1 00:00:05,520 --> 00:00:08,200 >>GOOD GOOD MORNING EVERYBODY, 2 00:00:08,200 --> 00:00:08,840 WE ARE GOING TO GET STARTED PER 3 00:00:08,840 --> 00:00:13,400 DAY 2. MY NAME IS CHRISTINA-- 4 00:00:13,400 --> 00:00:14,040 NEW FACULTY FOR THE UNIVERSITY 5 00:00:14,040 --> 00:00:20,800 OF MINNESOTA, INSTITUTE OF 6 00:00:20,800 --> 00:00:22,800 AGING AND METABOLISM. WHAT CAN 7 00:00:22,800 --> 00:00:23,360 TODAY TO FOR THE SESSION 8 00:00:23,360 --> 00:00:24,000 INITIATED YESTERDAY ON ADVANCES 9 00:00:24,000 --> 00:00:24,600 IN AGING, IMMUNITY AND CHRONIC 10 00:00:24,600 --> 00:00:27,880 INFLAMMATORY DISEASES -- I 11 00:00:27,880 --> 00:00:29,160 WANTED TO START BY GIVING A 12 00:00:29,160 --> 00:00:32,800 SHORT FIVE MINUTE RECAP, OR A 13 00:00:32,800 --> 00:00:33,720 10 MINUTE RECAP, AND THEN WE 14 00:00:33,720 --> 00:00:34,280 WILL ROLL INTO THE FIRST 15 00:00:34,280 --> 00:00:35,680 SPEAKER FOR THE DAY, KATRINA 16 00:00:35,680 --> 00:00:41,120 ANDERSON. 17 00:00:41,120 --> 00:00:41,720 ONE OF THE THINGS I WANTED TO 18 00:00:41,720 --> 00:00:43,120 SORT OF HIGHLIGHT IS THAT THIS 19 00:00:43,120 --> 00:00:43,720 WORKSHOP IS SUPPOSED TO BRING 20 00:00:43,720 --> 00:00:53,600 TOGETHER IMMUNOLOGISTS, 21 00:00:53,600 --> 00:00:54,000 NEUROSCIENTISTS, 22 00:00:54,000 --> 00:00:54,560 GEROSCIENTISTS ALL OF THOSE 23 00:00:54,560 --> 00:01:01,200 WITH EXPERTISE IN OUR 24 00:01:01,200 --> 00:01:01,840 BACKGROUND, TO GET INSIGHT INTO 25 00:01:01,840 --> 00:01:02,440 KEY FINDINGS AND RECENT WORK 26 00:01:02,440 --> 00:01:04,440 AND GENERATE NEW 27 00:01:04,440 --> 00:01:05,040 COLLABORATIONS. THAT ARE 28 00:01:05,040 --> 00:01:15,160 ONGOING. 29 00:01:31,400 --> 00:01:33,200 >>YESTERDAY HIGHLIGHTED AND 30 00:01:33,200 --> 00:01:34,040 EVERYBODY AGREES THAT THE 31 00:01:34,040 --> 00:01:34,640 IMMUNE SYSTEM IS CRITICAL TO 32 00:01:34,640 --> 00:01:37,000 THE FIELD OF AGING. THIS IS 33 00:01:37,000 --> 00:01:37,520 BOTH THE AGING WITHIN THE 34 00:01:37,520 --> 00:01:42,040 IMMUNE CELL OR HOW THE IMMUNE 35 00:01:42,040 --> 00:01:52,560 CELL IS RESPONDING TO CELLULAR 36 00:01:52,960 --> 00:01:53,520 STRESS OR CATHOGENIC STRESSAS 37 00:01:53,520 --> 00:02:01,600 TIME DEVELOPS. TO MAKE BETTER 38 00:02:01,600 --> 00:02:02,200 UNDERSTAND HOW THE AGING WITHIN 39 00:02:02,200 --> 00:02:02,720 THE IMMUNE CELL FOR THE 40 00:02:02,720 --> 00:02:11,600 INTERACTION OF THAT IMMUNE 41 00:02:11,600 --> 00:02:12,240 CELL, WORKS WITH THE PATHOCITES 42 00:02:12,240 --> 00:02:22,520 WITH FIBROBLAST. 43 00:02:41,480 --> 00:02:44,160 >>CHANGES IN EPIGENETIC, WE 44 00:02:44,160 --> 00:02:49,000 HEARD ABOUT -- -- OF 45 00:02:49,000 --> 00:02:49,560 INDETERMINATE POTENTIAL AND 46 00:02:49,560 --> 00:02:52,320 THAT WILL CHANGE IN THE GENOME 47 00:02:52,320 --> 00:02:53,080 OVER TIME OF THESE AGE CELLS 48 00:02:53,080 --> 00:02:54,040 THAT LEAD TO CELLULAR 49 00:02:54,040 --> 00:02:56,960 DYSFUNCTION AND THEN THUS 50 00:02:56,960 --> 00:03:03,880 AFFECTING TISSUE DYSFUNCTION. 51 00:03:03,880 --> 00:03:04,480 WE KNOW THERE CAN BE CHANGES IN 52 00:03:04,480 --> 00:03:05,120 SIGNALING PATHWAYS AND WHETHER 53 00:03:05,120 --> 00:03:08,800 THOSE SIGNALING 54 00:03:08,800 --> 00:03:16,040 PATHWAYS ARE CHANGED FROM THE 55 00:03:16,040 --> 00:03:21,840 INSIDE OUT OR FROM ANOTHER 56 00:03:21,840 --> 00:03:22,440 PERSPECTIVE, WE HEARD CHANGES 57 00:03:22,440 --> 00:03:24,880 IN TELOMERE LENGTH ALL OF THESE 58 00:03:24,880 --> 00:03:25,400 THINGS PHENOMENONS THAT 59 00:03:25,400 --> 00:03:28,520 CONTRIBUTE TO THE BIOLOGY OF 60 00:03:28,520 --> 00:03:29,040 AGING, WITH AN INSULT TO 61 00:03:29,040 --> 00:03:29,640 CONTRIBUTE TO THE ABILITY TO 62 00:03:29,640 --> 00:03:32,760 APPROPRIATELY SENSE CELLULAR 63 00:03:32,760 --> 00:03:33,600 STRANDS A RESPONSE. 64 00:03:33,600 --> 00:03:34,000 >> 65 00:03:34,000 --> 00:03:40,080 >> 66 00:03:40,080 --> 00:03:40,400 >> 67 00:03:40,400 --> 00:03:40,680 >> 68 00:03:40,680 --> 00:03:50,680 >> 69 00:05:20,520 --> 00:05:21,040 >> 70 00:05:21,040 --> 00:05:25,760 >> 71 00:05:25,760 --> 00:05:32,760 >>I WAS EXCITED BY IH TO 72 00:05:32,760 --> 00:05:39,920 TRACK IMMUNOLOGICALLY, A 73 00:05:39,920 --> 00:05:40,520 REQUIRED COMPONENT THE LEASE 74 00:05:40,520 --> 00:05:42,920 GERIOSCIENCE AND IMMUNE FIELD. 75 00:05:42,920 --> 00:05:43,480 AND IMPACTED BY THE NEED TO 76 00:05:43,480 --> 00:05:54,000 BETTER SHARE INFORMATION AND 77 00:06:20,960 --> 00:06:26,480 TISSUES, DEVELOP PIPELINES. 78 00:06:26,480 --> 00:06:34,400 >>I AM DELIGHTED TO WELCOME 79 00:06:34,400 --> 00:06:38,960 KATRIN ANDREDASSON, DEPARTMENT 80 00:06:38,960 --> 00:06:40,520 OF NEUROLOGY AND NEUROLOGICAL 81 00:06:40,520 --> 00:06:41,120 SCIENCES STANFORD UNIVERSITY 82 00:06:41,120 --> 00:06:48,680 SCHOOL OF MEDICINE. 83 00:06:48,680 --> 00:06:49,280 >>THANK YOU TO THE ORGANIZERS 84 00:06:49,280 --> 00:06:49,880 WHO HAVE BEEN TERRIFIC, I AM 85 00:06:49,880 --> 00:06:50,400 LEARNING A LOT. 86 00:06:50,400 --> 00:07:00,400 >> 87 00:07:25,520 --> 00:07:26,760 >>I'M GOING TO CONTINUE THE 88 00:07:26,760 --> 00:07:28,560 NEUROSCIENCE THEME, THERE HAVE 89 00:07:28,560 --> 00:07:29,120 BEEN ASSOCIATION STUDIES 90 00:07:29,120 --> 00:07:32,960 LOOKING AT RISK FOR ALZHEIMER'S 91 00:07:32,960 --> 00:07:33,600 DISEASE AND WHAT HAS TRANSPIRED 92 00:07:33,600 --> 00:07:44,120 OVER THE LAST MAY BE DECADE OR 93 00:07:46,440 --> 00:07:48,640 SO HAS BEEN REALLY GAME 94 00:07:48,640 --> 00:07:51,680 CHANGING, AND POLYMORPHISMS 95 00:07:51,680 --> 00:07:52,200 CROPPING UP PARTICULARLY 96 00:07:52,200 --> 00:07:53,160 EXPRESSED IN THE MYELOID OF THE 97 00:07:53,160 --> 00:07:54,720 IMMUNE SYSTEM. 98 00:07:54,720 --> 00:08:00,440 OH BOY. I HOPE THIS WORKS. 99 00:08:00,440 --> 00:08:02,440 AND NOW THE FIELD IS REALLY 100 00:08:02,440 --> 00:08:07,960 FOCUSED ON MICRO GLIAL, 101 00:08:07,960 --> 00:08:08,520 RESIDENT MACROPHAGES OF THE 102 00:08:08,520 --> 00:08:12,960 BRAIN. HOWEVER A NUMBER OF 103 00:08:12,960 --> 00:08:16,240 THESE PROTEINS THAT HAVE 104 00:08:16,240 --> 00:08:17,040 POLYMORPHISMS ARE ALSO 105 00:08:17,040 --> 00:08:19,200 EXPRESSED PERIPHERALLY IN THE 106 00:08:19,200 --> 00:08:22,600 MACROPHAGES, IN THE MONOCYTES. 107 00:08:22,600 --> 00:08:32,360 SO, I DRAW YOUR ATTENTION TO 108 00:08:32,360 --> 00:08:41,760 TREM2, MENTIONED YESTERDAY, THE 109 00:08:41,760 --> 00:08:42,400 BIG AREA OF INVESTIGATION BOTH 110 00:08:42,400 --> 00:08:43,200 IN ACADEMIA AND PHARMA WITH 111 00:08:43,200 --> 00:08:45,880 ANTIBODIES, TREM2 IS ALSO 112 00:08:45,880 --> 00:08:50,080 EXPRESSED IN THE PERIPHERY. I 113 00:08:50,080 --> 00:08:50,640 THINK WHAT WE NEED TO START 114 00:08:50,640 --> 00:08:53,200 THINKING ABOUT IS THE FIELD, 115 00:08:53,200 --> 00:08:58,760 THIS COULD BE SOMETHING WE CAN 116 00:08:58,760 --> 00:08:59,360 DISCUSS IN THE AREA OF NEURAL 117 00:08:59,360 --> 00:08:59,920 INFORMATION, NOT JUST BEING 118 00:08:59,920 --> 00:09:02,880 MICRO GLIAL CENTRIC BUT ALSO 119 00:09:02,880 --> 00:09:03,840 THINKING BIGGER, AND 120 00:09:03,840 --> 00:09:05,640 INCORPORATING THE PERIPHERY. I 121 00:09:05,640 --> 00:09:16,120 WILL GET TO THAT IN A BIT. 122 00:09:19,720 --> 00:09:20,240 THE OTHER NICE SPREAD OF 123 00:09:20,240 --> 00:09:24,040 RESEARCH HAS BEEN EPIDEMIOLOGY. 124 00:09:24,040 --> 00:09:25,440 OBSERVATIONAL STUDIES HAVE 125 00:09:25,440 --> 00:09:27,160 LOOKED AT NORMAL, AGING 126 00:09:27,160 --> 00:09:30,760 POPULATIONS, COGNITIVELY NORMAL. 127 00:09:30,760 --> 00:09:31,360 WHO SOMEHOW DID NOT DEVELOP 128 00:09:31,360 --> 00:09:33,840 ALZHEIMER'S DISEASE. AND THEY 129 00:09:33,840 --> 00:09:41,560 ACTUALLY WERE TAKING ANSET, 130 00:09:41,560 --> 00:09:44,960 THERE AT LEAST FOUR 131 00:09:44,960 --> 00:09:45,480 OBSERVATIONAL STUDIES, 132 00:09:45,480 --> 00:09:48,000 INDICATING OUT OF THE VA, 133 00:09:48,000 --> 00:09:53,080 COGNITIVELY NORMAL VETS THINGS 134 00:09:53,080 --> 00:09:54,280 LIKE IBUPROFEN AND-- DID NOT 135 00:09:54,280 --> 00:09:55,520 DEVELOP ALZHEIMER'S DISEASE, 136 00:09:55,520 --> 00:09:56,920 BUT YOU HAVE TO TAKE IT FOR 137 00:09:56,920 --> 00:10:04,760 ABOUT 4-5 YEARS CONSISTENT WITH 138 00:10:04,760 --> 00:10:10,160 THESE DEGENERATIVE DISEASES. 139 00:10:10,160 --> 00:10:12,800 SO, WE WERE VERY INTERESTED IN 140 00:10:12,800 --> 00:10:15,960 AT THE BEGINNING, THIS IS WHAT 141 00:10:15,960 --> 00:10:16,600 MY LAB IS CONSISTENTLY WORKING 142 00:10:16,600 --> 00:10:18,960 ON SINCE THE BEGINNING. 143 00:10:18,960 --> 00:10:25,600 IS THIS PATHWAY COX-2 TO PGE2? 144 00:10:25,600 --> 00:10:35,160 COX-2 IS A MOTHER LOAD OF 145 00:10:35,160 --> 00:10:35,800 INFLAMMATORY ENZYMES, GENERATES 146 00:10:35,800 --> 00:10:46,280 DOWNSTREAM AS PGE2 AND PGE2 147 00:10:55,200 --> 00:10:59,880 SIGNALS THROUGH A NUMBER OF-- 148 00:10:59,880 --> 00:11:03,840 SHOWING US WHICH WE SHOWING 149 00:11:03,840 --> 00:11:05,120 THIS PREVENTIVE EFFECT AND HEAR 150 00:11:05,120 --> 00:11:06,920 ENOUGH HOURS PATIENTS PGE2 WAS 151 00:11:06,920 --> 00:11:12,800 VERY HIGH. WHAT WE WERE, 152 00:11:12,800 --> 00:11:13,440 EVENTUALLY AFTER A LOT OF WORK 153 00:11:13,440 --> 00:11:14,840 AND A LOT OF YEARS, A LOT OF 154 00:11:14,840 --> 00:11:18,000 NIH FUNDING, WE WERE ABLE TO 155 00:11:18,000 --> 00:11:24,960 IDENTIFY THE EP2 RECEPTOR A 156 00:11:24,960 --> 00:11:30,880 MASTER SUPPRESSOR, A FAIRLY 157 00:11:30,880 --> 00:11:39,960 NEFARIOUS RECEPTOR. IT IS 158 00:11:39,960 --> 00:11:40,560 VITALLY EXPRESSED IN NEURONS 159 00:11:40,560 --> 00:11:44,720 EMBRYONICALLY, POST NATALY. EP2 160 00:11:44,720 --> 00:11:55,200 INHIBITS AND BLOCKS SEVERAL 161 00:11:56,200 --> 00:12:03,160 (INDISCERNIBLE) INCLUDING 162 00:12:03,160 --> 00:12:05,320 PHAGCYTOSIS AND IN THE BRAIN. 163 00:12:05,320 --> 00:12:11,440 IN OUR EXPERIMENTS WAS 164 00:12:11,440 --> 00:12:21,880 CONDITIONAL -- WE FOUND WE 165 00:12:21,880 --> 00:12:22,520 COULD RESTORE AND A LOT OF THE 166 00:12:22,520 --> 00:12:25,360 NORMAL HOMEOSTASIS FUNCTIONS 167 00:12:25,360 --> 00:12:28,240 REDUCING THE LEVEL OF EP2 IN 168 00:12:28,240 --> 00:12:38,440 THE BRAIN. 169 00:12:40,240 --> 00:12:40,760 AGING IS CHARACTERIZED BY 170 00:12:40,760 --> 00:12:41,400 INFLAMMATION AND I THINK IT IS 171 00:12:41,400 --> 00:12:43,040 REALLY WONDERFUL THIS IDEA OF 172 00:12:43,040 --> 00:12:48,120 (AUDIO CUTTING IN AND OUT) -- 173 00:12:48,120 --> 00:12:52,400 MALADAPTIVE. I DON'T KNOW WHAT 174 00:12:52,400 --> 00:12:55,440 IS WRONG WITH THE SOUND. IT 175 00:12:55,440 --> 00:13:05,880 KEEPS CUTTING IN AND OUT. 176 00:13:22,320 --> 00:13:22,880 SO WE ALL ARE VERY FAMILIAR 177 00:13:22,880 --> 00:13:23,480 WITH THE CONCEPT AND THE IDEA 178 00:13:23,480 --> 00:13:24,360 THAT AGE ASSOCIATED 179 00:13:24,360 --> 00:13:24,880 INFLAMMATION IS HITTING 180 00:13:24,880 --> 00:13:25,480 EVERYTHING INCLUDING THE BRAIN 181 00:13:25,480 --> 00:13:28,640 RIGHT HERE. AND SO ONE OF THE 182 00:13:28,640 --> 00:13:31,280 MECHANISMS WE ARE INTERESTED 183 00:13:31,280 --> 00:13:32,760 IN, IS WHAT IS DRIVING THIS AGE 184 00:13:32,760 --> 00:13:34,480 ASSOCIATED INFLAMMATION, 185 00:13:34,480 --> 00:13:35,040 ESPECIALLY FOCUSING ON THE 186 00:13:35,040 --> 00:13:37,040 MYELOID; WE ARE NOT ADAPTIVE 187 00:13:37,040 --> 00:13:40,040 IMMUNE PEOPLE. 188 00:13:40,040 --> 00:13:40,640 ONE PROCESS WE HAVE BEEN VERY 189 00:13:40,640 --> 00:13:45,800 INTERESTED IN IS ENERGY 190 00:13:45,800 --> 00:13:46,640 METABOLISM, BY ENERGETICS OF 191 00:13:46,640 --> 00:13:50,760 MYELOID SALES. AND DECLINING 192 00:13:50,760 --> 00:13:57,200 GLYCOLS AND --. 193 00:13:57,200 --> 00:13:59,120 ONE OF THE EARLIER STUDIES 194 00:13:59,120 --> 00:14:00,960 THAT WE HAVE CARRIED OUT WAS 195 00:14:00,960 --> 00:14:01,840 SIMPLY COMPARING YOUNG AND OLD 196 00:14:01,840 --> 00:14:12,360 MACROPHAGES. WE LOOKED AT BOTH 197 00:14:14,400 --> 00:14:14,960 MOUSE PRIMARY MACROPHAGES FROM 198 00:14:14,960 --> 00:14:15,480 THE PERITONEUM, BUT ALSO 199 00:14:15,480 --> 00:14:17,600 EVALUATED HUMAN MACROPHAGES. 200 00:14:17,600 --> 00:14:25,640 WE ARE REGULAR CUSTOMERS. WE 201 00:14:25,640 --> 00:14:26,240 BY BLOOD FROM YOUNG DONORS, 35 202 00:14:26,240 --> 00:14:27,280 YEARS OR OR YOUNGER OR OLD 203 00:14:27,280 --> 00:14:31,120 DONORS, 65 OR OVER. AND LOOK 204 00:14:31,120 --> 00:14:33,960 AT METABOLOMICS. YOU CAN SEE 205 00:14:33,960 --> 00:14:38,760 IN THE AGED HUMAN MACROPHAGES 206 00:14:38,760 --> 00:14:39,320 THERE IS REALLY A MARKED 207 00:14:39,320 --> 00:14:46,280 DEPLETION OF GLYCOLITIC 208 00:14:46,280 --> 00:14:50,680 INTERMEDIATE AND PHOSPHATE 209 00:14:50,680 --> 00:14:56,000 INTERMEDIATE AND THERE IS A 210 00:14:56,000 --> 00:15:02,080 (INDISCERNIBLE). 211 00:15:02,080 --> 00:15:02,600 AND THAT WHAT WE NOTED WAS 212 00:15:02,600 --> 00:15:08,720 WHEN WE DID KEY HORSE 213 00:15:08,720 --> 00:15:15,320 (PHONETIC), WHICH MEASURES BOTH 214 00:15:15,320 --> 00:15:15,920 PHOSPHORYLATION-- IT WAS VERY 215 00:15:15,920 --> 00:15:16,520 LOW AND AGED MACROPHAGES AND 216 00:15:16,520 --> 00:15:17,120 THEN ALSO COUNTER TO WHAT WE 217 00:15:17,120 --> 00:15:23,320 COME TO EXPECT WITH THE WARBIRD 218 00:15:23,320 --> 00:15:27,400 PHENOMENA, GLYCOLYSIS WAS ALSO 219 00:15:27,400 --> 00:15:28,440 LOWER AND WE GOT A BIT OF 220 00:15:28,440 --> 00:15:29,080 PUSHBACK FROM THE REVIEWERS BUT 221 00:15:29,080 --> 00:15:33,520 IT IS WHAT IT IS. AGING I 222 00:15:33,520 --> 00:15:34,120 THINK IS METABOLICALLY QUITE 223 00:15:34,120 --> 00:15:35,440 DIFFERENT FROM THE RUBRIC, 224 00:15:35,440 --> 00:15:36,000 WHICH IS WHAT YOU GET WITH 225 00:15:36,000 --> 00:15:38,040 CANCER. 226 00:15:38,040 --> 00:15:44,720 WE WONDERED WHETHER THE EP2 227 00:15:44,720 --> 00:15:48,120 RECEPTOR WHICH MEDIATES A LOT 228 00:15:48,120 --> 00:15:48,680 OF NEUROTOXIC INFLAMMATORY 229 00:15:48,680 --> 00:15:49,320 RESPONSES, MAYBE IT IS WORKING 230 00:15:49,320 --> 00:15:50,640 BY SUPPRESSING BIOENERGETICS 231 00:15:50,640 --> 00:15:52,440 BECAUSE WE KNOW THAT METABOLISM 232 00:15:52,440 --> 00:15:56,760 REALLY DOES REGULATE A LOT OF 233 00:15:56,760 --> 00:15:57,760 INFORMATION. AND I DON'T HAVE 234 00:15:57,760 --> 00:15:59,400 TIME TO GO INTO ALL OF THAT, 235 00:15:59,400 --> 00:16:03,440 BUT THERE ARE AMPLE EXAMPLES OF 236 00:16:03,440 --> 00:16:09,880 TCA METABOLITES FOR EXAMPLE 237 00:16:09,880 --> 00:16:10,360 REGULATING INFLAMMATORY 238 00:16:10,360 --> 00:16:10,960 PROCESSES NOT TO MENTION LACK 239 00:16:10,960 --> 00:16:14,080 OF ATP. 240 00:16:14,080 --> 00:16:16,960 WHAT WE DID IS WE DID ADULT 241 00:16:16,960 --> 00:16:27,400 RESPONSE OF PGE2 IN HUMAN 242 00:16:29,600 --> 00:16:30,080 MACROPHAGES AND LOOKED AT 243 00:16:30,080 --> 00:16:30,680 OXIDATIVE PHOSPHORYLATION IN 244 00:16:30,680 --> 00:16:38,600 GLYCOLYSIS. WE ADDED THE PORE 245 00:16:38,600 --> 00:16:44,120 (PHONETIC) -- WE ALSO TURNED TO 246 00:16:44,120 --> 00:16:44,720 GENETICS AND I AM VERY MUCH A 247 00:16:44,720 --> 00:16:47,320 MOUSE LAB. WE USE GENETICS 248 00:16:47,320 --> 00:16:49,960 QUITE A BIT. CONDITIONAL AND 249 00:16:49,960 --> 00:16:53,440 INDUCIBLE MODELS. IF WE NOW 250 00:16:53,440 --> 00:16:57,080 LOOK AT MITOCHONDRIA IN 251 00:16:57,080 --> 00:17:01,360 MACROPHAGES FROM YOUNG AND AGED 252 00:17:01,360 --> 00:17:01,920 UNCONDITIONALLY KNOCKED OUT 253 00:17:01,920 --> 00:17:05,280 YOUNG AND AGED MICE, YOU SEE 254 00:17:05,280 --> 00:17:05,840 IMMEDIATELY THE DIFFERENCE 255 00:17:05,840 --> 00:17:06,400 BETWEEN THE YOUNG AND AGED 256 00:17:06,400 --> 00:17:07,000 MITOCHONDRIA, THEY LOOK 257 00:17:07,000 --> 00:17:11,960 TERRIBLE. THEY ARE NOT VERY 258 00:17:11,960 --> 00:17:13,360 ELECTRON DANCE, THEY ARE 259 00:17:13,360 --> 00:17:15,320 BALLOON SHAPED. 260 00:17:15,320 --> 00:17:18,000 BUT IF YOU NOW LOOK AT THE OLD 261 00:17:18,000 --> 00:17:26,760 EP2 MICE, THE MITOCHONDRIA 262 00:17:26,760 --> 00:17:27,360 LOOKS INDISTINGUISHABLE FROM 263 00:17:27,360 --> 00:17:30,640 THE YOUNG SOMEHOW BUT PREVENTED 264 00:17:30,640 --> 00:17:31,280 THE DEGRADATION OF MITOCHONDRIA 265 00:17:31,280 --> 00:17:33,600 BY REDUCING EP2 JUST BY 50% AND 266 00:17:33,600 --> 00:17:40,320 I THOUGHT THIS WAS WOW! COOL! 267 00:17:40,320 --> 00:17:42,600 AND THEN WE TURNED THEN TO I 268 00:17:42,600 --> 00:17:50,840 GUESS AGING. RIGHT. AGING IS 269 00:17:50,840 --> 00:17:53,560 THE PRIMARY ASPECT OF 270 00:17:53,560 --> 00:17:54,760 ALZHEIMER'S BUT HE WE CAN CRACK 271 00:17:54,760 --> 00:17:55,360 THE AGING PROBLEM FIRST THAT 272 00:17:55,360 --> 00:18:00,960 WOULD BE NICE. THAT IS FAR AND 273 00:18:00,960 --> 00:18:02,200 ABOVE THE BIGGEST FACTOR FOR A 274 00:18:02,200 --> 00:18:02,760 LOT OF THESE AGE ASSOCIATED 275 00:18:02,760 --> 00:18:04,960 NEURODEGENERATIVE DISORDERS. 276 00:18:04,960 --> 00:18:09,880 LOOKING AT THIS PATHWAY NOW, -- 277 00:18:09,880 --> 00:18:14,960 HOW DO I GO BACK? 278 00:18:14,960 --> 00:18:17,560 IF WE LOOKED AT-- WE HAD A LOT 279 00:18:17,560 --> 00:18:24,760 OF PGE2 THAT THE HUMAN 280 00:18:24,760 --> 00:18:25,400 MACROPHAGES-- THIS IS SOMEHOW 281 00:18:25,400 --> 00:18:26,480 SHOWING IN DIFFERENT-- I 282 00:18:26,480 --> 00:18:34,360 APOLOGIZE -- ANYWAY, WHAT IT IS 283 00:18:34,360 --> 00:18:34,960 SUPPOSED TO SHOW IS THAT EVERY 284 00:18:34,960 --> 00:18:35,560 CULTURE HUMAN MACROPHAGES WE 285 00:18:35,560 --> 00:18:39,080 LOOK AT PGE2 LEVEL AND WHEN YOU 286 00:18:39,080 --> 00:18:40,000 LOOK AT YOUNG VERSUS OLD A 287 00:18:40,000 --> 00:18:44,520 LEVEL OF PGE2 IN THE CELL AND 288 00:18:44,520 --> 00:18:45,160 IN THE-- ARE SKYHIGH IN THE OLD 289 00:18:45,160 --> 00:18:47,320 COMPARED TO THE YOUNG. HUMAN 290 00:18:47,320 --> 00:18:53,120 MACROPHAGES ACTUALLY MAKE A LOT 291 00:18:53,120 --> 00:18:53,680 MORE PGE2 WHEN WE ARE OLDER 292 00:18:53,680 --> 00:18:54,280 THAN WHEN WE ARE YOUNGER AND 293 00:18:54,280 --> 00:18:54,800 THEN WE TOOK THE SAME 294 00:18:54,800 --> 00:18:57,000 MACROPHAGES AND LOOKED AT THE 295 00:18:57,000 --> 00:18:58,240 EP2 RECEPTOR DISTRIBUTION FOUND 296 00:18:58,240 --> 00:19:01,440 INCREASED EP2 RECEPTORS THERE. 297 00:19:01,440 --> 00:19:03,400 IT IS VERY SPECIFIC. 298 00:19:03,400 --> 00:19:08,000 THE NICE THING AGAIN, ALIGNING 299 00:19:08,000 --> 00:19:10,080 HUMAN WITH MOUSE WHICH IS SUPER 300 00:19:10,080 --> 00:19:10,680 IMPORTANT, IS THAT IF WE LOOK 301 00:19:10,680 --> 00:19:11,280 AT THE MOUSE AGAIN WE SEE IN 302 00:19:11,280 --> 00:19:13,160 THE OLD MILES TONS OF PGE2 IN 303 00:19:13,160 --> 00:19:15,040 THE PLASMA. THESE MEASUREMENTS 304 00:19:15,040 --> 00:19:18,840 WERE DONE BY OUR COLLABORATORS 305 00:19:18,840 --> 00:19:27,120 AT KAO (PHONETIC), PGE2 306 00:19:27,120 --> 00:19:27,640 RECEPTORS ARE SUPREMELY 307 00:19:27,640 --> 00:19:30,800 DIFFICULT TO MEASURE. PGE2 WERE 308 00:19:30,800 --> 00:19:31,440 UP IN THE PLASMA AS WELL AS IN 309 00:19:31,440 --> 00:19:36,960 THE BRAIN BUT THE OTHER -- WERE 310 00:19:36,960 --> 00:19:38,120 UNCHANGED WITH AGE. THIS WAS A 311 00:19:38,120 --> 00:19:41,960 VERY SPECIFIC EFFECT AND IN THE 312 00:19:41,960 --> 00:19:42,560 EP2 RECEPTORS WERE ALSO HIGH IN 313 00:19:42,560 --> 00:19:46,440 MOUSE ROCK OF (CORRECTION) 314 00:19:46,440 --> 00:19:50,320 MACROPHAGES. 315 00:19:50,320 --> 00:19:50,880 WE AGE THIS MICE AND COMPARE 316 00:19:50,880 --> 00:19:52,960 YOUNG TO OLD, BOTH GENOTYPES 317 00:19:52,960 --> 00:19:56,240 AND FOUND THAT IN THE PLASMA AS 318 00:19:56,240 --> 00:20:00,960 WELL AS IN THE HIPPOCAMPUS WE 319 00:20:00,960 --> 00:20:02,760 HAD THIS BEAUTIFUL, BASICALLY 320 00:20:02,760 --> 00:20:03,680 REJUVENATION OF THE PLASMA, IN 321 00:20:03,680 --> 00:20:06,080 TERMS OF IMMUNE FACTORS. AND 322 00:20:06,080 --> 00:20:06,720 PRETTY MUCH THE HIPPOCAMPUS AS 323 00:20:06,720 --> 00:20:09,760 WELL. 324 00:20:09,760 --> 00:20:11,920 HERE ON THE LEFT OR THE OLD 325 00:20:11,920 --> 00:20:16,560 CONTROLLED MICE. YOU CAN SEE 326 00:20:16,560 --> 00:20:22,160 YOUR FAVORITE INFLAMMAZOME IO1 327 00:20:22,160 --> 00:20:25,080 BETA VERY HIGH AND BASICALLY 328 00:20:25,080 --> 00:20:27,960 THE AGE CONDITIONAL KNOCKOUTS 329 00:20:27,960 --> 00:20:28,600 ARE INDISTINGUISHABLE FROM THE 330 00:20:28,600 --> 00:20:30,640 YOUNG. THAT WAS VERY 331 00:20:30,640 --> 00:20:32,440 INTERESTING. 332 00:20:32,440 --> 00:20:36,920 DR. -- TALK ABOUT YESTERDAY 333 00:20:36,920 --> 00:20:41,200 VERY NICELY, WE CAN LOOK AT 334 00:20:41,200 --> 00:20:41,760 HIPPOCAMPUS SPECIAL MEMORY 335 00:20:41,760 --> 00:20:43,320 USING THE SPECIAL MEMORY TEST; 336 00:20:43,320 --> 00:20:43,920 THE HIPPOCAMPUS IS EXQUISITELY 337 00:20:43,920 --> 00:20:47,240 SENSITIVE TO INFLAMMATION. I 338 00:20:47,240 --> 00:20:47,880 WANT TO DRAW YOUR ATTENTION TO 339 00:20:47,880 --> 00:20:49,560 THIS DIAGRAM HERE, THIS IS A 340 00:20:49,560 --> 00:20:53,000 DIAGRAM OF THE PATH TAKEN BY 341 00:20:53,000 --> 00:20:54,480 THE MOUSE AFTER FOUR DAYS OF 342 00:20:54,480 --> 00:20:57,000 TRAINING. THESE ARE BOTH OLD 343 00:20:57,000 --> 00:21:01,800 MICE. THE OLD MILES REALLY 344 00:21:01,800 --> 00:21:02,440 CANNOT REMEMBER AT ALL HOW TO 345 00:21:02,440 --> 00:21:06,280 ESCAPE TO THE TARGET HOLE. BUT 346 00:21:06,280 --> 00:21:10,320 THE OLD EP2 KNOCKOUT REALLY HAS 347 00:21:10,320 --> 00:21:16,960 NO PROBLEM, GOES RIGHT TO IT. 348 00:21:16,960 --> 00:21:17,560 SO WE SOMEHOW PREVENTED AGE- 349 00:21:17,560 --> 00:21:21,520 ASSOCIATED COGNITIVE DECLINE. 350 00:21:21,520 --> 00:21:21,920 SIMILARLY FOR THE 351 00:21:21,920 --> 00:21:25,040 NEUROSCIENTISTS IN THE 352 00:21:25,040 --> 00:21:27,800 AUDIENCE, WE LOOKED 353 00:21:27,800 --> 00:21:28,440 ORTHOGONALLY, LOOKING A MEASURE 354 00:21:28,440 --> 00:21:32,600 OF THE SYNAPTIC STRENGTH IN 355 00:21:32,600 --> 00:21:33,200 HIPPOCAMPUS AND WHAT YOU CAN 356 00:21:33,200 --> 00:21:38,480 APPRECIATE HERE IS HOW PALTRY 357 00:21:38,480 --> 00:21:40,200 THE SIGNAL IS IN THE AGED 358 00:21:40,200 --> 00:21:41,720 CONTROLS WHERE IN GREEN THE 359 00:21:41,720 --> 00:21:48,520 AGED EP2 KNOCKOUTS ARE UP THERE 360 00:21:48,520 --> 00:21:49,080 BASICALLY INDISTINGUISHABLE 361 00:21:49,080 --> 00:21:53,120 SWITCHABLE FROM THE YOUNG. WE 362 00:21:53,120 --> 00:21:53,760 ESSENTIALLY RESTORE NOT JUST 363 00:21:53,760 --> 00:21:56,880 SPATIAL MEMORY FUNCTION BUT AT 364 00:21:56,880 --> 00:21:58,560 A CELLULAR, MOLECULAR LEVEL WE 365 00:21:58,560 --> 00:21:59,160 ACTUALLY RESCUED THE SYNAPTIC 366 00:21:59,160 --> 00:21:59,880 STRENGTH IN THESE OLD MICE. 367 00:21:59,880 --> 00:22:04,800 SO, TO CUT A LONG STORY SHORT, 368 00:22:04,800 --> 00:22:05,400 THERE IS A TREMENDOUS AMOUNT OF 369 00:22:05,400 --> 00:22:15,880 WORK THAT OUR STUDENTS DID 370 00:22:21,160 --> 00:22:22,440 USING METABOLOMIC, MASS 371 00:22:22,440 --> 00:22:25,320 LABELING, ORTHOGONAL APPROACHES 372 00:22:25,320 --> 00:22:25,840 WE DON'T KNOW IF ANYTHING 373 00:22:25,840 --> 00:22:29,880 HAPPENED IN THE T CELLS OR P 374 00:22:29,880 --> 00:22:33,000 CELLS BUT AT LEAST IN THE PGE2 375 00:22:33,000 --> 00:22:34,160 PATHWAY WE HAD NICE SIGNALING 376 00:22:34,160 --> 00:22:40,960 THROUGH EP2 IMPROPER GLUCOSE -- 377 00:22:40,960 --> 00:22:45,720 FEEDING THE ATP TRANSFERRED AND 378 00:22:45,720 --> 00:22:46,280 ENABLES NORMAL HOMEOSTATIC 379 00:22:46,280 --> 00:22:49,080 IMMUNE FUNCTIONS. 380 00:22:49,080 --> 00:22:50,080 HOWEVER IN THE AGED MYELOID 381 00:22:50,080 --> 00:22:50,680 CELL, I SHOWED YOU THAT WE HAVE 382 00:22:50,680 --> 00:22:53,720 A LOT MORE PGE2 FLOATING AROUND 383 00:22:53,720 --> 00:22:58,440 AND WE HAVE AN UP REGULATION OF 384 00:22:58,440 --> 00:22:59,080 EP2 RECEPTORS ON THE SURFACE OF 385 00:22:59,080 --> 00:23:02,440 OUR MYELOID. AND WHAT I ALLUDED 386 00:23:02,440 --> 00:23:04,560 TO BEFORE IS THAT THERE IS 387 00:23:04,560 --> 00:23:08,360 ACTUALLY A SHUNT, EP2 DRIVES 388 00:23:08,360 --> 00:23:15,320 THE SHUNTING OF GLYCOGEN. IT 389 00:23:15,320 --> 00:23:15,920 IS SEQUESTERED IT IS NOT ABLE 390 00:23:15,920 --> 00:23:22,360 TO FEED LIKE ALL INTO THE TCA, 391 00:23:22,360 --> 00:23:22,880 AND WE HAVE THIS ENERGY 392 00:23:22,880 --> 00:23:23,440 DEPLETED, LIMPING ALONG OLD 393 00:23:23,440 --> 00:23:26,520 MYELOID CELL. THAT IS NOT 394 00:23:26,520 --> 00:23:27,080 GOING TO BE ABLE TO SUPPORT 395 00:23:27,080 --> 00:23:28,000 HOMEOSTATIC IMMUNE RESPONSES. 396 00:23:28,000 --> 00:23:33,920 OKAY. SO I JUST WANTED TO 397 00:23:33,920 --> 00:23:35,760 FINISH UP WITH SOME 398 00:23:35,760 --> 00:23:36,560 INTERESTING, SORT OF 399 00:23:36,560 --> 00:23:40,960 TRANSLATIONAL FINDINGS. SO 400 00:23:40,960 --> 00:23:42,640 THAT NOW OF COURSE, WE WANT TO 401 00:23:42,640 --> 00:23:47,080 TEST WHETHER WE CAN ELICIT A 402 00:23:47,080 --> 00:23:47,440 SIMILAR THING 403 00:23:47,440 --> 00:23:50,760 PHARMACOLOGICALLY. YES WE CAN. 404 00:23:50,760 --> 00:23:54,000 THIS IS AN EP2-SELECTED 405 00:23:54,000 --> 00:23:54,480 INHIBITOR THAT IS BRAIN 406 00:23:54,480 --> 00:23:56,680 PENETRANT. SO WE BASICALLY 407 00:23:56,680 --> 00:24:02,200 LOOKED AT THE SAME THREE 408 00:24:02,200 --> 00:24:02,840 OUTCOMES, IMMUNE FACTORS IN THE 409 00:24:02,840 --> 00:24:06,120 PLASMA AND THE HIPPOCAMPUS; 410 00:24:06,120 --> 00:24:06,720 SPATIAL MEMORY, AND SYNAPTIC 411 00:24:06,720 --> 00:24:08,920 PLASTICITY. 412 00:24:08,920 --> 00:24:10,360 AND AGAIN WHAT WE FOUND IN THE 413 00:24:10,360 --> 00:24:13,760 PLASMA, THE OLD VEHICLE CONTROL 414 00:24:13,760 --> 00:24:15,680 MICE ARE SEGREGATING OVER HERE. 415 00:24:15,680 --> 00:24:22,280 THE OLD EP2-INHIBITOR TREATED 416 00:24:22,280 --> 00:24:22,920 ONES ARE INDISTINGUISHABLE FROM 417 00:24:22,920 --> 00:24:24,040 THE YOUNG AND WE FIND A SIMILAR 418 00:24:24,040 --> 00:24:25,640 PATTERN IN THE HIPPOCAMPUS. 419 00:24:25,640 --> 00:24:30,280 WE ALSO CAN RESCUE HIPPOCAMPAL 420 00:24:30,280 --> 00:24:31,040 MEMORY, SPECIAL MEMORY AND 421 00:24:31,040 --> 00:24:33,800 PLASTICITY. BUT THE 422 00:24:33,800 --> 00:24:37,120 INTERESTING THING-- THIS IS 423 00:24:37,120 --> 00:24:37,640 GREAT-- BUT THE REALLY 424 00:24:37,640 --> 00:24:38,240 INTERESTING THING IS THAT WE 425 00:24:38,240 --> 00:24:41,720 COULD SEE THIS AFTER TWO WEEKS. 426 00:24:41,720 --> 00:24:42,320 SO THIS HAS KIND OF SMACKED 427 00:24:42,320 --> 00:24:49,840 THE METABOLISM IN OUR VIEW. AND 428 00:24:49,840 --> 00:24:50,400 MAYBE ALL THE CIRCUITS ARE 429 00:24:50,400 --> 00:24:51,000 RIGHT THERE; THEY MAY NOT BE 430 00:24:51,000 --> 00:24:54,320 ALL THAT PERFECTLY TUNED BUT 431 00:24:54,320 --> 00:24:54,840 THEY ARE THERE AND THE 432 00:24:54,840 --> 00:24:57,480 STRUCTURE IS THERE. YOU JUST 433 00:24:57,480 --> 00:25:00,560 KIND OF HAVE TO WAKE UP THE 434 00:25:00,560 --> 00:25:01,160 NEURONS; IN ORDER TO WAKE UP 435 00:25:01,160 --> 00:25:10,760 THE NEURONS YOU HAVE TO 436 00:25:10,760 --> 00:25:11,320 BASICALLY IMPROVE THE LOCAL 437 00:25:11,320 --> 00:25:21,840 MILIEU, ENVIRONMENTAL MILIEU. 438 00:25:27,000 --> 00:25:30,760 IN THE BRAIN WE CAN DO TEM; 439 00:25:30,760 --> 00:25:32,760 AND LOOK AT MITOCHONDRIA AND 440 00:25:32,760 --> 00:25:38,080 MICHAEL -- (CORRECTION) MICRO 441 00:25:38,080 --> 00:25:40,440 GLIAL CELLS. YOU CAN SEE IT 442 00:25:40,440 --> 00:25:46,760 AGAIN IN THE OLD MICRO GLIAL 443 00:25:46,760 --> 00:25:47,800 YOU HAVE THESE GLOBULAR PALE 444 00:25:47,800 --> 00:25:48,400 MITOCHONDRIA BUT THIS IS ONLY 445 00:25:48,400 --> 00:25:52,920 ABOUT 2-4 WEEKS, WE START TO 446 00:25:52,920 --> 00:25:54,720 SEE ELONGATION OF THE 447 00:25:54,720 --> 00:25:55,280 MITOCHONDRIA, SLIGHTLY MORE 448 00:25:55,280 --> 00:25:58,960 ELECTRON DENSITY, AND THIS IS 449 00:25:58,960 --> 00:26:01,240 CHRONIFIED OVER HERE. 450 00:26:01,240 --> 00:26:03,640 THIS IS OUR FIRST MODEL. THIS 451 00:26:03,640 --> 00:26:06,360 IS BROAD STROKES. BUT IT HELPS 452 00:26:06,360 --> 00:26:08,840 US THINK ABOUT THINGS AND DRILL 453 00:26:08,840 --> 00:26:11,680 DOWN IN THE RIGHT PLACES SO 454 00:26:11,680 --> 00:26:19,000 THAT DECREASING MYELOID 455 00:26:19,000 --> 00:26:19,480 BIOENERGETICS DRIVES 456 00:26:19,480 --> 00:26:20,080 MALADAPTIVE INFORMATION AS WE 457 00:26:20,080 --> 00:26:21,240 AGE. 458 00:26:21,240 --> 00:26:23,160 ONE MECHANISM IS THROUGH THE 459 00:26:23,160 --> 00:26:26,280 EP2 RECEPTOR, PGE2 SIGNALING 460 00:26:26,280 --> 00:26:29,840 THROUGH THE EP2 RECEPTOR AND 461 00:26:29,840 --> 00:26:36,640 THERE IS NOTHING LEFT FOR THE 462 00:26:36,640 --> 00:26:37,280 PCA IN THE TRANSPORT AND I WANT 463 00:26:37,280 --> 00:26:39,600 TO FINISH NOW WITH A VERY 464 00:26:39,600 --> 00:26:40,240 TANTALIZING FINDING THAT WE CAN 465 00:26:40,240 --> 00:26:41,160 ACTUALLY ACHIEVE THE SAME THING 466 00:26:41,160 --> 00:26:43,000 WITH A NON-BRAIN PENETRANT EP2 467 00:26:43,000 --> 00:26:45,640 INHIBITOR. 468 00:26:45,640 --> 00:26:49,640 AND SO WHAT WE CAN DO IS 469 00:26:49,640 --> 00:26:51,920 EXACTLY THE SAME THING. THIS 470 00:26:51,920 --> 00:26:55,400 IS A NON-BRAIN PENETRANT EP2 471 00:26:55,400 --> 00:26:57,320 DEVELOPED BY PFIZER, WENT INTO 472 00:26:57,320 --> 00:27:01,000 PHASE 1 SAFETY FILES. THAT WAS 473 00:27:01,000 --> 00:27:08,560 ABORTED. NOT SURE WHY. 474 00:27:08,560 --> 00:27:09,120 PRESUMABLY THE REASON MOST 475 00:27:09,120 --> 00:27:09,720 THINGS GET ABORTED IS BECAUSE 476 00:27:09,720 --> 00:27:13,400 THERE IS TOXICITY. 477 00:27:13,400 --> 00:27:13,920 IN MICE WE WENT AHEAD AND 478 00:27:13,920 --> 00:27:16,880 TRIED IT IN YOUNG AND OLD MICE. 479 00:27:16,880 --> 00:27:17,440 AGAIN AS WE EXPECTED WE SAW 480 00:27:17,440 --> 00:27:21,400 THIS VERY NICE RESCUE OF IMMUNE 481 00:27:21,400 --> 00:27:23,000 FACTORS IN THE PLASMA BUT WHAT 482 00:27:23,000 --> 00:27:24,520 WE DID NOT EXPECT WAS TO ALSO 483 00:27:24,520 --> 00:27:27,960 SEE RESCUE IN THE HIPPOCAMPUS. 484 00:27:27,960 --> 00:27:32,520 THAT WAS VERY PUZZLING. THAT IS 485 00:27:32,520 --> 00:27:36,160 NOT BRAIN PENETRANT. 486 00:27:36,160 --> 00:27:36,640 WE ALSO SAW A RESCUE OF 487 00:27:36,640 --> 00:27:38,400 SPECIAL MEMORY AND PLASTICITY. 488 00:27:38,400 --> 00:27:39,000 THIS INDICATES THAT AT LEAST 489 00:27:39,000 --> 00:27:41,840 FOR THIS PATHWAY, PERIPHERAL 490 00:27:41,840 --> 00:27:46,320 INNOVATION OF THIS INFLAMMATORY 491 00:27:46,320 --> 00:27:48,800 PGE2 PATHWAY IS SUFFICIENT TO 492 00:27:48,800 --> 00:27:51,400 RESCUE AGING. 493 00:27:51,400 --> 00:27:54,280 THIS IS OUR SECOND MODEL. WE 494 00:27:54,280 --> 00:27:56,320 ARE WONDERING HOW THIS IS 495 00:27:56,320 --> 00:27:58,640 HAPPENING. AND IF YOU THINK, IF 496 00:27:58,640 --> 00:28:01,000 YOU CONSIDER MYELOID CELLS IN 497 00:28:01,000 --> 00:28:03,760 THE BODY AND THIS IS AN PEOPLE 498 00:28:03,760 --> 00:28:05,080 IN OUR BRAINS WE HAVE ABOUT 25 499 00:28:05,080 --> 00:28:08,520 BILLION MICROGLIA. WE ALSO 500 00:28:08,520 --> 00:28:14,240 HAVE-- BUT THAT'S REALLY 501 00:28:14,240 --> 00:28:14,840 DWARFED BY THE NUMBER OF 502 00:28:14,840 --> 00:28:18,480 MACROPHAGES AND MONOCYTES IN 503 00:28:18,480 --> 00:28:19,120 THE PERIPHERY WHERE YOU HAVE 27 504 00:28:19,120 --> 00:28:20,160 BILLION AND 200 BILLION 505 00:28:20,160 --> 00:28:23,080 MACROPHAGES. 506 00:28:23,080 --> 00:28:25,280 WHAT WE ARE THINKING IS THAT, 507 00:28:25,280 --> 00:28:25,880 REALLY IT IS A PERIPHERY THAT 508 00:28:25,880 --> 00:28:31,240 IS DRIVING A LOT. HOW? THAT IS 509 00:28:31,240 --> 00:28:31,800 REALLY INTERESTING. WE ARE 510 00:28:31,800 --> 00:28:34,840 LOOKING AT THAT, AND A NUMBER 511 00:28:34,840 --> 00:28:35,480 OF FOLKS IN THE LAB ARE LOOKING 512 00:28:35,480 --> 00:28:37,680 AT THAT. 513 00:28:37,680 --> 00:28:38,280 SO IT IS POSSIBLE THAT WE MAY 514 00:28:38,280 --> 00:28:40,400 BE ABLE TO KEEP THE BRAIN 515 00:28:40,400 --> 00:28:46,800 HEALTHY BY TWEAKING THE 516 00:28:46,800 --> 00:28:47,440 PERIPHERAL MYELOID SYSTEM. THAT 517 00:28:47,440 --> 00:28:50,760 IS AN OVERSIMPLIFICATION. BUT 518 00:28:50,760 --> 00:28:53,680 THAT IS ONGOING. 519 00:28:53,680 --> 00:28:56,960 ANYWAY I WANTED TO ACKNOWLEDGE 520 00:28:56,960 --> 00:28:57,600 MOST IMPORTANT SLIDE, ALL THE 521 00:28:57,600 --> 00:29:01,520 FOLKS IN THE LAB ESPECIALLY -- 522 00:29:01,520 --> 00:29:01,960 -- AND A WONDERFUL 523 00:29:01,960 --> 00:29:02,560 COLLABORATORS AND I WANT TO 524 00:29:02,560 --> 00:29:08,440 HIGHLIGHT MAKATO AND YUKI, 525 00:29:08,440 --> 00:29:09,880 REALLY GOOD BIOCHEMISTS. AND OF 526 00:29:09,880 --> 00:29:17,760 COURSE BIG SHOUT OUT TO THE NIH 527 00:29:17,760 --> 00:29:18,360 FOR SUPPORTING THIS THANK YOU 528 00:29:18,360 --> 00:29:20,040 VERY MUCH. 529 00:29:20,040 --> 00:29:21,480 >>THAT WAS TERRIFIC. LIZ OVER 530 00:29:21,480 --> 00:29:26,600 HERE. I AM WONDERING IF THESE 531 00:29:26,600 --> 00:29:28,560 TREATMENTS DECREASE OR SOMEHOW 532 00:29:28,560 --> 00:29:35,320 ALTER THE NUMBER OF MICROGLIA 533 00:29:35,320 --> 00:29:35,880 EITHER IN THE REGION WHERE 534 00:29:35,880 --> 00:29:36,480 THERE IS A LESION OR ANYWHERE 535 00:29:36,480 --> 00:29:36,880 ELSE. 536 00:29:36,880 --> 00:29:45,600 >>WE LOOKED AT THAT. NO 537 00:29:45,600 --> 00:29:46,200 DIFFERENCE IN THE MICRO GLIAL 538 00:29:46,200 --> 00:29:46,800 NUMBER. WE HAVE NOT LOOKED AT 539 00:29:46,800 --> 00:29:49,120 IT AT THE NON-BRAIN PENETRANT 540 00:29:49,120 --> 00:29:49,760 YET BUT IN BRAIN PENETRANT NOT 541 00:29:49,760 --> 00:29:54,360 MUCH DIFFERENCE. 542 00:29:54,360 --> 00:29:55,840 >>BEHIND THE PILLAR AGAIN. 543 00:29:55,840 --> 00:29:58,600 GREAT TALK. AFTER YOU TREAT 544 00:29:58,600 --> 00:30:02,680 YOUR ANIMALS WITH EP2 INHIBITOR 545 00:30:02,680 --> 00:30:03,080 DID YOU LOOK AT THE 546 00:30:03,080 --> 00:30:06,680 MITOCHONDRIA? DID THEIR NUMBER 547 00:30:06,680 --> 00:30:07,240 OR THE QUALITY DECREASE OR 548 00:30:07,240 --> 00:30:10,040 CHANGE? 549 00:30:10,040 --> 00:30:11,840 >>YES THAT WAS THE SLIDE WITH 550 00:30:11,840 --> 00:30:12,960 THE BRAIN PENETRANT, EP2 551 00:30:12,960 --> 00:30:14,720 INHIBITOR. WE ARE LOOKING NOW 552 00:30:14,720 --> 00:30:16,360 AT THE NON-BRAIN PENETRANT EP2 553 00:30:16,360 --> 00:30:19,480 INHIBITOR. I SUSPECT THEY ARE 554 00:30:19,480 --> 00:30:20,800 COMPLETELY DIFFERENT MECHANISMS. 555 00:30:20,800 --> 00:30:25,040 THE BRAIN PENETRANT, LOTS OF 556 00:30:25,040 --> 00:30:29,040 EP2 ON MICROGLIA. WE ALSO DID 557 00:30:29,040 --> 00:30:29,560 SOME MASS LABELING AND 558 00:30:29,560 --> 00:30:31,400 BIOCHEMISTRY TO SHOW THAT THE 559 00:30:31,400 --> 00:30:31,920 EP2 IS SIGNALING TO THE 560 00:30:31,920 --> 00:30:35,880 MICROGLIA. BUT FOR THE 561 00:30:35,880 --> 00:30:36,520 NON-BRAIN PENETRANT IT IS GOING 562 00:30:36,520 --> 00:30:38,080 TO BE SOMETHING ELSE, WHICH IS 563 00:30:38,080 --> 00:30:44,360 KIND OF INTRIGUING. THANK YOU. 564 00:30:44,360 --> 00:30:44,960 >>THANK YOU VERY MUCH FOR THE 565 00:30:44,960 --> 00:30:48,920 TALK. IT WAS REALLY EXCITING. 566 00:30:48,920 --> 00:30:49,480 LET'S GET SLIDES UP FOR THE 567 00:30:49,480 --> 00:30:54,320 NEXT SPEAKER. 568 00:30:54,320 --> 00:30:55,000 AND I WOULD LIKE TO WELCOME 569 00:30:55,000 --> 00:31:03,520 BERNARD KHOR FROM BENAROYA WHO 570 00:31:03,520 --> 00:31:04,040 WILL SPEAK ON AGING AND 571 00:31:04,040 --> 00:31:04,560 AUTOIMMUNITY DURING DOWN 572 00:31:04,560 --> 00:31:07,320 SYNDROME. 573 00:31:07,320 --> 00:31:07,880 >>I WOULD LIKE TO THANK THE 574 00:31:07,880 --> 00:31:08,760 COMMITTEE FOR THE PRIVILEGE OF 575 00:31:08,760 --> 00:31:11,680 SHARING A WORK ON IMMUNE 576 00:31:11,680 --> 00:31:12,320 DYSREGULATION WITH PEOPLE WITH 577 00:31:12,320 --> 00:31:17,840 DOWN SYNDROME, AGING AND OTHER 578 00:31:17,840 --> 00:31:18,320 LARGE-- THESE ARE MY 579 00:31:18,320 --> 00:31:18,880 DISCLOSURES AND NOTHING 580 00:31:18,880 --> 00:31:23,560 RELEVANT IN TODAY'S TALK. 581 00:31:23,560 --> 00:31:24,080 OWNER REMIND EVERYONE THAT 582 00:31:24,080 --> 00:31:24,600 PEOPLE WITH DOWN SYNDROME 583 00:31:24,600 --> 00:31:26,440 INCLUDING THESE LUMINARIES HERE 584 00:31:26,440 --> 00:31:26,920 HAVE AN EXTRA COPY OF 585 00:31:26,920 --> 00:31:29,840 CHROMOSOME 21, THE MOST COMMON 586 00:31:29,840 --> 00:31:30,400 COMMENTS ON CONDITION THAT 587 00:31:30,400 --> 00:31:32,840 AFFECTS ABOUT ONE IN 700, AND 588 00:31:32,840 --> 00:31:33,400 THESE INDIVIDUALS ALL HAVE 589 00:31:33,400 --> 00:31:38,480 PROFOUND IMMUNE DYSREGULATION. 590 00:31:38,480 --> 00:31:39,080 MANY FEATURES OF THIS IMMUNE 591 00:31:39,080 --> 00:31:39,640 DYSREGULATION LOOK LIKE THE 592 00:31:39,640 --> 00:31:40,240 INFLAMMATORY FEATURES THAT 593 00:31:40,240 --> 00:31:43,240 ACCOMPANY AGING, WHICH IS TO 594 00:31:43,240 --> 00:31:49,560 SAY INFLAAGING. 595 00:31:49,560 --> 00:31:50,160 IN THIS IS A DEFINED MODEL OF 596 00:31:50,160 --> 00:31:51,080 INFLAMMATION CLINICAL FEATURES 597 00:31:51,080 --> 00:31:51,480 INCLUDE INCREASED 598 00:31:51,480 --> 00:31:52,720 PREDISPOSITION TO AUTOIMMUNITY 599 00:31:52,720 --> 00:32:03,000 UP TO 100 FOLD. BECAUSE THE 600 00:32:03,000 --> 00:32:03,600 LIFESPAN OF PEOPLE WITH DOWN 601 00:32:03,600 --> 00:32:04,200 SYNDROME IS OVER 60 AND GROWING 602 00:32:04,200 --> 00:32:06,960 IN AUTO IMMUNITY, THIS CHRONIC 603 00:32:06,960 --> 00:32:07,480 MORBIDITY IS IMPACT LATIN 604 00:32:07,480 --> 00:32:08,040 CLINICAL FEATURES INCLUDE 605 00:32:08,040 --> 00:32:09,440 IMPAIRED RESPONSE INFECTION 606 00:32:09,440 --> 00:32:17,080 PARTICULARLY RESPIRATORY 607 00:32:17,080 --> 00:32:17,720 INFECTION. IMPAIRED RESPONSE TO 608 00:32:17,720 --> 00:32:18,360 VACCINES INCLUDING THE VACCINES 609 00:32:18,360 --> 00:32:18,960 TO PROTECT AGAINST INFECTION 610 00:32:18,960 --> 00:32:26,120 AND IN ADDITION, THERE IS 611 00:32:26,120 --> 00:32:26,720 INCREASING EVIDENCE BETWEEN THE 612 00:32:26,720 --> 00:32:27,360 LINK OF IMMUNE DYSFUNCTION LIKE 613 00:32:27,360 --> 00:32:27,880 WE HEARD BETWEEN IMMUNE 614 00:32:27,880 --> 00:32:34,120 DYSFUNCTION IN DOWN SYNDROME 615 00:32:34,120 --> 00:32:34,760 AND MANY NEUROLOGICAL FEATURES 616 00:32:34,760 --> 00:32:35,400 THAT WE OBSERVE IN PEOPLE WITH 617 00:32:35,400 --> 00:32:35,960 DOWN SYNDROME INCLUDING THE 618 00:32:35,960 --> 00:32:36,560 HIGHLY INCREASED INCIDENCE OF 619 00:32:36,560 --> 00:32:37,160 EARLY ONSET OF ALZHEIMER'S AS 620 00:32:37,160 --> 00:32:39,200 WELL AS THIS REGRESSION 621 00:32:39,200 --> 00:32:41,240 SYNDROME THAT WILL TALK MORE 622 00:32:41,240 --> 00:32:46,640 AND REFERRED EARLIER YESTERDAY 623 00:32:46,640 --> 00:32:51,280 ABOUT PERIO --. 624 00:32:51,280 --> 00:32:51,880 TAKEN TOGETHER WE THINK OF ME 625 00:32:51,880 --> 00:32:52,520 IN THIS RELATION IS A CLEAR AND 626 00:32:52,520 --> 00:32:53,120 PRESENT AND GROWING THREAT OF 627 00:32:53,120 --> 00:32:57,040 THE HEALTH OF PEOPLE WITH DOWN 628 00:32:57,040 --> 00:32:57,520 SYNDROME AND AFTER THAT 629 00:32:57,520 --> 00:33:00,320 CHROMOSOME 21 IS THE SMALLEST, 630 00:33:00,320 --> 00:33:00,920 AND WE SEE UNIQUE OPPORTUNITY 631 00:33:00,920 --> 00:33:08,800 AND NEED TO UNDERSTAND WHICH OF 632 00:33:08,800 --> 00:33:09,440 THE 225 GENES IN CRUMBS AND 21 633 00:33:09,440 --> 00:33:10,040 ARE DRIVING WHICH ASPECT OF 634 00:33:10,040 --> 00:33:10,680 IMMUNE THIS REVELATION AND HOW 635 00:33:10,680 --> 00:33:17,760 WE CAN LEVERAGE THAT ALTOGETHER 636 00:33:17,760 --> 00:33:18,280 TO DEVELOP NEW PRECISION 637 00:33:18,280 --> 00:33:20,280 THERAPIES TO HELP NOT ONLY 638 00:33:20,280 --> 00:33:20,880 PEOPLE WITH DOWN SYNDROME IS 639 00:33:20,880 --> 00:33:25,200 WITH PEOPLE WITHOUT. 640 00:33:25,200 --> 00:33:25,680 WE NEEDED A MUCH HIGHER 641 00:33:25,680 --> 00:33:26,320 DEFINITION OF UNDERSTANDING HOW 642 00:33:26,320 --> 00:33:26,960 IMMUNE ARCHITECTURE IS ALTERED 643 00:33:26,960 --> 00:33:29,640 IN PEOPLE WITH DOWN SYNDROME. 644 00:33:29,640 --> 00:33:30,240 SO TO DO THAT WE PUT TOGETHER 645 00:33:30,240 --> 00:33:32,760 A COHORT OF 28 INDIVIDUALS WITH 646 00:33:32,760 --> 00:33:35,280 DOWN SYNDROME. THEY SPAN A 647 00:33:35,280 --> 00:33:35,880 WIDE RANGE OF AGES BECAUSE WE 648 00:33:35,880 --> 00:33:36,560 WANTED TO UNDERSTAND HOW THINGS 649 00:33:36,560 --> 00:33:39,720 CHANGE WITH AGE. 650 00:33:39,720 --> 00:33:40,320 WE SPECIFICALLY SELECTED THESE 651 00:33:40,320 --> 00:33:40,800 INDIVIDUALS DO NOT HAVE 652 00:33:40,800 --> 00:33:46,680 AUTOIMMUNITY. THAT IS 653 00:33:46,680 --> 00:33:47,240 IMPORTANT AND UNUSUAL FOR A 654 00:33:47,240 --> 00:33:48,960 TYPICAL DOWN SYNDROME STUDY, 655 00:33:48,960 --> 00:33:49,960 BECAUSE WE UNDERSTAND THAT 656 00:33:49,960 --> 00:33:54,960 AUTOIMMUNITY ITSELF CAN ALSO 657 00:33:54,960 --> 00:33:55,560 ALTER THE IMMUNE ARCHITECTURE 658 00:33:55,560 --> 00:34:00,280 AND WE HAVE CONTROL 659 00:34:00,280 --> 00:34:00,920 INDIVIDUALS WHO DO HAVE TYPE I 660 00:34:00,920 --> 00:34:01,520 DIABETES IS A REPRESENTATIVE 661 00:34:01,520 --> 00:34:02,120 AUTOIMMUNE DISEASE NOT TREATED 662 00:34:02,120 --> 00:34:06,920 WITH IMMUNE MODULATION. AND WII 663 00:34:06,920 --> 00:34:07,360 IMMUNOPHENOTYPE THESE 664 00:34:07,360 --> 00:34:07,920 INDIVIDUALS USING DIFFERENT 665 00:34:07,920 --> 00:34:08,840 TECHNOLOGIES AND MOST OF THE 666 00:34:08,840 --> 00:34:14,920 TALK IS ABOUT (INDISCERNIBLE) 667 00:34:14,920 --> 00:34:15,520 -- ABOUT A MILLION CELLS PER 668 00:34:15,520 --> 00:34:16,880 PERSON GENERATE A LOT OF DATA 669 00:34:16,880 --> 00:34:17,400 AND GENERATE A BRAND-NEW 670 00:34:17,400 --> 00:34:19,120 ALGORITHM TO ANALYZE THE DATA 671 00:34:19,120 --> 00:34:27,080 CALLED IMPACD. LUNG STORIES IS 672 00:34:27,080 --> 00:34:27,680 THAT THIS HELPS US BUILD THE 673 00:34:27,680 --> 00:34:29,040 HIGH-RESOLUTION MAP OF THE 674 00:34:29,040 --> 00:34:29,640 IMMUNE ARCHITECTURE OF PEOPLE 675 00:34:29,640 --> 00:34:30,240 WITH DOWN SYNDROME TO DATE WE 676 00:34:30,240 --> 00:34:35,040 CAN IDENTIFY THE FULL DISCOVERY 677 00:34:35,040 --> 00:34:38,240 CORRECTION AND 621 SUBSETS OR 678 00:34:38,240 --> 00:34:38,880 MARKER COMBINATIONS AND SPREAD 679 00:34:38,880 --> 00:34:42,520 THROUGH ALL MAJOR PHENOTYPES, 680 00:34:42,520 --> 00:34:45,560 YOU CAN SEE THIS IN RED, THEY 681 00:34:45,560 --> 00:34:46,160 CLUSTER AWAY FROM PEOPLE WITH 682 00:34:46,160 --> 00:34:48,800 DOWN SYNDROME AND THIS GRANULAR 683 00:34:48,800 --> 00:34:50,400 DATA ALLOWS US TO DO A LOT OF 684 00:34:50,400 --> 00:34:51,040 ANALYSES, I DO NOT HAVE TIME TO 685 00:34:51,040 --> 00:34:55,560 TELL YOU ABOUT, BUT WE CAN DO 686 00:34:55,560 --> 00:34:56,160 INTEGRATED ANALYSES WITH MANY 687 00:34:56,160 --> 00:34:56,960 EXTERNAL DATA SETS INCLUDING 688 00:34:56,960 --> 00:35:01,480 COMPANION OMICS, AND WHAT I'M 689 00:35:01,480 --> 00:35:02,080 GOING TO TALK TO YOU TODAY IS 690 00:35:02,080 --> 00:35:02,760 INTEGRATED ANALYSIS WITH 691 00:35:02,760 --> 00:35:03,640 CLINICAL METADATA, SPECIFICALLY 692 00:35:03,640 --> 00:35:04,800 WITH ONE METADATA WHICH IS AGE. 693 00:35:04,800 --> 00:35:09,520 OKAY? 694 00:35:09,520 --> 00:35:14,040 WHAT WE WANTED TO DO WAS TO 695 00:35:14,040 --> 00:35:14,600 BUILD A SIMPLE LINEAR MODEL 696 00:35:14,600 --> 00:35:15,160 THAT DESCRIBES HOW IMMUNE 697 00:35:15,160 --> 00:35:17,600 ARCHITECTURE CHANGES WITH AGE. 698 00:35:17,600 --> 00:35:18,200 THIS HAS HISTORICALLY BEEN A 699 00:35:18,200 --> 00:35:24,600 VERY CHALLENGING EXERCISE. WE 700 00:35:24,600 --> 00:35:25,200 REALIZED THAT WE CAN ACTUALLY 701 00:35:25,200 --> 00:35:35,680 SUCCEED USING OUR IMPACD 702 00:35:36,080 --> 00:35:36,600 PIPELINE IN FOR EXAMPLE IN A 703 00:35:36,600 --> 00:35:37,080 FIRST CONTROL MODEL IS 704 00:35:37,080 --> 00:35:37,680 IMMUNOLOGY COMING IN WITH HER 705 00:35:37,680 --> 00:35:40,960 FAVORITE SUBSETS. 706 00:35:40,960 --> 00:35:41,520 WHAT IT MEANS IS THAT WE CAN 707 00:35:41,520 --> 00:35:46,680 IDENTIFY THE INFORMATION 708 00:35:46,680 --> 00:35:47,280 SUBSETS TO CORRELATE WITH AGE 709 00:35:47,280 --> 00:35:47,880 AND THERE'S A LONG WINDED WAY 710 00:35:47,880 --> 00:35:48,520 OF SAYING LINEAR MODELS TO BEST 711 00:35:48,520 --> 00:35:51,040 WITH LINEAR PARAMETERS. WHEN 712 00:35:51,040 --> 00:35:51,640 YOU PUT IN THE NEW PARAMETERS 713 00:35:51,640 --> 00:35:52,280 YOU CAN GET A LINEAR MODEL THAT 714 00:35:52,280 --> 00:35:52,800 WORKS VERY WELL. 715 00:35:52,800 --> 00:36:01,040 THIS IS AN R2=0.92. .5 IS 716 00:36:01,040 --> 00:36:01,640 CONSIDERED REALLY GOOD. 717 00:36:01,640 --> 00:36:03,880 BECAUSE OF THE SIMPLE LINEAR 718 00:36:03,880 --> 00:36:07,600 MODEL, WHY DO WE DO THIS? 719 00:36:07,600 --> 00:36:08,160 BECAUSE IN A SIMPLE LINEAR 720 00:36:08,160 --> 00:36:08,800 MODEL WE CAN IMMEDIATELY SUBMIT 721 00:36:08,800 --> 00:36:09,440 THE DATA FROM OUR PARTICIPANTS 722 00:36:09,440 --> 00:36:12,360 WITH DOWN SYNDROME. WHEN WE DO 723 00:36:12,360 --> 00:36:12,880 THAT WHAT WE FIND IS THAT 724 00:36:12,880 --> 00:36:14,920 UNBALANCED IMMUNE ARCHITECTURE 725 00:36:14,920 --> 00:36:15,560 OF A PERSON WITH DOWN SYNDROME 726 00:36:15,560 --> 00:36:18,120 LIKE THIS INDIVIDUAL, RESEMBLES 727 00:36:18,120 --> 00:36:21,360 THAT OF A CONTROLLED WHO IS 5.2 728 00:36:21,360 --> 00:36:23,200 YEARS OLD WHEN WE SEE ADVANCED 729 00:36:23,200 --> 00:36:24,000 IMMUNE AGING AND DOWN SYNDROME 730 00:36:24,000 --> 00:36:28,160 OF +5.2 YEARS. 