:23,695
AND SO, YOU KNOW, I LIKE TO SAW

3350
01:56:23,695 --> 01:56:25,430
NO TUMOR IS AN ISLAND, IT EXISTS

3351
01:56:25,430 --> 01:56:29,567
IN THIS MILIEU OF FIBROBLASTS

3352
01:56:29,567 --> 01:56:30,869
AND ENDOTHELIAL CELLS AND FAT

3353
01:56:30,869 --> 01:56:33,104
CELLS AS WELL AS THE BIOPHYSICAL

3354
01:56:33,104 --> 01:56:33,905
MATRICES THAT SOME OF THESE

3355
01:56:33,905 --> 01:56:34,973
CELLS CREATE.

3356
01:56:34,973 --> 01:56:37,275
WE HAVE FOCUSED LARGELY ON THE

3357
01:56:37,275 --> 01:56:41,279
FIBROBLAST POPULATION IN

3358
01:56:41,279 --> 01:56:42,280
MELANOMA, BECAUSE IT'S A CANCER

3359
01:56:42,280 --> 01:56:44,215
OF THE SKIN AND THE MELANOMA

3360
01:56:44,215 --> 01:56:46,050
CELL SPENDS MUCH OF ITS LIFE

3361
01:56:46,050 --> 01:56:47,485
RIGHT HERE AT THE EPIDERMIS AND

3362
01:56:47,485 --> 01:56:49,387
THE DERMIS BECOMING MALIGNANT

3363
01:56:49,387 --> 01:56:51,923
AND THE DERMIS IS LARGELY

3364
01:56:51,923 --> 01:56:53,992
INSTRUCTED BY THESE FIBROBLASTS

3365
01:56:53,992 --> 01:56:55,326
WHICH WE CALL THE CONSTRUCTION

3366
01:56:55,326 --> 01:56:56,628
WORKERS OF THE SKIN BECAUSE THEY

3367
01:56:56,628 --> 01:56:58,563
LAY DOWN ALL THE BIOPHYSICAL

3368
01:56:58,563 --> 01:56:59,564
SCAFFOLDS AND WE HAVE FOUND THAT

3369
01:56:59,564 --> 01:57:01,432
OVER TIME, THESE CHANGE AND

3370
01:57:01,432 --> 01:57:03,701
THOSE SCAFFOLDS CAN THEN FURTHER

3371
01:57:03,701 --> 01:57:07,305
CONTRIBUTE TO THE WAY TUMOR

3372
01:57:07,305 --> 01:57:08,907
CELLS MOVE THROUGH THIS DERMIS

3373
01:57:08,907 --> 01:57:11,142
TO BECOME METASTATIC.

3374
01:57:11,142 --> 01:57:12,610
THE QUESTION I'M OFTEN ASKED IS,

3375
01:57:12,610 --> 01:57:14,445
WELL, DON'T THESE FIBROBLASTS

3376
01:57:14,445 --> 01:57:17,215
TURN OVER, AND BEAUTIFUL WORK

3377
01:57:17,215 --> 01:57:18,950
FROM VAL TINA GRECO SHOWS

3378
01:57:18,950 --> 01:57:21,252
THERE'S A LOT OF FIBROBLAST

3379
01:57:21,252 --> 01:57:24,522
HOMEOSTASIS IN THE SKIN WHICH --

3380
01:57:24,522 --> 01:57:27,759
SO INSTEAD OF WHEN CELLS DIE OR

3381
01:57:27,759 --> 01:57:28,726
DURING AGING THAT ARE LOST,

3382
01:57:28,726 --> 01:57:30,261
INSTEAD OF THE OTHER CELLS

3383
01:57:30,261 --> 01:57:31,429
RAPIDLY PROLIFERATING TO FILL IN

3384
01:57:31,429 --> 01:57:32,430
THOSE GAPS, INSTEAD WHAT WE SEE

3385
01:57:32,430 --> 01:57:33,965
ARE THE EXISTING CELLS KIND OF

3386
01:57:33,965 --> 01:57:35,366
STRETCHING THEIR WAY IN TO THOSE

3387
01:57:35,366 --> 01:57:37,101
GAPS TO MAINTAIN THE POSITIONAL

3388
01:57:37,101 --> 01:57:41,139
STABILITY OF THESE FIBROBLASTS.

3389
01:57:41,139 --> 01:57:43,007
IN ADDITION, I'M OFTEN ASKED

3390
01:57:43,007 --> 01:57:45,710
ABOUT SENESCENCE, AND I HAVE, I

3391
01:57:45,710 --> 01:57:47,045
GUESS, A SOMEWHAT CONTROVERSIAL

3392
01:57:47,045 --> 01:57:48,479
VIEW ON SENESCENCE.

3393
01:57:48,479 --> 01:57:50,281
AGING AND SENESCENCE ARE OFTEN

3394
01:57:50,281 --> 01:57:50,548
CONFLATED.

3395
01:57:50,548 --> 01:57:51,883
THEY ARE NOT THE SAME THING.

3396
01:57:51,883 --> 01:57:52,817
WE SEE A LOT OF DIFFERENCE

3397
01:57:52,817 --> 01:57:55,019
BETWEEN OUR AGING FIBROBLASTS

3398
01:57:55,019 --> 01:57:57,055
AND SENESCENT FIBROBLASTS, AND

3399
01:57:57,055 --> 01:57:58,289
REMEMBER THAT SENESCENCE OCCURS

3400
01:57:58,289 --> 01:58:00,425
ACROSS THE LIFESPAN, EVEN IN

3401
01:58:00,425 --> 01:58:02,860
EMRYOGENESIS.

3402
01:58:02,860 --> 01:58:04,696
SO THERE ARE BEAUTIFUL REVIEWS

3403
01:58:04,696 --> 01:58:07,632
ON SENESCENCE, BUT I WOULD ADD

3404
01:58:07,632 --> 01:58:10,501
OF COURSE JUDY CAMPISI IS

3405
01:58:10,501 --> 01:58:11,903
ACTUALLY THE PERSON WHO INSPIRED

3406
01:58:11,903 --> 01:58:13,871
ME TO GO INTO ANY OF THE THIS

3407
01:58:13,871 --> 01:58:15,073
AGING FIBROBLAST WORK AS HER

3408
01:58:15,073 --> 01:58:16,574
WORK SHOWED SO BEAUTIFULLY THAT

3409
01:58:16,574 --> 01:58:18,876
THESE SENESCENT CELLS CAN DRIVE

3410
01:58:18,876 --> 01:58:19,544
TUMORIGENESIS.

3411
01:58:19,544 --> 01:58:21,012
BUT PLEASE REMEMBER NOT ALL

3412
01:58:21,012 --> 01:58:22,447
SENESCENCE IS CREATED EQUAL.

3413
01:58:22,447 --> 01:58:25,049
NOT ALL SENESCENCE IS TERMINAL.

3414
01:58:25,049 --> 01:58:27,318
AND AGING AND SENESCENCE ARE NOT

3415
01:58:27,318 --> 01:58:28,886
INTERCHANGEABLE.

3416
01:58:28,886 --> 01:58:32,390
SO HAVING SAID THAT, I KNOW MY

3417
01:58:32,390 --> 01:58:33,491
FRIEND SHE THAT STEWART IS ON

3418
01:58:33,491 --> 01:58:34,626
THIS CALL AND SHE ALWAYS ASKED

3419
01:58:34,626 --> 01:58:38,062
ME WHAT KIND OF FIBROBLASTS ARE

3420
01:58:38,062 --> 01:58:39,664
OUR AGING -- ARE AGING

3421
01:58:39,664 --> 01:58:40,331
FIBROBLASTS.

3422
01:58:40,331 --> 01:58:43,534
THE SIMPLE ANSWER IS THAT THEY

3423
01:58:43,534 --> 01:58:45,603
EXPRESS MANY OF THE FEATURES OF

3424
01:58:45,603 --> 01:58:47,338
THE DIFFERENT SUBTYPES OF

3425
01:58:47,338 --> 01:58:49,841
FIBROBLASTS, SO THIS IS FROM A

3426
01:58:49,841 --> 01:58:52,243
REVIEW WRITTEN BY A VERY

3427
01:58:52,243 --> 01:58:55,380
BRILLIANT FACULTY IN MY LAB.

3428
01:58:55,380 --> 01:59:00,852
SHEILA HAD TELL YOU ABOUT

3429
01:59:00,852 --> 01:59:02,387
ICAFs, ANTIGEN PRESENTING, BUT

3430
01:59:02,387 --> 01:59:06,290
WHAT WE SEE IS THAT EACH

3431
01:59:06,290 --> 01:59:07,425
FIBROBLAST ACTUALLY EXPRESSES

3432
01:59:07,425 --> 01:59:09,594
DIFFERENT FEATURES OF EACH OF

3433
01:59:09,594 --> 01:59:10,862
THESE FIBROBLASTS AND WE THINK

3434
01:59:10,862 --> 01:59:12,697
REALLY WITH AGING, IT PRIMES THE

3435
01:59:12,697 --> 01:59:13,598
FIBROBLASTS SUCH THAT THEY JUST

3436
01:59:13,598 --> 01:59:16,300
NEED A LITTLE NUDGE TO BE PUSHED

3437
01:59:16,300 --> 01:59:19,037
OVER INTO A CANCER ASSOCIATED

3438
01:59:19,037 --> 01:59:21,439
FIBROBLAST FE PHENOTYPE, AND THT

3439
01:59:21,439 --> 01:59:23,374
ENDS UP OCCURRING WHEN THERE ARE

3440
01:59:23,374 --> 01:59:25,810
INITIATED TUMOR CELLS IN THE

3441
01:59:25,810 --> 01:59:27,345
MICROENVIRONMENT.

3442
01:59:27,345 --> 01:59:30,214
OVER THE YEARS WE'VE FOUND AGING

3443
01:59:30,214 --> 01:59:30,848
FIBROBLASTS DRIVE MULTIPLE

3444
01:59:30,848 --> 01:59:32,216
CHANGES THAT LEAD TO TUMOR

3445
01:59:32,216 --> 01:59:34,285
PROGRESSION FROM CHANGES IN THE

3446
01:59:34,285 --> 01:59:36,554
MATRIX DRIVING METASTASIS TO

3447
01:59:36,554 --> 01:59:38,856
THERAPY RESISTANCE,

3448
01:59:38,856 --> 01:59:40,291
ANGIOGENESIS, METABOLISM, THE

3449
01:59:40,291 --> 01:59:41,826
IMMUNE MICROENVIRONMENT, I'LL

3450
01:59:41,826 --> 01:59:44,295
TALK A LITTLE BIT ABOUT OUR NEW

3451
01:59:44,295 --> 01:59:49,367
WORK IN SEXUAL DIMORPHISM AND

3452
01:59:49,367 --> 01:59:51,369
AGING AND SOME RECENT DORMANCY

3453
01:59:51,369 --> 01:59:52,270
WORK AS WELL.

3454
01:59:52,270 --> 01:59:53,805
SO LIKE I SAID, WE ARE

3455
01:59:53,805 --> 01:59:59,877
INTERESTED IN MELANOMA AND WE

3456
01:59:59,877 --> 02:00:01,479
COLLABORATED WITH FORMER

3457
02:00:01,479 --> 02:00:02,380
COLLEAGUES AT THE NATIONAL

3458
02:00:02,380 --> 02:00:04,782
INSTITUTE ON AGING INITIALLY,

3459
02:00:04,782 --> 02:00:07,185
AND THEN STARTED USING THESE

3460
02:00:07,185 --> 02:00:09,153
FIBROBLASTS FROM THE CORIEL

3461
02:00:09,153 --> 02:00:10,555
DATABASE THAT COME FROM THE

3462
02:00:10,555 --> 02:00:12,090
BALTIMORE LONGITUDAL STUDY OF

3463
02:00:12,090 --> 02:00:14,358
AGE, AND WE TOOK FIBROBLASTS

3464
02:00:14,358 --> 02:00:16,561
FROM HEALTHY DONOR, EITHER IN

3465
02:00:16,561 --> 02:00:19,063
THAIRD MID 20s TO MID 30s OR

3466
02:00:19,063 --> 02:00:21,265
MID 50s TO MID 60s WHICH IS

3467
02:00:21,265 --> 02:00:22,700
WHERE THE INCIDENCE OF MELANOMA

3468
02:00:22,700 --> 02:00:25,169
TAKES OFF AND WE USE THEM TO

3469
02:00:25,169 --> 02:00:26,037
MAKE ARTIFICIAL SKIN.

3470
02:00:26,037 --> 02:00:28,005
IF WE PLACE MELANOMA CELLS IN

3471
02:00:28,005 --> 02:00:29,974
THOSE ARTIFICIAL SKIN THEY WILL

3472
02:00:29,974 --> 02:00:32,143
INVADE RAPIDLY INTO THIS DERMIS,

3473
02:00:32,143 --> 02:00:33,111
AS THEY WERE IN THE DERMIS OF

3474
02:00:33,111 --> 02:00:35,313
THE ACTUAL SKIN AND WE SEE THAT

3475
02:00:35,313 --> 02:00:37,248
PREDOMINANTLY WITH THE AGED

3476
02:00:37,248 --> 02:00:38,015
FIBROBLAST.

3477
02:00:38,015 --> 02:00:40,985
SO MITCH FANE IN MY LAB WANTED

3478
02:00:40,985 --> 02:00:43,020
TO KNOW WHETHER THEY METASTASIZE

3479
02:00:43,020 --> 02:00:44,956
MORE QUICKLY IN YOUNG OR AGED,

3480
02:00:44,956 --> 02:00:47,558
AND WHAT HE SAW IS THAT IN

3481
02:00:47,558 --> 02:00:48,659
YOUNG -- THE TUMOR CELLS WOULD

3482
02:00:48,659 --> 02:00:52,296
GET TO THE LUNG AND THEY WOULD

3483
02:00:52,296 --> 02:00:54,232
GROW OUT FAR MORE RAPIDLY IN THE

3484
02:00:54,232 --> 02:00:55,833
AGED LUNGS THAN THE YOUNG LUNGS.

3485
02:00:55,833 --> 02:00:57,068
THIS HAS ALREADY BEEN PUBLISHED

3486
02:00:57,068 --> 02:00:58,770
SO I'M JUST SKIPPING VERY

3487
02:00:58,770 --> 02:01:00,304
QUICKLY THROUGH THIS, BUT WHAT

3488
02:01:00,304 --> 02:01:02,173
MITCH ALSO SAW, HE LACKED FOR

3489
02:01:02,173 --> 02:01:03,341
WHAT COULD BE DRIVING THAT AND

3490
02:01:03,341 --> 02:01:05,943
HE LOOKED AT LUNG FIBROBLASTS.

3491
02:01:05,943 --> 02:01:08,780
HE IDENTIFIED SECRETED FACTORS

3492
02:01:08,780 --> 02:01:10,448
IN THE AGED LUNG FIBROBLASTS

3493
02:01:10,448 --> 02:01:11,916
THAT COULD CONTRIBUTE TO THE

3494
02:01:11,916 --> 02:01:13,551
OUTGROWTH, THIS RAPID OUTGROWTH

3495
02:01:13,551 --> 02:01:14,786
WE WERE SEEING OF MELANOMA

3496
02:01:14,786 --> 02:01:15,086
CELLS.

3497
02:01:15,086 --> 02:01:19,490
AND WHEN HE QUERIES WHETHER OR

3498
02:01:19,490 --> 02:01:21,125
NOT MANIPULATING THOSE FACTORS

3499
02:01:21,125 --> 02:01:23,327
CAN IMPACT TUMOR CELLS, HE FINDS

3500
02:01:23,327 --> 02:01:25,530
THAT INDEED THEY CAN.

3501
02:01:25,530 --> 02:01:27,799
SO IF HE TAKES OUR AGED MICE, HE

3502
02:01:27,799 --> 02:01:31,736
GIVES THEM THESE MELANOMA CELLS,

3503
02:01:31,736 --> 02:01:32,937
ALLOWS THREE WEEKS FOR THE

3504
02:01:32,937 --> 02:01:36,641
INITIAL DISSEMINATION, LETS THEM

3505
02:01:36,641 --> 02:01:38,409
GET TO THE LUNG, THEN HE TREATS

3506
02:01:38,409 --> 02:01:41,312
WITH AN ANTIBODY AGAINST THIS

3507
02:01:41,312 --> 02:01:44,615
PARTICULAR PROTEIN, SFRP1.

3508
02:01:44,615 --> 02:01:45,917
HE FINDS HE CAN KEEP THESE CELLS

3509
02:01:45,917 --> 02:01:46,984
IN THEIR SINGLE CELL STATE IN

3510
02:01:46,984 --> 02:01:49,654
THE AGED LUNGS, WHEN HE CAN

3511
02:01:49,654 --> 02:01:51,489
REALLY REDUCE THE OUTGROWTH OF

3512
02:01:51,489 --> 02:01:53,157
THESE METASTATIC COLONIES.

3513
02:01:53,157 --> 02:01:54,692
WE'VE ALSO BEEN VERY INTERESTED

3514
02:01:54,692 --> 02:01:56,427
ON HOW AGE IMPACTS CANCER

3515
02:01:56,427 --> 02:01:57,295
THERAPY.

3516
02:01:57,295 --> 02:01:58,496
AGAIN, IF WE LOOK AT THE HALL

3517
02:01:58,496 --> 02:02:00,231
MARKS OF CANCER, WE HAVE

3518
02:02:00,231 --> 02:02:02,533
MULTIPLE GREAT INHIBITORS, BUT

3519
02:02:02,533 --> 02:02:03,734
MOST OF THE CLINICAL TRIALS

3520
02:02:03,734 --> 02:02:05,570
DON'T REALLY TAKE AGE INTO

3521
02:02:05,570 --> 02:02:07,004
ACCOUNT EXCEPT TO EXCLUDE

3522
02:02:07,004 --> 02:02:08,506
PATIENTS WHO ARE OLDER AND LESS

3523
02:02:08,506 --> 02:02:10,908
HEALTHY, SO THAT DOESN'T REALLY

3524
02:02:10,908 --> 02:02:12,243
HELP.

3525
02:02:12,243 --> 02:02:14,478
WE FOUND THAT IN TUMORS GROWING

3526
02:02:14,478 --> 02:02:17,248
IN AGED ANIMALS, THERE WAS FAR

3527
02:02:17,248 --> 02:02:18,549
MORE ANGIOGENESIS.

3528
02:02:18,549 --> 02:02:20,418
HOWEVER, THAT ANGIOGENESIS WAS

3529
02:02:20,418 --> 02:02:23,554
NOT DRIVEN BY VEGF, AND IN FACT,

3530
02:02:23,554 --> 02:02:26,057
IF WE LOOK AT VEGF AND ITS

3531
02:02:26,057 --> 02:02:27,525
RECEPTORS ACROSS AGING, THE

3532
02:02:27,525 --> 02:02:28,459
EXPRESSION OF THOSE WERE

3533
02:02:28,459 --> 02:02:30,761
ACTUALLY REDUCED, AND SO WE

3534
02:02:30,761 --> 02:02:33,264
ASKED THE QUESTION, WHETHER THAT

3535
02:02:33,264 --> 02:02:34,365
MEANT THESE PATIENTS WOULD BE

3536
02:02:34,365 --> 02:02:38,636
LESS RESPONSIVE TO EFASTIN.

3537
02:02:38,636 --> 02:02:40,605
THERE WAS THIS HUGE STUDY

3538
02:02:40,605 --> 02:02:42,340
CONDUCTED IN THE UK WHERE A

3539
02:02:42,340 --> 02:02:44,308
THOUSAND MELANOMA PATIENTS WERE

3540
02:02:44,308 --> 02:02:46,477
GIVEN AVASTIN AND THE CONCLUSION

3541
02:02:46,477 --> 02:02:47,879
OF THE STUDY WAS THERE'S NO REAL

3542
02:02:47,879 --> 02:02:49,313
CHANGE IN OUTCOME SO WE ASKED

3543
02:02:49,313 --> 02:02:51,616
THE INVESTIGATORS TO GO BACK,

3544
02:02:51,616 --> 02:02:54,085
REANALYZE THE DATA AND THEN BY

3545
02:02:54,085 --> 02:02:56,520
AGE WHICH THEY VERY KINDLY DID.

3546
02:02:56,520 --> 02:02:58,155
SORRY, MY TIMER IS ON FOR SOME

3547
02:02:58,155 --> 02:02:58,589
REASON.

3548
02:02:58,589 --> 02:03:00,725
AND WHAT WE SEE IS THAT ACTUALLY

3549
02:03:00,725 --> 02:03:03,728
PATIENTS UNDER THE AGE OF 45 DO

3550
02:03:03,728 --> 02:03:06,364
RESPOND TO AVASTIN, WHEREAS

3551
02:03:06,364 --> 02:03:07,131
THOSE 65 AND OLDER DO NOT

3552
02:03:07,131 --> 02:03:10,468
RESPOND TO AVASTIN.

3553
02:03:10,468 --> 02:03:11,669
SO WE WANTED TO KNOW WHAT WERE

3554
02:03:11,669 --> 02:03:13,104
THE MECHANISMS BEHIND THIS.

3555
02:03:13,104 --> 02:03:14,171
WHAT WE FOUND WAS THAT THIS

3556
02:03:14,171 --> 02:03:15,806
OTHER MOLECULE, SO A SISTER

3557
02:03:15,806 --> 02:03:18,175
MOLECULE TO THE ONE I JUST

3558
02:03:18,175 --> 02:03:22,680
TALKED ABOUT CALLED

3559
02:03:22,680 --> 02:03:24,782
SFRP2 SECRETED FRIZZ EL RELATED

3560
02:03:24,782 --> 02:03:26,951
PROTEIN 2 IS A DRIVER OF ANG

3561
02:03:26,951 --> 02:03:29,353
GENESIS SPECIFICALLY IN TUMORS

3562
02:03:29,353 --> 02:03:31,422
IN AGED MICE AND AGED HUMANS

3563
02:03:31,422 --> 02:03:33,024
WHEREAS THOSE SAME TUMORS HAVE

3564
02:03:33,024 --> 02:03:35,326
FAR LESS EXPRESSION OF VEGF.

3565
02:03:35,326 --> 02:03:38,095
AND SO THE CONCLUSION FROM THIS

3566
02:03:38,095 --> 02:03:42,633
STUDY WAS THAT DURING AGING

3567
02:03:42,633 --> 02:03:43,834
SFRP2 INCREASES AND VEGF

3568
02:03:43,834 --> 02:03:46,437
INCREASES, AND IT'S SFR PSM

3569
02:03:46,437 --> 02:03:48,105
2 THAT DRIVES ANGIOGENESIS SO

3570
02:03:48,105 --> 02:03:50,074
THERE'S NO POINT IN TREATING

3571
02:03:50,074 --> 02:03:51,709
WITH AVASTIN BECAUSE IT'S NOT

3572
02:03:51,709 --> 02:03:53,177
THE DRIVER OF ANGIOGENESIS IN

3573
02:03:53,177 --> 02:03:53,678
THIS CASE.

3574
02:03:53,678 --> 02:03:54,979
SO I'M TRYING TO SHOW YOU

3575
02:03:54,979 --> 02:03:56,180
SNAPSHOTS OF THESE STUDIES TO

3576
02:03:56,180 --> 02:03:57,248
SAY HOW IMPORTANT IT IS TO

3577
02:03:57,248 --> 02:03:59,216
CONSIDER WHAT'S HAPPENING IN THE

3578
02:03:59,216 --> 02:04:01,085
AGING MICROENVIRONMENT SO THAT

3579
02:04:01,085 --> 02:04:02,420
WE CAN PROPERLY TREAT OUR CANCER

3580
02:04:02,420 --> 02:04:03,621
PATIENTS.

3581
02:04:03,621 --> 02:04:05,489
HERE'S ANOTHER EXAMPLE.

3582
02:04:05,489 --> 02:04:08,426
WE FOUND THAT AGED FIBROBLASTS

3583
02:04:08,426 --> 02:04:09,293
SECRETE LIPIDS.

3584
02:04:09,293 --> 02:04:11,462
WHEN THEY SECRETE THOSE LIPIDS,

3585
02:04:11,462 --> 02:04:14,198
MELANOMA CELLS EXPOSED TO AGED

3586
02:04:14,198 --> 02:04:16,400
FIBROBLASTS BUT NOT YOUNG

3587
02:04:16,400 --> 02:04:17,902
FIBROBLASTS UPREGULATE THIS

3588
02:04:17,902 --> 02:04:21,105
RECEPTOR TON THEIR -- FATTY ACID

3589
02:04:21,105 --> 02:04:22,306
PROTEIN TRANSPORTER 2 AND WHEN

3590
02:04:22,306 --> 02:04:24,241
THEY DO THAT, THEY'RE ABLE TO

3591
02:04:24,241 --> 02:04:26,677
ACCUMULATE THE LIPIDS.

3592
02:04:26,677 --> 02:04:30,147
WE FOUND FATP2 IS EXPRESSED IN

3593
02:04:30,147 --> 02:04:31,082
MELANOMA PATIENT OVER THE AGE OF

3594
02:04:31,082 --> 02:04:32,550
50 SO WE ASKED THE QUESTION WHAT

3595
02:04:32,550 --> 02:04:36,721
HAPPENS WHEN WE TARGET FATP2 IN

3596
02:04:36,721 --> 02:04:37,588
TUMORS.

3597
02:04:37,588 --> 02:04:40,858
SO WE TOOK OUR MOUSE TUMORS AND

3598
02:04:40,858 --> 02:04:43,361
WHAT WE SEE -- AND WE TREATED

3599
02:04:43,361 --> 02:04:44,662
THEM WITH -- SORRY, I SHOULD

3600
02:04:44,662 --> 02:04:45,196
BACK UP.

3601
02:04:45,196 --> 02:04:47,732
SO WHAT WE FOUND WITH THE

3602
02:04:47,732 --> 02:04:49,567
ACCUMULATION OF THESE FATTY

3603
02:04:49,567 --> 02:04:51,869
ACIDS CREATED A FATTY ACID

3604
02:04:51,869 --> 02:04:53,704
OXIDATION IN THESE MELANOMA

3605
02:04:53,704 --> 02:04:55,706
CELLS THAT WE SUSPECTED WOULD

3606
02:04:55,706 --> 02:05:00,745
MAKE THEM RESISTANT TO TARGETED

3607
02:05:00,745 --> 02:05:02,046
THERAPY IN MELANOMA.

3608
02:05:02,046 --> 02:05:03,781
THE THERAPY THAT WE USED TO

3609
02:05:03,781 --> 02:05:07,184
TARGET MELANOMA IS TARGETED

3610
02:05:07,184 --> 02:05:13,090
AGAINST A MUTANT BRAF ONCOGENE,

3611
02:05:13,090 --> 02:05:15,693
AND SO WHAT WE DID WAS TO TREAT

3612
02:05:15,693 --> 02:05:17,561
TUMORS IN YOUNG AND AGED MICE

3613
02:05:17,561 --> 02:05:20,965
WITH BRAF MEK INHIBITORS IN THE

3614
02:05:20,965 --> 02:05:23,134
ABSENCE OR PRESENCE OF FATP2.

3615
02:05:23,134 --> 02:05:26,303
WHAT WE SEE IS THAT HAVING THE

3616
02:05:26,303 --> 02:05:27,038
FATP2 THERE DOESN'T REALLY

3617
02:05:27,038 --> 02:05:29,673
AFFECT THE GROWTH AT ALL OF THE

3618
02:05:29,673 --> 02:05:30,875
TUMORS, AND IN YOUNG MICE, WHEN

3619
02:05:30,875 --> 02:05:35,346
WE TARGET THE TUMORS WITH THE

3620
02:05:35,346 --> 02:05:37,081
BRAF INHIBITORS THEY RESPOND AND

3621
02:05:37,081 --> 02:05:37,948
THEY EVENTUALLY COME BACK.

3622
02:05:37,948 --> 02:05:39,150
THIS IS SOMETHING WE SEE

3623
02:05:39,150 --> 02:05:39,583
ROUTINELY.

3624
02:05:39,583 --> 02:05:41,886
IF WE FIRST KNOCK DOWN FATP2,

3625
02:05:41,886 --> 02:05:42,987
THEY DO EXACTLY THE SAME THING.

3626
02:05:42,987 --> 02:05:44,121
THERE'S NO IMPACT IN THE YOUNG

3627
02:05:44,121 --> 02:05:44,321
MICE.

3628
02:05:44,321 --> 02:05:46,023
IN THE AGED MICE, HOWEVER, IT'S

3629
02:05:46,023 --> 02:05:51,095
A VERY DIFFERENT STORY.

3630
02:05:51,095 --> 02:05:52,730
WHAT WE SEE IN THE AGED MICE,

3631
02:05:52,730 --> 02:05:54,231
THOSE TUMORS TREATED WITH BRAF

3632
02:05:54,231 --> 02:06:00,371
ME CMEK INHIBITORS, STOM  STOP A

3633
02:06:00,371 --> 02:06:02,440
SECOND, THINK ABOUT IT AND KEEP

3634
02:06:02,440 --> 02:06:02,807
ON GOING.

3635
02:06:02,807 --> 02:06:05,376
>> SPEAKER, YOU HAVE 2
MINUTES

3636
02:06:05,376 --> 02:06:05,643
REMAINING.

3637
02:06:05,643 --> 02:06:06,277
>> GREAT.

3638
02:06:06,277 --> 02:06:06,610
THANK YOU.

3639
02:06:06,610 --> 02:06:09,046
IF WE DEPLETE FATP2, THESE

3640
02:06:09,046 --> 02:06:10,114
TUMORS DISSOLVE AND GO AWAY.

3641
02:06:10,114 --> 02:06:11,415
SO I'LL FINISH WITH JUST A

3642
02:06:11,415 --> 02:06:13,617
COUPLE OF SLIDES FROM THIS VERY

3643
02:06:13,617 --> 02:06:16,554
TALENTED FACULTY IN MY LAB.

3644
02:06:16,554 --> 02:06:19,390
YASH CHHABRA, WHO HAS BEEN

3645
02:06:19,390 --> 02:06:22,660
LOOKING AT THE INTERSECTIONALITY

3646
02:06:22,660 --> 02:06:24,161
OF AGE AND MELANOMA.

3647
02:06:24,161 --> 02:06:25,930
WHILE YOU CAN SEE THAT WHILE

3648
02:06:25,930 --> 02:06:27,231
MORTALITY AND INCIDENCE

3649
02:06:27,231 --> 02:06:28,866
INCREASES IN BOTH SEXES BY AGE,

3650
02:06:28,866 --> 02:06:31,569
IT'S WORSE IN THE MALES, AND

3651
02:06:31,569 --> 02:06:32,703
YASH HAS DONE THIS HUGE AMOUNT

3652
02:06:32,703 --> 02:06:35,306
OF WORK THAT SHOWING AGED MALE

3653
02:06:35,306 --> 02:06:37,374
FIBROBLASTS AND AGED FEMALE

3654
02:06:37,374 --> 02:06:38,676
FIBROBLASTS UNDERGO VERY

3655
02:06:38,676 --> 02:06:39,110
DIFFERENT CHANGES.

3656
02:06:39,110 --> 02:06:40,644
I'M SHOWING YOU THIS VERY

3657
02:06:40,644 --> 02:06:41,545
QUICKLY IN THE INTEREST OF TIME.

3658
02:06:41,545 --> 02:06:44,882
THE AGED MALE FIBROBLASTS UNDER

3659
02:06:44,882 --> 02:06:46,383
UNDERGO AGE-RELATED SENESCENCE.

3660
02:06:46,383 --> 02:06:47,818
THERE IS AN INCREASE IN THE

3661
02:06:47,818 --> 02:06:49,253
INVASION OF MELANOMA CELLS, BUT

3662
02:06:49,253 --> 02:06:53,157
I WANT TO GET TO THE IB  THE INO

3663
02:06:53,157 --> 02:06:53,924
DATA.

3664
02:06:53,924 --> 02:06:55,025
YASH DID THIS BIG EXPERIMENT

3665
02:06:55,025 --> 02:06:57,795
WHERE HE TOOK MALE AND FEMALE

3666
02:06:57,795 --> 02:06:59,196
MELANOMA CELLS AND PUT THEM IN

3667
02:06:59,196 --> 02:07:01,065
EITHER MALE OR FEMALE YOUNG AND

3668
02:07:01,065 --> 02:07:01,532
AGED MICE.

3669
02:07:01,532 --> 02:07:03,234
HE DID THIS BIG CRISSCROSS

3670
02:07:03,234 --> 02:07:04,768
EXPERIMENT AND HE FOUND NO

3671
02:07:04,768 --> 02:07:06,637
MATTER WHAT THE SEX OF THE

3672
02:07:06,637 --> 02:07:08,305
MELANOMA CELL WAS, IT GREW

3673
02:07:08,305 --> 02:07:11,775
SLOWER IN THE AGED MALE MICE BUT

3674
02:07:11,775 --> 02:07:13,744
METASTASIZED -- I'M SORRY.

3675
02:07:13,744 --> 02:07:16,046
METASTASIZED MORE EFFECTIVELY IN

3676
02:07:16,046 --> 02:07:17,348
THE AGED MALE MICE.

3677
02:07:17,348 --> 02:07:19,216
SO THE AGED MALE

3678
02:07:19,216 --> 02:07:20,651
MICROENVIRONMENT WAS DRIVING

3679
02:07:20,651 --> 02:07:22,953
CHANGES IN METASTASIS, CHANGES

3680
02:07:22,953 --> 02:07:24,255
IN DNA DAMAGE.

3681
02:07:24,255 --> 02:07:25,556
AGAIN, NO MATTER THE SEX OF THE

3682
02:07:25,556 --> 02:07:28,492
TUMOR CELLS, THE AGED MALE MOUSE

3683
02:07:28,492 --> 02:07:31,996
DN KENTUCKY SHOWED M

3684
02:07:31,996 --> 02:07:37,268
SHOWED MORE INCREASES IN -- BMPD

3685
02:07:37,268 --> 02:07:39,970
SPECIFICALLY IN THE AGED MALE

3686
02:07:39,970 --> 02:07:40,938
MICROENVIRONMENT, AND EXPRESSED

3687
02:07:40,938 --> 02:07:43,340
IN TUMORS THAT GROW IN THE AGED

3688
02:07:43,340 --> 02:07:46,043
MALE MICROENVIRONMENT.

3689
02:07:46,043 --> 02:07:47,711
THIS PROTEIN WHEN WE GIVE TO THE

3690
02:07:47,711 --> 02:07:49,213
AGED MALE MICE, IT INCREASES

3691
02:07:49,213 --> 02:07:50,648
THEIR METASTASIS.

3692
02:07:50,648 --> 02:07:52,049
IT ALSO MAKES THEM MORE

3693
02:07:52,049 --> 02:07:53,584
RESISTANT TO THERAPY.

3694
02:07:53,584 --> 02:07:55,853
AND SO I HOPE THAT I'VE SHOWN

3695
02:07:55,853 --> 02:07:59,356
YOU ALL THAT UNDERSTANDING, IT'S

3696
02:07:59,356 --> 02:08:00,324
REALLY CRITICAL FOR US TO

3697
02:08:00,324 --> 02:08:04,061
UNDERSTAND ALL OF THESE

3698
02:08:04,061 --> 02:08:05,162
ENVIRONMENTAL FACTORS, IT'S

3699
02:08:05,162 --> 02:08:06,664
CRITICAL FOR SUCCESSFUL THERAPY

3700
02:08:06,664 --> 02:08:09,600
IN CANCER, CANCER REALLY IS A

3701
02:08:09,600 --> 02:08:12,036
DISEASE OF AGING, AND OUR GOAL

3702
02:08:12,036 --> 02:08:13,437
OF THIS IS TO TRY TO FIGURE OUT

3703
02:08:13,437 --> 02:08:14,338
HOW TO TARGET THE INTERSECTION

3704
02:08:14,338 --> 02:08:17,174
OF ALL OF THESE DIFFERENT

3705
02:08:17,174 --> 02:08:19,310
PARAMETERS IN MELANOMA, AND

3706
02:08:19,310 --> 02:08:21,212
FIGURE OUT HOW TO HARNESS ONE TO

3707
02:08:21,212 --> 02:08:22,513
DISRUPT THE IMPACT OF THE

3708
02:08:22,513 --> 02:08:23,814
OTHERS.

3709
02:08:23,814 --> 02:08:24,815
THESE WERE SOME OF THE THINGS

3710
02:08:24,815 --> 02:08:26,684
YOU ASKED ME TO LIST.

3711
02:08:26,684 --> 02:08:28,319
I GUESS I WENT A LITTLE BIT

3712
02:08:28,319 --> 02:08:28,852
ROGUE HERE.

3713
02:08:28,852 --> 02:08:30,487
THERE'S A TON OF STUFF.

3714
02:08:30,487 --> 02:08:32,356
WE NEED MORE MECHANISTIC

3715
02:08:32,356 --> 02:08:33,657
UNDERSTANDING, WE NEED

3716
02:08:33,657 --> 02:08:37,294
BIOMARKERS THAT ALLOW US TO COME

3717
02:08:37,294 --> 02:08:40,931
IN AND MAYBE IMPACT CANCER RISK

3718
02:08:40,931 --> 02:08:41,432
WITH AGE.

3719
02:08:41,432 --> 02:08:43,300
WE NEED TO BETTER UNDERSTAND HOW

3720
02:08:43,300 --> 02:08:44,735
ENVIRONMENTAL FACTORS INTERSECT

3721
02:08:44,735 --> 02:08:46,937
WITH LIFESTYLE, AND AGING.

3722
02:08:46,937 --> 02:08:48,772
WE NEED MORE LONGITUDAL STUDIES

3723
02:08:48,772 --> 02:08:50,641
OF CANCER AND AGING, AND

3724
02:08:50,641 --> 02:08:51,809
UNDERSTANDING THE HETEROGENEITY

3725
02:08:51,809 --> 02:08:53,043
OF BOTH OF THESE DISEASES AND

3726
02:08:53,043 --> 02:08:55,579
HOW WE CAN TARGET THOSE

3727
02:08:55,579 --> 02:08:56,447
INTERSECTIONS IS GOING TO BE

3728
02:08:56,447 --> 02:08:57,781
CRITICAL.

3729
02:08:57,781 --> 02:08:59,450
OBVIOUSLY UNDERSTANDING CHANGES

3730
02:08:59,450 --> 02:09:04,221
IN THE IMMUNE SYSTEM WITH AGE IS

3731
02:09:04,221 --> 02:09:05,889
CRITICAL, GIVEN IMMUNOTHERAPY

3732
02:09:05,889 --> 02:09:07,391
AND CANCER AND WE HAVE A LOT OF

3733
02:09:07,391 --> 02:09:08,926
ONGOING PROJECTS HERE AS WELL.

3734
02:09:08,926 --> 02:09:10,160
AND OVER THE NEXT FIVE YEARS,

3735
02:09:10,160 --> 02:09:12,229
WE'RE GOING TO NEED MORE

3736
02:09:12,229 --> 02:09:14,198
RELIABLE ANIMAL MODELS, BETTER

3737
02:09:14,198 --> 02:09:16,834
ACCESS TO AGING MICE, CLEARER

3738
02:09:16,834 --> 02:09:19,536
MANDATE ON THE DESIGN OF BOTH

3739
02:09:19,536 --> 02:09:21,272
PRE-CLINICAL AND CLINICAL TRIALS

3740
02:09:21,272 --> 02:09:23,140
TO INCLUDE AGE AS A FACTOR IN

3741
02:09:23,140 --> 02:09:26,644
CANCER TRIALS.

3742
02:09:26,644 --> 02:09:30,581
AS WELL AS DEVELOPING ORGANOID

3743
02:09:30,581 --> 02:09:32,583
MODELS, AND BUILDING ACCESSIBLE

3744
02:09:32,583 --> 02:09:34,718
DATABASES FOR TUMORS THAT

3745
02:09:34,718 --> 02:09:36,920
INCLUDE AGING AND OUTCOME, AS

3746
02:09:36,920 --> 02:09:38,355
WELL AS NORMAL TISSUE ACROSS THE

3747
02:09:38,355 --> 02:09:39,757
SPECTRUM OF AGING.

3748
02:09:39,757 --> 02:09:41,392
SO I'LL STOP THERE.

3749
02:09:41,392 --> 02:09:43,560
I WANT TO THANK -- OH, MY SLIDE

3750
02:09:43,560 --> 02:09:44,128
FELL OFF.

3751
02:09:44,128 --> 02:09:47,031
I HAD AN ACKNOWLEDGMENT SLIDE

3752
02:09:47,031 --> 02:09:49,566
FOR EVERYONE IN THE LAB WHO HAVE

3753
02:09:49,566 --> 02:09:51,802
JUST BEEN AMAZING.

3754
02:09:51,802 --> 02:09:54,605
>> THANKS, ASHANI, GREAT.

3755
02:09:54,605 --> 02:09:54,938
AWESOME STUFF.

3756
02:09:54,938 --> 02:09:56,373
I THINK WE HAVE TIME FOR ONE

3757
02:09:56,373 --> 02:10:03,247
QUESTION.

3758
02:10:03,247 --> 02:10:04,682
I DON'T SEE ANY IN THE Q &
A.

3759
02:10:04,682 --> 02:10:06,650
SO DO YOU THINK THIS IS ALL

3760
02:10:06,650 --> 02:10:08,519
GROWTH FACTORS FROM THE

3761
02:10:08,519 --> 02:10:10,587
FIBROBLASTS OR IS IT ALSO THE

3762
02:10:10,587 --> 02:10:12,556
ECM, LIKE THE COLLAGEN AND --

3763
02:10:12,556 --> 02:10:14,058
>> YEAH.

3764
02:10:14,058 --> 02:10:16,060
>> HOW DO YOU THINK THIS
WORKS?

3765
02:10:16,060 --> 02:10:17,695
>> YEAH, IT'S DEFINITELY A

3766
02:10:17,695 --> 02:10:18,462
MIXTURE OF BOTH.

3767
02:10:18,462 --> 02:10:20,964
SO WE'VE SHOWN THAT FIBROBLASTS

3768
02:10:20,964 --> 02:10:22,599
THAT ARE AGED LAY DOWN A VERY

3769
02:10:22,599 --> 02:10:25,402
DIFFERENT ECM THAN FIBROBLASTS

3770
02:10:25,402 --> 02:10:28,238
THAT ARE YOUNG, AND THAT ECM IS

3771
02:10:28,238 --> 02:10:31,608
PERMISSIVE TO TUMOR INVASION,

3772
02:10:31,608 --> 02:10:33,243
BUT RESTRICTIVE TO IMMUNE CELL

3773
02:10:33,243 --> 02:10:35,779
INFILTRATION.

3774
02:10:35,779 --> 02:10:38,682
AND SO THAT'S DEFINITELY ONE

3775
02:10:38,682 --> 02:10:40,484
ASPECT.

3776
02:10:40,484 --> 02:10:42,386
THE OTHER ASPECT IS THE GROWTH

3777
02:10:42,386 --> 02:10:43,554
FACTORS, AND THEN WE ARE FINDING

3778
02:10:43,554 --> 02:10:46,657
CHANGES IN AGE-RELATED OWE DIP

3779
02:10:46,657 --> 02:10:49,026
SITES, AGE-RELATED ENDOTHELIAL

3780
02:10:49,026 --> 02:10:51,095
CELLS, BREAKDOWN IN VASCULARITY

3781
02:10:51,095 --> 02:10:55,165
AND PERMEABILITY.

3782
02:10:55,165 --> 02:10:56,533
SO HOST OF FACTORS.

3783
02:10:56,533 --> 02:10:57,468
>> YEAH, PROBABLY LOTS
THERE.

3784
02:10:57,468 --> 02:11:00,904
ALL RIGHT.

3785
02:11:00,904 --> 02:11:02,673
I THINK WE CAN SAVE OTHER

3786
02:11:02,673 --> 02:11:03,540
QUESTIONS FOR THE PANEL.

3787
02:11:03,540 --> 02:11:05,676
WE'LL TRY TO STAY ON TIME SINCE

3788
02:11:05,676 --> 02:11:06,810
THE PANEL IS A LITTLE BIT SHORT

3789
02:11:06,810 --> 02:11:08,245
SO THANKS, ASHANI.

3790
02:11:08,245 --> 02:11:11,281
COMING UP, ZORINA IS PROMPTING

3791
02:11:11,281 --> 02:11:12,149
ME SO THIS IS GREAT.

3792
02:11:12,149 --> 02:11:15,219
I REMEMBER ANYWAYS, MIRANDA ORR.

3793
02:11:15,219 --> 02:11:17,287
HERE IT IS ON THE SLIDE.

3794
02:11:17,287 --> 02:11:22,025
PLN TALKING ABOUT SENESCENT CEL.

3795
02:11:22,025 --> 02:11:23,627
LET'S SEE IF SHE CAN COME BACK

3796
02:11:23,627 --> 02:11:23,994
AND RESCUE THEM.

3797
02:11:23,994 --> 02:11:25,028
ALL RIGHT, MIRANDA.

3798
02:11:25,028 --> 02:11:26,697
>> THANKS SO MUCH FOR THE

3799
02:11:26,697 --> 02:11:27,364
INTRODUCTION, AND I'M SO HAPPY

3800
02:11:27,364 --> 02:11:28,132
TO BE HERE.

3801
02:11:28,132 --> 02:11:30,200
MY NAME IS MIRANDA ORR.

3802
02:11:30,200 --> 02:11:31,702
I'M AN ASSOCIATE PROFESSOR AT

3803
02:11:31,702 --> 02:11:33,270
WAKE FOREST UNIVERSITY SCHOOL OF

3804
02:11:33,270 --> 02:11:33,537
MEDICINE.

3805
02:11:33,537 --> 02:11:34,872
AND A RESEARCH HEALTH SCIENTIST

3806
02:11:34,872 --> 02:11:38,008
AT THE SALISBURY VA IN NORTH

3807
02:11:38,008 --> 02:11:40,310
CAROLINA.

3808
02:11:40,310 --> 02:11:42,479
MY LAB, WE ARE A TRANSLATIONAL

3809
02:11:42,479 --> 02:11:43,247
NEUROBIOLOGY LAB AND WHAT WE'RE

3810
02:11:43,247 --> 02:11:44,481
INTERESTED IN IS UNDERSTANDING

3811
02:11:44,481 --> 02:11:46,650
WHAT IS THIS BLACK BOX OF AGING,

3812
02:11:46,650 --> 02:11:49,253
AND HOW IS IT THAT A VERY YOUNG,

3813
02:11:49,253 --> 02:11:50,587
HEALTHY, VIBRANT MIND, MY

3814
02:11:50,587 --> 02:11:53,390
EXAMPLE HERE IS MY MATERNAL

3815
02:11:53,390 --> 02:11:54,725
GRANDMOTHER, SHE GRADUATED HER

3816
02:11:54,725 --> 02:11:56,226
CLASS VALEDICTORIAN, THROUGH THE

3817
02:11:56,226 --> 02:11:59,096
COURSE OF A LIFESPAN CAN TURN

3818
02:11:59,096 --> 02:12:00,397
THIS ONCE VIBRANT ORGAN INTO

3819
02:12:00,397 --> 02:12:01,532
SOMETHING VERY DYSFUNCTIONAL

3820
02:12:01,532 --> 02:12:03,033
THAT'S NOT ONLY FRUSTRATING FOR

3821
02:12:03,033 --> 02:12:05,736
THE PERSON EXPERIENCING IT, BUT

3822
02:12:05,736 --> 02:12:07,171
DEVASTATING TO THE FAMILY.

3823
02:12:07,171 --> 02:12:08,372
SO TO ANSWER THIS QUESTION, OUR

3824
02:12:08,372 --> 02:12:10,274
LAB REALLY FOCUSES ON LESSONS

3825
02:12:10,274 --> 02:12:11,775
FROM THE BIOLOGY OF AGING FIELD

3826
02:12:11,775 --> 02:12:13,744
THAT HAVE IDENTIFIED FUNDAMENTAL

3827
02:12:13,744 --> 02:12:15,712
CELLULAR AND MOLECULAR PROCESSES

3828
02:12:15,712 --> 02:12:17,915
THAT NOT ONLY CO-OCCUR WITH

3829
02:12:17,915 --> 02:12:19,416
AGING BUT IF THEY'RE PERTURBED,

3830
02:12:19,416 --> 02:12:21,385
THEY CAN INCREASE THE -- OR

3831
02:12:21,385 --> 02:12:22,953
DECREASE THE AGE IN WHICH

3832
02:12:22,953 --> 02:12:23,821
AGE-ASSOCIATED DISEASES HAPPEN,

3833
02:12:23,821 --> 02:12:25,456
BUT IF THEY'RE INTERVENED UPON

3834
02:12:25,456 --> 02:12:26,657
APPROPRIATELY, YOU CAN DELAY THE

3835
02:12:26,657 --> 02:12:30,394
ONSET OF THESE DISEASES.

3836
02:12:30,394 --> 02:12:31,595
SO ONCE WE IDENTIFIED SOMETHING

3837
02:12:31,595 --> 02:12:32,763
WE THOUGHT MIGHT BE RELEVANT TO

3838
02:12:32,763 --> 02:12:33,630
ALZHEIMER'S DISEASE, THE NEXT

3839
02:12:33,630 --> 02:12:34,665
STEP IS TO LOOK FOR EVIDENCE IN

3840
02:12:34,665 --> 02:12:35,098
PEOPLE.

3841
02:12:35,098 --> 02:12:36,433
SO WE SPENT A LOT OF TIME

3842
02:12:36,433 --> 02:12:38,168
LOOKING AT POSTMORTEM HUMAN

3843
02:12:38,168 --> 02:12:40,137
BRAINS AND DATASETS GENERATED BY

3844
02:12:40,137 --> 02:12:41,638
OTHERS IN THE FIELD AND ONCE WE

3845
02:12:41,638 --> 02:12:43,974
DO FIND EVIDENCE THAT THESE ARE

3846
02:12:43,974 --> 02:12:46,243
ABERRANTLY PERTURBED IN

3847
02:12:46,243 --> 02:12:47,044
ALZHEIMER'S, THEN WE CAN TAKE

3848
02:12:47,044 --> 02:12:48,879
THIS BACK TO THE LAB, IDENTIFY

3849
02:12:48,879 --> 02:12:50,447
MICE TO TEST MECHANISTIC

3850
02:12:50,447 --> 02:12:51,648
STUDIES, DO INTERVENTIONS

3851
02:12:51,648 --> 02:12:53,617
FOCUSING ON CLINICALLY RELEVANT

3852
02:12:53,617 --> 02:12:55,586
OUTCOMES LAKE BEHAVIOR, BRAIN

3853
02:12:55,586 --> 02:12:56,687
IMAGING, NEUROPATHOLOGY AND IF

3854
02:12:56,687 --> 02:12:58,422
TRIALS WORK IN MICE, WE MOVE TO

3855
02:12:58,422 --> 02:12:59,423
EARLY PHASE CLINICAL TRIALS.

3856
02:12:59,423 --> 02:13:01,525
SO THAT IS THE PERSPECTIVE IN

3857
02:13:01,525 --> 02:13:04,428
WHICH YOU WILL HEAR MY

3858
02:13:04,428 --> 02:13:05,062
PRESENTATION, AND BRIEFLY WHAT

3859
02:13:05,062 --> 02:13:06,363
I'M GOING TO TRY TO ACCOMPLISH

3860
02:13:06,363 --> 02:13:08,165
IN THE NEXT 12 MINUTES OR SO IS

3861
02:13:08,165 --> 02:13:10,901
TALK ABOUT SHARED AND UNIQUE

3862
02:13:10,901 --> 02:13:13,437
CO-MORBID CONDITIONS OF POOR

3863
02:13:13,437 --> 02:13:16,840
BRAIN AGING WITH RELATED FOCUS

3864
02:13:16,840 --> 02:13:19,109
ON DEMENTIA, TALK ABOUT

3865
02:13:19,109 --> 02:13:20,410
BIOLOGICAL AGING DRIVERS OF

3866
02:13:20,410 --> 02:13:21,845
BRAIN HEALTH DECLINE WITH FOCUS

3867
02:13:21,845 --> 02:13:24,581
ON CELLULAR SENESCENCE, THAT IS

3868
02:13:24,581 --> 02:13:27,651
MY LAB'S EXPERTISE, AND TALKING

3869
02:13:27,651 --> 02:13:30,187
ABOUT SENESCENCE AS A SHARED

3870
02:13:30,187 --> 02:13:31,088
RISK AND TALK ABOUT PRESSING

3871
02:13:31,088 --> 02:13:32,456
NEEDS MOVING FORWARD AT LEAST

3872
02:13:32,456 --> 02:13:34,458
FROM MY PERSPECTIVE.

3873
02:13:34,458 --> 02:13:36,460
SO RECENTLY, DEMENTIA HAS BECOME

3874
02:13:36,460 --> 02:13:38,428
THE NUMBER ONE MOST FEARED

3875
02:13:38,428 --> 02:13:39,963
HEALTH CONDITION OF GROWING

3876
02:13:39,963 --> 02:13:41,265
OLDER ACROSS THE GLOBE, SO

3877
02:13:41,265 --> 02:13:42,599
PEOPLE FEAR THIS MORE THAN

3878
02:13:42,599 --> 02:13:44,668
DEVELOPING CANCER OR STROKE.

3879
02:13:44,668 --> 02:13:46,303
AND BY FAR THE GREATEST RISK

3880
02:13:46,303 --> 02:13:48,605
FACTOR FOR DEVELOPING DEMENTIA

3881
02:13:48,605 --> 02:13:49,373
IS ADVANCED AGE.

3882
02:13:49,373 --> 02:13:50,541
THROUGHOUT THE WORKSHOP, YOU

3883
02:13:50,541 --> 02:13:53,277
WILL HEAR LOTS OF ADVICE ON

3884
02:13:53,277 --> 02:13:54,745
HEALTHY LIFESTYLE CHOICES TO

3885
02:13:54,745 --> 02:13:56,480
REDUCE YOUR RISK OF DISEASES AND

3886
02:13:56,480 --> 02:13:59,082
MANY OF THEM ARE SHARED WITH

3887
02:13:59,082 --> 02:14:00,150
DEMENTIA, SO CONTROLLING HIGH

3888
02:14:00,150 --> 02:14:02,586
BLOOD PRESSURE, GETTING ENOUGH

3889
02:14:02,586 --> 02:14:05,455
SLEEP, HEALTHY DIET, PHYSICALLY

3890
02:14:05,455 --> 02:14:07,190
ACTIVE, REALLY THE MANTRA OF

3891
02:14:07,190 --> 02:14:07,991
HEALTHY AGING, AS WELL AS

3892
02:14:07,991 --> 02:14:08,825
STAYING CONNECTED WITH FAMILY

3893
02:14:08,825 --> 02:14:09,393
AND FRIENDS.

3894
02:14:09,393 --> 02:14:10,627
BUT EVEN INDIVIDUALS THAT MANAGE

3895
02:14:10,627 --> 02:14:11,795
TO DO ALL OF THESE THINGS TO THE

3896
02:14:11,795 --> 02:14:13,263
BEST OF THEIR ABILITY, THERE IS

3897
02:14:13,263 --> 02:14:14,998
AN INCREASED CHANCE OF

3898
02:14:14,998 --> 02:14:15,866
DEVELOPING DEMENTIA IN LATER

3899
02:14:15,866 --> 02:14:18,402
LIFE.

3900
02:14:18,402 --> 02:14:19,903
SO TRYING TO THINK ABOUT RISK

3901
02:14:19,903 --> 02:14:21,638
FACTORS THAT MIGHT BE DRIVING

3902
02:14:21,638 --> 02:14:23,006
DEMENTIA, SOME CLUES HAVE BEEN

3903
02:14:23,006 --> 02:14:24,975
TAKEN FROM COMMON CO-MORBID

3904
02:14:24,975 --> 02:14:26,043
CONDITIONS THAT PEOPLE WITH

3905
02:14:26,043 --> 02:14:27,377
ALZHEIMER'S AND DEMENTIA

3906
02:14:27,377 --> 02:14:27,678
EXPERIENCE.

3907
02:14:27,678 --> 02:14:29,546
SO SOME OF THEM ARE LISTED HERE.

3908
02:14:29,546 --> 02:14:32,883
SO GOING FROM ASSOCIATION STU

3909
02:14:32,883 --> 02:14:34,251
STUDIES IN HUMAN POPULATIONS TO

3910
02:14:34,251 --> 02:14:35,118
UNDERSTANDING THE MECHANISM

3911
02:14:35,118 --> 02:14:36,553
DRIVING THIS, WE REALLY -- MY

3912
02:14:36,553 --> 02:14:38,288
LAB REALLY FOCUSES ON THE

3913
02:14:38,288 --> 02:14:39,723
BIOLOGY OF AGING WITH A

3914
02:14:39,723 --> 02:14:42,893
PARTICULAR EMPHASIS ON CELLULAR

3915
02:14:42,893 --> 02:14:43,860
SENESCENCE.

3916
02:14:43,860 --> 02:14:45,729
NOT ONLY BECAUSE WE WERE VERY

3917
02:14:45,729 --> 02:14:47,698
CURIOUS, WI BUT BECAUSE THERE WS

3918
02:14:47,698 --> 02:14:48,699
EMERGING DATA IN THE LITERATURE

3919
02:14:48,699 --> 02:14:50,000
THAT SENESCENT CELLS WERE

3920
02:14:50,000 --> 02:14:50,801
ACCUMULATING IN ALL OF THESE

3921
02:14:50,801 --> 02:14:54,838
DIFFERENT CONDITIONS.

3922
02:14:54,838 --> 02:14:56,573
WE'VE HEARD DID SENESCENCE

3923
02:14:56,573 --> 02:14:58,108
ALREADY BUT I DID PUT TOGETHER A

3924
02:14:58,108 --> 02:15:00,043
FEW SLIDES AND ANIMATION OF WHAT

3925
02:15:00,043 --> 02:15:01,411
CELLULAR SENESCENCE IS TO GET

3926
02:15:01,411 --> 02:15:02,245
EVERYBODY ON THE SAME PAGE, SO

3927
02:15:02,245 --> 02:15:03,947
IF YOU THINK OF THESE CELLS,

3928
02:15:03,947 --> 02:15:05,916
THESE OVALS AS HEALTHY CELLS AND

3929
02:15:05,916 --> 02:15:08,352
YOU CAN THINK OF THIS AS NATISH

3930
02:15:08,352 --> 02:15:10,354
EU, AND YOUR CELL UNDERGOES

3931
02:15:10,354 --> 02:15:11,922
DAMAGE AND IF WE THINK OF THIS

3932
02:15:11,922 --> 02:15:13,890
AS SKIN, SAY YOU'RE OUTSIDE ON A

3933
02:15:13,890 --> 02:15:15,125
HOT SUMMER DAY AND YOU GET UV

3934
02:15:15,125 --> 02:15:17,227
DAMAGE, THE CELL HAS CELL FATE

3935
02:15:17,227 --> 02:15:17,694
OPTIONS.

3936
02:15:17,694 --> 02:15:19,830
ONE IS THAT IT CAN CONTINUE TO

3937
02:15:19,830 --> 02:15:21,164
DIVIDE WITH DAMAGE AND THIS IS

3938
02:15:21,164 --> 02:15:23,367
BAD, IT CAN BECOME CANCER.

3939
02:15:23,367 --> 02:15:26,770
ANOTHER IS THAT IT MAY UND UNDEO

3940
02:15:26,770 --> 02:15:27,904
APOPTOSIS.

3941
02:15:27,904 --> 02:15:29,373
IF THIS IS A REGENERATIVE

3942
02:15:29,373 --> 02:15:30,374
TISSUE, THAT CELL CAN BE

3943
02:15:30,374 --> 02:15:30,907
REPLACED.

3944
02:15:30,907 --> 02:15:33,076
THE THIRD, HOWEVER, IS NEITHER

3945
02:15:33,076 --> 02:15:34,544
PROLIFERATION NOR APOPTOSIS BUT

3946
02:15:34,544 --> 02:15:36,046
IT CHANGES CELL FATE.

3947
02:15:36,046 --> 02:15:37,914
THESE CELLS CHANGE THEIR

3948
02:15:37,914 --> 02:15:39,616
MORPHOLOGY, THEIR TRANSCRIPTOME,

3949
02:15:39,616 --> 02:15:40,317
THEIR PROTEOME.

3950
02:15:40,317 --> 02:15:42,285
THEY REALLY CANNOT DIE, THEY

3951
02:15:42,285 --> 02:15:43,654
REALLY RELY ON THE IMMUNE SYSTEM

3952
02:15:43,654 --> 02:15:46,156
TO CLEAR THEM AND THEY RELEASE A

3953
02:15:46,156 --> 02:15:49,326
BUNCH OF FACTORS, EXTRACELLULAR

3954
02:15:49,326 --> 02:15:51,962
MATRIX REMODELING PROTEINS, SO

3955
02:15:51,962 --> 02:15:53,497
IF AN IMMUNE SYSTEM DOESN'T

3956
02:15:53,497 --> 02:15:55,565
CLEAR THEM, THEY ACCUMULATE WITH

3957
02:15:55,565 --> 02:15:57,768
TIME, THEY CAUSE HEALTHY CELLS

3958
02:15:57,768 --> 02:16:00,037
TO UNDERGO APOPTOSIS OR

3959
02:16:00,037 --> 02:16:01,405
TRANSFORM THEM INTO SENESCENT

3960
02:16:01,405 --> 02:16:02,039
CELLS.

3961
02:16:02,039 --> 02:16:04,441
SO OUR QUESTION REALLY WAS, DO

3962
02:16:04,441 --> 02:16:05,509
SENESCENT CELLS ACCUMULATE IN

3963
02:16:05,509 --> 02:16:06,076
THE BRAIN?

3964
02:16:06,076 --> 02:16:08,679
WHEN WE FIRST STARTED TESTING

3965
02:16:08,679 --> 02:16:09,513
THIS, OR INVESTIGATING THIS, WE

3966
02:16:09,513 --> 02:16:11,648
HAD A HYPOTHESIS-DRIVEN

3967
02:16:11,648 --> 02:16:13,183
QUESTION, AND THAT WAS TO LOOK

3968
02:16:13,183 --> 02:16:16,053
AT BRAIN CELLS IN ALZHEIMER'S

3969
02:16:16,053 --> 02:16:17,254
THAT ARGUABLY HAD THE HIGHEST

3970
02:16:17,254 --> 02:16:18,321
LEVEL OF DAMAGE.

3971
02:16:18,321 --> 02:16:21,725
AND THAT ARE NEURONS WITH

3972
02:16:21,725 --> 02:16:25,562
NEUROFIB LEFIBRILLARY TANGLES.

3973
02:16:25,562 --> 02:16:29,499
YOU CAN SEE THIS CELL SO REALLY

3974
02:16:29,499 --> 02:16:34,237
ENCASED IN THIS PURPLE DYE.

3975
02:16:34,237 --> 02:16:38,175
THEY ARE PREDICTED TO SURVIVE

3976
02:16:38,175 --> 02:16:40,610
MANY DECADES IN THE HUMAN BRAIN

3977
02:16:40,610 --> 02:16:44,414
BUT THEY CLOSELY CORRELATE WITH

3978
02:16:44,414 --> 02:16:45,849
DEMENTIA.

3979
02:16:45,849 --> 02:16:47,250
WE DID FIND A SENESCENT

3980
02:16:47,250 --> 02:16:48,585
SIGNATURE IN NEURONS WITH

3981
02:16:48,585 --> 02:16:49,386
TANGLES.

3982
02:16:49,386 --> 02:16:51,221
THE NEXT STEP WAS TO USE AN

3983
02:16:51,221 --> 02:16:52,422
UNBIASED APPROACH TO REALLY GET

3984
02:16:52,422 --> 02:16:54,624
A BETTER SURVEY OF SENESCENT

3985
02:16:54,624 --> 02:16:55,392
CELLS IN THE BRAIN.

3986
02:16:55,392 --> 02:16:58,328
SO WE LOOKED AT ABOUT 140,000

3987
02:16:58,328 --> 02:17:01,098
CELLS DERIVED FROM 76 POSTMORTEM

3988
02:17:01,098 --> 02:17:03,066
HUMAN BRAINS WITH DIFFERENT

3989
02:17:03,066 --> 02:17:04,601
LEVELS OF ALZHEIMER'S DISEASE,

3990
02:17:04,601 --> 02:17:06,136
NEUROPATHOLOGY AND USED FOUR

3991
02:17:06,136 --> 02:17:07,237
EMBRYONIC BRAINS AS CONTROL.

3992
02:17:07,237 --> 02:17:08,805
WHAT WE FOUND WAS ABOUT 2% OF

3993
02:17:08,805 --> 02:17:11,174
THE BRAIN CELLS WERE SENESCENT,

3994
02:17:11,174 --> 02:17:12,709
AND LARGELY OVERLAPPED WITH

3995
02:17:12,709 --> 02:17:13,577
NEURONS WITH TANGLES.

3996
02:17:13,577 --> 02:17:15,679
SO NOW THAT WE KNEW THAT WE

3997
02:17:15,679 --> 02:17:17,514
COULD FIND SENESCENT CELLS IN

3998
02:17:17,514 --> 02:17:19,983
THE BRAIN, THE QUESTION IS, DO

3999
02:17:19,983 --> 02:17:21,151
THEY MATTER?

4000
02:17:21,151 --> 02:17:23,553
TO ANSWER THIS, WE TREATED TAU

4001
02:17:23,553 --> 02:17:25,655
TRANSGENIC MICE WITH ADVANCED

4002
02:17:25,655 --> 02:17:27,190
NEUROPATHOLOGY SO HIGH LEVELS OF

4003
02:17:27,190 --> 02:17:28,825
THESE TANGLES WITH DRUGS THAT

4004
02:17:28,825 --> 02:17:29,793
SELECTIVELY CLEAR THESE

4005
02:17:29,793 --> 02:17:30,360
SENESCENT CELLS.

4006
02:17:30,360 --> 02:17:32,763
YOU WILL HEAR A LOT MORE ABOUT

4007
02:17:32,763 --> 02:17:33,797
THIS THERAPY IN THE LATER

4008
02:17:33,797 --> 02:17:35,832
SESSION, BUT IN OUR EXPERIMENT,

4009
02:17:35,832 --> 02:17:39,369
WHEN WE TREATED THESE MICE, WE

4010
02:17:39,369 --> 02:17:40,904
SAW THAT CLEARING SENESCENT

4011
02:17:40,904 --> 02:17:42,472
CELLS IMPROVED BRAIN STRUCTURE

4012
02:17:42,472 --> 02:17:44,074
AND FUNCTION, REALLY PROVIDING

4013
02:17:44,074 --> 02:17:45,375
EVIDENCE THAT THESE SENESCENT

4014
02:17:45,375 --> 02:17:47,144
CELLS WERE DETRIMENTAL.

4015
02:17:47,144 --> 02:17:49,112
SO MOVING THAT FORWARD, WE

4016
02:17:49,112 --> 02:17:51,181
RECENTLY COMPLETED A PHASE ONE

4017
02:17:51,181 --> 02:17:54,017
CLINICAL TRIAL WHERE WE WERE

4018
02:17:54,017 --> 02:17:55,352
INTERESTED IN DETERMINING BLOOD

4019
02:17:55,352 --> 02:17:58,555
BRAIN BARRIER PENETRANCE OF THE

4020
02:17:58,555 --> 02:18:02,692
16 LYTICS, SAFETY AS WELL AS --

4021
02:18:02,692 --> 02:18:04,594
RELEVANT TO SENESCENCE AND

4022
02:18:04,594 --> 02:18:05,028
ALZHEIMER'S DISEASE.

4023
02:18:05,028 --> 02:18:06,329
THIS WAS DONE IN COLLABORATION

4024
02:18:06,329 --> 02:18:08,932
WITH A FANTASTIC TEAM AT UT

4025
02:18:08,932 --> 02:18:12,135
HEALTH IN SAN ANTONIO.

4026
02:18:12,135 --> 02:18:15,972
THIS IS -- YOU CAN SEE IT

4027
02:18:15,972 --> 02:18:17,274
ONLINE, I'M GOING TO BRIEFLY

4028
02:18:17,274 --> 02:18:18,575
DISCUSS OUR PRIMARY OUTCOMES.

4029
02:18:18,575 --> 02:18:21,578
SO IN THIS TRIAL WE RECRUITED

4030
02:18:21,578 --> 02:18:22,779
OLDER ADULTS WITH MILD

4031
02:18:22,779 --> 02:18:24,848
ALZHEIMER'S DISEASE AND WE HAD

4032
02:18:24,848 --> 02:18:27,083
FIVE PEOPLE THAT COMPLETED THE

4033
02:18:27,083 --> 02:18:30,487
STUDY AND WE WERE LOOKING AT

4034
02:18:30,487 --> 02:18:32,589
ONE, BLOOD BRAIN BARRIER

4035
02:18:32,589 --> 02:18:34,825
PENETRANCE AND PHARMACOLOGY.

4036
02:18:34,825 --> 02:18:36,459
SO SHOWN HERE ARE THE BLOOD

4037
02:18:36,459 --> 02:18:38,762
LEVELS, THESE WERE GIVEN ORALLY,

4038
02:18:38,762 --> 02:18:39,663
INTERMITTENTLY FOR THREE MONTHS

4039
02:18:39,663 --> 02:18:41,398
AND COMPARED TO PRE-TREATMENT

4040
02:18:41,398 --> 02:18:42,933
VERSUS POST TREATMENT, YOU CAN

4041
02:18:42,933 --> 02:18:45,101
SEE THAT WE DID FIND ELEVATED

4042
02:18:45,101 --> 02:18:47,003
AMOUNTS OF THESE DRUGS IN THE

4043
02:18:47,003 --> 02:18:47,304
PLASMA.

4044
02:18:47,304 --> 02:18:51,141
WHEN WE LOOKED IN THE C IS SF,

4045
02:18:51,141 --> 02:18:55,212
WE FOUND DASATINIB IN FOUR OF

4046
02:18:55,212 --> 02:18:55,645
THE FIVE.

4047
02:18:55,645 --> 02:18:58,381
WE DID NOT FIND -- I'M HAPPY TO

4048
02:18:58,381 --> 02:18:59,850
TALK TO YOU ABOUT THAT IN THE Q

4049
02:18:59,850 --> 02:19:00,350
& A.

4050
02:19:00,350 --> 02:19:02,118
OVERALL THE TREATMENT WAS WELL

4051
02:19:02,118 --> 02:19:03,320
TOLERATED, WE DIDN'T HAVE ANY

4052
02:19:03,320 --> 02:19:04,621
EARLY DISCONTINUATIONS.

4053
02:19:04,621 --> 02:19:07,290
WE SAW SEVERAL FACTORS THAT

4054
02:19:07,290 --> 02:19:08,825
MODESTLY DECREASED AND OVERALL

4055
02:19:08,825 --> 02:19:12,329
WE INTERPRETED THE ORAL -- WAS

4056
02:19:12,329 --> 02:19:15,198
WELL TOLERATED, DEEP PENETRATED

4057
02:19:15,198 --> 02:19:16,833
THE CENTRAL NERVOUS SYSTEM AND

4058
02:19:16,833 --> 02:19:22,873
THERE WERE SUBTLE HINTS FOR CSF

4059
02:19:22,873 --> 02:19:23,173
BIOMARKERS.

4060
02:19:23,173 --> 02:19:24,507
WITH THAT WE HAVE NOW MOVED TO

4061
02:19:24,507 --> 02:19:25,008
PHASE 2.

4062
02:19:25,008 --> 02:19:26,376
THIS IS FUNDED BY THE

4063
02:19:26,376 --> 02:19:27,611
ALZHEIMER'S DRUG DISCOVERY

4064
02:19:27,611 --> 02:19:27,911
FOUNDATION.

4065
02:19:27,911 --> 02:19:29,980
IT IS  A MULTISITE TRIAL AND IT

4066
02:19:29,980 --> 02:19:32,716
RUN HERE AT WAKE FOREST AND SITE

4067
02:19:32,716 --> 02:19:37,120
PIs IN SAN ANTONIO, AND IN

4068
02:19:37,120 --> 02:19:38,955
THIS TRIAL WE ARE INCLUDING A

4069
02:19:38,955 --> 02:19:41,258
PLACEBO ARM ADDING MORE

4070
02:19:41,258 --> 02:19:41,791
PARTICIPANTS.

4071
02:19:41,791 --> 02:19:43,460
OUR TARGET ENROLLMENT IS 48.

4072
02:19:43,460 --> 02:19:45,528
WE ALSO HAVE INCLUDED AN

4073
02:19:45,528 --> 02:19:46,963
EXTENDED FOLLOW-UP.

4074
02:19:46,963 --> 02:19:49,199
AFTER THE INDIVIDUALS OR STUDY

4075
02:19:49,199 --> 02:19:50,333
PARTICIPANTS COMPLETE TREATMENT,

4076
02:19:50,333 --> 02:19:52,068
THEY REMAIN ENROLLED AND WE

4077
02:19:52,068 --> 02:19:54,571
COLLECT DATA FROM THEM EVERY

4078
02:19:54,571 --> 02:19:55,906
THREE MONTHS OR NINE MONTHS TO

4079
02:19:55,906 --> 02:19:57,674
DETERMINE IF AND WHEN SENESCENT

4080
02:19:57,674 --> 02:19:59,209
CELLS RE-APPEAR AND WE ALSO

4081
02:19:59,209 --> 02:20:01,411
ADDED AGING OUTCOMES THANKS TO

4082
02:20:01,411 --> 02:20:03,480
THE PEPPER CENTER.

4083
02:20:03,480 --> 02:20:05,015
BECAUSE SENESCENT CELLS ARE

4084
02:20:05,015 --> 02:20:06,249
ACCUMULATING IN ALL OF OUR

4085
02:20:06,249 --> 02:20:07,684
TISSUES AS WE GROW OLDER, WE

4086
02:20:07,684 --> 02:20:09,085
THINK THAT REMOVING THEM, THERE

4087
02:20:09,085 --> 02:20:11,054
IS A CHANCE TO IMPACT OVERALL

4088
02:20:11,054 --> 02:20:12,622
HEALTH, AND THIS FIGURE IS FROM

4089
02:20:12,622 --> 02:20:17,560
A REVIEW THAT WAS PUBLISHED IN

4090
02:20:17,560 --> 02:20:17,861
2019.

4091
02:20:17,861 --> 02:20:20,397
AT THAT TIME THE STATUS OF THE

4092
02:20:20,397 --> 02:20:23,366
FIELD, SENESCENT CELLS HAD BEEN

4093
02:20:23,366 --> 02:20:24,301
IDENTIFIED AND WHAT DISEASES

4094
02:20:24,301 --> 02:20:25,001
THEY CONTRIBUTED TO.

4095
02:20:25,001 --> 02:20:26,770
SO IN ADDITION TO OUR TRIAL

4096
02:20:26,770 --> 02:20:27,637
OUTCOMES OF TRADITIONAL

4097
02:20:27,637 --> 02:20:29,072
ALZHEIMER'S MEASURES, COGNITION,

4098
02:20:29,072 --> 02:20:30,340
BRAIN IMAGING AND ALZHEIMER'S

4099
02:20:30,340 --> 02:20:33,810
DISEASE MARKERS AND BIOFLUIDS,

4100
02:20:33,810 --> 02:20:35,645
WE HAVE ADDED A LOT OF OUTCOMES

4101
02:20:35,645 --> 02:20:37,380
REALLY RELEVANT TO BIOLOGICAL

4102
02:20:37,380 --> 02:20:38,248
AGING.

4103
02:20:38,248 --> 02:20:43,320
SO OF COURSE SENESCENCE AND --

4104
02:20:43,320 --> 02:20:44,921
WE'RE NOT COLLECTING DATA ON

4105
02:20:44,921 --> 02:20:47,057
STEM CELL EXHAUSTION OR TELOMERE

4106
02:20:47,057 --> 02:20:48,224
ATTRITION BUT REALLY TRYING TO

4107
02:20:48,224 --> 02:20:49,592
COVER ALL OF THE OTHER HALL

4108
02:20:49,592 --> 02:20:50,160
MARKS.

4109
02:20:50,160 --> 02:20:51,361
WE'VE ALSO INCLUDED

4110
02:20:51,361 --> 02:20:57,267
PHYSIOLOGICAL MEASURES OF AGING,

4111
02:20:57,267 --> 02:20:58,835
AS WELL AS GRIP STRENGTH.

4112
02:20:58,835 --> 02:21:00,603
SO WE ARE HOPING TO BE FULLY

4113
02:21:00,603 --> 02:21:02,339
ENROLLED NEXT SPRING WITH DATA

4114
02:21:02,339 --> 02:21:07,277
IN 2025.

4115
02:21:07,277 --> 02:21:08,178
NEUROSCIENCE FIELD WAS A BIT

4116
02:21:08,178 --> 02:21:10,246
LATE TO STUDY SENESCENCE IN OUR

4117
02:21:10,246 --> 02:21:12,215
FAVORITE TISSUES IN THE BRAIN

4118
02:21:12,215 --> 02:21:15,185
AND CENTRAL NERVOUS SYSTEM IN

4119
02:21:15,185 --> 02:21:17,153
GENERAL, BUT WHAT I'VE PUT HERE,

4120
02:21:17,153 --> 02:21:18,788
I'M GOING TO TOGGLE BACK AND

4121
02:21:18,788 --> 02:21:20,090
FORTH BETWEEN THESE TWO SLIDES

4122
02:21:20,090 --> 02:21:22,625
REALLY TO HIGHLIGHT WHAT

4123
02:21:22,625 --> 02:21:24,728
ACTIVITY IS IN THE NEUROSCIENCE

4124
02:21:24,728 --> 02:21:28,798
FIELD EVALUATING SENESCENCE.

4125
02:21:28,798 --> 02:21:30,467
THESE ARE FROM 2018 AND BEYOND,

4126
02:21:30,467 --> 02:21:31,968
SO REALLY A LOT OF ACTIVE

4127
02:21:31,968 --> 02:21:33,636
RESEARCH SHOWING HOW IMPORTANT

4128
02:21:33,636 --> 02:21:36,039
SENESCENT CELLS MIGHT BE IN MANY

4129
02:21:36,039 --> 02:21:37,140
NEURODEGENERATIVE DISEASES.

4130
02:21:37,140 --> 02:21:39,876
SO THEN THINKING ABOUT WHAT

4131
02:21:39,876 --> 02:21:42,178
FACTORS COULD IMPACT THE ONSET

4132
02:21:42,178 --> 02:21:43,380
OF SENESCENT CELLS IN THE BRAIN

4133
02:21:43,380 --> 02:21:45,448
AND LEAD TO DEMENTIA, A LOT OF

4134
02:21:45,448 --> 02:21:47,550
THOSE CLUES HAVE COME FROM

4135
02:21:47,550 --> 02:21:48,885
COLLEAGUES IN THE NEUROSCIENCE

4136
02:21:48,885 --> 02:21:49,319
SPACE.

4137
02:21:49,319 --> 02:21:50,720
SO THERE HAVE BEEN RESEARCH

4138
02:21:50,720 --> 02:21:52,155
GROUPS THAT HAVE SHOWN

4139
02:21:52,155 --> 02:21:53,456
PERIPHERAL INSULIN RESISTANCE

4140
02:21:53,456 --> 02:21:54,924
CAN DRIVE SENESCENCE IN THE

4141
02:21:54,924 --> 02:21:57,527
BRAIN, OBESITY, DEPRESSION AND

4142
02:21:57,527 --> 02:21:59,129
AKITE, VIRAL INFECTION AND

4143
02:21:59,129 --> 02:21:59,729
TRAUMATIC BRAIN INJURY.

4144
02:21:59,729 --> 02:22:01,798
SO ALL OF THESE ARE DRIVING

4145
02:22:01,798 --> 02:22:03,533
SENESCENCE IN THE BRAIN, AND

4146
02:22:03,533 --> 02:22:06,036
DRIVING THE INCREASED ONSET OF

4147
02:22:06,036 --> 02:22:06,770
NEURODEGENERATIVE DISEASES.

4148
02:22:06,770 --> 02:22:08,838
SO WE THINK THAT THERE MAY BE A

4149
02:22:08,838 --> 02:22:11,174
PUSH TOWARDS A DEGENERATIVE

4150
02:22:11,174 --> 02:22:12,042
TRAJECTORY WITH SENESCENCE.

4151
02:22:12,042 --> 02:22:14,044
AND WE HEARD THE BEAUTIFUL TALK

4152
02:22:14,044 --> 02:22:15,011
EARLIER ABOUT CLONAL

4153
02:22:15,011 --> 02:22:15,779
HEMATOPOIESIS, AND THAT PAPER

4154
02:22:15,779 --> 02:22:17,547
WAS REALLY INTERESTING TO ME

4155
02:22:17,547 --> 02:22:20,517
BECAUSE IT HAD AN INVERSE

4156
02:22:20,517 --> 02:22:21,484
CORRELATION WITH ALZHEIMER'S

4157
02:22:21,484 --> 02:22:23,987
DISEASE, SO PERHAPS IN THIS WAY

4158
02:22:23,987 --> 02:22:26,423
SENESCENCE, IF A CELL HAS A CELL

4159
02:22:26,423 --> 02:22:27,957
FATE OPTION TO MAKE, IT IS

4160
02:22:27,957 --> 02:22:29,492
BLOCKING THE PROLIFERATIVE

4161
02:22:29,492 --> 02:22:30,960
TRAJECTORY.

4162
02:22:30,960 --> 02:22:32,662
BUT OF COURSE THIS IS ALL VERY

4163
02:22:32,662 --> 02:22:35,632
COMPLICATECOMPLICATED AND THERES

4164
02:22:35,632 --> 02:22:37,000
ENVIRONMENT, AGE, GENETICS AND

4165
02:22:37,000 --> 02:22:38,601
WHAT TYPE OF STRESSORS NEED TO

4166
02:22:38,601 --> 02:22:39,969
BE CONSIDERED AND WHEN WE'RE

4167
02:22:39,969 --> 02:22:41,371
INTEGRATING ALL OF THESE DATA,

4168
02:22:41,371 --> 02:22:42,372
WE THINK IT'S ALSO REALLY

4169
02:22:42,372 --> 02:22:45,675
IMPORTANT TO GET BEYOND JUST

4170
02:22:45,675 --> 02:22:47,077
BULK TRANSCRIPTOMICS OR EVEN

4171
02:22:47,077 --> 02:22:48,845
SINGLE CELL TRANSCRIPTOMICS AND

4172
02:22:48,845 --> 02:22:51,815
REALLY LOOK AT HIGH RESOLUTION,

4173
02:22:51,815 --> 02:22:52,682
HIGH-PLEX MULTI-OMICS DATA

4174
02:22:52,682 --> 02:22:54,451
WITHIN A CELL AND SUBCELLULAR

4175
02:22:54,451 --> 02:22:55,452
RESOLUTION TO SEE WHAT'S

4176
02:22:55,452 --> 02:22:58,088
HAPPENING IN THAT CELL IN ITS

4177
02:22:58,088 --> 02:22:59,622
NEIGHBORING ENVIRONMENT AND

4178
02:22:59,622 --> 02:23:00,023
BEYOND.

4179
02:23:00,023 --> 02:23:01,024
SO IN THE LAST FEW MINUTES THAT

4180
02:23:01,024 --> 02:23:02,492
I HAVE, I'M GOING TO TOUCH ON

4181
02:23:02,492 --> 02:23:04,661
SOME KEY RESEARCH GAPS AND

4182
02:23:04,661 --> 02:23:06,196
OPPORTUNITIES FROM MY

4183
02:23:06,196 --> 02:23:07,864
PERSPECTIVE AND I'VE BROKEN

4184
02:23:07,864 --> 02:23:10,166
THESE INTO BOTH CLINICAL AND

4185
02:23:10,166 --> 02:23:10,600
DISCOVERY SCIENCE.

4186
02:23:10,600 --> 02:23:12,702
ON THE CLINICAL SIDE, I THINK

4187
02:23:12,702 --> 02:23:14,471
THERE IS A BIG NEED TO

4188
02:23:14,471 --> 02:23:15,805
UNDERSTAND BRAIN HEALTH AND RATE

4189
02:23:15,805 --> 02:23:17,640
OF AGING ACROSS DIVERSE

4190
02:23:17,640 --> 02:23:18,975
POPULATIONS AND ACROSS THE

4191
02:23:18,975 --> 02:23:19,642
LIFESPAN.

4192
02:23:19,642 --> 02:23:20,643
SO WE REALLY DON'T KNOW MUCH

4193
02:23:20,643 --> 02:23:22,245
ABOUT BRAIN HEALTH AND AGING IN

4194
02:23:22,245 --> 02:23:24,581
RACIAL AND ETHNIC MINORITIES,

4195
02:23:24,581 --> 02:23:25,915
SEXUAL AND GENDER MINORITIES,

4196
02:23:25,915 --> 02:23:27,884
INDIVIDUALS FROM RURAL AND

4197
02:23:27,884 --> 02:23:31,688
UNDERSERRED AREAS, ACROSS THE

4198
02:23:31,688 --> 02:23:32,622
ECONOMIC STRATA AND MILITARY

4199
02:23:32,622 --> 02:23:34,124
VETERANS AND UNDERSTANDING HOW

4200
02:23:34,124 --> 02:23:35,758
THESE BRAINS ARE CHANGING WILL

4201
02:23:35,758 --> 02:23:36,793
REALLY HELP US BETTER ANSWER

4202
02:23:36,793 --> 02:23:37,861
THIS QUESTION, WHAT ARE COMMON

4203
02:23:37,861 --> 02:23:39,496
AND SHARED RISK FACTORS.

4204
02:23:39,496 --> 02:23:42,132
WE ALSO REALLY DON'T HAVE A GOOD

4205
02:23:42,132 --> 02:23:43,733
IDEA OF HOW PEOPLE WITH DEMENTIA

4206
02:23:43,733 --> 02:23:44,134
AGE.

4207
02:23:44,134 --> 02:23:45,602
THEY ARE TYPICALLY EXCLUDED FROM

4208
02:23:45,602 --> 02:23:46,636
AGING STUDIES.

4209
02:23:46,636 --> 02:23:47,971
WE'VE HEARD THAT IN THE LAST

4210
02:23:47,971 --> 02:23:48,972
TALK.

4211
02:23:48,972 --> 02:23:50,607
THERE'S DIFFERENT EXCLUSION

4212
02:23:50,607 --> 02:23:52,675
CRITERIA FOR AGE BASED ON WHAT

4213
02:23:52,675 --> 02:23:55,445
DISEASE OF AGING YOU'RE

4214
02:23:55,445 --> 02:23:56,746
STUDYING, SO I'D LIKE TO SEE

4215
02:23:56,746 --> 02:23:57,947
PEOPLE WITH DEMENTIA INCLUDED IN

4216
02:23:57,947 --> 02:23:59,382
THESE STUDIES IF AND WHEN

4217
02:23:59,382 --> 02:24:00,283
POSSIBLE.

4218
02:24:00,283 --> 02:24:01,284
ANOTHER POINT IS THAT MANY

4219
02:24:01,284 --> 02:24:04,020
METRICS OF BRAIN HEALTH AND

4220
02:24:04,020 --> 02:24:06,489
PERFORMANCE PEAK IN THE 30s

4221
02:24:06,489 --> 02:24:08,291
BUT AGING STUDIES BEGIN MUCH

4222
02:24:08,291 --> 02:24:08,625
LATER.

4223
02:24:08,625 --> 02:24:10,026
I THINK WE NEED TO START

4224
02:24:10,026 --> 02:24:10,260
YOUNGER.

4225
02:24:10,260 --> 02:24:11,494
THAT WAS ANOTHER POINT THAT WAS

4226
02:24:11,494 --> 02:24:12,562
BROUGHT UP EARLIER AS WELL.

4227
02:24:12,562 --> 02:24:13,796
I THINK WE NEED A BETTER

4228
02:24:13,796 --> 02:24:15,198
DEFINITION OF AGING FOR RESEARCH

4229
02:24:15,198 --> 02:24:15,598
PURPOSES.

4230
02:24:15,598 --> 02:24:17,200
IT'S REALLY CHALLENGING TO

4231
02:24:17,200 --> 02:24:18,168
IDENTIFY INTERVENTIONS AND

4232
02:24:18,168 --> 02:24:19,602
DESIGN TRIALS WITHOUT A CLEAR

4233
02:24:19,602 --> 02:24:23,907
DIFFICULT NIGDEFINITION OF OUTC.

4234
02:24:23,907 --> 02:24:25,775
I THINK WE NEED A MORE

4235
02:24:25,775 --> 02:24:26,643
AGGRESSIVE TRANSLATION OF

4236
02:24:26,643 --> 02:24:27,577
PROMISING PRE-CLINICAL

4237
02:24:27,577 --> 02:24:28,077
THERAPIES.

4238
02:24:28,077 --> 02:24:29,379
ON THE DISCOVERY SIDE, THERE'S A

4239
02:24:29,379 --> 02:24:31,347
LOT OF NEED TO BETTER UNDERSTAND

4240
02:24:31,347 --> 02:24:35,084
MIMECHANISMS MEDIATING WITHIN

4241
02:24:35,084 --> 02:24:35,552
TISSUES.

4242
02:24:35,552 --> 02:24:37,220
WE KNOW THAT NOT ALL OF OUR

4243
02:24:37,220 --> 02:24:38,288
ORGANS ARE AGING AT THE SAME

4244
02:24:38,288 --> 02:24:38,721
RATE.

4245
02:24:38,721 --> 02:24:40,156
IT'S LIKELY THAT OUR CELLS

4246
02:24:40,156 --> 02:24:42,058
AREN'T AGING AT THE SAME RATE

4247
02:24:42,058 --> 02:24:43,893
EITHER, AND I PROVIDE SENESCENCE

4248
02:24:43,893 --> 02:24:44,894
AS ONE EXAMPLE BUT THERE ARE A

4249
02:24:44,894 --> 02:24:47,030
LOT OF OTHER BIOLOGICAL AGING

4250
02:24:47,030 --> 02:24:48,331
HALLMARKS THAT ARE IMPORTANT TO

4251
02:24:48,331 --> 02:24:48,965
INCORPORATE.

4252
02:24:48,965 --> 02:24:50,433
I MENTIONED INCORPORATING

4253
02:24:50,433 --> 02:24:53,269
SPATIAL OMICS DATA --

4254
02:24:53,269 --> 02:24:54,804
>> SPEAKER, YOU HAVE 2
MINUTES

4255
02:24:54,804 --> 02:24:55,271
REMAINING.

4256
02:24:55,271 --> 02:24:57,540
>> THANK YOU SO MUCHMENT I
ALSO

4257
02:24:57,540 --> 02:24:59,108
THINK THAT WE MIGHT BE AT A

4258
02:24:59,108 --> 02:25:00,743
PLACE OR GETTING CLOSE TO A

4259
02:25:00,743 --> 02:25:02,412
PLACE FOR PRECISION MEDICINE

4260
02:25:02,412 --> 02:25:04,514
APPROACHES FOR AGING, SO REALLY

4261
02:25:04,514 --> 02:25:05,615
TESTING COMBINATION THERAPIES

4262
02:25:05,615 --> 02:25:09,085
THAT TARGET MULTIPLE AGING HALL

4263
02:25:09,085 --> 02:25:10,653
MARKS, DOING THIS IN MODEL

4264
02:25:10,653 --> 02:25:11,788
ORGANISMS AND IDENTIFYING THE

4265
02:25:11,788 --> 02:25:12,488
APPROPRIATE AGES FOR EACH

4266
02:25:12,488 --> 02:25:16,125
THERAPY.

4267
02:25:16,125 --> 02:25:17,427
SO THEN JUST CLOSING WITH THE

4268
02:25:17,427 --> 02:25:20,563
NEEDS OVER THE NEXT FIVE YEARS,

4269
02:25:20,563 --> 02:25:21,664
THIS IS SOMETHING THAT A LOT OF

4270
02:25:21,664 --> 02:25:23,433
US SAY THAT STUDY AGING, THERE'S

4271
02:25:23,433 --> 02:25:25,068
A NEED FOR GREATER AND LONGER

4272
02:25:25,068 --> 02:25:26,536
BUDGET PERIODS FOR IN VIVO

4273
02:25:26,536 --> 02:25:28,805
MAMMALIAN AG AGING STUDIES.

4274
02:25:28,805 --> 02:25:29,973
THESE ARE LONG AND EXTENSIVE.

4275
02:25:29,973 --> 02:25:32,542
I MENTIONED THIS IN MY PRIOR

4276
02:25:32,542 --> 02:25:34,110
SLIDE BUT I THINK IT WOULD BE

4277
02:25:34,110 --> 02:25:37,180
REALLY IMPORTANT TO HAVE -- FOR

4278
02:25:37,180 --> 02:25:39,282
OBSERVATIONAL AND INTERVENTIONAL

4279
02:25:39,282 --> 02:25:41,517
RESEARCH SIMILAR AS FOR

4280
02:25:41,517 --> 02:25:42,452
ALZHEIMER'S DISEASE.

4281
02:25:42,452 --> 02:25:44,220
SO FOCUSING ON A BIOLOGICAL

4282
02:25:44,220 --> 02:25:45,989
FRAMEWORK WHICH THE AGING FIELD

4283
02:25:45,989 --> 02:25:52,095
ALREADY HAS AND NOT BIOLOGICAL

4284
02:25:52,095 --> 02:25:53,329
CONSEQUENCES.

4285
02:25:53,329 --> 02:25:54,897
REALLY CATAPULT THESE CLINICAL

4286
02:25:54,897 --> 02:25:55,531
STUDIES.

4287
02:25:55,531 --> 02:25:56,866
IF WE'RE NOT HERE, I THINK WE

4288
02:25:56,866 --> 02:25:59,068
NEED A PLAN TO GET HERE QUICKLY.

4289
02:25:59,068 --> 02:26:01,037
I THINK IT'S ALSO IMPORTANT TO

4290
02:26:01,037 --> 02:26:02,672
HARMONIZE A CONSISTENT LIST OF

4291
02:26:02,672 --> 02:26:04,307
AGING OUTCOMES FOR CLINICAL

4292
02:26:04,307 --> 02:26:06,476
TRIALS THAT INCLUDE BRAIN AND

4293
02:26:06,476 --> 02:26:07,010
COGNITIVE HEALTH.

4294
02:26:07,010 --> 02:26:08,077
I DON'T KNOW IF THIS WOULD

4295
02:26:08,077 --> 02:26:10,179
REQUIRE A CONSENSUS GROUP, BUT

4296
02:26:10,179 --> 02:26:11,781
THERE ARE A LOT OF METRICS TO

4297
02:26:11,781 --> 02:26:12,048
CONSIDER.

4298
02:26:12,048 --> 02:26:16,019
HOW ARE WE ASSESSING BRAIN AGING

4299
02:26:16,019 --> 02:26:17,020
THROUGH THE LIFESPAN.

4300
02:26:17,020 --> 02:26:18,788
IS IT BIOMARKERS IN FLUIDS,

4301
02:26:18,788 --> 02:26:20,323
THERE'S A LOT OF ACTIVE AND

4302
02:26:20,323 --> 02:26:22,425
FANTASTIC RESEARCH IN DIGITAL

4303
02:26:22,425 --> 02:26:22,725
BIOMARKERS.

4304
02:26:22,725 --> 02:26:24,193
AND THEN INCORPORATE METRICS OF

4305
02:26:24,193 --> 02:26:25,662
BRAIN HEALTH IN AGING STUDIES,

4306
02:26:25,662 --> 02:26:28,865
WHICH I THINK INTERDISCIPLINARY

4307
02:26:28,865 --> 02:26:29,699
COLLABORATIONS WILL BEST TACKLE

4308
02:26:29,699 --> 02:26:29,899
THAT.

4309
02:26:29,899 --> 02:26:31,968
I WOULD LIKE TO END WITH A QUOTE

4310
02:26:31,968 --> 02:26:33,670
FROM MY FATHER-IN-LAW THAT HE

4311
02:26:33,670 --> 02:26:34,937
GAVE ME OVER DINNER ONE NIGHT,

4312
02:26:34,937 --> 02:26:36,439
AND THAT WAS, "IF I FOLLOWED ALL

4313
02:26:36,439 --> 02:26:38,374
OF THE HEALTHY LIFESTYLE ADVICE,

4314
02:26:38,374 --> 02:26:38,941
I WOULDN'T HAVE TIME FOR

4315
02:26:38,941 --> 02:26:39,742
ANYTHING ELSE."

4316
02:26:39,742 --> 02:26:41,244
I THINK THAT KIND OF SUMS UP OUR

4317
02:26:41,244 --> 02:26:41,577
FIELD.

4318
02:26:41,577 --> 02:26:42,945
THERE'S SO MUCH INFORMATION

4319
02:26:42,945 --> 02:26:44,781
THAT'S COMING UP, COMING OUT,

4320
02:26:44,781 --> 02:26:51,921
TRYING TO COH COHESIVELY UNDERSD

4321
02:26:51,921 --> 02:26:53,356
IT IS CHALLENGING BUT WE ARE

4322
02:26:53,356 --> 02:26:54,457
GETTING THERE.

4323
02:26:54,457 --> 02:26:56,359
WE DO NEED TO TAKE TIME TO FOCUS

4324
02:26:56,359 --> 02:26:57,860
ON OUR HEALTHY LIFE.

4325
02:26:57,860 --> 02:26:59,295
AND SO WITH THAT, I WOULD JUST

4326
02:26:59,295 --> 02:27:01,397
LIKE TO ACKNOWLEDGE MY AMAZING

4327
02:27:01,397 --> 02:27:03,099
LAB, MY COLLABORATORS HERE AT

4328
02:27:03,099 --> 02:27:05,468
WAKE FOREST AND AT OTHER

4329
02:27:05,468 --> 02:27:08,438
INSTITUTIONS AND MY FUNDING

4330
02:27:08,438 --> 02:27:09,639
SUPPORT ALLOWS ME TO CONTINUE

4331
02:27:09,639 --> 02:27:10,873
DOING THIS EXCITING RESEARCH.

4332
02:27:10,873 --> 02:27:11,808
SO THANK YOU SO MUCH FOR YOUR

4333
02:27:11,808 --> 02:27:14,644
TIME AND I THINK I HAVE LEFT

4334
02:27:14,644 --> 02:27:16,145
TIME FOR SOME QUESTIONS.

4335
02:27:16,145 --> 02:27:17,046
>> YOU HAVE.

4336
02:27:17,046 --> 02:27:19,582
GREAT TALK.

4337
02:27:19,582 --> 02:27:21,351
YOU ONLY HAVE TO FOLLOW THE GOOD

4338
02:27:21,351 --> 02:27:23,219
ADVICE, YOU CAN IGNORE ALL THE

4339
02:27:23,219 --> 02:27:23,986
BAD.

4340
02:27:23,986 --> 02:27:26,055
ANYWAY, LET'S START WITH ONE

4341
02:27:26,055 --> 02:27:28,424
FROM DR. YAZ IN THE Q & A.

4342
02:27:28,424 --> 02:27:29,292
DR. ORR, YOU PREVIOUSLY

4343
02:27:29,292 --> 02:27:30,793
PRESENTED AN ABSTRACT ON

4344
02:27:30,793 --> 02:27:39,168
SUPPLEMENTING NAD WITH --

4345
02:27:39,168 --> 02:27:41,471
RIBOSIDE TO ADDRESS MILD

4346
02:27:41,471 --> 02:27:43,206
COGNITIVE IMPAIRMENT.

4347
02:27:43,206 --> 02:27:44,640
HOW DOES THIS IMPACT SENESCENCE

4348
02:27:44,640 --> 02:27:45,208
IN THIS STUDY?

4349
02:27:45,208 --> 02:27:46,309
>> THAT IS A GREAT
QUESTION.

4350
02:27:46,309 --> 02:27:50,146
SO THAT PAPER IS CURRENTLY UNDER

4351
02:27:50,146 --> 02:27:50,580
REVIEW.

4352
02:27:50,580 --> 02:27:51,914
WE DID NOT LOOK AT CELLULAR

4353
02:27:51,914 --> 02:27:54,283
SENESCENCE IN THAT CLINICAL

4354
02:27:54,283 --> 02:27:55,518
STUDY.

4355
02:27:55,518 --> 02:27:56,252
WE ABSOLUTELY SHOULD HAVE.

4356
02:27:56,252 --> 02:27:56,853
WE DIDN'T.

4357
02:27:56,853 --> 02:27:57,954
BUT I DO KNOW THAT THERE IS A

4358
02:27:57,954 --> 02:27:59,622
LOT OF ACTIVE RESEARCH IN THAT

4359
02:27:59,622 --> 02:28:00,723
BY OTHER LABS IN THE FIELD

4360
02:28:00,723 --> 02:28:04,026
LOOKING AT HOW NICK TIN MIGHT OR

4361
02:28:04,026 --> 02:28:06,429
ANY NAD BOOSTERS MAY ALTER

4362
02:28:06,429 --> 02:28:07,830
CELLULAR SENESCENCE.

4363
02:28:07,830 --> 02:28:11,801
THAT'S A REALLY GOOD QUESTION.

4364
02:28:11,801 --> 02:28:13,770
>> LIKE SENESCENT CELLS,
DO

4365
02:28:13,770 --> 02:28:15,938
SENESCENT NEURONS SECRETE SAS

4366
02:28:15,938 --> 02:28:17,206
FACTORS WHICH AFFECT OTHER

4367
02:28:17,206 --> 02:28:22,678
NEIGHBORING YOUNG NEURONS?

4368
02:28:22,678 --> 02:28:24,547
>> I CAN TELL YOU WHAT WE
ARE

4369
02:28:24,547 --> 02:28:28,785
SEEING PRELIMINARILY.

4370
02:28:28,785 --> 02:28:29,886
PLEAS DON'T TAKE THIS TO THE

4371
02:28:29,886 --> 02:28:30,920
BANK BECAUSE IT NEEDS TO BE

4372
02:28:30,920 --> 02:28:31,354
REPEATED.

4373
02:28:31,354 --> 02:28:32,555
SO ONE THING THAT WE ARE TRYING

4374
02:28:32,555 --> 02:28:37,093
TO IDENTIFY IS WHAT MAY BE

4375
02:28:37,093 --> 02:28:38,394
NEURONAL SPECIFIC SAS.

4376
02:28:38,394 --> 02:28:39,562
NEURONS ARE REALLY INTERESTING

4377
02:28:39,562 --> 02:28:40,930
BRAIN CELLS IN THAT THEY

4378
02:28:40,930 --> 02:28:41,831
COMMUNICATE TO EACH OTHER IN A

4379
02:28:41,831 --> 02:28:42,899
VERY DIFFERENT WAY THAN OTHER

4380
02:28:42,899 --> 02:28:44,000
CELLS SO WE'RE TRYING TO FIGURE

4381
02:28:44,000 --> 02:28:45,468
OUT WHEN NEURONS BECOME

4382
02:28:45,468 --> 02:28:47,203
SENESCENT IF THEY CHANGE THAT

4383
02:28:47,203 --> 02:28:48,538
MESSAGE, AND IF THEY'RE

4384
02:28:48,538 --> 02:28:52,241
IMPACTING THEIR LOCAL

4385
02:28:52,241 --> 02:28:54,110
ENVIRONMENT AS WELL AS THEIR

4386
02:28:54,110 --> 02:28:54,877
SYNAPTICALLY CONNECTED

4387
02:28:54,877 --> 02:28:55,178
ENVIRONMENT.

4388
02:28:55,178 --> 02:28:56,045
WE HAVE EVIDENCE THEY ARE

4389
02:28:56,045 --> 02:28:56,579
IMPACTING BOTH.

4390
02:28:56,579 --> 02:28:57,814
I AM DEFINITELY NOT BRAVE ENOUGH

4391
02:28:57,814 --> 02:29:01,517
TO GIVE YOU ANY CONCRETE ANSWERS

4392
02:29:01,517 --> 02:29:02,618
BEYOND THAT BUT WE'RE ACTIVELY

4393
02:29:02,618 --> 02:29:05,087
LOOKING INTO THAT.

4394
02:29:05,087 --> 02:29:07,857
>> BY DEFINITION, THEY
SHOULD BE

4395
02:29:07,857 --> 02:29:08,858
EXPRESSING, THAT'S HOW WE FIND

4396
02:29:08,858 --> 02:29:11,060
SENESCENT CELLS, SO THEY MUST BE

4397
02:29:11,060 --> 02:29:12,929
EXPRESSING THEM SOMEHOW.

4398
02:29:12,929 --> 02:29:17,533
COOL.

4399
02:29:17,533 --> 02:29:20,670
THERE'S SOME OTHER COMMENTS HE 

4400
02:29:20,670 --> 02:29:20,870
HERE.

4401
02:29:20,870 --> 02:29:21,637
OH, SAME QUESTION UP HERE.

4402
02:29:21,637 --> 02:29:25,708
I HAVE A QUESTION WHICH IS ABOUT

4403
02:29:25,708 --> 02:29:26,609
THE -- SO REALLY SHARP PEOPLE,

4404
02:29:26,609 --> 02:29:28,911
DO THEY HAVE MORE OR LESS

4405
02:29:28,911 --> 02:29:32,849
SENESCENT CELLS IN THEIR BRAIN?

4406
02:29:32,849 --> 02:29:36,152
I COULD ARGUE IT EITHER WAY.

4407
02:29:36,152 --> 02:29:38,054
>> SO I CAN ALSO TELL YOU
SOME

4408
02:29:38,054 --> 02:29:38,588
PRELIMINARY DATA.

4409
02:29:38,588 --> 02:29:41,858
WE HAVE AN R01, THE GOAL IS TO

4410
02:29:41,858 --> 02:29:43,493
DETERMINE WHEN IN THE ADULT

4411
02:29:43,493 --> 02:29:44,660
LIFESPAN DO SENESCENT CELLS

4412
02:29:44,660 --> 02:29:45,027
FIRST APPEAR.

4413
02:29:45,027 --> 02:29:46,762
SO WE'RE LOOKING AT POSTMORTEM

4414
02:29:46,762 --> 02:29:48,331
VIEW OF BRAINS ACROSS THE ENTIRE

4415
02:29:48,331 --> 02:29:50,766
ADULT LIFESPAN, AGE 20 TO

4416
02:29:50,766 --> 02:29:51,734
100-PLUS, AND THEN ONCE WE HIT

4417
02:29:51,734 --> 02:29:54,170
THE AGE OF 60, WE'RE LOOKING AT

4418
02:29:54,170 --> 02:29:55,705
THOSE WITH DEMENTIA VERSUS THOSE

4419
02:29:55,705 --> 02:29:56,706
THAT DON'T.

4420
02:29:56,706 --> 02:29:59,675
I DON'T KNOW THE TRUE COGNITIVE

4421
02:29:59,675 --> 02:30:02,445
STATUS ON OUR DEMENTIA-NEGATIVE

4422
02:30:02,445 --> 02:30:03,779
PEOPLE TO KNOW IF THEY'RE SUPER

4423
02:30:03,779 --> 02:30:05,014
SHARP, BUT I CAN TELL YOU THAT

4424
02:30:05,014 --> 02:30:06,215
WE'RE FINDING SENESCENT CELLS

4425
02:30:06,215 --> 02:30:08,050
FAR YOUNGER IN THE LIFESPAN THAN

4426
02:30:08,050 --> 02:30:10,586
I EVER HOPED.

4427
02:30:10,586 --> 02:30:11,787
WE'RE DEFINITELY FINDING THEM AS

4428
02:30:11,787 --> 02:30:13,122
EARLY AS THE 40s.

4429
02:30:13,122 --> 02:30:14,557
I DON'T KNOW IF WE WILL FIND

4430
02:30:14,557 --> 02:30:17,393
THEM EARLIER.

4431
02:30:17,393 --> 02:30:21,697
BUT THEY'RE HAPPENING.

4432
02:30:21,697 --> 02:30:23,099
I'M SURE I HAVE SOME IN MY

4433
02:30:23,099 --> 02:30:23,299
BRAIN.

4434
02:30:23,299 --> 02:30:24,934
>> WELL, WE ALL DO, JUST
LIKE WE

4435
02:30:24,934 --> 02:30:27,803
ALL HAVE C.H. CELLS APPARENTLY.

4436
02:30:27,803 --> 02:30:29,372
ALL RIGHT.

4437
02:30:29,372 --> 02:30:35,011
>> ANOTHER QUESTION, MIKE.

4438
02:30:35,011 --> 02:30:36,112
SO ALZHEIMER'S DISEASE IS ALMOST

4439
02:30:36,112 --> 02:30:37,079
TWICE AS COMMON IN WOMEN

4440
02:30:37,079 --> 02:30:39,982
COMPARED TO MEN SO DO THE WOMEN

4441
02:30:39,982 --> 02:30:41,217
ACCUMULATE MORE SENESCENT CELLS,

4442
02:30:41,217 --> 02:30:42,151
DO YOU KNOW?

4443
02:30:42,151 --> 02:30:44,620
>> SO RIGHT NOW WE HAVE
NOT SEEN

4444
02:30:44,620 --> 02:30:46,489
A SEX DIFFERENCE, BUT THAT IS

4445
02:30:46,489 --> 02:30:49,559
JUST ON TOTAL SENESCENT CELL

4446
02:30:49,559 --> 02:30:50,226
BURDEN.

4447
02:30:50,226 --> 02:30:51,527
BUT WE'RE TRYING TO GET BETTER

4448
02:30:51,527 --> 02:30:54,297
WITH OUR REFINEMENT AND LOOKING

4449
02:30:54,297 --> 02:30:55,197
AT DIFFERENT TYPES OF SENESCENT

4450
02:30:55,197 --> 02:30:55,731
CELLS.

4451
02:30:55,731 --> 02:30:57,166
NOT ALL SENESCENT CELLS ARE BAD.

4452
02:30:57,166 --> 02:30:57,934
SO STAY TUNED.

