1 00:00:05,680 --> 00:00:08,440 >>WELCOME TO THE 2 00:00:08,440 --> 00:00:10,440 WEDNESDAY AFTERNOON LECTURE 3 00:00:10,440 --> 00:00:18,480 SERIES. I'M AMANDA B. I AM 4 00:00:18,480 --> 00:00:20,920 THRILLED TO INTRODUCE TODAY'S 5 00:00:20,920 --> 00:00:24,080 SPEAKER. HELEN BLAU. I'D LIKE 6 00:00:24,080 --> 00:00:26,040 TO ACKNOWLEDGE MY COHOSTS 7 00:00:26,040 --> 00:00:34,000 DR. JOHN WILLIAMS FROM NIA AND 8 00:00:34,000 --> 00:00:36,240 DOCTORS KAITLYN. THIS GROUP 9 00:00:36,240 --> 00:00:40,600 SPONSORS MANY N ISNIH LECTURES 10 00:00:40,600 --> 00:00:41,080 I THINK MANY FOLKS WILL BE 11 00:00:41,080 --> 00:00:42,520 INTERESTED IN. 12 00:00:42,520 --> 00:00:43,920 DR. BLAU IS A 13 00:00:43,920 --> 00:00:45,720 FOUNDATION PROFESSOR AND 14 00:00:45,720 --> 00:00:48,960 DIRECTOR OF THE BAXTER 15 00:00:48,960 --> 00:00:51,160 LABORATORY FOR BIOLOGY. SHE IS 16 00:00:51,160 --> 00:00:53,800 WORLD RENOWNED FOR HER WORK ON 17 00:00:53,800 --> 00:00:55,280 NUCLEAR REPROGRAMMING. HER BODY 18 00:00:55,280 --> 00:00:57,800 OF RESEARCH HAS PROVIDED THE 19 00:00:57,800 --> 00:01:01,080 UNDERPINNINGS FROM CLONING AND 20 00:01:01,080 --> 00:01:04,240 POTENT STEM CELLS. AMONG HER 21 00:01:04,240 --> 00:01:07,920 MANY LANDMARK DISCOVERIES HAS 22 00:01:07,920 --> 00:01:09,560 BEEN THE NICHE PROTEINS THAT 23 00:01:09,560 --> 00:01:12,880 REGENERATE, EXPAND AND ENHANCE 24 00:01:12,880 --> 00:01:15,920 THE FUNCTION OF MUSCLE STEM 25 00:01:15,920 --> 00:01:19,920 CELLS. HER LAB RECENTLY 26 00:01:19,920 --> 00:01:21,400 IDENTIFIED A HALLMARK NOVEL 27 00:01:21,400 --> 00:01:26,440 AGING 15 PGDH AND SHOWED ITS 28 00:01:26,440 --> 00:01:29,040 INHIBITION AUGMENTS MUSCLE MASS 29 00:01:29,040 --> 00:01:32,960 AND STRENGTH. HER LAB WAS THE 30 00:01:32,960 --> 00:01:40,520 FIRST TO DIRECT STEM CELL. MORE 31 00:01:40,520 --> 00:01:42,760 RECENTLY THEY DETERMINED 32 00:01:42,760 --> 00:01:43,920 MUSCULAR DYSTROPHY INTO THE 33 00:01:43,920 --> 00:01:46,560 DEVELOPMENT OF THE DISEASE AND 34 00:01:46,560 --> 00:01:47,720 POTENTIAL TREATMENTS. 35 00:01:47,720 --> 00:01:49,680 DR. BLAU'S WORK HAS LED TO THE 36 00:01:49,680 --> 00:01:50,920 DEVELOPMENT OF NOVEL 37 00:01:50,920 --> 00:01:52,400 TECHNOLOGIES INCLUDING THE 38 00:01:52,400 --> 00:01:54,200 DISCOVERY OF THE COMPLEMENTATION 39 00:01:54,200 --> 00:01:57,040 WHICH IS NOW WIDELY USED IN DRUG 40 00:01:57,040 --> 00:02:00,040 DISCOVERY. NOT SURPRISINGLY SHE 41 00:02:00,040 --> 00:02:02,040 HAS AT LAST COUNT ELEVEN PATENTS 42 00:02:02,040 --> 00:02:03,960 WITH AT LEAST TWO OTHERS FILED. 43 00:02:03,960 --> 00:02:06,120 THIS IS JUST A SNAPSHOT OF HER 44 00:02:06,120 --> 00:02:08,880 REMARKABLE CAREER, HER HONORS 45 00:02:08,880 --> 00:02:14,280 FITTINGLY HAVE BEEN AS NUMEROUS 46 00:02:14,280 --> 00:02:18,560 AS HER ACCOMPLISHMENTS. WITH 47 00:02:18,560 --> 00:02:20,880 THE NATIONAL ACADEMY OF INSULIN 48 00:02:20,880 --> 00:02:23,600 TORS A NATIVE OF THE UK EARNED 49 00:02:23,600 --> 00:02:28,440 HER BA AT THE UNIVERSITY OF YORK 50 00:02:28,440 --> 00:02:31,240 IN ENGLAND AND KEPT MOVING WEST 51 00:02:31,240 --> 00:02:34,280 AFTER THAT RECEIVING 52 00:02:34,280 --> 00:02:37,080 POST-DOCTORAL TRAINING BEFORE 53 00:02:37,080 --> 00:02:39,240 JOINING STANFORD UNIVERSITY. 54 00:02:39,240 --> 00:02:41,080 LASTLY I'M PROUD TO NOTE THAT 55 00:02:41,080 --> 00:02:44,000 DR. BLAU IS A GRANT RECIPIENT ON 56 00:02:44,000 --> 00:02:46,520 THE NATIONAL INSTITUTE ON AGING. 57 00:02:46,520 --> 00:02:47,400 THANK YOU SO MUCH FOR BEING WITH 58 00:02:47,400 --> 00:02:48,600 US TODAY ON BEHALF OF THE STAFF 59 00:02:48,600 --> 00:02:51,640 I WELCOME YOU TO THE NIH. 60 00:02:51,640 --> 00:02:55,480 >>THANK YOU SO MUCH AMMANDA. 61 00:02:55,480 --> 00:02:57,000 IT'S REALLY AN HONOR TO GIVE 62 00:02:57,000 --> 00:02:58,200 THIS LECTURE AND I THANK YOU FOR 63 00:02:58,200 --> 00:03:01,080 THIS INVITATION. SO WHAT I WANT 64 00:03:01,080 --> 00:03:04,080 TO TELL YOU ABOUT TODAY IS OUR 65 00:03:04,080 --> 00:03:07,400 DISCOVERY OF A JER ROW SOMETIMES 66 00:03:07,400 --> 00:03:13,920 AND IT'S ROLE IN REJUVENATING 67 00:03:13,920 --> 00:03:16,560 MUSCLES AND HOW WE CAN TARGET IT 68 00:03:16,560 --> 00:03:18,320 TO REJUVENATE AGING. IT'S AN 69 00:03:18,320 --> 00:03:19,920 ENZYME THAT APPEAR TO HAVE A 70 00:03:19,920 --> 00:03:24,480 PIVOTAL ROLE IN AGING AND 71 00:03:24,480 --> 00:03:29,720 REJUVENATION. AS YOU WILL SEE. 72 00:03:29,720 --> 00:03:33,360 FIRST A DISCLOSURE. I'M A 73 00:03:33,360 --> 00:03:35,920 COFOUNDER OF TWO COMPANIES. 74 00:03:35,920 --> 00:03:37,560 AGEING IS DEPICTED HERE BY ONE 75 00:03:37,560 --> 00:03:41,160 OF MY FAVORITE ARTISTS. YOU SEE 76 00:03:41,160 --> 00:03:43,880 THE YOUNG BABE AND THEN GLOWING 77 00:03:43,880 --> 00:03:45,240 MOTHERHOOD AND THEN DECREPED 78 00:03:45,240 --> 00:03:46,160 AGING AND THE QUESTION IS, DOES 79 00:03:46,160 --> 00:03:50,000 IT REALLY HAVE TO BE THAT WAY? 80 00:03:50,000 --> 00:03:53,080 AND AS SHOWN HERE, IN NATURE, 81 00:03:53,080 --> 00:03:55,720 JUST A FEW YEARS AGO, WE ARE 82 00:03:55,720 --> 00:03:59,080 LIVING LONGER, BOTH THE LIFE 83 00:03:59,080 --> 00:04:00,200 EXPECTANCY OF MEN AND OF WOMEN 84 00:04:00,200 --> 00:04:03,680 IS LONGER. BUT THESE ARE NOT 85 00:04:03,680 --> 00:04:05,040 YEARS THAT ARE QUALITY YEARS 86 00:04:05,040 --> 00:04:08,840 THEY'RE YEARS SPENT WITH CHRONIC 87 00:04:08,840 --> 00:04:11,720 DISEASE. THE YEARS OF HEALTHY 88 00:04:11,720 --> 00:04:13,880 LIVING ARE STAYING STABLE. SO 89 00:04:13,880 --> 00:04:16,000 THE GOAL OF REGENERATIVE 90 00:04:16,000 --> 00:04:18,360 MEDICINE OR STEM CELL BIOLOGY IS 91 00:04:18,360 --> 00:04:19,880 TO INCREASE HEALTH SPAN OR 92 00:04:19,880 --> 00:04:22,600 QUALITY OF LIFE SO THAT THE 93 00:04:22,600 --> 00:04:23,920 PROPORTION OF YOUR LIFE SPAN 94 00:04:23,920 --> 00:04:25,560 THAT IS SPENT DOING THE THINGS 95 00:04:25,560 --> 00:04:27,920 YOU LOVE TO DO LIKE RUNNING A 96 00:04:27,920 --> 00:04:31,880 MARATHON OR SKIING OR HIKING ARE 97 00:04:31,880 --> 00:04:34,080 PROLONGED. LESS TIME WITH 98 00:04:34,080 --> 00:04:37,080 CHRONIC DISEASE. AND I THINK 99 00:04:37,080 --> 00:04:40,200 THIS IS HIGHLIGHTED, THIS NOTION 100 00:04:40,200 --> 00:04:45,520 OF HEALTH SPAN IN THE MYTH, THE 101 00:04:45,520 --> 00:04:50,960 ROMAN MYTHOLOGY OF AURORA AND 102 00:04:50,960 --> 00:04:53,080 TIE THON NEWS. AURORA WAS THE 103 00:04:53,080 --> 00:04:55,480 GODDESS OF DAWN AND FELL IN LOVE 104 00:04:55,480 --> 00:04:59,920 WITH TIE THON US. DEPICTED HERE 105 00:04:59,920 --> 00:05:02,360 AT THE VATICAN WHERE THE ACADEMY 106 00:05:02,360 --> 00:05:04,560 MEETS AND FELL IN LOVE WITH THIS 107 00:05:04,560 --> 00:05:06,560 MORTAL AND WENT TO JUPITER, THE 108 00:05:06,560 --> 00:05:09,080 KING OF THE GODS AND SAID PLEASE 109 00:05:09,080 --> 00:05:12,920 GRANT ME JUST ONE WISH. I WANT 110 00:05:12,920 --> 00:05:13,920 TIE THON US TO LIVE FOREVER, TO 111 00:05:13,920 --> 00:05:16,240 HAVE ETERNAL LIFE AND SO JUPITER 112 00:05:16,240 --> 00:05:25,360 GRANTED HER WISH. GAVE HIM 113 00:05:25,360 --> 00:05:27,040 ETERNAL LIFE AND DID NOT ASK FOR 114 00:05:27,040 --> 00:05:29,760 ETERNAL YOUTH AND WHAT HAPPENED 115 00:05:29,760 --> 00:05:32,320 WAS TIE THON US AGED AND BECAME 116 00:05:32,320 --> 00:05:36,840 DECREPED AND LIVID FOREVER AS A 117 00:05:36,840 --> 00:05:40,520 DECREPIT OLD MAN. NOT ONLY DO 118 00:05:40,520 --> 00:05:43,920 WE WANT AN INCREASE IN LIFE SPAN 119 00:05:43,920 --> 00:05:47,000 BUT ALSO HEALTH SPAN AND WHAT IS 120 00:05:47,000 --> 00:05:48,840 CRUCIAL TO YOUR HEALTH SPAN? 121 00:05:48,840 --> 00:05:50,840 MUSCLE IS ONE OF THE THINGS THAT 122 00:05:50,840 --> 00:05:52,080 IS ABSOLUTELY CENTRAL TO 123 00:05:52,080 --> 00:05:53,080 EVERYTHING YOU DO IN LIFE 124 00:05:53,080 --> 00:05:56,440 WHETHER YOU'RE A DANCER IN A 125 00:05:56,440 --> 00:05:59,200 BALLET, OR YOU ARE ROW DAN'S 126 00:05:59,200 --> 00:06:01,360 THINKER AND USING YOUR MUSCLES 127 00:06:01,360 --> 00:06:03,280 TO THINK AND FOR POSTURE AND IF 128 00:06:03,280 --> 00:06:07,920 YOU'RE STEF CURRY OF THE GOLDEN 129 00:06:07,920 --> 00:06:09,240 STATE WARRIORS YOU'RE USE L 130 00:06:09,240 --> 00:06:11,320 EVERY MUSCLE IN YOUR BODY TO 131 00:06:11,320 --> 00:06:12,720 SHOOT THOSE THREE POINTERS. 132 00:06:12,720 --> 00:06:13,960 MUSCLE IS VERY IMPORTANT. AND 133 00:06:13,960 --> 00:06:16,520 WITH AGING WE LOSE MUSCLE MASS 134 00:06:16,520 --> 00:06:19,760 AND STRENGTH. HUMANS LOSE 10% 135 00:06:19,760 --> 00:06:21,080 OF MUSCLE MASS PER DECADE AFTER 136 00:06:21,080 --> 00:06:24,040 THE AGE OF 50. AND 5% OF PEOPLE 137 00:06:24,040 --> 00:06:28,080 OVER THE AGE OF 60 ARE AFFECTED 138 00:06:28,080 --> 00:06:31,280 BY SAR KOE PEÑA WHICH IS THE 139 00:06:31,280 --> 00:06:33,520 DEBILITATING LOSS OF MUSCLE MASS 140 00:06:33,520 --> 00:06:35,360 AND STRENGTH. BY THE AGE OF 80, 141 00:06:35,360 --> 00:06:37,920 ONE-THIRD OF PEOPLE ARE AFFECTED 142 00:06:37,920 --> 00:06:42,000 BY SARCOPENIA. SO WHAT IS 143 00:06:42,000 --> 00:06:43,560 SARCOPENIA. AN INCREASE IN 144 00:06:43,560 --> 00:06:46,360 FRAILTY, LOSS OF MUSCLE MASS, 145 00:06:46,360 --> 00:06:47,440 REDUCES THE ABILITY TO PERFORM 146 00:06:47,440 --> 00:06:49,640 ROUTINE TASKS LIKE GETTING UP 147 00:06:49,640 --> 00:06:51,880 OUT OF A CHAIR. THERE'S AN 148 00:06:51,880 --> 00:06:54,640 INCREASED INCIDENCE IN FALLS, 149 00:06:54,640 --> 00:06:57,800 AND THIS COSTS BILLIONS OF 150 00:06:57,800 --> 00:06:58,960 DOLLARS BECAUSE PEOPLE BECOME 151 00:06:58,960 --> 00:06:59,880 DEPENDENT AFTER THAT. THEY 152 00:06:59,880 --> 00:07:02,720 OFTEN END UP IN INSTITUTIONS, 153 00:07:02,720 --> 00:07:05,720 AND ASSISTED LIVING AND THEIR 154 00:07:05,720 --> 00:07:12,160 MORTALITY IS ACCELERATED. SO 155 00:07:12,160 --> 00:07:13,280 WHAT I WANT TO TELL YOU ABOUT 156 00:07:13,280 --> 00:07:19,240 TODAY IS OUR DISCOVERY OF A WAY 157 00:07:19,240 --> 00:07:22,320 TO POTENTIALLY MEDIATE AND AVOID 158 00:07:22,320 --> 00:07:25,080 THIS DOWNWARD SPIRAL AND THAT IS 159 00:07:25,080 --> 00:07:26,640 THE DISCOVERY OF THIS GEROZYME 160 00:07:26,640 --> 00:07:29,800 AND OUR FINDING THAT INHIBITING 161 00:07:29,800 --> 00:07:32,440 THIS GEROZYME INCREASES NOT ONLY 162 00:07:32,440 --> 00:07:34,040 STEM CELL FUNCTION AND 163 00:07:34,040 --> 00:07:36,200 REGENERATION BUT ALSO 164 00:07:36,200 --> 00:07:36,760 REJUVENATES MUSCLE TISSUE 165 00:07:36,760 --> 00:07:39,400 FUNCTION AND IT ACTS BY 166 00:07:39,400 --> 00:07:41,680 ENHANCING THE BODY'S OWN HEALING 167 00:07:41,680 --> 00:07:45,760 MECHANISMS, THE NATURAL HEALING 168 00:07:45,760 --> 00:07:47,960 MECHANISMS. SO WE'VE TAKEN TWO 169 00:07:47,960 --> 00:07:49,160 APPROACHES, TO TARGET MUSCLE 170 00:07:49,160 --> 00:07:51,960 STEM CELLS AND FIBERS. THE STEM 171 00:07:51,960 --> 00:07:54,600 CELLS LIE ALONG THE MATURE 172 00:07:54,600 --> 00:07:56,000 MUSCLE FIBERS. THEY ARE 173 00:07:56,000 --> 00:07:59,080 DEDICATED STEM CELLS THAT ARE IN 174 00:07:59,080 --> 00:08:02,400 A QUIESCENT STATE READY TO 175 00:08:02,400 --> 00:08:05,960 REPLENISH THE MUSCLE FIBERS AND 176 00:08:05,960 --> 00:08:07,160 WE'RE TARGETING BOTH THESE STEM 177 00:08:07,160 --> 00:08:09,800 CELLS AND THE MUSCLE FIBERS. 