731 00:36:28,160 --> 00:36:28,760 WE CAN PLAY WITH THIS APPROACH 732 00:36:28,760 --> 00:36:30,800 IN DIFFERENT WAYS. SO INSPIRED 733 00:36:30,800 --> 00:36:34,880 BY GENE ENRICHMENT ANALYSIS -- 734 00:36:34,880 --> 00:36:37,920 WHAT WE SAID IS, WHAT HAPPENS 735 00:36:37,920 --> 00:36:40,640 IF WE START WITH 651 SUBSETS 736 00:36:40,640 --> 00:36:41,240 DIFFERENT BETWEEN PEOPLE WITH 737 00:36:41,240 --> 00:36:49,520 AND WITHOUT TOWN CENTER? THIS 738 00:36:49,520 --> 00:36:50,040 IS WHAT WE CALL THE DOWN 739 00:36:50,040 --> 00:36:50,680 SYNDROME LENS MODEL, IT BRINGS 740 00:36:50,680 --> 00:36:58,520 IN A FLAVOR OF DANCE AND 741 00:36:58,520 --> 00:36:59,120 BIOLOGY, IT STILL HAS CONTROL 742 00:36:59,120 --> 00:36:59,760 DATA AND GENERATE A MODEL THAT 743 00:36:59,760 --> 00:37:03,480 WORKS VERY WELL. 744 00:37:03,480 --> 00:37:04,000 MORE IMPORTANT THAN THE 745 00:37:04,000 --> 00:37:05,400 QUANTITATIVE DIFFERENT IS WHAT 746 00:37:05,400 --> 00:37:07,560 WE THINK OF THIS MODEL SHOWING 747 00:37:07,560 --> 00:37:08,160 A QUALITATIVE DIFFERENCES I'M 748 00:37:08,160 --> 00:37:11,240 GOING TO GET IN THE NEXT SLIDE. 749 00:37:11,240 --> 00:37:11,840 NOW I DON'T HAVE TIME TO SHOW 750 00:37:11,840 --> 00:37:15,920 YOU DATA. WHEN WE LOOK AT 751 00:37:15,920 --> 00:37:16,560 PARTICIPANTS WITH DOWN SYNDROME 752 00:37:16,560 --> 00:37:19,920 AND OTHER IMMUNE DISEASE, WHAT 753 00:37:19,920 --> 00:37:20,520 WE FIND IS THAT THE ADVANCED 754 00:37:20,520 --> 00:37:21,160 IMMUNE AGING IS EXACERBATED AND 755 00:37:21,160 --> 00:37:24,920 THOSE INDIVIDUALS. AGAIN 756 00:37:24,920 --> 00:37:25,520 SUPPORTING THE IDEA THAT THIS 757 00:37:25,520 --> 00:37:26,120 SIGNATURE CAN PICK UP THINGS 758 00:37:26,120 --> 00:37:26,560 THAT ARE BIOLOGICALLY 759 00:37:26,560 --> 00:37:27,000 IMPORTANT. 760 00:37:27,000 --> 00:37:33,480 THIS LETTER IS TO ASK, WHAT 761 00:37:33,480 --> 00:37:34,120 HAPPENS TO INDIVIDUAL WHO DON'T 762 00:37:34,120 --> 00:37:34,760 HAVE DOWN SYNDROME WHO DO HAVE 763 00:37:34,760 --> 00:37:35,280 AUTO IMMUNITY? NOW WE ARE 764 00:37:35,280 --> 00:37:40,560 GETTING TO A TYPE I DIABETES 765 00:37:40,560 --> 00:37:41,160 COHORT AND OUR FIRST CONTROL 766 00:37:41,160 --> 00:37:41,800 LENS MODEL WE SEE NO DIFFERENCE 767 00:37:41,800 --> 00:37:42,840 ON AVERAGE IN IMMUNE AGING IN 768 00:37:42,840 --> 00:37:47,120 PEOPLE WITH TYPE I DIABETES. 769 00:37:47,120 --> 00:37:47,680 BUT TO OUR SURPRISE WHAT WE 770 00:37:47,680 --> 00:37:53,440 FOUND IS THAT THE DOWN SYNDROME 771 00:37:53,440 --> 00:37:54,000 LENS MODEL REVEALS ADVANCED 772 00:37:54,000 --> 00:37:54,560 IMMUNE AGING IN PEOPLE WITH 773 00:37:54,560 --> 00:37:55,120 TYPE I DIABETES ACROSS 3.9 774 00:37:55,120 --> 00:38:01,120 YEARS. THIS TELLS US THAT 775 00:38:01,120 --> 00:38:01,720 THERE IS SOMETHING ABOUT HOW 776 00:38:01,720 --> 00:38:02,280 THE IMMUNE ARCHITECTURE IS 777 00:38:02,280 --> 00:38:02,880 ALTERED WITH PEOPLE WITH DOWN 778 00:38:02,880 --> 00:38:05,840 SYNDROME, BUT SHARE SIMILAR 779 00:38:05,840 --> 00:38:06,480 DYSREGULATION, SIMILAR FEATURES 780 00:38:06,480 --> 00:38:08,000 IN PEOPLE WITH TYPE I DIABETES 781 00:38:08,000 --> 00:38:08,560 WHICH IS TO SAY THAT DOWN 782 00:38:08,560 --> 00:38:12,400 SYNDROME CAN BE USED AS A LENS 783 00:38:12,400 --> 00:38:12,960 THROUGH WHICH TO UNDERSTAND 784 00:38:12,960 --> 00:38:16,760 TYPE I DIABETES. WE ARE TRYING 785 00:38:16,760 --> 00:38:17,360 TO BREAK DOWN THE MECHANISTIC 786 00:38:17,360 --> 00:38:21,080 BASIS OF ALL OF THAT. 787 00:38:21,080 --> 00:38:21,600 AND ANOTHER REASON WHY WE 788 00:38:21,600 --> 00:38:23,640 THINK THESE METRICS ARE 789 00:38:23,640 --> 00:38:24,280 IMPORTANT, IS WE FOUND ANOTHER 790 00:38:24,280 --> 00:38:27,080 CORRELATION THAT WAS REALLY 791 00:38:27,080 --> 00:38:27,640 INTRIGUING, WHICH IS TO SAY 792 00:38:27,640 --> 00:38:28,520 THAT THE MORE ADVANCED THE 793 00:38:28,520 --> 00:38:29,120 PERSON'S IMMUNE AGE THE HIGHER 794 00:38:29,120 --> 00:38:33,720 THE ARE IN THIS GROUP. RIGHT? 795 00:38:33,720 --> 00:38:34,320 THE YOUNG THAT THEY TEND TO BE 796 00:38:34,320 --> 00:38:36,960 WHEN THEY DEVELOP TYPE I 797 00:38:36,960 --> 00:38:40,240 DIABETES. THIS RELATIONSHIP 798 00:38:40,240 --> 00:38:40,800 HOLDS AFTER WE CORRECT FOR 799 00:38:40,800 --> 00:38:41,360 CONFOUNDERS INCLUDING THE 800 00:38:41,360 --> 00:38:42,000 RELATIONSHIP OF THE AGE, AND SO 801 00:38:42,000 --> 00:38:46,080 FORTH. 802 00:38:46,080 --> 00:38:46,600 IT SUGGESTS THAT THE MORE 803 00:38:46,600 --> 00:38:47,640 PRECOCIOUS IMMUNE SYSTEM MAY BE 804 00:38:47,640 --> 00:38:53,640 ABLE TO MORE EFFECTIVELY 805 00:38:53,640 --> 00:38:54,240 DESTROY ISLET BETA CELLS A 806 00:38:54,240 --> 00:38:57,480 YOUNGER AGE. 807 00:38:57,480 --> 00:39:00,640 WE CAN DO THIS EXERCISE WITH 808 00:39:00,640 --> 00:39:01,280 OTHER DATA, ROOM WITH THE SAME 809 00:39:01,280 --> 00:39:01,920 INDIVIDUALS AND WE CAN BUILD A 810 00:39:01,920 --> 00:39:03,160 VERY NICE PERFORMING MODEL 811 00:39:03,160 --> 00:39:03,720 ENTIRELY OF CONTROL DATE ON 812 00:39:03,720 --> 00:39:05,360 THIS MODEL SHOWS ADVANCED 813 00:39:05,360 --> 00:39:13,360 AGING IN DOWN SYNDROME OF +12.4 814 00:39:13,360 --> 00:39:13,960 YEARS; WE SEE THIS PHENOTYPE 815 00:39:13,960 --> 00:39:14,560 VERY ROBUSTLY BUT NOT BECAUSE 816 00:39:14,560 --> 00:39:15,160 GENE FUNCTION IS MUCH BETTER 817 00:39:15,160 --> 00:39:17,760 ANNOTATED THAN CELL PHENOTYPE 818 00:39:17,760 --> 00:39:18,400 AND WE CAN TAKE THE GENES THAT 819 00:39:18,400 --> 00:39:20,240 CORRELATE WITH AGING, AND OTHER 820 00:39:20,240 --> 00:39:25,440 PATHWAYS THAT ARE ENRICHED IN 821 00:39:25,440 --> 00:39:26,840 THEM. WE CAN DO THIS WITH GENE 822 00:39:26,840 --> 00:39:33,840 ENRICHMENT ANALYSIS, THAT 823 00:39:33,840 --> 00:39:34,480 TAPS INTO TEAM AT A BLOSSOM AND 824 00:39:34,480 --> 00:39:34,960 TURNS OUT THIS IS VERY 825 00:39:34,960 --> 00:39:36,520 REASSURING BECAUSE OF THE 826 00:39:36,520 --> 00:39:37,000 ANALYSIS OF DATA ALSO 827 00:39:37,000 --> 00:39:37,600 IDENTIFIED AS A PATHWAY MOST 828 00:39:37,600 --> 00:39:38,160 TIGHTLY LINKED AGENT WAS A 829 00:39:38,160 --> 00:39:39,080 STRONG ENRICHMENT OF IMMUNE 830 00:39:39,080 --> 00:39:43,680 SIGNALING PATHWAYS, WHICH IS 831 00:39:43,680 --> 00:39:45,360 VERY REASSURING FOR 832 00:39:45,360 --> 00:39:45,960 IMMUNOLOGISTS WHO STUDY THIS 833 00:39:45,960 --> 00:39:49,360 PROCESS. 834 00:39:49,360 --> 00:39:50,120 WHAT THIS REALLY DOES I THINK 835 00:39:50,120 --> 00:39:54,600 IS HIGHLIGHT AN APPROACH TO 836 00:39:54,600 --> 00:39:57,640 CONTINUE TO DIG INTO MECHANISMS 837 00:39:57,640 --> 00:39:58,240 WHICH WE ARE NOW APPLYING IN 838 00:39:58,240 --> 00:39:58,800 MORE PRECISE WAYS TO MORE 839 00:39:58,800 --> 00:40:05,080 TARGETED CELL TYPES. RIGHT? 840 00:40:05,080 --> 00:40:10,720 NOW I WANT TO TURN FOR LITTLE 841 00:40:10,720 --> 00:40:11,360 BIT TO AN OBSERVATION REMEMBER 842 00:40:11,360 --> 00:40:12,000 THAT PEOPLE WITH DOWN SYNDROME 843 00:40:12,000 --> 00:40:12,960 ARE HIGHLY PREDISPOSED TO 844 00:40:12,960 --> 00:40:15,240 AUTOIMMUNITY. SO WE SCOURED THE 845 00:40:15,240 --> 00:40:15,880 LITERATURE, PUT TOGETHER A LIST 846 00:40:15,880 --> 00:40:26,280 OF ABOUT 33 SUBSETS THAT ARE 847 00:40:26,280 --> 00:40:26,800 DYSREGULATED IN DIFFERENT 848 00:40:26,800 --> 00:40:30,280 AUTOIMMUNE DISEASES LISTED HERE. 849 00:40:30,280 --> 00:40:30,800 AND WHAT HAPPENS IN THE 850 00:40:30,800 --> 00:40:31,400 SUBSETS WITH PEOPLE WITH DOWN 851 00:40:31,400 --> 00:40:32,960 SYNDROME THE DON'T HAVE 852 00:40:32,960 --> 00:40:33,400 IMMUNITY. 853 00:40:33,400 --> 00:40:35,880 THIS IS A VOLCANO PART OF THE 854 00:40:35,880 --> 00:40:36,520 RESULTS. EACH THOUGHT IS ONE OF 855 00:40:36,520 --> 00:40:37,640 THOSE 33 SUBSETS AND THE Y AXIS 856 00:40:37,640 --> 00:40:46,440 IS THE P VALUE. AND YOU SEE 857 00:40:46,440 --> 00:40:46,920 THAT ALL 33 SUBSETS ARE 858 00:40:46,920 --> 00:40:48,520 SIGNIFICANTLY ALTERED IN PEOPLE 859 00:40:48,520 --> 00:40:49,120 WITH DOWN SYNDROME WHO DON'T 860 00:40:49,120 --> 00:40:52,280 HAVE IMMUNITY. SOME SUBSETS GO 861 00:40:52,280 --> 00:40:54,760 UP AND SOME SUBSETS GO DOWN. 862 00:40:54,760 --> 00:40:55,360 ALL SUBSETS ARE ALTERED IN 863 00:40:55,360 --> 00:40:56,440 EXACTLY THE SAME DIRECTION AS 864 00:40:56,440 --> 00:40:57,880 YOU SEE IN PEOPLE WITH 865 00:40:57,880 --> 00:41:01,920 AUTOIMMUNITY. OKAY? 866 00:41:01,920 --> 00:41:02,440 THIS IS A MORE TRADITIONAL 867 00:41:02,440 --> 00:41:02,960 VIEW OF THREE OF THOSE 868 00:41:02,960 --> 00:41:04,680 REPRESENTATIVE SUBSETS. THE 869 00:41:04,680 --> 00:41:05,200 NAMES ARE NOT TERRIBLY 870 00:41:05,200 --> 00:41:09,160 IMPORTANT. BUT WHAT THIS IS 871 00:41:09,160 --> 00:41:09,760 TELLING US IS THAT IN PEOPLE 872 00:41:09,760 --> 00:41:10,560 WITH DOWN SYNDROME WE DON'T 873 00:41:10,560 --> 00:41:12,680 HAVE OUR IMMUNITY IT'S ALSO 874 00:41:12,680 --> 00:41:17,400 THAT THE TRISOME 21 IS 875 00:41:17,400 --> 00:41:17,920 SUFFICIENT TO REMODEL THE 876 00:41:17,920 --> 00:41:21,080 ARCHITECTURE FOR AUTOIMMUNITY. 877 00:41:21,080 --> 00:41:21,680 WE ARE CERTAINLY INTERESTED IN 878 00:41:21,680 --> 00:41:28,800 WHAT THE MECHANISM IS. THE 879 00:41:28,800 --> 00:41:29,440 FIRST OBVIOUS THING TO LOOK FOR 880 00:41:29,440 --> 00:41:29,960 WAS, IS THIS RELATED TO 881 00:41:29,960 --> 00:41:32,000 ADVANCED IMMUNE AGING? WE KNOW 882 00:41:32,000 --> 00:41:32,640 THAT INCIDENCE OF AUTOIMMUNITY 883 00:41:32,640 --> 00:41:37,000 CAN INCREASE WITH AGE, SO FOR 884 00:41:37,000 --> 00:41:37,600 EACH OF THE 33 SUBSETS WE TRY 885 00:41:37,600 --> 00:41:38,200 TO DRAW A LINE AND WE ASK THE 886 00:41:38,200 --> 00:41:38,840 COMPUTER TO TELL US WHAT IS THE 887 00:41:38,840 --> 00:41:41,680 P VALUE OF THAT LINE ON THE 888 00:41:41,680 --> 00:41:52,160 Y-AXIS AND WHAT IS THE SLOPE. 889 00:41:52,560 --> 00:41:53,120 THIS IS AGAIN A VOLCANO PLOT 890 00:41:53,120 --> 00:41:53,800 OF THAT EXERCISE, IF IT CHANGES 891 00:41:53,800 --> 00:41:54,400 WITH AGE WE EXPECT THE DOCTOR 892 00:41:54,400 --> 00:41:58,880 FROM THE RED BOXES. LONG STORY 893 00:41:58,880 --> 00:41:59,480 SHORT ONLY ONE FALLS IN THE 894 00:41:59,480 --> 00:42:00,120 RED BOX IN ONE WAY TO INTERPRET 895 00:42:00,120 --> 00:42:00,680 THIS IS TO SUGGEST THAT THE 896 00:42:00,680 --> 00:42:01,280 MECHANISMS THAT REGULATE THIS 897 00:42:01,280 --> 00:42:05,000 AUTOIMMUNE SEEM TO BE QUITE 898 00:42:05,000 --> 00:42:05,600 DISTINCT FROM THOSE REGULATE 899 00:42:05,600 --> 00:42:06,200 IMMUNE AGING WHICH IS TO SAY 900 00:42:06,200 --> 00:42:07,080 THAT WE THINK THE DOWN SYNDROME 901 00:42:07,080 --> 00:42:17,640 IS AT -- HAS AT LEAST TWO VERY 902 00:42:18,480 --> 00:42:20,080 IMPORTANT BIOLOGICAL ASPECT OF 903 00:42:20,080 --> 00:42:21,720 IMMUNE REGULATION. 904 00:42:21,720 --> 00:42:28,000 IF YOU LOOK AT PUBMED, 905 00:42:28,000 --> 00:42:29,240 MECHANISMS OF IMMUNE THIS 906 00:42:29,240 --> 00:42:32,280 RELATION IN DOWN SYNDROME 99% 907 00:42:32,280 --> 00:42:40,480 ARE -- AND (INDISCERNIBLE) -- 908 00:42:40,480 --> 00:42:45,480 INTERFERENCE IS VERY IMPORTANT. 909 00:42:45,480 --> 00:42:46,040 THE SIMPLE QUESTION WAS IS 910 00:42:46,040 --> 00:42:51,520 INTERFERON DOING EVERYTHING? 911 00:42:51,520 --> 00:42:52,120 THIS IS ONE PANEL FROM A WHOLE 912 00:42:52,120 --> 00:42:54,760 SET OF -- TO SHOW ME THE 913 00:42:54,760 --> 00:43:00,960 INFLAMMATORY -- -- DISABILITY 914 00:43:00,960 --> 00:43:01,600 IS A LARGE BODY OF WORK BUT WE 915 00:43:01,600 --> 00:43:02,200 ARE NOT THE FIRST TO OBSERVE 916 00:43:02,200 --> 00:43:04,960 THAT. 917 00:43:04,960 --> 00:43:05,560 BUT NOW WHAT WE CAN DO IS PAIR 918 00:43:05,560 --> 00:43:06,160 THAT WITH WHAT WE ARE FINDING 919 00:43:06,160 --> 00:43:09,400 IN OUR IMPACT ANALYSIS. AND 920 00:43:09,400 --> 00:43:13,640 ONE OF THE THINGS IMPACTING FOR 921 00:43:13,640 --> 00:43:14,280 US IN THE COMPETITION LOGARITHM 922 00:43:14,280 --> 00:43:14,920 IS TO CLEARLY SHOW HOW EACH AND 923 00:43:14,920 --> 00:43:21,040 EVERY SINGLE MARKER IS THIS 924 00:43:21,040 --> 00:43:24,200 (CORRECTION) DYSREGULATED, IN 925 00:43:24,200 --> 00:43:24,680 VARIOUS CELL SUBSETS OF 926 00:43:24,680 --> 00:43:25,280 BIOLOGICAL INTEREST. 927 00:43:25,280 --> 00:43:25,880 WHAT YOU WILL IMMEDIATELY SEE 928 00:43:25,880 --> 00:43:33,280 IS THE NAïVE CD4S A 929 00:43:33,280 --> 00:43:33,920 QUALITATIVELY REMODELING PEOPLE 930 00:43:33,920 --> 00:43:34,480 WITH DOWN SYNDROME AND THE 931 00:43:34,480 --> 00:43:35,040 STARS TELL YOU EXACTLY WHAT 932 00:43:35,040 --> 00:43:35,920 MARKERS TO PAY ATTENTION TO. 933 00:43:35,920 --> 00:43:38,880 NOW WE HAVE A GUIDE, A MAP, A 934 00:43:38,880 --> 00:43:43,720 TREASURE MAP IF YOU WILL. WE 935 00:43:43,720 --> 00:43:44,920 CAN DO A VERY SIMPLE 936 00:43:44,920 --> 00:43:45,440 EXPERIMENT. WE CAN TREAT 937 00:43:45,440 --> 00:43:49,680 HEALTHY CONTROLLED PBMCS, CAN 938 00:43:49,680 --> 00:43:50,800 WE RECAPITULATE ANY OF THESE 939 00:43:50,800 --> 00:43:51,640 DIFFERENCES? THE ANSWER TO OUR 940 00:43:51,640 --> 00:43:55,600 SURPRISE WAS NO. 941 00:43:55,600 --> 00:43:56,160 THE SAME TIME WE HAD DONE A 942 00:43:56,160 --> 00:43:56,760 PARALLEL EXPERIMENT WHICH WAS 943 00:43:56,760 --> 00:43:59,680 CAN ISLE 6 DRIVE ANY OF THESE 944 00:43:59,680 --> 00:44:03,040 DIFFERENCES? ISLE 6 CAN DRIVE 945 00:44:03,040 --> 00:44:04,960 THREE OF THESE DIFFERENCES. SO 946 00:44:04,960 --> 00:44:08,840 SOME BUT NOT ALL. RIGHT? 947 00:44:08,840 --> 00:44:09,400 SO THE LINE IN THE PAPER IS 948 00:44:09,400 --> 00:44:16,200 THAT WE HAVE IDENTIFIED IL6 IS 949 00:44:16,200 --> 00:44:16,720 A NOVEL DRIVER OF IMMUNE 950 00:44:16,720 --> 00:44:17,320 DYSREGULATION IN PEOPLE WITH 951 00:44:17,320 --> 00:44:20,040 DOWN SYNDROME. THIS WAS THE 952 00:44:20,040 --> 00:44:25,680 WORK BY -- -- WELL DONE, BUT 953 00:44:25,680 --> 00:44:26,240 WHAT I WANT TO POINT OUT IS 954 00:44:26,240 --> 00:44:26,880 THAT THERE IS A LOT LEFT TO BE 955 00:44:26,880 --> 00:44:30,680 UNDERSTOOD. IMMUNE 956 00:44:30,680 --> 00:44:31,280 DYSREGULATION IN PEOPLE WITH 957 00:44:31,280 --> 00:44:31,800 DOWN SYNDROME IS NOT ALL 958 00:44:31,800 --> 00:44:33,120 INTERFERON; NOT ALL INTERFERON 959 00:44:33,120 --> 00:44:42,920 AND IL6, WE HAD IDENTIFY THE 960 00:44:42,920 --> 00:44:43,560 THIRD PLAGUE WHICH I DON'T HAVE 961 00:44:43,560 --> 00:44:47,280 TIME TO SHOW. 962 00:44:47,280 --> 00:44:47,840 WHAT AM SHOWING YOU IS THAT 963 00:44:47,840 --> 00:44:50,520 DOWN SYNDROME CAN BE USED AS A 964 00:44:50,520 --> 00:44:51,040 LENS THROUGH WHICH WE CAN 965 00:44:51,040 --> 00:44:51,680 UNDERSTAND SPECIFIC PATHWAYS IN 966 00:44:51,680 --> 00:44:57,000 AGING AND AUTOIMMUNITY. WE ARE 967 00:44:57,000 --> 00:44:57,640 BUSY UNRAVELING THE MECHANISMS 968 00:44:57,640 --> 00:44:58,280 OF THAT LENS AND I WANT TO WRAP 969 00:44:58,280 --> 00:44:58,920 WITH SOME DISCUSSION OF WHAT WE 970 00:44:58,920 --> 00:45:04,400 SEE IS FUTURE OPPORTUNITY. 971 00:45:04,400 --> 00:45:04,960 WE ARE REALLY EXCITED ABOUT 972 00:45:04,960 --> 00:45:05,600 THE IDEA OF USING DOWN SYNDROME 973 00:45:05,600 --> 00:45:07,240 AS A LENS TO IDENTIFY AND 974 00:45:07,240 --> 00:45:07,800 UNDERSTAND BROADLY RELEVANT 975 00:45:07,800 --> 00:45:09,840 PATHWAYS OF PATHOBIOLOGY. 976 00:45:09,840 --> 00:45:12,960 THERE ARE AT LEAST TWO THE 977 00:45:12,960 --> 00:45:15,360 POP-UP ALREADY: AGING AND WHAT 978 00:45:15,360 --> 00:45:16,000 WE THINK THE ANSWER WAS HELPING 979 00:45:16,000 --> 00:45:16,560 US DO SOME STANDING AGING 980 00:45:16,560 --> 00:45:25,000 BEYOND THE MONOLITHIC PROCESS. 981 00:45:25,000 --> 00:45:25,600 AGING IS NOT JUST THE ONE 982 00:45:25,600 --> 00:45:26,200 THING THAT HAPPENS. THERE ARE 983 00:45:26,200 --> 00:45:26,760 SPECIFIC PROCESSES OF AGING 984 00:45:26,760 --> 00:45:27,400 THAT SEEMED TO BE THIS RELATED 985 00:45:27,400 --> 00:45:27,840 IN DOWN SYNDROME THAT 986 00:45:27,840 --> 00:45:30,040 PREDISPOSES A SPECIFIC OUTCOME. 987 00:45:30,040 --> 00:45:30,600 SO WE ARE GENERATING THE 988 00:45:30,600 --> 00:45:31,200 ABILITY TO BUILD THESE IMMUNE 989 00:45:31,200 --> 00:45:35,680 BLOCKS IN MANY DIFFERENT WAYS; 990 00:45:35,680 --> 00:45:36,320 USE TRANSLATIONAL IMPLICATIONS 991 00:45:36,320 --> 00:45:36,960 AND FOR EXAMPLE YOU THINK OF A 992 00:45:36,960 --> 00:45:38,240 HIGH DOSE OF FLU VACCINE, THOSE 993 00:45:38,240 --> 00:45:38,840 ARE SAFE AND EFFICACIOUS FOR 994 00:45:38,840 --> 00:45:41,720 PEOPLE OVER 65 YEARS OLD. THAT 995 00:45:41,720 --> 00:45:42,360 IS DRIVEN BUT WHAT I WOULD LIKE 996 00:45:42,360 --> 00:45:44,800 TO CALL DRIVERS LICENSE AGE, 997 00:45:44,800 --> 00:45:45,320 THE NUMBER OF A PIECE OF 998 00:45:45,320 --> 00:45:45,960 PLASTIC AND WHAT YOU WANT IS A 999 00:45:45,960 --> 00:45:50,160 BIOLOGICAL OUTCOME. 1000 00:45:50,160 --> 00:45:51,840 SO WE BUILT AN IMMUNE CLOCK TO 1001 00:45:51,840 --> 00:45:52,440 GIVE A BIOLOGICAL METRIC THAT 1002 00:45:52,440 --> 00:46:02,960 DOES BETTER. CAN WE USE THIS 1003 00:46:03,280 --> 00:46:03,840 TO PREDICT LIKELIHOOD OF OTHER 1004 00:46:03,840 --> 00:46:04,480 DISEASES BEGAN TYPE I DIABETES, 1005 00:46:04,480 --> 00:46:05,080 ALZHEIMER'S, UNHEALTHY AGING 1006 00:46:05,080 --> 00:46:05,680 OUTCOME? CAN WE BUILD OTHER 1007 00:46:05,680 --> 00:46:07,520 LENSES? 1008 00:46:07,520 --> 00:46:12,680 AND USING OTHER COHORTS TO GET 1009 00:46:12,680 --> 00:46:13,200 TO THIS IN A MUCH MORE 1010 00:46:13,200 --> 00:46:13,800 COORDINATED AND COMPREHENSIVE 1011 00:46:13,800 --> 00:46:14,400 FASHION AND WE THINK IT DOWN 1012 00:46:14,400 --> 00:46:15,040 SYNDROME TEACHES US A LOT MORE 1013 00:46:15,040 --> 00:46:18,960 ABOUT AUTOIMMUNITY. WITH 1014 00:46:18,960 --> 00:46:19,440 THINK IT IS A UNIQUE 1015 00:46:19,440 --> 00:46:19,960 OPPORTUNITY TO WATCH THE 1016 00:46:19,960 --> 00:46:20,560 PROGRESSION LONGITUDINALLY OF 1017 00:46:20,560 --> 00:46:21,120 AUTOIMMUNITY AND THIS IS 1018 00:46:21,120 --> 00:46:21,760 RELEVANT, NOT ONLY TRADITIONAL 1019 00:46:21,760 --> 00:46:30,000 THINGS IN THE NIAID PORTFOLIO 1020 00:46:30,000 --> 00:46:30,600 BUT PEOPLE WITH DOWN SYNDROME 1021 00:46:30,600 --> 00:46:31,200 ARE PREDISPOSED TO REGRESSION 1022 00:46:31,200 --> 00:46:35,480 SYNDROME WHICH HAS A LOT OF 1023 00:46:35,480 --> 00:46:35,960 THINGS REMINISCENT OF 1024 00:46:35,960 --> 00:46:36,600 AUTOIMMUNE DIMENSION AND WE ARE 1025 00:46:36,600 --> 00:46:37,160 CERTAINLY INTERESTED IN THE 1026 00:46:37,160 --> 00:46:37,800 MECHANISMS AND I WILL THANK THE 1027 00:46:37,800 --> 00:46:38,520 PEOPLE WHO DID THE WORK. I 1028 00:46:38,520 --> 00:46:39,080 CERTAINLY NEED TO THANK THE 1029 00:46:39,080 --> 00:46:42,520 PARTICIPANTS IN THE FAMILIES. 1030 00:46:42,520 --> 00:46:42,960 WONDERFUL CLINICAL 1031 00:46:42,960 --> 00:46:46,440 COLLABORATORS, UNIQUE CLINICAL 1032 00:46:46,440 --> 00:46:47,040 COLLABORATIONS THAT ALLOWS US 1033 00:46:47,040 --> 00:46:47,680 TO DO THIS WORK IN SEATTLE HARD 1034 00:46:47,680 --> 00:46:48,320 TO DO ELSEWHERE IN MY LONGTIME 1035 00:46:48,320 --> 00:46:52,240 COLLABORATOR JANE BUCKNER AND 1036 00:46:52,240 --> 00:47:00,040 GAUTAM GOEL, LONG-TERM 1037 00:47:00,040 --> 00:47:00,640 COLLABORATOR AND THIS IS OUR 1038 00:47:00,640 --> 00:47:01,960 FUNDING AND THANK YOU. I AM 1039 00:47:01,960 --> 00:47:09,880 HAPPY TO TAKE YOUR QUESTIONS. 1040 00:47:09,880 --> 00:47:12,960 >>(INDISCERNIBLE), PATIENTS 1041 00:47:12,960 --> 00:47:16,600 WITH DOWN SYNDROME, 1042 00:47:16,600 --> 00:47:17,280 AUTOIMMUNITY IS THERE 1043 00:47:17,280 --> 00:47:19,600 (INDISCERNIBLE). 1044 00:47:19,600 --> 00:47:20,160 >>THAT IS AN EXCELLENT 1045 00:47:20,160 --> 00:47:23,520 QUESTION. IT DEPENDS ON THE 1046 00:47:23,520 --> 00:47:24,120 OTHER IMMUNE DISEASE YOU ARE 1047 00:47:24,120 --> 00:47:28,360 TALKING ABOUT. FOR EXAMPLE IF 1048 00:47:28,360 --> 00:47:30,440 YOU LOOK AT CELIAC, THERE IS 1049 00:47:30,440 --> 00:47:36,800 STILL PREVALENCE OF RISK MAC 1050 00:47:36,800 --> 00:47:40,680 ALLELE ASSOCIATED, BUT THERE IS 1051 00:47:40,680 --> 00:47:41,200 INCREASED EVIDENCE THAT 1052 00:47:41,200 --> 00:47:41,800 SUGGESTED THAT ASSOCIATION IS 1053 00:47:41,800 --> 00:47:42,400 NOT AS TIGHT SO THERE SEEM TO 1054 00:47:42,400 --> 00:47:47,440 BE HLA RISKS, BUT THE TIGHTNESS 1055 00:47:47,440 --> 00:47:48,000 OF THAT ASSOCIATION MAY BE 1056 00:47:48,000 --> 00:47:49,680 ALTERED. 1057 00:47:49,680 --> 00:47:57,400 >>(INDISCERNIBLE) FROM 1058 00:47:57,400 --> 00:48:00,800 NATIONAL INSTIUTE ON AGING. I 1059 00:48:00,800 --> 00:48:04,080 SEE (INDISCERNIBLE) -- SO DOES 1060 00:48:04,080 --> 00:48:10,320 TI MEAN THAT T REX (PHONETIC) 1061 00:48:10,320 --> 00:48:18,440 NCREASE? OR DOES IT MEAN 1062 00:48:18,440 --> 00:48:20,640 (INDISCERNIBLE) INCREASES ON TD 1063 00:48:20,640 --> 00:48:27,480 4 CELLS. 1064 00:48:27,480 --> 00:48:28,080 >>WE THOUGHT THIS WOULD BE A T 1065 00:48:28,080 --> 00:48:33,240 REG PHENOTYPE. T REG NUMBERS 1066 00:48:33,240 --> 00:48:33,800 ARE NOT INCREASED IN PEOPLE 1067 00:48:33,800 --> 00:48:34,320 WITH DOWN SYNDROME AND 1068 00:48:34,320 --> 00:48:34,920 EXPRESSION I SHOWED WAS NOT IN 1069 00:48:34,920 --> 00:48:38,720 T REG, MOSTLY IT WAS AN 1070 00:48:38,720 --> 00:48:40,960 EXPRESSION IN DYSREGULATION, 1071 00:48:40,960 --> 00:48:46,160 WHAT WE CALL NAïVE TD 4 1072 00:48:46,160 --> 00:48:46,760 POSITIVE CELLS CLOSER TO WHAT 1073 00:48:46,760 --> 00:48:48,480 YOU ARE DESCRIBING. GREAT 1074 00:48:48,480 --> 00:48:50,320 QUESTION. 1075 00:48:50,320 --> 00:48:56,080 >>REALLY NICE. I AM CURIOUS. 1076 00:48:56,080 --> 00:48:57,000 NOW THAT WE HAVE A LITTLE 1077 00:48:57,000 --> 00:48:58,600 BETTER IDEA OF WHAT WE HEARD 1078 00:48:58,600 --> 00:49:04,960 YESTERDAY THE IMMUNOLOGICAL 1079 00:49:04,960 --> 00:49:05,560 (INDISCERNIBLE) GIVING US AN 1080 00:49:05,560 --> 00:49:08,760 IDEA OF CONNECTING IMMUNOLOGY 1081 00:49:08,760 --> 00:49:12,520 THROUGH DISEASE, DOWN SYNDROME 1082 00:49:12,520 --> 00:49:23,000 PATIENTS HAVE A LOSS OF -- 1083 00:49:24,280 --> 00:49:24,840 (INDISCERNIBLE) CAN YOU PREDICT 1084 00:49:24,840 --> 00:49:25,440 THAT SOMEONE CAN MATCH WITHIN 1085 00:49:25,440 --> 00:49:28,040 NORMAL OLDER INDIVIDUAL. 1086 00:49:28,040 --> 00:49:28,640 >>I HAVE SOME ANSWERS BUT NOT 1087 00:49:28,640 --> 00:49:29,120 ALL THE ANSWERS TO THAT 1088 00:49:29,120 --> 00:49:31,840 QUESTION. CERTAINLY ONE OF THE 1089 00:49:31,840 --> 00:49:33,520 MOST PROMINENT FINDS YOU WILL 1090 00:49:33,520 --> 00:49:34,320 FIND IS A PROMINENT DECREASE IN 1091 00:49:34,320 --> 00:49:40,720 NAïVE CD4 AND NAïVE CD5S. 1092 00:49:40,720 --> 00:49:41,280 REPERTORY ANALYSES WE HAVE A 1093 00:49:41,280 --> 00:49:43,120 LITTLE BIT OF DATA, BUT 1094 00:49:43,120 --> 00:49:43,680 HONESTLY WE DON'T HAVE THE 1095 00:49:43,680 --> 00:49:47,160 MONEY. WE HAVE NOT HAD THE 1096 00:49:47,160 --> 00:49:53,800 MONEY TO ACT THAT RIGOROUSLY 1097 00:49:53,800 --> 00:49:59,280 YET. ALL OF THIS GETS INTO HOW 1098 00:49:59,280 --> 00:49:59,840 WE DEFINE AGING AND HOW WE 1099 00:49:59,840 --> 00:50:03,920 DEFINE AGING MATTERS. BECAUSE 1100 00:50:03,920 --> 00:50:04,560 TO ME THE GOLD STANDARD IS NOT 1101 00:50:04,560 --> 00:50:05,840 SIMPLY TO GET BACK TO WHAT MY 1102 00:50:05,840 --> 00:50:08,760 DRIVERS LICENSE TELLS ME. BUT 1103 00:50:08,760 --> 00:50:16,120 REALLY TOGETHER THIS IDEA OF, 1104 00:50:16,120 --> 00:50:16,680 HOW CAN WE LEVERAGE THIS TO 1105 00:50:16,680 --> 00:50:18,200 IDENTIFY WHO IS MOST AT RISK? 1106 00:50:18,200 --> 00:50:18,800 THAT IS A TYPE OF QUESTION WE 1107 00:50:18,800 --> 00:50:20,000 NEED TO ADDRESS. THANK YOU FOR 1108 00:50:20,000 --> 00:50:21,280 THAT. 1109 00:50:21,280 --> 00:50:29,040 >>HI. NICK-- UNIVERSITY OF 1110 00:50:29,040 --> 00:50:33,920 VIRGINIA. REALLY WONDERFUL TALK 1111 00:50:33,920 --> 00:50:34,520 LOOKS LIKE CELL SITE RELATION 1112 00:50:34,520 --> 00:50:36,160 WAS PART OF THE DOWN SYNDROME 1113 00:50:36,160 --> 00:50:36,800 TRANSCRIPTION NO PATHWAYS. YOU 1114 00:50:36,800 --> 00:50:37,560 HAVE AN IDEA OF WHAT THE ROLE 1115 00:50:37,560 --> 00:50:38,840 OF SELF-REGULATION IS? THE YOU 1116 00:50:38,840 --> 00:50:41,960 SEE MORE (INDISCERNIBLE), OR 1117 00:50:41,960 --> 00:50:48,200 SOME OTHER TYPE OF REGULATION? 1118 00:50:48,200 --> 00:50:49,960 >>WHAT WE ARE SEEING THERE IS 1119 00:50:49,960 --> 00:50:50,560 GENES AND RICH ANALYSIS FROM 1120 00:50:50,560 --> 00:50:53,960 FULL BLOOD RNC. WHERE IS THE 1121 00:50:53,960 --> 00:51:04,480 SIGNAL COMING FROM? I THINK IT 1122 00:51:04,880 --> 00:51:05,440 SUGGESTS THERE IS A PHENOTYPE 1123 00:51:05,440 --> 00:51:06,040 PROLIFERATION SOMEWHERE ACROSS 1124 00:51:06,040 --> 00:51:09,800 DIFFERENT SUBTYPES. IS IT IN 1125 00:51:09,800 --> 00:51:11,800 ONE TYPE OF CELL TYPE? THOSE OF 1126 00:51:11,800 --> 00:51:12,440 THE TYPES OF QUESTIONS WE NEED 1127 00:51:12,440 --> 00:51:13,920 TO ASK. 1128 00:51:13,920 --> 00:51:17,040 >>WONDERFUL TALK. I CANNOT 1129 00:51:17,040 --> 00:51:18,360 HELP BUT NOTE THAT YOUR 1130 00:51:18,360 --> 00:51:22,080 COMPLEMENT PATHWAY IS 1131 00:51:22,080 --> 00:51:23,400 HIGHLIGHTED; YOU DO NOT 1132 00:51:23,400 --> 00:51:24,040 HIGHLIGHTED, BUT IT IS LISTED 1133 00:51:24,040 --> 00:51:27,920 THERE. DOWN SYNDROME HAS NO 1134 00:51:27,920 --> 00:51:30,000 (INDISCERNIBLE) 21 THAT 1135 00:51:30,000 --> 00:51:35,240 INCLUDES ATP? THAT PREDISPOSES 1136 00:51:35,240 --> 00:51:35,720 THOSE INDIVIDUALS TO 1137 00:51:35,720 --> 00:51:44,400 ALZHEIMER'S DISEASE. IN THE 1138 00:51:44,400 --> 00:51:45,040 LAST REFERENCE SHOWED YESTERDAY 1139 00:51:45,040 --> 00:51:45,640 THIS PAPER THE PROFILE THOSE 1140 00:51:45,640 --> 00:51:48,960 COMPLEMENT PATHWAYS BETWEEN 1141 00:51:48,960 --> 00:51:52,200 AGING AND ALZHEIMER'S. I WAS 1142 00:51:52,200 --> 00:51:52,840 WONDERING IF YOU WOULD LOOKING 1143 00:51:52,840 --> 00:51:53,440 AT THIS COMPLEMENT PATHWAY IN 1144 00:51:53,440 --> 00:51:56,960 YOUR COHORT, AND WITH LATER 1145 00:51:56,960 --> 00:51:57,600 COHORTS AND WHETHER YOU CAN USE 1146 00:51:57,600 --> 00:51:59,480 SOME KIND OF-- 1147 00:51:59,480 --> 00:52:01,520 >>THAT IS A GREAT QUESTION. 1148 00:52:01,520 --> 00:52:06,000 AFTER THAT TALK, I REALIZED I 1149 00:52:06,000 --> 00:52:06,600 NEEDED TO GO AND DO THAT MORE 1150 00:52:06,600 --> 00:52:07,200 CAREFULLY, THAT IS THE SHORT 1151 00:52:07,200 --> 00:52:10,920 ANSWER. (LAUGHTER) I HAD THE 1152 00:52:10,920 --> 00:52:12,800 DRAWBACK THAT I CAME TO, THE 1153 00:52:12,800 --> 00:52:20,080 MOUSE T CELL BIOLOGY. WHAT WE 1154 00:52:20,080 --> 00:52:20,680 ARE LEARNING HERE IS THAT THERE 1155 00:52:20,680 --> 00:52:21,280 IS A LOT OF INTERPLAY BETWEEN 1156 00:52:21,280 --> 00:52:22,640 ALL THE DIFFERENT CELL TYPES. 1157 00:52:22,640 --> 00:52:24,960 AND SO I THINK THAT WOULD BE 1158 00:52:24,960 --> 00:52:25,640 GREAT. IF THERE ARE 1159 00:52:25,640 --> 00:52:26,280 COLLABORATIVE OPPORTUNITIES IT 1160 00:52:26,280 --> 00:52:36,760 WOULD BE GREAT. 1161 00:52:36,760 --> 00:52:47,080 >>THANK YOU. 1162 00:52:47,080 --> 00:52:47,680 THANK YOU ALL VERY MUCH FOR THE 1163 00:52:47,680 --> 00:52:52,720 WONDERFUL TALKS AND SHARE YOUR 1164 00:52:52,720 --> 00:52:53,320 DATA YESTERDAY AND IF YOU COULD 1165 00:52:53,320 --> 00:52:56,360 MAYBE START BY TWO MINUTES, A 1166 00:52:56,360 --> 00:52:56,960 COUPLE OF SENTENCES MAJOR GAPS 1167 00:52:56,960 --> 00:52:57,600 IN THE FIELD. 1168 00:52:57,600 --> 00:53:05,360 >>HI. I THINK YOU SHOULD GET 1169 00:53:05,360 --> 00:53:09,680 INTO IT. SO THE KEY ASPECT OF 1170 00:53:09,680 --> 00:53:10,640 MY TALK YESTERDAY WAS 1171 00:53:10,640 --> 00:53:17,880 UNDERSTANDING THE ROLE OF -- 1172 00:53:17,880 --> 00:53:19,680 INNOVATION AND (INDISCERNIBLE) 1173 00:53:19,680 --> 00:53:22,360 TO REJUVENATE TISSUE. HOW IS 1174 00:53:22,360 --> 00:53:24,600 THIS DONE? WE ARE WORKING ON IT 1175 00:53:24,600 --> 00:53:35,120 RIGHT NOW. -- I BELIEVE THAT 1176 00:54:09,960 --> 00:54:11,840 THERE ARE ACTIONS AND 1177 00:54:11,840 --> 00:54:13,440 ACTIVITIES THAT ARE IMPORTANT 1178 00:54:13,440 --> 00:54:16,120 IN HOMEOSTASIS, MAY BE ALTERED 1179 00:54:16,120 --> 00:54:19,040 IN VARIOUS DISEASES. THAT IS 1180 00:54:19,040 --> 00:54:19,920 ALL I HAVE TO SAY. 1181 00:54:19,920 --> 00:54:29,920 >> 1182 00:54:48,560 --> 00:54:51,440 >>I THINK THAT IS SOMETHING 1183 00:54:51,440 --> 00:54:54,520 VERY NICE THAT YOU JUST SAID. 1184 00:54:54,520 --> 00:54:56,720 BECAUSE EVERYTHING LINKS SO 1185 00:54:56,720 --> 00:55:07,280 MUCH, IT IS NOT TO THINK ABOUT 1186 00:55:11,080 --> 00:55:11,600 WAYS THAT WE CAN SET UP OUR 1187 00:55:11,600 --> 00:55:18,280 EXPERIMENT TO ENABLE OTHERS. I 1188 00:55:18,280 --> 00:55:28,840 AM NOT A PERIPHERAL NEUROLOGIST 1189 00:55:28,840 --> 00:55:29,320 BY ANY STRETCH OF THE 1190 00:55:29,320 --> 00:55:29,920 IMAGINATION BUT MEETINGS LIKE 1191 00:55:29,920 --> 00:55:30,520 THIS BRING CONNECTIONS ON HOW 1192 00:55:30,520 --> 00:55:31,080 WE CAN SET OF NUMBERS OF 1193 00:55:31,080 --> 00:55:33,920 MATERIALS. 1194 00:55:33,920 --> 00:55:34,520 >>THERE IS INCREASING INTEREST 1195 00:55:34,520 --> 00:55:37,000 IN HOW TO DO THE IMMUNE SYSTEM 1196 00:55:37,000 --> 00:55:38,800 FOR NEURODEGENERATIVE DISEASES, 1197 00:55:38,800 --> 00:55:39,320 PARTICULARLY ALZHEIMER'S 1198 00:55:39,320 --> 00:55:44,840 DISEASE. MY TALK YESTERDAY 1199 00:55:44,840 --> 00:55:46,120 SORT OF SUPPORTED THE PREMISE 1200 00:55:46,120 --> 00:55:50,480 THAT WE NEED TO REDUCE THE 1201 00:55:50,480 --> 00:55:53,920 IMMUNE SYSTEM BY TARGETING FOR 1202 00:55:53,920 --> 00:55:57,840 EXAMPLE THE COMPLEMENT PATHWAY. 1203 00:55:57,840 --> 00:56:00,640 THAT IS SUPPORTED BY OTHER 1204 00:56:00,640 --> 00:56:03,240 STUDIES. 1205 00:56:03,240 --> 00:56:03,840 ON THE OTHER HAND THE IMMUNE 1206 00:56:03,840 --> 00:56:08,760 SYSTEM NEEDS TO BE ACTIVATED. 1207 00:56:08,760 --> 00:56:10,040 A GOOD EXAMPLE IS 1208 00:56:10,040 --> 00:56:11,720 (INDISCERNIBLE). SO WHAT 1209 00:56:11,720 --> 00:56:13,960 HAPPENS IN THE (INDISCERNIBLE) 1210 00:56:13,960 --> 00:56:21,160 CASE, THE GENETIC POLYMORPHISM 1211 00:56:21,160 --> 00:56:22,560 INCREASES; THAT LEADS TO LOSS 1212 00:56:22,560 --> 00:56:29,080 OF FUNCTION. AND OF THOSE 1213 00:56:29,080 --> 00:56:37,320 MICROGLIA CANNOT BE ACTIVATED. 1214 00:56:37,320 --> 00:56:39,400 THE QUESTION IS, DO YOU REALLY 1215 00:56:39,400 --> 00:56:41,880 WANT TO ACTIVATE IT? DO YOU 1216 00:56:41,880 --> 00:56:44,480 WANT TO INACTIVATE IT? AT WHAT 1217 00:56:44,480 --> 00:56:46,640 POINT DO YOU WANT TO ACTIVATE 1218 00:56:46,640 --> 00:56:47,560 IT? AT WHAT POINT DO YOU WANT 1219 00:56:47,560 --> 00:56:49,400 TO INACTIVATE IT? WHAT IS THE 1220 00:56:49,400 --> 00:56:54,440 DURATION? ANOTHER IMPORTANT 1221 00:56:54,440 --> 00:56:56,920 POINT I WANT TO APPLY IS THE 1222 00:56:56,920 --> 00:56:59,400 PERIPHERAL EXPRESSION. IF YOU 1223 00:56:59,400 --> 00:57:00,480 JUST TARGET THE PERIPHERAL 1224 00:57:00,480 --> 00:57:03,160 EXPRESSION, YOU ALSO SEE THE 1225 00:57:03,160 --> 00:57:04,600 (INDISCERNIBLE), HOW DOES THIS 1226 00:57:04,600 --> 00:57:09,800 (INDISCERNIBLE)? THOSE ARE ALL 1227 00:57:09,800 --> 00:57:10,400 IMPORTANT QUESTIONS AND GAPS 1228 00:57:10,400 --> 00:57:15,280 AND OPPORTUNITIES IN THE FIELD. 1229 00:57:15,280 --> 00:57:18,000 >>YEAH, I ABSOLUTELY AGREE 1230 00:57:18,000 --> 00:57:22,120 WITH EVERYBODY. I THINK 1231 00:57:22,120 --> 00:57:25,560 THINKING OF OUR FIELD, IN A 1232 00:57:25,560 --> 00:57:30,320 MORE NARROW WAY, SO THE FIELD 1233 00:57:30,320 --> 00:57:37,040 OF TRYING TO TACKLE NEURO- 1234 00:57:37,040 --> 00:57:41,640 INFLAMMATORY, 1235 00:57:41,640 --> 00:57:42,120 NEURODEGENERATION, LIKE 1236 00:57:42,120 --> 00:57:42,680 ALZHEIMER'S OR PARKINSON'S 1237 00:57:42,680 --> 00:57:43,240 WHICH OF THESE REALLY LONG 1238 00:57:43,240 --> 00:57:45,120 PERIODS. PARKINSON'S FOR 1239 00:57:45,120 --> 00:57:48,360 EXAMPLE YOU HAVE GI SYSTEMS TWO 1240 00:57:48,360 --> 00:57:51,320 DECADES BEFORE PRESENTATION. 1241 00:57:51,320 --> 00:57:53,480 SO I THINK A HUGE CHALLENGE IS 1242 00:57:53,480 --> 00:57:58,560 PRETTY OBVIOUS. HOW DO YOU 1243 00:57:58,560 --> 00:58:02,040 ACTUALLY ANTICIPATE WHO'S GOING 1244 00:58:02,040 --> 00:58:06,400 TO GET THESE DISEASES? WE NEED 1245 00:58:06,400 --> 00:58:10,440 BETTER BIOMARKERS. PROBABLY 1246 00:58:10,440 --> 00:58:12,360 IMMUNE BIOMARKERS. PROBABLY. I 1247 00:58:12,360 --> 00:58:13,720 SUSPECT AT LEAST IN 1248 00:58:13,720 --> 00:58:14,640 ALZHEIMER'S, THE GENETICS IS 1249 00:58:14,640 --> 00:58:18,080 QUITE CLEAR. THE MYELOID SYSTEM 1250 00:58:18,080 --> 00:58:22,640 IS QUITE IMPORTANT. I WOULD 1251 00:58:22,640 --> 00:58:23,200 SAY IT PROBABLY IS NOT JUST 1252 00:58:23,200 --> 00:58:27,000 MICROGLIA BUT THE PERIPHERY. 1253 00:58:27,000 --> 00:58:29,520 THERE IS LITTLE BIT OF DOGMA IN 1254 00:58:29,520 --> 00:58:30,120 OUR AREA WHERE PEOPLE ARE NOT 1255 00:58:30,120 --> 00:58:32,720 THINKING OUTSIDE OF THE BRAIN. 1256 00:58:32,720 --> 00:58:34,920 BUT WHAT WE REALLY NEED, I 1257 00:58:34,920 --> 00:58:35,560 THINK THE BIGGEST PROBLEM IS WE 1258 00:58:35,560 --> 00:58:39,040 DO NOT HAVE BIOMARKERS. WE DO 1259 00:58:39,040 --> 00:58:39,560 NOT HAVE PROPER IMMUNE 1260 00:58:39,560 --> 00:58:42,280 BIOMARKERS TO ANTICIPATE OR TO 1261 00:58:42,280 --> 00:58:42,680 TRACK THESE FOLKS 1262 00:58:42,680 --> 00:58:45,440 LONGITUDINALLY. AND I KNOW IN 1263 00:58:45,440 --> 00:58:49,000 THE ALZHEIMER'S FIELD AND IN 1264 00:58:49,000 --> 00:58:51,240 PARKINSON'S, IT IS A BIG AREA 1265 00:58:51,240 --> 00:58:53,440 OF INVESTIGATION. IT IS GOING 1266 00:58:53,440 --> 00:59:00,200 TO BE TRICKY. YOU'RE TALKING 1267 00:59:00,200 --> 00:59:00,840 ABOUT LONGITUDINAL STUDIES WITH 1268 00:59:00,840 --> 00:59:10,200 20 YEAR TIMELINES. 1269 00:59:10,200 --> 00:59:10,720 >>I WILL OPEN IT UP TO THE 1270 00:59:10,720 --> 00:59:11,280 AUDIENCE IF THERE ARE OTHER 1271 00:59:11,280 --> 00:59:11,880 CONTRIBUTIONS OR GAPS IN THE 1272 00:59:11,880 --> 00:59:17,600 FIELD. 1273 00:59:17,600 --> 00:59:22,280 >>THAT WAS REALLY A NICE 1274 00:59:22,280 --> 00:59:22,840 PHRASE, THINK OUTSIDE THE 1275 00:59:22,840 --> 00:59:33,360 BRAIN. I'M GOING TO USE IT. I 1276 00:59:36,360 --> 00:59:36,920 THINK YOUR DATA WITH PERIPHERAL 1277 00:59:36,920 --> 00:59:38,840 EFFECTS IS REALLY GOOD. I WAS 1278 00:59:38,840 --> 00:59:39,480 WONDERING IF YOU HAVE ANY MORE 1279 00:59:39,480 --> 00:59:40,040 THOUGHTS ABOUT HOW THIS IS 1280 00:59:40,040 --> 00:59:43,560 AFFECTING THIS, OR IF THERE IS 1281 00:59:43,560 --> 00:59:45,000 -- THAT GOES BACK TO THE BRAIN. 1282 00:59:45,000 --> 00:59:51,360 A LOT OF CNS PEOPLE HAVE 1283 00:59:51,360 --> 00:59:55,160 FORGOTTEN ABOUT AFFERENCE AND 1284 00:59:55,160 --> 00:59:58,840 INFERENCE (PHONETIC). 1285 00:59:58,840 --> 01:00:02,280 DO YOU KNOW IF THERE ARE EP2 1286 01:00:02,280 --> 01:00:06,320 EFFECTS (INDISCERNIBLE), OR IS 1287 01:00:06,320 --> 01:00:10,520 THIS A HEMORAL EFFECT? 1288 01:00:10,520 --> 01:00:11,120 >>THAT IS A GREAT QUESTION WE 1289 01:00:11,120 --> 01:00:14,000 HAVE NOT THOUGHT ABOUT 1290 01:00:14,000 --> 01:00:18,920 EFERENCE. AGAIN, GETTING BACK 1291 01:00:18,920 --> 01:00:20,160 TO THE IDEA OF PERIPHERAL 1292 01:00:20,160 --> 01:00:22,480 NERVOUS SYSTEM, I THINK IT IS 1293 01:00:22,480 --> 01:00:26,360 REALLY IMPORTANT TO LOOK AT 1294 01:00:26,360 --> 01:00:26,840 IMMUNE EFFECTS ON THE 1295 01:00:26,840 --> 01:00:28,360 PERIPHERAL NERVOUS SYSTEM, 1296 01:00:28,360 --> 01:00:29,000 PARTICULARLY ON AGING AND MAYBE 1297 01:00:29,000 --> 01:00:31,040 IN THESE DISEASES. I WOULD 1298 01:00:31,040 --> 01:00:31,680 REALLY THINK ABOUT PARKINSON'S 1299 01:00:31,680 --> 01:00:36,240 HERE. BUT WE HAVE NOT LOOKED. 1300 01:00:36,240 --> 01:00:38,360 WE DON'T REALLY KNOW YET WHAT 1301 01:00:38,360 --> 01:00:42,680 IS DRIVING THIS, I SUSPECT THE 1302 01:00:42,680 --> 01:00:43,880 REDUCTIONIST APPROACH IS NOT 1303 01:00:43,880 --> 01:00:46,080 GOING TO BE VERY USEFUL. 1304 01:00:46,080 --> 01:00:48,080 PROBABLY MANY DIFFERENT THINGS, 1305 01:00:48,080 --> 01:00:52,160 ALL KIND OF SYNERGIZING TO 1306 01:00:52,160 --> 01:00:52,600 CHANGE PROBABLY THE 1307 01:00:52,600 --> 01:00:55,600 BLOOD-BRAIN BARRIER, 1308 01:00:55,600 --> 01:00:58,680 ENDOTHELIAL CELLS, WE ARE 1309 01:00:58,680 --> 01:01:02,200 SEEING CHANGES IN ASTROCYTES 1310 01:01:02,200 --> 01:01:05,120 WHEN WE DO TRANSCRIPTOMIC. 1311 01:01:05,120 --> 01:01:06,840 IT'S GOING TO BE A REALLY FUN 1312 01:01:06,840 --> 01:01:10,840 PROBLEM TO CRACK. YEAH. 1313 01:01:10,840 --> 01:01:18,160 >>MAYBE I WANT TO ADD. SO I 1314 01:01:18,160 --> 01:01:19,720 HAVEN'T HEARD ABOUT MENINGY. 1315 01:01:19,720 --> 01:01:22,320 THERE'S A LOT OF -- CELLS OVER 1316 01:01:22,320 --> 01:01:32,720 THERE (INDISCERNIBLE). 1317 01:01:34,640 --> 01:01:35,240 >>FOR ME IT IS A BALANCE OF 1318 01:01:35,240 --> 01:01:43,400 TRYING TO APPRECIATE THE 1319 01:01:43,400 --> 01:01:43,960 COMPLEXITY OF THE SYSTEM, I 1320 01:01:43,960 --> 01:01:44,560 HEARD A MENTION OF LOOKING AT 1321 01:01:44,560 --> 01:01:46,200 AN OVERLAP BETWEEN DIFFERENT 1322 01:01:46,200 --> 01:01:46,800 DISEASES, ALSO INCORPORATING 1323 01:01:46,800 --> 01:01:48,720 SYSTEM BIOLOGY AND ANALYSIS 1324 01:01:48,720 --> 01:01:52,760 THAT ALLOWS YOU TO APPRECIATE 1325 01:01:52,760 --> 01:01:53,360 THAT IMMUNE CELLS CAN INTEGRATE 1326 01:01:53,360 --> 01:01:54,200 MULTIPLE SIGNALS OVER A VERY 1327 01:01:54,200 --> 01:01:56,480 SHORT PERIOD OF TIME. AND 1328 01:01:56,480 --> 01:01:57,360 OFTEN TIMES THEY ARE QUITE 1329 01:01:57,360 --> 01:02:01,680 FLEXIBLE. RIGHT? HOW CAN WE 1330 01:02:01,680 --> 01:02:05,840 APPROPRIATELY TEASE OUT WHAT IS 1331 01:02:05,840 --> 01:02:06,360 HAPPENING IN THE PATHWAYS 1332 01:02:06,360 --> 01:02:09,640 MANNER? IT IS NOT ALWAYS 1333 01:02:09,640 --> 01:02:13,440 STRAIGHT. 1334 01:02:13,440 --> 01:02:13,920 THERE HAS BEEN A LOT OF 1335 01:02:13,920 --> 01:02:14,480 ADVANCES RECENTLY AS FAR AS 1336 01:02:14,480 --> 01:02:18,320 SINGLE CELL RNA SEQUENCING, AND 1337 01:02:18,320 --> 01:02:21,320 SYSTEM BIOLOGY WORK. I THINK 1338 01:02:21,320 --> 01:02:23,880 HOPEFULLY THAT WILL HELP 1339 01:02:23,880 --> 01:02:24,320 INTEGRATE MORE OF A 1340 01:02:24,320 --> 01:02:25,160 REDUCTIONIST APPROACH WITH A 1341 01:02:25,160 --> 01:02:28,200 BIGGER, BROADER APPROACH. I 1342 01:02:28,200 --> 01:02:31,720 DON'T KNOW IF-- I KNOW 1343 01:02:31,720 --> 01:02:32,280 PERIPHERAL NERVES ARE QUITE 1344 01:02:32,280 --> 01:02:34,400 DIFFICULT TO STUDY FROM SINGLE 1345 01:02:34,400 --> 01:02:41,520 CELLULAR APPROACH. PERHAPS 1346 01:02:41,520 --> 01:02:42,360 MOUSE MODELS OUT THERE WOULD BE 1347 01:02:42,360 --> 01:02:44,280 USEFUL. 1348 01:02:44,280 --> 01:02:49,520 >>SO WE DO NOT HAVE THE TOOLS 1349 01:02:49,520 --> 01:02:50,040 TO SPECIFICALLY LOOK AT 1350 01:02:50,040 --> 01:02:54,520 LOCATION. YOU CAN INTERRUPT 1351 01:02:54,520 --> 01:02:55,120 THE WHOLE SYSTEM, PERIPHERAL 1352 01:02:55,120 --> 01:02:56,160 NERVOUS SYSTEM, BUT HOW DO YOU 1353 01:02:56,160 --> 01:02:59,520 CONTROL THAT? SO WE CAN TREAT 1354 01:02:59,520 --> 01:03:02,520 WITH DIFFERENT DRUGS, YOU CAN 1355 01:03:02,520 --> 01:03:08,360 TREAT WITH DIFFERENT 1356 01:03:08,360 --> 01:03:08,960 (INDISCERNIBLE), BUT YOU WILL 1357 01:03:08,960 --> 01:03:11,920 ELIMINATE YOUR VEIN FROM 1358 01:03:11,920 --> 01:03:13,680 EVERYWHERE, (INDISCERNIBLE) IT 1359 01:03:13,680 --> 01:03:17,680 IS EVERYWHERE. 1360 01:03:17,680 --> 01:03:18,200 HOW CAN WE GET IT TO BE 1361 01:03:18,200 --> 01:03:21,560 SPECIFIC FOR LOCATION? THE 1362 01:03:21,560 --> 01:03:22,160 OTHER THINGS WE HAVE NO IDEA 1363 01:03:22,160 --> 01:03:22,760 HOW TO INTERACT WITH ALL THE 1364 01:03:22,760 --> 01:03:24,120 IMMUNE CELLS. THERE ARE A LOT 1365 01:03:24,120 --> 01:03:27,920 OF IMMUNE CELLS! WE ALL TALKED 1366 01:03:27,920 --> 01:03:28,520 ABOUT THE DIVERSITY OF THE 1367 01:03:28,520 --> 01:03:33,320 IMMUNE CELLS. HOW CAN WE PICK 1368 01:03:33,320 --> 01:03:33,880 OUT THE SYSTEM? THAT IS THE 1369 01:03:33,880 --> 01:03:36,200 COMPLEXITY HERE. 1370 01:03:36,200 --> 01:03:36,800 WE KNOW THAT THERE IS A LOT OF 1371 01:03:36,800 --> 01:03:38,600 INTERACTION WITH MACROPHAGES; 1372 01:03:38,600 --> 01:03:40,280 WITH THE PANCREAS, 1373 01:03:40,280 --> 01:03:44,920 PANCREATITIS. WHAT DO WE SEE? 1374 01:03:44,920 --> 01:03:45,560 A LOT OF MACROPHAGES ATTACHING 1375 01:03:45,560 --> 01:03:47,440 TO THOSE NERVES. SO IT IS 1376 01:03:47,440 --> 01:03:48,840 SOMETHING TO BE THINKING ABOUT. 1377 01:03:48,840 --> 01:03:55,600 THE IMMUNE CONNECTION. THE 1378 01:03:55,600 --> 01:03:56,120 NEURAL IMMUNE CONNECTION 1379 01:03:56,120 --> 01:03:58,000 OUTSIDE OF THE BRAIN AS WELL. 1380 01:03:58,000 --> 01:04:00,480 I DON'T STUDY THE BRAIN. THAT 1381 01:04:00,480 --> 01:04:00,960 IS BECAUSE I DON'T KNOW 1382 01:04:00,960 --> 01:04:04,560 ANYTHING ABOUT IT. SO, IT'S 1383 01:04:04,560 --> 01:04:09,160 VERY DIFFICULT. WE CAN DEVELOP 1384 01:04:09,160 --> 01:04:09,800 TOOLS TO BE ABLE TO INVESTIGATE 1385 01:04:09,800 --> 01:04:13,360 IT FURTHER. IT IS GOING TO BE 1386 01:04:13,360 --> 01:04:15,840 FURTHER STUDIED BY YOU GUYS. I 1387 01:04:15,840 --> 01:04:24,080 THINK THAT IS VERY IMPORTANT. 1388 01:04:24,080 --> 01:04:30,120 >>I THINK COMPLEXITY, WE HAVE 1389 01:04:30,120 --> 01:04:30,720 TO LOOK AT WHAT STAGE THE ONSET 1390 01:04:30,720 --> 01:04:32,520 OF DISEASES OCCURRING. AND WHY 1391 01:04:32,520 --> 01:04:36,360 IT IS ASSOCIATED WITH AGING. 1392 01:04:36,360 --> 01:04:44,280 WE KNOW THAT IN AGING, 1393 01:04:44,280 --> 01:04:45,280 MYELOPOESIS IS INCREASED AND 1394 01:04:45,280 --> 01:04:53,880 (INDISCERNIBLE) -- ACTIVATION 1395 01:04:53,880 --> 01:04:55,960 OF IMMUNE CELLS. 1396 01:04:55,960 --> 01:05:02,440 (INDISCERNIBLE) OR FROM BRAIN, 1397 01:05:02,440 --> 01:05:03,160 AND THEN ADAPTIVE IMMUNITY IS 1398 01:05:03,160 --> 01:05:06,920 DOING BAD THINGS. OR IS IT DUE 1399 01:05:06,920 --> 01:05:10,440 TO ACTIVATION IN ALZHEIMER'S 1400 01:05:10,440 --> 01:05:14,440 DISEASE? THESE ARE MYELOID T 1401 01:05:14,440 --> 01:05:20,760 CELLS (INDISCERNIBLE). 1402 01:05:20,760 --> 01:05:26,240 >>SO ALMOST EVERY TALK WE HAVE 1403 01:05:26,240 --> 01:05:30,680 HAD SINGLE CELL-- DATA. ONE 1404 01:05:30,680 --> 01:05:33,280 QUESTION WHICH WE HAVE IS 1405 01:05:33,280 --> 01:05:35,680 RELATED TO IMMUNE CELLS. DO YOU 1406 01:05:35,680 --> 01:05:36,200 DEFINE THEM BY SURFACE 1407 01:05:36,200 --> 01:05:41,200 PHENOTYPE? OR DO YOU DEFINE 1408 01:05:41,200 --> 01:05:51,720 THEM BY AUTOGENIC TRANSPORT? 1409 01:05:53,480 --> 01:05:53,960 MANY TIMES WRITING PAPERS 1410 01:05:53,960 --> 01:06:01,440 PEOPLE SAY CERTAIN THINGS, AND 1411 01:06:01,440 --> 01:06:02,040 YOU LOOK AT WHAT TRANSCRIPT 1412 01:06:02,040 --> 01:06:02,640 WERE USED AND I THINK THERE'S A 1413 01:06:02,640 --> 01:06:03,160 BIG GAP THAT LEADS INTO 1414 01:06:03,160 --> 01:06:03,800 COMPLICATED INTERPRETATIONS OF 1415 01:06:03,800 --> 01:06:06,680 THE DATA 1416 01:06:06,680 --> 01:06:07,280 THERE HAS TO BE SOME KIND OF 1417 01:06:07,280 --> 01:06:09,760 NOT CONSENSUS BUT SOME KIND OF 1418 01:06:09,760 --> 01:06:10,400 PLAN WE DECIDE HOW YOU DEFINE 1419 01:06:10,400 --> 01:06:12,320 THE IMMUNE CELLS OF TYPE. DO 1420 01:06:12,320 --> 01:06:16,000 YOU GO BY TRANSCRIPT? THE 1421 01:06:16,000 --> 01:06:16,560 ACTUALLY LOOK FOR PROTEIN 1422 01:06:16,560 --> 01:06:18,840 EXCRETION ON THE SURFACE? 1423 01:06:18,840 --> 01:06:21,200 >>I WOULD ADD, I TOTALLY 1424 01:06:21,200 --> 01:06:26,800 AGREE. WE HAVE BEEN BURNED BY 1425 01:06:26,800 --> 01:06:27,400 TRANSCRIPTOMIC SEVERAL TIMES 1426 01:06:27,400 --> 01:06:31,840 NOW. THERE IS A HUGE UP 1427 01:06:31,840 --> 01:06:32,400 REGULATION IN A PARTICULAR 1428 01:06:32,400 --> 01:06:33,000 PATHWAY, AND IT TURNS OUT THE 1429 01:06:33,000 --> 01:06:41,720 PROTEINS ARE DOWN. SO YOU 1430 01:06:41,720 --> 01:06:42,280 KNOW, IT HAS TO BE COUPLED; 1431 01:06:42,280 --> 01:06:47,720 WITH IMMUNE CELLS YOU CAN CHECK 1432 01:06:47,720 --> 01:06:48,320 SURFACE EXPRESSIONS BUT WITH 1433 01:06:48,320 --> 01:06:48,880 OTHER CELL TYPES TO BECOME 1434 01:06:48,880 --> 01:06:49,640 PROBLEMATIC. 1435 01:06:49,640 --> 01:06:56,240 >>CAN I ADD TO THAT? IT MIGHT 1436 01:06:56,240 --> 01:06:59,120 BE THAT CELL SURFACE MARKERS 1437 01:06:59,120 --> 01:06:59,760 CHANGE WITH AGING AND WE ASSUME 1438 01:06:59,760 --> 01:07:02,720 A CELL IS LOST IF YOU USE FLOW 1439 01:07:02,720 --> 01:07:04,040 CYTOMETRY OR ANY SURFACE 1440 01:07:04,040 --> 01:07:09,280 STAINING; THAT TERRIFIES ME. 1441 01:07:09,280 --> 01:07:11,880 >>OR CELLS UPREGULATE A MARKER 1442 01:07:11,880 --> 01:07:14,800 FOR DIFFERENT REASONS. I KNOW 1443 01:07:14,800 --> 01:07:15,360 THERE WAS A QUESTION IN THE 1444 01:07:15,360 --> 01:07:17,000 BACK. 1445 01:07:17,000 --> 01:07:19,760 >>SORRY. BEHIND THE COLUMN 1446 01:07:19,760 --> 01:07:25,520 AGAIN. I WANTED TO SAY THIS IS 1447 01:07:25,520 --> 01:07:27,560 A SIMILAR GAP THAT I BROUGHT UP 1448 01:07:27,560 --> 01:07:33,240 YESTERDAY. TO DEEPEN THE 1449 01:07:33,240 --> 01:07:33,840 DISCUSSION, IF WE THINK ABOUT 1450 01:07:33,840 --> 01:07:40,240 THE DEFINITION OF THE CELL 1451 01:07:40,240 --> 01:07:40,880 SUBPOPULATION, REALISTICALLY IF 1452 01:07:40,880 --> 01:07:42,320 YOU SHOW THAT IT IS 1453 01:07:42,320 --> 01:07:43,600 TRANSCRIPTIONALLY DIFFERENT, 1454 01:07:43,600 --> 01:07:44,200 DRIVEN BY A DIFFERENT SET OF 1455 01:07:44,200 --> 01:07:46,240 TRANSCRIPTION FACTORS AND THE 1456 01:07:46,240 --> 01:07:50,520 EPIGENETIC REVIEW, IS THE GOLD 1457 01:07:50,520 --> 01:07:51,120 STANDARD TO CALL THAT A CELL 1458 01:07:51,120 --> 01:07:56,720 TYPE. CAN YOU TRULY DEFINE IT 1459 01:07:56,720 --> 01:07:57,240 BY THE EXISTING SET OF 1460 01:07:57,240 --> 01:07:58,280 CYTOMETRY MARKERS? HOW WELL 1461 01:07:58,280 --> 01:08:00,040 DOES IT MATCH? THAT IS A BIG 1462 01:08:00,040 --> 01:08:02,640 CHALLENGE. DOES NOT MATCH 1463 01:08:02,640 --> 01:08:05,240 NECESSARILY RIGHT NOW. 1464 01:08:05,240 --> 01:08:05,800 EVEN MORE SO YOU CAN TALK 1465 01:08:05,800 --> 01:08:10,160 ABOUT THE SET OF MARKERS THAT 1466 01:08:10,160 --> 01:08:10,640 MATCH IT IN PARTICULAR 1467 01:08:10,640 --> 01:08:13,600 CONDITION SUCH AS HOMEOSTATIC 1468 01:08:13,600 --> 01:08:14,080 ONE; BUT ONCE YOU HAVE 1469 01:08:14,080 --> 01:08:17,600 INFLAMMATION AS YOU MENTIONED 1470 01:08:17,600 --> 01:08:19,960 SOME OF THE SURFACE MARKERS CAN 1471 01:08:19,960 --> 01:08:21,480 BEGIN TO LOSE EVEN BEFORE THE 1472 01:08:21,480 --> 01:08:26,440 (INDISCERNIBLE) CHANGES. 