4453
02:30:57,934 --> 02:31:02,038
WE DON'T KNOW THAT ANSWER YET.

4454
02:31:02,038 --> 02:31:04,006
>> VERY NICE TALK.

4455
02:31:04,006 --> 02:31:05,975
HOW MUCH SYSTEMIC INFLAMMATION

4456
02:31:05,975 --> 02:31:11,647
PLAYS A ROLE, AND IS SENESCENCE

4457
02:31:11,647 --> 02:31:14,116
SORT OF DISGUISED BY SYSTEMIC

4458
02:31:14,116 --> 02:31:15,518
INFLAMMATION OR VICE VERSA?

4459
02:31:15,518 --> 02:31:17,153
>> THAT IS A QUESTION THAT
I GET

4460
02:31:17,153 --> 02:31:18,955
ALL THE TIME AND I DON'T HAVE A

4461
02:31:18,955 --> 02:31:21,157
FANTASTIC ANSWER BECAUSE IT'S SO

4462
02:31:21,157 --> 02:31:21,791
CHALLENGING.

4463
02:31:21,791 --> 02:31:23,159
HOW DO YOU DETERMINE

4464
02:31:23,159 --> 02:31:24,026
INFLAMMATION COMING FROM

4465
02:31:24,026 --> 02:31:25,261
SENESCENT CELLS VERSUS

4466
02:31:25,261 --> 02:31:25,895
INFLAMMATION COMING FROM OTHER

4467
02:31:25,895 --> 02:31:26,329
SOURCES.

4468
02:31:26,329 --> 02:31:27,997
I THINK THE BEST WAY TO LOOK AT

4469
02:31:27,997 --> 02:31:29,966
THAT IS IN ANIMAL MODELS, BUT

4470
02:31:29,966 --> 02:31:36,005
THE.WITH OUR CLINICAL TRIAL, A T

4471
02:31:36,005 --> 02:31:37,974
OF OUR FACTORS WE'RE MEASURING

4472
02:31:37,974 --> 02:31:39,542
ARE GOING TO BE DIFFICULT TO

4473
02:31:39,542 --> 02:31:40,509
ATTRIBUTE ONLY TO SENESCENT

4474
02:31:40,509 --> 02:31:41,978
CELLS.

4475
02:31:41,978 --> 02:31:44,280
IF WE COULD FIND SENESCENT CELL

4476
02:31:44,280 --> 02:31:45,414
SPECIFIC BIOMARKERS OF

4477
02:31:45,414 --> 02:31:49,218
INFLAMMATION, THAT WOULD BE FABE

4478
02:31:49,218 --> 02:31:49,552
FANTASTIC.

4479
02:31:49,552 --> 02:31:51,320
I DON'T KNOW IF WE EVER WILL.

4480
02:31:51,320 --> 02:31:52,088
>> WELL THANKS VERY MUCH.

4481
02:31:52,088 --> 02:31:53,522
WE BETTER MOVE TO THE NEXT

4482
02:31:53,522 --> 02:31:57,026
SPEAKER WHICH I THINK SEGUES

4483
02:31:57,026 --> 02:32:00,129
REALLY NICELY.

4484
02:32:00,129 --> 02:32:02,565
FILIP SWIRSKI IS GOING TO TELL

4485
02:32:02,565 --> 02:32:06,535
BUS LIFE STYLE EFFECTS ON BRA 

4486
02:32:06,535 --> 02:32:07,503
BRAIN-BODY COMMUNICATION.

4487
02:32:07,503 --> 02:32:08,004
>> THANK YOU VERY MUCH.

4488
02:32:08,004 --> 02:32:09,538
THIS IS A FANTASTIC WORKSHOP,

4489
02:32:09,538 --> 02:32:10,506
VERY HAPPY TO BE HERE.

4490
02:32:10,506 --> 02:32:11,707
WHAT I WANT TO DO FOR THE NEXT

4491
02:32:11,707 --> 02:32:14,143
15 MINUTES IS TO SHARE WITH YOU

4492
02:32:14,143 --> 02:32:18,948
THE WORK THAT WE DO, AND HERE WE

4493
02:32:18,948 --> 02:32:20,216
VERY MUCH STUDY LIFE STYLE

4494
02:32:20,216 --> 02:32:22,351
FACTORS ON BRAIN-BODY

4495
02:32:22,351 --> 02:32:23,953
COMMUNICATION AND WE APPROACH

4496
02:32:23,953 --> 02:32:24,620
THIS FROM THE PERSPECTIVE THAT

4497
02:32:24,620 --> 02:32:25,821
WE'RE NOT HERE -- OUR STUDIES

4498
02:32:25,821 --> 02:32:28,524
ARE NOT DESIGNED TO DETERMINE

4499
02:32:28,524 --> 02:32:29,792
WHETHER A PARTICULAR LIFESTYLE

4500
02:32:29,792 --> 02:32:34,630
IS GOOD OR BAD FOR YOU.

4501
02:32:34,630 --> 02:32:35,765
WE CERTAINLY KNOW THE BENEFITS

4502
02:32:35,765 --> 02:32:38,367
OF SLEEP, THE DIET, AVOIDING OR

4503
02:32:38,367 --> 02:32:39,035
MANAGING STRESS.

4504
02:32:39,035 --> 02:32:41,003
RATHER, WE ARE MOTIVATED BY THE

4505
02:32:41,003 --> 02:32:42,972
QUESTION, YOU KNOW, HOW DOES

4506
02:32:42,972 --> 02:32:45,408
THIS HAPPEN, AT A TISSUE PLE LAR

4507
02:32:45,408 --> 02:32:50,446
AND CELLULAR SCALE.

4508
02:32:50,446 --> 02:32:52,415
SO BEFORE I LAUNCH INTO WHERE

4509
02:32:52,415 --> 02:32:53,783
OUR SPECIFIC STUDIES HAVE TAKEN

4510
02:32:53,783 --> 02:32:55,518
US, I WANT TO INTRODUCE OR AT

4511
02:32:55,518 --> 02:32:57,053
LEAST TOUCH ON SOME CONCEPTS

4512
02:32:57,053 --> 02:32:58,821
THAT HAVE ALREADY BEEN ACTUALLY

4513
02:32:58,821 --> 02:32:59,822
INTRODUCED TODAY VERY

4514
02:32:59,822 --> 02:33:03,693
BEAUTIFULLY BY PREVIOUS SPEAKERS

4515
02:33:03,693 --> 02:33:05,261
THAT I THINK SERVE TO REALLY

4516
02:33:05,261 --> 02:33:07,229
ANIMATE AND CONTEXTUALIZE SOME

4517
02:33:07,229 --> 02:33:12,535
OF THE STUDIES.

4518
02:33:12,535 --> 02:33:15,037
SO THE FIRST IS THIS IDEA THAT

4519
02:33:15,037 --> 02:33:17,273
HOMEOSTASIS AND DEVIATION FROM

4520
02:33:17,273 --> 02:33:18,474
HOMEOSTASIS THAT CAN ULTIMATELY

4521
02:33:18,474 --> 02:33:20,209
LEAD TO DISEASE REALLY ENGAGES

4522
02:33:20,209 --> 02:33:21,877
MULTIPLE SYSTEMS.

4523
02:33:21,877 --> 02:33:27,516
IT'S ALREADY A TRANS SYSTEM

4524
02:33:27,516 --> 02:33:28,517
PHENOMENON, AND IN ORDER TO

4525
02:33:28,517 --> 02:33:31,687
UNDERSTAND HOW DISEASES ACCRUE

4526
02:33:31,687 --> 02:33:32,922
AND WHAT EFFECTS DO THEY HAVE,

4527
02:33:32,922 --> 02:33:35,991
WE REALLY NEED TO DO STUDIES

4528
02:33:35,991 --> 02:33:39,729
THAT GO BEYOND STUDYING A SINGLE

4529
02:33:39,729 --> 02:33:40,062
SYSTEM.

4530
02:33:40,062 --> 02:33:41,731
SO IF WE ENGAGE AND BETTER

4531
02:33:41,731 --> 02:33:43,165
UNDERSTAND HOW THE NERVOUS

4532
02:33:43,165 --> 02:33:45,134
SYSTEM, HOW THE IMMUNE SYSTEM,

4533
02:33:45,134 --> 02:33:48,671
HOW THE METABOLIC SYSTEM AND

4534
02:33:48,671 --> 02:33:52,942
CIRCULATORY SYSTEMS ENGAGE

4535
02:33:52,942 --> 02:33:54,143
TOGETHER, THAT I THINK ALLOWS US

4536
02:33:54,143 --> 02:33:55,611
TO BETTER UNDERSTAND HOW WE

4537
02:33:55,611 --> 02:33:57,913
ACCRUE DISEASES DURING AGING.

4538
02:33:57,913 --> 02:33:59,215
SO WHILE A PARTICULAR DISEASE

4539
02:33:59,215 --> 02:34:01,584
MAY HAVE ONE CAUSE, ONE MUTATED

4540
02:34:01,584 --> 02:34:05,087
GENE, THE EFFECTS OF THAT REALLY

4541
02:34:05,087 --> 02:34:06,722
DOES ENGAGE MULTIPLE PATHWAYS.

4542
02:34:06,722 --> 02:34:07,957
THE SECOND IS A CONCEPT THAT

4543
02:34:07,957 --> 02:34:09,191
WE'VE ALREADY HEARD A NUMBER OF

4544
02:34:09,191 --> 02:34:11,260
TIMES HERE, SO THIS IDEA OF

4545
02:34:11,260 --> 02:34:12,328
CHRONOLOGICAL AND BIOLOGICAL

4546
02:34:12,328 --> 02:34:15,664
AGE, SO I WON'T DWELL ON THIS,

4547
02:34:15,664 --> 02:34:19,502
EXCEPT TO SAY THAT IN ASKING HOW

4548
02:34:19,502 --> 02:34:21,837
DOES CHRONOLOGICAL AGE DEVIATE

4549
02:34:21,837 --> 02:34:22,838
FROM BIOLOGICAL AGE, WE HAVE

4550
02:34:22,838 --> 02:34:24,707
THIS VERY HANDY CONCEPT OF THE

4551
02:34:24,707 --> 02:34:26,108
EXPOSOME, WHICH AGAIN WAS ALSO

4552
02:34:26,108 --> 02:34:26,709
INTRODUCED.

4553
02:34:26,709 --> 02:34:30,880
AND HERE WE CAN LOOK AT SO

4554
02:34:30,880 --> 02:34:32,748
CALLED PERSONAL EXPOSOME, MUCH

4555
02:34:32,748 --> 02:34:34,817
OF WHICH MAY BE RELATED TO

4556
02:34:34,817 --> 02:34:35,851
LIFESTYLE FACTORS SUCH AS

4557
02:34:35,851 --> 02:34:37,787
EXERCISE, DIET, SLEEP AND

4558
02:34:37,787 --> 02:34:39,655
STRESS, AND MORE OF A GENERAL

4559
02:34:39,655 --> 02:34:41,257
EXPOSOME OVER WHICH WE PERHAPS

4560
02:34:41,257 --> 02:34:47,163
HAVE LESS CONTROL, SUCH AS OUR

4561
02:34:47,163 --> 02:34:49,999
ENVIRONMENT, CLIMATE CHANGE

4562
02:34:49,999 --> 02:34:50,766
ENVIRONMENT, EVEN THINGS LIKE

4563
02:34:50,766 --> 02:34:51,267
INFECTION.

4564
02:34:51,267 --> 02:34:53,903
SO WITH THAT IN MIND, KEEPING

4565
02:34:53,903 --> 02:34:56,505
THESE IDEAS, WHAT I WANT TO DO

4566
02:34:56,505 --> 02:34:57,807
IS GIVE YOU VERY SPECIFIC

4567
02:34:57,807 --> 02:35:00,843
EXAMPLES OF HOW WITH THESE

4568
02:35:00,843 --> 02:35:02,812
CONCEPTS WE STUDY HOW LIFESTYLE

4569
02:35:02,812 --> 02:35:04,980
FACTORS AFFECT BIOLOGY AND

4570
02:35:04,980 --> 02:35:08,217
LIFESTYLE FACTORS, EITHER

4571
02:35:08,217 --> 02:35:09,318
PROTECT AGAINST DISEASE OR

4572
02:35:09,318 --> 02:35:12,388
ELEVATE RISK FOR DISEASE.

4573
02:35:12,388 --> 02:35:14,290
THE FOUR HERE THAT I HAVE ARE

4574
02:35:14,290 --> 02:35:15,624
STRESS, DIET, EXERCISE AND

4575
02:35:15,624 --> 02:35:16,926
SLEEP, JUST BECAUSE THAT'S WHAT

4576
02:35:16,926 --> 02:35:18,928
WE'VE BEEN WORKING ON FOR THE

4577
02:35:18,928 --> 02:35:20,629
LAST SEVEN OR EIGHT YEARS.

4578
02:35:20,629 --> 02:35:22,064
THERE'S OF COURSE OTHERS, AND I

4579
02:35:22,064 --> 02:35:23,299
THINK I'M JUST GOING TO TOUCH ON

4580
02:35:23,299 --> 02:35:24,800
THREE OF THEM JUST IN THE

4581
02:35:24,800 --> 02:35:26,268
INTEREST OF TIME.

4582
02:35:26,268 --> 02:35:28,804
SO LET'S START WITH SLEEP.

4583
02:35:28,804 --> 02:35:30,439
SO ONE OF THE WAYS THAT WE

4584
02:35:30,439 --> 02:35:32,575
STUDIED THIS IS, AGAIN, TO

4585
02:35:32,575 --> 02:35:35,177
REALLY ENGAGE WITH MULTIPLE

4586
02:35:35,177 --> 02:35:37,046
SYSTEMS USING TOOLS OF

4587
02:35:37,046 --> 02:35:38,681
NEUROSCIENCE, OF IMMUNOLOGY, OF

4588
02:35:38,681 --> 02:35:41,150
VASCULAR BIOLOGY, OF HEMATOLOGY.

4589
02:35:41,150 --> 02:35:42,885
SO FOR EXAMPLE, IN UNDERSTANDING

4590
02:35:42,885 --> 02:35:45,221
HOW SLEEP MAY PROTECT US AGAINST

4591
02:35:45,221 --> 02:35:47,089
DISEASE OR CONVERSELY HOW SLEEP

4592
02:35:47,089 --> 02:35:49,291
DEPRIVATION MAY ELEVATE RISK FOR

4593
02:35:49,291 --> 02:35:50,059
CARDIOVASCULAR DISEASE OR OTHER

4594
02:35:50,059 --> 02:35:52,394
TYPES OF DISEASES, WHAT WE WANT

4595
02:35:52,394 --> 02:35:53,929
TO UNDERSTAND IS, FIRST, HOW

4596
02:35:53,929 --> 02:35:55,464
DOES THE NERVOUS SYSTEM, HOW

4597
02:35:55,464 --> 02:35:57,266
DOES THE CENTRAL NERVOUS SYSTEM,

4598
02:35:57,266 --> 02:36:00,436
THE BRAIN SORT OF UNDERSTAND

4599
02:36:00,436 --> 02:36:04,673
SLEEP AND PERTURBATIONS OF

4600
02:36:04,673 --> 02:36:06,041
SLEEP, AND THEN CONNECT THAT

4601
02:36:06,041 --> 02:36:07,810
WITH PLACES WHERE THE IMMUNE

4602
02:36:07,810 --> 02:36:09,678
SYSTEM IS VERY RELEVANT.

4603
02:36:09,678 --> 02:36:12,348
SO THE BONE MARROW, WHICH IS

4604
02:36:12,348 --> 02:36:14,750
WHERE IMMUNE CELLS ARE BORN OR

4605
02:36:14,750 --> 02:36:18,153
LYMPHOID ORGANS WHERE THERE IS

4606
02:36:18,153 --> 02:36:19,455
GENERATION OF MEMORY, AND THEN

4607
02:36:19,455 --> 02:36:21,156
CONNECT THAT TO IF WE'RE

4608
02:36:21,156 --> 02:36:22,925
STUDYING, FOR EXAMPLE,

4609
02:36:22,925 --> 02:36:23,893
CARDIOVASCULAR DISEASE TO

4610
02:36:23,893 --> 02:36:27,029
VESSELS, TO THE VESSEL WALLS AND

4611
02:36:27,029 --> 02:36:29,765
THE PROCESSES THAT OCCUR DURING

4612
02:36:29,765 --> 02:36:30,933
ATHEROSCLEROSIS AND ITS

4613
02:36:30,933 --> 02:36:31,400
COMPLICATIONS.

4614
02:36:31,400 --> 02:36:34,770
SO JUST AS AN EXAMPLE OF, YOU

4615
02:36:34,770 --> 02:36:37,907
KNOW, WHERE DOES WORK LIKE

4616
02:36:37,907 --> 02:36:39,541
THIS -- WHERE IT CAN LEAD US, SO

4617
02:36:39,541 --> 02:36:40,910
JUST A CARTOON OF SUMMARIZING

4618
02:36:40,910 --> 02:36:44,213
SOME OF THE STUDIES THAT WE'VE

4619
02:36:44,213 --> 02:36:45,414
DONE OVER THE LAST FEW YEARS.

4620
02:36:45,414 --> 02:36:46,715
SO FOR EXAMPLE, AND I HOPE YOU

4621
02:36:46,715 --> 02:36:51,387
CAN SEE MY MOUSE HERE, FOR

4622
02:36:51,387 --> 02:36:53,222
EXAMPLE, ONE INSIGHT THAT WE CAN

4623
02:36:53,222 --> 02:36:56,625
GAIN FROM ST STUDYING SLEEP

4624
02:36:56,625 --> 02:36:58,360
DISRUPTION ON THIS BRAIN-BODY

4625
02:36:58,360 --> 02:37:00,429
COMMUNICATION IS THAT IN THE

4626
02:37:00,429 --> 02:37:02,431
HYPOTHALAMUS, THERE IS A

4627
02:37:02,431 --> 02:37:05,834
NEUROPEPTIDE THAT REALLY CONT 

4628
02:37:05,834 --> 02:37:06,502
CONTROLS HEMATOPOIESIS.

4629
02:37:06,502 --> 02:37:07,903
WE KNOW THIS BY LOOKING AT

4630
02:37:07,903 --> 02:37:10,673
HEMATOPOIESIS IN THE BONE MARROW

4631
02:37:10,673 --> 02:37:13,075
AND FINDING THAT THERE ARE IN

4632
02:37:13,075 --> 02:37:14,777
BONE MARROW NICHES SPECIFIC

4633
02:37:14,777 --> 02:37:21,016
CELLS THAT RESPOND TO

4634
02:37:21,016 --> 02:37:22,217
HYPERCRETIN AND REGULATE THE

4635
02:37:22,217 --> 02:37:23,052
PRODUCTION OF IMMUNE CELLS.

4636
02:37:23,052 --> 02:37:24,486
WE ALSO KNOW FROM STUDIES THAT

4637
02:37:24,486 --> 02:37:25,487
WE HAVE DONE IN THE MOUSE AS

4638
02:37:25,487 --> 02:37:27,790
WELL AS IN THE HUMANS THAT SLEEP

4639
02:37:27,790 --> 02:37:29,792
DISRUPTION REALLY ACCELERATES

4640
02:37:29,792 --> 02:37:31,193
HEMATOPOIESIS, AND WE HEARD

4641
02:37:31,193 --> 02:37:32,194
ABOUT CLONAL HEMATOPOIESIS.

4642
02:37:32,194 --> 02:37:34,530
THIS IS AN EXAMPLE OF SO-CALLED

4643
02:37:34,530 --> 02:37:37,633
REVERSE CAUSATION WHERE A

4644
02:37:37,633 --> 02:37:39,268
LIFESTYLE FACTOR, IN THE ABSENCE

4645
02:37:39,268 --> 02:37:42,037
OF ANY DRIVER OF MUTATIONS, CAN

4646
02:37:42,037 --> 02:37:43,872
ACTUALLY INCREASE PROLIFERATION

4647
02:37:43,872 --> 02:37:46,742
AND, THUS, BY INCREASING

4648
02:37:46,742 --> 02:37:50,679
PROLIFERATION, VIA A SO CALLED

4649
02:37:50,679 --> 02:37:54,683
NEUTRAL DRIFT CAN INCREASE THE

4650
02:37:54,683 --> 02:37:56,986
HETEROGENEITY OF MYELOID CELLS

4651
02:37:56,986 --> 02:38:04,026
THUS INCREASE CL CLONALITY.

4652
02:38:04,026 --> 02:38:05,694
STRESS IS VERY COMPLICATED,

4653
02:38:05,694 --> 02:38:07,730
THERE IS THIS CONCEPT OF USE

4654
02:38:07,730 --> 02:38:09,598
STRESS OR BENEFICIAL STRESS

4655
02:38:09,598 --> 02:38:10,132
VERSUS DISTRESS.

4656
02:38:10,132 --> 02:38:12,201
THERE'S, OF COURSE, THIS IDEA OF

4657
02:38:12,201 --> 02:38:16,271
THE DIFFERENCE BETWEEN ACUTE

4658
02:38:16,271 --> 02:38:17,639
STRESS AND CHRONIC STRESS AND IT

4659
02:38:17,639 --> 02:38:21,710
REALLY HAS ALL SORTS OF

4660
02:38:21,710 --> 02:38:24,013
DIFFERENT EFFECTS ON OUR

4661
02:38:24,013 --> 02:38:25,080
PHYSIOLOGY, BUT REALLY A LOT OF

4662
02:38:25,080 --> 02:38:27,316
WHAT WE CALL STRESS STARTS IN

4663
02:38:27,316 --> 02:38:29,084
THE BRAIN, AND THE QUESTION IS,

4664
02:38:29,084 --> 02:38:33,756
HOW DOES THE BRAIN UNDERSTAND

4665
02:38:33,756 --> 02:38:35,457
WHAT WE WOULD THEN CALL STRESS.

4666
02:38:35,457 --> 02:38:40,963
SO HERE IS ONE EXAMPLE OF

4667
02:38:40,963 --> 02:38:42,398
STUDIES WE HAVE DONE RECENTLY

4668
02:38:42,398 --> 02:38:44,099
LOOKING AT ONE EXAMPLE OF WHAT

4669
02:38:44,099 --> 02:38:45,634
ACUTE STRESS CAN DO AND AGAIN

4670
02:38:45,634 --> 02:38:49,772
I'M JUST GOING TO FOLLOW THIS,

4671
02:38:49,772 --> 02:38:51,540
SO ONE OF THE THINGS THAT WE

4672
02:38:51,540 --> 02:38:52,674
FOUND IS THAT UNDER CONDITIONS

4673
02:38:52,674 --> 02:38:54,343
OF ACUTE STRESS, CERTAIN REGIONS

4674
02:38:54,343 --> 02:38:57,846
IN THE BRAIN, FOR EXAMPLE, THE

4675
02:38:57,846 --> 02:39:00,115
HORMONES IN THE PERIVENTRICULAR

4676
02:39:00,115 --> 02:39:03,052
HYPOTHALAMUS LEAD TO THE

4677
02:39:03,052 --> 02:39:05,754
PRODUCTION OF CORTICOSTERONE

4678
02:39:05,754 --> 02:39:10,959
WHICH INDUCES CXCR4, A CHEMOKINE

4679
02:39:10,959 --> 02:39:12,594
RECEPTOR ON MONOCYTES THAT

4680
02:39:12,594 --> 02:39:15,764
ESSENTIALLY GUIDES MONOCYTE

4681
02:39:15,764 --> 02:39:17,499
RECRUITMENT AND PROVOKES THEIR

4682
02:39:17,499 --> 02:39:19,768
ENTRY INTO THE BONE MARROW.

4683
02:39:19,768 --> 02:39:21,937
ALTERNATIVELY OTHER AREAS OF THE

4684
02:39:21,937 --> 02:39:23,772
BRAIN, NOTABLY HERE THE MOTOR

4685
02:39:23,772 --> 02:39:25,674
CORTEX, VIA COMMUNICATION WITH

4686
02:39:25,674 --> 02:39:27,709
SKELETAL MUSCLE, INCREASES

4687
02:39:27,709 --> 02:39:30,079
ANOTHER CHEMOKINE THAT HAS SORT

4688
02:39:30,079 --> 02:39:32,047
OF AN OPPOSING EFFECT ON

4689
02:39:32,047 --> 02:39:33,916
NEUTROPHILS WHICH ARE RAPIDLY

4690
02:39:33,916 --> 02:39:34,883
MOBILIZED OUT OF THE BONE

4691
02:39:34,883 --> 02:39:35,117
MARROW.

4692
02:39:35,117 --> 02:39:36,385
SO THIS IS REALLY AN EXAMPLE

4693
02:39:36,385 --> 02:39:39,655
WHERE ON THE ONE HAND, ACUTE

4694
02:39:39,655 --> 02:39:40,923
STRESS ENGAGES DIFFERENT REGIONS

4695
02:39:40,923 --> 02:39:43,659
IN THE BRAIN THAT HAVE A

4696
02:39:43,659 --> 02:39:46,295
PROFOUND EFFECT ON THE

4697
02:39:46,295 --> 02:39:48,464
REORGANIZATION OF THE MAJOR

4698
02:39:48,464 --> 02:39:51,066
LEUKOCYTE CLASSES THROUGHOUT THE

4699
02:39:51,066 --> 02:39:53,702
BODY.

4700
02:39:53,702 --> 02:39:55,337
OF COURSE THERE'S OTHER AREAS OF

4701
02:39:55,337 --> 02:39:57,005
STRESS AND PARTS OF THAT STRESS

4702
02:39:57,005 --> 02:39:59,374
RESPONSE SUCH AS THE SYMPATHETIC

4703
02:39:59,374 --> 02:40:01,243
NERVOUS SYSTEM WHICH WE KNOW HAS

4704
02:40:01,243 --> 02:40:04,113
AN EFFECT ON ADHESION, AND THIS

4705
02:40:04,113 --> 02:40:06,682
IS AN EXAMPLE OF ACUTE STRESS

4706
02:40:06,682 --> 02:40:07,249
THAT WE KNOW UNDER CHRONIC

4707
02:40:07,249 --> 02:40:08,650
STRESS CONDITIONS, WE SEE AN

4708
02:40:08,650 --> 02:40:10,486
UNCREASE IN PROLIFERATION, AND

4709
02:40:10,486 --> 02:40:11,954
AN INCREASE IN THE PRODUCTION OF

4710
02:40:11,954 --> 02:40:13,622
IMMUNE CELLS IN THE BONE MARROW

4711
02:40:13,622 --> 02:40:15,924
AND THIS IS MEDIATED BY THE

4712
02:40:15,924 --> 02:40:17,292
SYMPATHETIC NERVOUS SYSTEM.

4713
02:40:17,292 --> 02:40:20,262
SO JUST LASTLY, JUST VERY

4714
02:40:20,262 --> 02:40:21,797
BRIEFLY I WOULD LIKE TO TOUCH ON

4715
02:40:21,797 --> 02:40:22,764
DIET.

4716
02:40:22,764 --> 02:40:23,765
AGAIN, THERE'S MANY, MANY

4717
02:40:23,765 --> 02:40:28,237
DIFFERENT WAYS THAT WE CAN STUDY

4718
02:40:28,237 --> 02:40:30,739
DIETMENT WEDIET.

4719
02:40:30,739 --> 02:40:33,442
WE CAN STUDY DIET IN TERMS OF

4720
02:40:33,442 --> 02:40:34,743
WHAT WE EETD, COMPONENTS OF

4721
02:40:34,743 --> 02:40:37,112
FOOD, FAT, PROTEIN, SUGAR, ET

4722
02:40:37,112 --> 02:40:37,880
CETERA.

4723
02:40:37,880 --> 02:40:40,182
WE CAN STUDY WHEN WE EAT, AND

4724
02:40:40,182 --> 02:40:42,684
THAT REALLY ENGAGES MULTIPLE

4725
02:40:42,684 --> 02:40:44,653
DIFFERENT SYSTEMS.

4726
02:40:44,653 --> 02:40:47,222
AND SO AGAIN I'LL JUST GIVE YOU

4727
02:40:47,222 --> 02:40:48,223
A VERY BRIEF SUMMARY OF SOME OF

4728
02:40:48,223 --> 02:40:51,160
THE WORK THAT WE HAVE DONE IN

4729
02:40:51,160 --> 02:40:53,695
THINKING ABOUT DIET.

4730
02:40:53,695 --> 02:40:54,897
THIS IS WORK LOOKING

4731
02:40:54,897 --> 02:40:56,765
SPECIFICALLY AT FASTING, AND SO

4732
02:40:56,765 --> 02:41:00,302
AGAIN HERE, WE FIND THAT FASTING

4733
02:41:00,302 --> 02:41:01,503
ENGAGES SPECIFIC REGIONS IN THE

4734
02:41:01,503 --> 02:41:02,704
BRAIN, SO I'M JUST GOING TO

4735
02:41:02,704 --> 02:41:06,308
START ON THE RIGHT SIDE HERE,

4736
02:41:06,308 --> 02:41:09,111
RECENTLY GENERATED WHERE WE FIND

4737
02:41:09,111 --> 02:41:12,714
THAT SPECIFIC NEURONS IN THE

4738
02:41:12,714 --> 02:41:17,419
LATERAL HYPOTHALAMUS, INDUCE

4739
02:41:17,419 --> 02:41:18,787
EXPRESSION OF CHEMOKINE

4740
02:41:18,787 --> 02:41:21,089
RECEPTORS, WE HAVE A PROFOUND

4741
02:41:21,089 --> 02:41:22,524
EFFECT ON THE REORGANIZATION OF

4742
02:41:22,524 --> 02:41:23,725
IMMUNE CELLS THROUGHOUT THE

4743
02:41:23,725 --> 02:41:24,726
BODY.

4744
02:41:24,726 --> 02:41:28,363
AND OF COURSE MIGRATION IS ONE

4745
02:41:28,363 --> 02:41:30,866
KEY FEATURE OF LEUKOCYTES.

4746
02:41:30,866 --> 02:41:32,801
THIS IS ONE OF THEIR DEFINING

4747
02:41:32,801 --> 02:41:34,803
FACTOR, THIS IS WHAT ALLOWS THEM

4748
02:41:34,803 --> 02:41:36,638
TO ACCESS VARIOUS ORGANS, ACCESS

4749
02:41:36,638 --> 02:41:38,140
THE CIRCULATORY SYSTEM.

4750
02:41:38,140 --> 02:41:40,442
THEIR MOTILITY IS CENTRAL TO

4751
02:41:40,442 --> 02:41:42,611
THEIR FUNCTION.

4752
02:41:42,611 --> 02:41:45,180
BUT THIS IS NOT THE ONLY WAY BY

4753
02:41:45,180 --> 02:41:45,981
WHICH, FOR EXAMPLE, FASTING

4754
02:41:45,981 --> 02:41:48,350
REALLY ENGAGES BRAIN-BODY

4755
02:41:48,350 --> 02:41:48,917
COMMUNICATION.

4756
02:41:48,917 --> 02:41:50,352
WE KNOW FROM OTHER WORK THAT

4757
02:41:50,352 --> 02:41:51,453
UNDER CONDITIONS OF FASTING,

4758
02:41:51,453 --> 02:41:52,521
THERE IS COMMUNICATION BETWEEN

4759
02:41:52,521 --> 02:41:54,556
THE BRAIN AND THE LIVER AND THE

4760
02:41:54,556 --> 02:41:57,159
BONE MARROW, WHICH RESULTS IN

4761
02:41:57,159 --> 02:41:59,928
THE PRODUCTION OF SPECIFIC

4762
02:41:59,928 --> 02:42:01,230
CHEMOKINES THAT TRAP THE

4763
02:42:01,230 --> 02:42:02,764
MONOCYTES IN THE BONE MARROW,

4764
02:42:02,764 --> 02:42:05,033
PREVENTING THEIR RE-ENTRY, AND

4765
02:42:05,033 --> 02:42:08,203
THIS HAS IMPLICATIONS ON AGING

4766
02:42:08,203 --> 02:42:09,805
OF THE HEMATOPOIETIC SYSTEM

4767
02:42:09,805 --> 02:42:10,939
BECAUSE WHAT WE FIND IS THAT

4768
02:42:10,939 --> 02:42:12,975
WHEN MONOCYTES MIGRATE BACK OR

4769
02:42:12,975 --> 02:42:14,943
RE-ENTER THE BONE MARROW, THEY

4770
02:42:14,943 --> 02:42:16,144
HIBERNATE IN THE BONE MARROW,

4771
02:42:16,144 --> 02:42:18,180
THEIR LIFESPAN IS PROLONGED AND

4772
02:42:18,180 --> 02:42:19,715
THAT CHANGES THEIR CAPACITY TO

4773
02:42:19,715 --> 02:42:23,318
RESPOND TO INFLAMMATORY CUES.

4774
02:42:23,318 --> 02:42:27,889
AND SO JUST TO FINISH HERE, THE

4775
02:42:27,889 --> 02:42:29,324
QUESTION IS WHAT ARE THE KEY

4776
02:42:29,324 --> 02:42:30,959
RESEARCH GAPS AND OPPORTUNITIES.

4777
02:42:30,959 --> 02:42:31,627
CERTAINLY WE'RE VERY MUCH

4778
02:42:31,627 --> 02:42:33,428
INTERESTED IN THIS IDEA OF

4779
02:42:33,428 --> 02:42:34,062
BRAIN-BODY COMMUNICATION AND HOW

4780
02:42:34,062 --> 02:42:35,631
DOES THIS ALTER BIOLOGICAL AGE.

4781
02:42:35,631 --> 02:42:40,369
WE WANT TO BETTER UNDERSTAND

4782
02:42:40,369 --> 02:42:41,169
WHAT COMMUNICATION NODES ARE

4783
02:42:41,169 --> 02:42:42,804
RELEVANT TO DISEASE RESILIENCE,

4784
02:42:42,804 --> 02:42:43,905
WE'VE ALREADY HEARD ABOUT

4785
02:42:43,905 --> 02:42:46,742
RESILIENCE IN EARLIER TALKS AND

4786
02:42:46,742 --> 02:42:48,343
SUSCEPTIBILITY, AND WHAT ARE THE

4787
02:42:48,343 --> 02:42:51,313
LIMITATIONS OF RESILIENCE AND

4788
02:42:51,313 --> 02:42:53,849
SUSCEPTIBILITY AS WE THINK ABOUT

4789
02:42:53,849 --> 02:42:55,284
SPATIAL AND OTHER COMPONENTS.

4790
02:42:55,284 --> 02:42:56,151
NEEDS OVER THE NEXT FIVE YEARS,

4791
02:42:56,151 --> 02:42:57,552
WE CERTAINLY NEED TO KEEP

4792
02:42:57,552 --> 02:42:58,553
DEVELOPING NEW TECHNOLOGIES.

4793
02:42:58,553 --> 02:43:04,393
IT IS TECHNOLOGY SUCH AS CHEMO

4794
02:43:04,393 --> 02:43:08,997
AND OPTIGENETICS -- TO ALLOW US

4795
02:43:08,997 --> 02:43:10,866
TO BETTER UNDERSTAND BRAIN-BODY

4796
02:43:10,866 --> 02:43:11,500
COMMUNICATION AND BRING THAT IN

4797
02:43:11,500 --> 02:43:13,769
THE CONTEXT OF CARDIOVASCULAR

4798
02:43:13,769 --> 02:43:14,202
DISEASE.

4799
02:43:14,202 --> 02:43:16,171
AND CERTAINLY WE NEED TO DEVELOP

4800
02:43:16,171 --> 02:43:19,741
FUNDING MECHANISMS.

4801
02:43:19,741 --> 02:43:21,143
AS THIS IS A WORKSHOP, I THINK

4802
02:43:21,143 --> 02:43:25,947
THIS IS AN IMPORTANTIS ISSUE TO

4803
02:43:25,947 --> 02:43:28,116
RAISE, TO SUPPORT -- NOT JUST

4804
02:43:28,116 --> 02:43:31,186
THAT FOCUS ON THE IMMUNE SYSTEM

4805
02:43:31,186 --> 02:43:34,623
OR METABOLISM, NERVOUS SYSTEM,

4806
02:43:34,623 --> 02:43:36,291
ET, THIS IS ABOUT REALLY MOVING

4807
02:43:36,291 --> 02:43:38,126
BEYOND AND REALLY WORKING IN THE

4808
02:43:38,126 --> 02:43:39,728
IN BETWEEN, THAT SPAN THESE

4809
02:43:39,728 --> 02:43:41,997
VARIOUS SYSTEMS, BECAUSE IT'S

4810
02:43:41,997 --> 02:43:43,098
SOMETIMES DIFFICULT TO FIND

4811
02:43:43,098 --> 02:43:46,835
SPECIFIC PLACES WHERE SUCH WORK

4812
02:43:46,835 --> 02:43:47,669
CAN BE FUNDED.

4813
02:43:47,669 --> 02:43:49,871
AND THEN ALLOW US TO CONNECT

4814
02:43:49,871 --> 02:43:51,606
THESE MECHANISTIC STUDIES THAT

4815
02:43:51,606 --> 02:43:53,075
WE OBTAIN IN ANIMAL MODELS WHICH

4816
02:43:53,075 --> 02:43:55,077
I SHOWED YOU, WITH OBSERVATIONAL

4817
02:43:55,077 --> 02:43:56,478
STUDIES IN HUMANS.

4818
02:43:56,478 --> 02:43:58,647
AND AGAIN TOUCHING ON SOMETHING

4819
02:43:58,647 --> 02:44:00,182
THAT WAS ALREADY BEAUTIFULLY

4820
02:44:00,182 --> 02:44:04,453
DISCUSSED EARLIER TODAY, THRFERS

4821
02:44:04,453 --> 02:44:13,729
A NETOBETTER DEFINE HEALTH AND H

4822
02:44:13,729 --> 02:44:14,696
TO DISEASE TRANSITIONS.

4823
02:44:14,696 --> 02:44:16,031
SO HOW CAN WE APPLY THIS

4824
02:44:16,031 --> 02:44:16,331
INFORMATION?

4825
02:44:16,331 --> 02:44:18,400
WE'LL NEED TO DEFINE MODES OF

4826
02:44:18,400 --> 02:44:18,934
COMMUNICATION.

4827
02:44:18,934 --> 02:44:20,369
THIS IS WHAT DRIVES A LOT OF OUR

4828
02:44:20,369 --> 02:44:20,602
WORK.

4829
02:44:20,602 --> 02:44:24,973
IT'S NOT THAT WE WANT TO

4830
02:44:24,973 --> 02:44:25,907
UNDERSTAND WHETHER LIFESTYLES

4831
02:44:25,907 --> 02:44:29,111
ARE GOOD OR BAD FOR YOU, IT'S

4832
02:44:29,111 --> 02:44:30,479
THAT WE WANT TO UNDERSTAND HOW

4833
02:44:30,479 --> 02:44:32,481
IT IS THAT THEY CONFER RISK OR

4834
02:44:32,481 --> 02:44:34,149
PROTECT US AGAINST RISK.

4835
02:44:34,149 --> 02:44:36,551
>> SPEAK E YOU HAVE 2
MINUTES

4836
02:44:36,551 --> 02:44:36,818
REMAINING.

4837
02:44:36,818 --> 02:44:39,221
>> AND I WILL BE DONE IN

4838
02:44:39,221 --> 02:44:41,123
30 SECONDS.

4839
02:44:41,123 --> 02:44:42,557
SO THIS GETS US TO THIS WHOLE

4840
02:44:42,557 --> 02:44:44,726
IDEA THAT LIFESTYLES ALSO CHANGE

4841
02:44:44,726 --> 02:44:45,660
AS WE AGE.

4842
02:44:45,660 --> 02:44:46,528
THIS IS AN IMPORTANT CONCEPT.

4843
02:44:46,528 --> 02:44:47,629
OUR SLEEP NEEDS BECOME DIFFERENT

4844
02:44:47,629 --> 02:44:51,933
AS WE AGE, CAPACITY TO EXERCISE

4845
02:44:51,933 --> 02:44:53,335
BECOMES DIFFERENT, OF COURSE.

4846
02:44:53,335 --> 02:44:54,403
THIS IS WHERE WE CAN DISCUSS

4847
02:44:54,403 --> 02:44:58,140
ISSUES OF FRAILTY, AND JUST

4848
02:44:58,140 --> 02:45:00,709
GENERAL AGING IN TERMS OF HOW

4849
02:45:00,709 --> 02:45:02,711
HIGH OUR HEARTBEAT CAN GET TO AS

4850
02:45:02,711 --> 02:45:03,211
WE AGE.

4851
02:45:03,211 --> 02:45:04,546
THIS IS SOMETHING THAT EVERY

4852
02:45:04,546 --> 02:45:08,483
RUNNER UNDERSTANDS AS WE

4853
02:45:08,483 --> 02:45:09,851
EXERCISE THROUGHOUT LIFE AND OUR

4854
02:45:09,851 --> 02:45:10,952
CHANGING METABOLISM, AND THIS,

4855
02:45:10,952 --> 02:45:12,921
OF COURSE, WE CAN PUT IN THE

4856
02:45:12,921 --> 02:45:14,055
CONTEXT OF BRAIN-BODY

4857
02:45:14,055 --> 02:45:14,389
COMMUNICATION.

4858
02:45:14,389 --> 02:45:15,424
SO I WILL STOP HERE.

4859
02:45:15,424 --> 02:45:17,492
THIS IS MY LAB AND SOME OF THE

4860
02:45:17,492 --> 02:45:19,694
PEOPLE WHO HAVE DONE SOME OF THE

4861
02:45:19,694 --> 02:45:21,329
WORK AND A LIST OF

4862
02:45:21,329 --> 02:45:23,365
COLLABORATORS, SO THANK YOU VERY

4863
02:45:23,365 --> 02:45:26,234
MUCHMENT

4864
02:45:26,234 --> 02:45:27,202
>> GREAT, THANKS.

4865
02:45:27,202 --> 02:45:29,237
LOTS TO UNPACK THERE.

4866
02:45:29,237 --> 02:45:30,572
SO MAYBE I'LL START WHILE THE

4867
02:45:30,572 --> 02:45:34,276
QUESTIONS COME IN.

4868
02:45:34,276 --> 02:45:35,911
SO I THOUGHT FASTING ACTUALLY

4869
02:45:35,911 --> 02:45:39,514
INDUCED, YOU KNOW, APOPTOSIS OF

4870
02:45:39,514 --> 02:45:41,583
YOUR BAD AND WIMPY CELLS, MAYBE

4871
02:45:41,583 --> 02:45:45,420
YOUR SENESCENT CELLS.

4872
02:45:45,420 --> 02:45:47,289
IS THAT BEING MEDIATED THROUGH

4873
02:45:47,289 --> 02:45:48,356
SOME OF THESE CYTOKINES OR WHAT

4874
02:45:48,356 --> 02:45:49,691
DO YOU THINK IS GOING ON THERE?

4875
02:45:49,691 --> 02:45:52,794
>> I THINK, YOU KNOW,
FASTING IS

4876
02:45:52,794 --> 02:45:55,497
NOT A -- AN ALL-ENCOMPASSING

4877
02:45:55,497 --> 02:45:56,631
TERM WHICH IS TO SAY THAT WE

4878
02:45:56,631 --> 02:45:58,366
HAVE TO BE VERY CAREFUL, AND OF

4879
02:45:58,366 --> 02:45:59,334
COURSE I WENT IN THE INTEREST OF

4880
02:45:59,334 --> 02:46:02,103
TIME VERY CAREFULLY, VERY

4881
02:46:02,103 --> 02:46:02,737
BROADLY HERE.

4882
02:46:02,737 --> 02:46:06,541
IT REALLY DEPENDS ON WHEN THE

4883
02:46:06,541 --> 02:46:09,444
FAST OCCURS AND FOR HOW LONG.

4884
02:46:09,444 --> 02:46:12,147
SO THAT'S -- YOU KNOW, THE

4885
02:46:12,147 --> 02:46:13,482
ULTIMATE CONSEQUENCE OF FASTING

4886
02:46:13,482 --> 02:46:14,082
IS DEATH.

4887
02:46:14,082 --> 02:46:15,383
IF YOU DON'T BREAK THE FAST, YOU

4888
02:46:15,383 --> 02:46:16,485
WILL DIE.

4889
02:46:16,485 --> 02:46:18,353
RIGHT?

4890
02:46:18,353 --> 02:46:22,057
AND SO I THINK THERE WAS A

4891
02:46:22,057 --> 02:46:25,093
LEGITIMATE DISCUSSION TO HAVE

4892
02:46:25,093 --> 02:46:28,029
ABOUT WHEN -- THE BENEFITS OF

4893
02:46:28,029 --> 02:46:31,967
FASTING VERSUS WHEN DOES FASTING

4894
02:46:31,967 --> 02:46:32,834
BECOME A PROBLEM.

4895
02:46:32,834 --> 02:46:34,269
AND A LOT HAS TO DO WITH TIMING

4896
02:46:34,269 --> 02:46:35,470
AND DURATION.

4897
02:46:35,470 --> 02:46:37,672
IN THE CONTEXT OF THE SPECIFIC

4898
02:46:37,672 --> 02:46:41,309
STUDY TO WHICH I ALLUDED, THIS

4899
02:46:41,309 --> 02:46:44,112
WAS A FASTING THAT WAS

4900
02:46:44,112 --> 02:46:45,614
RELATIVELY LONG WHERE WE DO NOT

4901
02:46:45,614 --> 02:46:48,250
ACTUALLY SEE DEATH OF THOSE

4902
02:46:48,250 --> 02:46:49,117
PARTICULAR CELLS.

4903
02:46:49,117 --> 02:46:50,685
THE IMMUNE CELLS, MONOCYTES

4904
02:46:50,685 --> 02:46:53,154
WHICH ARE TYPICALLY FAIRLY SHORT

4905
02:46:53,154 --> 02:46:55,056
LIVED, ACTUALLY LIVE MUCH LONGER

4906
02:46:55,056 --> 02:46:59,160
UNDER CONDITIONS OF FASTING, AND

4907
02:46:59,160 --> 02:47:00,362
THERE'S, I THINK, A VERY

4908
02:47:00,362 --> 02:47:01,463
INTERESTING CONCEPT THAT WE CAN

4909
02:47:01,463 --> 02:47:03,598
EXPLORE HERE, BECAUSE FASTING

4910
02:47:03,598 --> 02:47:06,568
DECREASES HEMATOPOIESIS, AND

4911
02:47:06,568 --> 02:47:08,637
HEMATOPOIESIS IS AN

4912
02:47:08,637 --> 02:47:09,838
ENERGETICALLY COSTLY PROCESS

4913
02:47:09,838 --> 02:47:11,373
THAT GIVES RISE TO ALL OF THESE

4914
02:47:11,373 --> 02:47:12,774
IMMUNE CELLS, SOME OF WHICH ARE

4915
02:47:12,774 --> 02:47:14,075
LONG LIVED, SOME OF WHICH ARE

4916
02:47:14,075 --> 02:47:15,744
SHORT LIVED DEPENDING ON WHETHER

4917
02:47:15,744 --> 02:47:17,479
WE'RE TALKING ABOUT LYMPHOCYTES

4918
02:47:17,479 --> 02:47:21,182
AND NEUTROPHILS, SO AS TO

4919
02:47:21,182 --> 02:47:24,653
PRESERVE ENERGY, ONE COULD SORT

4920
02:47:24,653 --> 02:47:29,157
OF THINK ABOUT THE DECREASE OF

4921
02:47:29,157 --> 02:47:30,025
HEMATOPOIESIS NECESSITATING AN

4922
02:47:30,025 --> 02:47:30,892
INCREASE IN THE LIFESPAN OF

4923
02:47:30,892 --> 02:47:32,193
THESE OTHERWISE SHORT LIVED

4924
02:47:32,193 --> 02:47:32,527
CELLS.

4925
02:47:32,527 --> 02:47:34,062
SO I THINK THERE'S A LOT TO

4926
02:47:34,062 --> 02:47:34,930
UNPACK HERE, AND SOMETHING THAT

4927
02:47:34,930 --> 02:47:36,031
I DON'T THINK WE'RE GOING TO BE

4928
02:47:36,031 --> 02:47:39,634
ABLE TO GET TO JUST WITH THE

4929
02:47:39,634 --> 02:47:39,968
TIME WE HAVE.

4930
02:47:39,968 --> 02:47:41,269
>> GREAT, THANKS.

4931
02:47:41,269 --> 02:47:41,703
OKAY.

4932
02:47:41,703 --> 02:47:46,541
WE HAVE A QUESTION IN THE Q
& A

4933
02:47:46,541 --> 02:47:47,375
FROM FRANK.

4934
02:47:47,375 --> 02:47:49,778
DOOL POOR HABITS LIKE DIET, LACK

4935
02:47:49,778 --> 02:47:51,947
OF EXERCISE, ET CETERA, GENERATE

4936
02:47:51,947 --> 02:47:53,481
AN EARLY AGE PHENOTYPE IN YOUNG

4937
02:47:53,481 --> 02:47:56,685
PEOPLE TOO?

4938
02:47:56,685 --> 02:47:58,219
>> THAT'S THE CONCEPT I
THINK

4939
02:47:58,219 --> 02:48:02,724
THAT IS SOMETHING THAT WOULD HE

4940
02:48:02,724 --> 02:48:06,094
NEED TO DISCUSS, AND MIRANDA

4941
02:48:06,094 --> 02:48:08,363
WOULD HELP US AS WELL IN TERMS

4942
02:48:08,363 --> 02:48:11,433
OF SENESCENCE.

4943
02:48:11,433 --> 02:48:12,767
CLEARLY FROM THE STUDIES THAT

4944
02:48:12,767 --> 02:48:14,302
WE'VE DONE AND FROM THE WORK

4945
02:48:14,302 --> 02:48:17,672
THAT IS BEING DONE ACROSS, THE

4946
02:48:17,672 --> 02:48:20,275
ANSWER WOULD BE YES, THAT THERE

4947
02:48:20,275 --> 02:48:22,777
IS THIS ACCELERATED AGING IN THE

4948
02:48:22,777 --> 02:48:25,313
ABSENCE OF SOME OF THESE

4949
02:48:25,313 --> 02:48:25,880
LIFESTYLE FACTORS.

4950
02:48:25,880 --> 02:48:27,182
SO THIS IS REALLY A QUESTION

4951
02:48:27,182 --> 02:48:30,452
THAT GOES DEEP INTO THIS IDEA OF

4952
02:48:30,452 --> 02:48:31,753
THAT SORT OF CHRONOLOGICAL AGE,

4953
02:48:31,753 --> 02:48:34,956
WHICH IS THE PASS  PASSAGE OF TE

4954
02:48:34,956 --> 02:48:36,891
WHICH WE CELEBRATE EVERY TIME WE

4955
02:48:36,891 --> 02:48:38,526
HAVE A BIRTHDAY IN THE

4956
02:48:38,526 --> 02:48:40,495
BIOLOGICAL AGE, AND HOW THE

4957
02:48:40,495 --> 02:48:41,930
EXPOSOME AND LIFESTYLE FACTORS

4958
02:48:41,930 --> 02:48:42,797
AND ENVIRONMENTAL FACTORS

4959
02:48:42,797 --> 02:48:44,899
MODULATE THIS, AND CERTAINLY

4960
02:48:44,899 --> 02:48:49,504
BAD, QUOTE-UNQUOTE BAD LIFESTYLE

4961
02:48:49,504 --> 02:48:51,606
HABITS SHIFT US TOWARD OLDER

4962
02:48:51,606 --> 02:48:52,607
BIOLOGICAL AGE, AND THERE'S

4963
02:48:52,607 --> 02:48:54,909
DIFFERENT WAYS WE CAN, OF

4964
02:48:54,909 --> 02:48:58,279
COURSE, LOOK AT THIS EPIGENETIC

4965
02:48:58,279 --> 02:49:00,849
MODIFIER, THE HETEROGENEITY OF

4966
02:49:00,849 --> 02:49:05,854
T --SENESCENCE AND SO ON.

4967
02:49:05,854 --> 02:49:07,656
>> OR AT LEAST HOW IT'S
THOUGHT.

4968
02:49:07,656 --> 02:49:09,858
I WOULD ARGUE MAY NOT BE GOOD

4969
02:49:09,858 --> 02:49:11,326
DEFINITIVE STUDIES OUT THERE

4970
02:49:11,326 --> 02:49:12,594
LIKE WE'D LIKE TO SEE, PERHAPS.

4971
02:49:12,594 --> 02:49:15,196
YOU HAVE ANOTHER QUESTION HERE

4972
02:49:15,196 --> 02:49:16,197
FROM BETHANY EVERETT.

4973
02:49:16,197 --> 02:49:20,435
LET'S SEE.

4974
02:49:20,435 --> 02:49:21,770
DISCLAIMER, SHE'S A SOCIOLOGIST,

4975
02:49:21,770 --> 02:49:23,304
YOU DON'T HAVE TO WORRY ABOUT

4976
02:49:23,304 --> 02:49:24,072
THAT, BETHANY.

4977
02:49:24,072 --> 02:49:26,341
WOULD APPRECIATE IF YOU COULD

4978
02:49:26,341 --> 02:49:29,244
SPEAK ABOUT CARDIOVASCULAR

4979
02:49:29,244 --> 02:49:33,114
DISEASE RISK AND

4980
02:49:33,114 --> 02:49:35,850
CARDIOVASCULAR -- I SLEEP DURING

4981
02:49:35,850 --> 02:49:37,919
THE NEWBORN PERIOD WHICH

4982
02:49:37,919 --> 02:49:39,487
THEORETICALLY RETURNS NORMAL

4983
02:49:39,487 --> 02:49:41,956
WITH LONG TERM ISSUES OVER THE

4984
02:49:41,956 --> 02:49:42,257
LIFE COURSE.

4985
02:49:42,257 --> 02:49:43,625
SO HOW ABOUT TEMPORARY

4986
02:49:43,625 --> 02:49:43,992
PERTURBATIONS --

4987
02:49:43,992 --> 02:49:45,393
>> VERY GOOD QUESTION, A
VERY

4988
02:49:45,393 --> 02:49:46,695
RICH QUESTION THAT AGAIN WE

4989
02:49:46,695 --> 02:49:47,862
COULD SPEND A LONG TIME

4990
02:49:47,862 --> 02:49:48,196
DISCUSSING.

4991
02:49:48,196 --> 02:49:50,298
I WILL JUST MENTION VERY BRIEFLY

4992
02:49:50,298 --> 02:49:53,902
THAT THE AMERICAN HEART

4993
02:49:53,902 --> 02:49:57,072
ASSOCIATION, LAST YEAR, INCLUDED

4994
02:49:57,072 --> 02:50:01,710
SLEEP AS ONE OF LIFE'S

4995
02:50:01,710 --> 02:50:03,344
ESSENTIAL -- ONE OF LIFE'S

4996
02:50:03,344 --> 02:50:04,312
SIMPLE SEVEN, SLEEP WAS ADDED

4997
02:50:04,312 --> 02:50:06,347
AND NOW IT'S ESSENTIAL EIGHT.

4998
02:50:06,347 --> 02:50:07,515
SO I HOPE ONE DAY STRESS WILL BE

4999
02:50:07,515 --> 02:50:10,085
ADDED AND THEN WE WILL HAVE ONE

5000
02:50:10,085 --> 02:50:12,320
OF THE NECESSARY NINE, LIFE'S

5001
02:50:12,320 --> 02:50:13,755
NECESSARY NINE.

5002
02:50:13,755 --> 02:50:16,491
SO SLEEP IS RECOGNIZED AS THE

5003
02:50:16,491 --> 02:50:19,327
MAJOR CONTRIBUTOR TO

5004
02:50:19,327 --> 02:50:20,628
CARDIOVASCULAR HEALTH.

5005
02:50:20,628 --> 02:50:23,698
THERE HAS BEEN MANY STUDIES

5006
02:50:23,698 --> 02:50:25,266
OBSERVATIONAL HUMAN, SOME LARGE,

5007
02:50:25,266 --> 02:50:29,704
SOME SMALL, THAT HAVE SHOWN HOW

5008
02:50:29,704 --> 02:50:30,805
DISRUPTION IN SLEEP, EITHER

5009
02:50:30,805 --> 02:50:36,511
SLEEP FRAGMENTATION, OR JUST

5010
02:50:36,511 --> 02:50:39,247
SLEEP REDUCTION ACCELERATES RISK

5011
02:50:39,247 --> 02:50:42,517
FOR VARIOUS CARDIOMETABOLIC

5012
02:50:42,517 --> 02:50:42,784
PHENOMENA.

5013
02:50:42,784 --> 02:50:44,352
A LOT OF THIS WORK HAS BEEN DONE

5014
02:50:44,352 --> 02:50:47,288
IN THE CONTEXT OF SLEEP APNEA.

5015
02:50:47,288 --> 02:50:50,458
OF COURSE SLEEP APNEA ALSO

5016
02:50:50,458 --> 02:50:51,760
INCORPORATES HYPOXIA, BUT THERE

5017
02:50:51,760 --> 02:50:54,229
HAS BEEN A NUMBER OF STUDIES

5018
02:50:54,229 --> 02:50:55,730
THAT HAVE LOOKED AT SLEEP, PER

5019
02:50:55,730 --> 02:50:56,831
SE.

5020
02:50:56,831 --> 02:51:00,668
AND SO -- AND OF COURSE SORT OF

5021
02:51:00,668 --> 02:51:01,770
THE SECOND PART OF QUESTION IS

5022
02:51:01,770 --> 02:51:05,673
ABOUT SORT OF THE ACCRUAL, LIKE

5023
02:51:05,673 --> 02:51:07,008
IF YOU DON'T SLEEP FOR A WHILE,

5024
02:51:07,008 --> 02:51:10,712
LET'S SAY BECAUSE YOU HAVE A N 

5025
02:51:10,712 --> 02:51:12,213
NEWBORN, WHAT IS THE LASTING

5026
02:51:12,213 --> 02:51:12,847
IMPACT OF THIS?

5027
02:51:12,847 --> 02:51:16,451
I THINK THAT'S ANOTHER

5028
02:51:16,451 --> 02:51:17,318
CONVERSATION WHERE SOME OF THE

5029
02:51:17,318 --> 02:51:20,088
STUDIES THAT ARE EMERGING

5030
02:51:20,088 --> 02:51:23,458
SUGGEST THAT CERTAINLY WE HAVE A

5031
02:51:23,458 --> 02:51:24,859
FANTASTIC CAPACITY TO

5032
02:51:24,859 --> 02:51:28,163
REGENERATE, SO IT'S NOT LIKE

5033
02:51:28,163 --> 02:51:29,664
ABANDON ALL HOPE YE WHO ENTER

5034
02:51:29,664 --> 02:51:31,232
HERE THAT WE HAVE IN THE GATES

5035
02:51:31,232 --> 02:51:32,967
OF -- AT THE ENTRANCE TO THE

5036
02:51:32,967 --> 02:51:37,105
INFERNO, BUT THERE ARE CERTAIN

5037
02:51:37,105 --> 02:51:42,710
ECHOES, EPIGENETIC ECHOES AT THE

5038
02:51:42,710 --> 02:51:43,611
HEMATOPOIETIC SYSTEM THAT REMAIN

5039
02:51:43,611 --> 02:51:45,613
FOR LONGER THAN WE HOPED THEY

5040
02:51:45,613 --> 02:51:46,681
WOULD REMAIN FOR.

5041
02:51:46,681 --> 02:51:47,882
THOSE ARE SOME OF THE WORK THAT

5042
02:51:47,882 --> 02:51:49,851
ARE COMING OUT IN MICE AND ALSO

5043
02:51:49,851 --> 02:51:50,318
IN HUMANS.

5044
02:51:50,318 --> 02:51:52,353
SO AGAIN, A LOT TO UNPACK HERE,

5045
02:51:52,353 --> 02:51:54,389
BUT THAT'S SORT OF THE OVERALL

5046
02:51:54,389 --> 02:51:56,024
WAY THAT I THINK A LOT OF PEOPLE

5047
02:51:56,024 --> 02:51:58,426
ARE THINKING ABOUT IT.

5048
02:51:58,426 --> 02:52:00,128
>> GREAT, THANKS.

5049
02:52:00,128 --> 02:52:02,897
SO LET'S NOW MOVE TO -- THANKS

5050
02:52:02,897 --> 02:52:04,499
AND LET'S MOVE TO OUR LAST

5051
02:52:04,499 --> 02:52:06,901
SPEAKER BEFORE THE BREAK.

5052
02:52:06,901 --> 02:52:08,002
I'LL REMIND PEOPLE -- OR I

5053
02:52:08,002 --> 02:52:08,536
SHOULD SAY PANEL.

5054
02:52:08,536 --> 02:52:10,405
WE HAVE A 20-MINUTE PANEL, SO

5055
02:52:10,405 --> 02:52:11,706
SAVE UP SOME QUESTIONS FOR THE

5056
02:52:11,706 --> 02:52:14,242
PANEL.

5057
02:52:14,242 --> 02:52:16,477
AND YEAH, ESPECIALLY PROFOUND

5058
02:52:16,477 --> 02:52:16,678
ONES.

5059
02:52:16,678 --> 02:52:18,913
ALL QUESTIONS WELCOME.

5060
02:52:18,913 --> 02:52:23,051
STO OSO OUR LAST SPEAKER IS GOIO

5061
02:52:23,051 --> 02:52:26,821
BE TUDOR OPREA, TALKING ABOUT

5062
02:52:26,821 --> 02:52:29,524
MAPPING DISEASE TRAJECTORIES IN

5063
02:52:29,524 --> 02:52:29,891
DRUG DISCOVERY.

5064
02:52:29,891 --> 02:52:31,726
TAKE IT AWAY, TUDOR.

5065
02:52:31,726 --> 02:52:34,329
>> CAN YOU GUYS SEE ME AND
HEAR

5066
02:52:34,329 --> 02:52:35,363
ME AND SEE MY SCREEN?

5067
02:52:35,363 --> 02:52:36,631
>> YOU'RE GOOD, YEP.

5068
02:52:36,631 --> 02:52:38,499
>> OKAY.

5069
02:52:38,499 --> 02:52:39,901
BECAUSE I CAN'T SEE MY SLIDES,

5070
02:52:39,901 --> 02:52:43,137
BUT HOPEFULLY --

5071
02:52:43,137 --> 02:52:44,405
>> THEY'RE FINE, WE CAN
TELL

5072
02:52:44,405 --> 02:52:46,007
YOU.

5073
02:52:46,007 --> 02:52:46,941
I GUESS THAT'S BEEN HAPPENING.

5074
02:52:46,941 --> 02:52:52,213
>> I WANT TO THANK THE
ORGANI 

5075
02:52:52,213 --> 02:52:53,548
ORGANIZERS, DR. RISCUTA AND

5076
02:52:53,548 --> 02:52:54,649
GALIS FOR ORGANIZING THIS

5077
02:52:54,649 --> 02:52:56,517
MEETING AND REALLY EXCELLENT

5078
02:52:56,517 --> 02:52:58,353
TALKS BY DRS. FERRUCCI AND

5079
02:52:58,353 --> 02:53:00,221
SNYDER AND, OF COURSE, THE

5080
02:53:00,221 --> 02:53:02,991
ESTEEMED MEMBERS OF THE PANEL.

5081
02:53:02,991 --> 02:53:04,826
SO I AM PROBABLY THE ODD PERSON

5082
02:53:04,826 --> 02:53:07,762
IN THIS SESSION SINCE MY

5083
02:53:07,762 --> 02:53:09,430
INTEREST IS ARTIFICIAL

5084
02:53:09,430 --> 02:53:10,198
INTELLIGENCE AND MACHINE

5085
02:53:10,198 --> 02:53:12,267
LEARNING.

5086
02:53:12,267 --> 02:53:13,902
AND I'LL JUST BRIEFLY MENTION IN

5087
02:53:13,902 --> 02:53:16,070
THE INTEREST OF DISCLOSURE THAT

5088
02:53:16,070 --> 02:53:18,039
I CURRENTLY AM NOT NIH-FUNDED.

5089
02:53:18,039 --> 02:53:20,875
I ACTUALLY WORK AT A STARTUP

5090
02:53:20,875 --> 02:53:22,410
CALLED EXPERT SYSTEMS IN

5091
02:53:22,410 --> 02:53:24,145
SAN DIEGO, AND HAVE PREVIOUSLY

5092
02:53:24,145 --> 02:53:26,214
CONSULTED WITH THE INDUSTRY AND

5093
02:53:26,214 --> 02:53:28,082
HAVE BEEN WORKING WITH A NUMBER

5094
02:53:28,082 --> 02:53:29,517
OF INDUSTRIAL COMPANIES

5095
02:53:29,517 --> 02:53:32,787
PREVIOUSLY.

5096
02:53:32,787 --> 02:53:34,355
SO WHEN I WAS APPROACHED TO TRY

5097
02:53:34,355 --> 02:53:36,190
TO PUT SOME THOUGHTS ON THIS

5098
02:53:36,190 --> 02:53:38,593
TOPIC, I WAS GIVEN THE TASK OF

5099
02:53:38,593 --> 02:53:41,195
LOOKING AT RESILIENCE AND

5100
02:53:41,195 --> 02:53:42,430
LONGEVITY AND OF COURSE I

5101
02:53:42,430 --> 02:53:44,933
STARTED BY SEARCHING THINGS ON

5102
02:53:44,933 --> 02:53:47,468
THE INTERNET, AND IF YOU GO TO

5103
02:53:47,468 --> 02:53:50,305
GOOGLE, THIS IS PERHAPS A FEW

5104
02:53:50,305 --> 02:53:51,706
MONTHS BEFORE BART SO MAYBE

5105
02:53:51,706 --> 02:53:52,674
THINGS HAVE CHANGED A LITTLE BIT

5106
02:53:52,674 --> 02:53:54,342
BUT IT CAME UP IN THESE WISE

5107
02:53:54,342 --> 02:53:56,611
CHOICES LIKE GET MOVING, DON'T

5108
02:53:56,611 --> 02:53:58,479
SMOKE, KEEP YOUR BRAIN ACTIVE,

5109
02:53:58,479 --> 02:53:59,681
BE GOOD TO YOURSELF.

5110
02:53:59,681 --> 02:54:02,283
AND OF COURSE I ADDED STAY

5111
02:54:02,283 --> 02:54:03,251
HYDRATED BECAUSE NHLBI HAD

5112
02:54:03,251 --> 02:54:04,485
RECENTLY POINTED OUT THE

5113
02:54:04,485 --> 02:54:05,486
IMPORTANCE OF HYDRATION.

5114
02:54:05,486 --> 02:54:06,921
SO I THOUGHT, YEAH, THAT'S A

5115
02:54:06,921 --> 02:54:09,190
GOOD START.

5116
02:54:09,190 --> 02:54:12,460
AND ALSO THANKS TO THE EARLIER

5117
02:54:12,460 --> 02:54:13,661
SPEAKER, WE GOT THE INTRODUCTION

5118
02:54:13,661 --> 02:54:15,430
TO THE EXPOSOME SO I'M GLAD HE

5119
02:54:15,430 --> 02:54:16,264
MENTIONED THAT BECAUSE IT MEANS

5120
02:54:16,264 --> 02:54:18,900
I DON'T HAVE TO EXPLAIN IT.

5121
02:54:18,900 --> 02:54:21,002
EVERYONE SEEMS TO BE INTERESTED

5122
02:54:21,002 --> 02:54:23,771
IN THE INTERSECTION BETWEEN

5123
02:54:23,771 --> 02:54:24,973
GENES, PHENOTYPES AND THE

5124
02:54:24,973 --> 02:54:26,808
ENVIRONMENT, AND WE'RE TRYING TO

5125
02:54:26,808 --> 02:54:28,276
SOLVE THE HUMAN HEALTH EQUATION

5126
02:54:28,276 --> 02:54:31,112
BASED ON TERMS THAT FEED INTO

5127
02:54:31,112 --> 02:54:32,680
THIS AREA.

5128
02:54:32,680 --> 02:54:36,150
AND OF COURSE WE'RE INTERESTED

5129
02:54:36,150 --> 02:54:38,653
IN BIOCHEMICAL ASPECTS OF

5130
02:54:38,653 --> 02:54:39,487
PHARMACOLOGY, ET CETERA, ET

5131
02:54:39,487 --> 02:54:40,521
CETERA, AND HOW ALL THESE THINGS

5132
02:54:40,521 --> 02:54:43,458
AT THE MOLECULAR LEVEL ARE

5133
02:54:43,458 --> 02:54:43,891
INFLUENCED.

5134
02:54:43,891 --> 02:54:45,093
SO IT SEEMS LIKE A GOOD WAY

5135
02:54:45,093 --> 02:54:47,061
FORWARD.

5136
02:54:47,061 --> 02:54:48,830
BEFORE I CONTINUE WITH MY

5137
02:54:48,830 --> 02:54:53,267
THOUGHT ON THIS, I'D LIKE TO

5138
02:54:53,267 --> 02:54:54,302
JUST PUT A PLUG ON SOME OF THE

5139
02:54:54,302 --> 02:54:56,571
RESEARCH I'VE BEEN DOING BECAUSE

5140
02:54:56,571 --> 02:54:58,973
I THINK WE CAN EXTEND TO THE

5141
02:54:58,973 --> 02:54:59,841
TYPES OF QUESTIONS THAT ARE

5142
02:54:59,841 --> 02:55:01,809
BEING ASKED AND I WILL CLOSE

5143
02:55:01,809 --> 02:55:05,513
THAT LOOP AT THE END OF MY TALK.

5144
02:55:05,513 --> 02:55:07,382
JUST VERY BRIEFLY WE SEE A DRUG

5145
02:55:07,382 --> 02:55:10,018
DISCOVERY AS HAVING THREE

5146
02:55:10,018 --> 02:55:13,621
PILLARS THAT RELY ON DISEASES,

5147
02:55:13,621 --> 02:55:15,023
TARGETS AND DRUGS AND EACH OF

5148
02:55:15,023 --> 02:55:19,527
THESE AREAS, I'VE OPINION BEEN D

5149
02:55:19,527 --> 02:55:20,928
WITH MACHINE LEARNING AND

5150
02:55:20,928 --> 02:55:21,796
MODEL-TYPE DEVELOPMENT AND

5151
02:55:21,796 --> 02:55:26,934
THERE'S A RECENT REVIEW IN

5152
02:55:26,934 --> 02:55:28,269
ANNALS OF PHARMACOLOGY

5153
02:55:28,269 --> 02:55:29,771
TOXICOLOGY THAT COVERS THIS.

5154
02:55:29,771 --> 02:55:31,072
PART OF THE TOOLS I'VE BEEN

5155
02:55:31,072 --> 02:55:32,173
CO-DEVELOPING FOR THIS INCLUDES

5156
02:55:32,173 --> 02:55:38,579
A DATABASE THAT WAS STARTED AT

5157
02:55:38,579 --> 02:55:39,380
THE UNIVERSITY IN DENMARK WHICH

5158
02:55:39,380 --> 02:55:40,681
IS CALLED DISEASES.

5159
02:55:40,681 --> 02:55:42,650
AND ESSENTIALLY WITH DISEASE,

5160
02:55:42,650 --> 02:55:48,356
YOU CAN RAPIDLY PRETTY MUCH READ

5161
02:55:48,356 --> 02:55:50,191
USING A COMPUTER ALL OF PUBMED.

5162
02:55:50,191 --> 02:55:52,293
THIS DATABASE IS UPDATED ON A

5163
02:55:52,293 --> 02:55:54,462
WEEKLY BASIS AND IT USES NAMED

5164
02:55:54,462 --> 02:55:57,732
ENTITY RECOGNITION AND

5165
02:55:57,732 --> 02:55:59,267
ESSENTIALLY TRIES TO IDENTIFY

5166
02:55:59,267 --> 02:56:00,701
LINKS BETWEEN DISEASES AND GENES

5167
02:56:00,701 --> 02:56:02,470
SO I THINK IT'S A VERY POWERFUL

5168
02:56:02,470 --> 02:56:06,040
SORT OF PRECURSOR TO WHAT WE

5169
02:56:06,040 --> 02:56:10,178
CURRENTLY EXPERIENCE WITH 

5170
02:56:10,178 --> 02:56:12,380
GPT4 AND BART AND CLOT.

5171
02:56:12,380 --> 02:56:14,449
BUT JUST ESSENTIALLY IF YOU CAN

5172
02:56:14,449 --> 02:56:19,253
THINK OF INTERACTION AT THE

5173
02:56:19,253 --> 02:56:20,888
PAPER BETWEEN A PROTEIN AND THE

5174
02:56:20,888 --> 02:56:23,324
DISEASE, IF YOU HAVE 100 PAPERS

5175
02:56:23,324 --> 02:56:26,394
DISCUSSING, SAY, TYPE OF

5176
02:56:26,394 --> 02:56:27,995
DIABETES AND 100 PAPERS

5177
02:56:27,995 --> 02:56:29,197
DISCUSSING INSULIN, THEN THE

5178
02:56:29,197 --> 02:56:33,468
INTERSECTION OF THAT GIVES YOU

5179
02:56:33,468 --> 02:56:34,335
INFERENCE OF THAT STRENGTH.

5180
02:56:34,335 --> 02:56:36,204
OF COURSE WE HAVE TO ADJUST BY

5181
02:56:36,204 --> 02:56:38,706
THE NUMBER OF OTHER DISEASES AND

5182
02:56:38,706 --> 02:56:39,907
GENES OR PROTEINS THAT ARE

5183
02:56:39,907 --> 02:56:40,775
MENTIONED IN THAT PAPER SO

5184
02:56:40,775 --> 02:56:42,276
THERE'S A FEW ADJUSTMENTS THAT

5185
02:56:42,276 --> 02:56:44,712
ARE MADE, IT'S CALLED A FRACTION

5186
02:56:44,712 --> 02:56:50,184
FRACTIONAL PAPER COUNT.

5187
02:56:50,184 --> 02:56:51,219
WE USE IT ALL THE TIME.

5188
02:56:51,219 --> 02:56:53,621
WORK FROM JEREMY IN MY GROUP

5189
02:56:53,621 --> 02:56:55,690
ADDED AN EXPERIMENTAL CHANNEL TO

5190
02:56:55,690 --> 02:57:00,595
THE DISEASES DATABASE WHICH

5191
02:57:00,595 --> 02:57:02,130
PRETTY MUCH POST PROCESSES DATA

5192
02:57:02,130 --> 02:57:03,331
FROM THE GWAS CATALOG.

5193
02:57:03,331 --> 02:57:05,233
SO WITH THAT IN MIND, WE USED

5194
02:57:05,233 --> 02:57:07,368
THIS COMBINED RESOURCE TO

5195
02:57:07,368 --> 02:57:09,437
DEVELOP A KNOWLEDGE GRAPH WHICH

5196
02:57:09,437 --> 02:57:12,173
FEEDS A DISEASE CHANNEL AND A

5197
02:57:12,173 --> 02:57:14,242
MOLECULE CHANNEL AND I DON'T GO

5198
02:57:14,242 --> 02:57:16,978
INTO DETAILS HOW WE BUILD THOSE,

5199
02:57:16,978 --> 02:57:21,149
BUT VERY BRIEFLY THIS IS PRETTY

5200
02:57:21,149 --> 02:57:22,984
MUCH BASED ON THAT DATABASE, AND

5201
02:57:22,984 --> 02:57:27,021
IT'S SISTERS LIKE CLINVAR,

5202
02:57:27,021 --> 02:57:29,223
CLINGEN AND A NUMBER OF

5203
02:57:29,223 --> 02:57:30,224
RESOURCES.

5204
02:57:30,224 --> 02:57:31,759
AND ON THE MOLECULES WE PRETTY

5205
02:57:31,759 --> 02:57:33,828
MUCH LOOK AT PATHWAYS,

5206
02:57:33,828 --> 02:57:37,098
EXPRESSION DATA, SMALL

5207
02:57:37,098 --> 02:57:38,266
MOLECULES, PROTEINS, GENES, ET

5208
02:57:38,266 --> 02:57:38,533
CETERA.

5209
02:57:38,533 --> 02:57:40,168
SO ALL THAT IS FED INTO A

5210
02:57:40,168 --> 02:57:43,604
KNOWLEDGE GRAPH WHICH IS SORT OF

5211
02:57:43,604 --> 02:57:45,506
DEPICTED HERE WITH FUZZY LITTLE

5212
02:57:45,506 --> 02:57:47,275
COLORED CIRCLES, AND ON TOP OF

5213
02:57:47,275 --> 02:57:49,010
THAT, WE USE A TECHNOLOGY CALLED

5214
02:57:49,010 --> 02:57:51,412
META PATH, WHICH ALLOWS US TO

5215
02:57:51,412 --> 02:57:54,415
FOLLOW THE PATH BY WHICH TWO

5216
02:57:54,415 --> 02:57:56,450
NODES ARE CONNECTED, SO IT'S

5217
02:57:56,450 --> 02:57:57,351
LITERALLY LOOKING AT THE EDGES

5218
02:57:57,351 --> 02:58:00,388
THAT CONNECT THE NODES.

5219
02:58:00,388 --> 02:58:01,589
AND OF COURSE THE NODES CAN BE

5220
02:58:01,589 --> 02:58:04,358
DISEASES OR PHENOTYPES OR

5221
02:58:04,358 --> 02:58:05,760
CHEMICALS, ET CETERA, ET CETERA,

5222
02:58:05,760 --> 02:58:08,729
AND THEN THE EDGES ARE THINGS

5223
02:58:08,729 --> 02:58:11,666
LIKE EXPRESSION DATA, INCUBATION

5224
02:58:11,666 --> 02:58:12,767
OR ANTAGONISM, THAT SORT OF

5225
02:58:12,767 --> 02:58:13,267
THING.

5226
02:58:13,267 --> 02:58:17,038
ONCE WE GENERATE FEATURES, WE

5227
02:58:17,038 --> 02:58:19,006
SEPARATE THE DATA INTO TESTS AND

5228
02:58:19,006 --> 02:58:20,341
TRAINING SET, TRAINING SET WE

5229
02:58:20,341 --> 02:58:22,176
BUILD TO USE MAN LEARNING MODELS

5230
02:58:22,176 --> 02:58:23,277
AND THEN OF COURSE THE TEST THAT

5231
02:58:23,277 --> 02:58:27,215
IS USED TO PROTECT.

5232
02:58:27,215 --> 02:58:28,616
AND PART OF THE STORY AND WHAT

5233
02:58:28,616 --> 02:58:30,618
WE DID, WE JUST PUBLISHED THIS

5234
02:58:30,618 --> 02:58:31,552
LAST YEAR IN COMMUNICATIONS

5235
02:58:31,552 --> 02:58:33,554
BIOLOGY SO WE WROTE A SUPPLEMENT

5236
02:58:33,554 --> 02:58:37,258
FOR THE ALZHEIMER'S DISEASE AS

5237
02:58:37,258 --> 02:58:40,561
PART OF AN NIH FUNDED GENOME

5238
02:58:40,561 --> 02:58:42,763
PROJECT, AND IN THAT MACHINE

5239
02:58:42,763 --> 02:58:44,398
LEARNING MODEL, WE ESSENTIALLY

5240
02:58:44,398 --> 02:58:46,133
USED SOMETHING SIMILAR TO WHAT I

5241
02:58:46,133 --> 02:58:48,202
JUST DESCRIBED AND WE LOOKED AT

5242
02:58:48,202 --> 02:58:53,741
THE TOP 20 GENES AND WROTE A

5243
02:58:53,741 --> 02:58:55,276
PROPOSAL, IT GOT FUNDED AND IT

5244
02:58:55,276 --> 02:58:56,410
ACTUALLY ALLOWED US TO RUN THE

5245
02:58:56,410 --> 02:58:56,744
EXPERIMENTS.

5246
02:58:56,744 --> 02:58:58,412
SO OUT OF THE TOP 20 GENES, THE

5247
02:58:58,412 --> 02:59:00,181
VALIDATION WHICH IS SHOWN IN THE

5248
02:59:00,181 --> 02:59:02,416
FIRST PANEL HERE ON THE LEFT

5249
02:59:02,416 --> 02:59:12,693
SIDE, WE TOOK --

5250
02:59:29,877 --> 02:59:40,121
[PLEASE STAND BY]

5251
03:00:31,372 --> 03:00:32,907
AND WE PUBLISHED A PAPER SIX

5252
03:00:32,907 --> 03:00:34,709
MONTHS AFTER WE PUBLISHED

5253
03:00:34,709 --> 03:00:36,010
SCIENCE HAD THIS INVESTIGATION

5254
03:00:36,010 --> 03:00:38,212
WHERE THEY PRETTY MUCH SHOWED --

5255
03:00:38,212 --> 03:00:40,614
I REALLY LOVE THE WORK OF

5256
03:00:40,614 --> 03:00:42,583
ELIZABETH BIK, SHE PRETTY MUCH

5257
03:00:42,583 --> 03:00:44,452
SAID THAT THE EXPERIMENTAL

5258
03:00:44,452 --> 03:00:46,787
RESULTS MIGHT NOT HAVE BEEN THE

5259
03:00:46,787 --> 03:00:47,855
DESIRED RESULTS AND DATA MIGHT

5260
03:00:47,855 --> 03:00:49,690
HAVE BEEN CHANGED TO BETTER FIT

5261
03:00:49,690 --> 03:00:52,660
THE HYPOTHESIS.

5262
03:00:52,660 --> 03:00:54,628
IN OTHER WORDS, WE PROBABLY

5263
03:00:54,628 --> 03:00:56,564
WOULD HAVE BEEN GIVEN MORE

5264
03:00:56,564 --> 03:01:00,201
ATTENTION WITH OUR THEORY OF

5265
03:01:00,201 --> 03:01:01,702
INFECTION IF THIS HAD BEEN

5266
03:01:01,702 --> 03:01:05,439
PUBLISHED EARLIER.

5267
03:01:05,439 --> 03:01:06,207
THE OTHER PROBLEM OF COURSE IS

5268
03:01:06,207 --> 03:01:08,075
WHEN YOU BUILD MACHINE LEARNING

5269
03:01:08,075 --> 03:01:09,543
MODELS, YOU HAVE TO BE AWARE TO

5270
03:01:09,543 --> 03:01:12,146
FEED THE TRUE DATA IN THE

5271
03:01:12,146 --> 03:01:13,013
MACHINE LEARNING MODEL SO YOU

5272
03:01:13,013 --> 03:01:14,882
KIND OF HAVE TO BE AWARE WHAT

5273
03:01:14,882 --> 03:01:16,817
TYPE OF PUBLICATIONS YOU INCLUDE

5274
03:01:16,817 --> 03:01:19,053
IN YOUR TRAININGS OR WHAT TYPE

5275
03:01:19,053 --> 03:01:21,555
OF DATA EMERGES FROM THOSE

5276
03:01:21,555 --> 03:01:22,256
PUBLICATIONS.

5277
03:01:22,256 --> 03:01:23,524
AND OF COURSE THE OTHER

5278
03:01:23,524 --> 03:01:24,125
PHILOSOPHICAL THING THAT COMES

5279
03:01:24,125 --> 03:01:25,126
FROM THIS IS THAT MACHINE

5280
03:01:25,126 --> 03:01:27,995
LEARNING BIAS IS INTRODUCED BY

5281
03:01:27,995 --> 03:01:28,863
HUMANS, EITHER AT INCEPTION

5282
03:01:28,863 --> 03:01:29,964
WHICH IS WHEN YOU SELECT THE

5283
03:01:29,964 --> 03:01:32,032
DATA, OR WHEN YOU GET THE

5284
03:01:32,032 --> 03:01:32,366
RESULTS.

5285
03:01:32,366 --> 03:01:34,535
BUT AS LONG AS YOU KEEP IT

5286
03:01:34,535 --> 03:01:37,838
UNBIASED, YOU'RE FINE.

5287
03:01:37,838 --> 03:01:39,673
ANOTHER MODEL THAT WE PUBLISHED,

5288
03:01:39,673 --> 03:01:42,076
THIS WAS A SLIGHTLY DIFFERENT

5289
03:01:42,076 --> 03:01:46,480
EXPERIMENT, I PUBLISHED THIS IN

5290
03:01:46,480 --> 03:01:56,290
2019 ON A -- ARCHI BIORXIV.

5291
03:01:56,290 --> 03:01:57,792
I LEFT ACADEMIA, SO A STUDENT

5292
03:01:57,792 --> 03:01:59,460
PICKED IT UP 3 1/2 YEARS LATER

5293
03:01:59,460 --> 03:02:01,295
AND WE LOOKED AT WHAT WE HAD

5294
03:02:01,295 --> 03:02:03,397
PREDICTED IN 2019 AND 3 1/2

5295
03:02:03,397 --> 03:02:09,437
YEARS LATER, SEVEN OF THE TOP 40

5296
03:02:09,437 --> 03:02:10,371
PREDICTED GENES HAD CONFIRMED

5297
03:02:10,371 --> 03:02:11,972
AND SOME OF THE BOTTOM ONES HAD

5298
03:02:11,972 --> 03:02:13,707
CONFIRMED TOO, SO THAT SORT OF

5299
03:02:13,707 --> 03:02:17,244
LED ME TO ANOTHER QUESTION, CAN

5300
03:02:17,244 --> 03:02:19,313
WE REALLY LEARN FROM THE BOTTOM

5301
03:02:19,313 --> 03:02:20,948
RANKED GENES IN A BINARY MODEL.

5302
03:02:20,948 --> 03:02:22,750
AND THE ANSWER IN MY OPINION IS

5303
03:02:22,750 --> 03:02:25,686
DEFINITELY YES, SO CERTAINLY

5304
03:02:25,686 --> 03:02:27,121
WHEN YOU RUN KNOWLEDGE GAP

5305
03:02:27,121 --> 03:02:28,088
PREDICTIONS AND YOU FEED THE

5306
03:02:28,088 --> 03:02:29,757
LIST OF POSITIVE GENES THAT ARE

5307
03:02:29,757 --> 03:02:30,891
ASSOCIATED WITH THE PHENOTYPE

5308
03:02:30,891 --> 03:02:32,359
YOU'RE INTERESTED IN AND A SET

5309
03:02:32,359 --> 03:02:35,663
OF NEGATIVE GENES, THEN THE

5310
03:02:35,663 --> 03:02:37,665
MODEL HAS TO DECIDE BETWEEN

5311
03:02:37,665 --> 03:02:37,998
1 AND 0.

5312
03:02:37,998 --> 03:02:40,668
SO THE TRUTH IS IF IT DECIDES

5313
03:02:40,668 --> 03:02:41,569
1 OR 0, IT DOESN'T NECESSARILY

5314
03:02:41,569 --> 03:02:43,037
MEAN THAT THE BOTTOM ONES ARE

5315
03:02:43,037 --> 03:02:45,973
REALLY NEGATIVE.

5316
03:02:45,973 --> 03:02:47,408
THE ONES THAT ARE REALLY

5317
03:02:47,408 --> 03:02:49,043
UNDECIDED AND WHAT THE MODELS

5318
03:02:49,043 --> 03:02:50,144
CONSIDERS TO BE NOT INTERESTING

5319
03:02:50,144 --> 03:02:51,846
AT ALL ARE THE ONES WITH THE

5320
03:02:51,846 --> 03:02:54,849
SCORE CLOSE TO 0.5.

5321
03:02:54,849 --> 03:02:56,584
SO AS A COMMON PRACTICE FOR MAN

5322
03:02:56,584 --> 03:02:58,185
LEARNERS, WE CURRENTLY RECOMMEND

5323
03:02:58,185 --> 03:02:59,620
THAT EVERYONE LOOKS AT THE

5324
03:02:59,620 --> 03:03:03,657
BOTTOM PREDICTIONS, NO T NOT JUE

5325
03:03:03,657 --> 03:03:04,625
TOP PREDICTIONS.

5326
03:03:04,625 --> 03:03:06,293
SO WITH THAT, I THOUGHT I WOULD

5327
03:03:06,293 --> 03:03:09,897
GIVE YOU A PITCH ON WORK DONE BY

5328
03:03:09,897 --> 03:03:17,004
THE GROUP AT THE UNIVERSITY OF

5329
03:03:17,004 --> 03:03:18,105
COPENHAGEN, CENTER FOR PROTEIN

5330
03:03:18,105 --> 03:03:19,640
RESEARCH, WHICH IS DISEASE

5331
03:03:19,640 --> 03:03:20,708
TRAJECTORIES.

5332
03:03:20,708 --> 03:03:22,476
I THOUGHT DISEASE TRAJECTORIES

5333
03:03:22,476 --> 03:03:23,777
ARE RELEVANT TO EVERYONE ON THE

5334
03:03:23,777 --> 03:03:29,083
PANEL AND EVERYONE INTERESTED IN

5335
03:03:29,083 --> 03:03:29,717
UNDERSTANDING SENESCENCE BECAUSE

5336
03:03:29,717 --> 03:03:31,085
IT PRETTY MUCH GIVES YOU THE

5337
03:03:31,085 --> 03:03:34,388
POSSIBILITY TO STUDY PATIENT

5338
03:03:34,388 --> 03:03:36,423
STRATIFICATION AND HOW DIFFERENT

5339
03:03:36,423 --> 03:03:37,758
DISEASES MAY PROGRESS FROM ONE

5340
03:03:37,758 --> 03:03:39,326
TO ANOTHER, AND IT ALSO BRINGS

5341
03:03:39,326 --> 03:03:42,696
IN A MORE CLEAR DATASET FOR

5342
03:03:42,696 --> 03:03:44,298
STUDYING THE IMPACT OF THE

5343
03:03:44,298 --> 03:03:45,466
EXPOSOME.

5344
03:03:45,466 --> 03:03:47,001
AND I WON'T GO INTO THE

5345
03:03:47,001 --> 03:03:48,903
TECHNICAL DETAILS, JUST SUFFICE

5346
03:03:48,903 --> 03:03:51,305
TO SAY THIS HAS PROCESSED THE

5347
03:03:51,305 --> 03:03:53,807
ENTIRE POPULATION REGISTRY OF

5348
03:03:53,807 --> 03:03:56,877
DEB MARK MORE THAN 20 YEARS OF

5349
03:03:56,877 --> 03:03:57,878
DATA, 7 MILLION PATIENTS, ET

5350
03:03:57,878 --> 03:04:01,815
CETERA, ET CETERA, THEY USE --

5351
03:04:01,815 --> 03:04:12,860
CORRECTIOBONFERONNI SIGNALS, YON

5352
03:04:12,860 --> 03:04:14,295
INTERACT WITH THE BROWSER

5353
03:04:14,295 --> 03:04:16,697
YOURSELF SO IF YOU ASK THE

5354
03:04:16,697 --> 03:04:20,301
QUESTION ABOUT IBS IN WOMEN, YOU

5355
03:04:20,301 --> 03:04:22,269
GET THIS TAPE OF TRAJECTORY, AND

5356
03:04:22,269 --> 03:04:27,441
I SORT OF LIST IT HERE BY HAND,

5357
03:04:27,441 --> 03:04:28,342
I EXTRACTED THE DATA BECAUSE YOU

5358
03:04:28,342 --> 03:04:29,977
CAN JUST SEE THE PATIENT NUMBERS

5359
03:04:29,977 --> 03:04:30,945
HERE, BUT IT'S INTERESTING TO

5360
03:04:30,945 --> 03:04:35,916
LACK LOOK AT PERCENTAGES AS WEL.

5361
03:04:35,916 --> 03:04:38,652
IT LOOKS AS YOU PROGRESS FROM

5362
03:04:38,652 --> 03:04:40,087
DIABETES 1 ALL THE WAY TO

5363
03:04:40,087 --> 03:04:41,922
DIVERTICULITIS, THERE'S A

5364
03:04:41,922 --> 03:04:43,023
DECREASED PERCENTAGE IN THE

5365
03:04:43,023 --> 03:04:44,358
FEMALE POPULATION, AND THAT

5366
03:04:44,358 --> 03:04:45,759
TRAJECTORY SEEMS TO CONFIRM IF

5367
03:04:45,759 --> 03:04:47,895
YOU START FROM A DIFFERENT

5368
03:04:47,895 --> 03:04:49,063
DISEASE AS WELL.

5369
03:04:49,063 --> 03:04:54,201
SO IT'S NOT LIKE IT'S A SINGLE

5370
03:04:54,201 --> 03:04:55,836
TRAJECTORY.

5371
03:04:55,836 --> 03:04:57,171
IN MEN IT'S A DIFFERENT

5372
03:04:57,171 --> 03:04:57,605
TRAJECTORY.

5373
03:04:57,605 --> 03:05:00,107
IT STARTS MOSTLY WITH F10, WHICH

5374
03:05:00,107 --> 03:05:02,142
IS PRETTY MUCH MENTAL PROBLEMS

5375
03:05:02,142 --> 03:05:06,146
RELATED TO THE USE OF ALCOHOL.

5376
03:05:06,146 --> 03:05:07,781
AND LEADS TO GI INFLAMMATION,

5377
03:05:07,781 --> 03:05:08,649
AND OF COURSE YOU CAN SEE THAT

5378
03:05:08,649 --> 03:05:11,318
WITH THE MALES, IT'S THE

5379
03:05:11,318 --> 03:05:12,953
PREDOMINANT FACTOR IN THAT

5380
03:05:12,953 --> 03:05:17,691
TRAJECTORY.

5381
03:05:17,691 --> 03:05:18,892
I ALSO THOUGHT I'D BE INTERESTED

5382
03:05:18,892 --> 03:05:22,630
IN LOOKING AT A NEUROLOGICAL

5383
03:05:22,630 --> 03:05:24,498
PROBLEM, SO STATUS EPILEPTICUS

5384
03:05:24,498 --> 03:05:27,468
AND THE EVOLUTION STARTED FROM

5385
03:05:27,468 --> 03:05:30,170
TYPE 2 DIABETES, ANGINA AND THE

5386
03:05:30,170 --> 03:05:32,172
F10 ALCOHOL-INDUCED BEHAVIORAL

5387
03:05:32,172 --> 03:05:33,073
PROBLEMS, AND AGAIN, IF YOU

5388
03:05:33,073 --> 03:05:34,808
FOLLOW THE TRAJECTORY ALL THE

5389
03:05:34,808 --> 03:05:39,947
WAY TO EPILEPSY AND IS THAT TUS

5390
03:05:39,947 --> 03:05:41,248
EPILEPTICUS, YOU CAN PRETTY MUCH

5391
03:05:41,248 --> 03:05:42,916
SEE HOW IT MIGRATES INITIALLY AT

5392
03:05:42,916 --> 03:05:47,721
LEAST WITH F10, THERE'S ONLY 25%

5393
03:05:47,721 --> 03:05:49,690
WOMEN, BUT BY THE TIME YOU GET

5394
03:05:49,690 --> 03:05:51,659
TO CEREBRAL INFARCTION OR STROKE

5395
03:05:51,659 --> 03:05:54,561
AND GO TO EPILEPSY, THE NUMBERS

5396
03:05:54,561 --> 03:05:57,965
SORT OF EQUILIBRATE.

5397
03:05:57,965 --> 03:05:59,199
CONVERSELY YOU SEE THE OPPOSITE

5398
03:05:59,199 --> 03:06:00,567
WITH A LARGER PERCENTAGE OF MEN

5399
03:06:00,567 --> 03:06:02,870
WHEN YOU START FROM THE F10 NODE

5400
03:06:02,870 --> 03:06:04,738
OR THAT FIRST DIAGNOSIS ALL THE

5401
03:06:04,738 --> 03:06:10,344
WAY TO STATUS EPILEPTICUS.

5402
03:06:10,344 --> 03:06:11,545
WHAT I'M BASICALLY SAYING, AND

5403
03:06:11,545 --> 03:06:12,746
THIS IS ONE OF THE MOST PRESSING

5404
03:06:12,746 --> 03:06:14,415
NEEDS IN MY OPINION, WE REALLY

5405
03:06:14,415 --> 03:06:15,482
NEED TO ESTABLISH A U.S.

5406
03:06:15,482 --> 03:06:16,583
EQUIVALENT OF THIS.

5407
03:06:16,583 --> 03:06:19,086
THIS IS NOT EPIDEMIOLOGY AS WE

5408
03:06:19,086 --> 03:06:22,723
KNOW IT, IT DOESN'T LOOK JUST AS

5409
03:06:22,723 --> 03:06:24,058
COMORBIDITIES AS A COOCCURRENCE.

5410
03:06:24,058 --> 03:06:25,793
IT TRIES TO IDENTIFY

5411
03:06:25,793 --> 03:06:26,994
COMORBIDITIES IN A TEMPORAL

5412
03:06:26,994 --> 03:06:28,529
FASHION, SO WHEN YOU LOOK AT

5413
03:06:28,529 --> 03:06:30,164
TEMPORAL DISEASE TRAJECTORIES,

5414
03:06:30,164 --> 03:06:33,033
YOU PRETTY MUCH CAN TRY TO

5415
03:06:33,033 --> 03:06:34,101
UNDERSTAND THIS RELATIONSHIP,

5416
03:06:34,101 --> 03:06:36,070
AND OF COURSE THE PRINCIPLE

5417
03:06:36,070 --> 03:06:37,204
WOULD START TO LOOK AT THE GENES

5418
03:06:37,204 --> 03:06:39,473
THAT ARE RELATED TO DISEASE ONE

5419
03:06:39,473 --> 03:06:41,775
AND THEN HOW THEY EVOLVE INTO

5420
03:06:41,775 --> 03:06:46,146
DISEASE TWO, THREE, 4 FOUR, FIVE

5421
03:06:46,146 --> 03:06:46,947
AND SIX.

5422
03:06:46,947 --> 03:06:48,682
THE DATABASE ALLOWS YOU TO

5423
03:06:48,682 --> 03:06:50,417
PURSUE UP TO SIX DISEASES.

5424
03:06:50,417 --> 03:06:51,085
THE PROBLEM, THE LIMITATION WITH

5425
03:06:51,085 --> 03:06:53,954
THE STUDY IN DENMARK IS

5426
03:06:53,954 --> 03:06:55,022
7 MILLION PATIENTS BUT ONCE YOU

5427
03:06:55,022 --> 03:06:56,557
BREAK DOWN THE DISEASE

5428
03:06:56,557 --> 03:06:57,558
TRAJECTORY FOR FIVE, SIX

5429
03:06:57,558 --> 03:07:00,094
DISEASE, THE NUMBERS BECOME VERY

5430
03:07:00,094 --> 03:07:01,061
SMALL, SO IT'S REALLY IMPORTANT

5431
03:07:01,061 --> 03:07:01,862
TO HAVE MORE DATA.

5432
03:07:01,862 --> 03:07:04,031
>> SPEAKER, YOU HAVE 2
MINUTE

5433
03:07:04,031 --> 03:07:04,364
REMAINING.

5434
03:07:04,364 --> 03:07:07,534
>> I WAS THINKING WHAT'S

5435
03:07:07,534 --> 03:07:10,137
MISSING, AND I CAME UP WITH

5436
03:07:10,137 --> 03:07:11,138
THIS, THE POWER OF THOUGHT.

5437
03:07:11,138 --> 03:07:12,973
SO THIS IS SOMETHING THAT HAS

5438
03:07:12,973 --> 03:07:14,241
BEEN POORLY DESCRIBED AND I

5439
03:07:14,241 --> 03:07:18,712
THINK THIS IS A GAP IN FUNDING

5440
03:07:18,712 --> 03:07:22,216
IN HEALTHCARE AND PARTICULARLY

5441
03:07:22,216 --> 03:07:23,617
I'D LIKE TO INTRODUCE A NEW

5442
03:07:23,617 --> 03:07:27,888
TERM, WHICH IS THE PSYCHOME.

5443
03:07:27,888 --> 03:07:32,392
THIS IS PARTLY INSPIRED BY THE

5444
03:07:32,392 --> 03:07:37,731
WISE CHARGES THAT GOOGLE

5445
03:07:37,731 --> 03:07:38,198
SUGGESTED.

5446
03:07:38,198 --> 03:07:39,833
THE INDIVIDUAL'S PSYCHOLOGICAL

5447
03:07:39,833 --> 03:07:40,934
TRAITS AND COGNITIVE PROCESS

5448
03:07:40,934 --> 03:07:44,104
SHOULD BE TAKEN INTO ACCOUNT

5449
03:07:44,104 --> 03:07:46,073
WITH RESILIENCE AND AGING.

5450
03:07:46,073 --> 03:07:48,275
THE TERM WAS FIRST INTRODUCED BY

5451
03:07:48,275 --> 03:07:51,211
ANDREW LIPPMAN FROM MIT.

5452
03:07:51,211 --> 03:07:51,879
HE WAS COMING FROM THE

5453
03:07:51,879 --> 03:07:52,980
PERSPECTIVE OF GOOGLE AND THE

5454
03:07:52,980 --> 03:07:56,817
ABILITY OF MARKING TRACKING

5455
03:07:56,817 --> 03:07:58,252
DEVICES TO KNOW MORE ABOUT YOU.

5456
03:07:58,252 --> 03:07:59,553
SOMEBODY MENTIONED CREDIT CARD,

5457
03:07:59,553 --> 03:08:01,522
SO IF YOU STUDY YOUR CREDIT CARD

5458
03:08:01,522 --> 03:08:02,856
HISTORY, YOU'LL KNOW MORE ABOUT

5459
03:08:02,856 --> 03:08:03,490
THE PSYCHOLOGY OF THE PERSON.

5460
03:08:03,490 --> 03:08:04,825
BUT THE PROBLEM IS HOW DO WE PUT

5461
03:08:04,825 --> 03:08:06,560
THAT INTO THE DISEASE CONTEXT?

5462
03:08:06,560 --> 03:08:10,297
AND I THINK THIS IS A GREAT

5463
03:08:10,297 --> 03:08:14,101
OPPORTUNITY FOR NIH OR PERHAPS

5464
03:08:14,101 --> 03:08:15,302
ARPA-H TO TRY TO STUDY THE

5465
03:08:15,302 --> 03:08:16,570
IMPACT OF THE MIND ON DISEASE

5466
03:08:16,570 --> 03:08:20,107
AND HOW WE CAN FIGURE OUT THE

5467
03:08:20,107 --> 03:08:22,075
MENTAL BIOMARKERS AND THE MENTAL

5468
03:08:22,075 --> 03:08:23,510
HEALTH BIOMARKERS TO STUDY THAT.

5469
03:08:23,510 --> 03:08:26,580
TO UNDERSTAND THE RESILIENCE.

5470
03:08:26,580 --> 03:08:29,116
SO HOW DO RELATIONSHIPS IN EARLY

5471
03:08:29,116 --> 03:08:30,784
DEVELOPMENT IN CHILDHOOD

5472
03:08:30,784 --> 03:08:33,620
INFLUENCE A PERSON DURING HER

5473
03:08:33,620 --> 03:08:35,889
LIFETIME OF SELF-REFLECTION,

5474
03:08:35,889 --> 03:08:36,557
UNDERSTANDING, ET CETERA.

5475
03:08:36,557 --> 03:08:41,061
THESE ARE THINGS THAT OF COURSE

5476
03:08:41,061 --> 03:08:41,728
PSYCHOLOGISTS HAVE BEEN

5477
03:08:41,728 --> 03:08:43,063
INTERESTED IN FOR QUITE SOME

5478
03:08:43,063 --> 03:08:45,365
TIME BUT NOBODY HAS REALLY PUT

5479
03:08:45,365 --> 03:08:47,968
TOGETHER THE IMPACT OF

5480
03:08:47,968 --> 03:08:49,403
GENOMICS -- AND EXPOSOMES INTO

5481
03:08:49,403 --> 03:08:49,870
THE FUTURE.

5482
03:08:49,870 --> 03:08:51,438
SO TRYING TO LOOK INTO THAT I

5483
03:08:51,438 --> 03:08:52,873
THINK IS A TREMENDOUS

5484
03:08:52,873 --> 03:08:53,841
OPPORTUNITY THAT NIH MIGHT BE

5485
03:08:53,841 --> 03:08:54,274
INTERESTED IN.

5486
03:08:54,274 --> 03:08:56,777
SO HOW DO WE APPROACH THIS IN

5487
03:08:56,777 --> 03:08:58,011
THE NEXT FIVE YEARS?

5488
03:08:58,011 --> 03:09:00,314
AND THIS IS WHERE STRATEGIES

5489
03:09:00,314 --> 03:09:01,615
MIGHT COME IN.

5490
03:09:01,615 --> 03:09:05,752
WE CLEARLY NEED AN ASSOCIATION

5491
03:09:05,752 --> 03:09:07,321
WITH GWAS STUDIES TO TRY TO

5492
03:09:07,321 --> 03:09:08,622
UNDERSTAND VARIANTS WHICH MAY OR

5493
03:09:08,622 --> 03:09:10,624
MAY NOT LEAD TO SPECIFIC

5494
03:09:10,624 --> 03:09:11,258
PSYCHOLOGICAL TRAITS.

5495
03:09:11,258 --> 03:09:15,329
WE SORT OF DISCUSS MENTAL

5496
03:09:15,329 --> 03:09:16,763
DISABILITIES OR INTELLIGENCE AS

5497
03:09:16,763 --> 03:09:18,198
BEING GENETICALLY PREDISPOSED SO

5498
03:09:18,198 --> 03:09:21,501
I THINK THERE ARE DIFFERENT

5499
03:09:21,501 --> 03:09:22,469
FACTORS THAT CAN BE APPLIED.

5500
03:09:22,469 --> 03:09:24,972
OF COURSE LONGITUDAL STUDIES, WE

5501
03:09:24,972 --> 03:09:26,506
HEARD FROM DR. SNYDER AND

5502
03:09:26,506 --> 03:09:29,042
FERRUCCI ABOUT THE IMPORTANCE OF

5503
03:09:29,042 --> 03:09:31,778
THIS, SO WE REALLY SHOULD START

5504
03:09:31,778 --> 03:09:34,081
TO INCLUDE MENTAL HEALTH, NOT

5505
03:09:34,081 --> 03:09:39,219
NNECESSARILY MENTAL ILLNESS BUT

5506
03:09:39,219 --> 03:09:40,020
MENTAL ILLNESS BIOMARKERS INTO

5507
03:09:40,020 --> 03:09:41,421
THE TOPIC.

5508
03:09:41,421 --> 03:09:43,523
EQUALLY IMPORTANT IT'S TIME TO

5509
03:09:43,523 --> 03:09:45,959
ADD THE FMRI AND PETs AND

5510
03:09:45,959 --> 03:09:46,793
UNDERSTAND WHAT PARTS OF THE

5511
03:09:46,793 --> 03:09:48,795
BRAIN MIGHT BE LIGHTING UP

5512
03:09:48,795 --> 03:09:52,866
DURING THE IMPACT OF -- I KNOW

5513
03:09:52,866 --> 03:09:55,035
PEOPLE HAVE STUDIED METADATA, SO

5514
03:09:55,035 --> 03:09:57,437
HIGHLY SKILLED BUDDHISTS, WHEN

5515
03:09:57,437 --> 03:09:59,640
THEY MEDITATE, I THINK THAT'S

5516
03:09:59,640 --> 03:10:00,641
TIME TO DO THAT WITH THE MORE

5517
03:10:00,641 --> 03:10:03,076
GENERAL POPULATION, NOT

5518
03:10:03,076 --> 03:10:04,678
NECESSARILY MEDITATING, AND

5519
03:10:04,678 --> 03:10:05,679
EQUALLY IMPORTANT UNDERSTANDING

5520
03:10:05,679 --> 03:10:06,213
CAUSALITY.

5521
03:10:06,213 --> 03:10:08,849
I THINK THE INFLUENCE OF

5522
03:10:08,849 --> 03:10:14,221
POSITIVE THINKING HAS BEEN SORT

5523
03:10:14,221 --> 03:10:15,689
OF UNDERSTOOD WHEN WE LOOK AT

5524
03:10:15,689 --> 03:10:17,224
THINGS LIKE SAY THE PLACEBO

5525
03:10:17,224 --> 03:10:17,557
EFFECT.

5526
03:10:17,557 --> 03:10:19,293
SO WE LOOK AT PLACEBO AND SAY

5527
03:10:19,293 --> 03:10:21,061
OH, YEAH, PEOPLE THINK THEY'RE

5528
03:10:21,061 --> 03:10:22,362
BEING VISITED BY A DOCTOR

5529
03:10:22,362 --> 03:10:23,363
BECAUSE THEY'RE WEARING A WHITE

5530
03:10:23,363 --> 03:10:24,665
COAT AND SUDDENLY THEY FEEL

5531
03:10:24,665 --> 03:10:25,666
BETTER.

5532
03:10:25,666 --> 03:10:25,966
WHY IS THAT?

5533
03:10:25,966 --> 03:10:27,100
DO WE EVEN UNDERSTAND WHAT'S

5534
03:10:27,100 --> 03:10:28,302
GOING ON WITH THE PATIENT?

5535
03:10:28,302 --> 03:10:30,504
AND THEN THAT'S WHERE I COME IN,

5536
03:10:30,504 --> 03:10:32,072
BIG DATA, AND I WOULD REALLY

5537
03:10:32,072 --> 03:10:34,007
LIKE TO HAVE A CHANCE TO DEPLOY

5538
03:10:34,007 --> 03:10:35,809
SOME MACHINE LEARNING,

5539
03:10:35,809 --> 03:10:39,980
ARTIFICIAL INTELLIGENCE, GPT IF

5540
03:10:39,980 --> 03:10:41,815
YOU WANT, MAYBE GEMINI IF IT'S

5541
03:10:41,815 --> 03:10:42,983
IN FIVE YEARS FROM NOW, TO TRY

5542
03:10:42,983 --> 03:10:44,685
TO MAKE THIS WORK BETTER.

5543
03:10:44,685 --> 03:10:47,287
SO MY TAKE-HOME MESSAGE FOR

5544
03:10:47,287 --> 03:10:51,158
EVERYONE I IN THIS WORKSHOP IS

5545
03:10:51,158 --> 03:10:52,359
IT'S TIME TO STUDY THE CYCLE.