178 00:08:09,800 --> 00:08:13,880 THE MATURE MUSCLE FIBERS. SO 179 00:08:13,880 --> 00:08:14,560 MUSCLE STEM CELLS SHOWN HERE 180 00:08:14,560 --> 00:08:18,040 RESIDE IN A NICHE ALONG THE 181 00:08:18,040 --> 00:08:20,720 MUSCLE FIBER AND AS SHOWN HERE 182 00:08:20,720 --> 00:08:24,480 BY ALECK SANDRO MARROW HE 183 00:08:24,480 --> 00:08:26,840 IDENTIFIED A MICROGRAPH THAT 184 00:08:26,840 --> 00:08:28,800 THIS WAS A SATELLITE CELL. IT 185 00:08:28,800 --> 00:08:31,080 WAS LYING ALONG THE MUSCLE FINER 186 00:08:31,080 --> 00:08:33,800 AND HE PREDICTED IT WAS THE STEM 187 00:08:33,800 --> 00:08:36,920 CELL IT WASN'T UNTIL MANY 188 00:08:36,920 --> 00:08:39,720 DECADES LATER THAT THIS WAS 189 00:08:39,720 --> 00:08:41,960 PROVEN TRUE AND THESE STEM CELLS 190 00:08:41,960 --> 00:08:45,640 EXPRESS PAC 7 AND THAT IS 191 00:08:45,640 --> 00:08:47,400 ESSENTIAL TO THEIR SELF RENEWAL 192 00:08:47,400 --> 00:08:48,960 AND IF THERE'S AN INJURY THEY 193 00:08:48,960 --> 00:08:51,440 SPRING INTO ACTION, BECOME 194 00:08:51,440 --> 00:08:52,880 ACTIVATED. 195 00:08:52,880 --> 00:08:55,080 COMMITTED PROGENITORS AND FUSE 196 00:08:55,080 --> 00:08:57,440 INTO THE MYOFIBERS TO REFUEL THE 197 00:08:57,440 --> 00:09:00,680 MY OWE FIBER. WELL IN ORDER TO 198 00:09:00,680 --> 00:09:02,120 STUDY THE STEM CELLS AND 199 00:09:02,120 --> 00:09:05,280 UNDERSTAND THEIR REGULATION, WE 200 00:09:05,280 --> 00:09:07,920 HAD TO IDENTIFY WAYS TO ISOLATE 201 00:09:07,920 --> 00:09:10,400 THEM AND FOR THIS PURPOSE WE 202 00:09:10,400 --> 00:09:13,120 USED A POTENT TRANSGENIC MODEL 203 00:09:13,120 --> 00:09:16,440 THAT EXPRESSES GFP AND LIEU 204 00:09:16,440 --> 00:09:18,520 SIEVE RACE IN ALL THE CELLS OF 205 00:09:18,520 --> 00:09:21,240 THE BODY AND WE ISOLATED SINGLE 206 00:09:21,240 --> 00:09:23,600 CELLS AND WE DID MANY 207 00:09:23,600 --> 00:09:25,920 EXPERIMENTS INJECTING SINGLE 208 00:09:25,920 --> 00:09:29,520 CELLS INTO THE INJURED LIMBS OF 209 00:09:29,520 --> 00:09:33,840 MICE. LOOK FOR ENGRAPHMENT AND 210 00:09:33,840 --> 00:09:38,400 EXPANSION OF THE STEM CELLS BY 211 00:09:38,400 --> 00:09:41,280 BIO LUMINESCENT IMAGING. AND WE 212 00:09:41,280 --> 00:09:43,000 IDENTIFIED USING THIS, THESE 213 00:09:43,000 --> 00:09:44,560 THREE MARKERS THAT ALLOW 214 00:09:44,560 --> 00:09:46,960 ISOLATION OF THE STEM CELLS. 215 00:09:46,960 --> 00:09:48,760 AND THIS SHOWS YOU THE KEY 216 00:09:48,760 --> 00:09:51,360 EXPERIMENT THAT WE DID. WE 217 00:09:51,360 --> 00:09:54,360 ISOLATED SINGLE CELLS, INJECTED 218 00:09:54,360 --> 00:09:56,160 THEM INTO THE INJURED HIGH LIMB 219 00:09:56,160 --> 00:09:58,560 OF A MUSCLE AND YOU CAN SEE 220 00:09:58,560 --> 00:10:00,680 THREE OUT OF 72 TRANSPLANTS GAVE 221 00:10:00,680 --> 00:10:04,680 A ROBUST IMAGING SIGNAL THAT YOU 222 00:10:04,680 --> 00:10:07,240 CAN DETECT HERE IN A CCD CAMERA 223 00:10:07,240 --> 00:10:10,160 AND THOSE CELLS ALSO CONTRIBUTED 224 00:10:10,160 --> 00:10:12,240 TO MATURE MYOFIBERS AS YOU CAN 225 00:10:12,240 --> 00:10:16,920 SEE HERE BY GFP. SO THEY MET 226 00:10:16,920 --> 00:10:17,560 THE QUINTESSENTIAL DIFFERENT IN 227 00:10:17,560 --> 00:10:21,160 ADDITION OF A STEM CELL OF KREFL 228 00:10:21,160 --> 00:10:25,200 RENEWAL AND DIFFERENTIATION. 229 00:10:25,200 --> 00:10:27,200 ONCE WE HAD THE STEM CELLS WE 230 00:10:27,200 --> 00:10:28,920 THOUGHT, NOW WE CAN STUDY THE 231 00:10:28,920 --> 00:10:30,800 FACTORS THAT REGULATE THEM BUT 232 00:10:30,800 --> 00:10:33,520 WE ENCOUNTER YET ANOTHER 233 00:10:33,520 --> 00:10:35,520 PROBLEM. ANOTHER CHALLENGE. 234 00:10:35,520 --> 00:10:39,840 WHICH WAS THAT IF YOU INJECTED 235 00:10:39,840 --> 00:10:41,800 FRESH STEM CELLS INTO THE 236 00:10:41,800 --> 00:10:44,720 INJURED HIND LIMB OF A MUSCLE 237 00:10:44,720 --> 00:10:47,040 THEY EXPAND ROBUSTLY BUT AS YOU 238 00:10:47,040 --> 00:10:49,760 SEE HERE IF YOU CULTURE THEM ON 239 00:10:49,760 --> 00:10:51,840 PLASTIC, THE USUAL CULTURE 240 00:10:51,840 --> 00:10:54,680 DISHES YOU SEE A LOSS OF STEM 241 00:10:54,680 --> 00:10:58,560 CELL FUNCTION, REDUCTION IN BLI 242 00:10:58,560 --> 00:11:01,600 SIGNAL AND THAT'S HIGHLIGHTED 243 00:11:01,600 --> 00:11:03,120 HERE SO THE STEM CELLS LOSE 244 00:11:03,120 --> 00:11:07,240 THEIR FUNCTION IN TISSUE CULT 245 00:11:07,240 --> 00:11:09,840 CULTURE. SO WE WONDERED HOW TO 246 00:11:09,840 --> 00:11:12,480 OVERCOME THIS. WE DECONSTRUCTED 247 00:11:12,480 --> 00:11:15,960 THE NICHE IN DIFFERENT MATERIALS 248 00:11:15,960 --> 00:11:22,080 THIS WORK WAS DONE BY A 249 00:11:22,080 --> 00:11:23,680 MULTIDISCIPLINARY TEAM. BY 250 00:11:23,680 --> 00:11:27,800 PENNY GILBERT. WHO SPECIALIZED 251 00:11:27,800 --> 00:11:30,680 IN ARTIFICIAL INTELLIGENCE WHO 252 00:11:30,680 --> 00:11:35,000 HELPED US DEVELOP ALGORITHMS. 253 00:11:35,000 --> 00:11:38,440 AND BEN COSGROVE A CHEMICAL 254 00:11:38,440 --> 00:11:41,040 ENGINEER. AND WHAT THEY FOUND 255 00:11:41,040 --> 00:11:43,840 WAS THAT MUSCLE, WHEN THEY 256 00:11:43,840 --> 00:11:46,640 LOOKED AT THE RIGIDITY OF MUSCLE 257 00:11:46,640 --> 00:11:49,480 THEY FOUND THAT IT HAS A 258 00:11:49,480 --> 00:11:51,920 STIFFNESS OF TWELVE KILO PASCALS 259 00:11:51,920 --> 00:11:54,040 WELL HOW DOES THAT COMPARE TO 260 00:11:54,040 --> 00:11:56,720 PLASTIC WHEN WE DID REE I DON'T 261 00:11:56,720 --> 00:12:00,920 MEAN TRY OF PLASTIC. PLASTIC IS 262 00:12:00,920 --> 00:12:04,240 FIVE ORDERS OF MAGNITUDE STIFFER 263 00:12:04,240 --> 00:12:07,760 THAN HEALTHY TISSUE SO IT IS A 264 00:12:07,760 --> 00:12:08,800 RIGIDITY THAT MUSCLES WOULD 265 00:12:08,800 --> 00:12:12,200 NEVER ENCOUNTER IN THE BODY. SO 266 00:12:12,200 --> 00:12:15,240 WE ENGINEERED HYDRO JELLS AND 267 00:12:15,240 --> 00:12:18,040 MADE SINGLE CELL MICRO WELLS AND 268 00:12:18,040 --> 00:12:21,720 BIO LIEU METTIC NICHES BY 269 00:12:21,720 --> 00:12:23,800 COMBINING TWO DIFFERENT PEG 270 00:12:23,800 --> 00:12:26,320 MONOMERS IN DIFFERENT 271 00:12:26,320 --> 00:12:27,840 CONCENTRATIONS SO THAT WE COULD 272 00:12:27,840 --> 00:12:32,880 ACHIEVE DIFFERENT RIGIDITIES AND 273 00:12:32,880 --> 00:12:35,960 THESE HYDRO JELLS HAVE MANY 274 00:12:35,960 --> 00:12:37,320 DIFFERENT ADVANTAGES. NOTHING 275 00:12:37,320 --> 00:12:39,880 STICKS TO THEM. THEY'RE WELL 276 00:12:39,880 --> 00:12:45,840 DEFINED UNLIKE OTHER GELS AND 277 00:12:45,840 --> 00:12:47,720 THEY HAVE MECHANICS. AND YOU 278 00:12:47,720 --> 00:12:49,920 CAN CONTROL LIGAN PRINTING WHICH 279 00:12:49,920 --> 00:12:51,840 IS IMPORTANT FOR MIMICKING 280 00:12:51,840 --> 00:12:55,880 VARIOUS ECM EXTRACELLULAR MATRIX 281 00:12:55,880 --> 00:12:57,600 COMPONENTS IN THE MICRO WELLS 282 00:12:57,600 --> 00:13:00,640 AND THEY CAN BE USED FOR SINGLE 283 00:13:00,640 --> 00:13:09,480 CELL CLDOAL ASSAYS HERE YOU CANE 284 00:13:09,480 --> 00:13:13,400 THE MICRO WAYS. 285 00:13:13,400 --> 00:13:19,240 SO DOES IT MATTER? PENNY 286 00:13:19,240 --> 00:13:22,040 DESIGNED THE STEM CELLS USING 287 00:13:22,040 --> 00:13:24,600 OUR PARAMETERS AND PLATED THEM 288 00:13:24,600 --> 00:13:28,080 IN SINGLE WELL HYDRO JELLS. OF 289 00:13:28,080 --> 00:13:30,960 DIFFERENT RIGIDITY. TWO IS 290 00:13:30,960 --> 00:13:32,920 ABOUT THE RIGID DID I OF BRAIN, 291 00:13:32,920 --> 00:13:36,160 TWELVE IS MUSCLE, 22 IS A LITTLE 292 00:13:36,160 --> 00:13:38,920 STIFFER AND 10 TO THE 6TH IS THE 293 00:13:38,920 --> 00:13:43,040 RIGIDITY OF PLASTIC AND AFTER 294 00:13:43,040 --> 00:13:47,800 ONE WEEK SHE TRANSPLANTED THE 295 00:13:47,800 --> 00:13:50,000 CELLS INTO THE INJURED HIND LIMB 296 00:13:50,000 --> 00:13:52,680 MUSCLES OF A MOUSE AND LOOKED 297 00:13:52,680 --> 00:13:56,040 FOR ENGRAPHMENT IN TERMS OF THE 298 00:13:56,040 --> 00:13:57,960 POTENT ASSAY WE HAVE FOR STEM 299 00:13:57,960 --> 00:13:59,680 CELL EXPANSION AND ENGRAPHMENT. 300 00:13:59,680 --> 00:14:01,280 WHAT SHE FOUND WAS THAT IT MAKES 301 00:14:01,280 --> 00:14:04,120 A HUGE DIFFERENCE. AND THAT 302 00:14:04,120 --> 00:14:06,880 WHEN YOU LOOK HERE ON THE LEFT, 303 00:14:06,880 --> 00:14:08,520 ARE A LARGE NUMBER OF DIFFERENT 304 00:14:08,520 --> 00:14:12,320 MOUSE LIMBS BUT IN THE MIDDLE 305 00:14:12,320 --> 00:14:15,120 YOU CAN SEE TYPICAL EXAMPLES AND 306 00:14:15,120 --> 00:14:18,320 WHEN THE HYDROGEN WAS TOO SOFT, 307 00:14:18,320 --> 00:14:21,520 AS IN TWO KILO PASCALS ARE STIFF 308 00:14:21,520 --> 00:14:24,480 AS IN 42 THEY DON'T ENGRAPH AS 309 00:14:24,480 --> 00:14:27,840 WELL AS IF THE CELLS ARE ON A 310 00:14:27,840 --> 00:14:31,080 MODULUS OF TWELVE KILO PASCALS 311 00:14:31,080 --> 00:14:33,280 WHICH IS TYPICAL OF THAT OF 312 00:14:33,280 --> 00:14:34,320 HEALTHY MUSCLE TISSUE AND YOU 313 00:14:34,320 --> 00:14:35,480 CAN SEE ON THE APPROPRIATE 314 00:14:35,480 --> 00:14:38,800 MODULUS THAT MIMICS THE STEM 315 00:14:38,800 --> 00:14:41,520 CELL NICHE OF THE HEALTHY TISSUE 316 00:14:41,520 --> 00:14:51,160 50% OF THE CELLS ENGRAPHED. TO 317 00:14:51,160 --> 00:14:53,680 SUMMARIZE THIS PART OF THE TALK, 318 00:14:53,680 --> 00:14:55,320 ONE IS TWO SOFT, ONE IS TOO 319 00:14:55,320 --> 00:14:58,360 STIFF AND ONE IS JUST RIGHT AND 320 00:14:58,360 --> 00:15:00,040 THE STEM CELLS CARE JUST AS WE 321 00:15:00,040 --> 00:15:04,160 DO ABOUT THE STIFFNESS OF THEIR 322 00:15:04,160 --> 00:15:07,160 BEDS. AND THIS IS A PARAMETER 323 00:15:07,160 --> 00:15:11,480 THAT IS KEY FOR MAINTAINING 324 00:15:11,480 --> 00:15:13,000 CULTURE AND HAS BEEN USED NOW 325 00:15:13,000 --> 00:15:16,640 FOR NUMEROUS DIFFERENT STEM CELL 326 00:15:16,640 --> 00:15:20,400 TYPES. NOW THAT WE CAN MAINTAIN 327 00:15:20,400 --> 00:15:24,360 THESE STEM CELLS WE CAN LOOK FOR 328 00:15:24,360 --> 00:15:26,800 REGULATORS OF THEIR -- THAT 329 00:15:26,800 --> 00:15:27,600 COULD CONTROL THEIR EXPANSION 330 00:15:27,600 --> 00:15:29,800 AND MAYBE EVEN REJUVENATION SO 331 00:15:29,800 --> 00:15:31,000 WE WERE INTERESTED IN WHAT 332 00:15:31,000 --> 00:15:33,160 HAPPENS WITH AGING AND WE 333 00:15:33,160 --> 00:15:39,320 ISOLATED STEM CELLS FROM AGED 334 00:15:39,320 --> 00:15:42,680 MICE AND FOUND IF WE INJECTED 335 00:15:42,680 --> 00:15:44,880 TEN CELLS AT A TIME INTO THE 336 00:15:44,880 --> 00:15:46,800 INJURED HIND LIMBS WE FOUND THAT 337 00:15:46,800 --> 00:15:48,480 THE FUNCTION OF THESE STEM CELLS 338 00:15:48,480 --> 00:15:51,520 FALLS OFF WITH AGING. AND YOU 339 00:15:51,520 --> 00:15:55,960 SEE THIS DROP FROM 56% 340 00:15:55,960 --> 00:15:59,000 ENGRAPHMENT IN ONE TO 21% IN THE 341 00:15:59,000 --> 00:16:00,600 AGED THAT'S EVIDENT IN THE 342 00:16:00,600 --> 00:16:01,600 IMAGING AND ALSO BY CONTRIBUTION 343 00:16:01,600 --> 00:16:04,800 TO THE MUSCLE FIBERS AS 344 00:16:04,800 --> 00:16:09,440 EVIDENCED BY GFP. WHEN WE DID 345 00:16:09,440 --> 00:16:10,360 LIMITING DILL SOLUTION ANALYSIS 346 00:16:10,360 --> 00:16:13,560 WE FOUND THAT TWO-THIRDS OF THE 347 00:16:13,560 --> 00:16:17,640 CELLS ARE NONFUNCTIONAL IN THE 348 00:16:17,640 --> 00:16:19,160 AGED ONLY ONE-THIRD ARE 349 00:16:19,160 --> 00:16:21,120 FUNCTIONAL AND WE WONDERED IF WE 350 00:16:21,120 --> 00:16:24,920 COULD FIND WAY TO RESTORE THAT 351 00:16:24,920 --> 00:16:28,840 FUNCTION. SO BEN COSGROVE IN 352 00:16:28,840 --> 00:16:31,160 THE LAB DID THIS IN THE DRUG 353 00:16:31,160 --> 00:16:32,600 SCREEN AND FOUND A SMALL 354 00:16:32,600 --> 00:16:36,800 MOLECULE THAT INHIBITS P 38 355 00:16:36,800 --> 00:16:38,000 KINASE AND HEAR YOU CAN SEE THAT 356 00:16:38,000 --> 00:16:41,760 IN AGED STEM CELLS THERE IS AN 357 00:16:41,760 --> 00:16:45,480 INCREASE IN THE TARGET PHOSPHO-P 358 00:16:45,480 --> 00:16:47,640 38 SO TO TEST WHETHER THIS WOULD 359 00:16:47,640 --> 00:16:50,680 HAVE AN EFFECT WHAT BEN DID WAS 360 00:16:50,680 --> 00:16:52,240 ISOLATE AGED MUSCLE STEM CELLS 361 00:16:52,240 --> 00:16:53,920 AND YOUNG MUSCLE STEM CELLS AND 362 00:16:53,920 --> 00:16:56,800 PLATE THEM EITHER ON PLASTIC OR 363 00:16:56,800 --> 00:16:59,840 ON HYDRO GEL IN THE PRESENCE OR 364 00:16:59,840 --> 00:17:04,280 ABSENCE OF THE DRUG THE SB 202 365 00:17:04,280 --> 00:17:08,840 INHIBITOR OF MAP KINASE AND 366 00:17:08,840 --> 00:17:11,000 TRANSPLANTED THE CELLS INTO THE 367 00:17:11,000 --> 00:17:12,560 INJURED HUNDREDED LIMBS OF A 368 00:17:12,560 --> 00:17:18,040 MASS AND THIS WAS DONE BY SNAKE 369 00:17:18,040 --> 00:17:20,840 VENOM TOXIN THAT DOES EXTENSIVE 370 00:17:20,840 --> 00:17:22,320 DAMAGE TO THE FIBERS THIS IS 371 00:17:22,320 --> 00:17:24,720 WHAT HE FOUND. THE YOUNG MUSCLE 372 00:17:24,720 --> 00:17:26,960 STEM CELLS ARE DOING SO WELL ON 373 00:17:26,960 --> 00:17:31,320 HYDRO GEL THAT THE DRUG MAKES NO 374 00:17:31,320 --> 00:17:32,960 DIFFERENCE BEING GRAPHED AS YOU 375 00:17:32,960 --> 00:17:35,240 CAN SEE HERE AND THE AGED ON 376 00:17:35,240 --> 00:17:37,600 PLASTIC ARE DOING SO POORLY THAT 377 00:17:37,600 --> 00:17:39,320 EVEN IN THE PRESENCE OF THE 378 00:17:39,320 --> 00:17:43,280 DRUG, THEY'RE NOT RESTORED. 