1473 01:08:26,440 --> 01:08:32,760 YESTERDAY IN THE TALK, THEY 1474 01:08:32,760 --> 01:08:33,360 START UP REGULATING SOME OF THE 1475 01:08:33,360 --> 01:08:33,920 MARKERS AND LOSING OTHERS 1476 01:08:33,920 --> 01:08:34,560 BEFORE THE GLOBALLY CHANGE OUR 1477 01:08:34,560 --> 01:08:35,800 FROM THE NAïVE CELLS. AND THE 1478 01:08:35,800 --> 01:08:36,400 FIRST STEP IN MATCHING THE 1479 01:08:36,400 --> 01:08:41,120 EXISTING SINGLE CELL RNA DATA, 1480 01:08:41,120 --> 01:08:41,680 IDEALLY I WOULD SAY SINGLE 1481 01:08:41,680 --> 01:08:45,040 CELLED RNA DATA SUCH AS IN -- 1482 01:08:45,040 --> 01:08:50,600 PAPER WAS DONE. AND MATCHING 1483 01:08:50,600 --> 01:08:53,080 THE STATES TO DATING STRATEGIES 1484 01:08:53,080 --> 01:08:53,560 THAT WOULD BE IDEALLY 1485 01:08:53,560 --> 01:08:56,280 POPULATING. IT IS A HUGE 1486 01:08:56,280 --> 01:08:57,240 CHALLENGE AND I WANTED TO 1487 01:08:57,240 --> 01:09:00,120 UNDERSCORE THAT. THANK YOU. 1488 01:09:00,120 --> 01:09:05,640 >>I WOULD AGREE WITH THAT. I 1489 01:09:05,640 --> 01:09:06,200 DON'T THINK THAT THERE IS A 1490 01:09:06,200 --> 01:09:06,800 NEED TO SAY-- I AM NOT QUITE 1491 01:09:06,800 --> 01:09:07,960 SURE THAT WE ARE AT THAT POINT 1492 01:09:07,960 --> 01:09:08,560 THAT WE CAN DEFINE THAT THERE 1493 01:09:08,560 --> 01:09:09,800 IS ONE GOAL STANDARD WAY TO 1494 01:09:09,800 --> 01:09:13,160 GROUP THEM ALL. RATHER I THINK 1495 01:09:13,160 --> 01:09:20,040 THEY ALL PROVIDE IMPORTANT AND 1496 01:09:20,040 --> 01:09:23,360 COMPLEMENTARY DATA. 1497 01:09:23,360 --> 01:09:23,920 THE TRANSCRIPTION OF DATA IS 1498 01:09:23,920 --> 01:09:30,480 IMPORTANT. WE HAVE 1499 01:09:30,480 --> 01:09:31,120 (INDISCERNIBLE), AT THE END OF 1500 01:09:31,120 --> 01:09:31,720 THE DAY A LOT OF WHAT WE ARE 1501 01:09:31,720 --> 01:09:32,240 TALKING ABOUT IS PROTEIN 1502 01:09:32,240 --> 01:09:34,440 INTERACTION. AND DOES REQUIRE 1503 01:09:34,440 --> 01:09:36,320 PROTEINS. SO THEY ALL GIVE US 1504 01:09:36,320 --> 01:09:39,600 IMPORTANT IDEAS, AND IMPORTANT 1505 01:09:39,600 --> 01:09:41,280 LENSES, AND WE ALSO KNOW THESE 1506 01:09:41,280 --> 01:09:45,000 IMMUNE CELLS OR MORE OF THE 1507 01:09:45,000 --> 01:09:51,120 SPECTRUM. RIGHT? 1508 01:09:51,120 --> 01:09:51,720 >>I SUPPOSE MY COMMENT AT THIS 1509 01:09:51,720 --> 01:09:53,120 POINT WOULD BE RECOGNIZING THAT 1510 01:09:53,120 --> 01:09:57,680 MANUSCRIPT ARE PDF IN THE 1511 01:09:57,680 --> 01:10:01,920 COMPUTER AND OFTEN TIMES 1512 01:10:01,920 --> 01:10:02,440 SCIENTISTS THAT TRY TO 1513 01:10:02,440 --> 01:10:04,560 INCORPORATE WHAT THE LAB HAS 1514 01:10:04,560 --> 01:10:05,200 PUBLISHED CAN HAVE DIFFICULTIES 1515 01:10:05,200 --> 01:10:06,720 LOOKING AT THE HEAT MAP OR 1516 01:10:06,720 --> 01:10:10,440 EXPORTING EXCEL FILES. SO 1517 01:10:10,440 --> 01:10:14,200 PIPELINES THAT GET SINGLE CELL 1518 01:10:14,200 --> 01:10:19,080 RNA SEQUENCING TO THE PUBLIC ON 1519 01:10:19,080 --> 01:10:22,480 WEB-BASED PLATFORMS WOULD BE 1520 01:10:22,480 --> 01:10:23,120 HELPFUL; IN A WAY THAT YOU CAN 1521 01:10:23,120 --> 01:10:23,640 SEARCH FOR YOUR GENE OF 1522 01:10:23,640 --> 01:10:24,200 INTEREST OR YOUR PATHWAY OF 1523 01:10:24,200 --> 01:10:26,480 INTEREST. I KNOW THERE'S SOME 1524 01:10:26,480 --> 01:10:27,160 REALLY NICE ONES OUT THERE THAT 1525 01:10:27,160 --> 01:10:33,160 CAN BE USED TO SORT OF HAVE AS 1526 01:10:33,160 --> 01:10:34,320 A BACKDROP AND HOW TO SET THAT 1527 01:10:34,320 --> 01:10:38,720 UP. MAYBE. ANY FINAL COMMENTS 1528 01:10:38,720 --> 01:10:43,040 FROM OUR SPEAKERS? 1529 01:10:43,040 --> 01:10:43,640 WELL THANK YOU VERY MUCH FOR A 1530 01:10:43,640 --> 01:10:50,880 REALLY NICE SESSION. AND -- WE 1531 01:10:50,880 --> 01:11:01,480 WILL NOW TAKE A 15-MINUTE BREK 1532 01:11:01,480 --> 01:11:05,000 >>I WOULD LIKE 1533 01:11:05,000 --> 01:11:11,240 TO INTRODUCE DR. LAUREN -- FROM 1534 01:11:11,240 --> 01:11:11,880 THE UNIVERSITY OF MINNESOTA WHO 1535 01:11:11,880 --> 01:11:14,240 WILL BE TALKING TO US ABOUT THE 1536 01:11:14,240 --> 01:11:19,800 ROLE OF -- CELLS IN AGE-RELATED 1537 01:11:19,800 --> 01:11:20,440 DISEASES AND WE ARE VERY HAPPY 1538 01:11:20,440 --> 01:11:22,880 TO HAVE HER WITH US BECAUSE SHE 1539 01:11:22,880 --> 01:11:23,960 HAS BEEN FIGHTING A BUG AND SHE 1540 01:11:23,960 --> 01:11:25,000 HAS BEEN VERY KIND TO BE 1541 01:11:25,000 --> 01:11:34,680 PRESENT. THANK YOU LAURA. 1542 01:11:34,680 --> 01:11:40,480 >>THANK YOU VERY MUCH. IT IS 1543 01:11:40,480 --> 01:11:41,080 APPROVERS TO BE HEARD FROM AN 1544 01:11:41,080 --> 01:11:45,000 AGING PERSPECTIVE. I AM NOT AN 1545 01:11:45,000 --> 01:11:45,640 IMMUNOLOGIST BUT I LOOK FORWARD 1546 01:11:45,640 --> 01:11:47,680 TO COLLABORATING WITH YOU. 1547 01:11:47,680 --> 01:11:48,880 I WANT TO CONGRATULATE THE 1548 01:11:48,880 --> 01:11:52,680 MEETING'S ORGANIZER. THIS IS 1549 01:11:52,680 --> 01:11:53,280 BEEN AN EXCEPTIONAL COLLECTION 1550 01:11:53,280 --> 01:11:53,920 OF DIVERSE TOPICS COMING 1551 01:11:53,920 --> 01:11:54,560 TOGETHER THAT ARE REALLY GOING 1552 01:11:54,560 --> 01:11:55,960 TO BE IMPACTFUL. THANK YOU 1553 01:11:55,960 --> 01:12:01,360 VERY MUCH. 1554 01:12:01,360 --> 01:12:02,640 I DID ADD INFLAMMATION TO MY 1555 01:12:02,640 --> 01:12:10,480 TITLE. I AM SHOCKED THAT 1556 01:12:10,480 --> 01:12:11,080 SENESCENT CELLS HAVE NOT BEEN 1557 01:12:11,080 --> 01:12:11,640 FORMALLY INTRODUCED AT THIS 1558 01:12:11,640 --> 01:12:12,760 MEETING YET. I AM SURE MANY OF 1559 01:12:12,760 --> 01:12:16,760 YOU ARE FAMILIAR WITH SENESCENT 1560 01:12:16,760 --> 01:12:23,960 CELLS. 1561 01:12:23,960 --> 01:12:24,560 THERE IS A SET OF FACTORS BOTH 1562 01:12:24,560 --> 01:12:25,160 INTRINSIC AND ENDOGENOUS THAT 1563 01:12:25,160 --> 01:12:31,720 CAN TRIGGER SENESCENT CELLS. WE 1564 01:12:31,720 --> 01:12:32,320 NEED TO ARREST THIS IN ORDER TO 1565 01:12:32,320 --> 01:12:32,880 DUPLICATE CELLS THAT ARE 1566 01:12:32,880 --> 01:12:33,440 STRESSED OR DAMAGE. 1567 01:12:33,440 --> 01:12:36,760 SO HALLMARK FEATURES OF 1568 01:12:36,760 --> 01:12:39,800 SENESCENT CELLS ARE UP 1569 01:12:39,800 --> 01:12:50,240 REGULATION OF P53, P21, P16, SO 1570 01:12:50,240 --> 01:12:52,040 THAT WILL STABLY ARREST THE 1571 01:12:52,040 --> 01:12:52,640 CELLS ANOTHER HALLMARK GENOME 1572 01:12:52,640 --> 01:12:53,280 IS THERE IS ALWAYS EVIDENCE OF 1573 01:12:53,280 --> 01:12:55,600 GENE OF TOXIC STRESS. DOES NOT 1574 01:12:55,600 --> 01:12:56,200 HAVE TO BE AN INSTIGATOR BUT 1575 01:12:56,200 --> 01:13:06,720 YOU END UP WITH TELOMERE AND -- 1576 01:13:07,040 --> 01:13:08,120 OTHER EVIDENCE OF GENOTOPIC 1577 01:13:08,120 --> 01:13:17,360 STRESS. 1578 01:13:17,360 --> 01:13:17,800 THERE IS MITOCHONDRIAL 1579 01:13:17,800 --> 01:13:19,440 CHANGES, TYPICALLY DNA IN THE 1580 01:13:19,440 --> 01:13:23,360 CELLS AND OF COURSE THE 1581 01:13:23,360 --> 01:13:27,480 SENESCENT ASSOCIATED PHENOTYPE, 1582 01:13:27,480 --> 01:13:28,080 THERE'S A NUMBER OF FACTORS 1583 01:13:28,080 --> 01:13:28,520 LISTED HERE MOSTLY 1584 01:13:28,520 --> 01:13:29,280 PRO-INFLAMMATORY BUT ALSO 1585 01:13:29,280 --> 01:13:32,440 INCLUDING A LOT OF PROTEASES, 1586 01:13:32,440 --> 01:13:34,760 AND THINGS THAT CAN MANIPULATE 1587 01:13:34,760 --> 01:13:35,480 THE EXTERNAL ENVIRONMENT OF 1588 01:13:35,480 --> 01:13:40,120 THESE CELLS. THESE ARE VERY 1589 01:13:40,120 --> 01:13:40,640 TISSUE DISRUPTING, AND 1590 01:13:40,640 --> 01:13:42,160 PRO-INFLAMMATORY CELLS. 1591 01:13:42,160 --> 01:13:47,600 THE IDEA IS THAT THIS -- 1592 01:13:47,600 --> 01:13:48,200 ATTRACTS THE IMMUNE SYSTEM TO 1593 01:13:48,200 --> 01:13:50,280 TRY AND COME AND CLEAR THE 1594 01:13:50,280 --> 01:13:52,200 CELLS, BECAUSE THEY ARE 1595 01:13:52,200 --> 01:13:52,840 RESISTANT OR REALLY DON'T LIKE 1596 01:13:52,840 --> 01:13:56,240 TO UNDERGO APOPTOSIS AT ALL SO 1597 01:13:56,240 --> 01:13:57,200 WE COUNT ON THE IMMUNE SYSTEM 1598 01:13:57,200 --> 01:13:59,320 GETTING RID OF THE SENESCENT 1599 01:13:59,320 --> 01:14:03,480 CELLS. 1600 01:14:03,480 --> 01:14:04,080 ANOTHER POINT THAT I WANT TO 1601 01:14:04,080 --> 01:14:08,080 MAKE ABOUT THIS IS THAT THEY 1602 01:14:08,080 --> 01:14:11,120 ARE EXTREMELY HETEROGENEOUS. 1603 01:14:11,120 --> 01:14:11,720 THAT IS NOT A SINGLE THING ON 1604 01:14:11,720 --> 01:14:15,720 THE SLIDE THAT IS UNIQUE TO 1605 01:14:15,720 --> 01:14:16,240 SENESCENT CELLS SO YOU 1606 01:14:16,240 --> 01:14:16,840 OBLIGATED TO MEASURE THREE OR 1607 01:14:16,840 --> 01:14:17,400 FOUR ENDPOINTS TO DECLARE A 1608 01:14:17,400 --> 01:14:21,760 CELL SENESCENT. 1609 01:14:21,760 --> 01:14:22,360 THIS IS USUALLY A TRANSCRIPT 1610 01:14:22,360 --> 01:14:23,320 LIKE A CELL REGULATOR, EVIDENCE 1611 01:14:23,320 --> 01:14:26,680 OF DNA DAMAGE, AND LYSOSOMAL 1612 01:14:26,680 --> 01:14:29,880 ACTIVITY. SO BE VERY CAUTIOUS 1613 01:14:29,880 --> 01:14:30,440 WHEN YOU'RE LOOKING AT THE 1614 01:14:30,440 --> 01:14:32,960 LITERATURE AND YOU SEE OH, P16 1615 01:14:32,960 --> 01:14:35,760 POSITIVE CELLS, THESE ARE ALL 1616 01:14:35,760 --> 01:14:41,280 SENESCENT. THAT IS NOT 1617 01:14:41,280 --> 01:14:45,840 ADEQUATE SO PAY ATTENTION. 1618 01:14:45,840 --> 01:14:46,320 IT IS THOUGHT THAT THE 1619 01:14:46,320 --> 01:14:46,840 MICROENVIRONMENT AND CELL 1620 01:14:46,840 --> 01:14:47,360 LINEAGE WILL IMPACT THE 1621 01:14:47,360 --> 01:14:49,320 PHENOTYPE OF THE SENESCENT 1622 01:14:49,320 --> 01:14:53,040 CELL. SO THERE IS A HUGE 1623 01:14:53,040 --> 01:14:57,800 CONSORTIUM TO TRY TO 1624 01:14:57,800 --> 01:14:58,400 CHARACTERIZE THIS ACROSS 18 1625 01:14:58,400 --> 01:15:00,000 TISSUES THE FULL LIFE SPAN OF 1626 01:15:00,000 --> 01:15:00,600 HUMANS AND MICE AND WE HAVE OUR 1627 01:15:00,600 --> 01:15:03,200 WORK CUT OUT FOR US. 1628 01:15:03,200 --> 01:15:03,800 THE OTHER POINT THAT I WANTED 1629 01:15:03,800 --> 01:15:04,400 TO MAKE IS WHAT FASCINATES ME 1630 01:15:04,400 --> 01:15:06,480 ABOUT SENESCENT CELLS COMING 1631 01:15:06,480 --> 01:15:08,240 FROM THE PERSPECTIVE OF AGING, 1632 01:15:08,240 --> 01:15:11,960 IT REALLY GIVES AN OPPORTUNITY 1633 01:15:11,960 --> 01:15:12,600 TO THINK ABOUT OKAY THERE IS A 1634 01:15:12,600 --> 01:15:20,080 DAMAGE AND A STRESSED CELL. I 1635 01:15:20,080 --> 01:15:20,600 COME FROM A BAKKEN OF DNA 1636 01:15:20,600 --> 01:15:21,160 DAMAGE AND REPAIR ANYTHING 1637 01:15:21,160 --> 01:15:21,760 ABOUT THE CELL RESPONDING BY 1638 01:15:21,760 --> 01:15:26,680 CHOOSING A CELL PHATE. THAT IS 1639 01:15:26,680 --> 01:15:33,040 ONLY ONE OF THE CELL. 1640 01:15:33,040 --> 01:15:33,600 IT GIVES THE OPPORTUNITY FOR 1641 01:15:33,600 --> 01:15:34,200 THE PHENOTYPE TO CORRUPT THE 1642 01:15:34,200 --> 01:15:38,000 MICROENVIRONMENT EVEN 1643 01:15:38,000 --> 01:15:38,520 SYSTEMICALLY THROUGH THE 1644 01:15:38,520 --> 01:15:39,160 RELEASE OF THESE STRESS FACTORS 1645 01:15:39,160 --> 01:15:46,040 WE GIVES IT DAMAGED STRESSED 1646 01:15:46,040 --> 01:15:51,680 CELL TO SPREAD THAT. 1647 01:15:51,680 --> 01:15:52,280 THERE IS DEFINITIVE IMAGE THAT 1648 01:15:52,280 --> 01:15:52,920 THERE IS ONE HALLMARK OF AGING 1649 01:15:52,920 --> 01:15:55,520 THAT DOES CAUSE AGING, NOT 1650 01:15:55,520 --> 01:15:56,160 JUST HAPPENS BECAUSE OF AGING 1651 01:15:56,160 --> 01:15:56,720 AND THIS COMES FROM ELEGANT 1652 01:15:56,720 --> 01:15:57,360 WORK IN THE MAYO CLINIC. THEY 1653 01:15:57,360 --> 01:16:05,280 USE THE EPIGENETIC PRICK TO 1654 01:16:05,280 --> 01:16:07,120 PEAL OFF (INDISCERNIBLE) -- 1655 01:16:07,120 --> 01:16:10,840 THEY ALSO ADDED A 1656 01:16:10,840 --> 01:16:12,880 (INDISCERNIBLE) DOMAIN. WHEN 1657 01:16:12,880 --> 01:16:23,320 YOU START ACCUMULATING 1658 01:16:23,880 --> 01:16:24,440 SENESCENT CELLS WITH AGING, IT 1659 01:16:24,440 --> 01:16:27,360 IS NOT UNTIL (INDISCERNIBLE). 1660 01:16:27,360 --> 01:16:37,640 BAKER AND COLLEAGUES 1661 01:16:37,640 --> 01:16:38,200 ORIGINALLY DID THIS IN THE 1662 01:16:38,200 --> 01:16:39,600 PROGENIC MODEL THERE ARE 1663 01:16:39,600 --> 01:16:40,200 DIFFERENT MODELS, THERE IS 1664 01:16:40,200 --> 01:16:40,800 DIFFERENCES WITH ANIMALS THAT 1665 01:16:40,800 --> 01:16:42,200 HAD SENESCENT CELLS VS. THOSE 1666 01:16:42,200 --> 01:16:45,240 THAT DID NOT. 1667 01:16:45,240 --> 01:16:47,440 THEN THEY WENT OUT IN THE WILD. 1668 01:16:47,440 --> 01:16:48,040 THE KEY FIGURE IN THE PAPER 1669 01:16:48,040 --> 01:16:52,160 FOR ME WAS THAT MEDIAN LIFESPAN 1670 01:16:52,160 --> 01:16:58,120 WAS EXTENDED BY CLEARANCE OF 1671 01:16:58,120 --> 01:16:58,720 THE SENESCENT CELLS WHAT THIS 1672 01:16:58,720 --> 01:17:03,320 SAYS TO ME IS THAT ALL CAUSE 1673 01:17:03,320 --> 01:17:10,600 MORTALITY WITH (INDISCERNIBLE). 1674 01:17:10,600 --> 01:17:11,240 SO YOU GET THESE DISEASES THAT 1675 01:17:11,240 --> 01:17:11,840 KILL MICE YOU DO NOT GET THE 1676 01:17:11,840 --> 01:17:12,520 LIFESPAN OF THE SPECIES IN THIS 1677 01:17:12,520 --> 01:17:15,720 CASE. 1678 01:17:15,720 --> 01:17:16,240 THIS IS REALLY IMPORTANT 1679 01:17:16,240 --> 01:17:17,800 BECAUSE IT TIES BACK TO THE 1680 01:17:17,800 --> 01:17:18,360 HYPOTHESIS THAT IF YOU DID 1681 01:17:18,360 --> 01:17:18,840 SOMETHING TO TREAT THE 1682 01:17:18,840 --> 01:17:19,480 FUNDAMENTAL BIOLOGY OF AGING, 1683 01:17:19,480 --> 01:17:25,520 YOU ACTUALLY COULD IMPACT 1684 01:17:25,520 --> 01:17:26,160 HEALTH SPAN AS OPPOSED TO JUST 1685 01:17:26,160 --> 01:17:27,400 EXTENDING LIFESPAN. 1686 01:17:27,400 --> 01:17:30,400 TWO KEY STUDIES IN THE FIELD 1687 01:17:30,400 --> 01:17:34,240 CAME FROM -- LAB. THIS IS FROM 1688 01:17:34,240 --> 01:17:38,480 KRISTIN BURDE, ON A PAPER 1689 01:17:38,480 --> 01:17:39,120 WORKING WITH HIM NOT A FACULTY 1690 01:17:39,120 --> 01:17:40,480 MEMBER AT OHIO STATE 1691 01:17:40,480 --> 01:17:41,760 UNIVERSITY. THAT BUILD THE 1692 01:17:41,760 --> 01:17:43,920 FIRST SENESCENT REPORT AND IT 1693 01:17:43,920 --> 01:17:49,720 TOOK THAT P16 REPORTER AND 1694 01:17:49,720 --> 01:17:52,720 MONITORED MICE AS THEY AGED OUT. 1695 01:17:52,720 --> 01:17:53,160 THIS IS TOTAL BODY 1696 01:17:53,160 --> 01:17:54,400 LUMINESCENCE AND AS YOU CAN SEE 1697 01:17:54,400 --> 01:17:55,040 THERE IS MORE BLUE TO THE RIGHT 1698 01:17:55,040 --> 01:17:58,880 OF THE SCREEN. THE SENESCENT 1699 01:17:58,880 --> 01:17:59,440 CELLS IS THE FIRST EVIDENCE 1700 01:17:59,440 --> 01:18:00,040 THAT THEY DO ACCUMULATE WITH 1701 01:18:00,040 --> 01:18:04,280 AGING. BUT YOU CAN ALSO SEE 1702 01:18:04,280 --> 01:18:07,240 INCREDIBLE HETEROGENEITY; 1703 01:18:07,240 --> 01:18:07,880 SOMETIMES THERE IS EVEN MICE WE 1704 01:18:07,880 --> 01:18:08,520 SEE THE SIGNAL AND THEN HE GOES 1705 01:18:08,520 --> 01:18:09,760 AWAY. THERE IS A LOT OF OTHER 1706 01:18:09,760 --> 01:18:13,600 REASONS TO HAVE P16. 1707 01:18:13,600 --> 01:18:16,080 WHEN YOU GRAPH THE DATA, WHAT 1708 01:18:16,080 --> 01:18:16,680 IS INTRIGUING IS THAT AT THE 1709 01:18:16,680 --> 01:18:17,320 YOUNG AGE YOU SEE ALL THE MICE 1710 01:18:17,320 --> 01:18:19,600 THAT HAD A LOW SIGNAL. BY THE 1711 01:18:19,600 --> 01:18:20,320 TIME YOU GET OUT TO THE MIDDLE 1712 01:18:20,320 --> 01:18:21,960 AGE HERE, YOU SEE THE 1713 01:18:21,960 --> 01:18:23,040 INCREDIBLE HETEROGENEITY IN THE 1714 01:18:23,040 --> 01:18:25,240 SIGNAL. THIS IS WHAT WE HAVE 1715 01:18:25,240 --> 01:18:26,360 TO DEAL WITH. 1716 01:18:26,360 --> 01:18:32,240 THERE ARE SENESCENT CELLS 1717 01:18:32,240 --> 01:18:35,880 ACCUMULATING WITH AGING BUT 1718 01:18:35,880 --> 01:18:36,520 VERY HETEROGENEOUS, HOW DO YOU 1719 01:18:36,520 --> 01:18:37,120 ACCOMMODATE WHEN YOU THINK 1720 01:18:37,120 --> 01:18:40,560 ABOUT ALL OF THE SENESCENT 1721 01:18:40,560 --> 01:18:43,520 CELLS IN IMMUNE REGULATION FOR 1722 01:18:43,520 --> 01:18:43,880 EXAMPLE? 1723 01:18:43,880 --> 01:18:44,440 THIS IS A GRAPH LOOKING AT 1724 01:18:44,440 --> 01:18:47,160 HUMAN AGE. WHAT IS THE LEVEL OF 1725 01:18:47,160 --> 01:18:53,640 P16? THIS IS NOW IN CD3+ CELLS. 1726 01:18:53,640 --> 01:18:56,120 BUT I WANT TO POINT OUT HERE 1727 01:18:56,120 --> 01:18:57,280 IS THAT SENESCENT CELLS ON 1728 01:18:57,280 --> 01:18:58,600 AVERAGE GO UP LOGARITHMICALLY 1729 01:18:58,600 --> 01:19:01,240 EVERY DECADE OF YOUR LIFE. BUT 1730 01:19:01,240 --> 01:19:07,200 AGAIN INCREDIBLE HETEROGENEITY. 1731 01:19:07,200 --> 01:19:07,760 AND SO WHAT I WANT TO SAY IS 1732 01:19:07,760 --> 01:19:15,120 WE HAVE TO ACCOMMODATE THE 1733 01:19:15,120 --> 01:19:15,720 METHOD IMMUNE CELLS ANOTHER 1734 01:19:15,720 --> 01:19:16,360 METHODS IN OUR STUDY WHICH GOES 1735 01:19:16,360 --> 01:19:17,240 UP IN OUR AGE. 1736 01:19:17,240 --> 01:19:17,760 ON TOP OF THAT THEY ARE 1737 01:19:17,760 --> 01:19:22,240 MODIFIABLE THE LEVEL OF P16 IN 1738 01:19:22,240 --> 01:19:22,840 THE PERIPHERY SO IF YOU'RE A 1739 01:19:22,840 --> 01:19:23,640 SMOKER THE CURVE GOES UP, IF 1740 01:19:23,640 --> 01:19:27,080 YOU EXERCISE THE CURVE GOES UP. 1741 01:19:27,080 --> 01:19:27,680 THIS IS AGAIN ADDING ANOTHER 1742 01:19:27,680 --> 01:19:31,080 LAYER OF HETEROGENEITY. 1743 01:19:31,080 --> 01:19:32,360 SO THIS IS THE MODEL SYSTEM 1744 01:19:32,360 --> 01:19:33,280 THAT WE USE, I WANT TO 1745 01:19:33,280 --> 01:19:36,680 INTRODUCE THIS BRIEFLY TO YOU. 1746 01:19:36,680 --> 01:19:37,280 THIS IS WANT TO START WHEN I 1747 01:19:37,280 --> 01:19:38,600 WAS A POSTDOCTORAL FELLOW. WE 1748 01:19:38,600 --> 01:19:46,000 FOUND A NOVEL HUMAN PROGEROID 1749 01:19:46,000 --> 01:19:49,240 SYNDROME THAT IS IS CAUSED BY A 1750 01:19:49,240 --> 01:19:49,760 DEFECT THAT LEADS TO THE 1751 01:19:49,760 --> 01:19:52,760 DISEASE WERE DEVELOPMENT IS 1752 01:19:52,760 --> 01:19:53,400 PERFECTLY NORMAL BUT WITHIN THE 1753 01:19:53,400 --> 01:19:55,720 SECOND DECADE OF LIFE, THESE 1754 01:19:55,720 --> 01:19:56,240 INDIVIDUALS ACCUMULATIVE 1755 01:19:56,240 --> 01:19:56,800 VIRTUALLY EVERY AGE-RELATED 1756 01:19:56,800 --> 01:20:00,680 DISEASE. I HAVE TO SAY 1757 01:20:00,680 --> 01:20:01,200 INCREDIBLY WE DON'T KNOW 1758 01:20:01,200 --> 01:20:01,840 ANYTHING ABOUT THE IMMUNE 1759 01:20:01,840 --> 01:20:02,400 SYSTEM IN THESE PATIENTS AT 1760 01:20:02,400 --> 01:20:05,040 THIS POINT. 1761 01:20:05,040 --> 01:20:05,640 A LITTLE BIT MORE ABOUT THIS 1762 01:20:05,640 --> 01:20:09,080 ENDONUCLEASE. BOTH GENES 1763 01:20:09,080 --> 01:20:12,280 CREATE A PROTEIN THAT MUST 1764 01:20:12,280 --> 01:20:13,240 HETERODYMERIZE (PHONETIC) IN 1765 01:20:13,240 --> 01:20:16,320 VIVO. AND THEY REPAIR THE 1766 01:20:16,320 --> 01:20:17,720 NUCLEASE. IT TURNS OUT THAT IF 1767 01:20:17,720 --> 01:20:24,200 YOU KNOCKOUT EITHER GENE YOU 1768 01:20:24,200 --> 01:20:27,680 LOSE ALL ENZYME AND SO IN THE 1769 01:20:27,680 --> 01:20:28,280 MICE WE ARE ABOUT TO SHOW YOU 1770 01:20:28,280 --> 01:20:29,520 WE ASCRIBE THIS TO A LOSS OF 1771 01:20:29,520 --> 01:20:30,600 THE ENZYME AND DNA REPAIR 1772 01:20:30,600 --> 01:20:32,560 CAPACITY. 1773 01:20:32,560 --> 01:20:33,240 IT TURNS OUT THIS IS A 1774 01:20:33,240 --> 01:20:36,000 PROMISCUOUS ENZYME. IT IS 1775 01:20:36,000 --> 01:20:36,640 INVOLVED IN MULTIPLE DIFFERENT 1776 01:20:36,640 --> 01:20:42,240 REPAIR PATHWAYS. AND THE OTHER 1777 01:20:42,240 --> 01:20:42,840 POINT I WOULD LIKE TO MAKE 1778 01:20:42,840 --> 01:20:43,400 ABOUT THE ENZYME IS WE ONLY 1779 01:20:43,400 --> 01:20:46,080 FIND IT IN THE NUCLEI. SO ALL 1780 01:20:46,080 --> 01:20:48,360 OF THE PHENOTYPES THAT YOU SEE 1781 01:20:48,360 --> 01:20:49,520 AGAIN WE ASCRIBED TO FAILURE TO 1782 01:20:49,520 --> 01:20:51,920 PROTECT THE NUCLEAR GENOME FROM 1783 01:20:51,920 --> 01:20:55,040 ENDOGENOUS DNA DAMAGE. WE 1784 01:20:55,040 --> 01:20:55,640 NEVER REALLY TREAT OUR MICE 1785 01:20:55,640 --> 01:21:00,160 WITH ANYTHING. IT IS JUST 1786 01:21:00,160 --> 01:21:00,800 ENDOGENOUS DNA DAMAGE THEY ARE 1787 01:21:00,800 --> 01:21:03,080 GRAPPLING WITH. 1788 01:21:03,080 --> 01:21:04,000 THIS IS A MOUSE MODEL WE MADE 1789 01:21:04,000 --> 01:21:14,520 CREATED BY (INDISCERNIBLE)-- A 1790 01:21:15,840 --> 01:21:21,000 HYPOMORPHIC ALEAL. IN MICE THE 1791 01:21:21,000 --> 01:21:23,280 ANIMALS ACTUALLY AS ADULTS HAVE 1792 01:21:23,280 --> 01:21:23,880 BEEN QUITE HEALTHY AND IN THE 1793 01:21:23,880 --> 01:21:27,160 FALL APART VERY QUICKLY. AND 1794 01:21:27,160 --> 01:21:27,800 SPONTANEOUSLY DEVELOP VIRTUALLY 1795 01:21:27,800 --> 01:21:32,120 EVERY AGE-RELATED DISEASE YOU 1796 01:21:32,120 --> 01:21:35,560 CAN IMAGINE. LIKE CANCER IN 1797 01:21:35,560 --> 01:21:36,920 THEIR SIX OR SEVEN MONTH 1798 01:21:36,920 --> 01:21:40,800 LIFESPAN. AND THEY ALSO 1799 01:21:40,800 --> 01:21:42,360 DEVELOP THERAPIES THAT TARGET 1800 01:21:42,360 --> 01:21:45,640 SENESCENT CELLS. 1801 01:21:45,640 --> 01:21:46,200 IF YOU IMPORTANT POINT ABOUT 1802 01:21:46,200 --> 01:21:48,320 ANIMALS. THEY DO ACTUALLY 1803 01:21:48,320 --> 01:21:54,360 ACCUMULATING EXCESSIVE OXIDATE 1804 01:21:54,360 --> 01:21:56,160 ENDOGENOUS DNA DAMAGE AND YOU 1805 01:21:56,160 --> 01:22:00,000 SEE THESE VERY ELEGANT BASED 1806 01:22:00,000 --> 01:22:01,120 ASSAYS TO MEASURE LOW ABUNDANCE 1807 01:22:01,120 --> 01:22:05,000 OXIDATIVE SOLUTION. THESE 1808 01:22:05,000 --> 01:22:06,520 REQUIRE (INDISCERNIBLE) FOR 1809 01:22:06,520 --> 01:22:10,640 REPAIR. AND IT IS MEASURED IN 1810 01:22:10,640 --> 01:22:13,800 TISSUES THAT ARE MICE. 1811 01:22:13,800 --> 01:22:14,320 THIS HISTOGRAM SHOWS THE 1812 01:22:14,320 --> 01:22:19,960 CUMULATIVE TOTAL OF THE LESION 1813 01:22:19,960 --> 01:22:21,640 AND RENAL TISSUE. 1814 01:22:21,640 --> 01:22:25,960 IMMUNE ANIMALS ARE IN RED. WE 1815 01:22:25,960 --> 01:22:26,560 FOUND THAT IN EARLY 80S WHEN 1816 01:22:26,560 --> 01:22:27,840 THE MICE DO NOT HAVE GENOTYPE 1817 01:22:27,840 --> 01:22:33,400 THE LEVELS OF THESE OXIDATIVE 1818 01:22:33,400 --> 01:22:34,000 DNA LESIONS ARE NOT ELEVATED 1819 01:22:34,000 --> 01:22:34,600 BUT BY THE TIME THEY ARE OLD 1820 01:22:34,600 --> 01:22:35,120 THEY ARE SIGNIFICANTLY 1821 01:22:35,120 --> 01:22:35,520 ELEVATED. 1822 01:22:35,520 --> 01:22:37,440 THIS IS THE MOST IMPORTANT BAR 1823 01:22:37,440 --> 01:22:43,800 IN THIS GRAPH. THIS IS WILD 1824 01:22:43,800 --> 01:22:47,800 TYPE MICE A TWO AND HALF YEARS. 1825 01:22:47,800 --> 01:22:48,360 EVEN IF YOUR ARE FULLY DNA 1826 01:22:48,360 --> 01:22:48,840 REPAIR COMPETENT YOUR 1827 01:22:48,840 --> 01:22:50,680 COMMUNITIES ACTIVATED DNA 1828 01:22:50,680 --> 01:22:51,320 LESIONS WITH AGING AND THEY CAN 1829 01:22:51,320 --> 01:22:51,960 BE DETECTED IN HUMAN SAMPLES AS 1830 01:22:51,960 --> 01:22:56,840 WELL. 1831 01:22:56,840 --> 01:22:57,320 WHAT WE THINK IS WHAT IS 1832 01:22:57,320 --> 01:22:57,880 HAPPENING IN OUR MICE IS A 1833 01:22:57,880 --> 01:22:58,400 COMPRESSION OF WHAT IS 1834 01:22:58,400 --> 01:22:59,280 HAPPENING WITH NORMAL AGING. 1835 01:22:59,280 --> 01:23:01,960 IT IS VERY SIMILAR AT THE LEVEL 1836 01:23:01,960 --> 01:23:05,440 OF SENESCENT. THIS IS A 1837 01:23:05,440 --> 01:23:11,560 HISTOGRAM, P16 MRNA LEVELS IN 1838 01:23:11,560 --> 01:23:12,160 TISSUES AND ALL WHILE TYPES 1839 01:23:12,160 --> 01:23:14,040 COMPARED TO YOUNG COUNTERPARTS 1840 01:23:14,040 --> 01:23:15,920 AND THEN OUR MUTANT ANIMALS AT 1841 01:23:15,920 --> 01:23:19,840 4 TO 5 MONTHS OF AGE. 1842 01:23:19,840 --> 01:23:20,400 WHAT WAS SURPRISING TO US IS 1843 01:23:20,400 --> 01:23:21,040 SORT OF THE RANK ORDER OF HIGH 1844 01:23:21,040 --> 01:23:30,000 TO LOW OF P16 LEVELS, VIRTUALLY 1845 01:23:30,000 --> 01:23:30,600 IDENTICAL FOR MUTANT ANIMALS 1846 01:23:30,600 --> 01:23:31,240 COMPARED TO AGING AND ARE MICE 1847 01:23:31,240 --> 01:23:34,520 NEVER EXCEED THE LEVELS OF 1848 01:23:34,520 --> 01:23:36,280 SENESCENTS THAT OCCUR WITH 1849 01:23:36,280 --> 01:23:36,920 NORMAL AGING. WE DID THIS WITH 1850 01:23:36,920 --> 01:23:37,920 A NUMBER OF DIFFERENT MARKERS 1851 01:23:37,920 --> 01:23:41,880 FOR SENESCENT CELLS; OUR MICE 1852 01:23:41,880 --> 01:23:43,240 AGAIN ARE EXPERIENCING 1853 01:23:43,240 --> 01:23:47,480 SENESCENT AT 4-5 MONTHS AS 1854 01:23:47,480 --> 01:23:52,160 OPPOSED TO TWO AND HALF YEARS. 1855 01:23:52,160 --> 01:23:52,760 THESE AGAIN HAVE BEEN VALUABLE 1856 01:23:52,760 --> 01:23:54,320 FOR TESTING DRUGS TO TARGET 1857 01:23:54,320 --> 01:23:57,000 SENESCENT CELLS. WHAT WE HAVE 1858 01:23:57,000 --> 01:23:59,960 BEEN UP TO SINCE THEN HAS 1859 01:23:59,960 --> 01:24:02,280 REALLY BEEN TO ASK WHICH TYPE 1860 01:24:02,280 --> 01:24:02,920 OF SENESCENT CELLS ARE THE MOST 1861 01:24:02,920 --> 01:24:05,800 DELETERIOUS? THE REASON I'M 1862 01:24:05,800 --> 01:24:06,400 HERE TODAY IS BECAUSE OF THE 1863 01:24:06,400 --> 01:24:09,480 IMMUNE CELL. THE WAY WE HAVE 1864 01:24:09,480 --> 01:24:10,120 BEEN TACKLING THIS IS WE HAVE 1865 01:24:10,120 --> 01:24:20,160 BEEN DELETING ERRC1 IN ONE 1866 01:24:20,160 --> 01:24:20,840 TISSUE OR ANOTHER TO UNDERSTAND 1867 01:24:20,840 --> 01:24:24,040 THIS. IN EVERY SINGLE CASE WE 1868 01:24:24,040 --> 01:24:29,720 END UP WITH AN AGE-RELATED 1869 01:24:29,720 --> 01:24:35,760 DISEASE OF THE TARGETED TISSUE. 1870 01:24:35,760 --> 01:24:36,280 SUPPORTS THE NOTION THAT 1871 01:24:36,280 --> 01:24:36,880 ENDOGENOUS DNA DAMAGE IS AN 1872 01:24:36,880 --> 01:24:37,720 IMPORTANT DRIVER OF AGING. AND 1873 01:24:37,720 --> 01:24:38,360 NOW WE ARE LOOKING AT SPECIFIC 1874 01:24:38,360 --> 01:24:40,520 CELL TYPES. 1875 01:24:40,520 --> 01:24:41,120 I WANT TO HIDE IN THREE IT IS 1876 01:24:41,120 --> 01:24:44,360 VERY QUICKLY. MYOCITES, B-CELLS 1877 01:24:44,360 --> 01:24:47,760 AND (INDISCERNIBLE). ONE OF 1878 01:24:47,760 --> 01:24:50,200 THE FIRST MODELS WE MADE WAS WE 1879 01:24:50,200 --> 01:24:57,080 DELETED ERCC1 IN DIFFERENT 1880 01:24:57,080 --> 01:24:57,680 MYOCITES WE SAW THAT THE MICE 1881 01:24:57,680 --> 01:25:00,800 DIED VERY PREMATURELY. IT 1882 01:25:00,800 --> 01:25:03,640 TURNED OUT THAT IT WAS FROM 1883 01:25:03,640 --> 01:25:04,240 DILATED CARDIOMYOPATHY. WHAT IS 1884 01:25:04,240 --> 01:25:04,840 IMPORTANT TO KNOW IS HERE'S A 1885 01:25:04,840 --> 01:25:12,520 MUTANT ANIMAL. THE PARCEL 1886 01:25:12,520 --> 01:25:22,840 PERFECTLY FINE AT A YOUNG AGE. 1887 01:25:22,840 --> 01:25:23,400 BUT BY 4-5 MONTHS OF AGE TO 1888 01:25:23,400 --> 01:25:23,960 HAVE DILATED VENTRICLES. WE 1889 01:25:23,960 --> 01:25:24,440 ARGUED THAT THIS IS A 1890 01:25:24,440 --> 01:25:26,400 DEGENERATIVE DISEASE PROCESS. 1891 01:25:26,400 --> 01:25:27,040 AND THEY HAVE THE HEART FAILURE 1892 01:25:27,040 --> 01:25:27,680 MARKERS AND WHAT IS INTERESTING 1893 01:25:27,680 --> 01:25:29,560 IN THIS MODEL THOUGH, IS WE 1894 01:25:29,560 --> 01:25:31,520 NEVER FOUND THE SENESCENT 1895 01:25:31,520 --> 01:25:35,680 CELLS. AND LIKE EVERYBODY ELSE 1896 01:25:35,680 --> 01:25:36,280 IF YOU GRIND UP IN ALL HEART 1897 01:25:36,280 --> 01:25:41,520 YOU CAN FIND THE SENESCENT 1898 01:25:41,520 --> 01:25:42,160 MARKER BUT I DON'T BELIEVE THAT 1899 01:25:42,160 --> 01:25:52,480 THE DIFFERENT -- 1900 01:25:52,800 --> 01:25:53,360 (INDISCERNIBLE) ANOTHER EXAMPLE 1901 01:25:53,360 --> 01:25:55,560 IS WE DELETED THE ERCC1 IN 1902 01:25:55,560 --> 01:26:03,360 B-CELLS. WE STARTED TO SEE 1903 01:26:03,360 --> 01:26:03,960 IMPAIRED GLUCOSE HOMEOSTASIS; 1904 01:26:03,960 --> 01:26:05,760 IN THE MUTANT ANIMALS ARE IN 1905 01:26:05,760 --> 01:26:10,280 SOLID RED BARS. FASTING GLUCOSE 1906 01:26:10,280 --> 01:26:13,960 ALSO WAS ALTERED. WE FOUND 1907 01:26:13,960 --> 01:26:14,960 THAT WE CHALLENGE THE ANIMAL 1908 01:26:14,960 --> 01:26:25,320 WITH AN ORAL GLUCOSE BULLET, 1909 01:26:25,320 --> 01:26:25,920 THEY HAVE IMPAIRED TOLERANCE 1910 01:26:25,920 --> 01:26:26,520 AND THEY CANNOT BRING SERUM 1911 01:26:26,520 --> 01:26:27,080 GLUCOSE LEVELS BACK DOWN TO 1912 01:26:27,080 --> 01:26:29,200 NORMAL AND THIS IS DUE IN PART. 1913 01:26:29,200 --> 01:26:31,360 THIS IS 15 MINUTES AFTER THE 1914 01:26:31,360 --> 01:26:31,960 ORAL GLUCOSE BULLETIN YOU CAN 1915 01:26:31,960 --> 01:26:36,600 SEE THE AMOUNT OF -- IN MICE. 1916 01:26:36,600 --> 01:26:37,160 CREATES A MODEL OF TYPE II 1917 01:26:37,160 --> 01:26:41,680 DIABETES. 1918 01:26:41,680 --> 01:26:42,280 WHAT IS INTERESTING IS WHEN WE 1919 01:26:42,280 --> 01:26:42,880 LOOK AT THE PERIPHERAL ORGANS 1920 01:26:42,880 --> 01:26:43,480 OF THESE MICE WE SEE A LOT OF 1921 01:26:43,480 --> 01:26:46,160 DAMAGE AS WELL. THE MICE DUES 1922 01:26:46,160 --> 01:26:48,520 CONTINUALLY DEVELOP STEATOSIS, 1923 01:26:48,520 --> 01:26:52,920 AND HAVE LOTS OF MARKERS OF 1924 01:26:52,920 --> 01:26:53,480 SENESCENT, INFLAMMATION AND 1925 01:26:53,480 --> 01:26:55,480 INSULIN RESISTANCE IN THE LIVER 1926 01:26:55,480 --> 01:26:56,080 AS WELL AS IN THE FAT BUT NOT 1927 01:26:56,080 --> 01:26:58,320 THE SKELETAL MUSCLE. 1928 01:26:58,320 --> 01:27:04,560 HERE WE ARE SEEING PERIPHERAL 1929 01:27:04,560 --> 01:27:05,200 SENESCENT, NOT IN THE TARGETED 1930 01:27:05,200 --> 01:27:06,960 CELLS BUT PERIPHERALLY, WHAT 1931 01:27:06,960 --> 01:27:09,360 YOU WOULD EXPECT IN DIABETES. 1932 01:27:09,360 --> 01:27:11,760 WE ARE TRYING TO SEE IF THIS IS 1933 01:27:11,760 --> 01:27:14,240 BECAUSE OF INSULIN RESISTANCE 1934 01:27:14,240 --> 01:27:17,200 OR HIGH GLUCOSE ALL THE TIME. 1935 01:27:17,200 --> 01:27:19,920 WE NEED MORE DATA PAST OUR 1936 01:27:19,920 --> 01:27:22,000 VIEWERS AND ENDOCRINOLOGISTS. 1937 01:27:22,000 --> 01:27:22,480 THIS IS THE ONE YOU ARE 1938 01:27:22,480 --> 01:27:23,600 PROBABLY INTERESTED IN WHEN WE 1939 01:27:23,600 --> 01:27:26,880 HAVE ERCC1 IN HEMATOPOIETIC 1940 01:27:26,880 --> 01:27:34,880 CELLS. THE INDUCED ANIMALS ARE 1941 01:27:34,880 --> 01:27:35,320 IN RED AND THE HAVE A 1942 01:27:35,320 --> 01:27:37,680 PROGRESSIVE LEUKEMIA. WE LOOK 1943 01:27:37,680 --> 01:27:41,960 FOR SENESCENT IN YOUNG ANIMALS 1944 01:27:41,960 --> 01:27:42,520 AND WE DO NOT SEE IT IN THE 1945 01:27:42,520 --> 01:27:43,120 IMMUNE COMPARTMENT. BUT OLDER 1946 01:27:43,120 --> 01:27:46,040 ANIMALS SAY OUT TO ABOUT A YEAR 1947 01:27:46,040 --> 01:27:46,600 THEY SAID TO HAVE ELEVATED 1948 01:27:46,600 --> 01:27:54,480 LEVELS OF P16, P21 AND SOFT 1949 01:27:54,480 --> 01:27:55,120 FACTORS, VERY ANALOGOUS TO WHAT 1950 01:27:55,120 --> 01:27:57,320 HAPPENS IN NORMAL AGING. I 1951 01:27:57,320 --> 01:27:57,920 SHOULD POINT OUT THAT ALL OF 1952 01:27:57,920 --> 01:28:02,400 THESE MICE ARE IN >>F 1 1953 01:28:02,400 --> 01:28:05,080 BACKGROUND. 1954 01:28:05,080 --> 01:28:05,600 WE ARE ACTUALLY LOOKING AT 1955 01:28:05,600 --> 01:28:07,000 PROTEIN LEVELS. 1956 01:28:07,000 --> 01:28:14,560 WHAT WAS SURPRISING IS WE SEE 1957 01:28:14,560 --> 01:28:15,160 SENESCENTS EVERYWHERE IN THE 1958 01:28:15,160 --> 01:28:15,760 SLIDE LOOKING AT SOLID ORGANS 1959 01:28:15,760 --> 01:28:18,240 LOOKING AT ELEVATED LEVELS OF 1960 01:28:18,240 --> 01:28:18,880 P16 IN OTHER MARKETS AND WE USE 1961 01:28:18,880 --> 01:28:21,480 FISH TO SHOW THAT P16 IS 1962 01:28:21,480 --> 01:28:23,880 UPREGULATED IN RENAL EPITHELIAL 1963 01:28:23,880 --> 01:28:27,960 CELLS -- -- NOT JUST IMMUNE 1964 01:28:27,960 --> 01:28:31,080 CELLS IN THESE ORGANS. 1965 01:28:31,080 --> 01:28:33,440 SURPRISINGLY, THIS IS ENOUGH 1966 01:28:33,440 --> 01:28:34,000 TO CAUSE DAMAGE TO MANY OF 1967 01:28:34,000 --> 01:28:39,240 THESE ORGANS. WE SEE ELEVATED 1968 01:28:39,240 --> 01:28:39,840 SERUM-- EXPRESSED IN THERE IS 1969 01:28:39,840 --> 01:28:48,760 LIVER DAMAGE. THERE IS ALSO 1970 01:28:48,760 --> 01:28:49,360 PROTEINURIA IN MY SO THERE IS 1971 01:28:49,360 --> 01:28:49,840 LIVER, RENAL AS WELL AS 1972 01:28:49,840 --> 01:28:57,240 PANCREATIC DAMAGE. THERE ARE 1973 01:28:57,240 --> 01:28:59,480 CHANGES IN GLYCOSAMINOGLYCANS. 1974 01:28:59,480 --> 01:29:04,240 AND ACTUALLY THESE MICE ARE 1975 01:29:04,240 --> 01:29:07,080 SHORT-LIVED, WHEN THEY HAVE A 1976 01:29:07,080 --> 01:29:07,680 REDUCED MAXIMUM LIFESPAN AND 1977 01:29:07,680 --> 01:29:10,600 MEDIAN LIFESPAN. 1978 01:29:10,600 --> 01:29:11,200 THERE IS A LOT OF DAMAGE GOING 1979 01:29:11,200 --> 01:29:11,800 ON IN THESE MICE JUST BECAUSE 1980 01:29:11,800 --> 01:29:15,800 WE GROW THE DNA DAMAGE AND THE 1981 01:29:15,800 --> 01:29:18,240 SENESCENT OF THE IMMUNE 1982 01:29:18,240 --> 01:29:19,680 COMPARTMENT. SOME OF THE CELLS 1983 01:29:19,680 --> 01:29:19,960 DIE. 1984 01:29:19,960 --> 01:29:22,800 WE ARE ACCUSING THE SENESCENT 1985 01:29:22,800 --> 01:29:25,240 CELLS OF WREAKING HAVOC; THE 1986 01:29:25,240 --> 01:29:25,840 WAY TO TEST THIS IS TO ADOPT 1987 01:29:25,840 --> 01:29:27,720 THE TRANSFER AND WE TOOK -- 1988 01:29:27,720 --> 01:29:31,080 FROM MICE AND PUT THEM IN AS 1989 01:29:31,080 --> 01:29:35,680 P16 AND WE SEE ELEVATED SIGNALS 1990 01:29:35,680 --> 01:29:40,720 UP IN THE RECIPIENT MICE. THIS 1991 01:29:40,720 --> 01:29:41,360 GOES UP WITHIN A WEEK AND LASTS 1992 01:29:41,360 --> 01:29:48,640 FOR ABOUT FIVE WEEKS. AND THEN 1993 01:29:48,640 --> 01:29:51,240 (INDISCERNIBLE), AND EVEN 1994 01:29:51,240 --> 01:29:55,120 ELEVATED -- FACTORS AND 1995 01:29:55,120 --> 01:29:55,720 INFORMATION IN THE RECIPIENT 1996 01:29:55,720 --> 01:29:57,200 MICE. 1997 01:29:57,200 --> 01:29:57,760 THE OPPOSITE IS ALSO TRUE 1998 01:29:57,760 --> 01:30:00,880 THOUGH. IT TURNS OUT IF YOU 1999 01:30:00,880 --> 01:30:11,400 TAKE YOUNG PHENOCYTE AND PUT 2000 01:30:16,080 --> 01:30:16,520 IT INTO THE PROGENERATIVE 2001 01:30:16,520 --> 01:30:18,640 ANIMAL -- WHAT IS GOING ON IS 2002 01:30:18,640 --> 01:30:20,800 TWO THINGS. AGAIN A FUNCTION 2003 01:30:20,800 --> 01:30:26,560 WHICH THE FACT WITH THE 2004 01:30:26,560 --> 01:30:27,120 SENESCENT CELLS, AS WELL IS 2005 01:30:27,120 --> 01:30:27,560 LOSS OF FUNCTION WITH 2006 01:30:27,560 --> 01:30:35,200 FUNCTIONAL RED CELLS TO CLEAR 2007 01:30:35,200 --> 01:30:36,240 (INDISCERNIBLE). 2008 01:30:36,240 --> 01:30:40,880 -- -- SO FAR IT LOOKS LIKE 2009 01:30:40,880 --> 01:30:41,480 MACROPHAGES ARE GOING TO HAVE 2010 01:30:41,480 --> 01:30:45,480 THE GREATEST IMPACT. I WOULD 2011 01:30:45,480 --> 01:30:46,080 PREDICT T CELLS ARE GOING TO BE 2012 01:30:46,080 --> 01:30:46,720 IMPORTANT BUT WE ARE BEHIND IN 2013 01:30:46,720 --> 01:30:52,080 STUDYING THESE ANIMALS. CX 2014 01:30:52,080 --> 01:30:57,960 WITH THE 3CR1 PROMOTER, I THINK 2015 01:30:57,960 --> 01:30:58,560 THE MICRO GLIAL ARE GOING TO 2016 01:30:58,560 --> 01:31:05,800 WIN AT THE DOMINANT PHENOTYPE. 2017 01:31:05,800 --> 01:31:06,400 THESE MICE ARE IN HIGH INPUT 2018 01:31:06,400 --> 01:31:09,360 WITH ME IN IF ANYBODY WANTS 2019 01:31:09,360 --> 01:31:10,000 MICE TISSUE TALK TO ME THERE'S 2020 01:31:10,000 --> 01:31:12,040 A LOT OF WORK TO DO. 2021 01:31:12,040 --> 01:31:15,600 IN AN AGED SENESCENT IMMUNE 2022 01:31:15,600 --> 01:31:19,280 SYSTEM CAN DRIVE SENESCENT IN 2023 01:31:19,280 --> 01:31:19,840 TRANS, THE GAIN OR LOSS OF 2024 01:31:19,840 --> 01:31:22,560 FUNCTION MECHANISMS. THIS CELL 2025 01:31:22,560 --> 01:31:26,880 NON-AUTONOMOUS SENESCENT IS 2026 01:31:26,880 --> 01:31:27,480 SIGNIFICANT ENOUGH TO DAMAGE, 2027 01:31:27,480 --> 01:31:28,560 AND IT IS IMPORTANT FOR AGING. 2028 01:31:28,560 --> 01:31:33,040 I WANT TO TELL YOU A COVID 2029 01:31:33,040 --> 01:31:33,600 STORY, WITH A LOT OF GREAT 2030 01:31:33,600 --> 01:31:37,080 COLLABORATION FROM CHRISTINA 2031 01:31:37,080 --> 01:31:39,440 KAMELL (PHONETIC) WHO LED THE 2032 01:31:39,440 --> 01:31:40,040 STUDY BUT IT WAS EARLY IN THE 2033 01:31:40,040 --> 01:31:46,320 PANDEMIC. ONE OF THE THINGS IN 2034 01:31:46,320 --> 01:31:46,920 COMMON OF THOSE AT RISK WITH 2035 01:31:46,920 --> 01:31:49,240 SEVERE OUTCOMES FROM COVID-19 2036 01:31:49,240 --> 01:31:50,040 IS THAT A LOT HAD SENESCENT 2037 01:31:50,040 --> 01:31:59,600 CELLS. WE TAKE YOUR SPF MICE 2038 01:31:59,600 --> 01:32:00,200 AND EXPOSE THEM TO PET STORE 2039 01:32:00,200 --> 01:32:03,560 MICE THIS IS GOING TO, PARADIGM 2040 01:32:03,560 --> 01:32:04,160 EXPOSURE TO NORMAL MICROBIAL 2041 01:32:04,160 --> 01:32:06,920 EXPERIENCE. WHAT WE LEARNED 2042 01:32:06,920 --> 01:32:10,200 VERY QUICKLY TO OUR HORROR, 2043 01:32:10,200 --> 01:32:10,800 YOUNG MICE ARE FINE UPON THIS 2044 01:32:10,800 --> 01:32:17,480 EXPOSURE. BUT OLD MICE ARE 2045 01:32:17,480 --> 01:32:23,040 100% DEAD WITHIN TWO WEEKS. 2046 01:32:23,040 --> 01:32:23,440 IT TURNS OUT THAT BY 2047 01:32:23,440 --> 01:32:26,840 SERENDIPITY THE KILLER IS A 2048 01:32:26,840 --> 01:32:32,440 BETA CORONAVIRUS. WHAT WE FOUND 2049 01:32:32,440 --> 01:32:33,040 IS BEFORE THEY WERE ALL DEAD 2050 01:32:33,040 --> 01:32:35,120 THE ONLY EVIDENCE OF ALL THE 2051 01:32:35,120 --> 01:32:35,680 BUGS SUBMITTED BY THESE PET 2052 01:32:35,680 --> 01:32:37,240 STORE MICE WERE ANTIBODIES 2053 01:32:37,240 --> 01:32:40,760 AGAINST MAC. IT LOOKS LIKE THIS 2054 01:32:40,760 --> 01:32:43,320 BETA CORONAVIRUS WAS HARMFUL TO 2055 01:32:43,320 --> 01:32:53,920 THE NAïVE, OLD, WILD-TYPE MICE. 2056 01:32:54,200 --> 01:32:54,760 YOU CAN SEE THIS IN THE LIVER 2057 01:32:54,760 --> 01:32:55,320 OF THE OLD MICE BUT NOT THE 2058 01:32:55,320 --> 01:32:56,560 YOUNG AND A CRUCIAL EXPERIMENT 2059 01:32:56,560 --> 01:32:58,240 RUN BY THE CENTER OF IMMUNOLOGY 2060 01:32:58,240 --> 01:32:58,880 WAS TO INOCULATE YOUNG AND OLD 2061 01:32:58,880 --> 01:33:05,160 MICE WITH MHC PRIOR TO EXPOSURE 2062 01:33:05,160 --> 01:33:06,320 TO THE PET STORE MICE FOR 2063 01:33:06,320 --> 01:33:06,920 NORMAL MICROBIAL EXPERIENCE AND 2064 01:33:06,920 --> 01:33:11,600 SURE ENOUGH THAT RESCUE, THE 2065 01:33:11,600 --> 01:33:13,200 BLUE LINE, RESCUED ALL OF THE 2066 01:33:13,200 --> 01:33:20,360 ANIMALS WHICH IS THE BETA 2067 01:33:20,360 --> 01:33:20,920 CORONAVIRUS KILLING THE OLD 2068 01:33:20,920 --> 01:33:22,000 MICE AND WE WANTED TO ASK IF 2069 01:33:22,000 --> 01:33:32,280 GETTING RID OF THE SENOLYTIC 2070 01:33:32,280 --> 01:33:35,360 FISINT PROTECTS THE ANIMALS. WE 2071 01:33:35,360 --> 01:33:35,960 STARTED TREATING THE ANIMALS 2072 01:33:35,960 --> 01:33:36,560 AND IN TRANSLATIONAL APPROACH 2073 01:33:36,560 --> 01:33:37,800 AND IN THIS CASE 50% OF THE 2074 01:33:37,800 --> 01:33:41,960 MICE DIED UPON EXPOSURE OF THE 2075 01:33:41,960 --> 01:33:43,560 ENVIRONMENTAL PATHOGEN. 2076 01:33:43,560 --> 01:33:49,160 FISETIN IS A LOPPY DRUGR, 2077 01:33:49,160 --> 01:33:52,000 SENESCENT CELLS SETTING UP 2078 01:33:52,000 --> 01:33:54,360 THESE MICE WERE FAILURE. WE 2079 01:33:54,360 --> 01:33:56,120 DID A COUPLE MORE EXPERIMENTS 2080 01:33:56,120 --> 01:34:00,160 WHERE WE USED THE MAYO CLINIC 2081 01:34:00,160 --> 01:34:04,720 ABLATION OF THE SENESCENT 2082 01:34:04,720 --> 01:34:05,320 CELLS, IT WAS PRETTY GOOD AT 2083 01:34:05,320 --> 01:34:06,160 RESCUING THE MICE, NOT AS GOOD 2084 01:34:06,160 --> 01:34:10,360 BECAUSE IT IS ONLY TARGETING 2085 01:34:10,360 --> 01:34:11,000 P16-POSITIVE CELLS AND THEN WE 2086 01:34:11,000 --> 01:34:15,200 USE OUR FAVORITE COCKTAIL, 2087 01:34:15,200 --> 01:34:18,000 RESCUED THE SAME EXTENT. 2088 01:34:18,000 --> 01:34:20,120 WE THINK THE REASONS FOR 2089 01:34:20,120 --> 01:34:22,960 SENESCENT CELLS MAKING ANIMALS 2090 01:34:22,960 --> 01:34:23,560 VULNERABLE IS THAT THE CAUSE 2091 01:34:23,560 --> 01:34:26,960 AND TO OVERREACT TO INFECTION. 2092 01:34:26,960 --> 01:34:27,560 AND SO THIS IS AN EXAMPLE IN 2093 01:34:27,560 --> 01:34:29,000 VITRO WHERE WE WERE COMPARING 2094 01:34:29,000 --> 01:34:34,480 NON-SENESCENT CELLS CHALLENGED 2095 01:34:34,480 --> 01:34:41,480 WITH LPS, THE SENESCENT CELLS 2096 01:34:41,480 --> 01:34:45,440 HYPER REACT. IL6 GO TO THE ROOF 2097 01:34:45,440 --> 01:34:46,360 IF YOU ARE OLD BUT NOT YOUNG. 2098 01:34:46,360 --> 01:34:53,880 HE WE DID THIS IN AN NME, IL6 2099 01:34:53,880 --> 01:34:54,400 IS NOT ELEVATED IN YOUNG 2100 01:34:54,400 --> 01:34:55,200 ANIMALS BUT TO THE ROOF AND OLD. 2101 01:34:55,200 --> 01:35:01,200 AND IF WE TREAT ANIMALS WITH 2102 01:35:01,200 --> 01:35:02,040 FISETIN, WE CAN BRING THESE 2103 01:35:02,040 --> 01:35:05,080 LEVELS DOWN. 2104 01:35:05,080 --> 01:35:05,680 WE THINK THAT THE OVERREACTION 2105 01:35:05,680 --> 01:35:10,760 IS WHAT SETS THESE ANIMALS UP 2106 01:35:10,760 --> 01:35:11,280 FOR CYTOKINE STORM AND 2107 01:35:11,280 --> 01:35:11,760 MULTIORGAN FAILURE AND 2108 01:35:11,760 --> 01:35:12,360 ULTIMATELY IN FACT THIS COULD 2109 01:35:12,360 --> 01:35:14,440 IMPROVE RESPONSE TO THE VIRUS 2110 01:35:14,440 --> 01:35:16,720 IF WE LOWER THE AMOUNT OF 2111 01:35:16,720 --> 01:35:18,040 TRANSCRIPT FROM THE VIRUS, 2112 01:35:18,040 --> 01:35:23,120 PROTECTED IN THE 2113 01:35:23,120 --> 01:35:26,840 FISETIN-TREATED ANIMALS AND 2114 01:35:26,840 --> 01:35:27,440 HAVE AN APPROPRIATE ANTIBODY 2115 01:35:27,440 --> 01:35:28,040 RESPONSE EQUIVALENT TO YOUNG 2116 01:35:28,040 --> 01:35:28,680 MICE COMPARED TO THE UNTREATED 2117 01:35:28,680 --> 01:35:30,200 ANIMAL. 2118 01:35:30,200 --> 01:35:36,120 SO QUICK THOUGHTS. HERE 2119 01:35:36,120 --> 01:35:37,560 STUDYING AGING, IMMUNITY AND 2120 01:35:37,560 --> 01:35:40,360 CHRONIC INFLAMMATORY DISEASES 2121 01:35:40,360 --> 01:35:43,680 IN SPF MICE MAY NOT MAKE A LOT 2122 01:35:43,680 --> 01:35:45,840 OF SENSE. WE HAVE TO THINK 2123 01:35:45,840 --> 01:35:52,920 ABOUT THE REALITY IN THE WORLD. 2124 01:35:52,920 --> 01:35:55,920 SENOLYTICS REDUCE ADVERSE 2125 01:35:55,920 --> 01:35:56,480 OUTCOMES IN ORGANISMS ABOUT 2126 01:35:56,480 --> 01:35:56,960 INFECTION WITH A NOVEL 2127 01:35:56,960 --> 01:35:59,640 PATHOGEN. I THINK THIS WAS ONE 2128 01:35:59,640 --> 01:36:02,520 OF THE STRONGEST EVIDENCE FOR 2129 01:36:02,520 --> 01:36:03,160 GEROSCIENCE. I UNDERSTAND THAT 2130 01:36:03,160 --> 01:36:12,480 IF YOU BUILD UP SENESCENT CELLS 2131 01:36:12,480 --> 01:36:13,120 WITH AGING AND CHRONIC DISEASE 2132 01:36:13,120 --> 01:36:14,840 WHICH IS DISTINCT IN AN OLDER 2133 01:36:14,840 --> 01:36:15,400 PERSON, THEIR PRIME TO BE 2134 01:36:15,400 --> 01:36:25,920 VULNERABLE TO INFECTION AS WELL 2135 01:36:27,320 --> 01:36:27,880 AND SENESCENT CELLS, THE WAY WE 2136 01:36:27,880 --> 01:36:28,520 ARE THINKING ABOUT THIS IS, SET 2137 01:36:28,520 --> 01:36:39,000 OF CLIENTS FROM (CORRECTION) 2138 01:36:43,600 --> 01:36:44,040 CYTOKLINE FROM THE CELL 2139 01:36:44,040 --> 01:36:48,440 CONFUSES THE PATHOGEN. 2140 01:36:48,440 --> 01:36:50,640 THE OTHER PAGE I WANT TO MAKE 2141 01:36:50,640 --> 01:36:51,240 IS, I THINK THERE IS A LOT TO 2142 01:36:51,240 --> 01:36:52,280 LEARN FROM CANCER, AND CANCER 2143 01:36:52,280 --> 01:36:55,600 IMMUNOLOGY. IT WILL BE 2144 01:36:55,600 --> 01:36:59,800 EXCITING TO SEE NCI JOIN YOU 2145 01:36:59,800 --> 01:37:00,360 GUYS AT SOME POINT OF THIS 2146 01:37:00,360 --> 01:37:00,960 COMES MAINLY FROM TWO RECENT 2147 01:37:00,960 --> 01:37:01,480 PUBLICATIONS IN CANCER 2148 01:37:01,480 --> 01:37:03,600 DISCOVERY, 2023. EMMANEUL -- 2149 01:37:03,600 --> 01:37:10,080 AND SCOTT LOWE (PHONETIC) THIS 2150 01:37:10,080 --> 01:37:10,720 IS AN INTERESTING PARADIGM, YOU 2151 01:37:10,720 --> 01:37:11,360 ARE OLD AND YOU HAVE CANCER YOU 2152 01:37:11,360 --> 01:37:13,520 HAVE SENESCENT CELLS, YOU HAVE 2153 01:37:13,520 --> 01:37:14,160 CHEMOTHERAPY AND THEN YOU HAVE 2154 01:37:14,160 --> 01:37:17,240 MORE SENESCENT CELLS AND 2155 01:37:17,240 --> 01:37:17,840 IMMUNOSUPPRESSION, THAT LEADS 2156 01:37:17,840 --> 01:37:20,960 TO MORE SENESCENT CELLS. 2157 01:37:20,960 --> 01:37:22,840 INCREDIBLY COMPLICATED CASCADE. 2158 01:37:22,840 --> 01:37:31,040 WE KNOW THAT RECRUITMENT 2159 01:37:31,040 --> 01:37:34,640 ANTIGEN PRESENTATION AND 2160 01:37:34,640 --> 01:37:36,200 INTERFERON ARE DISRUPTED BY 2161 01:37:36,200 --> 01:37:45,960 SENESCENT CELLS. 2162 01:37:45,960 --> 01:37:46,440 BONE TRANSPLANT IS ALSO 2163 01:37:46,440 --> 01:37:47,080 COMPLICATED. THERE IS A LOT OF 2164 01:37:47,080 --> 01:37:48,280 EVIDENCE OF ACCELERATED AGING. 2165 01:37:48,280 --> 01:37:48,920 IT IS TIED TO COGNITION AND IT 2166 01:37:48,920 --> 01:37:56,840 IS A FULL ALLOGENEIC TRANSPLANT 2167 01:37:56,840 --> 01:37:58,800 THE DRIVES COMMISSION DEFICIT. 2168 01:37:58,800 --> 01:38:04,000 THE AMOUNT OF DNA DAMAGE AND 2169 01:38:04,000 --> 01:38:10,120 SENESCENT CELLS IS THAT FROM A 2170 01:38:10,120 --> 01:38:10,720 FULL OR PARTIAL ALLOGENEIC 2171 01:38:10,720 --> 01:38:13,560 TRANSPLANT. 