5546
03:10:52,359 --> 03:10:54,194
THIS IS AN INVITATION, IF YOU

5547
03:10:54,194 --> 03:10:54,795
ARE PARTICIPATING IN THIS

5548
03:10:54,795 --> 03:10:55,963
WORKSHOP AND YOU HAVE SOME

5549
03:10:55,963 --> 03:11:00,267
REALLY GOOD THOUGHTS ABOUT THIS,

5550
03:11:00,267 --> 03:11:01,768
WE WOULD LIKE TO PUT A POSITION

5551
03:11:01,768 --> 03:11:02,369
PAPER OUT THERE.

5552
03:11:02,369 --> 03:11:03,770
SO FAR WE HAVE CONTRIBUTORS THAT

5553
03:11:03,770 --> 03:11:05,973
ARE LISTED HERE.

5554
03:11:05,973 --> 03:11:08,508
PETER ROBINSON, NOMI HARRIS,

5555
03:11:08,508 --> 03:11:12,412
MELVIN MCINNIS, MARCIA MORIARTA,

5556
03:11:12,412 --> 03:11:13,547
WE WOULD LIKE TO HEAR FROM YOU,

5557
03:11:13,547 --> 03:11:14,648
SO PLEASE CONTACT ME.

5558
03:11:14,648 --> 03:11:23,657
MY EMAIL IS IN THIS SLIDE SO

5559
03:11:23,657 --> 03:11:27,160
TOPREA@EXPERTSYSTEMS.INC.

5560
03:11:27,160 --> 03:11:29,596
WITH THAT I'D LIKE TO ANSWER

5561
03:11:29,596 --> 03:11:29,863
QUESTIONS.

5562
03:11:29,863 --> 03:11:30,998
>> I THINK WE'RE KIND OF
AT THE

5563
03:11:30,998 --> 03:11:35,168
END OF YOUR TIME ALIQUOT SO I

5564
03:11:35,168 --> 03:11:36,269
THINK WE'LL MOVE RIGHT INTO THE

5565
03:11:36,269 --> 03:11:38,238
PANEL TO GIVE US MORE TIME AND

5566
03:11:38,238 --> 03:11:39,239
PEOPLE CAN ASK YOU QUESTIONS

5567
03:11:39,239 --> 03:11:40,640
DURING THAT PERIOD.

5568
03:11:40,640 --> 03:11:42,509
SO DO PUT YOUR QUESTIONS IN THE

5569
03:11:42,509 --> 03:11:43,076
CHAT.

5570
03:11:43,076 --> 03:11:44,111
THERE'S SOME SPECIFIC QUESTIONS

5571
03:11:44,111 --> 03:11:45,445
FOR YOU, THOUGH, THAT YOU MIGHT

5572
03:11:45,445 --> 03:11:49,850
PICK UP ON IN THE CHAT, I'M NOT

5573
03:11:49,850 --> 03:11:51,685
SURE HOW TO MOVE THEM INTO THE Q

5574
03:11:51,685 --> 03:11:53,286
& A THERE, TUDOR, SO AGAIN,

5575
03:11:53,286 --> 03:11:53,687
THANKS.

5576
03:11:53,687 --> 03:11:56,790
SO HERE'S A -- IF ALL THE

5577
03:11:56,790 --> 03:11:59,826
PANELISTS CAN PUT THEIR VIDEOS

5578
03:11:59,826 --> 03:12:01,261
ON SO WE CAN SEE THEM.

5579
03:12:01,261 --> 03:12:05,332
NOW YOU'RE ALL TINY, BUT MAYBE

5580
03:12:05,332 --> 03:12:09,002
IT'S BET INVENTORY TER TO HAVE T

5581
03:12:09,002 --> 03:12:10,037
PICTURE WITH THEIR NAMES

5582
03:12:10,037 --> 03:12:11,405
UNDERNEATH THAN THIS BIG DIAGRAM

5583
03:12:11,405 --> 03:12:12,039
HERE.

5584
03:12:12,039 --> 03:12:14,441
WE COVERED A LOT OF SPACE, WE

5585
03:12:14,441 --> 03:12:17,344
COVERED CLONAL HEMATOPOIESIS,

5586
03:12:17,344 --> 03:12:18,545
TUMOR MICRO ENVIRONMENTS AND

5587
03:12:18,545 --> 03:12:21,515
THESE TRAJECTORIES, SO REALLY

5588
03:12:21,515 --> 03:12:25,185
QUITE A BIT DR.,  THERE.

5589
03:12:25,185 --> 03:12:27,020
ONE COMMON THEME THAT'S COME UP,

5590
03:12:27,020 --> 03:12:28,789
ESPECIALLY ONE YOU BROUGHT UP AT

5591
03:12:28,789 --> 03:12:30,590
THE END, TUDOR, SO WAY TO DRAW

5592
03:12:30,590 --> 03:12:31,992
YOU RIGHT IN, IS THIS

5593
03:12:31,992 --> 03:12:32,759
LONGITUDINAL PROFILE.

5594
03:12:32,759 --> 03:12:33,560
YOU THINK EVERYBODY MADE A

5595
03:12:33,560 --> 03:12:34,828
LITTLE BIT OF AN ARGUMENT THAT

5596
03:12:34,828 --> 03:12:36,863
WE NEED LONGITUDINAL PROFILES

5597
03:12:36,863 --> 03:12:37,798
FOR STUDIES.

5598
03:12:37,798 --> 03:12:40,901
THERE REALLY IS A DERTH OF SUCH

5599
03:12:40,901 --> 03:12:41,802
STUDIES IN THE AGING FIELD,

5600
03:12:41,802 --> 03:12:45,872
WHICH IS KIND OF SURPRI SURPRISG

5601
03:12:45,872 --> 03:12:48,341
BECAUSE AGING IS THE MOST

5602
03:12:48,341 --> 03:12:50,310
OBVIOUS ONE.

5603
03:12:50,310 --> 03:12:51,611
MAYBE YOU COULD EACH SUMMARIZE

5604
03:12:51,611 --> 03:12:54,281
WHAT YOUR IDEAL THING,

5605
03:12:54,281 --> 03:12:55,382
LONGITUDAL PROFILE WOULD LOOK

5606
03:12:55,382 --> 03:12:57,350
LIKE, WHAT KINDS OF COMMON

5607
03:12:57,350 --> 03:12:59,086
THINGS, AND MAYBE WE SHOULDN'T

5608
03:12:59,086 --> 03:13:00,353
HAVE 10 DIFFERENT COHORTS

5609
03:13:00,353 --> 03:13:01,421
RUNNING ACROSS, MAYBE YOU SHOULD

5610
03:13:01,421 --> 03:13:02,722
HAVE ONE COHORT THAT'S STUDYING

5611
03:13:02,722 --> 03:13:03,924
ALL THE DIFFERENT PARAMETERS.

5612
03:13:03,924 --> 03:13:05,392
I JUST HEARD ABOUT IN THIS

5613
03:13:05,392 --> 03:13:08,762
MORNING'S SESSION OR MORNING FOR

5614
03:13:08,762 --> 03:13:10,363
ME, SORRY, PROBABLY AFTERNOON

5615
03:13:10,363 --> 03:13:10,597
FOR YOU.

5616
03:13:10,597 --> 03:13:11,765
SO WHY DON'T WE START, I GUESS

5617
03:13:11,765 --> 03:13:13,166
WE'LL GO IN THE ORDER OF

5618
03:13:13,166 --> 03:13:14,768
SPEAKERS, IF YOU WANT TO START,

5619
03:13:14,768 --> 03:13:17,037
PEGGY, SOME OF YOUR THOUGHTS ON

5620
03:13:17,037 --> 03:13:18,371
LONGITUDAL PROFILING, HOW IT CAN

5621
03:13:18,371 --> 03:13:19,473
IMPACT THIS WHOLE FIELD.

5622
03:13:19,473 --> 03:13:20,340
>> SURE, THANK YOU.

5623
03:13:20,340 --> 03:13:24,644
WELL, AS WE TALKED ABOUT, CLONAL

5624
03:13:24,644 --> 03:13:26,513
HEMATOPOIESIS IS REALLY

5625
03:13:26,513 --> 03:13:27,180
INTERESTING, AND MOSTLY IT'S

5626
03:13:27,180 --> 03:13:28,548
BEEN MEASURED AT ONE POINT IN

5627
03:13:28,548 --> 03:13:31,551
TIME AND THEN KIND OF POPULATION

5628
03:13:31,551 --> 03:13:33,019
LEVEL ASSOCIATED WITH VARIOUS

5629
03:13:33,019 --> 03:13:33,553
DISEASE STATES.

5630
03:13:33,553 --> 03:13:35,956
AND WE REALLY DON'T UNDERSTAND

5631
03:13:35,956 --> 03:13:37,190
HOW IT VARIES OVER TIME.

5632
03:13:37,190 --> 03:13:38,325
THERE'S A SMALL NUMBER OF

5633
03:13:38,325 --> 03:13:40,494
STUDIES THAT HAVE LOOKED AT AND

5634
03:13:40,494 --> 03:13:41,595
INTERVIEWED PEOPLE BUT WE NEED

5635
03:13:41,595 --> 03:13:43,597
TO UNDERSTAND HOW IT VARIES OVER

5636
03:13:43,597 --> 03:13:45,765
TIME AND HOW IT RELATES TO

5637
03:13:45,765 --> 03:13:46,533
PATHOLOGIES OR EFFECTS IN

5638
03:13:46,533 --> 03:13:49,269
INDIVIDUALS.

5639
03:13:49,269 --> 03:13:50,971
AND ACTUALLY CLONAL

5640
03:13:50,971 --> 03:13:51,505
HEMATOPOIESIS IS NOT THAT

5641
03:13:51,505 --> 03:13:53,440
EXPENSIVE TO LOOK AT ESPECIALLY

5642
03:13:53,440 --> 03:13:54,674
IF YOU USE A PANEL OF GENES, I

5643
03:13:54,674 --> 03:13:56,076
THINK IT'S QUITE ACCESSIBLE.

5644
03:13:56,076 --> 03:13:57,244
WE ALREADY HAVE SOME COHORTS

5645
03:13:57,244 --> 03:13:58,445
ACROSS THE NIH THAT THIS KIND OF

5646
03:13:58,445 --> 03:13:59,546
THING CAN BE APPLIED TO.

5647
03:13:59,546 --> 03:14:01,548
IN FACT, THERE ARE BLOOD SAMPLES

5648
03:14:01,548 --> 03:14:04,484
FROM SOME OF THESE COHORTS THAT

5649
03:14:04,484 --> 03:14:05,886
ARE -- THAT HAVE BEEN TAKEN OVER

5650
03:14:05,886 --> 03:14:07,387
TIME THAT ARE BEING MINED FOR

5651
03:14:07,387 --> 03:14:08,355
SOME OF THESE QUESTIONS RIGHT

5652
03:14:08,355 --> 03:14:12,492
NOW.

5653
03:14:12,492 --> 03:14:14,995
>> MAYBE I'LL THROW IN A

5654
03:14:14,995 --> 03:14:16,863
COMMENT, I DON'T THINK THE CHAT

5655
03:14:16,863 --> 03:14:17,998
IS AVAILABLE TO ALL OUR

5656
03:14:17,998 --> 03:14:20,934
PARTICIPANTS.

5657
03:14:20,934 --> 03:14:21,935
SHE SALES -- FUNDS A LOT OF

5658
03:14:21,935 --> 03:14:22,736
THESE INCLUDING LARGE

5659
03:14:22,736 --> 03:14:23,236
POPULATION.

5660
03:14:23,236 --> 03:14:25,572
I DON'T KNOW ABOUT THE DETAILED

5661
03:14:25,572 --> 03:14:28,542
PROFILES THAT COME OUT.

5662
03:14:28,542 --> 03:14:29,309
ASHANI, IF YOU WANT TO ADD

5663
03:14:29,309 --> 03:14:30,477
ANYTHING TO THIS, YOUR THOUGHTS

5664
03:14:30,477 --> 03:14:34,648
ON THE LONGITUDAL?

5665
03:14:34,648 --> 03:14:36,016
>> I MEAN, I THINK THESE
ARE

5666
03:14:36,016 --> 03:14:37,918
GOING TO BE ABSOLUTELY CRITICAL

5667
03:14:37,918 --> 03:14:42,355
FOR US IN THE CANCER FIELD.

5668
03:14:42,355 --> 03:14:43,390
BECAUSE AS I SAID A LOT OF THE

5669
03:14:43,390 --> 03:14:44,457
CLINICAL TRIALS ARE NOT TAKING

5670
03:14:44,457 --> 03:14:49,129
AGE AS A FACTOR INTO ACCOUNT.

5671
03:14:49,129 --> 03:14:50,564
AND TRYING TO UNDERSTAND CANCER

5672
03:14:50,564 --> 03:14:53,166
HEALTH DISPARITIES AS WELL.

5673
03:14:53,166 --> 03:14:54,968
IT'S GOING TO BE IMPORTANT TO GO

5674
03:14:54,968 --> 03:14:56,169
BACK THROUGH ALL OF THESE

5675
03:14:56,169 --> 03:14:59,339
STUDIES BUT ALSO TO HAVE

5676
03:14:59,339 --> 03:15:00,974
INTENTIONAL STUDIES THAT INCLUDE

5677
03:15:00,974 --> 03:15:04,177
RACE, AGE, ET CETERA, OVER A

5678
03:15:04,177 --> 03:15:05,512
PERIOD OF TIME OVER THE NEXT 10

5679
03:15:05,512 --> 03:15:08,648
TO 20 YEARS.

5680
03:15:08,648 --> 03:15:09,849
BECAUSE WE'RE NOT REALLY GOING

5681
03:15:09,849 --> 03:15:11,551
TO UNDERSTAND HOW TO TREAT THIS

5682
03:15:11,551 --> 03:15:13,186
DISEASE UNTIL WE HAD THOSE.

5683
03:15:13,186 --> 03:15:15,021
>> MIRANDA, I'M SURE YOU
HAVE

5684
03:15:15,021 --> 03:15:18,325
PLENTY TO SAY WHEN IT COMES TO

5685
03:15:18,325 --> 03:15:18,992
DEMENTIA AND ALZHEIMER'S.

5686
03:15:18,992 --> 03:15:20,760
>> I THINK IT'S REALLY
IMPORTANT

5687
03:15:20,760 --> 03:15:21,928
THAT EVERYBODY BECOMES THEIR OWN

5688
03:15:21,928 --> 03:15:23,396
BASELINE AND THE ONLY WAY WE CAN

5689
03:15:23,396 --> 03:15:26,566
DO THAT IS LONGITUDAL, BUT THOSE

5690
03:15:26,566 --> 03:15:27,567
STUDIES, THEY HAVEN'T REALLY

5691
03:15:27,567 --> 03:15:30,637
BEEN DONE WELL OR AT ALL.

5692
03:15:30,637 --> 03:15:32,372
I THINK GETTING BACK TO WHAT

5693
03:15:32,372 --> 03:15:33,607
METRICS OF BRAIN AGING ARE WE

5694
03:15:33,607 --> 03:15:35,709
LOOKING AT, AN ARGUMENT AGAINST

5695
03:15:35,709 --> 03:15:36,576
ENROLLING PEOPLE AT A YOUNGER

5696
03:15:36,576 --> 03:15:38,111
AGE IS BECAUSE THERE'S A CEILING

5697
03:15:38,111 --> 03:15:38,445
EFFECT.

5698
03:15:38,445 --> 03:15:42,515
ALL OF OUR COGNITIVE TESTS, MOST

5699
03:15:42,515 --> 03:15:45,619
OF US WOULD HAVE A CEILING

5700
03:15:45,619 --> 03:15:47,053
EFFECT ACROSS THE LIFESPAN UNTIL

5701
03:15:47,053 --> 03:15:48,021
SOMETHING MAJOR IS HAPPENING, SO

5702
03:15:48,021 --> 03:15:49,623
I THINK WE NEED TO RE-EVALUATE

5703
03:15:49,623 --> 03:15:50,824
THAT TO MAYBE HAVE SOME MORE

5704
03:15:50,824 --> 03:15:52,125
SENSITIVE TESTS OR JUST THINK

5705
03:15:52,125 --> 03:15:54,294
ABOUT SOME DIFFERENT METRICS.

5706
03:15:54,294 --> 03:15:56,696
AND THEN IN TERMS OF SENESCENCE,

5707
03:15:56,696 --> 03:15:58,865
THERE'S A LOT OF WORK, LARGE

5708
03:15:58,865 --> 03:16:01,301
EFFORTS BY THE NIH, THE COMMON

5709
03:16:01,301 --> 03:16:03,370
FUND, WITH THE -- TRYING TO

5710
03:16:03,370 --> 03:16:04,804
IDENTIFY TISSUE-SPECIFIC MARKERS

5711
03:16:04,804 --> 03:16:06,706
OF SENESCENT CELLS WHICH WILL BE

5712
03:16:06,706 --> 03:16:07,574
REALLY IMPORTANT TO KNOW WHICH

5713
03:16:07,574 --> 03:16:10,543
TISSUES ARE CONTRIBUTING AND AT

5714
03:16:10,543 --> 03:16:11,177
WHAT AGE.

5715
03:16:11,177 --> 03:16:14,347
BUT YEAH, I AGREE WITH

5716
03:16:14,347 --> 03:16:15,515
EVERYBODY, THE LONGITUDAL

5717
03:16:15,515 --> 03:16:16,783
STUDIES ARE REALLY CRITICAL.

5718
03:16:16,783 --> 03:16:20,120
>> I WOULD THINK ADDING,
FIL,

5719
03:16:20,120 --> 03:16:20,920
PUTTING WHAT YOU DO WITH THE

5720
03:16:20,920 --> 03:16:22,222
LIFESTYLE MEASUREMENTS ON TOP OF

5721
03:16:22,222 --> 03:16:23,857
EVERYTHING WE JUST HEARD IN

5722
03:16:23,857 --> 03:16:27,661
TERMS OF CH AND DEMENTIA AND

5723
03:16:27,661 --> 03:16:29,296
SUCH JUST SEEM SO CRITICAL.

5724
03:16:29,296 --> 03:16:30,497
WE'RE FOLLOWING PEOPLE'S SLEEP,

5725
03:16:30,497 --> 03:16:32,766
WE CAN SEE ALL THESE ADVERSE

5726
03:16:32,766 --> 03:16:35,001
EFFECTS, INCLUDING TUMOR

5727
03:16:35,001 --> 03:16:35,669
MICROENVIRONMENTS, HOW ALL THAT

5728
03:16:35,669 --> 03:16:35,902
SHIFTS.

5729
03:16:35,902 --> 03:16:37,871
SO M SO OF YOUR THOUGHTS THERE?

5730
03:16:37,871 --> 03:16:39,739
>> EXACTLY.

5731
03:16:39,739 --> 03:16:41,841
SO JUST TO PUT THIS IN THE

5732
03:16:41,841 --> 03:16:44,244
PERSPECTIVE OF CARDIOVASCULAR

5733
03:16:44,244 --> 03:16:46,913
DISEASE, BY THE WAY,

5734
03:16:46,913 --> 03:16:48,114
NEURODEGENERATIVE DISEASES AND

5735
03:16:48,114 --> 03:16:49,115
CARDIOVASCULAR DISEASES HAVE SO

5736
03:16:49,115 --> 03:16:50,216
MANY SHARED PATHWAYS.

5737
03:16:50,216 --> 03:16:51,651
WHEN WE THINK ABOUT

5738
03:16:51,651 --> 03:16:52,352
CARDIOVASCULAR DISEASE, OFTEN

5739
03:16:52,352 --> 03:16:56,056
WHAT THAT MEANS FOR A LOT OF

5740
03:16:56,056 --> 03:16:57,390
PEOPLE IS THAT ACUTE EVENT,

5741
03:16:57,390 --> 03:16:58,792
STROKE, M.I., THAT YOU HAVE

5742
03:16:58,792 --> 03:17:00,293
HEART FAILURE, BUT IT'S

5743
03:17:00,293 --> 03:17:01,394
RECOGNIZING THAT THESE -- THAT

5744
03:17:01,394 --> 03:17:05,365
MOST OF THE DISEASES ARE

5745
03:17:05,365 --> 03:17:06,499
ACTUALLY SUBCLINICAL.

5746
03:17:06,499 --> 03:17:07,767
YOU WERE MENTIONING, MICHAEL,

5747
03:17:07,767 --> 03:17:09,035
ABOUT WE GO TO THE DOCTOR, WE

5748
03:17:09,035 --> 03:17:11,037
GET OUR CHOLESTEROL, WE GET OUR

5749
03:17:11,037 --> 03:17:12,772
BLOOD PRESSURE, AND THIS ONE

5750
03:17:12,772 --> 03:17:14,407
LITTLE POINT, NOT REALLY

5751
03:17:14,407 --> 03:17:17,177
MONITORING OVER TIME, AND WHAT

5752
03:17:17,177 --> 03:17:18,511
LONGITUDAL STUDY ALSO ALLOW US

5753
03:17:18,511 --> 03:17:22,015
TO BETTER UNDERSTAND IS HOW DOES

5754
03:17:22,015 --> 03:17:23,616
THE DISEASE PROGRESS OVER TIME.

5755
03:17:23,616 --> 03:17:25,585
BECAUSE THE GUIDELINES TELL US,

5756
03:17:25,585 --> 03:17:27,253
DON'T GIVE A PERSON STATIN UNTIL

5757
03:17:27,253 --> 03:17:27,687
THEY'RE 50.

5758
03:17:27,687 --> 03:17:29,289
THAT MIGHT BE WAY, WAY TOO LATE.

5759
03:17:29,289 --> 03:17:31,524
WHAT HAPPENS IF YOU HAVE

5760
03:17:31,524 --> 03:17:32,759
INFLUENZA INFECTION AT 20 AND

5761
03:17:32,759 --> 03:17:33,727
THAT DAMAGES YOUR HEART?

5762
03:17:33,727 --> 03:17:36,963
YOU DON'T EVEN KNOW THAT BECAUSE

5763
03:17:36,963 --> 03:17:38,598
YOU'RE NOT GOING TO DO A CALCIUM

5764
03:17:38,598 --> 03:17:39,733
TEST, YOU'RE NOT NECESSARILY

5765
03:17:39,733 --> 03:17:41,634
GOING TO DO A VERY THOROUGH

5766
03:17:41,634 --> 03:17:42,202
UNDERSTANDING OF YOUR HEART

5767
03:17:42,202 --> 03:17:43,370
FUNCTION, BUT IT MAY HAVE AN

5768
03:17:43,370 --> 03:17:44,571
IMPACT.

5769
03:17:44,571 --> 03:17:46,439
I THINK STUDIES THAT CAN REALLY

5770
03:17:46,439 --> 03:17:47,340
TRACK HEALTHY INDIVIDUALS OVER

5771
03:17:47,340 --> 03:17:49,209
TIME INCORPORATING THE EXPOSOME

5772
03:17:49,209 --> 03:17:55,248
AND INCORPORATING VARIOUS

5773
03:17:55,248 --> 03:17:56,015
EXPOSURES, NOT JUST LIFESTYLE

5774
03:17:56,015 --> 03:17:57,784
BUT ALSO COMORBIDITIES THAT

5775
03:17:57,784 --> 03:17:59,419
OCCUR, BECAUSE OF COURSE ACCRUAL

5776
03:17:59,419 --> 03:18:00,453
OF COMORBIDITIES IS SUCH A

5777
03:18:00,453 --> 03:18:02,188
HALLMARK OF AGING, IS GOING TO

5778
03:18:02,188 --> 03:18:04,924
REALLY HELP US UNDERSTAND, YOU

5779
03:18:04,924 --> 03:18:06,159
KNOW, THE ETIOLOGY OF THESE

5780
03:18:06,159 --> 03:18:07,794
DISEASES AND HOW WE CAN PREVENT

5781
03:18:07,794 --> 03:18:09,662
THEM BEFORE IT'S TOO LATE,

5782
03:18:09,662 --> 03:18:12,766
BEFORE THEY MANIFEST THEMSELVES.

5783
03:18:12,766 --> 03:18:14,634
>> I'M GOING TO GET TO
SOME

5784
03:18:14,634 --> 03:18:15,935
COMMENTS LIZ HAS IN THE CHAT,

5785
03:18:15,935 --> 03:18:17,604
BUT I THINK THE TOOLS YOU'RE

5786
03:18:17,604 --> 03:18:19,372
BRINGING UP, TUDOR, AND ALSO THE

5787
03:18:19,372 --> 03:18:20,507
IDEA ABOUT BRINGING IN THE --

5788
03:18:20,507 --> 03:18:25,245
YOU CALL IT THE PSYCHOME KIND OF

5789
03:18:25,245 --> 03:18:26,079
MEASUREMENTS, I THINK WE ALL

5790
03:18:26,079 --> 03:18:26,980
AGREE WITH THAT.

5791
03:18:26,980 --> 03:18:27,947
I'M SURE YOU'RE GOING TO GET A

5792
03:18:27,947 --> 03:18:30,083
LOT OF PEOPLE REACHING OUT TO

5793
03:18:30,083 --> 03:18:30,850
YOU AFTER YOUR LAST COMMENT.

5794
03:18:30,850 --> 03:18:32,051
BUT I WOULD THINK THE TOOLS

5795
03:18:32,051 --> 03:18:35,054
YOU'RE BUILDING WOULD BE VERY,

5796
03:18:35,054 --> 03:18:38,658
VERY VALUABLE FOR PEOPLE, DRA

5797
03:18:38,658 --> 03:18:38,925
DRAWING --

5798
03:18:38,925 --> 03:18:40,293
>> SO I CAN SEE IN THE
CHAT THAT

5799
03:18:40,293 --> 03:18:44,063
PEOPLE ARE TALKING ABOUT ONGOING

5800
03:18:44,063 --> 03:18:45,832
LONGITUDAL STUDIES THAT THE NIA

5801
03:18:45,832 --> 03:18:47,066
IS SPONSORING AND I THINK THAT'S

5802
03:18:47,066 --> 03:18:47,400
COOL.

5803
03:18:47,400 --> 03:18:51,671
PART OF THE QUESTION IS HOW MUCH

5804
03:18:51,671 --> 03:18:53,239
DETAIL DO WE CAPTURE IN THOSE

5805
03:18:53,239 --> 03:18:54,541
LONGITUDINAL STUDIES, DO WE LOOK

5806
03:18:54,541 --> 03:18:56,142
AT COGNITIVE FUNCTION LIKE

5807
03:18:56,142 --> 03:18:58,878
MEMORY TESTS AND REACTION TIMES.

5808
03:18:58,878 --> 03:19:00,747
DO WE LOOK AT THE PSYCHOLOGICAL

5809
03:19:00,747 --> 03:19:02,582
WELL-BEING, LIKE THE WHOLE PART

5810
03:19:02,582 --> 03:19:07,821
OF THE PSYCHOME, RESILIENCE,

5811
03:19:07,821 --> 03:19:09,556
DEPRESSION, DO WE CATCH THOSE.

5812
03:19:09,556 --> 03:19:11,791
I READ THAT THE JAPANESE, FOR

5813
03:19:11,791 --> 03:19:12,792
INSTANCE, USE SMART WATCHES TO

5814
03:19:12,792 --> 03:19:14,661
KIND OF PREDICT SUICIDAL

5815
03:19:14,661 --> 03:19:16,429
TENDENCIES, AND HOW DO WE EVEN

5816
03:19:16,429 --> 03:19:18,331
TRACK THAT, RIGHT?

5817
03:19:18,331 --> 03:19:19,199
SENSORY MOTOR FUNCTIONS?

5818
03:19:19,199 --> 03:19:21,067
DO WE CAPTURE ALL THAT?

5819
03:19:21,067 --> 03:19:23,036
OF COURSE COMORBIDITIES HAVE

5820
03:19:23,036 --> 03:19:26,473
BEEN MENTIONED AND THE EXPOSOME

5821
03:19:26,473 --> 03:19:28,107
THAT FIL IS CLEARLY STUDYING.

5822
03:19:28,107 --> 03:19:29,776
HOW ABOUT MITOCHONDRIA?

5823
03:19:29,776 --> 03:19:32,312
DO WE LOOK AT MITOCHONDRIAL

5824
03:19:32,312 --> 03:19:32,745
FUNCTION?

5825
03:19:32,745 --> 03:19:34,380
HOW MANY MEDICATIONS?

5826
03:19:34,380 --> 03:19:34,714
POLYPHARMACY.

5827
03:19:34,714 --> 03:19:36,716
A LOT OF AMERICANS TAKE, YOU

5828
03:19:36,716 --> 03:19:39,118
KNOW, FIVE, 10 DRUGS ON A DAILY

5829
03:19:39,118 --> 03:19:41,955
BASIS, THEY HAVE A WHOLE MEAL,

5830
03:19:41,955 --> 03:19:42,789
THEY COUNT CALORIES WITH THEIR

5831
03:19:42,789 --> 03:19:43,323
MEDICATION.

5832
03:19:43,323 --> 03:19:44,757
ALL THESE THINGS ARE NOT REALLY

5833
03:19:44,757 --> 03:19:46,926
WELL UNDERSTOOD OR STUDIED FOR

5834
03:19:46,926 --> 03:19:47,227
THAT MATTER.

5835
03:19:47,227 --> 03:19:48,728
SO WE NEED TO START PUTTING A

5836
03:19:48,728 --> 03:19:50,697
LOT MORE PRESSURE INTO THE KIND

5837
03:19:50,697 --> 03:19:53,199
OF DATA WE NEED FROM LONGITUDAL

5838
03:19:53,199 --> 03:19:53,833
STUDIES.

5839
03:19:53,833 --> 03:19:56,669
>> 100% AGREE.

5840
03:19:56,669 --> 03:19:57,871
SO WHAT TUDOR WAS REFERRING TO

5841
03:19:57,871 --> 03:20:00,006
IN THE CHAT, LIZ NIELSEN PUT A

5842
03:20:00,006 --> 03:20:02,075
COMMENT, THERE ARE ALREADY MANY

5843
03:20:02,075 --> 03:20:03,042
LONGITUDAL AND LIFE COURSE

5844
03:20:03,042 --> 03:20:04,878
STUDIES OF AGING SUPPORTED BY

5845
03:20:04,878 --> 03:20:09,582
NIA, MANY OF THEM ARE POPULATION

5846
03:20:09,582 --> 03:20:10,717
REPRESENTATIVE AND DIVERSE,

5847
03:20:10,717 --> 03:20:12,585
WHICH I APPLAUD THEM FOR.

5848
03:20:12,585 --> 03:20:13,953
EXACTLY WHAT ARE THEY SAMPLING,

5849
03:20:13,953 --> 03:20:15,655
WHAT ARE THEY MEASURING, AND

5850
03:20:15,655 --> 03:20:16,823
WHAT'S THE FREQUENCY?

5851
03:20:16,823 --> 03:20:18,691
BECAUSE I'VE BEEN ARGUING WE

5852
03:20:18,691 --> 03:20:20,093
STILL DON'T KNOW THE

5853
03:20:20,093 --> 03:20:22,061
FREQUENCIES, MEASURES ONCE EVERY

5854
03:20:22,061 --> 03:20:23,196
SEVEN YEARS, THAT'S NOT ENOUGH

5855
03:20:23,196 --> 03:20:24,464
TO BUILD RESILIENCE MODELS, IN

5856
03:20:24,464 --> 03:20:25,131
MY OPINION.

5857
03:20:25,131 --> 03:20:26,900
I'M NOT EVEN SURE ONCE A YEAR IS

5858
03:20:26,900 --> 03:20:28,568
ENOUGH TO BUILD GOOD RESILIENCE

5859
03:20:28,568 --> 03:20:33,139
MODELS IF YOU WANT MY OPINION.

5860
03:20:33,139 --> 03:20:36,709
WE CERTAINLY GET A LOT OF

5861
03:20:36,709 --> 03:20:38,545
INFORMATION BY SAMPLING EVERY

5862
03:20:38,545 --> 03:20:38,912
THREE MONTHS.

5863
03:20:38,912 --> 03:20:42,982
>> A VIRTUAL HUMAN WHERE
YOU

5864
03:20:42,982 --> 03:20:44,517
HAVE THE TRANSCRIPTOME AT 20 AND

5865
03:20:44,517 --> 03:20:46,152
SEE HOW IT EVOLVES ALL THE WAY

5866
03:20:46,152 --> 03:20:47,887
FROM 20 TO 80 AND SEE ALL THE

5867
03:20:47,887 --> 03:20:48,321
CHANGES THAT HAPPEN.

5868
03:20:48,321 --> 03:20:49,289
I WOULD LIKE TO SEE THE

5869
03:20:49,289 --> 03:20:51,257
TRANSITION WITH ALL THE NETWORKS

5870
03:20:51,257 --> 03:20:54,260
AND ALL THE EPIGENETICS, ALL THE

5871
03:20:54,260 --> 03:20:55,361
METHYLATIONS, THE POST

5872
03:20:55,361 --> 03:20:56,129
TRANSLATION, THAT WOULD BE

5873
03:20:56,129 --> 03:20:56,763
REALLY FASCINATING.

5874
03:20:56,763 --> 03:20:58,565
AND I THINK WE ARE ALMOST THERE,

5875
03:20:58,565 --> 03:21:01,501
WE CERTAINLY HAVE THE DATA, WE

5876
03:21:01,501 --> 03:21:02,602
JUST NEED TO TAG IT PROPERLY AND

5877
03:21:02,602 --> 03:21:04,470
BUILD THE MACHINE LEARNING --

5878
03:21:04,470 --> 03:21:06,940
>> WELL, I'M NOT SO SURE,
I

5879
03:21:06,940 --> 03:21:08,341
DON'T KNOW IF WE HAVE FREQUENT

5880
03:21:08,341 --> 03:21:09,108
SAMPLING ENOUGH.

5881
03:21:09,108 --> 03:21:10,577
>> OKAY, WE CAN DO IT ON
THE

5882
03:21:10,577 --> 03:21:11,210
SNYDER LAB DATA.

5883
03:21:11,210 --> 03:21:13,079
>> I THINK THAT'S A
HEALTHY

5884
03:21:13,079 --> 03:21:13,746
ARGUMENT.

5885
03:21:13,746 --> 03:21:15,048
OUR DATA IS ALL, BY THE WAY,

5886
03:21:15,048 --> 03:21:15,315
PUBLIC.

5887
03:21:15,315 --> 03:21:18,418
I DIDN'T BRING THAT UP, BUT 85%

5888
03:21:18,418 --> 03:21:22,188
IS PUBLIC, INCLUDING GENOME

5889
03:21:22,188 --> 03:21:22,822
SEQUENCING.

5890
03:21:22,822 --> 03:21:24,457
I PERSONALLY WOULD START BEFORE

5891
03:21:24,457 --> 03:21:25,592
CONCEPTION, BY THE WAY, TAKE IT

5892
03:21:25,592 --> 03:21:28,027
ALL THE WAY UNTIL POST DEATH.

5893
03:21:28,027 --> 03:21:30,730
>> I SAID 20 FOR -- YEAH.

5894
03:21:30,730 --> 03:21:32,065
>> OKAY.

5895
03:21:32,065 --> 03:21:37,837
FEEL FREE TO KEEP JUMPING IN.

5896
03:21:37,837 --> 03:21:39,038
SO ANYWAY, IF SOME OF THE FOLKS

5897
03:21:39,038 --> 03:21:40,473
WANT TO UNMUTE, WE'RE GETTING A

5898
03:21:40,473 --> 03:21:43,176
LOT OF CHAT STUFF UP HERE --

5899
03:21:43,176 --> 03:21:50,817
>> I HAVE A QUESTION TO --
SO

5900
03:21:50,817 --> 03:21:53,152
PEGGY, ABOUT THE CLONAL

5901
03:21:53,152 --> 03:21:57,724
HEMATOPOIESIS, AND OF COURSE IN

5902
03:21:57,724 --> 03:21:58,725
AGING, HEMATOPOIESIS INCREASES

5903
03:21:58,725 --> 03:22:02,295
AND SO ON.

5904
03:22:02,295 --> 03:22:06,165
DATA THAT THE MONOCYTES DURING

5905
03:22:06,165 --> 03:22:07,166
CALORIC RESTRICTION GO BACK TO

5906
03:22:07,166 --> 03:22:08,034
BONE MARROW AND NO IDEA WHAT

5907
03:22:08,034 --> 03:22:09,569
HAPPENS WITH THOSE MONOCYTES,

5908
03:22:09,569 --> 03:22:13,640
WHETHER THEY DIFFERENTIATE INTO

5909
03:22:13,640 --> 03:22:17,710
OTHER MYELOID SUBSETS OR NOT, SO

5910
03:22:17,710 --> 03:22:19,779
QUESTION IS, IN THE AGING

5911
03:22:19,779 --> 03:22:24,517
SETTING, AND IN SETTING OF

5912
03:22:24,517 --> 03:22:25,184
VARIOUS CALORIC RESTRICTION AND

5913
03:22:25,184 --> 03:22:30,990
SO ON, WHAT HAPPENS WITH CLONAL

5914
03:22:30,990 --> 03:22:31,824
HEMATOPOIESIS?

5915
03:22:31,824 --> 03:22:33,726
>> I DON'T REALLY KNOW
THAT THAT

5916
03:22:33,726 --> 03:22:34,861
HAS BEEN EXAMINED.

5917
03:22:34,861 --> 03:22:36,863
AGAIN, YOU WOULD NEED A COHORT

5918
03:22:36,863 --> 03:22:38,698
OF INDIVIDUAL, FIL MAY HAVE

5919
03:22:38,698 --> 03:22:41,167
OTHER DATA ON THAT, BUT YOU'D

5920
03:22:41,167 --> 03:22:41,901
NEED A COHORT OF INDIVIDUALS

5921
03:22:41,901 --> 03:22:43,036
THAT YOU WOULD REALLY FOLLOW.

5922
03:22:43,036 --> 03:22:45,371
I MEAN, I THINK FOR THE MOST

5923
03:22:45,371 --> 03:22:45,972
PART, CLONAL HEMATOPOIESIS IS

5924
03:22:45,972 --> 03:22:47,040
NOT SOMETHING THAT CHANGES

5925
03:22:47,040 --> 03:22:47,607
QUICKLY, RIGHT?

5926
03:22:47,607 --> 03:22:49,242
SO IF YOU HAD A COHORT THAT WAS

5927
03:22:49,242 --> 03:22:51,277
FASTING OR HAD A CERTAIN

5928
03:22:51,277 --> 03:22:52,245
LIFESTYLE OVER A PERIOD OF TIME,

5929
03:22:52,245 --> 03:22:54,981
THAT MIGHT BE OF MORE INTEREST

5930
03:22:54,981 --> 03:22:57,483
THAN THE SHORT TERM

5931
03:22:57,483 --> 03:22:57,950
PERTURBATIONS.

5932
03:22:57,950 --> 03:22:59,619
SHORT TERM PERTURBATIONS, I

5933
03:22:59,619 --> 03:23:00,920
THINK YOU WOULD SEE THINGS

5934
03:23:00,920 --> 03:23:02,455
CHANGING IN THE BLOOD AND FIL

5935
03:23:02,455 --> 03:23:04,290
AND OTHER PEOPLE HAVE SHOWN BUT

5936
03:23:04,290 --> 03:23:05,458
YOU'RE NOT GOING TO SEE MAJOR

5937
03:23:05,458 --> 03:23:06,659
CLONAL CHANGES IN THEIR OUTPUT

5938
03:23:06,659 --> 03:23:08,428
IN THE BONE MARROW.

5939
03:23:08,428 --> 03:23:11,264
>> BUT WOULD IT EVEN
DURING

5940
03:23:11,264 --> 03:23:16,235
SHORT TERM, GIVE PRESSURE FOR

5941
03:23:16,235 --> 03:23:19,539
SURVIVAL -- CLONES CHANGE THAT

5942
03:23:19,539 --> 03:23:19,806
SURVIVAL.

5943
03:23:19,806 --> 03:23:21,340
>> WELL, I THINK THAT IS A
GREAT

5944
03:23:21,340 --> 03:23:22,608
QUESTION, AND I WOULD SAY AGAIN

5945
03:23:22,608 --> 03:23:23,643
ONE OF THE FRONTIERS OF THE

5946
03:23:23,643 --> 03:23:26,045
FIELD IS UNDERSTANDING HOW LET'S

5947
03:23:26,045 --> 03:23:29,348
SAY A SMALL CLONE, 5% OF THE

5948
03:23:29,348 --> 03:23:30,983
BLOOD OF THE BONE MARROW LIKE A

5949
03:23:30,983 --> 03:23:32,518
TET2 CLONE WHICH WE THINK IS

5950
03:23:32,518 --> 03:23:35,121
VERY HYPERINFLAMMATORY, HOW DOES

5951
03:23:35,121 --> 03:23:38,391
THAT HAVE AN OUTSIDE EFFECT ON

5952
03:23:38,391 --> 03:23:39,358
CARDIOVASCULAR DISEASE?

5953
03:23:39,358 --> 03:23:40,359
PROBABLY THOSE CELLS ARE

5954
03:23:40,359 --> 03:23:42,128
INTERACTING IN A MALIGNANT

5955
03:23:42,128 --> 03:23:43,896
FASHION WITH WILD TYPE CELLS OR

5956
03:23:43,896 --> 03:23:46,199
OTHER CELLS IN -- ACROSS THE

5957
03:23:46,199 --> 03:23:47,734
BODY, AND SO REALLY THAT'S

5958
03:23:47,734 --> 03:23:48,234
SOMETHING THAT WE DON'T

5959
03:23:48,234 --> 03:23:48,835
UNDERSTAND.

5960
03:23:48,835 --> 03:23:49,702
IT'S ACTUALLY TECHNICALLY

5961
03:23:49,702 --> 03:23:54,140
DIFFICULT TO STUDY, THESE CELLS

5962
03:23:54,140 --> 03:23:57,043
ARE ALL INTERACTING, SO THAT'S

5963
03:23:57,043 --> 03:23:58,377
REALLY KIND OF THE NEXT FRONTIER

5964
03:23:58,377 --> 03:23:59,212
IN MY VIEW.

5965
03:23:59,212 --> 03:24:01,080
MAYBE PHIL HAS ADDITIONAL

5966
03:24:01,080 --> 03:24:01,347
COMMENTS.

5967
03:24:01,347 --> 03:24:03,750
>> MAYBE JUST ADDITIONAL
-- A

5968
03:24:03,750 --> 03:24:06,786
FEW THINGS.

5969
03:24:06,786 --> 03:24:08,654
SO IT IS ABSOLUTELY NOT MUTUALLY

5970
03:24:08,654 --> 03:24:12,492
EXCLUSIVE THAT THERE IS SORT OF

5971
03:24:12,492 --> 03:24:15,661
THIS BIDIRECTIONAL RELATIONSHIP

5972
03:24:15,661 --> 03:24:17,063
BETWEEN WHERE DOES CLONAL

5973
03:24:17,063 --> 03:24:17,730
HEMATOPOIESIS SIT WITHIN SORT OF

5974
03:24:17,730 --> 03:24:21,167
THE FABRIC OF WHAT WE CALL, YOU

5975
03:24:21,167 --> 03:24:22,301
KNOW, HOMEOSTASIS AND DEVIATION

5976
03:24:22,301 --> 03:24:23,136
FROM IT.

5977
03:24:23,136 --> 03:24:25,772
SO ONE CAN THINK OF IT AS OVER

5978
03:24:25,772 --> 03:24:28,241
TIME THERE IS THIS ACCRUAL OF

5979
03:24:28,241 --> 03:24:30,643
MUTATIONS WHICH ENDOW CLONES

5980
03:24:30,643 --> 03:24:32,478
WITH THE SURVIVAL ADVANTAGE,

5981
03:24:32,478 --> 03:24:33,613
PROLIFERATIVE ADVANTAGE, MAYBE

5982
03:24:33,613 --> 03:24:35,381
THERE IS A CONNECTION BETWEEN

5983
03:24:35,381 --> 03:24:39,051
TET2 AS A DRIVER MUTATION AND

5984
03:24:39,051 --> 03:24:40,586
IL-1 BETA PRODUCTION.

5985
03:24:40,586 --> 03:24:41,354
ON THE OTHER HAND, AGAIN I WANT

5986
03:24:41,354 --> 03:24:43,356
TO STRESS THIS, THESE ARE NOT

5987
03:24:43,356 --> 03:24:44,557
MUTUALLY EXCLUSIVE IDEAS,

5988
03:24:44,557 --> 03:24:48,127
ALTHOUGH SOME PEOPLE THINK THE

5989
03:24:48,127 --> 03:24:49,662
REFLECTIVE KIND OF DEFENSE

5990
03:24:49,662 --> 03:24:51,297
MECHANISM IS THES ARE MUTUALLY

5991
03:24:51,297 --> 03:24:52,665
EXCLUSIVE, THAT THERE'S A

5992
03:24:52,665 --> 03:24:55,067
REVERSE CAUSALITY, WHICH IS TO

5993
03:24:55,067 --> 03:24:56,903
SAY -- AND VERY TALENTED PEOPLE

5994
03:24:56,903 --> 03:24:59,172
WHO APPLY MATHEMATICAL MODELS TO

5995
03:24:59,172 --> 03:25:01,440
THIS WOULD SAY THAT SOME OF

5996
03:25:01,440 --> 03:25:06,312
THOSE PRESSURES, EXPOSOMEAL

5997
03:25:06,312 --> 03:25:08,014
PRESSURES IF YOU WILL,

5998
03:25:08,014 --> 03:25:09,448
COMORBIDITIES, SO ON AND SO

5999
03:25:09,448 --> 03:25:11,851
FORTH, JUST BY THE SHEER IMPACT

6000
03:25:11,851 --> 03:25:13,519
ON THE HEMATOPOIETIC SYSTEM AND

6001
03:25:13,519 --> 03:25:15,822
SPECIFICALLY ON INCREASING

6002
03:25:15,822 --> 03:25:20,026
PROLIFERATION, THOSE

6003
03:25:20,026 --> 03:25:21,561
PERTURBATIONS BY THE NATURE OF

6004
03:25:21,561 --> 03:25:24,564
PURE SORT OF MATHEMATICS,

6005
03:25:24,564 --> 03:25:27,066
DECREASE DIVERSITY OF THE

6006
03:25:27,066 --> 03:25:28,935
HYDROXYCHLOROQUINE CYST AND SORT

6007
03:25:28,935 --> 03:25:29,802
OF INCREASE CLONAL

6008
03:25:29,802 --> 03:25:33,739
HEMATOPOIESIS, IN FACT, 50% OF

6009
03:25:33,739 --> 03:25:34,307
CLONAL HEMATOPOIESIS DOESN'T

6010
03:25:34,307 --> 03:25:36,142
HAVE A KNOWN DRIVER MUTATION.

6011
03:25:36,142 --> 03:25:37,910
I THINK WE ARE NOW APPROACHING A

6012
03:25:37,910 --> 03:25:39,512
POINT WHERE WE'RE GETTING A MUCH

6013
03:25:39,512 --> 03:25:42,114
MORE SOPHISTICATED -- WELL OF

6014
03:25:42,114 --> 03:25:42,882
COURSE BECAUSE A LOT OF PEOPLE

6015
03:25:42,882 --> 03:25:44,917
ARE WORKING ON THIS, MORE

6016
03:25:44,917 --> 03:25:47,119
NUANCED AND SOPHISTICATED

6017
03:25:47,119 --> 03:25:48,421
UNDERSTANDING OF WHERE CLONAL

6018
03:25:48,421 --> 03:25:49,188
HEMATOPOIESIS RESIDES WITHIN

6019
03:25:49,188 --> 03:25:50,790
THIS FABRIC THAT WE WOULD

6020
03:25:50,790 --> 03:25:54,493
GENERALLY SORT OF CALL

6021
03:25:54,493 --> 03:25:56,162
HOMEOSTASIS AND A DEVIATION.

6022
03:25:56,162 --> 03:25:58,564
ONE LAST POINT HERE BECAUSE YOU

6023
03:25:58,564 --> 03:26:01,934
ASKED ABOUT AGING.

6024
03:26:01,934 --> 03:26:03,569
THERE IS THIS VERY INTERESTING

6025
03:26:03,569 --> 03:26:05,538
PHENOMENON CERTAINLY VERY WELL

6026
03:26:05,538 --> 03:26:06,172
DOCUMENTED IN THE MOUSE ABOUT

6027
03:26:06,172 --> 03:26:08,674
SORT OF A MYELOID BOY AS AS WE

6028
03:26:08,674 --> 03:26:11,410
AGE, THIS IDEA THAT WHEN YOU

6029
03:26:11,410 --> 03:26:12,278
LOOK AT THE HYDROXYCHLOROQUINE

6030
03:26:12,278 --> 03:26:13,713
TREE, THERE IS A PREPONDERANCE

6031
03:26:13,713 --> 03:26:16,949
OF PRODUCING MYELOID CELLS,

6032
03:26:16,949 --> 03:26:18,050
NEUTROPHILS, MONOCYTES IN

6033
03:26:18,050 --> 03:26:19,385
RESPONSE TO VARIOUS STIM LAY AT

6034
03:26:19,385 --> 03:26:20,953
THE EXPENSE OF LYMPHOID CELLS, I

6035
03:26:20,953 --> 03:26:22,288
THINK THERE'S A LOT OF THINGS

6036
03:26:22,288 --> 03:26:24,156
THAT WITH THIS CONCEPT WE CAN

6037
03:26:24,156 --> 03:26:28,995
ALSO EXPLORE AGING ABOUT THIS

6038
03:26:28,995 --> 03:26:30,963
IDEA OF INFLAMMATORY TONE OR

6039
03:26:30,963 --> 03:26:35,001
INFLAMMATORY FITNESS, BECAUSE I

6040
03:26:35,001 --> 03:26:37,236
THINK INFLAMMATION IS SUCH A KEY

6041
03:26:37,236 --> 03:26:43,476
ELEMENT OF AGING AND -- MAY

6042
03:26:43,476 --> 03:26:45,778
BE PART OF THAT, THAT ALSO

6043
03:26:45,778 --> 03:26:48,314
DOVETAILS WITH CLONAL

6044
03:26:48,314 --> 03:26:48,648
HEMATOPOIESIS.

6045
03:26:48,648 --> 03:26:49,115
>> GREAT.

6046
03:26:49,115 --> 03:26:50,149
WE'VE GOT A FEW MORE QUESTIONS

6047
03:26:50,149 --> 03:26:51,951
SO I WANT TO KEEP IT MOVING.

6048
03:26:51,951 --> 03:26:53,853
WE'LL PROBABLY SHOOT FOR SHORT

6049
03:26:53,853 --> 03:26:54,287
ANSWERS IF YOU CAN.

6050
03:26:54,287 --> 03:26:54,987
>> SORRY.

6051
03:26:54,987 --> 03:26:57,189
>> NO, NO WORRIES, THAT
WAS

6052
03:26:57,189 --> 03:26:57,823
GREAT.

6053
03:26:57,823 --> 03:26:59,425
THAT WASN'T MEANT TO CHASTISE

6054
03:26:59,425 --> 03:26:59,592
YOU.

6055
03:26:59,592 --> 03:27:01,193
THAT WAS JUST TO TRY -- WE HAVE

6056
03:27:01,193 --> 03:27:02,194
FOUR MINUTES LEFT SO I WANT TO

6057
03:27:02,194 --> 03:27:03,496
PACK AS MUCH INFO IN AS

6058
03:27:03,496 --> 03:27:04,463
POSSIBLE.

6059
03:27:04,463 --> 03:27:05,765
SO THIS ONE IS FOR MIRANDA, I

6060
03:27:05,765 --> 03:27:06,532
THINK, IN THE Q & A.

6061
03:27:06,532 --> 03:27:09,936
WE KNOW THE SENESCENT CELLS OF

6062
03:27:09,936 --> 03:27:11,404
NORMAL BENEFICIAL PSYCHOLOGICAL

6063
03:27:11,404 --> 03:27:12,838
FUNCTION, BUT EXCESS SENESCENCE

6064
03:27:12,838 --> 03:27:14,674
IS DETRIMENTAL AND CONTRIBUTES

6065
03:27:14,674 --> 03:27:17,076
TO AGE-RELATED DISEASE AND

6066
03:27:17,076 --> 03:27:17,376
CONDITIONS.

6067
03:27:17,376 --> 03:27:17,743
YEAH.

6068
03:27:17,743 --> 03:27:20,146
SO BASICALLY GETTING AT THIS

6069
03:27:20,146 --> 03:27:23,382
ISSUE OF TITERING IN SENESCENT

6070
03:27:23,382 --> 03:27:24,283
CELLS.

6071
03:27:24,283 --> 03:27:25,584
MAYBE, ASHANI, YOU'D LIKE TO

6072
03:27:25,584 --> 03:27:27,053
WEIGH IN ON THIS ONE TOO.

6073
03:27:27,053 --> 03:27:27,853
START WITH MIRANDA.

6074
03:27:27,853 --> 03:27:36,162
>> SO THE Z WE'RE NOT
GIVING TRT

6075
03:27:36,162 --> 03:27:37,830
EVERY DAY, IT IS CYCLICAL.

6076
03:27:37,830 --> 03:27:39,899
IN OUR STUDY PEOPLE GET THIS FOR

6077
03:27:39,899 --> 03:27:41,100
TWO DAYS, THEN THEY HAVE TWO

6078
03:27:41,100 --> 03:27:43,669
WEEKS OFF, SO THE GOAL IS NOT TO

6079
03:27:43,669 --> 03:27:45,137
PREVENT SENESCENCE FROM ARE

6080
03:27:45,137 --> 03:27:46,772
HAPPENING FOR THE REASONS

6081
03:27:46,772 --> 03:27:48,074
MENTIONED BY THE -- WHOEVER

6082
03:27:48,074 --> 03:27:49,542
SUBMITTED THE QUESTION, BUT TO

6083
03:27:49,542 --> 03:27:52,812
CLEAR THEM WHEN THEY START TO

6084
03:27:52,812 --> 03:27:53,112
ACCUMULATE.

6085
03:27:53,112 --> 03:27:55,681
AND PART OF THE PHASE TWO TRIAL

6086
03:27:55,681 --> 03:27:56,849
IS TO DETERMINE HOW LONG IT

6087
03:27:56,849 --> 03:28:00,052
TAKES FOR THIS RE-EMERGENCE OF

6088
03:28:00,052 --> 03:28:00,820
SENESCENT CELLS AND THINKING

6089
03:28:00,820 --> 03:28:02,121
ABOUT HOW FREQUENTLY YOU MIGHT

6090
03:28:02,121 --> 03:28:03,789
NEED TO CLEAR SENESCENT CELLS.

6091
03:28:03,789 --> 03:28:04,924
>> GOT IT.

6092
03:28:04,924 --> 03:28:06,592
>> I WOULD JUST ADD ALSO
THAT I

6093
03:28:06,592 --> 03:28:08,427
THINK WE DON'T FULLY UNDERSTAND

6094
03:28:08,427 --> 03:28:10,730
SENESCENCE YET.

6095
03:28:10,730 --> 03:28:12,765
IT DESCRIBED AS SO MANY THINGS.

6096
03:28:12,765 --> 03:28:14,200
IT'S DESCRIBED AS TERMINAL BUT

6097
03:28:14,200 --> 03:28:15,067
IT'S NOT TERMINAL.

6098
03:28:15,067 --> 03:28:19,305
YOU CAN THROW BACK SOME ROY BOW

6099
03:28:19,305 --> 03:28:19,905
NUCLEOTIDES AND REACTIVATE

6100
03:28:19,905 --> 03:28:20,206
SENESCENCE.

6101
03:28:20,206 --> 03:28:21,707
WE HAVE SEEN SENESCENT CELLS

6102
03:28:21,707 --> 03:28:23,642
THAT PHYSICALLY MOVE FROM THE

6103
03:28:23,642 --> 03:28:25,878
SKIN TO THE LUNG AND THEN GROW

6104
03:28:25,878 --> 03:28:29,582
OUT WHILE EXPRESSING BETA -- AND

6105
03:28:29,582 --> 03:28:32,084
KI67 AT THE SAME TIME.

6106
03:28:32,084 --> 03:28:33,853
SO UNTIL WE HAVE A BETTER

6107
03:28:33,853 --> 03:28:34,954
UNDERSTANDING OF SENESCENCE AND

6108
03:28:34,954 --> 03:28:36,389
WHAT IT DOES, SOMETHING THAT I

6109
03:28:36,389 --> 03:28:39,125
KIND OF VERY QUICKLY SKIMMED

6110
03:28:39,125 --> 03:28:43,829
OVER IN MYRA PID FIRE TALK WAS

6111
03:28:43,829 --> 03:28:44,997
THE FACT THAT WE SEE SENESCENCE

6112
03:28:44,997 --> 03:28:47,500
IN YOUNG FEMALE FIBROBLASTS THAT

6113
03:28:47,500 --> 03:28:49,702
ACTS TO REPAIR DNA DAMAGE, AND

6114
03:28:49,702 --> 03:28:51,404
SO THOSE FIBROBLASTS BECOME LESS

6115
03:28:51,404 --> 03:28:54,040
SUSCEPTIBLE TO THE GENOMIC

6116
03:28:54,040 --> 03:28:56,475
INSTABILITY DRIVEN BY AGE,

6117
03:28:56,475 --> 03:28:57,276
WHEREAS AGING MALE FIBROBLASTS

6118
03:28:57,276 --> 03:28:58,577
HAVE A DIFFERENT KIND OF

6119
03:28:58,577 --> 03:29:01,213
SENESCENCE THAT SECRETE A

6120
03:29:01,213 --> 03:29:02,948
SENESCENCE ASSOCIATED SECRETORY

6121
03:29:02,948 --> 03:29:05,217
PHENOTYPE AND THEREFORE ARE MORE

6122
03:29:05,217 --> 03:29:07,620
CONDUCIVE TO PROMOTING TUMOR

6123
03:29:07,620 --> 03:29:07,953
PROGRESSION.

6124
03:29:07,953 --> 03:29:10,122
SO UNTIL WE FULLY UNDERSTAND

6125
03:29:10,122 --> 03:29:12,825
THIS PHENOMENON OF SENESCENCE,

6126
03:29:12,825 --> 03:29:15,561
WE HAVE A LONG WAY TO GO, I

6127
03:29:15,561 --> 03:29:16,028
THINK.

6128
03:29:16,028 --> 03:29:20,699
>> OKAY, GREAT.

6129
03:29:20,699 --> 03:29:23,135
ZORINA REMINDED US THERE'S MORE

6130
03:29:23,135 --> 03:29:24,537
SENESCENCE TALKS COMING UP SO IF

6131
03:29:24,537 --> 03:29:26,505
YOU'RE INTO THAT, MAKE SURE YOU

6132
03:29:26,505 --> 03:29:27,239
ATTEND THOSE.

6133
03:29:27,239 --> 03:29:28,441
OKAY, THERE'S A TON OF COMMENTS

6134
03:29:28,441 --> 03:29:30,409
IN THE CHAT ABOUT RESOURCES AND

6135
03:29:30,409 --> 03:29:33,112
STUDYISTUDIES RUNNING.

6136
03:29:33,112 --> 03:29:34,447
AGAIN, I DON'T KNOW IF ALL THE

6137
03:29:34,447 --> 03:29:35,314
PARTICIPANTS CAN SEE THAT.

6138
03:29:35,314 --> 03:29:37,149
SOMETIMES IT'S JUST RESTRICTED

6139
03:29:37,149 --> 03:29:38,551
TO THE PANELISTS, I DON'T KNOW

6140
03:29:38,551 --> 03:29:39,852
HOW THIS IS STRUCTURED, BUT

6141
03:29:39,852 --> 03:29:40,953
MAYBE THERE'S A WAY TO SEND

6142
03:29:40,953 --> 03:29:41,887
THESE OUT TO THE WHOLE --

6143
03:29:41,887 --> 03:29:43,856
>> WE JUST ACTIVATED THE
OPTION

6144
03:29:43,856 --> 03:29:46,725
FOR ALL PANELISTS TO BE ABLE

6145
03:29:46,725 --> 03:29:47,793
TO -- WITH EVERYONE.

6146
03:29:47,793 --> 03:29:48,828
>> IT WOULD BE HARD TO

6147
03:29:48,828 --> 03:29:49,495
SUMMARIZE, THERE'S SO MANY

6148
03:29:49,495 --> 03:29:50,062
COMMENTS HERE.

6149
03:29:50,062 --> 03:29:51,630
SO PLEASE TAKE A LOOK AT THESE.

6150
03:29:51,630 --> 03:29:52,832
I DON'T KNOW ALL THE DETAILS OF

6151
03:29:52,832 --> 03:29:55,801
THEM, LIKE I SAY, I DON'T KNOW

6152
03:29:55,801 --> 03:29:57,303
EXACTLY WHAT THEY'RE MEASURING,

6153
03:29:57,303 --> 03:29:58,370
THEIR FREQUENCY AND ALL THAT.

6154
03:29:58,370 --> 03:29:59,805
IT WOULD BE FUN TO GET THAT ALL

6155
03:29:59,805 --> 03:30:01,740
COLLECTED AND SEE DO WE HAVE THE

6156
03:30:01,740 --> 03:30:04,810
ULTIMATE LONGITUDAL STUDY THERE.

6157
03:30:04,810 --> 03:30:06,112
>> THERE WAS ONE QUESTION
I

6158
03:30:06,112 --> 03:30:11,817
WANTED TO HIGHLIGHT ABOUT AGING

6159
03:30:11,817 --> 03:30:17,590
AND WHEN DO WE -- DO WE AGE FROM

6160
03:30:17,590 --> 03:30:20,426
MOMENT ZERO ON, AND SO WHEN DO

6161
03:30:20,426 --> 03:30:25,498
WE CONSIDER AGING AND IS AGING

6162
03:30:25,498 --> 03:30:26,499
EQUAL FOAL.

6163
03:30:26,499 --> 03:30:28,701
GLL THE COMMENT IS AGING ISN'T

6164
03:30:28,701 --> 03:30:29,935
ASSOCIATED WITH BEING OLD BUT

6165
03:30:29,935 --> 03:30:32,371
AGING, I WOULD ARGUE, WOULD GO

6166
03:30:32,371 --> 03:30:33,973
THROUGHOUT THE ENTIRE LIFESPAN.

6167
03:30:33,973 --> 03:30:35,307
>> I CAN CLARIFY THE
QUESTION.

6168
03:30:35,307 --> 03:30:37,042
I WASN'T SAYING THAT AGING

6169
03:30:37,042 --> 03:30:37,576
EQUALS OLD.

6170
03:30:37,576 --> 03:30:40,980
I SAID THE WAY WE STUDIED AGING

6171
03:30:40,980 --> 03:30:43,048
IS THAT IT SEEMED LIKE WE SAY

6172
03:30:43,048 --> 03:30:47,419
AGING EQUALS OLD, AND SO IF WE

6173
03:30:47,419 --> 03:30:49,655
VIEW IT THAT WAY, YOU SEE

6174
03:30:49,655 --> 03:30:50,756
LONGITUDAL STUDIES OF AGING

6175
03:30:50,756 --> 03:30:51,957
STARTING AT THE AGE OF 45.

6176
03:30:51,957 --> 03:30:54,360
WELL, THAT'S NOT AGING.

6177
03:30:54,360 --> 03:30:56,629
THAT IS A STUDY FOR PEOPLE 45

6178
03:30:56,629 --> 03:30:57,596
YEARS AND OLDER.

6179
03:30:57,596 --> 03:31:01,333
BECAUSE AGING IN MY MIND IS A

6180
03:31:01,333 --> 03:31:02,301
PROCESS THAT STARTS FROM THE DAY

6181
03:31:02,301 --> 03:31:05,771
YOU GO FROM ONE CELL TO TWO

6182
03:31:05,771 --> 03:31:07,072
CELLS, BECAUSE IT'S A CELL

6183
03:31:07,072 --> 03:31:07,740
DIVISION PROCESS.

6184
03:31:07,740 --> 03:31:08,807
THAT'S WHAT MAKES AGING START

6185
03:31:08,807 --> 03:31:10,309
AND THAT'S A PROCESS THAT

6186
03:31:10,309 --> 03:31:12,044
CONTINUES.

6187
03:31:12,044 --> 03:31:14,146
AND SO MAYBE THE WAY WE LOOKED

6188
03:31:14,146 --> 03:31:15,581
AT AGING, EVEN THOUGH SOMETIMES

6189
03:31:15,581 --> 03:31:17,516
IS THE WAY FUNDING AGENCY MAKE

6190
03:31:17,516 --> 03:31:21,987
US LOOK AT AGING, IS BY STARTING

6191
03:31:21,987 --> 03:31:23,088
AT AN OLDER AGE.

6192
03:31:23,088 --> 03:31:25,691
SO SHOULDN'T WE BE THINKING,

6193
03:31:25,691 --> 03:31:27,426
ESPECIALLY IN THIS WORKSHOP, AT

6194
03:31:27,426 --> 03:31:29,295
LOOKING AT THE WHOLE AGING

6195
03:31:29,295 --> 03:31:30,663
PHENOMENON AS SOMETHING THAT

6196
03:31:30,663 --> 03:31:32,097
STARTS THE DAY YOU GO FROM ONE

6197
03:31:32,097 --> 03:31:33,966
TO TWO CELLS AND AS SUCH, MAYBE

6198
03:31:33,966 --> 03:31:34,833
THAT DIFFERENTIATES A LOT OF

6199
03:31:34,833 --> 03:31:36,702
THESE THAT WILL HELP US REDEFINE

6200
03:31:36,702 --> 03:31:38,270
THE WAY WE LOOK AT AGING STUDIES

6201
03:31:38,270 --> 03:31:41,307
OR DESIGNING AGING STUDIES IN

6202
03:31:41,307 --> 03:31:42,841
PARTICULAR, BECAUSE WHAT WE'VE

6203
03:31:42,841 --> 03:31:45,144
DONE IS TRY TO WORK BACKWARDS BY

6204
03:31:45,144 --> 03:31:46,679
STUDYING ALL THE PEOPLE AND SAY

6205
03:31:46,679 --> 03:31:48,280
OKAY, WHAT HAPPENED IN THE

6206
03:31:48,280 --> 03:31:48,480
1920s?

6207
03:31:48,480 --> 03:31:49,582
WELL, FOR CHRIST SAKE, WE DON'T

6208
03:31:49,582 --> 03:31:51,250
KNOW WHAT HAPPENED IN 1920s.

6209
03:31:51,250 --> 03:31:55,921
WE CAN ONLY INFER, BUT IF WE

6210
03:31:55,921 --> 03:31:58,190
HAVE STARTED IN THE 1920s, WE

6211
03:31:58,190 --> 03:31:59,291
WILL KNOW EXACTLY WHAT WAS

6212
03:31:59,291 --> 03:32:01,660
HAPPENING IN THE 1920s, RATHER

6213
03:32:01,660 --> 03:32:03,195
THAN STUDYING AN 80-YEAR-OLD AND

6214
03:32:03,195 --> 03:32:05,297
WONDERING WHAT HAPPENED TO THE

6215
03:32:05,297 --> 03:32:06,899
80-YEAR-OLD FROM 1920 FROM

6216
03:32:06,899 --> 03:32:07,866
RECOLLECTION AND HISTORICAL

6217
03:32:07,866 --> 03:32:09,134
RECORDS AND THINGS LIKE THAT.

6218
03:32:09,134 --> 03:32:12,504
>> I WOULD SAY THAT -- YOU
KNOW,

6219
03:32:12,504 --> 03:32:13,305
ENGLISH IS NOT MY FIRST

6220
03:32:13,305 --> 03:32:13,639
LANGUAGE.

6221
03:32:13,639 --> 03:32:15,741
WHEN WAYS LEARNING ENGLISH, I

6222
03:32:15,741 --> 03:32:17,443
WAS PERPLEXED BY WHEN YOU'RE

6223
03:32:17,443 --> 03:32:20,179
ASKING SOMEBODY ABOUT, YOU KNOW,

6224
03:32:20,179 --> 03:32:21,180
HOW MANY YEARS THEY'VE BEEN

6225
03:32:21,180 --> 03:32:23,816
ALIVE ON THE PLANET, YOU ASK

6226
03:32:23,816 --> 03:32:25,084
THEM HOW OLD ARE YOU.

6227
03:32:25,084 --> 03:32:27,519
NOT HOW YOUNG ARE YOU.

6228
03:32:27,519 --> 03:32:31,890
SO THAT'S A GOOD POINT.

6229
03:32:31,890 --> 03:32:33,058
>> I THINK MAYBE BECAUSE
WE'RE

6230
03:32:33,058 --> 03:32:34,460
AT THE END OF THE HOUR, I THINK

6231
03:32:34,460 --> 03:32:35,995
WE'D ALL HAVE -- I THINK WE'D

6232
03:32:35,995 --> 03:32:37,496
ALL AGREE THAT WE SHOULD BE

6233
03:32:37,496 --> 03:32:38,831
REALLY STUDYING PEOPLE AS WE

6234
03:32:38,831 --> 03:32:40,332
SAID AS EARLY AS POSSIBLE.

6235
03:32:40,332 --> 03:32:42,067
AND IT'S AMAZING HOW FEW

6236
03:32:42,067 --> 03:32:43,936
CHILDHOOD STUDIES ARE THERE FOR

6237
03:32:43,936 --> 03:32:45,004
LONGITUDAL STUDIES.

6238
03:32:45,004 --> 03:32:48,607
IT'S INCREDIBLE.

6239
03:32:48,607 --> 03:32:49,708
ALTHOUGH WE'LL PROBABLY GET A

6240
03:32:49,708 --> 03:32:51,610
LOT OF THINGS IN CHAT, MAYBE

6241
03:32:51,610 --> 03:32:53,078
THEY'RE OUT THERE AND I DON'T

6242
03:32:53,078 --> 03:32:53,979
KNOW ABOUT IT.

6243
03:32:53,979 --> 03:32:55,047
BECAUSE WE'RE AT THE END OF THE

6244
03:32:55,047 --> 03:32:57,082
HOUR, I'LL LET US ALL PONDER ON

6245
03:32:57,082 --> 03:32:58,617
THAT' WITH MOVE INTO THE NEXT

6246
03:32:58,617 --> 03:32:59,051
SESSIONS COMING UP.

6247
03:32:59,051 --> 03:33:00,386
SO I WANT TO THANK ALL THE

6248
03:33:00,386 --> 03:33:01,220
PANELISTS.

6249
03:33:01,220 --> 03:33:02,087
I THINK FOR ME, IT WAS A LOT OF

6250
03:33:02,087 --> 03:33:03,155
FUN.

6251
03:33:03,155 --> 03:33:04,923
I LEARNED A TON, WHICH TO ME IS

6252
03:33:04,923 --> 03:33:06,558
A SIGN OF A GOOD PANEL, AND I DO

6253
03:33:06,558 --> 03:33:07,793
WANT TO THANK ALL THE SPEAKERS

6254
03:33:07,793 --> 03:33:09,295
AND ALL THE GREAT COMMENTS WE'VE

6255
03:33:09,295 --> 03:33:11,430
HAD, AND SO I THINK WE RECONVENE

6256
03:33:11,430 --> 03:33:12,298
AT WHAT TIME?

6257
03:33:12,298 --> 03:33:13,732
DOES SOMEONE WANT TO JUMP IN AND

6258
03:33:13,732 --> 03:33:18,570
SAY WHEN DO WE RECONVENE?

6259
03:33:18,570 --> 03:33:19,705
>> 1:50.

6260
03:33:19,705 --> 03:33:20,606
>> 1:50.

6261
03:33:20,606 --> 03:33:20,939
THANK YOU.

6262
03:33:20,939 --> 03:33:21,807
ALL RIGHT.

6263
03:33:21,807 --> 03:33:23,642
WHICH IS 10:50 MY TIME.

6264
03:33:23,642 --> 03:33:24,209
ALL RIGHT.

6265
03:33:24,209 --> 03:33:27,246
SO HAVE A QUICK LUNCH OR A SNACK

6266
03:33:27,246 --> 03:33:28,681
AT BREAKFAST, WHEREVER YOU ARE,

6267
03:33:28,681 --> 03:33:30,449
AND WE'LL SEE YOU GUYS IN A HALF

6268
03:33:30,449 --> 03:33:31,050
AN HOUR.

6269
03:33:31,050 --> 03:33:31,886
THANKS, ALL.

6270
03:33:31,886 --> 03:33:32,253
>> WONDERFUL.

6271
03:33:32,253 --> 03:33:34,355
SO I WOULD LIKE TO WELCOME, MY

6272
03:33:34,355 --> 03:33:37,792
NAME IS ANIL WALI, PROGRAM

6273
03:33:37,792 --> 03:33:39,327
DIRECTOR AT THE CENTER TO REDUCE

6274
03:33:39,327 --> 03:33:42,030
CANCER HEALTH DISPARITIES AT

6275
03:33:42,030 --> 03:33:42,597
NATIONAL CANCER INSTITUTE.

6276
03:33:42,597 --> 03:33:46,034
AND WE WILL BE MANAGING SESSION

6277
03:33:46,034 --> 03:33:50,038
2 WITH MY TWO ESTEEMED

6278
03:33:50,038 --> 03:33:54,442
COLLEAGUES, DR. LOUISE

6279
03:33:54,442 --> 03:34:03,551
MCCOLLOUGH AND DR. KOTLIARO VA.

6280
03:34:03,551 --> 03:34:05,353
>> HI, EVERYONE.

6281
03:34:05,353 --> 03:34:06,921
I'M LOUISE MCCOLLOUGH, A STROKE

6282
03:34:06,921 --> 03:34:07,989
YEUROLOGIST AND CHAIR OF

6283
03:34:07,989 --> 03:34:09,857
NEUROLOGY HERE AT U.T. HEALTH

6284
03:34:09,857 --> 03:34:10,191
HOUSTON.

6285
03:34:10,191 --> 03:34:12,427
WE'RE REALLY LOOKING FORWARD TO

6286
03:34:12,427 --> 03:34:12,961
THIS SECOND SESSION THAT'S

6287
03:34:12,961 --> 03:34:14,295
REALLY GOING TO TALK ABOUT

6288
03:34:14,295 --> 03:34:16,965
MOLECULAR MECHANISMS OF CHRONIC

6289
03:34:16,965 --> 03:34:18,299
AGE-RELATED DISEASES AND WE'LL

6290
03:34:18,299 --> 03:34:20,868
BE HITTING IT OFF WITH

6291
03:34:20,868 --> 03:34:31,079
DR. KIRKLAND

6292
03:34:44,225 --> 03:34:46,594
>> DR. KIRKLAND, IT'S ALL
YOURS,

6293
03:34:46,594 --> 03:34:47,028
THE FLOOR IS YOURS.

6294
03:34:47,028 --> 03:34:47,395
GO AHEAD.

6295
03:34:47,395 --> 03:34:48,596
>> THANKS VERY MUCH.

6296
03:34:48,596 --> 03:34:49,664
CAN EVERYONE SEE MY SLIDES ALL

6297
03:34:49,664 --> 03:34:50,898
RIGHT?

6298
03:34:50,898 --> 03:34:51,499
>> YES.

6299
03:34:51,499 --> 03:34:53,034
>> PERFECT.

6300
03:34:53,034 --> 03:34:53,768
OKAY.

6301
03:34:53,768 --> 03:34:56,004
SO I'M KIRKLAND, CURRENTLY AT

6302
03:34:56,004 --> 03:34:56,571
MAYO.

6303
03:34:56,571 --> 03:34:59,340
I HAPPEN TO BE FOR NOW PRESIDENT

6304
03:34:59,340 --> 03:35:01,442
OF OUR CONFEDERATION FOR AGING

6305
03:35:01,442 --> 03:35:02,443
RESEARCH.

6306
03:35:02,443 --> 03:35:03,511
TOM RANDALL WILL TAKE OVER,

6307
03:35:03,511 --> 03:35:05,546
THANK GOD, IN JANUARY, AND IT'S

6308
03:35:05,546 --> 03:35:07,615
A GREAT ROLE, BUT IT'S VERY BUSY

6309
03:35:07,615 --> 03:35:09,584
AND I'M ALSO PRINCIPAL

6310
03:35:09,584 --> 03:35:11,586
INVESTIGATOR OF THE

6311
03:35:11,586 --> 03:35:12,587
TRANSLATIONAL NEUROSCIENCE

6312
03:35:12,587 --> 03:35:13,554
NETWORK, WHICH I'LL EXPLAIN A

6313
03:35:13,554 --> 03:35:16,658
BIT ABOUT.

6314
03:35:16,658 --> 03:35:19,294
SO MUCH OF THE SESSION I THINK

6315
03:35:19,294 --> 03:35:20,695
PAUL ROBINS AND OTHERS FOLLOWING

6316
03:35:20,695 --> 03:35:26,334
ME WILL BE TALKING ABOUT SOLAR

6317
03:35:26,334 --> 03:35:28,936
SENESCENCE, A SULFATE LIKE

6318
03:35:28,936 --> 03:35:31,005
REPLICATION -- IT OCCURS ACROSS

6319
03:35:31,005 --> 03:35:33,508
THE VERTEBRATES AND MANY

6320
03:35:33,508 --> 03:35:34,809
INVERTEBRATE IT IS CAN OCCUR AT

6321
03:35:34,809 --> 03:35:35,710
ANY POINT DURING LIFE.

6322
03:35:35,710 --> 03:35:38,313
FOR EXAMPLE, DOWN SYNDROME

6323
03:35:38,313 --> 03:35:39,714
APPEARS TO BE -- WHICH IS

6324
03:35:39,714 --> 03:35:44,185
RELATED TO AGING OF THE OOCYTE

6325
03:35:44,185 --> 03:35:47,455
APPEARS TO BE A SOLAR SENESCENCE

6326
03:35:47,455 --> 03:35:50,058
DRIVEN SYNDROME SUSCEPTIBLE TO

6327
03:35:50,058 --> 03:35:52,460
SOME OF THE -- SO SENESCENCE IS

6328
03:35:52,460 --> 03:35:58,599
A RESPONSE TO DAMAGE, SO CELLS

6329
03:35:58,599 --> 03:36:00,368
CAN ENTER THE SENESCENT CELL

6330
03:36:00,368 --> 03:36:00,601
FATE.

6331
03:36:00,601 --> 03:36:02,603
IT TAKES A LONG TIME FOR A CELL

6332
03:36:02,603 --> 03:36:04,172
TO BECOME FULLY SENESCENT, AT

6333
03:36:04,172 --> 03:36:06,341
LEAST A WEEK, UP TO SIX WEEKS,

6334
03:36:06,341 --> 03:36:07,375
INCLUDING IN VIVO.

6335
03:36:07,375 --> 03:36:10,545
SO IT VERY SLOW TO DEVELOP.

6336
03:36:10,545 --> 03:36:12,747
THERE'S A RANGE OF INSULTS THAT

6337
03:36:12,747 --> 03:36:15,416
CAN TEND TO PUSH A CELL INTO THE

6338
03:36:15,416 --> 03:36:16,050
SENESCENT CELL FATE.

6339
03:36:16,050 --> 03:36:17,852
THES CAN BE REPLY KAYTIVE STRESS

6340
03:36:17,852 --> 03:36:22,156
AND THAT INCLUDES THE EFFECTS OF

6341
03:36:22,156 --> 03:36:23,458
ONCOGENES, IGF1 AND SO FORTH

6342
03:36:23,458 --> 03:36:25,426
THAT CAN DRIVE REPLICATION AND

6343
03:36:25,426 --> 03:36:27,161
SENESCENCE IS GENERALLY A

6344
03:36:27,161 --> 03:36:33,267
DEFENSE AGAINST CANCER.

6345
03:36:33,267 --> 03:36:35,970
SO SENESCENCE ENTAILS

6346
03:36:35,970 --> 03:36:38,272
ESSENTIALLY -- ALTHOUGH

6347
03:36:38,272 --> 03:36:41,175
SENESCENT CELLS CAN CONTINUE TO

6348
03:36:41,175 --> 03:36:42,043
MUTATE, IT IS GENERALLY A

6349
03:36:42,043 --> 03:36:43,378
DEFENSE AGAINST CANCER SO IF YOU

6350
03:36:43,378 --> 03:36:44,579
INTERFERE WITH THE ABILITY OF A

6351
03:36:44,579 --> 03:36:48,483
CELL TO BECOME SENESCENT, YOU

6352
03:36:48,483 --> 03:36:57,225
CAN DRIVE TUMORIGENESIS.

6353
03:36:57,225 --> 03:36:58,760
THERE ARE ALSO MECHANICAL AND

6354
03:36:58,760 --> 03:37:01,996
SHEER STRESS CAN DRIVE A CELL TO

6355
03:37:01,996 --> 03:37:09,137
BECOME SENESCENT, BUY FUR CA BI,

6356
03:37:09,137 --> 03:37:10,338
AND PATHOGENS CAN DRIVE CELLS

6357
03:37:10,338 --> 03:37:18,446
TOWARDS SENESCENCE.

6358
03:37:18,446 --> 03:37:20,314
MOST DEVELOP SASP.

6359
03:37:20,314 --> 03:37:22,049
THE SASP IS HIGHLY VARIABLE.

6360
03:37:22,049 --> 03:37:23,451
IT DEPENDS ON THE KIND OF CELL

6361
03:37:23,451 --> 03:37:24,952
THAT BECAME SENESCENT, WHAT

6362
03:37:24,952 --> 03:37:27,054
INDUCED SENESCENCE AND THE

6363
03:37:27,054 --> 03:37:27,922
MICROENVIRONMENT.

6364
03:37:27,922 --> 03:37:29,991
AND THE SASP CAN ENTAIL

6365
03:37:29,991 --> 03:37:31,259
PRODUCTION OF A RANGE OF

6366
03:37:31,259 --> 03:37:33,561
PROTEINS, PEPTIDES, BIOACTIVE

6367
03:37:33,561 --> 03:37:35,496
MOLECULES INCLUDING BIOACTIVE

6368
03:37:35,496 --> 03:37:38,332
LIPIDS LIKE FOS SPHENOIDS AND A

6369
03:37:38,332 --> 03:37:41,068
RANGE OF NOT COATING NUCLEOTIDES

6370
03:37:41,068 --> 03:37:44,772
INCLUDING VARIOUS MICRORNAs

6371
03:37:44,772 --> 03:37:46,841
AND THINGS LIKE MITOCHONDRIAL

6372
03:37:46,841 --> 03:37:47,175
DNA.

6373
03:37:47,175 --> 03:37:49,911
SOME OF THESE COMPONENTS CAN BE

6374
03:37:49,911 --> 03:37:50,845
EXOSOME RELATED, BUT SENESCENT

6375
03:37:50,845 --> 03:37:56,951
CELLS ALSO PRODUCE -- THEY CAN

6376
03:37:56,951 --> 03:37:58,686
PRODUCE CELL-FREE NUCLEOTIDES

6377
03:37:58,686 --> 03:38:00,855
THAT APPEAR TO BE RESPONSIBLE

6378
03:38:00,855 --> 03:38:03,491
FOR MUCH OF THE EFFECT THAT

6379
03:38:03,491 --> 03:38:04,192
SENESCENT CELLS HAVE, IN

6380
03:38:04,192 --> 03:38:08,062
ADDITION TO THE CYTOKINES,

6381
03:38:08,062 --> 03:38:08,696
EXTRACELLULAR PROTEASES AND SO

6382
03:38:08,696 --> 03:38:10,164
FORTH THAT THEY CAN PRODUCE.

6383
03:38:10,164 --> 03:38:11,699
SENESCENT CELLS ARE RESISTANT TO

6384
03:38:11,699 --> 03:38:14,936
DYING AND THIS IS BECAUSE OF THE

6385
03:38:14,936 --> 03:38:16,471
ACTION -- THERE ARE AT LEAST 10

6386
03:38:16,471 --> 03:38:20,074
PATHWAYS.

6387
03:38:20,074 --> 03:38:24,111
SO IF YOU TAKE THE SUBSET OF

6388
03:38:24,111 --> 03:38:24,979
SENESCENT CELLS THAT ARE TISSUE

6389
03:38:24,979 --> 03:38:25,947
DAMAGING AND TRANSPLANT THEM

6390
03:38:25,947 --> 03:38:27,949
INTO ANIMALS AND IN THIS CASE

6391
03:38:27,949 --> 03:38:31,352
WE'RE TAKING FIBROBLASTS THAT

6392
03:38:31,352 --> 03:38:34,021
HAVE BECOME SENESCENT BY

6393
03:38:34,021 --> 03:38:38,726
RADIATION.

6394
03:38:38,726 --> 03:38:40,695
IT TAKES 1 IN 10,000 CELLS IN

6395
03:38:40,695 --> 03:38:42,396
THE TRANSPLANTED ANIMAL TO

6396
03:38:42,396 --> 03:38:43,464
DEVELOP A FRAILTY-LIKE STATE

6397
03:38:43,464 --> 03:38:45,433
AFTER A FEW MONTHS AND TO DIE

6398
03:38:45,433 --> 03:38:47,635
EARLY AND THEY DIE EARLY OF ALL

6399
03:38:47,635 --> 03:38:49,370
DISEASES THAT MICE NATURALLY DIE

6400
03:38:49,370 --> 03:38:50,137
FROM.

6401
03:38:50,137 --> 03:38:51,539
EVEN THOUGH THERE'S A VERY SMALL

6402
03:38:51,539 --> 03:38:53,941
NUMBER OF SENESCENT CELLS AND

6403
03:38:53,941 --> 03:38:55,543
EVEN THOUGH THEY REMAIN WITHIN

6404
03:38:55,543 --> 03:38:56,410
THE PERITONEUM.

6405
03:38:56,410 --> 03:38:57,845
THERE'S A THRESHOLD EFFECT.

6406
03:38:57,845 --> 03:39:00,715
SO 1 IN 10,000 CELLS MEANS THAT

6407
03:39:00,715 --> 03:39:02,917
YOU'VE TRANSPLANTED INTO

6408
03:39:02,917 --> 03:39:03,718
1 MILLION SENESCENT CELLS.

6409
03:39:03,718 --> 03:39:10,858
IF INSTEAD YOU TRANSPLANT

6410
03:39:10,858 --> 03:39:12,260
500,000 CELLS NOTHING HAPPENS.

6411
03:39:12,260 --> 03:39:14,295
IF YOU TRANSPLANT THEM INTO AN

6412
03:39:14,295 --> 03:39:18,332
OLD MOUSE THEN THEY DEVELOP THIS

6413
03:39:18,332 --> 03:39:19,467
SYNDROME.

6414
03:39:19,467 --> 03:39:21,369
SENESCENCE SPREADS BOTH LOCALLY

6415
03:39:21,369 --> 03:39:22,904
AND SYSTEMICALLY SO IF YOU

6416
03:39:22,904 --> 03:39:24,338
TRANSPLANT AND LABEL THEM SO YOU

6417
03:39:24,338 --> 03:39:25,673
KNOW WHICH ARE THE TRANSPLANTED

6418
03:39:25,673 --> 03:39:27,508
CELLS YOU FIND SENESCENT CELLS

6419
03:39:27,508 --> 03:39:28,576
START APPEARING IN THE ARMS,

6420
03:39:28,576 --> 03:39:30,344
LEGS AND BRAIN AND ELSEWHERE.

6421
03:39:30,344 --> 03:39:33,347
FROM THE RECIPIENTS' OWN CELLS.

6422
03:39:33,347 --> 03:39:34,549
SO SENESCENCE SPREADS.

6423
03:39:34,549 --> 03:39:36,083
THIS IS PARTLY RELATED TO

6424
03:39:36,083 --> 03:39:37,618
PROTEINS AND PEPTIDES THAT ARE

6425
03:39:37,618 --> 03:39:39,787
PART OF THE SASP, PARTLY RELATED

6426
03:39:39,787 --> 03:39:42,623
TO REACTIVE SMALL MOLECULES BUT

6427
03:39:42,623 --> 03:39:44,892
MAINLY RESPONSE TO EXTRACELLULAR

6428
03:39:44,892 --> 03:39:48,496
KNEW CNUCLEOTIDES.

6429
03:39:48,496 --> 03:39:50,031
SO NED SHARPLESS HAD A VERY

6430
03:39:50,031 --> 03:39:53,701
IMPORTANT PAPERBACK IN 2004 IN

6431
03:39:53,701 --> 03:39:55,102
JOURNAL OF CLINICAL

6432
03:39:55,102 --> 03:39:55,703
INVESTIGATION WHEN HE SHOWED

6433
03:39:55,703 --> 03:39:58,539
THAT INTERVENTIONS THAT ENHANCE

6434
03:39:58,539 --> 03:40:00,775
HEALTHSPAN IN EXPERIMENTAL

6435
03:40:00,775 --> 03:40:03,177
ANIMALS, CALORIC RESTRICTION OR

6436
03:40:03,177 --> 03:40:05,246
RELATIVE IGF1 DEFICIENCY ARE

6437
03:40:05,246 --> 03:40:06,881
LINKED TO DECREASE?

6438
03:40:06,881 --> 03:40:07,415
SENESCENT CELL BURDEN.

6439
03:40:07,415 --> 03:40:09,450
THAT LED US TO BEGIN TO ASK BACK

6440
03:40:09,450 --> 03:40:12,153
IN 2004, IS THIS AN ASSOCIATION

6441
03:40:12,153 --> 03:40:14,522
OR IS IT -- SO WE BEGAN TO TRY

6442
03:40:14,522 --> 03:40:15,556
TO DEVELOP SENOLYTICS.

6443
03:40:15,556 --> 03:40:19,293
WE WORKED WITH OTHERS FOR A LONG

6444
03:40:19,293 --> 03:40:21,362
TIME TRYING TO DEVELOP FUSION

6445
03:40:21,362 --> 03:40:22,763
PROTEINS THAT WOULD BIND ON ONE

6446
03:40:22,763 --> 03:40:24,865
END TO THE SENESCENT CELL AND

6447
03:40:24,865 --> 03:40:28,135
CARRY IT -- GOT NOWHERE, TRIED

6448
03:40:28,135 --> 03:40:30,438
HIGH-THROUGHPUT SCREENS WITH

6449
03:40:30,438 --> 03:40:32,907
SANFORD BARNUM IN SAN DIEGO, GOT

6450
03:40:32,907 --> 03:40:34,909
NOWHERE THEN IT EVENTUALLY HIT

6451
03:40:34,909 --> 03:40:36,777
US, THE 30 TO 70% OF SENESCENT

6452
03:40:36,777 --> 03:40:39,413
CELLS ARE TISSUE DAMAGING,

6453
03:40:39,413 --> 03:40:40,948
THEY'RE KILLING CELLS AROUND

6454
03:40:40,948 --> 03:40:43,217
THEM DESPITE THE FACT THEY

6455
03:40:43,217 --> 03:40:44,318
THEMSELVES SURVIVE.

6456
03:40:44,318 --> 03:40:46,721
WE ASK IF THEY USED SURVIVAL

6457
03:40:46,721 --> 03:40:48,255
NETWORK TO DEFEND THEMSELVES

6458
03:40:48,255 --> 03:40:51,092
AGAINST THE THINGS THEY'RE USING

6459
03:40:51,092 --> 03:40:52,893
TO KILL CELLS AROUND THEM AND

6460
03:40:52,893 --> 03:40:54,729
AVOID COMMITTING SUICIDE.

6461
03:40:54,729 --> 03:40:59,634
WE FOUND THESE PATHWAYS.

6462
03:40:59,634 --> 03:41:03,170
THERE ARE 10 OF THEM.

6463
03:41:03,170 --> 03:41:04,372
THAT HE TOGETHER IN A NETWORK

6464
03:41:04,372 --> 03:41:09,310
AND DIFFERENT SENESCENT CELLS OF

6465
03:41:09,310 --> 03:41:19,720
UPREGULATION -- AND THIS

6466
03:41:23,257 --> 03:41:24,392
DIFFERED BETWEEN DIFFERENT KINDS

6467
03:41:24,392 --> 03:41:26,227
OF HUMAN SENESCENT CELLS WHICH

6468
03:41:26,227 --> 03:41:27,128
NODES WE HAD TO HIT.

6469
03:41:27,128 --> 03:41:35,102
SO WITH HUMAN NSCs, WE HAD TO

6470
03:41:35,102 --> 03:41:38,039
HIT -- KINASE-RELATED PATHWAYS.

6471
03:41:38,039 --> 03:41:39,440
WHEREAS WITH ENDOTHELIAL CELLS,

6472
03:41:39,440 --> 03:41:42,777
WE MAINLY TARGETED PATHWAYS

6473
03:41:42,777 --> 03:41:47,314
RELATED TO BCL2 AND CERTAIN

6474
03:41:47,314 --> 03:41:51,252
OTHER THINGS, ABL AND -- PAUL

6475
03:41:51,252 --> 03:41:52,286
ROBINS MAY TALK MORE ABOUT THAT

6476
03:41:52,286 --> 03:41:52,753
LATER.

6477
03:41:52,753 --> 03:41:56,257
SO WE LOOKED FOR DRUGS THAT WERE

6478
03:41:56,257 --> 03:41:58,292
REPURPOSED OR ALREADY IN HUMAN

6479
03:41:58,292 --> 03:41:59,794
USE OR NATURAL PRODUCTS THAT

6480
03:41:59,794 --> 03:42:02,530
WOULD TARGET THESE NODES THAT

6481
03:42:02,530 --> 03:42:03,731
ARE AVAILABLE OR THAT COULD BE

6482
03:42:03,731 --> 03:42:07,735
ADMINISTERED ORALLY AND THAT

6483
03:42:07,735 --> 03:42:08,335
EXTRAORDINARILY LIMITED HALF

6484
03:42:08,335 --> 03:42:08,703
LIVES.

6485
03:42:08,703 --> 03:42:10,838
WE FOUND A TYROSINE KINASE

6486
03:42:10,838 --> 03:42:14,341
INHIBITOR BUT UNLIKE OTHERS, IT

6487
03:42:14,341 --> 03:42:19,346
TARGETS THE AFRIN DEPENDENT --

6488
03:42:19,346 --> 03:42:20,314
KINASE.

6489
03:42:20,314 --> 03:42:24,952
WE FOUND THAT CONCENTRATIONS

6490
03:42:24,952 --> 03:42:29,056
THAT WOULD KILL 30 TO 70% OF

6491
03:42:29,056 --> 03:42:30,825
SENESCENT SITES THAT ARE TISSUE

6492
03:42:30,825 --> 03:42:33,527
DAMAGING AND PRO APOPTOTIC.

6493
03:42:33,527 --> 03:42:39,400
IT DID NOT TOUCH HUMANS.

6494
03:42:39,400 --> 03:42:43,671
CONVERSELY -- SELECTIVELY KILLED

6495
03:42:43,671 --> 03:42:46,207
SENESCENT HUMAN EPITHELIAL CELLS

6496
03:42:46,207 --> 03:42:49,009
BUT NOT PREADIPOCYTES.

6497
03:42:49,009 --> 03:42:50,311
THERE'S NO COMBINATION THAT I'M

6498
03:42:50,311 --> 03:42:51,545
AWARE OF THAT WILL KILL EVERY

6499
03:42:51,545 --> 03:42:53,514
KIND OF SENESCENT CELL.

6500
03:42:53,514 --> 03:42:56,217
SO SINCE THEN, MANY OTHER

6501
03:42:56,217 --> 03:42:57,351
SENOLYTICS HAVE BEEN DISCOVERED

6502
03:42:57,351 --> 03:43:00,020
USING THAT ORIGINAL MECHANISM

6503
03:43:00,020 --> 03:43:02,356
BASED HYPOTHESIS DRIVEN APPROACH

6504
03:43:02,356 --> 03:43:03,324
AND HIGH-THROUGHPUT SCREENS NOW

6505
03:43:03,324 --> 03:43:05,526
HAVE BEEN SET UP AND WHERE

6506
03:43:05,526 --> 03:43:06,927
PEOPLE HAVE LOOKED AT DRUGS THAT

6507
03:43:06,927 --> 03:43:14,335
HAVE A HISTORY OF TARGETING

6508
03:43:14,335 --> 03:43:15,102
MULTI-MORBIDITY LIKE THOSE

6509
03:43:15,102 --> 03:43:16,971
TREATING FOR OSTEOPOROSIS BUT IS

6510
03:43:16,971 --> 03:43:18,038
NOTED TO DECREASE INCIDENCE OF

6511
03:43:18,038 --> 03:43:19,473
CANCERS AND DIABETES AND OTHER

6512
03:43:19,473 --> 03:43:21,742
THINGS, IT TURNS OUT TO BE

6513
03:43:21,742 --> 03:43:23,110
PARTLY SENOLYTIC.

6514
03:43:23,110 --> 03:43:24,545
CAR-T APPROACHES AND VACCINES

6515
03:43:24,545 --> 03:43:25,880
HAVE BEEN DEVELOPED INCLUDING A

6516
03:43:25,880 --> 03:43:27,181
VACCINE DEVELOPED BY A PERSON

6517
03:43:27,181 --> 03:43:28,916
WHO'S NOW IN MY LAB, HE

6518
03:43:28,916 --> 03:43:30,417
ORIGINALLY DEVELOPED ONE WHEN HE

6519
03:43:30,417 --> 03:43:38,526
WAS IN JAPAN AGAINST A GPNMB.

6520
03:43:38,526 --> 03:43:41,028
IF YOU TREAT ANIMALS WITH

6521
03:43:41,028 --> 03:43:42,129
ORAL -- THAT HAVE BEEN

6522
03:43:42,129 --> 03:43:45,032
TRANSPLANTED WITH SENESCENT

6523
03:43:45,032 --> 03:43:48,035
CELLS, YOU KILL 30 TO 70% AND

6524
03:43:48,035 --> 03:43:49,904
YOU TEND TO LEAVE NORMAL CELLS

6525
03:43:49,904 --> 03:43:50,738
ALONE.

6526
03:43:50,738 --> 03:43:54,708
IF YOU TAKE HUMAN TISSUE

6527
03:43:54,708 --> 03:43:56,811
EX-PLANTS FROM DIABETIC YOUNGER

6528
03:43:56,811 --> 03:43:58,245
WOMEN WITH RENAL FAILURE WHO

6529
03:43:58,245 --> 03:43:59,580
HAVE A LOT OF SENESCENT CELLS IN

6530
03:43:59,580 --> 03:44:01,182
THEIR ABDOMINAL FAT TISSUE, YOU

6531
03:44:01,182 --> 03:44:02,449
FIND THAT IT TAKES A 30 MINUTE

6532
03:44:02,449 --> 03:44:06,153
TO THREE-HOUR EXPOSURE FOR AN

6533
03:44:06,153 --> 03:44:06,687
IRREVERSIBLE PROCESS OF

6534
03:44:06,687 --> 03:44:10,090
APOPTOSIS TO OCCUR WHICH TAKES

6535
03:44:10,090 --> 03:44:12,393
18 HOURS AFTER SENOLYTICS HAVE

6536
03:44:12,393 --> 03:44:13,894
BEEN APPLIED.

6537
03:44:13,894 --> 03:44:15,262
SO YOU CAN APPLY SENOLYTICS FOR

6538
03:44:15,262 --> 03:44:16,864
30 MINUTES TO THREE HOURS,

6539
03:44:16,864 --> 03:44:19,266
REMOVE THEM AND IRREVERSIBLE

6540
03:44:19,266 --> 03:44:21,001
APOPTOSIS IS INITIATED WITHIN

6541
03:44:21,001 --> 03:44:21,869
SENESCENT CELLS BY THAT.

6542
03:44:21,869 --> 03:44:23,204
SO IN OTHER WORDS A VERY SHORT

6543
03:44:23,204 --> 03:44:24,572
EXPOSURE TO SENOLYTICS IS

6544
03:44:24,572 --> 03:44:28,209
SUFFICIENT TO DRIVE SENESCENT

6545
03:44:28,209 --> 03:44:29,510
CELLS DEATH THROUGH APOPTOSIS.

6546
03:44:29,510 --> 03:44:31,812
AS I MENTIONED BEFORE,

6547
03:44:31,812 --> 03:44:34,048
SENESCENCE TAKES 1 TO 6 WEEKS TO

6548
03:44:34,048 --> 03:44:36,350
DEVELOP, SO THESE DRUGS CAN BE

6549
03:44:36,350 --> 03:44:37,351
GIVEN INTERMITTENTLY BECAUSE

6550
03:44:37,351 --> 03:44:40,254
THEY TEND NOT TO DIVIDE, SO THIS

6551
03:44:40,254 --> 03:44:42,356
MEANS IN VARIOUS DISEASE STATES,

6552
03:44:42,356 --> 03:44:44,091
WE FIND WE CAN ADMINISTER THESE

6553
03:44:44,091 --> 03:44:45,993
DRUGS ONCE EVERY TWO WEEKS OR

6554
03:44:45,993 --> 03:44:48,963
ONCE A MONTH, AND WE PERSONALLY

6555
03:44:48,963 --> 03:44:51,031
SELECT THE DRUGS -- SO THAT THEY

6556
03:44:51,031 --> 03:44:53,033
WOULD BE GONE AND WE COULD DEAL

6557
03:44:53,033 --> 03:44:55,536
THEN AND TRY TO REMOVE OFF

6558
03:44:55,536 --> 03:44:57,938
TARGET AND SIDE EFFECTS.

6559
03:44:57,938 --> 03:44:59,573
SO IF YOU BLAST ONE LEG OF THE

6560
03:44:59,573 --> 03:45:01,542
MOUSE WITH SUFFICIENT RADIATION

6561
03:45:01,542 --> 03:45:03,811
TO MAKE THE -- LEG GO GREY AND

6562
03:45:03,811 --> 03:45:05,779
IT HAS TROUBLE WALKING A

6563
03:45:05,779 --> 03:45:06,981
TREADMILL, IF YOU GIVE A SINGLE

6564
03:45:06,981 --> 03:45:08,616
DOSE OF SENOLYTICS, THAT CAN

6565
03:45:08,616 --> 03:45:10,150
PARTIALLY RESTORE THE ABILITY --

6566
03:45:10,150 --> 03:45:11,352
ITS ABILITY TO RUN ON A

6567
03:45:11,352 --> 03:45:13,387
TREADMILL FOR THE REMAINDER OF

6568
03:45:13,387 --> 03:45:14,388
ITS LIFE BECAUSE UNLIKE CANCER

6569
03:45:14,388 --> 03:45:16,357
CELLS, SENESCENT CELLS GENERALLY

6570
03:45:16,357 --> 03:45:16,924
DON'T DIVIDE.

6571
03:45:16,924 --> 03:45:19,927
WITH THOSE TRANSPLANTED ANIMALS,

6572
03:45:19,927 --> 03:45:24,665
WE RESTORE -- ALLEVIATE FRAILTY

6573
03:45:24,665 --> 03:45:26,333
PARAMETERS, SO NOW THERE ARE

6574
03:45:26,333 --> 03:45:28,669
AROUND 70 CONDITIONS IN

6575
03:45:28,669 --> 03:45:32,840
EXPERIMENTAL ANIMAL MODELS, MI 

6576
03:45:32,840 --> 03:45:37,411
MICE, AND OTHER SPECIES WHERE IT

6577
03:45:37,411 --> 03:45:40,714
LOOKS LIKE SENOLYTICS HAVE AN

6578
03:45:40,714 --> 03:45:42,716
EFFECT.

6579
03:45:42,716 --> 03:45:44,051
RAPALOGS, METFORMIN WHICH DOES

6580
03:45:44,051 --> 03:45:47,655
AS WELL OR NAD PRECURSORS.

6581
03:45:47,655 --> 03:45:49,390
SO SOMETHING THAT'S BEEN SET UP,

6582
03:45:49,390 --> 03:45:50,824
I DON'T HAVE MUCH TIME LEFT SO

6583
03:45:50,824 --> 03:45:51,926
I'LL JUST GO THROUGH IT BRIEFLY,

6584
03:45:51,926 --> 03:45:55,529
IS THE TRANSLATIONAL GEROSCIENCE

6585
03:45:55,529 --> 03:45:59,934
NETWORK FUND FUNDED BY THE NATIL

6586
03:45:59,934 --> 03:46:02,002
INSTITUTES OF HEALTH, TRYING TO

6587
03:46:02,002 --> 03:46:02,870
CONDUCT CLINICAL TRIALS IN

6588
03:46:02,870 --> 03:46:04,305
PARALLEL OF NOT JUST SENOLYTICS

6589
03:46:04,305 --> 03:46:06,674
BUT OTHER AGENTS THAT TARGET

6590
03:46:06,674 --> 03:46:07,241
FUNDAMENTAL AGING PROCESSES.

6591
03:46:07,241 --> 03:46:08,709
CURRENTLY THERE ARE 82 CLINICAL

6592
03:46:08,709 --> 03:46:09,743
TRIALS UNDERWAY THAT ARE

6593
03:46:09,743 --> 03:46:11,211
ASSISTED BY THE NETWORK, 30 OF

6594
03:46:11,211 --> 03:46:14,448
WHICH ARE WITH SENOLYTICS, AND

6595
03:46:14,448 --> 03:46:16,216
THEY RANGE -- THESE ARE TRIALS

6596
03:46:16,216 --> 03:46:18,352
FOR PEOPLE WITH VERY SERIOUS

6597
03:46:18,352 --> 03:46:19,153
CONDITIONS FOR WHICH THERE ARE

6598
03:46:19,153 --> 03:46:20,321
NO GOOD INTERVENTIONS BECAUSE

6599
03:46:20,321 --> 03:46:22,423
WE'RE WORRIED ABOUT THE

6600
03:46:22,423 --> 03:46:23,891
RISK-BENEFIT RICCIOS AND WE'RE

6601
03:46:23,891 --> 03:46:24,792
WORRIED ABOUT SIDE EFFECTS.

6602
03:46:24,792 --> 03:46:30,397
AND THEY RANGE FROM TRIALS FOR

6603
03:46:30,397 --> 03:46:35,402
ADULTS -- SURVIVORS OF CHILDHOOD

6604
03:46:35,402 --> 03:46:37,771
CANCER WHO CAN DEVELOP AN

6605
03:46:37,771 --> 03:46:38,939
ACCELERATED AGING STATE DUE TO

6606
03:46:38,939 --> 03:46:44,311
THINGS LIKE COVID, SPACE TRAVEL,

6607
03:46:44,311 --> 03:46:46,914
ALZHEIMER'S DISEASE AND MIRANDA

6608
03:46:46,914 --> 03:46:48,582
ORR WILL SPEAK ABOUT THAT OR HAS

6609
03:46:48,582 --> 03:46:51,185
SPOKEN ABOUT THAT, FOR LT AND A

6610
03:46:51,185 --> 03:46:52,753
WHOLE RANGE OF OTHER DISORDERS

6611
03:46:52,753 --> 03:46:53,320
AND DISEASES.

6612
03:46:53,320 --> 03:46:54,521
EARLY TRIALS WERE PUBLISHED

6613
03:46:54,521 --> 03:46:58,492
LOOKING AT IDIOPATHIC PULMONARY

6614
03:46:58,492 --> 03:46:59,660
FIBROSIS OPEN LABEL TRIAL WITH

6615
03:46:59,660 --> 03:47:01,562
ALL THEIR BIASES BUT IT DID LOOK

6616
03:47:01,562 --> 03:47:03,731
LIKE THAT MIGHT HAVE BEEN SOME

6617
03:47:03,731 --> 03:47:04,298
IMPROVEMENT IN FRAILTY

6618
03:47:04,298 --> 03:47:07,234
PARAMETERS IN THESE PEOPLE.

6619
03:47:07,234 --> 03:47:10,204
IT'S A CENSUS DRIVEN DISORDER

6620
03:47:10,204 --> 03:47:11,939
AND THEIR MAIN PROBLEM IS

6621
03:47:11,939 --> 03:47:13,474
FRAILTY.

6622
03:47:13,474 --> 03:47:14,041
ANOTHER EARLY TRIAL THAT WAS

6623
03:47:14,041 --> 03:47:15,376
PUBLISHED THAT THERE'S TARGET

6624
03:47:15,376 --> 03:47:18,612
ENGAGEMENT, SO IN OBESE DIABETIC

6625
03:47:18,612 --> 03:47:20,781
WOMEN WITH INCIPIENT RENAL FAIL

6626
03:47:20,781 --> 03:47:21,815
EU WE FIND WE CAN GET REDUCTION

6627
03:47:21,815 --> 03:47:23,550
IN MARKERS OF SENESCENCE WITH

6628
03:47:23,550 --> 03:47:26,720
THREE DAYS OF ORAL -- AND WHEN

6629
03:47:26,720 --> 03:47:28,822
WE DO THE SECOND BIOPSY 11 DAYS

6630
03:47:28,822 --> 03:47:30,691
AFTER LAST DOSE WHEN THESE DRUGS

6631
03:47:30,691 --> 03:47:32,192
ARE LONG GONE BECAUSE THEY HAVE

6632
03:47:32,192 --> 03:47:34,328
SHORTY LIMB NATION HALF LIVES.

6633
03:47:34,328 --> 03:47:35,596
WE FIND THESE PROCESSES ARE

6634
03:47:35,596 --> 03:47:37,131
INTERLINKED SO IN 20 OUT OF 20

6635
03:47:37,131 --> 03:47:39,867
PEOPLE WHEN WE LOOKED AT

6636
03:47:39,867 --> 03:47:41,802
ALPHA -- A JAIR YOE PROTECTIVE

6637
03:47:41,802 --> 03:47:43,237
PROTEIN IN URINE, WE FOUND THAT

6638
03:47:43,237 --> 03:47:45,305
IT WAS INCREASED IN ALL 20

6639
03:47:45,305 --> 03:47:46,073
SUBJECTS.