379 00:17:43,280 --> 00:17:45,840 HOWEVER IF YOU PLATE THE AGED 380 00:17:45,840 --> 00:17:52,800 STEM CELLS ON A HYDRO GEL THAT 381 00:17:52,800 --> 00:17:55,560 MIMICS THE NICHE WITH THE MAP 382 00:17:55,560 --> 00:17:56,960 KINASE INHIBITOR YOU SEE ROBUST 383 00:17:56,960 --> 00:18:00,640 EXPANSION OF THE STEM CELLS. 384 00:18:00,640 --> 00:18:02,120 AND THAT IS DEPICTED OVER HERE 385 00:18:02,120 --> 00:18:03,880 FOR A LARGE NUMBER AND YOU CAN 386 00:18:03,880 --> 00:18:06,000 SEE THAT WE'VE RESTORED THE 387 00:18:06,000 --> 00:18:09,320 POTENTIAL OF THE AGED BACK TO 388 00:18:09,320 --> 00:18:15,240 THAT OF YOUNG. SO THIS SHOWS 389 00:18:15,240 --> 00:18:16,960 THERE'S A SYNERGY OF THE 390 00:18:16,960 --> 00:18:19,160 BIOCHEMICAL AND PHYSICAL 391 00:18:19,160 --> 00:18:20,960 PROPERTIES. THE HYDRO GEL RIGID 392 00:18:20,960 --> 00:18:27,480 DID I -- RIGIDITY AND A 393 00:18:27,480 --> 00:18:27,880 SIGNALLING PATHWAY. 394 00:18:27,880 --> 00:18:29,720 WELL THAT WAS ALL GOOD AND WELL 395 00:18:29,720 --> 00:18:31,680 FOR ENGRAPHMENT BUT WHAT ABOUT 396 00:18:31,680 --> 00:18:34,080 FUNCTION? WE NOW SOUGHT TO FIND 397 00:18:34,080 --> 00:18:37,320 OUT WHETHER THIS INCREASED 398 00:18:37,320 --> 00:18:38,160 MUSCLE STRENGTH. 399 00:18:38,160 --> 00:18:40,760 SO IN THIS CASE BEN ISOLATED THE 400 00:18:40,760 --> 00:18:43,440 STEM CELLS FROM 24 MONTH OLD 401 00:18:43,440 --> 00:18:45,880 MOUSE, CULTURED THEM ON HYDRO 402 00:18:45,880 --> 00:18:47,000 GELS IN THE PRESENCE OR ABSENCE 403 00:18:47,000 --> 00:18:51,360 OF THE P 38 MAP KINASE INHIBITOR 404 00:18:51,360 --> 00:18:53,440 SB AND TRANSPLANTED THEM INTO 405 00:18:53,440 --> 00:18:56,720 INJURED, AGED TA MUSCLES OF THE 406 00:18:56,720 --> 00:19:00,120 LEG. AND WHAT YOU SEE HERE IS 407 00:19:00,120 --> 00:19:03,880 THAT YOUNG -- YOUNG MICE HAVE A 408 00:19:03,880 --> 00:19:04,960 HIGH TWITCH FORCE STRENGTH. 409 00:19:04,960 --> 00:19:06,360 THIS IS THE MEASURE OF THEIR 410 00:19:06,360 --> 00:19:08,920 STRENGTH AND WITH AGING THAT 411 00:19:08,920 --> 00:19:15,880 DECREASES NEARLY 50% AND AFTER 412 00:19:15,880 --> 00:19:18,760 INJURY WITH NO TECH SIN IT 413 00:19:18,760 --> 00:19:19,880 INCREASES FURTHER. 414 00:19:19,880 --> 00:19:22,920 IF WE INCREASE THE PROGENY THAT 415 00:19:22,920 --> 00:19:25,040 WERE CULTURED ON THE HYDRO GEL 416 00:19:25,040 --> 00:19:27,560 TOGETHER WITH THE P 38 MAP 417 00:19:27,560 --> 00:19:30,120 KINASE INHIBITOR YOU NOW RESTORE 418 00:19:30,120 --> 00:19:31,640 STRENGTH TO THAT YOUNG. THIS IS 419 00:19:31,640 --> 00:19:33,040 SHOWN FOR ONE EXAMPLE HERE. 420 00:19:33,040 --> 00:19:34,880 BUT WE DID A NUMBER OF DIFFERENT 421 00:19:34,880 --> 00:19:38,160 MICE AND THAT'S SUMMARIZED HERE 422 00:19:38,160 --> 00:19:39,640 AND YOU CAN SEE THAT WE'VE 423 00:19:39,640 --> 00:19:43,480 RESTORED THE STRENGTH OF THE 424 00:19:43,480 --> 00:19:45,320 AGED MUSCLES THAT OF YOUNG 425 00:19:45,320 --> 00:19:47,680 MUSCLES BY THIS TREATMENT. SO 426 00:19:47,680 --> 00:19:50,160 THIS STANDS AS A VERY USEFUL 427 00:19:50,160 --> 00:19:52,960 CELL THERAPEUTIC APPROACH FOR 428 00:19:52,960 --> 00:19:55,000 ISOLATING THE CELLS, 429 00:19:55,000 --> 00:19:56,000 REJUVENATING THEM AND PUTTING 430 00:19:56,000 --> 00:19:57,800 THEM BACK INTO THE MUSCLE BUT 431 00:19:57,800 --> 00:20:00,840 THAT'S QUITE A LABOR-INTENSIVE 432 00:20:00,840 --> 00:20:03,120 AND NOT VERY COST-EFFECTIVE 433 00:20:03,120 --> 00:20:05,840 APPROACH AND SO WE SOUGHT OTHER 434 00:20:05,840 --> 00:20:08,040 APPROACHES. WE ALSO MORE 435 00:20:08,040 --> 00:20:11,040 RECENTLY HAD DESCRIBED ANOTHER 436 00:20:11,040 --> 00:20:12,760 MARKER OF AGING STEM CELLS THAT 437 00:20:12,760 --> 00:20:17,720 AND THAT IS CD 47 AND THIS WAS 438 00:20:17,720 --> 00:20:20,960 DISCOVERED BY ERE MA USING A 439 00:20:20,960 --> 00:20:24,960 HIGHLY DIMENSIONAL ANALYSIS. 440 00:20:24,960 --> 00:20:34,160 WHERE YOU CAN STAIN STAIN CELLS 441 00:20:34,160 --> 00:20:37,880 AND SUBJECT THEM TO -- YOU 442 00:20:37,880 --> 00:20:40,960 NEBULIZE THEM AND DO TIME OF 443 00:20:40,960 --> 00:20:45,280 FLIGHT. AND YOU CAN LOOK AT THE 444 00:20:45,280 --> 00:20:48,200 CLUSTER OF MARKERS AT THE 445 00:20:48,200 --> 00:20:49,760 INDIVIDUAL CELLS BY X-SHIFT 446 00:20:49,760 --> 00:20:51,240 ANALYSIS. YOU CAN SEE HERE WHEN 447 00:20:51,240 --> 00:20:53,440 WE LOOK AT THE AGED STEM CELLS 448 00:20:53,440 --> 00:20:55,480 THEY'RE EXPRESSING THE HALLMARK 449 00:20:55,480 --> 00:20:56,280 TRANSCRIPTION FACTOR OF THE STEM 450 00:20:56,280 --> 00:21:00,240 CELL AND THEY HAVE ELEVATED CD 451 00:21:00,240 --> 00:21:05,280 47 ON THEIR CELL SURFACE. AND 452 00:21:05,280 --> 00:21:07,080 WHEN WE LOOKED AT SEPARATION YOU 453 00:21:07,080 --> 00:21:09,520 CAN SEE THAT THE PROPORTION OF 454 00:21:09,520 --> 00:21:13,280 CELLS EXPRESSING HIGH CD47 IS 455 00:21:13,280 --> 00:21:15,680 INCREASED WITH AGING, THAT'S 456 00:21:15,680 --> 00:21:17,440 SHOWN HERE DOWN BELOW. 457 00:21:17,440 --> 00:21:20,720 80% OF THE AGED STEM CELLS HAVE 458 00:21:20,720 --> 00:21:23,920 ELEVATED CD47 ON THEIR CELL 459 00:21:23,920 --> 00:21:26,120 SURFACE AND THIS AFFECTS THEIR 460 00:21:26,120 --> 00:21:27,880 ENGRAPHMENT POTENTIAL. 461 00:21:27,880 --> 00:21:29,280 YOU CAN SEE NOW THAT THEIR 462 00:21:29,280 --> 00:21:31,960 ENGRAPHMENT WHEN YOU LOOK AT THE 463 00:21:31,960 --> 00:21:36,080 CD47 HIGH FROM YOUNG AND AGED 464 00:21:36,080 --> 00:21:36,880 ENGRAPHMENT POTENTIAL DROPS 465 00:21:36,880 --> 00:21:39,880 REMARKABLY AND THIS TURNS OUT TO 466 00:21:39,880 --> 00:21:43,120 BE DUE TO ALTERNATIVE 467 00:21:43,120 --> 00:21:43,720 POLYADENYLATION CHOICE THAT 468 00:21:43,720 --> 00:21:46,680 LEADS TO MORE OF THE LOCK 469 00:21:46,680 --> 00:21:49,880 ISOFORM OF CD 47 THAT IS 470 00:21:49,880 --> 00:21:53,080 LOCALIZED TO THE CELL MEMBRANE. 471 00:21:53,080 --> 00:21:55,280 WHEREAS THE INTRACELLULAR FORM 472 00:21:55,280 --> 00:21:57,600 IS NOT THE ALTERNATE FORM IS NOT 473 00:21:57,600 --> 00:22:00,000 EXPRESSED ON THE CELL SURFACE. 474 00:22:00,000 --> 00:22:02,360 IT IS THE CELL SURFACE FORM THAT 475 00:22:02,360 --> 00:22:04,680 HAS THIS DELL LE TIERS YOU 476 00:22:04,680 --> 00:22:07,600 AFFECT AND IN FACT CD47 IS A 477 00:22:07,600 --> 00:22:08,600 VERY INTERESTING MOLECULE. 478 00:22:08,600 --> 00:22:10,480 YOU PROBABLY KNOW IT AS THE 479 00:22:10,480 --> 00:22:11,960 DON'T EAT ME SIGNAL THAT IS 480 00:22:11,960 --> 00:22:14,280 EXPRESSED ON CANCER CELLS TO 481 00:22:14,280 --> 00:22:15,840 AVOID THE IMMUNE SYSTEM AND IN 482 00:22:15,840 --> 00:22:18,440 FACT IT MEDIATES BY DIRECTIONAL 483 00:22:18,440 --> 00:22:20,360 SIGNALLING. IT'S A LIGAND FOR 484 00:22:20,360 --> 00:22:26,960 ALMA WHICH IS THE DON'T EAT ME 485 00:22:26,960 --> 00:22:28,400 SIGNAL AND PROBABLY THE STEM 486 00:22:28,400 --> 00:22:30,880 CELLS, IT PREVENTS THE IMMUNE 487 00:22:30,880 --> 00:22:31,480 SYSTEM FROM CLEARING THE STEM 488 00:22:31,480 --> 00:22:35,120 CELLS AS WELL. AND IT'S ALSO A 489 00:22:35,120 --> 00:22:37,360 COMPONENT OF THIS COMPLEX AND 490 00:22:37,360 --> 00:22:39,120 IMPORTANTLY FOR OUR PURPOSES, 491 00:22:39,120 --> 00:22:41,000 IT'S A RECEPTOR FOR THROMBO 492 00:22:41,000 --> 00:22:44,960 RESPONSE DIN ONE AND WE REASON 493 00:22:44,960 --> 00:22:45,920 THAT THROMBO RESPONSE DIN MIGHT 494 00:22:45,920 --> 00:22:48,320 BE PLAYING A ROLE. WE FOUND 495 00:22:48,320 --> 00:22:51,240 THAT THE AGED STEM CELLS, 496 00:22:51,240 --> 00:22:53,680 SUBSTANTIVE AGE STEM CELLS ARE 497 00:22:53,680 --> 00:22:55,440 SECRETING THROMBO RESPONSE DIN 498 00:22:55,440 --> 00:22:57,760 ONE AND THAT INHIBITS THE 499 00:22:57,760 --> 00:22:59,320 PROLIFERATION OF THE AGED STEM 500 00:22:59,320 --> 00:23:00,720 CELLS. 501 00:23:00,720 --> 00:23:04,120 IN FACT, IF WE TREAT THE CELLS 502 00:23:04,120 --> 00:23:06,880 WITH AN ANTIBODY, A BLOCKADE OF 503 00:23:06,880 --> 00:23:08,720 THE THROMBO RESPONSE DIN WE CAN 504 00:23:08,720 --> 00:23:11,840 OVERCOME THIS BLOCK AND ENHANCE 505 00:23:11,840 --> 00:23:16,360 THE ENGRAPHMENT OF THE STEM 506 00:23:16,360 --> 00:23:26,880 CELLS. SO CD IS REGULATED BY 507 00:23:27,160 --> 00:23:30,280 AYDENLATION AND CAN BE OVERCOME 508 00:23:30,280 --> 00:23:33,720 BY A THROMBO RESPONSE DIN 509 00:23:33,720 --> 00:23:36,600 BLOCKADE. I WANT TO NOT DISCUSS 510 00:23:36,600 --> 00:23:37,280 THIS FURTHER ALTHOUGH WE HAVE 511 00:23:37,280 --> 00:23:38,760 VERY INTERESTING LINES OF DATA 512 00:23:38,760 --> 00:23:40,880 THERE BUT I WANT TO TURN TO THIS 513 00:23:40,880 --> 00:23:44,400 GEROZYME AND HOW WEALTHOUGH WE 514 00:23:44,400 --> 00:23:45,040 INTERESTING LINES OF DATA THERE 515 00:23:45,040 --> 00:23:45,600 BUT I WANT TO TURN TO THIS 516 00:23:45,600 --> 00:23:46,240 GEROZYME AND HOW WE DISCOVERED 517 00:23:46,240 --> 00:23:50,440 IT. THE GEROZYME REGULATES PD 2 518 00:23:50,440 --> 00:23:53,040 LEVELS. A NATURAL INFLAMMATORY 519 00:23:53,040 --> 00:23:55,240 MEDIATOR THAT STIMULATES MUSCLE 520 00:23:55,240 --> 00:23:57,120 STEM CELL FUNCTION AND WE 521 00:23:57,120 --> 00:23:59,440 DISCOVERED IT BECAUSE WE WERE 522 00:23:59,440 --> 00:24:00,880 LOOKING FOR SOMETHING THAT MIGHT 523 00:24:00,880 --> 00:24:02,800 BE IN THIS WAVE OF INFLAMMATION 524 00:24:02,800 --> 00:24:04,080 IMMEDIATELY AFTER DAMAGE. WHEN 525 00:24:04,080 --> 00:24:05,520 THERE'S DAMAGE TO THE MUSCLE AND 526 00:24:05,520 --> 00:24:08,920 TO MANY TISSUES PGE 2 IS 527 00:24:08,920 --> 00:24:10,720 ELEVATED AND THERE'S THIS WAVE 528 00:24:10,720 --> 00:24:12,920 OF INFLAMMATION. AND WE REASON 529 00:24:12,920 --> 00:24:15,240 THAT HAD THE STEM CELLS MIGHT BE 530 00:24:15,240 --> 00:24:16,960 EXQUISITELY SENSITIVE TO 531 00:24:16,960 --> 00:24:18,680 SOMETHING IN THAT INFLAMMATORY 532 00:24:18,680 --> 00:24:20,880 WAVE AND THIS WORK WAS DONE BY 533 00:24:20,880 --> 00:24:26,280 VERY TWO TALENTED POSTDOCS. 534 00:24:26,280 --> 00:24:28,880 ANDREW HO AND ADA LAY DA PAULA. 