2172 01:38:13,560 --> 01:38:16,160 THE SECOND LIKE THE WILD WEST. 2173 01:38:16,160 --> 01:38:16,720 THERE'S A LOT YOU CAN LEARN 2174 01:38:16,720 --> 01:38:17,600 FROM THEM IN THE START WITH 2175 01:38:17,600 --> 01:38:19,440 CANCER, THEY GET CHEMOTHERAPY, 2176 01:38:19,440 --> 01:38:20,280 THEY FAIL AND THAT DRIVES 2177 01:38:20,280 --> 01:38:22,880 SENESCENT CELLS. THEY GET 2178 01:38:22,880 --> 01:38:23,880 ABLATION AND YOU GET MORE 2179 01:38:23,880 --> 01:38:28,240 SENESCENT CELLS AND THEN MORE 2180 01:38:28,240 --> 01:38:29,760 THERAPY. AND IF THAT DOES NOT 2181 01:38:29,760 --> 01:38:31,080 WORK YOU GET IMMUNOSUPPRESSION, 2182 01:38:31,080 --> 01:38:31,720 POSSIBLY ABLATION AND A LOT OF 2183 01:38:31,720 --> 01:38:35,440 SENESCENT CELLS. SO THERE'S A 2184 01:38:35,440 --> 01:38:36,040 TON OF CLINICAL DATA ON THESE 2185 01:38:36,040 --> 01:38:36,640 PATIENTS AND I WOULD URGE YOU 2186 01:38:36,640 --> 01:38:39,080 TO THINK ABOUT THIS. YOU ARE 2187 01:38:39,080 --> 01:38:42,760 SMARTER THAN ME. 2188 01:38:42,760 --> 01:38:43,240 MY SUGGESTION IS MORE 2189 01:38:43,240 --> 01:38:45,960 INTERDISCIPLINARY WORKSHOPS, 2190 01:38:45,960 --> 01:38:48,080 REVIEWS OF DISCIPLINES REPAIRED 2191 01:38:48,080 --> 01:38:51,200 AND WE WILL NEED AI TO FIND THE 2192 01:38:51,200 --> 01:38:51,960 PHENOTYPES AND KEEP TRACK OF IT 2193 01:38:51,960 --> 01:38:54,400 WITH COVID. IT IS WELL BEYOND 2194 01:38:54,400 --> 01:38:59,040 THE HUMAN. 2195 01:38:59,040 --> 01:39:02,040 A LOT OF CARDIOMIC. TRANSFER 2196 01:39:02,040 --> 01:39:02,640 IS ONE THING THAT WE NEED TO 2197 01:39:02,640 --> 01:39:08,040 THINK ABOUT THE BIOLOGY. ALSO 2198 01:39:08,040 --> 01:39:11,160 MAKING A PLUG FOR SPATIAL 2199 01:39:11,160 --> 01:39:12,360 (INDISCERNIBLE). SINGLE CELLS 2200 01:39:12,360 --> 01:39:16,040 DO NOT CAPTURE SENESCENT CELLS. 2201 01:39:16,040 --> 01:39:17,320 THINK ABOUT YOUR METHODS VERY 2202 01:39:17,320 --> 01:39:19,080 CAREFULLY BEFORE YOU SAY 2203 01:39:19,080 --> 01:39:19,560 SENESCENT CELLS ARE NOT 2204 01:39:19,560 --> 01:39:23,640 IMPORTANT. 2205 01:39:23,640 --> 01:39:24,240 ULTIMATELY WHERE WE ARE HEADED 2206 01:39:24,240 --> 01:39:24,760 TOWARDS THIS CHANGES IN 2207 01:39:24,760 --> 01:39:35,280 CLINICAL PRACTICE. YOU GET NEW 2208 01:39:35,800 --> 01:39:36,120 DIAGNOSES. 2209 01:39:36,120 --> 01:39:40,280 QUICK THINGS TO PAUL ROBBINS, 2210 01:39:40,280 --> 01:39:43,480 CHRISTINA CARNELL, OUR 2211 01:39:43,480 --> 01:39:47,520 COLLEAGUES AT THE MAYO CLINIC. 2212 01:39:47,520 --> 01:39:49,360 MATT YOUSEFZADEH FACULTY MEMBER 2213 01:39:49,360 --> 01:39:51,840 AT COLUMBIA -- MY LABORATORY 2214 01:39:51,840 --> 01:39:58,120 POST DOC, INCREDIBLE CREW OF 2215 01:39:58,120 --> 01:39:58,840 GRADUATES AND UNDERGRADUATES. 2216 01:39:58,840 --> 01:39:59,440 AND GRATEFUL FOR OUR FUNDING 2217 01:39:59,440 --> 01:40:05,360 SOURCE. THANK YOU VERY MUCH. 2218 01:40:05,360 --> 01:40:07,600 >>THANK YOU LAURA. TIME FOR 2219 01:40:07,600 --> 01:40:14,240 QUESTIONS. >>THAT WAS SO 2220 01:40:14,240 --> 01:40:17,240 INTERESTING. I HAVE STARTED 2221 01:40:17,240 --> 01:40:18,160 DEVELOPING AND REGENERATION OF 2222 01:40:18,160 --> 01:40:21,040 SENESCENT CELLS BY THEIR ROLE 2223 01:40:21,040 --> 01:40:24,560 IN THE NICHE. I WAS WONDERING 2224 01:40:24,560 --> 01:40:27,960 IF YOU GET (INDISCERNIBLE), 2225 01:40:27,960 --> 01:40:30,080 THINKING ABOUT CANCER AS WELL, 2226 01:40:30,080 --> 01:40:30,560 I THINK IT WOULD BE AN 2227 01:40:30,560 --> 01:40:31,160 IMPORTANT ASPECT OF 2228 01:40:31,160 --> 01:40:33,400 FUNDAMENTALLY UNDERSTAND NICHE 2229 01:40:33,400 --> 01:40:36,120 POPULATIONS OF SENESCENT CELLS. 2230 01:40:36,120 --> 01:40:38,240 WHAT DO YOU THINK? 2231 01:40:38,240 --> 01:40:41,040 >>THAT IS A BRILLIANT IDEA. 2232 01:40:41,040 --> 01:40:45,120 CHICKEN AND EGG. REALLY HARD. 2233 01:40:45,120 --> 01:40:52,240 I SHOULD HAVE POINTED OUT THAT 2234 01:40:52,240 --> 01:40:52,880 SENESCENT CELLS ARE NOT ALL BAD 2235 01:40:52,880 --> 01:40:53,280 WE NEED THEM FOR 2236 01:40:53,280 --> 01:40:56,920 (INDISCERNIBLE) -- WHEN WE CAN 2237 01:40:56,920 --> 01:40:57,640 CLEAR THAT YOU'RE IN GOOD 2238 01:40:57,640 --> 01:41:03,720 SHAPE. IT IS A COMBINATION OF 2239 01:41:03,720 --> 01:41:04,280 THE NICHE CHANGING AND YOUR 2240 01:41:04,280 --> 01:41:05,800 IMMUNE SYSTEM NOT RESPONDING. 2241 01:41:05,800 --> 01:41:07,960 >>ALSO (INDISCERNIBLE) WITH 2242 01:41:07,960 --> 01:41:18,480 THE CELLS RIGHT NEXT TO THEM. 2243 01:41:20,000 --> 01:41:20,520 UNDERSTANDING THAT THE NICHE 2244 01:41:20,520 --> 01:41:21,080 AND THE CELLS THAT WILL BE 2245 01:41:21,080 --> 01:41:21,600 COMMUNICATING WITH -- 2246 01:41:21,600 --> 01:41:24,400 (INDISCERNIBLE). 2247 01:41:24,400 --> 01:41:29,840 >>REALLY COOL, THE -- MOUSE 2248 01:41:29,840 --> 01:41:32,360 EXPOSURE WAS REALLY INTERESTING. 2249 01:41:32,360 --> 01:41:35,760 I WANTED TO ASK YOU IF YOU 2250 01:41:35,760 --> 01:41:36,360 THOUGHT THAT THE PET SHOP MICE 2251 01:41:36,360 --> 01:41:38,200 BECAUSE THEY HAD THE 2252 01:41:38,200 --> 01:41:42,520 CORONAVIRUS WOULD NOT MAKE IT 2253 01:41:42,520 --> 01:41:44,360 FOR TWO YEARS OR THE REASON 2254 01:41:44,360 --> 01:41:44,920 THAT THE MICE DIED WAS THE 2255 01:41:44,920 --> 01:41:48,840 FIRST EXPOSURE. 2256 01:41:48,840 --> 01:41:49,400 >>I THINK THE OLD MICE ARE 2257 01:41:49,400 --> 01:41:53,520 NAïVE. I DON'T KNOW ABOUT THE 2258 01:41:53,520 --> 01:41:54,120 PET STORE MICE AND HOW LONG 2259 01:41:54,120 --> 01:41:58,760 THEY LIVE. OBVIOUSLY THEY ARE 2260 01:41:58,760 --> 01:41:59,280 MEANT FOR PREDATION OR 2261 01:41:59,280 --> 01:41:59,880 SOMETHING BUT MICE LIVE FOR A 2262 01:41:59,880 --> 01:42:00,720 LONG TIME AS PETS. IF YOU 2263 01:42:00,720 --> 01:42:04,240 PROTECT THEM, THEY ARE FINE AND 2264 01:42:04,240 --> 01:42:05,600 THE YOUNG MICE SURVIVE WHEN 2265 01:42:05,600 --> 01:42:06,160 THEY'RE EXPOSED TO THE PET 2266 01:42:06,160 --> 01:42:08,360 STORE MICE. I DON'T THINK THAT 2267 01:42:08,360 --> 01:42:11,880 IS A LIFESPAN CHANGER, BUT A 2268 01:42:11,880 --> 01:42:13,360 CHRONIC DISEASE. 2269 01:42:13,360 --> 01:42:20,760 >>HI. MARI -- SPAIN. 2270 01:42:20,760 --> 01:42:21,280 CONGRATULATIONS FOR YOUR 2271 01:42:21,280 --> 01:42:23,000 BRILLIANT WORK. I WAS WONDERING 2272 01:42:23,000 --> 01:42:26,320 IF YOUR MUTANT MICE JUST IN THE 2273 01:42:26,320 --> 01:42:35,520 IMMUNE SYSTEM, IS THE PREMATURE 2274 01:42:35,520 --> 01:42:36,160 SENESCENTS PHENOTYPES COULD BE 2275 01:42:36,160 --> 01:42:36,840 RELATED TO DYSREGULATION IN THE 2276 01:42:36,840 --> 01:42:38,240 MICE (INDISCERNIBLE). 2277 01:42:38,240 --> 01:42:43,320 >>YES. I AM CONFIDENT THAT 2278 01:42:43,320 --> 01:42:44,520 THAT PLAYS A ROLE IN THAT; WE 2279 01:42:44,520 --> 01:42:46,360 HAVE NOT STUDIED IT THOROUGHLY. 2280 01:42:46,360 --> 01:42:47,800 ACTUALLY THOSE MICE ARE NOW IN 2281 01:42:47,800 --> 01:42:52,480 THE MME EXPOSURE PARADIGM NOW. 2282 01:42:52,480 --> 01:42:53,160 WE ARE LOOKING FOR HELP THROUGH 2283 01:42:53,160 --> 01:43:03,400 ANALYZING THE MICROBIO. I 2284 01:43:03,400 --> 01:43:04,000 DON'T THINK WE KNOW A LOT OF 2285 01:43:04,000 --> 01:43:05,560 HOW THE ENEMY CHANGES THAT. 2286 01:43:05,560 --> 01:43:16,120 THERE IS A CAVEAT, MME MICE DO 2287 01:43:20,200 --> 01:43:20,800 NOT COME IN ONE FLAVOR BUT THAT 2288 01:43:20,800 --> 01:43:21,400 IS A WEAKNESS THE MICROBIOME 2289 01:43:21,400 --> 01:43:22,480 WILL BE CRITICAL. 2290 01:43:22,480 --> 01:43:23,040 >>THANK YOU FOR A WONDERFUL 2291 01:43:23,040 --> 01:43:26,880 TALK. THERE IS A LOT OF WORK 2292 01:43:26,880 --> 01:43:27,520 IN THE IMMUNOLOGY FIELD RELATES 2293 01:43:27,520 --> 01:43:31,680 TO T CELL EXHAUSTION. I AM 2294 01:43:31,680 --> 01:43:37,920 WONDERING HOW YOUR SENESCENT 2295 01:43:37,920 --> 01:43:38,480 T-CELLS LOOK OR THEY ARE 2296 01:43:38,480 --> 01:43:39,040 SIMILAR TO THE EXHAUSTED T 2297 01:43:39,040 --> 01:43:42,000 CELLS. IN YOUR COMMENTS ABOUT 2298 01:43:42,000 --> 01:43:42,600 SENESCENT CELLS BEING LARGER 2299 01:43:42,600 --> 01:43:44,800 AND MORE FRAGILE. AND I KNOW 2300 01:43:44,800 --> 01:43:55,320 THAT IT LOOKED AT IT A LOT IN 2301 01:43:56,080 --> 01:43:56,600 VITRO AND I WAS WONDERING IF 2302 01:43:56,600 --> 01:43:57,240 THERE WAS EVIDENCE IN VIVO, AND 2303 01:43:57,240 --> 01:43:57,720 THE PEOPLE WERE DOING 2304 01:43:57,720 --> 01:43:59,040 AUGMENTING IMAGING. THERE IS 2305 01:43:59,040 --> 01:44:06,280 SOME QUESTION ABOUT THAT. 2306 01:44:06,280 --> 01:44:06,840 >>THESE ARE GREAT QUESTIONS. 2307 01:44:06,840 --> 01:44:07,320 WE HAVE PRELIMINARY AND 2308 01:44:07,320 --> 01:44:10,000 SUPERFICIAL EVIDENCE THAT 2309 01:44:10,000 --> 01:44:13,720 REVEAL THERE ARE 2310 01:44:13,720 --> 01:44:14,320 (INDISCERNIBLE)-- WE HAVE A LOT 2311 01:44:14,320 --> 01:44:14,920 OF WORK TO DO AND HOPEFULLY 2312 01:44:14,920 --> 01:44:16,240 CHRISTINA CAN HELP WITH THAT. 2313 01:44:16,240 --> 01:44:18,560 >>YOU ARE ABSOLUTELY CORRECT. 2314 01:44:18,560 --> 01:44:20,520 MOST OF THE DATA ABOUT FRAGILE 2315 01:44:20,520 --> 01:44:23,320 STATE SENESCENT CELLS COMES 2316 01:44:23,320 --> 01:44:26,200 FROM IN VITRO. WE ARE SEEING 2317 01:44:26,200 --> 01:44:27,600 EVIDENCE OF THAT IN VIVO AS 2318 01:44:27,600 --> 01:44:38,120 WELL; MOSTLY THEY ARE POLYPRO 2319 01:44:39,960 --> 01:44:42,000 NUCLEI (PHONETIC) -- AND HOW TO 2320 01:44:42,000 --> 01:44:46,360 DECIPHER THAT. WE NEED A LOT 2321 01:44:46,360 --> 01:44:52,200 MORE SPECIAL WORK. BUT 2322 01:44:52,200 --> 01:44:52,840 PRELIMINARY EVIDENCE SHOWS THAT 2323 01:44:52,840 --> 01:44:53,480 HAS BEEN CARRIED THROUGH TO IN 2324 01:44:53,480 --> 01:45:00,440 VIVO. YEAH? 2325 01:45:00,440 --> 01:45:01,000 >>DID I UNDERSTAND CORRECTLY 2326 01:45:01,000 --> 01:45:03,120 THAT WHAT YOU CALL SENESCENT 2327 01:45:03,120 --> 01:45:03,560 CELLS IS CAPABLE OF 2328 01:45:03,560 --> 01:45:04,160 PROLIFERATION? 2329 01:45:04,160 --> 01:45:07,360 >>NO. I HAVE NOT COMMENTED ON 2330 01:45:07,360 --> 01:45:11,120 THAT. 2331 01:45:11,120 --> 01:45:11,680 >>WHEN YOU DO THE TRANSFER 2332 01:45:11,680 --> 01:45:12,240 EXPERIMENT THERE IS A SMALL 2333 01:45:12,240 --> 01:45:15,320 NUMBER OF CELLS. THE ONLY WAY 2334 01:45:15,320 --> 01:45:15,840 IT WORKS IS IF THERE IS 2335 01:45:15,840 --> 01:45:16,440 PROLIFERATION IN THE TRANSIT 2336 01:45:16,440 --> 01:45:19,120 CELL. LET ME ASK YOU THIS, 2337 01:45:19,120 --> 01:45:23,000 HAVE YOU DONE DRDU? 2338 01:45:23,000 --> 01:45:23,560 >>WE HAVE NOT AND THAT IS A 2339 01:45:23,560 --> 01:45:28,760 GOOD POINT. WE HAVE TO MAP THE 2340 01:45:28,760 --> 01:45:30,360 CELLS AND WE DO NOT SEE A LOT; 2341 01:45:30,360 --> 01:45:31,000 THEY DID NOT APPEAR TO BE A LOT 2342 01:45:31,000 --> 01:45:32,800 OF PROLIFERATION. 2343 01:45:32,800 --> 01:45:35,000 >>YOU SPOKE A LOT ABOUT 2344 01:45:35,000 --> 01:45:41,640 MULTIPLE -- (INDISCERNIBLE) IN 2345 01:45:41,640 --> 01:45:42,280 SENESCENT, AND IF I UNDERSTOOD 2346 01:45:42,280 --> 01:45:42,920 IN THE FOLLOWING SLIDE YOU SHOW 2347 01:45:42,920 --> 01:45:44,600 THE ONLY DEFINITIVE PROOF OF 2348 01:45:44,600 --> 01:45:49,400 THE CAUSALITY OF THE P16 2349 01:45:49,400 --> 01:45:49,920 KNOCKOUT OR CONDITIONAL 2350 01:45:49,920 --> 01:45:52,160 KNOCKOUT. AND TAKING THE 2351 01:45:52,160 --> 01:45:56,000 IMMUNOLOGY SIDE OF THINGS, P16 2352 01:45:56,000 --> 01:45:56,560 IS ALSO HIGHLY EXPRESSED IN 2353 01:45:56,560 --> 01:45:59,480 TUMORS SO REMOVING P16 POSITIVE 2354 01:45:59,480 --> 01:46:00,080 DOES NOT MEAN YOU REMOVE ONLY 2355 01:46:00,080 --> 01:46:04,080 THE SENESCENT CELLS. SO THE 2356 01:46:04,080 --> 01:46:06,400 LOAN EXPERIMENT, IS APPROVED 2357 01:46:06,400 --> 01:46:07,160 FOR THE CAUSALITY OF THE 2358 01:46:07,160 --> 01:46:12,120 SENESCENT CELLS? OR THE P16 2359 01:46:12,120 --> 01:46:15,600 POSITIVE CELLS? 2360 01:46:15,600 --> 01:46:18,960 >>EXCELLENT POINTS. SO THERE 2361 01:46:18,960 --> 01:46:29,360 ARE NOW NEW TOOLS, P21 2362 01:46:30,000 --> 01:46:30,440 OPERATORS THAT I WOULD 2363 01:46:30,440 --> 01:46:31,000 ENCOURAGE YOU GUYS WHO ARE 2364 01:46:31,000 --> 01:46:31,640 IMMUNOLOGIST TO CONSIDER THESE 2365 01:46:31,640 --> 01:46:33,960 MODELS FROM THE MAYO CLINIC. 2366 01:46:33,960 --> 01:46:34,520 ON THE FLIPSIDE WE HAVE NOT 2367 01:46:34,520 --> 01:46:39,720 SEEN AN ADVERSE EFFECT FROM A A 2368 01:46:39,720 --> 01:46:45,880 -- ABLATING P16 CELLS. WE ARE 2369 01:46:45,880 --> 01:46:46,440 DOING OUR BEST BUT IT IS A 2370 01:46:46,440 --> 01:46:47,480 LITTLE BIT OF A CAVEAT INDEED 2371 01:46:47,480 --> 01:46:48,080 SO THANK YOU FOR POINTING IT 2372 01:46:48,080 --> 01:46:55,520 OUT. >>HOW TO DIFFERENTIATE 2373 01:46:55,520 --> 01:46:56,320 INFLAMMATION AND 2374 01:46:56,320 --> 01:46:58,040 (INDISCERNIBLE)? 2375 01:46:58,040 --> 01:47:01,720 >>IMPOSSIBLE. 2376 01:47:01,720 --> 01:47:02,160 >>WHAT YOU THINK ABOUT 2377 01:47:02,160 --> 01:47:05,560 TOLERANCE OR LACK OF IN MME IN 2378 01:47:05,560 --> 01:47:07,680 ADULT MICE? 2379 01:47:07,680 --> 01:47:08,960 >>WAY BEYOND MY EXPERTISE. I 2380 01:47:08,960 --> 01:47:11,360 AM SORRY. 2381 01:47:11,360 --> 01:47:12,000 >>HOW DO YOU EXPLAIN THE 2382 01:47:12,000 --> 01:47:19,480 INCREASE OF P16 IN CANCER BUT 2383 01:47:19,480 --> 01:47:20,000 ENDS UP HAVING A FASTER 2384 01:47:20,000 --> 01:47:20,560 RELATION BETWEEN AGING AND 2385 01:47:20,560 --> 01:47:24,800 CANCER AND P16 ACTIVATION? 2386 01:47:24,800 --> 01:47:30,640 >>WHAT IS REALLY-- THE BIG 2387 01:47:30,640 --> 01:47:32,080 QUESTION IS IF YOU START 2388 01:47:32,080 --> 01:47:36,920 ABLATING P16 CELLS YOU'RE GOING 2389 01:47:36,920 --> 01:47:37,520 TO SET YOURSELF UP FOR CANCER 2390 01:47:37,520 --> 01:47:38,160 AND THAT IS NEVER THE CASE AT 2391 01:47:38,160 --> 01:47:43,680 ALL. WHEN YOU HAVE A DAMAGED 2392 01:47:43,680 --> 01:47:44,320 STRESS CELL, REGARDLESS OF WHAT 2393 01:47:44,320 --> 01:47:44,960 IS GOING ON, IF YOU CAN PUT OUT 2394 01:47:44,960 --> 01:47:51,520 A TECH POINT THAT'S GOOD. 2395 01:47:51,520 --> 01:47:52,080 >>I HAVE A QUESTION YOU MAY 2396 01:47:52,080 --> 01:47:54,040 NOT KNOW THE ANSWER FOR, BUT 2397 01:47:54,040 --> 01:47:54,640 THERE WAS SOMEBODY WHO ALLUDED 2398 01:47:54,640 --> 01:48:01,680 TO THE WORK OF LONGO AND THE -- 2399 01:48:01,680 --> 01:48:02,280 DIET AND CALORIC RESTRICTION 2400 01:48:02,280 --> 01:48:06,720 AND THAT WHOLE FIELD. I AM 2401 01:48:06,720 --> 01:48:07,320 SURE SOMEBODY HAS TRIED TO LOOK 2402 01:48:07,320 --> 01:48:08,000 AT TO SEE IF ONE OF THE 2403 01:48:08,000 --> 01:48:09,040 MECHANISMS IS ENHANCED 2404 01:48:09,040 --> 01:48:13,440 (INDISCERNIBLE) AND CLEARANCE 2405 01:48:13,440 --> 01:48:15,880 OF SUBOPTIMAL CELLS. DOES 2406 01:48:15,880 --> 01:48:17,720 ANYBODY LOOK TO SEE IF 2407 01:48:17,720 --> 01:48:19,000 SENESCENT CELLS ARE CLEARED IN 2408 01:48:19,000 --> 01:48:21,400 THE MODEL? 2409 01:48:21,400 --> 01:48:23,200 >>YES, FLOW RESTRICTION AND 2410 01:48:23,200 --> 01:48:28,200 EXERCISE TO CLEAR SENESCENT 2411 01:48:28,200 --> 01:48:33,680 CELLS. I WOULD ALSO SAY IN OUR 2412 01:48:33,680 --> 01:48:36,880 MODEL (INDISCERNIBLE) IT IS 2413 01:48:36,880 --> 01:48:41,320 AMAZING. THAT DEFINITELY 2414 01:48:41,320 --> 01:48:46,120 WORKED. THE OTHER THING I 2415 01:48:46,120 --> 01:48:46,560 WOULD POINT OUT IS WE 2416 01:48:46,560 --> 01:48:47,160 SYSTEMATICALLY LOOKED AT ALL 2417 01:48:47,160 --> 01:48:47,800 THE HALLMARKS OF AGING IN OUR 2418 01:48:47,800 --> 01:48:50,200 MUTANT ANIMALS. WE KNOW WE 2419 01:48:50,200 --> 01:48:52,480 STARTED WITH THE PRIMARY 2420 01:48:52,480 --> 01:48:54,680 PROBLEM OF GENOTYPE EXPRESSED; 2421 01:48:54,680 --> 01:48:55,200 EVERY SINGLE HALLMARK IS 2422 01:48:55,200 --> 01:48:59,240 ALTERED. AND SO I THINK THESE 2423 01:48:59,240 --> 01:49:01,240 ARE ALL VERY INTEGRATED. 2424 01:49:01,240 --> 01:49:03,240 >>I HAD A QUESTION. MAY BE 2425 01:49:03,240 --> 01:49:10,600 TOO SIMPLISTIC. THINKING ABOUT 2426 01:49:10,600 --> 01:49:11,240 SENELITICS FOR HUMANS MAY BE IN 2427 01:49:11,240 --> 01:49:11,960 THE T CELL COMPARTMENT, THE 2428 01:49:11,960 --> 01:49:22,640 MAJORITY OF THE T CELLS ARE 2429 01:49:22,640 --> 01:49:23,160 SENESCENT AND YOU ELIMINATE 2430 01:49:23,160 --> 01:49:23,720 THEM WITH VISITS SENELITIC, 2431 01:49:23,720 --> 01:49:25,000 THERE IS NO NEW PIECE OF 2432 01:49:25,000 --> 01:49:28,920 (INDISCERNIBLE) TO SPEAK OF. 2433 01:49:28,920 --> 01:49:29,520 >>HARD FOR ME TO ANSWER BUT I 2434 01:49:29,520 --> 01:49:31,680 WILL SAY THAT THERE HAS BEEN A 2435 01:49:31,680 --> 01:49:32,320 LOT OF THOUGHT ON THIS BECAUSE 2436 01:49:32,320 --> 01:49:33,080 THE OTHER QUESTION IS THERE IS 2437 01:49:33,080 --> 01:49:36,040 EVIDENCE THAT SENESCENT CELLS 2438 01:49:36,040 --> 01:49:37,840 PLAY A BIG ROLE IN ALZHEIMER'S 2439 01:49:37,840 --> 01:49:43,120 DISEASE. SOME PEOPLE SAY IT IS 2440 01:49:43,120 --> 01:49:45,720 A NEURON SENESCENT, I AM NOT 2441 01:49:45,720 --> 01:49:46,320 SURE I AGREE BUT IF YOU CLEAR 2442 01:49:46,320 --> 01:49:48,840 THE NEURONS, IS THAT BETTER 2443 01:49:48,840 --> 01:49:53,560 THAN HAVING-- I DON'T KNOW-- NO 2444 01:49:53,560 --> 01:49:54,120 NEURONS BETTER THAN HAVING 2445 01:49:54,120 --> 01:50:00,120 THICK NEURONS?BIG QUESTION. I 2446 01:50:00,120 --> 01:50:03,560 DON'T KNOW. THERE'S 40 OR SO 2447 01:50:03,560 --> 01:50:05,760 CLINICAL TRIALS GOING ON NOW. 2448 01:50:05,760 --> 01:50:06,440 I THINK IT IS SCREAMING FOR 2449 01:50:06,440 --> 01:50:09,200 HELP. 2450 01:50:09,200 --> 01:50:16,480 >>WANT TO MAKE A COMMENT. 2451 01:50:16,480 --> 01:50:17,080 MANY MUCOSAL EPITHELIAL CELLS 2452 01:50:17,080 --> 01:50:21,000 AS THE AGE ARE SENESCENT. IN 2453 01:50:21,000 --> 01:50:27,560 MANY IN OUR BODY ARE SENESCENT, 2454 01:50:27,560 --> 01:50:28,160 GIVEN ANY KIND OF PRESSURE OR 2455 01:50:28,160 --> 01:50:28,760 INSULT THEY WILL FALL OFF A 2456 01:50:28,760 --> 01:50:31,600 RETREAT WITH SENELITICS WE 2457 01:50:31,600 --> 01:50:32,560 COULD HAVE DETRIMENTAL EFFECTS 2458 01:50:32,560 --> 01:50:34,480 ON BARRIER FUNCTIONS. 2459 01:50:34,480 --> 01:50:37,280 >>GREAT POINT. ONE COMMENT I 2460 01:50:37,280 --> 01:50:38,800 WOULD MAKE ABOUT THAT IS THE 2461 01:50:38,800 --> 01:50:42,360 THOUGHT ABOUT SENELITICS IS YOU 2462 01:50:42,360 --> 01:50:42,960 GIVE THEM QUARTERLY AND CLEAR 2463 01:50:42,960 --> 01:50:46,400 OUT AND RECOVER. WHEN YOU HAVE 2464 01:50:46,400 --> 01:50:47,920 SOMETIMES IT CAN RECOVER, THAT 2465 01:50:47,920 --> 01:50:49,160 MAY BE BENEFICIAL BUT WE DON'T 2466 01:50:49,160 --> 01:50:57,160 KNOW. THANK YOU. 2467 01:50:57,160 --> 01:50:57,760 >>THANK YOU LAURA FOR A GREAT 2468 01:50:57,760 --> 01:50:58,360 TALK. MY QUESTION GOES TO DNA 2469 01:50:58,360 --> 01:51:01,800 DAMAGE. YOU VERY NICELY SHOWED 2470 01:51:01,800 --> 01:51:02,760 THE ACUMEN LEADING DNA DAMAGE 2471 01:51:02,760 --> 01:51:04,800 IS SUFFICIENT TO DRIVE THE 2472 01:51:04,800 --> 01:51:10,200 SENESCENT PHENOTYPES. IS THERE 2473 01:51:10,200 --> 01:51:12,400 ANY DATA LOOKING AT THE 2474 01:51:12,400 --> 01:51:19,680 CAUSALITY? AND THE BOOST TO THE 2475 01:51:19,680 --> 01:51:20,280 PROTECTIVE MECHANISMS AGAINST 2476 01:51:20,280 --> 01:51:21,560 DNA DAMAGE IF THEY HAVE AN 2477 01:51:21,560 --> 01:51:23,240 EFFECT ON THE COMMISSION OF 2478 01:51:23,240 --> 01:51:24,680 SENESCENT CELLS WITH AGING? THE 2479 01:51:24,680 --> 01:51:26,720 OTHER SIDE OF THE COIN. 2480 01:51:26,720 --> 01:51:28,840 >>THAT IS A GREAT QUESTION. 2481 01:51:28,840 --> 01:51:29,400 WE HAVE BEEN THINKING ABOUT 2482 01:51:29,400 --> 01:51:32,200 THIS FOREVER. I HEARD A LOT OF 2483 01:51:32,200 --> 01:51:33,000 TALK ABOUT DNA REPAIR IS 2484 01:51:33,000 --> 01:51:38,160 IMPORTANT. ARE THERE MMETICS 2485 01:51:38,160 --> 01:51:44,120 THE CAN IMPROVE IT (PHONETIC)? 2486 01:51:44,120 --> 01:51:54,120 IT WORRIES ME. (INDISCERNIBLE) 2487 01:51:54,120 --> 01:51:54,760 IS A GOOD METHOD TO DO THAT BUT 2488 01:51:54,760 --> 01:51:57,320 I DO THINK THAT IT'S THE 2489 01:51:57,320 --> 01:52:03,000 CHRONIC STIMULATION FROM DNA 2490 01:52:03,000 --> 01:52:03,640 DAMAGE, HARD TO GET RID OF DNA 2491 01:52:03,640 --> 01:52:05,200 DAMAGE THAN SIGNALING 2492 01:52:05,200 --> 01:52:08,320 DOWNSTREAM. THANK YOU. 2493 01:52:08,320 --> 01:52:08,880 >>THANK YOU FOR A FANTASTIC 2494 01:52:08,880 --> 01:52:19,080 DISCUSSION. 2495 01:52:33,640 --> 01:52:41,160 >>I CAN NOW OPEN SESSION 4, 2496 01:52:41,160 --> 01:52:45,600 IMMUNO METABOLIC CHECKPOINTS OF 2497 01:52:45,600 --> 01:52:47,200 INFLAMMAGING. 2498 01:52:47,200 --> 01:52:48,520 THE FIRST SPEAKER IS VISHAW 2499 01:52:48,520 --> 01:52:55,080 DEEP DIXIT FROM YALE. HE WILL 2500 01:52:55,080 --> 01:52:55,680 TALK ABOUT THE MODULATION OF 2501 01:52:55,680 --> 01:52:56,280 DIET AND THE IMPACT ON IMMUNE 2502 01:52:56,280 --> 01:52:57,880 FUNCTION. YOU WILL HAVE 15 2503 01:52:57,880 --> 01:53:00,880 MINUTES FOR YOUR PRESENTATION. 2504 01:53:00,880 --> 01:53:04,880 AFTER 13 MINUTES SHE WILL START 2505 01:53:04,880 --> 01:53:05,520 MAKING SOME SIGN THAT YOU HAVE 2506 01:53:05,520 --> 01:53:08,120 TO START WRAPPING UP. PLEASE 2507 01:53:08,120 --> 01:53:10,720 DEEP. 2508 01:53:10,720 --> 01:53:14,320 >>THANK YOU DANIELA. THANK 2509 01:53:14,320 --> 01:53:20,160 YOU TO PREEDE AND MECY AND -- 2510 01:53:20,160 --> 01:53:25,480 GREAT TO BE HERE. THIS NEXT 2511 01:53:25,480 --> 01:53:26,120 LECTURE, LEAVE $10 WHEN YOU'RE 2512 01:53:26,120 --> 01:53:29,360 DONE WITH THE COFFEE. 2513 01:53:29,360 --> 01:53:37,840 (CHUCKLING). 2514 01:53:37,840 --> 01:53:38,320 WE HEARD YESTERDAY FROM 2515 01:53:38,320 --> 01:53:48,800 GEORGE. AND FROM EMMANUEL. 2516 01:53:49,560 --> 01:53:50,160 IL-1 BETA REGULATED STEM CELLS 2517 01:53:50,160 --> 01:53:51,480 AND AGING IN YOUR FROM 2518 01:53:51,480 --> 01:53:59,440 KATHERINE ANDERSON ABOUT IL-18 2519 01:53:59,440 --> 01:54:00,040 IS ONE OF THE COMPONENTS THAT 2520 01:54:00,040 --> 01:54:00,640 SHOWS UP ON THE AGING PLASMA 2521 01:54:00,640 --> 01:54:11,120 AND MORE DATA FROM LAURA BUT 2522 01:54:12,880 --> 01:54:14,160 THE CYTOKINES REGULATING 2523 01:54:14,160 --> 01:54:16,920 INFLAMMATION. 2524 01:54:16,920 --> 01:54:19,520 THIS WORK WAS DONE BY MY 2525 01:54:19,520 --> 01:54:23,280 COLLEAGUE YUN YOUM, SHE IS IN 2526 01:54:23,280 --> 01:54:25,280 THE BACK OVER THERE. WHAT WE 2527 01:54:25,280 --> 01:54:27,840 FOUND WAS THAT IN AGING, THERE 2528 01:54:27,840 --> 01:54:31,400 IS THIS MULTI-PROTEIN COMPLEX 2529 01:54:31,400 --> 01:54:39,480 CALLED THE NLRP3 INFLAMMASOME 2530 01:54:39,480 --> 01:54:48,040 EXPRESSED IN THE -- AND IT IS 2531 01:54:48,040 --> 01:54:48,640 PROMISCUOUS IN ITS ABILITY TO 2532 01:54:48,640 --> 01:54:54,760 SENSE DAMAGE, WHICH IS WHY YOU 2533 01:54:54,760 --> 01:54:55,360 THINK IT IS IMPORTANT FOR 2534 01:54:55,360 --> 01:54:55,880 AGENT BECAUSE IT CAN SEND 2535 01:54:55,880 --> 01:54:56,480 STRUCTURALLY DIVERSE DAMAGE 2536 01:54:56,480 --> 01:54:57,000 ASSOCIATED WITH MOLECULAR 2537 01:54:57,000 --> 01:54:58,000 PATTERNS LISTED HERE. 2538 01:54:58,000 --> 01:54:58,600 ALL OF THEM GO UP IN AGE AND 2539 01:54:58,600 --> 01:55:00,640 THE KEY PART WITHIN THAT IS 2540 01:55:00,640 --> 01:55:02,200 ONCE IT SENSES THE DAMAGE IT 2541 01:55:02,200 --> 01:55:05,640 ASSEMBLES, CLEAVES AND -- THE 2542 01:55:05,640 --> 01:55:11,080 TWO PRIMARY RECEPTORS ARE IL-1B 2543 01:55:11,080 --> 01:55:15,720 AND IL-18. WHAT STRUCK US WHEN 2544 01:55:15,720 --> 01:55:24,400 WE LOOKED AT THESE ANIMALS 2, 2 2545 01:55:24,400 --> 01:55:25,040 1/2 YEARS OLD THEY WERE IN FACT 2546 01:55:25,040 --> 01:55:26,480 PROTECTED FROM MULTIPLE 2547 01:55:26,480 --> 01:55:27,080 FEATURES LISTED HERE, RANGING 2548 01:55:27,080 --> 01:55:35,080 FROM BONE LOSS TO MAINTENANCE 2549 01:55:35,080 --> 01:55:36,680 OF SENSITIVITY INCLUDING LESS 2550 01:55:36,680 --> 01:55:37,280 TIME IN EVOLUTION BECAUSE OF 2551 01:55:37,280 --> 01:55:40,120 RESIDENT MACROPHAGES AND LESS 2552 01:55:40,120 --> 01:55:40,600 CNS INFLAMMATION AND 2553 01:55:40,600 --> 01:55:42,040 IMPROVEMENT OF COGNITIVE 2554 01:55:42,040 --> 01:55:44,440 FUNCTION, WHICH REALLY APPROVED 2555 01:55:44,440 --> 01:55:45,080 WHAT PEOPLE HAVE BEEN PREDICTED 2556 01:55:45,080 --> 01:55:48,040 100 YEARS AGO. 2557 01:55:48,040 --> 01:55:48,480 RESIDENT MACROPHAGE 2558 01:55:48,480 --> 01:55:52,760 INFLAMMATION IS KEY. THIS WORK 2559 01:55:52,760 --> 01:55:54,720 BASICALLY SETS THE TONE FOR US, 2560 01:55:54,720 --> 01:55:55,320 AND I THINK SEVERAL OTHERS IN 2561 01:55:55,320 --> 01:56:00,920 THE FIELD, THAT THE MECHANISM 2562 01:56:00,920 --> 01:56:09,040 THAT REALLY CONTROLS 2563 01:56:09,040 --> 01:56:17,520 INFLAMMAGING CONTROLS-- --. 2564 01:56:17,520 --> 01:56:18,000 WHAT WE HAVE BEEN VERY 2565 01:56:18,000 --> 01:56:18,640 INTERESTED IN IS THE ORIGIN OF 2566 01:56:18,640 --> 01:56:23,080 INFLAMMATION WITH AGE. THIS IS 2567 01:56:23,080 --> 01:56:25,920 A SLIDE FROM A COLLEAGUE DARCY 2568 01:56:25,920 --> 01:56:34,200 JOHANSSON AT NIH. YOU CAN SEE 2569 01:56:34,200 --> 01:56:36,880 THE INDIVIDUALS WITH THE SAME 2570 01:56:36,880 --> 01:56:47,400 BODY MASS INDEX IN THE SAME 2571 01:56:47,400 --> 01:56:47,920 BMI, AND THE PRESENCE OF 2572 01:56:47,920 --> 01:56:48,440 ECTOPIC FAT IS EVIDENT 2573 01:56:48,440 --> 01:56:49,040 INCLUDING ECTOPIC FAT IN THE 2574 01:56:49,040 --> 01:56:57,000 LIVER. THERE'S A LOT OF 2575 01:56:57,000 --> 01:56:57,640 INTEREST IN TERMS OF WHAT THIS 2576 01:56:57,640 --> 01:56:58,280 ECTOPIC MAP MEANS IMPORTANT IN 2577 01:56:58,280 --> 01:56:59,080 THE REGULATION OF SEVERAL 2578 01:56:59,080 --> 01:57:03,480 CLINICAL DISORDERS. 2579 01:57:03,480 --> 01:57:04,000 ONE THING I WOULD LIKE TO 2580 01:57:04,000 --> 01:57:06,680 EMPHASIZE IS THAT IN FACT -- 2581 01:57:06,680 --> 01:57:16,320 THE TISSUE IS AN ACTIVE 2582 01:57:16,320 --> 01:57:16,960 IMMUNOLOGICAL ORGAN AND WE ARE 2583 01:57:16,960 --> 01:57:17,440 LOOKING AT MILARD CELLS 2584 01:57:17,440 --> 01:57:24,240 INDELIBLY MARKED. BY THE WAY 2585 01:57:24,240 --> 01:57:25,480 THESE ARE HEALTHY AS ADIPOSE 2586 01:57:25,480 --> 01:57:28,680 TISSUE. 2587 01:57:28,680 --> 01:57:31,320 ESSENTIALLY THIS IS IMPORTANT 2588 01:57:31,320 --> 01:57:34,560 IN (INDISCERNIBLE), AN ACID 2589 01:57:34,560 --> 01:57:35,120 EXPANDS WITH H WE HAVE BEEN 2590 01:57:35,120 --> 01:57:35,720 INTERESTED IN THIS ORGAN AND 2591 01:57:35,720 --> 01:57:36,240 EMILY TOUCHED UPON THIS 2592 01:57:36,240 --> 01:57:38,480 YESTERDAY. ONE OF THE THINGS 2593 01:57:38,480 --> 01:57:40,000 THAT WE FOUND EARLY ON IN 2594 01:57:40,000 --> 01:57:41,440 ADDITION TO LOSS OF INNATE 2595 01:57:41,440 --> 01:57:46,920 CELLS LIKE ILCS, WAS A 2596 01:57:46,920 --> 01:57:47,440 REDUCTION OF HOMEOSTATIC 2597 01:57:47,440 --> 01:57:51,200 MACROPHAGES THROUGH AGE. BY 2598 01:57:51,200 --> 01:57:51,760 THE WAY THIS IS OPPOSITE TO 2599 01:57:51,760 --> 01:57:58,080 WHAT YOU MIGHT EXPECT WITH 2600 01:57:58,080 --> 01:57:58,720 OBESITY; OBESITY IS NOT ALWAYS 2601 01:57:58,720 --> 01:57:59,280 ACCELERATION OF AGING. WITH 2602 01:57:59,280 --> 01:57:59,880 OBESITY YOU GET EXPANSION OF 2603 01:57:59,880 --> 01:58:04,600 MACROPHAGES. 2604 01:58:04,600 --> 01:58:05,080 WE ARE INTERESTED IN THE 2605 01:58:05,080 --> 01:58:05,720 RESIDENT MACROPHAGES AND WHAT 2606 01:58:05,720 --> 01:58:06,920 THEY HAVE BEEN DOING THE 2607 01:58:06,920 --> 01:58:07,560 ORIGINAL DISCOVERY WAS MADE BY 2608 01:58:07,560 --> 01:58:08,200 CHRISTINA, A COLLEAGUE OF MEAN 2609 01:58:08,200 --> 01:58:16,120 WHAT SHE WAS STILL IN MY LAB. 2610 01:58:16,120 --> 01:58:16,680 AND THE MAIN THING WE FIND 2611 01:58:16,680 --> 01:58:19,160 QUITE SERENDIPITOUSLY WAS THAT 2612 01:58:19,160 --> 01:58:21,600 THE MACROPHAGES ARE INFLAMED. 2613 01:58:21,600 --> 01:58:22,160 ONE THING WE ARE DOING IS 2614 01:58:22,160 --> 01:58:26,840 BASICALLY BREAKING DOWN THE 2615 01:58:26,840 --> 01:58:27,360 NEUROTRANSMITTERS LIKE 2616 01:58:27,360 --> 01:58:29,440 CATECHOLAMINES MADE BY THE 2617 01:58:29,440 --> 01:58:30,000 NERVOUS SYSTEM AND THE UP 2618 01:58:30,000 --> 01:58:37,680 REGULATION OF THE ENZYME. THE 2619 01:58:37,680 --> 01:58:38,320 KEY FINDING WAS THAT CHRISTINA 2620 01:58:38,320 --> 01:58:38,960 WAS ABLE TO SHOW THE REDUCTION 2621 01:58:38,960 --> 01:58:42,760 OF LIPOLYSIS THAT HAPPENS WITH 2622 01:58:42,760 --> 01:58:43,360 AGES DUE TO THE BREAKDOWN OF 2623 01:58:43,360 --> 01:58:44,000 THIS INFLAMED MACROPHAGES THAT 2624 01:58:44,000 --> 01:58:44,360 BREAKS DOWN THE 2625 01:58:44,360 --> 01:58:49,720 (INDISCERNIBLE). 2626 01:58:49,720 --> 01:58:53,680 THAT LED US INTO THIS AREA 2627 01:58:53,680 --> 01:58:54,320 WHICH WE COVERED AND LED TO THE 2628 01:58:54,320 --> 01:58:54,920 DISCOVERY OF WHAT WE THINK OF 2629 01:58:54,920 --> 01:58:55,400 THE CELLS IS NOW NERVE 2630 01:58:55,400 --> 01:58:56,360 ASSOCIATED MACROPHAGES. 2631 01:58:56,360 --> 01:59:02,920 THIS IS A PHOTON IMAGE DONE BY 2632 01:59:02,920 --> 01:59:08,680 CHRISTINA ON MG ANIMALS. YOU 2633 01:59:08,680 --> 01:59:13,840 CAN IDENTIFY THE SYMPATHETIC 2634 01:59:13,840 --> 01:59:17,760 NATURE, AND YOU NOTICE THE 2635 01:59:17,760 --> 01:59:20,200 CELLS, BECAUSE THERE ARE CELLS 2636 01:59:20,200 --> 01:59:20,760 THAT ARE RESIDENTS ON THE 2637 01:59:20,760 --> 01:59:24,720 NERVES. YOU CAN SEE THAT THEY 2638 01:59:24,720 --> 01:59:29,440 ARE BASICALLY HAVING DENDRITES 2639 01:59:29,440 --> 01:59:32,040 AND SOME ARE STRETCHED OUT. 2640 01:59:32,040 --> 01:59:32,600 THEY ARE OBVIOUSLY QUITE 2641 01:59:32,600 --> 01:59:33,760 DISTINCT. 2642 01:59:33,760 --> 01:59:35,400 BECAUSE WE WERE REALLY 2643 01:59:35,400 --> 01:59:38,480 INTRIGUED, CHRISTINA AND I, IF 2644 01:59:38,480 --> 01:59:39,680 THEY HAVE THESE MONOAMINE 2645 01:59:39,680 --> 01:59:43,920 OXIDASE, WHERE ARE THE -- FROM? 2646 01:59:43,920 --> 01:59:48,600 AND THEY LET US TO FIND 2647 01:59:48,600 --> 01:59:50,600 NERVES-- NERVES ARE REALLY 2648 01:59:50,600 --> 01:59:51,200 IMPORTANT-- THERE ARE NERVES 2649 01:59:51,200 --> 01:59:55,200 THAT RESIDE ON THE CELLS. AT 2650 01:59:55,200 --> 01:59:55,760 THE TIME WE THOUGHT IT WAS 2651 01:59:55,760 --> 01:59:57,440 DEGRADATION OF CATECHOLAMINES. 2652 01:59:57,440 --> 01:59:58,120 WE KNOW NOW THAT THERE IS MUCH 2653 01:59:58,120 --> 02:00:01,680 MORE HAPPENING IN THE AGE TO 2654 02:00:01,680 --> 02:00:02,400 VISCERAL FAT, NOT ONLY 2655 02:00:02,400 --> 02:00:02,880 DEGRADATION BUT ALSO 2656 02:00:02,880 --> 02:00:07,280 (INDISCERNIBLE). 2657 02:00:07,280 --> 02:00:07,800 HERE YOU ARE LOOKING AT 2658 02:00:07,800 --> 02:00:08,600 CLARIFIED IMAGES OF VISCERAL 2659 02:00:08,600 --> 02:00:11,400 ADIPOSE TISSUE. IT IS PRETTY 2660 02:00:11,400 --> 02:00:13,880 OBVIOUS. THIS WAS DONE IN 2661 02:00:13,880 --> 02:00:18,640 COLLABORATION WITH -- --. YOU 2662 02:00:18,640 --> 02:00:19,280 CAN SEE CLEARLY THAT WITH AGING 2663 02:00:19,280 --> 02:00:20,280 NOT ONLY DO YOU HAVE MACHINERY 2664 02:00:20,280 --> 02:00:22,960 THAT DEGRADES CATECHOLAMINE, 2665 02:00:22,960 --> 02:00:24,520 BUT YOU HAVE LESS SYMPATHETIC 2666 02:00:24,520 --> 02:00:28,760 NERVES. WHAT IS GOING ON? 2667 02:00:28,760 --> 02:00:29,360 SO THIS IS A PROJECT THAT HAS 2668 02:00:29,360 --> 02:00:33,080 BEEN GOING ON FOR A WHILE IN 2669 02:00:33,080 --> 02:00:33,600 THE LAB AND IT HAS BEEN 2670 02:00:33,600 --> 02:00:35,760 CHALLENGING AND IT IS GREAT TO 2671 02:00:35,760 --> 02:00:36,360 HAVE FANTASTIC SCIENTISTS IN 2672 02:00:36,360 --> 02:00:44,080 THE LAB -- -- A POST DOC AND A 2673 02:00:44,080 --> 02:00:44,720 STUDENT IN THE LAB LEADING THIS 2674 02:00:44,720 --> 02:00:49,880 PROJECT AND BASICALLY LC IS 2675 02:00:49,880 --> 02:00:50,480 TRYING TO UNDERSTAND WHAT ARE 2676 02:00:50,480 --> 02:00:58,400 THE CELLS AND WHAT ARE THEY 2677 02:00:58,400 --> 02:00:58,960 DOING? LC EMPLOYED SCANNED 2678 02:00:58,960 --> 02:01:06,760 ELECTRON MICROSCOPY. YOU CAN 2679 02:01:06,760 --> 02:01:07,280 FIND THE NERVE ASSOCIATED 2680 02:01:07,280 --> 02:01:07,840 MACROPHAGES RIGHT NEXT TO A 2681 02:01:07,840 --> 02:01:13,840 MYELINATED AXON. 2682 02:01:13,840 --> 02:01:14,440 AND YOU WILL FIND THE COMPLETE 2683 02:01:14,440 --> 02:01:15,000 WITH ADULT ANIMALS THE OLD 2684 02:01:15,000 --> 02:01:15,560 MACROPHAGES ARE LOADED WITH 2685 02:01:15,560 --> 02:01:16,160 MYELIN; IT MAY HAVE SOMETHING 2686 02:01:16,160 --> 02:01:16,640 TO DO WITH POTENTIALLY 2687 02:01:16,640 --> 02:01:19,960 IMPAIRMENT OF NERVE FUNCTION. 2688 02:01:19,960 --> 02:01:23,800 SO THE APPROACH WE TOOK WAS TO 2689 02:01:23,800 --> 02:01:24,440 SEE-- MY COLLABORATORS GET OLD 2690 02:01:24,440 --> 02:01:27,040 COLLABORATING WITH ME, TOO MUCH 2691 02:01:27,040 --> 02:01:32,160 STRESS, TOO MUCH STRESS! BUT 2692 02:01:32,160 --> 02:01:34,920 YOU KNOW, BECAUSE THE APPROACH 2693 02:01:34,920 --> 02:01:37,360 WE TOOK WAS AN REACH CELLS THAT 2694 02:01:37,360 --> 02:01:45,400 ARE TRULY RESIDENTS. EMILY HAD 2695 02:01:45,400 --> 02:01:46,040 ESTABLISHED THIS PROCEDURE SHE 2696 02:01:46,040 --> 02:01:53,760 TOLD ABOUT-- SELF SEQUENCING 2697 02:01:53,760 --> 02:01:54,280 AND CHRISTINA FOUND THAT 2698 02:01:54,280 --> 02:01:55,280 MONOAMINE OXIDASE IS ONE OF THE 2699 02:01:55,280 --> 02:01:55,840 GENES THAT IS EXPRESSED IN 2700 02:01:55,840 --> 02:01:58,520 NERVE ASSOCIATED MACROPHAGES. 2701 02:01:58,520 --> 02:01:59,120 WHAT WE DID IN COLLABORATION 2702 02:01:59,120 --> 02:02:07,600 WITH MY FRIEND AND COLLEAGUE -- 2703 02:02:07,600 --> 02:02:08,200 -- THE ANALYZE WHAT DATA WAS 2704 02:02:08,200 --> 02:02:10,280 OUT THERE TO SEE IF WE COULD 2705 02:02:10,280 --> 02:02:11,360 IDENTIFY NERVE ASSOCIATED 2706 02:02:11,360 --> 02:02:12,120 MACROPHAGE SIGNATURES 2707 02:02:12,120 --> 02:02:14,400 TRANSCRIPTIONALLY. THERE'S A 2708 02:02:14,400 --> 02:02:15,000 COUPLE OF CLUSTERS THAT ENRICH 2709 02:02:15,000 --> 02:02:18,000 FOR IT. MONOAMINE OXIDASE IS 2710 02:02:18,000 --> 02:02:20,040 ONE OF THE THINGS THAT 2711 02:02:20,040 --> 02:02:23,080 REGULATES IT. THE OFFICE 2712 02:02:23,080 --> 02:02:23,720 QUESTIONS IS WHAT HAPPENED WITH 2713 02:02:23,720 --> 02:02:26,800 AGE? 2714 02:02:26,800 --> 02:02:27,360 HE A RESIDENT MACROPHAGES IN 2715 02:02:27,360 --> 02:02:28,200 THE ADULT MOUSE, AND ON THE 2716 02:02:28,200 --> 02:02:31,040 RIGHT ARE THE OLD ANIMALS. AND 2717 02:02:31,040 --> 02:02:33,240 SO WHAT YOU WILL SEE IS THAT 2718 02:02:33,240 --> 02:02:33,880 THERE ARE CERTAIN CLUSTERS THAT 2719 02:02:33,880 --> 02:02:35,120 ARE DISAPPEARING. YOU CAN SEE 2720 02:02:35,120 --> 02:02:40,160 THIS HERE. AND THINGS 2721 02:02:40,160 --> 02:02:40,760 COMPLETELY EMERGE, WHICH ARE 2722 02:02:40,760 --> 02:02:42,840 NOT PRESENT IN YOUNG ANIMALS. 2723 02:02:42,840 --> 02:02:46,840 WHAT STRUCK US WAS THAT THESE 2724 02:02:46,840 --> 02:02:47,440 TWO CLUSTERS OF THE CLUSTERS 2725 02:02:47,440 --> 02:02:49,680 THAT WE THINK ARE RICH FOR 2726 02:02:49,680 --> 02:02:54,680 NERVE ASSOCIATED MACROPHAGES. 2727 02:02:54,680 --> 02:02:55,320 AND ALSO WITH H1 OF THE THINGS 2728 02:02:55,320 --> 02:02:58,760 THAT IS HAPPENING IN THE CELLS 2729 02:02:58,760 --> 02:02:59,400 IS ACTIVATION OF THE COMPLEMENT 2730 02:02:59,400 --> 02:03:00,120 WHICH I THINK WE HAVE HEARD 2731 02:03:00,120 --> 02:03:02,200 OVER AND OVER AGAIN THROUGHOUT 2732 02:03:02,200 --> 02:03:02,800 THIS MEETING SO IT IS REALLY 2733 02:03:02,800 --> 02:03:11,240 IMPORTANT MOLECULE. 2734 02:03:11,240 --> 02:03:11,720 I'M NOT GOING TO GO INTO 2735 02:03:11,720 --> 02:03:12,320 DETAILS THERE IS A POSTER 2736 02:03:12,320 --> 02:03:12,960 OUTSIDE AND YOU CAN TALK TO OUT 2737 02:03:12,960 --> 02:03:15,760 ELSE ABOUT IT. 2738 02:03:15,760 --> 02:03:16,360 HERE'S ANOTHER INTRIGUING FIND 2739 02:03:16,360 --> 02:03:22,960 THAT LC MADE. THESE MACROPHAGES 2740 02:03:22,960 --> 02:03:24,160 ARE NOT ONLY VERY NEURAL BUT 2741 02:03:24,160 --> 02:03:27,640 ALSO INTRA-NEURAL. IN THE 2742 02:03:27,640 --> 02:03:28,240 GREEN AT THE NERVE ASSOCIATED 2743 02:03:28,240 --> 02:03:33,160 MACROPHAGES. AND WE HAVE NOT A 2744 02:03:33,160 --> 02:03:33,680 WAY TO ISOLATE THEM AND 2745 02:03:33,680 --> 02:03:35,040 CHARACTERIZE THEM. I DO HAVE 2746 02:03:35,040 --> 02:03:37,160 TIME TO GO OVER IT OTHERWISE -- 2747 02:03:37,160 --> 02:03:43,440 WILL KICK ME OUT. HERE ARE A 2748 02:03:43,440 --> 02:03:46,160 FEW TAKE-HOME POINTS. NUMBER 2749 02:03:46,160 --> 02:03:52,720 ONE IS NAMS ARE PRESENT IN 2750 02:03:52,720 --> 02:04:01,480 NICHES IN ADIPOSE TISSUE. AND 2751 02:04:01,480 --> 02:04:02,040 ARE TRANSCRIPTIONALLY 2752 02:04:02,040 --> 02:04:05,520 HETEROGENOUS. 2753 02:04:05,520 --> 02:04:08,960 MAOA ENRICHES FOR A SUBSET OF 2754 02:04:08,960 --> 02:04:13,160 NAMS. 2755 02:04:13,160 --> 02:04:13,920 LOSS OF ADIPOSE INNOVATION IS 2756 02:04:13,920 --> 02:04:16,040 ASSOCIATED WITH NAM ACTIVATION 2757 02:04:16,040 --> 02:04:17,720 IN AGING. 2758 02:04:17,720 --> 02:04:24,120 DOES TARGETING NAMS CONTROLLER 2759 02:04:24,120 --> 02:04:28,800 FUNCTION ORGANISMAL AGING? WE 2760 02:04:28,800 --> 02:04:30,960 HAVE TENTATIVE EVIDENCE THAT 2761 02:04:30,960 --> 02:04:31,560 SUGGEST THE INFLUENCE ON THE 2762 02:04:31,560 --> 02:04:32,880 INTEGRITY OF THE NERVES. I HAVE 2763 02:04:32,880 --> 02:04:35,840 TWO MINUTES? THREE MINUTES. 2764 02:04:35,840 --> 02:04:38,800 THAT IS A LOT. 2765 02:04:38,800 --> 02:04:41,040 I WOULD END BY SHOWING YOU 2766 02:04:41,040 --> 02:04:44,080 SOME DATA THAT WE HAVE RECENTLY 2767 02:04:44,080 --> 02:04:45,200 PUBLISHED, WITH THE IDEA THAT, 2768 02:04:45,200 --> 02:04:51,520 YOU KNOW, WHEN THE HOST HAS AN 2769 02:04:51,520 --> 02:04:52,120 NEGATIVE BALANCE HOW DOES IT 2770 02:04:52,120 --> 02:04:52,720 INTEGRATE WITH THE IMMUNE 2771 02:04:52,720 --> 02:05:00,040 SYSTEM AND INFLAMMATION?WE HAVE 2772 02:05:00,040 --> 02:05:02,520 KNOWN FOR AGES. AT THIS POINT 2773 02:05:02,520 --> 02:05:04,400 IT HAS TO INTEGRATE MULTIPLE 2774 02:05:04,400 --> 02:05:05,000 RESPONSES, MULTIPLE NEURAL 2775 02:05:05,000 --> 02:05:06,840 RESPONSES. 2776 02:05:06,840 --> 02:05:08,280 ONE PROBLEM WITH THIS THOUGH, 2777 02:05:08,280 --> 02:05:12,400 WE DO GET LONGEVITY IN RODENTS 2778 02:05:12,400 --> 02:05:13,000 AND IN MODEL ORGANISMS BUT IT 2779 02:05:13,000 --> 02:05:15,320 COMES WITH THE TRADE-OFF. 2780 02:05:15,320 --> 02:05:16,800 SOMETHING THAT WE HAVE KNOWN 2781 02:05:16,800 --> 02:05:17,400 FOREVER, BUT WE DON'T WANT TO 2782 02:05:17,400 --> 02:05:21,720 SAY IT TOO LONG. 2783 02:05:21,720 --> 02:05:22,320 ONE IS THAT THE ANIMALS HAVE 2784 02:05:22,320 --> 02:05:22,920 PROBLEMS REGULATING CORE BODY 2785 02:05:22,920 --> 02:05:26,760 TEMPERATURE. THEY HAVE 2786 02:05:26,760 --> 02:05:35,000 REPRODUCTIVE STATUS, THEY DO 2787 02:05:35,000 --> 02:05:35,640 NOT REPRODUCE WELL AND THEY DIE 2788 02:05:35,640 --> 02:05:36,280 OF INFECTIONS BECAUSE OF IMMUNE 2789 02:05:36,280 --> 02:05:38,720 RESPONSE PROBLEMS. YOU WONDER 2790 02:05:38,720 --> 02:05:40,960 WHETHER IT IS PHYSIOLOGICALLY 2791 02:05:40,960 --> 02:05:41,600 RELEVANT. WHAT SHOULD WE BOTHER 2792 02:05:41,600 --> 02:05:43,640 TO STUDY IT? AND THAT IS WHAT 2793 02:05:43,640 --> 02:05:45,920 THE NIH WANTED TO DO. THERE 2794 02:05:45,920 --> 02:05:50,720 ARE ACTUALLY STUDIES THAT SHOW 2795 02:05:50,720 --> 02:05:51,280 THAT IN ANIMALS OF CERTAIN 2796 02:05:51,280 --> 02:05:55,120 STRAINS NOT ONLY DID NOT LIVE 2797 02:05:55,120 --> 02:05:59,880 LONGER BUT IN FACT LIVE SHORTER. 2798 02:05:59,880 --> 02:06:00,480 I'M NOT GOING TO BELABOR THE 2799 02:06:00,480 --> 02:06:01,040 POINT THAT MARK DAVIS SAID 2800 02:06:01,040 --> 02:06:05,160 ENOUGH ABOUT IT. 2801 02:06:05,160 --> 02:06:05,800 THE KEY POINT IS THAT I THINK 2802 02:06:05,800 --> 02:06:06,800 RANDOMIZED CONTROLLED TRIALS 2803 02:06:06,800 --> 02:06:07,400 REALLY CRITICAL, ESPECIALLY FOR 2804 02:06:07,400 --> 02:06:13,920 THE DIET IN HUMANS. AND 2805 02:06:13,920 --> 02:06:14,440 WORKING WITH A GROUP OF 2806 02:06:14,440 --> 02:06:15,040 PSYCHOLOGISTS AND PSYCHIATRISTS 2807 02:06:15,040 --> 02:06:15,600 I REALIZED ONE OF THE KEY 2808 02:06:15,600 --> 02:06:16,840 THINGS WE DO NOT PAY ATTENTION 2809 02:06:16,840 --> 02:06:24,680 TO IS THAT OUR MICE AND FLIES 2810 02:06:24,680 --> 02:06:25,280 DO NOT SIGN CONSENT FORMS TO 2811 02:06:25,280 --> 02:06:25,880 LIMIT THE CALORIES AND HUMANS 2812 02:06:25,880 --> 02:06:27,320 DO. THERE IS A BIG VARIABLE 2813 02:06:27,320 --> 02:06:29,400 BECAUSE PEOPLE ARE MOTIVATED; 2814 02:06:29,400 --> 02:06:31,920 THEY KNOW THEY ARE NOT GOING TO 2815 02:06:31,920 --> 02:06:32,560 STARVE. THE DOES NOT INDUCE THE 2816 02:06:32,560 --> 02:06:42,840 STRESS RESPONSE. 2817 02:06:43,560 --> 02:06:44,120 THE IDEA WAS THAT WE STUDIED 2818 02:06:44,120 --> 02:06:44,680 THIS WITH RELEVANCE TO THE 2819 02:06:44,680 --> 02:06:45,240 HUMAN PHYSIOLOGY, AND IF WE 2820 02:06:45,240 --> 02:06:45,840 COULD IDENTIFY CAUSALITY WE 2821 02:06:45,840 --> 02:06:47,520 COULD DISCOVER SOMETHING NEW. 2822 02:06:47,520 --> 02:06:48,080 THAT IS A TRIAL AND I'M NOT 2823 02:06:48,080 --> 02:06:48,680 GOING TO SHOW YOU BECAUSE IT 2824 02:06:48,680 --> 02:06:55,280 WAS PUBLISHED, DONE BY CALERIE. 2825 02:06:55,280 --> 02:06:55,800 THE IDEA IS TO RESTRICT 2826 02:06:55,800 --> 02:06:56,320 CALORIES FOR TWO YEARS IN 2827 02:06:56,320 --> 02:06:58,600 HEALTHY PEOPLE, AND STUDY THEM. 2828 02:06:58,600 --> 02:07:08,200 PEOPLE CAN RESTRICT ONLY 15% 2829 02:07:08,200 --> 02:07:08,800 AND END TO MAKE AN IMPORTANT 2830 02:07:08,800 --> 02:07:10,560 POINT. WE ARE GOING TO LOOK AT 2831 02:07:10,560 --> 02:07:13,000 BIOMARKERS. WHAT WILL IT TELL 2832 02:07:13,000 --> 02:07:13,600 YOU? DID YOU ALTER THE COURSE 2833 02:07:13,600 --> 02:07:15,400 OF ANYTHING? LUCKILY THIS IS 2834 02:07:15,400 --> 02:07:18,880 WHY PEOPLE SHOULD STUDY 2835 02:07:18,880 --> 02:07:20,280 IMMUNOLOGY. BECAUSE AGING OF 2836 02:07:20,280 --> 02:07:21,200 CERTAIN ORGANS RECEIPT AGING OF 2837 02:07:21,200 --> 02:07:28,760 OTHER ORGANS. 2838 02:07:28,760 --> 02:07:29,320 AND YOU LOOK AT THE CHEMICAL 2839 02:07:29,320 --> 02:07:29,960 SHIFT OF THE MRI OF THE THYMUS 2840 02:07:29,960 --> 02:07:30,520 IN A HEALTHY PERSON ON THE 2841 02:07:30,520 --> 02:07:34,720 LEFT. EVERYTHING IS ALMOST 2842 02:07:34,720 --> 02:07:39,320 COMPLETELY INTO FAT. WE 2843 02:07:39,320 --> 02:07:39,920 FOCUSED ON THE CORNER AND WAS 2844 02:07:39,920 --> 02:07:43,160 STRUCK US WAS AMAZING. WHEN THE 2845 02:07:43,160 --> 02:07:47,600 DATA WAS UNBLINDED, WE FOUND 2846 02:07:47,600 --> 02:07:50,920 WAS IN FACT THIS IS A 2847 02:07:50,920 --> 02:07:51,560 REPRESENTATIVE INDIVIDUAL THAT 2848 02:07:51,560 --> 02:07:52,160 CAME AS A BASELINE AFTER TWO 2849 02:07:52,160 --> 02:07:57,360 YEARS OF CR. , YOU ARE LOOKING 2850 02:07:57,360 --> 02:07:57,920 AT FAT SATURATION SIGNAL IN 2851 02:07:57,920 --> 02:07:58,560 THIS CASE YOU ARE LOOKING AT A 2852 02:07:58,560 --> 02:07:59,200 SIGNAL FROM THE WATER. LYMPHOID 2853 02:07:59,200 --> 02:08:07,600 TISSUE. 2854 02:08:07,600 --> 02:08:08,200 SO THIS INTERVENTION WAS WHAT 2855 02:08:08,200 --> 02:08:18,320 ENABLED THE REVERSE. YOU 2856 02:08:18,320 --> 02:08:21,920 MOBILIZE THE LIPID. I DON'T 2857 02:08:21,920 --> 02:08:22,480 HAVE TIME BUT YESTERDAY WE 2858 02:08:22,480 --> 02:08:23,120 HEARD THERE ARE MARKERS WE CAN 2859 02:08:23,120 --> 02:08:26,240 STUDY. I'M GOING TO END BY 2860 02:08:26,240 --> 02:08:29,440 SHOWING YOU WORK FROM OLGA 2861 02:08:29,440 --> 02:08:39,080 SPADARO. WE ALSO SEQUENCED THE 2862 02:08:39,080 --> 02:08:39,680 ADIPOSE, IN THOSE DAYS THERE 2863 02:08:39,680 --> 02:08:40,320 WAS NO SINGLE CELL SEQUENCING. 2864 02:08:40,320 --> 02:08:41,480 I STARTED MY LAB IN 2007. MAX 2865 02:08:41,480 --> 02:08:42,000 YOU ARE NOT THE ONLY ONE 2866 02:08:42,000 --> 02:08:44,840 GETTING OLDER. 2867 02:08:44,840 --> 02:08:46,080 I WILL AND BY SHOWING YOU THE 2868 02:08:46,080 --> 02:08:56,600 SUMMARY THAT WE WERE ABLE TO 2869 02:08:58,240 --> 02:08:58,680 FIND REALLY REMARKABLE 2870 02:08:58,680 --> 02:08:59,240 DIFFERENCES WITH CALORIE 2871 02:08:59,240 --> 02:08:59,760 RESTRICTION IN THE HUMAN 2872 02:08:59,760 --> 02:09:01,640 TRANSCRIPTOME. THIS TRIAL HAS 2873 02:09:01,640 --> 02:09:05,240 ENDED THE DEBATE WHETHER CR IS 2874 02:09:05,240 --> 02:09:06,640 RELEVANT TO HUMAN PHYSIOLOGY OR 2875 02:09:06,640 --> 02:09:09,320 NOT. ABSOLUTELY IT IS RELEVANT. 2876 02:09:09,320 --> 02:09:15,920 IT AFFECTS LONGEVITY. THE 15% 2877 02:09:15,920 --> 02:09:16,480 REDUCTION DOES NOT SEEM TO 2878 02:09:16,480 --> 02:09:17,120 MATTER WHAT TIME OF THE DAY YOU 2879 02:09:17,120 --> 02:09:17,720 EAT YOUR FOOD OR WHAT YOU EAT 2880 02:09:17,720 --> 02:09:18,920 AS LONG AS YOU REDUCE YOUR 2881 02:09:18,920 --> 02:09:21,800 CALORIES. 2882 02:09:21,800 --> 02:09:24,320 VERY CRITICAL POINT. I THINK 2883 02:09:24,320 --> 02:09:27,240 THE HOLY GRAIL OF IMMUNOLOGY. 2884 02:09:27,240 --> 02:09:30,280 THYMIC AGING IS REVERSIBLE IN 2885 02:09:30,280 --> 02:09:30,920 HUMANS. IF YOU CAN TARGET IT IN 2886 02:09:30,920 --> 02:09:34,640 THE RIGHT WAY. I DO NOT SHOW 2887 02:09:34,640 --> 02:09:35,240 YOU THE DATE OF THIS WAS JUST 2888 02:09:35,240 --> 02:09:35,800 PUBLISHED LAST YEAR THAT WE 2889 02:09:35,800 --> 02:09:36,440 WERE ABLE TO HARNESS AT LEAST 2890 02:09:36,440 --> 02:09:46,960 TWO MOLECULES PLA2G7 AND SPARC. 