6640
03:47:46,073 --> 03:47:47,741
WE'RE LOOKING AT DEVELOPING

6641
03:47:47,741 --> 03:47:50,611
ACROSS THE NETWORK GERODIKE NOS

6642
03:47:50,611 --> 03:47:55,716
TICS ANGERODIAGNOSTICS, THESE WE

6643
03:47:55,716 --> 03:47:58,352
THINGS ACCEPTABLE TO THE FDA AS

6644
03:47:58,352 --> 03:48:00,421
POTENTIALLY MAYBE ONE DAY SER

6645
03:48:00,421 --> 03:48:03,824
GAT END POINT.

6646
03:48:03,824 --> 03:48:07,961
 SER

6647
03:48:07,961 --> 03:48:08,729
SURROGATE END POINTS.

6648
03:48:08,729 --> 03:48:10,030
THE IDEA IS TO GO AFTER THINGS

6649
03:48:10,030 --> 03:48:11,698
THAT RESPOND TO INTERVENTIONS.

6650
03:48:11,698 --> 03:48:12,833
BIOLOGICAL CLOCKS ARE NOT GOOD

6651
03:48:12,833 --> 03:48:13,067
ENOUGH.

6652
03:48:13,067 --> 03:48:15,235
IN OUR VIEW THEY HAVE TO RESPOND

6653
03:48:15,235 --> 03:48:16,870
TO INTERVENTIONS, PICK WHICH

6654
03:48:16,870 --> 03:48:18,272
INTERVENTION TO USE AND

6655
03:48:18,272 --> 03:48:19,006
PREDICTIVE AFTER THE

6656
03:48:19,006 --> 03:48:20,340
INTERVENTION IS GIVEN IF THERE'S

6657
03:48:20,340 --> 03:48:21,975
A CHANGE OF PHENOTYPIC

6658
03:48:21,975 --> 03:48:23,177
IMPROVEMENT.

6659
03:48:23,177 --> 03:48:26,780
SO THE FIRST GERODIAGNOSTIC

6660
03:48:26,780 --> 03:48:29,049
SCORE BASED ON SENESCENCE WE DID

6661
03:48:29,049 --> 03:48:31,518
REALLY DRIVEN BY DAVID ALISON --

6662
03:48:31,518 --> 03:48:33,120
>> DOCTOR, YOU HAVE TWO
MINUTES

6663
03:48:33,120 --> 03:48:33,387
REMAINING.

6664
03:48:33,387 --> 03:48:35,089
>> OKAY, WAS WITH A SMALL
NUMBER

6665
03:48:35,089 --> 03:48:36,490
OF SUBJECTS AND IT LOOKED LIKE

6666
03:48:36,490 --> 03:48:38,258
IT SORT OF WORKED.

6667
03:48:38,258 --> 03:48:40,661
SO IN THE NETWORK, WE'RE

6668
03:48:40,661 --> 03:48:41,662
MEASURING LITERALLY HUNDREDS OF

6669
03:48:41,662 --> 03:48:42,296
PARAMETERS ACROSS ALL THE

6670
03:48:42,296 --> 03:48:42,830
TRIALS.

6671
03:48:42,830 --> 03:48:44,932
THE SAME THINGS WERE BEING

6672
03:48:44,932 --> 03:48:49,169
MEASURED BY THE FACILITY FOR

6673
03:48:49,169 --> 03:48:50,104
GEROSCIENCE WHICH IS FUNDED BY

6674
03:48:50,104 --> 03:48:51,905
THE NIH.

6675
03:48:51,905 --> 03:48:53,107
OTHER THINGS ARE BEING MEASURED

6676
03:48:53,107 --> 03:48:54,942
IN BLOOD INCLUDING NON-COATING

6677
03:48:54,942 --> 03:48:55,375
NUCLEOTIDES.

6678
03:48:55,375 --> 03:48:56,810
THERE ARE 35 PARAMETERS BEING

6679
03:48:56,810 --> 03:48:57,344
MEASURED IN URINE.

6680
03:48:57,344 --> 03:48:59,713
WHEN WE CAN GET IT, THERE ARE 50

6681
03:48:59,713 --> 03:49:00,848
PARAMETERS IN CSF.

6682
03:49:00,848 --> 03:49:02,683
THERE ARE PARAMETERS THAT ARE

6683
03:49:02,683 --> 03:49:04,751
BEING MEASURED IN SALIVA, TEARS,

6684
03:49:04,751 --> 03:49:08,322
AND THEN WE'RE KEEPING SAMPLES,

6685
03:49:08,322 --> 03:49:09,890
BUCCAL SWABS AND THINGS LIKE

6686
03:49:09,890 --> 03:49:11,325
THAT FOR METHYLATION ANALYSIS AS

6687
03:49:11,325 --> 03:49:14,328
WELL AS HAIR CLIPPINGS, NAIL

6688
03:49:14,328 --> 03:49:15,562
CLIPPINGS, MICROBIOME, ET

6689
03:49:15,562 --> 03:49:18,866
CETERA.

6690
03:49:18,866 --> 03:49:20,267
I DON'T HAVE TIME TO GO THROUGH

6691
03:49:20,267 --> 03:49:21,268
IT, BUT ONE OF THE THINGS THAT

6692
03:49:21,268 --> 03:49:22,703
WE'RE WORKING ON IN

6693
03:49:22,703 --> 03:49:25,839
COLLABORATION WITH THE GROUP AT

6694
03:49:25,839 --> 03:49:29,243
HARVARD IS TRYING TO REHA BILL

6695
03:49:29,243 --> 03:49:30,677
TATE ORGANS FROM YOUNGER DONORS

6696
03:49:30,677 --> 03:49:32,012
SO THEY CAN BE USED IN

6697
03:49:32,012 --> 03:49:33,247
RECIPIENTS, SO THERE ARE TRIALS

6698
03:49:33,247 --> 03:49:34,314
UNDERWAY NOW LOOKING AT THIS

6699
03:49:34,314 --> 03:49:36,250
WITH RENAL TRANSPLANTS AT THE

6700
03:49:36,250 --> 03:49:37,417
BRIGHAM AND HEPATIC TRANSPLANTS

6701
03:49:37,417 --> 03:49:41,255
WITH THE GROUP IN HOLLAND WHERE

6702
03:49:41,255 --> 03:49:44,791
I AM RIGHT NOW.

6703
03:49:44,791 --> 03:49:46,393
PAUL ROBINSON AND -- MAY SPEAK

6704
03:49:46,393 --> 03:49:47,327
ABOUT THIS MORE BUT THERE'S A

6705
03:49:47,327 --> 03:49:49,963
LINK BETWEEN SENESCENCE AND

6706
03:49:49,963 --> 03:49:52,065
CORONAVIRUS.

6707
03:49:52,065 --> 03:49:54,701
CORONAVIRUS DRIVE SENESCENCE,

6708
03:49:54,701 --> 03:49:55,702
SENESCENT CELLS TAKE OUT MORE

6709
03:49:55,702 --> 03:50:07,114
CORONAVIRUS TH -- SOIN A STUDY,N

6710
03:50:07,114 --> 03:50:10,450
FROM A -- REMOVING HE?

6711
03:50:10,450 --> 03:50:10,984
TICK CELLS GENETICALLY.

6712
03:50:10,984 --> 03:50:18,458
IT LOOKS LIKE QUERCETIN GIVEN IN

6713
03:50:18,458 --> 03:50:21,094
DAILY DOSES REDUCED

6714
03:50:21,094 --> 03:50:22,629
HOSPITALIZATION PERCENT NEEDING

6715
03:50:22,629 --> 03:50:23,730
ICU ADMISSION.

6716
03:50:23,730 --> 03:50:28,101
WE RECENTLY FOUND, WORKING WITH

6717
03:50:28,101 --> 03:50:29,636
VEIL THAT THERE'S SOME EVIDENCE

6718
03:50:29,636 --> 03:50:32,206
THAT CLEAR SENESCENT CELLS IN

6719
03:50:32,206 --> 03:50:37,778
HUMANS, IT'S CLOSELY RELATED TO

6720
03:50:37,778 --> 03:50:39,079
QUERCITIN SO THERE ARE TRIALS

6721
03:50:39,079 --> 03:50:39,546
UNDERWAY.

6722
03:50:39,546 --> 03:50:41,315
IN CONCLUSION, PERSISTENT

6723
03:50:41,315 --> 03:50:42,616
SENESCENT CELLS CAN CAUSE

6724
03:50:42,616 --> 03:50:43,150
DYSFUNCTION, SPREAD OF

6725
03:50:43,150 --> 03:50:44,818
SENESCENCE AN BE RELATED TO

6726
03:50:44,818 --> 03:50:46,153
MULTIPLE DISORDERS IN

6727
03:50:46,153 --> 03:50:47,120
EXPERIMENTAL ANIMALS.

6728
03:50:47,120 --> 03:50:51,592
THE TARGET OF SENOLYTICS IS --

6729
03:50:51,592 --> 03:50:52,626
THE BRANCH OF THE FDA WE'RE

6730
03:50:52,626 --> 03:50:56,230
DEALING WITH IS THAT DE BRANCH T

6731
03:50:56,230 --> 03:50:58,065
DEALS WITH ANTIBIOTICS WHERE

6732
03:50:58,065 --> 03:51:08,642
THEY DON'T CARE SO MUCH ABOUT 

6733
03:51:09,610 --> 03:51:11,044
ABOUT -- -- TREATMENT INDUCED

6734
03:51:11,044 --> 03:51:13,580
SENESCENT CELLS IN CONTEXT OF

6735
03:51:13,580 --> 03:51:13,814
CANCER.

6736
03:51:13,814 --> 03:51:14,781
HIT-AND-RUN APPROACH APPEARS TO

6737
03:51:14,781 --> 03:51:16,550
BE AS OR MORE EFFECTIVE THAN

6738
03:51:16,550 --> 03:51:17,651
CONTINUOUS DOSING.

6739
03:51:17,651 --> 03:51:19,953
30 TRIALS WERE UNDERWAY AND

6740
03:51:19,953 --> 03:51:23,357
THESE AGENTS MAY BE, JUST MAYBE

6741
03:51:23,357 --> 03:51:26,093
MIGHT LEAD TO INTERVENTIONS IN

6742
03:51:26,093 --> 03:51:29,096
HUMANS IF THE TRIALS WORK.

6743
03:51:29,096 --> 03:51:30,697
I VIEW THERE'S REALLY NO PLACE

6744
03:51:30,697 --> 03:51:32,165
FOR GIVING THESE AGENTS OUTSIDE

6745
03:51:32,165 --> 03:51:34,067
CONTEXT OF CAREFULLY CONTROLLED

6746
03:51:34,067 --> 03:51:36,236
FDA OR EMA MONITORED CLINICAL

6747
03:51:36,236 --> 03:51:37,904
TRIALS UNTIL WE KNOW IF THEY'RE

6748
03:51:37,904 --> 03:51:40,641
SAFE AND EFFECTIVE.

6749
03:51:40,641 --> 03:51:41,975
SO I'LL JUST CONCLUDE BY

6750
03:51:41,975 --> 03:51:43,176
THANKING A LOT OF PEOPLE

6751
03:51:43,176 --> 03:51:46,713
INCLUDING SHEILA, PAUL ROBINSON

6752
03:51:46,713 --> 03:51:50,651
WHO'S FOLLOWING ME AND ALSO

6753
03:51:50,651 --> 03:51:52,319
LAURA NIEDERNHOFER AND TAMARA

6754
03:51:52,319 --> 03:51:54,588
WHO WORK WITH ME ON DEVELOPING

6755
03:51:54,588 --> 03:51:54,921
SENOLYTICS.

6756
03:51:54,921 --> 03:51:58,358
THANKS.

6757
03:51:58,358 --> 03:52:01,628
>> THANK YOU, DR.
KIRKLAND.

6758
03:52:01,628 --> 03:52:03,363
WE HAVE ONE QUESTION AND HARDLY

6759
03:52:03,363 --> 03:52:04,264
A COUPLE OF MINUTES LEFT.

6760
03:52:04,264 --> 03:52:07,234
SO WE HAVE A QUESTION ON IF YOU

6761
03:52:07,234 --> 03:52:10,837
COULD TALK ABOUT DIFFERENT

6762
03:52:10,837 --> 03:52:12,372
SUSCEPTIBILITY TOXICITY OR

6763
03:52:12,372 --> 03:52:13,573
EFFECTS OF SENOLYTICS ON

6764
03:52:13,573 --> 03:52:15,609
DIFFERENT TYPES OF ENDOTHELIAL

6765
03:52:15,609 --> 03:52:16,143
CELLS.

6766
03:52:16,143 --> 03:52:19,613
>> WELL, DIFFERENT
SENOLYTICS

6767
03:52:19,613 --> 03:52:20,947
WORK ON DIFFERENT CELL TYPES.

6768
03:52:20,947 --> 03:52:22,949
SO THERE'S A HUGE NUMBER OF

6769
03:52:22,949 --> 03:52:23,450
SENOLYTICS.

6770
03:52:23,450 --> 03:52:24,351
NOW THERE ARE SEVERAL HUNDRED,

6771
03:52:24,351 --> 03:52:25,585
THERE ARE DOZENS OF COMPANIES

6772
03:52:25,585 --> 03:52:27,554
WORKING ON THEM.

6773
03:52:27,554 --> 03:52:30,857
BUT IN VIVO, THAT MAY BE -- CELL

6774
03:52:30,857 --> 03:52:34,394
SPECIFICITY MAY BE A LITTLE BIT

6775
03:52:34,394 --> 03:52:36,229
LESS OF AN ISSUE THAN IN VITRO.

6776
03:52:36,229 --> 03:52:37,664
THE THRESHOLD PHENOMENON RESULTS

6777
03:52:37,664 --> 03:52:38,799
FROM SPREAD OF SENESCENCE AND

6778
03:52:38,799 --> 03:52:40,100
THE FACT THAT SENESCENT CELLS

6779
03:52:40,100 --> 03:52:41,501
ARE CLEARED BY THE IMMUNE

6780
03:52:41,501 --> 03:52:42,703
SYSTEM, ESPECIALLY NATURAL

6781
03:52:42,703 --> 03:52:45,138
KILLER CELLS, BUT ALSO CERTAIN T

6782
03:52:45,138 --> 03:52:46,340
LYMPHOCYTE SUBSETS.

6783
03:52:46,340 --> 03:52:48,208
SO OUR VIEW IS IF YOU GET BELOW

6784
03:52:48,208 --> 03:52:50,043
THE THRESHOLD IN THE BODY, AND

6785
03:52:50,043 --> 03:52:52,612
WE'VE GOT SOME EVIDENCE FOR TH 

6786
03:52:52,612 --> 03:52:54,047
THIS, YOUR OWN IMMUNE SYSTEM

6787
03:52:54,047 --> 03:52:55,816
STARTS TAKING OUT REMAINING

6788
03:52:55,816 --> 03:52:57,184
SENESCENT CELLS THAT MAY BE

6789
03:52:57,184 --> 03:52:58,685
RESISTANT TO SENOLYTICS.

6790
03:52:58,685 --> 03:53:00,253
AND WE'VE ACTUALLY GOT DATA

6791
03:53:00,253 --> 03:53:01,722
SHOWING THAT WITH RESPECT TO THE

6792
03:53:01,722 --> 03:53:02,255
BRAIN.

6793
03:53:02,255 --> 03:53:04,324
SO IF WE CLEAR SENESCENT CELLS

6794
03:53:04,324 --> 03:53:05,992
ONLY IN ADIPOSE TISSUE IN THE

6795
03:53:05,992 --> 03:53:08,228
CONTEXT OF OBESITY, WE START

6796
03:53:08,228 --> 03:53:09,463
SEEING CLEARANCE OF SENESCENT

6797
03:53:09,463 --> 03:53:13,066
CELLS IN THE BRAIN BY ASTROCYTES

6798
03:53:13,066 --> 03:53:14,968
AND MICROGLIA, SO THE BODY'S OWN

6799
03:53:14,968 --> 03:53:15,969
IMMUNE SYSTEM IS ABLE TO TAKE

6800
03:53:15,969 --> 03:53:16,503
OVER.

6801
03:53:16,503 --> 03:53:17,938
FURTHERMORE, ONCE YOU GET ABOVE

6802
03:53:17,938 --> 03:53:19,473
A THRESHOLD OF SENESCENT CELLS,

6803
03:53:19,473 --> 03:53:23,577
THEY START POISONING THE IMMUNE

6804
03:53:23,577 --> 03:53:25,746
SYSTEM.

6805
03:53:25,746 --> 03:53:27,614
SO THEY RESULT IN IL-23

6806
03:53:27,614 --> 03:53:29,383
PRODUCTION, THEY PRODUCE

6807
03:53:29,383 --> 03:53:31,351
IL-6 WITH INTERFERES WITH

6808
03:53:31,351 --> 03:53:33,887
MACROPHAGE, THESE MITOCHONDRIAL

6809
03:53:33,887 --> 03:53:35,989
DNAs AFFECT DENDRITIC CELLS,

6810
03:53:35,989 --> 03:53:37,190
SO ONCE YOU'RE BEYOND A

6811
03:53:37,190 --> 03:53:38,925
THRESHOLD, YOU ENABLE THE IMMUNE

6812
03:53:38,925 --> 03:53:40,193
SYSTEM TO START KILLING CELLS,

6813
03:53:40,193 --> 03:53:42,062
SO YOU MAY NOT NEED THE KIND

6814
03:53:42,062 --> 03:53:44,831
OF -- YOU MAY NOT NEED CELL TYPE

6815
03:53:44,831 --> 03:53:45,599
SPECIFICITY IF YOU'RE ACTUALLY

6816
03:53:45,599 --> 03:53:47,701
DOING A CLINICAL TRIAL.

6817
03:53:47,701 --> 03:53:49,536
>> THANK YOU, THANK YOU SO
VERY

6818
03:53:49,536 --> 03:53:49,770
MUCH.

6819
03:53:49,770 --> 03:53:51,538
IN THE INTEREST OF TIME, I WOULD

6820
03:53:51,538 --> 03:53:55,041
LIKE TO ASK DR. ROBINS TO GO

6821
03:53:55,041 --> 03:53:57,377
AHEAD WITH HIS PRESENTATION.

6822
03:53:57,377 --> 03:54:00,781
>> FANTASTIC.

6823
03:54:00,781 --> 03:54:01,214
>> GREAT.

6824
03:54:01,214 --> 03:54:02,516
CAN YOU SEE MY SLIDES?

6825
03:54:02,516 --> 03:54:03,750
>> YES.

6826
03:54:03,750 --> 03:54:04,918
>> GREAT.

6827
03:54:04,918 --> 03:54:06,653
AND JIM, THANK YOU VERY MUCH FOR

6828
03:54:06,653 --> 03:54:11,057
A WONDERFUL OVERVIEW OF

6829
03:54:11,057 --> 03:54:11,825
SENESCENCE AND SENOLYTICS.

6830
03:54:11,825 --> 03:54:13,994
WHAT I'D LIKE TO DO IS ACTUALLY

6831
03:54:13,994 --> 03:54:21,802
FOCUS ON A FEW DIFFERENT

6832
03:54:21,802 --> 03:54:23,136
SENOTHERAPEUTICS, HOW WE CAN USE

6833
03:54:23,136 --> 03:54:24,337
THEM TO TREAT DIFFERENT

6834
03:54:24,337 --> 03:54:24,671
DISEASES.

6835
03:54:24,671 --> 03:54:26,640
SO TO CHARACTERIZE WHAT MY LAB

6836
03:54:26,640 --> 03:54:29,810
HAS DONE OVER THE LAST 10 YEARS,

6837
03:54:29,810 --> 03:54:31,745
WE'VE DONE NUMEROUS TYPES OF

6838
03:54:31,745 --> 03:54:33,680
ASSAYS TO IDENTIFY SENOLYTICS.

6839
03:54:33,680 --> 03:54:37,217
SO FOR EXAMPLE, WE SCREEN

6840
03:54:37,217 --> 03:54:38,618
LIBRARIES OF NATURAL COMPOUNDS

6841
03:54:38,618 --> 03:54:42,422
AND IDENTIFY THING SUCH AS HSB

6842
03:54:42,422 --> 03:54:48,762
INHIBITORS AND  FISETIN, IDENTIY

6843
03:54:48,762 --> 03:54:50,130
VARIANTS IN CENTENARIANS AND TRY

6844
03:54:50,130 --> 03:54:51,431
TO IDENTIFY DRUGS WHICH MIMIC

6845
03:54:51,431 --> 03:54:54,801
THE EFFECTS OF THOSE VARIANTS.

6846
03:54:54,801 --> 03:54:56,603
IT TURNS OUT SOME OF THESE DRUGS

6847
03:54:56,603 --> 03:54:58,905
ACTUALLY AFFECT HE?

6848
03:54:58,905 --> 03:55:03,910
CENTS, WE SCREEN CLINICALLY USED

6849
03:55:03,910 --> 03:55:07,380
COMPOUNDS, ZOLEDRONIC ACID,

6850
03:55:07,380 --> 03:55:15,622
THOSE THAT HAVE 16 THERAPEUTIC C

6851
03:55:15,622 --> 03:55:16,056
ACTIVITY.

6852
03:55:16,056 --> 03:55:17,691
SEE IF WE CAN IMPROVE THEIR

6853
03:55:17,691 --> 03:55:18,291
ACTIVITY AND IMPROVE THEIR

6854
03:55:18,291 --> 03:55:20,494
SAFETY PROFILE.

6855
03:55:20,494 --> 03:55:23,797
WE'VE DONE BIOINFORMATIC

6856
03:55:23,797 --> 03:55:25,065
ANALYSIS, ALSO OTHER CLASSES OF

6857
03:55:25,065 --> 03:55:26,800
COMPOUNDS THAT HAVE BEEN

6858
03:55:26,800 --> 03:55:27,901
IDENTIFIED WITH USE OF THESE

6859
03:55:27,901 --> 03:55:28,235
METHODS.

6860
03:55:28,235 --> 03:55:30,537
AND THEN WE'VE ALSO SHOWN THAT

6861
03:55:30,537 --> 03:55:32,305
YOUNG FUNCTIONAL ADULT STEM

6862
03:55:32,305 --> 03:55:33,940
CELLS RELEASE VESICLES THAT CAN

6863
03:55:33,940 --> 03:55:34,708
SUPPRESS SENESCENCE.

6864
03:55:34,708 --> 03:55:40,780
AND WE HAVE IDENTIFIED

6865
03:55:40,780 --> 03:55:41,348
MICRORNAs IN OLDER MICE AS

6866
03:55:41,348 --> 03:55:42,883
WELL AS OTHER MICRORNAs THAT

6867
03:55:42,883 --> 03:55:46,052
MODULATE SENESCENCE, SO THEIR

6868
03:55:46,052 --> 03:55:47,454
BIOLOGICS, DO THIS NATURALLY

6869
03:55:47,454 --> 03:55:47,754
WITH AGING.

6870
03:55:47,754 --> 03:55:49,289
BUT I'D LIKE TO JUST HIGHLIGHT

6871
03:55:49,289 --> 03:55:49,789
TWO OF THESE.

6872
03:55:49,789 --> 03:55:51,658
I LIKE TO REFER TO WORK WE'VE

6873
03:55:51,658 --> 03:55:53,126
DONE OVER THE LAST 10 YEARS

6874
03:55:53,126 --> 03:55:57,430
LOOKING AT N OF KB -- AND THEN

6875
03:55:57,430 --> 03:55:59,232
CLOSE WITH A FEW EXAMPLES OF HOW

6876
03:55:59,232 --> 03:56:04,371
WE CAN USE FISETIN, THAT HAS

6877
03:56:04,371 --> 03:56:05,839
SENOLYTIC ACTIVITY.

6878
03:56:05,839 --> 03:56:07,908
SO NF KB IS SOMETHING I THINK

6879
03:56:07,908 --> 03:56:10,076
MOST PEOPLE HAVE SOME KNOWLEDGE.

6880
03:56:10,076 --> 03:56:12,879
IT CAN BE INDUCED BY A VARIETY

6881
03:56:12,879 --> 03:56:14,581
OF INFLAMMATORY FACTORS,

6882
03:56:14,581 --> 03:56:17,117
INFECTION AND STRESS, BUT NF KB

6883
03:56:17,117 --> 03:56:18,184
ALSO CAN BE INDUCED BY DNA

6884
03:56:18,184 --> 03:56:19,686
DAMAGE.

6885
03:56:19,686 --> 03:56:22,155
SO FOR EXAMPLE, IT CAN ACTIVATE

6886
03:56:22,155 --> 03:56:31,798
ATM, WHICH LEADS TO SUMMALATION,

6887
03:56:31,798 --> 03:56:33,833
NEMO CAN TRAP IT BACK TO THE

6888
03:56:33,833 --> 03:56:34,868
CYTOPLASM WHERE NOW IT CAN WORK

6889
03:56:34,868 --> 03:56:36,870
THROUGH THE CANONICAL ACTIVATION

6890
03:56:36,870 --> 03:56:40,040
PATHWAY LOADING TO

6891
03:56:40,040 --> 03:56:41,775
PHOSPHORYLATION OF I KB,

6892
03:56:41,775 --> 03:56:43,410
UBIQUINATION OF THIS REGULATORY

6893
03:56:43,410 --> 03:56:44,611
SUBUNIT, DEGRADATION, AND THEN

6894
03:56:44,611 --> 03:56:46,846
AN ACTIVE TRANSCRIPTION FACTOR

6895
03:56:46,846 --> 03:56:47,414
TRANSPORTED TO THE NUCLEUS,

6896
03:56:47,414 --> 03:56:49,349
WHERE IT CAN TURN ON A VARIETY

6897
03:56:49,349 --> 03:56:52,319
OF THINGS WHICH ARE IMPORTANT

6898
03:56:52,319 --> 03:56:53,520
FOR NORMAL SURVIVAL.

6899
03:56:53,520 --> 03:56:58,558
BUT IF IT'S ABERRANTLY REGULATED

6900
03:56:58,558 --> 03:57:00,994
IT WILL LEAD TO A VARIETY OF

6901
03:57:00,994 --> 03:57:02,495
DIFFERENT DISEASES, AGING AND

6902
03:57:02,495 --> 03:57:03,229
STEM CELL DYSFUNCTION.

6903
03:57:03,229 --> 03:57:04,631
SO JUST TO HIGHLIGHT THE REASON

6904
03:57:04,631 --> 03:57:07,167
WHY WE FOCUSED ON NF KB, IT'S

6905
03:57:07,167 --> 03:57:08,935
BEEN SHOWN THAT IT'S

6906
03:57:08,935 --> 03:57:10,370
DOWNREGULATED BY LONGEVITY

6907
03:57:10,370 --> 03:57:13,340
FACTORS SUCH AS SIRTUINS, B53,

6908
03:57:13,340 --> 03:57:17,944
BUT UPREGULATED BY INSULIN, IGFO

6909
03:57:17,944 --> 03:57:20,480
ALTHOUGH NF KB HAS A LOT OF

6910
03:57:20,480 --> 03:57:22,549
NORMAL FUNCTIONS, IF IT'S

6911
03:57:22,549 --> 03:57:23,516
MISREGULATED, IT CAN DRIVE A

6912
03:57:23,516 --> 03:57:25,585
VARIETY OF ADVERSE OUTCOMES.

6913
03:57:25,585 --> 03:57:29,856
AND WORKING WITH -- WE PUBLISHED

6914
03:57:29,856 --> 03:57:31,091
RECENTLY IN CENTENARIANS, THERE

6915
03:57:31,091 --> 03:57:33,426
ARE NOP CODING VARIANTS IN

6916
03:57:33,426 --> 03:57:36,630
DIFFERENT SUBUNITS OF NF KB,

6917
03:57:36,630 --> 03:57:38,064
ALTHOUGH IT DAMPENS ACTIVITY.

6918
03:57:38,064 --> 03:57:42,969
SO REDUCING NF KB LATER IN LIFE

6919
03:57:42,969 --> 03:57:44,771
CAN EXTEND HEALTHSPAN AND

6920
03:57:44,771 --> 03:57:45,438
POTENTIALLY LIFESPAN.

6921
03:57:45,438 --> 03:57:47,407
SO SOME YEARS AGO WE LOOKED TO

6922
03:57:47,407 --> 03:57:50,710
SEE WHERE NF CAP PA B WAS

6923
03:57:50,710 --> 03:57:54,447
ACTIVATED WITH AGING.

6924
03:57:54,447 --> 03:58:01,254
WE SHOWED THAT IN THE MOUSE

6925
03:58:01,254 --> 03:58:02,689
MODEL, THIS IS DRIVEN BY

6926
03:58:02,689 --> 03:58:05,558
REDUCTION IN THE DM REPAIR

6927
03:58:05,558 --> 03:58:07,761
COMPLEX, THAT MICE THAT LIVE SIX

6928
03:58:07,761 --> 03:58:09,195
MONTHS, THE MINUS DELTA MICE

6929
03:58:09,195 --> 03:58:11,398
SHOW EVIDENCE OF UPREGULATION OF

6930
03:58:11,398 --> 03:58:14,467
NF KB IN KIDNEY WHICH WE SEE IN

6931
03:58:14,467 --> 03:58:15,902
THE MOUSE MODEL WAS ONE MONTH

6932
03:58:15,902 --> 03:58:18,571
WHICH IS THE MINUS MINUS CCOC

6933
03:58:18,571 --> 03:58:20,440
MICE BUT ALSO IN NATURAL AGING,

6934
03:58:20,440 --> 03:58:25,512
WE SEE UPREGULATION OF NF KB IN

6935
03:58:25,512 --> 03:58:36,890
A SCAS T SEW CASS  SOC, A SASTI.

6936
03:58:41,728 --> 03:58:43,530
SO WE THEN SET OUT TO SEE IF WE

6937
03:58:43,530 --> 03:58:45,832
COULD INHIBIT NF KB AND THE WAY

6938
03:58:45,832 --> 03:58:47,167
WE FIRST DID THIS IN THE CONTEXT

6939
03:58:47,167 --> 03:58:49,836
OF AGED MICE WAS UTE A PEPTIDE

6940
03:58:49,836 --> 03:58:50,637
LINK TODAY A PROTEIN

6941
03:58:50,637 --> 03:58:52,605
TRANSDUCTION DOMAIN THAT

6942
03:58:52,605 --> 03:58:53,673
DISRUPTS INTERACTION BETWEEN

6943
03:58:53,673 --> 03:58:56,376
NEMO, THE REGULATORY SUBUNIT AND

6944
03:58:56,376 --> 03:58:59,312
THE CATALYTIC KINASES.

6945
03:58:59,312 --> 03:59:00,847
SO WITH THIS PEPTIDE, WE SHOWED

6946
03:59:00,847 --> 03:59:03,483
THAT IF YOU TREATED THIS

6947
03:59:03,483 --> 03:59:05,285
ACCELERATED AGING MODEL THAT

6948
03:59:05,285 --> 03:59:07,120
LAURA DEVELOPED IN THE DELTA

6949
03:59:07,120 --> 03:59:09,756
MOUSE THAT WE COULD ACTUALLY SEE

6950
03:59:09,756 --> 03:59:11,224
AT LEAST APPEARANCE-WISE THAT

6951
03:59:11,224 --> 03:59:13,059
MICE LOOK MUCH HEALTHIER AFTER

6952
03:59:13,059 --> 03:59:14,094
TREATMENT AND THIS TREATMENT WAS

6953
03:59:14,094 --> 03:59:16,196
THREE DAYS A WEEK, STARTING AT

6954
03:59:16,196 --> 03:59:17,230
FOUR WEEKS OF AGE.

6955
03:59:17,230 --> 03:59:19,532
AND THIS LED TO A DELAY OF ONSET

6956
03:59:19,532 --> 03:59:20,200
OF MULTIPLE SYMPTOMS.

6957
03:59:20,200 --> 03:59:22,102
THERE WASN'T A DRAMATIC DELAY IN

6958
03:59:22,102 --> 03:59:24,404
ONSET BUT THIS COMBINATION OF

6959
03:59:24,404 --> 03:59:27,140
DELAY OF MULTIPLE MEASUREMENTS

6960
03:59:27,140 --> 03:59:30,477
OF HEALTHSPAN LED TO A VISIBLE

6961
03:59:30,477 --> 03:59:31,544
CHANGE IN THE APPEARANCE OF THE

6962
03:59:31,544 --> 03:59:32,212
MICE.

6963
03:59:32,212 --> 03:59:36,816
WE SAW EFFECTS ON -- AND LIVER,

6964
03:59:36,816 --> 03:59:39,853
THE KIDNEY, EFFECTS ON GLIOSIS

6965
03:59:39,853 --> 03:59:40,954
IN THE BRAIN AND EFFECTS

6966
03:59:40,954 --> 03:59:42,355
ACTUALLY ON OSTEOPOROSIS,

6967
03:59:42,355 --> 03:59:43,356
LOOKING AT THE VERTEBRAE OF

6968
03:59:43,356 --> 03:59:47,093
THESE MICE.

6969
03:59:47,093 --> 03:59:48,461
THE PROBLEM WITH THE PEPTIDE IS

6970
03:59:48,461 --> 03:59:50,230
IT'S NOT ORALLY ACTIVE, IT'S

6971
03:59:50,230 --> 03:59:51,231
EXPENSIVE, SO WE SET OUT SOME

6972
03:59:51,231 --> 03:59:52,999
YEARS AGO TO DEVELOP A SMALL

6973
03:59:52,999 --> 03:59:54,300
MOLECULE WHICH MIMICS THIS

6974
03:59:54,300 --> 03:59:55,001
PEPTIDE.

6975
03:59:55,001 --> 03:59:56,402
AND SO USING THE CRYSTAL

6976
03:59:56,402 --> 03:59:57,837
STRUCTURE OF THIS INTERACTION

6977
03:59:57,837 --> 04:00:02,242
BETWEEN THE NEMO REGULATORY

6978
04:00:02,242 --> 04:00:04,644
DOMAIN AND THE CATALYTIC KINASE,

6979
04:00:04,644 --> 04:00:07,413
WE IDENTIFIED THROUGH A

6980
04:00:07,413 --> 04:00:08,515
PHARMACO -- MODELING SYSTEM

6981
04:00:08,515 --> 04:00:09,816
FOLLOWED BY SEVERAL ROUNDS OF

6982
04:00:09,816 --> 04:00:13,920
SAR, A SMALL MOLECULE CALLED

6983
04:00:13,920 --> 04:00:16,122
SR12343 ACTUALLY INSERTS ITSELF

6984
04:00:16,122 --> 04:00:18,792
INTO THE HYDROPHOBIC POCKET OF

6985
04:00:18,792 --> 04:00:20,593
NEMO, SO THIS WILL NOW BLOCK THE

6986
04:00:20,593 --> 04:00:21,728
INTERACTION BETWEEN THESE TWO

6987
04:00:21,728 --> 04:00:23,563
SUBUNITS OF THE KINASE THAT

6988
04:00:23,563 --> 04:00:26,800
ACTIVATES NF CA KB.

6989
04:00:26,800 --> 04:00:27,867
SO THIS MOLECULE WHICH WE'VE

6990
04:00:27,867 --> 04:00:29,169
SHOWN DISRUPTS THIS COMPLEX IN

6991
04:00:29,169 --> 04:00:31,838
CELL CULTURE WILL INHIBIT NF KB

6992
04:00:31,838 --> 04:00:33,606
ACTIVITY IN A LUCIFERASE ASSAY

6993
04:00:33,606 --> 04:00:35,475
IN CELL CULTURE, BUT IF YOU

6994
04:00:35,475 --> 04:00:37,177
TREAT DIFFERENT ANIMAL MODELS OF

6995
04:00:37,177 --> 04:00:39,045
DISEASE, IN PARTICULAR, WE

6996
04:00:39,045 --> 04:00:41,781
TREATED THE DUCHENNE'S MUSCULAR

6997
04:00:41,781 --> 04:00:44,417
DYSTROPHY MOUSE MODEL, TREATING

6998
04:00:44,417 --> 04:00:45,785
IT THREE TIMES A WEEK FOR FOUR

6999
04:00:45,785 --> 04:00:48,087
WEEKS, WE SEE A DRAMATIC

7000
04:00:48,087 --> 04:00:50,223
IMPROVEMENT IN THE MUSCLE

7001
04:00:50,223 --> 04:00:51,858
PATHOLOGY AND REDUCTION IN

7002
04:00:51,858 --> 04:00:53,159
INFLAMMATION, IF WE TREAT

7003
04:00:53,159 --> 04:00:56,196
LAURA'S MOUSE MODEL -- MINUS

7004
04:00:56,196 --> 04:00:57,497
DELTA, STARTING AT 6 TO 7 WEEKS

7005
04:00:57,497 --> 04:00:59,933
OF AGE, WE HAVE A DELAY IN ONSET

7006
04:00:59,933 --> 04:01:02,302
OF SYMPTOMS AND NOT SHOWN HERE,

7007
04:01:02,302 --> 04:01:04,337
REDUCTION IN SEVERITY OF

7008
04:01:04,337 --> 04:01:04,904
SYMPTOMS.

7009
04:01:04,904 --> 04:01:07,106
WE'VE ALSO TREATED A MOUSE MODEL

7010
04:01:07,106 --> 04:01:10,710
OF HUTCHINSON GILFORD PROGERIA

7011
04:01:10,710 --> 04:01:12,879
SYNDROME, REDUCING FIBROSIS.

7012
04:01:12,879 --> 04:01:13,746
INTERESTINGLY, WE CAN ALSO PUT

7013
04:01:13,746 --> 04:01:17,984
THIS ON THE SKIN AND SHOW ON THE

7014
04:01:17,984 --> 04:01:19,385
MOUSE MODEL IMPROVEMENTS IN THE

7015
04:01:19,385 --> 04:01:20,687
SKIN APPEARANCE AS WELL AS

7016
04:01:20,687 --> 04:01:22,388
REDUCTION IN MARKERS OF

7017
04:01:22,388 --> 04:01:26,426
SENESCENCE SUCH AS P16.

7018
04:01:26,426 --> 04:01:30,597
WE'VE GONE ON TO

7019
04:01:30,597 --> 04:01:31,464
TREAT ---YEAR-OLD MICE, WE

7020
04:01:31,464 --> 04:01:33,032
TREATED THEM THREE TIMES A WEEK

7021
04:01:33,032 --> 04:01:34,934
FOR 17 WEEKS.

7022
04:01:34,934 --> 04:01:37,003
AND WE SHOWED IN LIVER THIS

7023
04:01:37,003 --> 04:01:42,408
REDUCES PHOSPHORYLATION OF THE

7024
04:01:42,408 --> 04:01:46,779
P65 SUBUNIT OF NF KB BUT ALSO

7025
04:01:46,779 --> 04:01:48,314
P21 IN THE LIVER.

7026
04:01:48,314 --> 04:01:49,616
YOU SEE A REDUCTION IN

7027
04:01:49,616 --> 04:01:52,452
SENESCENCE MARKERS AND SASP

7028
04:01:52,452 --> 04:01:52,986
MARKERS IN THE LIVER.

7029
04:01:52,986 --> 04:01:54,854
WE ALSO SEE THIS IN DIFFERENT

7030
04:01:54,854 --> 04:01:55,088
MUSCLES.

7031
04:01:55,088 --> 04:01:58,491
THIS IS THE QUADRICEPS BUT ALSO

7032
04:01:58,491 --> 04:02:01,327
IN GASTROC WE SEE A REDUCTION IN

7033
04:02:01,327 --> 04:02:02,528
SENESCENCE MARKERS.

7034
04:02:02,528 --> 04:02:03,396
AND JUST THE APPEARANCE OF THE

7035
04:02:03,396 --> 04:02:07,267
MUSCLE IS DIFFERENT.

7036
04:02:07,267 --> 04:02:09,002
SO DRAMATIC EFFECTS WITH 17

7037
04:02:09,002 --> 04:02:15,608
WEEKS OF TREATMENT OF OLD MICE.

7038
04:02:15,608 --> 04:02:16,943
RECENTLY WE TRIED TO APPLY THIS

7039
04:02:16,943 --> 04:02:18,144
TO OTHER MODELS.

7040
04:02:18,144 --> 04:02:20,680
WE EXAMINED THE EFFECT OF THIS

7041
04:02:20,680 --> 04:02:22,015
COMPOUND IN BLOCKING THE ADVERSE

7042
04:02:22,015 --> 04:02:23,416
EFFECTS OF A CHEMOTHERAPY

7043
04:02:23,416 --> 04:02:24,284
COCKTAIL THAT'S USED TO TREAT

7044
04:02:24,284 --> 04:02:28,421
MANY TYPES OF CANCERS AND SHOWED

7045
04:02:28,421 --> 04:02:30,089
THE CO-DELIVERY OF THIS DRUG

7046
04:02:30,089 --> 04:02:32,692
WITH THIS CHEMOTHERAPEUTIC

7047
04:02:32,692 --> 04:02:36,029
COCKTAIL, SO THE DRUG IS IN RED,

7048
04:02:36,029 --> 04:02:39,098
TREATING WITH SR12343 IS IN

7049
04:02:39,098 --> 04:02:40,867
GREEN, WE CAN PREVENT REDUCTION

7050
04:02:40,867 --> 04:02:43,970
OF BODY WEIGHT -- MASS AND THE

7051
04:02:43,970 --> 04:02:48,241
LOSS OF FAT MASS BY BLOCKING IKK

7052
04:02:48,241 --> 04:02:50,743
NF KB, AND SIMILARLY IF YOU LOOK

7053
04:02:50,743 --> 04:02:51,577
AT LIVER AS WELL AS OTHER

7054
04:02:51,577 --> 04:02:52,912
TISSUES, TREATMENT WITH

7055
04:02:52,912 --> 04:02:53,980
CHEMOTHERAPY DRIVES MARKERS OF

7056
04:02:53,980 --> 04:02:55,515
SENESCENCE IN SASP BUT THIS DRUG

7057
04:02:55,515 --> 04:02:57,150
PREVENT THIS INCREASE.

7058
04:02:57,150 --> 04:02:59,686
SUGGESTING IT COULD BE USED FOR

7059
04:02:59,686 --> 04:03:01,454
BLOCKING ADVERSE EFFECTS OF

7060
04:03:01,454 --> 04:03:03,690
CHEMOTHERAPY BUT ALSO CANCER

7061
04:03:03,690 --> 04:03:07,293
CACHEXIA.

7062
04:03:07,293 --> 04:03:11,197
WHAT ACTIVATES NF KB WITH AGING?

7063
04:03:11,197 --> 04:03:13,499
THE HYPOTHESIS WAS THIS WAS

7064
04:03:13,499 --> 04:03:15,268
PREDOMINANTLY THROUGH DNA DAMAGE

7065
04:03:15,268 --> 04:03:19,238
AND NOT FACTORS SUCH AT -- OR

7066
04:03:19,238 --> 04:03:19,505
IL-1 BETA.

7067
04:03:19,505 --> 04:03:22,508
WE USED A MOUSE MODEL WHERE

7068
04:03:22,508 --> 04:03:24,711
MUTATIONS WERE INSERTED IN NEMO

7069
04:03:24,711 --> 04:03:26,279
TO BLOCK ITS SIMULATION AFTER

7070
04:03:26,279 --> 04:03:26,846
DNA DAMAGE.

7071
04:03:26,846 --> 04:03:31,617
THIS IS MADE BY SHIGEKI MIYAMOT

7072
04:03:31,617 --> 04:03:32,051
OSM.

7073
04:03:32,051 --> 04:03:36,356
IF YOU RADIATE SPLENOCYTES, IF

7074
04:03:36,356 --> 04:03:37,924
YOU MAKE THIS TWO AMINO ACID

7075
04:03:37,924 --> 04:03:39,325
CHANGE IN NEMO THAT'S NOT

7076
04:03:39,325 --> 04:03:40,960
SIMULATED, THIS ACTIVATION GOES

7077
04:03:40,960 --> 04:03:44,063
DOWN, BUT THE ACTIVATION BY LPS

7078
04:03:44,063 --> 04:03:45,531
IS NOT IMPAIRED BECAUSE THAT'S

7079
04:03:45,531 --> 04:03:46,399
THROUGH A DIFFERENT SIGNALING

7080
04:03:46,399 --> 04:03:46,833
PATHWAY.

7081
04:03:46,833 --> 04:03:51,270
SO THIS HAS REDUCED NF K KB

7082
04:03:51,270 --> 04:03:52,572
SIGNALING WITH DNA DAMAGE.

7083
04:03:52,572 --> 04:03:54,140
INTERESTING IF YOU CROSS THIS

7084
04:03:54,140 --> 04:03:54,907
MOUSE MODEL INTO THE PROGERIA

7085
04:03:54,907 --> 04:03:56,275
MOUSE MODEL, WE SEE A REDUCTION

7086
04:03:56,275 --> 04:03:57,643
OF MARKERS OF SENESCENCE IN

7087
04:03:57,643 --> 04:03:59,379
EVERY TISSUE THAT WE'VE ANALYZED

7088
04:03:59,379 --> 04:04:01,280
THAT'S SHOWN HERE FOR LIVER,

7089
04:04:01,280 --> 04:04:05,284
REDUCTION IN P16 AND PSM 21 AND

7090
04:04:05,284 --> 04:04:05,618
SASP FACTORS.

7091
04:04:05,618 --> 04:04:07,153
IF YOU ISOLATE STEM CELLS FROM

7092
04:04:07,153 --> 04:04:08,588
THE MUSCLE, THEY NOW

7093
04:04:08,588 --> 04:04:10,323
DIFFERENTIATE THE MYOFIBERS MUCH

7094
04:04:10,323 --> 04:04:13,026
MORE EFFECTIVELY, SHOWING THIS

7095
04:04:13,026 --> 04:04:15,595
INHIBITION OF NF KAPPA BY

7096
04:04:15,595 --> 04:04:16,763
ACTIVATION WITH DNA DAMAGE

7097
04:04:16,763 --> 04:04:17,897
ALLOWS STEM CELLS TO

7098
04:04:17,897 --> 04:04:19,232
DIFFERENTIATE MORE EFFECTIVELY,

7099
04:04:19,232 --> 04:04:22,502
AND THE MUSCLE FIBERS LOOK MUCH

7100
04:04:22,502 --> 04:04:24,003
MORE LIKE A YOUNGER MUSCLE FIBER

7101
04:04:24,003 --> 04:04:25,505
WITH A YOUNGER SIZE, SUGGESTING

7102
04:04:25,505 --> 04:04:28,775
THAT DNA DAMAGE DRIVES NF KB

7103
04:04:28,775 --> 04:04:29,409
ACTIVATION WITH AGING WHICH

7104
04:04:29,409 --> 04:04:32,612
DRIVES SENESCENCE AND SASP.

7105
04:04:32,612 --> 04:04:34,814
SO I'D LIKE TO CLOSE BY SHOWING

7106
04:04:34,814 --> 04:04:36,983
A FEW EXAMPLE FS A DIFFERENT

7107
04:04:36,983 --> 04:04:37,750
COMPOUND.

7108
04:04:37,750 --> 04:04:43,289
THIS IS A FLAVONOID FISETIN, WE

7109
04:04:43,289 --> 04:04:45,925
SHOWED AT LOW DOSES OF THESE

7110
04:04:45,925 --> 04:04:50,496
DIFFERENT FLAVONOIDS THAT FI

7111
04:04:50,496 --> 04:04:52,932
FISETIN WAS MORE EFFECTIVE.

7112
04:04:52,932 --> 04:04:56,269
IN OTHER CELL TYPES IT

7113
04:04:56,269 --> 04:04:58,671
FUNCTIONED AS -- MORPHIC.

7114
04:04:58,671 --> 04:04:59,872
WE SHOWED A FEW YEARS AGO WITH

7115
04:04:59,872 --> 04:05:04,444
JIM THAT IF YOU TREATED OLD --

7116
04:05:04,444 --> 04:05:08,648
MICE THAT ALLOWS US TO ASSESS BY

7117
04:05:08,648 --> 04:05:10,716
EXPRESSION THE P16 PROMOTER THAT

7118
04:05:10,716 --> 04:05:12,718
FIVE DAYS OF ACUTE TREATMENT

7119
04:05:12,718 --> 04:05:15,788
WITH FICETIN REDUCED SA BETA --

7120
04:05:15,788 --> 04:05:18,124
BUT ALSO REDUCED THE PERCENT OF

7121
04:05:18,124 --> 04:05:18,791
DIFFERENT TYPES OF CELLS OR

7122
04:05:18,791 --> 04:05:19,826
DIFFERENT TYPES OF SENESCENT

7123
04:05:19,826 --> 04:05:23,096
CELLS INCLUDING CD4s, CD8s

7124
04:05:23,096 --> 04:05:25,364
AND NK CELLS WITH THIS ACUTE

7125
04:05:25,364 --> 04:05:26,466
TREATMENT.

7126
04:05:26,466 --> 04:05:31,904
WE SHOWED ALSO IF YOU PUT FIC 

7127
04:05:31,904 --> 04:05:36,175
FICETIN IN THE -- IF THEY TAKE

7128
04:05:36,175 --> 04:05:37,009
IT TAILY -- SUGGESTING

7129
04:05:37,009 --> 04:05:38,211
IMPROVEMENT IN PANCREATIC

7130
04:05:38,211 --> 04:05:40,413
FUNCTION, LIVER FUNCTION, AND

7131
04:05:40,413 --> 04:05:43,015
WHAT HISTOPATHOLOGY WITH THE

7132
04:05:43,015 --> 04:05:45,118
GEROPATHOLOGY GRADING PLATFORM

7133
04:05:45,118 --> 04:05:46,285
WE SEE AN IMPROVEMENT IN

7134
04:05:46,285 --> 04:05:49,989
PATHOLOGY IN BRAIN, KIDNEY, THE

7135
04:05:49,989 --> 04:05:52,325
LUNG AND THE PAW, SO DRAMATIC

7136
04:05:52,325 --> 04:05:54,494
EFFECTS OF EXPOSURE OF THESE

7137
04:05:54,494 --> 04:05:56,329
MICE TO FICETIN.

7138
04:05:56,329 --> 04:05:57,964
THE LAST EXAMPLE I WANT TO GIVE

7139
04:05:57,964 --> 04:06:03,402
OF HOW WE CAN USE S

7140
04:06:03,402 --> 04:06:04,837
SENOTHERAPEUTICS, WE'VE USED THE

7141
04:06:04,837 --> 04:06:06,672
MODEL EXTENSIVELY WHERE YOU

7142
04:06:06,672 --> 04:06:10,042
ACTUALLY EXPOSE AN SPF MOUSE TO

7143
04:06:10,042 --> 04:06:11,144
A PET STORE MOUSE.

7144
04:06:11,144 --> 04:06:12,879
WE CALL THIS THE NORMAL

7145
04:06:12,879 --> 04:06:17,483
MICROBIAL EXPERIENCE AN, DEVELOD

7146
04:06:17,483 --> 04:06:18,184
AT THE UNIVERSITY OF MINNESOTA,

7147
04:06:18,184 --> 04:06:21,487
BUT EXPOSING THE SPF MOUTH TO

7148
04:06:21,487 --> 04:06:22,355
PATHOGENS HAD AN INTERESTING

7149
04:06:22,355 --> 04:06:24,524
RESULT.

7150
04:06:24,524 --> 04:06:25,958
SHOWN IN GREY ARE YOUNG MICE

7151
04:06:25,958 --> 04:06:27,160
EXPOSED TO A PET STORE MOUSE,

7152
04:06:27,160 --> 04:06:30,630
AND THEY SURVIVE ALMOST 100%.

7153
04:06:30,630 --> 04:06:35,268
BUT A 2-YEAR-OLD -- MOUSE DIED

7154
04:06:35,268 --> 04:06:35,801
WITHIN 14 DAYS.

7155
04:06:35,801 --> 04:06:38,204
SO WE VIEW THIS AS A LOSS OF

7156
04:06:38,204 --> 04:06:42,241
RESILIENCE DUE TO A UNEDUCATED

7157
04:06:42,241 --> 04:06:42,675
IMMUNE SYSTEM.

7158
04:06:42,675 --> 04:06:43,776
WHAT WAS INTERESTING WAS LOOKING

7159
04:06:43,776 --> 04:06:45,344
AT THE ANTIBODIES TO THE

7160
04:06:45,344 --> 04:06:46,779
PATHOGENS THAT COULD BE

7161
04:06:46,779 --> 04:06:48,347
TRANSFERRED, THE FIRST PATHOGEN

7162
04:06:48,347 --> 04:06:51,584
WHERE AN ANTIBODY WAS DEVELOPED

7163
04:06:51,584 --> 04:06:54,587
AGAINST THESE OLD MICE WAS MHV,

7164
04:06:54,587 --> 04:06:57,223
THE MURINE CORONAVIRUS MOUSE

7165
04:06:57,223 --> 04:06:57,690
HEPATITIS VIRUS.

7166
04:06:57,690 --> 04:06:59,825
SO WHAT WE SHOWED WAS THAT IF

7167
04:06:59,825 --> 04:07:01,460
YOU INFECT OR EXPOSE OLD MICE TO

7168
04:07:01,460 --> 04:07:02,995
PATHOGENS AS SHOWN HERE IN BLACK

7169
04:07:02,995 --> 04:07:05,631
WITH THE OLD MOUSE, THAT THESE

7170
04:07:05,631 --> 04:07:08,868
PATHOGENS DRAMATICALLY INCREASE

7171
04:07:08,868 --> 04:07:10,102
SENESCENCE AS COMPARED TO THE

7172
04:07:10,102 --> 04:07:13,005
OLD SPF MOUSE SHOWN IN MAGENTA.

7173
04:07:13,005 --> 04:07:14,740
SO DRAMATIC EFFECTS IN

7174
04:07:14,740 --> 04:07:17,910
INCREASING SENESCENCE, BUT ALSO

7175
04:07:17,910 --> 04:07:22,381
IMFLAM TRI MARKERS SUCH AS IL-6,

7176
04:07:22,381 --> 04:07:24,584
MCP1 AND TNF ALPHA.

7177
04:07:24,584 --> 04:07:26,352
SO -- DRIVE INCREASE IN

7178
04:07:26,352 --> 04:07:27,720
SENESCENCE AND INCREASE IN SASP.

7179
04:07:27,720 --> 04:07:29,589
AND THEN WE'VE ACTUALLY EXPOSED

7180
04:07:29,589 --> 04:07:32,391
THESE MICE OR TREATED THEM WITH

7181
04:07:32,391 --> 04:07:33,492
INTERMITTENTLY WITH FI SE TIN.

7182
04:07:33,492 --> 04:07:35,261
BY PUTTING IT INTO THE CHOW.

7183
04:07:35,261 --> 04:07:37,230
AND WE SHOWED THAT WE CAN

7184
04:07:37,230 --> 04:07:38,764
PROTECT 50% OF THESE MICE FROM

7185
04:07:38,764 --> 04:07:41,033
DEATH.

7186
04:07:41,033 --> 04:07:42,602
WHY IT'S ALWAYS 50% IS STILL IN

7187
04:07:42,602 --> 04:07:45,471
QUESTION BUT FISETIN AND OTHER

7188
04:07:45,471 --> 04:07:46,939
SENOLYTICS ALWAYS SEEM TO HAVE

7189
04:07:46,939 --> 04:07:48,341
AN EFFECT OF RESCUING 50% --

7190
04:07:48,341 --> 04:07:56,816
>> YOU HAVE 2 MINUTES
LEFT.

7191
04:07:56,816 --> 04:07:59,919
>> THERE ARE NOW 16
CLINICAL

7192
04:07:59,919 --> 04:08:01,254
TRIALS, YOU CAN SEE THEY'RE

7193
04:08:01,254 --> 04:08:02,421
AGAINST A VARIETY OF DIFFERENT

7194
04:08:02,421 --> 04:08:04,290
CONDITIONS INCLUDING CARPAL

7195
04:08:04,290 --> 04:08:06,993
TUNNEL SYNDROME, COVID,

7196
04:08:06,993 --> 04:08:08,060
OSTEOARTHRITIS, KIDNEY DISEASE,

7197
04:08:08,060 --> 04:08:10,963
FRAILTY, SKELETAL HEALTH, CANCER

7198
04:08:10,963 --> 04:08:11,497
SURVIVORS, OBESITY AND

7199
04:08:11,497 --> 04:08:12,598
DEPRESSION.

7200
04:08:12,598 --> 04:08:15,001
SO CLEARLY A WIDE RANGE IN

7201
04:08:15,001 --> 04:08:16,102
DISEASE TARGETS.

7202
04:08:16,102 --> 04:08:17,837
SO WITH THAT, I'D JUST LIKE TO

7203
04:08:17,837 --> 04:08:20,239
CLOSE BY TALKING ABOUT KIND OF

7204
04:08:20,239 --> 04:08:23,542
WHAT THIS DATA AND HOW IT MAY

7205
04:08:23,542 --> 04:08:27,213
ALTER OUR THOUGHTS ABOUT WHAT

7206
04:08:27,213 --> 04:08:28,614
CAN DRIVE RESILIENCE AND

7207
04:08:28,614 --> 04:08:29,382
INTERCEPT DISEASES.

7208
04:08:29,382 --> 04:08:31,017
I THINK WE'VE SHOWN DNA DAMAGE

7209
04:08:31,017 --> 04:08:33,519
PLAYS A KEY ROLE IN DRIVING

7210
04:08:33,519 --> 04:08:35,621
ACTIVATION OF NF KB AND THE

7211
04:08:35,621 --> 04:08:37,023
SUBSEQUENT EFFECTS INCLUDING

7212
04:08:37,023 --> 04:08:39,158
SENESCENCE, INFLAMMATION, STEM

7213
04:08:39,158 --> 04:08:44,730
CELL DYSFUNCTION.

7214
04:08:44,730 --> 04:08:50,603
SENOTHERAPEUTICS CAN -- BECAUSE

7215
04:08:50,603 --> 04:08:51,671
OF THE FACT THEY'VE NOT

7216
04:08:51,671 --> 04:08:52,905
EXPERIENCED ANY EXPOSURE OF THE

7217
04:08:52,905 --> 04:08:54,206
PATHOGENS SO WE SHOULD BE

7218
04:08:54,206 --> 04:08:54,940
CONSIDERING THAT IN THE FUTURE.

7219
04:08:54,940 --> 04:08:56,575
AND WE CAN APPLY

7220
04:08:56,575 --> 04:08:58,010
SENOTHERAPEUTICS TO A WIDE

7221
04:08:58,010 --> 04:09:00,446
SPECTRUM OF DISEASES AND

7222
04:09:00,446 --> 04:09:01,714
DISORDERS.

7223
04:09:01,714 --> 04:09:03,115
I DIDN'T TALK ABOUT THIS BUT WE

7224
04:09:03,115 --> 04:09:04,417
PUBLISHED A FEW YEARS AGO THAT

7225
04:09:04,417 --> 04:09:05,851
IMMUNE CELLS LIKELY ARE A KEY

7226
04:09:05,851 --> 04:09:07,286
TARGET FOR SENOTHERAPEUTICS,

7227
04:09:07,286 --> 04:09:09,288
BECAUSE OF THE FACT THAT THEY

7228
04:09:09,288 --> 04:09:11,057
CAN INFILTRATE INTO A VARIETY OF

7229
04:09:11,057 --> 04:09:12,558
TISSUES.

7230
04:09:12,558 --> 04:09:14,794
AND I THINK IN THE NEXT THREE OR

7231
04:09:14,794 --> 04:09:16,829
FOUR YEARS, THESE ONGOING

7232
04:09:16,829 --> 04:09:18,397
CLINICAL TRIALS ARE REALLY

7233
04:09:18,397 --> 04:09:19,031
DOCUMENTING THE HEALTH BENEFITS

7234
04:09:19,031 --> 04:09:20,933
OF REDUCING THE SENESCENT CELL

7235
04:09:20,933 --> 04:09:21,500
BURDEN.

7236
04:09:21,500 --> 04:09:23,436
SO WHAT ARE THE KEY GAPS?

7237
04:09:23,436 --> 04:09:25,237
QUESTION IS, WHAT CELLS DO YOU

7238
04:09:25,237 --> 04:09:27,873
SEE SENESCENCE OCCURRING IN AND

7239
04:09:27,873 --> 04:09:30,543
NF KAPPA BY ACTIVATION, AND THEN

7240
04:09:30,543 --> 04:09:31,243
WHAT ARE THE SUBSET OF THESE

7241
04:09:31,243 --> 04:09:35,848
CELLS WHICH ACTUALLY CONTRIBUTE

7242
04:09:35,848 --> 04:09:37,283
TO AGING AND AGE-RELATED

7243
04:09:37,283 --> 04:09:38,417
DISEASES?

7244
04:09:38,417 --> 04:09:39,018
AND THEN THE QUESTION IS WHAT

7245
04:09:39,018 --> 04:09:40,052
ACTUALLY DRIVES THIS ACTIVATION,

7246
04:09:40,052 --> 04:09:41,387
WHAT TYPE OF STRESS?

7247
04:09:41,387 --> 04:09:43,422
THIS COULD BE PSYCHOSOCIAL

7248
04:09:43,422 --> 04:09:44,623
STRESS, INFLAMMATORY STRESS,

7249
04:09:44,623 --> 04:09:46,726
MECHANICAL STRESS, COULD BE

7250
04:09:46,726 --> 04:09:50,329
OXIDATIVE STRESS, PATHOGEN

7251
04:09:50,329 --> 04:09:51,397
EXPOSURE, SO WHAT ACTUALLY

7252
04:09:51,397 --> 04:09:53,032
DRIVES THESE AGENTS WITH AGE, AT

7253
04:09:53,032 --> 04:09:55,234
LEAST IF YOU EXPOSE A MOUSE TO A

7254
04:09:55,234 --> 04:09:58,070
NORMAL MICROBIAL EXPERIENCE.

7255
04:09:58,070 --> 04:09:59,505
SO I THINK WHAT WE NEED OVER THE

7256
04:09:59,505 --> 04:10:01,841
NEXT FEW YEARS IS WE REALLY HAVE

7257
04:10:01,841 --> 04:10:04,710
TO IDENTIFY THE KEY CELL TYPES

7258
04:10:04,710 --> 04:10:07,580
WHERE SENESCENCE AND NF KB OR

7259
04:10:07,580 --> 04:10:09,448
INFLAMMATION ARE BEING ACTIVATED

7260
04:10:09,448 --> 04:10:09,949
AND THERE ARE DIFFERENT

7261
04:10:09,949 --> 04:10:11,183
APPROACHES WE CAN TAKE USING

7262
04:10:11,183 --> 04:10:12,518
TRANSGENIC MOUSE MODELS AS WELL

7263
04:10:12,518 --> 04:10:14,320
AS ADOPT A TRANSFER OF DIFFERENT

7264
04:10:14,320 --> 04:10:15,287
TYPES OF SENESCENT CELLS.

7265
04:10:15,287 --> 04:10:19,592
AND I THINK WE REALLY NEED TO

7266
04:10:19,592 --> 04:10:23,796
OPTIMIZE SENOMORPHIC AND

7267
04:10:23,796 --> 04:10:28,067
SENOLYTIC DRUGS -- TARGETING THE

7268
04:10:28,067 --> 04:10:29,602
KEY CELL TYPES RESPONSE IIBLE

7269
04:10:29,602 --> 04:10:39,178
RIBLE FOR DRRESPONSIBLE FORDRIV.

7270
04:10:39,178 --> 04:10:39,912
WITH THAT, I'LL STOP AND ANSWER

7271
04:10:39,912 --> 04:10:41,213
ANY QUESTIONS.

7272
04:10:41,213 --> 04:10:41,847
THANK YOU.

7273
04:10:41,847 --> 04:10:44,283
>> THANK YOU SO MUCH.

7274
04:10:44,283 --> 04:10:47,153
THAT WAS VERY, VERY INTERESTING

7275
04:10:47,153 --> 04:10:48,053
AND THOROUGH.

7276
04:10:48,053 --> 04:10:50,689
I THINK OUR FIRST QUESTION IS

7277
04:10:50,689 --> 04:10:55,094
ACTUALLY COMING FROM SVETLANA

7278
04:10:55,094 --> 04:10:56,429
ABOUT ADJUNCTIVE OR ADDITIVE

7279
04:10:56,429 --> 04:10:57,830
THERAPIES.

7280
04:10:57,830 --> 04:11:02,201
>> YES, SO MY COUPLE OF

7281
04:11:02,201 --> 04:11:03,469
QUESTIONS ARE HOW WE CAN

7282
04:11:03,469 --> 04:11:06,005
OPTIMIZE THE TIMING AND DURATION

7283
04:11:06,005 --> 04:11:09,942
OF SENOLYTIC AGENTS FOR MAXIMUM

7284
04:11:09,942 --> 04:11:12,211
BENEFIT IN AGE-RELATED DES AND

7285
04:11:12,211 --> 04:11:16,449
WHEDISEASESAND WHETHER WE CAN C-

7286
04:11:16,449 --> 04:11:17,049
SECOND PART OF THE QUESTION --

7287
04:11:17,049 --> 04:11:18,217
WHETHER WE CAN COMBINE

7288
04:11:18,217 --> 04:11:19,952
SENOLYTICS WITH OTHER POTENTIALS

7289
04:11:19,952 --> 04:11:25,391
LIKE EXERCISE -- CHANGES.

7290
04:11:25,391 --> 04:11:26,492
>> GREAT QUESTIONS.

7291
04:11:26,492 --> 04:11:27,993
I THINK -- I DON'T KNOW IF JIM

7292
04:11:27,993 --> 04:11:30,095
IS STILL ON, HE MIGHT BE ABLE TO

7293
04:11:30,095 --> 04:11:31,564
ANSWER THE ONE ABOUT TIMING.

7294
04:11:31,564 --> 04:11:33,098
I DON'T KNOW IF WE KNOW THE

7295
04:11:33,098 --> 04:11:34,333
RIGHT TIMING WHERE IF YOU DON'T

7296
04:11:34,333 --> 04:11:38,237
HAVE ACTIVATION OF NF KB OR

7297
04:11:38,237 --> 04:11:40,840
INCREASE IN CELL BURDEN, IT

7298
04:11:40,840 --> 04:11:42,174
MIGHT HAVE MINIMAL EFFECT SO WE

7299
04:11:42,174 --> 04:11:44,076
HAVE TO HAVE WAYS OF MEASURING

7300
04:11:44,076 --> 04:11:46,278
THESE CHANGES, A BIOMARKER THAT

7301
04:11:46,278 --> 04:11:47,713
CAN INCREASE ABSENCE OF

7302
04:11:47,713 --> 04:11:49,949
SENESCENCE WILL BE ABSOLUTELY

7303
04:11:49,949 --> 04:11:50,216
ESSENTIAL.

7304
04:11:50,216 --> 04:11:50,983
YOU DON'T WANT TO TREAT SOMEBODY

7305
04:11:50,983 --> 04:11:54,286
THAT HAS NO BURDEN WITH A

7306
04:11:54,286 --> 04:11:54,653
SENOLYTIC.

7307
04:11:54,653 --> 04:11:57,623
AND I THINK A COCKTAIL IS WHAT

7308
04:11:57,623 --> 04:11:57,990
WE END UP WITH.

7309
04:11:57,990 --> 04:11:59,592
IT'S NOT GOING TO BE ONE

7310
04:11:59,592 --> 04:12:02,728
SENOLYTIC OR SENOMORPHIC THAT

7311
04:12:02,728 --> 04:12:04,497
GOING TO I THINK CROSS THE

7312
04:12:04,497 --> 04:12:06,131
SPECTRUM OF ALL THE DIFFERENT

7313
04:12:06,131 --> 04:12:07,233
SENESCENT CELLS AS WELL AS

7314
04:12:07,233 --> 04:12:08,934
PENETRATE THE BRAIN AND OTHER

7315
04:12:08,934 --> 04:12:09,168
TISSUES.

7316
04:12:09,168 --> 04:12:09,835
SO I THINK WE'RE GOING TO HAVE

7317
04:12:09,835 --> 04:12:10,836
TO HAVE A COCKTAIL.

7318
04:12:10,836 --> 04:12:12,037
AND WHEN TO START THOSE

7319
04:12:12,037 --> 04:12:13,739
TREATMENTS WITH THOSE DIFFERENT

7320
04:12:13,739 --> 04:12:14,373
COMPONENTS OF THE COCKTAIL WILL

7321
04:12:14,373 --> 04:12:16,509
STILL HAVE TO BE DETERMINED

7322
04:12:16,509 --> 04:12:17,510
THROUGH FDA-APPROVED CLINICAL

7323
04:12:17,510 --> 04:12:18,844
TRIALS.

7324
04:12:18,844 --> 04:12:21,614
>> AND DO YOU THINK THERE
WILL

7325
04:12:21,614 --> 04:12:23,682
BE ADDITIVE THINGS TO SENOLYTICS

7326
04:12:23,682 --> 04:12:25,651
LIKE LIFESTYLE FACTORS OR --

7327
04:12:25,651 --> 04:12:28,053
>> OH, YES.

7328
04:12:28,053 --> 04:12:29,121
ABSOLUTELY.

7329
04:12:29,121 --> 04:12:32,858
IN FACT, LIFESTYLE FACTORS ARE

7330
04:12:32,858 --> 04:12:35,160
PROBABLY AS GOOD AS A LOT OF THE

7331
04:12:35,160 --> 04:12:35,628
SENOLYTICS WE HAVE.

7332
04:12:35,628 --> 04:12:37,129
IT'S BEEN SHOWN THEY REDUCE

7333
04:12:37,129 --> 04:12:37,429
SENESCENCE.

7334
04:12:37,429 --> 04:12:38,964
THE PROBLEM IS I WOULD ARGUE

7335
04:12:38,964 --> 04:12:40,399
100% OF AMERICANS ARE NOT GOING

7336
04:12:40,399 --> 04:12:42,868
TO BE EXERCISING, EATING WELL,

7337
04:12:42,868 --> 04:12:44,069
SLEEPING WELL AND DOING ALL THE

7338
04:12:44,069 --> 04:12:45,471
THINGS WE'RE SUPPOSED TO BE

7339
04:12:45,471 --> 04:12:47,406
DOING.

7340
04:12:47,406 --> 04:12:49,174
SO IT'S FOR THE 80% WHO CAN'T OR

7341
04:12:49,174 --> 04:12:50,242
DON'T THAT WE'RE TRYING TO

7342
04:12:50,242 --> 04:12:51,343
DEVELOP THESE DRUGS FOR.

7343
04:12:51,343 --> 04:12:52,311
>> FANTASTIC.

7344
04:12:52,311 --> 04:12:54,079
AND WE'RE GOING TO HEAR MORE

7345
04:12:54,079 --> 04:12:54,980
FROM LAURA AS WELL.

7346
04:12:54,980 --> 04:12:57,149
I HAD A QUESTION ALSO, IF

7347
04:12:57,149 --> 04:12:58,684
DR. KIRKLAND IS STILL ON.

7348
04:12:58,684 --> 04:13:01,620
ONE OF THE THINGS ABOUT THESE

7349
04:13:01,620 --> 04:13:02,721
SENESCENT CELLS IS THEY MAY BE

7350
04:13:02,721 --> 04:13:05,324
VERY IMPORTANT IN HOMEOSTASIS.

7351
04:13:05,324 --> 04:13:08,060
HAVE THERE BEEN LONG TERM

7352
04:13:08,060 --> 04:13:10,029
CHRONIC STUDIES, BECAUSE THERE'S

7353
04:13:10,029 --> 04:13:12,731
ALWAYS THE CONCERN THAT THIS

7354
04:13:12,731 --> 04:13:13,832
COULD LEAD TO DYSFUNCTION OF THE

7355
04:13:13,832 --> 04:13:16,502
IMMUNE SYSTEM AND IT'S ALWAYS

7356
04:13:16,502 --> 04:13:18,304
THE SECOND SIDE OF THE COIN WITH

7357
04:13:18,304 --> 04:13:21,540
THINGS LIKE CANCER.

7358
04:13:21,540 --> 04:13:23,208
SO HAS THAT BEEN KIND OF

7359
04:13:23,208 --> 04:13:23,642
EVALUATED YET?

7360
04:13:23,642 --> 04:13:26,478
IS THAT ONE OF THE AREAS OF

7361
04:13:26,478 --> 04:13:29,715
CONCERN THAT YOU HAVE WITH THESE

7362
04:13:29,715 --> 04:13:29,949
AGENTS?

7363
04:13:29,949 --> 04:13:31,317
>> ACTUALLY I'LL JUMP IN
FIRST.

7364
04:13:31,317 --> 04:13:33,619
I THINK THE DATA REALLY SUGGESTS

7365
04:13:33,619 --> 04:13:35,421
THAT CLEARING SENESCENT CELLS

7366
04:13:35,421 --> 04:13:38,824
DELAYS ONSET OF CANCER, BECAUSE

7367
04:13:38,824 --> 04:13:41,160
SENESCENT CELLS AND ANTICANCER

7368
04:13:41,160 --> 04:13:42,027
MECHANISM -- BREAK THROUGH

7369
04:13:42,027 --> 04:13:43,395
SENESCENCE LEAD TO CANCER, SO

7370
04:13:43,395 --> 04:13:46,365
THAT HASN'T BEEN A CONCERN.

7371
04:13:46,365 --> 04:13:48,934
YOU KNOW, LIFELONG TREATMENT, AT

7372
04:13:48,934 --> 04:13:52,972
LEAST IN MOUSE MODELS WITH THE

7373
04:13:52,972 --> 04:14:02,014
INITIAL D PLUS Q IF  F -- WE HAT

7374
04:14:02,014 --> 04:14:02,681
OBSERVED ANY AT LEAST WITH THE

7375
04:14:02,681 --> 04:14:03,882
END POINTS THAT HAVE BEEN

7376
04:14:03,882 --> 04:14:04,149
MEASURED.

7377
04:14:04,149 --> 04:14:05,184
>> I BELIEVE THERE WAS
ANOTHER

7378
04:14:05,184 --> 04:14:06,885
QUESTION ABOUT THE CLINICAL

7379
04:14:06,885 --> 04:14:10,856
TRIALS FROM DR. GEHLS, WONDERING

7380
04:14:10,856 --> 04:14:12,791
IF THERE WAS ANY RANDOMIZED OR

7381
04:14:12,791 --> 04:14:13,826
CLINICAL TRIALS FOR

7382
04:14:13,826 --> 04:14:15,027
CARDIOVASCULAR DISEASE.

7383
04:14:15,027 --> 04:14:16,128
AS SHE DIDN'T SEE IT ON THE

7384
04:14:16,128 --> 04:14:18,731
LIST, WHICH IS A MAJOR

7385
04:14:18,731 --> 04:14:20,966
AGE-RELATED DISEASE.

7386
04:14:20,966 --> 04:14:23,002
>> IF JIM IS STILL ON,
I'LL LET

7387
04:14:23,002 --> 04:14:23,869
HIM ANSWER THAT ONE.

7388
04:14:23,869 --> 04:14:24,837
I KNOW THERE'S DISCUSSION OF A

7389
04:14:24,837 --> 04:14:27,206
TRIAL STARTING AT THE MAYO

7390
04:14:27,206 --> 04:14:27,740
CLINIC.

7391
04:14:27,740 --> 04:14:31,944
JIM, CAN YOU --

7392
04:14:31,944 --> 04:14:34,880
>> HE MAY NOT BE ABLE TO
GET ON

7393
04:14:34,880 --> 04:14:38,250
BECAUSE HE'S IN HOLLAND.

7394
04:14:38,250 --> 04:14:39,985
>> ONE HASN'T STARTED BUT
IT'S

7395
04:14:39,985 --> 04:14:40,853
PLANNED AT THE MAYO CLINIC.

7396
04:14:40,853 --> 04:14:44,623
>> THIS ONE IS FROM ME.

7397
04:14:44,623 --> 04:14:45,824
BASICALLY IT WAS VERY

7398
04:14:45,824 --> 04:14:47,693
INTERESTING WITH KIND OF WILD

7399
04:14:47,693 --> 04:14:50,229
TYPE VERSUS DIRTY PET STORE, AND

7400
04:14:50,229 --> 04:14:53,098
THIS COMES BACK TO THE COVID

7401
04:14:53,098 --> 04:14:53,432
STUDY.

7402
04:14:53,432 --> 04:14:55,000
DO YOU THINK THIS HAS ANYTHING

7403
04:14:55,000 --> 04:14:58,604
TO DO WITH COVID SPECIFICALLY?

7404
04:14:58,604 --> 04:15:03,442
OR WILL ANY VIRAL INFECTION OR

7405
04:15:03,442 --> 04:15:04,643
ANY TYPE OF OVERWHELMING SEPSIS,

7406
04:15:04,643 --> 04:15:06,812
IT'S JUST THAT WE SAW SUCH A

7407
04:15:06,812 --> 04:15:08,714
LARGE NUMBER DURING THE

7408
04:15:08,714 --> 04:15:09,815
PANDEMIC, IS THIS ANY DIFFERENCE

7409
04:15:09,815 --> 04:15:13,018
THAN ARDS OR BEING ON ECMO OR

7410
04:15:13,018 --> 04:15:14,253
BEING INTUBATED FROM THE FLU,

7411
04:15:14,253 --> 04:15:15,921
FOR EXAMPLE, DO YOU THINK

7412
04:15:15,921 --> 04:15:17,356
THERE'S SOMETHING SPECIFIC THAT

7413
04:15:17,356 --> 04:15:19,258
IS PRO SENESCENT ABOUT COVID OR

7414
04:15:19,258 --> 04:15:20,726
DO YOU THINK THAT IT'S JUST WE

7415
04:15:20,726 --> 04:15:21,760
HAVE THIS HUGE POPULATION THAT

7416
04:15:21,760 --> 04:15:25,397
WE'RE NOW STUDYING?

7417
04:15:25,397 --> 04:15:26,699
>> THERE'S BEEN REPORTS
THAT

7418
04:15:26,699 --> 04:15:28,300
COVID ACTUALLY CAUSES DNA DAMAGE

7419
04:15:28,300 --> 04:15:29,101
AND THAT MIGHT CONTRIBUTE TO

7420
04:15:29,101 --> 04:15:30,436
DRIVING SENESCENCE.

7421
04:15:30,436 --> 04:15:35,074
OUR DATA SUGGESTS THAT MAYBE AN

7422
04:15:35,074 --> 04:15:35,708
INFLAMMATORY RESPONSE DRIVES THE

7423
04:15:35,708 --> 04:15:36,175
SECONDARY SENESCENCE.

7424
04:15:36,175 --> 04:15:38,043
BUT HAVING SAID THAT, WE HAVE A

7425
04:15:38,043 --> 04:15:40,979
COLLEAGUE, SCOTT BUDDING EV R AT

7426
04:15:40,979 --> 04:15:42,314
NORTHWESTERN WHO'S LOOKING AT

7427
04:15:42,314 --> 04:15:44,049
THE EFFECT OF FLU INDUCING THESE

7428
04:15:44,049 --> 04:15:45,551
SAME FACTORS AND HE THINKS THAT

7429
04:15:45,551 --> 04:15:47,352
ALL VIRUSES OR MOST PATHOGENS

7430
04:15:47,352 --> 04:15:48,787
WILL HAVE A SIMILAR EFFECT.

7431
04:15:48,787 --> 04:15:50,556
THAT MAYBE THE MAGNITUDE IS

7432
04:15:50,556 --> 04:15:51,890
DIFFERENT, BUT I THINK THEY'LL

7433
04:15:51,890 --> 04:15:53,759
ALL CONTRIBUTE TO DRIVING NOT

7434
04:15:53,759 --> 04:15:55,060
ONLY IMMUNE EXHAUSTION BUT ALSO

7435
04:15:55,060 --> 04:15:58,464
SENESCENCE.

7436
04:15:58,464 --> 04:15:59,732
>> FANTASTIC.

7437
04:15:59,732 --> 04:16:01,066
A LOT OF THE COVID TRIALS DON'T

7438
04:16:01,066 --> 04:16:03,469
HAVE NON-COVID INFECTED DISEASE

7439
04:16:03,469 --> 04:16:05,437
MATCHED CONTROLS, AND THAT IS --

7440
04:16:05,437 --> 04:16:05,704
>> RIGHT.

7441
04:16:05,704 --> 04:16:07,239
>>  -- THE LIMITATIONS OF
SOME

7442
04:16:07,239 --> 04:16:08,140
OF THOSE STUDIES.

7443
04:16:08,140 --> 04:16:10,209
I DON'T SEE ANY OTHER QUESTIONS

7444
04:16:10,209 --> 04:16:11,710
IN THE CHAT.

7445
04:16:11,710 --> 04:16:13,112
GO AHEAD, PAUL.

7446
04:16:13,112 --> 04:16:14,680
>> IF I COULD JUST THROW
IN, I

7447
04:16:14,680 --> 04:16:16,582
THINK THAT THERE'S DATA AND JIM

7448
04:16:16,582 --> 04:16:18,550
COULD COMMENT ON IF HE WAS STILL

7449
04:16:18,550 --> 04:16:20,085
ON THAT LONG COVID PATIENTS HAVE

7450
04:16:20,085 --> 04:16:21,620
AN INCREASE IN SENESCENCE.

7451
04:16:21,620 --> 04:16:24,089
AND SO THE QUESTION IS, IS

7452
04:16:24,089 --> 04:16:25,190
WHETHER LONG COVID COULD BE

7453
04:16:25,190 --> 04:16:27,059
TREATED PARTIALLY USING

7454
04:16:27,059 --> 04:16:27,392
SENOLYTICS.

7455
04:16:27,392 --> 04:16:29,094
SO THAT'S ANOTHER AREA OF

7456
04:16:29,094 --> 04:16:30,596
INVESTIGATION.

7457
04:16:30,596 --> 04:16:31,563
>> FANTASTIC.

7458
04:16:31,563 --> 04:16:32,765
AND I THINK WE ARE OUT OF TIME,

7459
04:16:32,765 --> 04:16:34,800
SO WE ARE GOING TO NOW MOVE ON

7460
04:16:34,800 --> 04:16:37,202
TO LAURA.

7461
04:16:37,202 --> 04:16:39,705
LAURA, I BELIEVE YOU ARE UP

7462
04:16:39,705 --> 04:16:49,815
NEXT.

7463
04:16:54,486 --> 04:16:56,121
SHE'S GOING TO BE TALKING ABOUT

7464
04:16:56,121 --> 04:16:57,556
EXOGENOUS MEDIATORS OF CELLULAR

7465
04:16:57,556 --> 04:16:59,525
SENESCENCE.

7466
04:16:59,525 --> 04:17:09,668
HIT IT!

7467
04:17:16,141 --> 04:17:16,842
LAURA, YOU'RE MUTED.

7468
04:17:16,842 --> 04:17:18,477
WE HAVE TO SAY THAT AT LEAST

7469
04:17:18,477 --> 04:17:20,245
ONCE IN EVERY BIG ZOOM MEETING.

7470
04:17:20,245 --> 04:17:21,380
LAURA, I THINK YOU ARE STILL

7471
04:17:21,380 --> 04:17:31,490
MUTED.

7472
04:17:34,593 --> 04:17:35,627
I THINK WE WILL BE TALKING A

7473
04:17:35,627 --> 04:17:38,730
LITTLE BIT ABOUT PATHOGENS AND

7474
04:17:38,730 --> 04:17:39,932
OTHER THINGS AS WELL IN THE

7475
04:17:39,932 --> 04:17:40,933
DISCUSSION, SO HOPEFULLY YOU'LL

7476
04:17:40,933 --> 04:17:43,235
ALL STAY ON AFTER THIS SESSION

7477
04:17:43,235 --> 04:17:46,271
TO BE PART OF THE PANEL.

7478
04:17:46,271 --> 04:17:47,339
LAURA, I BELIEVE YOU'RE NOW OFF

7479
04:17:47,339 --> 04:17:47,773
MUTE.

7480
04:17:47,773 --> 04:17:48,173
HIT IT.

7481
04:17:48,173 --> 04:17:48,574
>> GREAT.

7482
04:17:48,574 --> 04:17:49,541
THANK YOU.

7483
04:17:49,541 --> 04:17:51,543
I APOLOGIZE FOR THAT.

7484
04:17:51,543 --> 04:17:52,211
DIDN'T MEAN TO THROW A MONKEY

7485
04:17:52,211 --> 04:17:53,512
WRENCH IN YOUR TIMING HERE, BUT

7486
04:17:53,512 --> 04:17:54,613
I ONLY HAVE ONE ARM.

7487
04:17:54,613 --> 04:17:57,282
SO IF I FALL OFF MY CHAIR, OR

7488
04:17:57,282 --> 04:17:58,617
ANYTHING STRANGE HAPPENS, PLEASE

7489
04:17:58,617 --> 04:18:00,018
CARRY ON WITHOUT ME.

7490
04:18:00,018 --> 04:18:02,254
SO YEAH, I'M GOING TO EXPAND ON

7491
04:18:02,254 --> 04:18:03,589
A COUPLE OF TOPICS THAT BOTH

7492
04:18:03,589 --> 04:18:05,457
PAUL AND DR. KIRKLAND HIT ON AND

7493
04:18:05,457 --> 04:18:07,125
JUST TO TRY AND MAKE OTHER

7494
04:18:07,125 --> 04:18:08,660
POINTS AND IDEALLY PROVOKE SOME

7495
04:18:08,660 --> 04:18:09,428
MORE CONVERSATION DURING THE

7496
04:18:09,428 --> 04:18:10,195
PANEL DISCUSSION AT THE END OF

7497
04:18:10,195 --> 04:18:18,503
THE DAY.

7498
04:18:18,503 --> 04:18:25,677
SO I'M GOING TO START WITH MY

7499
04:18:25,677 --> 04:18:27,446
RATIONALE FOR FOCUSING ON

7500
04:18:27,446 --> 04:18:29,748
CELLULAR SENESCENCE, AS BOTH JIM

7501
04:18:29,748 --> 04:18:31,884
AND PAUL VERY WELL JUSTIFIED,

7502
04:18:31,884 --> 04:18:33,752
BUT I'VE ALWAYS SPENT MY CAREER

7503
04:18:33,752 --> 04:18:35,187
VERY INTERESTED IN THE HEALTH

7504
04:18:35,187 --> 04:18:37,789
IMPACT OF ENDOGENOUS DNA DAMAGE.

7505
04:18:37,789 --> 04:18:40,659
SO DNA DAMAGE, WE CAUSE THROUGH

7506
04:18:40,659 --> 04:18:43,829
NORMAL METABOLISM AND NORMAL

7507
04:18:43,829 --> 04:18:45,197
HUMAN EXPOSURES.

7508
04:18:45,197 --> 04:18:47,065
SO WE START FROM A VANTAGE POINT

7509
04:18:47,065 --> 04:18:48,734
OF THERE.

7510
04:18:48,734 --> 04:18:49,067
 THIS.

7511
04:18:49,067 --> 04:18:51,270
WE KNOW THIS IS A POTENT DRIVER

7512
04:18:51,270 --> 04:18:52,638
OF CELLULAR SENESCENCE, AND THEN

7513
04:18:52,638 --> 04:18:54,506
WE'VE LED TO ATTACKING CELLULAR

7514
04:18:54,506 --> 04:18:56,975
SENESCENCE WITH DRUGS.

7515
04:18:56,975 --> 04:19:03,548
SO PART OF MY INTEREST IN THIS

7516
04:19:03,548 --> 04:19:07,252
COMES FROM THINKING ABOUT

7517
04:19:07,252 --> 04:19:09,488
GEROTHERAPEUTIC -- I WANT TO

7518
04:19:09,488 --> 04:19:12,324
GIVE A SHOUT OUT TO THOSE

7519
04:19:12,324 --> 04:19:13,759
CHAMPIONING THIS APPROACH OF

7520
04:19:13,759 --> 04:19:16,361
TARGETING FUNDAMENTAL BIOLOGY OF

7521
04:19:16,361 --> 04:19:17,429
AGING AND NOT INDIVIDUAL HALL

7522
04:19:17,429 --> 04:19:19,498
MARKS NECESSARILY BUT

7523
04:19:19,498 --> 04:19:20,265
FUNDAMENTAL AGING BIOLOGY

7524
04:19:20,265 --> 04:19:21,800
BECAUSE I THINK THAT'S GOING TO

7525
04:19:21,800 --> 04:19:22,968
BE MORE PRODUCTIVE THAN

7526
04:19:22,968 --> 04:19:25,304
TARGETING ANY PARTICULAR

7527
04:19:25,304 --> 04:19:33,011
AGE-RELATED DISEASE TRAJECTORY.

7528
04:19:33,011 --> 04:19:34,980
SO THE REASON WE FOCUSED ON

7529
04:19:34,980 --> 04:19:35,847
SENESCENCE IS WHEN WE LOOK

7530
04:19:35,847 --> 04:19:38,850
ACROSS TISSUES OF AGED WILD TYPE

7531
04:19:38,850 --> 04:19:40,085
MICE, WHICH IS SHOWN HERE IN A

7532
04:19:40,085 --> 04:19:43,021
HEAT MAP FOR P16 MESSENGER RNA,

7533
04:19:43,021 --> 04:19:45,557
WE SEE EVIDENCE OF SENESCENCE IN

7534
04:19:45,557 --> 04:19:48,260
MANY, MANY TISSUES.

7535
04:19:48,260 --> 04:19:50,462
AND WHAT'S INTRIGUING TO US IS

7536
04:19:50,462 --> 04:19:52,297
THESE DNA REPAIR-DEFICIENT MICE

7537
04:19:52,297 --> 04:19:54,566
THAT PAUL IS USING IN HIS

7538
04:19:54,566 --> 04:19:56,034
STUDIES, THEY ACTUALLY HAVE A

7539
04:19:56,034 --> 04:19:58,170
VERY SIMILAR HEAT MAP TO NATURAL

7540
04:19:58,170 --> 04:19:59,204
AGING.

7541
04:19:59,204 --> 04:20:01,006
SO I WOULD LIKE TO THINK OF THIS

7542
04:20:01,006 --> 04:20:02,975
AS EVIDENCE THAT ENDOGENOUS DNA

7543
04:20:02,975 --> 04:20:05,610
DAMAGE IS ONE OF THE POTENT

7544
04:20:05,610 --> 04:20:08,213
DRIVERS OF CELLULAR SENESCENCE

7545
04:20:08,213 --> 04:20:09,614
IN VIVO UNDER NORMAL PHYSIOLOGIC

7546
04:20:09,614 --> 04:20:10,382
CONDITIONS.

7547
04:20:10,382 --> 04:20:15,587
THIS IS WORK OF MATT

7548
04:20:15,587 --> 04:20:17,022
YOUSEFZADEH, FACULTY MEMBER AND

7549
04:20:17,022 --> 04:20:17,456
COLUMBIA.

7550
04:20:17,456 --> 04:20:19,124
HE REALLY TORE THE MICE APART

7551
04:20:19,124 --> 04:20:20,559
AND LOOKED AT DIFFERENT MEASURES

7552
04:20:20,559 --> 04:20:21,259
OF SENESCENCE.

7553
04:20:21,259 --> 04:20:22,594
THEY ALWAYS MATCHED NORMAL,

7554
04:20:22,594 --> 04:20:24,730
AGING AND WILD TYPE MICE.

7555
04:20:24,730 --> 04:20:27,733
SO ANOTHER KEY STUDY FROM NED

7556
04:20:27,733 --> 04:20:28,900
SHARPLESS THAT REALLY GOT MY

7557
04:20:28,900 --> 04:20:30,469
ATTENTION AS WELL IS, HE SHOWED

7558
04:20:30,469 --> 04:20:32,070
WELL OVER A DECADE AGO THAT P16

7559
04:20:32,070 --> 04:20:35,107
GOES UP IN HUMANS AS THEY AGE.

7560
04:20:35,107 --> 04:20:37,275
SO THIS IS SHOWING JUST HIS

7561
04:20:37,275 --> 04:20:40,245
ASSAY OF MEASURING P16 MESSENGER

7562
04:20:40,245 --> 04:20:42,714
RNA IN PERIPHERAL BLOOD

7563
04:20:42,714 --> 04:20:43,682
CD3 POSITIVE CELLS, AND YOU SEE

7564
04:20:43,682 --> 04:20:45,884
IT GO UP EXPONENTIALLY WITH

7565
04:20:45,884 --> 04:20:47,552
EVERY DECADE OF LIFE.

7566
04:20:47,552 --> 04:20:50,022
BUT IMPORTANTLY, NED SHOWED IN

7567
04:20:50,022 --> 04:20:52,357
THE SAME EXACT PAPER THAT

7568
04:20:52,357 --> 04:20:53,325
THEY'RE ALSO MODIFIABLE.

7569
04:20:53,325 --> 04:20:56,528
SO THIS IS SHOWING SAME MEASURE

7570
04:20:56,528 --> 04:20:57,262
OF P16 MESSENGER RNA, BUT YOU

7571
04:20:57,262 --> 04:20:59,765
SEE THAT SMOKERS IN THE ORANGE

7572
04:20:59,765 --> 04:21:01,400
CURVE ACTUALLY HAVE A GREATER

7573
04:21:01,400 --> 04:21:02,901
SLOPE WHEREAS EXERCISES CAN

7574
04:21:02,901 --> 04:21:03,869
REDUCE THAT SLOPE.

7575
04:21:03,869 --> 04:21:12,911
SO THIS GIVES US A GER

7576
04:21:12,911 --> 04:21:15,414
GEROTHERAPEUTIC TARGET THAT WE

7577
04:21:15,414 --> 04:21:16,681
CAN BE THOUGHTFUL.

7578
04:21:16,681 --> 04:21:17,949
I WANTED TO COVER FOUR TOPICS

7579
04:21:17,949 --> 04:21:19,518
BEING AND THIS IS LARGELY THE

7580
04:21:19,518 --> 04:21:21,820
WORK OF OTHER FOLKS SO CANCER

7581
04:21:21,820 --> 04:21:23,388
THERAPY, INFECTIOUS DISEASE,

7582
04:21:23,388 --> 04:21:26,324
PSYCHOSOCIAL STRESS, AND ORGAN

7583
04:21:26,324 --> 04:21:26,691
TRANSPLANTATION.

7584
04:21:26,691 --> 04:21:28,226
SO I'M GOING TO START WITH

7585
04:21:28,226 --> 04:21:29,428
CANCER THERAPY, AND THIS IS THE

7586
04:21:29,428 --> 04:21:33,465
WORK OF BESHAY ZORDOKY, WHO'S AT

7587
04:21:33,465 --> 04:21:37,602
THE UNIVERSITY OF MINNESOTA.

7588
04:21:37,602 --> 04:21:41,873
AND HE -- BEFORE I JUMP INTO HIS

7589
04:21:41,873 --> 04:21:42,774
WORK, LET ME MAKE ONE OTHER

7590
04:21:42,774 --> 04:21:43,642
COMMENT.

7591
04:21:43,642 --> 04:21:44,776
TO THIS GROUP, BECAUSE I THINK

7592
04:21:44,776 --> 04:21:46,511
THIS IS FOOD FOR THOUGHT TOO.

7593
04:21:46,511 --> 04:21:47,879
I THINK WE HAVE TO BE THINKING

7594
04:21:47,879 --> 04:21:49,881
ABOUT HEALTH TRAJECTORIES OF

7595
04:21:49,881 --> 04:21:52,084
DISEASE SURVIVORS, AND NOT JUST

7596
04:21:52,084 --> 04:21:52,484
CANCER SURVIVORS.

7597
04:21:52,484 --> 04:21:53,752
AND THE REASON I BRING THIS UP

7598
04:21:53,752 --> 04:21:57,322
IS I'M GETTING ASKED TO RUN

7599
04:21:57,322 --> 04:21:58,790
CLINICAL TRIALS BY PEDIATRICIANS

7600
04:21:58,790 --> 04:22:00,292
IN EVERY DISCIPLINE YOU CAN

7601
04:22:00,292 --> 04:22:00,759
IMAGINE.

7602
04:22:00,759 --> 04:22:03,261
IN RESPONSE TO YOUR QUESTION,

7603
04:22:03,261 --> 04:22:04,763
LOUISE, WE'RE PLANNING ONE IN

7604
04:22:04,763 --> 04:22:06,598
SEPSIS USING A SENOLYTIC, SO IT

7605
04:22:06,598 --> 04:22:09,634
WILL BE ALLCOMERS OF INFECTIOUS

7606
04:22:09,634 --> 04:22:10,035
DISEASE BASICALLY.

7607
04:22:10,035 --> 04:22:11,837
BUT WHAT WE'VE NOTICED IS

7608
04:22:11,837 --> 04:22:13,371
PATIENTS WITH RARE GENOME

7609
04:22:13,371 --> 04:22:14,473
INSTABILITY DISORDERS KIND OF

7610
04:22:14,473 --> 04:22:17,843
LIKE OUR MICE, THEY ARE LIVING

7611
04:22:17,843 --> 04:22:19,811
UNPRECEDENTED LIFESPANS, AND

7612
04:22:19,811 --> 04:22:22,114
THEY'RE AGING VERY QUICKLY.

7613
04:22:22,114 --> 04:22:24,483
THERE'S CLEARLY METABOLIC

7614
04:22:24,483 --> 04:22:27,219
DISORDERS THAT DRIVE MORE RAPID

7615
04:22:27,219 --> 04:22:30,288
AGING, AND AS JIM HIT ON,

7616
04:22:30,288 --> 04:22:31,957
TRANSPLANTATION HAS NEGATIVE

7617
04:22:31,957 --> 04:22:33,225
EFFECTS ON YOUR HEALTH

7618
04:22:33,225 --> 04:22:33,658
TRAJECTORY.

7619
04:22:33,658 --> 04:22:35,727
AS DOES TREATMENT IN CHILDHOOD

7620
04:22:35,727 --> 04:22:37,362
WITH CANCER KEEM THERAPEUTICS.

7621
04:22:37,362 --> 04:22:39,097
SO THE POINT OF ALL OF THIS IS

7622
04:22:39,097 --> 04:22:40,732
JUST THAT I THINK WE'RE ACTUALLY

7623
04:22:40,732 --> 04:22:42,701
UNDERESTIMATING THE CHALLENGES

7624
04:22:42,701 --> 04:22:43,902
WE ARE FACING WITH AGING

7625
04:22:43,902 --> 04:22:44,169
BIOLOGY.

7626
04:22:44,169 --> 04:22:45,370
IT'S NOT JUST OLD PEOPLE, BUT A

7627
04:22:45,370 --> 04:22:48,807
LOT OF DISEASE SURVIVORS.

7628
04:22:48,807 --> 04:22:50,242
AND I THINK THIS ALSO PROVIDES A

7629
04:22:50,242 --> 04:22:52,310
WINDOW OF OPPORTUNITY FOR

7630
04:22:52,310 --> 04:22:53,044
SPECIALIZED CLINICAL TRIALS AS

7631
04:22:53,044 --> 04:22:56,548
JIM ELEGANTLY POINTED OUT.

7632
04:22:56,548 --> 04:22:58,517
SO THIS IS THE WORK OF BESHAY

7633
04:22:58,517 --> 04:23:01,753
AND HE WAS USING HUMAN

7634
04:23:01,753 --> 04:23:02,387
ENDOTHELIAL CELLS, TREATING THEM

7635
04:23:02,387 --> 04:23:05,690
WITH A CANCER CHEMOTHERAPEUTIC

7636
04:23:05,690 --> 04:23:06,691
AGENT DOCKS REUB SON AND

7637
04:23:06,691 --> 04:23:08,026
MEASURING SENESCENCE IN A

7638
04:23:08,026 --> 04:23:08,727
VARIETY OF DIFFERENT WAYS.

7639
04:23:08,727 --> 04:23:11,997
THIS IS JUST AN EXAMPLE OF

7640
04:23:11,997 --> 04:23:15,333
MEASURING BETA GLAK TA CYDASE

7641
04:23:15,333 --> 04:23:16,768
ACTIVITY WHICH GOES UP

7642
04:23:16,768 --> 04:23:19,738
SIGNIFICANTLY AND AT THE PROTEIN

7643
04:23:19,738 --> 04:23:23,875
LEVEL, STABLE EXHAUSTION OF P53,

7644
04:23:23,875 --> 04:23:27,379
P21, CYCLIN D1.

7645
04:23:27,379 --> 04:23:30,882
HE SHOWS THAT ALSO THIS CANCER

7646
04:23:30,882 --> 04:23:33,685
CAME IN -- OTHER EVIDENCE OF

7647
04:23:33,685 --> 04:23:36,121
CELLULAR SENESCENCE LIKE THESE

7648
04:23:36,121 --> 04:23:40,725
SCAPs.

7649
04:23:40,725 --> 04:23:42,394
SO OBVIOUSLY THERE'S AN

7650
04:23:42,394 --> 04:23:44,963
ABUNDANCE OF EVIDENCE THAT

7651
04:23:44,963 --> 04:23:45,931
CHEMOTHERAPEUTICS DRIVE

7652
04:23:45,931 --> 04:23:47,232
ACCELERATED AGING, THEY WORSEN

7653
04:23:47,232 --> 04:23:49,534
YOUR HEALTH TRAJECTORY, BUT I

7654
04:23:49,534 --> 04:23:50,368
WOULD ARGUE THAT HAS ANYTHING TO

7655
04:23:50,368 --> 04:23:53,038
DO WITH YOUR EXPOSOME THAT

7656
04:23:53,038 --> 04:23:56,641
HAS -- THAT TOUCHES ON GINO GENC

7657
04:23:56,641 --> 04:23:56,875
STRESS.

7658
04:23:56,875 --> 04:23:57,542
SO THERE'S LOTS OF OTHER THINGS

7659
04:23:57,542 --> 04:23:58,777
WE SHOULD BE THINKING ABOUT IN

7660
04:23:58,777 --> 04:24:00,845
OUR ENVIRONMENT, INCLUDING EVEN

7661
04:24:00,845 --> 04:24:04,649
SOME DIETARY SUPPLEMENTS AS WELL

7662
04:24:04,649 --> 04:24:07,285
AS ADDITIVES.

7663
04:24:07,285 --> 04:24:08,820
SO JUMPING BACK ON THE

7664
04:24:08,820 --> 04:24:13,491
INFECTIOUS DISEASE STORY, I WANT

7665
04:24:13,491 --> 04:24:15,260
TO FIRST ACKNOWLEDGE THOSE WHO

7666
04:24:15,260 --> 04:24:18,330
CONTRIBUTED TO THIS COVID-19

7667
04:24:18,330 --> 04:24:19,531
STORY.

7668
04:24:19,531 --> 04:24:21,266
JIM, PAUL, CHRISTINA AND MATT.

7669
04:24:21,266 --> 04:24:23,235
SO AS WAS INTRODUCED, WE ARE

7670
04:24:23,235 --> 04:24:26,738
COMBINING THESE PRISTINE NIA

7671
04:24:26,738 --> 04:24:28,607
AGED WILD TYPE MICE WITH PET

7672
04:24:28,607 --> 04:24:31,209
STORE MICE TO GIVE THEM A MORE

7673
04:24:31,209 --> 04:24:35,046
HUMANIZED IMMUNE SYSTEM OR

7674
04:24:35,046 --> 04:24:36,815
NORMAL MICROBIAL EXPERIENCE.

7675
04:24:36,815 --> 04:24:38,617
THESE STUDIES ARE VERY TRICKY

7676
04:24:38,617 --> 04:24:39,351
BECAUSE ALL THE OLD MICE DIED

7677
04:24:39,351 --> 04:24:40,452
VERY RAPIDLY.

7678
04:24:40,452 --> 04:24:44,889
AS PAUL SHOWED YOU THAT MHV IS

7679
04:24:44,889 --> 04:24:46,258
THE AGENT THAT SEEMS TO BE

7680
04:24:46,258 --> 04:24:48,159
KILLING THE OLD WILD TYPE MICE

7681
04:24:48,159 --> 04:24:49,594
BECAUSE JUST BEFORE THEIR DEATH

7682
04:24:49,594 --> 04:24:52,530
AT TWO WEEKS, THAT'S THE ONLY

7683
04:24:52,530 --> 04:24:53,632
ANTIBODY WE FIND IN THEIR SERUM

7684
04:24:53,632 --> 04:24:54,966
DESPITE THE PET STORE MICE

7685
04:24:54,966 --> 04:24:56,401
CARRYING A WHOLE BUNCH OF

7686
04:24:56,401 --> 04:24:58,336
DIFFERENT MICROBES.

7687
04:24:58,336 --> 04:25:01,640
THE ANIMALS GET PATHOGNOMIC

7688
04:25:01,640 --> 04:25:03,275
IMAGE STAINING LESIONS,

7689
04:25:03,275 --> 04:25:05,677
POSITIVELY FOR HEPATITIS VIRUS,

7690
04:25:05,677 --> 04:25:07,379
AS WELL AS SHOWING THESE LARGE

7691
04:25:07,379 --> 04:25:08,146
SIN SI SHA IN THE LIVER.

7692
04:25:08,146 --> 04:25:10,448
SO THE POINT I WANT TO MAKE IS

7693
04:25:10,448 --> 04:25:12,784
THIS IS A FECAL-ORAL

7694
04:25:12,784 --> 04:25:13,118
TRANSMISSION.

7695
04:25:13,118 --> 04:25:14,919
SO THIS IS CLEARLY SOMETHING

7696
04:25:14,919 --> 04:25:16,321
WHERE THE MICROBIOME OF YOUR GUT

7697
04:25:16,321 --> 04:25:18,757
IS TIED IN, AND THERE'S ALL SORT

7698
04:25:18,757 --> 04:25:20,025
OF EXPOSURES THAT WE NOW KNOW

7699
04:25:20,025 --> 04:25:21,826
CAN REALLY ACCELERATE YOUR

7700
04:25:21,826 --> 04:25:24,396
AGING.

7701
04:25:24,396 --> 04:25:26,264
SO THE IMMUNOLOGISTS IN OUR

7702
04:25:26,264 --> 04:25:28,333
GROUP VACCINATED OUR ANIMALS

7703
04:25:28,333 --> 04:25:29,534
AGAINST MHV, AND THIS WAS

7704
04:25:29,534 --> 04:25:31,836
ADEQUATE TO RESCUE 100% OF THE

7705
04:25:31,836 --> 04:25:34,239
OLD WILD TYPE MICE AS SHOWN IN

7706
04:25:34,239 --> 04:25:34,673
BLUE.

7707
04:25:34,673 --> 04:25:38,576
SO IT REALLY SHOWS THAT MHV WAS

7708
04:25:38,576 --> 04:25:41,313
THE DEADLY KILLER, AND THEN THIS

7709
04:25:41,313 --> 04:25:42,847
IS THE EXPOSURES THROUGH THE GUT

7710
04:25:42,847 --> 04:25:43,748
BASICALLY.

7711
04:25:43,748 --> 04:25:47,118
PLAWSH SO AS PAUL SHOWED YOU, WE

7712
04:25:47,118 --> 04:25:48,720
ARE ABLE TO RESCUE THESE

7713
04:25:48,720 --> 04:25:50,488
ANIMALS, THE OLD WILD TYPE MICE

7714
04:25:50,488 --> 04:25:54,092
THAT ARE EXPOSED TO NME EITHER

7715
04:25:54,092 --> 04:25:55,627
WITH THE MAYO CLINIC GENETIC

7716
04:25:55,627 --> 04:25:57,595
OPPORTUNITY TO CLEAR SENESCENT

7717
04:25:57,595 --> 04:26:03,768
CELLS, OR WITH EITHER -- PLUS

7718
04:26:03,768 --> 04:26:09,674
THE FLAVONOID FESETIN.

7719
04:26:09,674 --> 04:26:12,077
THIS IS AGAIN GOING BACK TO

7720
04:26:12,077 --> 04:26:13,411
BESHAY'S WORK WHERE HE

7721
04:26:13,411 --> 04:26:15,480
CHALLENGED HIS CELLS IN VITRO

7722
04:26:15,480 --> 04:26:21,052
WITH LPS, SO BACTERIAL PAMP, AND

7723
04:26:21,052 --> 04:26:23,221
DOES SO EITHER IN SENESCENT

7724
04:26:23,221 --> 04:26:26,725
CELLS EXPOSED TO DOCKS REUB SON,

7725
04:26:26,725 --> 04:26:28,326
VEHICLE-TREATED CELLS OR CELLS

7726
04:26:28,326 --> 04:26:30,862
THAT GOT BOTH DOCKS REUB SON AND

7727
04:26:30,862 --> 04:26:31,629
METFORMIN.

7728
04:26:31,629 --> 04:26:34,366
WHAT'S INTERESTING TO SEE IS

7729
04:26:34,366 --> 04:26:37,569
THIS PRO INFLAMMATORY CHEMO

7730
04:26:37,569 --> 04:26:39,104
TRACK TIN FOAS THROUGH THE ROOF

7731
04:26:39,104 --> 04:26:40,772
PARTICULARLY IN SENESCENT CELLS

7732
04:26:40,772 --> 04:26:44,609
AS DOES P21 AND THIS ACTIVATED

7733
04:26:44,609 --> 04:26:44,943
NF KB.

7734
04:26:44,943 --> 04:26:47,312
SO THAT'S JUST QUANTITATED IN

7735
04:26:47,312 --> 04:26:50,014
THE THREE GRAPHS HERE WHERE YOU

7736
04:26:50,014 --> 04:26:52,350
SEE A SIGNIFICANT INCREASE IN

7737
04:26:52,350 --> 04:26:59,691
THE RED HATCHED BARS IN THE

7738
04:26:59,691 --> 04:27:02,427
DOXORUBICIN -- CHALLENGED WITH

7739
04:27:02,427 --> 04:27:02,594
LPS.

7740
04:27:02,594 --> 04:27:05,196
IF YOU USE A GEROTHERAPEUTIC,

7741
04:27:05,196 --> 04:27:09,100
IT'S NOT NECESSARILY TACKING ATG

7742
04:27:09,100 --> 04:27:12,036
SENESCENT CELLS, IT'S MORE A

7743
04:27:12,036 --> 04:27:13,671
SENOMORPHIC WHICH IS ALTERING

7744
04:27:13,671 --> 04:27:14,239
THE INFLAMMATORY RESPONSE.