535 00:24:28,880 --> 00:24:31,440 THEY WERE LOOKING FOR REGULATORS 536 00:24:31,440 --> 00:24:34,080 OF INFLAMMATION ON AC DID I 537 00:24:34,080 --> 00:24:36,920 VATED STEM CELLS WE SEARCHED THE 538 00:24:36,920 --> 00:24:38,880 DATABASE FROM OUR OWN LAB AND 539 00:24:38,880 --> 00:24:39,200 TWO OTHERS. 540 00:24:39,200 --> 00:24:43,760 LOOK FOR REGULATORS OF 541 00:24:43,760 --> 00:24:46,000 INFLAMMATION. IMMEDIATELY AFTER 542 00:24:46,000 --> 00:24:49,480 INJURY. IN THE STEM CELLS AND 543 00:24:49,480 --> 00:24:53,720 EP 4 WAS ONE OF THE HIGHEST 544 00:24:53,720 --> 00:24:56,880 HITS. A RECEPTOR FOR 545 00:24:56,880 --> 00:24:58,480 PROSTAGLANDIN E 2. IT IS ON THE 546 00:24:58,480 --> 00:25:00,720 CELL SURFACE. 547 00:25:00,720 --> 00:25:04,080 AND WE REASONED THAT VERY LITTLE 548 00:25:04,080 --> 00:25:07,600 HAS BEEN DONE TO ELUCIDATE THE 549 00:25:07,600 --> 00:25:11,880 ROLE OF PGE 2 MAYBE BECAUSE IT 550 00:25:11,880 --> 00:25:12,920 DOESN'T APPEAR ON A 551 00:25:12,920 --> 00:25:16,360 TRANSCRIPTOME BECAUSE IT IS A 552 00:25:16,360 --> 00:25:19,280 METABOLITE. IT IS DRIVE FROM 553 00:25:19,280 --> 00:25:22,760 MEMBRANE PHOSPHOLIPIDS GIVING 554 00:25:22,760 --> 00:25:27,000 RISE TO IRAQNY DONNIC ACID. 555 00:25:27,000 --> 00:25:28,200 AND THAT CONNECT ON ANY ONE OF 556 00:25:28,200 --> 00:25:30,320 FOUR RECEPTORS. 557 00:25:30,320 --> 00:25:32,160 ON MUSCLE STEM CELLS AND ON 558 00:25:32,160 --> 00:25:36,120 MUSCLE FIBERS EP 4 IS THE 559 00:25:36,120 --> 00:25:41,040 PREDOMINANT GBCR THAT IS 560 00:25:41,040 --> 00:25:45,480 EXPRESSED AND THAT IS BY EMP. 561 00:25:45,480 --> 00:25:51,360 IMPORTANTLY, NSAIDS, LIKE 562 00:25:51,360 --> 00:25:55,000 IBUPROFEN BLOCK THE SYNTHESIS OF 563 00:25:55,000 --> 00:25:58,960 PGE 2. THEY BLOCK YOUR NATURAL 564 00:25:58,960 --> 00:26:05,840 HEALING RESPONSE. TO FIND OUT 565 00:26:05,840 --> 00:26:07,320 WHETHER THIS PATHWAY WAS 566 00:26:07,320 --> 00:26:09,080 IMPORTANT WE CONDUCTED AN 567 00:26:09,080 --> 00:26:12,960 OBLATION OF EP 4 ON STEM CELLS 568 00:26:12,960 --> 00:26:16,280 BY CREATING THIS MOUSE MODEL 569 00:26:16,280 --> 00:26:19,280 WHERE PAX 7 LEADS TO OBLATION OF 570 00:26:19,280 --> 00:26:23,200 THE EP 4 RECEPTOR ON STEM CELLS 571 00:26:23,200 --> 00:26:24,920 SPECIFICALLY THEN PERFORM AN 572 00:26:24,920 --> 00:26:27,840 INJURY. AN INJECTION AND THEN 573 00:26:27,840 --> 00:26:29,160 ASSAY STRENGTH SEVERAL WEAKS 574 00:26:29,160 --> 00:26:31,120 LATER AND WHAT WE FOUND WAS THAT 575 00:26:31,120 --> 00:26:33,320 IN THE ABSENCE OF BEING ABLE TO 576 00:26:33,320 --> 00:26:36,400 DETECT THIS SIGNALLING PATHWAY, 577 00:26:36,400 --> 00:26:39,480 THE MICE ACTUALLY GOT WEAKER. 578 00:26:39,480 --> 00:26:42,760 YOU SEE TWITCH FORCE DROP AND 579 00:26:42,760 --> 00:26:46,760 TIM TE TANNIC FORCE DROP. AND 580 00:26:46,760 --> 00:26:50,960 THE CELLS IN IN CULTURE IN THE 581 00:26:50,960 --> 00:26:53,800 ABSENCE OF THIS BARELY 582 00:26:53,800 --> 00:26:55,520 PROLIFERATE. THIS IS A CRUCIAL 583 00:26:55,520 --> 00:26:57,160 PATHWAY IN REGENERATION. AND WE 584 00:26:57,160 --> 00:26:59,560 LOOKED AT A LARGE NUMBER OF MICE 585 00:26:59,560 --> 00:27:02,200 AND WE CAN SEE TWITCH FORCE AND 586 00:27:02,200 --> 00:27:04,320 TE TANNIC FORCE DECLINE. YOUNG 587 00:27:04,320 --> 00:27:05,320 MICE GET WEAKER IF THEY 588 00:27:05,320 --> 00:27:08,440 REGENERATE THEIR MUSCLES IN THE 589 00:27:08,440 --> 00:27:09,240 ABSENCE OF THE SIGNALLING 590 00:27:09,240 --> 00:27:11,480 PATHWAY IN STEM CELLS. WE DID 591 00:27:11,480 --> 00:27:14,080 ANOTHER EXPERIMENT TO LOOK AT 592 00:27:14,080 --> 00:27:18,440 THE SIGNIFICANCE OF THE PATHWAY. 593 00:27:18,440 --> 00:27:21,880 AND HERE WE MADE A DIFFERENT 594 00:27:21,880 --> 00:27:26,760 MASS MODEL WHERE THE 595 00:27:26,760 --> 00:27:29,320 TRANSCRIPTION FACTORS DRIVE. 596 00:27:29,320 --> 00:27:30,960 YOU CAN SEE AFTER AN INJURY IF 597 00:27:30,960 --> 00:27:34,920 WE GIVE THE MICE AN NSAID LIKE 598 00:27:34,920 --> 00:27:37,040 IBUPROFEN WE BLOCK ENDOGENOUS 599 00:27:37,040 --> 00:27:39,440 SYNTHESIS AND THAT LEADS TO A 600 00:27:39,440 --> 00:27:40,960 DECLINE IN STEM CELLS. THEY 601 00:27:40,960 --> 00:27:43,040 CANNOT EXPAND. THEY NEED THE 602 00:27:43,040 --> 00:27:45,480 SIGNALLING PATHWAY TO 603 00:27:45,480 --> 00:27:48,640 PROLIFERATE AND EXPAND AND 604 00:27:48,640 --> 00:27:51,200 ENGRAFT. AND THIS IS ALSO 605 00:27:51,200 --> 00:27:53,440 REFLECTED IN A LOSS OF STRENGTH, 606 00:27:53,440 --> 00:27:56,760 A LOSS OF FORCE, THE YOUNG MICE 607 00:27:56,760 --> 00:27:59,000 GET WEAKER AND THIS WAS PICKED 608 00:27:59,000 --> 00:28:01,520 UP, THIS STORY BY THE NEW YORK 609 00:28:01,520 --> 00:28:03,320 TIMES, BRING ON THE EXERCISE AND 610 00:28:03,320 --> 00:28:05,280 HOLD THE PAINKILLERS. NO PAIN 611 00:28:05,280 --> 00:28:07,720 NO GAIN. BECAUSE WHEN YOU 612 00:28:07,720 --> 00:28:09,160 EXERCISE, WHEN YOU RUN A 613 00:28:09,160 --> 00:28:11,360 MARATHON OR YOU WORK OUT IN A 614 00:28:11,360 --> 00:28:12,120 GYM, YOU ARE DOING DAMAGE TO 615 00:28:12,120 --> 00:28:14,320 YOUR MUSCLES. IT'S A GOOD 616 00:28:14,320 --> 00:28:16,760 DAMAGE, IT'S THE WAY YOU BUILD 617 00:28:16,760 --> 00:28:18,400 MUSCLE BUT YOU ABSOLUTELY NEED 618 00:28:18,400 --> 00:28:22,320 THIS PGE 2 SIGNALLING PATHWAY 619 00:28:22,320 --> 00:28:23,640 AND IF YOU TAKE2 SIGNALLING PATD 620 00:28:23,640 --> 00:28:27,800 IF YOU TAKE AN IBUPROFEN RIGHT 621 00:28:27,800 --> 00:28:30,160 AFTER YOU FEEL ACHY BECAUSE YOU 622 00:28:30,160 --> 00:28:31,000 EXERCISED YOU'RE PROBABLY 623 00:28:31,000 --> 00:28:35,400 NEGATING THE WORK THAT YOU DID 624 00:28:35,400 --> 00:28:37,360 SO WHAT ABOUT THE ROLE OF PGE2 625 00:28:37,360 --> 00:28:40,960 IN AGING. IT WAS NOT CLEAR THIS 626 00:28:40,960 --> 00:28:43,080 WOULD HAVE A BENEFICIAL EFFECT. 627 00:28:43,080 --> 00:28:48,000 UNLIKE THE NICHE WHERE YOU SEE 628 00:28:48,000 --> 00:28:51,880 THE ORDERLY SEQUENTIAL OF CELL 629 00:28:51,880 --> 00:28:53,520 TYPES THE AGE NICHE IS 630 00:28:53,520 --> 00:28:54,640 DYSREGULATED AND YOU SEE THIS 631 00:28:54,640 --> 00:28:58,440 CHRONIC INCREASE IN INFLAMMATORY 632 00:28:58,440 --> 00:29:02,120 CELLS IN PARTICULAR IN 633 00:29:02,120 --> 00:29:05,600 FIBROBLASTS. SO WE WONDERED 634 00:29:05,600 --> 00:29:06,280 WHETHER PGE 2 WOULD HAVE A 635 00:29:06,280 --> 00:29:06,720 BENEFICIAL EFFECT. 636 00:29:06,720 --> 00:29:09,200 WE LOOKED AT THE MUSCLES, YOUNG 637 00:29:09,200 --> 00:29:12,120 AND AGED AND YOU CAN SEE HERE 638 00:29:12,120 --> 00:29:15,000 THE EP 4 RECEPTOR IS PRESENT 639 00:29:15,000 --> 00:29:16,760 ROBUSTLY ON YOUNG MUSCLE STEM 640 00:29:16,760 --> 00:29:18,760 CELLS BUT NOT ON AGED IN THE 641 00:29:18,760 --> 00:29:20,600 MUSCLE TISSUE. THIS IS A CROSS 642 00:29:20,600 --> 00:29:22,000 SECTION OR A LONGITUDINAL 643 00:29:22,000 --> 00:29:25,600 SECTION OF A MUSCLE FIBER. AND 644 00:29:25,600 --> 00:29:27,680 YOU CAN SEE HERE THAT THE 645 00:29:27,680 --> 00:29:32,120 PERCENTAGE OF RECEPTOR POSITIVE 646 00:29:32,120 --> 00:29:33,880 STEM CELLS DECREASES AND THE 647 00:29:33,880 --> 00:29:37,160 INTENSITY OR THE NUMBER OF 648 00:29:37,160 --> 00:29:38,640 RECEPTORS ALSO DECREASES AND 649 00:29:38,640 --> 00:29:44,240 ALSO SIGNALLING BY A TOS TO KREB 650 00:29:44,240 --> 00:29:47,720 IS DECREASED RELATIVE TO THE 651 00:29:47,720 --> 00:29:47,960 YOUNG. 652 00:29:47,960 --> 00:29:53,400 AND IN ADDITION WE DID RNA SEEK 653 00:29:53,400 --> 00:29:55,760 ANALYSIS TO UNDERSTAND THE ROLE 654 00:29:55,760 --> 00:29:57,600 OF THE PGE2 SIGNALLING PATHWAY 655 00:29:57,600 --> 00:30:00,760 AND MY OWE GENESIS, IN YOUNG AND 656 00:30:00,760 --> 00:30:00,960 AGED. 657 00:30:00,960 --> 00:30:05,440 AND WHEN WE DID THAT, WE WERE 658 00:30:05,440 --> 00:30:09,400 ABLE TO SEE TWO TRAJECTORITRAJE 659 00:30:09,400 --> 00:30:11,120 THERE WAS A CYCLING TRAJECTORY 660 00:30:11,120 --> 00:30:14,640 WHERE THE CELLS EXPAND, THEY 661 00:30:14,640 --> 00:30:16,160 PROLIFERATE AND THEIR NUMBERS 662 00:30:16,160 --> 00:30:19,680 INCREASE AND A DIRECT COMMITMENT 663 00:30:19,680 --> 00:30:22,000 TRAJECTORY WHERE THEY 664 00:30:22,000 --> 00:30:24,520 PREMATURELY COMMIT, STOP 665 00:30:24,520 --> 00:30:26,520 PROLIFERATING AND BECOME 666 00:30:26,520 --> 00:30:27,400 DIFFERENTIATED AND COMMITTED 667 00:30:27,400 --> 00:30:28,960 CELLS AND WHAT WE FOUND WAS THAT 668 00:30:28,960 --> 00:30:32,000 THE YOUNG MUSCLE STEM CELLS 669 00:30:32,000 --> 00:30:33,760 PRIMARILY ADOPT THIS SELF 670 00:30:33,760 --> 00:30:36,040 CYCLING PATHWAY WHICH IS THE 671 00:30:36,040 --> 00:30:36,680 REASON THEY BELIEVING REGENERATE 672 00:30:36,680 --> 00:30:40,280 SO EFFECTIVELY BECAUSE THEY CAN 673 00:30:40,280 --> 00:30:42,480 EXPAND AND CYCLE WHEREAS THE AGE 674 00:30:42,480 --> 00:30:44,880 PREMATURELY COMMIT, MORE OF THEM 675 00:30:44,880 --> 00:30:46,560 ADOPT THIS DIRECT COMMITMENT 676 00:30:46,560 --> 00:30:47,240 TRAJECTORY. 677 00:30:47,240 --> 00:30:49,720 AND WHEN WE LOOKED AT THE KINDS 678 00:30:49,720 --> 00:30:53,760 OF MOLECULES THAT ARE EXPRESSED 679 00:30:53,760 --> 00:30:56,960 IN THE CYCLING PATHWAY, PGE2 680 00:30:56,960 --> 00:30:58,600 SIGNALLING WAS ONE OF THE MOST 681 00:30:58,600 --> 00:31:00,320 PROMINENT. YOU CAN SEE THE 682 00:31:00,320 --> 00:31:01,960 ENTIRE CASCADE IS HIGHLY 683 00:31:01,960 --> 00:31:03,880 REPRESENTED. AND THAT IS PART 684 00:31:03,880 --> 00:31:06,880 OF THIS CYCLING TRAJECTORY THAT 685 00:31:06,880 --> 00:31:08,960 IS LOST IN THE AGED AND 686 00:31:08,960 --> 00:31:12,160 REPRESENTED VERY STRONGLY IN THE 687 00:31:12,160 --> 00:31:18,280 YOUNG. THIS IS ALSO REFLECTED 688 00:31:18,280 --> 00:31:20,360 IN THE EPIGENETIC SIGNATURE. WE 689 00:31:20,360 --> 00:31:22,040 DID A SEEK OF THE AGED AND YOUNG 690 00:31:22,040 --> 00:31:26,080 STEM CELLS AFTER EXPOSURE TO PGE 691 00:31:26,080 --> 00:31:28,400 2 FOR JUST TWO HOURS. WHEN WE 692 00:31:28,400 --> 00:31:30,400 WOULD SEE AN EXPANSION OF THEIR 693 00:31:30,400 --> 00:31:31,400 PROLIFERATION. 694 00:31:31,400 --> 00:31:33,160 AND WHAT YOU SEE IS THAT THE 695 00:31:33,160 --> 00:31:37,840 AGED MUSCLE STEM CELLS HAVE OPEN 696 00:31:37,840 --> 00:31:40,240 MOTIFS, CHROMATIN IS OPEN AT THE 697 00:31:40,240 --> 00:31:44,640 AP 1 MOTIF AT THE CBP MOTIF IN 698 00:31:44,640 --> 00:31:48,480 THE EBOXES THAT ARE SO CRUCIAL 699 00:31:48,480 --> 00:31:50,880 ARE CLOSED. AFTER TWO HOURS OF 700 00:31:50,880 --> 00:31:53,200 EXPOSURE TO PGE2 WE FOUND THAT 701 00:31:53,200 --> 00:31:57,880 THE AGE BECOME REJUVENATED. 702 00:31:57,880 --> 00:32:02,400 THAT CREB MOTIF IS OPENED AND 703 00:32:02,400 --> 00:32:05,480 THE AP 1 MOTIF IS SHUT. 704 00:32:05,480 --> 00:32:07,680 THERE'S A DRAMATIC CHANGE IN 705 00:32:07,680 --> 00:32:12,480 CHROMATIN TO REFLECT A MORE 706 00:32:12,480 --> 00:32:15,040 REJUVENATED EPIGENETIC 707 00:32:15,040 --> 00:32:16,960 SIGNATURE. AND THIS IS ALSO 708 00:32:16,960 --> 00:32:19,000 SEEN HERE BY TIME LAPSE. SO 709 00:32:19,000 --> 00:32:20,880 HERE YOU CAN SEE AN ANALYSIS BY 710 00:32:20,880 --> 00:32:23,120 TIME LAPSE. MICROSCOPY AT THE 711 00:32:23,120 --> 00:32:25,160 FUNCTION OF THE AGED MUSCLE STEM 712 00:32:25,160 --> 00:32:26,880 CELLS IN THE PRESENCE AND 713 00:32:26,880 --> 00:32:28,720 ABSENCE OF PGE2 SO THIS GIVES 714 00:32:28,720 --> 00:32:31,680 YOU AN EXAMPLE OF ONE OF THESE 715 00:32:31,680 --> 00:32:36,960 HYDRO GEL MICRO WELLS WHERE 716 00:32:36,960 --> 00:32:39,680 WE'RE MICROWAVES THE STEM CELLS. 