2891 02:09:47,960 --> 02:09:48,520 ONLY THE FUTURE WILL TELL US 2892 02:09:48,520 --> 02:09:49,120 WHETHER WE CAN ACTUALLY DEPLOY 2893 02:09:49,120 --> 02:09:55,320 THESE INTERVENTIONS. 2894 02:09:55,320 --> 02:09:55,920 LAST THIS THING WOULD NEVER BE 2895 02:09:55,920 --> 02:09:59,800 POSSIBLE UNLESS THERE WAS A 2896 02:09:59,800 --> 02:10:00,400 TEAM SCIENCE APPROACH LED BY A 2897 02:10:00,400 --> 02:10:01,000 GROUP OF INVESTIGATORS THAT 2898 02:10:01,000 --> 02:10:03,520 WERE PART OF THE CALORIE. SORRY 2899 02:10:03,520 --> 02:10:09,640 I WENT A LITTLE BIT OVER. 2900 02:10:09,640 --> 02:10:12,240 >>THANK YOU. ALWAYS GREAT 2901 02:10:12,240 --> 02:10:16,200 TALK FROM YOU. YES PLEASE 2902 02:10:16,200 --> 02:10:16,840 SARAH? 2903 02:10:16,840 --> 02:10:20,680 >>I CANNOT HELP BUT ASK. THE 2904 02:10:20,680 --> 02:10:21,280 FIRST IS ABOUT THE LEVEL OF 2905 02:10:21,280 --> 02:10:31,720 INNOVATION. (CORRECTION) 2906 02:10:35,120 --> 02:10:35,680 INTERVENTION. DO YOU THINK THAT 2907 02:10:35,680 --> 02:10:36,480 HYPER INTERVENTION RESULTS 2908 02:10:36,480 --> 02:10:47,040 (INDISCERNIBLE)? I AM WONDERING 2909 02:10:51,920 --> 02:10:52,480 IF THE MACROPHAGE POPULATION 2910 02:10:52,480 --> 02:10:57,480 COULD BE EXPANDED? HOW CAN IT 2911 02:10:57,480 --> 02:11:00,440 BE ATTRACTED SYNTHETICALLY? 2912 02:11:00,440 --> 02:11:02,520 >>I DID NOT SHOW YOU THE DATA, 2913 02:11:02,520 --> 02:11:03,080 THE LINEAGE TRACKING OF THE 2914 02:11:03,080 --> 02:11:06,080 CELLS AND WHERE THEY COME FROM. 2915 02:11:06,080 --> 02:11:06,680 THEY ARE NOT AS CLEAN-CUT AS 2916 02:11:06,680 --> 02:11:09,640 THE MICROGLIA. THEY ARE ONLY 2917 02:11:09,640 --> 02:11:10,240 PARTIAL FROM THE YOLK SAC AND 2918 02:11:10,240 --> 02:11:16,720 PARTIAL FROM THE FETAL LIVER. 2919 02:11:16,720 --> 02:11:17,320 A CRITICAL POINT YOU RAISE IF 2920 02:11:17,320 --> 02:11:18,640 WE CAN JUST EXPAND THE 2921 02:11:18,640 --> 02:11:19,280 HOMEOSTATIC MACROPHAGES I THINK 2922 02:11:19,280 --> 02:11:19,880 IT WILL BE VERY BENEFICIAL IN 2923 02:11:19,880 --> 02:11:22,080 CLEANING UP STUFF. HOW TO DO 2924 02:11:22,080 --> 02:11:24,920 THAT? WE ARE NOT AT THAT POINT. 2925 02:11:24,920 --> 02:11:35,400 THESE MACROPHAGES OR MAMS ARE 2926 02:11:37,920 --> 02:11:41,000 DEDICATED TO THE NERVES. THEY 2927 02:11:41,000 --> 02:11:42,360 ARE VERY UNIQUE AND TIME WILL 2928 02:11:42,360 --> 02:11:43,000 TELL WHAT THEY REALLY MEAN FOR 2929 02:11:43,000 --> 02:11:46,320 THIS. RIGHT NOW THERE IS NO 2930 02:11:46,320 --> 02:11:49,040 WAY TO TARGET THEM. WE ARE IN 2931 02:11:49,040 --> 02:11:49,600 THE PROCESS OF DISCOVERING 2932 02:11:49,600 --> 02:11:53,520 THOSE PATHWAYS. 2933 02:11:53,520 --> 02:12:03,800 >>ANOTHER QUESTION? 2934 02:12:04,040 --> 02:12:04,600 >>I SAW A LECTURE RECENTLY 2935 02:12:04,600 --> 02:12:09,360 FROM-- ACETYLCHOLINE 2936 02:12:09,360 --> 02:12:09,960 (INDISCERNIBLE)-- INTERESTED 2937 02:12:09,960 --> 02:12:10,520 ABOUT EXERCISE AND CALORIC 2938 02:12:10,520 --> 02:12:21,080 RESTRICTION. I AM WONDERING IF 2939 02:12:21,080 --> 02:12:21,560 THERE IS AN EXERCISE 2940 02:12:21,560 --> 02:12:22,200 EQUIVALENCY ALSO WITH YOUR 15% 2941 02:12:22,200 --> 02:12:23,040 REDUCTION? 2942 02:12:23,040 --> 02:12:25,640 >>IT WAS-- WHO FIRST SHOWED 2943 02:12:25,640 --> 02:12:29,160 THAT (INDISCERNIBLE) -- I THINK 2944 02:12:29,160 --> 02:12:31,480 IT COULD BE REALLY IMPORTANT. 2945 02:12:31,480 --> 02:12:32,120 WE HAVE NOT LOOKED INTO IT AND 2946 02:12:32,120 --> 02:12:36,320 IT COULD BE IMPORTANT BECAUSE 2947 02:12:36,320 --> 02:12:37,840 -- DOES NOT HAVE 2948 02:12:37,840 --> 02:12:41,000 PARASYMPATHETIC INTERRELATION. 2949 02:12:41,000 --> 02:12:41,600 I DON'T HAVE DATA TO SAY THE 2950 02:12:41,600 --> 02:12:42,200 SECOND QUESTION WAS EXERCISE 2951 02:12:42,200 --> 02:12:46,080 AND CR? 2952 02:12:46,080 --> 02:12:49,000 >>LOOKING AT ATHLETES, EATING 2953 02:12:49,000 --> 02:12:52,920 IS A BIG PART OF IT. AND I 2954 02:12:52,920 --> 02:12:53,560 WONDER OF EXERCISES EQUIVALENT 2955 02:12:53,560 --> 02:12:55,200 OF THE -- PART OF 2956 02:12:55,200 --> 02:12:57,360 (INDISCERNIBLE). 2957 02:12:57,360 --> 02:13:02,760 >>I MUST TELL YOU THIS. I WAS 2958 02:13:02,760 --> 02:13:04,880 RECENTLY GIVING A TALK 2959 02:13:04,880 --> 02:13:05,400 SOMEPLACE AND SOMEONE GET 2960 02:13:05,400 --> 02:13:07,080 REALLY ANNOYED WITH ME. THEY 2961 02:13:07,080 --> 02:13:13,920 THINK THAT I'M SOME SORT OF CR 2962 02:13:13,920 --> 02:13:14,560 PROPONENT AGAINST EXERCISE. I'M 2963 02:13:14,560 --> 02:13:19,720 NOT. BUT THERE ARE LOTS OF 2964 02:13:19,720 --> 02:13:21,600 STUDIES DONE BY PEOPLE THAT 2965 02:13:21,600 --> 02:13:22,120 HAVE SHOWN CLEARLY THAT 2966 02:13:22,120 --> 02:13:22,760 EXERCISE DOES NOT CAUSE WEIGHT 2967 02:13:22,760 --> 02:13:26,760 LOSS. THIS IS VERY 2968 02:13:26,760 --> 02:13:27,320 CONTROVERSIAL POINT. PEOPLE 2969 02:13:27,320 --> 02:13:31,440 HATE IT WHEN I SAY THAT. 2970 02:13:31,440 --> 02:13:32,080 BUT UNDER THEORY OF NEGATIVE 2971 02:13:32,080 --> 02:13:34,480 ENERGY BALANCE, UNLESS YOU ARE 2972 02:13:34,480 --> 02:13:35,080 IN NEGATIVE ENERGY BALANCE THE 2973 02:13:35,080 --> 02:13:38,280 EFFECTS OF CR AND EXERCISE ARE 2974 02:13:38,280 --> 02:13:38,880 NOT ANALOGOUS AND THAT IS THE 2975 02:13:38,880 --> 02:13:44,920 KEY POINT. IN CR YOU ARE IN 2976 02:13:44,920 --> 02:13:46,120 NEGATIVE ENERGY BALANCE AND 2977 02:13:46,120 --> 02:13:47,320 OTHER EFFECTS WHICH ARE NOT 2978 02:13:47,320 --> 02:13:48,400 ENERGY NEUTRAL ARE OBVIOUSLY 2979 02:13:48,400 --> 02:13:50,600 MEDIATED. CALORIE SHOWED THAT 2980 02:13:50,600 --> 02:13:57,200 IN PHASE 1, DONE WITH EXERCISE 2981 02:13:57,200 --> 02:13:57,800 AND DIET AND THERE WAS NO THE 2982 02:13:57,800 --> 02:13:59,320 EFFECT OF EXERCISE. SORRY. 2983 02:13:59,320 --> 02:13:59,840 >>BUT IT COULD BE STRESS 2984 02:13:59,840 --> 02:14:01,320 REDUCTION. 2985 02:14:01,320 --> 02:14:02,920 >>ABSOLUTELY. 2986 02:14:02,920 --> 02:14:06,080 >>THANK YOU DEEP. THANK YOU 2987 02:14:06,080 --> 02:14:08,000 FOR THE QUESTIONS. 2988 02:14:08,000 --> 02:14:08,520 I'M GOING TO INTRODUCE THE 2989 02:14:08,520 --> 02:14:13,040 NEXT SPEAKER MARIA MITTELBRUNN, 2990 02:14:13,040 --> 02:14:17,920 UNIVERSITY OF MADRID, SPAIN. 2991 02:14:17,920 --> 02:14:18,440 SHE WILL TALK ABOUT THE 2992 02:14:18,440 --> 02:14:21,040 MITOCHONDRIA DYSFUNCTION. 2993 02:14:21,040 --> 02:14:21,560 >>HELLO AND THANK YOU VERY 2994 02:14:21,560 --> 02:14:24,680 MUCH. THANK YOU TO THE 2995 02:14:24,680 --> 02:14:26,240 ORGANIZERS FOR THIS AMAZING 2996 02:14:26,240 --> 02:14:30,800 MEETING. 2997 02:14:30,800 --> 02:14:33,200 WHAT DO THEY HAVE IN COMMON? 2998 02:14:33,200 --> 02:14:36,640 THE HUMAN PATHOLOGIES, 2999 02:14:36,640 --> 02:14:40,160 CARDIOVASCULAR DISEASE, 3000 02:14:40,160 --> 02:14:43,160 METABOLIC DISORDERS, BONE AND 3001 02:14:43,160 --> 02:14:44,080 MUSCULAR DISEASES, AUTOIMMUNE 3002 02:14:44,080 --> 02:14:46,200 DISEASE? THEY HAVE THREE 3003 02:14:46,200 --> 02:14:48,080 FEATURES IN COMMON. THEY 3004 02:14:48,080 --> 02:14:51,400 DISRUPT THE (INDISCERNIBLE) 3005 02:14:51,400 --> 02:14:51,920 SPACES, THEY INVOLVE 3006 02:14:51,920 --> 02:14:58,280 INFLAMMATION -- AND THE THIRD 3007 02:14:58,280 --> 02:15:02,280 IS THEY INCREASE IN A SO THEY 3008 02:15:02,280 --> 02:15:06,200 ARE CONSIDERED AGE ASSOCIATED. 3009 02:15:06,200 --> 02:15:06,800 IN FACT WE KNOW THAT AGING IS 3010 02:15:06,800 --> 02:15:07,320 ASSOCIATED WITH CHRONIC 3011 02:15:07,320 --> 02:15:12,120 INFLAMMATION. WE LEARNED 3012 02:15:12,120 --> 02:15:12,720 YESTERDAY THAT WE CAN PREDICT 3013 02:15:12,720 --> 02:15:13,600 HOW WE AGE BY MEASURING 3014 02:15:13,600 --> 02:15:20,120 INFLAMMATORY -- IN OUR BLOOD. 3015 02:15:20,120 --> 02:15:21,480 WHAT IS THE CONTRIBUTION OF THE 3016 02:15:21,480 --> 02:15:24,280 DIFFERENT (INDISCERNIBLE)? ONE 3017 02:15:24,280 --> 02:15:24,880 OF THE QUESTIONS THAT WE HAVE 3018 02:15:24,880 --> 02:15:30,120 IN THE LAB. 3019 02:15:30,120 --> 02:15:30,680 WE ARE ESPECIALLY INTERESTED 3020 02:15:30,680 --> 02:15:36,120 IN T CELLS. IT WAS JUST 3021 02:15:36,120 --> 02:15:39,040 MENTIONED THAT THYMUS 3022 02:15:39,040 --> 02:15:39,560 INVOLUTION IS THE FIRST 3023 02:15:39,560 --> 02:15:44,080 MANIFESTATION OF AGING. THERE 3024 02:15:44,080 --> 02:15:50,280 IS A DRAMATIC CHANGE IN T CELL 3025 02:15:50,280 --> 02:15:58,360 REPERTOIRE. IF YOU HAVE HIGH 3026 02:15:58,360 --> 02:15:58,960 NUMBERS OF NAïVE CELLS, WE 3027 02:15:58,960 --> 02:16:02,640 START TO ACTUALLY T CELLS WITH 3028 02:16:02,640 --> 02:16:06,520 MEMORY, EFFECTOR AND SENESCENT 3029 02:16:06,520 --> 02:16:14,640 FEATURES. 3030 02:16:14,640 --> 02:16:15,240 SO IN THE T CELL COMPARTMENT 3031 02:16:15,240 --> 02:16:16,320 THIS MAKES US MORE VULNERABLE 3032 02:16:16,320 --> 02:16:24,680 TO INFECTIONS, CANCER, LOW 3033 02:16:24,680 --> 02:16:25,120 VACCINATION RESPONSE, 3034 02:16:25,120 --> 02:16:26,160 AUTOIMMUNITY AND COULD ALSO 3035 02:16:26,160 --> 02:16:31,120 CHRONIC INFLAMMATION. 3036 02:16:31,120 --> 02:16:32,400 SO A SUCCESSFUL INFLAMMATORY 3037 02:16:32,400 --> 02:16:36,920 RESPONSE AS YOU KNOW IS 3038 02:16:36,920 --> 02:16:40,960 (INDISCERNIBLE) THERE IS A PEAK 3039 02:16:40,960 --> 02:16:41,440 AND AFTER RESOLVING THE 3040 02:16:41,440 --> 02:16:43,760 CHANNELS YOU NEED TO STOP DOWN 3041 02:16:43,760 --> 02:16:45,440 THE INFORMATION FOR THE 3042 02:16:45,440 --> 02:16:55,080 INFLAMMATORY RESPONSE. IT IS 3043 02:16:55,080 --> 02:16:55,680 ESSENTIAL TO CONTROL CHRONIC 3044 02:16:55,680 --> 02:16:56,320 INFLAMMATION. WHILE THE IMMUNE 3045 02:16:56,320 --> 02:16:56,880 CELLS ADAPTER METABOLISM TO 3046 02:16:56,880 --> 02:16:59,560 THIS RESPONSE. AND WHEN THERE 3047 02:16:59,560 --> 02:17:06,160 IS (INDISCERNIBLE) THE DIESELS 3048 02:17:06,160 --> 02:17:07,680 DEPEND ON MITOCHONDRIA 3049 02:17:07,680 --> 02:17:18,000 (INDISCERNIBLE). 3050 02:17:18,920 --> 02:17:19,480 ONCE THE CHALLENGE IS FINAL 3051 02:17:19,480 --> 02:17:20,080 THEY HAVE INCREASED 3052 02:17:20,080 --> 02:17:26,680 (INDISCERNIBLE). 3053 02:17:26,680 --> 02:17:30,880 THEY COME BACK TO MORE 3054 02:17:30,880 --> 02:17:37,280 QUIESCENT METABOLISM. 3055 02:17:37,280 --> 02:17:37,800 THIS IS WHAT HAPPENS IN A 3056 02:17:37,800 --> 02:17:38,320 SUCCESSFUL INFLAMMATORY 3057 02:17:38,320 --> 02:17:39,320 RESPONSE WHEN WE ARE YOUNG. 3058 02:17:39,320 --> 02:17:43,880 WHEN WE ARE OLD, THE HYPOTHESIS 3059 02:17:43,880 --> 02:17:44,560 IS THAT IN MANY OF THE CELLS IN 3060 02:17:44,560 --> 02:17:48,480 THE BODY, IMMUNE CELLS ALSO 3061 02:17:48,480 --> 02:17:51,800 HAVE MITOCHONDRIA DECLINED. AND 3062 02:17:51,800 --> 02:17:52,360 AS A CONSEQUENCE HE ARE NOT 3063 02:17:52,360 --> 02:17:54,320 ABLE TO WRAP AROUND THE 3064 02:17:54,320 --> 02:17:59,840 METABOLISM TO FULFILL THE 3065 02:17:59,840 --> 02:18:00,440 (INDISCERNIBLE) RESPONSE AND 3066 02:18:00,440 --> 02:18:04,120 STOP INFORMATION. THIS IS THE 3067 02:18:04,120 --> 02:18:04,640 HYPOTHESIS WE HAVE BEEN 3068 02:18:04,640 --> 02:18:05,200 STUDYING IN THE LAB FOR THE 3069 02:18:05,200 --> 02:18:07,160 LAST YEARS. 3070 02:18:07,160 --> 02:18:09,360 FIRST TO CONFIRM THIS 3071 02:18:09,360 --> 02:18:10,240 HYPOTHESIS, WHAT WE DID IS WE 3072 02:18:10,240 --> 02:18:15,760 CONFIRMED IF T CELLS-- IF THERE 3073 02:18:15,760 --> 02:18:16,320 IS A MITOCHONDRIAL DECLINE 3074 02:18:16,320 --> 02:18:18,920 DURING AGING. IT IS WELL-KNOWN 3075 02:18:18,920 --> 02:18:23,200 THAT MITOCHONDRIA DNA IS 3076 02:18:23,200 --> 02:18:25,200 ESPECIALLY SENSITIVE TO DAMAGE. 3077 02:18:25,200 --> 02:18:28,320 IN CONTRAST TO NUCLEAR DNA, 3078 02:18:28,320 --> 02:18:32,840 MITOCHONDRIAL DNA IS NAKED, 3079 02:18:32,840 --> 02:18:38,720 UNPROTECTED FROM STRESS. THERE 3080 02:18:38,720 --> 02:18:41,160 ARE VERY FEW REPAIR MECHANISMS, 3081 02:18:41,160 --> 02:18:46,120 MITOCHONDRIAL DNA IS LOCATED IN 3082 02:18:46,120 --> 02:18:49,200 THE MITOCHONDRIA WHERE THERE 3083 02:18:49,200 --> 02:18:50,360 ARE A LOT OF EXPRESSED 3084 02:18:50,360 --> 02:18:57,040 OXIDATIVE STRESSORS. 3085 02:18:57,040 --> 02:18:57,440 T CELLS ACCUMULATE 3086 02:18:57,440 --> 02:18:58,000 MITOCHONDRIAL DAMAGE DURING 3087 02:18:58,000 --> 02:19:06,920 AGING. WE ISOLATED THEM FROM A 3088 02:19:06,920 --> 02:19:12,360 DIFFERENT AGES. AS YOU CAN SEE 3089 02:19:12,360 --> 02:19:13,320 HERE IN THIS PLOT, WE OBSERVED 3090 02:19:13,320 --> 02:19:23,800 THAT YOUNG T-CELLS FROM YOUNG 3091 02:19:25,080 --> 02:19:27,600 MICE HAVE MITOCHONDRIA WITH 3092 02:19:27,600 --> 02:19:29,800 HIGH MITOCHONDRIAL POTENTIAL. 3093 02:19:29,800 --> 02:19:36,000 WE FOUND THAT THERE IS 3094 02:19:36,000 --> 02:19:36,640 MITOCHONDRIA WITH LOW MEMBRANE 3095 02:19:36,640 --> 02:19:40,440 POTENTIAL. THE ACCUMULATION OF 3096 02:19:40,440 --> 02:19:42,120 THIS DAMAGE MITOCHONDRIA 3097 02:19:42,120 --> 02:19:42,720 PERFECTLY CORRELATES WITH THE 3098 02:19:42,720 --> 02:19:46,000 AGE OF THE MICE. 3099 02:19:46,000 --> 02:19:46,440 WE CONFIRMED THIS 3100 02:19:46,440 --> 02:19:49,120 MITOCHONDRIAL DECLINE IN 3101 02:19:49,120 --> 02:19:57,680 T-CELLS BY T-FORCE ANALYSIS AND 3102 02:19:57,680 --> 02:19:58,080 WE OBSERVED THAT 3103 02:19:58,080 --> 02:20:02,720 (INDISCERNIBLE) IS PRODUCED IN 3104 02:20:02,720 --> 02:20:03,960 OLD T-CELLS COMPARED TO YOUNG 3105 02:20:03,960 --> 02:20:05,000 T-CELLS. 3106 02:20:05,000 --> 02:20:09,680 ALSO T-CELLS DECLINING 3107 02:20:09,680 --> 02:20:10,240 MITOCHONDRIAL FUNCTION WITH 3108 02:20:10,240 --> 02:20:14,080 AGING. THE NEXT STEP WAS TO 3109 02:20:14,080 --> 02:20:15,480 MIMIC THIS AGE ASSOCIATED 3110 02:20:15,480 --> 02:20:16,080 MITOCHONDRIAL DYSFUNCTION IN 3111 02:20:16,080 --> 02:20:21,520 YOUNG MICE. TO DO THIS, WHAT 3112 02:20:21,520 --> 02:20:23,720 WE DID IS WE TAKE ADVANTAGE OF 3113 02:20:23,720 --> 02:20:24,920 MITOCHONDRIAL TRANSCRIPTION 3114 02:20:24,920 --> 02:20:31,360 FACTOR A. THIS IS A 3115 02:20:31,360 --> 02:20:31,960 TRANSACTION FACTOR ENCODED BY 3116 02:20:31,960 --> 02:20:32,600 THE NUCLEAR GENOME THE CONTROL 3117 02:20:32,600 --> 02:20:34,400 THE TRANSCRIPTION REPLICATION 3118 02:20:34,400 --> 02:20:35,400 AND STABILITY OF MITOCHONDRIAL 3119 02:20:35,400 --> 02:20:39,480 BEGINNING SO YOU DO YOU DEPLETE 3120 02:20:39,480 --> 02:20:39,960 TFAM, AND YOU PRODUCE 3121 02:20:39,960 --> 02:20:45,000 MITOCHONDRIAL DNA AND INDUCE 3122 02:20:45,000 --> 02:20:45,480 DRAMATIC MITOCHONDRIAL 3123 02:20:45,480 --> 02:20:47,200 DYSFUNCTION. 3124 02:20:47,200 --> 02:20:52,080 WE TAKE ADVANTAGE OF TFAM MICE 3125 02:20:52,080 --> 02:20:56,120 GENERATED IN THE LAB AND CROSS 3126 02:20:56,120 --> 02:21:00,560 THEM WITH CD4 MICE. BY 3127 02:21:00,560 --> 02:21:03,240 FOLLOWING THIS STRATEGY WE DID 3128 02:21:03,240 --> 02:21:07,600 TFAM IN ALL CELLS INCLUDING TB4 3129 02:21:07,600 --> 02:21:13,480 AND TB 8. 3130 02:21:13,480 --> 02:21:16,240 USING THE STRATEGY, WE OBSERVE 3131 02:21:16,240 --> 02:21:18,080 THAT OUR MUTANT MICE, T CELLS 3132 02:21:18,080 --> 02:21:20,080 FROM THE MUTANT MICE WHEN THEY 3133 02:21:20,080 --> 02:21:27,520 ARE YOUNG THEY HAVE 3134 02:21:27,520 --> 02:21:31,080 (INDISCERNIBLE) MITOCHONDRIAL 3135 02:21:31,080 --> 02:21:31,720 RESPIRATION. THESE MICE ARE IN 3136 02:21:31,720 --> 02:21:32,320 RED AND WE COMPARED THEM WITH 3137 02:21:32,320 --> 02:21:35,360 OLD CONTROLS THAT ARE IN BLUE. 3138 02:21:35,360 --> 02:21:40,440 SO WE HAVE MIMICKED THE SAME 3139 02:21:40,440 --> 02:21:42,240 AGE-ASSOCIATED MITOCHONDRIAL 3140 02:21:42,240 --> 02:21:44,040 DECLINE THAT OCCURS NATURALLY 3141 02:21:44,040 --> 02:21:46,920 IN T-CELLS FROM THE MUTANT 3142 02:21:46,920 --> 02:21:48,640 MICE. 3143 02:21:48,640 --> 02:21:55,080 BY DOING THIS, BY MIMICKING 3144 02:21:55,080 --> 02:21:56,080 THESE DEFECTS ASSOCIATED WITH 3145 02:21:56,080 --> 02:21:57,520 MITOCHONDRIAL DECLINE, WE 3146 02:21:57,520 --> 02:21:58,280 REPLICATE THE MAIN FORMAT OF 3147 02:21:58,280 --> 02:22:04,560 T-CELL AGING. WE OBSERVED IN 3148 02:22:04,560 --> 02:22:05,200 THE YOUNG MICE REDUCTION IN THE 3149 02:22:05,200 --> 02:22:07,360 NAïVE POOL OF T-CELLS AND 3150 02:22:07,360 --> 02:22:09,480 REGULATION OF MEMORY T-CELLS 3151 02:22:09,480 --> 02:22:14,560 THAT ACQUIRE SENESCENT AND 3152 02:22:14,560 --> 02:22:15,200 INFLAMMATORY MARKERS INCLUDING 3153 02:22:15,200 --> 02:22:18,480 THE INFORMATION FOR T-CELLS 3154 02:22:18,480 --> 02:22:19,800 THAT START TO PRODUCE 3155 02:22:19,800 --> 02:22:24,880 INTERFERON, GAMMA AND TNF, AND 3156 02:22:24,880 --> 02:22:29,200 OTHER SENESCENT FEATURES. 3157 02:22:29,200 --> 02:22:29,680 BESIDES THIS MOLECULAR 3158 02:22:29,680 --> 02:22:33,840 HALLMARK OF T-CELL AGING ARE 3159 02:22:33,840 --> 02:22:38,320 MUTANT T CELLS ARE ALSO 3160 02:22:38,320 --> 02:22:38,880 IMMUNOCOMPROMISED WHERE WE 3161 02:22:38,880 --> 02:22:39,480 PERFORM INFECTION EXPERIMENTS 3162 02:22:39,480 --> 02:22:40,680 AND WHAT WE OBSERVE IS A YOUNG 3163 02:22:40,680 --> 02:22:43,640 MUTANT MICE DIE IN THE FIRST 10 3164 02:22:43,640 --> 02:22:54,200 DAYS FROM ECTOMELIA (PHONETIC) 3165 02:22:59,840 --> 02:23:00,280 INFECTION THAT ALSO 3166 02:23:00,280 --> 02:23:05,520 (INDISCERNIBLE). 3167 02:23:05,520 --> 02:23:06,120 WE MEASURE THE CYTOKINES IN A 3168 02:23:06,120 --> 02:23:08,280 YOUNG MUTANT MICE AND OBSERVED 3169 02:23:08,280 --> 02:23:10,000 SIMILAR LEVELS OF HIGH TNF AND 3170 02:23:10,000 --> 02:23:15,040 -- JUST BY MIMICKING IT 3171 02:23:15,040 --> 02:23:16,120 ASSOCIATED MITOCHONDRIAL 3172 02:23:16,120 --> 02:23:24,200 DECLINE IN T-CELLS WE 3173 02:23:24,200 --> 02:23:26,400 PRECIPITATE IMMUNOGENESIS AND 3174 02:23:26,400 --> 02:23:32,240 INFLAMMATION. 3175 02:23:32,240 --> 02:23:32,840 WHAT WE OBSERVED IS THAT THESE 3176 02:23:32,840 --> 02:23:36,000 MICE LOOK TO BE IN A BAD SHAPE. 3177 02:23:36,000 --> 02:23:40,160 THEY START LOSING WEIGHT. THEY 3178 02:23:40,160 --> 02:23:40,680 HAVE A REDUCTION IN THE 3179 02:23:40,680 --> 02:23:43,280 LIFESPAN ABOUT 50%. , 3180 02:23:43,280 --> 02:23:46,120 WHERE THE DYING? WE FIRST 3181 02:23:46,120 --> 02:23:53,440 LOOKED AT THE CARDIOVASCULAR 3182 02:23:53,440 --> 02:23:55,640 ARTERATIONS. WE FOUND DRAMATIC 3183 02:23:55,640 --> 02:24:06,040 ARTERATIONS (PHONETIC), 3184 02:24:08,000 --> 02:24:12,160 SIASTOLIC DYSFUNCTION, AORTIC 3185 02:24:12,160 --> 02:24:20,760 DILATION, LUNG CONGESTION. 3186 02:24:20,760 --> 02:24:22,160 WE ALSO OBSERVED BESIDES THE 3187 02:24:22,160 --> 02:24:24,120 CARDIOVASCULAR ALTERATIONS THE 3188 02:24:24,120 --> 02:24:24,720 YOUNG MUTANT MICE HAD ANEMIA, 3189 02:24:24,720 --> 02:24:29,000 COGNITIVE DECLINE, PHYSICAL 3190 02:24:29,000 --> 02:24:33,400 DISABILITY AND PREMATURE DEATH. 3191 02:24:33,400 --> 02:24:34,080 WE PROPOSE THAT DEATH BY 3192 02:24:34,080 --> 02:24:38,360 ACCELERATING AGING IN T-CELLS 3193 02:24:38,360 --> 02:24:41,880 CAN INDUCE AGE ASSOCIATED MULTI 3194 02:24:41,880 --> 02:24:42,480 MORBIDITY IN THE REST OF THE 3195 02:24:42,480 --> 02:24:44,360 TISSUE. 3196 02:24:44,360 --> 02:24:46,480 WE PUBLISH THE DATA AND LAURA 3197 02:24:46,480 --> 02:24:53,040 I THINK PROVIDES USING A 3198 02:24:53,040 --> 02:24:53,560 DIFFERENT STRATEGY AND 3199 02:24:53,560 --> 02:24:55,280 DIFFERENT MODELS, SIMILAR 3200 02:24:55,280 --> 02:24:57,760 RESULTS. 3201 02:24:57,760 --> 02:25:01,800 SO WE WONDER, WHAT IS THE 3202 02:25:01,800 --> 02:25:07,000 MOLECULAR MECHANISM? HOW CAN 3203 02:25:07,000 --> 02:25:11,480 AGE-RELATED CHANGES IN T-CELLS 3204 02:25:11,480 --> 02:25:12,040 RELATED TO DETERIORATION IN 3205 02:25:12,040 --> 02:25:14,360 OTHER TISSUES? 3206 02:25:14,360 --> 02:25:14,880 WE FOUND THIS PAPER VERY 3207 02:25:14,880 --> 02:25:17,680 INSPIRING. THE AUTHOR PROPOSE 3208 02:25:17,680 --> 02:25:25,280 THAT TH-1 INDUCED SENESCENT CAN 3209 02:25:25,280 --> 02:25:25,880 BE DONE IN TUMOR CELLS AND AS 3210 02:25:25,880 --> 02:25:28,440 THE AGE ASSOCIATED MITOCHONDRIA 3211 02:25:28,440 --> 02:25:31,440 T-CELLS SHOWED THEM 3212 02:25:31,440 --> 02:25:32,360 INFLAMMATORY PHENOTYPE WHEN 3213 02:25:32,360 --> 02:25:37,560 PRODUCED IN -- AND GAMMA AND 3214 02:25:37,560 --> 02:25:41,000 ALPHA (INDISCERNIBLE). 3215 02:25:41,000 --> 02:25:46,080 WE DETECTED CHANGES IN THE 3216 02:25:46,080 --> 02:25:46,680 LIVER, AND PANCREAS AND HEART 3217 02:25:46,680 --> 02:25:50,720 AND ADIPOSE TISSUE. GOING 3218 02:25:50,720 --> 02:25:55,400 FARTHER IN THE MOLECULAR 3219 02:25:55,400 --> 02:25:56,000 MECHANISM, WE TOOK THE SERUM 3220 02:25:56,000 --> 02:25:56,520 FROM THE MUTANT MICE AND 3221 02:25:56,520 --> 02:25:58,200 INCUBATED HEALTHY CELLS FOR 3222 02:25:58,200 --> 02:26:01,520 SEVEN DAYS AND THIS IS ENOUGH 3223 02:26:01,520 --> 02:26:12,000 TO INDUCE P21 CELL EXPRESSION. 3224 02:26:18,040 --> 02:26:18,640 AND WHEN WE PRODUCE THIS IN 3225 02:26:18,640 --> 02:26:20,120 VIVO WE PERFORMED MARROW 3226 02:26:20,120 --> 02:26:20,760 TRANSPORTATION. WE WAITED FOR A 3227 02:26:20,760 --> 02:26:23,120 MONTH. THIS IS HOW THEY LOOK, 3228 02:26:23,120 --> 02:26:28,040 TWO LITTER MATES. THIS ONE HAS 3229 02:26:28,040 --> 02:26:32,400 BEEN TRANSPLANTED WITH BONE 3230 02:26:32,400 --> 02:26:40,600 MARROW PRECURSOR FROM CONTROLS. 3231 02:26:40,600 --> 02:26:41,200 THIS IS BEEN TRANSPORTED WITH 3232 02:26:41,200 --> 02:26:41,800 BONE MARROW FROM THE MUTANT 3233 02:26:41,800 --> 02:26:42,400 MOUSE. IT LOOKS IN A VERY BAD 3234 02:26:42,400 --> 02:26:46,160 STATE AND THEY PRESENT 3235 02:26:46,160 --> 02:26:49,320 SENESCENT CHARACTERISTICS. 3236 02:26:49,320 --> 02:26:51,200 TO CONFIRM THE MOLECULAR 3237 02:26:51,200 --> 02:26:55,840 MECHANISM, WE HAVE THE DNA 3238 02:26:55,840 --> 02:26:56,480 ALPHA, IN THE QUESTION TO DELAY 3239 02:26:56,480 --> 02:27:00,920 AGE ASSOCIATED MULTI MORBIDITY. 3240 02:27:00,920 --> 02:27:03,520 HOW OLD T CELLS ACT AS AGING 3241 02:27:03,520 --> 02:27:04,640 ACCELERATORS? OUR DATA SUGGEST 3242 02:27:04,640 --> 02:27:10,560 THAT OLD T-CELLS ACQUIRE 3243 02:27:10,560 --> 02:27:11,080 PRO-INFLAMMATORY-- THIS 3244 02:27:11,080 --> 02:27:16,480 INFLAMMATION COULD INDUCE 3245 02:27:16,480 --> 02:27:17,120 SENESCENCE AND THE REST OF THE 3246 02:27:17,120 --> 02:27:17,680 TISSUE BUT ALSO -- 3247 02:27:17,680 --> 02:27:21,040 (INDISCERNIBLE) -- RECEPTORS 3248 02:27:21,040 --> 02:27:24,360 THAT CAUSE TISSUE DAMAGE IN THE 3249 02:27:24,360 --> 02:27:28,200 PTR-INDEPENDENT MANNER. AN 3250 02:27:28,200 --> 02:27:28,880 SPOILER ALERT. WE ALSO OBSERVED 3251 02:27:28,880 --> 02:27:34,320 THAT OUR OLD T-CELLS ARE WAKING 3252 02:27:34,320 --> 02:27:40,640 UP IN IMMUNITY. THERE IS A 3253 02:27:40,640 --> 02:27:43,320 CONTRIBUTION, PRETTY RESILIENT 3254 02:27:43,320 --> 02:27:46,720 BY INNATE IMMUNE CELLS. 3255 02:27:46,720 --> 02:27:47,360 BESIDES THESE PATHOGENIC 3256 02:27:47,360 --> 02:27:51,640 FUNCTIONS, ALL T-CELLS COULD 3257 02:27:51,640 --> 02:27:53,040 ALSO ACT AS AGENT ACCELERATED 3258 02:27:53,040 --> 02:27:56,240 BY LOSING THE PROTECTIVE 3259 02:27:56,240 --> 02:27:56,840 FUNCTIONS, SO THEY LOSE THEIR 3260 02:27:56,840 --> 02:27:58,040 ABILITY TO RECOGNIZE SENESCENT 3261 02:27:58,040 --> 02:28:04,360 CELLS TO DELETE THEM. 3262 02:28:04,360 --> 02:28:04,880 SOMETHING THAT IS QUITE 3263 02:28:04,880 --> 02:28:08,400 INTERESTING-- IS THAT OUR 3264 02:28:08,400 --> 02:28:15,000 IMMUNITY AND OUR IMMUNE SYSTEM 3265 02:28:15,000 --> 02:28:20,600 CONTROLS OUR GUT MICROBIOME. 3266 02:28:20,600 --> 02:28:22,200 ALL OF THE IMMUNE SYSTEM THE 3267 02:28:22,200 --> 02:28:24,480 DOES THIS, THIS COULD 3268 02:28:24,480 --> 02:28:25,080 CONTRIBUTE TO AGE ASSOCIATED 3269 02:28:25,080 --> 02:28:27,640 MULTI MORBIDITY. 3270 02:28:27,640 --> 02:28:28,240 I THINK I HAVE NO TIME TO GO 3271 02:28:28,240 --> 02:28:38,720 FARTHER. I WILL GO INTO THE 3272 02:28:42,560 --> 02:28:45,040 FUTURE PERSPECTIVE OF THE LAB. 3273 02:28:45,040 --> 02:28:51,240 WE INDUCED (INDISCERNIBLE) OF 3274 02:28:51,240 --> 02:28:51,880 T-CELLS AND ACCELERATE BOTH THE 3275 02:28:51,880 --> 02:28:53,440 AGING AND WE WANT IN THE NEXT 3276 02:28:53,440 --> 02:28:54,000 YEARS TRY TO REVERSE THE 3277 02:28:54,000 --> 02:28:58,760 PHENOTYPE. THE GENERAL IDEA OF 3278 02:28:58,760 --> 02:29:01,960 THE NEXT YEARS IS TO SEE IF WE 3279 02:29:01,960 --> 02:29:03,200 CAN BOOST RESILIENCE TO 3280 02:29:03,200 --> 02:29:11,120 INFLAMMATORY AND SENESCENCE BY 3281 02:29:11,120 --> 02:29:11,760 TARGETING IMMUNE CELLS AND FOR 3282 02:29:11,760 --> 02:29:12,360 THIS I FOUND SOME GAPS IN THE 3283 02:29:12,360 --> 02:29:14,600 FIELD. 3284 02:29:14,600 --> 02:29:15,160 FIRST I THINK WE HAVE TO BE 3285 02:29:15,160 --> 02:29:21,000 ABLE TO DECODE THE DRIVERS OF 3286 02:29:21,000 --> 02:29:21,560 T-CELLS AGING THAT INCLUDES 3287 02:29:21,560 --> 02:29:25,320 INTRINSIC AND EXTRINSIC FACTORS. 3288 02:29:25,320 --> 02:29:25,920 IF WE ARE ABLE TO FIND THESE 3289 02:29:25,920 --> 02:29:27,360 DRIVERS WE WILL FIND 3290 02:29:27,360 --> 02:29:28,280 VULNERABILITIES THAT MAKE US 3291 02:29:28,280 --> 02:29:37,240 TARGET T-CELLS. 3292 02:29:37,240 --> 02:29:37,640 IS ALSO IMPORTANT TO 3293 02:29:37,640 --> 02:29:38,200 UNDERSTAND THE MOLECULAR 3294 02:29:38,200 --> 02:29:38,840 MECHANISM BY WHICH ALL T CELLS 3295 02:29:38,840 --> 02:29:39,400 OR IMMUNE CELLS INDUCE OR 3296 02:29:39,400 --> 02:29:43,560 PRECIPITATE AGING. THIS COULD 3297 02:29:43,560 --> 02:29:53,960 BE IF THEY ARE QUITE 3298 02:29:56,160 --> 02:29:56,680 PATHOGENIC, OR BECAUSE THE 3299 02:29:56,680 --> 02:29:57,320 LOOSE PROTECTIVE FUNCTION THIS 3300 02:29:57,320 --> 02:29:57,880 IS ESSENTIALLY WANT TO FIND 3301 02:29:57,880 --> 02:29:59,320 STRATEGIES TO REVERSE, 3302 02:29:59,320 --> 02:30:07,560 DEPENDING ON IF THERE ARE 3303 02:30:07,560 --> 02:30:08,160 PATHOGENIC FUNCTIONS WE FIND 3304 02:30:08,160 --> 02:30:09,400 DIFFERENT STRATEGIES TO DEPLETE 3305 02:30:09,400 --> 02:30:14,760 OLD T-CELLS OR BLOCK THE 3306 02:30:14,760 --> 02:30:16,360 CYTOKINES OR REJUVENATE THE 3307 02:30:16,360 --> 02:30:23,120 METABOLISM OF OLD IMMUNE CELLS. 3308 02:30:23,120 --> 02:30:25,720 IF YOU LOOSEN THE PRODUCTION 3309 02:30:25,720 --> 02:30:28,120 FUNCTION WE WILL THINK ABOUT 3310 02:30:28,120 --> 02:30:29,720 STRATEGIES OF THYMUS 3311 02:30:29,720 --> 02:30:30,320 REJUVENATION, THYMUS 3312 02:30:30,320 --> 02:30:34,400 RESISTANCE. CAN ALSO IMPROVE 3313 02:30:34,400 --> 02:30:36,560 THE T-CELL RESILIENCE OR 3314 02:30:36,560 --> 02:30:41,160 IMPROVE THE CONTROL OF 3315 02:30:41,160 --> 02:30:46,440 COMMUNITY TO THE MICROBIOME. 3316 02:30:46,440 --> 02:30:46,960 WE THINK THAT WITH THE 3317 02:30:46,960 --> 02:30:47,560 STRATEGIES MAYBE WILL BE ABLE 3318 02:30:47,560 --> 02:30:52,160 TO DELAY INFLAMMATION IN AGE 3319 02:30:52,160 --> 02:30:52,960 ASSOCIATED MULTI MORBIDITY. 3320 02:30:52,960 --> 02:30:53,560 THANKS TO THE PEOPLE INVOLVED 3321 02:30:53,560 --> 02:30:54,920 IN THE WORK. AND ALL THE 3322 02:30:54,920 --> 02:30:56,200 FUNDING AND COLLABORATORS. 3323 02:30:56,200 --> 02:30:58,360 THANK YOU VERY MUCH. 3324 02:30:58,360 --> 02:31:08,120 >>THANK YOU MARIA. VERY 3325 02:31:08,120 --> 02:31:09,200 INTERESTING UNFORTUNATELY WE 3326 02:31:09,200 --> 02:31:10,560 HAVE TO STOP TALKING. DEEP, 3327 02:31:10,560 --> 02:31:12,000 FIRST QUESTION. 3328 02:31:12,000 --> 02:31:17,680 >>MARIA, THANK YOU. I THINK 3329 02:31:17,680 --> 02:31:19,760 THE TFAM AS YOUR WORK IS SHOWN 3330 02:31:19,760 --> 02:31:22,320 IS CRITICAL FOR T-CELL FUNCTION 3331 02:31:22,320 --> 02:31:25,360 IN GETTING RID OF THE TFAM 3332 02:31:25,360 --> 02:31:31,680 ALLELE IS DOING SOMETHING. I 3333 02:31:31,680 --> 02:31:32,280 CAN TELL YOU THAT WE DID THIS 3334 02:31:32,280 --> 02:31:32,880 EXPERIMENT ALMOST 7 YEARS AGO 3335 02:31:32,880 --> 02:31:42,400 WITH THE TFAM GLOBAL -- THERE 3336 02:31:42,400 --> 02:31:42,960 WAS NO PHENOTYPE IN THOSE 3337 02:31:42,960 --> 02:31:43,520 ANIMALS WITH LOTS OF JUST 3338 02:31:43,520 --> 02:31:51,200 LOWERING THE HETEROZYGOUS TFAM. 3339 02:31:51,200 --> 02:31:51,760 I'M WONDERING WHETHER THESE 3340 02:31:51,760 --> 02:31:52,320 MOLECULES THAT WE THINK ARE 3341 02:31:52,320 --> 02:31:54,800 REALLY DRIVING AGING ARE HAVING 3342 02:31:54,800 --> 02:31:55,400 AN EFFECT REALLY BECAUSE THEY 3343 02:31:55,400 --> 02:31:57,400 ARE CLEARLY IMPORTANT IN 3344 02:31:57,400 --> 02:31:58,000 BIOLOGY, BUT THEY MAY NOT BE 3345 02:31:58,000 --> 02:31:58,640 RELEVANT FOR ACTUAL BIOLOGICAL 3346 02:31:58,640 --> 02:32:00,520 AGING. BECAUSE IN AGING THERE 3347 02:32:00,520 --> 02:32:05,160 IS NO CHANGE IN TFAM, RIGHT? 3348 02:32:05,160 --> 02:32:07,240 >>WE OBSERVED A REDUCTION IN 3349 02:32:07,240 --> 02:32:10,800 TFAM IN T-CELLS ALSO. BUT IT 3350 02:32:10,800 --> 02:32:13,320 IS TRUE. THIS IS A DRAMATIC 3351 02:32:13,320 --> 02:32:16,360 SYSTEM. THE IMPORTANT POINT 3352 02:32:16,360 --> 02:32:23,000 IS, IT HIGHLIGHTS THE ROLE OF A 3353 02:32:23,000 --> 02:32:24,960 SUCCESSFUL IMMUNE SYSTEM DURING 3354 02:32:24,960 --> 02:32:28,520 AGING. I THINK THIS IS NOT THE 3355 02:32:28,520 --> 02:32:34,160 ONLY MODEL JUST BY 3356 02:32:34,160 --> 02:32:36,240 MANIPULATING-- 3357 02:32:36,240 --> 02:32:40,280 >>CLEARLY IMPORTANT BUT WHAT 3358 02:32:40,280 --> 02:32:40,920 I'M SAYING IS THE HETEROZYGOUS 3359 02:32:40,920 --> 02:32:41,520 DEFICIENCY KILL THE ANIMAL AT 3360 02:32:41,520 --> 02:32:44,080 THE AGE OF (INDISCERNIBLE). 3361 02:32:44,080 --> 02:32:46,160 >>YES, IT HAD NORMAL 3362 02:32:46,160 --> 02:32:50,880 MITOCHONDRIAL LEVELS. 3363 02:32:50,880 --> 02:32:54,280 >>I WANTED TO FOLLOW UP. IF 3364 02:32:54,280 --> 02:32:59,760 WE HAVE TFAM IN -- GLANDS, THIS 3365 02:32:59,760 --> 02:33:09,000 WAS CONDITIONAL LOCKOUT. WE 3366 02:33:09,000 --> 02:33:09,600 DID NOT GET ANY PHENOTYPE AT 3367 02:33:09,600 --> 02:33:14,640 ALL. WE GOT A VERY STRONG 3368 02:33:14,640 --> 02:33:20,360 PHENOTYPE DISEASE. YOUR 3369 02:33:20,360 --> 02:33:22,480 KNOCKOUT, IS NOT INDUCED? 3370 02:33:22,480 --> 02:33:24,480 >>NOT INDUCED. 3371 02:33:24,480 --> 02:33:27,040 >>IT IS AFFECTING -- SELECTION 3372 02:33:27,040 --> 02:33:29,040 IN YOUR MODEL? 3373 02:33:29,040 --> 02:33:35,240 >>20 WE HAVE TO BE AWARE WITH 3374 02:33:35,240 --> 02:33:38,400 TFAM KNOCKOUT -- IS THAT YOU 3375 02:33:38,400 --> 02:33:42,080 HAVE MITOCHONDRIAL DNA IN EACH 3376 02:33:42,080 --> 02:33:44,720 SET. WE STILL HAVE 3377 02:33:44,720 --> 02:33:49,320 MITOCHONDRIAL DNA. THE CELL 3378 02:33:49,320 --> 02:33:49,920 NEEDS TO DIVIDE TO GET RID OF 3379 02:33:49,920 --> 02:33:51,360 THE MITOCHONDRIAL DNA. IF YOU 3380 02:33:51,360 --> 02:33:56,360 CAN DEPLETE TFAM IN MANY CELLS 3381 02:33:56,360 --> 02:33:57,800 BUT THE CONCEPT DEPENDS ON THE 3382 02:33:57,800 --> 02:34:02,840 PROLIFERATION RATE OF T-CELLS. 3383 02:34:02,840 --> 02:34:06,120 IF THERE IS NO PROLIFERATION 3384 02:34:06,120 --> 02:34:06,680 RATE, THEY ARE STILL HAVING 3385 02:34:06,680 --> 02:34:07,200 MITOCHONDRIAL DNA. AND 3386 02:34:07,200 --> 02:34:09,720 EVERYTHING GOES WELL. 3387 02:34:09,720 --> 02:34:11,600 >>QUESTION IN THE BACK. THE 3388 02:34:11,600 --> 02:34:13,080 LAST QUESTION FROM THE AUDIENCE. 3389 02:34:13,080 --> 02:34:13,640 AND THEN WE HAVE ONLINE 3390 02:34:13,640 --> 02:34:15,880 QUESTIONS. 3391 02:34:15,880 --> 02:34:16,360 >>THANK YOU MARIA REALLY 3392 02:34:16,360 --> 02:34:19,720 BEAUTIFUL WORK. I WAS 3393 02:34:19,720 --> 02:34:20,360 WONDERING IF YOU COULD TELL US 3394 02:34:20,360 --> 02:34:20,960 MORE ABOUT WHAT YOU THINK THE 3395 02:34:20,960 --> 02:34:23,600 RELATIVE CONTRIBUTION OF THE 3396 02:34:23,600 --> 02:34:27,400 T-REG VERSUS THE T CONVENTIONAL 3397 02:34:27,400 --> 02:34:29,440 IS IN YOUR MICE? 3398 02:34:29,440 --> 02:34:30,000 >>THIS IS VERY IMPORTANT IF 3399 02:34:30,000 --> 02:34:34,240 YOU KNOCKOUT TFAM IN T REG YOU 3400 02:34:34,240 --> 02:34:40,880 HAVE A -- PHENOTYPE. THE MICE 3401 02:34:40,880 --> 02:34:45,200 DIED IN THE FIRST THREE WEEKS, 3402 02:34:45,200 --> 02:34:48,200 AN AUTOIMMUNE SYNDROME. THIS 3403 02:34:48,200 --> 02:34:48,800 REFLECTS THE BALANCE BETWEEN 3404 02:34:48,800 --> 02:34:51,240 THE DIFFERENCE SUBSTANCES IF 3405 02:34:51,240 --> 02:34:56,360 YOU DON'T HAVE FUNCTIONAL T REG 3406 02:34:56,360 --> 02:35:00,320 VERSUS UNCONVENTIONAL T REG YOU 3407 02:35:00,320 --> 02:35:02,600 HAVE (INDISCERNIBLE) IMMUTABLE 3408 02:35:02,600 --> 02:35:03,200 YOU HAVE CONVENTIONAL T-CELLS 3409 02:35:03,200 --> 02:35:08,640 NOT SO GOOD, T REG NOT SO GOOD, 3410 02:35:08,640 --> 02:35:09,400 YOU HAVE THIS CHRONIC 3411 02:35:09,400 --> 02:35:13,200 INFLAMMATION. WE HAVE NO TIME 3412 02:35:13,200 --> 02:35:19,880 FOR ANTIBODY PRODUCTION. I 3413 02:35:19,880 --> 02:35:20,400 THINK IT IS AN IMPORTANT 3414 02:35:20,400 --> 02:35:21,800 BALANCE BETWEEN THE DIFFERENT 3415 02:35:21,800 --> 02:35:25,200 T-CELLS. 3416 02:35:25,200 --> 02:35:30,440 >>THESE LOOK LIKE GLIAL CELL 3417 02:35:30,440 --> 02:35:35,400 MICE (INDISCERNIBLE) -- 3418 02:35:35,400 --> 02:35:40,960 >>THERE IS A DRAMATIC WEIGHT 3419 02:35:40,960 --> 02:35:45,160 LOSS IN OUR MICE. THEY LOOK 3420 02:35:45,160 --> 02:35:46,160 SICK BECAUSE OF THE CHRONIC 3421 02:35:46,160 --> 02:35:48,880 INFORMATION. WHAT WE DID WAS WE 3422 02:35:48,880 --> 02:35:58,640 FED THEM WITH A -- DIET, IS IN 3423 02:35:58,640 --> 02:36:00,120 A SLIDE THAT I HAVE NO TIME TO 3424 02:36:00,120 --> 02:36:07,880 PRESENT BUT THIS THERE IS THE 3425 02:36:07,880 --> 02:36:08,360 LIFESPAN OF THE MICE 3426 02:36:08,360 --> 02:36:10,200 SIGNIFICANTLY. 3427 02:36:10,200 --> 02:36:10,800 >>OTHERS HAVE OBSERVED THAT 3428 02:36:10,800 --> 02:36:21,280 THE OVARIES AGE BEFORE OTHER 3429 02:36:22,720 --> 02:36:32,280 ORGANS IN THE BODY. 3430 02:36:32,280 --> 02:36:34,720 >>WHAT I CAN SAY REGARDING 3431 02:36:34,720 --> 02:36:38,960 GENDER DIMENSION, IS IT IN OUR 3432 02:36:38,960 --> 02:36:43,000 MOUSE MODEL FEMALES ARE MORE 3433 02:36:43,000 --> 02:36:44,600 VULNERABLE TO THIS CHRONIC 3434 02:36:44,600 --> 02:36:52,560 INFLAMMATION ON HOW TO LOOK. 3435 02:36:52,560 --> 02:36:54,680 THE PHENOTYPE APPEARS. BUT IT 3436 02:36:54,680 --> 02:36:56,600 IS LATE. 3437 02:36:56,600 --> 02:37:00,040 >>ANOTHER QUESTION. 3438 02:37:00,040 --> 02:37:00,560 >>THANK YOU FOR YOUR GREAT 3439 02:37:00,560 --> 02:37:02,800 TALK. I WAS CURIOUS ABOUT YOUR 3440 02:37:02,800 --> 02:37:08,000 PERSPECTIVE ON THE STUDY CAME 3441 02:37:08,000 --> 02:37:15,520 OUT A LITTLE WHILE AGO ON MOUSE 3442 02:37:15,520 --> 02:37:16,040 T-CELLS THAT WERE KEPT IN 3443 02:37:16,040 --> 02:37:16,640 CULTURE FOR 10 YEARS AND WERE 3444 02:37:16,640 --> 02:37:18,200 STILL RATHER HEALTHY, 3445 02:37:18,200 --> 02:37:18,800 SUGGESTING THAT THESE CELLS DID 3446 02:37:18,800 --> 02:37:21,360 PRETTY WELL OVER A LONG TIME, 3447 02:37:21,360 --> 02:37:22,000 EVEN BEYOND THE LIFESPAN OF THE 3448 02:37:22,000 --> 02:37:25,200 ANIMAL. 3449 02:37:25,200 --> 02:37:28,200 AND THEN I WAS CURIOUS ABOUT 3450 02:37:28,200 --> 02:37:30,640 THE COMPENSATORY, BROADER 3451 02:37:30,640 --> 02:37:31,280 IMMUNE CHANGES WHEN YOU DO HAVE 3452 02:37:31,280 --> 02:37:37,960 YOUR DISRUPTION. ONE THING I 3453 02:37:37,960 --> 02:37:38,600 HAVE NOT MENTIONED MUCH AT THE 3454 02:37:38,600 --> 02:37:39,200 MEETING YET PARTICULARLY THE 3455 02:37:39,200 --> 02:37:43,600 GAMMA DELTA T-CELL WHICH 3456 02:37:43,600 --> 02:37:44,080 INCREASES WITH AGING, 3457 02:37:44,080 --> 02:37:44,720 PARTICULARLY WITH BARRIER AND 3458 02:37:44,720 --> 02:37:45,120 OTHER ANTIGROWTH 3459 02:37:45,120 --> 02:37:46,960 (INDISCERNIBLE). 3460 02:37:46,960 --> 02:37:47,520 >>THE FIRST QUESTION IS VERY 3461 02:37:47,520 --> 02:37:53,520 CHALLENGING. I THINK T-CELLS 3462 02:37:53,520 --> 02:37:58,040 COULD-- THERE IS A POOL OF 3463 02:37:58,040 --> 02:38:03,680 T-CELLS THAT CAN PROLIFERATE 3464 02:38:03,680 --> 02:38:04,280 FOREVER. THIS EXPERIMENT IS 3465 02:38:04,280 --> 02:38:07,720 PERFORMED IN YOUR MICE. I 3466 02:38:07,720 --> 02:38:08,360 WOULD LIKE TO SEE WHAT HAPPENS 3467 02:38:08,360 --> 02:38:15,280 IF YOU PERFORM THIS EXPERIMENT. 3468 02:38:15,280 --> 02:38:15,760 AND ALSO WE KNOW THE 3469 02:38:15,760 --> 02:38:19,160 ENVIRONMENT IS VERY IMPORTANT 3470 02:38:19,160 --> 02:38:27,200 FOR THE AGING OF T-CELLS. ALSO 3471 02:38:27,200 --> 02:38:27,840 I AGREE WITH YOU THAT THAT IS 3472 02:38:27,840 --> 02:38:28,440 IN THE FIELD THAT WE HAVE TO 3473 02:38:28,440 --> 02:38:29,480 LOOK AT. 3474 02:38:29,480 --> 02:38:32,040 >>THANK YOU SO MUCH. 3475 02:38:32,040 --> 02:38:34,000 >>THANK YOU TO THE AUDIENCE 3476 02:38:34,000 --> 02:38:43,240 FOR THE PARTICIPATION. SO WE 3477 02:38:43,240 --> 02:38:48,120 COME BACK AT 1:00 PLEASE, 3478 02:38:48,120 --> 02:38:49,000 SHARP, SO WE CAN START ON TIME, 3479 02:38:49,000 --> 02:38:49,440 AND WE CAN DO THE SECOND PART 3480 02:38:49,440 --> 02:38:50,600 OF THE SESSION. 3481 02:38:50,600 --> 02:38:51,160 >>WE MOVE ON QUICKLY TO THE 3482 02:38:51,160 --> 02:38:54,560 NEXT PRESENTATION FROM -- FROM 3483 02:38:54,560 --> 02:39:00,720 THE NIA, HE IS GOING TO TALK 3484 02:39:00,720 --> 02:39:01,320 ABOUT IMMUNE DYSREGULATION IN 3485 02:39:01,320 --> 02:39:02,120 AGING AND ITS ROLE IN CANCER. 3486 02:39:02,120 --> 02:39:08,560 >>GOOD AFTERNOON. FIRST OF 3487 02:39:08,560 --> 02:39:10,080 ALL THANK YOU SO MUCH FOR 3488 02:39:10,080 --> 02:39:10,600 ORGANIZING THIS FANTASTIC 3489 02:39:10,600 --> 02:39:13,600 MEETING. I LEARNED AN 3490 02:39:13,600 --> 02:39:16,960 INCREDIBLE AMOUNT OF THINGS. 3491 02:39:16,960 --> 02:39:17,840 ALMOST LIKE I AM ILLITERATE 3492 02:39:17,840 --> 02:39:21,240 NOW. 3493 02:39:21,240 --> 02:39:28,680 I'LL TALK ABOUT CANCER. IT 3494 02:39:28,680 --> 02:39:29,240 SEEMS HARDLY ANYONE TALKED 3495 02:39:29,240 --> 02:39:39,120 ABOUT CANCER. SO OF COURSE 3496 02:39:39,120 --> 02:39:41,440 NOW, EVERYONE TALKS ABOUT 3497 02:39:41,440 --> 02:39:42,040 MACROBIOTICS, MARIA ALLUDED A 3498 02:39:42,040 --> 02:39:42,960 LITTLE BIT ABOUT MACROBIOTICS. 3499 02:39:42,960 --> 02:39:43,600 NOT SURE IF IT IS THE CHICKEN 3500 02:39:43,600 --> 02:39:49,160 OR THE EGG. BUT IT SEEMS IT 3501 02:39:49,160 --> 02:39:50,240 CONTROLS EVERYTHING WHAT 3502 02:39:50,240 --> 02:39:52,560 HAPPENS IN AGING AND SO ON. 3503 02:39:52,560 --> 02:39:57,160 OF COURSE I WILL TALK ABOUT 3504 02:39:57,160 --> 02:40:00,880 LITTLE HUMANS. IN THIS LITTLE 3505 02:40:00,880 --> 02:40:04,800 HUMAN WE FIND THAT ACTUALLY IN 3506 02:40:04,800 --> 02:40:07,720 AGING, EVEN IN HEALTHY AGING, 3507 02:40:07,720 --> 02:40:10,520 IT IS JUST NORMAL HEALTHY AGING 3508 02:40:10,520 --> 02:40:12,920 MICROBIOTA CHANGE. 3509 02:40:12,920 --> 02:40:17,240 BECAUSE OF THIS CHANGE WE FIND 3510 02:40:17,240 --> 02:40:20,760 SOME PATHOGENIC INCREASE IN 3511 02:40:20,760 --> 02:40:27,000 GOOD COMMENSAL INCREASE, EVEN 3512 02:40:27,000 --> 02:40:32,640 ONE BACTERIA CALLED 3513 02:40:32,640 --> 02:40:35,840 (INDISCERNIBLE). 3514 02:40:35,840 --> 02:40:38,120 THE FIELD IS VERY INTERESTING. 3515 02:40:38,120 --> 02:40:44,160 ACTUALLY IT DOES A LOT OF 3516 02:40:44,160 --> 02:40:47,960 THINGS. IT RESTORES THE MUCUS 3517 02:40:47,960 --> 02:40:48,960 LAYER, AND SUPPORTS OTHER GOOD 3518 02:40:48,960 --> 02:40:52,400 THINGS. BECAUSE OF THE 3519 02:40:52,400 --> 02:40:59,720 DECREASE OF THIS -- WE SEE THE 3520 02:40:59,720 --> 02:41:01,440 MUCUS LAYER DECREASED IN THE 3521 02:41:01,440 --> 02:41:07,000 AGING AND TOGETHER SYSTEMICALLY 3522 02:41:07,000 --> 02:41:08,880 YOU CAN SEE THE ENDOCRINE 3523 02:41:08,880 --> 02:41:11,120 CIRCULATION IS DECREASED. 3524 02:41:11,120 --> 02:41:17,680 HOWEVER IF YOU TAKE 3525 02:41:17,680 --> 02:41:22,960 AKKERMANSIA MUCINIPHILA IN 3526 02:41:22,960 --> 02:41:23,560 HUMANS YOU CAN SEE THE MUCUS 3527 02:41:23,560 --> 02:41:25,280 LAYER IS RESTORED AND THE -- 3528 02:41:25,280 --> 02:41:32,800 DECREASES. 3529 02:41:32,800 --> 02:41:37,080 WHEN THE GUT IS LEAKING, 3530 02:41:37,080 --> 02:41:43,480 TOGETHER -- IS DECREASED. BUT 3531 02:41:43,480 --> 02:41:48,520 ALSO IN PERITONEAL CAVITY, 3532 02:41:48,520 --> 02:41:52,520 BUTYRATE IS DECREASED. YOU 3533 02:41:52,520 --> 02:41:54,280 KNOW SO MANY THINGS ABOUT 3534 02:41:54,280 --> 02:41:57,000 BUTYRATE, IT IS THIS INHIBITOR 3535 02:41:57,000 --> 02:42:00,600 FOR THE (INDISCERNIBLE). AND IN 3536 02:42:00,600 --> 02:42:06,960 LPS THE RATIO IS CHANGED. AND 3537 02:42:06,960 --> 02:42:10,960 THE ENDOTOXINE (PHONETIC) 3538 02:42:10,960 --> 02:42:14,960 ACTIVATES MONOCYTES. YOU SEE 3539 02:42:14,960 --> 02:42:21,320 THAT -- MONOTICES ARE RECRUITED 3540 02:42:21,320 --> 02:42:23,200 AND THEY PRODUCE MANY THINGS. 3541 02:42:23,200 --> 02:42:29,560 THIS IS OCCURRING IN THE 3542 02:42:29,560 --> 02:42:37,960 OMENTOM (PHONETIC), AND THEN 3543 02:42:37,960 --> 02:42:38,600 THROUGH THE PATHWAY INDICATED, 3544 02:42:38,600 --> 02:42:39,200 IT CONVERTS ADVANCES IN AGING, 3545 02:42:39,200 --> 02:42:39,680 IMMUNITY AND CHRONIC 3546 02:42:39,680 --> 02:42:42,040 INFLAMMATORY DISEASES (DAY 3547 02:42:42,040 --> 02:42:51,920 (CORRECTION) T 1 CELLS, THE 3548 02:42:51,920 --> 02:42:56,960 UPREGULATED -- AND IT EXPRESS 3549 02:42:56,960 --> 02:43:07,440 CLASS 1. AND THIS T 1 CELL 3550 02:43:13,360 --> 02:43:17,840 INDUCES (INDISCERNIBLE) IN 3551 02:43:17,840 --> 02:43:20,520 SQUIRRLES, MACAQUES AND ALSO 3552 02:43:20,520 --> 02:43:23,960 HUMANS. THE SAME PATHWAY 3553 02:43:23,960 --> 02:43:28,720 EXISTS. 3554 02:43:28,720 --> 02:43:29,240 I DON'T WANT TO TALK ABOUT 3555 02:43:29,240 --> 02:43:29,760 MECHANISMS BECAUSE IT IS 3556 02:43:29,760 --> 02:43:34,280 PUBLISHED. IF YOU BLOCK THIS 3557 02:43:34,280 --> 02:43:37,160 PATHWAY, EVERYTHING CHANGES. 3558 02:43:37,160 --> 02:43:41,400 YOU CAN WATCH THE MUCINIPHILA 3559 02:43:41,400 --> 02:43:51,200 AND THIS STOPS THE 3560 02:43:51,200 --> 02:43:51,800 (INDISCERNIBLE), AND IT ALSO 3561 02:43:51,800 --> 02:43:54,880 DECREASES AND IN MAXINE'S TALK 3562 02:43:54,880 --> 02:43:58,640 YOU HEARD ABOUT HOW THIS 3563 02:43:58,640 --> 02:43:59,240 INCREASES. BUT IN HUMANS AND 3564 02:43:59,240 --> 02:44:07,280 ELDERLY HUMANS, THE CD 8 CELLS 3565 02:44:07,280 --> 02:44:08,960 INCREASE. 3566 02:44:08,960 --> 02:44:19,360 HOWEVER B1A CELLS PEOPLE 3567 02:44:21,320 --> 02:44:22,120 ASSOCIATE WITH THE SUPRATING 3568 02:44:22,120 --> 02:44:28,280 (PHONETIC) NATURE. IN ELDERLY 3569 02:44:28,280 --> 02:44:28,880 PEOPLE INSULIN RESISTANCE IS 3570 02:44:28,880 --> 02:44:31,000 DECREASED AND THE SAME IN MICE. 3571 02:44:31,000 --> 02:44:33,160 THE QUESTION IS WHAT HAPPENS 3572 02:44:33,160 --> 02:44:35,240 WHEN THIS SALE BECOMES A 3573 02:44:35,240 --> 02:44:36,920 (INDISCERNIBLE) CELL? THEY 3574 02:44:36,920 --> 02:44:41,360 EXPRESS MUCH MORE IL-10. DO 3575 02:44:41,360 --> 02:44:41,880 YOU EXPECT IT WILL BLOCK 3576 02:44:41,880 --> 02:44:49,520 INSULIN RESISTANCE? WHAT IS IT 3577 02:44:49,520 --> 02:44:50,120 THAT IN EARLY HUMANS AND MICE 3578 02:44:50,120 --> 02:44:54,480 INSULIN RESISTANCE INCREASES? 3579 02:44:54,480 --> 02:44:55,000 YOU CAN SEE THAT INSULIN 3580 02:44:55,000 --> 02:45:01,080 RESISTANCE IS INCREASED IN ALL. 3581 02:45:01,080 --> 02:45:04,760 YOU CAN SEE THAT INSULIN 3582 02:45:04,760 --> 02:45:05,360 RESISTANCE GOES DOWN AND INTO 3583 02:45:05,360 --> 02:45:08,720 THE RECEPTOR SIGNALING GOES UP 3584 02:45:08,720 --> 02:45:19,160 AGAIN. BUT IF YOU TRANSFER 4BL 3585 02:45:19,160 --> 02:45:19,800 CELLS, INSULIN RESISTANCE WHICH 3586 02:45:19,800 --> 02:45:23,360 WAS RESTORED WILL BE BACK AGAIN 3587 02:45:23,360 --> 02:45:30,240 IN S&H. IF YOU TRANSFER -- ALL 3588 02:45:30,240 --> 02:45:35,840 THE B1A CELLS, INSULIN 3589 02:45:35,840 --> 02:45:38,880 RESISTANCE IS STILL HIGH WHICH 3590 02:45:38,880 --> 02:45:39,400 INDICATES THESE CELLS ARE 3591 02:45:39,400 --> 02:45:39,920 RESPONSIBLE FOR INSULIN 3592 02:45:39,920 --> 02:45:41,320 RESISTANCE AND AGING AT LEAST 3593 02:45:41,320 --> 02:45:43,120 THROUGH PPL. 3594 02:45:43,120 --> 02:45:52,800 SO OKAY, I WILL SHIFT GEARS TO 3595 02:45:52,800 --> 02:45:55,560 THE MAIN TOPIC, TODAY'S TOPIC. 3596 02:45:55,560 --> 02:46:01,720 B1A CELL SUPPRESSION. WE WOULD 3597 02:46:01,720 --> 02:46:02,240 EXPECT TUMOR INCREASES IN 3598 02:46:02,240 --> 02:46:08,320 AGING. HOWEVER I TOLD YOU THAT 3599 02:46:08,320 --> 02:46:18,800 FOR BL CELLS, WE ASKED THE 3600 02:46:21,440 --> 02:46:22,000 QUESTION, THERE IS A BEAUTIFUL 3601 02:46:22,000 --> 02:46:24,840 PAPER FROM-- USED TO BE AT THE 3602 02:46:24,840 --> 02:46:25,360 -- IS IT TOO LONG AGO AND 3603 02:46:25,360 --> 02:46:29,240 PUBLISHED IN THE EARLY 80S A 3604 02:46:29,240 --> 02:46:31,200 PAPER SHOWING THAT IN AGING 3605 02:46:31,200 --> 02:46:38,000 MELANOMA THE -- REDUCE GROWTH. 3606 02:46:38,000 --> 02:46:38,480 WHETHER THIS PATHWAY IS 3607 02:46:38,480 --> 02:46:48,920 RESPONSIBLE FOR THE REDUCTION 3608 02:46:48,920 --> 02:46:54,120 OF BL 16. 3609 02:46:54,120 --> 02:46:56,920 YOU CAN SEE HERE THAT THE 3610 02:46:56,920 --> 02:46:59,520 TUMOR GROWS VERY POORLY. AND 3611 02:46:59,520 --> 02:47:01,560 THEN YOU CAN ISSUE A TRANSFER, 3612 02:47:01,560 --> 02:47:08,000 YOUNG CD5 POSITIVE B CELLS, FOR 3613 02:47:08,000 --> 02:47:08,640 SUPPORT TUMOR GROWTH BUT IF YOU 3614 02:47:08,640 --> 02:47:13,480 INJECT ALL THE B1 CELLS WHICH 3615 02:47:13,480 --> 02:47:20,680 WILL BE ALL THE B1 CELLS, THE 3616 02:47:20,680 --> 02:47:22,000 TUMOR GROWTH BECAUSE OF THIS 3617 02:47:22,000 --> 02:47:27,560 EXPRESSION OF THE MELANOMA. 