7745
04:27:14,239 --> 04:27:16,174
SO BACK TO THIS FIGURE THAT JIM

7746
04:27:16,174 --> 04:27:17,375
SHOWED, WHAT WE THINK IS GOING

7747
04:27:17,375 --> 04:27:23,081
ON IS, IN A VIRAL INFECTION,

7748
04:27:23,081 --> 04:27:24,949
BACTERIAL INFECTION, IF YOU HAVE

7749
04:27:24,949 --> 04:27:26,050
SENESCENT CELLS BECAUSE YOU'RE

7750
04:27:26,050 --> 04:27:30,054
OLDER, THEN THIS LEADS TO DIRECT

7751
04:27:30,054 --> 04:27:31,389
IMPABLGHT ON HOW YOUR BODY

7752
04:27:31,389 --> 04:27:32,457
RESPONDS TO THAT VIRUS.

7753
04:27:32,457 --> 04:27:34,859
SO THERE'S UPREGULATION OF VIRAL

7754
04:27:34,859 --> 04:27:39,597
ENTRY PROTEINS, LOSS OF

7755
04:27:39,597 --> 04:27:40,665
ANTIVIRAL ACTIVITY.

7756
04:27:40,665 --> 04:27:42,200
THIS ALSO AFFECTS ADAPTIVE

7757
04:27:42,200 --> 04:27:44,936
IMMUNITY, AND NOW THERE IS

7758
04:27:44,936 --> 04:27:47,772
ABUNDANT EVIDENCE THAT VIRAL

7759
04:27:47,772 --> 04:27:49,541
INFECTION DIRECTLY INDUCES

7760
04:27:49,541 --> 04:27:50,208
ADDITIONAL DNA DAMAGE.

7761
04:27:50,208 --> 04:28:00,752
THIS IS WORK OF FABRIZIO DABDA,

7762
04:28:02,754 --> 04:28:03,888
VIRUS INFECTION WILL DRIVE

7763
04:28:03,888 --> 04:28:05,156
ADDITIONAL SENESCENCE, AND I

7764
04:28:05,156 --> 04:28:05,924
THINK WE HAVE MORE WORK TO

7765
04:28:05,924 --> 04:28:09,027
FIGURE OUT IF THERE'S FOREVER OR

7766
04:28:09,027 --> 04:28:10,028
A TRANSIENT PHASE.

7767
04:28:10,028 --> 04:28:11,696
SO THAT'S A GAP IN KNOWLEDGE FOR

7768
04:28:11,696 --> 04:28:13,164
SURE.

7769
04:28:13,164 --> 04:28:14,165
I THINK THIS IS REALLY

7770
04:28:14,165 --> 04:28:15,166
INTERESTING AND HAS NOT BEEN

7771
04:28:15,166 --> 04:28:16,768
BROUGHT UP YET AT THIS MEETING.

7772
04:28:16,768 --> 04:28:20,839
THIS IS THE WORK OF ALESSANDRO

7773
04:28:20,839 --> 04:28:21,973
BARTOLOMUCCI, ALSO AT THE

7774
04:28:21,973 --> 04:28:22,607
UNIVERSITY OF MINNESOTA, AND HE

7775
04:28:22,607 --> 04:28:24,142
GOT A DIRECTOR'S GRANT AT ONE

7776
04:28:24,142 --> 04:28:26,978
POINT TO STUDY THE EFFECT OF

7777
04:28:26,978 --> 04:28:29,347
PSYCHOSOCIAL STRESS ON AGING

7778
04:28:29,347 --> 04:28:29,681
PHENOTYPES.

7779
04:28:29,681 --> 04:28:32,650
SO WHAT HE DOES IS HE ACTUALLY

7780
04:28:32,650 --> 04:28:35,353
TAKES A REALLY AGGRESSIVE STRAIN

7781
04:28:35,353 --> 04:28:40,091
OF MICE, LETS IT -- PHYSICALLY

7782
04:28:40,091 --> 04:28:42,527
WITH KIND OF A WIMPY MOUSE

7783
04:28:42,527 --> 04:28:43,728
THAT'S SUBORDINATE, SO THESE

7784
04:28:43,728 --> 04:28:44,896
ANIMALS FIGHT IT OUT FOR A

7785
04:28:44,896 --> 04:28:45,897
PERIOD OF TIME, AND THEN THEY

7786
04:28:45,897 --> 04:28:47,332
ACTUALLY GET SEPARATED BUT SO

7787
04:28:47,332 --> 04:28:49,200
THAT THEY CAN SEE EACH OTHER

7788
04:28:49,200 --> 04:28:50,568
THROUGH PLEXIGLASS FOR THE REST

7789
04:28:50,568 --> 04:28:53,771
OF THEIR LIFE.

7790
04:28:53,771 --> 04:28:54,739
ALESSANDRO HAS BEEN ABLE TO GO

7791
04:28:54,739 --> 04:28:56,074
ON AND SHOW THAT THIS IS ENOUGH

7792
04:28:56,074 --> 04:29:00,044
TO SHORTEN THE SUBORDINATE

7793
04:29:00,044 --> 04:29:00,812
ANIMAL'S LIFESPAN.

7794
04:29:00,812 --> 04:29:05,316
IT MAKES THEM MORE PRONE TO

7795
04:29:05,316 --> 04:29:07,185
ALZHEIMER'S PATHOLOGY, AFFECTS

7796
04:29:07,185 --> 04:29:08,520
HEALTHSPAN, THE EPIGENETIC

7797
04:29:08,520 --> 04:29:08,720
CLOCK.

7798
04:29:08,720 --> 04:29:09,787
IT'S REALLY UNUSUAL BECAUSE SOME

7799
04:29:09,787 --> 04:29:11,122
OF THESE SUBORDINATE MICE WILL

7800
04:29:11,122 --> 04:29:13,825
ACTUALLY DIE OF CARDIOVASCULAR

7801
04:29:13,825 --> 04:29:14,592
DISEASE BUT IN THE ABSENCE OF A

7802
04:29:14,592 --> 04:29:19,664
HIGH FAT DIET OR ANY SORT OF

7803
04:29:19,664 --> 04:29:22,200
PECULIAR MANIPULATION.

7804
04:29:22,200 --> 04:29:23,601
SO REALLY A POTENT STRESSOR OF

7805
04:29:23,601 --> 04:29:24,736
ATTENUATING YOUR HEALTH

7806
04:29:24,736 --> 04:29:26,804
TRAJECTORY FOR SURE.

7807
04:29:26,804 --> 04:29:28,139
SO WHEN WE LOOK AT CELL

7808
04:29:28,139 --> 04:29:29,440
SENESCENCE IN THESE ANIMALS,

7809
04:29:29,440 --> 04:29:31,376
THIS IS USING THE NED SHARPLESS

7810
04:29:31,376 --> 04:29:35,680
ASSAY IN P BMCs, HE SEES P16

7811
04:29:35,680 --> 04:29:37,549
MESSENGER RNA GO UP AND IN A

7812
04:29:37,549 --> 04:29:38,416
REALLY SHORT PERIOD OF TIME

7813
04:29:38,416 --> 04:29:39,617
ACTUALLY, AND IF YOU QUANTIFY

7814
04:29:39,617 --> 04:29:42,020
THIS, YOU SEE THAT IT'S ALSO

7815
04:29:42,020 --> 04:29:42,353
PROGRESSIVE.

7816
04:29:42,353 --> 04:29:45,723
THIS IS LOOKING AT A HEAT MAP OF

7817
04:29:45,723 --> 04:29:47,492
P16 AND P21 IN A VARIETY OF

7818
04:29:47,492 --> 04:29:49,160
DIFFERENT TISSUES, AND I'D LIKE

7819
04:29:49,160 --> 04:29:53,231
TO POINT YOUR ATTENTION TO WHITE

7820
04:29:53,231 --> 04:29:54,532
ADIPOSE TISSUE, SO THIS IS

7821
04:29:54,532 --> 04:29:59,470
REALLY A STRONG RESPONDER TO

7822
04:29:59,470 --> 04:30:03,608
PSYCHOSOCIAL STRESS, AND SO THAT

7823
04:30:03,608 --> 04:30:06,144
ALSO, I THINK, ILLUMINATES THE

7824
04:30:06,144 --> 04:30:08,212
POSSIBILITY THAT THE STRESS PLUS

7825
04:30:08,212 --> 04:30:09,547
OBESITY OR METABOLIC SYNDROME

7826
04:30:09,547 --> 04:30:11,349
COULD BE PARTICULARLY HAZARDOUS.

7827
04:30:11,349 --> 04:30:13,651
SO I WANTED TO TOUCH BACK ON

7828
04:30:13,651 --> 04:30:14,185
TRANSPLANTATION.

7829
04:30:14,185 --> 04:30:18,690
AGAIN, THE WORK OF STEFFAN

7830
04:30:18,690 --> 04:30:19,557
TULLIUS AT HARVARD.

7831
04:30:19,557 --> 04:30:21,659
HE WAS ABLE TO SHOW THAT

7832
04:30:21,659 --> 04:30:23,361
DENDRITIC CELLS WHICH MODIFY THE

7833
04:30:23,361 --> 04:30:25,063
RESPONSE TO A TRANSPLANTED ORGAN

7834
04:30:25,063 --> 04:30:28,866
ACTUALLY HAVE AN EFFECT ON

7835
04:30:28,866 --> 04:30:31,169
OUTCOME, AND THIS IS IN A MODEL

7836
04:30:31,169 --> 04:30:31,869
OF CARDIAC TRANSPLANT.

7837
04:30:31,869 --> 04:30:33,838
SO WHAT HE DID WAS HE

7838
04:30:33,838 --> 04:30:37,508
TRANSPLANTED EITHER OLD OR YOUNG

7839
04:30:37,508 --> 04:30:38,409
DENDRITIC CELLS INTO RECIPIENT

7840
04:30:38,409 --> 04:30:39,310
MICE, THEN THEY DID THE

7841
04:30:39,310 --> 04:30:39,844
TRANSPLANT.

7842
04:30:39,844 --> 04:30:42,880
SO YOU SEE THE OLD MICE GETTING

7843
04:30:42,880 --> 04:30:44,449
OLD CELLS IN ORANGE.

7844
04:30:44,449 --> 04:30:47,385
BUT LOOK HOW THAT HAS SHIFTED IF

7845
04:30:47,385 --> 04:30:49,120
YOU GIVE THEM YOUNG DENDRITIC

7846
04:30:49,120 --> 04:30:50,021
CELLS.

7847
04:30:50,021 --> 04:30:51,189
SO YOU GET A MUCH HEALTHIER

7848
04:30:51,189 --> 04:30:54,792
RESPONSE TO THIS CH CHALLENGE OF

7849
04:30:54,792 --> 04:30:57,996
ORGAN TRANSPLANT.

7850
04:30:57,996 --> 04:31:01,399
SO STEFAN THINKS A LOT OF THIS

7851
04:31:01,399 --> 04:31:03,267
HAS TO DO WITH CELLULAR

7852
04:31:03,267 --> 04:31:03,935
SENESCENCE THAT'S PARTICULARLY

7853
04:31:03,935 --> 04:31:07,739
DRIVEN BY THIS MY TOE PLASMIC

7854
04:31:07,739 --> 04:31:13,344
DNA, AND IN FACT -- THINKS THAT

7855
04:31:13,344 --> 04:31:14,445
MITOCHONDRIAL DNA IS A KEY

7856
04:31:14,445 --> 04:31:16,914
DRIVER OF CELLULAR SENESCENCE,

7857
04:31:16,914 --> 04:31:18,049
YOU REALLY DON'T SEE MUCH

7858
04:31:18,049 --> 04:31:19,384
SENESCENCE OR SASP AT ALL.

7859
04:31:19,384 --> 04:31:22,654
SO IN THIS DATA, STEFAN SEES A

7860
04:31:22,654 --> 04:31:25,823
LOT OF MY T MITOCHONDRIAL DNA IN

7861
04:31:25,823 --> 04:31:27,859
OLDER DONORS IN THEIR PLASMA, SO

7862
04:31:27,859 --> 04:31:28,660
THIS IS USING TWO DIFFERENT

7863
04:31:28,660 --> 04:31:29,193
MARKERS.

7864
04:31:29,193 --> 04:31:30,828
SO THIS MIGHT HAVE SOMETHING TO

7865
04:31:30,828 --> 04:31:31,029
DO --

7866
04:31:31,029 --> 04:31:32,664
>> DOCTOR, YOU HAVE TWO
MINUTE

7867
04:31:32,664 --> 04:31:32,930
REMAINING.

7868
04:31:32,930 --> 04:31:33,498
>> THANK YOU VERY MUCH.

7869
04:31:33,498 --> 04:31:35,233
SO THIS MAY HAVE A LOT TO DO

7870
04:31:35,233 --> 04:31:38,036
WITH THE AGE CAP, BUT AS JIM

7871
04:31:38,036 --> 04:31:41,706
QUICKLY ALSO POINTED OUT, OTHER

7872
04:31:41,706 --> 04:31:43,141
PLACES WHERE THEY'RE ACTUALLY

7873
04:31:43,141 --> 04:31:45,143
PERFUSING ORGANS, THERE'S AN

7874
04:31:45,143 --> 04:31:46,511
OPPORTUNITY, I THINK, TO REALLY

7875
04:31:46,511 --> 04:31:47,945
TUNE UP THESE AGED ORGANS SO

7876
04:31:47,945 --> 04:31:50,815
THAT WE CAN HAVE HEALTHIER

7877
04:31:50,815 --> 04:31:51,616
OUTCOMES.

7878
04:31:51,616 --> 04:31:54,018
SO VERY QUICKLY AGAIN BACK TO

7879
04:31:54,018 --> 04:31:56,020
THE NED SHARPLESS ASSAY, WE ARE

7880
04:31:56,020 --> 04:31:56,654
FULL OF SENESCENT IMMUNE CELLS

7881
04:31:56,654 --> 04:32:01,225
AS WE GET TO CERTAIN AGES, AND

7882
04:32:01,225 --> 04:32:03,428
AS PAUL ALLUDED TO, WE SHOWED A

7883
04:32:03,428 --> 04:32:05,797
COUPLE YEARS AGO THAT IMMUNE

7884
04:32:05,797 --> 04:32:08,166
CELLS FROM AGED DONORS ARE VERY

7885
04:32:08,166 --> 04:32:08,633
DELETERIOUS.

7886
04:32:08,633 --> 04:32:10,401
SO THIS IS SORT OF CLIP CHAR

7887
04:32:10,401 --> 04:32:11,736
EXPERIMENT WHERE WE'RE DOING

7888
04:32:11,736 --> 04:32:16,207
ADOPTIVE TRANSFER OF SPLENOCYTES

7889
04:32:16,207 --> 04:32:17,542
FROM MUTANT ANIMALS WHERE WEE

7890
04:32:17,542 --> 04:32:24,248
DRIVEN SENESCENCE ONLY IN THE

7891
04:32:24,248 --> 04:32:25,983
HEMATOPOIETIC SYSTEM, DOCTOR WE

7892
04:32:25,983 --> 04:32:35,193
PUT T -- WE PUTTHEM IN A P16 RE,

7893
04:32:35,193 --> 04:32:35,860
MONITORED OUTCOMES AND WE FOUND

7894
04:32:35,860 --> 04:32:39,897
THAT THESE TRANSPLANTED

7895
04:32:39,897 --> 04:32:41,332
SPLENOCYTES COULD DRIVE

7896
04:32:41,332 --> 04:32:42,200
SENESCENCE THAT LASTED AT LEAST

7897
04:32:42,200 --> 04:32:43,534
FIVE WEEKS TO THE RECIPIENT

7898
04:32:43,534 --> 04:32:43,768
ANIMALS.

7899
04:32:43,768 --> 04:32:45,236
WE PROBABLY SHOULD GO BACK AND

7900
04:32:45,236 --> 04:32:46,637
DO LONGER TIME POINTS.

7901
04:32:46,637 --> 04:32:50,374
SO P21 IS ALSO ELEVATED -- I

7902
04:32:50,374 --> 04:32:52,777
WANTED TO POINT TO THE BRAIN TO

7903
04:32:52,777 --> 04:32:53,344
HIGHLIGHT MIRANDA'S WORK AS

7904
04:32:53,344 --> 04:32:53,544
WELL.

7905
04:32:53,544 --> 04:32:54,579
WE ARE SEEING A TON OF

7906
04:32:54,579 --> 04:32:55,346
SENESCENCE IN THE BRAIN OF

7907
04:32:55,346 --> 04:32:55,646
ANIMALS.

7908
04:32:55,646 --> 04:32:58,082
SO THIS IS JUST P16 MESSENGER

7909
04:32:58,082 --> 04:33:00,585
RNA IN WILD TYPE 2-YEAR-OLD AND

7910
04:33:00,585 --> 04:33:01,252
3-YEAR-OLD ANIMALS.

7911
04:33:01,252 --> 04:33:02,987
SO YOU CAN SEE THE LEVELS ARE

7912
04:33:02,987 --> 04:33:04,989
JUST THROUGH THE ROOF.

7913
04:33:04,989 --> 04:33:07,325
SASP IS ALSO HIGH, SO IN CASE WE

7914
04:33:07,325 --> 04:33:08,893
DIDN'T COVER IT, I JUST WANTED

7915
04:33:08,893 --> 04:33:09,827
TO SAY THERE'S NO DOUBT IN MY

7916
04:33:09,827 --> 04:33:11,896
MIND THAT CENTRAL NERVOUS SYSTEM

7917
04:33:11,896 --> 04:33:13,765
CELLULAR SENESCENCE IS A HUGE

7918
04:33:13,765 --> 04:33:16,734
DRIVER OF NEURODEGENERATION.

7919
04:33:16,734 --> 04:33:18,136
SO I THINK ALL OF THESE ARE

7920
04:33:18,136 --> 04:33:20,238
MODULATORS OF HEALTH

7921
04:33:20,238 --> 04:33:21,405
TRAJECTORIES, CANCER THERAPY,

7922
04:33:21,405 --> 04:33:22,173
ANY EXPOSURE FROM YOUR

7923
04:33:22,173 --> 04:33:23,941
ENVIRONMENT THAT GIVES YOU DNA

7924
04:33:23,941 --> 04:33:26,544
DAMAGE, ENVIRONMENTAL MICROBES,

7925
04:33:26,544 --> 04:33:27,745
PSYCHOSOCIAL STRESS, ORGAN

7926
04:33:27,745 --> 04:33:28,946
TRANSPLANT, BUT IT IS BETTER TO

7927
04:33:28,946 --> 04:33:31,048
BE ALIVE THAN DEAD, SO WE WANT

7928
04:33:31,048 --> 04:33:32,483
TO GIVE -- YOU KNOW, WE HAVE TO

7929
04:33:32,483 --> 04:33:33,985
TREAT PEOPLE BUT WE HAVE TO BE

7930
04:33:33,985 --> 04:33:36,621
THINKING ABOUT THEIR HEALTH

7931
04:33:36,621 --> 04:33:37,221
TRAJECTORIES FOR BEYOND WHAT'S

7932
04:33:37,221 --> 04:33:40,091
GOING ON WITH IMMEDIATE

7933
04:33:40,091 --> 04:33:40,491
EMERGENCY.

7934
04:33:40,491 --> 04:33:43,327
SO WE DID A VERY QUICK STUDY

7935
04:33:43,327 --> 04:33:44,896
WHERE WE WERE LOOKING AT

7936
04:33:44,896 --> 04:33:45,329
TRANSPLANT PATIENTS.

7937
04:33:45,329 --> 04:33:49,934
THIS IS THE WORK OF KIRCHNER AND

7938
04:33:49,934 --> 04:33:50,501
MILLER.

7939
04:33:50,501 --> 04:33:52,270
WHAT'S INTERESTING IS THE NED

7940
04:33:52,270 --> 04:33:53,571
SHARPLESS ASSAY ACTUALLY SHOWS A

7941
04:33:53,571 --> 04:33:54,438
SIGNIFICANT CORRELATION WITH

7942
04:33:54,438 --> 04:33:56,207
FRAILTY AND LENGTH OF STAY IN

7943
04:33:56,207 --> 04:33:58,075
THE HOSPITAL, BUT ACTUALLY HAD

7944
04:33:58,075 --> 04:34:00,144
NOTHING TO DO WITH THE

7945
04:34:00,144 --> 04:34:01,045
SERIOUSNESS OF THE LIVER DISEASE

7946
04:34:01,045 --> 04:34:02,947
OR THE CHRONOLOGIC AGE OF

7947
04:34:02,947 --> 04:34:04,882
INDIVIDUALS.

7948
04:34:04,882 --> 04:34:06,184
SO I THINK THERE'S A LOT TO BE

7949
04:34:06,184 --> 04:34:07,618
DONE IN THIS ASSAY.

7950
04:34:07,618 --> 04:34:09,821
INTERESTINGLY, A LOT OF THE

7951
04:34:09,821 --> 04:34:12,123
ONGOING CLINICAL TRIALS ARE

7952
04:34:12,123 --> 04:34:13,257
TARGETING THESE HALL MARKS OF

7953
04:34:13,257 --> 04:34:14,425
AGING AND NOT THE PRIMARY ONES,

7954
04:34:14,425 --> 04:34:17,929
AND I WOULD ARGUE THAT IT'S

7955
04:34:17,929 --> 04:34:18,462
BECAUSE THOSE ARE REALLY

7956
04:34:18,462 --> 04:34:19,730
DIFFICULT TO MEASURE, THEY'RE

7957
04:34:19,730 --> 04:34:24,302
TIGHTLY REGULATED, THEY'RE

7958
04:34:24,302 --> 04:34:26,737
EVOLUTION AIRILY HIGHLY

7959
04:34:26,737 --> 04:34:27,939
OPTIMIZED, I THINK IF YOU

7960
04:34:27,939 --> 04:34:28,906
OVERSHOOT CORRECTION IT WILL

7961
04:34:28,906 --> 04:34:30,441
HAVE VERY NEGATIVE CONSEQUENCES.

7962
04:34:30,441 --> 04:34:32,243
SO WE NEED MEASURABLE RISK

7963
04:34:32,243 --> 04:34:33,211
FACTORS AS MANY PEOPLE HAVE

7964
04:34:33,211 --> 04:34:33,744
TALKED ABOUT.

7965
04:34:33,744 --> 04:34:38,282
JUST A QUICK PLUG FOR A PAPER

7966
04:34:38,282 --> 04:34:42,253
FR,THERE'S A LOT OF FDA-APPROVED

7967
04:34:42,253 --> 04:34:44,121
DRUGS OUT THERE THAT REALLY

7968
04:34:44,121 --> 04:34:47,291
AFFECT HEALTHSPAN, LIFESPAN,

7969
04:34:47,291 --> 04:34:47,792
MULTIPLE ORGAN SYSTEMS.

7970
04:34:47,792 --> 04:34:49,927
WE'VE GOT A TON OF DATA IN

7971
04:34:49,927 --> 04:34:51,128
PRE-CLINICAL MODELS, EVEN IN

7972
04:34:51,128 --> 04:34:52,029
HUMANS.

7973
04:34:52,029 --> 04:34:53,865
SO I WOULD ARGUE WHAT WE NEED IS

7974
04:34:53,865 --> 04:34:55,099
MORE CLINICAL TRIALS, AND I WAS

7975
04:34:55,099 --> 04:34:58,936
GOING TO GIVE A SHOUT OUT TO PLN

7976
04:34:58,936 --> 04:34:59,704
MIRANDA, BECAUSE YOU JUST HAVE

7977
04:34:59,704 --> 04:35:00,338
TO BE BOLD.

7978
04:35:00,338 --> 04:35:03,074
THIS IS NOT A HUGE TRIAL, IT'S

7979
04:35:03,074 --> 04:35:04,075
GETTING INTO A GREAT JOURNAL AND

7980
04:35:04,075 --> 04:35:05,610
IT'S MOVING THE NEEDLE, SO I

7981
04:35:05,610 --> 04:35:06,477
WOULD ARGUE FOR MORE OF THIS.

7982
04:35:06,477 --> 04:35:09,247
THANK YOU VERY MUCHMENT

7983
04:35:09,247 --> 04:35:11,215
>> THANK YOU, LAURA, THANK
YOU

7984
04:35:11,215 --> 04:35:12,750
SO VERY MUCH FOR SUCH A

7985
04:35:12,750 --> 04:35:13,484
FASCINATING TALK.

7986
04:35:13,484 --> 04:35:15,786
SO IN ORDER FOR US TO REMAIN ON

7987
04:35:15,786 --> 04:35:19,390
TIME, I WOULD ASK DR. STEWART TO

7988
04:35:19,390 --> 04:35:21,158
TURN ON HER CAMERA AND GET

7989
04:35:21,158 --> 04:35:23,461
STARTED.

7990
04:35:23,461 --> 04:35:24,896
IN THE INTEREST OF TIME.

7991
04:35:24,896 --> 04:35:26,430
THANK YOU.

7992
04:35:26,430 --> 04:35:27,832
>> AND WE WILL HAVE TIME
FOR

7993
04:35:27,832 --> 04:35:29,033
QUESTION AND ANSWERS AND

7994
04:35:29,033 --> 04:35:31,235
DISCUSSION IN THE PANEL.

7995
04:35:31,235 --> 04:35:37,575
>> ABSOLUTELY.

7996
04:35:37,575 --> 04:35:45,917
YOU'RE UNMUTED.

7997
04:35:45,917 --> 04:35:46,784
YOU ARE MUTED.

7998
04:35:46,784 --> 04:35:47,785
STILL MUTED.

7999
04:35:47,785 --> 04:35:49,420
>> THERE.

8000
04:35:49,420 --> 04:35:49,620
OKAY.

8001
04:35:49,620 --> 04:35:50,721
>> GOOD, GOOD, GOOD.

8002
04:35:50,721 --> 04:35:52,590
>> YOU WOULD THINK AFTER
THIS

8003
04:35:52,590 --> 04:35:54,525
LONG IN DOING THIS, WE'D ALL

8004
04:35:54,525 --> 04:35:55,393
REMEMBER.

8005
04:35:55,393 --> 04:35:57,128
BUT LAURA, YOU AND I GET THE

8006
04:35:57,128 --> 04:35:58,129
PRIZE FOR THIS, RIGHT?

8007
04:35:58,129 --> 04:35:59,263
OKAY.

8008
04:35:59,263 --> 04:36:04,101
SO I WANT TO THANK EVERYONE FOR

8009
04:36:04,101 --> 04:36:05,069
THE INVITATION, EVERYONE FOR

8010
04:36:05,069 --> 04:36:07,038
STAYING ON.

8011
04:36:07,038 --> 04:36:13,878
HOPEFULLY YOU CAN ALL SEE THIS.

8012
04:36:13,878 --> 04:36:17,915
ARE WE GOOD?

8013
04:36:17,915 --> 04:36:19,016
YOU COMPLETELY SET ME UP AND I

8014
04:36:19,016 --> 04:36:20,751
DON'T HAVE TO DO A LOT OF

8015
04:36:20,751 --> 04:36:21,052
BACKGROUND.

8016
04:36:21,052 --> 04:36:22,586
I'M ACTUALLY GOING TO FOCUS ON

8017
04:36:22,586 --> 04:36:23,654
REALLY OUR THOUGHTS ABOUT THIS

8018
04:36:23,654 --> 04:36:29,126
IN RELATION TO CANCER.

8019
04:36:29,126 --> 04:36:29,694
USING SOMETHING JAMES WILL

8020
04:36:29,694 --> 04:36:30,661
PROBABLY SHOW LATER WHEN HE

8021
04:36:30,661 --> 04:36:32,797
TALKS, I DON'T HAVE TO REALLY

8022
04:36:32,797 --> 04:36:34,332
CONVINCE EVERYBODY, I THINK AGE

8023
04:36:34,332 --> 04:36:35,399
REMAINS THE LARGEST RISK FACTOR

8024
04:36:35,399 --> 04:36:36,600
FOR THE DEVELOPMENT OF CANCER.

8025
04:36:36,600 --> 04:36:38,402
AND WHEN ONE SEES THIS TYPE OF A

8026
04:36:38,402 --> 04:36:39,370
GRAPH, YOU HAVE TO TAKE THAT

8027
04:36:39,370 --> 04:36:40,438
STEP BACK AND ASK YOURSELF, WHAT

8028
04:36:40,438 --> 04:36:42,740
IS IT ABOUT AGING THAT DRIVES

8029
04:36:42,740 --> 04:36:44,408
NOT A SUBTLE BUT AN INCREDIBLY

8030
04:36:44,408 --> 04:36:46,077
RAPID INCREASE IN THE FIFTH TO

8031
04:36:46,077 --> 04:36:47,111
SIXTH DECADE OF LIFE.

8032
04:36:47,111 --> 04:36:49,146
AND YOU KNOW, IT'S OBVIOUSLY

8033
04:36:49,146 --> 04:36:50,181
GOING TO BE A COMPLICATED

8034
04:36:50,181 --> 04:36:52,049
ANSWER.

8035
04:36:52,049 --> 04:36:54,185
CANCER IS A DISEASE OR DISEASES

8036
04:36:54,185 --> 04:36:54,819
OF MULTIPLE MUTATIONS, AND IN

8037
04:36:54,819 --> 04:36:56,687
THE FACE OF ROBUST DNA REPAIR

8038
04:36:56,687 --> 04:36:57,288
MECHANISMS THAT HAVE ALREADY

8039
04:36:57,288 --> 04:37:01,459
BEEN DISCUSSED TODAY, IT'S GOING

8040
04:37:01,459 --> 04:37:02,727
TO TAKE TIME NOT JUST TO GET

8041
04:37:02,727 --> 04:37:03,694
MUTATIONS BUT THAT RIGHT

8042
04:37:03,694 --> 04:37:05,496
COCKTAIL OF MUTATIONS THAT

8043
04:37:05,496 --> 04:37:06,397
DRIVES A NORMAL CELL TO THAT

8044
04:37:06,397 --> 04:37:07,264
FULLY TRANSFORMED STATE.

8045
04:37:07,264 --> 04:37:08,566
BUT WE REALLY BECAME INTERESTED

8046
04:37:08,566 --> 04:37:09,967
IN THIS QUESTION WHEN WE STARTED

8047
04:37:09,967 --> 04:37:11,469
THINKING ABOUT A REALLY

8048
04:37:11,469 --> 04:37:12,436
INTERESTING PAPER THAT WAS

8049
04:37:12,436 --> 04:37:14,505
PUBLISHED NOW NEARLY TWO DECADES

8050
04:37:14,505 --> 04:37:17,408
AGO BY JUDY CAMPESE IN WHICH SHE

8051
04:37:17,408 --> 04:37:18,809
NOTED THAT SENESCENT CELLS WHICH

8052
04:37:18,809 --> 04:37:21,746
WE NOWAK LATE IN TISSUES ACROSS

8053
04:37:21,746 --> 04:37:22,780
AGE, YOU'VE HEARD QUITE A FEW

8054
04:37:22,780 --> 04:37:24,081
TALKS ABOUT THAT ALREADY TODAY,

8055
04:37:24,081 --> 04:37:26,951
BUT THAT THESE CELLS WHEN WE

8056
04:37:26,951 --> 04:37:27,551
THINK ABOUT THE STROMAL

8057
04:37:27,551 --> 04:37:30,254
COMPARTMENT, THE NON-TUMOR

8058
04:37:30,254 --> 04:37:32,790
CELLS, IF YOU WILL, SENESCENT

8059
04:37:32,790 --> 04:37:35,226
CELLS WERE ABLE TO RECAPITULATE

8060
04:37:35,226 --> 04:37:36,527
EVERY PHENOTYPE THAT HAD BEEN

8061
04:37:36,527 --> 04:37:38,329
ASCRIBED TO A CANCER ASSOCIATED

8062
04:37:38,329 --> 04:37:40,097
FIBROBLAST IN THEIR ABILITY TO

8063
04:37:40,097 --> 04:37:42,833
DRIVE TUMOR CELL PROLIFERATION,

8064
04:37:42,833 --> 04:37:45,136
MIGRATION INVASION, ALTER

8065
04:37:45,136 --> 04:37:46,103
ANGIOGENESIS AND ALSO TO REALLY

8066
04:37:46,103 --> 04:37:48,372
SET UP IMMUNOSUPPRESSIVE AREAS,

8067
04:37:48,372 --> 04:37:50,541
IF YOU WILL, AROUND TUMOR CELLS.

8068
04:37:50,541 --> 04:37:54,145
AND SO THIS DATA HAD BEEN OUT

8069
04:37:54,145 --> 04:37:55,579
THERE AND TRANSPLANT TYPES AND

8070
04:37:55,579 --> 04:37:56,747
JE NEIGHBORING STUDIES BUT I

8071
04:37:56,747 --> 04:37:58,282
THINK SOME OF THE BEST DATA TO

8072
04:37:58,282 --> 04:38:00,051
REALLY ARGUE THAT THESE CELLS

8073
04:38:00,051 --> 04:38:01,118
ARE IMPORTANT AND ALSO IN ANSWER

8074
04:38:01,118 --> 04:38:03,054
TO LUIS'S QUESTION EARLIER ON

8075
04:38:03,054 --> 04:38:05,523
WAS A PAPER THAT CAME OUT FROM

8076
04:38:05,523 --> 04:38:09,693
DARREN BAKER BACK IN 2016, WHERE

8077
04:38:09,693 --> 04:38:15,866
USING THE  INK ATTAC MOUSE,

8078
04:38:15,866 --> 04:38:16,834
YOU'RE ABLE TO INDUCE BLI KILL

8079
04:38:16,834 --> 04:38:18,069
SENESCENT CELLS WIDELY ACROSS

8080
04:38:18,069 --> 04:38:19,470
THE ANIMAL, IT DIDN'T MATTER IF

8081
04:38:19,470 --> 04:38:21,005
UR WERE MALE, DIDN'T MATTER IF

8082
04:38:21,005 --> 04:38:22,339
YOU WERE FEMALE, IT DIDN'T

8083
04:38:22,339 --> 04:38:23,841
MATTER IF UR WERE ON A PURE

8084
04:38:23,841 --> 04:38:25,276
BACKGROUND OR A MORE DOCILE

8085
04:38:25,276 --> 04:38:27,545
MIXED BACKGROUND AS LAURA JUST

8086
04:38:27,545 --> 04:38:33,250
INFORMED ME, SIMPLY BY

8087
04:38:33,250 --> 04:38:33,651
ILLUMINATING HE?

8088
04:38:33,651 --> 04:38:37,488
SEPTEMBER CELLS YOU WERE ABLE TO

8089
04:38:37,488 --> 04:38:39,490
SIGNIFICANTLY DELAY THE ONSET OF

8090
04:38:39,490 --> 04:38:39,824
TUMORIGENESIS.

8091
04:38:39,824 --> 04:38:41,692
IT DOES INDICATE THAT THESE

8092
04:38:41,692 --> 04:38:42,159
CELLS ARE IMPORTANT.

8093
04:38:42,159 --> 04:38:43,127
HOWEVER, I WILL REMIND YOU THESE

8094
04:38:43,127 --> 04:38:45,096
ARE NOT YOUR PET STORE MICE,

8095
04:38:45,096 --> 04:38:47,998
HAVING MORE HETEROGENEITY AND

8096
04:38:47,998 --> 04:38:48,966
DIFFERENT MICROBIOMES MIGHT

8097
04:38:48,966 --> 04:38:50,067
AFFECT THIS, WE JUST DON'T KNOW.

8098
04:38:50,067 --> 04:38:55,039
SO THE QUESTION IS, HOW DO THESE

8099
04:38:55,039 --> 04:38:56,440
CANCER ASSOCIATED FIBROBLASTS,

8100
04:38:56,440 --> 04:38:58,509
HOW DO THEY DO SO MANY DIFFERENT

8101
04:38:58,509 --> 04:39:01,278
THINGS IN THE CONTEXT OF

8102
04:39:01,278 --> 04:39:01,612
TUMORIGENESIS?

8103
04:39:01,612 --> 04:39:03,247
THE SASP OR THE SENESCENCE

8104
04:39:03,247 --> 04:39:04,682
ASSOCIATED SECRETORY PHENOTYPE

8105
04:39:04,682 --> 04:39:05,883
HAS ALSO ALREADY BEEN

8106
04:39:05,883 --> 04:39:06,317
INTRODUCED.

8107
04:39:06,317 --> 04:39:07,785
IN SHORT FROM THE CANCER

8108
04:39:07,785 --> 04:39:08,986
UNIVERSE, THEY MAKE EVERYTHING

8109
04:39:08,986 --> 04:39:09,887
YUMMY YOU CAN IMAGINE IF YOU

8110
04:39:09,887 --> 04:39:12,022
WANT TO BE A TUMOR CELL, THEY

8111
04:39:12,022 --> 04:39:13,057
CAN DRIVE PROLIFERATION THROUGH

8112
04:39:13,057 --> 04:39:19,196
THE EXPRESSION OF M MITOGENS,

8113
04:39:19,196 --> 04:39:21,932
SECRETE NUMEROUS FACTORS -- CAN

8114
04:39:21,932 --> 04:39:24,802
GREATLY CHANGE TRANSFORMATION

8115
04:39:24,802 --> 04:39:26,637
PROCESSES, AND THEY MAKE A LARGE

8116
04:39:26,637 --> 04:39:29,039
CADRE OF INFLAMMATORY CYTOKINES,

8117
04:39:29,039 --> 04:39:30,474
OF COURSE THE SECOND LARGEST

8118
04:39:30,474 --> 04:39:35,980
RISK FAR T FACTOR AFTER GETTINGS

8119
04:39:35,980 --> 04:39:37,214
CHRONIC INFLAMMATION.

8120
04:39:37,214 --> 04:39:39,316
AND SO WE GOT INTERESTED QUITE

8121
04:39:39,316 --> 04:39:40,618
SOME YEARS AGO IN TRYING TO

8122
04:39:40,618 --> 04:39:42,820
MODULATE SPECIFICALLY THE

8123
04:39:42,820 --> 04:39:48,225
STROMAL COMPARTMENT AND ASK HOW

8124
04:39:48,225 --> 04:39:49,960
DO THESE CELLS INFLUENCE

8125
04:39:49,960 --> 04:39:50,961
DIFFERENT COMPONENTS, DIFFERENT

8126
04:39:50,961 --> 04:39:52,363
STEPS IN THE TRANSFORMATION

8127
04:39:52,363 --> 04:39:53,397
PROCESS?

8128
04:39:53,397 --> 04:39:54,031
I'M GOING TO TRY TO GIVE YOU A

8129
04:39:54,031 --> 04:39:54,932
FLAVOR OF HOW WE THINK ABOUT

8130
04:39:54,932 --> 04:39:57,268
THESE CELLS.

8131
04:39:57,268 --> 04:39:59,370
SO SEVERAL YEARS AGO, WE MADE A

8132
04:39:59,370 --> 04:40:03,541
MOUSE THAT WE CALLED FASST MOU 

8133
04:40:03,541 --> 04:40:05,276
MOUSE, THEY GET TUMORS FASTER.

8134
04:40:05,276 --> 04:40:06,844
THE DETAILS AREN'T REALLY

8135
04:40:06,844 --> 04:40:07,444
IMPORTANT BUT SUFFICE TO SAY

8136
04:40:07,444 --> 04:40:09,680
THAT WE WERE ABLE TO INDUCE

8137
04:40:09,680 --> 04:40:11,115
SENESCENCE SPECIFICALLY WITHIN

8138
04:40:11,115 --> 04:40:14,752
FIBROBLASTS USING THIS MOUSE.

8139
04:40:14,752 --> 04:40:15,386
WHAT WAS INTERESTING, I'M JUST

8140
04:40:15,386 --> 04:40:16,520
GOING TO SUMMARIZE THIS IN

8141
04:40:16,520 --> 04:40:18,289
GRAPHICAL FORMAT, WE FOUND THIS

8142
04:40:18,289 --> 04:40:19,924
MOUSE IN TWO DIFFERENT STUDIES.

8143
04:40:19,924 --> 04:40:20,925
ON THE ONE HAND, WE COULD SHOW

8144
04:40:20,925 --> 04:40:22,560
THAT WHEN WE INDUCE SENESCENCE

8145
04:40:22,560 --> 04:40:24,662
SPECIFICALLY IN THIS COMPONENT

8146
04:40:24,662 --> 04:40:25,262
IN OSTEOBLASTS, THESE ARE THE

8147
04:40:25,262 --> 04:40:27,865
CELLS THAT NORMALLY MAKE YOUR

8148
04:40:27,865 --> 04:40:28,766
BONE, MINERALIZE YOUR BONE, IF

8149
04:40:28,766 --> 04:40:31,235
YOU WILL, THESE CELLS UNDERWENT

8150
04:40:31,235 --> 04:40:33,103
SENESCENCE, THEY SECRETED THEIR

8151
04:40:33,103 --> 04:40:35,873
OWN UNIQUE SAASP, AND IN DOING

8152
04:40:35,873 --> 04:40:38,209
SO, THEY WERE ABLE TO DRIVE

8153
04:40:38,209 --> 04:40:39,210
LOCALIZED OSTEOCLASS TOE GENESIS

8154
04:40:39,210 --> 04:40:41,178
THAT RESORBED THE BONE BUT MORE

8155
04:40:41,178 --> 04:40:42,746
IMPORTANTLY, ALLOWED TUMOR CELLS

8156
04:40:42,746 --> 04:40:45,216
TO SEED AND/OR PREFERENTIALLY

8157
04:40:45,216 --> 04:40:47,318
SURVIVE IN THESE AREAS, LEADING

8158
04:40:47,318 --> 04:40:48,852
TO HIGHER RATES OF METASTASIS IN

8159
04:40:48,852 --> 04:40:52,089
THESE ANIMALS.

8160
04:40:52,089 --> 04:40:52,957
HOWEVER WHEN WE LOOKED INTO THE

8161
04:40:52,957 --> 04:40:54,825
SKIN OF THESE ANIMALS WHERE WE

8162
04:40:54,825 --> 04:40:56,160
KNEW WE WERE ACTIVATING AGAINST

8163
04:40:56,160 --> 04:40:57,928
SENESCENCE IN THIS CONTEXT IN

8164
04:40:57,928 --> 04:40:59,430
FIBROBLASTS, WE WERE ACTUALLY

8165
04:40:59,430 --> 04:41:00,798
ABLE TO SHOW THAT THROUGH

8166
04:41:00,798 --> 04:41:02,766
SECRETION SPECIFICALLY OF

8167
04:41:02,766 --> 04:41:04,401
IL-6 FROM THE SENESCENT

8168
04:41:04,401 --> 04:41:06,637
FIBROBLASTS, WE WERE RECRUITING

8169
04:41:06,637 --> 04:41:09,406
IN IMMATURE MYELOID CELLS OR

8170
04:41:09,406 --> 04:41:13,510
MDSCs WHICH WERE CAPABLE OF

8171
04:41:13,510 --> 04:41:16,146
SPECIFICALLY INHIBITING CD-8

8172
04:41:16,146 --> 04:41:17,214
T-CELL RESPONSES ALMOST CREATED

8173
04:41:17,214 --> 04:41:19,016
IN A BUBBLE OF TUMOR

8174
04:41:19,016 --> 04:41:19,817
SUPPRESSION, IF YOU WILL, AROUND

8175
04:41:19,817 --> 04:41:22,653
THESE INCIPIENT TUMOR CELLS,

8176
04:41:22,653 --> 04:41:24,822
LEADING TO INCREASED

8177
04:41:24,822 --> 04:41:25,556
TUMORIGENESIS.

8178
04:41:25,556 --> 04:41:27,658
INTERESTINGLY WHEN WE LOOKED IN

8179
04:41:27,658 --> 04:41:31,061
HUMAN AGING SKIN, WE COULD ALSO

8180
04:41:31,061 --> 04:41:38,002
SEE THESE REGIONAL CHANGES

8181
04:41:38,002 --> 04:41:39,003
AROUND -- CERTAINLY THERE WAS A

8182
04:41:39,003 --> 04:41:41,171
PAPER THAT WAS JUST PUBLISHED BY

8183
04:41:41,171 --> 04:41:43,307
DARREN BAKER'S GROUP SHOWING

8184
04:41:43,307 --> 04:41:44,742
SENESCENT MACROPHAGES ACTUALLY

8185
04:41:44,742 --> 04:41:47,177
ARE ABLE TO INHIBIT T-CELL

8186
04:41:47,177 --> 04:41:48,646
RESPONSES IN THE CONTEXT OF LUNG

8187
04:41:48,646 --> 04:41:50,381
ADENOCARCINOMAS, LEADING TO

8188
04:41:50,381 --> 04:41:51,048
INCREASED TUMORIGENESIS.

8189
04:41:51,048 --> 04:41:52,850
SO TISSUES REALLY MATTER, AND

8190
04:41:52,850 --> 04:41:54,451
OUR FOCUS IN THE LAB FOR SOME

8191
04:41:54,451 --> 04:41:58,088
TIME HAS REALLY BEEN ON BREAST

8192
04:41:58,088 --> 04:41:58,789
CANCER.

8193
04:41:58,789 --> 04:42:00,758
SO JENNIFER YI, VERY TALENTED

8194
04:42:00,758 --> 04:42:03,894
GRAD STUDENT IN THE LAB, DECIDED

8195
04:42:03,894 --> 04:42:04,928
TO START LOOKING INTO PRIMARY

8196
04:42:04,928 --> 04:42:06,563
BREAST CANCER SAYING DO WE SEE

8197
04:42:06,563 --> 04:42:07,531
SENESCENT STROMAL CELLS AND IF

8198
04:42:07,531 --> 04:42:10,067
WE DO, ARE THEY IMPORTANT IN ANY

8199
04:42:10,067 --> 04:42:10,501
DEMONSTRABLE WAY.

8200
04:42:10,501 --> 04:42:11,568
SHE ACTUALLY FOUND THIS STUDY

8201
04:42:11,568 --> 04:42:13,003
THAT WAS BACK FROM 2011, WHERE

8202
04:42:13,003 --> 04:42:15,372
IT WAS REPORTED THAT PATIENTS

8203
04:42:15,372 --> 04:42:18,442
WITH DCIS WHO REPORTED -- OR

8204
04:42:18,442 --> 04:42:19,977
SORRY -- SHOWED POSITIVE P16

8205
04:42:19,977 --> 04:42:21,478
STAINING WITHIN THEIR STROMAL

8206
04:42:21,478 --> 04:42:23,080
COMPARTMENT EX-EXCLUSIVELY,

8207
04:42:23,080 --> 04:42:24,148
THOSE PATIENTS SUFFERED

8208
04:42:24,148 --> 04:42:24,581
RECURRENCES.

8209
04:42:24,581 --> 04:42:26,350
THEY DIDN'T DO AS WELL AS

8210
04:42:26,350 --> 04:42:28,786
PATIENTS THAT HAD P16 NEGATIVE

8211
04:42:28,786 --> 04:42:30,621
STROMA.

8212
04:42:30,621 --> 04:42:31,822
JENNIFER WAS ACTUALLY ABLE TO

8213
04:42:31,822 --> 04:42:34,124
OBTAIN THE EXACT SAME CASES THAT

8214
04:42:34,124 --> 04:42:34,758
WAS REPORTED IN THE STUDY, AND

8215
04:42:34,758 --> 04:42:37,795
DOING A LARGE MULTIPLEX STUDY, I

8216
04:42:37,795 --> 04:42:39,663
CAN'T REALLY TELL FROM THIS IF

8217
04:42:39,663 --> 04:42:40,464
YOU CAN ACTUALLY SEE THE

8218
04:42:40,464 --> 04:42:41,332
STAINING, BUT IMPORTANTLY WAS

8219
04:42:41,332 --> 04:42:45,269
ABLE TO SHOW THAT THOSE P16

8220
04:42:45,269 --> 04:42:47,371
POSITIVE STROMAL CELLS ARE, IN

8221
04:42:47,371 --> 04:42:48,138
FACT, FIBROBLASTS.

8222
04:42:48,138 --> 04:42:49,473
SHE WAS ABLE TO GO ON AND SHOW

8223
04:42:49,473 --> 04:42:51,375
THAT WHEN SHE COMPARED THIS TO

8224
04:42:51,375 --> 04:42:52,676
BREAST CANCER, LOOKING AT ALL

8225
04:42:52,676 --> 04:42:53,544
SUBTYPES, WHETHER WE'RE LOOKING

8226
04:42:53,544 --> 04:42:58,415
AT TRIPLE NEGATIVE, HR2 NEW OR

8227
04:42:58,415 --> 04:42:59,216
POSITIVE, SHE COULD AGAIN FIND A

8228
04:42:59,216 --> 04:43:00,417
LOT OF DIFFERENT STROMAL CELLS

8229
04:43:00,417 --> 04:43:01,952
BUT IMPORTANTLY, AND I'M NOT

8230
04:43:01,952 --> 04:43:03,220
SHOWING YOU ALL THE DATA IN THE

8231
04:43:03,220 --> 04:43:04,655
INTEREST OF TIME, SHE COULD FIND

8232
04:43:04,655 --> 04:43:07,958
P16 POSITIVE CELLS, AND SHE

8233
04:43:07,958 --> 04:43:08,959
COULD RECAPITULATE THIS WHEN SHE

8234
04:43:08,959 --> 04:43:11,695
LOOKED AT AN M M.T.V. MODEL OF

8235
04:43:11,695 --> 04:43:13,664
BREAST CANCER, AGAIN ABLE TO

8236
04:43:13,664 --> 04:43:15,265
DISTINCTLY FIND SENESCENT

8237
04:43:15,265 --> 04:43:16,900
FIBROBLASTS THAT WERE UNIQUELY

8238
04:43:16,900 --> 04:43:18,902
DEFINED BY THEIR EXPRESSION

8239
04:43:18,902 --> 04:43:20,337
PATTERNS FROM OTHER PATH

8240
04:43:20,337 --> 04:43:21,905
POPULATIONS OR CANCER ASSOCIATED

8241
04:43:21,905 --> 04:43:23,540
FIBROBLAST POPULATIONS,

8242
04:43:23,540 --> 04:43:25,943
SUGGESTING THAT SENESCENT CELLS

8243
04:43:25,943 --> 04:43:30,681
ARE NOT SOCASTICLY ARRIVING --

8244
04:43:30,681 --> 04:43:33,150
BUT THEY MAY IN FACT BE AN END

8245
04:43:33,150 --> 04:43:36,120
POINT FOR SPECIFIC CAF SUBTYPES.

8246
04:43:36,120 --> 04:43:37,421
I'M SKIPPING ALL THE DATA THAT

8247
04:43:37,421 --> 04:43:39,089
GOT ME TO THIS PARTICULAR GRAPH

8248
04:43:39,089 --> 04:43:40,591
HERE AGAIN IN THE INTEREST OF

8249
04:43:40,591 --> 04:43:41,458
TIME, BUT WHAT JENNIFER WAS ABLE

8250
04:43:41,458 --> 04:43:43,093
TO SHOW IN THE BREAST, WHICH IS

8251
04:43:43,093 --> 04:43:44,962
QUITE DISTINCT FROM WHAT DARREN

8252
04:43:44,962 --> 04:43:46,497
SAW IN THE LUNG AND WE SAW IN

8253
04:43:46,497 --> 04:43:48,599
THE SKIN, IS THAT THESE

8254
04:43:48,599 --> 04:43:50,567
SENESCENT FIBROBLASTS WERE

8255
04:43:50,567 --> 04:43:53,103
SPECIFICALLY MODIFYING NATURAL

8256
04:43:53,103 --> 04:43:54,772
KILLER CELLS AND THEIR ABILITY

8257
04:43:54,772 --> 04:43:56,673
TO CLEAR TUMOR CELLS.

8258
04:43:56,673 --> 04:43:57,875
SO I THINK IT'S IMPORTANT, WHEN

8259
04:43:57,875 --> 04:43:58,976
WE START THINKING ABOUT

8260
04:43:58,976 --> 04:44:00,377
CHALLENGES AND THINGS WE NEED TO

8261
04:44:00,377 --> 04:44:03,080
THINK ABOUT, IS TUMOR -- EXCUSE

8262
04:44:03,080 --> 04:44:05,816
ME -- SENESCENT CELLS CAN BE

8263
04:44:05,816 --> 04:44:06,984
POTENTLY ANTITEUM ROWGENIC.

8264
04:44:06,984 --> 04:44:08,285
THIS HAS BEEN BROUGHT UP ALREADY

8265
04:44:08,285 --> 04:44:10,421
PARTICULARLY WHEN IT OCCURS

8266
04:44:10,421 --> 04:44:11,088
WITHIN INCIPIENT TUMOR CELLS,

8267
04:44:11,088 --> 04:44:13,724
NATURAL KILLER CELLS,

8268
04:44:13,724 --> 04:44:15,058
MACROPHAGES CAN DIRECTLY CLEAR

8269
04:44:15,058 --> 04:44:16,260
THESE CELLS GIVEN THE RIGHT

8270
04:44:16,260 --> 04:44:19,363
SIGNALS, BUT THEY CAN BE

8271
04:44:19,363 --> 04:44:20,964
POTENTLY TUMOR-PROMOTING

8272
04:44:20,964 --> 04:44:21,965
PARTICULARLY WHEN THEY OCCUR IN

8273
04:44:21,965 --> 04:44:23,567
THE STROMAL COMPARTMENT.

8274
04:44:23,567 --> 04:44:24,701
SO I THINK AN IMPORTANT

8275
04:44:24,701 --> 04:44:25,803
CHALLENGE IS REALLY THE

8276
04:44:25,803 --> 04:44:26,437
SENESCENT CELL ITSELF.

8277
04:44:26,437 --> 04:44:27,838
I THINK IT'S INCREDIBLY

8278
04:44:27,838 --> 04:44:28,839
IMPORTANT THAT WE IDENTIFY WHAT

8279
04:44:28,839 --> 04:44:34,511
THE CELLS ARE THAT ARE

8280
04:44:34,511 --> 04:44:35,679
SENESCING, THE EXACT STROMAL

8281
04:44:35,679 --> 04:44:38,115
CELLS, AND WE HAVE TO THENG THIK

8282
04:44:38,115 --> 04:44:41,652
ABOUT THIS IN THE COU CONTEXT OE

8283
04:44:41,652 --> 04:44:43,887
TISSUE IN WHICH THEY ARISE.

8284
04:44:43,887 --> 04:44:44,421
THEY'RE NOT ALL THE SAME,

8285
04:44:44,421 --> 04:44:45,155
THEY'RE NOT MODULATING THINGS IN

8286
04:44:45,155 --> 04:44:45,556
THE SAME WAY.

8287
04:44:45,556 --> 04:44:49,993
I WANT TO TAKE A STEP BACK AND

8288
04:44:49,993 --> 04:44:51,862
BRING THIS PICTURE I ALREADY

8289
04:44:51,862 --> 04:44:53,163
SHOWED YOU SPECIFICALLY LOOKING

8290
04:44:53,163 --> 04:44:54,364
AT THE SECRETORY PHENOTYPE.

8291
04:44:54,364 --> 04:44:55,866
I THINK IT'S IMPORTANT TO START

8292
04:44:55,866 --> 04:44:56,600
THINKING ABOUT THE MOLECULAR

8293
04:44:56,600 --> 04:44:58,135
MECHANISMS THAT ACTUALLY DRIVE

8294
04:44:58,135 --> 04:45:02,239
EXPRESSION O.

8295
04:45:02,239 --> 04:45:05,809
QUITE SOME YEARS AGO, ALSPACH

8296
04:45:05,809 --> 04:45:10,380
WAS ABLE TO SHOW THAT P38

8297
04:45:10,380 --> 04:45:12,483
ACTATION THROUGH MK2 WAS ABLE TO

8298
04:45:12,483 --> 04:45:15,886
LEAD TO STABLE SAYS OF MANY OF

8299
04:45:15,886 --> 04:45:17,654
THESE SASP FACTORS AND THE

8300
04:45:17,654 --> 04:45:19,122
EXPRESSION OFTEN CORRELATED WITH

8301
04:45:19,122 --> 04:45:20,757
BETTER OUTCOMES IN BREAST CANCER

8302
04:45:20,757 --> 04:45:21,158
PATIENTS.

8303
04:45:21,158 --> 04:45:22,793
WE GOT REALLY INTERESTED IN THIS

8304
04:45:22,793 --> 04:45:24,661
IN THE CONTEXT OF METASTASIS,

8305
04:45:24,661 --> 04:45:25,462
WHICH OF COURSE WHEN WE'RE

8306
04:45:25,462 --> 04:45:26,864
THINKING ABOUT BREAST CANCER IS

8307
04:45:26,864 --> 04:45:30,767
WHAT KILLS MOST OF OUR PATIENTS,

8308
04:45:30,767 --> 04:45:32,469
AND WHEN MURULI WAS A GRADUATE

8309
04:45:32,469 --> 04:45:33,604
STUDENT IN THE LAB WAS ABLE TO

8310
04:45:33,604 --> 04:45:35,672
GO ON TO SHOW THAT EXPRESSION OF

8311
04:45:35,672 --> 04:45:37,074
MANY OF THESE SASP FACTORS,

8312
04:45:37,074 --> 04:45:39,042
THINGS WE THINK ABOUT ASSOCIATES

8313
04:45:39,042 --> 04:45:40,677
WITH SENESCENCE, CAN BE FOUND IN

8314
04:45:40,677 --> 04:45:44,047
THE STROMAL COMPARTMENT OF

8315
04:45:44,047 --> 04:45:45,215
METASTATIC LESIONS.

8316
04:45:45,215 --> 04:45:49,853
I'M SHOWING YOU A PICTURE -- THE

8317
04:45:49,853 --> 04:45:50,521
ORGAN THAT YOU SEE MOST

8318
04:45:50,521 --> 04:45:51,455
METASTASIS IN BREAST CANCER

8319
04:45:51,455 --> 04:45:51,722
PATIENTS.

8320
04:45:51,722 --> 04:45:54,825
SO SHE WANTED TO KNOW COULD SHE

8321
04:45:54,825 --> 04:45:55,292
ACTUALLY TARGET THIS.

8322
04:45:55,292 --> 04:45:55,926
SO WHAT SHE DID, AND I'M GOING

8323
04:45:55,926 --> 04:45:57,694
TO SHOW YOU DATA FROM ONE CELL

8324
04:45:57,694 --> 04:45:59,463
LINE, SHE'S DONE THIS IN MANY,

8325
04:45:59,463 --> 04:46:00,664
MANY CELL LINES, IS TO TAKE

8326
04:46:00,664 --> 04:46:02,099
ANIMALS AND TREAT THEM -- OR I

8327
04:46:02,099 --> 04:46:04,301
SHOULD SAY INDUCE TUMOR CELLS

8328
04:46:04,301 --> 04:46:06,303
AND THEN TREAT THEM WITH EITHER

8329
04:46:06,303 --> 04:46:10,440
P38 AS A SINGLE AGENT OR PT --

8330
04:46:10,440 --> 04:46:13,010
WHICH IS STILL USED IN THE

8331
04:46:13,010 --> 04:46:13,710
SETTING OF BREAST CANCER

8332
04:46:13,710 --> 04:46:14,011
PATIENTS.

8333
04:46:14,011 --> 04:46:15,145
AND IMPORTANTLY WHETHER SHE

8334
04:46:15,145 --> 04:46:16,647
LOOKED AT BONE METASTASIS ON THE

8335
04:46:16,647 --> 04:46:18,315
RIGHT OR VISCERAL METASTASIS AT

8336
04:46:18,315 --> 04:46:21,752
LARGE IN THE LEFT, P38 IS A

8337
04:46:21,752 --> 04:46:26,890
SINGLE AGENT, AS EFFECTIVE AS

8338
04:46:26,890 --> 04:46:29,459
PACK TACK SILL, BUT THIS BRINGS

8339
04:46:29,459 --> 04:46:30,460
UP ANOTHER CHALLENGE WE HAVE TO

8340
04:46:30,460 --> 04:46:32,195
THINK ABOUT, MOST OF US IN THE

8341
04:46:32,195 --> 04:46:34,631
CANCER UNIVERSE FOR PRACTICALITY

8342
04:46:34,631 --> 04:46:35,432
AND FINANCIAL REASONS, WE DO OUR

8343
04:46:35,432 --> 04:46:36,533
EXPERIMENTS IN YOUNG ANIMALS.

8344
04:46:36,533 --> 04:46:37,601
THE QUESTION IS, DOES THIS

8345
04:46:37,601 --> 04:46:39,002
ALWAYS REPEAT WHEN WE THINK

8346
04:46:39,002 --> 04:46:40,404
ABOUT OLD ANIMALS?

8347
04:46:40,404 --> 04:46:42,806
IN THE CONTEXT OF THE P38

8348
04:46:42,806 --> 04:46:45,042
INHIBITOR, IT DOES, WHEN WE DO

8349
04:46:45,042 --> 04:46:46,043
THE EXACT TYPE OF AN EXPERIMENT

8350
04:46:46,043 --> 04:46:47,477
USING 18-YEAR-OLD MICE, AGAIN

8351
04:46:47,477 --> 04:46:50,147
USING P38 AS A SINGLE AGENT, WE

8352
04:46:50,147 --> 04:46:51,782
DO, IN FACT, SEE THAT IT'S

8353
04:46:51,782 --> 04:46:53,417
EFFECTIVE AT LIMITING VISCERAL

8354
04:46:53,417 --> 04:46:55,085
METASTASIS AND BONE M METASTASIS

8355
04:46:55,085 --> 04:46:56,987
WHICH I'M NOT SHOWING YOU, BUT I

8356
04:46:56,987 --> 04:46:57,854
SHOULD POINT OUT THIS IS NOT

8357
04:46:57,854 --> 04:46:58,488
ALWAYS THE CASE.

8358
04:46:58,488 --> 04:46:59,323
THERE ARE PLENTY OF THERAPYS

8359
04:46:59,323 --> 04:47:00,857
THAT HAVE BEEN SHOWN TO NOT BE

8360
04:47:00,857 --> 04:47:03,160
AS EFFECTIVE IN OLDER

8361
04:47:03,160 --> 04:47:03,493
INDIVIDUALS.

8362
04:47:03,493 --> 04:47:04,795
AND I THINK THAT BRINGS UP

8363
04:47:04,795 --> 04:47:06,430
ANOTHER CHALLENGE WHICH IS HOW

8364
04:47:06,430 --> 04:47:09,366
DO WE START TO LOOK AT THESE

8365
04:47:09,366 --> 04:47:09,666
DIFFERENCES?

8366
04:47:09,666 --> 04:47:10,834
SOMETIMES IT MATTERS, SOMETIMES

8367
04:47:10,834 --> 04:47:14,104
IT DOESN'T, BUT MOST OF THE

8368
04:47:14,104 --> 04:47:14,871
TIME, EXPERIMENTS ARE NOT BEING

8369
04:47:14,871 --> 04:47:16,406
DONE IN OLDER ANIMALS AND THE

8370
04:47:16,406 --> 04:47:17,608
OTHER QUESTION IS ARE OLDER

8371
04:47:17,608 --> 04:47:19,509
ANIMALS ACTUALLY GOOD ENOUGH.

8372
04:47:19,509 --> 04:47:20,377
PAUL BROUGHT UP THIS IDEA OF THE

8373
04:47:20,377 --> 04:47:23,013
PET STORE MOUSE.

8374
04:47:23,013 --> 04:47:24,548
WE'RE LOOKING AT A VERY

8375
04:47:24,548 --> 04:47:25,882
HOMOGENEOUS, OLD POPULATION.

8376
04:47:25,882 --> 04:47:26,316
IS THAT GOOD ENOUGH?

8377
04:47:26,316 --> 04:47:27,250
THE ANSWER IS I THINK WE DON'T

8378
04:47:27,250 --> 04:47:28,652
KNOW, WE HAVEN'T DONE ENOUGH IN

8379
04:47:28,652 --> 04:47:31,655
THAT AR RENA.

8380
04:47:31,655 --> 04:47:33,190
IT'S ALSO BEEN BROUGHT UP THAT

8381
04:47:33,190 --> 04:47:34,391
MOST OF OUR CLINICAL TRIALS ARE

8382
04:47:34,391 --> 04:47:36,460
NOT DONE IN OLDER INDIVIDUALS,

8383
04:47:36,460 --> 04:47:37,461
SO ARE THE CLINICAL TRIALS THAT

8384
04:47:37,461 --> 04:47:39,062
WE'RE DOING REALLY REFLECTING

8385
04:47:39,062 --> 04:47:40,731
MOST OF WHAT'S GOING TO HAPPEN

8386
04:47:40,731 --> 04:47:45,702
IN OUR PATIENT POPULATION?

8387
04:47:45,702 --> 04:47:48,538
FINALLY, OUR CO-MOR COMORBIDITIT

8388
04:47:48,538 --> 04:47:50,807
ARE INDUCED WE BRING TO BEAR TO

8389
04:47:50,807 --> 04:47:52,709
SAVE PEOPLE'S LIVES CAN HAVE

8390
04:47:52,709 --> 04:47:53,310
DRASTICALLY DIFFERENT EFFECTS

8391
04:47:53,310 --> 04:47:57,047
WHEN WE LOOK AT AGED VERSUS

8392
04:47:57,047 --> 04:47:57,447
YOUNGER PATIENTS.

8393
04:47:57,447 --> 04:48:00,984
THIS IS ONE EXAMPLE LOOKING AT

8394
04:48:00,984 --> 04:48:03,086
PERIPHERAL NEUROPATHY, STINGING

8395
04:48:03,086 --> 04:48:05,756
PAIN, AFTER CHEMO, 70% OF ALL

8396
04:48:05,756 --> 04:48:08,058
PATIENTS TREATED WITH PACLITAXEL

8397
04:48:08,058 --> 04:48:09,693
WILL EXPERIENCE SOME LEVEL OF

8398
04:48:09,693 --> 04:48:11,395
NEUROPATHY BUT IF YOU'RE OVER

8399
04:48:11,395 --> 04:48:12,295
THE AGE OF 65 WHEN TREATED

8400
04:48:12,295 --> 04:48:13,730
YOU'RE MUCH LESS LIKELY TO RE

8401
04:48:13,730 --> 04:48:15,232
SOLVE THAT.

8402
04:48:15,232 --> 04:48:17,300
LUCKILY OUR MICE SEEM TO

8403
04:48:17,300 --> 04:48:17,634
RESEMBLE THAT.

8404
04:48:17,634 --> 04:48:19,603
THIS IS A MEASURE OF CIPN.

8405
04:48:19,603 --> 04:48:20,737
I'M NOT GOING TO GO INTO THE

8406
04:48:20,737 --> 04:48:22,439
DETAILS OF THE ASSAY, BUT YOU'LL

8407
04:48:22,439 --> 04:48:24,007
NOTICE WHEN YOU START OUT AS AN

8408
04:48:24,007 --> 04:48:26,043
18 MONTH OLD MOUSE, YOU'RE

8409
04:48:26,043 --> 04:48:28,111
ACTUALLY ALREADY IN MORE TROUBLE

8410
04:48:28,111 --> 04:48:30,047
THAN A YOUNGER MOUSE, AND YOUR

8411
04:48:30,047 --> 04:48:30,847
NEUROPATHY GETS WORSE.

8412
04:48:30,847 --> 04:48:32,983
I'M NOT SHOWING THE FUNCTIONAL

8413
04:48:32,983 --> 04:48:33,617
READOUT, BUT IT'S MUCH WORSE.

8414
04:48:33,617 --> 04:48:36,386
SO HOW DO WE MODEL?

8415
04:48:36,386 --> 04:48:38,021
COULD WE BE USING THE PROGERIA

8416
04:48:38,021 --> 04:48:39,923
MICE THAT WERE MENTIONED BY PAUL

8417
04:48:39,923 --> 04:48:40,590
AND LAURA?

8418
04:48:40,590 --> 04:48:42,759
ARE THEY GOOD ENOUGH?

8419
04:48:42,759 --> 04:48:44,828
DO WE NEED TO THINK OF DIFFERENT

8420
04:48:44,828 --> 04:48:45,062
MODELS?

8421
04:48:45,062 --> 04:48:45,762
FINALLY IN THE LAST THREE

8422
04:48:45,762 --> 04:48:46,963
MINUTES I WANT TO GO BACK TO

8423
04:48:46,963 --> 04:48:47,531
THIS PARTICULAR SLIDE.

8424
04:48:47,531 --> 04:48:49,299
SO I MENTIONED ALREADY THAT IN

8425
04:48:49,299 --> 04:48:50,534
THE CONTEXT OF YOUNG AND OLD

8426
04:48:50,534 --> 04:48:53,070
MICE, THANKFULLY, P38 IS A

8427
04:48:53,070 --> 04:48:56,940
SINGLE AGENT IS AS EFFECTIVE AS

8428
04:48:56,940 --> 04:48:58,241
PACK LA TAX ILL AS TREATING MICE

8429
04:48:58,241 --> 04:49:00,343
BUT OUR GOAL IS NOT TO BE AS

8430
04:49:00,343 --> 04:49:01,478
GOOD AS CURRENT THERAPY.

8431
04:49:01,478 --> 04:49:03,747
OUR GOAL IS TO PUSH THE CURVE TO

8432
04:49:03,747 --> 04:49:04,047
THE RIGHT.

8433
04:49:04,047 --> 04:49:05,782
SO THERE THERE WAYS TO ACTUALLY

8434
04:49:05,782 --> 04:49:07,517
MAKE THESE TREATMENTS BETTER?

8435
04:49:07,517 --> 04:49:09,019
ARE WE TREATING SENESCENT CELLS

8436
04:49:09,019 --> 04:49:10,220
IN THE CONTEXT OF THESE YOUNG

8437
04:49:10,220 --> 04:49:11,855
ANIMALS OR ARE WE FOE CAN

8438
04:49:11,855 --> 04:49:13,557
CUSSING MORE ON

8439
04:49:13,557 --> 04:49:14,224
CANCER-ASSOCIATED FIBROBLASTS?

8440
04:49:14,224 --> 04:49:15,325
I DON'T KNOW THE ANSWER TO THAT

8441
04:49:15,325 --> 04:49:17,427
TODAY BUT WHAT I CAN TELL YOU IS

8442
04:49:17,427 --> 04:49:18,061
THROUGH A SERIES OF EXPERIMENTS

8443
04:49:18,061 --> 04:49:19,062
THAT WERE RECENTLY PUBLISHED,

8444
04:49:19,062 --> 04:49:22,599
WHAT WE FOUND IS THAT P38 IS

8445
04:49:22,599 --> 04:49:24,267
ACTUALLY FUNCTIONING BOTH

8446
04:49:24,267 --> 04:49:27,104
THROUGH MACROPHAGES AS WELL AS

8447
04:49:27,104 --> 04:49:29,106
CD4 T-CELLS TO LIMIT TUMOR

8448
04:49:29,106 --> 04:49:29,439
GROWTH.

8449
04:49:29,439 --> 04:49:31,475
BUT NONE OF THIS AS I SAID

8450
04:49:31,475 --> 04:49:32,476
PUSHED THAT CURVE TO THE RIGHT.

8451
04:49:32,476 --> 04:49:35,345
>> DOCTOR, YOU HAVE TWO
MINUTES

8452
04:49:35,345 --> 04:49:35,612
REMAINING.

8453
04:49:35,612 --> 04:49:37,481
>> WHEN WE STARTED LOOKING
AT

8454
04:49:37,481 --> 04:49:39,683
THE ACTUAL METASTATIC LESIONS,

8455
04:49:39,683 --> 04:49:41,251
WHAT WE FOUND IS WHAT WAS

8456
04:49:41,251 --> 04:49:44,421
MISSING IN OUR ANIMALS WAS THE

8457
04:49:44,421 --> 04:49:46,189
ACTIVATION OF OX40 WHICH IS LIKE

8458
04:49:46,189 --> 04:49:47,290
GAS ON YOUR T-CELLS.

8459
04:49:47,290 --> 04:49:48,692
AND THIS WAS TRUE IN HUMAN

8460
04:49:48,692 --> 04:49:49,326
DATASETS AS WELL.

8461
04:49:49,326 --> 04:49:50,961
AND SO WHAT WE FOUND IS WHEN WE

8462
04:49:50,961 --> 04:49:54,131
COUPLED THE P38 INHIBITOR WITH

8463
04:49:54,131 --> 04:49:57,000
AN OX40 AGONIST, WE WERE ABLE TO

8464
04:49:57,000 --> 04:49:58,902
SIGNIFICANTLY REDUCE METASTATIC

8465
04:49:58,902 --> 04:49:59,136
TUMORS.

8466
04:49:59,136 --> 04:50:03,640
WHAT I DIDN'T TELL YOU IS THAT

8467
04:50:03,640 --> 04:50:04,841
CD8 T-CELLS ARE NOT INVOLVED IN

8468
04:50:04,841 --> 04:50:05,776
THIS.

8469
04:50:05,776 --> 04:50:06,576
EVEN THOUGH WE COULD PUSH THE

8470
04:50:06,576 --> 04:50:06,910
CURVE OUT.

8471
04:50:06,910 --> 04:50:09,412
SO WHAT WE DID WAS TO PUT IN A

8472
04:50:09,412 --> 04:50:12,682
SLEDGEHAMMER OV A WHICH

8473
04:50:12,682 --> 04:50:14,651
ACTIVATES CD4 AND CD8 SCH

8474
04:50:14,651 --> 04:50:15,986
T-CELLS AND IN DOING SO WE WERE

8475
04:50:15,986 --> 04:50:17,921
ABLE TO CURE 100% OF OUR ANIMALS

8476
04:50:17,921 --> 04:50:19,322
AND CREATE DURABLE MEMORY.

8477
04:50:19,322 --> 04:50:22,125
AGAIN BY COUPLING BOTH THE

8478
04:50:22,125 --> 04:50:23,360
STROMAL INHIBITOR OF P38,

8479
04:50:23,360 --> 04:50:24,561
ACTIVATING OUR T-CELLS AND

8480
04:50:24,561 --> 04:50:27,297
FORCING OUR CD8 T-CELLS TO BE

8481
04:50:27,297 --> 04:50:27,531
ENGAGED.

8482
04:50:27,531 --> 04:50:28,131
SO FINALLY, WHAT ARE THE NEXT

8483
04:50:28,131 --> 04:50:28,498
STEPS?

8484
04:50:28,498 --> 04:50:29,266
THERE'S A LOT OF THEM.

8485
04:50:29,266 --> 04:50:31,301
I DON'T HAVE ENOUGH TIME TO GO

8486
04:50:31,301 --> 04:50:32,636
THROUGH ALL OF THESE.

8487
04:50:32,636 --> 04:50:34,070
MOST OF THESE HAVE ALREADY BEEN

8488
04:50:34,070 --> 04:50:34,938
MENTIONED BY MY COLLEAGUES

8489
04:50:34,938 --> 04:50:37,073
BEFORE ME BUT I THINK WE NEED TO

8490
04:50:37,073 --> 04:50:38,508
BE THINKING OF WHAT IS THE

8491
04:50:38,508 --> 04:50:38,842
TARGET.

8492
04:50:38,842 --> 04:50:39,943
WE NEED TO BE THINKING ABOUT

8493
04:50:39,943 --> 04:50:43,446
WHAT IS THE ADVANTAGE OF

8494
04:50:43,446 --> 04:50:45,982
SENOLYTICS OVER SENOMORPHICS.

8495
04:50:45,982 --> 04:50:49,252
WE'VE ALREADY HEARD NOT ALL HIT

8496
04:50:49,252 --> 04:50:50,787
THE SAME EXACT CELLS.

8497
04:50:50,787 --> 04:50:53,290
NOT ALL SENESCENCE IS BAD.

8498
04:50:53,290 --> 04:50:53,957
WE NEED TO THINK ABOUT HOW WE'RE

8499
04:50:53,957 --> 04:50:54,724
IMPACTING THOSE GOOD CELLS.

8500
04:50:54,724 --> 04:50:57,127
IS JUST PERIODIC TREATMENT GOOD

8501
04:50:57,127 --> 04:50:57,360
ENOUGH?

8502
04:50:57,360 --> 04:50:58,461
WE NEED TO KNOW WHAT THE CELLS

8503
04:50:58,461 --> 04:50:58,695
ARE.

8504
04:50:58,695 --> 04:50:59,996
WITH THAT, I'LL END WITH THE

8505
04:50:59,996 --> 04:51:02,132
MOST IMPORTANT SLIDE WHICH IS

8506
04:51:02,132 --> 04:51:02,933
THE PEOPLE THAT DO ALL THE WORK,

8507
04:51:02,933 --> 04:51:04,467
AND I'D BE HAPPY TO TAKE ANY

8508
04:51:04,467 --> 04:51:05,569
QUESTIONS IF I'VE LEFT ANY TIME.

8509
04:51:05,569 --> 04:51:05,869
THANK YOU.

8510
04:51:05,869 --> 04:51:08,071
>> THANK YOU SO MUCH.

8511
04:51:08,071 --> 04:51:11,775
I THINK DR. DEGREGORI HAS A

8512
04:51:11,775 --> 04:51:12,042
QUESTION.

8513
04:51:12,042 --> 04:51:13,276
>> THANKS.

8514
04:51:13,276 --> 04:51:13,844
SHEILA, REALLY GREAT STUFF.

8515
04:51:13,844 --> 04:51:15,245
I HAVE A QUESTION THAT KIND OF

8516
04:51:15,245 --> 04:51:17,113
RELATES BACK TO WHAT YOU WERE

8517
04:51:17,113 --> 04:51:18,582
TALKING ABOUT EARLIER AND THAT

8518
04:51:18,582 --> 04:51:19,482
SOME OF THE OTHER SPEAKERS HAVE

8519
04:51:19,482 --> 04:51:21,051
TOUCHED UPON WHICH IS THIS

8520
04:51:21,051 --> 04:51:22,919
HETEROGENEITY OF SENESCENCE, IN

8521
04:51:22,919 --> 04:51:23,753
TERMS OF BOTH DIFFERENT CELL

8522
04:51:23,753 --> 04:51:25,288
TYPES AND EVEN DIFFERENT FLAVORS

8523
04:51:25,288 --> 04:51:26,156
WITHIN CELL TYPES.

8524
04:51:26,156 --> 04:51:28,458
I'M WONDERING, HAS ANYONE REALLY

8525
04:51:28,458 --> 04:51:30,293
DONE THIS COMPREHENSIVELY,

8526
04:51:30,293 --> 04:51:32,562
REALLY THE SAME GROUP BUT THE

8527
04:51:32,562 --> 04:51:34,331
SAME METHODS, LOOKING AT CHEMO,

8528
04:51:34,331 --> 04:51:37,200
OLD AGE, OTHER CONTEXTS, AND

8529
04:51:37,200 --> 04:51:39,302
ASKING -- DO WE GET SORT OF

8530
04:51:39,302 --> 04:51:41,071
DIFFER FLAVORS AND TYPES FOR

8531
04:51:41,071 --> 04:51:42,505
DIFFERENT INSULTS?

8532
04:51:42,505 --> 04:51:43,273
WHEN YOU COMPARE BETWEEN GROUPS,

8533
04:51:43,273 --> 04:51:43,940
IT'S ALWAYS HARD TO KNOW.

8534
04:51:43,940 --> 04:51:45,442
>> THE ANSWER IS WE
HAVEN'T DONE

8535
04:51:45,442 --> 04:51:47,010
IT WELL ENOUGH AS A FIELD.

8536
04:51:47,010 --> 04:51:47,644
PART OF THE CHALLENGE HAS BEEN

8537
04:51:47,644 --> 04:51:49,579
WE DON'T HAVE GREAT MARKERS.

8538
04:51:49,579 --> 04:51:52,616
I CAN HONESTLY TELL YOU IN THE

8539
04:51:52,616 --> 04:51:54,017
QUICK STUDY I SHOWED, IT TOOK US

8540
04:51:54,017 --> 04:51:56,486
THREE YEARS TO FIND THOSE CELLS

8541
04:51:56,486 --> 04:51:58,188
AND CHASE THEM DOWN SO THIS

8542
04:51:58,188 --> 04:51:59,723
ISN'T A TRIVIAL PROBLEM.

8543
04:51:59,723 --> 04:52:03,894
BUT I THINK MARCOUX DEMAROIO

8544
04:52:03,894 --> 04:52:05,662
PROBABLY HAS THE BEST DATA ON

8545
04:52:05,662 --> 04:52:05,862
THIS.

8546
04:52:05,862 --> 04:52:07,063
ANY OTHER DATA HE COULD FIND

8547
04:52:07,063 --> 04:52:08,164
PUBLICLY AVAILABLE, I CAN TELL

8548
04:52:08,164 --> 04:52:09,699
YOU, CELLS KNOW WHERE THEY CAME

8549
04:52:09,699 --> 04:52:10,667
FROM AND THEY KNOW HOW THEY GOT

8550
04:52:10,667 --> 04:52:11,101
HURT.

8551
04:52:11,101 --> 04:52:13,503
THAT'S TO SAY YOU TAKE THE SAME

8552
04:52:13,503 --> 04:52:15,238
FIBROBLAST AND YOU HIT IT WITH

8553
04:52:15,238 --> 04:52:16,439
DIFFERENT INSULTS, THE SASP HAS

8554
04:52:16,439 --> 04:52:17,741
THE SAME GO TERMS BUT THE

8555
04:52:17,741 --> 04:52:20,076
DETAILS ARE COMPLEECTLY

8556
04:52:20,076 --> 04:52:21,177
DIFFERENT.

8557
04:52:21,177 --> 04:52:23,146
YOU CAN TAKE FIBROBLASTS FROM

8558
04:52:23,146 --> 04:52:24,447
TWO DIFFERENT SOURCES, HIT THEM

8559
04:52:24,447 --> 04:52:25,749
WITH THE SAME DAMAGE, IT'S THE

8560
04:52:25,749 --> 04:52:26,416
SAME STORY.

8561
04:52:26,416 --> 04:52:28,351
SO IT'S INCREDIBLY HETEROGENEOUS

8562
04:52:28,351 --> 04:52:29,686
AND I THINK THIS IS, IN FACT,

8563
04:52:29,686 --> 04:52:30,320
THE CHALLENGE.

8564
04:52:30,320 --> 04:52:32,422
IF WE DON'T IDENTIFY THE CELL

8565
04:52:32,422 --> 04:52:33,023
TYPE AND WHAT IT DOING, WE'RE

8566
04:52:33,023 --> 04:52:34,124
NEVER GOING TO KNOW WHERE THE

8567
04:52:34,124 --> 04:52:36,293
POSITIVE AND NEGATIVES ARE HERE.

8568
04:52:36,293 --> 04:52:36,960
IT'S A GREAT QUESTION AND IT'S

8569
04:52:36,960 --> 04:52:39,162
AN IMPORTANT PROBLEM.

8570
04:52:39,162 --> 04:52:39,696
>> THANKS.

8571
04:52:39,696 --> 04:52:41,231
>> FANTASTIC.

8572
04:52:41,231 --> 04:52:43,500
REALLY INTERESTING TALK,

8573
04:52:43,500 --> 04:52:43,800
DR. STEWART.

8574
04:52:43,800 --> 04:52:46,903
I THINK WE ARE ACTUALLY ON TIME

8575
04:52:46,903 --> 04:52:48,738
FOR OUR 10-MINUTE BREAK.

8576
04:52:48,738 --> 04:52:53,443
WHICH WILL BE FROM NOW UNTIL

8577
04:52:53,443 --> 04:52:54,311
3:10 IF YOU'RE ON THE EASTERN

8578
04:52:54,311 --> 04:52:56,313
TIME, SO 10-MINUTE BREAK.

8579
04:52:56,313 --> 04:53:00,150
THERE IS ANOTHER QUESTION.

8580
04:53:00,150 --> 04:53:03,219
COULD DDR TARGETING IN

8581
04:53:03,219 --> 04:53:03,987
SENOLYTICS SYNERGIZE?

8582
04:53:03,987 --> 04:53:05,956
I DO THINK THAT'S SOMETHING WE

8583
04:53:05,956 --> 04:53:07,290
WILL TALK ABOUT IN THE PANEL

8584
04:53:07,290 --> 04:53:09,426
DISCUSSION, SO WE HAVE SAVED A

8585
04:53:09,426 --> 04:53:10,327
HALF AN HOUR FOR THAT.

8586
04:53:10,327 --> 04:53:12,696
WE WILL COME BACK AT 3:20, AND

8587
04:53:12,696 --> 04:53:15,098
WE WILL BE HEARING ABOUT HEALTHY

8588
04:53:15,098 --> 04:53:24,708
HEARTBEAT TRAJECTORIES, BY

8589
04:53:24,708 --> 04:53:27,410
DR. LAKATTA AT 3:20, SO WE HAVE

8590
04:53:27,410 --> 04:53:28,866
A 9-MINUTE BREAK.

8591
04:53:28,866 --> 04:53:30,634
SO FOR THE SAKE OF TIME, WE WILL

8592
04:53:30,634 --> 04:53:33,403
CONTINUE.

8593
04:53:33,403 --> 04:53:34,938
AND THANK YOU FOR JOINING US

8594
04:53:34,938 --> 04:53:35,572
THIS AFTERNOON.

8595
04:53:35,572 --> 04:53:39,142
FOR THOSE WHO JUST JOINED OUR

8596
04:53:39,142 --> 04:53:41,578
ZOOM MEETING AND VIDEOCAST, WE

8597
04:53:41,578 --> 04:53:42,779
PROCEED WITH SESSION 2,

8598
04:53:42,779 --> 04:53:45,182
MOLECULAR MECHANISMS OF CHRONIC

8599
04:53:45,182 --> 04:53:47,684
AGE-RELATED DISEASES.

8600
04:53:47,684 --> 04:53:52,389
AND I'M THE PROGRAM DIRECTOR,

8601
04:53:52,389 --> 04:53:54,124
TOGETHER WITH ANIL, WE'RE

8602
04:53:54,124 --> 04:53:55,425
CHAIRING THIS SESSION.

8603
04:53:55,425 --> 04:53:58,262
AND BEFORE THE BREAK, WE LEARNED

8604
04:53:58,262 --> 04:54:01,999
ABOUT EXCITING RESEARCH IN

8605
04:54:01,999 --> 04:54:05,969
CELLULAR SENESCENCE AND STROMAL

8606
04:54:05,969 --> 04:54:06,403
CHANGES.

8607
04:54:06,403 --> 04:54:08,171
IN THE SECOND PART OF THIS

8608
04:54:08,171 --> 04:54:12,876
SESSION PROMISES TO BE JUST AS

8609
04:54:12,876 --> 04:54:14,645
EXCITED WITH TOPICS INCLUDING

8610
04:54:14,645 --> 04:54:17,114
THOSE THAT YOU CAN SEE IN THE

8611
04:54:17,114 --> 04:54:21,952
PROGRAM, HEARTBEAT TRAJECTORIES,

8612
04:54:21,952 --> 04:54:22,953
CELLULAR DYSFUNCTION,

8613
04:54:22,953 --> 04:54:26,990
ENVIRONMENTAL DETERMINANTS,

8614
04:54:26,990 --> 04:54:28,392
VASCULAR SENESCENCE AND ROLE OF

8615
04:54:28,392 --> 04:54:28,725
MICROBIOME.

8616
04:54:28,725 --> 04:54:34,364
SO PREPARE TO BE EXCITED, AND

8617
04:54:34,364 --> 04:54:37,567
DR. MCCOLLOUGH WILL CONTINUE TO

8618
04:54:37,567 --> 04:54:38,669
MODERATE THE SESSION AND THE

8619
04:54:38,669 --> 04:54:40,003
FOLLOWING PANEL DISCUSSION.

8620
04:54:40,003 --> 04:54:41,305
SO OUR FIRST SPEAKER FOR THIS

8621
04:54:41,305 --> 04:54:47,911
PART IS DR. EDWARD LAKATTA, FROM

8622
04:54:47,911 --> 04:54:49,012
NATIONAL INSTITUTE OF AGING AT

8623
04:54:49,012 --> 04:54:51,315
NIH AND THE TITLE OF THE TALK IS

8624
04:54:51,315 --> 04:54:55,018
HEALTHY HEARTBEAT TRAJECTORIES

8625
04:54:55,018 --> 04:54:58,388
WANE AS HEARTBEAT DEMENTIA

8626
04:54:58,388 --> 04:54:59,523
TRAJECTORIES EMERGES IN ADVANCED

8627
04:54:59,523 --> 04:55:01,124
AGE IN THE CONTEXT OF THE WHOLE

8628
04:55:01,124 --> 04:55:01,992
BODY FRAILTY.

8629
04:55:01,992 --> 04:55:08,231
THANK YOU.

8630
04:55:08,231 --> 04:55:08,966
TAKE IT AWAY.

8631
04:55:08,966 --> 04:55:10,133
>> GOOD AFTERNOON, LADIES
AND

8632
04:55:10,133 --> 04:55:10,400
GENTLEMEN.

8633
04:55:10,400 --> 04:55:15,872
I'M THE LAB CHIE LABORATORY OF

8634
04:55:15,872 --> 04:55:16,840
CARDIOVASCULAR SCIENCE IN THE

8635
04:55:16,840 --> 04:55:17,374
INTRAMURAL PROGRAM IN THE

8636
04:55:17,374 --> 04:55:19,009
NATIONAL INSTITUTE ON AGING, AND

8637
04:55:19,009 --> 04:55:20,644
WE'RE GOING TO TALK ABOUT

8638
04:55:20,644 --> 04:55:27,617
HEARTBEAT FRAILTY TODAY.

8639
04:55:27,617 --> 04:55:29,386
SICK SINUS SYNDROME IS A

8640
04:55:29,386 --> 04:55:31,521
CONDITION IN WHICH YOUR HEART'S

8641
04:55:31,521 --> 04:55:32,923
PACEMAKER FAILS TO INITIATE

8642
04:55:32,923 --> 04:55:36,660
HEART BEATS, AND IT REQUIRES

8643
04:55:36,660 --> 04:55:38,795
ELECTRONIC PACEMAKER INSERTION.

8644
04:55:38,795 --> 04:55:42,099
THIS IS THE ANNUAL INCIDENCE OF

8645
04:55:42,099 --> 04:55:43,300
SICK SINUS SYNDROME, AND YOU CAN

8646
04:55:43,300 --> 04:55:46,069
SEE THAT THE TRAJECTORY IS

8647
04:55:46,069 --> 04:55:48,038
MOVING UPWARD SEVERELY DUE TO

8648
04:55:48,038 --> 04:55:58,515
THE DEMOGRAPHIC IMPERATIVE.

8649
04:56:01,351 --> 04:56:11,595
HANG ON A MINUTE.

8650
04:56:16,066 --> 04:56:16,500
OKAY.

8651
04:56:16,500 --> 04:56:17,901
SORRY ABOUT THAT, FOLKS.

8652
04:56:17,901 --> 04:56:23,607
I WANT TO START BY GOING THIS

8653
04:56:23,607 --> 04:56:24,474
WAY.

8654
04:56:24,474 --> 04:56:27,711
SO WE HAVE BEEN INTERESTED IN

8655
04:56:27,711 --> 04:56:29,012
HEARTBEAT REGULATION IN THE

8656
04:56:29,012 --> 04:56:30,313
BALTIMORE LONGITUDAL STUDY ON

8657
04:56:30,313 --> 04:56:30,647
AGING.

8658
04:56:30,647 --> 04:56:33,350
WE HEARD A LOT ABOUT LONGITUDAL

8659
04:56:33,350 --> 04:56:33,583
STUDIES.

8660
04:56:33,583 --> 04:56:35,118
THIS STUDY IS 65 YEARS OLD AND

8661
04:56:35,118 --> 04:56:39,156
I'VE BEEN WITH IT FOR ABOUT 50

8662
04:56:39,156 --> 04:56:43,894
YEARS.

8663
04:56:43,894 --> 04:56:45,128
THIS IS THE HEART RATE RESERVE

8664
04:56:45,128 --> 04:56:46,730
IN BALTIMORE LONGITUDAL STUDY

8665
04:56:46,730 --> 04:56:47,731
PARTICIPANTS WHO ENTER AT

8666
04:56:47,731 --> 04:56:52,002
DIFFERENT AGES AND ARE FOLLOWED

8667
04:56:52,002 --> 04:56:53,437
FOR DIFFERENT PERIODS OF TIME.

8668
04:56:53,437 --> 04:56:56,506
AND THIS IS THE ONLY

8669
04:56:56,506 --> 04:57:00,010
CARDIOVASCULAR BIOMARKER THAT IS

8670
04:57:00,010 --> 04:57:02,279
NOT CHANGED BY ANY KNOWN

8671
04:57:02,279 --> 04:57:03,613
INTERVENTION.

8672
04:57:03,613 --> 04:57:04,848
AND THIS SHOWS THE RATE OF

8673
04:57:04,848 --> 04:57:11,254
CHANGE OF DECLINE IN THIS

8674
04:57:11,254 --> 04:57:11,688
LONGITUDAL ANALYSIS.

8675
04:57:11,688 --> 04:57:13,457
IT'S ABOUT ONE BEAT PER YEAR.

8676
04:57:13,457 --> 04:57:16,560
SO TO GET MORE MECHANISTIC

8677
04:57:16,560 --> 04:57:20,330
INSIGHT, I CREATED THE BALTIMORE

8678
04:57:20,330 --> 04:57:22,065
LONGITUDAL STUDY OF AGING IN

8679
04:57:22,065 --> 04:57:26,870
MICE, AND THESE 58 MICE ARE

8680
04:57:26,870 --> 04:57:29,306
STUDIED WITH THE

8681
04:57:29,306 --> 04:57:31,374
ELECTROCARDIOGRAM, PLUS OR MINUS

8682
04:57:31,374 --> 04:57:36,012
BRAIN INPUT, AND ECHOCARDIOGRAM

8683
04:57:36,012 --> 04:57:36,713
FOR LEFT VENTRICULAR STRUCTURE

8684
04:57:36,713 --> 04:57:38,448
AND FUNCTION, AND THOSE ARE

8685
04:57:38,448 --> 04:57:39,649
MEASURED EVERY THREE MONTHS,

8686
04:57:39,649 --> 04:57:41,384
FROM 6 MONTHS OF AGE UNTIL THE

8687
04:57:41,384 --> 04:57:45,388
END OF LIFE.

8688
04:57:45,388 --> 04:57:47,257
SO THE AVERAGE MORTALITY CURVE

8689
04:57:47,257 --> 04:57:49,359
OF THE WHOLE COHORT IS IN THE

8690
04:57:49,359 --> 04:57:51,294
PINK, THE MEDIAN LIFESPAN IS 24

8691
04:57:51,294 --> 04:57:52,062
MONTHS OF AGE.

8692
04:57:52,062 --> 04:57:55,432
THOSE THAT DON'T MAKE IT, WE

8693
04:57:55,432 --> 04:57:57,634
REFER TO AS SHORT-LIVED, BUT

8694
04:57:57,634 --> 04:58:03,406
THOSE THAT ACHIEVE THE MEDIAN OR

8695
04:58:03,406 --> 04:58:05,275
BEYOND LIFESPAN, THOSE ARE

8696
04:58:05,275 --> 04:58:06,710
CALLED LONG-LIVED AND THEY'RE ON

8697
04:58:06,710 --> 04:58:09,212
THE GREEN LINE AND THEIR

8698
04:58:09,212 --> 04:58:13,183
HEALTHSPAN IS EXTENDED, AND

8699
04:58:13,183 --> 04:58:14,284
WE'RE GOING TO SEE WHAT HAPPENS

8700
04:58:14,284 --> 04:58:16,586
TO THOSE MICE WITH RESPECT TO

8701
04:58:16,586 --> 04:58:19,856
THEIR HEART RATE AND RHYTHM.

8702
04:58:19,856 --> 04:58:21,491
WE ACTUALLY DON'T TREAT THEM TO

8703
04:58:21,491 --> 04:58:23,160
MAKE THEM BACK LIKE THAT YET.

8704
04:58:23,160 --> 04:58:25,595
SO THIS IS HOW FRAILTY EMERGES.

8705
04:58:25,595 --> 04:58:33,036
THIS IS A FRAILTY INDEX IN THOSE

8706
04:58:33,036 --> 04:58:33,570
MICE.

8707
04:58:33,570 --> 04:58:35,438
NOT ONLY DOES IT INCREASE AT

8708
04:58:35,438 --> 04:58:38,241
THESE LATER AGES, THIS IS WHOLE

8709
04:58:38,241 --> 04:58:40,877
BODY FRAILTY.

8710
04:58:40,877 --> 04:58:42,612
BUT THE RATE AT WHICH IT

8711
04:58:42,612 --> 04:58:44,114
INCREASES ACCELERATES WITH

8712
04:58:44,114 --> 04:58:49,286
AGING.

8713
04:58:49,286 --> 04:58:52,022
THIS IS AN AUTONOMIC NEURAL

8714
04:58:52,022 --> 04:58:53,423
SURVEILLANCE CARTOON.

8715
04:58:53,423 --> 04:58:55,592
WE HEARD ABOUT HEART-BRAIN

8716
04:58:55,592 --> 04:58:58,428
SIGNALING EARLIER IN SOME OF THE

8717
04:58:58,428 --> 04:58:58,762
PRESENTATIONS.

8718
04:58:58,762 --> 04:59:00,463
I WANTED TO POINT -- ALTHOUGH

8719
04:59:00,463 --> 04:59:01,998
WE'RE GOING TO TALK ABOUT THAT

8720
04:59:01,998 --> 04:59:04,668
AS WELL HERE, IT'S WELL-KNOWN

8721
04:59:04,668 --> 04:59:06,303
NOW THAT THE HEART TALKS TO THE

8722
04:59:06,303 --> 04:59:09,339
BRAIN THROUGH THESE AFFERENT

8723
04:59:09,339 --> 04:59:09,906
SIGNALING PATHWAYS THAT ARE

8724
04:59:09,906 --> 04:59:13,310
SHOWN HERE.

8725
04:59:13,310 --> 04:59:15,812
WE BLOCKED THE AUTO NO MIBG

8726
04:59:15,812 --> 04:59:19,816
INPUT WITH DOUBLE AUTONOMIC

8727
04:59:19,816 --> 04:59:24,688
BLOCKADE WITH ADRENERGIC AND

8728
04:59:24,688 --> 04:59:31,161
CHOLINERGIC REACC RECEPTORS ON E

8729
04:59:31,161 --> 04:59:32,963
SIGH KNOW ATRIAL NODE.

8730
04:59:32,963 --> 04:59:35,065
THERE'S NOT MUCH HAPPENING UNTIL

8731
04:59:35,065 --> 04:59:36,132
ABOUT 21 MONTHS OF AGE AND THEN

8732
04:59:36,132 --> 04:59:39,436
WE SEE THIS MODEST INCREASE IN

8733
04:59:39,436 --> 04:59:42,539
THE RR INTERVAL, THAT MEANS THE

8734
04:59:42,539 --> 04:59:46,676
EKG RR INTERVAL, THE TIME

8735
04:59:46,676 --> 04:59:48,111
BETWEEN THEIR HEART BEATS.

8736
04:59:48,111 --> 04:59:49,279
WHEN THE AUTONOMIC INPUT IS

8737
04:59:49,279 --> 04:59:50,847
BLOCKED, WE SEE A SEVERE MARKED

8738
04:59:50,847 --> 04:59:51,281
INCREASE.

8739
04:59:51,281 --> 04:59:54,351
SO THE DIFFERENCE BETWEEN THE

8740
04:59:54,351 --> 04:59:55,986
TWO IS THE AUTONOMIC INPUT

8741
04:59:55,986 --> 04:59:57,954
EFFECT, THE SIGNATURE OF THE

8742
04:59:57,954 --> 05:00:00,290
AUTONOMIC SURVEILLANCE.

8743
05:00:00,290 --> 05:00:00,991
AND THAT'S NET SYMPATHETIC,

8744
05:00:00,991 --> 05:00:04,027
BECAUSE IT'S REDUCING THE TIME

8745
05:00:04,027 --> 05:00:06,563
BETWEEN THE MEAN HEARTBEAT

8746
05:00:06,563 --> 05:00:08,365
INTERVAL, BUT NOT FULLY

8747
05:00:08,365 --> 05:00:10,033
RESTORING TO THIS YOUTHFUL

8748
05:00:10,033 --> 05:00:12,802
LEVEL.

8749
05:00:12,802 --> 05:00:15,238
THIS IS AN ELECTROCARDIOGRAM,

8750
05:00:15,238 --> 05:00:17,307
AND AS A CARDIOLOGIST, I WOULD

8751
05:00:17,307 --> 05:00:21,444
SAY THAT'S NORMAL SINUS RHYTHM.

8752
05:00:21,444 --> 05:00:23,880
BUT AS A PHYSICIAN RESEARCHER,

8753
05:00:23,880 --> 05:00:26,683
WHEN WE LOOK MORE CLOSELY AT

8754
05:00:26,683 --> 05:00:31,187
THIS, THE SINOATRIAL NODE IS NOT

8755
05:00:31,187 --> 05:00:33,790
A METRO NOME AND ITS RHYTHM IS

8756
05:00:33,790 --> 05:00:39,229
NEVER IN A TRUE STEADY STATE,

8757
05:00:39,229 --> 05:00:42,032
AND THIS HEART INTERVAL

8758
05:00:42,032 --> 05:00:42,932
VARIABILITY IS SOMETIMES CALLED

8759
05:00:42,932 --> 05:00:46,202
THE HEART RATE INTERHEART RATE

8760
05:00:46,202 --> 05:00:46,536
VARIABILITY.

8761
05:00:46,536 --> 05:00:49,506
SO WE WANT TO KNOW WHAT -- NOT

8762
05:00:49,506 --> 05:00:51,875
WHAT'S THE MEAN HEART RATE WITH

8763
05:00:51,875 --> 05:00:53,510
AGING BUT WHEN WILL THE NEXT

8764
05:00:53,510 --> 05:00:58,915
HEARTBEAT OCCUR?

8765
05:00:58,915 --> 05:01:01,351
AND THIS IS IN THE PRESENCE OF

8766
05:01:01,351 --> 05:01:03,219
DOUBLE AUTONOMIC BLOCKADE, SO

8767
05:01:03,219 --> 05:01:06,289
THE SINOATRIAL NODE IS ON ITS

8768
05:01:06,289 --> 05:01:09,125
OWN AND AT 6 MONTHS OF AGE, THE

8769
05:01:09,125 --> 05:01:13,296
RR INTERVAL OCCURRENCE IS

8770
05:01:13,296 --> 05:01:14,597
BETWEEN 120 AND 130

8771
05:01:14,597 --> 05:01:15,031
MILLISECONDS.

8772
05:01:15,031 --> 05:01:16,700
THAT'S HOW LONG WE HAVE TO WAIT

8773
05:01:16,700 --> 05:01:20,570
FOR THE NEXT ONE.

8774
05:01:20,570 --> 05:01:23,239
DURING AUTONOMIC BLOCKADE IN THE

8775
05:01:23,239 --> 05:01:27,911
OLD, WE SEE NO INTERVALS OCCUR

8776
05:01:27,911 --> 05:01:29,446
BEFORE 225 MILLISECONDS, AND THE

8777
05:01:29,446 --> 05:01:34,150
DISTRIBUTION IS VERY DIFFERENT.

8778
05:01:34,150 --> 05:01:34,951
THIS IS IN THE RANGE IF YOU

8779
05:01:34,951 --> 05:01:36,853
CHANGE THE RR INTERVAL TO HERTZ,

8780
05:01:36,853 --> 05:01:43,860
IT'S BETWEEN 4 AND 8 HERTZ.

8781
05:01:43,860 --> 05:01:45,195
NOW IF WE LOOK IN THE PRESENCE

8782
05:01:45,195 --> 05:01:47,697
AND AK SENSE OF DOUBLE AUTONOMIC

8783
05:01:47,697 --> 05:01:48,898
MIBG BLOCKADE, THIS IS WHAT YOU

8784
05:01:48,898 --> 05:01:49,899
JUST SAW IN THE YOUNG.

8785
05:01:49,899 --> 05:01:52,302
THIS IS THE SAME MOUSE, BY THE

8786
05:01:52,302 --> 05:01:54,804
WAY, SAME MOUSE IN THE YOUNG AND

8787
05:01:54,804 --> 05:01:55,138
THE OLD.

8788
05:01:55,138 --> 05:01:58,375
NOW THE SAME MOUSE WITH THE

8789
05:01:58,375 --> 05:02:01,344
AUTONOMICS INTACT, YOU SEE THE

8790
05:02:01,344 --> 05:02:03,947
EFFECT AT SIX MONTHS, AND

8791
05:02:03,947 --> 05:02:05,815
ALTHOUGH THERE'S A MARKED

8792
05:02:05,815 --> 05:02:07,550
INCREASE IN THE HEART RATE OR

8793
05:02:07,550 --> 05:02:08,985
REDUCTION IN THE RR INTERVAL,

8794
05:02:08,985 --> 05:02:12,689
YOU SEE THESE OLD MICE HEARTS

8795
05:02:12,689 --> 05:02:14,958
CANNOT GET TO THESE FAST

8796
05:02:14,958 --> 05:02:16,693
INTERVALS OR EVEN PAST THIS

8797
05:02:16,693 --> 05:02:18,328
INTERVAL IF YOU LOOK AT THE

8798
05:02:18,328 --> 05:02:19,329
SHARP DISTRIBUTION HERE IN THIS

8799
05:02:19,329 --> 05:02:23,032
MOUSE.

8800
05:02:23,032 --> 05:02:28,972
SO THIS IS THE SAME MOUSE AND

8801
05:02:28,972 --> 05:02:32,142
HAD IS WHAT THE RR INTERVAL

8802
05:02:32,142 --> 05:02:33,576
ELECTROCARDIOGRAM WOULD LOOK

8803
05:02:33,576 --> 05:02:34,010
LIKE.

8804
05:02:34,010 --> 05:02:37,914
AT THE YOUNG AGE AND THE

8805
05:02:37,914 --> 05:02:39,149
AUTONOMIC INPUT INTACT YOU SEE

8806
05:02:39,149 --> 05:02:42,619
THESE RECURRENT CORRELATIONS IN

8807
05:02:42,619 --> 05:02:42,952
RR INTERVALS.

8808
05:02:42,952 --> 05:02:44,454
AND YOU SEE THE SAME MOUSE AT 30

8809
05:02:44,454 --> 05:02:49,192
MONTHS OF AGE, VERY LONG TIME,

8810
05:02:49,192 --> 05:02:50,860
SHORT STEPS TO GET UP AND DOWN,

8811
05:02:50,860 --> 05:02:52,295
SO YOU SEE TWO CORRELATIONS HERE

8812
05:02:52,295 --> 05:02:53,730
INSTEAD OF NINE.

8813
05:02:53,730 --> 05:02:58,401
 THERE.

8814
05:02:58,401 --> 05:03:05,108
AND WHAT WE WANTED TO DO WAS TO

8815
05:03:05,108 --> 05:03:07,544
THINK ABOUT WHETHER THOSE NOTES,

8816
05:03:07,544 --> 05:03:09,145
THOSE INTERVALS, MIGHT SOUND

8817
05:03:09,145 --> 05:03:11,981
LIKE MUSICAL NOTES AND WE TEAMED

8818
05:03:11,981 --> 05:03:16,553
UP WITH ELAINE CHEW IN LONDON,

8819
05:03:16,553 --> 05:03:19,589
AND THIS IS THE SAME MOUSE WITH

8820
05:03:19,589 --> 05:03:28,198
BRAIN INPUT.

8821
05:03:28,198 --> 05:03:30,834
SHE IMPROVISED AND PLAYED

8822
05:03:30,834 --> 05:03:32,836
DIFFERENT TYPES OF MUSIC THAT

8823
05:03:32,836 --> 05:03:36,473
SHE KNEW ABOUT.

8824
05:03:36,473 --> 05:03:37,774
LET'S TRY TO GO ALL THE WAY OVER

8825
05:03:37,774 --> 05:03:42,946
HERE NOW TO SAVE TIME.

8826
05:03:42,946 --> 05:03:45,915
THAT WAS A VIOLIN AT SIX MONTHS

8827
05:03:45,915 --> 05:03:46,983
AND THE SAME MOUSE AT 30 MONTHS,

8828
05:03:46,983 --> 05:03:51,321
THIS IS A BASE.

8829
05:03:51,321 --> 05:03:56,593
 BASS.

8830
05:03:56,593 --> 05:03:57,794
THERE GOES MY ANIMATION.

8831
05:03:57,794 --> 05:03:59,662
SORRY ABOUT THAT.

8832
05:03:59,662 --> 05:04:02,499
WE JUST HAVE TO WAIT IT OUT.

8833
05:04:02,499 --> 05:04:12,775
[MUSIC PLAYING]

8834
05:04:13,743 --> 05:04:21,251
NOW MAYBE WE CAN MOVE FORWARD.

8835
05:04:21,251 --> 05:04:23,987
SO THIS IS WHAT YOU JUST HEARD

8836
05:04:23,987 --> 05:04:25,822
AGAIN AT 30 MONTHS OF AGE

8837
05:04:25,822 --> 05:04:32,295
WITHOUT BRAIN INPUT.

8838
05:04:32,295 --> 05:04:34,063
THIS IS NEAR THE END OF THE

8839
05:04:34,063 --> 05:04:38,735
MOUSE'S LIFE.

8840
05:04:38,735 --> 05:04:41,037
OKAY, SO WE WANTED TO KNOW WHAT

8841
05:04:41,037 --> 05:04:45,708
HAPPENED, WHAT'S HAPPENING.