717 00:32:39,680 --> 00:32:41,840 AND AND WHAT YOU CAN SEE ON THE 718 00:32:41,840 --> 00:32:43,760 LEFT OF THE SINGLE AGED STEM 719 00:32:43,760 --> 00:32:45,320 CELL EXPOSED JUST TO VEHICLE. 720 00:32:45,320 --> 00:32:49,320 AND ON THE RIGHT EXPOSED TO PGE 721 00:32:49,320 --> 00:32:51,640 2 IT BECOMES READILY APPARENT 722 00:32:51,640 --> 00:32:52,800 THAT YOU HAVE THIS MASSIVE 723 00:32:52,800 --> 00:32:55,440 INCREASE IN CELL NUMBERS. 724 00:32:55,440 --> 00:32:57,880 BECAUSE YOU HAVE MORE 725 00:32:57,880 --> 00:32:59,360 PROLIFERATION AND IN PARTICULAR, 726 00:32:59,360 --> 00:33:01,280 YOU HAVE FEWER CELL DEATH EVENTS 727 00:33:01,280 --> 00:33:05,440 AS SHOWN AT THE BOTTOM HERE. SO 728 00:33:05,440 --> 00:33:08,040 PGE2 IS PROMOTING PROLIFERATION, 729 00:33:08,040 --> 00:33:11,760 SELF CYCLE AND ALSO PREVENTING 730 00:33:11,760 --> 00:33:12,640 CELL DEATH. 731 00:33:12,640 --> 00:33:14,600 LOOK AT THE NUMBER OF CELLS THAT 732 00:33:14,600 --> 00:33:15,800 ARE ACCUMULATING THERE. 733 00:33:15,800 --> 00:33:22,440 AND THIS IS REFLECTED IN THE 734 00:33:22,440 --> 00:33:23,960 TRANSCRIPTOMES. IF WE EXPOSE 735 00:33:23,960 --> 00:33:25,600 STEM CELLS TO PGE 2 FOR 24 HOURS 736 00:33:25,600 --> 00:33:31,320 IF YOU LOOK AT THE YOUNG, THE 737 00:33:31,320 --> 00:33:31,960 TRANSCRIPTOME ANALYSIS FOR THREE 738 00:33:31,960 --> 00:33:36,320 YOUNG, YOU CAN SEE THEY DON'T 739 00:33:36,320 --> 00:33:37,800 DIFFER MUCH BECAUSE THE YOUNG 740 00:33:37,800 --> 00:33:39,160 ARE DOING SO WELL IN THEIR 741 00:33:39,160 --> 00:33:40,960 FUNCTION AND THE AGED HOWEVER, 742 00:33:40,960 --> 00:33:42,240 THERE'S A BLOCK OF GENES THAT 743 00:33:42,240 --> 00:33:44,480 ARE HIGHLY EXPRESSED IN AND 744 00:33:44,480 --> 00:33:48,280 ANOTHER BLOCK OF GENES THAT ARE 745 00:33:48,280 --> 00:33:50,880 DECREASED BUT AFTER EXPOSURE TO 746 00:33:50,880 --> 00:33:53,360 PGE2 YOU NOW SEE A REJUVENATION 747 00:33:53,360 --> 00:33:57,840 OF THIS AGED MUSCLE STEM CELL 748 00:33:57,840 --> 00:33:59,880 TRANSCRIPTOME AND WHEN WE LOOK 749 00:33:59,880 --> 00:34:02,200 BY ANALYSIS THIS IS ALSO 750 00:34:02,200 --> 00:34:03,520 REFLECTIVE THERE. THERE WAS A 751 00:34:03,520 --> 00:34:04,920 NEGATIVE REGULATION OF CELL 752 00:34:04,920 --> 00:34:07,520 DEATH GENES, NEGATIVE REGULATION 753 00:34:07,520 --> 00:34:11,680 OF PROGRAMMED NECROTIC CELL 754 00:34:11,680 --> 00:34:15,880 DEATH. SO THIS MITOTIC 755 00:34:15,880 --> 00:34:17,720 CATASTROPHE IS OVERCOME BY PGE 2 756 00:34:17,720 --> 00:34:20,880 AND THERE'S AN INCREASE IN 757 00:34:20,880 --> 00:34:24,720 SURVIVAL AND SURVIVAL RELATED 758 00:34:24,720 --> 00:34:32,440 GENES. HOW DOES THIS AFFECT THE 759 00:34:32,440 --> 00:34:34,080 CELLS? FUNCTION IS THE MOST 760 00:34:34,080 --> 00:34:35,920 IMPORTANT. I HAVE SHOWN YOU 761 00:34:35,920 --> 00:34:36,920 LOSS OF FUNCTION EXPERIMENTS. 762 00:34:36,920 --> 00:34:40,920 IF WE COINHEKT AGED MUSCLE STEM 763 00:34:40,920 --> 00:34:43,200 CELLS WITH THE PGE 2 WHICH IS A 764 00:34:43,200 --> 00:34:45,880 MORE STABLE FORM OF 765 00:34:45,880 --> 00:34:47,680 PROSTAGLANDIN E 2 IT IS STILL 766 00:34:47,680 --> 00:34:49,760 ONLY IN THE CIRCULATION FOR 767 00:34:49,760 --> 00:34:52,120 THREE HOURS WE COINJECT AND LOOK 768 00:34:52,120 --> 00:34:56,720 AFTER INJURY AT THE BLI SIGNAL 769 00:34:56,720 --> 00:34:59,280 WHICH IS THE MEASURE OF STEM 770 00:34:59,280 --> 00:35:00,800 CELL EXPANSION. HERE YOU CAN 771 00:35:00,800 --> 00:35:03,840 SEE THE CELLS ENGRAPHED AND THIS 772 00:35:03,840 --> 00:35:07,320 IS A LOG SCALE, FAR MORE 773 00:35:07,320 --> 00:35:10,680 EFFICIENTLY AFTER A TRAN CHENT 774 00:35:10,680 --> 00:35:12,880 EXPOSURE TO PGE 2 AND IF WE GIVE 775 00:35:12,880 --> 00:35:15,760 IT A SECOND INJURY THEY FURTHER 776 00:35:15,760 --> 00:35:20,560 INCREASE IN THEIR ENGRAPHMENT 777 00:35:20,560 --> 00:35:23,160 SHOWING THESE ARE STILL STEM 778 00:35:23,160 --> 00:35:24,320 CELLS AND THEIR STEM CELL 779 00:35:24,320 --> 00:35:26,360 POTENTIAL IS PRESENT. THIS 780 00:35:26,360 --> 00:35:27,000 SHOWS ALSO THAT THERE IS A 781 00:35:27,000 --> 00:35:31,600 MEMORY THAT IS INDUCED BY THIS 782 00:35:31,600 --> 00:35:34,280 SHORT-TERM EXPOSURE OF THE STEM 783 00:35:34,280 --> 00:35:35,840 CELLS TO A PGE 2 WHICH IS WHAT 784 00:35:35,840 --> 00:35:41,080 WE SAW REFLECTED IN THE ATTACK 785 00:35:41,080 --> 00:35:42,720 SEEK CHROMATIN SIGNATURE AS 786 00:35:42,720 --> 00:35:44,840 WELL. ANOTHER LINE OF EVIDENCE 787 00:35:44,840 --> 00:35:45,480 WE CAN ALSO SEE THAT PGE 2 788 00:35:45,480 --> 00:35:50,120 ENHANCES THE ENDOGENOUS STEM 789 00:35:50,120 --> 00:35:51,520 CELL REFUNCTION DURING 790 00:35:51,520 --> 00:35:54,120 REGENERATION AND LEADING TO 791 00:35:54,120 --> 00:35:56,160 INCREASED STRENGTH. 792 00:35:56,160 --> 00:35:58,520 IN THIS CASE WE INJECTED THIS 793 00:35:58,520 --> 00:36:00,560 INTO THE MUSCLE OF AGED MICE. 794 00:36:00,560 --> 00:36:03,800 IN THIS CASE, GERIATRIC MICE AND 795 00:36:03,800 --> 00:36:05,800 THANK YOU NIA FOR MAKING THESE 796 00:36:05,800 --> 00:36:07,840 MICE AVAILABLE TO US FOR THESE 797 00:36:07,840 --> 00:36:09,120 STUDIES WHICH HAS BEEN 798 00:36:09,120 --> 00:36:12,920 INVALUABLE TO THESE DISCOVERIES. 799 00:36:12,920 --> 00:36:18,400 AND WE SEE THAT IF WE GIVE A DM 800 00:36:18,400 --> 00:36:19,880 PGE 2 TWO DAYS AFTER INJURY SO 801 00:36:19,880 --> 00:36:22,680 WE'RE ENHANCING THE HEALING 802 00:36:22,680 --> 00:36:24,480 RESPONSE OF PGE 2. ON DAY 14, 803 00:36:24,480 --> 00:36:28,080 JUST TWO WEEKS LATER WE SEE AN 804 00:36:28,080 --> 00:36:29,680 INCREASE IN CROSS-SECTIONAL 805 00:36:29,680 --> 00:36:32,400 AREA, THE SIZE, THE DIAMETER OF 806 00:36:32,400 --> 00:36:36,920 THE MUSCLE FIBERS, YOU SEE A 807 00:36:36,920 --> 00:36:38,960 SHIFT IN THESE DIAMETERS AND 808 00:36:38,960 --> 00:36:41,720 THAT'S REFLECTED HERE ALSO A 809 00:36:41,720 --> 00:36:44,120 GREATER NUMBER IN PAX 7 POSITIVE 810 00:36:44,120 --> 00:36:46,280 MUSCLE STEM CELLS. AND SO 811 00:36:46,280 --> 00:36:48,120 REGENERATION IS ENHANCED, 812 00:36:48,120 --> 00:36:51,840 DECISION WE SEE AN INCREASE IN 813 00:36:51,840 --> 00:36:54,720 MUSCLE MASS OF THE TIBIALIS 814 00:36:54,720 --> 00:36:56,920 ANTERIOR AND IN STRENGTH 815 00:36:56,920 --> 00:36:59,680 MEASURED BY TE TANNIC FORCE AND 816 00:36:59,680 --> 00:37:03,520 IN ABSOLUTE FORCE OR TORQUE. 817 00:37:03,520 --> 00:37:07,280 ENDOGENOUS STEM CELLS RESPOND 818 00:37:07,280 --> 00:37:08,920 ROBUSTLY TO PGE 2 INTRAMUSCULAR 819 00:37:08,920 --> 00:37:11,600 INJECTION LEADING TO INCREASED 820 00:37:11,600 --> 00:37:13,200 SIZES OF THE MUSCLE AND 821 00:37:13,200 --> 00:37:16,440 INCREASED FUNCTION IN TERMS OF 822 00:37:16,440 --> 00:37:21,600 STRENGTH. WELL NOW THIS IS ONE 823 00:37:21,600 --> 00:37:22,880 WAY TO DO DAMAGE SO WE DECIDED 824 00:37:22,880 --> 00:37:26,200 TO LOOK AT A MORE PHYSIOLOGICAL 825 00:37:26,200 --> 00:37:28,160 DAMAGE BY SUBJECTING THE MICE TO 826 00:37:28,160 --> 00:37:30,920 DOWNHILL RUNNING. RUNNING 827 00:37:30,920 --> 00:37:33,520 DOWNHILL ON A TREADMILL AND THEY 828 00:37:33,520 --> 00:37:35,840 RUN FOR TEN MINUTES A DAY FOR 829 00:37:35,840 --> 00:37:37,680 ONE WEEK AND AFTER EACH DAY WE 830 00:37:37,680 --> 00:37:40,440 GAVE THEM A SHOT. THEY RAN FOR 831 00:37:40,440 --> 00:37:41,800 ANOTHER WEEK AND AT THE END OF 832 00:37:41,800 --> 00:37:44,040 FOUR WEEKS WE LOOKED AT THAFR 833 00:37:44,040 --> 00:37:44,720 STRENGTH AND AS YOU CAN SEE HERE 834 00:37:44,720 --> 00:37:46,840 THERE'S A ROBUST INCREASE IN 835 00:37:46,840 --> 00:37:49,240 THEIR TWITCH FORCE AND IN THEIR 836 00:37:49,240 --> 00:37:50,040 TE TANNIC FORCE THAT IS SHOWN 837 00:37:50,040 --> 00:37:52,040 HERE FOR A NUMBER OF MICE. 838 00:37:52,040 --> 00:37:55,800 SO STRENGTH IS ROBUSTLY 839 00:37:55,800 --> 00:38:00,480 INCREASED BY AN ACUTE -- A 840 00:38:00,480 --> 00:38:02,280 SHORT-TERM TREATMENT WITH PGE 2 841 00:38:02,280 --> 00:38:03,960 HAS A LONG-TERM EFFECT IN 842 00:38:03,960 --> 00:38:07,440 INCREASING THE STRENGTH OF AGED 843 00:38:07,440 --> 00:38:14,400 MICE. WE WONDERED WHETHER WE 844 00:38:14,400 --> 00:38:16,240 COULD GLOBALLY INCREASE FUNCTION 845 00:38:16,240 --> 00:38:18,360 WITH PGE 2 INSTEAD OF JUST 846 00:38:18,360 --> 00:38:20,280 INCORRECTING IT LOCALLY. AND 847 00:38:20,280 --> 00:38:23,240 THIS IS WHAT LEAD US TO THE 848 00:38:23,240 --> 00:38:24,920 DISCOVERY OF THE GEROZYME, AND 849 00:38:24,920 --> 00:38:28,920 THIS WORK WAS DONE BY THREE VERY 850 00:38:28,920 --> 00:38:33,880 TALENTED POSTDOCSED A LAY DA AND 851 00:38:33,880 --> 00:38:37,240 WILL WANG. AND WHAT THEY 852 00:38:37,240 --> 00:38:39,200 REASONED WAS THAT MAYBE WE CAN 853 00:38:39,200 --> 00:38:41,360 INCREASE PGE2 LEVELS BY 854 00:38:41,360 --> 00:38:44,960 TARGETING THE DEGRADING ENZYME 855 00:38:44,960 --> 00:38:51,440 WITH PGE 2, 15 PDGH. SO WE 856 00:38:51,440 --> 00:38:52,800 THOUGHT THESE LEVELS MIGHT 857 00:38:52,800 --> 00:38:55,360 DECLINE WITH AGING. WE ANALYZED 858 00:38:55,360 --> 00:38:58,040 USING A VERY SENSITIVE MASS SPEC 859 00:38:58,040 --> 00:38:59,480 METHOD THAT CAN DISTINGUISH 860 00:38:59,480 --> 00:39:01,960 THESE CLOSELY RELATED 861 00:39:01,960 --> 00:39:03,880 PROSTAGLANDINS THAT DIFFER MAYBE 862 00:39:03,880 --> 00:39:06,360 BY A HYDROXYL GROUP AND YOU CAN 863 00:39:06,360 --> 00:39:08,560 SEE HERE THAT THEY DECLINE BY 864 00:39:08,560 --> 00:39:11,240 MAYBE 30% WITH AGING. AND 865 00:39:11,240 --> 00:39:15,360 THAT'S SHOWN HERE RESOLVED BY 866 00:39:15,360 --> 00:39:21,680 MASS SPEC. AND WHEN WE LOOK AT 867 00:39:21,680 --> 00:39:24,400 WHAT MIGHT BE RESPONSIBLE WE 868 00:39:24,400 --> 00:39:25,360 FOUND THAT THE SPECIFIC ACTIVITY 869 00:39:25,360 --> 00:39:27,920 THAT WAS DEGRADING THE ENZYME IS 870 00:39:27,920 --> 00:39:31,800 INCREASED IN MUSCLE IF YOU LOOK 871 00:39:31,800 --> 00:39:34,240 HERE AT AGED VERSUS YOUNG YOU 872 00:39:34,240 --> 00:39:36,000 SEE THAT IT'S INCREASED IN 873 00:39:36,000 --> 00:39:37,960 MUSCLE AND COLON AND SPLEEN AND 874 00:39:37,960 --> 00:39:39,880 SKIN AND HEART. SO IT'S NOT 875 00:39:39,880 --> 00:39:42,480 JUST SPECIFIC TO MUSCLE. IT'S 876 00:39:42,480 --> 00:39:44,520 ELEVATED IN THE NUMBER OF 877 00:39:44,520 --> 00:39:46,120 TISSUES. AND WE SOMEHOW HERE 878 00:39:46,120 --> 00:39:47,800 FOR MUSCLE THAT IT'S INCREASED 879 00:39:47,800 --> 00:39:51,600 AT THE RNA LEVEL. IT'S 880 00:39:51,600 --> 00:39:56,320 INCREASED BY BLOT AND ALSO 881 00:39:56,320 --> 00:39:57,680 SPECIFIC ACTIVITY. IMPORTANTLY 882 00:39:57,680 --> 00:39:59,440 THIS IS NOT JUST A FUNCTION OF 883 00:39:59,440 --> 00:40:02,400 AGED MICE BUT ALSO RELEVANT TO 884 00:40:02,400 --> 00:40:04,720 AGED HUMANS. WE RAN A 885 00:40:04,720 --> 00:40:06,040 MICROARRAY DATABASE AND FOUND 886 00:40:06,040 --> 00:40:15,840 THAT AGED HUMANS ON AVERAGE, 887 00:40:15,840 --> 00:40:17,120 15-PGDH. SOME PEOPLE ARE YOUNG 888 00:40:17,120 --> 00:40:21,600 IN LEVELS AS IS TRUE FOR ALL 889 00:40:21,600 --> 00:40:23,160 MARKERS. BUT ON AVERAGE IT'S 890 00:40:23,160 --> 00:40:24,960 ELEVATED. SO WE REASONED THAT 891 00:40:24,960 --> 00:40:29,200 IF WE COULD TARGET THIS ENZYME, 892 00:40:29,200 --> 00:40:34,800 THE GEROZYME, THAT DEGRADES PGE 893 00:40:34,800 --> 00:40:37,400 2 WE MIGHT BE ABLE TO ELEVATE IT 894 00:40:37,400 --> 00:40:39,560 GLOBALLY AND IN A PHYSIOLOGIC 895 00:40:39,560 --> 00:40:43,040 RANGE. JUST RESTORING IT BACK 896 00:40:43,040 --> 00:40:43,600 TO YOUTHFUL LEVELS. 