3618 02:47:27,560 --> 02:47:28,120 AND IN THIS PATHWAY YOU CAN 3619 02:47:28,120 --> 02:47:30,680 ALSO REVERT WITH 3620 02:47:30,680 --> 02:47:37,280 (INDISCERNIBLE) OR ENROFLOXIN 3621 02:47:37,280 --> 02:47:39,760 TREATMENT. YOU CAN SEE THAT 3622 02:47:39,760 --> 02:47:49,440 AFTER THE TREATMENT WITH 3623 02:47:49,440 --> 02:47:50,000 ENROFLOXICIN, THE TUMOR IS 3624 02:47:50,000 --> 02:47:54,160 INCREASED. IT CORRELATES WITH 3625 02:47:54,160 --> 02:47:56,160 INVERSELY EXPRESSION OF OPL 3626 02:47:56,160 --> 02:47:59,840 CELLS AND (INDISCERNIBLE). 3627 02:47:59,840 --> 02:48:05,280 YOU ASK, OKAY WE KNOW THAT IN 3628 02:48:05,280 --> 02:48:05,880 AGING ALL OF THESE CANCERS GO 3629 02:48:05,880 --> 02:48:11,040 UP. WHAT ARE YOU TALKING ABOUT? 3630 02:48:11,040 --> 02:48:12,800 SO THERE ARE OTHER MOTIVES. 3631 02:48:12,800 --> 02:48:21,160 YOU CAN SEE THAT AT3 TUMOR 3632 02:48:21,160 --> 02:48:21,680 GROWTH, IN AGING IT HAS 3633 02:48:21,680 --> 02:48:24,480 BEAUTIFULLY GROWN. IF YOU 3634 02:48:24,480 --> 02:48:30,040 DEPLETE THE ACD20 CELLS IT 3635 02:48:30,040 --> 02:48:39,840 GROWS. MORE ANTITUMOR 3636 02:48:39,840 --> 02:48:41,240 (INDISCERNIBLE). IS THAT WHY IT 3637 02:48:41,240 --> 02:48:48,000 INCREASED? NO, IF YOU TAKE 3638 02:48:48,000 --> 02:48:48,600 (INDISCERNIBLE), ESSENTIALLY 3639 02:48:48,600 --> 02:48:52,240 THE TUMOR DOES NOT GROW. IT 3640 02:48:52,240 --> 02:48:55,160 HAS NO EFFECT. THIS INDICATES 3641 02:48:55,160 --> 02:48:57,920 SOMEHOW -- INVOLVED IN THIS 3642 02:48:57,920 --> 02:49:00,080 PROCESS BUT NOT THROUGH 4BL 3643 02:49:00,080 --> 02:49:03,600 CELL. AND TO UNDERSTAND HOW IT 3644 02:49:03,600 --> 02:49:05,960 IS IN THE WALL, WE DECIDED TO 3645 02:49:05,960 --> 02:49:06,560 FIRST CHECK WHAT IS HAPPENING 3646 02:49:06,560 --> 02:49:14,760 IN JUST TUMOR-FREE NAïVE AND 3647 02:49:14,760 --> 02:49:18,160 AGING AND YOUNG MICE? 3648 02:49:18,160 --> 02:49:19,600 WE DID SOME SCREENING, SIMPLE 3649 02:49:19,600 --> 02:49:25,040 SCREENING. ONE THING CAME OUT. 3650 02:49:25,040 --> 02:49:27,800 YOU CAN SEE THAT AGED ITSELF 3651 02:49:27,800 --> 02:49:32,800 COMPARED TO AGED CD4 OR EVEN 3652 02:49:32,800 --> 02:49:37,960 AGED CD CELLS COMPARED TO YOUNG 3653 02:49:37,960 --> 02:49:39,320 ONES, YOU CAN SEE A LOT OF 3654 02:49:39,320 --> 02:49:42,520 EXERTION. ONE INTERESTING 3655 02:49:42,520 --> 02:49:46,160 THING IS THAT THEY ARE RELATED 3656 02:49:46,160 --> 02:49:56,640 TWO ENZYMES, CD 58, CD39 AND 3657 02:49:58,840 --> 02:50:01,080 (INDISCERNIBLE). 3658 02:50:01,080 --> 02:50:02,160 YOU CAN SEE THAT IN THE YOUNG 3659 02:50:02,160 --> 02:50:06,480 CD CELLS, IN ALL CELLS THE CD 3660 02:50:06,480 --> 02:50:16,000 39, 73 AND EXERTION MARKER 3661 02:50:16,000 --> 02:50:22,040 CONTAINING UP REGULATORS, ALL 3662 02:50:22,040 --> 02:50:22,600 UPREGULATIONS DECREASED. IT 3663 02:50:22,600 --> 02:50:24,120 LOOKS LIKE WITH THIS EXERTION 3664 02:50:24,120 --> 02:50:33,480 OF CD CELLS, I CALL THAT 3665 02:50:33,480 --> 02:50:36,480 EXPLOSION (INDISCERNIBLE) IT 3666 02:50:36,480 --> 02:50:42,800 SHOWS PD1 IS INCREASED. 3667 02:50:42,800 --> 02:50:46,200 SORRY THERE IS A MISTAKE. NO, 3668 02:50:46,200 --> 02:50:47,920 NO, THERE IS SOMETHING WRONG. 3669 02:50:47,920 --> 02:50:50,400 IT IS SUPPOSED TO BE PD1 3670 02:50:50,400 --> 02:50:54,800 INCREASED IN AGING AND 3671 02:50:54,800 --> 02:50:57,880 (INDISCERNIBLE) DECREASES. 3672 02:50:57,880 --> 02:51:00,280 SORRY MY LABELS ARE TYPOS. 3673 02:51:00,280 --> 02:51:07,040 ANYWAY, ALL THIS EXERTION. 3674 02:51:07,040 --> 02:51:15,200 THEN TO UNDERSTAND, WHAT IS 3675 02:51:15,200 --> 02:51:15,840 THIS? INCREASED IN CIRCULATION 3676 02:51:15,840 --> 02:51:17,280 AND HOW IT AFFECTS CANCER 3677 02:51:17,280 --> 02:51:18,520 OUTCOME? WE DID THIS 3678 02:51:18,520 --> 02:51:22,680 SIDE-BY-SIDE, B16 MELANOMA, AT3 3679 02:51:22,680 --> 02:51:27,000 IN MICE ALL YOUNG, THIN 3680 02:51:27,000 --> 02:51:28,400 CONDITIONS EXCEPT THROUGH CD 3681 02:51:28,400 --> 02:51:32,400 57. THE BACKGROUND IS THE SAME 3682 02:51:32,400 --> 02:51:36,960 AGAIN YOU CAN SEE THAT WHILE IN 3683 02:51:36,960 --> 02:51:41,280 B16 MELANOMA IT DECREASES, YOU 3684 02:51:41,280 --> 02:51:43,600 CAN SEE THAT IN ALL TUMOR 3685 02:51:43,600 --> 02:51:44,200 INFILTRATING LYMPHOCYTES YOU 3686 02:51:44,200 --> 02:51:49,200 CAN SEE THE CELLS DO NOT HAVE 3687 02:51:49,200 --> 02:51:51,840 DOUBLE POSITIVITY FOR ENZYMES. 3688 02:51:51,840 --> 02:51:59,080 YOU CAN SEE IN AGED AT3 TUMOR 3689 02:51:59,080 --> 02:52:01,600 GROWTH IS INCREASED. 3690 02:52:01,600 --> 02:52:03,040 YOU CAN SEE IT IS AN EFFECTIVE 3691 02:52:03,040 --> 02:52:07,640 PIPE FOR CELLS, 3692 02:52:07,640 --> 02:52:08,240 (INDISCERNIBLE)-- OPPOSITE 3693 02:52:08,240 --> 02:52:11,320 EVERYTHING. 3694 02:52:11,320 --> 02:52:14,200 AND THEN, WE SEE THAT BECAUSE 3695 02:52:14,200 --> 02:52:24,560 AT TUMOR ALREADY HAD 3696 02:52:26,000 --> 02:52:29,280 PRE-EXISTING (INDISCERNIBLE) 3697 02:52:29,280 --> 02:52:29,960 COMPARED TO MELANOMA EXISTING 3698 02:52:29,960 --> 02:52:33,240 CONDITIONS. 3699 02:52:33,240 --> 02:52:35,000 YOU CAN COMPARE AGAIN THE 3700 02:52:35,000 --> 02:52:39,040 TUMOR INFILTRATED DH CELLS AND 3701 02:52:39,040 --> 02:52:39,560 YOU CAN APPRECIATE THE 3702 02:52:39,560 --> 02:52:42,840 INFILTRATED CELLS IN AT 3 3703 02:52:42,840 --> 02:52:45,600 TUMOR, INCREASING THE ENZYMES 3704 02:52:45,600 --> 02:52:53,320 AND THE EXERTION MARKERS. AND 3705 02:52:53,320 --> 02:52:55,160 THIS EXOENZYME EXPRESSES ITSELF 3706 02:52:55,160 --> 02:53:00,120 AND IT IS MORE IN CLUSTER 22. 3707 02:53:00,120 --> 02:53:02,040 ALTHOUGH IT IS PRESENT IN 3708 02:53:02,040 --> 02:53:08,440 ALMOST CDH CELL OF AT3. 3709 02:53:08,440 --> 02:53:14,040 YOU CAN PROVE THAT THESE CDH 3710 02:53:14,040 --> 02:53:14,640 CELLS ARE DOING SOMETHING YOU 3711 02:53:14,640 --> 02:53:19,280 CAN SEE WITH RAG KO WITH AT3 3712 02:53:19,280 --> 02:53:29,720 AND WITH YOUNG ADOPTIVE 3713 02:53:30,160 --> 02:53:30,560 TRANSFER IT ALL HAD A 3714 02:53:30,560 --> 02:53:31,200 SIGNIFICANT DEFECT. ANOTHER WAY 3715 02:53:31,200 --> 02:53:36,360 IS IT THAT THE AT3 TUMOR 3716 02:53:36,360 --> 02:53:39,040 (INDISCERNIBLE), AND THE 3717 02:53:39,040 --> 02:53:40,360 CREATION OF THE CD REDUCES THE 3718 02:53:40,360 --> 02:53:45,320 TUMOR GROWTH, INDICATING THE CD 3719 02:53:45,320 --> 02:53:46,360 ITSELF RECRUITMENT INTO TUMOR 3720 02:53:46,360 --> 02:53:48,400 DOING (INDISCERNIBLE). 3721 02:53:48,400 --> 02:53:51,040 IN SUMMARY, I SHOWED YOU THAT 3722 02:53:51,040 --> 02:53:55,120 THE B CELLS IN AGING ARE 3723 02:53:55,120 --> 02:53:55,680 CHANGING AND THERE ARE MANY 3724 02:53:55,680 --> 02:54:00,000 DIFFERENT TYPES OF B CELLS, AND 3725 02:54:00,000 --> 02:54:02,720 THE OUTCOME CHANGES. THROUGH 3726 02:54:02,720 --> 02:54:08,760 (INDISCERNIBLE) CHANGE, IT CAN 3727 02:54:08,760 --> 02:54:09,400 EITHER INCREASE TUMOR GROWTH IN 3728 02:54:09,400 --> 02:54:11,280 ALL OR DECREASE. IT INCREASES 3729 02:54:11,280 --> 02:54:13,360 TUMOR GROWTH AND ALL OF THOSE 3730 02:54:13,360 --> 02:54:16,200 CD8 CELLS RECRUITED INTO THE 3731 02:54:16,200 --> 02:54:22,040 TUMOR. THANK YOU. 3732 02:54:22,040 --> 02:54:26,840 >>THANK YOU ARIA. THANK YOU 3733 02:54:26,840 --> 02:54:27,480 VERY MUCH AND WE HAVE TIME FOR 3734 02:54:27,480 --> 02:54:37,960 A FEW QUESTIONS. MICROPHONE 3735 02:54:38,360 --> 02:54:40,120 PLEASE. 3736 02:54:40,120 --> 02:54:43,600 >>WITH AT CELLS, IT IS VERY 3737 02:54:43,600 --> 02:54:48,760 INTERESTING. DO YOU OBSERVE 3738 02:54:48,760 --> 02:54:49,600 THE RECEPTORS BECOMING MUCH 3739 02:54:49,600 --> 02:54:54,160 MORE CONAL WITH AGING? 3740 02:54:54,160 --> 02:54:55,880 >>THIS IS A MUTUAL QUESTION. 3741 02:54:55,880 --> 02:54:58,440 WE DID NOT CHECK ANY B CELL 3742 02:54:58,440 --> 02:55:08,960 RECEPTORS. VERY GOOD QUESTION. 3743 02:55:15,480 --> 02:55:18,560 >>IN OLDER TUMORS, IS THERE A 3744 02:55:18,560 --> 02:55:19,080 DIFFERENCE IN IMMUNE CELL 3745 02:55:19,080 --> 02:55:26,680 INFILTRATES? MELANOMAS 3746 02:55:26,680 --> 02:55:27,200 (INDISCERNIBLE), I WAS 3747 02:55:27,200 --> 02:55:27,840 WONDERING IF YOU SEE A SHIFT IN 3748 02:55:27,840 --> 02:55:28,800 TERMS OF THE INFILTRATE? 3749 02:55:28,800 --> 02:55:33,560 >>ANOTHER GOOD QUESTION. THAT 3750 02:55:33,560 --> 02:55:36,320 IS EXACTLY OUR GOAL, TO FIND 3751 02:55:36,320 --> 02:55:39,040 THE IMPORTANT DATA 3752 02:55:39,040 --> 02:55:39,920 COLLABORATING WITH 3753 02:55:39,920 --> 02:55:45,400 (INDISCERNIBLE). WE DO NOT 3754 02:55:45,400 --> 02:55:47,680 HAVE ACCESS TO TUMORS FROM ALL 3755 02:55:47,680 --> 02:55:49,160 (INDISCERNIBLE), BUT CERTAINLY 3756 02:55:49,160 --> 02:55:52,640 CD8 CELLS ARE THERE. WE ARE 3757 02:55:52,640 --> 02:55:57,400 TALKING -- TUMORS. 3758 02:55:57,400 --> 02:55:59,400 >>I CAN MAYBE ADD THE COMMENT 3759 02:55:59,400 --> 02:56:04,320 FROM THE B CELL SIDE. THERE IS 3760 02:56:04,320 --> 02:56:05,600 A LOT OF INFILTRATION OF 3761 02:56:05,600 --> 02:56:08,680 INFLAMMATORY B CELLS IN BREAT 3762 02:56:08,680 --> 02:56:12,360 CANCER IN WOMEN THAT ARE OLDER, 3763 02:56:12,360 --> 02:56:18,880 OVER THE AGE OF 60. REALLY, 3764 02:56:18,880 --> 02:56:25,600 REALLY A LOT AND ALMOST ALL THE 3765 02:56:25,600 --> 02:56:27,040 CELLS THAT INFILTRATE HAVE THE 3766 02:56:27,040 --> 02:56:28,120 PRO-INFLAMMATORY PHENOTYPE OF 3767 02:56:28,120 --> 02:56:30,120 THE DOUBLE NEGATIVE. THEY TAKE 3768 02:56:30,120 --> 02:56:33,160 THE LEAD AMONG THE 3769 02:56:33,160 --> 02:56:33,800 (INDISCERNIBLE) INSIDE BREAST 3770 02:56:33,800 --> 02:56:36,400 CANCER. 3771 02:56:36,400 --> 02:56:37,560 ARE THERE OTHER QUESTIONS FOR 3772 02:56:37,560 --> 02:56:42,240 ARIA? WELL IF NOT THANK YOU SO 3773 02:56:42,240 --> 02:56:46,760 MUCH. 3774 02:56:46,760 --> 02:56:51,640 AND NOW, IT IS TIME FOR MY 3775 02:56:51,640 --> 02:56:55,040 PRESENTATION. I WILL TALK TO 3776 02:56:55,040 --> 02:57:00,880 YOU TODAY ABOUT A RESEARCH 3777 02:57:00,880 --> 02:57:01,440 TOPIC THAT IS BECOMING VERY 3778 02:57:01,440 --> 02:57:03,080 INTERESTING TO ME IN THE RECENT 3779 02:57:03,080 --> 02:57:05,840 YEARS. IT IS THE METABOLIC 3780 02:57:05,840 --> 02:57:09,680 RELATION OF HUMORAL RESPONSES 3781 02:57:09,680 --> 02:57:15,840 IN B CELL FUNCTION IN MICE AND 3782 02:57:15,840 --> 02:57:16,440 INDIVIDUALS WITH INFLAMMATORY 3783 02:57:16,440 --> 02:57:21,520 CONDITIONS. MY MAIN INTEREST IS 3784 02:57:21,520 --> 02:57:22,120 IN OBESITY AND TYPE II DIABETES 3785 02:57:22,120 --> 02:57:26,720 ESPECIALLY IN THE -- TISSUE AND 3786 02:57:26,720 --> 02:57:27,360 ALSO AGING AND TODAY I'M GOING 3787 02:57:27,360 --> 02:57:29,760 TO SHOW YOU THAT AGING CHANGES 3788 02:57:29,760 --> 02:57:30,360 THE METABOLIC PHENOTYPE OF B 3789 02:57:30,360 --> 02:57:32,760 CELLS. I'M GOING TO SHOW YOU 3790 02:57:32,760 --> 02:57:37,680 THAT AGING ALSO INDUCES OTHER 3791 02:57:37,680 --> 02:57:38,320 PRO-INFLAMMATORY IMMUNE CELLS, 3792 02:57:38,320 --> 02:57:38,800 AND I WILL TALK TO YOU 3793 02:57:38,800 --> 02:57:41,640 SPECIFICALLY ABOUT CD4. WE 3794 02:57:41,640 --> 02:57:44,640 ALSO HAVE DATA ON MONOCYTES. 3795 02:57:44,640 --> 02:57:47,280 I WILL SHOW YOU THE EFFECT OF 3796 02:57:47,280 --> 02:57:47,880 LACTATE, WHICH IS ONE OF THEM 3797 02:57:47,880 --> 02:57:49,080 METABOLIZES THEIR MASSIVELY 3798 02:57:49,080 --> 02:57:57,640 SECRETED BY AGED B CELLS AND 3799 02:57:57,640 --> 02:58:01,520 ALSO OTHER IMMUNO CELLS. AND 3800 02:58:01,520 --> 02:58:03,560 FOR THE FIRST POINT. I DON'T 3801 02:58:03,560 --> 02:58:10,080 NEED TO INTRODUCE YOU TO THE 3802 02:58:10,080 --> 02:58:17,840 SEAHORSE TECHNOLOGY. WE USE 3803 02:58:17,840 --> 02:58:18,800 THE MITRAL STRESS TEST TO 3804 02:58:18,800 --> 02:58:21,720 MEASURE IN REAL-TIME 3805 02:58:21,720 --> 02:58:22,240 (INDISCERNIBLE) AND THE 3806 02:58:22,240 --> 02:58:22,840 ACIDIFICATION RATES WHICH ARE 3807 02:58:22,840 --> 02:58:29,160 MEASURES OF OXPHOS AND 3808 02:58:29,160 --> 02:58:31,040 ANAEROBIC GLYCOLYSIS AND 3809 02:58:31,040 --> 02:58:31,640 LACTATE SECRETION IN THIS IS 3810 02:58:31,640 --> 02:58:42,160 DONE IN REAL-TIME. WE DID IT 3811 02:58:44,440 --> 02:58:45,440 IN UNSTIMULATED CELLS BECAUSE 3812 02:58:45,440 --> 02:58:47,840 THE (INDISCERNIBLE). 3813 02:58:47,840 --> 02:58:50,320 WHILE THESE ARE THE RESULTS 3814 02:58:50,320 --> 02:58:50,960 FROM THE ELDERLY INDIVIDUALS AT 3815 02:58:50,960 --> 02:58:55,560 A HIGHER END IN BOTH MEASURES 3816 02:58:55,560 --> 02:58:56,080 ESPECIALLY IN ANAEROBIC 3817 02:58:56,080 --> 02:58:59,080 GLYCOLYSIS. WE WANTED TO 3818 02:58:59,080 --> 02:58:59,680 CONFIRM THE SEAHORSE RESULTS BY 3819 02:58:59,680 --> 02:59:04,280 MEASURING RNA TRANSFERS FOR 3820 02:59:04,280 --> 02:59:05,320 ENZYME SYMBOL IN THIS METABOLIC 3821 02:59:05,320 --> 02:59:07,560 PATHWAY, PARTICULARLY 3822 02:59:07,560 --> 02:59:11,200 REMEASURED PDHX, A COMPONENT OF 3823 02:59:11,200 --> 02:59:15,120 THE PYRUVATE DNA COMPLEX 3824 02:59:15,120 --> 02:59:17,800 RESPONSIBLE FOR CONVERSION OF 3825 02:59:17,800 --> 02:59:23,520 PYRUVATE INTO (INDISCERNIBLE) A 3826 02:59:23,520 --> 02:59:24,760 LINK BETWEEN GLYCOLYSIS AND 3827 02:59:24,760 --> 02:59:26,160 (INDISCERNIBLE). 3828 02:59:26,160 --> 02:59:33,960 WE MEASURED LDAH, LACTATE -- 3829 02:59:33,960 --> 02:59:34,600 THE ENZYME RESPONSIBLE FOR THE 3830 02:59:34,600 --> 02:59:37,360 SECRETION OF LACTATE. 3831 02:59:37,360 --> 02:59:37,920 EVERYTHING STARTS WITH AN 3832 02:59:37,920 --> 02:59:41,400 UPTAKE OF NUTRIENT, THE UPTAKE 3833 02:59:41,400 --> 02:59:42,160 OF GLUCOSE. THE FIRST MEASURE 3834 02:59:42,160 --> 02:59:52,840 WE DID WAS STEALING AND -- 3835 02:59:52,840 --> 02:59:59,400 UNSTIMULATED B CELLS, IN OLDER 3836 02:59:59,400 --> 03:00:00,040 ADULTS COMPARED TO YOUNGER ONES 3837 03:00:00,040 --> 03:00:03,160 AND CONCOMITANTLY WE HAD MUCH 3838 03:00:03,160 --> 03:00:05,640 MORE GLUCOSE UPTAKE USING THIS 3839 03:00:05,640 --> 03:00:06,840 GLUCOSE CODE TO 3840 03:00:06,840 --> 03:00:09,240 (INDISCERNIBLE). 3841 03:00:09,240 --> 03:00:16,360 AND THE PATHWAYS OF OXI 3842 03:00:16,360 --> 03:00:17,000 PHOSPHORYLATION WERE CONFIRMED 3843 03:00:17,000 --> 03:00:22,680 BY AN EXPRESSION OF THE PDHX 3844 03:00:22,680 --> 03:00:26,120 MARKER, AS WELL AS THE ROS 3845 03:00:26,120 --> 03:00:33,320 SECRETION AND THIS IS THE CITO 3846 03:00:33,320 --> 03:00:35,080 (INDISCERNIBLE)-- FROM THE 3847 03:00:35,080 --> 03:00:38,240 MITOCHONDRIA. 3848 03:00:38,240 --> 03:00:38,800 THE MAJOR DIFFERENCE BETWEEN 3849 03:00:38,800 --> 03:00:39,400 THE YOUNG AND OLD WAS SEEN AT 3850 03:00:39,400 --> 03:00:40,640 THE LEVEL OF ANAEROBIC 3851 03:00:40,640 --> 03:00:41,120 GLYCOLYSIS AND LACTATE 3852 03:00:41,120 --> 03:00:42,120 SECRETION SO THIS IS IN FACT 3853 03:00:42,120 --> 03:00:43,160 THE RESULTS FROM THESE 3854 03:00:43,160 --> 03:00:47,200 INDIVIDUALS. THAT HAVE A LOT OF 3855 03:00:47,200 --> 03:00:47,840 LDHA TRANSCRIPTS AND THESE ARE 3856 03:00:47,840 --> 03:00:49,040 ASSOCIATED WITH INCREASED 3857 03:00:49,040 --> 03:00:59,600 SECRETION OF LACTATING CULTURE 3858 03:01:00,400 --> 03:01:00,920 AFTER STIMULATION FOR EIGHT 3859 03:01:00,920 --> 03:01:01,560 HOURS WITH A MITOGEN. THE SAME 3860 03:01:01,560 --> 03:01:06,080 CULTURE WAS ABLE TO SECRETE BIG 3861 03:01:06,080 --> 03:01:06,720 AMOUNTS OF LACTATE AND WE WERE 3862 03:01:06,720 --> 03:01:07,360 ALSO ABLE TO SECRETE ANTIBODIES 3863 03:01:07,360 --> 03:01:08,000 THE TWO MAJORS WERE CORRELATED, 3864 03:01:08,000 --> 03:01:08,480 AND NOW WE HAVE MORE 3865 03:01:08,480 --> 03:01:11,120 INDIVIDUALS IN THIS PANEL. 3866 03:01:11,120 --> 03:01:15,720 AND SO TO SUMMARIZE THIS FIRST 3867 03:01:15,720 --> 03:01:18,520 RESULT, WE DEMONSTRATED THAT 3868 03:01:18,520 --> 03:01:21,880 THE B CELLS FROM OLDER 3869 03:01:21,880 --> 03:01:29,600 INDIVIDUALS ARE -- AND 3870 03:01:29,600 --> 03:01:30,080 UPREGULATED ANAEROBIC 3871 03:01:30,080 --> 03:01:31,360 GLYCOLYSIS, ONE OF THE FIRST 3872 03:01:31,360 --> 03:01:31,880 EVIDENCE OF SECRETION OF 3873 03:01:31,880 --> 03:01:39,560 LACTATE OF HUMAN B CELLS. 3874 03:01:39,560 --> 03:01:40,160 AND THEN WE WANTED TO SEE THEY 3875 03:01:40,160 --> 03:01:41,400 ARE SO HYPER METABOLIC AND ARE 3876 03:01:41,400 --> 03:01:43,440 ABLE TO TURN ON INFLAMMATORY 3877 03:01:43,440 --> 03:01:43,960 RESPONSE. WE DID THIS IN 3878 03:01:43,960 --> 03:01:44,600 CULTURES AND WE PUT AT THE TOP 3879 03:01:44,600 --> 03:01:53,280 OF THE TRANSWELL CD4 T-CELLS 3880 03:01:53,280 --> 03:01:53,920 ISOLATED FROM YOUNG INDIVIDUALS 3881 03:01:53,920 --> 03:01:54,480 AT THE BOTTOM B CELLS FROM 3882 03:01:54,480 --> 03:01:54,960 OTHER YOUNG OR ELDERLY 3883 03:01:54,960 --> 03:01:57,320 INDIVIDUALS. AND THEN WE WERE 3884 03:01:57,320 --> 03:02:02,880 ABLE TO SEE IN ONLY 24 HOURS, 3885 03:02:02,880 --> 03:02:03,520 VERY QUICKLY IN THE ABSENCE OF 3886 03:02:03,520 --> 03:02:09,720 ANY EXOGENOUS STIMULATION THE 3887 03:02:09,720 --> 03:02:10,320 T-CELLS WERE ABLE TO TURN ON 3888 03:02:10,320 --> 03:02:15,160 GLUTON AND LDHA, AND THEY 3889 03:02:15,160 --> 03:02:22,280 BECOME GLYCOLYTIC, AND THEY 3890 03:02:22,280 --> 03:02:25,160 BECOME MARKERS OF ANAEROBIC 3891 03:02:25,160 --> 03:02:25,800 GLYCOLYSIS, AND THEY WERE ABLE 3892 03:02:25,800 --> 03:02:27,240 TO TURN ON WITH THE SAME 3893 03:02:27,240 --> 03:02:28,360 MECHANISMS THAT HAPPEN IN B 3894 03:02:28,360 --> 03:02:31,400 CELLS. 3895 03:02:31,400 --> 03:02:35,080 IN THIS CULTURE, WE HAVE 3896 03:02:35,080 --> 03:02:35,720 SECRETION OF LACTATE, NOT SO 3897 03:02:35,720 --> 03:02:37,800 MUCH AS THE ONE THAT I SHOWED 3898 03:02:37,800 --> 03:02:39,120 YOU BEFORE AFTER MITOGEN 3899 03:02:39,120 --> 03:02:41,200 STIMULATION. THESE LIKE THAT 3900 03:02:41,200 --> 03:02:45,360 COME FROM THE -- ONLY BECAUSE 3901 03:02:45,360 --> 03:02:51,680 THE CD4 HAD TO BE HEAVILY 3902 03:02:51,680 --> 03:02:52,320 STIMULATED IN ORDER TO PRODUCE 3903 03:02:52,320 --> 03:02:52,920 LACTATE AND WE HAVE SECRETION 3904 03:02:52,920 --> 03:02:53,560 OF PRO-INFLAMMATORY CYTOKINES, 3905 03:02:53,560 --> 03:02:57,000 AND THIS IS SHOWN AS INCREASE 3906 03:02:57,000 --> 03:02:59,760 INTEGRATION COMPARED TO THE CD4 3907 03:02:59,760 --> 03:03:02,360 ALONE IN CULTURE AND BECAUSE OF 3908 03:03:02,360 --> 03:03:02,960 THE PRESENCE OF LACTATE, WE 3909 03:03:02,960 --> 03:03:05,320 WANTED TO SEE IF THERE IS 3910 03:03:05,320 --> 03:03:14,840 POSSIBLE TO BLOCK THIS PATHWAY 3911 03:03:14,840 --> 03:03:15,240 OF ACTIVATION OF 3912 03:03:15,240 --> 03:03:15,840 PRO-INFLAMMATORY CD4 BY USING 3913 03:03:15,840 --> 03:03:19,640 SPECIFIC LACTATING INHIBITORS, 3914 03:03:19,640 --> 03:03:20,240 WE CREATED THE CELLS FROM ALL 3915 03:03:20,240 --> 03:03:24,880 INDIVIDUALS WITH TWO DIFFERENT 3916 03:03:24,880 --> 03:03:26,360 LACTATE, ONE IS THE SMALL 3917 03:03:26,360 --> 03:03:32,720 MOLECULE, FX11, AND WE HAVE 3918 03:03:32,720 --> 03:03:36,200 INCREASE SECRETION OF 3919 03:03:36,200 --> 03:03:36,840 (INDISCERNIBLE) AND USING AN 3920 03:03:36,840 --> 03:03:37,400 ANTIBODY THE BLOCK SELECTED 3921 03:03:37,400 --> 03:03:46,080 TRANSPORTER SLC BLAH BLAH BLAH, 3922 03:03:46,080 --> 03:03:46,600 A LONG NAME. THIS IS VERY 3923 03:03:46,600 --> 03:03:47,280 EFFECTIVE IN BLOCKING SECRETION 3924 03:03:47,280 --> 03:03:47,840 OF THE CYTOKINES. 3925 03:03:47,840 --> 03:03:52,880 THIS MEANS THAT B CELLS USE 3926 03:03:52,880 --> 03:03:55,960 THE PATHWAYS THAT ARE LIKELY 3927 03:03:55,960 --> 03:03:56,520 DRIVEN IN ORDER TO TURN ON 3928 03:03:56,520 --> 03:03:57,080 INFLAMMATORY CD4, AND I CAN 3929 03:03:57,080 --> 03:04:02,120 TELL YOU (INDISCERNIBLE). 3930 03:04:02,120 --> 03:04:02,680 WHAT IS THE LIKELY DOING TO 3931 03:04:02,680 --> 03:04:05,520 THE T CELLS, THE B CELLS 3932 03:04:05,520 --> 03:04:10,280 THEMSELVES? WE USED TO GET IN 3933 03:04:10,280 --> 03:04:10,840 THE SEAHORSE TECHNOLOGY AND 3934 03:04:10,840 --> 03:04:12,040 USING GLYCOLYTIC TEST DONE IN 3935 03:04:12,040 --> 03:04:12,680 THE PRESENCE OF THREE DIFFERENT 3936 03:04:12,680 --> 03:04:17,320 INJECTIONS OF GLUCOSE, 3937 03:04:17,320 --> 03:04:23,240 OLIGOMYCIN ANDN -- AND IT COMES 3938 03:04:23,240 --> 03:04:25,080 FROM INDIVIDUALS AFTER 3939 03:04:25,080 --> 03:04:25,640 OVERNIGHT STIMULATE IN THE 3940 03:04:25,640 --> 03:04:26,840 ABSENCE OR PRESENCE OF LACTATE 3941 03:04:26,840 --> 03:04:27,440 IN THE PRESENCE OF LACTATE 3942 03:04:27,440 --> 03:04:32,840 THERE IS A HIGHER GLYCOLYTIC 3943 03:04:32,840 --> 03:04:33,440 PHENOTYPE AND IS CONFIRMED BY 3944 03:04:33,440 --> 03:04:33,880 THE EXPRESSION OF THE 3945 03:04:33,880 --> 03:04:34,440 UPREGULATED EXPRESSION OF 3946 03:04:34,440 --> 03:04:37,880 MARKERS LIKE GLUT 1 AND LDHA, 3947 03:04:37,880 --> 03:04:43,520 NOT SO MUCH PDHX. 3948 03:04:43,520 --> 03:04:44,080 WE PUT THE OLDER INDIVIDUALS 3949 03:04:44,080 --> 03:04:46,360 IN THIS PICTURE, AND IT LOOKS 3950 03:04:46,360 --> 03:04:47,000 EXACTLY LIKE THE YOUNG TREATED 3951 03:04:47,000 --> 03:04:50,760 WITH LACTATE. SO LACTATE 3952 03:04:50,760 --> 03:04:55,440 INDUCES IMMUNO SENESCENCE AND 3953 03:04:55,440 --> 03:04:56,040 WHEN WE LOOK AT THIS TRANSCRIPT 3954 03:04:56,040 --> 03:04:57,440 THEY WERE ABSOLUTELY 3955 03:04:57,440 --> 03:04:59,120 OVERLAPPING. THE TWO GROUPS, 3956 03:04:59,120 --> 03:05:02,960 THE YOUNG WITH LACTATE AND 3957 03:05:02,960 --> 03:05:06,680 ELDERLY ARE SIMILAR. THE CELLS 3958 03:05:06,680 --> 03:05:07,280 ARE ABLE TO SECRETE MULTIPLE 3959 03:05:07,280 --> 03:05:10,080 TRANSCRIPT FOR INFLAMMATORY 3960 03:05:10,080 --> 03:05:10,640 MARKERS, SOME OF WHICH ARE 3961 03:05:10,640 --> 03:05:15,920 MEMBERS OF THIS SAS, 3962 03:05:15,920 --> 03:05:19,640 PRO-INFLAMMATORY MICRO RNA, 3963 03:05:19,640 --> 03:05:20,160 MANY MARKERS OF IMMUNE 3964 03:05:20,160 --> 03:05:25,160 ACTIVATION AND CANONICAL 3965 03:05:25,160 --> 03:05:25,800 SENESCENT MARKERS BUT NOT ONLY 3966 03:05:25,800 --> 03:05:26,320 THIS BUT THEY'RE ABLE TO 3967 03:05:26,320 --> 03:05:28,680 SECRETE IN VITRO AUTOIMMUNE 3968 03:05:28,680 --> 03:05:29,280 ANTIBODIES AFTER THE EXPOSURE 3969 03:05:29,280 --> 03:05:30,680 TO LACTATE IS SIMILAR TO WHAT 3970 03:05:30,680 --> 03:05:32,960 HAPPENS AGAIN TO B CELLS FROM 3971 03:05:32,960 --> 03:05:37,120 ELDERLY INDIVIDUALS; THEY WERE 3972 03:05:37,120 --> 03:05:38,320 ALSO ABLE TO SECRETE THE 3973 03:05:38,320 --> 03:05:39,680 PRO-INFLAMMATORY CYTOKINES IN 3974 03:05:39,680 --> 03:05:43,680 IL6 AND (INDISCERNIBLE). 3975 03:05:43,680 --> 03:05:54,120 WHY DID WE DO THIS? THIS IS 3976 03:05:58,400 --> 03:06:03,480 CONSTITUVILEY EXPRESSED. USING 3977 03:06:03,480 --> 03:06:04,080 THE ANTIBODY SHORTENED BEFORE 3978 03:06:04,080 --> 03:06:04,680 IS POSSIBLE TO DOWN REGULATE 3979 03:06:04,680 --> 03:06:06,920 THE EXPRESSION OF THE LACTATE, 3980 03:06:06,920 --> 03:06:07,440 AND AT THE SAME TIME DOWN 3981 03:06:07,440 --> 03:06:07,960 DIRECTLY COMPLETED THE 3982 03:06:07,960 --> 03:06:10,200 SECRETION OF ANTIBODIES AND 3983 03:06:10,200 --> 03:06:13,520 PRO-INFLAMMATORY CYTOKINES. 3984 03:06:13,520 --> 03:06:14,280 AND WITH THE PRESENCE OF 3985 03:06:14,280 --> 03:06:16,000 LACTATE (INDISCERNIBLE). 3986 03:06:16,000 --> 03:06:21,160 WHEN WE TALK ABOUT B CELLS AND 3987 03:06:21,160 --> 03:06:21,800 AGING, THERE IS A DISTRIBUTION 3988 03:06:21,800 --> 03:06:24,960 OF B CELLS. THERE IS NOTHING 3989 03:06:24,960 --> 03:06:25,600 SIMILAR TO WHAT WE SEE IN YOUNG 3990 03:06:25,600 --> 03:06:29,720 PEOPLE. IN THIS AND MANY OTHER 3991 03:06:29,720 --> 03:06:30,760 GROUPS WE WERE PARTICULARLY 3992 03:06:30,760 --> 03:06:33,880 INTERESTED IN THE EXPANSION OF 3993 03:06:33,880 --> 03:06:35,640 THIS DOUBLE NEGATIVE; WHEN WE 3994 03:06:35,640 --> 03:06:42,320 STAIN WITH CD27 AND IDG, THE 3995 03:06:42,320 --> 03:06:42,920 MOST AND PRO-INFLAMMATORY THE 3996 03:06:42,920 --> 03:06:43,520 GROSS UP IN ALL INFLAMMATORY 3997 03:06:43,520 --> 03:06:48,280 CONDITIONS, AGING, OBESITY, 3998 03:06:48,280 --> 03:06:51,120 TYPE II DIABETES, CHRONIC 3999 03:06:51,120 --> 03:06:51,720 INFECTIONS WITH BUYERS AND 4000 03:06:51,720 --> 03:06:54,840 PARASITES AND ALSO IN ACUTE 4001 03:06:54,840 --> 03:06:55,360 COVID AS HAS BEEN SHOWN 4002 03:06:55,360 --> 03:06:55,960 RECENTLY THAT THIS HAS TAKEN 4003 03:06:55,960 --> 03:06:57,080 THE LEAD IN THE BLOOD OF PEOPLE 4004 03:06:57,080 --> 03:07:00,000 WITH COVID. 4005 03:07:00,000 --> 03:07:03,000 SO WHY ARE WE INTERESTED IN 4006 03:07:03,000 --> 03:07:05,400 THIS? BECAUSE WE SHOWED MANY 4007 03:07:05,400 --> 03:07:07,640 YEARS AGO THAT THESE DOUBLE 4008 03:07:07,640 --> 03:07:09,640 NEGATIVES, FIRST OF ALL MEMORY, 4009 03:07:09,640 --> 03:07:13,440 BUT NOT NAïVE, IN BOTH THE 4010 03:07:13,440 --> 03:07:14,040 ELDERLY AND IN THE YOUNG ARE 4011 03:07:14,040 --> 03:07:21,560 ABLE TO SECRETE 4012 03:07:21,560 --> 03:07:22,200 PRO-INFLAMMATORY MEDIATORS AND 4013 03:07:22,200 --> 03:07:23,160 EXPRESS TRANSCRIPTS LIKE IN 4014 03:07:23,160 --> 03:07:23,800 THIS PARTICULAR CASE BUT THESE 4015 03:07:23,800 --> 03:07:24,840 MEDIATORS. 4016 03:07:24,840 --> 03:07:26,480 WE TESTED MANY OF THESE 4017 03:07:26,480 --> 03:07:29,440 INCLUDING SASP MARKERS AND WHEN 4018 03:07:29,440 --> 03:07:33,320 YOU DO AN ANALYSIS YOU SEE THAT 4019 03:07:33,320 --> 03:07:33,920 THE DOUBLE NEGATIVE TAKES THE 4020 03:07:33,920 --> 03:07:38,240 LEAD IN THE MEMORY OF B CELLS. 4021 03:07:38,240 --> 03:07:38,880 BECAUSE THEY ARE THE HIGHEST IN 4022 03:07:38,880 --> 03:07:41,640 TERMS OF SECRETION, AND ALSO IN 4023 03:07:41,640 --> 03:07:47,160 TERMS OF METABOLIC SUPPORT. WHY 4024 03:07:47,160 --> 03:07:47,680 ARE THEY SO METABOLICALLY 4025 03:07:47,680 --> 03:07:58,240 SUPPORTIVE? BECAUSE THIS MAKES 4026 03:07:59,240 --> 03:08:04,120 PRO-INFLAMMATORY CYTOKINES AND 4027 03:08:04,120 --> 03:08:04,760 ANTIBODIES AND THEY HAVE LEVELS 4028 03:08:04,760 --> 03:08:08,080 OF INFLAMMATION THEY HAVE TO 4029 03:08:08,080 --> 03:08:08,720 PERFORM A METABOLIC INVITATION 4030 03:08:08,720 --> 03:08:09,200 TO THESE INFLAMMATORY 4031 03:08:09,200 --> 03:08:11,200 CONDITIONS TO PERFORM THEIR 4032 03:08:11,200 --> 03:08:11,800 JOB, WITH THE SECRETION OF 4033 03:08:11,800 --> 03:08:12,240 IMMUNE ANTIBODIES AND 4034 03:08:12,240 --> 03:08:22,480 CYTOKINES. 4035 03:08:23,080 --> 03:08:23,640 YOU SEE THAT THESE CYTOKINE 4036 03:08:23,640 --> 03:08:24,240 NEGATIVES AGAIN ARE NOT ONLY 4037 03:08:24,240 --> 03:08:26,080 VERY HIGH, AND THEY ARE 4038 03:08:26,080 --> 03:08:26,680 INFLAMMATORY MARKERS IN GENERAL 4039 03:08:26,680 --> 03:08:32,480 BUT THEY ARE ABLE IN THE 4040 03:08:32,480 --> 03:08:33,120 EXPRESSION OF ALL THESE MARKERS 4041 03:08:33,120 --> 03:08:33,720 AND WE WILL LOOK CAREFULLY TO 4042 03:08:33,720 --> 03:08:44,200 THE DIFFERENT PATHWAYS IN THE 4043 03:08:46,000 --> 03:08:47,560 ANAEROBIC GLYCOLYSIS, THERE ARE 4044 03:08:47,560 --> 03:08:49,240 MANY MARKERS. 4045 03:08:49,240 --> 03:08:51,040 THIS IS MY LAST SLIDE OF 4046 03:08:51,040 --> 03:08:56,680 RESULTS. I DON'T THINK I HAVE 4047 03:08:56,680 --> 03:08:59,400 TIME TO MAKE A SUMMARY. I WANT 4048 03:08:59,400 --> 03:09:01,600 TO INTRODUCE EFFECTIVE IN THE 4049 03:09:01,600 --> 03:09:02,200 LAB WE ARE ALSO WORKING WITH 4050 03:09:02,200 --> 03:09:03,400 OTHER METABOLIC INHIBITORS LIKE 4051 03:09:03,400 --> 03:09:08,560 METFORMIN AND (INDISCERNIBLE) 4052 03:09:08,560 --> 03:09:09,200 -- BECAUSE THEY ARE ALREADY IN 4053 03:09:09,200 --> 03:09:10,320 THE CLINICAL TRIALS, AND THEY 4054 03:09:10,320 --> 03:09:12,600 HAVE BEEN APPROVED. 4055 03:09:12,600 --> 03:09:14,720 THIS IS MY THANK YOU SLIDE. 4056 03:09:14,720 --> 03:09:15,440 THIS WORK WAS DONE SPECIFICALLY 4057 03:09:15,440 --> 03:09:19,120 BY MRIA, DENISSE AND KEVIN AND 4058 03:09:19,120 --> 03:09:22,520 KATE IN THE LAB. I WANT TO 4059 03:09:22,520 --> 03:09:23,440 ACKNOWLEDGE THE BE 4060 03:09:23,440 --> 03:09:26,520 COLLABORATION WITH THE CFAR 4061 03:09:26,520 --> 03:09:27,800 PEOPLE IN OUR DEPARTMENTS, 4062 03:09:27,800 --> 03:09:38,320 SURESH AND SAVITA PAHWA. THE 4063 03:09:44,280 --> 03:09:44,760 DOCTORS WHO HELPED WITH THE 4064 03:09:44,760 --> 03:09:47,160 STUDY AND THE FUNDING. IT IS 4065 03:09:47,160 --> 03:09:54,080 VERY IMPORTANT TO HAVE A GOOD 4066 03:09:54,080 --> 03:09:54,640 METABOLOMIC ANALYSIS AND A 4067 03:09:54,640 --> 03:09:57,960 SIGNATURE FOR EACH INDIVIDUAL. 4068 03:09:57,960 --> 03:10:00,560 THIS IS GOOD FOR HEALTHY AGING, 4069 03:10:00,560 --> 03:10:01,200 GOOD FOR EVERYTHING THAT IS NOW 4070 03:10:01,200 --> 03:10:04,160 ASSOCIATED WITH ANTIAGING. AND 4071 03:10:04,160 --> 03:10:04,800 IT HAS TO BE A REALLY THOROUGH 4072 03:10:04,800 --> 03:10:08,160 METABOLIC ANALYSIS. WE NEED TO 4073 03:10:08,160 --> 03:10:17,320 UNDERSTAND HOW THE METABOLIC 4074 03:10:17,320 --> 03:10:21,880 PHENOTYPE AND THE INFLAMMAGING 4075 03:10:21,880 --> 03:10:22,480 PHENOTYPE TALK TO EACH OTHER 4076 03:10:22,480 --> 03:10:22,960 AND HOW THESE TWO IN 4077 03:10:22,960 --> 03:10:23,560 COLLABORATION REGULATING THE 4078 03:10:23,560 --> 03:10:24,160 COMMUNICATION BETWEEN HEALTH 4079 03:10:24,160 --> 03:10:27,280 AND TISSUES, HEALTH AND ORGANS 4080 03:10:27,280 --> 03:10:28,240 NOT ONLY IN INFLAMMATORY 4081 03:10:28,240 --> 03:10:28,800 DISEASE BUT IN MANY OTHER 4082 03:10:28,800 --> 03:10:31,200 CONDITIONS. IT CAN BE RELEVANT 4083 03:10:31,200 --> 03:10:33,960 FOR CANCER, AUTOIMMUNE 4084 03:10:33,960 --> 03:10:38,560 DISEASES, AND SO ON. AND OF 4085 03:10:38,560 --> 03:10:39,120 COURSE THIS WILL ALLOW THE 4086 03:10:39,120 --> 03:10:42,440 IDENTIFICATION WITH OTHER 4087 03:10:42,440 --> 03:10:43,000 TARGETS, METABOLIC TARGETS, 4088 03:10:43,000 --> 03:10:45,920 THAT CAN BE USEFUL FOR TREATING 4089 03:10:45,920 --> 03:10:48,960 THESE CONDITIONS AND IMPROVE IN 4090 03:10:48,960 --> 03:10:51,320 YOUNG RESPONSE. 4091 03:10:51,320 --> 03:10:53,000 LAST BUT NOT LEAST, A BIG 4092 03:10:53,000 --> 03:10:58,440 THANK YOU TO -- --THIS IS BEEN 4093 03:10:58,440 --> 03:11:00,480 A FANTASTIC LOCATION FANTASTIC 4094 03:11:00,480 --> 03:11:04,120 MEETING AND I LEARNED A LOT. A 4095 03:11:04,120 --> 03:11:05,320 LOT OF NEW INTERACTION AND A 4096 03:11:05,320 --> 03:11:08,680 LOT OF OLD FACES, NOT BECAUSE 4097 03:11:08,680 --> 03:11:09,320 WE ARE IN AN AGING MEETING BUT 4098 03:11:09,320 --> 03:11:09,920 FACES THAT I HAVE KNOWN FOR A 4099 03:11:09,920 --> 03:11:13,160 LONG TIME. THANK YOU SO MUCH. 4100 03:11:13,160 --> 03:11:15,240 INCLUDING ONE IN THE BACK. 4101 03:11:15,240 --> 03:11:17,200 WELCOME REBECCA. GOOD TO SEE 4102 03:11:17,200 --> 03:11:17,680 YOU. 4103 03:11:17,680 --> 03:11:20,120 >>[APPLAUSE] 4104 03:11:20,120 --> 03:11:23,120 >>OKAY QUESTIONS? WE HAVE A 4105 03:11:23,120 --> 03:11:24,320 COUPLE OF MINUTES FOR 4106 03:11:24,320 --> 03:11:28,560 QUESTIONS. MY FRIEND CONNIE. 4107 03:11:28,560 --> 03:11:29,160 >>SO THIS IS ACTUALLY A VERY 4108 03:11:29,160 --> 03:11:29,640 EXCITING CONCEPT YOU'RE 4109 03:11:29,640 --> 03:11:32,600 PRESENTING HERE. YOU ARE 4110 03:11:32,600 --> 03:11:34,200 SAYING THAT AUTO ANTIBODY 4111 03:11:34,200 --> 03:11:34,800 PRODUCTION WILL DEPEND ON THE 4112 03:11:34,800 --> 03:11:38,640 TISSUE ENVIRONMENT. AND YOU 4113 03:11:38,640 --> 03:11:39,240 WOULD SAY THAT AUTOANTIBODY 4114 03:11:39,240 --> 03:11:42,080 PRODUCTION WOULD BE FAVORED IN 4115 03:11:42,080 --> 03:11:45,680 A LACTATE RICH ENVIRONMENT. 4116 03:11:45,680 --> 03:11:47,680 THAT I THINK IS A VERY 4117 03:11:47,680 --> 03:11:56,080 IMPORTANT THING FOR US TO ROLL 4118 03:11:56,080 --> 03:11:56,680 INTO OUR UNDERSTANDING OF HOW 4119 03:11:56,680 --> 03:12:04,640 WE LOOK AT AUTOIMMUNE DISEASE, 4120 03:12:04,640 --> 03:12:05,240 BECAUSE WE LOOK AT IT I THINK 4121 03:12:05,240 --> 03:12:05,720 IT HAS TO DO WITH THE 4122 03:12:05,720 --> 03:12:09,440 AVAILABILITY OF AUTO ANTIGEN. 4123 03:12:09,440 --> 03:12:10,000 THIS BRINGS A MODIFIER OF 4124 03:12:10,000 --> 03:12:11,000 AUTOIMMUNITY, VERY INTERESTING. 4125 03:12:11,000 --> 03:12:14,880 THANK YOU VERY MUCH. 4126 03:12:14,880 --> 03:12:15,480 >>I WANT TO TELL YOU SOMETHING 4127 03:12:15,480 --> 03:12:16,080 WE DID NOT HAVE TIME TO TALK 4128 03:12:16,080 --> 03:12:18,680 ABOUT. ANOTHER VERY, VERY 4129 03:12:18,680 --> 03:12:24,720 IMPORTANT WAY TO BLOCK THESE 4130 03:12:24,720 --> 03:12:29,800 POLARIZING EFFECT IS TO USE 4131 03:12:29,800 --> 03:12:35,040 ICOSLIGAN BLOCKAGE (PHONETIC), 4132 03:12:35,040 --> 03:12:35,600 YOU KNOW VERY WELL THIS IS 4133 03:12:35,600 --> 03:12:36,200 EXTREMELY RELEVANT FOR THE 4134 03:12:36,200 --> 03:12:41,240 GENERATION OF PATHOGENIC B AND 4135 03:12:41,240 --> 03:12:41,880 T-CELLS AND INFLAMED TISSUE OF 4136 03:12:41,880 --> 03:12:42,440 PATIENTS WITH RHEUMATOID 4137 03:12:42,440 --> 03:12:46,960 ARTHRITIS. 4138 03:12:46,960 --> 03:12:47,440 ACTUALLY THE BEST WAY TO 4139 03:12:47,440 --> 03:12:50,440 COMPLETELY AGGREGATE ANTIBODY 4140 03:12:50,440 --> 03:12:50,920 SECRETION, ALL ANTIBODY 4141 03:12:50,920 --> 03:12:51,560 SECRETION AND LACTATE SECRETION 4142 03:12:51,560 --> 03:12:59,040 IS BLOCKING THE B CELLS WITH AN 4143 03:12:59,040 --> 03:13:02,800 ANTI-LYCOS LIGAND ANTIBODY, 4144 03:13:02,800 --> 03:13:03,440 EXTREMELY POWERFUL AND THIS IS 4145 03:13:03,440 --> 03:13:04,080 ALSO POWERFUL WHEN WE ROLL INTO 4146 03:13:04,080 --> 03:13:04,760 THE TISSUE EVEN MORE BECAUSE OF 4147 03:13:04,760 --> 03:13:07,680 THE LEVEL OF INFORMATION. 4148 03:13:07,680 --> 03:13:16,840 >>SO THIS IS GOING TO -- THE 4149 03:13:16,840 --> 03:13:18,640 ABCS GO INTO THE 4150 03:13:18,640 --> 03:13:20,800 (INDISCERNIBLE) STRUCTURE? 4151 03:13:20,800 --> 03:13:21,480 >>YES WE SHOW THAT WITH THE 4152 03:13:21,480 --> 03:13:25,120 ABC IN MINE AND THE HUMAN 4153 03:13:25,120 --> 03:13:35,440 (INDISCERNIBLE). 4154 03:13:36,160 --> 03:13:38,600 >>ARE B CELLS PRESENTING 4155 03:13:38,600 --> 03:13:38,960 ANTIGEN? 4156 03:13:38,960 --> 03:13:41,160 >>THEY DO IT NORMALLY. I HAVE 4157 03:13:41,160 --> 03:13:43,320 NOT TESTED THE CAPACITY IN THIS 4158 03:13:43,320 --> 03:13:45,440 CONTEXT BUT YES. THEY DO AND I 4159 03:13:45,440 --> 03:13:47,800 AM EXPECTING -- THIS IS VERY 4160 03:13:47,800 --> 03:13:51,040 PRELIMINARY, WE STILL HAVE A 4161 03:13:51,040 --> 03:13:53,440 LOT OF PIECES TO ADD TO THE 4162 03:13:53,440 --> 03:13:53,960 PUZZLE, BUT I THINK IT IS 4163 03:13:53,960 --> 03:13:56,520 RELEVANT FOR B CELL BIOLOGY. 4164 03:13:56,520 --> 03:14:03,120 THANK YOU FOR THE QUESTION. YES? 4165 03:14:03,120 --> 03:14:03,720 >>I AM WONDERING IF YOU HAVE 4166 03:14:03,720 --> 03:14:05,920 HAD THE OPPORTUNITY TO EXPLORE 4167 03:14:05,920 --> 03:14:06,440 THE RELATIONSHIP OF THE 4168 03:14:06,440 --> 03:14:09,160 CHANGING B CELL REPERTOIRE WITH 4169 03:14:09,160 --> 03:14:11,800 IH WITH THE METABOLIC CHANGES? 4170 03:14:11,800 --> 03:14:14,200 >>THAT WOULD BE FANTASTIC. 4171 03:14:14,200 --> 03:14:15,000 MAYBE WE CAN TALK TO SCOTT AND 4172 03:14:15,000 --> 03:14:16,640 DO SOMETHING TOGETHER. I HAVE 4173 03:14:16,640 --> 03:14:21,480 NOT DONE ANYTHING LIKE THAT. 4174 03:14:21,480 --> 03:14:22,120 WE DO NOT HAVE THE POSSIBILITY 4175 03:14:22,120 --> 03:14:22,720 TO DO IT. WE HAVE TO GO WITH 4176 03:14:22,720 --> 03:14:23,240 THE BEST IN THE FIELD, 4177 03:14:23,240 --> 03:14:24,360 HOPEFULLY SOON. 4178 03:14:24,360 --> 03:14:28,480 >>ONLINE QUESTION. GREAT 4179 03:14:28,480 --> 03:14:29,880 TALK. YOU LOOK AT THE PPF CYCLE 4180 03:14:29,880 --> 03:14:34,680 OF (INDISCERNIBLE) OF AGE AND 4181 03:14:34,680 --> 03:14:35,320 DOUBLE NEGATIVE IN THE BALANCE 4182 03:14:35,320 --> 03:14:39,160 OF OCR IS CHANGING OR IS 4183 03:14:39,160 --> 03:14:41,440 EVERYTHING RAMPING UP EQUALLY? 4184 03:14:41,440 --> 03:14:41,960 >>WE HAVE DONE THIS IN THE 4185 03:14:41,960 --> 03:14:43,280 DOUBLE NEGATIVE AS COMPARED TO 4186 03:14:43,280 --> 03:14:53,760 THE OTHER MEMORY TOGETHER. 4187 03:14:56,080 --> 03:14:58,080 AND YES THEY ARE HIGHER, BUT 4188 03:14:58,080 --> 03:14:59,400 NOT TOO MANY CHANGES IN THE BCA 4189 03:14:59,400 --> 03:15:05,680 CYCLE. 4190 03:15:05,680 --> 03:15:07,080 >>A LOT OF YOUR GENES LOOK 4191 03:15:07,080 --> 03:15:09,200 LIKE TARGETING. HOW LONG DOES 4192 03:15:09,200 --> 03:15:11,440 THIS LAG ONCE YOU TAKE THE 4193 03:15:11,440 --> 03:15:13,240 LACTATE? 4194 03:15:13,240 --> 03:15:16,480 >>I DON'T KNOW THIS. THIS IS 4195 03:15:16,480 --> 03:15:17,000 SOMETHING THAT WE HAVE TO 4196 03:15:17,000 --> 03:15:20,160 CHECK. I CAN TELL YOU THAT 4197 03:15:20,160 --> 03:15:22,080 ONCE YOU HAVE THE LACTATE IN 4198 03:15:22,080 --> 03:15:26,000 CULTURE, THE -- SET CAN BE SEEN 4199 03:15:26,000 --> 03:15:29,520 FOR THREE DAYS. BUT I THINK IT 4200 03:15:29,520 --> 03:15:30,240 IS METABOLIZED. BUT I DON'T 4201 03:15:30,240 --> 03:15:32,040 KNOW VERY WELL IF IT REALLY IS 4202 03:15:32,040 --> 03:15:35,120 IN THIS CONDITION. IN VIVO IT 4203 03:15:35,120 --> 03:15:38,600 IS. IT IS DOWN REGULATED VERY 4204 03:15:38,600 --> 03:15:39,240 QUICKLY BECAUSE IT IS EXTREMELY 4205 03:15:39,240 --> 03:15:41,880 HIGH INFLAMMATORY. IN FACT IT 4206 03:15:41,880 --> 03:15:43,200 IS IMPOSSIBLE TO MEASURE IN 4207 03:15:43,200 --> 03:15:45,320 SERUM. IF YOU MEASURE THE 4208 03:15:45,320 --> 03:15:48,000 ENZYME YOU CAN MEASURE THE 4209 03:15:48,000 --> 03:15:48,560 PRODUCT; YOU MEASURE THE 4210 03:15:48,560 --> 03:15:49,720 LACTATE METABOLIZING, BUT 4211 03:15:49,720 --> 03:15:52,720 NOTHING ELSE. THAT IS 4212 03:15:52,720 --> 03:15:53,280 SOMETHING WE NEED TO CHECK 4213 03:15:53,280 --> 03:15:55,440 ESPECIALLY IN TISSUES. GOOD 4214 03:15:55,440 --> 03:16:00,560 FIND. ANOTHER QUESTION? 4215 03:16:00,560 --> 03:16:03,520 >>DO YOU HAVE ANY INFORMATION 4216 03:16:03,520 --> 03:16:07,720 ABOUT LACTATE TO THE GPR 4217 03:16:07,720 --> 03:16:11,840 (INDISCERNIBLE)? IT DOES? 4218 03:16:11,840 --> 03:16:12,360 >>ONE OF THE TRANSPORTERS 4219 03:16:12,360 --> 03:16:15,320 BELONGS TO THE FAMILY, YES. 4220 03:16:15,320 --> 03:16:18,040 THIS IS THE MAJOR ONE IN THE B 4221 03:16:18,040 --> 03:16:18,640 CELLS. YES THAT IS THE FAMILY 4222 03:16:18,640 --> 03:16:23,960 OF LACTATE TRANSPORTERS. 4223 03:16:23,960 --> 03:16:26,960 >>DOES INCREASE GLYCOLYSIS 4224 03:16:26,960 --> 03:16:27,640 INCREASE OXIDATIVE STRESS? 4225 03:16:27,640 --> 03:16:28,800 >>WELL ANAEROBIC GLYCOLYSIS 4226 03:16:28,800 --> 03:16:31,840 AND OXIDATIVE STRESS ARE BOTH 4227 03:16:31,840 --> 03:16:42,400 COMING FROM PYRATE (PHONETIC). 4228 03:16:43,600 --> 03:16:44,040 I THINK IN INFLAMMATORY 4229 03:16:44,040 --> 03:16:44,520 CONDITIONS YOU HAVE ONE 4230 03:16:44,520 --> 03:16:46,240 PREVAILING ON THE OTHER. IT IS 4231 03:16:46,240 --> 03:16:52,720 NOT 0 OR 100 OR VICE VERSA. 4232 03:16:52,720 --> 03:16:53,360 THERE IS A PROGRESS FROM ONE TO 4233 03:16:53,360 --> 03:16:53,920 THE OTHER DEPENDING ON THE 4234 03:16:53,920 --> 03:16:57,560 MICROENVIRONMENT. 4235 03:16:57,560 --> 03:16:58,120 IN THIS CONDITION AND AGAIN 4236 03:16:58,120 --> 03:16:59,080 AGING IS NOT THE MOST 4237 03:16:59,080 --> 03:16:59,640 INFLAMMATORY STATUS THAT WE 4238 03:16:59,640 --> 03:17:01,440 HAVE MEASURES. SO WHEN WE GO 4239 03:17:01,440 --> 03:17:09,640 TO THE TISSUE, THE HUMAN 4240 03:17:09,640 --> 03:17:10,200 ADIPOSE TISSUE THERE IS AN 4241 03:17:10,200 --> 03:17:10,800 ANAEROBIC GLYCOLYSIS THAT IS 4242 03:17:10,800 --> 03:17:12,280 ELEVATED. 4243 03:17:12,280 --> 03:17:16,640 YES SCOTT? 4244 03:17:16,640 --> 03:17:26,640 >> 4245 03:17:35,400 --> 03:17:36,000 >>WAS A DEFINING THE DOUBLE 4246 03:17:36,000 --> 03:17:36,480 NEGATIVE CELLS ARE MORE 4247 03:17:36,480 --> 03:17:40,040 ANAEROBIC GLYCOLYSIS- ORIENTED? 4248 03:17:40,040 --> 03:17:47,680 AND ON A PER CELL BASIS, IS 4249 03:17:47,680 --> 03:17:48,280 THAT MORE SO IN ELDERLY OR IS 4250 03:17:48,280 --> 03:17:50,240 IT THAT JUST ELDERLY PEOPLE 4251 03:17:50,240 --> 03:17:50,880 HAVE MORE DOUBLE NEGATIVE? 4252 03:17:50,880 --> 03:17:51,440 >>I CONTINUE TO HAVE MORE 4253 03:17:51,440 --> 03:17:53,480 DOUBLE NEGATIVES. THIS IS WHY 4254 03:17:53,480 --> 03:17:56,840 THE POOL OF B CELLS REFLECTING 4255 03:17:56,840 --> 03:18:00,080 THIS. BUT WHEN YOU LOOK AT THE 4256 03:18:00,080 --> 03:18:00,720 DOUBLE NEGATIVE FROM YOUNG AND 4257 03:18:00,720 --> 03:18:01,360 OLD AND YOU PULL THEM TOGETHER, 4258 03:18:01,360 --> 03:18:04,240 THERE IS A LOT OF THESE 4259 03:18:04,240 --> 03:18:06,000 PATHWAYS UPREGULATED. I THINK 4260 03:18:06,000 --> 03:18:09,640 IT IS BOTH. WHEN YOU LOOK AT 4261 03:18:09,640 --> 03:18:13,640 THE TOTAL DIFFERENCE POOL, THIS 4262 03:18:13,640 --> 03:18:14,160 HAPPENS BECAUSE OF THE 4263 03:18:14,160 --> 03:18:14,640 EXPANSION OF THE DOUBLE 4264 03:18:14,640 --> 03:18:19,200 NEGATIVE. IF YOU SORT THE 4265 03:18:19,200 --> 03:18:21,120 DOUBLE NEGATIVE-- -- IT GOES TO 4266 03:18:21,120 --> 03:18:23,800 THE LEVEL OF THE PHENOTYPE. 4267 03:18:23,800 --> 03:18:24,360 >>I WAS ALSO CURIOUS RELATED 4268 03:18:24,360 --> 03:18:29,600 TO THE -- QUESTION, IS THERE IN 4269 03:18:29,600 --> 03:18:32,400 ABOUT WHAT UPSTREAM FACTORS 4270 03:18:32,400 --> 03:18:34,400 MIGHT PREVENT THE CHANGE IN THE 4271 03:18:34,400 --> 03:18:34,920 METABOLIC PATTERN? 4272 03:18:34,920 --> 03:18:38,120 >>I CAN TELL YOU THAT I HAVE 4273 03:18:38,120 --> 03:18:45,400 NOT CHECKED IN THE PERIPHERAL 4274 03:18:45,400 --> 03:18:47,000 BLOCK, I HAVE IT IN THE ADIPOSE 4275 03:18:47,000 --> 03:18:48,400 TISSUE. LACTATE (INDISCERNIBLE) 4276 03:18:48,400 --> 03:18:55,880 -- ONLY IN ALPHA. IT IS VERY 4277 03:18:55,880 --> 03:18:56,480 STABILIZED BY OTHER SIGNALS 4278 03:18:56,480 --> 03:18:58,280 THAT HAPPEN IN THE ADIPOSE 4279 03:18:58,280 --> 03:19:01,120 TISSUE. THAT IS HOW IT HAS TO 4280 03:19:01,120 --> 03:19:05,080 WORK. YES ARIA? 4281 03:19:05,080 --> 03:19:09,560 >>VERY QUICK QUESTION. YOU 4282 03:19:09,560 --> 03:19:13,120 KNOW THAT IN INFANT CONDITION 4283 03:19:13,120 --> 03:19:16,600 CELLS, B CELL PROGENITORS CAN 4284 03:19:16,600 --> 03:19:21,400 EMIGRATE INTO CIRCULATION. 4285 03:19:21,400 --> 03:19:23,240 COULD IT BE SOME OF YOUR DOUBLE 4286 03:19:23,240 --> 03:19:29,680 NEGATIVES ACTUALLY BELONGING TO 4287 03:19:29,680 --> 03:19:31,000 THE IMMIGRANTS FROM BONE MARROW 4288 03:19:31,000 --> 03:19:33,760 TISSUE? 4289 03:19:33,760 --> 03:19:34,320 >>THIS IS NOT OUR WORK WITH 4290 03:19:34,320 --> 03:19:38,600 THE ANSWER IS THEY CANNOT BE. I 4291 03:19:38,600 --> 03:19:39,160 AM NOT SHARING MYSELF, JUST 4292 03:19:39,160 --> 03:19:39,800 RESPONDED TO THE QUESTION WHICH 4293 03:19:39,800 --> 03:19:42,520 IS A VERY (INDISCERNIBLE), I 4294 03:19:42,520 --> 03:19:43,160 CAN KEEP GOING BUT I THINK WE 4295 03:19:43,160 --> 03:19:47,160 HAVE TO STOP. IF YOU DON'T 4296 03:19:47,160 --> 03:19:49,320 WANT TO STOP I CAN KEEP GOING. 4297 03:19:49,320 --> 03:19:51,320 THANK YOU SO MUCH. 4298 03:19:51,320 --> 03:20:01,320 >> 4299 03:20:07,280 --> 03:20:17,720 >>(INDISCERNIBLE). >>MAYBE 4300 03:20:29,440 --> 03:20:32,800 WE CAN START OFF. WHO WANTS TO 4301 03:20:32,800 --> 03:20:35,880 GO FIRST ON YOUR GAP? WHICHEVER 4302 03:20:35,880 --> 03:20:38,800 WAY YOU WANT TO START. WHAT DO 4303 03:20:38,800 --> 03:20:49,360 YOU THINK ARE THE BIGGEST GAPS? 4304 03:20:51,240 --> 03:20:53,200 >>I WOULD LIKE TO START BY 4305 03:20:53,200 --> 03:20:59,000 SAYING THAT WE ALL AGREE THAT 4306 03:20:59,000 --> 03:21:00,840 INFLAMMATION IS AN IMPORTANT 4307 03:21:00,840 --> 03:21:01,400 SUBJECT, WITH ASSOCIATED 4308 03:21:01,400 --> 03:21:05,560 DISEASE. THE IMMUNE CELLS 4309 03:21:05,560 --> 03:21:07,360 COULD PLAY AN IMPORTANT ROLE 4310 03:21:07,360 --> 03:21:15,840 CONTROLLING THIS INFLAMMATION. 4311 03:21:15,840 --> 03:21:17,400 NOW IS THE MOMENT TO FIND THE 4312 03:21:17,400 --> 03:21:20,320 BEST WAY TO TRY TO RESOLVE 4313 03:21:20,320 --> 03:21:20,760 THESE AGE ASSOCIATED 4314 03:21:20,760 --> 03:21:21,320 INFLAMMATION BY TARGETING 4315 03:21:21,320 --> 03:21:27,040 IMMUNE CELLS. THERE ARE 4316 03:21:27,040 --> 03:21:28,480 DIFFERENT STRATEGIES. I THINK 4317 03:21:28,480 --> 03:21:29,480 THE GAP IS TO FIND WHAT IS THE 4318 03:21:29,480 --> 03:21:32,080 BEST STRATEGY TO FIND THIS. 4319 03:21:32,080 --> 03:21:35,640 AND ALSO, I WANT TO MENTION 4320 03:21:35,640 --> 03:21:44,560 THAT IN THE LAST 10 YEARS WE 4321 03:21:44,560 --> 03:21:45,200 OBSERVED HOW IMMUNOTHERAPY HAS 4322 03:21:45,200 --> 03:21:47,120 CHANGED AGING CELLS. I HOPE 4323 03:21:47,120 --> 03:21:50,840 THAT THE NEXT 10 YEARS WILL BE 4324 03:21:50,840 --> 03:21:55,680 THE TIME OF IMMUNOTHERAPY TO 4325 03:21:55,680 --> 03:22:00,200 CHANGE AGE ASSOCIATED DISEASES. 4326 03:22:00,200 --> 03:22:08,960 >>OKAY.YOU ALREADY HEARD HOW 4327 03:22:08,960 --> 03:22:11,400 IMPORTANT IT IS TO HAVE 4328 03:22:11,400 --> 03:22:12,040 METABOLIC INFORMATION FOR EACH 4329 03:22:12,040 --> 03:22:13,240 INDIVIDUAL BECAUSE IT IS 4330 03:22:13,240 --> 03:22:15,680 DICTATING WHAT IS THE METABOLIC 4331 03:22:15,680 --> 03:22:16,360 STATUS OF DIFFERENT IMMUNE 4332 03:22:16,360 --> 03:22:20,000 CELLS AND (INDISCERNIBLE). 