8842
05:04:45,708 --> 05:04:50,980
SO WE TAKE THE SINOATRIAL CELLS,

8843
05:04:50,980 --> 05:04:52,916
WE CAN STUDY THOSE IN SINGLE

8844
05:04:52,916 --> 05:04:56,452
CELLS, AND WE'VE DISCOVERED SOME

8845
05:04:56,452 --> 05:04:59,155
TIME BACK THE EXISTENCE OF A

8846
05:04:59,155 --> 05:05:01,791
COUPLED OSCILLATOR SYSTEM

8847
05:05:01,791 --> 05:05:03,760
THAT -- CALCIUM OSCILLATOR THAT

8848
05:05:03,760 --> 05:05:05,328
WE CALL THE CALCIUM CLOCK AND WE

8849
05:05:05,328 --> 05:05:07,530
RENAMED THE SURFACE MEMBRANE

8850
05:05:07,530 --> 05:05:10,633
ELECTROGENIC MOLECULES THE

8851
05:05:10,633 --> 05:05:11,000
MEMBRANE CLOCK.

8852
05:05:11,000 --> 05:05:12,602
AND LOCAL CALCIUM RELEASES

8853
05:05:12,602 --> 05:05:15,505
ACTIVATE THE MEMBRANE CLOCK TO

8854
05:05:15,505 --> 05:05:23,680
INITIATE ACTION POTENTIALS.

8855
05:05:23,680 --> 05:05:25,014
AND IF WE MEASURE CALCIUM

8856
05:05:25,014 --> 05:05:27,050
SIGNALS, I'LL SHOW YOU IN THESE

8857
05:05:27,050 --> 05:05:31,654
SINGLE SINOATRIAL NODAL CELLS,

8858
05:05:31,654 --> 05:05:33,056
THESE ARE SIMULTANEOUSLY

8859
05:05:33,056 --> 05:05:34,490
MEASURED MEMBRANE POTENTIAL IN

8860
05:05:34,490 --> 05:05:35,058
CALCIUM.

8861
05:05:35,058 --> 05:05:40,163
YOU SEE THIS FLICKERING.

8862
05:05:40,163 --> 05:05:41,831
THESE ARE SCAS TICK LOCAL

8863
05:05:41,831 --> 05:05:44,767
CALCIUM RELEASES THAT

8864
05:05:44,767 --> 05:05:45,201
SELF-ORGANIZE.

8865
05:05:45,201 --> 05:05:48,471
IT'S A STATE OF CONTINUOUS PHASE

8866
05:05:48,471 --> 05:05:49,806
TRANSITIONS THAT SELF-ORGANIZES,

8867
05:05:49,806 --> 05:05:53,109
WE CALL THAT A CRITICALITY

8868
05:05:53,109 --> 05:05:55,578
MECHANISM AND WHEN IT REACHES

8869
05:05:55,578 --> 05:05:56,346
CRITICALITY, WE SEE THE RAPID

8870
05:05:56,346 --> 05:05:58,848
UPSTROKE OF THE ACTION

8871
05:05:58,848 --> 05:06:01,017
POTENTIAL, AND THEN THE ACTION

8872
05:06:01,017 --> 05:06:06,055
POTENTIAL LEADS THE KALS SEUM.

8873
05:06:06,055 --> 05:06:08,124
WHEN WE TAKE THE SINOATRIAL NODE

8874
05:06:08,124 --> 05:06:09,993
TISSUE OUT AND MEASURE THE LOCAL

8875
05:06:09,993 --> 05:06:11,494
CALCIUM RELEASES WE SEE THIS

8876
05:06:11,494 --> 05:06:13,429
TYPE OF BEHAVIOR, LOCAL CALCIUM

8877
05:06:13,429 --> 05:06:17,233
RELEASES LIKE FIBRILLATION OCCUR

8878
05:06:17,233 --> 05:06:18,334
HETEROGENEOUSLY WITHIN WITHIN

8879
05:06:18,334 --> 05:06:19,769
AND AMONG PACEMAKER CELLS.

8880
05:06:19,769 --> 05:06:25,008
SO IF I SHOWED YOU IF I SHOWED

8881
05:06:25,008 --> 05:06:29,846
YOU CALCIUM SIGNALS IN A MOUSE'S

8882
05:06:29,846 --> 05:06:31,047
HEAD BRAIN AND THE HEART BRAIN,

8883
05:06:31,047 --> 05:06:32,248
YOU MIGHT HAVE TROUBLE IF YOU

8884
05:06:32,248 --> 05:06:35,084
HADN'T SEEN THE PREVIOUS SLIDE

8885
05:06:35,084 --> 05:06:36,085
AT KNOWING WHICH IS THE HEAD

8886
05:06:36,085 --> 05:06:37,053
BRAIN AND WHICH IS THE HEART

8887
05:06:37,053 --> 05:06:37,253
BRAIN.

8888
05:06:37,253 --> 05:06:39,689
OF COURSE THIS IS THE SINOATRIAL

8889
05:06:39,689 --> 05:06:41,124
NODE BRAIN SO WE'RE REFERRING TO

8890
05:06:41,124 --> 05:06:41,624
A BRAIN NOW.

8891
05:06:41,624 --> 05:06:44,127
IT HAS THE CYTOARCHITECTURE AND

8892
05:06:44,127 --> 05:06:45,928
FUNCTION VERY SIMILAR TO THE

8893
05:06:45,928 --> 05:06:47,730
HEAD BRAIN.

8894
05:06:47,730 --> 05:06:49,399
SO NOW I'M GOING TO SHOW YOU WHY

8895
05:06:49,399 --> 05:06:50,867
THE AGING HEART'S BRAIN OPERATES

8896
05:06:50,867 --> 05:06:54,604
AT THE EDGE OF DISEASE.

8897
05:06:54,604 --> 05:06:56,139
THESE ARE THE PACEMAKER CELLS

8898
05:06:56,139 --> 05:06:57,273
IMMUNOLABELED IN RED, THIS IS

8899
05:06:57,273 --> 05:06:59,509
THE CENTRAL SINOATRIAL NODE.

8900
05:06:59,509 --> 05:07:01,310
YOU CAN SEE THE MARKED CHANGE IN

8901
05:07:01,310 --> 05:07:04,480
STRUCTURE IN THIS EXAMPLE

8902
05:07:04,480 --> 05:07:06,015
BETWEEN FOUR MONTHS AND 29

8903
05:07:06,015 --> 05:07:06,249
MONTHS.

8904
05:07:06,249 --> 05:07:08,317
THESE ARE NOT THE SAME MOUSE, OF

8905
05:07:08,317 --> 05:07:08,551
COURSE.

8906
05:07:08,551 --> 05:07:10,820
AND YOU CAN SEE THAT THE

8907
05:07:10,820 --> 05:07:15,158
BEATING, RATE AND RHYTHM IS VERY

8908
05:07:15,158 --> 05:07:15,491
DIFFERENT.

8909
05:07:15,491 --> 05:07:19,595
SO AGAIN, WHAT HAPPENED?

8910
05:07:19,595 --> 05:07:21,397
THIS IS THE COUPLED CLOCK SYSTEM

8911
05:07:21,397 --> 05:07:25,501
THAT I TOLLED YOU ABOUT BEFORE

8912
05:07:25,501 --> 05:07:26,069
AND WITH AGING, SOME OF THE

8913
05:07:26,069 --> 05:07:27,236
CRUCIAL MOLECULES THAT PUMP

8914
05:07:27,236 --> 05:07:28,337
CALCIUM INTO THE STORAGE SITE

8915
05:07:28,337 --> 05:07:32,008
THAT'S THE CALCIUM CLOCK, THE

8916
05:07:32,008 --> 05:07:34,777
RELEASE CHANNELS, AND THE

8917
05:07:34,777 --> 05:07:38,081
SURFACE MEMBRANE PROTEIN THAT

8918
05:07:38,081 --> 05:07:40,383
THE CALCIUM TALKS TO ONCE IT'S

8919
05:07:40,383 --> 05:07:41,250
RELEASED CHANGE WITH AGING, AND

8920
05:07:41,250 --> 05:07:41,784
THAT'S SHOWN HERE.

8921
05:07:41,784 --> 05:07:44,787
THIS IS THE PERCENT REDUCTION

8922
05:07:44,787 --> 05:07:49,892
FROM THE YOUNG MOUSE, CIRCA 2,

8923
05:07:49,892 --> 05:07:53,930
THAT'S THE SODIUM CALCIUM

8924
05:07:53,930 --> 05:07:55,364
EXCHANGER ON THE RECEPTOR.

8925
05:07:55,364 --> 05:07:57,900
WE CAN STUDY THE CALCIUM CLOCK

8926
05:07:57,900 --> 05:07:58,434
DIRECTLY WITHOUT ANY

8927
05:07:58,434 --> 05:08:03,439
INTERFERENCE FROM THE MEMBRANE

8928
05:08:03,439 --> 05:08:06,976
CLOCK, WE SEE THESE LOCAL

8929
05:08:06,976 --> 05:08:09,846
CALCIUM RELEASES IN THE YOUNG

8930
05:08:09,846 --> 05:08:11,047
EXAMPLE HERE, THEY'RE VERY

8931
05:08:11,047 --> 05:08:13,549
DIFFERENT IN THE OLD, AND

8932
05:08:13,549 --> 05:08:19,021
PERFORMING A FAST FOUR YR

8933
05:08:19,021 --> 05:08:20,790
TRANSFORM ON THAT DATA WE CAN

8934
05:08:20,790 --> 05:08:22,558
SEE QUITE CAREERLY THAT THE

8935
05:08:22,558 --> 05:08:23,993
PREFERRED RESONANCE FREQUENCY IS

8936
05:08:23,993 --> 05:08:25,962
REDUCED IN OLDER AGE COMPARED TO

8937
05:08:25,962 --> 05:08:26,395
THE YOUNGER ADULT.

8938
05:08:26,395 --> 05:08:28,364
AND IF WE LOOK HERE, THIS IS

8939
05:08:28,364 --> 05:08:32,034
PROBABLY THE MOST CRITICAL SLIDE

8940
05:08:32,034 --> 05:08:36,172
THAT I'VE SHOWN YOU SO FAR, WITH

8941
05:08:36,172 --> 05:08:39,008
RESPECT TO MECHANISM, CALCIUM IS

8942
05:08:39,008 --> 05:08:40,576
THE ACYL TRI SUBSTRATE, OF

8943
05:08:40,576 --> 05:08:46,315
COURSE, AND THE FREQUENCY THAT

8944
05:08:46,315 --> 05:08:50,820
THIS CALCIUM CLOCK -- INCREASES

8945
05:08:50,820 --> 05:08:53,222
WITH CALCIUM -- I THANK YOU VERY

8946
05:08:53,222 --> 05:08:55,958
MUCH -- BUT YOU SEE THE CURVE

8947
05:08:55,958 --> 05:08:56,592
HAS SHIFTED DOWNWARD TO THE

8948
05:08:56,592 --> 05:08:57,794
RIGHT IN THE OLD, AND THIS

8949
05:08:57,794 --> 05:09:00,563
ORGANELLE, THE MEMORY OF THIS

8950
05:09:00,563 --> 05:09:03,966
ORGANELLE OF THE

8951
05:09:03,966 --> 05:09:04,667
CALCIUM CLOCK IS HOW MUCH

8952
05:09:04,667 --> 05:09:05,768
CALCIUM IS THERE, AND THE

8953
05:09:05,768 --> 05:09:08,171
CALCIUM THAT CAN LOAD INTO IT IS

8954
05:09:08,171 --> 05:09:11,240
REDUCED IN OLDER AGE.

8955
05:09:11,240 --> 05:09:14,744
SO IN SUMMARY, THEN, THE SAN

8956
05:09:14,744 --> 05:09:18,681
BRAIN WE CAN CONSIDER --

8957
05:09:18,681 --> 05:09:19,582
SINOATRIAL NODE BRAIN IS A

8958
05:09:19,582 --> 05:09:20,550
COMPUTER NETWORK IN WHICH

8959
05:09:20,550 --> 05:09:22,118
INDIVIDUAL COMPUTERS ARE HARD

8960
05:09:22,118 --> 05:09:23,753
WIRED WITH THIS COUPLED

8961
05:09:23,753 --> 05:09:24,387
OSCILLATOR SYSTEM.

8962
05:09:24,387 --> 05:09:28,457
DIFFERENT APPS ARE APPLIED TO

8963
05:09:28,457 --> 05:09:29,559
ENCODE VARIATIONS IN THE MEMORY

8964
05:09:29,559 --> 05:09:31,160
WITHIN THE INDIVIDUAL COMPUTERS

8965
05:09:31,160 --> 05:09:32,695
THAT DETERMINE ITS MEAN

8966
05:09:32,695 --> 05:09:34,463
PREFERRED RESONANCE FREQUENCY

8967
05:09:34,463 --> 05:09:35,331
AND VARIABILITY AROUND THAT

8968
05:09:35,331 --> 05:09:38,267
FREQUENCY.

8969
05:09:38,267 --> 05:09:40,469
I PREFER RESIDENCE FREQUENCIES

8970
05:09:40,469 --> 05:09:42,572
REQUIRE VERY SYNCHRONIZED

8971
05:09:42,572 --> 05:09:43,973
KINETICS OF THESE FUNCTIONAL

8972
05:09:43,973 --> 05:09:46,042
TRANSITIONS THAT I TOLD YOU

8973
05:09:46,042 --> 05:09:47,543
ABOUT, KINETIC TRANSITIONS, SO

8974
05:09:47,543 --> 05:09:51,714
THAT WITH AGING, WE HAVE A

8975
05:09:51,714 --> 05:09:53,583
SITUATION OF PROGRESSIVE

8976
05:09:53,583 --> 05:09:54,250
MOLECULAR DISORDER, AND I LIKE

8977
05:09:54,250 --> 05:09:56,552
TO ENVISION IT AS AGING EXTRACTS

8978
05:09:56,552 --> 05:09:58,621
CHAOS FROM ORDER, THERE'S

8979
05:09:58,621 --> 05:10:01,190
REDUCED MOLECULAR DENSITY, POST

8980
05:10:01,190 --> 05:10:04,093
TRANSLATIONAL MODIFICAT

8981
05:10:04,093 --> 05:10:05,394
MODIFICATIONS, DISORDERED AND

8982
05:10:05,394 --> 05:10:07,396
DESYNCHRONIZED MOLECULAR

8983
05:10:07,396 --> 05:10:09,465
INTERACTIONS, SEVERE DISTORTION

8984
05:10:09,465 --> 05:10:11,434
OF PROTEOSTASIS, INFLAMMATION,

8985
05:10:11,434 --> 05:10:15,037
FIBROSIS AND INCREASED ENTROPY

8986
05:10:15,037 --> 05:10:17,039
WITHIN CELLS, TISSUES, ORGANS

8987
05:10:17,039 --> 05:10:18,174
AND ORGANISMS.

8988
05:10:18,174 --> 05:10:20,409
AND THE OLD SAN CAN'T REMEMBER

8989
05:10:20,409 --> 05:10:21,477
HOW TO HIT THE HIGH NOTES, THAT

8990
05:10:21,477 --> 05:10:23,546
IS TO GENERATE THE SHORT

8991
05:10:23,546 --> 05:10:25,715
INTERVALS, BECAUSE BOTH THE

8992
05:10:25,715 --> 05:10:27,683
HARDWARE THAT IT HAS AND THE APP

8993
05:10:27,683 --> 05:10:29,986
THAT ENCODESSITY MEMORY FOR

8994
05:10:29,986 --> 05:10:34,757
THOSE HIGH FREQUENCY GENERATION,

8995
05:10:34,757 --> 05:10:36,525
THAT SYMPATHETIC, AUTONOMIC,

8996
05:10:36,525 --> 05:10:37,460
BOTH DETERIORATE IN ADVANCED

8997
05:10:37,460 --> 05:10:37,727
AGE.

8998
05:10:37,727 --> 05:10:41,364
IN OTHER TERMS, THE FRAIL SAN

8999
05:10:41,364 --> 05:10:43,966
BRAIN BECOMES DEMENTED IN

9000
05:10:43,966 --> 05:10:45,368
ADVANCED AGE AND THUS THE

9001
05:10:45,368 --> 05:10:47,570
HEART-BRAIN MEMORY FAILURE

9002
05:10:47,570 --> 05:10:48,838
UNDERPINS THE FLAT HEARTBEAT

9003
05:10:48,838 --> 05:10:50,573
MUSIC THAT RESULTS IN AN

9004
05:10:50,573 --> 05:10:52,008
INABILITY TO BEAT AT FASTER

9005
05:10:52,008 --> 05:10:54,644
RATES, AND WE REFER TO THAT AS

9006
05:10:54,644 --> 05:10:56,379
THE HEARTBEAT FRAILTY IN OLDER

9007
05:10:56,379 --> 05:10:58,247
AGE.

9008
05:10:58,247 --> 05:11:00,216
FINALLY, WE MIGHT CONSIDER THAT

9009
05:11:00,216 --> 05:11:05,054
THE ROAD TO HEARTBEAT FRAILTY IS

9010
05:11:05,054 --> 05:11:06,889
THE SYNCHRONIZED MOLECULAR

9011
05:11:06,889 --> 05:11:07,757
INTERACTIONS BECOME

9012
05:11:07,757 --> 05:11:08,758
DESYNCHRONIZED WITH AGING.

9013
05:11:08,758 --> 05:11:12,695
THIS LEADS TO HEART DISEASES AND

9014
05:11:12,695 --> 05:11:15,431
TO HEARTBEAT FRAILTY AS I JUST

9015
05:11:15,431 --> 05:11:17,266
DESCRIBED, AND AMONG THOSE IS

9016
05:11:17,266 --> 05:11:19,936
THE SICK SINUS SYNDROME WHERE WE

9017
05:11:19,936 --> 05:11:23,606
STARTED, OTHER ARRHYTHMIAS,

9018
05:11:23,606 --> 05:11:25,474
CONTRACTILE DYSFUNCTIONS AND

9019
05:11:25,474 --> 05:11:30,913
CHRONIC HEART FIT.

9020
05:11:30,913 --> 05:11:34,116
SO THANKS FOR YOUR ATTENTION.

9021
05:11:34,116 --> 05:11:38,254
>> THANK YOU VERY MUCH,

9022
05:11:38,254 --> 05:11:41,357
DR. LAKATTA.

9023
05:11:41,357 --> 05:11:42,625
>> THANK YOU.

9024
05:11:42,625 --> 05:11:44,193
I THINK WE HAD ONE QUESTION.

9025
05:11:44,193 --> 05:11:49,465
I DON'T KNOW IF YOU WANT TO

9026
05:11:49,465 --> 05:11:52,568
UNMUTE, DR.?

9027
05:11:52,568 --> 05:11:55,204
>> HI, DR. LAKATA.

9028
05:11:55,204 --> 05:11:56,605
VERY INTERESTING TALK AND VERY

9029
05:11:56,605 --> 05:11:57,173
ENTERTAINING.

9030
05:11:57,173 --> 05:12:00,643
I'M GOING TO ASK SORT OF A

9031
05:12:00,643 --> 05:12:01,277
PHILOSOPHICAL QUESTION THAT MAY

9032
05:12:01,277 --> 05:12:02,144
BE IMPORTANT TO ALL OF US.

9033
05:12:02,144 --> 05:12:03,579
IT LOOKS LIKE THE HEART CLOCK OR

9034
05:12:03,579 --> 05:12:05,748
THE BRAIN AND HEART CLOCK ARE

9035
05:12:05,748 --> 05:12:09,585
MEANT TO SLOW DOWN TOWARDS A

9036
05:12:09,585 --> 05:12:10,686
HALT, AND I WAS WONDERING

9037
05:12:10,686 --> 05:12:15,691
WHETHER THERE IS A WAY TO

9038
05:12:15,691 --> 05:12:17,927
PREDICT WHEN THEY WILL STOP.

9039
05:12:17,927 --> 05:12:19,762
SOME PEOPLE HAVE HIGHER HEART

9040
05:12:19,762 --> 05:12:21,530
BEATS AND EVEN SOME OF THE

9041
05:12:21,530 --> 05:12:26,068
GREATEST ATHLETES ARE SUPPOSED

9042
05:12:26,068 --> 05:12:27,136
TO HAVE VERY SLOW HEARTBEAT.

9043
05:12:27,136 --> 05:12:31,507
SO IS THIS A TYPE OF LONGITUDAL

9044
05:12:31,507 --> 05:12:32,708
MEASUREMENT THAT YOU MIGHT

9045
05:12:32,708 --> 05:12:34,777
ENVISION WE MIGHT NEED OR HOW

9046
05:12:34,777 --> 05:12:35,911
WOULD YOU GO ABOUT

9047
05:12:35,911 --> 05:12:36,245
INVESTIGATING?

9048
05:12:36,245 --> 05:12:38,014
>> ABSOLUTELY.

9049
05:12:38,014 --> 05:12:39,882
THE ATHLETES HAVE A SLOW HEART

9050
05:12:39,882 --> 05:12:42,351
RATE AT REST BECAUSE OF THE

9051
05:12:42,351 --> 05:12:44,754
VAGAL INPUT, BUT THE HEART RATE

9052
05:12:44,754 --> 05:12:49,325
RESERVE THAT I TALKED ABOUT IS

9053
05:12:49,325 --> 05:12:49,959
IMMUTABLE, SO IT'S THE SAME, THE

9054
05:12:49,959 --> 05:12:54,397
HEART RATE RESERVE FROM -- THE

9055
05:12:54,397 --> 05:12:55,631
MAXIMUM HEART RATE IN ATHLETES

9056
05:12:55,631 --> 05:12:59,101
AS WELL AS SEDENTARY OLDER

9057
05:12:59,101 --> 05:13:00,836
PERSONS, AND WE DO NEED

9058
05:13:00,836 --> 05:13:01,604
LONGITUDINAL STUDIES.

9059
05:13:01,604 --> 05:13:05,574
WE HAD A LOT OF DISCUSSION ON

9060
05:13:05,574 --> 05:13:07,543
THAT THIS MORNING BECAUSE

9061
05:13:07,543 --> 05:13:08,778
THERE'S VARIABILITY AT OLDER

9062
05:13:08,778 --> 05:13:13,682
AGES WHEN WE GET INTO THE HEART

9063
05:13:13,682 --> 05:13:16,118
RATE IN THE MOUSE, FOR EXAMPLE,

9064
05:13:16,118 --> 05:13:17,353
PAST 21 MONTHS OF AGE, THIS IS

9065
05:13:17,353 --> 05:13:18,754
WHERE ALL THE ACTION HAPPENS AND

9066
05:13:18,754 --> 05:13:23,592
WE GET AN EXPONENTIAL

9067
05:13:23,592 --> 05:13:24,827
ACCELERATION OF THE

9068
05:13:24,827 --> 05:13:26,128
DESYNCHRONIZATION WITHIN THE

9069
05:13:26,128 --> 05:13:28,597
SINOATRIAL NODE.

9070
05:13:28,597 --> 05:13:31,534
SO KNOWING WHEN THE AUTONOMIC

9071
05:13:31,534 --> 05:13:34,637
INPUT HAS TO BE APPLIED TO TRY

9072
05:13:34,637 --> 05:13:37,473
IT MAINTAIN THE YOUTHFUL

9073
05:13:37,473 --> 05:13:39,475
HEARTBEAT, THAT'S THE BEGINNING,

9074
05:13:39,475 --> 05:13:41,143
SO THAT CAN BE FOUND

9075
05:13:41,143 --> 05:13:44,647
LONGITUDALLY BY APPLYING DOUBLE

9076
05:13:44,647 --> 05:13:46,782
AUTONOMIC BLOCKADE, YOU GET THE

9077
05:13:46,782 --> 05:13:47,216
AUTONOMIC SIGNATURE.

9078
05:13:47,216 --> 05:13:48,617
THAT'S WHEN THE HEART IS TALKING

9079
05:13:48,617 --> 05:13:50,019
TO THE BRAIN TO SAY, GIVE ME

9080
05:13:50,019 --> 05:13:52,188
SOME MORE JUICE, THE BODY NEEDS

9081
05:13:52,188 --> 05:13:55,691
MORE BLOOD.

9082
05:13:55,691 --> 05:13:56,659
>> FANTASTIC.

9083
05:13:56,659 --> 05:13:57,193
THANK YOU.

9084
05:13:57,193 --> 05:13:59,528
AND I THINK YET AGAIN, WE ARE

9085
05:13:59,528 --> 05:14:00,129
RUNNING SHORT ON TIME AND WE

9086
05:14:00,129 --> 05:14:02,398
WILL HAVE THE PANEL DISCUSSION.

9087
05:14:02,398 --> 05:14:05,901
I THINK WE ARE NEXT SCHEDULED

9088
05:14:05,901 --> 05:14:12,408
FROM 4:00 TO 4:20, WITH DR. LISA

9089
05:14:12,408 --> 05:14:13,042
LESNIEWSKI FROM THE UNIVERSITY

9090
05:14:13,042 --> 05:14:14,777
OF UTAH WHO'S GOING TO BE

9091
05:14:14,777 --> 05:14:17,213
TALKING ABOUT TARGETING SULFUR

9092
05:14:17,213 --> 05:14:19,081
AMINO ACID METABOLISM FOR

9093
05:14:19,081 --> 05:14:26,422
LONGEVITY AND TUMOR SUPPRESSION.

9094
05:14:26,422 --> 05:14:28,257
OH, NO, APOLOGIES.

9095
05:14:28,257 --> 05:14:29,492
LISA, YOU'RE NOT TALKING ABOUT

9096
05:14:29,492 --> 05:14:30,893
SULFIDE, YOU'RE TALKING ABOUT

9097
05:14:30,893 --> 05:14:34,196
MECHANISMS AND CON QENSES OF

9098
05:14:34,196 --> 05:14:35,731
AGE-RELATED ENDOTHELIAL

9099
05:14:35,731 --> 05:14:36,232
DYSFUNCTION AND CAN WE

9100
05:14:36,232 --> 05:14:36,499
INTERVENE.

9101
05:14:36,499 --> 05:14:38,267
SO GO AHEAD AND HIT IT.

9102
05:14:38,267 --> 05:14:42,104
>> YEAH, I CAN'T SEEM TO
SEE THE

9103
05:14:42,104 --> 05:14:42,738
WHOLE SCREEN FOR LIKE THE ZOOM

9104
05:14:42,738 --> 05:14:44,106
SCREEN FOR SOME REASON.

9105
05:14:44,106 --> 05:14:46,208
>> I THINK YOU JUST NEED
TO HIT

9106
05:14:46,208 --> 05:14:47,877
THE PRESENTATION MODE OR THE

9107
05:14:47,877 --> 05:14:48,677
LITTLE SLIDE ICON DOWN IN THE

9108
05:14:48,677 --> 05:14:50,613
BOTTOM AND IT SHOULD COME UP.

9109
05:14:50,613 --> 05:14:52,648
>> ALL I CAN SEE IS LIKE
PEOPLE,

9110
05:14:52,648 --> 05:14:57,920
LIKE YOU AND MY FACE.

9111
05:14:57,920 --> 05:14:58,888
>> THAT'S UNFORTUNATE.

9112
05:14:58,888 --> 05:15:00,189
>> I'M NOT SURE HOW TO
MAKE THIS

9113
05:15:00,189 --> 05:15:00,956
WORK.

9114
05:15:00,956 --> 05:15:02,758
CAN YOU SEE THE --

9115
05:15:02,758 --> 05:15:04,827
>> TRY TO RESHARE,
SOMETIMES

9116
05:15:04,827 --> 05:15:05,194
THAT WORKS.

9117
05:15:05,194 --> 05:15:05,928
>> OH, WAIT.

9118
05:15:05,928 --> 05:15:06,695
DOES THAT WORK NOW?

9119
05:15:06,695 --> 05:15:09,665
>> THERE, PER FORECAST.

9120
05:15:09,665 --> 05:15:10,666
YEP.

9121
05:15:10,666 --> 05:15:13,602
>> LET ME SHRINK THIS BACK
DOWN

9122
05:15:13,602 --> 05:15:15,671
AGAIN.

9123
05:15:15,671 --> 05:15:17,873
SO I WOULD LIKE TO THANK THE

9124
05:15:17,873 --> 05:15:18,541
ORGANIZERS FOR INVITING ME TO

9125
05:15:18,541 --> 05:15:19,975
PRESENT, AND TODAY I'M GOING TO

9126
05:15:19,975 --> 05:15:22,611
SHARE SOME RECENT WORK FROM OUR

9127
05:15:22,611 --> 05:15:24,180
LABORATORY THAT'S BEEN EXPLORING

9128
05:15:24,180 --> 05:15:25,548
THE POTENTIAL ROLE FOR THE ENT

9129
05:15:25,548 --> 05:15:27,316
THELIUM IN MODULATING NOT ONLY

9130
05:15:27,316 --> 05:15:29,418
VASCULAR BUT METABOLIC FUNCTION

9131
05:15:29,418 --> 05:15:37,393
IN AGING.

9132
05:15:37,393 --> 05:15:38,894
SO BOTH METABOLIC AND VASCULAR

9133
05:15:38,894 --> 05:15:40,229
DISEASES ARE COMMON IN OLDER

9134
05:15:40,229 --> 05:15:41,864
ADULTS.

9135
05:15:41,864 --> 05:15:43,699
AND THIS GRAPH IS THE PREVALENCE

9136
05:15:43,699 --> 05:15:45,501
OF DIABETES AMONG U.S. ADULTS

9137
05:15:45,501 --> 05:15:46,535
AND WHAT CAN BE APPRECIATED IS

9138
05:15:46,535 --> 05:15:48,771
THAT THERE'S AN ALMOST LINEAR

9139
05:15:48,771 --> 05:15:50,239
INCREASE IN DIABETES WITH

9140
05:15:50,239 --> 05:15:50,773
ADVANCING AGE.

9141
05:15:50,773 --> 05:15:53,309
THIS AGE-ASSOCIATED INCREASE IN

9142
05:15:53,309 --> 05:15:54,643
METABOLIC DISEASE IS

9143
05:15:54,643 --> 05:15:56,111
CHARACTERIZED BY IMPAIRED

9144
05:15:56,111 --> 05:15:57,746
GLUCOSE TOLERANCE AND INSULIN

9145
05:15:57,746 --> 05:15:59,715
RESISTANCE, ADIPOSE TISSUE

9146
05:15:59,715 --> 05:16:02,218
DYSFUNCTION, ECTOPIC LIPID

9147
05:16:02,218 --> 05:16:03,852
ACCUMULATION AND LIPOTOXICITY,

9148
05:16:03,852 --> 05:16:05,754
CHRONIC STERILE INFLAMMATION AS

9149
05:16:05,754 --> 05:16:09,425
WELL AS TISSUE SENESCENCE.

9150
05:16:09,425 --> 05:16:10,759
LIKEWISE, AGING IS ALSO

9151
05:16:10,759 --> 05:16:11,727
ASSOCIATED WITH A LINEAR

9152
05:16:11,727 --> 05:16:13,796
INCREASE IN THE PREVALENCE OF

9153
05:16:13,796 --> 05:16:14,597
CARDIOVASCULAR DISEASES.

9154
05:16:14,597 --> 05:16:17,399
AND THIS INCREASE IS ASSOCIATED

9155
05:16:17,399 --> 05:16:20,102
WITH BOTH AGE-RELATED LARGE

9156
05:16:20,102 --> 05:16:22,004
ARTERY STIFFENING AND

9157
05:16:22,004 --> 05:16:23,539
ENDOTHELIAL DYSFUNCTION.

9158
05:16:23,539 --> 05:16:24,306
AND TODAY, ALTHOUGH WE HAVE DATA

9159
05:16:24,306 --> 05:16:25,608
ON THE LARGE ARTERY STIFFENING

9160
05:16:25,608 --> 05:16:27,743
PART OF THIS, WE'RE REALLY GOING

9161
05:16:27,743 --> 05:16:29,144
TO FOCUS ON ENDOTHELIAL

9162
05:16:29,144 --> 05:16:30,379
DYSFUNCTION.

9163
05:16:30,379 --> 05:16:32,581
IN MY LAB, WE'RE PARTICULARLY

9164
05:16:32,581 --> 05:16:34,116
INTERESTED IN THE MECHANISMS AND

9165
05:16:34,116 --> 05:16:35,684
CONSEQUENCES OF ENDOTHELIAL

9166
05:16:35,684 --> 05:16:35,985
DYSFUNCTION.

9167
05:16:35,985 --> 05:16:39,221
SO I JUST WANT TO TAKE A STEP

9168
05:16:39,221 --> 05:16:41,223
BACK AND LET EVERYTHING KNOW

9169
05:16:41,223 --> 05:16:43,292
ABOUT THE ENDOTHELIUM WHO MIGHT

9170
05:16:43,292 --> 05:16:43,492
NOT.

9171
05:16:43,492 --> 05:16:44,593
IT'S A SINGLE LAYER OF CELLS

9172
05:16:44,593 --> 05:16:46,462
THAT LINES THE INSIDE OF OUR

9173
05:16:46,462 --> 05:16:47,229
BLOOD VESSELS.

9174
05:16:47,229 --> 05:16:49,398
WHILE IT WAS ONCE THOUGHT TO BE

9175
05:16:49,398 --> 05:16:51,500
AN INNER BARRIER, THE

9176
05:16:51,500 --> 05:16:52,101
ENDOTHELIUM IS NOW APPRECIATED

9177
05:16:52,101 --> 05:16:53,435
TO BE A DYNAMIC ORGAN THAT PLAYS

9178
05:16:53,435 --> 05:16:56,005
A CRITICAL ROLE NOT ONLY IN THE

9179
05:16:56,005 --> 05:16:57,306
VASCULAR BARRIER FUNCTION BUT

9180
05:16:57,306 --> 05:17:00,476
ALSO CONTROLS VASCULAR TONE AND

9181
05:17:00,476 --> 05:17:02,044
AS A RESULT BOTH PERIPHERAL

9182
05:17:02,044 --> 05:17:03,345
RESISTANCE AND BLOOD FLOW

9183
05:17:03,345 --> 05:17:03,812
DISTRIBUTION.

9184
05:17:03,812 --> 05:17:06,515
AN THE THELIUM IS OF PARTICULAR

9185
05:17:06,515 --> 05:17:08,217
INTEREST TO US BECAUSE IT REALLY

9186
05:17:08,217 --> 05:17:10,185
INTERACTS WITH ALL TISSUES OF

9187
05:17:10,185 --> 05:17:10,786
THE BODY AS CAN BE APPRECIATED

9188
05:17:10,786 --> 05:17:12,821
BY LOOKING AT THIS VASCULAR

9189
05:17:12,821 --> 05:17:19,762
CASTING OF A HUMAN.

9190
05:17:19,762 --> 05:17:21,063
SO THE ENDO THELIUM PRODUCES A

9191
05:17:21,063 --> 05:17:22,831
NUMBER OF VASOACTIVE SUBSTANCES

9192
05:17:22,831 --> 05:17:24,433
BUT ONE IN PARTICULAR IS VERY

9193
05:17:24,433 --> 05:17:25,234
IMPORTANT, AND THAT'S NITRIC

9194
05:17:25,234 --> 05:17:27,102
OXIDE, SO THAT'S SHOWN HERE AS

9195
05:17:27,102 --> 05:17:27,670
NO.

9196
05:17:27,670 --> 05:17:30,406
NO IS PRODUCED BY THE ENZYME

9197
05:17:30,406 --> 05:17:32,041
ENDOTHELIAL NITRIC OXIDE

9198
05:17:32,041 --> 05:17:33,909
SYNTHASE IN RESPONSE TO EITHER

9199
05:17:33,909 --> 05:17:37,379
AGONISTS SUCH AS ACETYLCHOLINE

9200
05:17:37,379 --> 05:17:38,113
OR INSULIN OR SHEER STRESS.

9201
05:17:38,113 --> 05:17:40,215
AND THIS NITRIC OXIDE ACTS TO

9202
05:17:40,215 --> 05:17:42,985
RELAX THE SMOOTH MUSCLE AND

9203
05:17:42,985 --> 05:17:45,187
PRODUCE VASODILATION IN THE

9204
05:17:45,187 --> 05:17:45,954
VESSELS.

9205
05:17:45,954 --> 05:17:48,924
BUT NITRIC OXIDE ALSO HAS

9206
05:17:48,924 --> 05:17:51,126
IMPORTANT ANTI-INFLAMMATORY

9207
05:17:51,126 --> 05:17:54,196
EFFECTS BIM -- AS WELL AS

9208
05:17:54,196 --> 05:17:55,297
THROMBOTIC EFFECTS THROUGH

9209
05:17:55,297 --> 05:17:56,365
PLATELET INHIBITION.

9210
05:17:56,365 --> 05:17:59,335
AND IN ADDITION, NITRIC OXIDE

9211
05:17:59,335 --> 05:18:01,470
CAN ALSO INHIBIT PROLIFERATION

9212
05:18:01,470 --> 05:18:03,539
IN THE SMOOTH MUSCLE.

9213
05:18:03,539 --> 05:18:04,973
AND WHAT IS COMMONLY KNOWN WITH

9214
05:18:04,973 --> 05:18:08,477
AGING IS THAT WE HAVE A LOSS OF

9215
05:18:08,477 --> 05:18:09,445
ENDOTHELIAL FUNCTION THAT'S

9216
05:18:09,445 --> 05:18:11,447
CHARACTERIZED BY A REDUCTION IN

9217
05:18:11,447 --> 05:18:13,615
ENDOTHELIUM DEPENDENT DILATION

9218
05:18:13,615 --> 05:18:17,019
AND A REDUCTION IN NITRIC OXIDE.

9219
05:18:17,019 --> 05:18:18,320
SO WHILE IT'S EASY TO APPRECIATE

9220
05:18:18,320 --> 05:18:20,856
THAT THERE'S A ROLE FOR THE

9221
05:18:20,856 --> 05:18:21,724
ENDOTHELIUM IN CONTROLLING

9222
05:18:21,724 --> 05:18:22,424
VASCULAR FUNCTION, THERE'S

9223
05:18:22,424 --> 05:18:23,392
EVIDENCE IN THE LITERATURE THAT

9224
05:18:23,392 --> 05:18:25,160
THE ENDOTHELIUM MAY ALSO PLAY A

9225
05:18:25,160 --> 05:18:27,196
ROLE IN MODULATING METABOLISM.

9226
05:18:27,196 --> 05:18:28,997
SO WE SOUGHT TO DETERMINE IF

9227
05:18:28,997 --> 05:18:30,766
EXPERIMENTALLY IMPAIRING

9228
05:18:30,766 --> 05:18:32,067
ENDOTHELIAL FUNCTION WOULD HAVE

9229
05:18:32,067 --> 05:18:34,503
A DIRECT EFFECT ON SYSTEMIC

9230
05:18:34,503 --> 05:18:36,372
GLUCOSE AND INSULIN METABOLISM.

9231
05:18:36,372 --> 05:18:39,775
SO DO SO, WE UTILIZED A MODEL OF

9232
05:18:39,775 --> 05:18:41,310
ENDOTHELIAL R6 KNOCKOUT THAT WE

9233
05:18:41,310 --> 05:18:42,244
OBTAINED FROM A COLLEAGUE AT THE

9234
05:18:42,244 --> 05:18:45,414
UNIVERSITY OF UTAH.

9235
05:18:45,414 --> 05:18:47,483
SO R6 IS A SMALL GTP ACE IN THE

9236
05:18:47,483 --> 05:18:49,451
RAS FAMILY THAT IS SHOWN TO BE

9237
05:18:49,451 --> 05:18:51,253
INVOSMED IN SOME FUNCTIONS OF

9238
05:18:51,253 --> 05:18:52,221
THE ENDOTHELIUM INCLUDING THE

9239
05:18:52,221 --> 05:18:53,756
CONTROL OF PERMEABILITY AND

9240
05:18:53,756 --> 05:18:56,191
SENSING OF SHEER STRESS AS WELL

9241
05:18:56,191 --> 05:19:02,765
AS AN NF KAPPA BY -- R6 KNOCKOUT

9242
05:19:02,765 --> 05:19:06,735
MODEL THAT WAS CREATED USING A

9243
05:19:06,735 --> 05:19:10,339
CDH5 -- IN WHICH A ROLE FOR --

9244
05:19:10,339 --> 05:19:11,640
THIS ANIMAL HAD BEEN USED

9245
05:19:11,640 --> 05:19:17,012
PREVIOUSLY TO SHOW A ROLE FOR RN

9246
05:19:17,012 --> 05:19:19,047
IN THE SETTING OF DIABETIC

9247
05:19:19,047 --> 05:19:19,915
RETINOPATHY BUT WHAT HAD NOT

9248
05:19:19,915 --> 05:19:21,617
BEEN LOOKED AT IS IF THERE'S A

9249
05:19:21,617 --> 05:19:23,786
ROLE FOR R6 IN THE VASODIAL TRI

9250
05:19:23,786 --> 05:19:27,022
ACTIONS OF THE ENDOTHELIUM.

9251
05:19:27,022 --> 05:19:28,490
SO USING THIS MODEL, WE WERE

9252
05:19:28,490 --> 05:19:29,658
ABLE TO INDUCE A SIGNIFICANT

9253
05:19:29,658 --> 05:19:32,828
REDUCTION IN R6 PROTEIN

9254
05:19:32,828 --> 05:19:34,596
EXPRESSION AND ISOLATED LONG

9255
05:19:34,596 --> 05:19:36,231
PRIMARY ENDOTHELIAL CELLS AFTER

9256
05:19:36,231 --> 05:19:36,799
TAMOXIFEN TREAT M.

9257
05:19:36,799 --> 05:19:38,100
AND YOU CAN SEE THAT HERE.

9258
05:19:38,100 --> 05:19:40,135
SO USING THIS, WE THEN SOUGHT TO

9259
05:19:40,135 --> 05:19:42,838
EXPLORE THE ROLE OF R6 IN

9260
05:19:42,838 --> 05:19:44,339
ENDOTHELIUM DEPENDENT DILATION

9261
05:19:44,339 --> 05:19:46,074
AS WELL AS THE POTENTIAL IMPACT

9262
05:19:46,074 --> 05:19:47,309
OF THIS DYSFUNCTION ON GLUCOSE

9263
05:19:47,309 --> 05:19:51,013
AND INSULIN METABOLISM.

9264
05:19:51,013 --> 05:19:54,116
SO WE FIRST ASSESSED

9265
05:19:54,116 --> 05:19:56,118
VASODILATION IN FEED ARTERIES

9266
05:19:56,118 --> 05:19:57,286
EXCISED FROM THE GASTROCNEMIUS

9267
05:19:57,286 --> 05:19:58,420
JUST MUSCLE.

9268
05:19:58,420 --> 05:20:00,289
THESE ARTERIES ARE CANNULATED

9269
05:20:00,289 --> 05:20:03,525
INTO THE STAGE OF A MYOGRAPH AND

9270
05:20:03,525 --> 05:20:05,727
THEN VISUALIZED USING AN

9271
05:20:05,727 --> 05:20:06,328
INVERTED MICROSCOPE AND WE'RE

9272
05:20:06,328 --> 05:20:08,030
ABLE TO MEASURE THE LUMINAL

9273
05:20:08,030 --> 05:20:10,432
DIAMETER.

9274
05:20:10,432 --> 05:20:12,734
AND DEVELOPED CURVES IN RESPONSE

9275
05:20:12,734 --> 05:20:13,202
TO DIFFERENT AGONISTS.

9276
05:20:13,202 --> 05:20:15,471
AND IN THIS CASE, WE APPLIED

9277
05:20:15,471 --> 05:20:16,472
INCREASING CONCENTRATIONS OF

9278
05:20:16,472 --> 05:20:20,142
INSULIN TO THE BATH, AND WERE

9279
05:20:20,142 --> 05:20:22,978
ABLE TO ASSESS VASODILATION HERE

9280
05:20:22,978 --> 05:20:24,379
TO THE WILD TYPE ANIMALS IN

9281
05:20:24,379 --> 05:20:27,716
BLACK AND WE COULD SEE A ROBUST

9282
05:20:27,716 --> 05:20:30,118
STYDILATION IN THE FEED ARTERY N

9283
05:20:30,118 --> 05:20:31,320
RESPONSE TO INSULIN FROM THE

9284
05:20:31,320 --> 05:20:33,188
WILD TYPE ANIMALS.

9285
05:20:33,188 --> 05:20:35,190
BUT WHEN WE DID THIS IN THE

9286
05:20:35,190 --> 05:20:36,925
ENDOTHELIAL R6 KNOCKOUT ANIMALS

9287
05:20:36,925 --> 05:20:40,128
WE SAW ALMOST ABOLISHED DILATION

9288
05:20:40,128 --> 05:20:40,662
TO INSULIN.

9289
05:20:40,662 --> 05:20:46,134
WE COULD THEN PUT A NITRIC OXIDE

9290
05:20:46,134 --> 05:20:48,637
SYNTHASE INHIBITOR IN THE BATH

9291
05:20:48,637 --> 05:20:50,005
AND BLOCK NITRIC OXIDE COMPONENT

9292
05:20:50,005 --> 05:20:51,507
OF VIE SEW DILATION TO GET OUR

9293
05:20:51,507 --> 05:20:53,375
MEASURE OF NITRIC OXIDE

9294
05:20:53,375 --> 05:20:54,376
BIOAVAILABILITY.

9295
05:20:54,376 --> 05:20:55,043
WHEN WE DO THAT, THAT'S GRAPHED

9296
05:20:55,043 --> 05:20:56,245
HERE AND WE CAN SEE THIS

9297
05:20:56,245 --> 05:20:57,312
REDUCTION IN DILATION WAS

9298
05:20:57,312 --> 05:20:59,214
ASSOCIATED WITH AN ALMOST

9299
05:20:59,214 --> 05:21:00,415
COMPLETE LOSS OF NITRIC OXIDE

9300
05:21:00,415 --> 05:21:03,485
BIOAVAILABILITY.

9301
05:21:03,485 --> 05:21:05,220
I JUST WANT TO NOTE THESE ARE

9302
05:21:05,220 --> 05:21:06,889
DIFFERENCES TO WHAT WE'VE SEEN

9303
05:21:06,889 --> 05:21:08,524
PREVIOUSLY IN AGED MODELS.

9304
05:21:08,524 --> 05:21:11,360
SO TO DETERMINE IF THIS

9305
05:21:11,360 --> 05:21:13,595
ENDOTHELIAL FUNCTION OR

9306
05:21:13,595 --> 05:21:14,229
DYSFUNCTION IMPACTED GLUCOSE AND

9307
05:21:14,229 --> 05:21:15,864
INSULIN METABOLISM, WE FIRST

9308
05:21:15,864 --> 05:21:18,867
PERFORMED GLUCOSE TOLERANCE

9309
05:21:18,867 --> 05:21:20,502
TESTS SO TO DO THIS, MICE ARE

9310
05:21:20,502 --> 05:21:21,937
FASTED FOR SIX HOURS IN THE

9311
05:21:21,937 --> 05:21:23,272
MORNING AND A BLOOD GLUCOSE

9312
05:21:23,272 --> 05:21:24,940
MEASUREMENT IS MADE AND SHOWN

9313
05:21:24,940 --> 05:21:25,908
HERE AT TIME ZERO FOR OUR FASTED

9314
05:21:25,908 --> 05:21:28,610
MEASURE.

9315
05:21:28,610 --> 05:21:32,147
MICE ARE THEN INJECTED WITH

9316
05:21:32,147 --> 05:21:32,848
GLUCOSE AND WE THEN ASSESS

9317
05:21:32,848 --> 05:21:33,715
GLUCOSE OVER THE COURSE OF TWO

9318
05:21:33,715 --> 05:21:35,784
HOURS.

9319
05:21:35,784 --> 05:21:37,319
WE ALSO COLLECTED BASELINE BLOOD

9320
05:21:37,319 --> 05:21:40,188
AND BLOOD AT 15 MINUTES AFTER

9321
05:21:40,188 --> 05:21:41,590
GLUCOSE INJECTION IN ORDER TO

9322
05:21:41,590 --> 05:21:43,358
MEASURE THE INSULIN RESPONSE TO

9323
05:21:43,358 --> 05:21:47,696
THE INCREASE IN BLOOD GLUCOSE.

9324
05:21:47,696 --> 05:21:48,330
ALTHOUGH YOU CAN SEE HERE THERE

9325
05:21:48,330 --> 05:21:50,098
WAS NO DIFFERENCE IN GLUCOSE

9326
05:21:50,098 --> 05:21:51,300
TOLERANCE BETWEEN THE WILD TYPE

9327
05:21:51,300 --> 05:21:53,535
AND KNOCKOUT ANIMALS, THERE WAS

9328
05:21:53,535 --> 05:21:55,037
A DIFFERENCE IN INSULIN, AND SO

9329
05:21:55,037 --> 05:21:58,440
WE COULD SEE BOTH IN THE FASTED

9330
05:21:58,440 --> 05:21:59,641
STATE AND AFTER GLUCOSE

9331
05:21:59,641 --> 05:22:02,177
STIMULATION THE ENDOTHELIAL

9332
05:22:02,177 --> 05:22:03,211
R6 KNOCKOUT ANIMALS RESPONDED

9333
05:22:03,211 --> 05:22:05,280
WITH A GREATER INSULIN RELEASE.

9334
05:22:05,280 --> 05:22:07,716
THIS IS SUGGESTIVE OF IMPAIRED

9335
05:22:07,716 --> 05:22:08,350
INSULIN SENSITIVITY.

9336
05:22:08,350 --> 05:22:09,451
SO WE WANTED TO FOLLOW THAT UP

9337
05:22:09,451 --> 05:22:11,687
WITH MORE ADVANCED METABOLIC

9338
05:22:11,687 --> 05:22:12,554
TESTING.

9339
05:22:12,554 --> 05:22:17,359
SO TO DO THIS, WE PERFORMED

9340
05:22:17,359 --> 05:22:19,227
CLAMP STUDIES WITH THE HELP OF A

9341
05:22:19,227 --> 05:22:22,297
COLLEAGUE IN UTAH.

9342
05:22:22,297 --> 05:22:24,066
AND WHEN WE DO THESE STUDIES,

9343
05:22:24,066 --> 05:22:25,500
THE GLUCOSE INFUSION RATE

9344
05:22:25,500 --> 05:22:27,269
PROVIDES A MEASURE OF INSULIN

9345
05:22:27,269 --> 05:22:27,903
SENSITIVITY.

9346
05:22:27,903 --> 05:22:30,872
WITH A LOWER RATE OF GLUCOSE

9347
05:22:30,872 --> 05:22:33,275
INFUSION INDICATING INSULIN

9348
05:22:33,275 --> 05:22:34,910
RESISTANCE.

9349
05:22:34,910 --> 05:22:36,745
WHAT WE FOUND WAS THERE WAS

9350
05:22:36,745 --> 05:22:40,048
IMPAIRED INSULIN SENSITIVITY

9351
05:22:40,048 --> 05:22:41,116
HERE, AND THIS WAS ASSOCIATED

9352
05:22:41,116 --> 05:22:43,185
WITH A REDUCTION IN GLUCOSE UP

9353
05:22:43,185 --> 05:22:44,119
TAKE INTO THE SKELETAL MUSCLE,

9354
05:22:44,119 --> 05:22:46,421
WHICH WE ASSESSED BY INFUSING A

9355
05:22:46,421 --> 05:22:48,724
RADIO LABELED GLUCOSE DURING THE

9356
05:22:48,724 --> 05:22:51,693
CLAMP.

9357
05:22:51,693 --> 05:22:53,829
SO LASTLY TO SEE IF THE

9358
05:22:53,829 --> 05:22:54,930
ENDOTHELIAL DYSFUNCTION THAT WE

9359
05:22:54,930 --> 05:22:57,766
PREVIOUSLY SAW COULD UNDERLIE

9360
05:22:57,766 --> 05:22:59,167
THIS INSULIN RESISTANCE IN THE

9361
05:22:59,167 --> 05:23:02,270
MUSCLE, WE USED FLUORESCENTLY

9362
05:23:02,270 --> 05:23:04,806
LABELED MICROSPHERES TO ASSESS

9363
05:23:04,806 --> 05:23:07,209
BLOOD FLOW INTO THE SKELETAL

9364
05:23:07,209 --> 05:23:09,711
MUSCLE IN RESPONSE TO

9365
05:23:09,711 --> 05:23:12,280
EXOGENOUSLY ADMINISTERED

9366
05:23:12,280 --> 05:23:12,814
INSULIN.

9367
05:23:12,814 --> 05:23:14,249
WE DID FIND THERE WAS A SMALL

9368
05:23:14,249 --> 05:23:16,118
REDUCTION IN FASTED SKELETAL

9369
05:23:16,118 --> 05:23:18,987
MUSCLE GLUCOSE IN THE

9370
05:23:18,987 --> 05:23:21,189
ENDOTHELIAL R6 KNOCKOUT ANIMALS.

9371
05:23:21,189 --> 05:23:22,958
IN RESPONSE TO INSULIN ALTHOUGH

9372
05:23:22,958 --> 05:23:25,027
THERE WAS A ROBUST INCREASE IN

9373
05:23:25,027 --> 05:23:26,128
BLOOD FLOW TO THE MUSCLE IN WILD

9374
05:23:26,128 --> 05:23:28,296
TYPE ANIMALS, THIS WAS ABOLISHED

9375
05:23:28,296 --> 05:23:31,533
IN THE ENDOTHELIAL R6 KNOCKOUT

9376
05:23:31,533 --> 05:23:32,501
MICE.

9377
05:23:32,501 --> 05:23:33,268
SO THESE STUDIES PROVIDED

9378
05:23:33,268 --> 05:23:35,103
EVIDENCE THAT ENDOTHELIAL

9379
05:23:35,103 --> 05:23:38,974
DYSFUNCTION COULD INDEED IMPERIL

9380
05:23:38,974 --> 05:23:39,474
METABOLIC HOMEOSTASIS.

9381
05:23:39,474 --> 05:23:40,942
SO WE WANTED TO SEE IF THE

9382
05:23:40,942 --> 05:23:43,245
OPPOSITE MIGHT BE TRUE, IF AN

9383
05:23:43,245 --> 05:23:44,846
IMPROVEMENT IN ENDOTHELIAL

9384
05:23:44,846 --> 05:23:47,115
FUNCTION IN AGED MICE COULD

9385
05:23:47,115 --> 05:23:47,949
RESTORE METABOLIC FUNCTION AS

9386
05:23:47,949 --> 05:23:56,324
WELL.

9387
05:23:56,324 --> 05:23:59,494
SO WORK FROM OUR LAB AND OTHERS

9388
05:23:59,494 --> 05:24:02,998
HAS INDICATED THE HALLMARKS OF

9389
05:24:02,998 --> 05:24:04,833
AGING IN BOTH VASCULAR AND

9390
05:24:04,833 --> 05:24:06,168
METABOLIC AGING AND THESE

9391
05:24:06,168 --> 05:24:07,436
INCLUDED ALTERED CELLULAR

9392
05:24:07,436 --> 05:24:08,503
COMMUNICATIONS SUCH AS THE

9393
05:24:08,503 --> 05:24:09,971
INTERACTION OF IMMUNE CELLS WITH

9394
05:24:09,971 --> 05:24:11,873
TISSUES AND INFLAMMATION AS WELL

9395
05:24:11,873 --> 05:24:13,475
AS CELLULAR SENESCENCE AND

9396
05:24:13,475 --> 05:24:16,111
DEREGULATED NUTRIENT SENSING.

9397
05:24:16,111 --> 05:24:18,380
AMONG THESE, INCREASE MTOR

9398
05:24:18,380 --> 05:24:19,014
SIGNALING HAS BEEN DESCRIBED AS

9399
05:24:19,014 --> 05:24:21,583
A CULPRIT IN AGING AND

9400
05:24:21,583 --> 05:24:22,150
AGE-RELATED DYSFUNCTION.

9401
05:24:22,150 --> 05:24:26,688
SO MTOR IS A KINASE THAT

9402
05:24:26,688 --> 05:24:28,657
REGULATES SELF PROLIFERATION,

9403
05:24:28,657 --> 05:24:30,392
AUTOPHAGY AND APOPTOSIS.

9404
05:24:30,392 --> 05:24:33,762
WORK BY RICHARD MILLER'S GROUP

9405
05:24:33,762 --> 05:24:34,963
HAS DEMONSTRATED THAT INHIBITION

9406
05:24:34,963 --> 05:24:37,799
OF MTOR SIGNALING WITH RAPAMYCIN

9407
05:24:37,799 --> 05:24:40,001
CAN EXTEND LIFESPAN IN BOTH MALE

9408
05:24:40,001 --> 05:24:40,902
AND FEMALE MICE.

9409
05:24:40,902 --> 05:24:43,538
WE WERE INTERESTED IN SEEING IF

9410
05:24:43,538 --> 05:24:44,906
MTOR MIGHT ALSO BE PLAYING A

9411
05:24:44,906 --> 05:24:46,174
ROLE IN ENDOTHELIAL DYSFUNCTION.

9412
05:24:46,174 --> 05:24:49,478
SO TO EXPLORE THIS, WE BEGAN BY

9413
05:24:49,478 --> 05:24:51,780
TREATING YOUNG AND OLD MICE WITH

9414
05:24:51,780 --> 05:24:52,314
RAPAMYCIN.

9415
05:24:52,314 --> 05:24:55,183
SO FIRST WE EXAMINED

9416
05:24:55,183 --> 05:25:04,459
PHOSPHORYLAPHOSPHORYLATED S6K.

9417
05:25:04,459 --> 05:25:06,194
IF HE FOUND THERE WAS INDEED AN

9418
05:25:06,194 --> 05:25:09,498
INCREASE IN MTOR ACTIVATION WITH

9419
05:25:09,498 --> 05:25:11,800
AGING IN MTOR TISSUE AND

9420
05:25:11,800 --> 05:25:14,770
FOLLOWING RAPAMYCIN OR MTOR

9421
05:25:14,770 --> 05:25:15,971
INHIBITION, THERE WAS A

9422
05:25:15,971 --> 05:25:17,405
REDUCTION IN THIS PHOSPHORYLATED

9423
05:25:17,405 --> 05:25:17,973
S6K.

9424
05:25:17,973 --> 05:25:20,909
WE THEN EXAMINED ENDOTHELIAL

9425
05:25:20,909 --> 05:25:22,577
FUNCTION AND EXCISED ARTERIES

9426
05:25:22,577 --> 05:25:24,446
FROM THESE MICE AND FOUND THE

9427
05:25:24,446 --> 05:25:26,748
EXPECTED REDUCTION IN

9428
05:25:26,748 --> 05:25:29,618
ENDOTHELIUM-DEPENDENT DILATION

9429
05:25:29,618 --> 05:25:31,153
AS WELL AS REDUCTION IN NITRIC

9430
05:25:31,153 --> 05:25:32,487
OXIDE BIOAVAILABILITY IN AGING.

9431
05:25:32,487 --> 05:25:35,323
AND THAT BOTH OF THESE WERE

9432
05:25:35,323 --> 05:25:37,092
IMPROVED AFTER RAPAMYCIN

9433
05:25:37,092 --> 05:25:40,962
TREATMENT.

9434
05:25:40,962 --> 05:25:41,930
INTERESTINGLY AS PART OF THIS

9435
05:25:41,930 --> 05:25:44,199
STUDY, WE ALSO PERFORMED

9436
05:25:44,199 --> 05:25:44,966
METABOLIC TESTING ON THESE MICE.

9437
05:25:44,966 --> 05:25:46,601
AND HERE YOU CAN SEE THE AREA

9438
05:25:46,601 --> 05:25:48,804
UNDER THE CURVE DURING A GLUCOSE

9439
05:25:48,804 --> 05:25:50,539
TOLERANCE TEST AND THAT WITH

9440
05:25:50,539 --> 05:25:53,241
AGING, THERE WAS A SIGNIFICANT

9441
05:25:53,241 --> 05:25:55,010
INCREASE IN THE AREA UNDER THE

9442
05:25:55,010 --> 05:25:57,612
CURVE, INDICATIVE OF IMPAIRED

9443
05:25:57,612 --> 05:25:58,780
GLUCOSE TOLERANCE, AND THAT

9444
05:25:58,780 --> 05:26:00,215
RAPAMYCIN TREATMENT IN THE OLD

9445
05:26:00,215 --> 05:26:04,219
ANIMALS LED TO AN IMPROVEMENT IN

9446
05:26:04,219 --> 05:26:06,154
GLUCOSE TOLERANCE.

9447
05:26:06,154 --> 05:26:08,356
BUT RAPAMYCIN IS A SYSTEMIC

9448
05:26:08,356 --> 05:26:10,091
TREATMENT AND AS SUCH, THE

9449
05:26:10,091 --> 05:26:11,660
METABOLIC EFFECTS MAY HAVE BEEN

9450
05:26:11,660 --> 05:26:13,028
DUED TO ALTERED MTOR SIGNALING

9451
05:26:13,028 --> 05:26:17,599
IN ANY NUMBER OF TISSUES.

9452
05:26:17,599 --> 05:26:19,467
WE'RE STILL INTERESTED IN THE

9453
05:26:19,467 --> 05:26:21,469
IMPACT OF AGING ON MTOR IN THE

9454
05:26:21,469 --> 05:26:22,370
ENDOTHELIUM SPECIFICALLY, SO WE

9455
05:26:22,370 --> 05:26:24,139
WANTED TO SEE IF REDUCING

9456
05:26:24,139 --> 05:26:25,674
ENDOTHELIAL MTOR WAS SUFFICIENT

9457
05:26:25,674 --> 05:26:27,008
TO IMPROVE NOT ONLY VASCULAR

9458
05:26:27,008 --> 05:26:29,411
FUNCTION BUT METABOLIC FUNCTION

9459
05:26:29,411 --> 05:26:32,380
IN AGING AS WELL.

9460
05:26:32,380 --> 05:26:33,715
SO WE FIRST WANTED TO CONFIRM

9461
05:26:33,715 --> 05:26:35,150
THAT THERE WAS ACTUALLY AN

9462
05:26:35,150 --> 05:26:38,153
INCREASE IN ENDOTHELIAL MTOR

9463
05:26:38,153 --> 05:26:38,854
SIGNALING WITH AGING.

9464
05:26:38,854 --> 05:26:40,689
SINCE OUR PREVIOUS DATA WAS IN

9465
05:26:40,689 --> 05:26:45,460
WHOLE AORTIC LYSATES, IT'S

9466
05:26:45,460 --> 05:26:46,761
DIFFICULT TO DETERMINE WHICH

9467
05:26:46,761 --> 05:26:47,762
TISSUE WAS CONTRIBUTING TO THAT

9468
05:26:47,762 --> 05:26:48,630
INCREASE IN ACTIVATION.

9469
05:26:48,630 --> 05:26:52,100
SO HERE WE USE CONFOCAL

9470
05:26:52,100 --> 05:26:53,735
MICROSCOPY ON END PHASE

9471
05:26:53,735 --> 05:26:54,936
PREPARATIONS OF ARTERIES FROM

9472
05:26:54,936 --> 05:26:58,440
YOUNG AND OLD ANIMALS AND

9473
05:26:58,440 --> 05:27:01,443
EXPLORED THE EXPRESSION OF

9474
05:27:01,443 --> 05:27:03,311
PHOSPHORYLATED S6K.

9475
05:27:03,311 --> 05:27:05,580
YOU CAN SEE IN THE ENDOTHELIAL

9476
05:27:05,580 --> 05:27:06,948
CELLS SHOWN IN RED THERE WAS A

9477
05:27:06,948 --> 05:27:09,484
SIGNIFICANT INCREASE IN

9478
05:27:09,484 --> 05:27:10,552
PHOSPHORYLATED S6K.

9479
05:27:10,552 --> 05:27:12,287
AND ALTHOUGH THERE WAS ALSO AN

9480
05:27:12,287 --> 05:27:13,154
INCREASE IN THE SMOOTH MUSCLE,

9481
05:27:13,154 --> 05:27:14,556
IT REALLY WAS MUCH LESS THAN

9482
05:27:14,556 --> 05:27:17,759
WHAT WE SAW IN THE ENDOTHELIAL

9483
05:27:17,759 --> 05:27:20,528
CELL.

9484
05:27:20,528 --> 05:27:23,298
SO NEXT WE AGAIN UTILIZE DOLLARS

9485
05:27:23,298 --> 05:27:30,205
THE CDH5 CRE ANIMAL T TO GENERAE

9486
05:27:30,205 --> 05:27:32,073
AN INDUCIBLE ENDOTHELIAL

9487
05:27:32,073 --> 05:27:33,308
SPECIFIC KNOCKOUT MOUSE FOR

9488
05:27:33,308 --> 05:27:34,910
MTOR.

9489
05:27:34,910 --> 05:27:36,645
AFTER TAMOXIFEN TREATMENT WE SAW

9490
05:27:36,645 --> 05:27:39,247
APPROXIMATELY 75% REA DUCKS IN

9491
05:27:39,247 --> 05:27:40,916
MTOR EXPRESSION USING THIS

9492
05:27:40,916 --> 05:27:41,616
MODEL.

9493
05:27:41,616 --> 05:27:43,451
SO SIMILAR TO WHAT WE FOUND IN

9494
05:27:43,451 --> 05:27:46,321
THE RAPAMYCIN STUDIES, WE FOUND

9495
05:27:46,321 --> 05:27:49,658
THAT AGING IMPAIRED MAXIMUM

9496
05:27:49,658 --> 05:27:56,464
VASODILATION IN OUR OLD ANIMALS

9497
05:27:56,464 --> 05:27:58,099
AND ENDOTHELIAL DELETION OF MTOR

9498
05:27:58,099 --> 05:28:02,437
LED TO AN INCREASE IN BOTH

9499
05:28:02,437 --> 05:28:04,439
VASODILATION AND N.O.

9500
05:28:04,439 --> 05:28:04,806
BIOAVAILABILITY.

9501
05:28:04,806 --> 05:28:09,811
AND IN THESE AGED MICE, WE FOUND

9502
05:28:09,811 --> 05:28:11,913
THAT ENDOTHELIAL-SPECIFIC MTOR

9503
05:28:11,913 --> 05:28:14,015
KNOCKOUT WAS SUFFICIENT TO

9504
05:28:14,015 --> 05:28:15,083
IMPROVE GLUCOSE TOLERANCE.

9505
05:28:15,083 --> 05:28:18,753
AND THIS IS EVIDENCED BY A

9506
05:28:18,753 --> 05:28:20,322
REDUCTION ACROSS THE ENTIRE

9507
05:28:20,322 --> 05:28:21,623
CURVE OF THE GLUCOSE TOLERANCE

9508
05:28:21,623 --> 05:28:28,196
TEST.

9509
05:28:28,196 --> 05:28:30,098
SO LAST WE WERE INTERESTED IN

9510
05:28:30,098 --> 05:28:30,865
EXPLORING SOME OF THE POTENTIAL

9511
05:28:30,865 --> 05:28:32,934
MECHANISMS FOR THE METABOLIC

9512
05:28:32,934 --> 05:28:34,035
IMPROVEMENTS THAT WE SAW AND

9513
05:28:34,035 --> 05:28:35,770
CHOSE TO EXAMINE OTHER HALL

9514
05:28:35,770 --> 05:28:37,405
MARKS OF AGING SUCH AS IMMUNE

9515
05:28:37,405 --> 05:28:38,707
CELL ACCUMULATION, INFLAMMATION

9516
05:28:38,707 --> 05:28:39,674
AND SENESCENCE.

9517
05:28:39,674 --> 05:28:42,377
AND WE FOUND THAT BOTH CD3 AND

9518
05:28:42,377 --> 05:28:45,780
FOX P3, WHICH ARE MARKERS OF

9519
05:28:45,780 --> 05:28:47,649
T-CELL INFILTRATION, WERE BOTH

9520
05:28:47,649 --> 05:28:48,283
REDUCED IN THE ADIPOSE TISSUE OF

9521
05:28:48,283 --> 05:28:53,555
THE AGED END THEE ENDOTHELIAL KT

9522
05:28:53,555 --> 05:28:53,755
MICE.

9523
05:28:53,755 --> 05:28:54,956
>> DOCTOR, YOU HAVE TWO
MINUTES

9524
05:28:54,956 --> 05:28:55,223
REMAINING.

9525
05:28:55,223 --> 05:28:56,157
>> OKAY.

9526
05:28:56,157 --> 05:28:57,359
LIKEWISE, MEASURES OF

9527
05:28:57,359 --> 05:29:00,028
INFLAMMATORY FACTORS SUCH AS

9528
05:29:00,028 --> 05:29:04,432
MCP1, TNF ALPHA, CLCX2, IL-1

9529
05:29:04,432 --> 05:29:06,735
BETA AND IL-6 WERE ALSO REDUCED

9530
05:29:06,735 --> 05:29:08,603
IN THE ADIPOSE.

9531
05:29:08,603 --> 05:29:11,039
AS THESE INFLAMMATORY MEDIATORS

9532
05:29:11,039 --> 05:29:13,308
ARE OFTEN DESCRIBED AS SASP

9533
05:29:13,308 --> 05:29:15,410
FACTORS, AGING IS ASSOCIATED

9534
05:29:15,410 --> 05:29:17,045
WITH ADIPOSE TISSUE SENESCENCE,

9535
05:29:17,045 --> 05:29:19,381
WE NEXT ASSESSED MARKERS OF

9536
05:29:19,381 --> 05:29:21,883
SENESCENCE P16 AND P21 AND FOUND

9537
05:29:21,883 --> 05:29:22,784
THAT BOTH WERE ALSO REDUCED IN

9538
05:29:22,784 --> 05:29:24,853
THE ADIPOSE TISSUE OF THE AGED

9539
05:29:24,853 --> 05:29:27,989
MSM AGEMTOR KNOCKOUT MICE.

9540
05:29:27,989 --> 05:29:30,158
SO TAKEN TOGETHER, WE SEE THAT

9541
05:29:30,158 --> 05:29:35,430
AMELIORATING THE AGE H-RELATED

9542
05:29:35,430 --> 05:29:37,098
INCREASE IN MTOR SIGNALING CAN

9543
05:29:37,098 --> 05:29:38,900
IMPROVE BOTH VASCULAR AND

9544
05:29:38,900 --> 05:29:40,001
METABOLIC DYSFUNCTION.

9545
05:29:40,001 --> 05:29:41,436
THAT TARGETING THIS REDUCTION IN

9546
05:29:41,436 --> 05:29:43,772
MTOR TO THE END OF FAILURE MAY

9547
05:29:43,772 --> 05:29:44,639
BE SUFFICIENT TO PRODUCE THE

9548
05:29:44,639 --> 05:29:45,807
BENEFICIAL EFFECTS WE SAW.

9549
05:29:45,807 --> 05:29:48,009
AND LASTLY, THAT THE ENDOTHELIAL

9550
05:29:48,009 --> 05:29:49,677
REDUCTION IN MTOR MAY BE CAPABLE

9551
05:29:49,677 --> 05:29:52,547
OF REDUCING OTHER HALL MARKS OF

9552
05:29:52,547 --> 05:29:54,716
AGING, SUCH AS INFLAMMATION AND

9553
05:29:54,716 --> 05:29:55,617
SENESCENCE, EVEN IN TISSUES

9554
05:29:55,617 --> 05:29:57,185
OUTSIDE OF THE ENDOTHELIUM.

9555
05:29:57,185 --> 05:29:58,186
AND I DON'T THINK THE EFFECTS

9556
05:29:58,186 --> 05:29:59,754
THAT WE'RE SEEING HERE WOULD BE

9557
05:29:59,754 --> 05:30:00,955
LIMITED TO MTOR SIGNALING, BUT

9558
05:30:00,955 --> 05:30:03,291
RATHER IF WE COULD TARGET

9559
05:30:03,291 --> 05:30:05,193
INTERVENTIONS TO IMPROVE

9560
05:30:05,193 --> 05:30:06,728
ENDOTHELIAL FUNCTION THROUGH A

9561
05:30:06,728 --> 05:30:09,998
VARIETY OF MECHANISMS, I THINK

9562
05:30:09,998 --> 05:30:13,268
WE CAN HAVE THE SYSTEMIC

9563
05:30:13,268 --> 05:30:13,535
BENEFITS.

9564
05:30:13,535 --> 05:30:15,437
SO IN THE TITLE OF MY TALK, I

9565
05:30:15,437 --> 05:30:16,638
ASKED THE QUESTION, CAN WE

9566
05:30:16,638 --> 05:30:16,905
INTERVENE.

9567
05:30:16,905 --> 05:30:18,807
AND I THINK THAT THE ACCUMULATED

9568
05:30:18,807 --> 05:30:20,008
EVIDENCE IN A LOT OF THE TALKS

9569
05:30:20,008 --> 05:30:22,010
HERE WOULD SAY THAT

9570
05:30:22,010 --> 05:30:23,078
INTERVENTIONS TO IMPROVE

9571
05:30:23,078 --> 05:30:24,746
HEALTHSPAN WILL NEED TO IMPACT

9572
05:30:24,746 --> 05:30:26,614
ON MULTIPLE SYSTEMS, MULTIPLE

9573
05:30:26,614 --> 05:30:29,384
TISSUES, AS WELL AS MULTIPLE

9574
05:30:29,384 --> 05:30:29,918
MECHANISMS OF AGING TO BE

9575
05:30:29,918 --> 05:30:30,185
EFFECTIVE.

9576
05:30:30,185 --> 05:30:34,689
INTO AND OUR  AND OUR DATA SUGGT

9577
05:30:34,689 --> 05:30:36,024
THE ENDOTHELIUM MAY BE A VIABLE

9578
05:30:36,024 --> 05:30:36,991
TARGET TO HELP ACCOMPLISH THIS

9579
05:30:36,991 --> 05:30:37,225
GOAL.

9580
05:30:37,225 --> 05:30:38,760
SO WITH THAT, I JUST WANT TO

9581
05:30:38,760 --> 05:30:41,763
THANK MEMBERS OF MY LAB WHO

9582
05:30:41,763 --> 05:30:46,234
WORKED ON THESE PROJECTS BUT IN

9583
05:30:46,234 --> 05:30:50,772
PARTICULAR TORIKUL ISLAM, AND

9584
05:30:50,772 --> 05:30:51,906
COLLABORATORS AT THE UNIVERSITY

9585
05:30:51,906 --> 05:30:55,310
OF UTAH, WILL HOLLAND WHO

9586
05:30:55,310 --> 05:30:56,411
PERFORMED THE GLYCEMIC CLAMP

9587
05:30:56,411 --> 05:30:57,846
STUDIES AND WENDY WHO GAVE US

9588
05:30:57,846 --> 05:31:00,448
THE R6 KNOCKOUT ANIMALS AND THEN

9589
05:31:00,448 --> 05:31:00,882
MY FUNDING SOURCES.

9590
05:31:00,882 --> 05:31:02,016
SO WITH THAT, I CAN TAKE

9591
05:31:02,016 --> 05:31:03,918
QUESTIONS.

9592
05:31:03,918 --> 05:31:05,820
>> FANTASTIC.

9593
05:31:05,820 --> 05:31:06,454
AND I THINK WE HAVE TWO MINUTES

9594
05:31:06,454 --> 05:31:10,758
FOR QUESTIONS.

9595
05:31:10,758 --> 05:31:12,160
DID YOU DO BOTH MALES AND

9596
05:31:12,160 --> 05:31:14,195
FEMALES IN THOSE STUDIES, OR

9597
05:31:14,195 --> 05:31:15,697
MALE AND FEMALE ARTERIES?

9598
05:31:15,697 --> 05:31:18,933
>> YEAH, THEY WERE -- ALL
OF

9599
05:31:18,933 --> 05:31:21,736
THESE WITH THE GENETIC MODELS

9600
05:31:21,736 --> 05:31:22,537
WERE BOTH SEXES.

9601
05:31:22,537 --> 05:31:24,739
>> AND NO DIFFERENCES?

9602
05:31:24,739 --> 05:31:26,708
>> NO, WE HAVEN'T REALLY
FOUND

9603
05:31:26,708 --> 05:31:27,242
ANY DIFFERENCES TO SPEAK.

9604
05:31:27,242 --> 05:31:28,276
EVERY ONCE IN A WHILE THERE WILL

9605
05:31:28,276 --> 05:31:29,711
BE LIKE A SMALLER CHANGE IN ONE

9606
05:31:29,711 --> 05:31:31,146
GROUP OR THE OTHER BUT NOT

9607
05:31:31,146 --> 05:31:31,713
SOMETHING THAT WAS LIKE, YOU

9608
05:31:31,713 --> 05:31:32,747
KNOW, DIFFERENTIALLY CHANGED

9609
05:31:32,747 --> 05:31:33,848
BETWEEN THE SEXES.

9610
05:31:33,848 --> 05:31:35,550
>> GOT IT.

9611
05:31:35,550 --> 05:31:38,253
AND THEN WE HAVE A QUESTION FROM

9612
05:31:38,253 --> 05:31:38,920
MICHAEL SNYDER.

9613
05:31:38,920 --> 05:31:43,358
SO DOES NITRIC OXIDE -- DO

9614
05:31:43,358 --> 05:31:45,126
NITRIC OXIDE GENERATORS INCREASE

9615
05:31:45,126 --> 05:31:45,560
HEALTHSPAN?

9616
05:31:45,560 --> 05:31:49,397
FOR EXAMPLE, SOMETHING LIKE BEET

9617
05:31:49,397 --> 05:31:51,032
EXTRACT?

9618
05:31:51,032 --> 05:31:51,599
>> YOU KNOW, I THINK THAT

9619
05:31:51,599 --> 05:31:53,601
THERE'S PLENTY OF PEOPLE WHO

9620
05:31:53,601 --> 05:31:58,406
TAKE THOSE KINDS OF SUPPLEMENTS

9621
05:31:58,406 --> 05:32:00,241
AND I DON'T THINK WE HAVE THE

9622
05:32:00,241 --> 05:32:01,609
DATA YET TO KNOW IF THE

9623
05:32:01,609 --> 05:32:04,112
NUTRACEUTICALS ARE IMPROVING

9624
05:32:04,112 --> 05:32:05,580
HEALTHSPAN NECESSARILY.

9625
05:32:05,580 --> 05:32:06,347
I THINK THERE'S EVIDENCE FROM

9626
05:32:06,347 --> 05:32:07,782
PRE-CLINICAL MODELS THAT YOU CAN

9627
05:32:07,782 --> 05:32:12,887
GET IMPROVEMENTS IN METABOLIC

9628
05:32:12,887 --> 05:32:13,521
AND CARDIOVASCULAR OUTCOMES.

9629
05:32:13,521 --> 05:32:14,722
I DON'T KNOW -- I DON'T KNOW

9630
05:32:14,722 --> 05:32:16,324
THAT WE HAVE THE DATA OR THE

9631
05:32:16,324 --> 05:32:17,659
CLINICAL TRIALS HAVE BEEN DONE

9632
05:32:17,659 --> 05:32:18,726
TO PROVE THAT THEY'RE ACTUALLY,

9633
05:32:18,726 --> 05:32:19,928
LIKE, IMPROVING HEALTHSPAN OR

9634
05:32:19,928 --> 05:32:23,698
LIFESPAN AT THIS POINT.

9635
05:32:23,698 --> 05:32:27,001
>> I THINK THERE IS A
TRIAL FOR

9636
05:32:27,001 --> 05:32:28,069
BEET EXTRACT USING THIS

9637
05:32:28,069 --> 05:32:33,241
MECHANISM FOR PR PERIPHERAL

9638
05:32:33,241 --> 05:32:33,775
VASCULAR DISEASE PATIENTS

9639
05:32:33,775 --> 05:32:35,043
BECAUSE IT'S A PRETTY LOW RISK

9640
05:32:35,043 --> 05:32:36,544
INTERVENTION, SO MAYBE WE'LL GET

9641
05:32:36,544 --> 05:32:38,213
SOME DATAMENT THEN I HAVE

9642
05:32:38,213 --> 05:32:42,450
ANOTHER QUESTION FROM DR. GALIS.

9643
05:32:42,450 --> 05:32:44,752
CAN YOU PLEASE COMMENT ON THE

9644
05:32:44,752 --> 05:32:47,622
POTENTIAL ROLE OF MTOR SIGNALING

9645
05:32:47,622 --> 05:32:49,757
AS AN ANTITUMOR APPROACH?

9646
05:32:49,757 --> 05:32:50,825
>> WHOA.

9647
05:32:50,825 --> 05:32:52,227
I DON'T KNOW THAT MUCH ABOUT

9648
05:32:52,227 --> 05:32:54,128
TUMOR STUFF SO I WOULD LEAVE

9649
05:32:54,128 --> 05:32:54,729
THAT TO SOMEBODY WHO ACTUALLY

9650
05:32:54,729 --> 05:32:55,697
WORKS WITH TUMORS.

9651
05:32:55,697 --> 05:32:55,897
SORRY.

9652
05:32:55,897 --> 05:32:59,100
>> I THINK THEY HAVE SOME
LINK

9653
05:32:59,100 --> 05:33:00,635
TO METFORMIN, WHICH MIGHT REDUCE

9654
05:33:00,635 --> 05:33:03,605
CANCER, BUT I DON'T KNOW EITHER,

9655
05:33:03,605 --> 05:33:06,441
SO -- BUT IT TURNS OUT YOU'RE

9656
05:33:06,441 --> 05:33:08,309
SAVED BY THE BELL, BECAUSE IT IS

9657
05:33:08,309 --> 05:33:09,711
4:00 EASTERN STANDARD, SO WE

9658
05:33:09,711 --> 05:33:12,013
WILL GET BACK TO YOU IN THE

9659
05:33:12,013 --> 05:33:13,014
PANEL DISCUSSION.

9660
05:33:13,014 --> 05:33:14,816
NEXT WE'RE GOING TO HEAR ABOUT

9661
05:33:14,816 --> 05:33:17,118
TARGETING SULFUR AMINO ACID

9662
05:33:17,118 --> 05:33:19,220
METABOLISM FOR LONGEVITY AND

9663
05:33:19,220 --> 05:33:23,858
TUMOR SUPPRESSION BY CHRISTOPHER

9664
05:33:23,858 --> 05:33:25,593
HINE AT THE CLEVELAND CLINIC.

9665
05:33:25,593 --> 05:33:25,893
CHRISTOPHER.

9666
05:33:25,893 --> 05:33:26,594
>> THANK YOU VERY MUCH.

9667
05:33:26,594 --> 05:33:28,596
YOU CAN HEAR ME LOUD AND CLEAR?

9668
05:33:28,596 --> 05:33:30,031
>> YES, THAT'S QUITE GOOD.

9669
05:33:30,031 --> 05:33:32,000
>> OKAY.

9670
05:33:32,000 --> 05:33:42,110
GREAT.

9671
05:33:45,647 --> 05:33:46,481
YOU CAN SEE THE SLIDES?

9672
05:33:46,481 --> 05:33:47,548
>> YES.

9673
05:33:47,548 --> 05:33:47,849
>> PERFECT.

9674
05:33:47,849 --> 05:33:48,182
THANKS A LOT.

9675
05:33:48,182 --> 05:33:49,751
>> YOU MAY WANT TO MUTE.

9676
05:33:49,751 --> 05:33:51,919
THERE'S A FEW PEOPLE THAT AREN'T

9677
05:33:51,919 --> 05:33:52,520
MUTED.

9678
05:33:52,520 --> 05:33:54,455
>> THANKS A LOT FOR THE
KIND

9679
05:33:54,455 --> 05:33:55,123
INVITATION TO SPEAK AT THE

9680
05:33:55,123 --> 05:33:55,657
WORKSHOP.

9681
05:33:55,657 --> 05:33:59,827
IT'S BEEN FANTASTIC SO FAR.

9682
05:33:59,827 --> 05:34:05,366
MY NAME IS CHRIS HINE WITH THE

9683
05:34:05,366 --> 05:34:05,767
CLEVELAND CLINIC.

9684
05:34:05,767 --> 05:34:07,468
A MAJORITY OF THIS TALK IS GOING

9685
05:34:07,468 --> 05:34:10,305
TO BE FOCUSING ON TARGETING

9686
05:34:10,305 --> 05:34:13,207
SULFUR AMINO ACID, AGING AND

9687
05:34:13,207 --> 05:34:13,608
TUMOR SUPPRESSION.

9688
05:34:13,608 --> 05:34:14,242
SO A VERY BRIEF PRESENTATION

9689
05:34:14,242 --> 05:34:17,412
OVERVIEW.

9690
05:34:17,412 --> 05:34:19,380
POPULATION SHIFTS, MORBIDITIES

9691
05:34:19,380 --> 05:34:21,416
AND GEROSCIENCE APPROACHES TO

9692
05:34:21,416 --> 05:34:23,051
ADDRESS AGING AS A WHOLE.

9693
05:34:23,051 --> 05:34:26,087
NEXT WE'LL GO INTO INTRODUCTION

9694
05:34:26,087 --> 05:34:27,822
ON AN ENZYME, CGL.

9695
05:34:27,822 --> 05:34:31,592
OTHERS WILL ALSO CALL IT CSC OR

9696
05:34:31,592 --> 05:34:35,029
KRFLT TH, AND HYDROGEN SULFIDE

9697
05:34:35,029 --> 05:34:37,332
AS COMMON HALLMARKS IN

9698
05:34:37,332 --> 05:34:38,533
GEROSCIENCE APPROACHES.

9699
05:34:38,533 --> 05:34:40,234
DATA FOR ONGOING MOUSE LONGEVITY

9700
05:34:40,234 --> 05:34:41,336
PROJECTS TESTING THE REQUIREMENT

9701
05:34:41,336 --> 05:34:45,840
OF CGL AND HYDROGEN SULFIDE FOR

9702
05:34:45,840 --> 05:34:47,875
LIFESPAN AND HEALTHSPAN

9703
05:34:47,875 --> 05:34:48,409
EXTENSION RELATED TO DIET

9704
05:34:48,409 --> 05:34:48,710
RESTRICTION.

9705
05:34:48,710 --> 05:34:50,511
LAST BUT NOT LEAST WE'LL GO INTO

9706
05:34:50,511 --> 05:34:52,613
A MORE TRANSLATIONAL APPROACH

9707
05:34:52,613 --> 05:34:53,247
LOOKING AT PFAU TOUR CLINICAL

9708
05:34:53,247 --> 05:34:54,549
DIRECTIONS FOR HARNESSING

9709
05:34:54,549 --> 05:34:57,251
HYDROGEN SULFIDE AS A TUMOR

9710
05:34:57,251 --> 05:35:00,521
SUPPRESSOR IN GLIOBLASTOMA.

9711
05:35:00,521 --> 05:35:03,324
SO IF ANY OF YOU HAD NOTICED,

9712
05:35:03,324 --> 05:35:04,926
BACK IN NOVEMBER OF THIS PAST

9713
05:35:04,926 --> 05:35:06,794
YEAR, THE WORLD POPULATION HIT

9714
05:35:06,794 --> 05:35:07,061
8 BILLION.

9715
05:35:07,061 --> 05:35:08,296
NOW THAT RAPID INCREASE IN THE

9716
05:35:08,296 --> 05:35:10,498
WORLD POPULATION ISN'T EQUAL

9717
05:35:10,498 --> 05:35:12,300
AMONGST ALL AGE GROUPS.

9718
05:35:12,300 --> 05:35:18,106
AS WE CAN SEE HERE, DATA, THE

9719
05:35:18,106 --> 05:35:19,774
GLOBAL POPULATION AS A FUNCTION

9720
05:35:19,774 --> 05:35:22,643
OF AGE RANGE, FROM 1990 TO TO

9721
05:35:22,643 --> 05:35:25,613
2000, YOU CAN SEE THE YELLOW

9722
05:35:25,613 --> 05:35:28,783
GETS BIGGER AND BIGGER AS WE GO

9723
05:35:28,783 --> 05:35:32,553
DECADE BY DECADE AND BY THE YEAR

9724
05:35:32,553 --> 05:35:35,089
2050 IT'S ESTIMATED THE

9725
05:35:35,089 --> 05:35:40,628
POPULATION IS GOING TO BE 65 OR

9726
05:35:40,628 --> 05:35:41,195
OLDER.

9727
05:35:41,195 --> 05:35:44,031
 -- TRAVEL, DO GREAT THINGS WITH

9728
05:35:44,031 --> 05:35:45,800
FRIENDS.

9729
05:35:45,800 --> 05:35:48,870
WITH AGE COMES AGING-RELATED

9730
05:35:48,870 --> 05:35:49,303
MORBIDITIES.

9731
05:35:49,303 --> 05:35:52,173
WHAT THESE ARE, BRAIN AND

9732
05:35:52,173 --> 05:35:55,443
COGNITIVE DECLINE,

9733
05:35:55,443 --> 05:35:56,644
CARDIOVASCULAR DISEASE, DECLINES

9734
05:35:56,644 --> 05:35:57,945
IN IMMUNITY AND INFLAMMATION AND

9735
05:35:57,945 --> 05:36:01,349
MOST IMPORTANTLY, AN INCREASE IN

9736
05:36:01,349 --> 05:36:05,486
ONCOLOGICAL -- SUCH AS CANCERS.

9737
05:36:05,486 --> 05:36:07,588
SO CURRENTLY IN TERMS OF WESTERN

9738
05:36:07,588 --> 05:36:08,923
MEDICINE, THE WAY WE DEAL WITH

9739
05:36:08,923 --> 05:36:10,825
THESE AGE-RELATED MORBIDITIES

9740
05:36:10,825 --> 05:36:14,862
AND THESE DISEASE, WE TREAT THEM

9741
05:36:14,862 --> 05:36:15,196
INDIVIDUALLY.

9742
05:36:15,196 --> 05:36:17,865
A DRUG FOR CANCER, A DRUG FOR

9743
05:36:17,865 --> 05:36:24,605
HIGH BLOOD PRESSURE, FOR THE

9744
05:36:24,605 --> 05:36:26,174
MOST PART WHAT'S GOING TO

9745
05:36:26,174 --> 05:36:29,010
HAPPEN, YOU TREAT THE CANCER,

9746
05:36:29,010 --> 05:36:32,146
END OF -- ALL OF A SUDDEN YOU

9747
05:36:32,146 --> 05:36:35,116
TREAT THE CARDIOMYOPATHY, YOU'LL

9748
05:36:35,116 --> 05:36:36,984
GET NEURODEGENERATIVE DISORDER.

9749
05:36:36,984 --> 05:36:37,585
SO TREATING THEM INDIVIDUALLY

9750
05:36:37,585 --> 05:36:39,587
ISN'T THE WAY TO GO, AND IF WE

9751
05:36:39,587 --> 05:36:45,159
KEEP ON THAT TRAJECTORY, AND WE

9752
05:36:45,159 --> 05:36:47,028
DEVELOP FANTASTIC CHEMO

9753
05:36:47,028 --> 05:36:48,563
THERAPEUTICS, FANTASTIC

9754
05:36:48,563 --> 05:36:51,966
CARDIOMYOPATHY DRUGS, IN THE END

9755
05:36:51,966 --> 05:36:54,035
WE END UP EXTENDING LIFESPAN BUT

9756
05:36:54,035 --> 05:36:55,570
NOT NECESSARILY EXTENDING

9757
05:36:55,570 --> 05:36:58,439
HEALTHSPAN.

9758
05:36:58,439 --> 05:37:00,908
SO APPROACHES WHERE WE CAN APPLY

9759
05:37:00,908 --> 05:37:01,476
AN INTERVENTION WHEN HUMANS

9760
05:37:01,476 --> 05:37:03,978
START TO AGE, SAY IN SOMEONE'S

9761
05:37:03,978 --> 05:37:05,279
MID 30s WHEN DEVELOPMENT IS

9762
05:37:05,279 --> 05:37:07,281
OVER AND AGING BEGINS, THAT

9763
05:37:07,281 --> 05:37:09,050
SLOWS THE PROGRESSION OR THE

9764
05:37:09,050 --> 05:37:11,719
ONSET OF THESE AGING-RELATED

9765
05:37:11,719 --> 05:37:12,019
MORBIDITIES.

9766
05:37:12,019 --> 05:37:13,054
SO WE'RE NOT NECESSARILY

9767
05:37:13,054 --> 05:37:15,223
EXTENDING LIFESPAN TO ALMOST A

9768
05:37:15,223 --> 05:37:17,525
SCIENCE FICTION LEVEL, MAYBE

9769
05:37:17,525 --> 05:37:19,927
SOMEONE'S MID 90s TO 100s,

9770
05:37:19,927 --> 05:37:22,129
BUT WE'RE REALLY FOCUSING ON

9771
05:37:22,129 --> 05:37:24,031
EXTENDING THE HEALTHSPAN OF THE

9772
05:37:24,031 --> 05:37:24,665
INDIVIDUAL AND THE POPULATION AS

9773
05:37:24,665 --> 05:37:28,603
A WHOLE.

9774
05:37:28,603 --> 05:37:30,805
SO WHAT ARE THE OVERARCHES

9775
05:37:30,805 --> 05:37:32,707
QUESTIONS RELATED TO

9776
05:37:32,707 --> 05:37:33,007
GEROSCIENCE?

9777
05:37:33,007 --> 05:37:35,276
WHAT ARE THESE EXPERIMENTAL

9778
05:37:35,276 --> 05:37:37,144
GEROSCIENCE APPROACHES, WHAT ARE

9779
05:37:37,144 --> 05:37:38,112
THE MECHANISMS OF A BEINGTION,

9780
05:37:38,112 --> 05:37:39,313
CAN THEY BE LEVERAGED FOR

9781
05:37:39,313 --> 05:37:43,217
PREVENTION OR TREATMENT OF AGING

9782
05:37:43,217 --> 05:37:43,985
RELATED MORBIDITIES?

9783
05:37:43,985 --> 05:37:46,153
SO THERE'S REALLY THREE WE'RE

9784
05:37:46,153 --> 05:37:47,922
GOING TO ADDRESS HERE.

9785
05:37:47,922 --> 05:37:52,193
ONE IS DATING BACK TO THE LATE

9786
05:37:52,193 --> 05:37:54,295
1900s, DIETARY RESTRICTION.

9787
05:37:54,295 --> 05:37:56,230
REALLY AN UMBRELLA TERM, OVERALL

9788
05:37:56,230 --> 05:37:58,533
REDUCTION OF CALORIES WITHOUT

9789
05:37:58,533 --> 05:38:02,036
IMPINGING UPON THE RATIOS OF THE

9790
05:38:02,036 --> 05:38:03,905
PROTEIN AND CARBOHYDRATE.

9791
05:38:03,905 --> 05:38:05,473
INTERMITTENT FASTING OR

9792
05:38:05,473 --> 05:38:06,173
TIME-RESTRICTED FEEDING.

9793
05:38:06,173 --> 05:38:08,709
ALSO LOOKING AT PROTEIN

9794
05:38:08,709 --> 05:38:09,143
RESTRICTION.

9795
05:38:09,143 --> 05:38:12,613
LAST BUT NOT LEAST BUT VERY

9796
05:38:12,613 --> 05:38:14,815
POTENT IS METHIONINE

9797
05:38:14,815 --> 05:38:16,651
RESTRICTION, WHERE JUST THE

9798
05:38:16,651 --> 05:38:20,288
REDUCTION OF THE INTAKE OF

9799
05:38:20,288 --> 05:38:23,090
SULFUR METHIONINE CYSTINE HAS

9800
05:38:23,090 --> 05:38:25,393
BEEN SHOWN TO EXTEND LONGEVITY

9801
05:38:25,393 --> 05:38:27,028
IN MA  MAMMALS.

9802
05:38:27,028 --> 05:38:29,997
ANOTHER APPROACH WITH

9803
05:38:29,997 --> 05:38:32,533
GEROSCIENCE IS ENDOCRINE

9804
05:38:32,533 --> 05:38:37,672
MANIPULATION.

9805
05:38:37,672 --> 05:38:41,175
HORMONE LEVELS ARE DECREASED --

9806
05:38:41,175 --> 05:38:46,080
LONGEST LIVED MICE -- STUDIED

9807
05:38:46,080 --> 05:38:47,181
THOSE, AND ALL THESE FOR THE

9808
05:38:47,181 --> 05:38:48,916
MOST PART HAVE REDUCTION OF

9809
05:38:48,916 --> 05:38:52,186
GROWTH HORMONE, IGF-1 SIGNALING.

9810
05:38:52,186 --> 05:38:54,956
LAST BUT NOT LEAST THERE'S

9811
05:38:54,956 --> 05:38:56,057
PHARMACOLOGICAL INTERVENTIONS

9812
05:38:56,057 --> 05:39:00,428
THAT CAN BE USED TO EXTEND

9813
05:39:00,428 --> 05:39:03,164
HEALTHSPAN AND LIFESPAN, THREE

9814
05:39:03,164 --> 05:39:06,100
MAIN DRUGS RAPAMYCIN, MET FOR

9815
05:39:06,100 --> 05:39:09,770
MAN AND ACARBOSE, I'D ALSO LIKE

9816
05:39:09,770 --> 05:39:10,805
TO POINT OUT, THERE'S A TALK

9817
05:39:10,805 --> 05:39:12,039
LATER ON IN THE SESSION, THAT

9818
05:39:12,039 --> 05:39:14,308
MANY OF THESE DRUGS, AT LEAST

9819
05:39:14,308 --> 05:39:16,944
TWO OF THESE THREE ARE ALSO --

9820
05:39:16,944 --> 05:39:19,480
THAT TERM -- METABOLITES, HOW

9821
05:39:19,480 --> 05:39:22,116
DOES THE MICROBIOME PRODUCE SOME

9822
05:39:22,116 --> 05:39:22,783
OF THESE METABOLITES THAT COULD,

9823
05:39:22,783 --> 05:39:27,154
IN FACT, IMPINGE UPON OR

9824
05:39:27,154 --> 05:39:28,356
STIMULATE HEALTHY PATHWAYS IN

9825
05:39:28,356 --> 05:39:29,924
THE BODY IS REALLY AN AREA

9826
05:39:29,924 --> 05:39:31,292
THAT'S WIDE OPEN FOR RESEARCH IN

9827
05:39:31,292 --> 05:39:35,296
THE FUTURE.

9828
05:39:35,296 --> 05:39:38,299
SO ARE THERE COMMON PATHWAYS

9829
05:39:38,299 --> 05:39:39,200
IMPACTED BY ALL THREE OF THESE

9830
05:39:39,200 --> 05:39:40,534
INTERVENTIONS, AND CAN WE FOCUS

9831
05:39:40,534 --> 05:39:50,778
ON THAT PATHWAY.

9832
05:39:50,778 --> 05:39:54,415
THEY LIKED AT DIETARY

9833
05:39:54,415 --> 05:39:56,283
INTERVENTION, ENDOCRINE

9834
05:39:56,283 --> 05:39:59,020
MODELS -- IN MICE, ALSO

9835
05:39:59,020 --> 05:40:01,322
PHARMACOLOGICAL INTERVENTIONS.

9836
05:40:01,322 --> 05:40:03,491
WHAT THEY SAW AT LEAST LOOKING

9837
05:40:03,491 --> 05:40:05,026
NE LIVER OF THESE MICE WAS

9838
05:40:05,026 --> 05:40:07,128
INCREASED EXPRESSION OF AN

9839
05:40:07,128 --> 05:40:15,870
ENZYME CALLED GAMMA LYASE.

9840
05:40:15,870 --> 05:40:16,837
INCREASED BY MOST --

9841
05:40:16,837 --> 05:40:17,705
INTERVENTIONS THAT CAN BE USED

9842
05:40:17,705 --> 05:40:20,107
AS A SIMPLE MOLECULAR BIOMARKER

9843
05:40:20,107 --> 05:40:20,841
ASSOCIATED WITH LONGEVITY.

9844
05:40:20,841 --> 05:40:22,643
I REALLY WANT TO PUT SOME STRESS

9845
05:40:22,643 --> 05:40:24,912
ON THE ASSOCIATED BECAUSE AT

9846
05:40:24,912 --> 05:40:26,213
THIS POINT AT LEAST IN THE

9847
05:40:26,213 --> 05:40:26,947
MAMMAL, IT'S CORRELATIVE.

9848
05:40:26,947 --> 05:40:28,616
IT DOESN'T MEAN INCREASING CGL

9849
05:40:28,616 --> 05:40:30,518
IS GOING TO EXTEND LIFE SPAN BUT

9850
05:40:30,518 --> 05:40:31,018
AT LEAST WITH ALL THESE

9851
05:40:31,018 --> 05:40:34,155
DIFFERENT TYPES OF INTERVENT 

9852
05:40:34,155 --> 05:40:35,356
INTERVENTIONS, THEY DO EXTEND

9853
05:40:35,356 --> 05:40:37,058
LIFESPAN AND HEALTHSPAN, THERE

9854
05:40:37,058 --> 05:40:38,492
IS AN INCREASE IN CGL AT LEAST

9855
05:40:38,492 --> 05:40:39,093
IN THE LIVER.

9856
05:40:39,093 --> 05:40:42,229
SO WHAT DOES CGL DO?

9857
05:40:42,229 --> 05:40:43,431
WHAT I'M FOCUSING ON HERE IS

9858
05:40:43,431 --> 05:40:44,932
METABOLISM OF AMEA KNOW ACIDS.

9859
05:40:44,932 --> 05:40:47,668
SO WE START WITH METHIONINE,

9860
05:40:47,668 --> 05:40:50,404
ESSENTIAL AMINO ACID,

9861
05:40:50,404 --> 05:40:51,505
METABOLISM, YOU REACH

9862
05:40:51,505 --> 05:40:52,073
HOMOCYSTEINE.

9863
05:40:52,073 --> 05:40:54,575
THE HOMOCYSTEINE CONTINUES ON

9864
05:40:54,575 --> 05:40:57,978
THE TRANS OPERATION PATHWAY,

9865
05:40:57,978 --> 05:41:03,317
CBS, WHICH IS A PLP-DEPENDENT

9866
05:41:03,317 --> 05:41:11,859
ENZYME.

9867
05:41:11,859 --> 05:41:16,030
TO FORM CYSTINE.

9868
05:41:16,030 --> 05:41:17,665
HOWEVER, IT SHOULD BE NOTED THAT

9869
05:41:17,665 --> 05:41:20,267
CGL IS ACTUALLY QUITE PROMIS

9870
05:41:20,267 --> 05:41:21,602
QUEUE US IN THE SUBSTRATE OF

9871
05:41:21,602 --> 05:41:24,138
PRODUCTS THAT IT MAKES.

9872
05:41:24,138 --> 05:41:26,941
CGL CAN BRING IN CYSTINE ITSELF

9873
05:41:26,941 --> 05:41:30,044
AND HOMOCYSTEINE IN A VARIETY OF

9874
05:41:30,044 --> 05:41:31,612
PRODUCTS AND ALSO ONE BYPRODUCT

9875
05:41:31,612 --> 05:41:35,483
IN THIS PROCESS IS THE

9876
05:41:35,483 --> 05:41:37,118
TRANSMITTER HYDROGEN SULFIDE

9877
05:41:37,118 --> 05:41:37,351
GAS.

9878
05:41:37,351 --> 05:41:41,722
WHY ARE WE TALKING  I ABOUT IT N

9879
05:41:41,722 --> 05:41:42,623
AN AGING-RELATED STUDY?

9880
05:41:42,623 --> 05:41:45,025
FOR THE MOST PART IT'S AN

9881
05:41:45,025 --> 05:41:48,429
OCCUPATIONAL HAZARD ESPECIALLY

9882
05:41:48,429 --> 05:41:53,768
IN THE -- DON'T GO HOME AND

9883
05:41:53,768 --> 05:41:55,102
START SNIFFING IT BECAUSE IT IS

9884
05:41:55,102 --> 05:41:56,737
TOXIC AT HIGH LEVELS.

9885
05:41:56,737 --> 05:41:59,807
HOWEVER, LOOKING AT IT FROM A

9886
05:41:59,807 --> 05:42:02,309
MEDICAL STANDPOINT, ESPECIALLY

9887
05:42:02,309 --> 05:42:04,478
BACK IN THE LATE 1800s, EARLY

9888
05:42:04,478 --> 05:42:05,579
1900s, INDIVIDUALS WOULD

9889
05:42:05,579 --> 05:42:07,248
TRAVEL WIDE AND FAR AND SPEND

9890
05:42:07,248 --> 05:42:08,749
QUITE A BIT OF MONEY TO GO TO

9891
05:42:08,749 --> 05:42:10,718
THESE SULFIDE POOLS SUCH AS

9892
05:42:10,718 --> 05:42:13,420
THESE INDIVIDUALS HERE AND BATHE

9893
05:42:13,420 --> 05:42:14,488
IN THESE SULFIDE POOLS THINKING

9894
05:42:14,488 --> 05:42:15,756
IT WOULD BE CURATIVE OF WHAT

9895
05:42:15,756 --> 05:42:18,492
AILS THEM.

9896
05:42:18,492 --> 05:42:21,028
IT WASN'T A FOUNTAIN OF YOUTH.

9897
05:42:21,028 --> 05:42:21,629
HOWEVER, IN THE EARLY 2000s,

9898
05:42:21,629 --> 05:42:22,863
THERE WAS A RENAISSANCE IN

9899
05:42:22,863 --> 05:42:24,398
HYDROGEN SULFIDE BIOLOGY

9900
05:42:24,398 --> 05:42:27,568
RESEARCH.

9901
05:42:27,568 --> 05:42:28,235
ESPECIALLY WHEN IT CAME TO AGING

9902
05:42:28,235 --> 05:42:36,443
AND LI LIFESPAN EXTENSION.

9903
05:42:36,443 --> 05:42:38,112
THEY SAW BOTH IN WORMS AND FLIES

9904
05:42:38,112 --> 05:42:39,146
THAT INCREASING EXPOSURE TO

9905
05:42:39,146 --> 05:42:43,417
HYDROGEN SULFIDE GAS OR BOOSTING

9906
05:42:43,417 --> 05:42:44,185
ENDOGENOUS PRODUCTION OF THE GAS

9907
05:42:44,185 --> 05:42:47,988
BY THE ENZYME CGRCBS COULD

9908
05:42:47,988 --> 05:42:51,025
EXTEND LIFESPAN IN THESE MODEL

9909
05:42:51,025 --> 05:42:51,292
ORGANISMS.

9910
05:42:51,292 --> 05:42:52,293
BUT WHAT ABOUT IN THE MAMMAL?

9911
05:42:52,293 --> 05:42:54,795
SO WHAT I'VE SHOWN WHEN I WAS IT

9912
05:42:54,795 --> 05:42:57,064
THE HARVARD SCHOOL OF PUBLIC

9913
05:42:57,064 --> 05:42:57,698
HEALTH IN MY OWN LABORATORY OVER

9914
05:42:57,698 --> 05:43:00,134
THE LAST SIX YEARS IS THAT UNDER

9915
05:43:00,134 --> 05:43:01,268
DIETARY RESTRICTION,

9916
05:43:01,268 --> 05:43:05,973
INTERMITTENT FASTING AND

9917
05:43:05,973 --> 05:43:08,542
METHIONINE RESTRICTION --

9918
05:43:08,542 --> 05:43:10,377
THERE'S AN INCREASE IN CGL

9919
05:43:10,377 --> 05:43:11,846
EXPRESSION AND LEAST IN THE

9920
05:43:11,846 --> 05:43:13,614
LIVER AND INCREASED PRODUCTION

9921
05:43:13,614 --> 05:43:15,916
CAPACITY IN THE HYDROGEN SULFIDE

9922
05:43:15,916 --> 05:43:16,917
GAS.

9923
05:43:16,917 --> 05:43:19,320
THIS INCREASE WAS NECESSARY AND

9924
05:43:19,320 --> 05:43:20,387
SUFFICIENT TO GIVE STRESS

9925
05:43:20,387 --> 05:43:22,389
RESISTANCE, CARDIOVASCULAR

9926
05:43:22,389 --> 05:43:26,093
FITNESS AND MUSCLE ANGIOGENESIS

9927
05:43:26,093 --> 05:43:26,894
IN LATE LIFE.

9928
05:43:26,894 --> 05:43:28,429
ALSO ENDOCRINE AND METABOLIC

9929
05:43:28,429 --> 05:43:29,396
RESPONSES TO FASTING.

9930
05:43:29,396 --> 05:43:30,698
HOWEVER THE BIG QUESTION IS WHAT

9931
05:43:30,698 --> 05:43:32,566
ABOUT LONGEVITY AND LIFESPAN?

9932
05:43:32,566 --> 05:43:34,335
I MENTIONED BEFORE IT WAS SHOWN

9933
05:43:34,335 --> 05:43:36,437
TO BE NECESSARY TO DRIVE

9934
05:43:36,437 --> 05:43:40,975
EXTENSION IN THE FLIES AND WOR 

9935
05:43:40,975 --> 05:43:43,110
WORMS.

9936
05:43:43,110 --> 05:43:43,711
ONE OF THE VERY FIRST THINGS I

9937
05:43:43,711 --> 05:43:44,411
DID IN MY LABORATORY IS WE TOOK

9938
05:43:44,411 --> 05:43:50,451
MALE AND FEMALE WILD TYPE AND

9939
05:43:50,451 --> 05:43:56,290
KNOCKOUT MICE, -- AND SO ALL THE

9940
05:43:56,290 --> 05:43:58,359
ANIMALS WERE KEPT UNDER --

9941
05:43:58,359 --> 05:43:59,460
CONDITIONS FOR THE FIRST FIVE

9942
05:43:59,460 --> 05:44:04,131
MONTHS OF LIFE, AND THEN AROUND

9943
05:44:04,131 --> 05:44:07,768
MONTH SIX, THE CALORIC

9944
05:44:07,768 --> 05:44:09,603
RESTRICTION ARM WAS PUT ON DAILY

9945
05:44:09,603 --> 05:44:14,541
RESTRICTION OF CALLYS, OVERALL

9946
05:44:14,541 --> 05:44:15,509
REDUCTION BY 35%.

9947
05:44:15,509 --> 05:44:16,911
AT 10 MONTHS OF LIFE WE UPPED

9948
05:44:16,911 --> 05:44:19,446
THAT TO 45% CALORIC RESTRICTION

9949
05:44:19,446 --> 05:44:21,982
AND THEY WERE MAINTAINED ON THAT

9950
05:44:21,982 --> 05:44:26,086
45% CALORIC RESTRICTION TO FOR E

9951
05:44:26,086 --> 05:44:28,155
REMAINDER OF THEIR LIFE.