897 00:40:43,600 --> 00:40:48,320 AND SO WE DID THAT. USING SW WE 898 00:40:48,320 --> 00:40:50,160 TARGETED THE GEROZYME AND HERE 899 00:40:50,160 --> 00:40:52,920 YOU CAN SEE THAT WE RESTORED 900 00:40:52,920 --> 00:40:55,440 PGE2 LEVELS BACK TO YOUTHFUL 901 00:40:55,440 --> 00:41:00,800 LEVELS IF WE INJECTED THE 902 00:41:00,800 --> 00:41:02,840 INHIBITOR. AND DID THIS MAKE A 903 00:41:02,840 --> 00:41:07,800 DIFFERENCE? SO, WELL, WE 904 00:41:07,800 --> 00:41:10,200 INJECTED AGED MICE DAILY FOR ONE 905 00:41:10,200 --> 00:41:12,240 MONTH. AND YOU CAN SEE HERE 906 00:41:12,240 --> 00:41:13,760 THAT THE CROSS-SECTIONAL AREA OF 907 00:41:13,760 --> 00:41:17,680 THE MYOFIBERS IS DRAMATICALLY 908 00:41:17,680 --> 00:41:19,680 INCREASED. THERE'S A SHIFT IN 909 00:41:19,680 --> 00:41:21,560 MYOFIBER SIZES TO LARGER SIZES, 910 00:41:21,560 --> 00:41:22,720 HERE YOU CAN SEE THE 911 00:41:22,720 --> 00:41:24,680 QUANTIFICATION IS A MEAN 912 00:41:24,680 --> 00:41:26,240 CROSS-SECTIONAL AREA 913 00:41:26,240 --> 00:41:28,960 DRAMATICALLY INCREASING AFTER 914 00:41:28,960 --> 00:41:31,360 THIS TREATMENT. AFTER THIS 915 00:41:31,360 --> 00:41:32,440 GLOBAL SYSTEMIC ELEVATION OF PGE 916 00:41:32,440 --> 00:41:39,800 2 LEVELS. DUE TO TARGETING. 917 00:41:39,800 --> 00:41:40,760 AND IMPORTANTLY THIS IS NOT JUST 918 00:41:40,760 --> 00:41:43,280 SPECIFIC TO ONE FIBER TYPE. WE 919 00:41:43,280 --> 00:41:46,560 SEE THAT DIFFERENT FIBER TYPES 920 00:41:46,560 --> 00:41:49,680 THAT HAVE DIFFERENT MYOSIN HEAVY 921 00:41:49,680 --> 00:41:51,000 CHAINS ALSO EXHIBIT THIS 922 00:41:51,000 --> 00:41:55,520 INCREASE IN MY OWE FIBER 923 00:41:55,520 --> 00:41:56,760 DIAMETER. 924 00:41:56,760 --> 00:41:58,680 AND IMPORTANTLY, WE ALSO SEE 925 00:41:58,680 --> 00:42:02,640 THIS REFLECTED IN FUNCTION. SO 926 00:42:02,640 --> 00:42:06,600 IF WE INJECT MICE EITHER WITH 927 00:42:06,600 --> 00:42:10,200 VEHICLE CONTROL OR WITH THIS SW 928 00:42:10,200 --> 00:42:12,120 SMALL MOLECULE INHIBITOR DAILY 929 00:42:12,120 --> 00:42:15,200 FOR ONE MONTH, WE NOW SEE AN 930 00:42:15,200 --> 00:42:18,440 INCREASE IN MUSCLE MASS OF THE 931 00:42:18,440 --> 00:42:20,960 TA BUT WE ALSO LOOKED AS THEY 932 00:42:20,960 --> 00:42:22,880 ALL INCREASE IN MASS 933 00:42:22,880 --> 00:42:25,480 SIGNIFICANTLY. AND WE SEE AN 934 00:42:25,480 --> 00:42:28,520 INCREASE IN STRENGTH COMPARING 935 00:42:28,520 --> 00:42:30,000 THEIR STARTING STRENGTH TO THEIR 936 00:42:30,000 --> 00:42:31,960 STRENGTH AFTER ONE MONTH OF 937 00:42:31,960 --> 00:42:34,560 TREATMENT AND NOW YOU SEE THAT 938 00:42:34,560 --> 00:42:36,160 YOUNG ALSO INCREASE THEIR 939 00:42:36,160 --> 00:42:36,960 STRENGTH EVEN THOUGH THEY HAVE 940 00:42:36,960 --> 00:42:39,160 LESS OF THE ENZYME. THERE'S A 941 00:42:39,160 --> 00:42:41,440 MORE ROBUST EFFECT IN AGING. 942 00:42:41,440 --> 00:42:43,400 AND WE ALSO SEE THAT THERE'S AN 943 00:42:43,400 --> 00:42:46,000 EFFECT IN ENDURANCE, THE TIME TO 944 00:42:46,000 --> 00:42:48,920 EXHAUSTION RUNNING ON A 945 00:42:48,920 --> 00:42:50,960 TREADMILL IS INCREASED AND THAT 946 00:42:50,960 --> 00:42:53,280 SUGGESTS MORE THAN JUST MUSCLE 947 00:42:53,280 --> 00:42:57,840 IS AFFECTED BY ELEVATING PGE 2 948 00:42:57,840 --> 00:42:59,200 SYSTEMICALLY, MAYBE MORE TISSUES 949 00:42:59,200 --> 00:43:02,400 THAN JUST MUSCLE AN AREA THAT 950 00:43:02,400 --> 00:43:03,920 WE'RE VERY INTERESTED IN AND 951 00:43:03,920 --> 00:43:06,120 PURSUING ACTIVELY. TO SHOW THAT 952 00:43:06,120 --> 00:43:08,920 THIS WAS A SPECIFIC EFFECT SINCE 953 00:43:08,920 --> 00:43:11,200 SMALL MOLECULES CAN HAVE OFF 954 00:43:11,200 --> 00:43:15,400 TARGET EFFECTS WE DID AN SH RNA 955 00:43:15,400 --> 00:43:17,440 WE USED A GENE THERAPY APPROACH 956 00:43:17,440 --> 00:43:20,320 TO KNOCK DOWN THE ENZYME USING A 957 00:43:20,320 --> 00:43:24,920 SPECIFIC SH RNA TO 15-PGDH AND 958 00:43:24,920 --> 00:43:26,640 YOU CAN SEE HERE WE KNOCKED DOWN 959 00:43:26,640 --> 00:43:29,880 THE LEVELS OF THE M RNA, THE 960 00:43:29,880 --> 00:43:33,880 SPECIFIC ACTIVITY DECLINE JUST 961 00:43:33,880 --> 00:43:36,000 ENOUGH TO RESTORE LEVELS BACK TO 962 00:43:36,000 --> 00:43:37,760 YOUTHFUL LEVELS JUST LIKE WE SAW 963 00:43:37,760 --> 00:43:40,600 WITH THE INHIBITOR AND WE SAW AS 964 00:43:40,600 --> 00:43:44,760 WITH THE SMALL MOLECULE INHIBIT 965 00:43:44,760 --> 00:43:51,280 AN IN CREASE IN MASS AND 966 00:43:51,280 --> 00:43:53,080 RELATIVE STRENGTH TO BASELINE. 967 00:43:53,080 --> 00:43:55,320 SHOWING THE SPECIFICITY OF THE 968 00:43:55,320 --> 00:43:57,840 SMALL MOLECULE AND THE 969 00:43:57,840 --> 00:44:02,280 SPECIFICITY OF THIS EFFECT FOR 970 00:44:02,280 --> 00:44:03,080 15-PGDH. WE WANTED TO KNOW 971 00:44:03,080 --> 00:44:05,480 WHETHER THIS WAS THROUGH STEM 972 00:44:05,480 --> 00:44:07,760 CELLS SINCE WE'D SHOWN IT HAS A 973 00:44:07,760 --> 00:44:09,240 ROBUST EFFECT ON REGENERATION 974 00:44:09,240 --> 00:44:11,480 WAS THIS DUE TO AN EFFECT ON 975 00:44:11,480 --> 00:44:15,880 STEM CELLS OR WERE THEIR 976 00:44:15,880 --> 00:44:17,040 MICROFIBERS INVOLVED AND WE 977 00:44:17,040 --> 00:44:20,440 FOUND THAT ON THE TUBES ED 4 IS 978 00:44:20,440 --> 00:44:23,080 THE PREDOMINANT RECEPTOR AS IS 979 00:44:23,080 --> 00:44:24,760 STEM CELLS SO IN THIS CASE WE 980 00:44:24,760 --> 00:44:28,320 MADE A TRANSGENIC MODEL WHERE WE 981 00:44:28,320 --> 00:44:31,920 FLUXED THE EP 4 RECEPTOR IN THE 982 00:44:31,920 --> 00:44:34,680 MY OWE FIBER SPECIFICALLY BY 983 00:44:34,680 --> 00:44:41,360 DRIVING THE CRE WHICH IS MUSCLE 984 00:44:41,360 --> 00:44:44,920 KREE TIN CAY NICE WHICH IS 985 00:44:44,920 --> 00:44:47,040 SPECIFIC TO THE MUSCLE FIBERS. 986 00:44:47,040 --> 00:44:53,440 AND AFTER WE O OBLATED THESE. 987 00:44:53,440 --> 00:44:55,920 THEY WERE NO LONGER RESPONSIVE 988 00:44:55,920 --> 00:44:58,120 TO THE SMALL INHIBITOR SHOWING 989 00:44:58,120 --> 00:45:01,640 THAT IN FACT IT IS THROUGH 990 00:45:01,640 --> 00:45:02,720 MYOFIBERS AND IN FACT THIS DRUG 991 00:45:02,720 --> 00:45:06,440 IS A DOUBLE WHAMMY. THE PGE2 IS 992 00:45:06,440 --> 00:45:08,080 ACTING ON BOTH THE STEM CELLS 993 00:45:08,080 --> 00:45:10,200 AND THE MYOFIBERS AND THEN TO 994 00:45:10,200 --> 00:45:12,480 SEE WHETHER THIS IS REALLY A 995 00:45:12,480 --> 00:45:13,800 PIVOTAL REGULATOR AND WHY DO I 996 00:45:13,800 --> 00:45:16,520 CALL IT A GEROZYME AND A PIVOTAL 997 00:45:16,520 --> 00:45:19,160 REGULATOR? I THINK THIS 998 00:45:19,160 --> 00:45:23,040 EXPERIMENT IS THE NAIL IN THE 999 00:45:23,040 --> 00:45:24,680 COFFIN. THE PEACE DERESISTANCE. 1000 00:45:24,680 --> 00:45:29,200 WHAT WE DID HERE WAS OVEREXPRESS 1001 00:45:29,200 --> 00:45:31,280 PDGH IN YOUNG MOUSE MUSCLES. 1002 00:45:31,280 --> 00:45:34,000 USING A GENE THERAPY APPROACH TO 1003 00:45:34,000 --> 00:45:36,080 DELIVER THE PDGH WE INJECT IT 1004 00:45:36,080 --> 00:45:38,960 INTO THE MUSCLES OF A THREE 1005 00:45:38,960 --> 00:45:40,680 MONTH OLD MOUSE AND ONE MONTH 1006 00:45:40,680 --> 00:45:42,920 LATER WE ANALYZED THEIR 1007 00:45:42,920 --> 00:45:43,800 STRENGTH. YOU CAN SEE HERE 1008 00:45:43,800 --> 00:45:46,120 EVIDENCE THAT THE M RNA LEVEL OF 1009 00:45:46,120 --> 00:45:49,800 THE ENZYME IS INCREASED AND THAT 1010 00:45:49,800 --> 00:45:52,520 THE PGE 2 IS DECREASED BY MASS 1011 00:45:52,520 --> 00:45:54,560 SPEC ANALYSIS AND THEN WE LOOKED 1012 00:45:54,560 --> 00:45:57,920 AT FORCE AND YOU CAN SEE THIS 1013 00:45:57,920 --> 00:45:59,360 DRAMATIC DECLINE IN STRENGTH AND 1014 00:45:59,360 --> 00:46:02,200 IN TA MUSCLE MASS AS WELL. SO 1015 00:46:02,200 --> 00:46:05,200 THE MUSCLES IN RESPONSE TO 1016 00:46:05,200 --> 00:46:08,360 EXPRESSION OF THIS SINGLE ENZYME 1017 00:46:08,360 --> 00:46:11,000 ARE SHRINKING AND WEAKENING. 1018 00:46:11,000 --> 00:46:12,920 IT'S REALLY QUITE DRAMATIC AND 1019 00:46:12,920 --> 00:46:15,640 THAT REALLY IS THE EVIDENCE THAT 1020 00:46:15,640 --> 00:46:18,160 THIS IS A PIVOTAL REGULAR. I 1021 00:46:18,160 --> 00:46:20,600 NEVER THOUGHT THAT AGING IS SO 1022 00:46:20,600 --> 00:46:23,320 PLEA OWE TROPHIC THAT ONE SINGLE 1023 00:46:23,320 --> 00:46:26,320 MOLECULE WOULD HAVE SUCH A 1024 00:46:26,320 --> 00:46:29,680 ROBUST EFFECT. SO WHAT IS THE 1025 00:46:29,680 --> 00:46:33,640 SOURCE OF PDGH IN MUSCLE THAT IS 1026 00:46:33,640 --> 00:46:36,120 CAUSING THE DELETERIOUS EFFECTS 1027 00:46:36,120 --> 00:46:37,640 OF AGEING TO UNDERSTAND THAT WE 1028 00:46:37,640 --> 00:46:41,320 USED CODEX WHICH IS AN IMAGING 1029 00:46:41,320 --> 00:46:42,760 APPROACH BECAUSE IT TURNS OUT 1030 00:46:42,760 --> 00:46:45,920 THAT IT IS VERY DIFFICULT TO 1031 00:46:45,920 --> 00:46:50,080 VISUALIZE PDGH DEFINITIVELY BY 1032 00:46:50,080 --> 00:46:51,600 TRADITIONAL METHODS AND THIS 1033 00:46:51,600 --> 00:46:53,200 IMMUNO FLUORESCENCE METHOD 1034 00:46:53,200 --> 00:46:56,920 ALLOWS YOU TO LOOK AT UP TO 40 1035 00:46:56,920 --> 00:46:58,920 ANTIBODIES SIMULTANEOUSLY ON A 1036 00:46:58,920 --> 00:47:00,840 SINGLE TISSUE SECTION. 1037 00:47:00,840 --> 00:47:05,520 DEVELOPED BY MY NEIGHBOR AT THE 1038 00:47:05,520 --> 00:47:08,160 BAXTER LAB AND USES UNIQUE 1039 00:47:08,160 --> 00:47:11,360 NON-OVERLAPPING DNA BARCODES 1040 00:47:11,360 --> 00:47:18,040 THAT ARE CONJUGATED TO 1041 00:47:18,040 --> 00:47:22,680 ANTIBODIES AND THEN SECONDARILY 1042 00:47:22,680 --> 00:47:24,600 REVEALED BY FLOUR ROW FORS: YOU 1043 00:47:24,600 --> 00:47:26,640 CAN DO THREE ANTIBODIES AT A 1044 00:47:26,640 --> 00:47:26,840 TIME. 1045 00:47:26,840 --> 00:47:29,000 STAIN THE TISSUE AND THEN YOU 1046 00:47:29,000 --> 00:47:31,040 CAN RESOLVE IT BY MICROFLUIDIC 1047 00:47:31,040 --> 00:47:33,240 ANALYSIS AND WHO THIS LOOKS LIKE 1048 00:47:33,240 --> 00:47:36,120 IS AS FOLLOWS. SO NORMALLY YOU 1049 00:47:36,120 --> 00:47:38,320 CAN ONLY VISUALIZE MAYBE THREE 1050 00:47:38,320 --> 00:47:40,400 ANTIBODIES AT A TIME BUT USING 1051 00:47:40,400 --> 00:47:41,960 CODEX YOU CAN LOOK AT UP TO 40. 1052 00:47:41,960 --> 00:47:44,400 HERE YOU SEE A LONGITUDINAL 1053 00:47:44,400 --> 00:47:46,800 SECTION OF A MUSCLE. YOU SEE 1054 00:47:46,800 --> 00:47:50,120 LAM NAN OUTLINING THE MYOFIBERS. 