4333 03:22:20,000 --> 03:22:22,880 THIS IS EXTREMELY IMPORTANT TO 4334 03:22:22,880 --> 03:22:23,520 KNOW BECAUSE YOU JUST BROUGHT 4335 03:22:23,520 --> 03:22:32,400 UP THE IMMUNOTHERAPY. THERE 4336 03:22:32,400 --> 03:22:35,800 ARE SOME CHECKPOINTS AND 4337 03:22:35,800 --> 03:22:36,400 INHIBITORS THAT WORK ONLY IF 4338 03:22:36,400 --> 03:22:37,920 THE TARGETS ARE METABOLICALLY 4339 03:22:37,920 --> 03:22:46,680 OKAY. FOR EXAMPLE OXIDATIVE 4340 03:22:46,680 --> 03:22:47,280 PHOSPHORYLATION IS EXTREMELY 4341 03:22:47,280 --> 03:22:50,600 IMPORTANT IN PD1 THERAPY, THAT 4342 03:22:50,600 --> 03:22:56,240 HAS GOOD OXIDATIVE STATUS. 4343 03:22:56,240 --> 03:22:56,840 YESTERDAY SOMEBODY BROUGHT UP 4344 03:22:56,840 --> 03:22:58,320 THE IMPORTANCE TO LOOK AT 4345 03:22:58,320 --> 03:22:59,080 METABOLIC STATUS, WHICH 4346 03:22:59,080 --> 03:23:01,320 REFLECTS THE ENVIRONMENT, THE 4347 03:23:01,320 --> 03:23:01,920 DIET, THE CONDITION OF EACH 4348 03:23:01,920 --> 03:23:04,320 INDIVIDUAL. SO IT IS SOMETHING 4349 03:23:04,320 --> 03:23:07,720 THAT NEEDS TO BE AVAILABLE. 4350 03:23:07,720 --> 03:23:10,000 THIS MEANS THAT WE WILL HAVE, 4351 03:23:10,000 --> 03:23:13,120 WE WILL NEED REPOSITORIES FOR 4352 03:23:13,120 --> 03:23:14,560 DATA FOR HUMAN AND ANIMALS IN 4353 03:23:14,560 --> 03:23:17,440 ORDER TO ACCESS AND KNOW 4354 03:23:17,440 --> 03:23:22,040 EXACTLY WHERE TO GO AND WHAT TO 4355 03:23:22,040 --> 03:23:22,640 LOOK FOR, AND HOW TO DO THE 4356 03:23:22,640 --> 03:23:23,920 BEST WAY POSSIBLE THESE KINDS 4357 03:23:23,920 --> 03:23:25,280 OF STUDIES. 4358 03:23:25,280 --> 03:23:27,840 >> 4359 03:23:27,840 --> 03:23:30,160 >>YEAH, ALWAYS A CHALLENGING 4360 03:23:30,160 --> 03:23:33,760 QUESTION. WHAT IS NEXT? I 4361 03:23:33,760 --> 03:23:39,480 REALLY DON'T KNOW. A LOT OF 4362 03:23:39,480 --> 03:23:40,040 THINGS THAT WE ARE DOING WE 4363 03:23:40,040 --> 03:23:40,640 HAVE NO IDEA WE WERE DOING IT 4364 03:23:40,640 --> 03:23:43,520 FIVE YEARS AGO. WE HAVE NO 4365 03:23:43,520 --> 03:23:44,160 IDEA WHERE THE NEXT DISCOVERIES 4366 03:23:44,160 --> 03:23:47,080 GOING TO COME FROM. 4367 03:23:47,080 --> 03:23:47,640 FIRST THING TO ORGANIZE WHAT 4368 03:23:47,640 --> 03:23:49,080 WE HAVE, I THINK THERE IS 4369 03:23:49,080 --> 03:23:51,000 ENOUGH CONSENSUS IN RELATION TO 4370 03:23:51,000 --> 03:23:54,800 INFLAMMATION FROM AGING THAT -- 4371 03:23:54,800 --> 03:23:59,480 DATA AND -- ARE KEY TO DRIVING 4372 03:23:59,480 --> 03:23:59,960 MULTIPLE ASPECTS OF 4373 03:23:59,960 --> 03:24:02,160 INFLAMMATION. 4374 03:24:02,160 --> 03:24:02,600 ACTUALLY WE NOW HAVE 4375 03:24:02,600 --> 03:24:06,880 THERAPEUTICS AGAINST THEM. BUT 4376 03:24:06,880 --> 03:24:07,440 ALWAYS THE PROBLEM IS THAT 4377 03:24:07,440 --> 03:24:11,920 THOSE THERAPEUTICS ARE GIVEN TO 4378 03:24:11,920 --> 03:24:12,400 PEOPLE THAT ARE HAVING 4379 03:24:12,400 --> 03:24:13,040 AUTOIMMUNE DISEASES AND IF YOU 4380 03:24:13,040 --> 03:24:14,920 GO DOWNSTREAM AND BLOCK OUT -- 4381 03:24:14,920 --> 03:24:15,560 -- OBVIOUSLY YOU HAVE PROBLEMS 4382 03:24:15,560 --> 03:24:22,640 WITH INFECTIONS. 4383 03:24:22,640 --> 03:24:23,240 ONE OF THE GAPS I WOULD THINK 4384 03:24:23,240 --> 03:24:23,840 THAT SHE MOVES IN THE DIRECTION 4385 03:24:23,840 --> 03:24:27,000 OF TRANSLATION, WE HAVE DATA 4386 03:24:27,000 --> 03:24:30,360 WHICH COMPLEMENTS 4387 03:24:30,360 --> 03:24:31,000 (INDISCERNIBLE), ALWAYS SHOWING 4388 03:24:31,000 --> 03:24:33,000 UP IN INTERFERON RESPONSE. BUT 4389 03:24:33,000 --> 03:24:35,280 WHAT PEOPLE THINKING ABOUT IN 4390 03:24:35,280 --> 03:24:40,960 TERMS OF TRANSLATIONS, AND 4391 03:24:40,960 --> 03:24:41,520 EPIDEMIOLOGIST HAVE A MUCH 4392 03:24:41,520 --> 03:24:42,120 BETTER HANDLE ON THIS IS TO 4393 03:24:42,120 --> 03:24:45,080 ACTUALLY GO UPSTREAM. SO IN 4394 03:24:45,080 --> 03:24:45,680 THIS CASE FOR EXAMPLE YOU GO 4395 03:24:45,680 --> 03:24:47,200 UPSTREAM WHERE YOU BLOCK THE 4396 03:24:47,200 --> 03:24:57,200 PATHWAYS THAT CONTROL IL1 BETA, 4397 03:24:57,200 --> 03:24:59,000 WHICH IS CONTROLLED BY MULTIPLE 4398 03:24:59,000 --> 03:25:07,960 INFLAMMASOMES, CAN YOU BLOCK 4399 03:25:07,960 --> 03:25:08,560 THE INFLAMMASOME OR LOWER IT 4400 03:25:08,560 --> 03:25:12,840 THAT IS CRITICAL FOR AGING. 4401 03:25:12,840 --> 03:25:13,320 SO WE ALREADY HAVE A FEW 4402 03:25:13,320 --> 03:25:23,120 CHECKPOINTS IN MY VIEW. 4403 03:25:23,120 --> 03:25:23,720 COMPLEMENTARY INHIBITORS ARE 4404 03:25:23,720 --> 03:25:24,320 FDA APPROVED. IT IS ALWAYS UP 4405 03:25:24,320 --> 03:25:27,520 IN MULTIPLE PLACES. SEVERAL OF 4406 03:25:27,520 --> 03:25:30,600 US ARE NOT INTERESTED IN 4407 03:25:30,600 --> 03:25:31,160 LIFESPAN, BUT WE ARE REALLY 4408 03:25:31,160 --> 03:25:31,640 INTERESTED IN TARGETING 4409 03:25:31,640 --> 03:25:32,200 INFORMATION TO SEE BETTER 4410 03:25:32,200 --> 03:25:32,840 OUTCOMES WHICH I THINK CAN BE 4411 03:25:32,840 --> 03:25:33,160 DONE. 4412 03:25:33,160 --> 03:25:35,880 THE LAST PART IS THAT, YOU 4413 03:25:35,880 --> 03:25:38,400 KNOW, BIG KUDOS, BIG SHOUT OUT 4414 03:25:38,400 --> 03:25:40,920 TO THE TEAM THAT DID THE 4415 03:25:40,920 --> 03:25:47,040 CALORIE STUDY BY THE NIA. IT 4416 03:25:47,040 --> 03:25:49,000 HAD A LOT OF ISSUES WITH 4417 03:25:49,000 --> 03:25:49,600 CALORIE RESTRICTION AND DATA 4418 03:25:49,600 --> 03:25:53,320 GOING BOTH WAYS. BUT NOW WITH 4419 03:25:53,320 --> 03:25:53,920 THE STUDY HAS BEEN ABLE TO DO 4420 03:25:53,920 --> 03:25:59,000 IS PROVIDE REALLY GOOD 4421 03:25:59,000 --> 03:25:59,600 MECHANISTIC EVIDENCE THAT IF IN 4422 03:25:59,600 --> 03:26:00,240 HUMAN PHYSIOLOGY, IF YOU HAVE A 4423 03:26:00,240 --> 03:26:03,440 NEGATIVE ENERGY BALANCE, THERE 4424 03:26:03,440 --> 03:26:04,040 ARE LOTS AND LOTS OF PATHWAYS 4425 03:26:04,040 --> 03:26:05,440 THAT WERE PREVIOUSLY SHOWN TO 4426 03:26:05,440 --> 03:26:09,320 BE IMPORTANT, AND NOW SHOWING 4427 03:26:09,320 --> 03:26:11,000 UP IN PEOPLE. AND THE WORK FROM 4428 03:26:11,000 --> 03:26:14,960 THIS CONSORTIA WHICH IS NOW 4429 03:26:14,960 --> 03:26:15,600 COMING OUT OFFERS I THINK ALL 4430 03:26:15,600 --> 03:26:18,560 OF YOU APPROACH IS WHERE YOU 4431 03:26:18,560 --> 03:26:22,560 CAN LOOK FOR POTENTIAL, NEWER 4432 03:26:22,560 --> 03:26:26,160 TARGETS THAT ARE IMPACTED BY 4433 03:26:26,160 --> 03:26:26,800 INTERVENTION, BUT IT IS NOT TO 4434 03:26:26,800 --> 03:26:27,360 EXTEND LIFESPAN BUT IN THIS 4435 03:26:27,360 --> 03:26:27,960 CASE WITHOUT TRADE-OFFS AND 4436 03:26:27,960 --> 03:26:29,560 PEOPLE. SO I THINK THERE IS A 4437 03:26:29,560 --> 03:26:30,680 LOT THAT CAN BE DONE, IN A WILL 4438 03:26:30,680 --> 03:26:32,840 BE DONE. 4439 03:26:32,840 --> 03:26:35,600 AND LASTLY I THINK I WOULD SAY 4440 03:26:35,600 --> 03:26:36,160 THE SAME THING THAT SARAH 4441 03:26:36,160 --> 03:26:41,720 MENTIONED. THE PERIPHERAL 4442 03:26:41,720 --> 03:26:42,240 NERVOUS SYSTEM AND OTHER 4443 03:26:42,240 --> 03:26:44,280 PERIPHERAL NERVOUS SYSTEMS ARE 4444 03:26:44,280 --> 03:26:47,040 IMPORTANT NOT ONLY FOR THE 4445 03:26:47,040 --> 03:26:48,440 INTER-ORGAN PHYSIOLOGY BUT HOW 4446 03:26:48,440 --> 03:26:49,040 THE RESIDENT IMMUNE CELLS ON 4447 03:26:49,040 --> 03:26:50,840 THOSE NERVES ARE IMPORTANT. 4448 03:26:50,840 --> 03:26:51,480 THERE IS SO MUCH TO DO IN THAT 4449 03:26:51,480 --> 03:26:53,360 CASE. I THINK WE HAVE A LOT TO 4450 03:26:53,360 --> 03:26:54,240 LEARN. 4451 03:26:54,240 --> 03:27:02,800 F >>VERY GOOD COMMENTS TO ADD 4452 03:27:02,800 --> 03:27:06,040 TO THIS, I THINK ONE KEY THING, 4453 03:27:06,040 --> 03:27:08,160 WHAT WE ALL ASK, BUT VERY 4454 03:27:08,160 --> 03:27:11,080 LITTLE IS DEDICATED TO THIS 4455 03:27:11,080 --> 03:27:11,680 RESEARCH, WHY IS IT THAT MOST 4456 03:27:11,680 --> 03:27:15,240 CLINICAL TRIALS FAIL? IS IT 4457 03:27:15,240 --> 03:27:19,080 BECAUSE ALL OF OUR CASES ARE 4458 03:27:19,080 --> 03:27:22,880 MOSTLY DONE IN YOUNG MODELING 4459 03:27:22,880 --> 03:27:23,480 SYSTEMS? BECAUSE OF MONEY AND 4460 03:27:23,480 --> 03:27:29,760 SO ON? AND SOME WOULD SAY OKAY, 4461 03:27:29,760 --> 03:27:31,960 MICE ARE NOT REALLY HUMANS. 4462 03:27:31,960 --> 03:27:34,720 YOU CANNOT EXTRAPOLATE. 4463 03:27:34,720 --> 03:27:39,040 IN FACT WHAT WE SEE IS MANY OF 4464 03:27:39,040 --> 03:27:41,560 OUR INTERVENTIONS IN CANCER OR 4465 03:27:41,560 --> 03:27:43,920 EVEN INSULIN RESISTANCE, FOR 4466 03:27:43,920 --> 03:27:45,480 EXAMPLE ONLY WORK IN CERTAIN 4467 03:27:45,480 --> 03:27:47,440 WAYS, CONTEXT DEPENDENT WAYS IN 4468 03:27:47,440 --> 03:27:50,680 AGED ANIMALS. BUT IN THE YOUNG 4469 03:27:50,680 --> 03:27:58,960 IT CAN BE THE OPPOSITE. AND 4470 03:27:58,960 --> 03:27:59,520 THEREFORE THE APPROPRIATE 4471 03:27:59,520 --> 03:28:00,120 MODELING SYSTEM LOOKS LIKE IT 4472 03:28:00,120 --> 03:28:02,160 IS LACKING (INDISCERNIBLE). 4473 03:28:02,160 --> 03:28:02,840 LAST THING IS THAT WE SHOULD 4474 03:28:02,840 --> 03:28:05,480 NOT ALSO DISREGARD THE 4475 03:28:05,480 --> 03:28:13,600 IMPORTANCE OF METHODS THAT ARE 4476 03:28:13,600 --> 03:28:14,200 (INDISCERNIBLE), AND OF COURSE 4477 03:28:14,200 --> 03:28:14,720 EVERYONE AND ALL OF THE 4478 03:28:14,720 --> 03:28:16,720 POSTDOCS AND STUDENTS USE PLOT 4479 03:28:16,720 --> 03:28:17,200 DATA, BUT IT IS VERY 4480 03:28:17,200 --> 03:28:23,080 SUBJECTIVE. AND DEPENDING ON 4481 03:28:23,080 --> 03:28:25,000 WHAT KIND OF TISSUE IS USED, 4482 03:28:25,000 --> 03:28:26,960 IT MIGHT AS WELL DISAPPEAR. 4483 03:28:26,960 --> 03:28:33,800 THE EXAMPLE IS 138, DEPENDING 4484 03:28:33,800 --> 03:28:34,440 ON WHAT THE ASSOCIATION MARKER 4485 03:28:34,440 --> 03:28:37,040 YOU USE IT WON'T BE THERE. IN 4486 03:28:37,040 --> 03:28:37,600 THE CONCLUSION IS THAT THE 4487 03:28:37,600 --> 03:28:40,680 CELLS ARE NOT THERE. 4488 03:28:40,680 --> 03:28:41,360 THEREFORE WE NEED TO DEDICATE 4489 03:28:41,360 --> 03:28:43,400 TIME ALSO AND ENERGY ON PROPER 4490 03:28:43,400 --> 03:28:49,960 METHODS AND MODEL EXAMPLES. 4491 03:28:49,960 --> 03:28:52,040 >>ANYBODY FEEL FREE TO CHIME 4492 03:28:52,040 --> 03:28:56,320 IN OR VETO ANYTHING YOU HEARD. 4493 03:28:56,320 --> 03:28:58,880 I HAD A QUESTION. I KNOW MARIA 4494 03:28:58,880 --> 03:29:02,960 YOU BROUGHT UP THE CONCEPT OF 4495 03:29:02,960 --> 03:29:03,600 RESOLUTION IN YOUR GRAPHIC, THE 4496 03:29:03,600 --> 03:29:11,360 SECOND ONE ON THE AGED ONE. DO 4497 03:29:11,360 --> 03:29:16,800 WE KNOW ENOUGH ON REPRODUCTIVE 4498 03:29:16,800 --> 03:29:17,360 IMMUNITY? WE DO SEE WHAT IS 4499 03:29:17,360 --> 03:29:23,720 GOING AWRY, BUT IN TERMS OF 4500 03:29:23,720 --> 03:29:24,320 METABOLIC, IS THERE ANY LONG 4501 03:29:24,320 --> 03:29:24,920 HANGING FRUIT THAT WE CAN 4502 03:29:24,920 --> 03:29:32,560 (INDISCERNIBLE)? 4503 03:29:32,560 --> 03:29:35,680 >>I THINK IT IS A GAP, HOW TO 4504 03:29:35,680 --> 03:29:40,800 EMPLOY THIS RESOLUTION. IN 4505 03:29:40,800 --> 03:29:43,960 ACUTE INFLAMMATION IT IS WELL 4506 03:29:43,960 --> 03:29:46,280 KNOWN. BUT IN CHRONIC CARE, 4507 03:29:46,280 --> 03:29:48,160 CHRONIC INFLAMMATION, I THINK 4508 03:29:48,160 --> 03:29:51,800 IT IS COMPLETELY UNKNOWN. 4509 03:29:51,800 --> 03:29:57,840 METABOLICALLY. LIPID 4510 03:29:57,840 --> 03:30:00,640 METABOLITES CAN ALSO ISSUE. 4511 03:30:00,640 --> 03:30:04,400 >>I HEAR THAT. WE 4512 03:30:04,400 --> 03:30:05,840 (INDISCERNIBLE). AND OTHERS 4513 03:30:05,840 --> 03:30:12,240 THAT HAVE SOME EFFECT KNOWN. I 4514 03:30:12,240 --> 03:30:12,840 DON'T KNOW IF ANYBODY KNOWS, 4515 03:30:12,840 --> 03:30:18,360 THE AGING ASPECT OF IT. 4516 03:30:18,360 --> 03:30:18,840 >>REALLY INTERESTING 4517 03:30:18,840 --> 03:30:23,320 MOLECULES. OBVIOUSLY, RECENTLY 4518 03:30:23,320 --> 03:30:25,400 THEY HAVE ALSO BEEN 4519 03:30:25,400 --> 03:30:27,800 METHODOLOGICAL ISSUES THAT SOME 4520 03:30:27,800 --> 03:30:28,400 PEOPLE ARE CHALLENGING WHETHER 4521 03:30:28,400 --> 03:30:29,320 THEY ARE REAL OR NOT. YOU HAVE 4522 03:30:29,320 --> 03:30:32,880 TO BE CAUTIOUS. 4523 03:30:32,880 --> 03:30:34,240 >>I THINK IT IS ALSO A 4524 03:30:34,240 --> 03:30:34,880 METHODOLOGY OF LIPID 4525 03:30:34,880 --> 03:30:36,760 QUANTIFICATION. MY 4526 03:30:36,760 --> 03:30:37,480 UNDERSTANDING (INDISCERNIBLE) 4527 03:30:37,480 --> 03:30:42,880 AND YOU USE THAT BUT THEN THE 4528 03:30:42,880 --> 03:30:43,520 GROWING BIOLOGICAL APPLICATIONS 4529 03:30:43,520 --> 03:30:46,040 FROM IT. THERE IS CHEMISTRY AND 4530 03:30:46,040 --> 03:30:47,600 BIOLOGY FUNCTIONALITY. THAT IS 4531 03:30:47,600 --> 03:30:51,920 WHAT I WAS ASKING. THIS IS THE 4532 03:30:51,920 --> 03:30:54,280 ANGLE THAT IS MISSING, AND THE 4533 03:30:54,280 --> 03:30:55,080 PROGRESS THAT IS MADE. 4534 03:30:55,080 --> 03:30:58,080 (INDISCERNIBLE). 4535 03:30:58,080 --> 03:31:02,400 ANYBODY ELSE? ANY QUESTIONS 4536 03:31:02,400 --> 03:31:12,920 ONLINE? ANYBODY? OKAY. ARIA, 4537 03:31:19,920 --> 03:31:30,400 NORMAL B1A I HIGHLY CHOLGENIC. 4538 03:31:32,520 --> 03:31:33,080 DO YOU KNOW ANYTHING ABOUT THE 4539 03:31:33,080 --> 03:31:33,640 CHOLINERGIC STATUS OF THESE 4540 03:31:33,640 --> 03:31:34,280 ABNORMAL B1A CELLS? 4541 03:31:34,280 --> 03:31:37,240 >>NO WE WERE MOSTLY INTERESTED 4542 03:31:37,240 --> 03:31:42,400 IN CONVERTED T 1 CELLS, WHAT 4543 03:31:42,400 --> 03:31:46,560 THEY DO TO THE T-CELL, WHETHER 4544 03:31:46,560 --> 03:31:48,760 THEY CONVERT T-CELLS INTO 4545 03:31:48,760 --> 03:31:51,120 PATHOGENIC T-CELLS. WE DID NOT 4546 03:31:51,120 --> 03:32:01,320 CHECK THAT. 4547 03:32:04,040 --> 03:32:14,480 >> (INDISCERNIBLE) (READING 4548 03:32:18,280 --> 03:32:28,720 FROM CHAT) DO WE NEED TOOLS? 4549 03:32:31,520 --> 03:32:41,040 >>OF COURSE, WE SHOULD WORRY 4550 03:32:41,040 --> 03:32:41,680 ABOUT SECONDARY METABOLIC. WHAT 4551 03:32:41,680 --> 03:32:48,880 IS IT AN AGING THE MICROBE 4552 03:32:48,880 --> 03:32:49,480 DISAPPEARS? IS IT AN IMMUNE 4553 03:32:49,480 --> 03:32:53,520 PROCESS. IT QUESTIONS THE 4554 03:32:53,520 --> 03:32:59,720 POSSIBILITY OF REPLENISHING THE 4555 03:32:59,720 --> 03:33:00,360 MICROBES WHICH WOULD REDUCE THE 4556 03:33:00,360 --> 03:33:02,520 THAT, MAKING EVEN MORE. 4557 03:33:02,520 --> 03:33:05,400 BECAUSE IT IS IMMUNE DRIVEN, WE 4558 03:33:05,400 --> 03:33:09,320 WOULD INDUCE MORE RESPONSES. 4559 03:33:09,320 --> 03:33:11,200 ONE STUDY THAT WE DID NOT 4560 03:33:11,200 --> 03:33:12,520 PUBLISH, VERY LONG-TERM 4561 03:33:12,520 --> 03:33:18,840 PROJECT, WE ALL KNOW WHAT 4562 03:33:18,840 --> 03:33:19,440 (INDISCERNIBLE) REDUCES INSULIN 4563 03:33:19,440 --> 03:33:24,040 RESISTANCE. BUT NO ONE TESTED 4564 03:33:24,040 --> 03:33:25,880 LONG-TERM PROBLEM. WE ACTUALLY 4565 03:33:25,880 --> 03:33:30,680 ASKED THAT QUESTION. AND 4566 03:33:30,680 --> 03:33:35,520 ACTUALLY WE DO SEE LONG-TERM -- 4567 03:33:35,520 --> 03:33:36,160 (INDISCERNIBLE), A DIFFERENT 4568 03:33:36,160 --> 03:33:40,360 QUESTION IS ALL OF OUR 4569 03:33:40,360 --> 03:33:41,000 INTERVENTIONS, WHAT HAPPENS IF 4570 03:33:41,000 --> 03:33:43,640 WE DO IT LONG-TERM? WOULD WE 4571 03:33:43,640 --> 03:33:49,840 CAUSE HARM? IF WE HANDED A MORE 4572 03:33:49,840 --> 03:33:51,200 IMMUNOLOGIC PROCESS? 4573 03:33:51,200 --> 03:33:54,000 >>GOOD POINT. 4574 03:33:54,000 --> 03:33:59,200 >>I HAVE A QUESTION ONLINE. 4575 03:33:59,200 --> 03:33:59,760 WOULD FINDING A WAY TO SWITCH 4576 03:33:59,760 --> 03:34:00,360 FROM WARBURG TO OXPHOS HELP 4577 03:34:00,360 --> 03:34:04,520 INFLAMMAGING? 4578 03:34:04,520 --> 03:34:05,120 >>THESE THINGS ARE NOT VERY 4579 03:34:05,120 --> 03:34:10,320 BINARY IN VIVO. SO TO THE 4580 03:34:10,320 --> 03:34:13,520 EXTENT YOU COULD DO THAT-- 4581 03:34:13,520 --> 03:34:14,960 >>THE QUESTION IS SHOULD WE 4582 03:34:14,960 --> 03:34:19,200 NOT SWITCH BLANCE? 4583 03:34:19,200 --> 03:34:19,800 >>SOME OF THE HUMAN WORK THAT 4584 03:34:19,800 --> 03:34:20,720 CAME OUT PUTTING WORK FROM 4585 03:34:20,720 --> 03:34:27,920 CALORIE AND THE WORK FROM OTHER 4586 03:34:27,920 --> 03:34:29,720 INTERVENTIONS, IT IS CLEARLY 4587 03:34:29,720 --> 03:34:31,080 MITOCHONDRIAL OXIDATION, IT 4588 03:34:31,080 --> 03:34:34,640 APPEARS TO BE ONE OF THE KEY 4589 03:34:34,640 --> 03:34:35,280 COMPONENTS THAT IS LIGHTING UP 4590 03:34:35,280 --> 03:34:38,360 THESE PATHWAYS, LIGHTING UP NOT 4591 03:34:38,360 --> 03:34:39,000 ONLY PREVIOUS STUDIES FOR MODEL 4592 03:34:39,000 --> 03:34:40,560 ORGANISMS BUT ALSO HUMANS. I 4593 03:34:40,560 --> 03:34:41,120 THINK THAT'S WHICH IS VERY 4594 03:34:41,120 --> 03:34:42,240 IMPORTANT. 4595 03:34:42,240 --> 03:34:44,920 OBVIOUSLY WE KNOW THAT WORK IN 4596 03:34:44,920 --> 03:34:49,560 OUR GROUP AND OTHERS; FOR 4597 03:34:49,560 --> 03:34:50,120 EXAMPLE IF YOU SWITCH THE 4598 03:34:50,120 --> 03:34:50,960 METABOLISM AWAY FROM GLUCOSE IN 4599 03:34:50,960 --> 03:34:59,720 THE -- STATE, AND YOU START TO 4600 03:34:59,720 --> 03:35:00,280 CONSUME KETONES OR PRODUCE 4601 03:35:00,280 --> 03:35:00,720 KETONE BODIES -- 4602 03:35:00,720 --> 03:35:05,520 (INDISCERNIBLE) -- CLEARLY 4603 03:35:05,520 --> 03:35:07,000 THERE IS A METABOLIC COMPONENT 4604 03:35:07,000 --> 03:35:08,720 TO IT IN THE CONTEXT BUT THE 4605 03:35:08,720 --> 03:35:12,280 HOST HAS TO BE IN -- STATE. 4606 03:35:12,280 --> 03:35:14,960 WHETHER THE CELLS ARE TRUE 4607 03:35:14,960 --> 03:35:21,720 GLYCOLYSIS WORSENS THE OXO 4608 03:35:21,720 --> 03:35:22,360 STATE IS LESS BINARY IS WHAT WE 4609 03:35:22,360 --> 03:35:24,800 FIND IN VIVO, ALSO IN VITRO. 4610 03:35:24,800 --> 03:35:30,720 >>(OFF MIC) ANYBODY ELSE? 4611 03:35:30,720 --> 03:35:33,560 >>DO WE NEED A FIVE SECOND 4612 03:35:33,560 --> 03:35:35,800 STRETCH BREAK? THAT IS THE GAP 4613 03:35:35,800 --> 03:35:45,080 HERE. LET'S DO THAT! THANK YOU 4614 03:35:45,080 --> 03:35:47,280 >>THANK YOU EVERYONE. THANK 4615 03:35:47,280 --> 03:35:50,640 YOU FOR STAYING SO FAR. THIS 4616 03:35:50,640 --> 03:35:51,280 IS THE FINAL SESSION BEFORE WE 4617 03:35:51,280 --> 03:35:51,760 CLOSE THE FRONT OF THE 4618 03:35:51,760 --> 03:35:53,160 WORKSHOP. 4619 03:35:53,160 --> 03:35:55,480 THE FIRST SPEAKER IS PROFESSOR 4620 03:35:55,480 --> 03:36:03,680 ALBERT SHAW. PROFESSOR OF 4621 03:36:03,680 --> 03:36:04,320 MEDICINE AND INFECTIOUS DISEASE 4622 03:36:04,320 --> 03:36:04,920 AT YALE UNIVERSITY SCHOOL OF 4623 03:36:04,920 --> 03:36:07,960 MEDICINE. AND THE TITLE OF HIS 4624 03:36:07,960 --> 03:36:14,280 TALK IS THE EFFECTIVE AGE AND 4625 03:36:14,280 --> 03:36:14,920 INFLUENZA VACCINATION ON HUMAN 4626 03:36:14,920 --> 03:36:19,240 PLATELET FUNCTION. 4627 03:36:19,240 --> 03:36:19,840 >>FOR THIS SESSION WILL SHOW 4628 03:36:19,840 --> 03:36:20,440 YOU TWO FINGERS WHEN YOU HAVE 4629 03:36:20,440 --> 03:36:20,960 TWO MINUTES LEFT. 4630 03:36:20,960 --> 03:36:23,960 F I WILL DO MY >>I WILL DO MY 4631 03:36:23,960 --> 03:36:31,040 BEST. THANK YOU VERY MUCH FOR 4632 03:36:31,040 --> 03:36:31,680 THE ORGANIZERS FOR INVITING ME 4633 03:36:31,680 --> 03:36:34,240 TO SPEAK. IT HAS BEEN A 4634 03:36:34,240 --> 03:36:36,960 TERRIFIC, AMAZING WORKSHOP. 4635 03:36:36,960 --> 03:36:39,200 WHAT I'M GOING TO DO IS TALK 4636 03:36:39,200 --> 03:36:39,800 ABOUT SOME NEW AREAS THAT WE 4637 03:36:39,800 --> 03:36:42,000 HAVE BEEN WORKING ON IN TERMS 4638 03:36:42,000 --> 03:36:46,000 OF SOURCES FOR INFORMATION 4639 03:36:46,000 --> 03:36:48,440 INVOLVING HUMAN PLATELETS. IT 4640 03:36:48,440 --> 03:36:49,000 IS IN SESSION ON VACCINE 4641 03:36:49,000 --> 03:36:51,440 RESPONSE. THE DISCLOSURE I 4642 03:36:51,440 --> 03:36:56,080 HAVE A RESEARCH GRANT FROM 4643 03:36:56,080 --> 03:37:00,920 BOEHRINGER- UNIVERSITY. 4644 03:37:00,920 --> 03:37:01,440 WE HAVE BEEN INTERESTED IN 4645 03:37:01,440 --> 03:37:02,080 USING INFLUENZA VACCINATION IS 4646 03:37:02,080 --> 03:37:04,720 A TOOL TO PERTURB THE HUMAN 4647 03:37:04,720 --> 03:37:10,960 IMMUNE SYSTEM FOR YEARS. THE 4648 03:37:10,960 --> 03:37:11,560 BURDEN OF INFLUENZA IN OLDER 4649 03:37:11,560 --> 03:37:12,000 ADULT REMAINS QUITE 4650 03:37:12,000 --> 03:37:17,960 SUBSTANTIAL. THIS IS A TALE OF 4651 03:37:17,960 --> 03:37:20,880 TWO DISEASES. A FEW YEARS AGO 4652 03:37:20,880 --> 03:37:25,400 THERE WAS A LARGE NUMBER OF 4653 03:37:25,400 --> 03:37:25,960 HOSPITALIZATION WITH DEATHS 4654 03:37:25,960 --> 03:37:33,720 OCCURRING IN THE AGE 65, AND 4655 03:37:33,720 --> 03:37:36,680 THIS YEAR WE HAD A TRIPLE 4656 03:37:36,680 --> 03:37:37,280 ENDEMIC, THE DATA IS NOT ALL 4657 03:37:37,280 --> 03:37:38,120 AND FROM THE SEASON, ALL CDC 4658 03:37:38,120 --> 03:37:45,800 DATA. BUT YOU CAN SEE ILLNESSES 4659 03:37:45,800 --> 03:37:46,400 LIKE ILLNESSES IN OLDER ADULT 4660 03:37:46,400 --> 03:37:47,000 APPEAR FOR OUTSTRIPPED THAN ANY 4661 03:37:47,000 --> 03:37:50,200 OTHER GROUP. 4662 03:37:50,200 --> 03:37:50,720 AND THE VACCINATIONS HAVE 4663 03:37:50,720 --> 03:37:53,320 COMPLICATED THE STUDY OF THE 4664 03:37:53,320 --> 03:37:53,920 VACCINE. WE REGRET IT BECAUSE 4665 03:37:53,920 --> 03:38:00,240 IT IS MEMORY RESPONSE, QUITE 4666 03:38:00,240 --> 03:38:00,800 COMPLICATED AS PEOPLE HAVE 4667 03:38:00,800 --> 03:38:04,120 DISCUSSED. 4668 03:38:04,120 --> 03:38:04,560 REDUCING THE CHRONIC 4669 03:38:04,560 --> 03:38:05,160 INFLAMMATION HAS SOMETHING TO 4670 03:38:05,160 --> 03:38:08,680 DO WITH THIS DIMINISHED 4671 03:38:08,680 --> 03:38:13,360 RESPONSE, THE AGE ASSOCIATIVE 4672 03:38:13,360 --> 03:38:13,960 INFLAMMATORY STATE. MANY YEARS 4673 03:38:13,960 --> 03:38:16,760 AGO WE HAD SOME EVIDENCE OF 4674 03:38:16,760 --> 03:38:17,320 THIS, OLD DATA AND PRIMARY 4675 03:38:17,320 --> 03:38:27,800 DENDRITIC CELLS FROM HUMANS 4676 03:38:31,960 --> 03:38:32,480 WHERE YOU SEE A SUBSTANTIAL 4677 03:38:32,480 --> 03:38:36,920 ELEVATION IN CYTOKINE CREATION. 4678 03:38:36,920 --> 03:38:45,720 IN ALPHA, P40, IF YOU LOOK AT 4679 03:38:45,720 --> 03:38:46,360 THE CLEAR SYMBOLS LOOKING YOUNG 4680 03:38:46,360 --> 03:38:49,640 INDIVIDUALS. 4681 03:38:49,640 --> 03:38:50,200 IN ADDITION TO THIS WE ALSO 4682 03:38:50,200 --> 03:38:50,760 SAW SOME EVIDENCE FOR UP 4683 03:38:50,760 --> 03:39:01,160 REGULATION NOT ONLY OF 4684 03:39:01,760 --> 03:39:04,920 INFLAMMATORY CYTOKINES, 4685 03:39:04,920 --> 03:39:06,880 SPECIFICALLY MONO CYTOKINES IN 4686 03:39:06,880 --> 03:39:08,160 OLDER ADULTS THAT WE TRACED TO 4687 03:39:08,160 --> 03:39:09,840 ALTERED FUNCTION OF PHOSPHATASE 4688 03:39:09,840 --> 03:39:17,640 DUST 1 (PHONETIC). 4689 03:39:17,640 --> 03:39:18,240 THERE IS EVIDENCE FOR THE FACT 4690 03:39:18,240 --> 03:39:20,640 THAT INFLAMMATORY PATHWAYS SUCH 4691 03:39:20,640 --> 03:39:26,040 AS MONOCYTES PRIOR TO 4692 03:39:26,040 --> 03:39:28,200 INFLAMMATION ARE PREDICTABLE IN 4693 03:39:28,200 --> 03:39:33,600 ANTIBODY RESPONSE. 4694 03:39:33,600 --> 03:39:34,200 WE HAVE BEEN INTERESTED IN THIS 4695 03:39:34,200 --> 03:39:39,040 QUESTION AS WELL. THIS IS VERY 4696 03:39:39,040 --> 03:39:39,680 OLD DATA ON BLOOD TRANSCRIPTION 4697 03:39:39,680 --> 03:39:40,240 MODEL ACTIVITY IN YOUNG AND 4698 03:39:40,240 --> 03:39:41,480 OLDER ADULTS. THEY WERE VACCINE 4699 03:39:41,480 --> 03:39:44,680 RESPONDERS AND NONRESPONDERS. 4700 03:39:44,680 --> 03:39:50,240 WE ALSO HAD PERIPHERAL HOLDERS 4701 03:39:50,240 --> 03:39:50,800 AND WILL SPEAK ABOUT THAT A 4702 03:39:50,800 --> 03:39:51,400 LITTLE BIT LATER BUT WHAT WE 4703 03:39:51,400 --> 03:39:52,040 FOUND WERE SEVERAL SIGNATURES 4704 03:39:52,040 --> 03:39:52,720 OF TREATED ACTIVATION THAT 4705 03:39:52,720 --> 03:39:58,640 SEEMED TO BE PRESENT. THEY WERE 4706 03:39:58,640 --> 03:39:59,080 MODULATED FOLLOWING 4707 03:39:59,080 --> 03:40:01,000 VACCINATION. THIS IS AN 4708 03:40:01,000 --> 03:40:03,600 ANALYSIS OF PBMC, THEORETICALLY 4709 03:40:03,600 --> 03:40:06,200 THEY ARE NOT SUPPOSED TO BE 4710 03:40:06,200 --> 03:40:06,800 THERE, WE PRESUME THEY ARE 4711 03:40:06,800 --> 03:40:07,400 TAGGING ALONG FOR THE LINE IN 4712 03:40:07,400 --> 03:40:09,520 ADHERENCE TO LEUKOCYTE AND THIS 4713 03:40:09,520 --> 03:40:10,120 PROVOKES US TO START THINKING 4714 03:40:10,120 --> 03:40:11,600 MORE ABOUT IT, AND WHETHER WE 4715 03:40:11,600 --> 03:40:15,040 SHOULD START CONSIDERING THEM 4716 03:40:15,040 --> 03:40:17,640 IN KIND OF CONTRIBUTING TO 4717 03:40:17,640 --> 03:40:22,720 CHRONIC INFLAMMATORY STATE. 4718 03:40:22,720 --> 03:40:27,440 AND WHEN WE THOUGHT ABOUT IT 4719 03:40:27,440 --> 03:40:28,000 MORE, THEY ARE IN A UNIQUE 4720 03:40:28,000 --> 03:40:28,560 POSITION TO CONTRIBUTE TO 4721 03:40:28,560 --> 03:40:30,040 CHRONIC INFORMATION AND MOST OF 4722 03:40:30,040 --> 03:40:34,200 US KNOW THAT THIS IS BEEN 4723 03:40:34,200 --> 03:40:35,680 INVOLVED IN BLOOD CLOTTING OR 4724 03:40:35,680 --> 03:40:37,320 HEMOSTASIS, AND IT HAS 4725 03:40:37,320 --> 03:40:43,880 REFLECTIVE RECEPTORS, C3 4726 03:40:43,880 --> 03:40:44,520 REFLECTORS AND COMPLEMENT THREE 4727 03:40:44,520 --> 03:40:45,000 RECEPTORS AND SEVERAL 4728 03:40:45,000 --> 03:40:55,520 ACTIVATION MARKERS LIKE PSGL-1 4729 03:40:57,720 --> 03:41:06,040 AND ACTIVATION OF LYGONE 4730 03:41:06,040 --> 03:41:06,560 RECEPTORS, INTERESTING 4731 03:41:06,560 --> 03:41:07,160 COMPONENTS IN FACT THEY THEY 4732 03:41:07,160 --> 03:41:11,000 EXPRESS THE COMPONENTS OF 4733 03:41:11,000 --> 03:41:13,120 NF-KB, EVEN THOUGH THERE IS NO 4734 03:41:13,120 --> 03:41:14,560 TRANSCRIPTION WE KNOW OF IN THE 4735 03:41:14,560 --> 03:41:20,640 CELLS PRESUMABLY. 4736 03:41:20,640 --> 03:41:21,240 THERE IS EVIDENCE THAT THIS IS 4737 03:41:21,240 --> 03:41:21,800 IMPORTANT FOR OPTIMAL PLATE 4738 03:41:21,800 --> 03:41:22,440 ACTIVATION AND HOW IT DOES THIS 4739 03:41:22,440 --> 03:41:25,000 IS NOT CLEAR. REASONABLY 4740 03:41:25,000 --> 03:41:25,520 THROUGH A NONCANONICAL 4741 03:41:25,520 --> 03:41:27,120 ACTIVATION, ALSO EXPRESSED IS 4742 03:41:27,120 --> 03:41:37,600 STEP 1, STEP 3, NOTHING TO 4743 03:41:38,520 --> 03:41:39,080 TRANSLOCATE. IT IS DIFFERENT AS 4744 03:41:39,080 --> 03:41:43,480 WE START TO UNDERSTAND THIS. 4745 03:41:43,480 --> 03:41:44,680 I WILL GIVE YOU AN EXAMPLE OF 4746 03:41:44,680 --> 03:41:45,200 THIS INTERFACE BETWEEN 4747 03:41:45,200 --> 03:41:45,760 HEMOSTASIS AND INFLAMMATORY 4748 03:41:45,760 --> 03:41:46,320 RESPONSE ASSOCIATED WITH AN 4749 03:41:46,320 --> 03:41:47,240 INFECTION. THIS IS A PAPER 4750 03:41:47,240 --> 03:41:50,000 PUBLISHED MANY YEARS AGO, NOT 4751 03:41:50,000 --> 03:41:52,560 THAT LONG AGO, FIVE YEARS AGO 4752 03:41:52,560 --> 03:41:53,160 IN THE NEW ENGLAND JOURNAL OF 4753 03:41:53,160 --> 03:42:01,600 MEDICINE. IT LOOKED AT 4754 03:42:01,600 --> 03:42:02,120 ADMINISTRATIVE DATA FROM 4755 03:42:02,120 --> 03:42:02,720 ONTARIO CANADA, AND LOOKED AT 4756 03:42:02,720 --> 03:42:05,680 THE RISK FOR MYOCARDIAL 4757 03:42:05,680 --> 03:42:06,320 INFARCTION, HEART ATTACK CAUSED 4758 03:42:06,320 --> 03:42:12,080 BY CORONARY ARTERY THROMBOSIS 4759 03:42:12,080 --> 03:42:12,640 FOLLOWING INFLUENZA AND THE 4760 03:42:12,640 --> 03:42:13,800 RISK WAS ESTIMATED TO BE SIX 4761 03:42:13,800 --> 03:42:14,400 FULL HIGHER IN THE SEVEN DAYS 4762 03:42:14,400 --> 03:42:15,640 AFTER AN INFLUENZA DIAGNOSIS 4763 03:42:15,640 --> 03:42:16,280 COMPARED TO THE 51 OTHER WEEKS 4764 03:42:16,280 --> 03:42:20,240 OF THE YEAR. THIS IS STILL AN 4765 03:42:20,240 --> 03:42:25,040 ELEVATED RISK FOR RSV AND EVEN 4766 03:42:25,040 --> 03:42:25,480 FOR UNDIFFERENTIATED 4767 03:42:25,480 --> 03:42:27,440 RESPIRATORY INFECTION WITHOUT A 4768 03:42:27,440 --> 03:42:31,040 SPECIFIC VIRUS IDENTIFIED. AN 4769 03:42:31,040 --> 03:42:31,680 INTRIGUING SUGGESTION TO US AND 4770 03:42:31,680 --> 03:42:32,320 IT CAUSED US TO LOOK INTO THIS 4771 03:42:32,320 --> 03:42:34,360 CAREFULLY. 4772 03:42:34,360 --> 03:42:37,360 THIS WORK WAS LED IN MY LAB I 4773 03:42:37,360 --> 03:42:41,200 RESEARCH SCIENTIST SUBHASIS 4774 03:42:41,200 --> 03:42:44,080 MOHANTY WHO WORED WITH ANNA 4775 03:42:44,080 --> 03:42:47,880 KONSTORUM. 4776 03:42:47,880 --> 03:42:50,000 WHAT WE DID WAS RECRUIT A 4777 03:42:50,000 --> 03:42:52,520 POPULATION OF YOUNG AND OLDER 4778 03:42:52,520 --> 03:43:00,680 ADULTS AND OLDER ADULTS 4779 03:43:00,680 --> 03:43:01,280 RESIDENTS OF A SKILLED FACILITY 4780 03:43:01,280 --> 03:43:01,880 OR NURSING HOME AND EVERYBODY 4781 03:43:01,880 --> 03:43:02,520 RECEIVED THE SEASONAL INFLUENZA 4782 03:43:02,520 --> 03:43:04,000 VACCINE WE EVALUATED, AND I 4783 03:43:04,000 --> 03:43:08,200 WILL SHOW YOU SOME DATA ON THE 4784 03:43:08,200 --> 03:43:08,760 BASAL EXPRESSION OF SOME 4785 03:43:08,760 --> 03:43:14,160 ACTIVATION MARKERS. THIS IS 4786 03:43:14,160 --> 03:43:14,800 ONE OF THE FEW TALK THAT IS NOT 4787 03:43:14,800 --> 03:43:17,600 GOING TO HAVE ANY SINGLE CELL, 4788 03:43:17,600 --> 03:43:18,160 THE REASON FOR THIS IS THAT 4789 03:43:18,160 --> 03:43:18,760 THIS IS STILL A TECHNOLOGICAL 4790 03:43:18,760 --> 03:43:21,720 BARRIER IN PLATELETS. 4791 03:43:21,720 --> 03:43:22,240 IF YOU THINK ABOUT IT THE 4792 03:43:22,240 --> 03:43:22,800 TYPICAL RNA CONTENT OF THE 4793 03:43:22,800 --> 03:43:29,400 PLATELET IS ABOUT TWO 4794 03:43:29,400 --> 03:43:33,600 PHENTOGRAMS. AND SHOULD THIS 4795 03:43:33,600 --> 03:43:36,040 BECOME A POSSIBILITY, IT WILL 4796 03:43:36,040 --> 03:43:36,600 BE GREAT TO HAVE OUR HANDS 4797 03:43:36,600 --> 03:43:37,240 AROUND THIS BUT IT CAN BE BOTH 4798 03:43:37,240 --> 03:43:40,000 (INDISCERNIBLE). 4799 03:43:40,000 --> 03:43:41,560 LET ME MAKE ANOTHER COMMENT. 4800 03:43:41,560 --> 03:43:44,920 THAT WE ALSO EVALUATED FOLKS 4801 03:43:44,920 --> 03:43:49,960 FOR THE GERIATRIC SYNDROME OF 4802 03:43:49,960 --> 03:43:50,880 FRAILTY IN THE STUDY, THAT 4803 03:43:50,880 --> 03:43:56,560 REFLECTS A STATE OF DIMINISHED 4804 03:43:56,560 --> 03:43:57,200 (INDISCERNIBLE), AND DECREASED 4805 03:43:57,200 --> 03:43:57,680 STRESS RESISTANCE WELL 4806 03:43:57,680 --> 03:43:58,200 VALIDATED FOR A RISK OF 4807 03:43:58,200 --> 03:44:05,880 MORTALITY IN THE NURSING HOME, 4808 03:44:05,880 --> 03:44:06,480 BEING AT INCREASED DISABILITY 4809 03:44:06,480 --> 03:44:07,040 AND RISK FOR FALLS AND THE 4810 03:44:07,040 --> 03:44:07,560 LIKE. WE USED TO MEASURE 4811 03:44:07,560 --> 03:44:10,680 DEVELOPED BY -- THAT HAS A 4812 03:44:10,680 --> 03:44:11,280 MEASUREMENT BY GAIT SPEED AS 4813 03:44:11,280 --> 03:44:12,880 WELL AS SELF-REPORTS OF 4814 03:44:12,880 --> 03:44:14,840 UNINTENTIONAL WEIGHT LOSS, 4815 03:44:14,840 --> 03:44:18,120 EXHAUSTION AND DECREASED 4816 03:44:18,120 --> 03:44:19,400 PHYSICAL ACTIVITY USING 4817 03:44:19,400 --> 03:44:20,000 VALIDATED INSTRUMENTS AND IF 4818 03:44:20,000 --> 03:44:20,680 YOU HAVE THREE OUT OF THE FIVE 4819 03:44:20,680 --> 03:44:26,320 CRITERIA CONSIDERED FRAIL AND 4820 03:44:26,320 --> 03:44:26,920 ONE OR TWO YOU ARE CONSIDERED 4821 03:44:26,920 --> 03:44:27,400 PRE-FRAIL, ZERO YOU ARE 4822 03:44:27,400 --> 03:44:31,200 NON-FRAIL. 4823 03:44:31,200 --> 03:44:31,800 THE REASON I BRING THIS UP IS 4824 03:44:31,800 --> 03:44:32,440 THAT ONCE YOU LOOK AT THE ORDER 4825 03:44:32,440 --> 03:44:37,320 GROUP OF COMMUNITY DWELLING 4826 03:44:37,320 --> 03:44:37,960 INDIVIDUALS, MOST OF THEM WERE 4827 03:44:37,960 --> 03:44:40,280 NON-FRAIL WITH A FEW PRE-FRAIL. 4828 03:44:40,280 --> 03:44:41,720 NEARLY ALL OF THE RESIDENTS IN 4829 03:44:41,720 --> 03:44:43,120 NURSING HOMES MET THE CRITERIA 4830 03:44:43,120 --> 03:44:46,360 FOR PRE-FRAIL. GIVEN THE 4831 03:44:46,360 --> 03:44:46,880 OPPORTUNITY TO DO SOME 4832 03:44:46,880 --> 03:44:52,120 CORRELATIONS AS WELL. 4833 03:44:52,120 --> 03:44:53,960 LET ME SHOW YOU SOME OF THE 4834 03:44:53,960 --> 03:44:55,240 DATA. WE SAW THE EVALUATION OF 4835 03:44:55,240 --> 03:44:56,320 THE BASELINE, THERE WAS 4836 03:44:56,320 --> 03:45:01,560 SUBSTANTIAL EXPRESSION OF RNA 4837 03:45:01,560 --> 03:45:02,080 ASSOCIATED WITH PLATELET 4838 03:45:02,080 --> 03:45:02,920 ACTIVATION AND IT WAS 4839 03:45:02,920 --> 03:45:06,240 UPREGULATED IN PLATELETS FROM 4840 03:45:06,240 --> 03:45:08,840 OLDER INDIVIDUALS, COMMUNITY 4841 03:45:08,840 --> 03:45:10,640 DWELLING OLDER AND FURTHER 4842 03:45:10,640 --> 03:45:11,280 UPREGULATED IF ONE LOOKED EVEN 4843 03:45:11,280 --> 03:45:11,880 IN NURSING HOMES VERSUS OLDER 4844 03:45:11,880 --> 03:45:16,400 INDIVIDUALS. THESE ARE THE 4845 03:45:16,400 --> 03:45:17,000 PARTICULAR PATHWAYS THAT WERE 4846 03:45:17,000 --> 03:45:18,080 UPREGULATED FOR SIGNALING 4847 03:45:18,080 --> 03:45:18,680 PATHWAYS, EMULATION PATHWAYS 4848 03:45:18,680 --> 03:45:21,720 AND THE LIKE. 4849 03:45:21,720 --> 03:45:24,040 IF YOU LOOK AT THIS COMPONENT 4850 03:45:24,040 --> 03:45:24,600 ANALYSIS, THEY SEPARATE OUT 4851 03:45:24,600 --> 03:45:25,200 PRETTY WELL PARTICULARLY THE 4852 03:45:25,200 --> 03:45:27,560 NURSING HOME GROUP IN BLUE AND 4853 03:45:27,560 --> 03:45:28,040 THE GREEN IS A YOUNG 4854 03:45:28,040 --> 03:45:33,960 INDIVIDUALS. IF YOU LOOK AT 4855 03:45:33,960 --> 03:45:35,720 THIS PC1 AXIS IT EXPLAINED 4856 03:45:35,720 --> 03:45:40,800 ABOUT 72% VARIATION WHICH IS A 4857 03:45:40,800 --> 03:45:41,280 SUBSTANTIAL AMOUNT AND 4858 03:45:41,280 --> 03:45:41,880 SOMETHING WILL COME UP A BIT 4859 03:45:41,880 --> 03:45:42,760 LATER, THE PRIMARY BOUNDARY 4860 03:45:42,760 --> 03:45:52,880 REGULATING GENES-- NOT GENES, 4861 03:45:52,880 --> 03:45:54,120 RNAS-- WERE MEDIATING 4862 03:45:54,120 --> 03:45:54,720 TRANSLATION LIKE ELONGATION, 4863 03:45:54,720 --> 03:46:00,920 CHROMOSOMAL DROPPINGS AND CIS 4864 03:46:00,920 --> 03:46:01,520 DOWN REGULATE IN PLATELETS IN 4865 03:46:01,520 --> 03:46:06,560 OLDER ADULTS, AND ADULTS IN 4866 03:46:06,560 --> 03:46:07,200 NURSING HOME POPULATIONS AND I 4867 03:46:07,200 --> 03:46:08,680 SHOULD ALSO MENTION, FOR WHAT 4868 03:46:08,680 --> 03:46:11,800 IT'S WORTH, WE SAW AN H 4869 03:46:11,800 --> 03:46:12,400 ASSOCIATED INCREASE IN THE 4870 03:46:12,400 --> 03:46:12,880 BASAL EXPRESSION OF 4871 03:46:12,880 --> 03:46:14,000 MITOCHONDRIAL GENES. PLATELETS 4872 03:46:14,000 --> 03:46:22,040 TO HAVE ABOUT 4-5 MONO CHONDRIA 4873 03:46:22,040 --> 03:46:23,840 PER PLATELET. 4874 03:46:23,840 --> 03:46:28,080 AS MANY OF YOU KNOW THE 4875 03:46:28,080 --> 03:46:30,240 PRINCIPAL DNA-DEPENDENT RNA 4876 03:46:30,240 --> 03:46:40,800 POLYMERASE IS A (INDISCERNIBLE) 4877 03:46:51,120 --> 03:46:51,520 ENCODED IN THE GENE. 4878 03:46:51,520 --> 03:46:52,080 THEORETICALLY, WE DO SEE A 4879 03:46:52,080 --> 03:46:56,520 BASAL UP REGULATION PLATES. 4880 03:46:56,520 --> 03:46:57,080 WE DO SEE SOME EVIDENCE FOR 4881 03:46:57,080 --> 03:46:57,680 DYNAMIC REGULATION FOLLOWING 4882 03:46:57,680 --> 03:46:58,320 VACCINATION IN HERE WE SEE THE 4883 03:46:58,320 --> 03:47:06,880 METHOD THAT ANNA KASTORUM AND 4884 03:47:06,880 --> 03:47:08,840 -- USED ESSENTIALLY A 4885 03:47:08,840 --> 03:47:13,200 DECONVOLUTION OF METRICS, 4886 03:47:13,200 --> 03:47:13,800 INCLUDING PARTICULAR GENES OR 4887 03:47:13,800 --> 03:47:15,400 GENE SETS, AND THE ASSOCIATION 4888 03:47:15,400 --> 03:47:17,080 WITH A PARTICULAR GROUP, WITH A 4889 03:47:17,080 --> 03:47:20,840 VECTOR IN THIS CASE OF TIME. 4890 03:47:20,840 --> 03:47:23,840 THIS ALLOWS US TO ALSO RANK 4891 03:47:23,840 --> 03:47:24,440 ORDER, TO WHAT EXTENT CERTAIN 4892 03:47:24,440 --> 03:47:30,480 GENES ARE ASSOCIATIVE WITH 4893 03:47:30,480 --> 03:47:31,080 MEMBERS IN A CERTAIN GROUP AND 4894 03:47:31,080 --> 03:47:31,720 USING THIS KIND OF APPROACH WE 4895 03:47:31,720 --> 03:47:33,320 WERE ABLE TO IDENTIFY SOME 4896 03:47:33,320 --> 03:47:36,280 COMPONENTS THAT WERE 4897 03:47:36,280 --> 03:47:36,880 OVERLAPPING, AND IN THIS CASE 4898 03:47:36,880 --> 03:47:41,960 CONSISTED OF RNAS THAT 4899 03:47:41,960 --> 03:47:44,560 MEDIATING ACTIVATION, SHOWING A 4900 03:47:44,560 --> 03:47:45,040 DIFFERENTIAL MODULATION 4901 03:47:45,040 --> 03:47:47,960 POST-VACCINATION. 4902 03:47:47,960 --> 03:47:48,560 I DON'T KNOW IF YOU CAN SEE IT 4903 03:47:48,560 --> 03:47:57,760 BUT THIS IS IN RICH GREEN HERE, 4904 03:47:57,760 --> 03:47:58,320 COMPONENTS ENRICHED IN THE 4905 03:47:58,320 --> 03:47:58,920 YOUNG INDIVIDUALS THAT SHOWED 4906 03:47:58,920 --> 03:48:00,200 THIS PARTICULAR PATTERN OF UP 4907 03:48:00,200 --> 03:48:00,760 REGULATION, PLATEAU IN THE 4908 03:48:00,760 --> 03:48:02,880 NURSING HOME COHORT. WITH THE 4909 03:48:02,880 --> 03:48:04,600 ENRICHMENT OF THIS PARTICULAR 4910 03:48:04,600 --> 03:48:07,520 PLATELET ACTIVATION RNAS THAT 4911 03:48:07,520 --> 03:48:09,200 ARE DOWN REGULATED AND THEN IN 4912 03:48:09,200 --> 03:48:09,800 OLDER ADULTS SHOWING A LITTLE 4913 03:48:09,800 --> 03:48:15,640 INTERMEDIATE. 4914 03:48:15,640 --> 03:48:16,240 WE ALSO SAW SOME SUBCOMPONENTS 4915 03:48:16,240 --> 03:48:16,760 THAT ALSO MODULATED THOSE 4916 03:48:16,760 --> 03:48:17,360 TRANSLATION SIGNATURES THAT I 4917 03:48:17,360 --> 03:48:21,320 MENTIONED. THE QUESTION CAME 4918 03:48:21,320 --> 03:48:21,840 UP, THAT WE SEE ANYTHING 4919 03:48:21,840 --> 03:48:24,400 RELATED TO VACCINE RESPONSE? WE 4920 03:48:24,400 --> 03:48:25,000 DID NOT IN THE CASE OF OLDER 4921 03:48:25,000 --> 03:48:26,960 INDIVIDUALS BUT FOR THE YOUNG 4922 03:48:26,960 --> 03:48:27,600 VACCINE RESPONDERS WE ACTUALLY 4923 03:48:27,600 --> 03:48:31,240 DID SEE A COMPONENT AGAIN, WITH 4924 03:48:31,240 --> 03:48:33,560 RNAS ASSOCIATED WITH PLATELET 4925 03:48:33,560 --> 03:48:34,080 ACTIVATION THAT WERE DOWN 4926 03:48:34,080 --> 03:48:38,880 REGULATED BUT ONLY A DAY 28. 4927 03:48:38,880 --> 03:48:39,480 SO THE TYPICAL HALF-LIFE OF A 4928 03:48:39,480 --> 03:48:40,400 PLATELET OR THE LIFESPAN OF 4929 03:48:40,400 --> 03:48:41,040 HUMAN PLATELET IS ABOUT A WEEK 4930 03:48:41,040 --> 03:48:44,080 TO 10 DAYS. THIS IS FAR BEYOND 4931 03:48:44,080 --> 03:48:54,480 WHAT WE WOULD EXPECT. 4932 03:48:54,480 --> 03:48:55,080 THIS SPEAKS TO THE LIKELIHOOD 4933 03:48:55,080 --> 03:48:57,080 FOR NON-PLATELET AUTONOMOUS 4934 03:48:57,080 --> 03:48:58,000 FACTORS THAT CONTRIBUTE TO THIS 4935 03:48:58,000 --> 03:48:58,600 EVIDENCE OR ASSOCIATION WITH 4936 03:48:58,600 --> 03:49:01,880 INFLUENZA VACCINE RESPONSE. 4937 03:49:01,880 --> 03:49:02,440 ANOTHER QUESTION WE TRY TO 4938 03:49:02,440 --> 03:49:04,680 ANSWER WAS THE ISSUE OF UP 4939 03:49:04,680 --> 03:49:05,240 REGULATION OF SOME OF THESE 4940 03:49:05,240 --> 03:49:13,320 ACTIVATION MARKERS. MANY OF 4941 03:49:13,320 --> 03:49:13,800 THEM RESIDE IN PRE-FORM 4942 03:49:13,800 --> 03:49:16,560 GRANULES, OFFER GRANULES WITHIN 4943 03:49:16,560 --> 03:49:17,200 THE PLATELET TRANSPORTED TO THE 4944 03:49:17,200 --> 03:49:19,000 SURFACE LIKE LIGAND OR 4945 03:49:19,000 --> 03:49:22,280 PIECE-SELECTING. 4946 03:49:22,280 --> 03:49:24,160 IS THE EXPRESSION OF RNAS 4947 03:49:24,160 --> 03:49:24,720 MATTER? NOT SUCH AN EASY 4948 03:49:24,720 --> 03:49:34,160 QUESTION TO ANSWER. WITH A 4949 03:49:34,160 --> 03:49:34,760 START TO EVALUATE THIS USING 4950 03:49:34,760 --> 03:49:35,400 FLOW CYTOMETRY. YOU CAN DO THIS 4951 03:49:35,400 --> 03:49:36,880 ON PLATELETS AND WHAT WE FOUND 4952 03:49:36,880 --> 03:49:37,520 IS THAT FOR SOME MARKERS THERE 4953 03:49:37,520 --> 03:49:38,160 WAS AN ASSOCIATION BETWEEN GENE 4954 03:49:38,160 --> 03:49:40,280 EXPRESSION, FOR THE P-SELECTING 4955 03:49:40,280 --> 03:49:50,760 GENE CALLED THE CELL. IF ONE 4956 03:49:54,680 --> 03:49:55,200 LOOKS AT DAY TWO TO DAY SEVEN 4957 03:49:55,200 --> 03:49:56,680 TO NORMALIZE EXPRESSION RELATED 4958 03:49:56,680 --> 03:49:58,840 TO DAY ZERO, THEY ARE SIMILAR 4959 03:49:58,840 --> 03:50:05,800 PATTERNS OF EXPRESSION OF 4960 03:50:05,800 --> 03:50:06,360 HIGHEST IN THE NORMALIZED 4961 03:50:06,360 --> 03:50:06,960 EXPRESSION THE YOUNG GROUP AT 4962 03:50:06,960 --> 03:50:07,520 THE SEVEN WE SEE SOMETHING 4963 03:50:07,520 --> 03:50:08,200 SIMILAR IN ONE SEPARATE 4964 03:50:08,200 --> 03:50:08,760 EXPRESSION PROVIDED BY FLOW 4965 03:50:08,760 --> 03:50:17,120 CYTOMETRY. 4966 03:50:17,120 --> 03:50:18,120 AND FOR LIEGAND WE DID NOT SEE 4967 03:50:18,120 --> 03:50:28,680 ASSOCIATION. IF WE LOOK AT THE 4968 03:50:32,160 --> 03:50:32,760 OVERALL EXPRESSION OF PLATELET 4969 03:50:32,760 --> 03:50:33,400 ACTIVATION MARKERS HAD DAY TWO 4970 03:50:33,400 --> 03:50:34,000 AND DAY SEVEN OF POST VACCINE 4971 03:50:34,000 --> 03:50:34,600 WE SEE EXPRESSION OF LOVE IS 4972 03:50:34,600 --> 03:50:40,200 ACTIVATION MARKERS. 4973 03:50:40,200 --> 03:50:40,800 SURPRISINGLY IN THE NURSING 4974 03:50:40,800 --> 03:50:42,560 HOME GROUP THIS WAS MODULATED. 4975 03:50:42,560 --> 03:50:44,880 WITH ONE EXCEPTION. WE DON'T 4976 03:50:44,880 --> 03:50:48,440 TOTALLY UNDERSTAND THIS. THERE 4977 03:50:48,440 --> 03:50:49,040 HAVE BEEN SOME REPORTS IN THE 4978 03:50:49,040 --> 03:50:50,840 LITERATURE OF MODULATED 4979 03:50:50,840 --> 03:50:54,520 EXPRESSION, THINGS LIKE ROS IN 4980 03:50:54,520 --> 03:50:56,720 VERY OLDER INDIVIDUALS, THERE 4981 03:50:56,720 --> 03:51:02,440 IS WORK FROM-- OUR COLLEAGUE AT 4982 03:51:02,440 --> 03:51:02,920 YALE-- AND WE SAW THE 4983 03:51:02,920 --> 03:51:03,520 EXPRESSION OF THE TRANSLATION 4984 03:51:03,520 --> 03:51:06,040 PIECE THAT IS LOWEST IN THE 4985 03:51:06,040 --> 03:51:06,680 NURSING HOME GROUP, WHERE THAT 4986 03:51:06,680 --> 03:51:08,600 IS CONTRIBUTING. 4987 03:51:08,600 --> 03:51:14,640 I WILL SAY WE ARE LOOKING AT 4988 03:51:14,640 --> 03:51:15,160 -- EXPRESSION OF THESE 4989 03:51:15,160 --> 03:51:15,800 ACTIVATION GENES AND WE DO SEE 4990 03:51:15,800 --> 03:51:16,560 EVIDENCE THAT FOR SEVERAL 4991 03:51:16,560 --> 03:51:20,800 (INDISCERNIBLE) -- FOR WHAT 4992 03:51:20,800 --> 03:51:22,080 IT'S WORTH-- THE NURSING HOME 4993 03:51:22,080 --> 03:51:23,920 INDIVIDUALS HAD THE HIGHEST 4994 03:51:23,920 --> 03:51:28,760 EXPRESSION OF INFLAMMATORY 4995 03:51:28,760 --> 03:51:29,360 PHENOTYPE, IF ONE LOOKS AT EX 4996 03:51:29,360 --> 03:51:32,280 VIVO SIMULATION. 4997 03:51:32,280 --> 03:51:32,880 SO THIS IS A SUMMARY OF WHAT I 4998 03:51:32,880 --> 03:51:37,200 DISCUSSED. SO WE THINK THAT 4999 03:51:37,200 --> 03:51:44,680 THERE IS EVIDENCE FOR AN AGE 5000 03:51:44,680 --> 03:51:45,240 ASSOCIATIVE ENHANCEMENT IN 5001 03:51:45,240 --> 03:51:54,520 PLATELET ACTIVATION, MEDIATED 5002 03:51:54,520 --> 03:51:55,080 BY RNA EXPRESSION AND THEIR 5003 03:51:55,080 --> 03:51:57,080 DISTINCT TRAJECTORIES OF POST 5004 03:51:57,080 --> 03:51:58,400 VACCINE RESPONSE THAT TALKS 5005 03:51:58,400 --> 03:51:58,880 ABOUT PLATELET EXIT AND 5006 03:51:58,880 --> 03:52:03,440 INTRINSIC FACTORS. 5007 03:52:03,440 --> 03:52:05,320 THERE IS AN INTERESTING 5008 03:52:05,320 --> 03:52:06,040 VIROLOGY POTENTIAL ANALYSIS OF 5009 03:52:06,040 --> 03:52:09,200 WHAT RNAS ARE TRANSLATED AS 5010 03:52:09,200 --> 03:52:09,840 EVIDENCED BY THIS MODULATION A 5011 03:52:09,840 --> 03:52:12,440 BASAL ACTIVATION PHENOTYPE. WE 5012 03:52:12,440 --> 03:52:14,120 DO THINK THAT THERE IS GENERAL 5013 03:52:14,120 --> 03:52:20,040 EVIDENCE FOR AN ENHANCED 5014 03:52:20,040 --> 03:52:20,640 THROMBO INFLAMMATORY MILIEU IF 5015 03:52:20,640 --> 03:52:21,880 YOU WILL THAT CONTRIBUTES TO 5016 03:52:21,880 --> 03:52:26,080 PLATELET CHRONIC INFORMATION. 5017 03:52:26,080 --> 03:52:26,720 WE ARE REAUTHORIZING HOW SMALL 5018 03:52:26,720 --> 03:52:35,320 AND MIGHTY THEY ARE, THEY HAVE 5019 03:52:35,320 --> 03:52:37,920 LIKE 2W10 TO THE FIFTH PER 5020 03:52:37,920 --> 03:52:38,520 MICROLITER BLOOD. MAYBE I'M 5021 03:52:38,520 --> 03:52:39,960 GOING TO FINISH WITH MY FUTURE 5022 03:52:39,960 --> 03:52:41,840 QUESTION SLIDE. 5023 03:52:41,840 --> 03:52:42,360 WE ARE INTERESTED IN THE 5024 03:52:42,360 --> 03:52:47,240 BIOLOGY. WHAT IS GOING ON? HOW 5025 03:52:47,240 --> 03:52:48,320 IS IT THAT THE PLATELET HAS NO 5026 03:52:48,320 --> 03:52:50,000 POTENTIALLY (INDISCERNIBLE) TO 5027 03:52:50,000 --> 03:52:55,080 SPEAK OF YET? WE SEE 5028 03:52:55,080 --> 03:52:55,600 SEGREGATION IN TERMS OF 5029 03:52:55,600 --> 03:52:57,640 FUNCTIONAL APPEARING RNAS. WE 5030 03:52:57,640 --> 03:53:03,040 CAN TALK ABOUT THAT. 5031 03:53:03,040 --> 03:53:03,640 FOR THIS SESSION I AM GOING TO 5032 03:53:03,640 --> 03:53:04,240 TALK ABOUT A COUPLE OF OTHER 5033 03:53:04,240 --> 03:53:04,760 QUESTIONS IN THE AREA OF 5034 03:53:04,760 --> 03:53:05,400 GENERAL VACCINE RESPONSE, NOT 5035 03:53:05,400 --> 03:53:08,920 SO MUCH ABOUT T-CELLS BECAUSE 5036 03:53:08,920 --> 03:53:13,720 YOU ARE SUCH EXPERTS. BUT I 5037 03:53:13,720 --> 03:53:14,360 WILL SAY THAT MOTIVATED BY THE 5038 03:53:14,360 --> 03:53:19,600 CLINICAL QUESTIONS, WHAT IS THE 5039 03:53:19,600 --> 03:53:20,120 MECHANISM FOR INCREASED 5040 03:53:20,120 --> 03:53:22,200 DURATION OF ANTIBODY RESPONSES? 