9952
05:44:28,155 --> 05:44:30,357
ALSO HEALTHSPAN TESTS, BOTH

9953
05:44:30,357 --> 05:44:34,728
QUALITY AND QUANTITY OF LIFE.

9954
05:44:34,728 --> 05:44:40,100
 -- COGNITIVE IMPROVEMENTS.

9955
05:44:40,100 --> 05:44:44,138
26 TO 46 MICE PER GENOTYPE/DIET

9956
05:44:44,138 --> 05:44:47,007
GROUP.

9957
05:44:47,007 --> 05:44:48,642
5:00 P.M. DAILY, SEVEN DAYS A

9958
05:44:48,642 --> 05:44:50,110
WEEK FOR OVER 3 1/2 YEARS, SO

9959
05:44:50,110 --> 05:44:51,478
REALLY I HAVE TO GIVE PROPS TO

9960
05:44:51,478 --> 05:44:53,514
ALL THE PEOPLE IN MY LABORATORY,

9961
05:44:53,514 --> 05:44:54,248
ESPECIALLY DURING COVID, THEY

9962
05:44:54,248 --> 05:44:56,183
NEVER MISSED ONE DAY OVER THE

9963
05:44:56,183 --> 05:44:58,252
WHOLE 3 1/2, ALMOST FOUR YEARS

9964
05:44:58,252 --> 05:44:58,852
THAT SOME OF THESE MICE HAVE

9965
05:44:58,852 --> 05:44:59,053
LIVED.

9966
05:44:59,053 --> 05:45:02,022
THE CALORIE COMPOSITION OF THE

9967
05:45:02,022 --> 05:45:04,858
BASE DIET WAS 20% PROTEIN, 20%

9968
05:45:04,858 --> 05:45:06,593
FAT, 60% CARBOHYDRATES.

9969
05:45:06,593 --> 05:45:07,895
THE ANIMALS WERE ALL TRACKED

9970
05:45:07,895 --> 05:45:10,097
UNTIL FOUND DECEASED OR

9971
05:45:10,097 --> 05:45:14,935
EUTHANIZED AT SIGNS OF BEING

9972
05:45:14,935 --> 05:45:16,370
MORIBUND.

9973
05:45:16,370 --> 05:45:18,439
SO TO START IT OFF, WHAT WE

9974
05:45:18,439 --> 05:45:20,074
ACTUALLY SEE IS THERE'S ACTUALLY

9975
05:45:20,074 --> 05:45:22,810
NO DIFFERENCE IN LIFESPAN

9976
05:45:22,810 --> 05:45:26,480
BETWEEN CGL WILD TYPE AND

9977
05:45:26,480 --> 05:45:27,915
KNOCKOUT MICE WHICH IS ACTUALLY

9978
05:45:27,915 --> 05:45:28,549
GOOD.

9979
05:45:28,549 --> 05:45:34,922
MOCKING UP CGL -- PRO --

9980
05:45:34,922 --> 05:45:37,324
PHENOTYPE, SO NEXT LOOKING AT AT

9981
05:45:37,324 --> 05:45:38,592
THE CALORIC RESTRICTION AT THE

9982
05:45:38,592 --> 05:45:40,694
CLEVELAND CLINIC TO EXTEND MICE

9983
05:45:40,694 --> 05:45:42,997
LIFESPAN, AND WE SAW THAT IT DID

9984
05:45:42,997 --> 05:45:46,400
SO THE MICE ON CALORIC

9985
05:45:46,400 --> 05:45:47,935
RESTRICTION HAD 24% INCREASE IN

9986
05:45:47,935 --> 05:45:50,337
MEDIAN LIFESPAN SO THIS IS

9987
05:45:50,337 --> 05:45:50,971
BASICALLY HUMAN EQUIVALENT GOING

9988
05:45:50,971 --> 05:45:52,873
FROM 7 TO 8 YEARS FOR EXPECTED

9989
05:45:52,873 --> 05:45:57,044
LIFE SMAN TO -- AND THE MAXIMUM

9990
05:45:57,044 --> 05:45:58,712
WAS EXTENDED BY 11% IN THESE

9991
05:45:58,712 --> 05:46:01,415
MICE.

9992
05:46:01,415 --> 05:46:03,050
SO THE BIG QUESTION WAS IS

9993
05:46:03,050 --> 05:46:06,754
KNOCKING OUT CGL IMPINGE UPON

9994
05:46:06,754 --> 05:46:07,788
LIFESPAN EXTENSION UNDER CALORIC

9995
05:46:07,788 --> 05:46:08,322
RESTRICTION.

9996
05:46:08,322 --> 05:46:09,957
WE SAW IN FACT IT DID, WE SAW AN

9997
05:46:09,957 --> 05:46:14,862
8% DECLINE IN MEDIAN LIFESPAN

9998
05:46:14,862 --> 05:46:18,999
AND 8.5% DECLINE IN THE CGL

9999
05:46:18,999 --> 05:46:23,070
KNOCKOUTS COMPARED TO THE CGL

10000
05:46:23,070 --> 05:46:25,039
WILD TYPE MICE UNDER CALORIC

10001
05:46:25,039 --> 05:46:27,875
RESTRICTION.

10002
05:46:27,875 --> 05:46:30,277
ONE GRAPH HERE BEING LOOKING AT

10003
05:46:30,277 --> 05:46:35,315
CGL WILD TYPE -- KNOCKOUT, CORE

10004
05:46:35,315 --> 05:46:37,618
RESTRICTION BUT AGAIN THE CGL

10005
05:46:37,618 --> 05:46:40,154
WILD TYPE UNDER CALORIC

10006
05:46:40,154 --> 05:46:41,889
RESTRICTION MEDIAN SURVIVAL

10007
05:46:41,889 --> 05:46:43,290
AND -- SURVIVAL.

10008
05:46:43,290 --> 05:46:44,491
I'D LIKE TO REALLY POINT OUT

10009
05:46:44,491 --> 05:46:45,993
THERE'S NO NOTICEABLE DIFFERENCE

10010
05:46:45,993 --> 05:46:50,397
AT THE MAXIMUM BETWEEN CGL

10011
05:46:50,397 --> 05:46:52,766
KNOCKOUTS AND CGL KNOCKOUTS --

10012
05:46:52,766 --> 05:46:54,468
SO SLIGHT INCREASE, NOT

10013
05:46:54,468 --> 05:46:55,569
COMPLETELY ABLATED AT THE MEDIAN

10014
05:46:55,569 --> 05:46:58,038
BUT AT THE MAXIMUM IT'S

10015
05:46:58,038 --> 05:46:59,239
COMPLETELY ABLATED.

10016
05:46:59,239 --> 05:47:02,176
AND THEN JUST REALLY QUICK

10017
05:47:02,176 --> 05:47:07,181
LOOKING AT -- I MENTIONED THE --

10018
05:47:07,181 --> 05:47:07,815
HEALTHSPAN, WE SAW IMPROVEMENTS

10019
05:47:07,815 --> 05:47:10,551
IN BOTH THE WILD TYPES AND

10020
05:47:10,551 --> 05:47:13,287
KNOCKOUTS,

10021
05:47:13,287 --> 05:47:14,421
PHYSIOLOGICAL/MUSCULOSKELETAL

10022
05:47:14,421 --> 05:47:15,055
TESTS, METABOLIC AND COGNITIVE.

10023
05:47:15,055 --> 05:47:15,756
HOWEVER IN TERMS OF THE

10024
05:47:15,756 --> 05:47:16,824
METABOLIC AND COGNITIVE

10025
05:47:16,824 --> 05:47:18,792
IMPROVEMENTS THOSE WERE MAIN LOW

10026
05:47:18,792 --> 05:47:19,660
ONLY SEEN IN THE WILD TYPE SO

10027
05:47:19,660 --> 05:47:21,361
THAT IS -- FOR THE MOST PART IN

10028
05:47:21,361 --> 05:47:23,530
THE CGL KNOCKOUT MICE.

10029
05:47:23,530 --> 05:47:25,399
>> DOCTOR, YOU HAVE TWO
MINUTES

10030
05:47:25,399 --> 05:47:25,666
REMAINING.

10031
05:47:25,666 --> 05:47:29,570
>> THANKS A LOT.

10032
05:47:29,570 --> 05:47:32,606
AND SO JUST SUMMARIZING AT THIS

10033
05:47:32,606 --> 05:47:34,808
POINT, SO CALORIC

10034
05:47:34,808 --> 05:47:35,442
RESTRICTION/TIME RESTRICTED

10035
05:47:35,442 --> 05:47:37,845
FEEDING WE SAW A BOOST IN CGL,

10036
05:47:37,845 --> 05:47:42,716
BEAST IN H2S, AND MAXIMIZED

10037
05:47:42,716 --> 05:47:49,056
LIFESPAN BUT BY WHAT MECHANISM?

10038
05:47:49,056 --> 05:47:54,094
PERSULFIDATION AND LIKEWISE

10039
05:47:54,094 --> 05:47:55,529
MITOCHONDRIAL BIOENERGETICS, TO

10040
05:47:55,529 --> 05:48:02,336
MAKE ATP THROUGH SULFITE -- SQR,

10041
05:48:02,336 --> 05:48:05,739
OR UNDER TOXIC CONDITIONS,

10042
05:48:05,739 --> 05:48:08,876
COMPLEX 4 BASICALLY KILLS OFF

10043
05:48:08,876 --> 05:48:09,209
MITOCHONDRIA.

10044
05:48:09,209 --> 05:48:11,044
FOR THE FOCUS OF THIS TALK WE'LL

10045
05:48:11,044 --> 05:48:17,818
FOCUS ON PERSUL FI. DATION.

10046
05:48:17,818 --> 05:48:21,321
THE LIVER, KIDNEYS, MUSCLE AND

10047
05:48:21,321 --> 05:48:23,790
BRAIN, WE SAW REALLY NICE

10048
05:48:23,790 --> 05:48:26,927
ENRICHMENT IN PROTEIN, SO THIS

10049
05:48:26,927 --> 05:48:28,395
CAN MODIFY THE PROTEIN

10050
05:48:28,395 --> 05:48:30,430
STRUCTURE, ITS FUNCTION, IT CAN

10051
05:48:30,430 --> 05:48:31,498
ALSO PROTECT AGAINST

10052
05:48:31,498 --> 05:48:32,900
IRREVERSIBLE OXIDATIVE STRESS ON

10053
05:48:32,900 --> 05:48:38,705
THE CYSTINES THAT ARE MODIFIED.

10054
05:48:38,705 --> 05:48:40,407
QUITE A BIT OF CHANGES TO THE

10055
05:48:40,407 --> 05:48:40,674
PROTEOME.

10056
05:48:40,674 --> 05:48:42,009
THEN WE LOOKED AT THE DEPENDENCE

10057
05:48:42,009 --> 05:48:45,579
OF CGL FOR THAT SHIFT IN PER

10058
05:48:45,579 --> 05:48:46,480
SUFFICIENTLY DAITION, SO ALL THE

10059
05:48:46,480 --> 05:48:47,814
TISSUES COMBINE INTO ONE, IT'S

10060
05:48:47,814 --> 05:48:53,787
REALLY NICE ENRICHMENT UNDER

10061
05:48:53,787 --> 05:49:01,261
CALORIC RESTRICTION LOST ON CGF

10062
05:49:01,261 --> 05:49:02,663
KNOCKOUTS.

10063
05:49:02,663 --> 05:49:04,965
WE PLUG THEM INTO PATHWAY

10064
05:49:04,965 --> 05:49:06,066
ANALYSIS WE SEE THERE'S A

10065
05:49:06,066 --> 05:49:07,968
VARIETY OF AGING-RELATED

10066
05:49:07,968 --> 05:49:10,270
PATHWAYS THAT ARE IMPACTED OR AT

10067
05:49:10,270 --> 05:49:16,243
LEAST ENRICHED FOR THESE PER

10068
05:49:16,243 --> 05:49:17,744
SULFIDATED PROTEINS.

10069
05:49:17,744 --> 05:49:19,680
AT THE VERY LEAST ALL THESE

10070
05:49:19,680 --> 05:49:22,482
PATHWAYS HAVE ENRICHMENT FOR

10071
05:49:22,482 --> 05:49:24,451
PROTEIN PERSULFIDATION UNDER

10072
05:49:24,451 --> 05:49:25,552
CALORIC RESTRICTION.

10073
05:49:25,552 --> 05:49:27,421
SO AGAIN SUMMARY HERE, DIETARY

10074
05:49:27,421 --> 05:49:29,089
RESTRICTION IS GOING TO GIVE

10075
05:49:29,089 --> 05:49:31,491
MAXIMIZED LIFESPAN, MAXIMIZED

10076
05:49:31,491 --> 05:49:31,825
HEALTHSPAN.

10077
05:49:31,825 --> 05:49:34,995
WE FELT THIS PATHWAY BY

10078
05:49:34,995 --> 05:49:35,629
STIMULATING H2S PLAYS A PART IN

10079
05:49:35,629 --> 05:49:37,097
IT BUT IT'S PROBABLY NOT THE

10080
05:49:37,097 --> 05:49:39,199
ENTIRE PICTURE, THESE DOTTED

10081
05:49:39,199 --> 05:49:41,068
LINES OVER HERE, AND HOW DO WE

10082
05:49:41,068 --> 05:49:43,070
APPLY THIS MECHANISTIC KNOWLEDGE

10083
05:49:43,070 --> 05:49:44,037
FOR CLINICAL TRANSLATION.

10084
05:49:44,037 --> 05:49:46,373
REAL QUICK I'M LOOKING AT

10085
05:49:46,373 --> 05:49:47,574
HUMANS, I PUBLISHED THIS LAST

10086
05:49:47,574 --> 05:49:49,977
YEAR, IN IS A REDUCTION IN

10087
05:49:49,977 --> 05:49:52,179
CIRCULATING -- AS A RESULT OF

10088
05:49:52,179 --> 05:49:52,346
AGE.

10089
05:49:52,346 --> 05:49:54,982
LOOKING AT VERY DANGEROUS

10090
05:49:54,982 --> 05:49:58,952
AGE-RELATED DISEASE IN HUMANS IS

10091
05:49:58,952 --> 05:50:01,688
GLIOBLASTOMA, HOW DOES -- WE SAW

10092
05:50:01,688 --> 05:50:03,824
THERE WAS A MASSIVE LOSS IN

10093
05:50:03,824 --> 05:50:06,627
PROTEIN PERSULFIDATION IN HUMAN

10094
05:50:06,627 --> 05:50:08,095
BIOPSIES OF GLIOBLASTOMA TUMORS

10095
05:50:08,095 --> 05:50:10,497
COMPARED TO THE NON-TUMOR BRAIN

10096
05:50:10,497 --> 05:50:10,797
TISSUE.

10097
05:50:10,797 --> 05:50:13,267
SO THERE WAS A LOSS OF THE

10098
05:50:13,267 --> 05:50:13,767
SIGNALING THAT OCCURS.

10099
05:50:13,767 --> 05:50:15,402
AND ALSO WE SAW THAT IF WE

10100
05:50:15,402 --> 05:50:19,473
INHIBIT CGL THROUGH A BACTERIAL

10101
05:50:19,473 --> 05:50:23,410
METABOLITE, WE CAN ACTUALLY

10102
05:50:23,410 --> 05:50:24,845
ENHANCE GLIOBLASTOMA -- IN

10103
05:50:24,845 --> 05:50:26,046
CULTURE IN ADDITION TO

10104
05:50:26,046 --> 05:50:29,116
INHIBITING ITS H2S PRODUCTION.

10105
05:50:29,116 --> 05:50:32,185
LAST BUT NOT LEAST BY DELIVERING

10106
05:50:32,185 --> 05:50:35,789
H2S INTO THE TUMORS IN IN VIVO

10107
05:50:35,789 --> 05:50:37,224
MODEL, WE CAN DECREASE TUMOR

10108
05:50:37,224 --> 05:50:42,062
VOLUME AND ALSO DECREASE THE

10109
05:50:42,062 --> 05:50:42,729
TUMOR -- PHENOTYPE -- EXPRESSION

10110
05:50:42,729 --> 05:50:46,533
IN THE TUMORS OF THOSE MICE.

10111
05:50:46,533 --> 05:50:47,734
AGAIN, REAL, REAL QUICK, SO

10112
05:50:47,734 --> 05:50:50,837
ACTUALLY APPLYING THIS IN A

10113
05:50:50,837 --> 05:50:52,239
CLINICAL TRIAL, WE'RE ACTUALLY

10114
05:50:52,239 --> 05:50:54,741
LOOKING AT BOOSTING H2S

10115
05:50:54,741 --> 05:50:57,210
PRODUCTION NOT THROUGH DIET BUT

10116
05:50:57,210 --> 05:50:58,011
ACTUALLY THROUGH LOWERING

10117
05:50:58,011 --> 05:50:59,079
HORMONE ACTIVITY.

10118
05:50:59,079 --> 05:51:01,381
WE CAN ACTUALLY SEE IS BY

10119
05:51:01,381 --> 05:51:04,851
TREATING AT LEAST IN THIS CASE

10120
05:51:04,851 --> 05:51:13,126
MICE WITH PROPYL THIOURACIL, WE

10121
05:51:13,126 --> 05:51:15,095
CAN ENHANCE PRODUCTION CAPACITY

10122
05:51:15,095 --> 05:51:22,803
WENCAPACITY. -- EXPENDED PATIENL

10123
05:51:22,803 --> 05:51:23,303
THREE FOLD.

10124
05:51:23,303 --> 05:51:26,707
SO WE'RE GOING TO BE REVISITING

10125
05:51:26,707 --> 05:51:30,977
THIS AS A CLINICAL TRIAL USING A

10126
05:51:30,977 --> 05:51:35,615
SAFER DRUG METHIMAZOLE TO

10127
05:51:35,615 --> 05:51:38,452
ENHANCE H2S ACTIVITY -- CAN

10128
05:51:38,452 --> 05:51:41,521
BOOST THEIR H2S PRODUCTION AT

10129
05:51:41,521 --> 05:51:43,156
LEAST IN THEIR LIVERS.

10130
05:51:43,156 --> 05:51:45,025
THIS IS IN CLINICAL TRIAL RIGHT

10131
05:51:45,025 --> 05:51:46,893
NOW, WHERE PATIENTS WITH

10132
05:51:46,893 --> 05:51:49,529
RECURRENT GLIOBLASTOMA WILL BE

10133
05:51:49,529 --> 05:51:54,000
TREATED WITH -- THIS WILL BE

10134
05:51:54,000 --> 05:51:56,636
USED WITH STANDARD OF CARE

10135
05:51:56,636 --> 05:51:57,070
CHEMOTHERAPIES.

10136
05:51:57,070 --> 05:52:01,441
SO I'LL SKIP THIS FOR THE SAKE

10137
05:52:01,441 --> 05:52:05,746
OF TIME BUT -- COLLABORATORS,

10138
05:52:05,746 --> 05:52:06,646
FUNDING THAT MADE ALL THIS

10139
05:52:06,646 --> 05:52:07,080
POSSIBLE.

10140
05:52:07,080 --> 05:52:10,417
THANK YOU VERY MUCH.

10141
05:52:10,417 --> 05:52:12,152
>> THANK YOU VERY MUCH.

10142
05:52:12,152 --> 05:52:13,153
UNFORTUNATELY I THINK WE HAVE TO

10143
05:52:13,153 --> 05:52:15,956
MOVE ON BECAUSE WE ARE OUT OF

10144
05:52:15,956 --> 05:52:17,691
TIME.

10145
05:52:17,691 --> 05:52:20,660
COULD YOU INJECT THIS IN

10146
05:52:20,660 --> 05:52:23,964
PATIENTS WITH GLEE OWE BLASTOMA?

10147
05:52:23,964 --> 05:52:30,170
IS THAT A REE A FEASIBLE APPROA?

10148
05:52:30,170 --> 05:52:33,440
>>  -- WITH THE GAS IS

10149
05:52:33,440 --> 05:52:33,874
DANGEROUS.

10150
05:52:33,874 --> 05:52:35,976
 -- IT'S GOING TO BE THE SAFEST

10151
05:52:35,976 --> 05:52:37,177
AND MOST EFFECTIVE WAY.

10152
05:52:37,177 --> 05:52:38,512
>> ALL RIGHT.

10153
05:52:38,512 --> 05:52:39,613
FANTASTIC.

10154
05:52:39,613 --> 05:52:40,380
HOPEFULLY MORE IN THE PANEL

10155
05:52:40,380 --> 05:52:43,483
DISCUSSION.

10156
05:52:43,483 --> 05:52:47,254
OKAY, SO OUR NEXT TALK, OUR NEXT

10157
05:52:47,254 --> 05:52:50,791
SPEAKER WILL BE DR. PATTI LEE

10158
05:52:50,791 --> 05:52:52,492
FROM THE ICAHN SCHOOL OF

10159
05:52:52,492 --> 05:52:54,094
MEDICINE AT MOUNT SINAI.

10160
05:52:54,094 --> 05:52:55,962
SEAL BE SPEAKING ABOUT

10161
05:52:55,962 --> 05:52:57,564
ENVIRONMENTAL DETERMINANTS AND

10162
05:52:57,564 --> 05:52:59,666
MODELS OF LUNG VASCULAR

10163
05:52:59,666 --> 05:53:00,734
SENESCENCE.

10164
05:53:00,734 --> 05:53:10,710
DR. LEE?

10165
05:53:10,710 --> 05:53:13,280
IS DR. LEON?

10166
05:53:13,280 --> 05:53:16,316
>> I ACTUALLY DON'T SEE
HER.

10167
05:53:16,316 --> 05:53:16,883
GLRL ALL RIGHT.

10168
05:53:16,883 --> 05:53:19,386
LET'S GIVE HER A MINUTE OR TWO.

10169
05:53:19,386 --> 05:53:19,986
MAYBE ONE OF YOU CAN TEXT OR

10170
05:53:19,986 --> 05:53:21,621
EMAIL HER.

10171
05:53:21,621 --> 05:53:25,859
WE CAN RUN A MINUTE OR TWO LATE.

10172
05:53:25,859 --> 05:53:27,694
THIS IS A QUESTION FOR DR. HINE

10173
05:53:27,694 --> 05:53:29,095
IF YOU'RE STILL ON.

10174
05:53:29,095 --> 05:53:29,830
DISULFIDE BONDS ARE VERY

10175
05:53:29,830 --> 05:53:30,597
IMPORTANT IN THE FUNCTION OF

10176
05:53:30,597 --> 05:53:31,932
MANY MOLECULES.

10177
05:53:31,932 --> 05:53:34,935
DOES HYDROGEN SULFIDE REACT WITH

10178
05:53:34,935 --> 05:53:38,872
DISULFIDE BONDS?

10179
05:53:38,872 --> 05:53:42,909
>> THAT'S A GREAT
QUESTION.

10180
05:53:42,909 --> 05:53:45,445
>> GR GALIS, NOT ME.

10181
05:53:45,445 --> 05:53:46,613
>> THAT'S A GREAT
QUESTION.

10182
05:53:46,613 --> 05:53:48,715
SO THE PERSULFIDATION I SHOWED

10183
05:53:48,715 --> 05:53:50,116
YOU, THAT'S ACTUALLY NOT

10184
05:53:50,116 --> 05:53:51,885
FAVORABLE JUST TO ADD A SULFIDE

10185
05:53:51,885 --> 05:53:55,188
ON TO A -- MOST HAVE TO BE

10186
05:53:55,188 --> 05:53:59,793
PRIMED AND ONE WAY TO PRIME THEM

10187
05:53:59,793 --> 05:54:01,561
IS -- THROUGH DISULFIDES, AND IT

10188
05:54:01,561 --> 05:54:04,197
SHOWS YOU IN TERMS OF EACH

10189
05:54:04,197 --> 05:54:06,733
FEEDING ELECTRONS INTO ELECTRON

10190
05:54:06,733 --> 05:54:07,367
TRANSPORT CHAIN THROUGH THE --

10191
05:54:07,367 --> 05:54:09,102
SQR, IT ACTUALLY DOES THAT BY

10192
05:54:09,102 --> 05:54:11,705
MODIFYING THE DISULFIDE BONDS IN

10193
05:54:11,705 --> 05:54:13,907
THAT SQR.

10194
05:54:13,907 --> 05:54:17,878
SO IF THE DISULFIDE BONDS ARE ON

10195
05:54:17,878 --> 05:54:18,945
THE EXTERNAL SIDE OF THAT

10196
05:54:18,945 --> 05:54:20,947
PROTEIN, IT IS POSSIBLE THEY CAN

10197
05:54:20,947 --> 05:54:22,015
BE MODIFIED THROUGH

10198
05:54:22,015 --> 05:54:25,318
PERSULFIDATION PROCESS.

10199
05:54:25,318 --> 05:54:29,789
>> OKAY, FANTASTIC.

10200
05:54:29,789 --> 05:54:31,157
AND I'M NOT SURE IF OUR NEXT

10201
05:54:31,157 --> 05:54:34,427
SPEAKER IS ON, SO WE CAN GO

10202
05:54:34,427 --> 05:54:39,533
SLIGHTLY OUT OF ORDER AND I CAN

10203
05:54:39,533 --> 05:54:41,768
GO NEXT.

10204
05:54:41,768 --> 05:54:46,072
IS SHE ON?

10205
05:54:46,072 --> 05:54:46,840
>> NO.

10206
05:54:46,840 --> 05:54:49,776
>> OKAY.

10207
05:54:49,776 --> 05:54:50,644
ALL RIGHT.

10208
05:54:50,644 --> 05:54:52,479
SOMEBODY COULD EMAIL HER SO

10209
05:54:52,479 --> 05:54:53,847
MAYBE SHE CAN COME ON FOR THE

10210
05:54:53,847 --> 05:54:54,814
FINAL ONE, OTHERWISE WE'LL HAVE

10211
05:54:54,814 --> 05:54:57,951
A SLIGHTLY LONGER BREAK, OR I'LL

10212
05:54:57,951 --> 05:54:58,752
JUST RAM DELL BELL ON FOREVER.

10213
05:54:58,752 --> 05:55:00,186
NO, I WON'T, I PROMISE.

10214
05:55:00,186 --> 05:55:02,556
OR WE CAN HAVE A LONGER

10215
05:55:02,556 --> 05:55:03,089
DISCUSSION SECTION.

10216
05:55:03,089 --> 05:55:04,658
SO I'LL JUST INTRODUCE MYSELF.

10217
05:55:04,658 --> 05:55:06,960
MY NAME IS LOUISE MCCOLLOUGH,

10218
05:55:06,960 --> 05:55:10,797
I'M THE CHAIR OF NEUROLOGY SO

10219
05:55:10,797 --> 05:55:11,264
IT'S ALL ABOUT STROKE.

10220
05:55:11,264 --> 05:55:12,866
WE ARE GOING TO TALK ABOUT

10221
05:55:12,866 --> 05:55:15,268
AGE-RELATED CHANGES IN THE

10222
05:55:15,268 --> 05:55:15,769
MICROBIOME IN HEALTH AND

10223
05:55:15,769 --> 05:55:16,002
DISEASE.

10224
05:55:16,002 --> 05:55:16,937
SO FIRST OF ALL, WHAT IS THE

10225
05:55:16,937 --> 05:55:17,270
MICROBIOME?

10226
05:55:17,270 --> 05:55:19,873
IT'S REALLY THE COMMUNITY OF

10227
05:55:19,873 --> 05:55:20,240
MICROORGANISMS.

10228
05:55:20,240 --> 05:55:20,840
WE'VE HEARD A BIT ABOUT

10229
05:55:20,840 --> 05:55:23,710
PATHOGENS BUT IT INCLUDES FUNGI,

10230
05:55:23,710 --> 05:55:25,345
BACTERIA AND VIRUSES.

10231
05:55:25,345 --> 05:55:27,113
A LOT OF THE MICROBIOME WORK IS

10232
05:55:27,113 --> 05:55:28,515
REALLY FOCUSED ON BACTERIA, BUT

10233
05:55:28,515 --> 05:55:30,116
IT CAN EXIST IN MULTIPLE

10234
05:55:30,116 --> 05:55:30,617
DIFFERENT ENVIRONMENTS.

10235
05:55:30,617 --> 05:55:32,786
THE ONE I'M GOING TO SPEAK ABOUT

10236
05:55:32,786 --> 05:55:35,288
TODAY IS PRIMARILY FOCUSED ON

10237
05:55:35,288 --> 05:55:35,722
THE GUT MICROBIOME.

10238
05:55:35,722 --> 05:55:37,724
IT'S ACTUALLY INITIALLY

10239
05:55:37,724 --> 05:55:38,391
COLONIZED AT BIRTH.

10240
05:55:38,391 --> 05:55:40,226
SOME PEOPLE HAVE SUGGESTED THERE

10241
05:55:40,226 --> 05:55:40,894
MIGHT BE A PLACENTAL BIOME, BUT

10242
05:55:40,894 --> 05:55:42,429
THAT'S A LITTLE BIT DEBATABLE.

10243
05:55:42,429 --> 05:55:45,599
IT'S REALLY VERTICALLY

10244
05:55:45,599 --> 05:55:46,166
TRANSMITTED FROM THE MOTHER.

10245
05:55:46,166 --> 05:55:47,233
THAT WILL BECOME IMPORTANT AT

10246
05:55:47,233 --> 05:55:50,937
THE VERY END OF MY TALK.

10247
05:55:50,937 --> 05:55:53,106
THESE MICROORGANISMS ARE VERY

10248
05:55:53,106 --> 05:55:53,340
DYNAMIC.

10249
05:55:53,340 --> 05:55:54,574
THEY CAN CHANGE IN RESPONSE TO

10250
05:55:54,574 --> 05:55:56,443
DIET, MEDICATION, STRESSORS,

10251
05:55:56,443 --> 05:55:58,078
ENVIRONMENTAL EXPOSURES, ALL THE

10252
05:55:58,078 --> 05:55:59,846
THINGS WE'VE HEARD ABOUT THIS

10253
05:55:59,846 --> 05:56:02,182
MORNING AND THIS AFTERNOON.

10254
05:56:02,182 --> 05:56:04,884
THESE ORGANISMS MAKE A VARIETY

10255
05:56:04,884 --> 05:56:06,219
OF METABOLITES, SOME OF WHICH WE

10256
05:56:06,219 --> 05:56:11,558
CAN'T MAKE, SUCH AS INGULS

10257
05:56:11,558 --> 05:56:16,763
REALLY REQUIRE THE PRESENCE OF  

10258
05:56:16,763 --> 05:56:18,531
A -- ESPECIALLY WITH THEIR

10259
05:56:18,531 --> 05:56:20,066
METABOLIC PRODUCTION OR HARMFUL

10260
05:56:20,066 --> 05:56:22,569
OR PATHOGENIC AS WE SEE

10261
05:56:22,569 --> 05:56:24,904
ESPECIALLY IN STROKE WITH

10262
05:56:24,904 --> 05:56:25,672
POST-STROKE INFECTIONS BEING A

10263
05:56:25,672 --> 05:56:26,573
LEADING CAUSE OF DEATH.

10264
05:56:26,573 --> 05:56:28,375
WE DO KNOW THE BIOME CHANGES

10265
05:56:28,375 --> 05:56:31,144
WITH AGE WITH THE INCREASING

10266
05:56:31,144 --> 05:56:31,611
DYSBIOSIS.

10267
05:56:31,611 --> 05:56:34,080
MANY DON'T LIKE THAT WORD BUT

10268
05:56:34,080 --> 05:56:35,582
IT'S A PATHOLOGICAL SHIFT IN THE

10269
05:56:35,582 --> 05:56:36,016
MICROBIOME.

10270
05:56:36,016 --> 05:56:36,783
WHAT I'M GOING TO TALK ABOUT

10271
05:56:36,783 --> 05:56:38,718
TODAY IS, IS THE BIOME A

10272
05:56:38,718 --> 05:56:46,326
POSSIBLE SOURCE OR TRIGGER FOR

10273
05:56:46,326 --> 05:56:47,527
THAT SENESCENCE WE SEE WITH

10274
05:56:47,527 --> 05:56:47,761
AGING.

10275
05:56:47,761 --> 05:56:49,396
SO WE'RE GOING TO TALK ABOUT

10276
05:56:49,396 --> 05:56:49,629
STROKE.

10277
05:56:49,629 --> 05:56:50,530
AS YOU HEARD FROM THE OTHER

10278
05:56:50,530 --> 05:56:51,431
SPEAKERS, MANY OF THE DISEASES

10279
05:56:51,431 --> 05:56:53,700
WE'VE HEARD ABOUT LIKE CANCER

10280
05:56:53,700 --> 05:56:54,501
ARE AGE-RELATED DISEASES.

10281
05:56:54,501 --> 05:56:55,902
STROKE IS NO EXCEPTION.

10282
05:56:55,902 --> 05:56:57,771
THE VAST MAJORITY OF STROKE

10283
05:56:57,771 --> 05:57:00,106
PATIENTS ARE OVER 65, AND IF

10284
05:57:00,106 --> 05:57:00,774
YOU'LL RECALL THIS MORNING,

10285
05:57:00,774 --> 05:57:03,043
THERE WAS A SLIDE SHOWING COMMON

10286
05:57:03,043 --> 05:57:05,011
CAUSES OF DEATH, AND STROKE IS

10287
05:57:05,011 --> 05:57:06,646
ON THERE.

10288
05:57:06,646 --> 05:57:08,281
IT IS THE NUMBER -- ONE OF THE

10289
05:57:08,281 --> 05:57:09,716
LEADING CAUSES OF DEATH BUT I

10290
05:57:09,716 --> 05:57:11,284
THINK EVEN MORE IMPORTANTLY

10291
05:57:11,284 --> 05:57:13,987
ESPECIALLY AS A CLINICIAN, IT IS

10292
05:57:13,987 --> 05:57:16,189
THE MOST COMMON CAUSE OF LONG

10293
05:57:16,189 --> 05:57:19,025
TERM DISABILITY.

10294
05:57:19,025 --> 05:57:20,960
BOTH GLOBALLY AND IN THE U.S.

10295
05:57:20,960 --> 05:57:21,895
SO HOW DO WE MODEL STROKE?

10296
05:57:21,895 --> 05:57:23,730
WE USE A MOUSE MODEL, WE CAN USE

10297
05:57:23,730 --> 05:57:26,132
RATS, WE CAN USE PRIMATES, BUT

10298
05:57:26,132 --> 05:57:28,034
WE TEND TO USE THE MOUSE MODEL.

10299
05:57:28,034 --> 05:57:31,037
WE USE A MIDDLE CEREBRAL ARTERY

10300
05:57:31,037 --> 05:57:31,671
OCCLUSION, WHICH IS WHERE WE PUT

10301
05:57:31,671 --> 05:57:32,672
A FILAMENT, AND I'M NOT SURE IF

10302
05:57:32,672 --> 05:57:35,842
YOU CAN SEE MY LITTLE MOUSE

10303
05:57:35,842 --> 05:57:37,544
HERE, BUT WE PUT A FILAMENT UP

10304
05:57:37,544 --> 05:57:39,079
HERE INTO THE INTERNAL CAROTID

10305
05:57:39,079 --> 05:57:41,014
OF THE MOUSE, AND THAT BLOCKS

10306
05:57:41,014 --> 05:57:43,216
THE MIDDLE CEREBRAL ARTERY.

10307
05:57:43,216 --> 05:57:44,150
IT'S THE MOST COMMON STROKE THAT

10308
05:57:44,150 --> 05:57:47,320
WE SEE IN PATIENTS, AND THIS IS

10309
05:57:47,320 --> 05:57:48,955
VERY RELEVANT BECAUSE WE PULL

10310
05:57:48,955 --> 05:57:51,257
OUT THE SUTURE AND ALLOW FOR

10311
05:57:51,257 --> 05:57:52,192
REPERFUSION, WHICH IS ACTUALLY

10312
05:57:52,192 --> 05:57:53,326
WHAT WE DO CLINICALLY.

10313
05:57:53,326 --> 05:57:57,897
IT'S CALLED THROM BECKETT ME, TF

10314
05:57:57,897 --> 05:57:59,299
THE MOST POTENT TREATMENTS WE

10315
05:57:59,299 --> 05:58:01,367
HAVE IN MEDICINE WITH A NUMBER

10316
05:58:01,367 --> 05:58:02,869
NEEDED TO TREAT FOR BENEFIT OF

10317
05:58:02,869 --> 05:58:03,336
TWO.

10318
05:58:03,336 --> 05:58:04,571
THIS LEADS TO AN INFARCT, AND

10319
05:58:04,571 --> 05:58:06,439
YOU CAN SEE HERE THIS WHITE AREA

10320
05:58:06,439 --> 05:58:11,377
IS THE AREA OF INFARCT.

10321
05:58:11,377 --> 05:58:12,579
SO STROKE DAMAGE PROGRESSES OVER

10322
05:58:12,579 --> 05:58:15,448
TIME, BUT THE STROKE IS USUALLY

10323
05:58:15,448 --> 05:58:16,649
HISTOLOGICALLY COMPLETE IN THIS

10324
05:58:16,649 --> 05:58:19,586
MODEL BY 24 HOURS.

10325
05:58:19,586 --> 05:58:20,787
THIS WILL BECOME IMPORTANT

10326
05:58:20,787 --> 05:58:22,322
AFTER.

10327
05:58:22,322 --> 05:58:22,922
THESE ARE CORONAL SEC SHOULD

10328
05:58:22,922 --> 05:58:27,327
BEESSHOSECTIONS OF AMOUSE BRAIN.

10329
05:58:27,327 --> 05:58:29,195
THIS IS A THING CALLED A TTC

10330
05:58:29,195 --> 05:58:29,696
DYE.

10331
05:58:29,696 --> 05:58:36,536
IT'S PICKED UP BY MIGHT TOE CON.

10332
05:58:36,536 --> 05:58:38,738
YOU CAN SEE BETWEEN 24 HOURS,

10333
05:58:38,738 --> 05:58:41,207
3 DAYS, 7 DAYS, THERE ISN'T MUCH

10334
05:58:41,207 --> 05:58:41,741
CHANGE IN THE SIZE OF THE

10335
05:58:41,741 --> 05:58:42,642
STROKE, BUT THERE'S A LOT OF

10336
05:58:42,642 --> 05:58:44,844
STUFF GOING ON IN HERE AS FAR AS

10337
05:58:44,844 --> 05:58:46,579
INFLAMMATION.

10338
05:58:46,579 --> 05:58:47,213
AND AGAIN AS I MENTIONED, THIS

10339
05:58:47,213 --> 05:58:48,648
IS A CAT SCAN OF A STROKE

10340
05:58:48,648 --> 05:58:51,084
PATIENT WITH A RIGHT MIDDLE

10341
05:58:51,084 --> 05:58:52,519
CEREBRAL ARTERY STROKE.

10342
05:58:52,519 --> 05:58:53,620
SO YOU CAN SEE IT KIND OF

10343
05:58:53,620 --> 05:58:54,921
RECAPITULATES WHAT WE SEE.

10344
05:58:54,921 --> 05:58:57,190
NOW, TO GET TO THE BIOME, I

10345
05:58:57,190 --> 05:58:58,525
DIDN'T HAVE ANY SORT OF STRATEGY

10346
05:58:58,525 --> 05:58:58,892
FOR THIS.

10347
05:58:58,892 --> 05:59:00,860
I KIND OF STUMBLED UPON IT ABOUT

10348
05:59:00,860 --> 05:59:04,798
10 YEARS AGO, MAYBE EVEN LONGER

10349
05:59:04,798 --> 05:59:05,465
BECAUSE I STARTED ASKING

10350
05:59:05,465 --> 05:59:07,967
OURSELVES WHY ARE WE MODELING

10351
05:59:07,967 --> 05:59:10,937
STROKE, DISEASE THAT PRIMARILY

10352
05:59:10,937 --> 05:59:13,173
AFFECTS AGING IN 8 WEEK OLD C57

10353
05:59:13,173 --> 05:59:13,606
BLACK MICE.

10354
05:59:13,606 --> 05:59:16,910
SO WE STARTED TO SAY OKAY, THE

10355
05:59:16,910 --> 05:59:18,111
IMMUNE RESPONSE IS DIFFERENT IN

10356
05:59:18,111 --> 05:59:19,546
AGING, THE VASCULATURE IS

10357
05:59:19,546 --> 05:59:20,647
DIFFERENT, WE NEED TO USE AGED

10358
05:59:20,647 --> 05:59:21,948
MICE.

10359
05:59:21,948 --> 05:59:22,916
AND SURPRISINGLY, IN A YOUNG

10360
05:59:22,916 --> 05:59:24,918
MALE, YOU SEE THIS RELATIVELY

10361
05:59:24,918 --> 05:59:26,853
LARGE INFARCT, THESE MICE WITHIN

10362
05:59:26,853 --> 05:59:30,223
A WEEK ARE LIKE SCAMPERING

10363
05:59:30,223 --> 05:59:30,757
AROUND THEIR CAGE.

10364
05:59:30,757 --> 05:59:32,492
THIS IS AN AGED MALE AND YOU SEE

10365
05:59:32,492 --> 05:59:34,627
THE STROKE IS ACTUALLY SMALLER

10366
05:59:34,627 --> 05:59:35,395
AND IT'S NOT DUE TO A REDUCTION

10367
05:59:35,395 --> 05:59:37,130
IN BLOOD FLOW, WE CHECKED IT

10368
05:59:37,130 --> 05:59:37,931
EVERY WAY.

10369
05:59:37,931 --> 05:59:39,899
THEY JUST HAVE THESE SMALLER

10370
05:59:39,899 --> 05:59:40,133
STROKES.

10371
05:59:40,133 --> 05:59:41,534
THEY ALSO HAVE A VERY DIFFERENT

10372
05:59:41,534 --> 05:59:46,372
IMMUNE RESPONSE TO STROKE WITH A

10373
05:59:46,372 --> 05:59:48,408
PRIMARILY NEUTROPHIL IK

10374
05:59:48,408 --> 05:59:49,642
INFLAMMATION WHICH IS PROBABLY

10375
05:59:49,642 --> 05:59:51,744
WHY AGING ANIMALS AND THA HUMANS

10376
05:59:51,744 --> 05:59:53,780
HAVE HIGHER RATES OF BLEEDING

10377
05:59:53,780 --> 05:59:54,113
AFTER STROKE.

10378
05:59:54,113 --> 05:59:54,714
BUT INTERESTINGLY THESE AGED

10379
05:59:54,714 --> 05:59:56,182
STROKE ANIMALS DESPITE HAVING A

10380
05:59:56,182 --> 05:59:58,885
MUCH SMALLER STROKE ARE MUCH

10381
05:59:58,885 --> 05:59:59,552
WORSE NEUROLOGICAL DEFICITS AND

10382
05:59:59,552 --> 06:00:00,420
NEVER RECOVERED.

10383
06:00:00,420 --> 06:00:03,056
THEY ALSO HAD MUCH HIGHER

10384
06:00:03,056 --> 06:00:07,961
MORTALITY THAN THEIR YOUNG

10385
06:00:07,961 --> 06:00:08,294
COUNTERPARTS.

10386
06:00:08,294 --> 06:00:09,329
WHEN WE FIRST STARTED MODELING

10387
06:00:09,329 --> 06:00:11,364
STROKE IN AGED, WE DIDN'T KNOW

10388
06:00:11,364 --> 06:00:13,099
IF WE'D BE ABLE TO DO IT BECAUSE

10389
06:00:13,099 --> 06:00:14,467
70% OF OUR MICE WERE DYING.

10390
06:00:14,467 --> 06:00:15,468
WHEN WE STARTED TO UNDERSTAND A

10391
06:00:15,468 --> 06:00:17,837
LITTLE BIT MORE, WE HAVE A LOT

10392
06:00:17,837 --> 06:00:19,372
OF WAYS TO KEEP THESE MICE

10393
06:00:19,372 --> 06:00:21,441
ALIVE, IF ANY OF YOU ARE

10394
06:00:21,441 --> 06:00:22,075
INTERESTED I'M HAPPY TO SEND YOU

10395
06:00:22,075 --> 06:00:22,775
PROTOCOLS THAT HAVE TAKEN US

10396
06:00:22,775 --> 06:00:25,745
MANY YEARS TO ENHANCE SURVIVAL.

10397
06:00:25,745 --> 06:00:28,948
BULL YOU BUT YOU CAN SEE WHEN WD

10398
06:00:28,948 --> 06:00:31,284
AT WHY THEY WERE DYING, THEY

10399
06:00:31,284 --> 06:00:31,918
HAVE A VERY ROBUST INFLAMMATORY

10400
06:00:31,918 --> 06:00:33,052
RESPONSE TO STROKE.

10401
06:00:33,052 --> 06:00:34,354
IT'S NOT DIFFERENT THAN THE

10402
06:00:34,354 --> 06:00:38,992
YOUNG MICE, BUT IT'S MUCH MORE

10403
06:00:38,992 --> 06:00:40,093
CHRONIC.

10404
06:00:40,093 --> 06:00:40,960
AND YOU CAN SEE ELEVATIONS AND

10405
06:00:40,960 --> 06:00:43,062
THINGS LIKE IL-6, EVEN WEEKS TO

10406
06:00:43,062 --> 06:00:47,767
MONTHS AFTER STROKE, AND WE ALSO

10407
06:00:47,767 --> 06:00:50,870
SAW FEATURES OF IMMUNE

10408
06:00:50,870 --> 06:00:52,305
SUPPRESSION IN THE AGED MICE

10409
06:00:52,305 --> 06:01:00,213
BASED ON THEIR -- RATIOS.

10410
06:01:00,213 --> 06:01:01,047
SO MICE ARE DYING, THEY HAVE ALL

10411
06:01:01,047 --> 06:01:02,782
THIS INFLAMMATION, THEY LOOK

10412
06:01:02,782 --> 06:01:04,984
LIKE THEY'RE IMMUNE-SUPPRESSED,

10413
06:01:04,984 --> 06:01:05,418
WHAT'S KILLING THEM?

10414
06:01:05,418 --> 06:01:07,086
SO WE STARTED LOOKING AT ALL THE

10415
06:01:07,086 --> 06:01:09,522
ORGANS IN THE BODY, GRINDING

10416
06:01:09,522 --> 06:01:12,225
THEM OUT AND PLATING THEM.

10417
06:01:12,225 --> 06:01:14,527
YOU CAN DO ANAEROBIC FOR THE

10418
06:01:14,527 --> 06:01:15,895
MICROBIOME, AND YOU SEE ALL

10419
06:01:15,895 --> 06:01:16,729
THESE LITTLE WHITE DOTS HERE?

10420
06:01:16,729 --> 06:01:18,364
THESE ARE COLONY-FORMING UNITS

10421
06:01:18,364 --> 06:01:21,000
OF BACTERIA, AND YOU CAN SEE THE

10422
06:01:21,000 --> 06:01:24,938
AGED STROKE MICE HAS MUCH MORE

10423
06:01:24,938 --> 06:01:26,906
PERIPHERAL EFFECTS FROM THE

10424
06:01:26,906 --> 06:01:28,107
STROKE.

10425
06:01:28,107 --> 06:01:30,677
AND YOU CAN SEE THAT'S

10426
06:01:30,677 --> 06:01:31,044
QUANTIFIED HERE.

10427
06:01:31,044 --> 06:01:31,911
THEN WE TOOK THESE LITTLE

10428
06:01:31,911 --> 06:01:33,546
COLONIES AND SENT THEM FOR

10429
06:01:33,546 --> 06:01:33,880
SEQUENCING.

10430
06:01:33,880 --> 06:01:36,816
AND WHAT WE FOUND IS NOT ONLY

10431
06:01:36,816 --> 06:01:37,717
WERE THERE A LOT MORE -- THERE

10432
06:01:37,717 --> 06:01:40,253
WAS A LOT MORE LOSS OF BACTERIAL

10433
06:01:40,253 --> 06:01:41,220
CONTAINMENT, IF HAPPENS TO BE

10434
06:01:41,220 --> 06:01:44,290
THE MESENTERIC LYMPH NODES, THEY

10435
06:01:44,290 --> 06:01:45,725
ALSO WERE COMPLETELY DIFFERENT

10436
06:01:45,725 --> 06:01:46,059
BACTERIA.

10437
06:01:46,059 --> 06:01:48,561
SO THAT LED US TO SAY OKAY,

10438
06:01:48,561 --> 06:01:49,996
WELL, THESE BACTERIA FROM THE

10439
06:01:49,996 --> 06:01:51,331
MESENTERIC LYMPH NODES WHICH

10440
06:01:51,331 --> 06:01:52,632
DRAIN THE GUT, WHY ARE THEY

10441
06:01:52,632 --> 06:01:52,966
DIFFERENT?

10442
06:01:52,966 --> 06:01:54,867
NOT ONLY ARE THEY MORE, THEY'RE

10443
06:01:54,867 --> 06:01:55,134
DIFFERENT.

10444
06:01:55,134 --> 06:01:56,636
SO ARE THERE AGE-RELATED CHANGES

10445
06:01:56,636 --> 06:01:59,572
IN THE MICROBIOME ITSELF?

10446
06:01:59,572 --> 06:02:02,241
AND THE ANSWER IS YES, ALMOST

10447
06:02:02,241 --> 06:02:03,443
COMPLETELY NON-OVERLAPPING IN A

10448
06:02:03,443 --> 06:02:06,079
YOUNG BIOME AND AN AGED BIOME.

10449
06:02:06,079 --> 06:02:06,679
THIS IS FROM FECAL SAMPLES.

10450
06:02:06,679 --> 06:02:07,947
AND A QUICK WAY TO LOOK AT THIS

10451
06:02:07,947 --> 06:02:11,217
IS JUST A BACK TIER ROY

10452
06:02:11,217 --> 06:02:13,319
DECEMBER -- RATIO WHICH IS VERY

10453
06:02:13,319 --> 06:02:17,690
SHIFTED AND DYSBIOTIC WITH VERY

10454
06:02:17,690 --> 06:02:19,092
MORE -- IN THE AGED ANIMALS.

10455
06:02:19,092 --> 06:02:20,727
ALSO THE GUT ITSELF CHANGES WITH

10456
06:02:20,727 --> 06:02:20,893
AGE.

10457
06:02:20,893 --> 06:02:22,295
THIS IS A HISTOLOGICAL SECTION

10458
06:02:22,295 --> 06:02:22,595
OF THE GUT.

10459
06:02:22,595 --> 06:02:25,198
THIS IS THE LAMINA APPROPRIATE

10460
06:02:25,198 --> 06:02:25,365
REA.

10461
06:02:25,365 --> 06:02:26,299
THIS IS THE EPITHELIUM WHICH IS

10462
06:02:26,299 --> 06:02:27,300
US, THE HOST.

10463
06:02:27,300 --> 06:02:30,336
THIS HAS A LOT OF IMMUNE AND

10464
06:02:30,336 --> 06:02:30,937
INFLAMMATORY CELLS IN HERE BUT

10465
06:02:30,937 --> 06:02:33,639
WHAT I'M SHOWING YOU HERE IS

10466
06:02:33,639 --> 06:02:35,274
THIS RED, THIS IS A FISH STAIN,

10467
06:02:35,274 --> 06:02:38,111
WHICH STAINS THE BACTERIA, AND

10468
06:02:38,111 --> 06:02:39,879
YOU SEE THIS DISTANCE BETWEEN US

10469
06:02:39,879 --> 06:02:41,080
AND THE BACTERIA.

10470
06:02:41,080 --> 06:02:43,983
THE HOST AND THE POTENTIAL

10471
06:02:43,983 --> 06:02:44,250
PATHOGEN.

10472
06:02:44,250 --> 06:02:48,855
AND YOU SEE WITH AGING, YOU LOSE

10473
06:02:48,855 --> 06:02:50,623
THIS MUCOUS BARRIER BECAUSE OF A

10474
06:02:50,623 --> 06:02:52,692
REDUCTION IN GOBLET CELLS AND

10475
06:02:52,692 --> 06:02:53,359
THINGS THAT HAPPEN IN THE IMMUNE

10476
06:02:53,359 --> 06:02:53,993
COMPARTMENT WHICH I DON'T HAVE

10477
06:02:53,993 --> 06:02:55,261
TIME TO TALK ABOUT TODAY.

10478
06:02:55,261 --> 06:03:00,233
BUT AGING ITSELF CHANGES THE GUT

10479
06:03:00,233 --> 06:03:01,401
AND THE MUCOUS BARRIER, LOOK AT

10480
06:03:01,401 --> 06:03:04,170
WHAT HAPPENS WITH STROKE.

10481
06:03:04,170 --> 06:03:06,472
WE FOUND WITH STROKE IN AGED

10482
06:03:06,472 --> 06:03:10,009
ANIMALS, THEY HAD A LOT OF FITC,

10483
06:03:10,009 --> 06:03:11,511
WE COULD SEE IT IN THEIR BLOOD

10484
06:03:11,511 --> 06:03:13,513
AND IT WAS CORRELATED WITH

10485
06:03:13,513 --> 06:03:14,313
THEIR DEGREE OF NEUROLOGICAL

10486
06:03:14,313 --> 06:03:15,515
DISABILITY, AND CAN YOU SEE WHAT

10487
06:03:15,515 --> 06:03:17,483
HAPPENS WITH STROKE.

10488
06:03:17,483 --> 06:03:19,952
HERE IS A MOUSE AND HERE IS THE

10489
06:03:19,952 --> 06:03:22,021
BACTERIA, HERE'S THE EPITHELIUM,

10490
06:03:22,021 --> 06:03:23,756
NICE MUCOUS BARRIER.

10491
06:03:23,756 --> 06:03:26,225
IT'S COMPLETELY DESTROYED AFTER

10492
06:03:26,225 --> 06:03:26,459
STROKE.

10493
06:03:26,459 --> 06:03:28,694
AND YOU CAN SEE THESE BACTERIA

10494
06:03:28,694 --> 06:03:31,130
STARTING TO CLIMB INTO THE HOST.

10495
06:03:31,130 --> 06:03:33,132
SO WE WANTED TO SAY OKAY, NOW WE

10496
06:03:33,132 --> 06:03:34,901
SEE THAT THE BACTERIAL

10497
06:03:34,901 --> 06:03:36,769
COMPOSITION OF THE AGED BIOME IS

10498
06:03:36,769 --> 06:03:38,771
DIFFERENT, IS IT MALLEABLE, CAN

10499
06:03:38,771 --> 06:03:39,172
WE CHANGE IT?

10500
06:03:39,172 --> 06:03:40,940
SO AGAIN, USING THAT KIND OF

10501
06:03:40,940 --> 06:03:45,411
DIPSTICK OF DYSBIOSIS, THE F TO

10502
06:03:45,411 --> 06:03:47,513
B RATIO, WE FOUND, YES, WE CAN

10503
06:03:47,513 --> 06:03:48,815
CHANGE IT.

10504
06:03:48,815 --> 06:03:49,382
THIS IS A YOUNG MOUSE GIVEN

10505
06:03:49,382 --> 06:03:51,084
EITHER A YOUNG FECAL TRANSPLANT

10506
06:03:51,084 --> 06:03:55,021
OR AN AGED DONOR TRANSPLANT.

10507
06:03:55,021 --> 06:03:56,656
YOU CAN SEE IN THE YOUNG

10508
06:03:56,656 --> 06:03:59,425
RECIPIENT, WE RECAPITULATE

10509
06:03:59,425 --> 06:04:00,193
AGE-RELATED DYSBIOSIS.

10510
06:04:00,193 --> 06:04:01,594
SO IT DOES TAKE HOLD IN THE

10511
06:04:01,594 --> 06:04:02,595
HOST.

10512
06:04:02,595 --> 06:04:05,131
MORE IMPORTANTLY IN THE AGED

10513
06:04:05,131 --> 06:04:09,302
RECIPIENT THAT HAVE DYSBIOSIS AT

10514
06:04:09,302 --> 06:04:11,204
BASELINE HERE, YOU CAN SEE

10515
06:04:11,204 --> 06:04:13,272
GIVING THEM A YOUNG BIOME IS

10516
06:04:13,272 --> 06:04:13,739
REJUVENATING.

10517
06:04:13,739 --> 06:04:15,341
YOU HAVE TO DEPLETE THE NICHE TO

10518
06:04:15,341 --> 06:04:17,009
ENSURE A SUCCESSFUL FECAL

10519
06:04:17,009 --> 06:04:18,544
TRANSPLANT, WHICH MEANS YOU HAVE

10520
06:04:18,544 --> 06:04:19,645
TO USE ANTIBIOTICS.

10521
06:04:19,645 --> 06:04:21,747
YOU HAVE TO GIVE THE BACTERIA AN

10522
06:04:21,747 --> 06:04:23,483
AREA TO KIND OF COLONIZE.

10523
06:04:23,483 --> 06:04:24,917
SO THAT IS ONE OF THE

10524
06:04:24,917 --> 06:04:27,587
LIMITATIONS OF SOME OF THE

10525
06:04:27,587 --> 06:04:29,322
STUDIES WE'VE DONE.

10526
06:04:29,322 --> 06:04:31,090
WHEN WE TOOK AGED FECAL

10527
06:04:31,090 --> 06:04:33,259
TRANSPLANT AND PUT IT INTO YOUNG

10528
06:04:33,259 --> 06:04:36,796
HEALTHY ANIMALS AND GAVE THEM A

10529
06:04:36,796 --> 06:04:39,098
STROKE, YOU CAN SEE ALMOST NONE

10530
06:04:39,098 --> 06:04:41,167
OF OUR YOUNG MICE THAT GOT A

10531
06:04:41,167 --> 06:04:44,570
YOUNG BIOME, NONE OF THEM DIE.

10532
06:04:44,570 --> 06:04:45,705
OUR YOUNG MICE ARE VERY HARDY

10533
06:04:45,705 --> 06:04:47,106
EVEN AFTER A BIG STROKE.

10534
06:04:47,106 --> 06:04:49,709
BUT YOU CAN SEE WHAT TED, BY

10535
06:04:49,709 --> 06:04:50,610
GIVING AN AGED BIOME, IN IS

10536
06:04:50,610 --> 06:04:52,478
STILL A YOUNG HOST, THE

10537
06:04:52,478 --> 06:04:53,346
MORTALITY WAS 40%.

10538
06:04:53,346 --> 06:04:54,914
SO IT'S STILL A YOUNG MOUSE,

10539
06:04:54,914 --> 06:04:56,516
YOUNG BRAIN, YOUNG VASCULATURE.

10540
06:04:56,516 --> 06:04:57,750
THE ONLY THING THAT'S AGED IS

10541
06:04:57,750 --> 06:05:00,887
THE BIOME AND IT REDUCED

10542
06:05:00,887 --> 06:05:03,389
SURVIVAL BY 40%.

10543
06:05:03,389 --> 06:05:07,793
SO WE FIRST SEVERAL YEARS AGO,

10544
06:05:07,793 --> 06:05:10,463
PROBABLY EIGHT YEARS AGO NOW,

10545
06:05:10,463 --> 06:05:12,331
DID A BIOME TRANSPLANT ABOUT A

10546
06:05:12,331 --> 06:05:14,066
MONTH BEFORE STROKE AND WE FOUND

10547
06:05:14,066 --> 06:05:16,302
WE COULD RECAPITULATE THE

10548
06:05:16,302 --> 06:05:17,637
YOUTHFUL BIOME AND THAT THE AGED

10549
06:05:17,637 --> 06:05:19,272
MICE THAT GOT A YOUNG BIOME DID

10550
06:05:19,272 --> 06:05:21,841
MUCH BETTER AFTER STROKE.

10551
06:05:21,841 --> 06:05:22,508
HOWEVER, STROKE IS AN

10552
06:05:22,508 --> 06:05:22,975
UNPREDICTABLE EVENT.

10553
06:05:22,975 --> 06:05:24,710
I MAY NOT BE ABLE TO CHANGE YOUR

10554
06:05:24,710 --> 06:05:26,679
BIOME AFTER YOU COME IN WITH

10555
06:05:26,679 --> 06:05:27,313
YOUR STROKE, SO WHAT WE WANTED

10556
06:05:27,313 --> 06:05:30,082
TO DO IS SEE HOW MALLEABLE IT

10557
06:05:30,082 --> 06:05:31,317
WAS DAYS AFTER THE STROKE.

10558
06:05:31,317 --> 06:05:34,620
SO IN THIS EXPERIMENT, WE TOOK

10559
06:05:34,620 --> 06:05:36,155
AGED STROKE MICE, SO ALL OF THE

10560
06:05:36,155 --> 06:05:39,559
RECIPIENTS ARE AGED, AND WE GAVE

10561
06:05:39,559 --> 06:05:40,226
THEM EITHER AGED DONOR OR YOUNG

10562
06:05:40,226 --> 06:05:42,595
DONOR BIOME BY FECAL TRANSPLANT

10563
06:05:42,595 --> 06:05:43,062
GA VAJ.

10564
06:05:43,062 --> 06:05:45,898
WE GAVE THEM A STROKE FIRST, WE

10565
06:05:45,898 --> 06:05:46,933
GAVE THEM ANTIBIOTICS, WE HAD

10566
06:05:46,933 --> 06:05:48,334
THE APPROPRIATE ANTIBIOTIC

10567
06:05:48,334 --> 06:05:51,037
CONTROLS, AND THEN WE DID A

10568
06:05:51,037 --> 06:05:55,208
FECAL TRANSPLANT GAVAGE AND SACK

10569
06:05:55,208 --> 06:05:55,942
SACRIFICED THEM.

10570
06:05:55,942 --> 06:05:57,610
AS YOU CAN SEE HERE, THEY HAD

10571
06:05:57,610 --> 06:06:00,479
MUCH BETTER REGAIN OF WEIGHT,

10572
06:06:00,479 --> 06:06:01,714
THEY HAD BETTER MOTOR ACTIVITY

10573
06:06:01,714 --> 06:06:03,449
IN THE OPEN FIELD.

10574
06:06:03,449 --> 06:06:04,784
THEY HAD BETTER COGNITION IN THE

10575
06:06:04,784 --> 06:06:06,519
NOVEL OBJECT RECOGNITION, AND

10576
06:06:06,519 --> 06:06:14,160
THEY HAD A DOO CRE DECREASE IN

10577
06:06:14,160 --> 06:06:14,827
DEPRESSIVE-TYPE BEHAVIOR.

10578
06:06:14,827 --> 06:06:17,897
NOW, DO WE NEED TO USE A FECAL

10579
06:06:17,897 --> 06:06:18,197
TRANSPLANT.

10580
06:06:18,197 --> 06:06:18,898
WHAT IS THE BIOME DRIVING THIS

10581
06:06:18,898 --> 06:06:19,298
BENEFICIAL EFFECT?

10582
06:06:19,298 --> 06:06:20,866
SO WE REALLY FOCUSED INITIALLY

10583
06:06:20,866 --> 06:06:22,868
ON SHORT CHAIN FATTY ACIDS.

10584
06:06:22,868 --> 06:06:24,170
THEIR END PRODUCTS OF

10585
06:06:24,170 --> 06:06:25,605
FERMENTATION OF DIETARY FIBERS

10586
06:06:25,605 --> 06:06:27,373
BY THE MICROBIOTA.

10587
06:06:27,373 --> 06:06:28,374
WE KNOW THAT THEY MAINTAIN AND

10588
06:06:28,374 --> 06:06:31,410
ENHANCE GUT HEALTH, THEY ENHANCE

10589
06:06:31,410 --> 06:06:34,013
GUT BARRIER MUCOUS BARRIER

10590
06:06:34,013 --> 06:06:34,580
FUNCTION, IT REDUCES

10591
06:06:34,580 --> 06:06:36,782
INFLAMMATION, IT HAS POTENT

10592
06:06:36,782 --> 06:06:37,750
ANTI-INFLAMMATORY EFFECTS BOTH

10593
06:06:37,750 --> 06:06:39,552
ON THE PERIPHERAL IMMUNE

10594
06:06:39,552 --> 06:06:41,087
COMPARTMENT AND THE CNS IMMUNE

10595
06:06:41,087 --> 06:06:42,722
COMPARTMENT IN THE MICROGLIA,

10596
06:06:42,722 --> 06:06:45,424
AND WE THINK THEY'RE LIKELY,

10597
06:06:45,424 --> 06:06:45,992
EVEN MORE IMPORTANT THAN THE

10598
06:06:45,992 --> 06:06:47,226
BACTERIA, IT'S NOT THE BACTERIA,

10599
06:06:47,226 --> 06:06:50,696
IT'S WHAT THEY'RE PRODUCING.

10600
06:06:50,696 --> 06:06:52,798
SO WE LOOKED AT SHORT CHAIN AND

10601
06:06:52,798 --> 06:06:54,567
FATTY ACID LEVELS BY

10602
06:06:54,567 --> 06:06:55,234
METABOLOMICS AND YOU CAN SEE

10603
06:06:55,234 --> 06:06:57,436
HERE THE YOUNG BIOME IS VERY,

10604
06:06:57,436 --> 06:06:58,904
VERY ENRICHED IN THESE SHORT

10605
06:06:58,904 --> 06:07:02,642
CHAIN FATTY ACIDS AND THIS BOTH

10606
06:07:02,642 --> 06:07:04,710
IN -- CONTENT AND FECAL SAMPLES

10607
06:07:04,710 --> 06:07:06,712
AND THE AGED BIOME, YOU LOSE

10608
06:07:06,712 --> 06:07:08,481
THOSE SHORT CHAIN FATTY ACIDS.

10609
06:07:08,481 --> 06:07:09,682
SO WHAT WE WANTED TO DO THEN IS,

10610
06:07:09,682 --> 06:07:11,183
WELL, IF THE SHORT CHAIN FATTY

10611
06:07:11,183 --> 06:07:12,885
ACIDS OR THE METABOLITES ARE

10612
06:07:12,885 --> 06:07:15,087
MEDIATING THE EFFECT, CAN WE

10613
06:07:15,087 --> 06:07:16,088
REFINE OUR THERAPY?

10614
06:07:16,088 --> 06:07:18,758
ONE OF THE ISSUES WITH GIVING A

10615
06:07:18,758 --> 06:07:20,493
FECAL TRANSPLANT IS YOU

10616
06:07:20,493 --> 06:07:22,561
TRANSPLANT NOT ONLY BACTERIA BUT

10617
06:07:22,561 --> 06:07:24,830
POTENTIALLY VIRUS, FUNGUS AND

10618
06:07:24,830 --> 06:07:25,431
OTHER DETRIMENTAL THINGS.

10619
06:07:25,431 --> 06:07:29,502
SO WE DECIDED TO GIVE AGED

10620
06:07:29,502 --> 06:07:31,270
STROKE MICE, THIS IS THE SAME

10621
06:07:31,270 --> 06:07:32,638
DESIGN AS BEFORE WHERE THEY GOT

10622
06:07:32,638 --> 06:07:33,739
TREATMENT AFTER STROKE, WELL

10623
06:07:33,739 --> 06:07:35,908
AFTER THE STROKE WAS

10624
06:07:35,908 --> 06:07:40,279
HISTOLOGICALLY COMPLETE, WE GAVE

10625
06:07:40,279 --> 06:07:41,647
THEM A STROKE, GAVE THEM

10626
06:07:41,647 --> 06:07:42,882
ANTIBIOTICS AND THEN WE GAVAGED

10627
06:07:42,882 --> 06:07:45,484
THEM WITH A COCKTAIL OF SHORT

10628
06:07:45,484 --> 06:07:47,353
CHAIN FATTY ACID PRODUCING

10629
06:07:47,353 --> 06:07:48,220
BACTERIA.

10630
06:07:48,220 --> 06:07:50,323
VERY IMPORTANTLY, WE GOT VERY

10631
06:07:50,323 --> 06:07:52,391
LUCKY, A VERY CLEVER POSTDOC IN

10632
06:07:52,391 --> 06:07:53,526
THE LAB SAID SHOULDN'T WE GIVE

10633
06:07:53,526 --> 06:07:55,294
THEM SOMETHING TO EAT?

10634
06:07:55,294 --> 06:07:57,563
SO WE GAVE THEM A PREBIOTIC

10635
06:07:57,563 --> 06:08:00,666
KNOWN AS INNULIN, THAT WAS

10636
06:08:00,666 --> 06:08:01,100
IMPORTANT.

10637
06:08:01,100 --> 06:08:02,735
WHAT WE FIRST DID IS WE WANTED

10638
06:08:02,735 --> 06:08:05,871
TO SHOW THAT WE COULD INCREASE

10639
06:08:05,871 --> 06:08:06,605
SHORT CHAIN FATTY ACIDS, AND YOU

10640
06:08:06,605 --> 06:08:09,141
CAN SEE IN THE BLUE IS A VEHICLE

10641
06:08:09,141 --> 06:08:11,243
TREATED MOUSE OR MOUSE TREATED

10642
06:08:11,243 --> 06:08:14,647
WITHOUT THE ACTIVE METABOLITE,

10643
06:08:14,647 --> 06:08:16,182
AND BY GIVING THIS METABOLIC

10644
06:08:16,182 --> 06:08:17,983
COCKTAIL, WE WERE -- THIS

10645
06:08:17,983 --> 06:08:19,885
COCKTAIL OF BACTERIA THAT

10646
06:08:19,885 --> 06:08:21,287
PRODUCED THESE METABOLITES, WE

10647
06:08:21,287 --> 06:08:23,923
WERE ABLE TO REALLY INCREASE THE

10648
06:08:23,923 --> 06:08:25,358
SHORT CHAIN FATTY ACIDS.

10649
06:08:25,358 --> 06:08:27,259
SO IT WAS A COCKTAIL OF FOUR OR

10650
06:08:27,259 --> 06:08:31,130
FIVE SHORT CHAIN FATTY ACID

10651
06:08:31,130 --> 06:08:31,564
PRODUCING BACTERIA.

10652
06:08:31,564 --> 06:08:32,198
WE COULD INCREASE IT NOT JUST IN

10653
06:08:32,198 --> 06:08:35,368
THE GUT, BUT ALSO IN THE BRAIN.

10654
06:08:35,368 --> 06:08:37,470
>> DOCTOR, YOU HAVE TWO
MINUTES

10655
06:08:37,470 --> 06:08:37,737
REMAINING.

10656
06:08:37,737 --> 06:08:38,170
>> MM-HMM.

10657
06:08:38,170 --> 06:08:41,006
AND THAT WAS ENOUGH TO IMPROVE

10658
06:08:41,006 --> 06:08:42,775
OUTCOMES, SUGGESTING YOU DON'T

10659
06:08:42,775 --> 06:08:47,046
NEED THE WHOLE FECAL TRANSPLANT.

10660
06:08:47,046 --> 06:08:47,613
TRANSLATIONALLY THIS WAS

10661
06:08:47,613 --> 06:08:50,149
IMPORTANT BECAUSE WE DID MA

10662
06:08:50,149 --> 06:08:52,651
TABLEAU MIX IN OUR STROKE

10663
06:08:52,651 --> 06:08:52,918
PATIENTS.

10664
06:08:52,918 --> 06:08:54,553
YOU CAN SEE THEY COMPLETELY

10665
06:08:54,553 --> 06:08:55,755
DROPPED 24 HOURS AFTER STROKE

10666
06:08:55,755 --> 06:08:58,324
SUGGESTING THERE MAY BE A WINDOW

10667
06:08:58,324 --> 06:08:58,891
OF INTERVENTION WHERE WE CAN

10668
06:08:58,891 --> 06:09:02,261
GIVE THESE BENEFICIAL METABO 

10669
06:09:02,261 --> 06:09:02,561
METABOLITES.

10670
06:09:02,561 --> 06:09:03,929
I'M GOING TO GO THROUGH THIS

10671
06:09:03,929 --> 06:09:06,031
SECTION REALLY QUICKLY.

10672
06:09:06,031 --> 06:09:07,800
TRYPTOPHAN IS ANOTHER METABOLITE

10673
06:09:07,800 --> 06:09:10,536
WE'RE LOOKING AT.

10674
06:09:10,536 --> 06:09:12,671
INTERESTINGLY IT CAN BE MICRO

10675
06:09:12,671 --> 06:09:14,507
BIOTA OR HOST DERIVED.

10676
06:09:14,507 --> 06:09:17,977
THEY PRODUCED INDOLES WHICH WE

10677
06:09:17,977 --> 06:09:19,912
THINK ARE BENEFICIAL.

10678
06:09:19,912 --> 06:09:24,617
SO WHICH METABOLITES ARE -- WE

10679
06:09:24,617 --> 06:09:27,453
FOUND SOME OF THESE INDOLES, WE

10680
06:09:27,453 --> 06:09:29,255
DON'T MAKE THEM.

10681
06:09:29,255 --> 06:09:30,856
IN A GERM FREE MOUSE WITHOUT A

10682
06:09:30,856 --> 06:09:32,057
BIOME, NO INDOLES.

10683
06:09:32,057 --> 06:09:34,693
WE THEN GAVE SUPPLEMENTAL

10684
06:09:34,693 --> 06:09:36,796
INDOLES AFTER WE SAW THAT INDOLE

10685
06:09:36,796 --> 06:09:37,997
PRODUCING BACTERIA WERE

10686
06:09:37,997 --> 06:09:39,198
DECREASED WITH AGING, WE THEN

10687
06:09:39,198 --> 06:09:40,933
DID THE SAME THING AS WE DID IN

10688
06:09:40,933 --> 06:09:42,601
SHORT CHAIN FATTY ACIDS AND WE

10689
06:09:42,601 --> 06:09:45,671
FOUND THAT GIVING EXOGENOUS

10690
06:09:45,671 --> 06:09:47,706
INDOLES IMPROVED STROKE IN BOTH

10691
06:09:47,706 --> 06:09:49,442
WILD TYPE AND GERM-FREE MICE.

10692
06:09:49,442 --> 06:09:51,544
AND THIS IS NOT JUST STROKE.

10693
06:09:51,544 --> 06:09:53,512
IF YOU LOOK AT GERM-FREE MICE

10694
06:09:53,512 --> 06:09:54,680
AND YOU RECOLONIZE THEM WITH

10695
06:09:54,680 --> 06:09:58,584
EITHER YOUNG OR AGED MICROBIOME,

10696
06:09:58,584 --> 06:10:00,619
ANIMALS, THE GERM-FREE ANIMALS

10697
06:10:00,619 --> 06:10:03,389
THAT GET AN OLD BIOME DEVELOP

10698
06:10:03,389 --> 06:10:06,559
MEMORY IMPAIRMENT AND DEPRESSIVE

10699
06:10:06,559 --> 06:10:08,160
PHENOTYPES.

10700
06:10:08,160 --> 06:10:08,794
THE LAST TWO SLIDES ARE BECAUSE

10701
06:10:08,794 --> 06:10:11,297
OF S SOMETHING THAT I FOUND VERY

10702
06:10:11,297 --> 06:10:13,732
INTRIGUING TODAY, WHEN DOES

10703
06:10:13,732 --> 06:10:14,033
AGING BEGIN?

10704
06:10:14,033 --> 06:10:15,367
AGING BEGINS I GUESS AT

10705
06:10:15,367 --> 06:10:16,802
CONCEPTION OR PRECONCEPTION IF

10706
06:10:16,802 --> 06:10:19,104
YOU HAVE EPIGENETIC CHANGES IN

10707
06:10:19,104 --> 06:10:19,638
THE SPERM OR THE EGG, BUT

10708
06:10:19,638 --> 06:10:22,541
BECAUSE THE BIOME IS MATERNALLY

10709
06:10:22,541 --> 06:10:24,844
DERIVED AND ADVANCED MATERNAL

10710
06:10:24,844 --> 06:10:25,377
AGE IS BECOMING VERY, VERY

10711
06:10:25,377 --> 06:10:26,812
PREVALENT AND IT'S A MAJOR RISK

10712
06:10:26,812 --> 06:10:30,716
FACTOR FOR STROKE, WE

10713
06:10:30,716 --> 06:10:31,684
RECOLONIZED YOUNG FEMALE MICE

10714
06:10:31,684 --> 06:10:33,586
WITH EITHER YOUNG OR AGED BIOME,

10715
06:10:33,586 --> 06:10:36,088
AND WE FOUND A TREMENDOUS LOSS

10716
06:10:36,088 --> 06:10:41,293
IN FERTILITY AND PECUNDITY AND

10717
06:10:41,293 --> 06:10:42,928
WE FOUND A LARGE NUMBER OF

10718
06:10:42,928 --> 06:10:45,197
UNBORN PUPS, SO THESE ARE YOUNG

10719
06:10:45,197 --> 06:10:47,733
FEMALE MICE, GIVEN AGED BIOME

10720
06:10:47,733 --> 06:10:49,235
AND THEY LOSE PUPS.

10721
06:10:49,235 --> 06:10:50,336
WHAT'S INTERESTING IS WE LET

10722
06:10:50,336 --> 06:10:52,571
THESE ANIMALS AGE AND THESE

10723
06:10:52,571 --> 06:10:53,806
CHANGES IN THE BIOME THAT WERE

10724
06:10:53,806 --> 06:10:56,075
INDUCED BY GIVING AN AGED BIOME

10725
06:10:56,075 --> 06:10:58,177
CONTINUED INTO MIDDLE ADULTHOOD,

10726
06:10:58,177 --> 06:10:59,645
THEY CONTINUED TO HAVE

10727
06:10:59,645 --> 06:11:02,314
DYSBIOSIS, AND THIS WAS WORSE IN

10728
06:11:02,314 --> 06:11:04,550
MALE MICE, AND IT CAUSED A

10729
06:11:04,550 --> 06:11:05,251
METABOLIC PHENOTYPE.

10730
06:11:05,251 --> 06:11:07,987
THE ANIMALS THAT WERE BORN OF

10731
06:11:07,987 --> 06:11:11,023
DYSBIOTIC MOMS HAD A HIGHER

10732
06:11:11,023 --> 06:11:14,193
WEIGHTS, HAD METABOLIC FEATURES

10733
06:11:14,193 --> 06:11:17,563
AND GLUCOSE SENSITIVITY.

10734
06:11:17,563 --> 06:11:18,864
YOU CAN SEE THEY ALSO HAD

10735
06:11:18,864 --> 06:11:20,666
CHANGES IN BEHAVIOR, AND THIS

10736
06:11:20,666 --> 06:11:23,536
WAS MUCH MORE PRONOUNCED IN

10737
06:11:23,536 --> 06:11:23,869
MALES.

10738
06:11:23,869 --> 06:11:25,371
AND THOSE WERE THE ONES WHERE WE

10739
06:11:25,371 --> 06:11:27,439
REALLY FOUND THE MOST CHANGES IN

10740
06:11:27,439 --> 06:11:29,475
THEIR BIOME.

10741
06:11:29,475 --> 06:11:31,877
SO JUST TO SUMMARIZE AGING AND

10742
06:11:31,877 --> 06:11:33,412
STROKE LEAD TO SIGNIFICANT

10743
06:11:33,412 --> 06:11:34,680
DYSBIOSIS.

10744
06:11:34,680 --> 06:11:35,781
THIS LEADS TO A LOSS OF

10745
06:11:35,781 --> 06:11:36,682
BOTTOMS-UP SIGNALING FROM THE

10746
06:11:36,682 --> 06:11:37,416
GUT TO THE BRAIN.

10747
06:11:37,416 --> 06:11:40,119
WE THINK IT MIGHT BE MEDIATED BY

10748
06:11:40,119 --> 06:11:41,654
VAGAL NERVE FUNCTION.

10749
06:11:41,654 --> 06:11:44,156
ALTERING THE MICROBIOME CAN

10750
06:11:44,156 --> 06:11:46,625
REDUCE MICROGLIAL ACTIVATION AND

10751
06:11:46,625 --> 06:11:47,026
IMPROVE OUTCOME.

10752
06:11:47,026 --> 06:11:48,327
YOU CAN ENHANCE THE COMPOSITION

10753
06:11:48,327 --> 06:11:50,229
OF THE MICROBIOME TO GIVE

10754
06:11:50,229 --> 06:11:51,830
BENEFICIAL BACTERIA WHICH THEN

10755
06:11:51,830 --> 06:11:53,232
PRODUCE BENEFICIAL METABOLITES,

10756
06:11:53,232 --> 06:11:55,200
AND THE BIOME IS MALLEABLE.

10757
06:11:55,200 --> 06:11:57,636
JUST WANTED TO GIVE A SHOUT OUT

10758
06:11:57,636 --> 06:11:58,837
TO EVERYONE IN MY LAB WHO'S BEEN

10759
06:11:58,837 --> 06:12:00,205
VERY INVOLVED IN THESE STUDIES

10760
06:12:00,205 --> 06:12:02,074
OVER THE PAST DECADE, AND I HAVE

10761
06:12:02,074 --> 06:12:04,310
A COUPLE POINTS BUT I WILL SAVE

10762
06:12:04,310 --> 06:12:07,179
THEM FOR THE DISCUSSION ABOUT

10763
06:12:07,179 --> 06:12:09,114
KEY GAPS AND STRATEGIES THAT WE

10764
06:12:09,114 --> 06:12:09,982
WILL NEED FOR THE NEXT FIVE

10765
06:12:09,982 --> 06:12:10,916
YEARS.

10766
06:12:10,916 --> 06:12:12,251
SO THANK YOU VERY MUCH FOR

10767
06:12:12,251 --> 06:12:13,953
LISTENING, AND SORRY TO GO OUT

10768
06:12:13,953 --> 06:12:19,224
OF ORDER.

10769
06:12:19,224 --> 06:12:21,093
>> THANK YOU VERY MUCH FOR
THAT

10770
06:12:21,093 --> 06:12:21,460
EXCELLENT TALK.

10771
06:12:21,460 --> 06:12:26,198
WE HAVE ONE QUESTION FOR YOU.

10772
06:12:26,198 --> 06:12:29,301
SO WHAT KIND OF DIET CHOW WERE

10773
06:12:29,301 --> 06:12:38,143
THESE MICE ON, AND WERE THEY

10774
06:12:38,143 --> 06:12:38,444
[INAUDIBLE]

10775
06:12:38,444 --> 06:12:40,112
>> THAT'S A GREAT
QUESTION.

10776
06:12:40,112 --> 06:12:40,846
THEY'RE ON STANDARD LAB CHOW BUT

10777
06:12:40,846 --> 06:12:42,615
ALSO WHEN WE DO OUR INDOLE

10778
06:12:42,615 --> 06:12:44,883
STUDIES, WE'LL DO A RADIATED

10779
06:12:44,883 --> 06:12:46,285
CHOW LIKE WE USE FOR GERM-FREE

10780
06:12:46,285 --> 06:12:46,852
MICE.

10781
06:12:46,852 --> 06:12:48,687
THEY WERE XPF MICE BUT WE ALSO

10782
06:12:48,687 --> 06:12:50,589
HAVE SOME STUDIES THAT WE'VE

10783
06:12:50,589 --> 06:12:52,358
ALSO DONE IN GERM-FREE MICE.

10784
06:12:52,358 --> 06:12:55,628
AND AGAIN, HEARING THE EARLIER

10785
06:12:55,628 --> 06:12:59,398
TALKS ABOUT WILD CAUGHT VERSUS

10786
06:12:59,398 --> 06:13:03,035
WILD TYPE, AND THE HEPATIC VIRUS

10787
06:13:03,035 --> 06:13:05,738
CAN BE REALLY DEVASTATING FOR A

10788
06:13:05,738 --> 06:13:07,072
COLONY, THESE ARE PROBABLY NOT

10789
06:13:07,072 --> 06:13:08,540
COMPLETELY NORMAL MICE AND

10790
06:13:08,540 --> 06:13:10,175
INDEED THE MICE THAT WE GET FROM

10791
06:13:10,175 --> 06:13:12,111
THE NIA INTERESTINGLY WHICH HAVE

10792
06:13:12,111 --> 06:13:15,681
A SLIGHTLY DIFFERENT DIET HAVE A

10793
06:13:15,681 --> 06:13:16,782
BETTER AGING PHENOTYPE.

10794
06:13:16,782 --> 06:13:21,553
THEY ARE LESS FAT AND FASTER

10795
06:13:21,553 --> 06:13:22,187
THAN SOME OF THE MICE THAT WE

10796
06:13:22,187 --> 06:13:23,956
BREED IN-HOUSE, SO NOW WE DO

10797
06:13:23,956 --> 06:13:27,226
EVERYTHING IN-HOUSE.

10798
06:13:27,226 --> 06:13:28,727
TO CONTROL FOR THE DIETARY

10799
06:13:28,727 --> 06:13:34,099
FACTORS.

10800
06:13:34,099 --> 06:13:35,401
>> THANK YOU.

10801
06:13:35,401 --> 06:13:39,004
AND WE ARE ON TIME, AND WE HAVE

10802
06:13:39,004 --> 06:13:42,841
PATTI LEE JOINED US SO THAT'S

10803
06:13:42,841 --> 06:13:46,712
GREAT.

10804
06:13:46,712 --> 06:13:51,016
SO SHE'S PREPARING FOR HER TALK.

10805
06:13:51,016 --> 06:13:59,725
OKAY, WE CAN SEE THE SLIDES.

10806
06:13:59,725 --> 06:14:00,926
THE TOUTLE OF THE TALK IS

10807
06:14:00,926 --> 06:14:02,161
ENVIRONMENTAL DETERMINANTS AND

10808
06:14:02,161 --> 06:14:04,797
MODELS OF LUNG-VASCULAR

10809
06:14:04,797 --> 06:14:05,998
SENESCENCE.

10810
06:14:05,998 --> 06:14:06,965
GO AHEAD.

10811
06:14:06,965 --> 06:14:17,342
I THINK YOU'RE MUTED.

10812
06:14:19,211 --> 06:14:20,746
>> IT LOOKS LIKE YOU'RE
UNMUTED

10813
06:14:20,746 --> 06:14:22,681
ON YOUR MONITOR BUT WE CAN'T

10814
06:14:22,681 --> 06:14:22,948
HEAR YOU.

10815
06:14:22,948 --> 06:14:33,258
IS YOUR VOLUME UP?

10816
06:14:52,511 --> 06:14:58,984
I KIND OF HEAR A SOFT BEEP.

10817
06:14:58,984 --> 06:15:06,658
NOW YOU'RE ECHOING.

10818
06:15:06,658 --> 06:15:08,293
>> THIS IS MY BACKUP.

10819
06:15:08,293 --> 06:15:10,129
>> GOOD JOB!

10820
06:15:10,129 --> 06:15:20,672
THAT ONE SOUNDS GOOD.

10821
06:15:20,672 --> 06:15:20,906
HOW'S THAT?

10822
06:15:20,906 --> 06:15:21,240
>> YEP.

10823
06:15:21,240 --> 06:15:23,542
>> THIS IS GOOD?

10824
06:15:23,542 --> 06:15:24,877
>> YES, WE CAN HEAR YOU.

10825
06:15:24,877 --> 06:15:30,682
GO AHEAD.

10826
06:15:30,682 --> 06:15:31,750
>> I'LL HAVE TO SPEAK
EXTRA

10827
06:15:31,750 --> 06:15:32,284
FAST.

10828
06:15:32,284 --> 06:15:36,922
HOW IS THE SLIDES?

10829
06:15:36,922 --> 06:15:38,090
>> WE CAN'T SEE YOUR

10830
06:15:38,090 --> 06:15:38,657
PRESENTATION.

10831
06:15:38,657 --> 06:15:41,860
I THINK YOUR SETTING WINDOW IS

10832
06:15:41,860 --> 06:15:44,863
UP.

10833
06:15:44,863 --> 06:15:47,566
>> IT LOOKS LIKE YOU HAVE
TWO

10834
06:15:47,566 --> 06:15:49,568
COMPUTERS SO I'M HOPING THAT

10835
06:15:49,568 --> 06:15:59,945
THERE WILL BE NO ECHO.

10836
06:16:08,353 --> 06:16:10,322
>> HOW IS THIS?

10837
06:16:10,322 --> 06:16:11,657
>> PRESENTER MODE, AND
THAT

10838
06:16:11,657 --> 06:16:22,034
SHOULD BE GOOD TO GO.

10839
06:16:36,782 --> 06:16:38,550
>> IF YOU SELECT THE TAB
WHERE

10840
06:16:38,550 --> 06:16:41,954
IT SAYS "SLIDE," ON YOUR

10841
06:16:41,954 --> 06:16:44,489
POWERPOINT, IT SHOULD PUT YOU IN

10842
06:16:44,489 --> 06:16:45,557
WHERE YOU CAN SELECT PRESENTER

10843
06:16:45,557 --> 06:16:46,825
MODE.

10844
06:16:46,825 --> 06:16:51,763
WHERE IT SAYS SLIDE, YES.

10845
06:16:51,763 --> 06:16:54,766
SLIDESHOW.

10846
06:16:54,766 --> 06:17:05,177
WHERE IT SAYS SLIDESHOW.

10847
06:17:17,422 --> 06:17:19,524
>> THANK YOU FOR YOUR
PATIENCE.

10848
06:17:19,524 --> 06:17:21,793
I THOUGHT I WOULD START WITH

10849
06:17:21,793 --> 06:17:22,427
TRYING TO COVER SOME OF THE KEY

10850
06:17:22,427 --> 06:17:22,628
GAPS.

10851
06:17:22,628 --> 06:17:25,731
THE FIRST IS CLINICALLY RELEVANT

10852
06:17:25,731 --> 06:17:27,065
SENESCENCE IN AGING MODELS WHICH

10853
06:17:27,065 --> 06:17:28,734
IS WHAT MY LAB PARTICULARLY

10854
06:17:28,734 --> 06:17:29,735
WORKS ON.

10855
06:17:29,735 --> 06:17:31,737
IDENTIFYING AND MEASURING TISSUE

10856
06:17:31,737 --> 06:17:34,673
SENESCENCE AT SINGLE KREND AND

10857
06:17:34,673 --> 06:17:38,143
SINGLE ORGAN LEVELS, AND THAT IS

10858
06:17:38,143 --> 06:17:39,578
WHAT -- I'M PART OF THE

10859
06:17:39,578 --> 06:17:41,780
CONSORTIUM TISSUE MAPPING CENTER

10860
06:17:41,780 --> 06:17:45,150
TO ACHIEVE NUMBER TWO.

10861
06:17:45,150 --> 06:17:46,685
THIRDLY ALSO RELEVANT TO WHAT MY

10862
06:17:46,685 --> 06:17:50,622
LAB SPECIFICALLY WORKS ON IS --

10863
06:17:50,622 --> 06:17:52,758
IN MORE OF A LUNG AND VAST CLA

10864
06:17:52,758 --> 06:17:53,525
TRI TARGETED MANNER.

10865
06:17:53,525 --> 06:17:55,527
I WON'T HAVE TIME TO GO INTO

10866
06:17:55,527 --> 06:17:55,861
PRIMARY DATA.

10867
06:17:55,861 --> 06:17:58,030
I HAVE TWO DATA SUMMARY SLIDES.

10868
06:17:58,030 --> 06:18:01,600
JUST TO GIVE A TASTE.

10869
06:18:01,600 --> 06:18:02,901
BUT THESE ARE THE THREE AREAS I

10870
06:18:02,901 --> 06:18:05,003
THOUGHT I WOULD ADDRESSED TO.

10871
06:18:05,003 --> 06:18:06,238
SO MY RESEARCH GROUP FOCUSES ON

10872
06:18:06,238 --> 06:18:10,075
AGE AND CIGARETTE SMOKING

10873
06:18:10,075 --> 06:18:12,311
RELATED EMPHYSEMA, WHICH IS

10874
06:18:12,311 --> 06:18:14,179
PROBABLY THE MOST LETHAL FORM OF

10875
06:18:14,179 --> 06:18:16,481
A DISEASE SYNDROME CALLED

10876
06:18:16,481 --> 06:18:18,550
CHRONIC OBSTRUCTIVE PULMONARY

10877
06:18:18,550 --> 06:18:20,085
DISEASE OR COPD.

10878
06:18:20,085 --> 06:18:23,422
AND I INTENTIONALLY PUT MOST

10879
06:18:23,422 --> 06:18:25,424
LITERATURE, ESPECIALLY IN THE

10880
06:18:25,424 --> 06:18:28,327
PAST, KIND OF WHAT OUR MEDICAL

10881
06:18:28,327 --> 06:18:30,295
STUDENTS LEARNED, FOCUSES ON C

10882
06:18:30,295 --> 06:18:33,198
OMENT PD IN MEN, BUT I

10883
06:18:33,198 --> 06:18:33,966
INTENTIONALLY PUT WOMEN THERE

10884
06:18:33,966 --> 06:18:35,968
BECAUSE WOMEN ALSO DEVELOPED

10885
06:18:35,968 --> 06:18:41,106
SIGNIFICANT COPD, PROBABLY AT

10886
06:18:41,106 --> 06:18:43,642
AGES EARLIER THAN MOST OF OUR

10887
06:18:43,642 --> 06:18:44,643
MALE POPULATION, BUT IT LOOKS

10888
06:18:44,643 --> 06:18:45,644
DIFFERENT.

10889
06:18:45,644 --> 06:18:47,479
THE PHENOTYPICALLY CELLULARLY

10890
06:18:47,479 --> 06:18:51,616
MOLECULARLY IT TENDS TO BE

10891
06:18:51,616 --> 06:18:51,883
DIFFERENT.

10892
06:18:51,883 --> 06:18:53,352
I ALSO THINK THE

10893
06:18:53,352 --> 06:18:54,119
PHARMACOGENOMICS WILL SHOW THAT

10894
06:18:54,119 --> 06:18:58,523
WOMEN WILL RESPOND DIFFERENTLY

10895
06:18:58,523 --> 06:19:00,525
TO ANTI-COPD TREATMENTS OR

10896
06:19:00,525 --> 06:19:01,626
PREVENTIVES THAN MEN DO.

10897
06:19:01,626 --> 06:19:03,695
THAT'S PROBABLY A TOPIC FOR

10898
06:19:03,695 --> 06:19:07,733
ANOTHER SEPARATE TALK, BUT JUST

10899
06:19:07,733 --> 06:19:08,433
TO GIVE YOU SOME CONTEXT OF WHAT

10900
06:19:08,433 --> 06:19:09,101
WE'RE WORKING ON.

10901
06:19:09,101 --> 06:19:10,869
SO WHAT IS LONG AGING?

10902
06:19:10,869 --> 06:19:12,838
I THINK OF LONG AGING IN TERMS

10903
06:19:12,838 --> 06:19:14,940
OF CHRONOLOGY BUT ALSO THE

10904
06:19:14,940 --> 06:19:16,174
PHYSIOLOGY.

10905
06:19:16,174 --> 06:19:19,111
ON THE LEFT, STEVE HAD DEVELOPED

10906
06:19:19,111 --> 06:19:22,447
KIND OF WHAT I THINK IS STILL

10907
06:19:22,447 --> 06:19:24,983
QUITE ACCURATE OVER THE DECADES

10908
06:19:24,983 --> 06:19:26,084
OF WHAT HAPPENS TO LUNG FUNCTION

10909
06:19:26,084 --> 06:19:26,852
WITH AGE.

10910
06:19:26,852 --> 06:19:30,722
LIKE MOST ORGAN OR PHYSIOLOGIC

10911
06:19:30,722 --> 06:19:33,725
FUNCTIONS, LUNGS DO BECOME MORE

10912
06:19:33,725 --> 06:19:36,395
AND MORE TOWARDS THE DISABILITY

10913
06:19:36,395 --> 06:19:38,263
LINE WITH AGE, EVEN IF YOU'RE

10914
06:19:38,263 --> 06:19:39,765
NOT A SMOKER, AND THE PURPOSE OF

10915
06:19:39,765 --> 06:19:45,337
WHAT I SEE BEING THE MOST

10916
06:19:45,337 --> 06:19:47,639
POWERFUL IN LUNG

10917
06:19:47,639 --> 06:19:48,473
SENOTHERAPEUTICS WOULD BE TO TRY

10918
06:19:48,473 --> 06:19:49,941
TO SHIFT THE CURVES TO EITHER

10919
06:19:49,941 --> 06:19:52,210
SLOW DOWN THE DECLINE OR SHIFT

10920
06:19:52,210 --> 06:19:53,979
THE CURVE UP SO THAT LIMITATION

10921
06:19:53,979 --> 06:19:57,549
IS LESS WITH LUNG FUNCTION.

10922
06:19:57,549 --> 06:19:58,550
THEN A VERY GOOD COLLEAGUE OF

10923
06:19:58,550 --> 06:20:00,786
MINE WHO HAPPENED TO BE DOUBLE

10924
06:20:00,786 --> 06:20:02,888
TRAINED IN BOTH GERIATRICS AND

10925
06:20:02,888 --> 06:20:03,855
PULMONOLOGY HAS PUBLISHED REALLY

10926
06:20:03,855 --> 06:20:07,392
WHAT I THINK WERE SOME OF THE

10927
06:20:07,392 --> 06:20:08,927
SEMINAL CLINICAL PAPERS SHOWING

10928
06:20:08,927 --> 06:20:10,462
THAT LUNG FUNCTION INDEPENDENT

10929
06:20:10,462 --> 06:20:11,897
OF SMOKING OR OTHER

10930
06:20:11,897 --> 06:20:16,301
ENVIRONMENTAL RISK FACTORS SUCH

10931
06:20:16,301 --> 06:20:18,537
AS FLY ASH OR INDOOR COOKING

10932
06:20:18,537 --> 06:20:20,172
EXPOSURE, THAT HAPPENS MOSTLY

10933
06:20:20,172 --> 06:20:23,708
GLOBALLY, THAT LUNG FUNCTION --

10934
06:20:23,708 --> 06:20:24,309
A DECLINE IN LUNG FUNCTION IN

10935
06:20:24,309 --> 06:20:25,744
AND OF ITSELF CAN BE PREDICTIVE

10936
06:20:25,744 --> 06:20:28,313
OF SIGNIFICANT MORBIDITY AND

10937
06:20:28,313 --> 06:20:28,914
MORTALITY AND THAT'S PROBABLY

10938
06:20:28,914 --> 06:20:30,615
BECAUSE LUNG FUNCTION IS A

10939
06:20:30,615 --> 06:20:33,485
FAIRLY GOOD READOUT FOR

10940
06:20:33,485 --> 06:20:36,288
INTEGRATED OR MULTISYSTEM AREAS

10941
06:20:36,288 --> 06:20:38,824
THAT I'VE LISTED HERE.

10942
06:20:38,824 --> 06:20:44,296
I DEVELOPED THIS PICTORIAL BASED

10943
06:20:44,296 --> 06:20:49,301
ON A FEW OTHER PUBLICATIONS AND

10944
06:20:49,301 --> 06:20:50,869
IN THE LUNGS AT LEAST WHERE

10945
06:20:50,869 --> 06:20:51,970
THERE'S OVER 55 INDIVIDUAL CELL

10946
06:20:51,970 --> 06:20:52,204
TYPES.

10947
06:20:52,204 --> 06:20:55,140
I MEAN, QUITE PHENOTYPICALLY

10948
06:20:55,140 --> 06:20:56,608
MORPHOLOGICALLY DIFFERENT CELL

10949
06:20:56,608 --> 06:21:00,479
TYPES IN THE LUNG.

10950
06:21:00,479 --> 06:21:01,113
LOCATION IS KEY.

10951
06:21:01,113 --> 06:21:02,114
IT IS ALL ABOUT LOCATION IN

10952
06:21:02,114 --> 06:21:06,118
TERMS OF DYSFUNCTIONAL AGING, IN

10953
06:21:06,118 --> 06:21:11,857
TERMS OF ENVIRONMENTAL RESPONSES

10954
06:21:11,857 --> 06:21:13,992
TO INHALED TOXINS AS WELL AS

10955
06:21:13,992 --> 06:21:16,461
CIRCULATING TOXINS, LUNG IS

10956
06:21:16,461 --> 06:21:17,229
PROBABLY THE SECOND MOST

10957
06:21:17,229 --> 06:21:18,430
VASCULAR ORGAN IN THE HUMAN

10958
06:21:18,430 --> 06:21:19,965
BODY, SO IT HAS TO REALLY

10959
06:21:19,965 --> 06:21:21,967
INTEGRATE THE SIGNALS COMING

10960
06:21:21,967 --> 06:21:24,536
FROM THE ENVIRONMENT, THE AREA

10961
06:21:24,536 --> 06:21:27,072
AND FROM ITS CIRCULATION.

10962
06:21:27,072 --> 06:21:29,508
BUT ITS CONDUCTING ZONE, THE

10963
06:21:29,508 --> 06:21:30,108
RESPIRATORY ZONE AND THE AREA

10964
06:21:30,108 --> 06:21:32,911
THAT I WORK ON MOST WHICH IS

10965
06:21:32,911 --> 06:21:38,283
THESE ALVEOLAR SACS IS KIND OF

10966
06:21:38,283 --> 06:21:40,785
BUSINESS END, STROMAL CELLS,

10967
06:21:40,785 --> 06:21:44,656
FIBROBLASTS, MACROPHAGE,

10968
06:21:44,656 --> 06:21:45,290
RESIDENT MACROPHAGES AS WELL AS

10969
06:21:45,290 --> 06:21:51,029
THE MICRO CIRCULATION TO DO ITS

10970
06:21:51,029 --> 06:21:52,364
MAIN BUSINESS, AND ITS MAIN

10971
06:21:52,364 --> 06:21:53,999
BUSINESS IS GAS EXCHANGE.

10972
06:21:53,999 --> 06:21:56,701
GAS EXCHANGE AS WELL AS IMMUNE

10973
06:21:56,701 --> 06:22:02,307
FUNCTION.

10974
06:22:02,307 --> 06:22:04,843
THIS IS ANOTHER BLOWN UP

10975
06:22:04,843 --> 06:22:05,911
PICTORIAL OF WHAT HAPPENS WHEN

10976
06:22:05,911 --> 06:22:09,447
WE AGE YOU DON'T HAVE TO SMOKE

10977
06:22:09,447 --> 06:22:10,982
TO GO FROM A NORMAL ALVEOLUS

10978
06:22:10,982 --> 06:22:12,417
WHEN YOU'RE YOUTHFUL.

10979
06:22:12,417 --> 06:22:13,385
YOUR LUNG FUNCTION PROBABLY

10980
06:22:13,385 --> 06:22:16,421
PEAKS WHEN YOU'RE ABOUT 21,

10981
06:22:16,421 --> 06:22:17,422
BETWEEN 21 TO 25.

10982
06:22:17,422 --> 06:22:18,423
FROM THERE IT'S ALL ABOUT A LOSS

10983
06:22:18,423 --> 06:22:24,930
OF A 1 10 EE -- EQUIVALENT OF 10

10984
06:22:24,930 --> 06:22:26,765
CCs PER YEAR.

10985
06:22:26,765 --> 06:22:28,300
AS WE AGE WE ACTUALLY START

10986
06:22:28,300 --> 06:22:30,835
GETTING AN OBSTRUCTIVE PICTURE

10987
06:22:30,835 --> 06:22:33,238
BECAUSE OF A LOSS OF NORMAL ALAS

10988
06:22:33,238 --> 06:22:34,005
TIN.

10989
06:22:34,005 --> 06:22:36,808
THESE AIR SACS JUST BALLOON OUT,

10990
06:22:36,808 --> 06:22:37,809
THEY LOSE THEIR ABILITY TO HAVE

10991
06:22:37,809 --> 06:22:39,010
NORMAL GAS EXCHANGE AND THEIR

10992
06:22:39,010 --> 06:22:40,779
BLOOD DEVELOPS START BECOMING

10993
06:22:40,779 --> 06:22:44,583
EITHER -- THEY START GETTING

10994
06:22:44,583 --> 06:22:45,483
PRUNED AND/OR THE LARGER VESSELS

10995
06:22:45,483 --> 06:22:48,887
START GETTING REMODELED, ALMOST

10996
06:22:48,887 --> 06:22:52,557
A FIBROTIC PICTURE.

10997
06:22:52,557 --> 06:22:58,730
THIS, I ADAPTED FROM THE SUMMARY

10998
06:22:58,730 --> 06:23:00,165
PUBLICATION WHERE THERE'S BOTH

10999
06:23:00,165 --> 06:23:01,132
GENETIC AND VARIABILITY TALL

11000
06:23:01,132 --> 06:23:03,134
LUNG DETERMINANTS OF LUNG AGING.

11001
06:23:03,134 --> 06:23:06,304
AND AS EARLIER TALKS HAVE REALLY

11002
06:23:06,304 --> 06:23:10,175
KIND OF HIGHLIGHTED QUITE WELL,

11003
06:23:10,175 --> 06:23:12,043
PROBABLY THERE IS A

11004
06:23:12,043 --> 06:23:14,012
PREDISPOSITION AT THE GERMLINE

11005
06:23:14,012 --> 06:23:15,447
LEVEL, SO THERE'S PROBABLY

11006
06:23:15,447 --> 06:23:16,748
GENETIC COMPONENT TO HOW THE

11007
06:23:16,748 --> 06:23:20,252
LUNGS WILL REACT TO A VARIETY OF

11008
06:23:20,252 --> 06:23:22,754
ENVIRONMENTAL TOXINS, WHETHER

11009
06:23:22,754 --> 06:23:26,024
IT'S SMOKING, MICROBES, AIR

11010
06:23:26,024 --> 06:23:28,426
POLLUTION, OZONE, THAT WILL

11011
06:23:28,426 --> 06:23:31,162
MODIFY OR KIND OF COLOR, GIVE

11012
06:23:31,162 --> 06:23:32,364
DIFFERENT COLORS TO HOW THE

11013
06:23:32,364 --> 06:23:35,166
LUNGS ACTUALLY RESPOND TO THESE

11014
06:23:35,166 --> 06:23:36,701
ENVIRONMENTAL CHALLENGES AND

11015
06:23:36,701 --> 06:23:38,203
THAT'S WHERE EPIGENETICS COMES

11016
06:23:38,203 --> 06:23:38,837
IN.

11017
06:23:38,837 --> 06:23:41,072
THE EPIGENETICS, I ACTUALLY

11018
06:23:41,072 --> 06:23:41,706
BELIEVE THAT THERE'S PROBABLY A

11019
06:23:41,706 --> 06:23:43,108
PERMANENCE TO SOME OF THE

11020
06:23:43,108 --> 06:23:44,876
EPIGENETICS, BUT I ACTUALLY

11021
06:23:44,876 --> 06:23:47,178
BELIEVE THERE'S ALSO A

11022
06:23:47,178 --> 06:23:49,381
REVERSIBLE COMPONENT, AND THAT'S

11023
06:23:49,381 --> 06:23:50,282
SOMEWHAT SPECULATION BASED ON A

11024
06:23:50,282 --> 06:23:52,651
LITTLE BIT OF DATA, BUT THIS

11025
06:23:52,651 --> 06:23:54,519
EPIGENETICS WILL COLOR OUR

11026
06:23:54,519 --> 06:23:56,288
GENETIC PROGRAMMING TO DETERMINE

11027
06:23:56,288 --> 06:23:59,658
HOW THE LUNGS WILL REACT TO A

11028
06:23:59,658 --> 06:24:01,259
VARIETY OF ENVIRONMENTAL

11029
06:24:01,259 --> 06:24:02,494
CHALLENGES, WHETHER THAT IS THIS

11030
06:24:02,494 --> 06:24:04,596
OOBSTRUCTIVE PULMONARY LUNG

11031
06:24:04,596 --> 06:24:06,931
DISEASE I STUDY, WHETHER IT'S

11032
06:24:06,931 --> 06:24:08,033
ABNORMAL PROLIFERATION,

11033
06:24:08,033 --> 06:24:09,567
EFFICIENTLY TUMOR OR CANCER, OR

11034
06:24:09,567 --> 06:24:12,937
WHETHER IT'S THIS KIND OF

11035
06:24:12,937 --> 06:24:13,405
NON-MALIGNANT FIBROTIC

11036
06:24:13,405 --> 06:24:16,474
PHENOTYPE.

11037
06:24:16,474 --> 06:24:18,009
AGAIN JUST TO CLARIFY, I'M SURE

11038
06:24:18,009 --> 06:24:19,311
THIS GROUP KNOWS VERY WELL,

11039
06:24:19,311 --> 06:24:22,180
AGING IS NOT EQUIVALENT TO

11040
06:24:22,180 --> 06:24:22,480
SENESCENCE.

11041
06:24:22,480 --> 06:24:23,715
WHEN I REFER TO SENESCENCE, I

11042
06:24:23,715 --> 06:24:27,485
SEE IT MORE AS AN ASSOCIATED

11043
06:24:27,485 --> 06:24:29,154
CELL FATE DECISION OR CELL FATE

11044
06:24:29,154 --> 06:24:31,022
PROCESS IN AGING TISSUES.

11045
06:24:31,022 --> 06:24:33,224
AND SENESCENCE IS TYPICALLY

11046
06:24:33,224 --> 06:24:39,831
REALLY CLASSIFIED AS THE SECOND

11047
06:24:39,831 --> 06:24:41,399
DEPENDENT KINASE, JUST IN A

11048
06:24:41,399 --> 06:24:44,002
VERY, VERY RUDIMENTARY -- AT A

11049
06:24:44,002 --> 06:24:45,737
VERY RUDIMENTARY LEVEL.

11050
06:24:45,737 --> 06:24:46,438
WE OF COURSE KNOW IT'S MUCH MORE

11051
06:24:46,438 --> 06:24:47,405
COMPLEX THAN THIS.

11052
06:24:47,405 --> 06:24:48,406
AND AS A MATTER OF FACT, WE

11053
06:24:48,406 --> 06:24:53,044
PROBABLY DON'T HAVE A RELIABLE

11054
06:24:53,044 --> 06:24:54,746
OR WELL AGREED UPON SENESCENCE

11055
06:24:54,746 --> 06:24:55,947
BIOMARKERS, ESPECIALLY IN THE

11056
06:24:55,947 --> 06:24:56,514
LUNG.