1055 00:47:50,120 --> 00:47:52,640 HERE YOU SEE THE HEAVY CHAIN AND 1056 00:47:52,640 --> 00:47:54,240 NOW THE TENDON THAT CONNECTS THE 1057 00:47:54,240 --> 00:47:56,360 MUSCLE TO THE BONE. 1058 00:47:56,360 --> 00:48:00,560 AND YOU CAN SEE THE MOTOR 1059 00:48:00,560 --> 00:48:02,720 NEURONS AND THE JUNCTIONS AND 1060 00:48:02,720 --> 00:48:07,560 YOU CAN SEE THE IMMUNE CELLS AND 1061 00:48:07,560 --> 00:48:09,160 THE VASCULATURE WHICH IS 1062 00:48:09,160 --> 00:48:11,600 EXTENSIVE IN THE MUSCLE AND YOU 1063 00:48:11,600 --> 00:48:14,560 CAN LOOK AT INJURED AREAS AND 1064 00:48:14,560 --> 00:48:16,800 VERY CLEARLY SEE WHAT THEY ARE. 1065 00:48:16,800 --> 00:48:19,200 AND USING THIS ANALYSIS WHICH I 1066 00:48:19,200 --> 00:48:20,880 CAN'T DO JUSTICE TO RIGHT NOW 1067 00:48:20,880 --> 00:48:22,520 BUT I WANT TO WHET YOUR APPETITE 1068 00:48:22,520 --> 00:48:24,760 TO ITS POTENCY YOU CAN USE 1069 00:48:24,760 --> 00:48:26,360 NEURAL NETWORK AND MACHINE 1070 00:48:26,360 --> 00:48:27,640 LEARNING APPROACH TO ANALYZE 1071 00:48:27,640 --> 00:48:30,280 THIS MULTIPLEXED IMAGING AND 1072 00:48:30,280 --> 00:48:32,760 SEGMENT THE CELLS, IDENTIFY 1073 00:48:32,760 --> 00:48:38,400 UNIQUE FEATURES LIKE ECM 1074 00:48:38,400 --> 00:48:41,000 SCAFFOLDS AND SITES OF 1075 00:48:41,000 --> 00:48:42,440 REGENERATION AND YOU CAN COMPOSE 1076 00:48:42,440 --> 00:48:44,520 AND QUANTIFY THE TISSUE 1077 00:48:44,520 --> 00:48:48,960 COMPOSITION OF THE STEM CELLS 1078 00:48:48,960 --> 00:48:51,400 OVER TIME AND SPACE AND LOOK AT 1079 00:48:51,400 --> 00:48:53,920 CELL-CELL INTERACTIONS, TISSUE 1080 00:48:53,920 --> 00:48:55,040 ARCHITECTURE AND VARIOUS 1081 00:48:55,040 --> 00:48:57,040 MOLECULES IN A WAY THAT IS JUST 1082 00:48:57,040 --> 00:48:59,600 UNPRECEDENTED. AND THIS IS 1083 00:48:59,600 --> 00:49:01,320 ALLOWED US THROUGH WILL WANG'S 1084 00:49:01,320 --> 00:49:03,680 EFFORTS TO ANNOTATE MULTIPLE 1085 00:49:03,680 --> 00:49:04,880 CELL TYPES SHOWN HERE AND YOU 1086 00:49:04,880 --> 00:49:06,080 CAN SEE JUST THROUGH THE COLORS 1087 00:49:06,080 --> 00:49:07,840 AND THE CHANGES AFTER INJURY 1088 00:49:07,840 --> 00:49:10,920 THAT THE NEIGHBORHOODS, THE 1089 00:49:10,920 --> 00:49:12,280 CELL-CELL INTERACTIONS ARE 1090 00:49:12,280 --> 00:49:14,280 CHANGING OVER THIS TIME COURSE 1091 00:49:14,280 --> 00:49:15,840 OF RE GENERATION AND YOU CAN 1092 00:49:15,840 --> 00:49:18,680 LOOK AT SPECIFIC CHANGES HERE 1093 00:49:18,680 --> 00:49:23,440 THE M 1 MACROPHAGES ARE PEAKING 1094 00:49:23,440 --> 00:49:25,120 AT DAY THREE AND THE CELLS ARE 1095 00:49:25,120 --> 00:49:27,600 PEAKING AT DAY SIX AND YOU CAN 1096 00:49:27,600 --> 00:49:29,240 FIND THEIR NEIGHBORHOODS ARE 1097 00:49:29,240 --> 00:49:31,000 CHANGING AND YOU CAN GO INTO 1098 00:49:31,000 --> 00:49:33,680 MUCH MORE DETAIL LOOKING AT THE 1099 00:49:33,680 --> 00:49:35,680 INNATE RESPONSE, INNATE IMMUNE 1100 00:49:35,680 --> 00:49:37,880 RESPONSE, THE ADAPTIVE IMMUNE 1101 00:49:37,880 --> 00:49:39,760 RESPONSE AND SUBSETS OF CELLS 1102 00:49:39,760 --> 00:49:42,480 AND HOW THEY CHANGE IN THEIR 1103 00:49:42,480 --> 00:49:44,320 NEIGHBORHOODS WITH REGENERATION 1104 00:49:44,320 --> 00:49:45,880 AND WITH AGING. BUT FOR THE 1105 00:49:45,880 --> 00:49:47,880 PURPOSE OF THIS TALK, IT ENABLED 1106 00:49:47,880 --> 00:49:49,960 US TO LOCALIZE WHERE THE 1107 00:49:49,960 --> 00:49:51,760 GEROZYME IS. AND AS YOU CAN SEE 1108 00:49:51,760 --> 00:49:53,880 HERE, IT'S BARELY EXPRESSED IN 1109 00:49:53,880 --> 00:49:55,800 YOUNG MUSCLE. IT IS THERE BUT 1110 00:49:55,800 --> 00:49:58,200 AT LOW LEVELS BUT IN AGING YOU 1111 00:49:58,200 --> 00:50:01,960 SEE IT LOCALIZED IN THESE MUSCLE 1112 00:50:01,960 --> 00:50:03,640 FIBERS. IT'S ALSO PRESENT IN 1113 00:50:03,640 --> 00:50:06,240 AGED MACROPHAGES, IN THE MUSCLE 1114 00:50:06,240 --> 00:50:09,320 TISSUE AND THAT MAY BE THE 1115 00:50:09,320 --> 00:50:11,960 SOURCE OF THE PGDH IN OTHER 1116 00:50:11,960 --> 00:50:14,880 TISSUES WHERE IT'S ELEVATED WITH 1117 00:50:14,880 --> 00:50:19,040 AGING. AND HIGH DOES DR -- HOW 1118 00:50:19,040 --> 00:50:21,360 DOES IT WORK? HOW DOES IT HAVE 1119 00:50:21,360 --> 00:50:23,760 THIS PROFOUND AFFECT ON MUSCLE? 1120 00:50:23,760 --> 00:50:26,600 AND HAVE TARGETING IT, HOW DOES 1121 00:50:26,600 --> 00:50:28,960 IT INCREASE MUSCLE FUNCTION? WE 1122 00:50:28,960 --> 00:50:31,320 DID AN ANALYSIS AND WHAT YOU 1123 00:50:31,320 --> 00:50:34,200 FOUND WHEN YOU COMPARED THE 1124 00:50:34,200 --> 00:50:35,680 TRANSCRIPTOME OF THE TWO 1125 00:50:35,680 --> 00:50:37,680 TREATMENTS, AGED MOUSE MUSCLES, 1126 00:50:37,680 --> 00:50:39,880 YOU CAN SEE THAT THERE'S A DOWN 1127 00:50:39,880 --> 00:50:42,880 REGULATION OF UBIQUITIN RELATED 1128 00:50:42,880 --> 00:50:47,320 GENES. THESE ARE THE ENZYMES, 1129 00:50:47,320 --> 00:50:48,920 THE UBIQUITIN LIGASES THAT 1130 00:50:48,920 --> 00:50:50,480 DEGRADE PROTEINS WITH AGING AND 1131 00:50:50,480 --> 00:50:53,920 THAT BECOME MORE ABUNDANT. 1132 00:50:53,920 --> 00:50:55,240 WE'RE TURNING THEM DOWN. THE 1133 00:50:55,240 --> 00:50:56,880 SIGNALLING IS ALSO A PATHWAY 1134 00:50:56,880 --> 00:50:59,240 THAT ARISES WITH AGING AND HAS 1135 00:50:59,240 --> 00:51:06,920 DELETERIOUS EFFECTS, MY OWE -- 1136 00:51:06,920 --> 00:51:07,800 YOU CAN SEE AFTER TREATMENT WE 1137 00:51:07,800 --> 00:51:11,560 ARE DOWN REGULATING THIS 1138 00:51:11,560 --> 00:51:13,760 DELETERIOUS SIGNALLING AND WE 1139 00:51:13,760 --> 00:51:15,800 VALIDATED SOME OF THESE MARKERS. 1140 00:51:15,800 --> 00:51:20,560 BY QPCR AS WELL AND ALSO SHOWED 1141 00:51:20,560 --> 00:51:23,840 THAT THE PATHWAY IS INVOLVED 1142 00:51:23,840 --> 00:51:30,400 WITH FOXO AND WE ALSO VALIDATED 1143 00:51:30,400 --> 00:51:32,960 WITH THIS. NOT ONLY ARE THESE 1144 00:51:32,960 --> 00:51:37,600 PATHWAYS DOWN-REGULATED BY 1145 00:51:37,600 --> 00:51:39,360 MITOCHONDRIAL PATHWAYS ARE 1146 00:51:39,360 --> 00:51:40,600 UPREGULATED. YOU SEE A ROBUST 1147 00:51:40,600 --> 00:51:44,600 INCREASE IN COMPLEX ONE, THREE, 1148 00:51:44,600 --> 00:51:50,640 FOUR, FIVE, COMPONENTS OF 1149 00:51:50,640 --> 00:51:51,240 MITOCHONDRIAL FUNCTION. AND 1150 00:51:51,240 --> 00:51:53,880 ALSO, IF YOU LOOK AT THE MUSCLE 1151 00:51:53,880 --> 00:51:58,120 TISSUE I THINK THIS SAYS IT MORE 1152 00:51:58,120 --> 00:51:59,760 LOUDLY THAN ANY TRANSCRIPTOME 1153 00:51:59,760 --> 00:52:01,800 ANALYSIS IF YOU LOOK AT THE AGED 1154 00:52:01,800 --> 00:52:06,800 TISSUE YOU SEE THIS DISORGANIZED 1155 00:52:06,800 --> 00:52:08,920 MYOFIBRILS AND DISPERSED BETWEEN 1156 00:52:08,920 --> 00:52:12,280 THEM ARE THESE MITOCHONDRIA THAT 1157 00:52:12,280 --> 00:52:13,800 ARE VACUOUS AND EXTENDED AND 1158 00:52:13,800 --> 00:52:16,040 COMPARE THAT WITH THE TISSUE ON 1159 00:52:16,040 --> 00:52:18,440 THE RIGHT WHICH WAS FROM AGED 1160 00:52:18,440 --> 00:52:20,840 MICE THAT WERE TREATED FOR ONE 1161 00:52:20,840 --> 00:52:24,280 MONTH WITH THE SW SMALL MOLECULE 1162 00:52:24,280 --> 00:52:27,240 INHIBITOR PDGH AND WHAT YOU SEE 1163 00:52:27,240 --> 00:52:31,280 IS THIS ORDERLY TISSUE NOW AND 1164 00:52:31,280 --> 00:52:33,240 THESE COMPACT MITOCHONDRIA AND 1165 00:52:33,240 --> 00:52:35,960 THIS RESULTS FROM AN INCREASE IN 1166 00:52:35,960 --> 00:52:37,560 BIOGENESIS. WE SEE THAT 1167 00:52:37,560 --> 00:52:38,960 REFLECTED IN THE ALPHA 1168 00:52:38,960 --> 00:52:43,800 EXPRESSION. ALSO IN NUMBERS OF 1169 00:52:43,800 --> 00:52:45,480 MITOCHONDRIA AND THEY'RE MORE 1170 00:52:45,480 --> 00:52:46,800 COMPACT, MORE FUNCTIONAL THAN 1171 00:52:46,800 --> 00:52:49,200 THEY WERE BEFORE AND THERE'S AN 1172 00:52:49,200 --> 00:52:52,480 INCREASE IN ON OF THE GEE WHICH 1173 00:52:52,480 --> 00:52:56,280 IS RESPONSIBLE FOR THIS 1174 00:52:56,280 --> 00:52:58,600 EXTENSIVE REMODELLING OF THE 1175 00:52:58,600 --> 00:53:00,320 TISSUE. THERE ARE MORE AND MORE 1176 00:53:00,320 --> 00:53:01,880 FUNCTIONAL. IF WE LOOK AT 1177 00:53:01,880 --> 00:53:05,520 VARIOUS CREM CYCLE FUNCTIONS, 1178 00:53:05,520 --> 00:53:08,080 THIS GOES DOWN WITH AGING AND IS 1179 00:53:08,080 --> 00:53:12,560 RESTORED BY TREATMENT WITH SW 4. 1180 00:53:12,560 --> 00:53:15,920 ONE MONTH, THE HIGH DROJ NICE, 1181 00:53:15,920 --> 00:53:18,360 DECLINES WITH AGING AND IS 1182 00:53:18,360 --> 00:53:19,440 RESTORED AFTER TREATMENT FOR ONE 1183 00:53:19,440 --> 00:53:21,880 MONTH AND WE SEE THE MEMBRANE 1184 00:53:21,880 --> 00:53:23,280 POTENTIAL ALSO DECLINES WITH 1185 00:53:23,280 --> 00:53:25,080 AGING AND IS RESTORED BY THIS 1186 00:53:25,080 --> 00:53:31,120 TREATMENT. SO TO SUMMARIZE, 1187 00:53:31,120 --> 00:53:33,160 WHAT I'VE SHOWN YOU IS THAT 1188 00:53:33,160 --> 00:53:37,480 INHIBITION OF THE PROSTAGLANDIN 1189 00:53:37,480 --> 00:53:40,720 DEGRADING THIS INCREASES MUSCLE 1190 00:53:40,720 --> 00:53:43,880 STRENGTH IN MICE. SO IN THE 1191 00:53:43,880 --> 00:53:44,960 MUSCLE TISSUE THAT'S YOUNG ON 1192 00:53:44,960 --> 00:53:48,960 THE LEFT YOU SEE ORDERLY 1193 00:53:48,960 --> 00:53:50,800 MYOFIBRILSES AND CONDENSED 1194 00:53:50,800 --> 00:53:52,760 MITOCHONDRIA WITH AGING. WE SEE 1195 00:53:52,760 --> 00:53:55,880 THE DECREASE IN EXPRESSION AND 1196 00:53:55,880 --> 00:53:58,600 WE SEE THE METABOLIZED ACTIVE 1197 00:53:58,600 --> 00:54:02,000 FORM AND YOU GET THESE VACUOUS 1198 00:54:02,000 --> 00:54:03,440 MITOCHONDRIA AND DISORGANIZED 1199 00:54:03,440 --> 00:54:04,680 TISSUE BUT YOU CAN REJUVENATE 1200 00:54:04,680 --> 00:54:08,920 THAT TISSUE EITHER BY A SMALL 1201 00:54:08,920 --> 00:54:12,520 MOLECULE INHIBITOR OF 15-PGDH 1202 00:54:12,520 --> 00:54:18,520 AND THAT LEADS TO AN INCREASE IN 1203 00:54:18,520 --> 00:54:20,960 PGE 2 LEVELS. AND YOU SEE THE 1204 00:54:20,960 --> 00:54:27,520 SIGNALLING DECLINE. AND THE 1205 00:54:27,520 --> 00:54:29,560 MITOCHONDRIA BIOGENESIS 1206 00:54:29,560 --> 00:54:31,560 INCREASES. THIS IS REALLY 1207 00:54:31,560 --> 00:54:32,720 CRITICAL FOR THE REGENERATION 1208 00:54:32,720 --> 00:54:35,360 AND REJUVENATION OF MUSCLE. AND 1209 00:54:35,360 --> 00:54:38,240 WE THINK THAT ITS POTENCY 1210 00:54:38,240 --> 00:54:42,960 DERIVES FROM ITS DUAL TARGETS. 1211 00:54:42,960 --> 00:54:45,320 PG 2 REJUVENATES AND REPLENISHES 1212 00:54:45,320 --> 00:54:48,720 THE FUNCTION OF AGED MUSCLE STEM 1213 00:54:48,720 --> 00:54:49,960 CELLS. 1214 00:54:49,960 --> 00:54:51,040 SO IT TARGETS THE STEM CELLS TO 1215 00:54:51,040 --> 00:54:53,920 PROMOTE REGENERATION. IT'S PART 1216 00:54:53,920 --> 00:54:56,240 OF THIS ESSENTIAL INFLAMMATORY 1217 00:54:56,240 --> 00:55:00,280 PROCESS, THE BODY'S NATURAL 1218 00:55:00,280 --> 00:55:01,560 HEALING MECHANISM AND PGE 2 IS 1219 00:55:01,560 --> 00:55:03,440 REQUIRED AND EFFICIENT FOR THE 1220 00:55:03,440 --> 00:55:06,320 STEM CELL TO PROLIFERATE AND 1221 00:55:06,320 --> 00:55:08,920 SURVIVE AND ENDRAFT. IN 1222 00:55:08,920 --> 00:55:10,880 ADDITION PGE2 REJUVENATES THE MY 1223 00:55:10,880 --> 00:55:12,920 OWE FIBER FUNCTION AND WITH 1224 00:55:12,920 --> 00:55:15,080 AGING, THIS ENZYME, THIS 1225 00:55:15,080 --> 00:55:17,120 GEROZYME INCREASES IN 1226 00:55:17,120 --> 00:55:18,120 EXPRESSION. 1227 00:55:18,120 --> 00:55:21,320 AND AS I HAVE SHOWN YOU IT'S A 1228 00:55:21,320 --> 00:55:23,080 DETERMINATE OF MUSCLE AGING. 1229 00:55:23,080 --> 00:55:25,160 IT'S A NEW HALLMARK OF AGED 1230 00:55:25,160 --> 00:55:27,360 MUSCLES. A MASTER REGULATOR OF 1231 00:55:27,360 --> 00:55:29,040 MUSCLE AGING IN THAT IF YOU OVER 1232 00:55:29,040 --> 00:55:31,960 EXPRESS IT IN YOUNG, THE YOUNG 1233 00:55:31,960 --> 00:55:34,800 MICE BECOME WEAKER AND THEIR 1234 00:55:34,800 --> 00:55:36,800 MUSCLES BECOME SMALLER. AND IF 1235 00:55:36,800 --> 00:55:39,920 YOU INHIBIT THIS GEROZYME, JUST 1236 00:55:39,920 --> 00:55:42,560 PHYSIOLOGICALLY MODULATING IT 1237 00:55:42,560 --> 00:55:46,200 BACK TO A YOUTHFUL LEVEL IN 1238 00:55:46,200 --> 00:55:47,880 RESTORING PGE 2 LEVELS YOU 1239 00:55:47,880 --> 00:55:49,840 REGAIN STRENGTH IN ONE MONTH, 1240 00:55:49,840 --> 00:55:51,920 15% INCREASE IN STRENGTH. 