11057
06:24:56,514 --> 06:24:58,983
THESE ARE ALL THE DIFFERENT

11058
06:24:58,983 --> 06:25:00,518
AREAS OF KIND OF TRIGGERS OF

11059
06:25:00,518 --> 06:25:00,952
SENESCENCE.

11060
06:25:00,952 --> 06:25:03,254
WE HEARD ABOUT DNA DAMAGE,

11061
06:25:03,254 --> 06:25:05,156
CERTAINLY MITOCHONDRIAL

11062
06:25:05,156 --> 06:25:05,790
DYSFUNCTION, EPIGENETICS AND OF

11063
06:25:05,790 --> 06:25:09,527
COURSE THE CLA C CLASSIC TELOMEE

11064
06:25:09,527 --> 06:25:09,861
EROSION.

11065
06:25:09,861 --> 06:25:11,529
BUT THESE ARE THE OUTPUTS, OTHER

11066
06:25:11,529 --> 06:25:17,068
THAN THE P16/19/21/53, USUALLY

11067
06:25:17,068 --> 06:25:18,970
AT THE LEVEL OF TRANSCRIPT, STEM

11068
06:25:18,970 --> 06:25:20,605
CELL EXHAUSTION, AND OF COURSE

11069
06:25:20,605 --> 06:25:21,606
INFLAMMATION OF AGING.

11070
06:25:21,606 --> 06:25:24,309
THIS IS JUST TO GIVE YOU A BRIEF

11071
06:25:24,309 --> 06:25:25,143
OVERVIEW OF WHAT SOME OF MY LAB

11072
06:25:25,143 --> 06:25:26,711
HAS BEEN WORKING ON FOR NOW

11073
06:25:26,711 --> 06:25:30,648
ABOUT A DECADE.

11074
06:25:30,648 --> 06:25:32,884
SO JIN, WHO'S GOING TO BE

11075
06:25:32,884 --> 06:25:35,253
JOINING ME IN SINAI SHORTLY, HAS

11076
06:25:35,253 --> 06:25:36,454
WORKED OUT REALLY WHAT LOOKS TO

11077
06:25:36,454 --> 06:25:39,357
BE A SYNERGISTIC KIND OF SIGNAL

11078
06:25:39,357 --> 06:25:42,227
TRANSDUCTION THAT HAPPENS WHEN

11079
06:25:42,227 --> 06:25:44,095
YOU STRESS LUNGS, ESPECIALLY THE

11080
06:25:44,095 --> 06:25:46,431
LUNG VASCULATURE, WITH EXPOSURE

11081
06:25:46,431 --> 06:25:49,234
TO CIGARETTE SMOKE OR WHAT I PUT

11082
06:25:49,234 --> 06:25:50,568
AS INTERNAL STRESSOR JUST FOR

11083
06:25:50,568 --> 06:25:52,237
CONVENIENCE BUT REALLY JUST KIND

11084
06:25:52,237 --> 06:25:56,741
OF THE CHRONOLOGY OF JUST AGING

11085
06:25:56,741 --> 06:25:58,510
OUR MICE OR LOOKING AT AGED

11086
06:25:58,510 --> 06:26:00,278
HUMAN LUNG TISSUES.

11087
06:26:00,278 --> 06:26:01,012
SHE'S BEEN ABLE TO MAP OUT A

11088
06:26:01,012 --> 06:26:03,615
REALLY IMPORTANT ROLE FOR THE

11089
06:26:03,615 --> 06:26:05,817
INNATE IMMUNE RECEPTOR PATHWAY

11090
06:26:05,817 --> 06:26:07,886
TLR4, AND THAT IN ITS USUAL

11091
06:26:07,886 --> 06:26:14,993
CANONICAL CLASSICAL

11092
06:26:14,993 --> 06:26:16,761
TLR4 SIGNALING, PLAYS A

11093
06:26:16,761 --> 06:26:17,929
HOMEOSTATIC ROLE IN PREVENTING

11094
06:26:17,929 --> 06:26:19,230
LUNG SENESCENCE, AND THESE ARE

11095
06:26:19,230 --> 06:26:21,332
JUST SOME OF THE EPIGENETIC AS

11096
06:26:21,332 --> 06:26:23,201
WELL AS SOME OF THE CELL TYPES

11097
06:26:23,201 --> 06:26:24,135
AFFECTED.

11098
06:26:24,135 --> 06:26:27,439
THE FINAL PHENOTYPE WE SEE WHEN

11099
06:26:27,439 --> 06:26:30,074
YOU HAVE AGE PLUS CIGARETTE

11100
06:26:30,074 --> 06:26:32,143
SMOKE, ESPECIALLY IN MURINE

11101
06:26:32,143 --> 06:26:33,878
MODELS, WE'VE USED GENETIC

11102
06:26:33,878 --> 06:26:35,980
MURINE MODELS AS WELL AS JUST

11103
06:26:35,980 --> 06:26:38,783
WILD TYPE AGING.

11104
06:26:38,783 --> 06:26:40,251
WHEN YOU HAVE THE SYNERGISTIC

11105
06:26:40,251 --> 06:26:42,420
EFFECT, YOU GET ACTUALLY A LOSS

11106
06:26:42,420 --> 06:26:46,124
OF NORMAL INNATE IMMUNE

11107
06:26:46,124 --> 06:26:51,262
SIGNALING VIA TLR4 THAT LEADS TO

11108
06:26:51,262 --> 06:26:55,467
EXTRUSION OF SENESCENCE,

11109
06:26:55,467 --> 06:26:57,535
SECRETED PROTEIN, MITOCHONDRIAL

11110
06:26:57,535 --> 06:26:58,903
DYSFUNCTION, WE GET A VERY

11111
06:26:58,903 --> 06:27:01,739
SPECIFIC CELL DEATH, IT'S NOT

11112
06:27:01,739 --> 06:27:03,608
APOPTOSIS, IT TENDS TO BE MORE

11113
06:27:03,608 --> 06:27:04,809
OF A NECROTIC CELL DEATH, AND

11114
06:27:04,809 --> 06:27:06,211
THEN EVENTUALLY WE GET A

11115
06:27:06,211 --> 06:27:08,880
PHENOTYPE OF EMPHYSEMA OR COPD

11116
06:27:08,880 --> 06:27:09,747
IN OUR MICE.

11117
06:27:09,747 --> 06:27:12,484
THIS IS ANOTHER PART OF MY LAB

11118
06:27:12,484 --> 06:27:15,820
WITH CLOSE COLLABORATIONS WITH

11119
06:27:15,820 --> 06:27:19,257
RICK BUCALA AND MAOR SAULER.

11120
06:27:19,257 --> 06:27:21,593
WE WERE ABLE TO IDENTIFY WHAT WE

11121
06:27:21,593 --> 06:27:23,394
BELIEVE TO BE A LUNG VASCULAR

11122
06:27:23,394 --> 06:27:27,632
RESILIENCY PATHWAY THAT IS

11123
06:27:27,632 --> 06:27:29,067
SLOWLY DEGRADED WITH EITHER AGE,

11124
06:27:29,067 --> 06:27:31,503
EXPOSURE TO TOBACCO SMOKE,

11125
06:27:31,503 --> 06:27:32,036
PNEUMOCOCCAL PNEUMONIA.

11126
06:27:32,036 --> 06:27:36,174
THIS PATHWAY IS A MIF

11127
06:27:36,174 --> 06:27:36,841
CD74 PATHWAY.

11128
06:27:36,841 --> 06:27:38,576
WE HAVE HUMANIZED MICE THAT CAN

11129
06:27:38,576 --> 06:27:41,045
ACTUALLY MIMIC THE MIF GENETICS

11130
06:27:41,045 --> 06:27:42,280
THAT WE FIND IN PEOPLE, AND WE

11131
06:27:42,280 --> 06:27:47,252
FIND THAT THIS MIF C

11132
06:27:47,252 --> 06:27:47,785
CD74 SIGNALING PATHWAY IS

11133
06:27:47,785 --> 06:27:48,920
CRUCIAL FOR THE ABILITY OF THE

11134
06:27:48,920 --> 06:27:50,989
LUNGS TO WITHSTAND CIGARETTE

11135
06:27:50,989 --> 06:27:54,425
SMOKE OR PNEUMONIA AND EVEN AGE.

11136
06:27:54,425 --> 06:27:55,627
THIS IS SOME OF THE EXPERIMENTAL

11137
06:27:55,627 --> 06:27:57,061
MODELING THAT WE DO.

11138
06:27:57,061 --> 06:28:05,970
WE USE A VARIETY OF DNA TOXIC

11139
06:28:05,970 --> 06:28:07,639
DNAED INTERP LAY TORES OR

11140
06:28:07,639 --> 06:28:08,172
DAMAGERS.

11141
06:28:08,172 --> 06:28:10,608
WE'VE USED RADIATION CIGARETTE

11142
06:28:10,608 --> 06:28:14,746
SMOKE CLEARLY, JUST NORMAL

11143
06:28:14,746 --> 06:28:17,048
BILATERAL -- AND WE STARTED

11144
06:28:17,048 --> 06:28:18,683
TESTING SOME THERAPEUTICS TO SEE

11145
06:28:18,683 --> 06:28:20,652
IF WE CAN BRING ON SENESCENCE IN

11146
06:28:20,652 --> 06:28:22,687
LUNG CELLS, AND THEN WE TAKE IT

11147
06:28:22,687 --> 06:28:22,921
IN VIVO.

11148
06:28:22,921 --> 06:28:25,823
AND THEN WE GET HUMAN LUNG

11149
06:28:25,823 --> 06:28:33,164
EX-PLANTS OR HUMAN LUNG DONOR

11150
06:28:33,164 --> 06:28:36,768
SAMPLES TO CREATE ORGANOIDs.

11151
06:28:36,768 --> 06:28:38,870
AS WELL AS WHAT WE'RE WORKING ON

11152
06:28:38,870 --> 06:28:41,472
NOW, AN ALVEOLAR SPHERE WITH A

11153
06:28:41,472 --> 06:28:47,045
VESSEL TO TEST SOME OF OUR SINO

11154
06:28:47,045 --> 06:28:47,378
TRIGGERS.

11155
06:28:47,378 --> 06:28:51,316
THIS IS JUST A BLOWUP OF

11156
06:28:51,316 --> 06:28:51,816
ALVEOLUS WITH THE MICRO

11157
06:28:51,816 --> 06:28:52,417
CIRCULATION HERE AND A THEN

11158
06:28:52,417 --> 06:28:53,718
LISTING WHAT'S BEEN PUBLISHED

11159
06:28:53,718 --> 06:28:58,456
AND WHAT WE TRIED TO ASSAY IN

11160
06:28:58,456 --> 06:29:01,826
THE VARIOUS CELL COMPARTMENTS OF

11161
06:29:01,826 --> 06:29:06,531
THIS ALVEOLUS FOR SENESCENCE.

11162
06:29:06,531 --> 06:29:08,733
AGAIN THIS IS JUST ANOTHER WAY

11163
06:29:08,733 --> 06:29:09,300
TO LOOK AT SOME OF THE -- I

11164
06:29:09,300 --> 06:29:10,435
GUESS THE ARCHITECTURE OF WHAT

11165
06:29:10,435 --> 06:29:13,237
WE'RE LOOKING AT WHEN WE CREATE

11166
06:29:13,237 --> 06:29:19,344
THESE 3D ALVEOLUSPHERES.

11167
06:29:19,344 --> 06:29:20,645
THE ALVEOLAR STEM CELLS AS WELL

11168
06:29:20,645 --> 06:29:22,513
AS THE ENDOTHELIAL CELLS ARE

11169
06:29:22,513 --> 06:29:24,582
KEY, BUT THERE'S A COMPLEX 3D

11170
06:29:24,582 --> 06:29:26,451
STRUCTURE THAT WE HAVE NOT

11171
06:29:26,451 --> 06:29:28,820
REALLY QUITE RECAPITULATED VERY

11172
06:29:28,820 --> 06:29:31,556
WELL IN A 3D ORGANOID, BUT THAT

11173
06:29:31,556 --> 06:29:34,425
IS A PLAN FOR THE FUTURE.

11174
06:29:34,425 --> 06:29:34,959
AND THESE ARE SOME OF THE

11175
06:29:34,959 --> 06:29:38,262
SENESCENCE MARKERS.

11176
06:29:38,262 --> 06:29:38,963
 MARKERS THAT WE

11177
06:29:38,963 --> 06:29:41,432
ASSESS.

11178
06:29:41,432 --> 06:29:43,167
SO I TOLD YOU VERY BRIEFLY ABOUT

11179
06:29:43,167 --> 06:29:47,038
IT. LR4, MIF, THESE IMMUNE MADE

11180
06:29:47,038 --> 06:29:48,873
LAY TORES SENESCENCE.

11181
06:29:48,873 --> 06:29:49,774
I THINK THERE ARE POTENTIAL

11182
06:29:49,774 --> 06:29:51,976
OPPORTUNITIES FOR SENO

11183
06:29:51,976 --> 06:29:52,744
THERAPEUTIC, BUT OF COURSE THERE

11184
06:29:52,744 --> 06:29:54,746
ARE A VARIETY OF OTHER

11185
06:29:54,746 --> 06:29:56,748
CATEGORIES OF SENOTHERAPEUTICS

11186
06:29:56,748 --> 06:29:57,882
THAT HAVE BEEN PUBLISHED BY

11187
06:29:57,882 --> 06:30:00,551
PEOPLE WITHIN THIS GROUP AS WELL

11188
06:30:00,551 --> 06:30:04,322
AS THE JUDY CAMPISI GROUP.

11189
06:30:04,322 --> 06:30:05,957
AND WHAT WE'RE DOING IS PART OF

11190
06:30:05,957 --> 06:30:12,163
TAS PART OFMY SINAI INITIATIVE E

11191
06:30:12,163 --> 06:30:16,134
HELP OF OUR CONSORTIUM WHERE WE

11192
06:30:16,134 --> 06:30:18,503
ARE SAMPLING A VARIETY OF HUMAN

11193
06:30:18,503 --> 06:30:21,572
LUNG AS WELL AS HUMAN COLON

11194
06:30:21,572 --> 06:30:24,375
SAMPLES ACROSS THE AGE, COLON IS

11195
06:30:24,375 --> 06:30:27,979
18 TO OVER 65, LUNG, WE CAN

11196
06:30:27,979 --> 06:30:33,351
ACCESS FROM FETAL, FROM

11197
06:30:33,351 --> 06:30:35,887
UNFORTUNATE FETAL DEMICE BUT

11198
06:30:35,887 --> 06:30:37,455
OSTENSIBLY OTHERWISE NORMAL IN

11199
06:30:37,455 --> 06:30:39,157
THE LUNG TO OTHER 90.

11200
06:30:39,157 --> 06:30:42,460
>> DOCTOR, YOU HAVE TWO
MINUTES

11201
06:30:42,460 --> 06:30:42,727
REMAINING.

11202
06:30:42,727 --> 06:30:44,262
>> THIS IS THE TRAJECTORY
OF

11203
06:30:44,262 --> 06:30:45,563
WHAT I SEE HAPPENING ONCE WE

11204
06:30:45,563 --> 06:30:52,003
HAVE OUR DATASETS FOR HUMAN

11205
06:30:52,003 --> 06:30:52,470
TISSUE ACQUISITION FOR

11206
06:30:52,470 --> 06:30:53,304
SENESCENCE DETECTION.

11207
06:30:53,304 --> 06:30:56,140
IT'S REALLY GOING FROM OUR

11208
06:30:56,140 --> 06:31:00,144
PATIENTS IN PARTNERSHIP WITH OUR

11209
06:31:00,144 --> 06:31:02,013
CLINICIANS, OUR RESEARCHERS,

11210
06:31:02,013 --> 06:31:04,215
TRANSLATIONALLISTS AND OF COURSE

11211
06:31:04,215 --> 06:31:05,316
OUR EXPERIMENTALISTS.

11212
06:31:05,316 --> 06:31:07,685
AND BE ABLE TO INTEGRATE

11213
06:31:07,685 --> 06:31:08,653
CLINICAL AS WELL AS

11214
06:31:08,653 --> 06:31:09,987
TRANSLATIONAL AND BASIC SCIENCE

11215
06:31:09,987 --> 06:31:13,157
DATA TO MAKE SOME INRHODES AS TO

11216
06:31:13,157 --> 06:31:17,628
ROADS AS TOWHAT ARE THE SENESCET

11217
06:31:17,628 --> 06:31:20,231
BIOMARKERS IN LUNG TISSUE AND

11218
06:31:20,231 --> 06:31:21,632
COLON, AND WHAT ARE SOME OF THE

11219
06:31:21,632 --> 06:31:23,634
INTERVENTIONS OR THERAPEUTICS

11220
06:31:23,634 --> 06:31:26,604
THAT CAN BE DEVELOPED BASED ON

11221
06:31:26,604 --> 06:31:26,871
THE DATA.

11222
06:31:26,871 --> 06:31:27,472
THIS IS MADE POSSIBLE BY THE

11223
06:31:27,472 --> 06:31:28,206
FACT THAT I WAS FORTUNATE ENOUGH

11224
06:31:28,206 --> 06:31:32,477
TO BE ABLE TO GET A TISSUE

11225
06:31:32,477 --> 06:31:33,077
MAPPING CENTER FUNDED WHILE I

11226
06:31:33,077 --> 06:31:34,979
WAS AT DUKE.

11227
06:31:34,979 --> 06:31:36,481
IT HAS NOW EXTENDED TO MOUNT

11228
06:31:36,481 --> 06:31:38,583
SINAI AND THEN THESE ARE ALL THE

11229
06:31:38,583 --> 06:31:40,051
OTHER CENTERS INVOLVED.

11230
06:31:40,051 --> 06:31:41,819
THE GREEN ARE THE TISSUE MAPPING

11231
06:31:41,819 --> 06:31:42,120
CENTERS.

11232
06:31:42,120 --> 06:31:44,088
THERE ARE EIGHT OF THEM.

11233
06:31:44,088 --> 06:31:46,190
THERE ARE ALSO EIGHT IN KIND OF

11234
06:31:46,190 --> 06:31:48,926
THE BROWN TECHNOLOGY DEVELOPMENT

11235
06:31:48,926 --> 06:31:52,296
AWARDS, AND THEN OF COURSE THERE

11236
06:31:52,296 --> 06:31:59,337
ARE DATA COORDINATING CENTERS,

11237
06:31:59,337 --> 06:32:02,173
THE KODAK IN THE PURPLE, AND

11238
06:32:02,173 --> 06:32:03,207
INTERNATIONAL COLLABORATORS AS

11239
06:32:03,207 --> 06:32:05,109
WELL AS THE NATIONALLY BASED

11240
06:32:05,109 --> 06:32:05,443
COLLABORATORS.

11241
06:32:05,443 --> 06:32:07,678
I'D LIKE TO THANK THE NIH, THE

11242
06:32:07,678 --> 06:32:08,446
NCI, FOR THIS OPPORTUNITY TO

11243
06:32:08,446 --> 06:32:10,248
SHOW YOU SOME OF THE THINGS

11244
06:32:10,248 --> 06:32:20,458
WE'RE DOING.

11245
06:32:21,225 --> 06:32:25,129
>> THANK YOU SO MUCH.

11246
06:32:25,129 --> 06:32:27,165
>> GO AHEAD.

11247
06:32:27,165 --> 06:32:30,268
I THINK WE MOVE RIGHT INTO THE

11248
06:32:30,268 --> 06:32:31,602
PANEL DISCUSSION.

11249
06:32:31,602 --> 06:32:34,238
>> YES, THAT'S THE TIME,
YEAH.

11250
06:32:34,238 --> 06:32:37,074
WE ARE.

11251
06:32:37,074 --> 06:32:39,510
EXACTLY ON TIME FOR THAT AND WE

11252
06:32:39,510 --> 06:32:40,478
CAN TAKE ALL THE QUESTIONS

11253
06:32:40,478 --> 06:32:42,747
INCLUDING QUESTIONS FOR OUR LAST

11254
06:32:42,747 --> 06:32:43,881
SPEAKER, DR. LEE, DURING THE

11255
06:32:43,881 --> 06:32:46,984
PANEL DISCUSSION.

11256
06:32:46,984 --> 06:32:49,787
>> OKAY.

11257
06:32:49,787 --> 06:32:54,025
SO IF ALL THE SPEAKERS FROM THIS

11258
06:32:54,025 --> 06:32:56,694
LAST MAMMOTH MARATHON SESSION

11259
06:32:56,694 --> 06:33:01,766
CAN HOP ON AND HOPEFULLY PEOPLE

11260
06:33:01,766 --> 06:33:03,634
CAN JUST UNMUTE, THEY CAN SEND

11261
06:33:03,634 --> 06:33:05,236
TO EVERYONE IN THE ZOOM QUESTION

11262
06:33:05,236 --> 06:33:06,737
AND ANSWER FUNCTION, AND WE WILL

11263
06:33:06,737 --> 06:33:10,908
ADDRESS THEM IN TURN.

11264
06:33:10,908 --> 06:33:13,211
THERE WERE SOME QUESTIONS

11265
06:33:13,211 --> 06:33:17,114
EARLIER FOR BOTH DR. ROBBINS AND

11266
06:33:17,114 --> 06:33:18,316
DR. KIRKLAND, WHO'S HANGING IN

11267
06:33:18,316 --> 06:33:21,152
THERE DESPITE BEING IN HOLLAND.

11268
06:33:21,152 --> 06:33:23,221
SO THANK YOU AGAIN FOR REJOINING

11269
06:33:23,221 --> 06:33:24,622
US, DR. KIRKLAND.

11270
06:33:24,622 --> 06:33:26,057
IF PEOPLE HAVE QUESTIONS, THEY

11271
06:33:26,057 --> 06:33:30,895
CAN EITHER SEND THEM TO THE CHAT

11272
06:33:30,895 --> 06:33:31,529
FUNCTION OR JUST SIMPLY UNMUTE

11273
06:33:31,529 --> 06:33:32,930
AND ASK AND I WILL BE QUIET AND

11274
06:33:32,930 --> 06:33:36,133
SEE IF PEOPLE WANT TO ASK SOME

11275
06:33:36,133 --> 06:33:46,310
QUESTIONS.

11276
06:33:47,912 --> 06:33:50,314
>> WELL, I COULD GET
STARTED ON

11277
06:33:50,314 --> 06:33:50,648
THAT.

11278
06:33:50,648 --> 06:33:52,083
ON THE LAST TALK, DR. LEE

11279
06:33:52,083 --> 06:33:54,318
BROUGHT ME BACK TO MY PREVIOUS

11280
06:33:54,318 --> 06:33:55,586
LIFE, WHERE I STARTED MY

11281
06:33:55,586 --> 06:33:58,756
RESEARCH CAREER ON FETAL --

11282
06:33:58,756 --> 06:34:00,491
MATURITY AND LUNG SURFACTANTS,

11283
06:34:00,491 --> 06:34:02,927
AND THEN MOVING ON TO LUNG

11284
06:34:02,927 --> 06:34:04,128
CANCER AND MESOTHELIOMA.

11285
06:34:04,128 --> 06:34:07,198
SO IT ALL STARTED WITH TYPE

11286
06:34:07,198 --> 06:34:10,668
2 CELLS AND FETAL LUNG MATURITY.

11287
06:34:10,668 --> 06:34:12,403
SO I WAS JUST WONDERING,

11288
06:34:12,403 --> 06:34:13,905
SURFACTANT PROTEINS, DO THEY

11289
06:34:13,905 --> 06:34:17,408
TAKE ANY PART IN THE

11290
06:34:17,408 --> 06:34:18,376
CARCINOGENESIS EFFECT IN TERMS

11291
06:34:18,376 --> 06:34:22,446
OF WHAT WE USED TO CALL --

11292
06:34:22,446 --> 06:34:23,848
MALIGNANCIES?

11293
06:34:23,848 --> 06:34:26,617
BECAUSE ALL THE EXPOSOMES AFFECT

11294
06:34:26,617 --> 06:34:27,952
LUNG AS WELL AS OUR DIGESTIVE

11295
06:34:27,952 --> 06:34:29,687
SYSTEM.

11296
06:34:29,687 --> 06:34:31,555
HAVING SOME -- AS YOU STARTED

11297
06:34:31,555 --> 06:34:35,927
WITH YOUR WOMEN CASES, SO IT'S A

11298
06:34:35,927 --> 06:34:38,462
MYSTERY AS TO WHY NON-SMOKER

11299
06:34:38,462 --> 06:34:42,900
FEMALES TEND TO GET LUNG CANCER.

11300
06:34:42,900 --> 06:34:43,968
>> THAT'S RIGHT, YEAH.

11301
06:34:43,968 --> 06:34:45,603
I THINK THAT'S A REALLY KEY -- I

11302
06:34:45,603 --> 06:34:47,872
THINK THOSE ARE REALLY

11303
06:34:47,872 --> 06:34:49,807
IMPORTANT, ESPECIALLY BECAUSE WE

11304
06:34:49,807 --> 06:34:51,108
DON'T HAVE A GREAT

11305
06:34:51,108 --> 06:34:52,009
UNDERSTANDING, ALTHOUGH I THINK

11306
06:34:52,009 --> 06:34:54,645
IT'S KEY, JUST AS THE RECURRING

11307
06:34:54,645 --> 06:34:56,647
THEME IS, WHICH IS THE

11308
06:34:56,647 --> 06:34:58,082
TRAJECTORY FROM DEVELOPMENT, I

11309
06:34:58,082 --> 06:34:59,951
THINK WE HAVE TO GO ON TO

11310
06:34:59,951 --> 06:35:03,821
DEVELOPMENT ALL THE WAY INTO

11311
06:35:03,821 --> 06:35:05,056
OLDER AGE, AND SURFACTANT

11312
06:35:05,056 --> 06:35:06,357
PROTEINS, WE DON'T HAVE A LOT OF

11313
06:35:06,357 --> 06:35:08,726
DATA AS TO SURFACTANT PROTEIN

11314
06:35:08,726 --> 06:35:10,361
AND ITS ROLE IN SENESCENCE OR

11315
06:35:10,361 --> 06:35:14,799
LUNG AGING, PER SE.

11316
06:35:14,799 --> 06:35:18,836
BUT MY CO P.I. ON THIS

11317
06:35:18,836 --> 06:35:22,440
SENESCENCE WORK IS ACTUALLY A

11318
06:35:22,440 --> 06:35:22,873
SURFACTANT PERSON.

11319
06:35:22,873 --> 06:35:25,076
SHE STUDIES SPECIFICALLY

11320
06:35:25,076 --> 06:35:28,713
SURFACTANT PROTEIN A, AND SHE --

11321
06:35:28,713 --> 06:35:29,380
FOR ANTI-INFLAMMATORY EFFECTS,

11322
06:35:29,380 --> 06:35:30,748
SO THERE MAY BE, WE'LL PROBABLY

11323
06:35:30,748 --> 06:35:32,950
BE ABLE TO GENERATE THAT DATA

11324
06:35:32,950 --> 06:35:35,353
AND FIND OUT WHAT ITS ROLE IS IN

11325
06:35:35,353 --> 06:35:36,320
LUNG AGING AND SPECIFICALLY IN

11326
06:35:36,320 --> 06:35:40,491
SENESCENCE.

11327
06:35:40,491 --> 06:35:42,994
AND THIS ARROW DIGESTIVE, I

11328
06:35:42,994 --> 06:35:43,361
THINK IT'S KEY.

11329
06:35:43,361 --> 06:35:44,762
OTHER THAN THE MICROBIOTA WHICH

11330
06:35:44,762 --> 06:35:48,432
IS CRITICAL, THERE'S SIGNIFICANT

11331
06:35:48,432 --> 06:35:49,667
AMOUNTS OF AERO DIGESTIVE KIND

11332
06:35:49,667 --> 06:35:51,202
OF BIOCHEMICAL CHANGES HAPPENING

11333
06:35:51,202 --> 06:35:53,604
BECAUSE WE'RE CONSTANTLY

11334
06:35:53,604 --> 06:35:56,674
ASPIRATING, WE CONSTANTLY BRING

11335
06:35:56,674 --> 06:35:59,010
OUR MOUTH, NASAL AND G.I.

11336
06:35:59,010 --> 06:36:02,947
CONTENTS INTO OUR AIRWAYS.

11337
06:36:02,947 --> 06:36:05,583
THAT'S PART OF NORMAL BIOLOGY.

11338
06:36:05,583 --> 06:36:07,118
IT'S JUST AS WE GET OLDER, IT

11339
06:36:07,118 --> 06:36:09,653
HAPPENS MORE FREQUENTLY AT

11340
06:36:09,653 --> 06:36:11,288
LARGER VOLUMES, SO IT'S ACTUALLY

11341
06:36:11,288 --> 06:36:12,990
CHANGING THE MICROENVIRONMENT OF

11342
06:36:12,990 --> 06:36:15,593
OUR AIRWAYS.

11343
06:36:15,593 --> 06:36:17,962
>> I THINK AS A FOLLOW-UP
ON

11344
06:36:17,962 --> 06:36:20,131
THAT, BECAUSE THERE'S A LONG

11345
06:36:20,131 --> 06:36:22,433
LATENCY PERIOD OF DEVELOPING

11346
06:36:22,433 --> 06:36:24,402
MESOTHELIOMA AND LUNG CANCER.

11347
06:36:24,402 --> 06:36:25,970
IT TAKES 40 YEARS FOR CHILDREN

11348
06:36:25,970 --> 06:36:30,007
WHO MIGHT HAVE GOTTEN EXPOSED TO

11349
06:36:30,007 --> 06:36:31,976
ASBESTOS AND LONG LATENCY PERIOD

11350
06:36:31,976 --> 06:36:33,544
OF 40 YEARS, WE SEE THE

11351
06:36:33,544 --> 06:36:35,179
DEVELOPMENT OF MESOTHELIOMA.

11352
06:36:35,179 --> 06:36:37,314
AND DEPENDING UPON THE EXPOSURE

11353
06:36:37,314 --> 06:36:39,050
OF ASBESTOS, WHETHER IT WAS

11354
06:36:39,050 --> 06:36:41,619
INHALED INTO LUNG, VERSUS

11355
06:36:41,619 --> 06:36:43,020
DIGESTIVE SYSTEM, YOU GET

11356
06:36:43,020 --> 06:36:46,190
PERITONEAL OR PERIPHERAL

11357
06:36:46,190 --> 06:36:47,091
MESOTHELIOMA.

11358
06:36:47,091 --> 06:36:52,563
>> I THINK LAURA, YOU HAD
A

11359
06:36:52,563 --> 06:36:52,830
QUESTION?

11360
06:36:52,830 --> 06:36:53,464
>> THANK YOU.

11361
06:36:53,464 --> 06:36:55,399
SHEILA, THIS IS A QUESTION FOR

11362
06:36:55,399 --> 06:36:55,766
YOU.

11363
06:36:55,766 --> 06:36:59,070
I WAS SURPRISED TO HEAR FROM OUR

11364
06:36:59,070 --> 06:37:01,038
COLLEAGUES IN THE CENTER FOR

11365
06:37:01,038 --> 06:37:03,908
IMMUNOLOGY THAT IMMUNE CELLS

11366
06:37:03,908 --> 06:37:04,542
DON'T ALWAYS HAVE RECEPTORS FOR

11367
06:37:04,542 --> 06:37:07,645
ALL OF THESE THINGS SPEWED OUT

11368
06:37:07,645 --> 06:37:10,815
FROM THEIR PARTNERS IN THE

11369
06:37:10,815 --> 06:37:11,382
IMMUNE SYSTEM, BUT ALSO FOR

11370
06:37:11,382 --> 06:37:11,749
SENESCENT CELLS.

11371
06:37:11,749 --> 06:37:13,117
HAVE YOU THOUGHT ABOUT LIKE

11372
06:37:13,117 --> 06:37:14,518
SURFACE RECEPTORS AND WHICH

11373
06:37:14,518 --> 06:37:17,955
CELLS TYCELLTYPES ARE GOING TO O

11374
06:37:17,955 --> 06:37:18,956
CERTAIN SIGNALS.

11375
06:37:18,956 --> 06:37:22,359
I FEEL LIKE WE CAN MAKE EDUCATED

11376
06:37:22,359 --> 06:37:22,927
GUESSES ABOUT THE BIOLOGY.

11377
06:37:22,927 --> 06:37:23,661
HAVE YOU THOUGHT WITH THAT OR

11378
06:37:23,661 --> 06:37:24,295
HAD THAT OPPORTUNITY?

11379
06:37:24,295 --> 06:37:28,032
>> ARE YOU REFERRING TO
WHY IN

11380
06:37:28,032 --> 06:37:28,599
DIFFERENT TISSUES DIFFERENT

11381
06:37:28,599 --> 06:37:29,567
IMMUNE CELLS ARE RESPONDING?

11382
06:37:29,567 --> 06:37:30,968
IS THAT WHAT YOU'RE TRYING TO

11383
06:37:30,968 --> 06:37:31,368
GET AT?

11384
06:37:31,368 --> 06:37:38,109
>> YEAH, I MEAN, -- I
MEAN, THES

11385
06:37:38,109 --> 06:37:38,542
PROBABLY.

11386
06:37:38,542 --> 06:37:42,012
WHAT I CAN TELL YOU, WHAT WE'VE

11387
06:37:42,012 --> 06:37:43,681
DONE TENDS TO BE MORE CYTOKINES,

11388
06:37:43,681 --> 06:37:44,482
AS FAR AS WHAT WE'VE

11389
06:37:44,482 --> 06:37:45,449
SPECIFICALLY LOOKED AT.

11390
06:37:45,449 --> 06:37:50,921
BUT CLEARLY YOU GET DOWN

11391
06:37:50,921 --> 06:37:53,891
REGULATION, UPREGULATION OF -- I

11392
06:37:53,891 --> 06:37:55,759
THINK IT'S LIKELY TO BE A

11393
06:37:55,759 --> 06:37:58,329
COMBINATION OF BOTH SECRETED

11394
06:37:58,329 --> 06:38:00,264
FACTORS AS WELL AS ALL SURFACE

11395
06:38:00,264 --> 06:38:00,498
MARKERS.

11396
06:38:00,498 --> 06:38:01,365
>> OKAY, THANK YOU.

11397
06:38:01,365 --> 06:38:04,468
I WOULD JUST ADD TOO, I THINK WE

11398
06:38:04,468 --> 06:38:10,141
SHOULD MENT MENTION -- SENESCENT

11399
06:38:10,141 --> 06:38:14,712
CELLS CAN ALTER THEIR SURFASOME

11400
06:38:14,712 --> 06:38:20,384
AS WELL SO IT REALLY TRICKY.

11401
06:38:20,384 --> 06:38:23,821
>> I BELIEVE DR. ROBBINS
HAD A

11402
06:38:23,821 --> 06:38:24,088
QUESTION?

11403
06:38:24,088 --> 06:38:25,222
>> ACTUALLY A QUESTION FOR
YOU.

11404
06:38:25,222 --> 06:38:26,290
MICROBIOME AND STROKE, SO

11405
06:38:26,290 --> 06:38:28,726
ACTUALLY TWO QUESTIONS.

11406
06:38:28,726 --> 06:38:30,494
SO WE PUBLISH IN COLLABORATION

11407
06:38:30,494 --> 06:38:32,329
WITH -- MASTERMACK AND JIM

11408
06:38:32,329 --> 06:38:35,966
KIRKLAND AND LAURA A WHILE BACK

11409
06:38:35,966 --> 06:38:36,500
SHOWING -- CHANGED THE GUT

11410
06:38:36,500 --> 06:38:36,934
MICROBIOME.

11411
06:38:36,934 --> 06:38:38,802
I'VE BEEN ALWAYS ASKED DOES THE

11412
06:38:38,802 --> 06:38:41,672
GUT MICROBIOME INFLUENCE

11413
06:38:41,672 --> 06:38:41,972
SENESCENCE.

11414
06:38:41,972 --> 06:38:42,673
I WAS WONDERING IF YOU'VE LOOKED

11415
06:38:42,673 --> 06:38:44,909
AT THAT, AND THEN ALSO IF YOU

11416
06:38:44,909 --> 06:38:46,977
LOOKED AT SENESCENCE IN YOUR

11417
06:38:46,977 --> 06:38:47,778
AGED STROKE OR MICE -- OLDER

11418
06:38:47,778 --> 06:38:50,514
MICE WITH STROKE.

11419
06:38:50,514 --> 06:38:51,982
>> YES AND THERE'S
ACTUALLY

11420
06:38:51,982 --> 06:38:54,051
SOMEBODY IN THE LAB DOING BOTH A

11421
06:38:54,051 --> 06:38:56,020
CHRONIC STROKE AND A TBI WITH

11422
06:38:56,020 --> 06:38:57,021
SENOLYTICS AS WELL, BUT IT'S

11423
06:38:57,021 --> 06:39:00,124
VERY INTERESTING BECAUSE IF YOU

11424
06:39:00,124 --> 06:39:00,958
GIVE THIS AGED BIOME AND YOU CAN

11425
06:39:00,958 --> 06:39:02,493
SHOW EVEN WHEN WE DID IT EVEN

11426
06:39:02,493 --> 06:39:04,161
WITHOUT STROKE, YOU FOLLOW THE

11427
06:39:04,161 --> 06:39:06,363
AB MALLS FOR A MONTH, THE

11428
06:39:06,363 --> 06:39:08,566
ANIMALS THAT HAVE THE AGE

11429
06:39:08,566 --> 06:39:12,937
DYSBIOTIC BIOME NOT ONLY HAVE

11430
06:39:12,937 --> 06:39:15,406
CONTINUED CHANGES BASED BOTH ON

11431
06:39:15,406 --> 06:39:16,807
SHOTGUN SEQUENCING AND CHANGES

11432
06:39:16,807 --> 06:39:18,075
IN THEIR METABOLIC PROFILE.

11433
06:39:18,075 --> 06:39:21,979
THE GUT ITSELF LOOKS VERY

11434
06:39:21,979 --> 06:39:23,714
DIFFERENT AND LOOKS AGED.

11435
06:39:23,714 --> 06:39:24,348
THERE'S A LOT OF INFLAMMATION IN

11436
06:39:24,348 --> 06:39:28,586
THE LAMINA PROPRIA, THERE'S A

11437
06:39:28,586 --> 06:39:29,153
TREMENDOUS AMOUNT OF IMMUNE

11438
06:39:29,153 --> 06:39:30,254
CELLS IN THE GUT, AND WE FOUND

11439
06:39:30,254 --> 06:39:31,655
THAT THOSE IMMUNE CELLS CAN

11440
06:39:31,655 --> 06:39:33,591
ACTUALLY TRAFFIC TO THE BRAIN AS

11441
06:39:33,591 --> 06:39:37,494
OTHERS HAVE SHOWN, SO WE SEE

11442
06:39:37,494 --> 06:39:38,829
THESE GAMMA-DELTA T-CELLS WHICH

11443
06:39:38,829 --> 06:39:40,231
ARE KIND OF A BRIDGE BETWEEN

11444
06:39:40,231 --> 06:39:43,667
ADAPTIVE AND INNATE IMMUNITY,

11445
06:39:43,667 --> 06:39:45,536
THEY CHANGE WITH THESE GUT

11446
06:39:45,536 --> 06:39:46,537
MANIPULATIONS, AND THEN THOSE

11447
06:39:46,537 --> 06:39:48,906
CAN TRAP TO THE BRAIN AND I

11448
06:39:48,906 --> 06:39:50,708
DIDN'T SHOW ANY OF THIS DATA

11449
06:39:50,708 --> 06:39:53,010
BECAUSE IT WAS A SHORT TALK, BUT

11450
06:39:53,010 --> 06:39:55,012
WE FOUND CHANGES IN MOSTLY

11451
06:39:55,012 --> 06:39:57,648
T-CELL POPULATIONS, T REGS AND

11452
06:39:57,648 --> 06:39:59,016
GAMMA-DELTA T-CELLS, AND ONE OF

11453
06:39:59,016 --> 06:40:00,384
THE OTHER THINGS WE'VE SEEN IN

11454
06:40:00,384 --> 06:40:02,519
THE BRAIN WITH AGING, THIS IS

11455
06:40:02,519 --> 06:40:04,755
NOT WITH STROKE, BUT IN ANIMAL

11456
06:40:04,755 --> 06:40:05,723
MODELS OF ALZHEIMER'S AND EVEN

11457
06:40:05,723 --> 06:40:08,192
IN OUR HUMAN, WE HAVE A LARGE

11458
06:40:08,192 --> 06:40:09,860
HUMAN BRAIN BANK SO WE DO A LOT

11459
06:40:09,860 --> 06:40:12,730
OF MICROGLIA ASSESSMENT IN THESE

11460
06:40:12,730 --> 06:40:17,001
AGED HUMAN BRAINS AS WELL.

11461
06:40:17,001 --> 06:40:19,303
AND WE'VE FOWNDZ THERE'S THESE

11462
06:40:19,303 --> 06:40:20,838
REALLY PRONOUNCED PRO

11463
06:40:20,838 --> 06:40:21,705
INFLAMMATORY CHANGES OVER THE

11464
06:40:21,705 --> 06:40:23,574
LIFE THAT SEEM TO GET

11465
06:40:23,574 --> 06:40:24,174
ACCELERATED WITH ANY TYPE OF

11466
06:40:24,174 --> 06:40:25,909
INJURY, WHETHER IT'S A TBI, A

11467
06:40:25,909 --> 06:40:28,012
STROKE, IT REALLY SEEMS TO

11468
06:40:28,012 --> 06:40:28,979
ACCELERATE THE SENESCENCE THAT

11469
06:40:28,979 --> 06:40:32,283
YOU SEE THAT'S KIND OF THAT

11470
06:40:32,283 --> 06:40:35,753
BASAL INFLAMMAGING, YOU GIVE IT

11471
06:40:35,753 --> 06:40:36,954
AN INSULT AND KIND OF THE GATES

11472
06:40:36,954 --> 06:40:37,388
OPEN.

11473
06:40:37,388 --> 06:40:39,923
AND WITH AGING IN THE BRAIN, YOU

11474
06:40:39,923 --> 06:40:43,160
SEE A LOT MORE T AND B CELLS.

11475
06:40:43,160 --> 06:40:45,729
WE THINK THE B CELLS ARE VERY

11476
06:40:45,729 --> 06:40:51,368
IMPORTANT FOR COGNITION, WE ALSO

11477
06:40:51,368 --> 06:40:52,936
SAW -- COVID THAT HAVE COGNITIVE

11478
06:40:52,936 --> 06:40:55,739
IMPAIRTS SO WE THINK THOSE B

11479
06:40:55,739 --> 06:40:57,441
CELLS MAY BE DOING SOMETHING.

11480
06:40:57,441 --> 06:40:58,842
SO RIGHT NOW WE'RE DEPLETING THE

11481
06:40:58,842 --> 06:41:00,244
B CELLS USING A FEW DIFFERENT

11482
06:41:00,244 --> 06:41:01,879
MODELS.

11483
06:41:01,879 --> 06:41:02,746
B CELL DEPLETION THERAPIES ARE

11484
06:41:02,746 --> 06:41:05,382
AVAILABLE BECAUSE OF MULTIPLE

11485
06:41:05,382 --> 06:41:07,851
SCLEROSIS AND OTHER AUTOIMMUNE

11486
06:41:07,851 --> 06:41:08,118
DISEASES.

11487
06:41:08,118 --> 06:41:10,120
SO IT'S REALLY INTERESTING.

11488
06:41:10,120 --> 06:41:11,121
HAVEN'T PUT ALL THE DOTS

11489
06:41:11,121 --> 06:41:13,123
TOGETHER AND IT'S HARD TO KNOW

11490
06:41:13,123 --> 06:41:13,891
BECAUSE WITH THE BIOME, THAT'S

11491
06:41:13,891 --> 06:41:15,426
THE BOTTOMS-UP SIGNALING, THE

11492
06:41:15,426 --> 06:41:17,661
GUT TO THE BRAIN, BUT THE BRAIN

11493
06:41:17,661 --> 06:41:19,096
ALSO COMPLETELY CONTROLS THE

11494
06:41:19,096 --> 06:41:19,430
GUT.

11495
06:41:19,430 --> 06:41:21,298
YOU GIVE A STERILE STROKE INJURY

11496
06:41:21,298 --> 06:41:24,435
AND WITHIN SIX HOURS, THE GUT IS

11497
06:41:24,435 --> 06:41:24,735
DEVASTATED.

11498
06:41:24,735 --> 06:41:28,405
IT'S LEAKY, THE BACTERIA START

11499
06:41:28,405 --> 06:41:30,140
TO TRAFFIC IN, SO THAT'S GOT TO

11500
06:41:30,140 --> 06:41:31,942
BE -- IT COULD BE A HUMERAL

11501
06:41:31,942 --> 06:41:33,744
SIGNAL BUT WE THINK A LOT OF IT

11502
06:41:33,744 --> 06:41:36,146
IS MEDIATED BY THE VAGAL NERVE.

11503
06:41:36,146 --> 06:41:40,084
THE PROBLEM IS DOING VAGOTOMIES,

11504
06:41:40,084 --> 06:41:43,053
YOU HAVE TO DO SUBDIE A FRAG

11505
06:41:43,053 --> 06:41:44,822
MATIC, BUT WE'VE SHOWN A STROKE

11506
06:41:44,822 --> 06:41:46,757
ALSO REALLY SLOWS DOWN GUT

11507
06:41:46,757 --> 06:41:47,624
TRANSIT TIME.

11508
06:41:47,624 --> 06:41:51,028
AND THAT MAY ALLOW MORE OF THOSE

11509
06:41:51,028 --> 06:41:52,129
HARMFUL BACTERIA TO CROSS THIS

11510
06:41:52,129 --> 06:41:53,464
IMPAIRED BARRIER WITH AGING OR

11511
06:41:53,464 --> 06:41:56,567
WITH STROKE, AND THAT'S A BIG

11512
06:41:56,567 --> 06:41:58,535
COMPLAINT IN PATIENTS AS WELL.

11513
06:41:58,535 --> 06:42:00,671
ONE OF THE BIGGEST SYMPTOMS IS

11514
06:42:00,671 --> 06:42:01,505
CONS TA PAITION.

11515
06:42:01,505 --> 06:42:04,675
SO THEN THEY CAN GET THIS

11516
06:42:04,675 --> 06:42:05,576
BACTERIAL OVERGROWTH SYNDROME SO

11517
06:42:05,576 --> 06:42:06,777
WE THINK THE BRAIN CONTROLS THE

11518
06:42:06,777 --> 06:42:08,212
GUT MOTILITY AS WELL AND THEN

11519
06:42:08,212 --> 06:42:10,147
THE GUT FEEDS BACK TO THE BRAIN.

11520
06:42:10,147 --> 06:42:12,249
THERE'S ALSO A LIVER AND AN

11521
06:42:12,249 --> 06:42:12,916
ADIPOSE CONNECTION TOO.

11522
06:42:12,916 --> 06:42:15,219
SO IT'S ALL MORE COMPLICATED

11523
06:42:15,219 --> 06:42:16,887
THAN JUST ME KILLING OLD MICE.

11524
06:42:16,887 --> 06:42:18,322
LIKE, I KIND OF WENT DOWN THE

11525
06:42:18,322 --> 06:42:20,524
RABBIT HOLE, BUT IT'S VERY

11526
06:42:20,524 --> 06:42:21,525
INTERESTING AND PROBABLY ALSO

11527
06:42:21,525 --> 06:42:22,659
RELEVANT FOR ALZHEIMER'S

11528
06:42:22,659 --> 06:42:25,262
DISEASE, BECAUSE A LOT OF THESE

11529
06:42:25,262 --> 06:42:29,233
BACTERIA CAN PRODUCE THINGS

11530
06:42:29,233 --> 06:42:34,605
CALLED CURLIE WHICH ARE LIKE

11531
06:42:34,605 --> 06:42:35,205
SEEDS.

11532
06:42:35,205 --> 06:42:38,108
IN PARKINSON'S YOU SEE

11533
06:42:38,108 --> 06:42:44,415
CONSTIPATION, THE ALPHA

11534
06:42:44,415 --> 06:42:46,717
SYNUCLEIN PROAT NOP THEE CAN

11535
06:42:46,717 --> 06:42:48,886
START IN THE GUT, BUT THEN

11536
06:42:48,886 --> 06:42:51,188
TRAVELED BY THE VAGAL NERVE OR

11537
06:42:51,188 --> 06:43:01,632
SOMEHOW GET ADDRESSING THE

11538
06:43:19,216 --> 06:43:23,520
QUESTION TO?

11539
06:43:23,520 --> 06:43:26,156
>> I'M FROM NATIONAL
INSTITUTE

11540
06:43:26,156 --> 06:43:27,724
ON AGING.

11541
06:43:27,724 --> 06:43:28,392
HI, EVERYONE.

11542
06:43:28,392 --> 06:43:29,159
FANTASTIC TALKS.

11543
06:43:29,159 --> 06:43:31,628
SO QUESTION TO LOUISE.

11544
06:43:31,628 --> 06:43:35,699
SO WE PREVIOUSLY REPORTED THAT

11545
06:43:35,699 --> 06:43:38,168
WHEN IN AGING, OF COURSE

11546
06:43:38,168 --> 06:43:44,174
DYSBIOSIS AND SO OH, WE F ON, WD

11547
06:43:44,174 --> 06:43:46,443
ONE INTERESTING MICROBE --

11548
06:43:46,443 --> 06:43:57,221
DECREASES IN AGING, BUT THE AG 

11549
06:44:05,295 --> 06:44:07,097
WHAT -- PRIMARILY THROUGH

11550
06:44:07,097 --> 06:44:09,366
MONOCYTES, THEY WERE ACTIVATING

11551
06:44:09,366 --> 06:44:10,133
B CELLS.

11552
06:44:10,133 --> 06:44:15,138
AND SPEAKING ABOUT -- ACTUALLY

11553
06:44:15,138 --> 06:44:16,206
WE PUBLISHED LAST YEAR OR TWO

11554
06:44:16,206 --> 06:44:18,775
YEARS AGO NOW THAT B CELLS

11555
06:44:18,775 --> 06:44:22,379
ACTUALLY PLAY SIGNIFICANT ROLE

11556
06:44:22,379 --> 06:44:23,914
IN ALZHEIMER'S DISEASE IF YOU

11557
06:44:23,914 --> 06:44:25,682
REMOVE B CELLS, THEN ALZHEIMER'S

11558
06:44:25,682 --> 06:44:29,887
DISEASE STARTS PROGRESSING, SO

11559
06:44:29,887 --> 06:44:32,189
QUESTION FOR YOU IS THAT HAVE

11560
06:44:32,189 --> 06:44:37,961
YOU LOOKED TO -- BECAUSE --

11561
06:44:37,961 --> 06:44:39,930
ACTUALLY PROMOTES THE SURVIVAL

11562
06:44:39,930 --> 06:44:41,231
OF SHORT CHAIN PRODUCER

11563
06:44:41,231 --> 06:44:42,633
MICROBES.

11564
06:44:42,633 --> 06:44:45,202
>> IT'S A HUGE TARGET OF
HOURS.

11565
06:44:45,202 --> 06:44:48,906
WOF OURS.WE'RE DOING A SUPPLEMEN

11566
06:44:48,906 --> 06:44:51,108
STUDY IN SOCIALLY ISOLATED

11567
06:44:51,108 --> 06:44:51,341
ANIMALS.

11568
06:44:51,341 --> 06:44:51,975
YOU GUYS HEARD THIS IS ANOTHER

11569
06:44:51,975 --> 06:44:53,310
AREA WE DO IN THE LAB, IS

11570
06:44:53,310 --> 06:44:55,746
LOOKING AT THE DETRIMENTAL

11571
06:44:55,746 --> 06:44:56,313
EFFECTS OF SOCIAL ISOLATION

11572
06:44:56,313 --> 06:44:57,080
WHICH ARE VERY BIOLOGICAL.

11573
06:44:57,080 --> 06:44:58,181
IT'S NOT EVEN LIKE COMPLIANCE.

11574
06:44:58,181 --> 06:45:01,451
IF YOU SEPARATE TWO C57 BLACK

11575
06:45:01,451 --> 06:45:03,053
MICE FOR TWO WEEKS, THEIR

11576
06:45:03,053 --> 06:45:05,255
STROKES ARE TWICE AS LARGE.

11577
06:45:05,255 --> 06:45:08,025
EVEN IF YOU SEPARATE THEM AFTER

11578
06:45:08,025 --> 06:45:10,260
STROKE, THEIR MORTALITY

11579
06:45:10,260 --> 06:45:11,428
INCREASES AND WE FOUND THAT WAS

11580
06:45:11,428 --> 06:45:14,064
LINKED TO METABOLIC DYSFUNCTION

11581
06:45:14,064 --> 06:45:18,302
AND A LOSS OF -- IT'S ALSO MUCUS

11582
06:45:18,302 --> 06:45:19,303
DEGRADER.

11583
06:45:19,303 --> 06:45:21,138
SO WE SMARTLY WE'RE LIKE OH,

11584
06:45:21,138 --> 06:45:23,373
LET'S GIVE SOMETHING, THERE'S

11585
06:45:23,373 --> 06:45:27,544
THIS THING CALLED KAMU KAMU

11586
06:45:27,544 --> 06:45:29,947
WHICH THEY USE IN SOUTH AMERICA,

11587
06:45:29,947 --> 06:45:31,648
IT'S LIKE A PRO LONGEVITY THING,

11588
06:45:31,648 --> 06:45:33,884
SO WE SAID LET'S GIVE TO OUR

11589
06:45:33,884 --> 06:45:35,886
AGED MICE AND SEE WHAT HAPPENS.

11590
06:45:35,886 --> 06:45:38,488
IT TURNS OUT IT CAUSED THIS

11591
06:45:38,488 --> 06:45:40,357
DRAMATIC BLOOM AND WE WERE DOING

11592
06:45:40,357 --> 06:45:45,862
16S SEQUENTIALLY, AND THE BLOOM

11593
06:45:45,862 --> 06:45:48,065
PRECEDED DEATH IN THE MICE.

11594
06:45:48,065 --> 06:45:49,566
SO YOU HAVE TO BE VERY CAUTIOUS

11595
06:45:49,566 --> 06:45:51,568
IS WE GOT IT BLOOM, IT ATE ALL

11596
06:45:51,568 --> 06:45:53,637
THE MUCOUS, AND THEN THE ANIMALS

11597
06:45:53,637 --> 06:45:56,006
ALL GOT SEPTIC AND DIED.

11598
06:45:56,006 --> 06:45:56,506
SO I THINK WHENEVER YOU

11599
06:45:56,506 --> 06:45:57,140
MANIPULATE THE BIOME, YOU HAVE

11600
06:45:57,140 --> 06:45:58,642
TO BE VERY CAUTIOUS BECAUSE

11601
06:45:58,642 --> 06:46:02,045
THERE'S SO MANY DOWNSTREAM

11602
06:46:02,045 --> 06:46:02,646
EFFECTS THAT WE'RE NOT REALLY

11603
06:46:02,646 --> 06:46:03,880
YOU AWARE.

11604
06:46:03,880 --> 06:46:05,949
BUT ACT MAN'S YA IS A REALLY

11605
06:46:05,949 --> 06:46:08,752
IMPORTANT TARGET FOR METABOLIC

11606
06:46:08,752 --> 06:46:09,386
PHENOTYPES AS WELL SO WE'LL SEE

11607
06:46:09,386 --> 06:46:11,355
HOW THAT NEW STUDY GOES, THEN

11608
06:46:11,355 --> 06:46:13,590
ALSO MAKING SURE YOU CAN DELIVER

11609
06:46:13,590 --> 06:46:14,591
EITHER THE BACTERIA OR THE

11610
06:46:14,591 --> 06:46:15,692
METABOLITES THAT THEY PRODUCE TO

11611
06:46:15,692 --> 06:46:16,893
THE RIGHT AREA OF THE GUT IS

11612
06:46:16,893 --> 06:46:19,830
GOING TO BE ANOTHER CHALLENGE.

11613
06:46:19,830 --> 06:46:21,898
BUT I ACTUALLY AM SENDING TO THE

11614
06:46:21,898 --> 06:46:25,202
NIA A WHOLE COHORT OF TWO TO

11615
06:46:25,202 --> 06:46:26,570
FOUR MONTH, 12 MONTH, 18 MONTH

11616
06:46:26,570 --> 06:46:29,072
AND 24 MONTH WILD TYPE AND

11617
06:46:29,072 --> 06:46:33,844
GERM-FREE MOUSE BRAINS TO DO

11618
06:46:33,844 --> 06:46:34,478
SOME SEQUENCING, SO MAYBE WE'LL

11619
06:46:34,478 --> 06:46:40,751
GET SOME IDEAS FROM THAT DATA.

11620
06:46:40,751 --> 06:46:42,986
PATTY, SORRY, GO AHEAD.

11621
06:46:42,986 --> 06:46:43,820
>> SORRY.

11622
06:46:43,820 --> 06:46:45,455
LOUISE, I THINK THAT REALLY GOES

11623
06:46:45,455 --> 06:46:48,825
TO THE ENTIRE CONCEPT OF IS

11624
06:46:48,825 --> 06:46:50,594
AGING OR AT LEAST DYSFUNCTIONAL

11625
06:46:50,594 --> 06:46:52,062
AGING OR THE CHRONIC DISEASES

11626
06:46:52,062 --> 06:46:57,934
ASSOCIATED WITH AGING, REALLY

11627
06:46:57,934 --> 06:47:02,906
KIND OF THEMATICALLY LINKED BY

11628
06:47:02,906 --> 06:47:03,140
ENTROPY.

11629
06:47:03,140 --> 06:47:06,576
IT IS THIS INCREASING CHAOS OR

11630
06:47:06,576 --> 06:47:07,244
RANDOMNESS OR DISORDER AT LEAST

11631
06:47:07,244 --> 06:47:10,447
IN PHYSICS, BUT BIOLOGICALLY,

11632
06:47:10,447 --> 06:47:12,716
WHAT REALLY MAKES SENSE IS THAT

11633
06:47:12,716 --> 06:47:16,420
ENTRY INCREASES WITH TIME AND IN

11634
06:47:16,420 --> 06:47:16,953
ISOLATED SYSTEM.

11635
06:47:16,953 --> 06:47:20,557
SO IF YOU HAVE A MOUSE OR A

11636
06:47:20,557 --> 06:47:23,293
PERSON WHO IS ISOLATED AND WE

11637
06:47:23,293 --> 06:47:23,894
ALREADY KNOW FROM THE HARVARD

11638
06:47:23,894 --> 06:47:25,162
STUDY THAT SOCIAL ISOLATION IS

11639
06:47:25,162 --> 06:47:29,032
KIND OF ONE OF THE BIGGEST

11640
06:47:29,032 --> 06:47:29,633
PREDICTORS OF ACCELERATED

11641
06:47:29,633 --> 06:47:32,436
NEUROCOGNITIVE DECLINE AND

11642
06:47:32,436 --> 06:47:34,738
DEATH, THAT PERHAPS THAT'S WHERE

11643
06:47:34,738 --> 06:47:37,674
THERE'S SOME MECHANISM AS TO WHY

11644
06:47:37,674 --> 06:47:40,444
IS IT THAT SOCIAL ISOLATION FOR

11645
06:47:40,444 --> 06:47:41,878
A SINGLE -- BECAUSE WE ARE

11646
06:47:41,878 --> 06:47:45,315
SOCIAL BEINGS, WHY IS THIS

11647
06:47:45,315 --> 06:47:47,718
ISOLATION -- ALL THESE

11648
06:47:47,718 --> 06:47:50,454
DOWNSTREAM EFFECTS OF

11649
06:47:50,454 --> 06:47:51,021
NEUROCOGNITION, METABOLISM,

11650
06:47:51,021 --> 06:47:51,755
IMMUNE DEFICIENCIES, RIGHT?

11651
06:47:51,755 --> 06:47:53,557
>> I MEAN, IT'S
FASCINATING.

11652
06:47:53,557 --> 06:47:55,092
SOCIAL ISOLATION AND THE

11653
06:47:55,092 --> 06:47:56,526
SUBJECTIVE FEELING OF LONELINESS

11654
06:47:56,526 --> 06:47:58,862
WHICH OF COURSE YOU CAN'T GET IN

11655
06:47:58,862 --> 06:48:00,664
ANIMAL MODELS BUT YOU CAN IN

11656
06:48:00,664 --> 06:48:02,299
HUMANS COMPLETELY CHANGES THE

11657
06:48:02,299 --> 06:48:02,766
BIOME.

11658
06:48:02,766 --> 06:48:05,235
WHEN WE GET FECAL SAMPLES FROM

11659
06:48:05,235 --> 06:48:07,003
OUR PATIENTS AS WELL AS --

11660
06:48:07,003 --> 06:48:09,106
SOCIAL NETWORK SCORES AND UCLA

11661
06:48:09,106 --> 06:48:11,808
SCORES AND THERE'S DEFINITELY A

11662
06:48:11,808 --> 06:48:13,744
PATHOGENIC SHIFT IF PEOPLE FEEL

11663
06:48:13,744 --> 06:48:16,379
OR REPORT LONELINESS.

11664
06:48:16,379 --> 06:48:19,015
I THINK IT'S KIND OF AN

11665
06:48:19,015 --> 06:48:21,985
OVERARCHING THING, BUT THE WHOLE

11666
06:48:21,985 --> 06:48:23,620
ISSUE IS WHAT DO THESE THINGS

11667
06:48:23,620 --> 06:48:24,621
MEAN.

11668
06:48:24,621 --> 06:48:26,490
ARE THE REASON WE HAVE SENESCENT

11669
06:48:26,490 --> 06:48:29,192
CELLS, DO WE HAVE TO HAVE

11670
06:48:29,192 --> 06:48:30,761
SENESCENT CELLS TO SURVIVE IN

11671
06:48:30,761 --> 06:48:32,629
PROBABLY NOT, LOOKING AT

11672
06:48:32,629 --> 06:48:34,164
DR. KIRKLAND'S AND DR. ROBBINS'

11673
06:48:34,164 --> 06:48:36,032
WORK, BUT IT'S INTERESTING

11674
06:48:36,032 --> 06:48:36,666
BECAUSE THE SYSTEM ALWAYS TRIES

11675
06:48:36,666 --> 06:48:40,070
TO MAINTAIN HOMEOSTASIS.

11676
06:48:40,070 --> 06:48:43,473
SO I'M JUST NOT SURE, BUT SOCIAL

11677
06:48:43,473 --> 06:48:45,675
ISOLATION DEFINITELY DISTURBING

11678
06:48:45,675 --> 06:48:48,945
HOMEOSTASIS, BOTH MICROGLIA GET

11679
06:48:48,945 --> 06:48:51,014
ACTIVATED, ALL THESE IMMUNE

11680
06:48:51,014 --> 06:48:54,184
CHANGES, HOW IT'S MEDIATED, I'M

11681
06:48:54,184 --> 06:48:55,252
NOT SURE, BUT IT DEFINITELY

11682
06:48:55,252 --> 06:49:00,423
CHANGES THE BIOME AS WELL.

11683
06:49:00,423 --> 06:49:03,760
>>  -- JUST SAID YOU COULD

11684
06:49:03,760 --> 06:49:04,628
EXPERIMENTALLY REPRODUCE

11685
06:49:04,628 --> 06:49:07,097
ISOLATION.

11686
06:49:07,097 --> 06:49:09,432
>> AND THEY HAVE TO FEEL

11687
06:49:09,432 --> 06:49:11,468
SOCIALLY ISOLATED BECAUSE

11688
06:49:11,468 --> 06:49:12,769
PATIENTS, IF THEY DON'T FEEL

11689
06:49:12,769 --> 06:49:15,305
SOCIALLY ISOLATED, ARE NOT GOING

11690
06:49:15,305 --> 06:49:17,641
TO HAVE THAT DETRIMENTAL

11691
06:49:17,641 --> 06:49:17,908
PHENOTYPE.

11692
06:49:17,908 --> 06:49:20,777
THEY HAVE TO FEEL SUBJECTIVELY

11693
06:49:20,777 --> 06:49:22,045
LONELY OR DISCONNECTED.

11694
06:49:22,045 --> 06:49:24,347
LOTS OF PEOPLE LIVE ALONE AND

11695
06:49:24,347 --> 06:49:25,081
THEY'RE HAPPY TO LIVE ALONE.

11696
06:49:25,081 --> 06:49:26,917
SO THAT'S WHY YOU HAVE TO BE

11697
06:49:26,917 --> 06:49:29,786
PRETTY CAUTIOUS ABOUT USING LIKE

11698
06:49:29,786 --> 06:49:31,121
MARITAL STATUS OR -- BUT IT'S

11699
06:49:31,121 --> 06:49:32,756
SUPER BIOLOGICAL BECAUSE YOU CAN

11700
06:49:32,756 --> 06:49:34,791
RECAPITULATE IT IN ANIMALS THAT

11701
06:49:34,791 --> 06:49:35,559
ARE OF THE SAME GENETIC

11702
06:49:35,559 --> 06:49:36,793
BACKGROUND, FED THE SAME THING,

11703
06:49:36,793 --> 06:49:37,727
AND THEN THE OTHER THING IS,

11704
06:49:37,727 --> 06:49:41,765
WHEN YOU JUST ROOK  LOOK AT MIC,

11705
06:49:41,765 --> 06:49:44,501
THERE'S BEEN QUESTIONS ABOUT THE

11706
06:49:44,501 --> 06:49:45,101
ACTUAL DIET AND THE SPF.

11707
06:49:45,101 --> 06:49:46,570
WHAT'S INTERESTING IS IF YOU

11708
06:49:46,570 --> 06:49:49,239
LOOK AT THE BIOME IN A TWO

11709
06:49:49,239 --> 06:49:50,207
MONTH, SIX MONTH, 18 MONTH, THE

11710
06:49:50,207 --> 06:49:51,508
BIOME CHANGES, NOTHING ELSE

11711
06:49:51,508 --> 06:49:52,642
CHANGES IN THESE ANIMALS,

11712
06:49:52,642 --> 06:49:55,078
THEY'RE STILL HOUSED THE SAME,

11713
06:49:55,078 --> 06:49:55,745
THEY'RE STILL FED THE SAME CHOW,

11714
06:49:55,745 --> 06:49:57,080
SO THERE'S GOT TO BE A HOST

11715
06:49:57,080 --> 06:50:02,219
FACTOR THAT ALLOWS THAT MORE

11716
06:50:02,219 --> 06:50:03,987
PATHOGENIC DYSBIOTIC BIOME TO

11717
06:50:03,987 --> 06:50:05,522
TAKE HOLD AND KIND OF CONTINUE.

11718
06:50:05,522 --> 06:50:10,393
SO IT CAN'T ALL BE JUST BIOME

11719
06:50:10,393 --> 06:50:10,627
DRIVEN.

11720
06:50:10,627 --> 06:50:11,261
THERE'S OBVIOUSLY HOST FACTORS

11721
06:50:11,261 --> 06:50:14,564
THAT ARE GOING TO ENRICH FOR

11722
06:50:14,564 --> 06:50:20,804
MORE PATHOGENIC BACTERIA.

11723
06:50:20,804 --> 06:50:21,404
OKAY.

11724
06:50:21,404 --> 06:50:26,977
SORRY I'M JUGGLING.

11725
06:50:26,977 --> 06:50:29,145
>> IT WAS A NICE SEGUE
BECAUSE

11726
06:50:29,145 --> 06:50:31,181
COMING FROM THE CENTER TO REDUCE

11727
06:50:31,181 --> 06:50:31,982
CANCER AND HEALTH DISPARITIES,

11728
06:50:31,982 --> 06:50:38,021
SO WE HAVE TO LOOK INTO THE

11729
06:50:38,021 --> 06:50:38,521
RACIAL/ETHNIC DIVERSITY

11730
06:50:38,521 --> 06:50:39,155
PROPORTION AND THIS QUESTION IS

11731
06:50:39,155 --> 06:50:39,689
ESSENTIALLY FOR ALL THE

11732
06:50:39,689 --> 06:50:40,023
PANELISTS.

11733
06:50:40,023 --> 06:50:44,527
OF SO HAVE WE LOOKED INTO

11734
06:50:44,527 --> 06:50:45,195
VARIOUS ASPECTS OF BIOLOGICAL

11735
06:50:45,195 --> 06:50:49,432
VERSUS CHRONOLOGICAL AGING AMONG

11736
06:50:49,432 --> 06:50:51,468
VARIOUS RACIAL/ETHNIC GREUNS,

11737
06:50:51,468 --> 06:50:57,874
ANDGROUPS ANDDOES IT CORRELATE E

11738
06:50:57,874 --> 06:51:00,677
AGGRESSIVE EARLY ONSET DISEASES.

11739
06:51:00,677 --> 06:51:02,612
CANCER, WE SEE VERY AGGRESSIVE

11740
06:51:02,612 --> 06:51:03,713
PROSTATE CANCER AMONG AFRICAN

11741
06:51:03,713 --> 06:51:06,583
AMERICANS, THE INTENSITY, THE

11742
06:51:06,583 --> 06:51:08,885
PROGRESSION AND METASTASES

11743
06:51:08,885 --> 06:51:09,519
VARIES WITH THE VARIOUS RACIAL

11744
06:51:09,519 --> 06:51:11,488
AND ETHNIC POPULATION GROUPS.

11745
06:51:11,488 --> 06:51:14,190
IS IT TIED UP WITH SOCIAL

11746
06:51:14,190 --> 06:51:15,892
DETERMINANTS OF HEALTH?

11747
06:51:15,892 --> 06:51:19,429
DOES THE DIET, EXERCISE AND ALL

11748
06:51:19,429 --> 06:51:22,265
THOSE FACTORS AFFECT THE

11749
06:51:22,265 --> 06:51:23,934
CLINICAL MANIFESTATION OF

11750
06:51:23,934 --> 06:51:29,306
DISEASE AND CLINICAL OUTCOMES?

11751
06:51:29,306 --> 06:51:30,640
LONG WINDED QUESTION BUT PLEASE

11752
06:51:30,640 --> 06:51:31,474
PITCH IN, EVERYONE.

11753
06:51:31,474 --> 06:51:33,376
>> WELL, I WOULD JUMP IN
AND SAY

11754
06:51:33,376 --> 06:51:36,579
THAT DEPENDING ON YOUR ZIP CODE,

11755
06:51:36,579 --> 06:51:39,349
YOU CAN BE MUCH BIOLOGICALLY

11756
06:51:39,349 --> 06:51:42,018
OLDER THAN OTHER GROUPS.

11757
06:51:42,018 --> 06:51:43,620
SO I HAVE HEARD FROM CLINICIANS

11758
06:51:43,620 --> 06:51:45,956
THAT YOUR ZIP CODE IS THE BEST

11759
06:51:45,956 --> 06:51:48,525
PREDICTOR OF HOW YOU'RE GOING TO

11760
06:51:48,525 --> 06:51:49,759
LIVE, BETTER THAN YOUR

11761
06:51:49,759 --> 06:51:51,461
HEMOGLOBIN A1C OR ANYTHING ELSE,

11762
06:51:51,461 --> 06:51:53,830
WHICH IS SHOCKING AND APPALLING

11763
06:51:53,830 --> 06:51:56,299
ACTUALLY.

11764
06:51:56,299 --> 06:51:58,268
>> ACTUALLY, LAURA,
THERE'S DATA

11765
06:51:58,268 --> 06:52:00,437
TO SUPPORT THAT.

11766
06:52:00,437 --> 06:52:02,706
SO I RECENTLY -- I'M A

11767
06:52:02,706 --> 06:52:03,673
"NEW YORKER" FROM A LONG TIME

11768
06:52:03,673 --> 06:52:05,542
AGO BUT I WAS AWAY.

11769
06:52:05,542 --> 06:52:07,811
HAVING MOVED BACK TO NEW YORK,

11770
06:52:07,811 --> 06:52:08,979
THERE ARE THESE STUDIES, THESE

11771
06:52:08,979 --> 06:52:10,313
EPIDEMIOLOGIC STUDIES, PUBLIC

11772
06:52:10,313 --> 06:52:12,983
HEALTH AND EPIDEMIOLOGIC STUDIES

11773
06:52:12,983 --> 06:52:14,184
GOING ON LOOKING AT WHO THE

11774
06:52:14,184 --> 06:52:15,952
LONGEST LIVED ARE, IN WOMEN,

11775
06:52:15,952 --> 06:52:20,156
WITHIN WOMEN, AND IT WAS BY ZIP

11776
06:52:20,156 --> 06:52:20,357
CODE.

11777
06:52:20,357 --> 06:52:22,258
IT WAS BY ZIP CODE IN A VERY

11778
06:52:22,258 --> 06:52:23,793
SPECIFIC AREA IN NEW JERSEY OF

11779
06:52:23,793 --> 06:52:25,795
ALL PLACES.

11780
06:52:25,795 --> 06:52:27,931
IT WASN'T THE HAMPTONS, IT

11781
06:52:27,931 --> 06:52:28,365
WASN'T WESTCHESTER.

11782
06:52:28,365 --> 06:52:31,001
IT WAS NEW JERSEY.

11783
06:52:31,001 --> 06:52:32,335
SO THERE'S ACTUALLY DATA TO

11784
06:52:32,335 --> 06:52:35,105
SUPPORT THAT.

11785
06:52:35,105 --> 06:52:35,805
ANIL, I THINK YES TO ALL YOUR

11786
06:52:35,805 --> 06:52:36,873
QUESTIONS, ALL THOSE SOCIAL

11787
06:52:36,873 --> 06:52:38,708
DETERMINANTS OF HEALTH,

11788
06:52:38,708 --> 06:52:42,312
LIFESTYLE, I THINK THEY

11789
06:52:42,312 --> 06:52:43,646
ABSOLUTELY OVERRIDE SOME OF WHAT

11790
06:52:43,646 --> 06:52:45,915
WE UNDERSTAND AS BEING IMPORTANT

11791
06:52:45,915 --> 06:52:46,249
BIOLOGY.

11792
06:52:46,249 --> 06:52:49,052
IT'S JUST A MATTER OF HOW THEY

11793
06:52:49,052 --> 06:52:51,788
INTERACT AND HOW DO YOU START

11794
06:52:51,788 --> 06:52:53,323
TEASING APART WHAT THE RELATIVE

11795
06:52:53,323 --> 06:52:55,959
CONTRIBUTIONS ARE THAT IT GETS

11796
06:52:55,959 --> 06:52:58,595
VERY, VERY COMPLICATED.

11797
06:52:58,595 --> 06:52:59,996
BUT AGING AND HUMAN BIOLOGY IS

11798
06:52:59,996 --> 06:53:01,431
VERY COMPLICATED.

11799
06:53:01,431 --> 06:53:05,769
I THINK A BIG LIMITATION OF

11800
06:53:05,769 --> 06:53:06,403
THESE CLINICAL TRIALS WHICH ARE

11801
06:53:06,403 --> 06:53:07,070
REALLY IMPORTANT TO ANSWER SOME

11802
06:53:07,070 --> 06:53:11,107
OF THESE QUESTIONS IS A PROBLEM,

11803
06:53:11,107 --> 06:53:13,510
BECAUSE LESS THAN 5% OF AFRICAN

11804
06:53:13,510 --> 06:53:18,381
AMERICANS JOINED CLIN

11805
06:53:43,473 --> 06:53:44,808
SO WE HAVE TO IMPROVE

11806
06:53:44,808 --> 06:53:46,342
REPRESENTATION IN OUR CLINICAL

11807
06:53:46,342 --> 06:53:48,411
TRIALS.

11808
06:53:48,411 --> 06:53:49,179
ALZHEIMER'S, FOR EXAMPLE, IS A

11809
06:53:49,179 --> 06:53:50,246
MUCH MORE SIGNIFICANT DISEASE IN

11810
06:53:50,246 --> 06:53:51,247
WOMEN AND PEOPLE USED TO THINK

11811
06:53:51,247 --> 06:53:54,951
IT WAS JUST THEIR LONGEVITY.

11812
06:53:54,951 --> 06:53:55,385
BUT IT'S NOT.

11813
06:53:55,385 --> 06:53:58,688
AND STROKE IS ANOTHER EXAMPLE.

11814
06:53:58,688 --> 06:53:59,756
MOSTLY DRIVEN BY THE OLDER AGE

11815
06:53:59,756 --> 06:54:02,125
THAT WOMEN HAVE THEIR FIRST

11816
06:54:02,125 --> 06:54:02,759
STROKE, BUT I THINK IT'S VERY

11817
06:54:02,759 --> 06:54:03,226
IMPORTANT.

11818
06:54:03,226 --> 06:54:04,227
AND THE SOCIAL DETERMINANTS OF

11819
06:54:04,227 --> 06:54:05,428
HEALTH ARE VERY DIFFICULT TO

11820
06:54:05,428 --> 06:54:08,164
KIND OF UNRAVEL, AND THEY'RE

11821
06:54:08,164 --> 06:54:10,700
OBVIOUSLY HARDER TO MODEL IN

11822
06:54:10,700 --> 06:54:12,001
PRE-CLINICAL STUDIES.

11823
06:54:12,001 --> 06:54:15,438
I JUST WANTED TO ANSWER ONE

11824
06:54:15,438 --> 06:54:16,072
QUESTION BECAUSE THEY TEXTED ME

11825
06:54:16,072 --> 06:54:17,507
TO SAY, HAVE I INVESTIGATED

11826
06:54:17,507 --> 06:54:20,143
SHORT CHAIN FATTY ACIDS IN OTHER

11827
06:54:20,143 --> 06:54:20,376
SPECIES?

11828
06:54:20,376 --> 06:54:21,244
YES, INCLUDING HUMANS.

11829
06:54:21,244 --> 06:54:22,445
SO WE KNOW THAT SHORT CHAIN

11830
06:54:22,445 --> 06:54:25,782
FATTY ACIDS CHANGE IN HUMANS

11831
06:54:25,782 --> 06:54:26,216
AFTER STROKE.

11832
06:54:26,216 --> 06:54:28,384
WE'VE BEEN LOOKING AT INDOLES,

11833
06:54:28,384 --> 06:54:30,019
THOSE CHANGE, AND SOME OF THESE

11834
06:54:30,019 --> 06:54:32,689
CHANGE WITH OTHER

11835
06:54:32,689 --> 06:54:33,323
NEURODEGENERATIVE DISEASES, SO

11836
06:54:33,323 --> 06:54:35,692
YES, IT'S PROBABLY NOT JUST A

11837
06:54:35,692 --> 06:54:37,994
MOUSE THING.

11838
06:54:37,994 --> 06:54:40,396
SOME RUMINANTS LIKE WE WERE

11839
06:54:40,396 --> 06:54:41,364
USING A RABBIT MOTTLE, THAT'S

11840
06:54:41,364 --> 06:54:50,507
DIFFICMMODEL, THAT'SDIFFICULT W.

11841
06:54:50,507 --> 06:54:52,742
BUT THEY'RE PRI PRE TI SIMILAR

11842
06:54:52,742 --> 06:54:53,009
PATTERNS.

11843
06:54:53,009 --> 06:54:55,278
>> THERE IS ALSO A COMMENT
FROM

11844
06:54:55,278 --> 06:54:56,246
DR. FERRUCCI, I CAN'T REMEMBER

11845
06:54:56,246 --> 06:54:58,948
WHAT TIME IT IS IN VENICE BUT

11846
06:54:58,948 --> 06:55:00,617
APPARENTLY HE'S ON.

11847
06:55:00,617 --> 06:55:04,187
>> AND ALSO MICHAEL SNYDER
A --

11848
06:55:04,187 --> 06:55:04,988
HAD SOME GOOD COMMENTS.

11849
06:55:04,988 --> 06:55:06,156
>> I'M TRYING TO KEEP UP
WITH

11850
06:55:06,156 --> 06:55:07,624
THE QUESTIONS.

11851
06:55:07,624 --> 06:55:10,927
>> I KNOW, IT'S HARD.

11852
06:55:10,927 --> 06:55:13,129
>> MICHAEL SNYDER SAID
ONLY 16%

11853
06:55:13,129 --> 06:55:15,465
OF LONGEVITY IS EXPLAINED BY

11854
06:55:15,465 --> 06:55:15,732
GENETICS.

11855
06:55:15,732 --> 06:55:17,367
DO YOU WANT TO EXPOUND ON THAT,

11856
06:55:17,367 --> 06:55:19,903
DR. SNYDER?

11857
06:55:19,903 --> 06:55:20,970
>> SURE.

11858
06:55:20,970 --> 06:55:22,572
THERE'S A LOT OF TWIN STUDIES

11859
06:55:22,572 --> 06:55:23,606
OUT THERE THAT HAVE LOOKED AT --

11860
06:55:23,606 --> 06:55:25,275
I DON'T THINK THAT'S HEALTHSPAN,

11861
06:55:25,275 --> 06:55:27,177
I THINK THAT'S HOW LONG PEOPLE

11862
06:55:27,177 --> 06:55:27,377
LIVE.

11863
06:55:27,377 --> 06:55:28,811
BUT THAT'S BASICALLY WHERE THAT

11864
06:55:28,811 --> 06:55:32,615
NUMBER COMES FROM.

11865
06:55:32,615 --> 06:55:35,084
SO CLEARLY NON-GENETIC FACTORS

11866
06:55:35,084 --> 06:55:35,618
HAVE A BIGGER EFFECT THAN

11867
06:55:35,618 --> 06:55:35,885
GENETICS.

11868
06:55:35,885 --> 06:55:37,787
I'M CHAIR OF GENETICS TOO, SO I

11869
06:55:37,787 --> 06:55:37,987
CAN --

11870
06:55:37,987 --> 06:55:40,056
>> THAT'S SAYING
SOMETHING.

11871
06:55:40,056 --> 06:55:41,724
YES, I MEAN, THOSE ENVIRONMENTAL

11872
06:55:41,724 --> 06:55:44,227
FACTORS AND OTHER -- YOU KNOW,

11873
06:55:44,227 --> 06:55:46,696
THE MULTIPLE HITS, AND THEN

11874
06:55:46,696 --> 06:55:47,897
DR. FERRUCCI SAID IN THE

11875
06:55:47,897 --> 06:55:51,034
AUDIENCE, ONE IMPORTANT DETAIL

11876
06:55:51,034 --> 06:55:52,368
SAID IN AGING, THE NORMAL

11877
06:55:52,368 --> 06:55:55,305
CONDITION IS ALLOSTASIS, NOT

11878
06:55:55,305 --> 06:55:57,073
HOMEOSTASIS, TOTALLY CORRECT,

11879
06:55:57,073 --> 06:55:57,740
WHICH IS THE FLUCTUATION WITHIN

11880
06:55:57,740 --> 06:55:58,708
SPECIFIC BOUNDARIES OF

11881
06:55:58,708 --> 06:55:59,442
VARIABILITY.

11882
06:55:59,442 --> 06:56:01,744
THERE'S EVIDENCE THAT

11883
06:56:01,744 --> 06:56:03,780
PSYCHOLOGICAL STRESS COMPRESSES

11884
06:56:03,780 --> 06:56:04,380
EMOTION AND IS ASSOCIATED WITH

11885
06:56:04,380 --> 06:56:05,648
REDUCED CAPACITY TO RESPOND TO

11886
06:56:05,648 --> 06:56:06,182
STRESS.

11887
06:56:06,182 --> 06:56:08,785
AND THAT IS TRUE, I DON'T KNOW

11888
06:56:08,785 --> 06:56:10,587
IF YOU GUYS ALL SAW THE SURGEON

11889
06:56:10,587 --> 06:56:12,222
GENERAL'S REPORT SAYING SOCIAL

11890
06:56:12,222 --> 06:56:16,059
ISOLATION WAS BECOMING A PUBLIC

11891
06:56:16,059 --> 06:56:17,961
HEALTH CRISIS, AND CAN AFFECT SO

11892
06:56:17,961 --> 06:56:19,329
MANY DIFFERENT ASPECTS OF OUR

11893
06:56:19,329 --> 06:56:20,496
HEALTH AND WE'RE BECOMING MORE

11894
06:56:20,496 --> 06:56:24,067
AND MORE SOCIALLY DISCONNECTED.

11895
06:56:24,067 --> 06:56:24,934
DR. FERRUCCI, I DON'T KNOW IF

11896
06:56:24,934 --> 06:56:27,837
YOU WANTED TO ADD ANYTHING ELSE?

11897
06:56:27,837 --> 06:56:30,340
SORRY, I'M TRYING TO KEEP UP.

11898
06:56:30,340 --> 06:56:32,108
>> I THINK HE TO DROP OFF.

11899
06:56:32,108 --> 06:56:33,243
>> OKAY.

11900
06:56:33,243 --> 06:56:35,345
>> SO DR. KIRKLAND HAS HIS
HANDS

11901
06:56:35,345 --> 06:56:36,246
UP.

11902
06:56:36,246 --> 06:56:41,150
AND THEN WE CAN GO TO LAURA.

11903
06:56:41,150 --> 06:56:44,153
>> I JUST WANTED TO MAKE A

11904
06:56:44,153 --> 06:56:45,688
POLITICALLY INCORRECT STATEMENT,

11905
06:56:45,688 --> 06:56:47,490
BEYOND ZIP CODE, VOTING

11906
06:56:47,490 --> 06:56:49,559
PREFERENCES HAVE A MUCH STRONGER

11907
06:56:49,559 --> 06:56:54,998
INFLUENCE, ANYWHERE FROM 18.8 TO

11908
06:56:54,998 --> 06:56:57,433
19.2% YEARS' DIFFERENCE IN NEAR

11909
06:56:57,433 --> 06:57:00,770
MAXIMUM LIFE EXPECTANCY.

11910
06:57:00,770 --> 06:57:03,106
SO WHAT I'D ASK THE NIA IS

11911
06:57:03,106 --> 06:57:04,407
WHETHER THERE ARE GOING TO BE

11912
06:57:04,407 --> 06:57:06,409
COLONIES OF REPUBLICAN AND

11913
06:57:06,409 --> 06:57:07,477
DEMOCRATIC MICE.

11914
06:57:07,477 --> 06:57:08,311
[LAUGHTER]

11915
06:57:08,311 --> 06:57:11,481
>> IT DEPENDS ON THE
SHUTDOWN

11916
06:57:11,481 --> 06:57:12,048
PROBABLY.

11917
06:57:12,048 --> 06:57:14,417
>> WE'RE NOT DOING THAT.

11918
06:57:14,417 --> 06:57:18,721
>> THERE WAS A COMMENT
ABOUT

11919
06:57:18,721 --> 06:57:21,424
ZNA, ZIP CODE AND YOUR DNA.

11920
06:57:21,424 --> 06:57:25,228
SO KIND OF MULTI-PARAMETRIC

11921
06:57:25,228 --> 06:57:25,461
INDICES.

11922
06:57:25,461 --> 06:57:26,729
>> I THINK IT'S SUPER

11923
06:57:26,729 --> 06:57:29,032
INTERESTING BECAUSE THE

11924
06:57:29,032 --> 06:57:29,632
EPIGENETICS EFFECTS OF STRESS,

11925
06:57:29,632 --> 06:57:30,967
AND THAT'S THE ONLY REASON I PUT

11926
06:57:30,967 --> 06:57:33,836
IN THAT SMALL AMOUNT ABOUT HOW

11927
06:57:33,836 --> 06:57:38,775
THE MATERNAL BIOME MATTERS,

11928
06:57:38,775 --> 06:57:39,742
BECAUSE THESE ANIMALS THAT ARE

11929
06:57:39,742 --> 06:57:41,978
BORN OF THESE DYSBIOTIC MOMS

11930
06:57:41,978 --> 06:57:44,647
HAVE LONG LASTING CHANGES,

11931
06:57:44,647 --> 06:57:45,682
MIDDLE AGE, AND WE'RE NOW DOING

11932
06:57:45,682 --> 06:57:47,650
STROKES IN THEM AND THEY HAVE

11933
06:57:47,650 --> 06:57:48,885
INCREASED STROKE SENSITIVITY,

11934
06:57:48,885 --> 06:57:51,454
AND SO HOW IS THAT PUT FORWARD

11935
06:57:51,454 --> 06:57:55,992
AND IS THAT A PUBLIC HEALTH

11936
06:57:55,992 --> 06:57:57,894
ISSUE.

11937
06:57:57,894 --> 06:58:01,497
WE'RE SEEING INCREASE OF

11938
06:58:01,497 --> 06:58:06,969
DIABETES, OBESITY, HYPERTENSION,

11939
06:58:06,969 --> 06:58:09,205
ADVANCED MATERNAL AGE, IS THAT

11940
06:58:09,205 --> 06:58:12,575
AFFECTING THE NEXT YEAR -- WHEN

11941
06:58:12,575 --> 06:58:15,178
THEY GIVE BIRTH TO LOW BIRTH

11942
06:58:15,178 --> 06:58:15,712
WEIGHT CHILDREN BUT THOSE

11943
06:58:15,712 --> 06:58:17,113
CHILDREN WHEN THEY GROW TO

11944
06:58:17,113 --> 06:58:19,282
ADULTHOOD HAVE MUCH HIGHER RATES

11945
06:58:19,282 --> 06:58:22,552
OF CARDIOVASCULAR DISEASE,

11946
06:58:22,552 --> 06:58:24,987
DIABETES, OBESITY, SO THAT'S WHY

11947
06:58:24,987 --> 06:58:26,422
I WAS SHOUTING OUT, THAT

11948
06:58:26,422 --> 06:58:28,624
SOMETIMES AGING MAY BEGIN IN THE

11949
06:58:28,624 --> 06:58:30,226
WOMB OR AT CONCEPTION OR

11950
06:58:30,226 --> 06:58:31,094
PRECONCEPTION, SO IT'S JUST A

11951
06:58:31,094 --> 06:58:36,632
WAY OF THINKING ABOUT IT.

11952
06:58:36,632 --> 06:58:38,234
>> IT MAY 50 FOR
GENERATIONS.

11953
06:58:38,234 --> 06:58:39,969
>> THEY'RE HERITABLE.

11954
06:58:39,969 --> 06:58:43,139
>> SO WE KNOW THAT FROM
WARTIME

11955
06:58:43,139 --> 06:58:44,006
FAMINE, THAT IT'S LIKE -- IT

11956
06:58:44,006 --> 06:58:47,443
GOES -- THEY HAVE THESE MARKS,

11957
06:58:47,443 --> 06:58:50,146
THESE EPIGENETIC MARKS FROM THE

11958
06:58:50,146 --> 06:58:51,147
FAMINE THAT LASTS MULTIPLE

11959
06:58:51,147 --> 06:58:51,581
GENERATIONS.

11960
06:58:51,581 --> 06:58:52,415
>> AND THEY'RE INHERITED
AND

11961
06:58:52,415 --> 06:58:54,917
THIS IS THE SAME WITH

11962
06:58:54,917 --> 06:58:55,485
PREECLAMPSIA OR HYPERTENSIVE

11963
06:58:55,485 --> 06:58:56,552
DISORDER OF PREGNANCY, THE MOM

11964
06:58:56,552 --> 06:58:59,922
HAS A FOUR FOLD INCREASED RISK

11965
06:58:59,922 --> 06:59:00,590
OF HYPERTENSION WHEN SHE'S IN

11966
06:59:00,590 --> 06:59:02,458
HER 50s AND A TWOFOLD INCREASE

11967
06:59:02,458 --> 06:59:03,226
RISK OF STROKE.

11968
06:59:03,226 --> 06:59:07,363
SO DOES THE CHILD, HAS A TWOFOLD

11969
06:59:07,363 --> 06:59:08,464
INCREASE RISK OF STROKE AND A

11970
06:59:08,464 --> 06:59:09,966
FOUR FOLD INCREASED RISK OF

11971
06:59:09,966 --> 06:59:11,667
HYPERTENSION AND IT'S NOT ALL

11972
06:59:11,667 --> 06:59:12,301
GENETIC BECAUSE A SIBLING BORN

11973
06:59:12,301 --> 06:59:14,871
TO THE SAME MOTHER WHEN SHE WAS

11974
06:59:14,871 --> 06:59:19,308
NOT PREEE CL PREECLAMPSIA IK DOT

11975
06:59:19,308 --> 06:59:20,343
HAVE THAT RISK AND THERE ARE

11976
06:59:20,343 --> 06:59:22,211
GENETIC MARKERS OF ADVANCED

11977
06:59:22,211 --> 06:59:24,013
SENESCENCE IN AGING.

11978
06:59:24,013 --> 06:59:24,647
CHRISTOPHER, YOU HAD A QUESTION?

11979
06:59:24,647 --> 06:59:25,915
>> I'D JUST LIKE TO
MENTION THAT

11980
06:59:25,915 --> 06:59:27,183
PATTY HAD MENTIONED BEFORE IN

11981
06:59:27,183 --> 06:59:29,819
TERMS OF THE ZIP CODE IN

11982
06:59:29,819 --> 06:59:30,653
NEW YORK AND NEW JERSEY AND

11983
06:59:30,653 --> 06:59:31,554
THESE DIFFERENTIALS.

11984
06:59:31,554 --> 06:59:33,556
THE SAME THING ALSO EXISTS IN

11985
06:59:33,556 --> 06:59:35,825
THE CLEVELAND AREA.

11986
06:59:35,825 --> 06:59:36,926
CLINIC WE'RE LOCATED, IT'S

11987
06:59:36,926 --> 06:59:38,561
CALLED THE FAIRFAX NEIGHBORHOOD,

11988
06:59:38,561 --> 06:59:39,762
AND AVERAGE LIFE EXPECTANCY IN

11989
06:59:39,762 --> 06:59:42,432
THE NEIGHBORHOOD IS ONLY 65, AND

11990
06:59:42,432 --> 06:59:48,104
YOU GO 3 MILES EAST AND ANOTHER

11991
06:59:48,104 --> 06:59:49,939
SUBURB, LIFE EXPECTANCY IS 85.

11992
06:59:49,939 --> 06:59:52,175
SO EVEN WITHIN A 3-MILE RANGE,

11993
06:59:52,175 --> 06:59:53,376
YOU HAVE A 20-YEAR DIFFERENTIAL,

11994
06:59:53,376 --> 06:59:55,311
WHICH IS QUITE EXTREME.

11995
06:59:55,311 --> 06:59:57,580
WHAT'S ALSO REALLY INTERESTING

11996
06:59:57,580 --> 07:00:00,049
IS THAT I NEIGHBORHOOD WHERE ITS

11997
07:00:00,049 --> 07:00:01,217
85, IT'S NOT THE RICHEST

11998
07:00:01,217 --> 07:00:01,584
NEIGHBORHOOD.

11999
07:00:01,584 --> 07:00:03,619
IF YOU ACTUALLY GO TO THE

12000
07:00:03,619 --> 07:00:04,454
RICHEST NEIGHBORHOOD, IT

12001
07:00:04,454 --> 07:00:05,655
ACTUALLY DROPS BY ANOTHER FIVE

12002
07:00:05,655 --> 07:00:06,422
YEARS.

12003
07:00:06,422 --> 07:00:09,025
I THINK IT'S WHERE YOU GET TO

12004
07:00:09,025 --> 07:00:10,059
THAT SOCIAL ICIZATION, BIG

12005
07:00:10,059 --> 07:00:12,795
HOUSES, BIG YARDS, MAYBE YOU

12006
07:00:12,795 --> 07:00:13,763
HAVE THE STRESS OF A HUGE

12007
07:00:13,763 --> 07:00:15,565
MORTGAGE, YOU KNOW, THAT BRINGS

12008
07:00:15,565 --> 07:00:16,766
DOWN LIFE EXPECTANCY.

12009
07:00:16,766 --> 07:00:19,769
BUT I THINK DEFINITELY LIFESTYLE

12010
07:00:19,769 --> 07:00:23,940
IN THE ZIP CODE, YOU KNOW,

12011
07:00:23,940 --> 07:00:24,440
RELATED TO THE ZIP CODE

12012
07:00:24,440 --> 07:00:26,075
DEFINITELY IMPACTS LIFE

12013
07:00:26,075 --> 07:00:26,375
EXPECTANCY.

12014
07:00:26,375 --> 07:00:31,280
>> MAYBE THEIR SOCIAL

12015
07:00:31,280 --> 07:00:31,647
CONNECTEDNESS.

12016
07:00:31,647 --> 07:00:33,015
>> LAURA, PLEASE GO AHEAD.

12017
07:00:33,015 --> 07:00:33,983
YOU HAVE BEEN WAITING.

12018
07:00:33,983 --> 07:00:35,251
>> JUST A COUPLE OF QUICK

12019
07:00:35,251 --> 07:00:38,521
COMMENTS TO FOLLOW UP, PLEASE.

12020
07:00:38,521 --> 07:00:40,623
ONE IS I WOULDN'T DISMISS THE

12021
07:00:40,623 --> 07:00:41,390
GENETICS ENTIRELY.

12022
07:00:41,390 --> 07:00:45,928
THE WORK IN CENTENARIANS IS I

12023
07:00:45,928 --> 07:00:48,130
THINK REVEALING SOMETHING REALLY

12024
07:00:48,130 --> 07:00:49,265
UNEXPECTED SO IF HE WERE HERE,

12025
07:00:49,265 --> 07:00:52,568
HE WOULD SAY THAT CENTENARIANS

12026
07:00:52,568 --> 07:00:53,736
ACTUALLY HAVE SEQUENCE VARIANTS

12027
07:00:53,736 --> 07:00:55,171
THAT CONFER PROTECTION AGAINST

12028
07:00:55,171 --> 07:00:56,939
SOME OF THESE HEALTH TRAJECTORY

12029
07:00:56,939 --> 07:00:58,541
FEATURES.

12030
07:00:58,541 --> 07:01:01,277
SO FOR INSTANCE, CERTAIN

12031
07:01:01,277 --> 07:01:05,448
MUTATIONS OR SNPs CAN OVERCOME

12032
07:01:05,448 --> 07:01:07,149
AN APOE MUTATION, WHICH IS

12033
07:01:07,149 --> 07:01:07,450
INCREDIBLE.

12034
07:01:07,450 --> 07:01:08,484
SO I THINK THAT'S POWERFUL.

12035
07:01:08,484 --> 07:01:11,621
I JUST WANTED TO REITERATE THE

12036
07:01:11,621 --> 07:01:13,856
COMMENT ABOUT THE PSYCHOSOCIAL

12037
07:01:13,856 --> 07:01:15,758
STRESS, SO THAT MODEL THAT

12038
07:01:15,758 --> 07:01:20,196
ALESSANDRO IS WORKING IN, HE HAS

12039
07:01:20,196 --> 07:01:20,863
A GRANT THAT PROVIDES FUNDING IF

12040
07:01:20,863 --> 07:01:21,898
ANYBODY WANTS TO SORT OF ADD

12041
07:01:21,898 --> 07:01:25,568
WHAT THEY'RE DOING, THE

12042
07:01:25,568 --> 07:01:26,235
MICROBIOME WITH STRESS, BUT THIS

12043
07:01:26,235 --> 07:01:28,938
JUST -- IT'S THE EQUIVALENT OF

12044
07:01:28,938 --> 07:01:31,908
FEELING LIKE AN ETHNIC OR RACIAL

12045
07:01:31,908 --> 07:01:36,145
GROUP THAT'S PICKED ON.

12046
07:01:36,145 --> 07:01:37,380
SO IT'S A HUGE HEALTH DETERMINE

12047
07:01:37,380 --> 07:01:38,548
NAN.

12048
07:01:38,548 --> 07:01:40,516
THE LAST POINT I WANTED TO MAKE

12049
07:01:40,516 --> 07:01:42,752
JUST BEFORE WE GOT ON THE ZOOM

12050
07:01:42,752 --> 07:01:43,386
THIS MORNING, PAUL FOUND A LINK

12051
07:01:43,386 --> 07:01:44,820
THAT SAID THAT MORE THAN SEVEN

12052
07:01:44,820 --> 07:01:47,156
HOURS OF ZOOM A WEEK WILL ALSO

12053
07:01:47,156 --> 07:01:47,823
DESTROY YOUR MEL.

12054
07:01:47,823 --> 07:01:50,826
SO THE -- YOUR MENTALHEALTH.

12055
07:01:50,826 --> 07:01:54,230
SO THERE'S AN ACTION ITEM FOR --

12056
07:01:54,230 --> 07:01:56,132
>> THAT WAS PER WEEK, NOT
PER

12057
07:01:56,132 --> 07:01:56,299
DAY.

12058
07:01:56,299 --> 07:01:56,599
>> EXACTLY.

12059
07:01:56,599 --> 07:01:57,500
WE'RE GOING TO DIE TOMORROW.

12060
07:01:57,500 --> 07:02:00,736
SO A COUPLE COMMENTS.

12061
07:02:00,736 --> 07:02:01,304
EPIGENETICS IS AFFECTED BY

12062
07:02:01,304 --> 07:02:03,172
NUTRITION AND EXERCISE, FROM

12063
07:02:03,172 --> 07:02:04,307
MICHAEL SNYDER.

12064
07:02:04,307 --> 07:02:06,876
YES, ABSOLUTELY.

12065
07:02:06,876 --> 07:02:08,511
AND STRESS INCLUDING SOCIAL

12066
07:02:08,511 --> 07:02:13,249
STRESS, AND IMPLICIT BUY A

12067
07:02:13,249 --> 07:02:14,183
SYSTEMIC RACISM ARE OBVIOUSLY

12068
07:02:14,183 --> 07:02:16,852
GOING TO HAVE A LARGE EFFECT AS

12069
07:02:16,852 --> 07:02:17,053
WELL.

12070
07:02:17,053 --> 07:02:17,687
THERE WAS ANOTHER QUESTION,

12071
07:02:17,687 --> 07:02:18,654
DR. KIRKLAND, DID YOU HAVE

12072
07:02:18,654 --> 07:02:19,322
ANOTHER QUESTION?

12073
07:02:19,322 --> 07:02:24,193
I SEE YOUR HAND IS UP.

12074
07:02:24,193 --> 07:02:25,494
>> IT MIGHT BE A PREVIOUS

12075
07:02:25,494 --> 07:02:25,895
QUESTION.

12076
07:02:25,895 --> 07:02:27,330
I THINK HE DIDN'T LOWER DOWN HIS

12077
07:02:27,330 --> 07:02:30,933
HAND.

12078
07:02:30,933 --> 07:02:35,504
DR. KIRKLAND?

12079
07:02:35,504 --> 07:02:46,349
>> I ALSO SEE A QUESTION
FOR DR.

12080
07:02:48,284 --> 07:02:48,884
[MULTIPLE SPEAKERS]

12081
07:02:48,884 --> 07:02:50,953
>> I THINK WE COVERED THAT
ONE.

12082
07:02:50,953 --> 07:02:53,255
>> YEAH, I CHATTED TO
LAVERNE.

12083
07:02:53,255 --> 07:02:58,794
BUT ESSENTIALLY, KIND OF

12084
07:02:58,794 --> 07:02:59,295
CLASSICAL THINKING THAT

12085
07:02:59,295 --> 07:03:00,429
EPIGENETICS IS PERMANENT IS KIND

12086
07:03:00,429 --> 07:03:02,131
OF COMING UNDER QUESTION.

12087
07:03:02,131 --> 07:03:06,168
SO WE HAVE DATA THAT THERE ARE

12088
07:03:06,168 --> 07:03:09,739
THESE NEW CLASSES OF EPIGENETIC

12089
07:03:09,739 --> 07:03:14,210
PROTEINS, IF YOU WILL, TETs

12090
07:03:14,210 --> 07:03:17,179
AND DNMTs THAT MAY CONFER

12091
07:03:17,179 --> 07:03:19,215
SOME DEGREE OF REVERSIBILITY.

12092
07:03:19,215 --> 07:03:21,484
BUT IN WHAT TISSUES AND TO

12093
07:03:21,484 --> 07:03:22,818
WHAT DEGREE THEY'RE REVERSIBLE,

12094
07:03:22,818 --> 07:03:24,553
THOSE ARE STILL PENDING, PENDING

12095
07:03:24,553 --> 07:03:30,493
ANSWERS.

12096
07:03:30,493 --> 07:03:33,829
>> I SEE ALSO A QUESTION
FOR

12097
07:03:33,829 --> 07:03:37,533
LOUISE IN THE Q & A.

12098
07:03:37,533 --> 07:03:42,271
HAVE YOU INVESTIGATED THE --

12099
07:03:42,271 --> 07:03:44,073
SCFAs IN OTHER TISSUES?

12100
07:03:44,073 --> 07:03:45,074
>> YEP, I THINK I ANSWERED
THAT.

12101
07:03:45,074 --> 07:03:46,142
YES, WE HAVE.

12102
07:03:46,142 --> 07:03:51,847
IN HUMANS ESPECIALLY.

12103
07:03:51,847 --> 07:03:54,483
METABOLOMICS IS A HUGE AREA BUT

12104
07:03:54,483 --> 07:03:55,718
WE'RE PRETTY CRUDE WITH IT RIGHT

12105
07:03:55,718 --> 07:03:57,453
NOW, BUT YEAH, WE HAVE SHOWN

12106
07:03:57,453 --> 07:04:03,359
THAT IT'S NOT SPECIES-DEPENDENT.

12107
07:04:03,359 --> 07:04:06,529
AND I THINK SOMEBODY ASKED --

12108
07:04:06,529 --> 07:04:08,731
DAN Z ASKED IF ANYBODY COULD

12109
07:04:08,731 --> 07:04:09,565
SHARE THE REFERENCE PAPER ABOUT

12110
07:04:09,565 --> 07:04:13,736
THE ZIP CODE STUDY AND AGING.

12111
07:04:13,736 --> 07:04:16,105
SO IF SOMEBODY COULD SHARE THAT?

12112
07:04:16,105 --> 07:04:17,640
>> I'M RESPONDING TO HIM.

12113
07:04:17,640 --> 07:04:21,077
>> FANTASTIC.

12114
07:04:21,077 --> 07:04:23,579
AND I THINK WE ARE OUT OF TIME,

12115
07:04:23,579 --> 07:04:25,548
SO UNLESS THERE'S OTHER BURNING

12116
07:04:25,548 --> 07:04:27,950
QUESTIONS, DR. KIRKLAND, GO TAKE

12117
07:04:27,950 --> 07:04:32,121
A NAP.

12118
07:04:32,121 --> 07:04:34,190
[LAUGHTER]

12119
07:04:34,190 --> 07:04:36,025
>> YOU'RE A TROOPER.

12120
07:04:36,025 --> 07:04:37,593
>> IT'S GETTING CLOSE TO

12121
07:04:37,593 --> 07:04:37,860
MIDNIGHT.

12122
07:04:37,860 --> 07:04:38,861
>> IT IS.

12123
07:04:38,861 --> 07:04:40,629
IT IS CLOSE.

12124
07:04:40,629 --> 07:04:41,964
AND REMEMBER, SLEEP IS SUPER

12125
07:04:41,964 --> 07:04:44,467
IMPORTANT, SO -- AND CIRCADIAN

12126
07:04:44,467 --> 07:04:46,602
RHYTHMS, WHICH WE DIDN'T REALLY

12127
07:04:46,602 --> 07:04:47,703
TALK MUCH, BUT A GREAT FIRST

12128
07:04:47,703 --> 07:04:50,773
DAY, SO THANK YOU VERY MUCH.

12129
07:04:50,773 --> 07:04:53,743
I'LL LET ANIL AND -- TAKE IT

12130
07:04:53,743 --> 07:04:54,510
FROM HERE.

12131
07:04:54,510 --> 07:04:56,979
>> THANK YOU, THANK YOU SO
VERY

12132
07:04:56,979 --> 07:04:59,081
MUCH.

12133
07:04:59,081 --> 07:05:00,983
IT WAS THE WHOLE DAY EDUCATIONAL

12134
07:05:00,983 --> 07:05:02,585
AND INFORMATION OVERLOAD FOR ALL

12135
07:05:02,585 --> 07:05:03,185
OF US.

12136
07:05:03,185 --> 07:05:05,654
I WAS GLUED TO MY COMPUTER.

12137
07:05:05,654 --> 07:05:08,023
WHICH RARELY HAPPENS.

12138
07:05:08,023 --> 07:05:10,126
THANK YOU, THANK YOU SO VERY

12139
07:05:10,126 --> 07:05:14,196
MUCH FROM THE BOTT BOTTOM OF OUR

12140
07:05:14,196 --> 07:05:14,530
HEART.

12141
07:05:14,530 --> 07:05:16,799
IT'S NOT EASY TO GET ALL OF YOU

12142
07:05:16,799 --> 07:05:18,367
DISTINGUISHED SPEAKERS IN ONE

12143
07:05:18,367 --> 07:05:18,868
PLACE AT THE SAME TIME.

12144
07:05:18,868 --> 07:05:19,335
THANK YOU, THANK YOU.

12145
07:05:19,335 --> 07:05:21,871
>> SO ONE OF THE SECRETS
OF

12146
07:05:21,871 --> 07:05:24,573
HAVING ZOOM MEETINGS IS BECAUSE

12147
07:05:24,573 --> 07:05:27,309
YOU CAN ALL BE HERE WITHOUT

12148
07:05:27,309 --> 07:05:30,079
TRAVELING.

12149
07:05:30,079 --> 07:05:31,680
>> GOOD FOR THE BUDGET
TOO.

12150
07:05:31,680 --> 07:05:36,385
>> OF COURSE.

12151
07:05:36,385 --> 07:05:36,852
SWE

12152
07:05:36,852 --> 07:05:38,187
>> HOPE YOU CAN
PARTICIPATE

12153
07:05:38,187 --> 07:05:39,221
TOMORROW AS MUCH AS YOU CAN,

12154
07:05:39,221 --> 07:05:40,556
PLEASE.

12155
07:05:40,556 --> 07:05:42,024
OF COURSE.

12156
07:05:42,024 --> 07:05:42,658
SO THANK YOU VERY MUCH. I'M
GOING TO SIGN OFF.

12157
07:05:42,658 --> 07:05:52,658
THANK YOU ALL. BYE-BYE.