1241 00:55:51,920 --> 00:55:54,200 IN AGED MICE. IF THIS TRANSLATE 1242 00:55:54,200 --> 00:55:56,840 TO HUMANS, IT WILL BE SUPER 1243 00:55:56,840 --> 00:55:59,480 EXCITING BECAUSE HUMANS LOSE 1244 00:55:59,480 --> 00:56:01,800 GREATER THAN 50% -- THEY LOSE -- 1245 00:56:01,800 --> 00:56:04,800 AFTER AGE 50, 10% OF YOUR MUSCLE 1246 00:56:04,800 --> 00:56:08,240 MASS PER DECADE. SO WE 1247 00:56:08,240 --> 00:56:14,080 POSTULATE THAT THIS TARGETING OF 1248 00:56:14,080 --> 00:56:16,200 15-PGDH COULD BE A THERAPEUTIC 1249 00:56:16,200 --> 00:56:17,800 STRATEGY DUE TO IMMOBILIZATION, 1250 00:56:17,800 --> 00:56:21,200 AFTER PROLONGED BEDREST SEYDOU 1251 00:56:21,200 --> 00:56:26,320 TO COVID OR INJURY OR, 1252 00:56:26,320 --> 00:56:27,320 SARCOPENIA, MUSCLE WASTING WITH 1253 00:56:27,320 --> 00:56:28,600 AGING AND WITH THAT, I WANT TO 1254 00:56:28,600 --> 00:56:30,920 THANK YOU FOR YOUR ATTENTION. I 1255 00:56:30,920 --> 00:56:32,400 WANT TO ACKNOWLEDGE THE SUPER 1256 00:56:32,400 --> 00:56:34,360 PEOPLE I HAVE IN MY LAB. 1257 00:56:34,360 --> 00:56:36,960 FROM DIFFERENT COUNTRIES AND 1258 00:56:36,960 --> 00:56:38,680 DIFFERENT BACKGROUNDS, 1259 00:56:38,680 --> 00:56:39,960 MULTIDISCIPLINARY GROUP WHO HAVE 1260 00:56:39,960 --> 00:56:41,480 MADE THIS POSSIBLE AND MY 1261 00:56:41,480 --> 00:56:45,360 FUNDING SOURCES. AND THE NIA 1262 00:56:45,360 --> 00:56:46,560 FOR FUNDING AND FOR THE 1263 00:56:46,560 --> 00:56:48,920 PROVISION OF THESE AGED MICE 1264 00:56:48,920 --> 00:56:51,680 THAT MAKE THIS WORK POSSIBLE. 1265 00:56:51,680 --> 00:56:52,920 THANK YOU SO MUCH. 1266 00:56:52,920 --> 00:56:55,720 >>THANK YOU SO MUCH, DR. BLAU. 1267 00:56:55,720 --> 00:56:56,640 BEAUTIFUL PRESENTATION, 1268 00:56:56,640 --> 00:56:57,960 FASCINATING WORK. WE DO HAVE A 1269 00:56:57,960 --> 00:56:59,360 FEW QUESTIONS BUT ONLY A FEW 1270 00:56:59,360 --> 00:57:02,040 MINUTES SO I WILL JUST START AT 1271 00:57:02,040 --> 00:57:03,240 THE TOP. WE'LL MAYBE BE ABLE TO 1272 00:57:03,240 --> 00:57:05,360 ANSWER ONE OR TWO OF THESE. THE 1273 00:57:05,360 --> 00:57:06,520 FIRST QUESTION WE GOT WAS GOING 1274 00:57:06,520 --> 00:57:08,960 BACK TO THE BEGINNING AND 1275 00:57:08,960 --> 00:57:14,120 LOOKING AT THE STIFFNESS 1276 00:57:14,120 --> 00:57:15,560 STUDIES AND THE QUESTION IS DO 1277 00:57:15,560 --> 00:57:18,520 YOU KNOW WHAT WAS LOST OR GAINED 1278 00:57:18,520 --> 00:57:20,920 IN THE MUSCLES THAT WERE TOO 1279 00:57:20,920 --> 00:57:23,040 STIFF OR TOO SOFT. DID THEY ALL 1280 00:57:23,040 --> 00:57:25,360 FAIL OR DID THEY ALL FAIL TO 1281 00:57:25,360 --> 00:57:25,680 PROLIFERATE? 1282 00:57:25,680 --> 00:57:28,120 >>YES. THEY FAILED TO 1283 00:57:28,120 --> 00:57:30,800 PROLIFERATE. THEY TURN ON 1284 00:57:30,800 --> 00:57:32,320 SIGNALLING PATHWAYS THAT ARE 1285 00:57:32,320 --> 00:57:35,880 DELETERIOUS TO ENGRAPHMENT. 1286 00:57:35,880 --> 00:57:37,680 THEY SIMPLY DON'T EXPAND OR 1287 00:57:37,680 --> 00:57:39,600 REGENERATE THE TISSUE. 1288 00:57:39,600 --> 00:57:40,880 >>AND SOMEONE ELSE ASKED, 1289 00:57:40,880 --> 00:57:43,800 TALKING ABOUT THE EFFECTS OF 1290 00:57:43,800 --> 00:57:44,960 IBUPROFEN SPECIFICALLY DO YOU 1291 00:57:44,960 --> 00:57:49,640 KNOW IF METFORMIN HAS A SIMILAR 1292 00:57:49,640 --> 00:57:52,440 INHIBITOR EFFECT THAT IBUPROFEN 1293 00:57:52,440 --> 00:57:55,480 HAS AND FOLLOWED UP TO ASK HOW 1294 00:57:55,480 --> 00:57:57,120 LONG IBUPROFEN IS -- HOW LONG 1295 00:57:57,120 --> 00:57:59,720 THE EFFECTS LAST ONCE YOU TAKE 1296 00:57:59,720 --> 00:58:01,560 IT? PRESUMABLY AS A PILL AS A 1297 00:58:01,560 --> 00:58:01,760 HUMAN. 1298 00:58:01,760 --> 00:58:05,400 >>YEAH, PEOPLE ALWAYS ASK ME 1299 00:58:05,400 --> 00:58:07,280 THAT, HOW LONG DO YOU HAVE TO 1300 00:58:07,280 --> 00:58:08,240 WAIT AFTER EXERCISING UNTIL YOU 1301 00:58:08,240 --> 00:58:11,040 CAN TAKE THIS PAIN RELIEVER IN 1302 00:58:11,040 --> 00:58:15,960 AND WE REALLY DON'T KNOW AND 1303 00:58:15,960 --> 00:58:18,200 ALSO EXTRAPOLATING TO HUMAN WE 1304 00:58:18,200 --> 00:58:20,120 NEED TO DO HUMAN STUDIES TO 1305 00:58:20,120 --> 00:58:21,600 TOTALLY UNDERSTAND THIS BUT IT'S 1306 00:58:21,600 --> 00:58:23,320 JUST A CAUTIONARY NOTE THAT THIS 1307 00:58:23,320 --> 00:58:25,200 PATHWAY IS SUPER IMPORTANT TO 1308 00:58:25,200 --> 00:58:28,080 THE FUNCTION OF YOUR MUSCLES. 1309 00:58:28,080 --> 00:58:31,240 YOUR MUSCLE FIBERS, YOUR MUSCLE 1310 00:58:31,240 --> 00:58:33,200 STEM CELLS AND THAT INHIBITING 1311 00:58:33,200 --> 00:58:35,960 THE PATHWAY IS PROBABLY NOT A 1312 00:58:35,960 --> 00:58:38,920 GOOD THING, LIKE DAILY ASPIRIN 1313 00:58:38,920 --> 00:58:39,880 FOR INSTANCE THAT HAS BEEN 1314 00:58:39,880 --> 00:58:43,160 PRESCRIBED BUT IS LESS 1315 00:58:43,160 --> 00:58:44,960 PRESCRIBED NOW FOR MAINTAINING A 1316 00:58:44,960 --> 00:58:45,960 HEALTHY HEART FOR INSTANCE I 1317 00:58:45,960 --> 00:58:50,520 THINK PEOPLE ARE REVISITING 1318 00:58:50,520 --> 00:58:53,200 THAT. SO IT'S, YEAH, SOMETHING 1319 00:58:53,200 --> 00:58:54,960 TO USE IN MODERATION. 1320 00:58:54,960 --> 00:58:57,880 >>SURE. AND DO YOU KNOW IF -- 1321 00:58:57,880 --> 00:59:01,440 IS AN OVERLAP WITH METFORMIN. 1322 00:59:01,440 --> 00:59:04,480 DO YOU HAVE ANY IDEA OF THE 1323 00:59:04,480 --> 00:59:06,320 PATHWAYS, IF THEY ARE THE SAME 1324 00:59:06,320 --> 00:59:07,280 PATHWAYS? 1325 00:59:07,280 --> 00:59:08,080 >>I DON'T BELIEVE THEY ARE. 1326 00:59:08,080 --> 00:59:10,280 >>OKAY. SO THIS FINAL QUESTION 1327 00:59:10,280 --> 00:59:15,760 IS HERE IS COULD THE 15-PGDH 1328 00:59:15,760 --> 00:59:17,840 BLOCKADE HAVE ANY EFFECT ON 1329 00:59:17,840 --> 00:59:19,680 NEUROGENERATIVE DISEASES 1330 00:59:19,680 --> 00:59:26,400 INCREASED FROM A MONOAGING 1331 00:59:26,400 --> 00:59:26,760 IMMEDIATOLOGY? 1332 00:59:26,760 --> 00:59:28,960 >>THAT IS SOMETHING WE'RE 1333 00:59:28,960 --> 00:59:30,520 ACTIVELY INVESTIGATING. BECAUSE 1334 00:59:30,520 --> 00:59:34,120 WITH AGING, YOU LOSE 1335 00:59:34,120 --> 00:59:36,240 NEUROMUSCULAR CONNECTION. YOU 1336 00:59:36,240 --> 00:59:39,720 LOSE YOUR NEUROMUSCULAR 1337 00:59:39,720 --> 00:59:40,920 JUNCTIONS. DINNER VAGUS IS A 1338 00:59:40,920 --> 00:59:42,800 BIG PART OF MUSCLE FUNCTION LOSS 1339 00:59:42,800 --> 00:59:44,840 WITH AGING AND OF COURSE 1340 00:59:44,840 --> 00:59:48,760 ASSOCIATED WITH VARIOUS MUSCULAR 1341 00:59:48,760 --> 00:59:50,000 DYSTROPHIES. IN PARTICULAR 1342 00:59:50,000 --> 00:59:54,480 SPINAL ATROPHY. YOU LOSE THIS 1343 00:59:54,480 --> 00:59:55,840 CONNECTIVITY. WE'RE INTERESTED 1344 00:59:55,840 --> 00:59:59,880 IN ACTIVE LY PURSUING WHETHER 1345 00:59:59,880 --> 01:00:02,360 THIS CAN COUNTER THE JUNCTIONS 1346 01:00:02,360 --> 01:00:03,920 AND ENHANCE THE NEUROMUSCULAR 1347 01:00:03,920 --> 01:00:05,560 FUNCTION. THAT IS AN EXCELLENT 1348 01:00:05,560 --> 01:00:05,840 QUESTION. 1349 01:00:05,840 --> 01:00:07,680 >>AND I HAVE A QUICK QUESTION 1350 01:00:07,680 --> 01:00:09,840 THAT'S PERSONAL, SO ONE OF THE 1351 01:00:09,840 --> 01:00:11,240 THINGS IN THE FIELD THAT PEOPLE 1352 01:00:11,240 --> 01:00:12,760 ALWAYS TALKED ABOUT IS TRYING TO 1353 01:00:12,760 --> 01:00:15,000 SCALE UP MUSCLE STEM CELLS AND 1354 01:00:15,000 --> 01:00:16,920 BEING ABLE TO USE THEM AND OF 1355 01:00:16,920 --> 01:00:19,400 COURSE USING THE PROPER 1356 01:00:19,400 --> 01:00:23,000 STIFFNESS IN CULTURE. IS 1357 01:00:23,000 --> 01:00:24,560 THIS -- I GUESS THE QUESTION IS 1358 01:00:24,560 --> 01:00:28,760 IS THIS SCALEABLE AT ALL? WILL 1359 01:00:28,760 --> 01:00:30,760 WE BE ABLE TO MAKE QUANTITIES OF 1360 01:00:30,760 --> 01:00:32,040 THIS FOR TRANSPORTATION? 1361 01:00:32,040 --> 01:00:33,920 >>YES, IT IS SCALEABLE AND I 1362 01:00:33,920 --> 01:00:35,600 THINK IT WOULD BE POSSIBLE. NOT 1363 01:00:35,600 --> 01:00:36,920 OBVIOUSLY THROUGHOUT THE BODY 1364 01:00:36,920 --> 01:00:40,920 BUT FOR LOCALIZED TREATMENT FOR 1365 01:00:40,920 --> 01:00:43,000 STRENGTHENING MUSCLES, IN A 1366 01:00:43,000 --> 01:00:45,960 LOCALIZED WAY. I THINK IT'S 1367 01:00:45,960 --> 01:00:48,600 QUITE REASONABLE TO THINK THIS 1368 01:00:48,600 --> 01:00:51,120 COULD BE FLUENT. YES. 1369 01:00:51,120 --> 01:00:54,040 >>AND I DO HAVE TO REITERATE 1370 01:00:54,040 --> 01:00:56,240 THE CME NUMBER BEFORE ANYBODY 1371 01:00:56,240 --> 01:01:00,560 LEAVES IS 44442. AND I HAVE A 1372 01:01:00,560 --> 01:01:02,840 FINAL QUESTION HERE THAT IS I 1373 01:01:02,840 --> 01:01:04,440 THINK IS GREAT. THE QUESTION 1374 01:01:04,440 --> 01:01:06,720 WAS HOW DO YOU STAY SO 1375 01:01:06,720 --> 01:01:09,040 PASSIONATE AND EFFECTIVE THROUGH 1376 01:01:09,040 --> 01:01:10,840 YOUR CAREER? 1377 01:01:10,840 --> 01:01:12,280 >>YOU JUST HAVE TO LOVE WHAT 1378 01:01:12,280 --> 01:01:15,280 YOU'RE DOING AND I DO. AND I -- 1379 01:01:15,280 --> 01:01:18,080 PART OF THE THRILL IS BRINGING 1380 01:01:18,080 --> 01:01:19,600 PEOPLE TOGETHER FROM DIFFERENT 1381 01:01:19,600 --> 01:01:21,720 COUNTRIES, DIFFERENT 1382 01:01:21,720 --> 01:01:23,120 DISCIPLINES, AND THINGS HAPPEN 1383 01:01:23,120 --> 01:01:26,040 WHEN YOU HAVE AN ENGINEER 1384 01:01:26,040 --> 01:01:27,480 SITTING NEXT TO AN ARTIFICIAL 1385 01:01:27,480 --> 01:01:30,040 INTELLIGENCE EXPERT AND HELPING 1386 01:01:30,040 --> 01:01:30,760 PEOPLE REACH THEIR FULL 1387 01:01:30,760 --> 01:01:32,960 POTENTIAL. I LOVE TRAINING AND 1388 01:01:32,960 --> 01:01:34,560 TEACHING AND THE THOUGHT THAT 1389 01:01:34,560 --> 01:01:36,520 SOMETHING THAT WAS DEVELOPED, 1390 01:01:36,520 --> 01:01:39,960 I'VE SPENT MY ENTIRE CAREER 1391 01:01:39,960 --> 01:01:42,760 STUDYING FUNDAMENTAL QUESTIONS 1392 01:01:42,760 --> 01:01:44,560 OF NUCLEAR REPROGRAMMING AND HOW 1393 01:01:44,560 --> 01:01:46,360 THAT HAPPENS AND STEM CELL 1394 01:01:46,360 --> 01:01:48,200 FUNCTION. I'M PARTICULARLY 1395 01:01:48,200 --> 01:01:51,040 EXCITED NOW THAT THIS MAY BE 1396 01:01:51,040 --> 01:01:52,000 TRANSLATABLE. THAT WE -- 1397 01:01:52,000 --> 01:01:53,840 SOMETHING IN MY LAB MAY ACTUALLY 1398 01:01:53,840 --> 01:01:56,200 BENEFIT PEOPLE AND BECOME A DRUG 1399 01:01:56,200 --> 01:01:59,480 AND THAT IS VERY MOTIVATING. 1400 01:01:59,480 --> 01:02:01,720 AND I WANT TO UNDERSTAND HOW IT 1401 01:02:01,720 --> 01:02:03,160 WORKS. IT'S LIKE A GIFT TO FIND 1402 01:02:03,160 --> 01:02:04,960 SOMETHING THAT'S COMPLETELY NEW, 1403 01:02:04,960 --> 01:02:07,520 NO ONE EVER STUDIED THIS ENZYME 1404 01:02:07,520 --> 01:02:10,400 AND ITS UPREGULATION WITH AGING 1405 01:02:10,400 --> 01:02:12,120 AND THERE'S SO MUCH TO DISCOVER. 1406 01:02:12,120 --> 01:02:15,960 IT'S UNCHARTED TERRITORY AND 1407 01:02:15,960 --> 01:02:19,400 THAT MAKES ME VERY EXCITED. 1408 01:02:19,400 --> 01:02:21,360 >>I THINK EVERYBODY IS VERY 1409 01:02:21,360 --> 01:02:24,240 EXCITED AFTER LISTENING TO THE 1410 01:02:24,240 --> 01:02:26,280 PRESENTATION. I WOULD ENCOURAGE 1411 01:02:26,280 --> 01:02:28,200 ANYONE TO FOLLOW UP WITH YOU 1412 01:02:28,200 --> 01:02:30,520 WITH E-MAIL IF THERE ARE 1413 01:02:30,520 --> 01:02:31,920 QUESTIONS ABOUT THE PRESENTATION 1414 01:02:31,920 --> 01:02:33,280 AND IF THEY ARE INTERESTED IN 1415 01:02:33,280 --> 01:02:35,400 WORKING FOR THE LAB. I KNOW THE 1416 01:02:35,400 --> 01:02:38,520 NIH IS A RICH RESOURCE FOR 1417 01:02:38,520 --> 01:02:39,960 POSTDOCS. THANK YOU VERY MUCH 1418 01:02:39,960 --> 01:02:42,200 FOR THIS TALK. IT'S BEEN AN 1419 01:02:42,200 --> 01:02:43,400 HONOR AND WITH THAT I SAY THAT 1420 01:02:43,400 --> 01:02:46,640 THIS IS THE END OF THE WALS FOR 1421 01:02:46,640 --> 01:02:47,920 THIS WEEK AND THANKS, EVERYONE, 1422 01:02:47,920 --> 01:02:48,000 FOR JOINING. 1423 01:02:48,000 --> 01:02:59,680 >>THANK YOU.