5041 03:53:22,200 --> 03:53:22,800 WE ALL KNOW FOR EXAMPLE THERE 5042 03:53:22,800 --> 03:53:23,960 IS ACCELERATED DECAY IN 5043 03:53:23,960 --> 03:53:29,880 NEUTRALIZING ANTI SAR-COVID-2 5044 03:53:29,880 --> 03:53:30,480 ANTIBODIES AND THIS HAS BEEN 5045 03:53:30,480 --> 03:53:34,400 DOCUMENTED. IT REFLECTS THE 5046 03:53:34,400 --> 03:53:34,960 GENERAL RESPONSES BUT IT IS 5047 03:53:34,960 --> 03:53:35,600 INTERESTING TO UNDERSTAND WHAT 5048 03:53:35,600 --> 03:53:39,120 IS GOING ON. CAN WE HAVE 5049 03:53:39,120 --> 03:53:40,040 PLEASE BE LESS EFFECTIVE? IT IS 5050 03:53:40,040 --> 03:53:40,760 THE RELEVANT CLINICAL QUESTION 5051 03:53:40,760 --> 03:53:47,360 FOR (INDISCERNIBLE). PERHAPS-- 5052 03:53:47,360 --> 03:53:47,960 WE'LL TALK ABOUT THIS BUT I 5053 03:53:47,960 --> 03:53:48,480 ALWAYS WONDERED IF OTHER 5054 03:53:48,480 --> 03:53:49,040 CERTAIN ADJUTANTS THAT CAN 5055 03:53:49,040 --> 03:53:58,040 BYPASS THE -- I MENTIONED -- 5056 03:53:58,040 --> 03:53:58,600 THE COMPONENT IN THE ZOSTER 5057 03:53:58,600 --> 03:54:00,040 VACCINE THAT SHOWS NO 5058 03:54:00,040 --> 03:54:01,800 DIFFERENCE AS FAR AS WE CAN 5059 03:54:01,800 --> 03:54:04,440 TELL IN AGE EFFECTIVENESS. JUST 5060 03:54:04,440 --> 03:54:08,680 AS EFFECTIVE IN EIGHT-YEAR-OLDS 5061 03:54:08,680 --> 03:54:09,240 AND 60-YEAR-OLDS. 5062 03:54:09,240 --> 03:54:10,240 AND AT LEAST IN THE SHORT TERM 5063 03:54:10,240 --> 03:54:12,760 THE NANO PARTICLE RNA PLATFORM 5064 03:54:12,760 --> 03:54:16,160 WORK PRETTY WELL; IT SAVES A 5065 03:54:16,160 --> 03:54:16,720 LOT OF OLDER ADULTS WHEN IT 5066 03:54:16,720 --> 03:54:27,280 FIRST CAME OUT ALTHOUGH WE KNOW 5067 03:54:33,240 --> 03:54:33,760 THAT THE MECHANISMS OF THE 5068 03:54:33,760 --> 03:54:34,360 --ACCELERATED. THE LAST THING 5069 03:54:34,360 --> 03:54:37,680 IS THAT MUCOSAL IMMUNOLOGY SUCH 5070 03:54:37,680 --> 03:54:43,240 A BROAD FIELD NOT JUST TALKING 5071 03:54:43,240 --> 03:54:48,120 ABOUT SECRETORY 5072 03:54:48,120 --> 03:54:48,720 (INDISCERNIBLE), BUT ALL OF IT 5073 03:54:48,720 --> 03:54:55,520 SHOULD BE STUDIED AS A BARRIER, 5074 03:54:55,520 --> 03:54:56,080 AS A MUCUS BARRIER NOT WELL 5075 03:54:56,080 --> 03:54:56,960 UNDERSTOOD IN THE CONTEXT OF 5076 03:54:56,960 --> 03:54:59,200 AGE PARTICULARLY IN HUMANS. BUT 5077 03:54:59,200 --> 03:55:01,200 THAT IS FOR LATER I GUESS. 5078 03:55:01,200 --> 03:55:01,800 AND JUST TO THANK THE FOLKS 5079 03:55:01,800 --> 03:55:05,720 WHO HAVE DONE THIS WORK. AGAIN 5080 03:55:05,720 --> 03:55:08,760 SUBHASIS IN MY LAB AND WE 5081 03:55:08,760 --> 03:55:12,960 COLLABORATED WITH -- FORMER 5082 03:55:12,960 --> 03:55:15,600 POSTDOC IN MY LAB. STEVE -- LAB 5083 03:55:15,600 --> 03:55:21,160 AND -- AND -- AT THE UNIVERSITY 5084 03:55:21,160 --> 03:55:22,920 OF UTAH TELLS US ALL ABOUT 5085 03:55:22,920 --> 03:55:25,960 PLATELETS. IN THE PROGRAM ON 5086 03:55:25,960 --> 03:55:34,120 AGING BY TOM GILL, AND A GREAT 5087 03:55:34,120 --> 03:55:34,640 NURSE RESEARCHERS AND OUR 5088 03:55:34,640 --> 03:55:45,080 FUNDERS THANK YOU SO MUCH. 5089 03:55:48,320 --> 03:55:50,880 >>THAT WAS REALLY 5090 03:55:50,880 --> 03:55:53,600 INTERESTING. PLATELETS 5091 03:55:53,600 --> 03:56:00,000 (INDISCERNIBLE). HOW MUCH-- I 5092 03:56:00,000 --> 03:56:00,560 DO EXPRESS A LOT OF THESE 5093 03:56:00,560 --> 03:56:01,080 THINGS AND RNAS AND 5094 03:56:01,080 --> 03:56:06,200 (INDISCERNIBLE). HOW MUCH OF 5095 03:56:06,200 --> 03:56:07,000 THIS DO YOU THINK IS A PLATELET 5096 03:56:07,000 --> 03:56:09,800 ITSELF VERSUS (INDISCERNIBLE)? 5097 03:56:09,800 --> 03:56:13,440 >>IT IS A GREAT QUESTION. I 5098 03:56:13,440 --> 03:56:14,080 DON'T THINK IT IS WELL STUDIED. 5099 03:56:14,080 --> 03:56:16,760 YOU BRING UP THE TWO 5100 03:56:16,760 --> 03:56:17,320 POSSIBILITIES ABOUT WHAT IS 5101 03:56:17,320 --> 03:56:23,600 GOING ON. IS SOMEHOW 5102 03:56:23,600 --> 03:56:24,200 PARTITIONED IN SOME NONRANDOM 5103 03:56:24,200 --> 03:56:26,720 WAY? OR POTENTIALLY THERE ARE 5104 03:56:26,720 --> 03:56:28,400 FACTORS THAT REFLECT RNA 5105 03:56:28,400 --> 03:56:28,960 COLLECTIBILITY THAT SOMEHOW 5106 03:56:28,960 --> 03:56:30,920 MODULATE EXPRESSION SOME WAY. 5107 03:56:30,920 --> 03:56:31,520 WE DO NOT KNOW THE ANSWER TO 5108 03:56:31,520 --> 03:56:33,920 THAT. WE WOULD LIKE TO GET AN 5109 03:56:33,920 --> 03:56:38,360 IDEA ABOUT WHICH RNAS ARE 5110 03:56:38,360 --> 03:56:38,960 ACTUALLY TRANSLATED IN THEIR 5111 03:56:38,960 --> 03:56:39,960 WAYS TO DO THAT THROUGH THE 5112 03:56:39,960 --> 03:56:41,760 FOOTPRINT AND THE LIKE. IT IS 5113 03:56:41,760 --> 03:56:47,560 A GOOD QUESTION. YEAH? 5114 03:56:47,560 --> 03:56:50,160 >>I WAS REALLY INTERESTED IN 5115 03:56:50,160 --> 03:56:50,720 YOUR PLOT THAT YOU SHOWED, 5116 03:56:50,720 --> 03:56:55,120 WHERE YOU HAVE THE NURSING 5117 03:56:55,120 --> 03:57:05,680 ELDERS THE PC 101 SITE AND THE 5118 03:57:10,200 --> 03:57:10,720 YOUNGER, AND THE COMMUNITY 5119 03:57:10,720 --> 03:57:11,320 OLDER INDIVIDUALS. IS THAT A 5120 03:57:11,320 --> 03:57:11,960 REFLECTION OF BIOLOGICAL AGE OR 5121 03:57:11,960 --> 03:57:15,000 IS THERE HETEROGENEITY OF OLDER 5122 03:57:15,000 --> 03:57:18,200 INDIVIDUALS? 5123 03:57:18,200 --> 03:57:18,800 >>I THINK FOR SURE THERE IS 5124 03:57:18,800 --> 03:57:20,640 HETEROGENEITY. WE ARE NOT 5125 03:57:20,640 --> 03:57:22,000 PARTICULARLY RESTRICTIVE ABOUT 5126 03:57:22,000 --> 03:57:26,080 ENROLLING FOLKS. WE EXCLUDE 5127 03:57:26,080 --> 03:57:28,760 THINGS LIKE THAT WOULD CAUSE 5128 03:57:28,760 --> 03:57:30,080 OBVIOUS IMMUNOSUPPRESSION LIKE 5129 03:57:30,080 --> 03:57:33,680 CANCER THERAPY AND CIRRHOSIS 5130 03:57:33,680 --> 03:57:35,520 AND END STAGE KIDNEY DISEASE. 5131 03:57:35,520 --> 03:57:39,400 BY DIABETES AND THINGS LIKE 5132 03:57:39,400 --> 03:57:40,040 THAT WERE ALL INCLUDED I THINK 5133 03:57:40,040 --> 03:57:41,120 THEY ARE HEALTHY COHORT THAN 5134 03:57:41,120 --> 03:57:42,200 THE NURSING HOME POPULATION, 5135 03:57:42,200 --> 03:57:51,080 THAT IS FOR SURE. BUT THERE IS 5136 03:57:51,080 --> 03:57:51,720 A LOT OF HETEROGENEITY. I DON'T 5137 03:57:51,720 --> 03:57:52,240 KNOW IF WE HAVE A LOT OF 5138 03:57:52,240 --> 03:57:52,880 NUMBERS TO DIG DOWN INTO IT. 5139 03:57:52,880 --> 03:57:59,040 GOOD QUESTION. 5140 03:57:59,040 --> 03:58:02,880 >>REALLY NICE WORK. I WAS 5141 03:58:02,880 --> 03:58:03,480 CURIOUS DRILLING DOWN ON YOUR 5142 03:58:03,480 --> 03:58:05,080 LAST COMMENT A LITTLE MORE, HOW 5143 03:58:05,080 --> 03:58:10,960 HARD IS IT TO CONTROL FOR 5144 03:58:10,960 --> 03:58:11,560 DIAGNOSES OR MEDICATIONS THAT 5145 03:58:11,560 --> 03:58:12,720 AFFECT PLATELETS AND DIAGNOSIS 5146 03:58:12,720 --> 03:58:17,360 OF PLATELET DEFECTS? 5147 03:58:17,360 --> 03:58:22,000 >>SO WE ALLOW PEOPLE TO BE ON 5148 03:58:22,000 --> 03:58:23,040 MEDICATIONS THAT COULD CAUSE 5149 03:58:23,040 --> 03:58:25,160 ALTERATIONS IN PLATELETS. THIS 5150 03:58:25,160 --> 03:58:26,280 WOULD INCLUDE A VARIETY OF 5151 03:58:26,280 --> 03:58:29,200 THINGS: ASPIRIN, PLAVIX, A 5152 03:58:29,200 --> 03:58:34,480 VARIETY OF THINGS. MOST OF 5153 03:58:34,480 --> 03:58:35,080 THESE WOULD HAVE INHIBITORY 5154 03:58:35,080 --> 03:58:35,680 EFFECTS ON PLATELET FUNCTION. 5155 03:58:35,680 --> 03:58:40,560 WE DID NOT SEE-- ADJUSTING FOR 5156 03:58:40,560 --> 03:58:41,040 THIS-- DID NOT SEE A 5157 03:58:41,040 --> 03:58:43,800 SUBSTANTIAL EFFECT OF THE 5158 03:58:43,800 --> 03:58:44,440 PLATELET ACTIVE MEDICATIONS ON 5159 03:58:44,440 --> 03:58:45,040 THESE OUTCOMES WHEN WE SAW A 5160 03:58:45,040 --> 03:58:50,920 SMALL EFFECT OF -- BUT NOT A 5161 03:58:50,920 --> 03:58:54,600 LARGE ONE WE EVALUATED IT. 5162 03:58:54,600 --> 03:58:55,200 THERE ARE A LOT OF THINGS THAT 5163 03:58:55,200 --> 03:58:57,320 COULD AFFECT PLATELET FUNCTION. 5164 03:58:57,320 --> 03:59:07,320 >> 5165 03:59:10,040 --> 03:59:13,080 >>HLA LOGICAL AND PLATELETS. I 5166 03:59:13,080 --> 03:59:14,400 DON'T KNOW THE ANSWER. I WILL 5167 03:59:14,400 --> 03:59:19,080 HAVE TO LOOK IT UP. THERE ARE 5168 03:59:19,080 --> 03:59:19,720 A NUMBER WACKY THINGS THAT ARE 5169 03:59:19,720 --> 03:59:21,880 IN PLATELETS THAT SUGGEST KIND 5170 03:59:21,880 --> 03:59:22,480 OF POSSIBLY LONG AND I DON'T 5171 03:59:22,480 --> 03:59:24,440 KNOW THE ANSWER. 5172 03:59:24,440 --> 03:59:30,200 >>IF I MIGHT BE ABLE TO HELP, 5173 03:59:30,200 --> 03:59:30,680 IN MY LIMITED CLINICAL 5174 03:59:30,680 --> 03:59:31,320 EXPERTISE, THEY ARE EXPRESSIVE 5175 03:59:31,320 --> 03:59:31,880 PLATES. 5176 03:59:31,880 --> 03:59:39,680 >>OKAY. 5177 03:59:39,680 --> 03:59:47,000 >>OKAY. OUR NEXT SPEAKER, IS 5178 03:59:47,000 --> 03:59:54,080 DR. MICHELLE LINTERMAN, GROUP 5179 03:59:54,080 --> 03:59:58,560 LEADER AT ROTHERHAM INTO THE 5180 03:59:58,560 --> 03:59:59,120 CAMBRIDGE AND THANK YOU FOR 5181 03:59:59,120 --> 04:00:05,760 COMING. THE TITLE OF HER WORK 5182 04:00:05,760 --> 04:00:06,880 IS HOW AGING CHANGES TO IMMUNO 5183 04:00:06,880 --> 04:00:12,840 RESPONSE. 5184 04:00:12,840 --> 04:00:13,440 >>HI EVERYONE IT IS A PLEASURE 5185 04:00:13,440 --> 04:00:14,040 TO BE HERE. I HAVE ENJOYED IT 5186 04:00:14,040 --> 04:00:16,360 IMMENSELY THANK YOU AL FOR 5187 04:00:16,360 --> 04:00:18,720 HIGHLIGHTING THE 5188 04:00:18,720 --> 04:00:20,720 (INDISCERNIBLE) AN 5189 04:00:20,720 --> 04:00:21,320 UNDERSTANDING HOW AGE IS A KEY 5190 04:00:21,320 --> 04:00:21,920 AREA BECAUSE THAT IS WHAT I'M 5191 04:00:21,920 --> 04:00:23,720 GOING TO TELL YOU ABOUT. FOR 5192 04:00:23,720 --> 04:00:25,800 THOSE OF YOU WHO DO NOT KNOW, 5193 04:00:25,800 --> 04:00:29,880 THE BEAUTIFUL STRUCTURE OF THE 5194 04:00:29,880 --> 04:00:31,600 GERMINAL-- PROLIFERATE IS IN 5195 04:00:31,600 --> 04:00:36,400 BLUE AND THE (INDISCERNIBLE). 5196 04:00:36,400 --> 04:00:40,080 AND WHAT I WOULD LIKE TO 5197 04:00:40,080 --> 04:00:41,840 HIGHLIGHT FOR THE STAFF, IS 5198 04:00:41,840 --> 04:00:42,440 AWARE THAT I'M GOING TO PRESENT 5199 04:00:42,440 --> 04:00:45,560 WAS DONE BY A VILLAGE. THESE 5200 04:00:45,560 --> 04:00:46,160 ARE ALL THE WONDERFUL PEOPLE 5201 04:00:46,160 --> 04:00:48,880 THAT MAKE THE MAGIC HAPPEN. ON 5202 04:00:48,880 --> 04:00:49,560 THE QUESTION THAT WE REALLY 5203 04:00:49,560 --> 04:00:53,640 WANTED TO ADDRESS IS, WHAT IS 5204 04:00:53,640 --> 04:00:55,320 THE FUNDAMENTAL BIOLOGY THAT 5205 04:00:55,320 --> 04:01:02,200 UNDERPINS FOR ANTIBODY RESPONSE 5206 04:01:02,200 --> 04:01:05,080 IN AGING? 5207 04:01:05,080 --> 04:01:05,560 I TAKE YOU BACK TO THE 5208 04:01:05,560 --> 04:01:11,400 GERMINAL CENTER. THE RESPONSE 5209 04:01:11,400 --> 04:01:12,280 IS THE CELLULAR COURSE OF 5210 04:01:12,280 --> 04:01:18,720 LONG-LIVED HUMAN IMMUNITY. 5211 04:01:18,720 --> 04:01:19,360 FOLKS APPRECIATE THAT-- YOU MAY 5212 04:01:19,360 --> 04:01:20,000 NOT APPRECIATE IT BUT IT IS MY 5213 04:01:20,000 --> 04:01:23,480 FIRST LOVE, PROBABLY NOT 5214 04:01:23,480 --> 04:01:24,720 YOURS-- THE GERMINAL CENTER IS 5215 04:01:24,720 --> 04:01:26,880 INITIATED AT THE INFECTION FOR 5216 04:01:26,880 --> 04:01:32,520 IMMUNIZATION WHEN B CELLS 5217 04:01:32,520 --> 04:01:33,080 CLONES MOVING TO THE B CELL 5218 04:01:33,080 --> 04:01:35,880 FOLLICLE. ONCE IN THE B CELL 5219 04:01:35,880 --> 04:01:38,320 FOLLICLE THEY MULTIPLY. DURING 5220 04:01:38,320 --> 04:01:42,000 THE DIVISION PROCESS THEY 5221 04:01:42,000 --> 04:01:42,600 UNDERGO TARGETED MUTATION OF 5222 04:01:42,600 --> 04:01:43,200 THE GENES ENCODING THE BASAL 5223 04:01:43,200 --> 04:01:44,000 RECEPTORS. 5224 04:01:44,000 --> 04:01:47,840 SO THIS IS KNOWN AS 5225 04:01:47,840 --> 04:01:52,560 METACOGNITIVE MUTATION. 5226 04:01:52,560 --> 04:01:55,000 AFTER THIS MUTATION PROCESSES 5227 04:01:55,000 --> 04:01:55,640 THEY MOVED TO THE OPPOSITE POLE 5228 04:01:55,640 --> 04:01:56,240 OF THE GERMINAL CENTER CALLED 5229 04:01:56,240 --> 04:02:02,800 THE LIGHT ZONE, POPULATED BY 5230 04:02:02,800 --> 04:02:03,440 FOLLICULAR DENDRITIC CELLS, AND 5231 04:02:03,440 --> 04:02:04,080 DESPITE THEIR NAME THESE ARE 5232 04:02:04,080 --> 04:02:07,400 (INDISCERNIBLE) CELLS. 5233 04:02:07,400 --> 04:02:12,360 THIS IS ALSO FILLED WITH 5234 04:02:12,360 --> 04:02:13,960 FOLLICULAR B CELLS AND 5235 04:02:13,960 --> 04:02:16,160 FOLLICULAR (INDISCERNIBLE). 5236 04:02:16,160 --> 04:02:26,640 YOU SEE CXCR5 MIGRATION. YOU 5237 04:02:30,760 --> 04:02:31,280 CAN SEE THE NEWLY MUTATED B 5238 04:02:31,280 --> 04:02:31,880 CELL RECEPTOR TO SEE THEY CAN 5239 04:02:31,880 --> 04:02:41,360 BIND. IF THEY CAN AN 5240 04:02:41,360 --> 04:02:41,960 INVITATION PROCESS THAT'S THE B 5241 04:02:41,960 --> 04:02:42,600 CELL RECEPTOR FUNCTIONAL, THEY 5242 04:02:42,600 --> 04:02:43,160 CAN TAKE OF THE ANTIGEN AND 5243 04:02:43,160 --> 04:02:43,760 PROCESS IT AND PRESENTED TO 5244 04:02:43,760 --> 04:02:45,560 FOLLICULAR -- HEALTHY 5245 04:02:45,560 --> 04:02:48,600 POPULATIONS OF -- AND THE IDEA 5246 04:02:48,600 --> 04:02:51,400 IS THAT B CELLS COMPETE WITH 5247 04:02:51,400 --> 04:02:51,960 EACH OTHER IN THE GERMINAL 5248 04:02:51,960 --> 04:02:56,800 CENTER FOR T-CELL HELP. IT IS 5249 04:02:56,800 --> 04:02:57,320 OFTEN CALLED EVOLUTION IN 5250 04:02:57,320 --> 04:03:01,840 MINIATURE. 5251 04:03:01,840 --> 04:03:02,440 YOU HAVE THIS MUTATION PROCESS 5252 04:03:02,440 --> 04:03:03,080 AND THEN YOU NEED SELECTION TO 5253 04:03:03,080 --> 04:03:06,040 GET THE FITTED B CELLS WHO ARE 5254 04:03:06,040 --> 04:03:08,720 ABLE TO MIGRATE BACK TO THE 5255 04:03:08,720 --> 04:03:10,440 DARK ZONE WHERE THEY CAN DO THE 5256 04:03:10,440 --> 04:03:11,040 WHOLE PROCESS AGAIN SOME MORE 5257 04:03:11,040 --> 04:03:12,600 MUTATION AND MORE SELECTION. 5258 04:03:12,600 --> 04:03:14,760 OR EXIT THE GERMINAL CENTER AS 5259 04:03:14,760 --> 04:03:18,000 PLASMA CELLS THAT HARM THE BONE 5260 04:03:18,000 --> 04:03:18,600 MARROW AND THEY SET OUT THIS 5261 04:03:18,600 --> 04:03:22,000 LONG-TERM SOURCE OF ENERGY 5262 04:03:22,000 --> 04:03:24,880 PRODUCING CELLS AND CONNECTED 5263 04:03:24,880 --> 04:03:28,200 AS MEMORY B CELLS, THAT UPON 5264 04:03:28,200 --> 04:03:29,480 RESTIMULATION CAN RAPIDLY 5265 04:03:29,480 --> 04:03:30,080 DIFFERENTIATE INTO ANTIBODY 5266 04:03:30,080 --> 04:03:30,800 SECRETING CELLS. 5267 04:03:30,800 --> 04:03:38,560 NOW, WHILST IT HAS BEEN KNOWN 5268 04:03:38,560 --> 04:03:39,200 FOR A LONG TIME TO THE GERMINAL 5269 04:03:39,200 --> 04:03:46,400 CENTER RESPONSES MORE IN AGING, 5270 04:03:46,400 --> 04:03:47,000 ONE THING THAT REALLY HAD NOT 5271 04:03:47,000 --> 04:03:49,280 BEEN INVESTIGATED WAS HOW ITS 5272 04:03:49,280 --> 04:03:49,880 STRUCTURE CHANGES AND WE WERE 5273 04:03:49,880 --> 04:03:50,440 CAPTIVATED BY THIS QUESTION 5274 04:03:50,440 --> 04:03:51,080 AFTER A BIG CLINICAL STUDY WAS 5275 04:03:51,080 --> 04:03:57,600 DONE ON THE COVID-19 VACCINE. 5276 04:03:57,600 --> 04:03:58,080 YOU DON'T HAVE TO BE A 5277 04:03:58,080 --> 04:04:01,440 GERMINAL CENTER EXPERT TO LOOK 5278 04:04:01,440 --> 04:04:02,000 AT THESE TWO IMAGES AND SEE 5279 04:04:02,000 --> 04:04:03,960 THAT THE GERMINAL CENTER ON THE 5280 04:04:03,960 --> 04:04:05,960 TOP LOOKS NICE AND RUNNING 5281 04:04:05,960 --> 04:04:06,560 HOPEFULLY YOU CAN SEE THE TWO 5282 04:04:06,560 --> 04:04:08,440 FUNCTIONALLY DISTINCT ZONES, 5283 04:04:08,440 --> 04:04:10,640 LIGHT ZONE AND DARK ZONE. 5284 04:04:10,640 --> 04:04:11,240 BUT THE GERMINAL CENTER AT THE 5285 04:04:11,240 --> 04:04:13,960 BOTTOM LOOKS A BIT WEIRD. SO 5286 04:04:13,960 --> 04:04:18,240 WE WANTED TO QUANTITATIVELY DO 5287 04:04:18,240 --> 04:04:20,000 IMAGING STUDIES TO UNDERSTAND 5288 04:04:20,000 --> 04:04:23,440 WHETHER THIS 5289 04:04:23,440 --> 04:04:25,040 COMPARTMENTALIZATION OF THE 5290 04:04:25,040 --> 04:04:26,680 GERMINAL CENTER WAS CHANGED, 5291 04:04:26,680 --> 04:04:31,200 AND WHETHER THE POTENTIAL 5292 04:04:31,200 --> 04:04:31,800 CHANGE COULD LEAD TO A CHANGE 5293 04:04:31,800 --> 04:04:34,720 IN FUNCTION. 5294 04:04:34,720 --> 04:04:43,320 SO HERE WE ARE USING -- -- 5295 04:04:43,320 --> 04:04:43,960 THIS IS A POINT OF CONTROVERSY 5296 04:04:43,960 --> 04:04:45,120 AT THIS MEETING. WHAT I AM 5297 04:04:45,120 --> 04:04:54,520 SHOWING YOU HERE IS H -- AGED 5298 04:04:54,520 --> 04:05:00,040 (INDISCERNIBLE) AND AGED MICE. 5299 04:05:00,040 --> 04:05:05,200 THE BLACK IS MALE, THE -- IS 5300 04:05:05,200 --> 04:05:11,400 FEMALE. BUT I AM ALSO SHOWING 5301 04:05:11,400 --> 04:05:12,240 USED ARE NOT JUST ACROSS 5302 04:05:12,240 --> 04:05:14,120 GENETIC BACKGROUNDS BUT ALSO 5303 04:05:14,120 --> 04:05:16,360 EFFECTS. 5304 04:05:16,360 --> 04:05:22,240 WHAT WE NOTICED IN OUR AGED 5305 04:05:22,240 --> 04:05:22,880 MICE WAS THAT BY LOOKING AT THE 5306 04:05:22,880 --> 04:05:23,480 GERMINAL CENTERS YOU CAN SEE 5307 04:05:23,480 --> 04:05:28,160 THAT THE LIGHT ZONE LOOKED A 5308 04:05:28,160 --> 04:05:33,760 BIT WASHED. 5309 04:05:33,760 --> 04:05:34,280 WE MERGE MULTIPLE GERMINAL 5310 04:05:34,280 --> 04:05:34,880 CENTERS PER MOUSE AND USE THE 5311 04:05:34,880 --> 04:05:39,560 AVERAGE -- THE AGE DOT IS A 5312 04:05:39,560 --> 04:05:43,440 BIOLOGICAL REPLICATIVE, MADE UP 5313 04:05:43,440 --> 04:05:44,040 OF MULTIPLE GERMINAL CENTERS 5314 04:05:44,040 --> 04:05:44,600 AND YOU CAN SEE THE OVERALL 5315 04:05:44,600 --> 04:05:46,520 THERE IS A SMALLER FOLLICULAR 5316 04:05:46,520 --> 04:05:56,200 CENTRIC. WE HYPOTHESIZE THIS 5317 04:05:56,200 --> 04:05:56,800 MIGHT MEAN THAT THERE IS LESS 5318 04:05:56,800 --> 04:05:59,720 ANTIGEN IN B CELLS TO CAPTURE. 5319 04:05:59,720 --> 04:06:00,280 THE OTHER THING WHEN SHE WAS 5320 04:06:00,280 --> 04:06:02,000 LOOKING UNDER THE MICROSCOPE IS 5321 04:06:02,000 --> 04:06:07,400 THAT THE T-CELL LOOK LIKE THEY 5322 04:06:07,400 --> 04:06:08,040 WERE IN THE WRONG PLACE AND IF 5323 04:06:08,040 --> 04:06:08,880 YOU READ AND REVIEW THE 5324 04:06:08,880 --> 04:06:19,360 GERMINAL CENTERS, INCLUDING 5325 04:06:22,040 --> 04:06:22,600 ONES AUTHORED BY ME, THEY WILL 5326 04:06:22,600 --> 04:06:23,000 TELL YOU THAT THE 5327 04:06:23,000 --> 04:06:25,960 (INDISCERNIBLE). 5328 04:06:25,960 --> 04:06:26,440 WHAT WE NOTICE IS THE 5329 04:06:26,440 --> 04:06:35,680 POLARIZATION OF THE TFH CELL 5330 04:06:35,680 --> 04:06:36,320 WAS LOST AND AGING IN YOU COULD 5331 04:06:36,320 --> 04:06:36,880 ASK WHAT PROPORTION OF THE 5332 04:06:36,880 --> 04:06:43,600 DIESELS ARE IN THE DARK ZONE. 5333 04:06:43,600 --> 04:06:44,200 WE HYPOTHESIZE THIS WOULD MEAN 5334 04:06:44,200 --> 04:06:44,840 THAT THE HELP IS NOT WHETHER B 5335 04:06:44,840 --> 04:06:45,920 CELLS NEEDED IT. THEY ARE NOT 5336 04:06:45,920 --> 04:06:49,440 ABLE TO ACCESS HELP. 5337 04:06:49,440 --> 04:06:51,600 ALSO I WOULD LIKE TO ADD THAT 5338 04:06:51,600 --> 04:06:52,640 IT APPEARS THAT THESE ARE TWO 5339 04:06:52,640 --> 04:06:57,680 INDEPENDENT EFFECTS OF AGING 5340 04:06:57,680 --> 04:06:58,280 AND FIRST CHOSE TO INVESTIGATE 5341 04:06:58,280 --> 04:07:00,040 THE LOCATION OF B CELLS. 5342 04:07:00,040 --> 04:07:05,320 NOW, WE WANTED TO UNDERSTAND 5343 04:07:05,320 --> 04:07:05,920 WHY THE B CELLS MIGHT BE LOST 5344 04:07:05,920 --> 04:07:11,400 IN THE DARK ZONE IN AGING. IN 5345 04:07:11,400 --> 04:07:12,040 THE SIMPLEST HYPOTHESIS IS THAT 5346 04:07:12,040 --> 04:07:16,480 THEY WOULD EXPRESS AS 5347 04:07:16,480 --> 04:07:19,200 (INDISCERNIBLE), BECAUSE THE 5348 04:07:19,200 --> 04:07:22,360 THERMAL IN THE DARK ZONE 5349 04:07:22,360 --> 04:07:31,480 EXPRESSES CXCL12, AND THE UP 5350 04:07:31,480 --> 04:07:32,120 AND DOWN REGULATION IS WHAT IS 5351 04:07:32,120 --> 04:07:32,760 USED TO MIGRATE BETWEEN THE TWO 5352 04:07:32,760 --> 04:07:33,360 ZONES. AND WHAT WE COULD SEE 5353 04:07:33,360 --> 04:07:43,080 THAT THE FREQUENCY OF THE TFH 5354 04:07:43,080 --> 04:07:43,720 CELL THAT EXPRESSES THIS IS AN 5355 04:07:43,720 --> 04:07:44,320 INCREASED IN AGED MICE AND IF 5356 04:07:44,320 --> 04:07:49,400 YOU TAKE THOSE TFH CELLS, YOU 5357 04:07:49,400 --> 04:07:49,840 CAN SEE THE INCREASED 5358 04:07:49,840 --> 04:07:50,440 EXPRESSION THAT LEADS TO MORE 5359 04:07:50,440 --> 04:07:51,600 MIGRATION. 5360 04:07:51,600 --> 04:07:56,240 WE WANTED TO KNOW WHY TFH 5361 04:07:56,240 --> 04:07:59,320 CELLS EXPRESS MORE. THAT IS 5362 04:07:59,320 --> 04:08:00,800 NOT AN EASY QUESTION TO ANSWER. 5363 04:08:00,800 --> 04:08:10,120 REGULATION OF CXCR4 IS QUITE 5364 04:08:10,120 --> 04:08:10,720 COMPLICATED ONE THING THAT DOES 5365 04:08:10,720 --> 04:08:11,280 HAPPEN IS YOU GET LIGAND 5366 04:08:11,280 --> 04:08:16,360 INDEPENDENT (INDISCERNIBLE). 5367 04:08:16,360 --> 04:08:16,960 WHAT WE CAN THEN DO IS ASK IS 5368 04:08:16,960 --> 04:08:23,560 IF THE TFH MIGRATION WAS 5369 04:08:23,560 --> 04:08:29,000 (INDISCERNIBLE). AND THE AGED 5370 04:08:29,000 --> 04:08:31,320 TFH CELLS WERE LESS 5371 04:08:31,320 --> 04:08:31,800 INDEPENDENT, AT HIGH 5372 04:08:31,800 --> 04:08:32,600 CONCENTRATIONS OF LIGANDS THEY 5373 04:08:32,600 --> 04:08:36,280 CAN DO IT, BUT THEY ARE NOT AS 5374 04:08:36,280 --> 04:08:36,840 CAPABLE AS THE T CELLS FROM 5375 04:08:36,840 --> 04:08:38,920 YOUNGER MICE. 5376 04:08:38,920 --> 04:08:43,760 WE ALSO WANTED TO CHECK 5377 04:08:43,760 --> 04:08:45,320 WHETHER THIS REGULATION OF THE 5378 04:08:45,320 --> 04:08:48,680 EXAMPLE, WAS CONFERRED ACROSS 5379 04:08:48,680 --> 04:08:49,280 SPECIES AND WHY WE DON'T HAVE 5380 04:08:49,280 --> 04:08:54,200 ENOUGH SAMPLES TO LOOK AT TFH 5381 04:08:54,200 --> 04:08:54,800 FROM LYMPH NODES FROM YOUNGER 5382 04:08:54,800 --> 04:08:55,440 AND OLDER PEOPLE WOULD CONSIDER 5383 04:08:55,440 --> 04:08:56,680 IN THE PERIPHERAL BLOOD OF 5384 04:08:56,680 --> 04:08:57,840 OLDER PEOPLE THAT THEY TENDED 5385 04:08:57,840 --> 04:08:59,280 TO HAVE A HIGHER EXPRESSION OF 5386 04:08:59,280 --> 04:09:05,360 CXCR4. WE THINK THAT IS 5387 04:09:05,360 --> 04:09:05,960 SOMETHING THAT IS RELEVANT TO 5388 04:09:05,960 --> 04:09:09,080 HUMANS AS WELL. 5389 04:09:09,080 --> 04:09:09,680 BUT WE BASICALLY SAW IS THAT 5390 04:09:09,680 --> 04:09:11,640 IN AGING, THIS TENDS TO BE 5391 04:09:11,640 --> 04:09:12,160 SMALLER AND YOU HAVE THIS 5392 04:09:12,160 --> 04:09:15,120 LOCALIZATION OF TFH CELLS THAT 5393 04:09:15,120 --> 04:09:15,720 WE THINK IS DEPENDENT ON THE 5394 04:09:15,720 --> 04:09:18,480 EXPRESSION OF CXCR4, BUT YOU 5395 04:09:18,480 --> 04:09:19,080 KNOW THAT REALLY DOES BEG THE 5396 04:09:19,080 --> 04:09:22,080 QUESTION OF WHETHER CXCR4 DOES 5397 04:09:22,080 --> 04:09:23,240 INDEED CONTROL THE EFFECTS OF 5398 04:09:23,240 --> 04:09:25,960 GLOBALIZATION. AND WHETHER THE 5399 04:09:25,960 --> 04:09:30,760 LOCATION OF THF CELLS ACTUALLY 5400 04:09:30,760 --> 04:09:33,040 MATTERS TO THE GERMINAL CENTER. 5401 04:09:33,040 --> 04:09:34,280 AND IF IT DOES, CAN BE 5402 04:09:34,280 --> 04:09:39,840 CORRECTED BY SUPPLYING T-CELLS 5403 04:09:39,840 --> 04:09:42,120 THAT ARE LOCALIZED. 5404 04:09:42,120 --> 04:09:43,800 AND SO WE WANTED TO THE 5405 04:09:43,800 --> 04:09:46,120 QUESTION OF WHETHER CXCR4 CAN 5406 04:09:46,120 --> 04:09:48,360 MEDIATE THE CHANGE IN LOCATION 5407 04:09:48,360 --> 04:09:54,040 OF THE TFH CELLS. WITH THE 5408 04:09:54,040 --> 04:09:54,680 QUANTITATIVE IMAGING. WHAT WE 5409 04:09:54,680 --> 04:09:58,960 SAW IS THAT WHEN T-CELLS LACK 5410 04:09:58,960 --> 04:10:00,880 CXCR4 THERE IS NO CHANGE, THAT 5411 04:10:00,880 --> 04:10:03,800 WE DO SHIFT ALMOST ALL OF THE 5412 04:10:03,800 --> 04:10:08,960 T-CELLS INTO THE LIGHT ZONE. 5413 04:10:08,960 --> 04:10:09,440 WHAT WE FOUND THAT WE 5414 04:10:09,440 --> 04:10:12,240 ABSOLUTELY DID NOT EXPECT, IS 5415 04:10:12,240 --> 04:10:22,760 WHEN WE PUSH THE T-CELLS INTO A 5416 04:10:24,200 --> 04:10:24,720 LIGHT ON YOUR EXPANDED THE 5417 04:10:24,720 --> 04:10:25,280 NETWORK. THERE IS SOMETHING 5418 04:10:25,280 --> 04:10:29,920 ABOUT THE LOCATION OF 5419 04:10:29,920 --> 04:10:30,560 (INDISCERNIBLE), WHICH MAY MEAN 5420 04:10:30,560 --> 04:10:31,080 THAT THOSE TWO DEFECTS WE 5421 04:10:31,080 --> 04:10:31,680 OBSERVED ORIGINALLY IN AGING 5422 04:10:31,680 --> 04:10:32,840 MAY ACTUALLY BE LINKED 5423 04:10:32,840 --> 04:10:39,040 BIOLOGICALLY. 5424 04:10:39,040 --> 04:10:39,600 SO CAN WE DO THE OPPOSITE 5425 04:10:39,600 --> 04:10:40,200 EXPERIMENT? CAN WE GENETICALLY 5426 04:10:40,200 --> 04:10:42,200 FINO COPY AGING BY SHIFTING 5427 04:10:42,200 --> 04:10:44,040 T-CELLS TO THE DARK ZONE? TO DO 5428 04:10:44,040 --> 04:10:54,120 THIS WE MADE THE T-CELLS CXCR5, 5429 04:10:54,120 --> 04:10:54,720 WHICH IS MADE BY THE FOLLICULAR 5430 04:10:54,720 --> 04:10:55,480 DENDRITIC CELLS IN THE LIGHT 5431 04:10:55,480 --> 04:11:02,520 ZONE. AND WHEN THESE BLACK 5432 04:11:02,520 --> 04:11:03,080 CXCR5, YOU SHIFT OUT OF THE 5433 04:11:03,080 --> 04:11:03,720 LIGHT ZONE INTO THE DARK ZONE, 5434 04:11:03,720 --> 04:11:05,640 VERY SIMILAR TO AGING. 5435 04:11:05,640 --> 04:11:06,160 SO WHAT HAPPENED TO THE 5436 04:11:06,160 --> 04:11:10,320 GERMINAL CENTER? THE GERMINAL 5437 04:11:10,320 --> 04:11:12,440 CENTER IS SMALLER, SIMILAR TO 5438 04:11:12,440 --> 04:11:14,000 THE RESULTS YOU SEE IN AGING. 5439 04:11:14,000 --> 04:11:20,600 I THINK, YOU CAN SEE HERE THAT 5440 04:11:20,600 --> 04:11:21,120 THE NETWORK REALLY LOOKS 5441 04:11:21,120 --> 04:11:23,600 SQUASHED LIKE IN AGING, AND IF 5442 04:11:23,600 --> 04:11:24,160 YOU ENUMERATE THAT YOU CAN 5443 04:11:24,160 --> 04:11:28,040 NICELY SEE THAT IT SHIFTS THE 5444 04:11:28,040 --> 04:11:30,520 T-CELLS AWAY FROM THE NETWORK. 5445 04:11:30,520 --> 04:11:33,640 THE NETWORK IS SMALLER. 5446 04:11:33,640 --> 04:11:34,240 AND SO WE THINK THAT WHAT THIS 5447 04:11:34,240 --> 04:11:44,560 SHOWS IS THE LOCATION OF TFH 5448 04:11:44,560 --> 04:11:45,080 CELLS WITHIN THE GERMINAL 5449 04:11:45,080 --> 04:11:45,720 CENTER INFLUENCES THE RESPONSE 5450 04:11:45,720 --> 04:11:53,480 OF THE TFH CELLS. WE SHOULD BE 5451 04:11:53,480 --> 04:11:54,120 ABLE TO CORRECT THE DEFECTS IN 5452 04:11:54,120 --> 04:11:54,720 THE GERMINAL CENTER SIZE BY 5453 04:11:54,720 --> 04:11:56,560 SUPPLYING T-CELLS THAT ARE 5454 04:11:56,560 --> 04:11:59,360 LOCALIZED CORRECTLY. 5455 04:11:59,360 --> 04:12:00,840 WE DID A TRANSFER WHERE WE 5456 04:12:00,840 --> 04:12:02,920 TOOK T-CELLS FROM YOUNGER 5457 04:12:02,920 --> 04:12:05,840 ANIMALS AND TRANSFER THEM INTO 5458 04:12:05,840 --> 04:12:06,400 (INDISCERNIBLE), AND HOW IT 5459 04:12:06,400 --> 04:12:09,720 LOOKED 10 DAYS LATER. AND WHAT 5460 04:12:09,720 --> 04:12:10,360 YOU CAN ACTUALLY SEE IS YOU GET 5461 04:12:10,360 --> 04:12:15,360 IS BEAUTIFUL EXPANSION OF THE 5462 04:12:15,360 --> 04:12:16,000 FDC NETWORK QUALIFIED HERE, AND 5463 04:12:16,000 --> 04:12:18,480 YOU CAN ENHANCE THE SIZE OF THE 5464 04:12:18,480 --> 04:12:20,840 GERMINAL CENTER AND LIKEWISE 5465 04:12:20,840 --> 04:12:25,040 THE NUMBER. YOU REALLY ARE 5466 04:12:25,040 --> 04:12:26,160 BOOSTING THE AGE GERMINAL 5467 04:12:26,160 --> 04:12:28,000 CENTER BY GIVING IT YOUNG 5468 04:12:28,000 --> 04:12:30,400 T-CELLS. 5469 04:12:30,400 --> 04:12:32,680 WHAT WE REALLY WANTED TO 5470 04:12:32,680 --> 04:12:33,200 UNDERSTAND WAS, IS IT THE 5471 04:12:33,200 --> 04:12:36,520 LOCATION OF THE T-CELLS? NOT 5472 04:12:36,520 --> 04:12:37,680 THE EFFECT THAT WE HAVE GIVEN 5473 04:12:37,680 --> 04:12:47,720 THESE YOUNG MICE T-CELLS. CXCR5 5474 04:12:47,720 --> 04:12:48,160 IS REQUIRED FOR THE 5475 04:12:48,160 --> 04:12:49,520 LOCALIZATION AND REPEATED THE 5476 04:12:49,520 --> 04:12:50,080 EXPERIMENT BY TRANSFERRING 5477 04:12:50,080 --> 04:12:55,520 T-CELLS LACKED CXCR5 OR LACK 5478 04:12:55,520 --> 04:12:59,800 CONTROLS AND WHEN YOU GIVE THEM 5479 04:12:59,800 --> 04:13:00,440 -- YOU DON'T HAVE THIS INCREASE 5480 04:13:00,440 --> 04:13:02,160 GERMINAL CENTER AREA. YOU DO 5481 04:13:02,160 --> 04:13:06,000 NOT INCREASE THE FDC NETWORK 5482 04:13:06,000 --> 04:13:07,040 AND THE PROPORTION OF GERMINAL 5483 04:13:07,040 --> 04:13:10,160 CENTER T-CELLS. 5484 04:13:10,160 --> 04:13:14,600 SO TO SUMMARIZE WHAT I TOLD 5485 04:13:14,600 --> 04:13:15,240 YOU, WHAT WE THINK WE HAVE SEEN 5486 04:13:15,240 --> 04:13:15,840 IS THAT THERE IS SPECIAL THIS 5487 04:13:15,840 --> 04:13:18,640 RELATION OF THE GERMINAL 5488 04:13:18,640 --> 04:13:19,200 CENTER IN AGING AND THAT IS 5489 04:13:19,200 --> 04:13:19,840 POTENTIALLY CAUSED BY THE MISS 5490 04:13:19,840 --> 04:13:26,520 LOCALIZATION OF TFH TO THE 5491 04:13:26,520 --> 04:13:27,920 THOSE DARK ZONE BECAUSE THEY 5492 04:13:27,920 --> 04:13:32,000 EXPRESS CXCR4, MOST LIKELY 5493 04:13:32,000 --> 04:13:32,560 BECAUSE THEY HAVE IMPAIRED 5494 04:13:32,560 --> 04:13:33,080 INTERNALIZATION OF THIS 5495 04:13:33,080 --> 04:13:34,000 RECEPTOR. 5496 04:13:34,000 --> 04:13:34,600 WHAT WE HAVE DISCOVERED HERE 5497 04:13:34,600 --> 04:13:38,640 IS THAT TFH LOCATION ALTERS THE 5498 04:13:38,640 --> 04:13:44,400 FDC RESPONSE. THIS IS A REALLY 5499 04:13:44,400 --> 04:13:45,000 NICE EXAMPLE OF HOW STUDYING 5500 04:13:45,000 --> 04:13:45,520 THE RESPONSE TO AGING WE 5501 04:13:45,520 --> 04:13:47,880 ACTUALLY UNDERSTAND MORE ABOUT 5502 04:13:47,880 --> 04:13:51,840 PHYSIOLOGY IN GENERAL. THIS IS 5503 04:13:51,840 --> 04:13:52,440 THE INTERACTION THAT HAS NOT 5504 04:13:52,440 --> 04:13:55,000 BEEN REPORTED PREVIOUSLY. 5505 04:13:55,000 --> 04:13:56,720 AND I THINK IMPORTANTLY, 5506 04:13:56,720 --> 04:14:00,200 SUPPLYING T-CELLS THAT CAN 5507 04:14:00,200 --> 04:14:00,840 LOCALIZE TO THE LIGHT ZONE CAN 5508 04:14:00,840 --> 04:14:08,000 CORRECT THESE DEFECTS IN AGING. 5509 04:14:08,000 --> 04:14:08,600 AND SO I WANTED TO FINISH WITH 5510 04:14:08,600 --> 04:14:09,000 RESEARCH GAPS AND 5511 04:14:09,000 --> 04:14:12,400 OPPORTUNITIES. QUITE LIKE THIS 5512 04:14:12,400 --> 04:14:13,800 IS A WAY OF THINKING ABOUT 5513 04:14:13,800 --> 04:14:18,560 RESEARCH. ON THIS AXIS, IT IS 5514 04:14:18,560 --> 04:14:21,960 ASKING THE QUESTION, ARE YOU 5515 04:14:21,960 --> 04:14:24,240 JUST ADVANCING HUMAN KNOWLEDGE? 5516 04:14:24,240 --> 04:14:26,440 AND THEN THIS IS LIKE, IS THERE 5517 04:14:26,440 --> 04:14:27,840 AN IMMEDIATE APPLICATION FOR 5518 04:14:27,840 --> 04:14:29,960 THAT? UNASHAMEDLY, THIS 5519 04:14:29,960 --> 04:14:30,560 RESEARCH THAT WE ARE DOING IS 5520 04:14:30,560 --> 04:14:33,000 VERY MUCH IN THE FUNDAMENTAL 5521 04:14:33,000 --> 04:14:36,400 RESEARCH QUADRANT. I THINK WE 5522 04:14:36,400 --> 04:14:40,120 ABSOLUTELY NEED TO DO THAT. 5523 04:14:40,120 --> 04:14:40,720 BUT THE MAIN GAP IS HOW DO WE 5524 04:14:40,720 --> 04:14:43,200 MOVE THIS TYPE OF RESEARCH INTO 5525 04:14:43,200 --> 04:14:48,160 THE IMMEDIATE APPLICATION? 5526 04:14:48,160 --> 04:14:48,800 BECAUSE THERE IS AN URGENT NEED 5527 04:14:48,800 --> 04:14:49,400 FOR US TO MAKE VACCINE TO DO 5528 04:14:49,400 --> 04:14:50,280 WORK BETTER IN ALL THE PEOPLE. 5529 04:14:50,280 --> 04:14:51,320 AND I GUESS THE BIG QUESTION 5530 04:14:51,320 --> 04:14:57,680 IS, HOW? I HAVE SOME IDEAS. I 5531 04:14:57,680 --> 04:14:58,280 HAVE NOT DELIVERED ON ANY OF 5532 04:14:58,280 --> 04:14:58,880 THIS BUT MAYBE SOME OF YOU IN 5533 04:14:58,880 --> 04:15:01,800 THE ROOM WILL. 5534 04:15:01,800 --> 04:15:06,120 THE FIRST AND MOST OBVIOUS IS 5535 04:15:06,120 --> 04:15:06,680 THE VAX ANALOGY APPROACHES. 5536 04:15:06,680 --> 04:15:12,840 THANKS AGAIN TO AL YOU 5537 04:15:12,840 --> 04:15:16,960 HIGHLIGHTED A COUPLE OF 5538 04:15:16,960 --> 04:15:17,480 EXAMPLES, CHANGING THE 5539 04:15:17,480 --> 04:15:18,080 FORMULATION TO MAKE VACCINES 5540 04:15:18,080 --> 04:15:20,560 WORK BETTER FOR OLDER PEOPLE. 5541 04:15:20,560 --> 04:15:21,520 BUT I THINK WE CAN BE MORE 5542 04:15:21,520 --> 04:15:25,160 INNOVATIVE IN THE CLASSIC 5543 04:15:25,160 --> 04:15:28,680 VACCINOLOGY APPROACHES, 5544 04:15:28,680 --> 04:15:29,240 POTENTIALLY THINKING ABOUT 5545 04:15:29,240 --> 04:15:29,960 TARGETING SOME OF THE HALLMARKS 5546 04:15:29,960 --> 04:15:37,840 OF AGING IN THE CONTEXT OF 5547 04:15:37,840 --> 04:15:38,440 VACCINE MEDICINE AND THERE IS 5548 04:15:38,440 --> 04:15:39,360 BEAUTIFUL WORK FROM-- WHICH HE 5549 04:15:39,360 --> 04:15:44,240 HAS USED A COMPOUND THAT 5550 04:15:44,240 --> 04:15:46,440 MODULATES AUTOPHAGY TO IMPROVE 5551 04:15:46,440 --> 04:15:50,000 HUMERAL IMMUNITY IN AGED MICE. 5552 04:15:50,000 --> 04:15:51,920 BY TARGETING THE HALLMARKS OF 5553 04:15:51,920 --> 04:15:52,400 AGING, SOMETHING THAT 5554 04:15:52,400 --> 04:15:53,120 NECESSARILY SPECIFIC TO VACCINE 5555 04:15:53,120 --> 04:15:55,520 RESPONSE, YOU CAN REALLY IMPACT 5556 04:15:55,520 --> 04:16:01,760 THIS. AND POTENTIALLY AN 5557 04:16:01,760 --> 04:16:03,480 APPROACH WHICH ALSO USES 5558 04:16:03,480 --> 04:16:05,960 EVIDENCE FOR UNDERSTANDING WHAT 5559 04:16:05,960 --> 04:16:08,720 ARE THE SPECIFIC MOLECULES THAT 5560 04:16:08,720 --> 04:16:11,360 ARE CHANGED WITHIN CELLS ON THE 5561 04:16:11,360 --> 04:16:14,200 GERMINAL CENTER RESPONSE? AND 5562 04:16:14,200 --> 04:16:17,360 HOW THEY CHANGE IN AGING AND 5563 04:16:17,360 --> 04:16:19,240 TARGETING THOSE? THERE IS A 5564 04:16:19,240 --> 04:16:22,480 NICE PRESIDENT FROM -- -- WHERE 5565 04:16:22,480 --> 04:16:26,880 THE NOTED THAT TFH FROM AGED 5566 04:16:26,880 --> 04:16:29,560 MICE HAD INCREASED EXPRESSION 5567 04:16:29,560 --> 04:16:33,080 OF PD-1 AND BY BLOCKING THE 5568 04:16:33,080 --> 04:16:33,720 RECEPTOR THAT COULD ENHANCE THE 5569 04:16:33,720 --> 04:16:34,280 GERMINAL CENTER RESPONSE IN 5570 04:16:34,280 --> 04:16:35,840 AGING. I THINK THE GOOD THING 5571 04:16:35,840 --> 04:16:39,880 IS THAT WE HAVE LOTS OF 5572 04:16:39,880 --> 04:16:40,520 OPTIONS, AND THE CHALLENGE FOR 5573 04:16:40,520 --> 04:16:41,560 US IS REALLY TO IMPLEMENT THEM 5574 04:16:41,560 --> 04:16:44,000 IN A MEANINGFUL WAY. 5575 04:16:44,000 --> 04:16:46,000 WITH THAT I WOULD LIKE TO SAY 5576 04:16:46,000 --> 04:16:55,080 A BIG THANK YOU TO ALYSSA 5577 04:16:55,080 --> 04:16:55,720 SILVA-CAYETANO POSTDOC WHO DID 5578 04:16:55,720 --> 04:16:56,360 THE MOST WORK AND THANK YOU FOR 5579 04:16:56,360 --> 04:17:06,640 YOUR ATTENTION. 5580 04:17:07,800 --> 04:17:09,960 >>(INDISCERNIBLE) WHAT HAPPENS 5581 04:17:09,960 --> 04:17:15,600 TO THE T-CELL? WHAT HAPPENS TO 5582 04:17:15,600 --> 04:17:18,880 MEMORY FORMATION? IS THIS A 5583 04:17:18,880 --> 04:17:25,960 RESPONSE TO MAKE SURE THAT GETS 5584 04:17:25,960 --> 04:17:26,600 (INDISCERNIBLE)? 5585 04:17:26,600 --> 04:17:29,320 >>YOU ARE OFF THE MOON HOT. 5586 04:17:29,320 --> 04:17:36,520 WHEN YOU PUSH THE TFH INTO THE 5587 04:17:36,520 --> 04:17:37,960 LIGHT ZONE YOU GET ENHANCED 5588 04:17:37,960 --> 04:17:41,000 AFFINITY MATURATION, WHAT WE 5589 04:17:41,000 --> 04:17:41,640 SEE IN AGING WHICH TO BE HONEST 5590 04:17:41,640 --> 04:17:42,280 I WAS NOT EXPECTING BECAUSE THE 5591 04:17:42,280 --> 04:17:44,360 DOCUMENT IN THE LIGHT ZONE THEY 5592 04:17:44,360 --> 04:17:48,360 COMPETE FOR T-CELLS. SO IF YOU 5593 04:17:48,360 --> 04:17:51,680 COMPETE THE TFH THE LIGHT ZONE 5594 04:17:51,680 --> 04:17:52,320 IT SHOULD RELAX THE COMPETITION 5595 04:17:52,320 --> 04:17:53,200 HAVE A LOWER AFFINITY. BUT THAT 5596 04:17:53,200 --> 04:17:57,120 IS NOT WHAT WE SEE. THAT EITHER 5597 04:17:57,120 --> 04:17:57,720 TELLS YOU THAT OUR MODELS ARE 5598 04:17:57,720 --> 04:18:03,200 MISSING SOME INFORMATION WHICH 5599 04:18:03,200 --> 04:18:06,280 OBVIOUSLY IS OFTEN REQUIRES TFH 5600 04:18:06,280 --> 04:18:10,640 IN THE DARK ZONE. WE ARE 5601 04:18:10,640 --> 04:18:11,240 MISSING IT BECAUSE ALL OF YOU 5602 04:18:11,240 --> 04:18:13,960 SAY THE (INDISCERNIBLE) ARE IN 5603 04:18:13,960 --> 04:18:17,000 THE LIGHT ZONE. 5604 04:18:17,000 --> 04:18:17,960 WHEN YOU SHIFT THE OTHER WAY, 5605 04:18:17,960 --> 04:18:22,200 YOU HAVE A MORE GERMINAL CENTER 5606 04:18:22,200 --> 04:18:22,800 RESPONSE THAT AFFINITY IS NOT 5607 04:18:22,800 --> 04:18:24,920 AFFECTED. THERE IS AN 5608 04:18:24,920 --> 04:18:25,520 INTERESTING BOUNDS OF WHAT IS 5609 04:18:25,520 --> 04:18:29,680 GOING ON WITH IT. (CORRECTION) 5610 04:18:29,680 --> 04:18:30,320 INTERESTING BALANCE OF WHAT IS 5611 04:18:30,320 --> 04:18:40,760 GOING ON WITH IT.>>I WAS 5612 04:18:53,120 --> 04:18:53,560 WONDERING IF THERE IS AN 5613 04:18:53,560 --> 04:18:54,160 EXPANDED (INDISCERNIBLE), ARE 5614 04:18:54,160 --> 04:18:54,760 THESE MISLOCALIZED THAT YOU 5615 04:18:54,760 --> 04:18:55,040 ALSO FIND? 5616 04:18:55,040 --> 04:18:55,560 >>HONESTLY IT HAS BEEN 5617 04:18:55,560 --> 04:18:56,400 COMPLICATED BY THE FACT THAT 5618 04:18:56,400 --> 04:19:04,840 TFH IS CHANGED BY THE FLOW 5619 04:19:04,840 --> 04:19:06,520 (INDISCERNIBLE). IF YOU INCLUDE 5620 04:19:06,520 --> 04:19:11,160 THE TFH PRECURSOR WHICH IS THE 5621 04:19:11,160 --> 04:19:14,440 (INDISCERNIBLE) INTERMEDIATE 5622 04:19:14,440 --> 04:19:14,960 GATE, IT SEEMS THAT THOSE 5623 04:19:14,960 --> 04:19:16,520 ACCUMULATE IN AGING. THIS IS 5624 04:19:16,520 --> 04:19:19,680 WHAT WE HAVE FOUND THIS AND 5625 04:19:19,680 --> 04:19:24,200 LAURA ALSO DESCRIBED IT. IT 5626 04:19:24,200 --> 04:19:29,760 -- INTO THE (INDISCERNIBLE). 5627 04:19:29,760 --> 04:19:31,800 WE ALSO ENUMERATED -- BY 5628 04:19:31,800 --> 04:19:34,640 IMAGING. THAT ULTIMATELY IS 5629 04:19:34,640 --> 04:19:39,520 WHAT YOU CARE ABOUT. IF YOU 5630 04:19:39,520 --> 04:19:40,880 NORMALIZE THE SMALLER GERMINAL 5631 04:19:40,880 --> 04:19:41,520 CENTER YOU DON'T HAVE A DEFECT 5632 04:19:41,520 --> 04:19:46,200 IN THE T-CELL NUMBER IN THE 5633 04:19:46,200 --> 04:19:47,200 GERMINAL CENTER THEY TEND TO BE 5634 04:19:47,200 --> 04:19:47,760 FEWER BECAUSE THE GERMINAL 5635 04:19:47,760 --> 04:19:49,640 CENTER IS SMALLER BUT THE TFH 5636 04:19:49,640 --> 04:19:51,640 IS NOT AFFECTED. IT JUST SEEMS 5637 04:19:51,640 --> 04:19:54,240 LOCATION THAT WAS CHANGED. 5638 04:19:54,240 --> 04:19:54,760 >>ONE MORE POINT MAY BE 5639 04:19:54,760 --> 04:19:56,960 TOTALLY UNRELATED. WITH AGE, 5640 04:19:56,960 --> 04:20:07,440 THE -- (INDISCERNIBLE) THAT 5641 04:20:09,400 --> 04:20:09,840 OCCURS IN SPAIN THAT THAT 5642 04:20:09,840 --> 04:20:10,360 CONTRIBUTE TO THE MISS 5643 04:20:10,360 --> 04:20:10,960 LOCALIZATION OF FORMATION OF 5644 04:20:10,960 --> 04:20:16,800 THE GERMINAL CENTER? 5645 04:20:16,800 --> 04:20:17,400 >>WE HAVE LYMPH NODE WORK WITH 5646 04:20:17,400 --> 04:20:19,160 A CONSCIOUS DECISION TO MAKE 5647 04:20:19,160 --> 04:20:19,760 SURE WE WERE AS CLOSE TO THE 5648 04:20:19,760 --> 04:20:20,920 HUMAN SITUATION AS POSSIBLE. 5649 04:20:20,920 --> 04:20:21,520 BECAUSE WANTED TO IMMUNIZE 5650 04:20:21,520 --> 04:20:23,120 PEOPLE (INDISCERNIBLE). 5651 04:20:23,120 --> 04:20:26,720 >>TWO THINGS. ONE IS HAVE YOU 5652 04:20:26,720 --> 04:20:32,320 CHECKED THE ROLE OF -- IN T 5653 04:20:32,320 --> 04:20:32,880 REG, WHICH IS INCREASED IN 5654 04:20:32,880 --> 04:20:35,640 AGING? 5655 04:20:35,640 --> 04:20:36,200 >>WE DID THE MOST EXPENSIVE 5656 04:20:36,200 --> 04:20:40,680 AND BORING EXPERIMENT. WE MADE 5657 04:20:40,680 --> 04:20:44,840 T-CELL 5 BLOCKS, WITH A 50% 5658 04:20:44,840 --> 04:20:51,680 REDUCTION OF TFR CELLS IN THE 5659 04:20:51,680 --> 04:20:52,280 GERMINAL CENTER AND WE THINK 5660 04:20:52,280 --> 04:20:58,840 THAT THE. INCREASED NUMBER OF 5661 04:20:58,840 --> 04:21:03,280 TFR CELLS WAS LIMITING. SO 5662 04:21:03,280 --> 04:21:09,600 HALVING THE NUMBER OF T-CELLS 5663 04:21:09,600 --> 04:21:12,200 IN AGED MICE MADE NO 5664 04:21:12,200 --> 04:21:14,640 DIFFERENCE. 5665 04:21:14,640 --> 04:21:17,520 >>OLDER DATA FOR SIGNALING, 5666 04:21:17,520 --> 04:21:21,400 WHEN IT (INDISCERNIBLE) IN HIGH 5667 04:21:21,400 --> 04:21:22,040 CONCENTRATION IT CAN BE 5668 04:21:22,040 --> 04:21:23,480 REPELLED. ACTUALLY IT CAN CAUSE 5669 04:21:23,480 --> 04:21:27,080 INSTEAD OF CHEMOTAXIS, IT CAN 5670 04:21:27,080 --> 04:21:30,240 CAUSE -- VERY OLD DATA FROM 5671 04:21:30,240 --> 04:21:32,600 CHEMOTAXIS STILL. 5672 04:21:32,600 --> 04:21:38,520 >>WE QUANTIFIED -- BY LOCAL 5673 04:21:38,520 --> 04:21:39,160 IMAGING AND WE DID NOT SEE THE 5674 04:21:39,160 --> 04:21:40,760 DIFFERENCE IN AGING, THAT WE 5675 04:21:40,760 --> 04:21:43,200 THINK IS A PREDICTOR OF 5676 04:21:43,200 --> 04:21:45,120 (INDISCERNIBLE) LIGANDS. 5677 04:21:45,120 --> 04:21:48,480 >>FINAL QUESTION. WONDERFUL 5678 04:21:48,480 --> 04:21:53,120 WORK. MY NAME IS MICHELLE-- 5679 04:21:53,120 --> 04:21:53,600 DREXEL UNIVERSITY IN 5680 04:21:53,600 --> 04:21:54,200 PHILADELPHIA, AND WORK WITH 5681 04:21:54,200 --> 04:21:59,880 VACCINES. AS I WATCHED YOU 5682 04:21:59,880 --> 04:22:00,480 WORK, SO WONDERFUL THE TOOLS 5683 04:22:00,480 --> 04:22:01,760 AND WHAT YOU HAVE SHOWN YOU 5684 04:22:01,760 --> 04:22:02,480 HAVE A SENSE OF WHAT IS GOING 5685 04:22:02,480 --> 04:22:07,240 ON (INDISCERNIBLE) WITH T-CELL 5686 04:22:07,240 --> 04:22:13,080 DEFICIENT IN THE GUT? 5687 04:22:13,080 --> 04:22:13,680 POTENTIALLY AGING IS A MAJOR 5688 04:22:13,680 --> 04:22:17,840 RISK FACTOR FOR C DEF 5689 04:22:17,840 --> 04:22:20,920 (PHONETIC), IT IS RELATED 5690 04:22:20,920 --> 04:22:22,160 PERHAPS OF NET LYMPH NODES, DO 5691 04:22:22,160 --> 04:22:25,960 YOU SEE THIS IN THE MUCOSAL 5692 04:22:25,960 --> 04:22:28,760 SITES? 5693 04:22:28,760 --> 04:22:29,360 >>WE DID LOOK AT THE GERMINAL 5694 04:22:29,360 --> 04:22:32,000 CENTER THERE. THEY ARE LIKEWISE 5695 04:22:32,000 --> 04:22:32,640 REDUCED; WE HAD AN INTERESTING 5696 04:22:32,640 --> 04:22:38,480 SURPRISE IN THAT -- 5697 04:22:38,480 --> 04:22:39,120 TRANSPORTATION CAN REVERSE THAT 5698 04:22:39,120 --> 04:22:49,640 EFFECT. I THINK I THE GUT YOU 5699 04:22:51,200 --> 04:22:51,760 SEE THE SAME THING BUT THE COOL 5700 04:22:51,760 --> 04:23:02,280 THING ABOUT THAT IS IT IS VERY 5701 04:23:04,200 --> 04:23:06,080 BUT THE COOL THINGS THAT YOU 5702 04:23:06,080 --> 04:23:06,680 SEE AN OPPORTUNITY IF YOU GIVE 5703 04:23:06,680 --> 04:23:10,760 IT A STRONG --. 5704 04:23:10,760 --> 04:23:14,440 >>(INDISCERNIBLE). 5705 04:23:14,440 --> 04:23:15,040 >>THE ONLY THING WE LOOKED WAS 5706 04:23:15,040 --> 04:23:16,360 A HIGH-LEVEL DATA. WITH NOT 5707 04:23:16,360 --> 04:23:19,520 SEE ANY CHANGES. BUT WE HAVE 5708 04:23:19,520 --> 04:23:22,800 NOT DONE LIKE A BORDER SURVEY. 5709 04:23:22,800 --> 04:23:23,440 I WOULD LOVE TO THINK THAT WHAT 5710 04:23:23,440 --> 04:23:26,880 WE HAVE SEEN IS ACTUALLY 5711 04:23:26,880 --> 04:23:31,240 SOMETHING THAT REQUIRES MARKER 5712 04:23:31,240 --> 04:23:33,840 FOUR DYSREGULATION. I DON'T 5713 04:23:33,840 --> 04:23:44,200 HAVE THE DATA TO BACK THAT UP. 5714 04:23:44,200 --> 04:23:45,640 >>SO OUR NEXT SPEAKER IS 5715 04:23:45,640 --> 04:23:56,120 DOCTOR -- DIRECTOR OF THE-- 5716 04:23:58,040 --> 04:23:58,600 PRGORAM AND SENIOR PHYSICIAN IN 5717 04:23:58,600 --> 04:23:59,240 PEDIATRICS AT BOSTON CHILDREN'S 5718 04:23:59,240 --> 04:24:01,560 HOSPITAL, ALSO PROFESSOR AT THE 5719 04:24:01,560 --> 04:24:05,160 (INDISCERNIBLE). THE TITLE OF 5720 04:24:05,160 --> 04:24:07,360 THIS TOPIC IS DEVELOPMENT OF 5721 04:24:07,360 --> 04:24:08,000 ADJUVANT FOR IMPROVING COST IN 5722 04:24:08,000 --> 04:24:10,280 RESPONSE. HE WILL BE GIVEN THE 5723 04:24:10,280 --> 04:24:13,960 TALK VIRTUALLY VIA ZOOM. DR. 5724 04:24:13,960 --> 04:24:16,720 LEVY? 5725 04:24:16,720 --> 04:24:17,160 >>THANK YOU FOR THE 5726 04:24:17,160 --> 04:24:18,320 OPPORTUNITY TO SPEAK TODAY AT 5727 04:24:18,320 --> 04:24:19,520 THIS REALLY WONDERFUL 5728 04:24:19,520 --> 04:24:24,080 CONFERENCE. AND I SALUTE NIA 5729 04:24:24,080 --> 04:24:24,600 FOR PUTTING TOGETHER THIS 5730 04:24:24,600 --> 04:24:26,000 IMPORTANT TOPIC. CAN YOU HEAR 5731 04:24:26,000 --> 04:24:27,560 ME OKAY? 5732 04:24:27,560 --> 04:24:29,200 >>YES WE CAN HEAR YOU. 5733 04:24:29,200 --> 04:24:36,000 >>AS MENTIONED MY NAME IS OFER 5734 04:24:36,000 --> 04:24:36,560 LEVY, A PHYSICIAN SCIENTIST 5735 04:24:36,560 --> 04:24:37,120 BASED AT BOSTON CHILDREN'S 5736 04:24:37,120 --> 04:24:37,640 HOSPITAL WHERE A DIRECTOR 5737 04:24:37,640 --> 04:24:38,840 POSITION VACCINES PROGRAM, I AM 5738 04:24:38,840 --> 04:24:39,440 ALSO PROFESSOR OF PEDIATRICS AT 5739 04:24:39,440 --> 04:24:41,640 HARVARD MEDICAL SCHOOL. AND I 5740 04:24:41,640 --> 04:24:43,880 AM ALSO A PART-TIME EMPLOYEE OF 5741 04:24:43,880 --> 04:24:50,000 US FDA WHERE I SERVE ON THE 5742 04:24:50,000 --> 04:24:50,640 VACCINE AND RELATED BIOLOGICAL 5743 04:24:50,640 --> 04:24:51,200 PRODUCTS ADVISORY COMMITTEE 5744 04:24:51,200 --> 04:24:51,880 ALTHOUGH MY COMMENTS TODAY WILL 5745 04:24:51,880 --> 04:24:54,320 BE MY OWN PERSONAL OPINION. 5746 04:24:54,320 --> 04:24:56,360 I WILL TALK TO YOU TODAY ABOUT 5747 04:24:56,360 --> 04:24:56,960 POSITION ADJUVANTS TO IMPROVE 5748 04:24:56,960 --> 04:24:58,200 VACCINE IMMUNOGENICITY IN OLDER 5749 04:24:58,200 --> 04:25:01,120 ADULTS. 5750 04:25:01,120 --> 04:25:02,000 AS WE KNOW TRADITIONALLY 5751 04:25:02,000 --> 04:25:04,200 VACCINE DEVELOPMENT WAS PURSUED 5752 04:25:04,200 --> 04:25:08,840 OVER THE PAST 100 YEARS AS A 5753 04:25:08,840 --> 04:25:10,840 ONE-SIZE-FITS-ALL ENDEAVOR, 5754 04:25:10,840 --> 04:25:11,440 THAT THE VACCINE PIPELINE WAS 5755 04:25:11,440 --> 04:25:15,080 DEVELOPED THE SAME WAY 5756 04:25:15,080 --> 04:25:15,680 TRADITIONALLY, REGARDLESS OF 5757 04:25:15,680 --> 04:25:18,520 THE TARGET POPULATION WHETHER 5758 04:25:18,520 --> 04:25:20,800 IT WAS MALE OR FEMALE OR 5759 04:25:20,800 --> 04:25:21,560 WHETHER YOUNG INFANT OR AN 5760 04:25:21,560 --> 04:25:22,120 OLDER ADULT OR WHETHER THE 5761 04:25:22,120 --> 04:25:23,840 VACCINE IS GIVEN IN ONE SEASON 5762 04:25:23,840 --> 04:25:26,200 OR IN ANOTHER, GIVEN ALONE OR 5763 04:25:26,200 --> 04:25:31,120 WITH ANOTHER VACCINE. GIVEN IS 5764 04:25:31,120 --> 04:25:31,640 ONE TYPE OF PLATFORM LIVE 5765 04:25:31,640 --> 04:25:33,280 ATTENUATED SUBUNIT MRNA OR 5766 04:25:33,280 --> 04:25:33,920 ANOTHER OR GIVEN IN ONE PART OF 5767 04:25:33,920 --> 04:25:37,400 THE WORLD OR ANOTHER. 5768 04:25:37,400 --> 04:25:38,000 OF COURSE ONE-SIZE-FITS-ALL IS 5769 04:25:38,000 --> 04:25:38,560 THE MOST PRACTICAL APPROACH 5770 04:25:38,560 --> 04:25:39,000 FROM A PUBLIC HEALTH 5771 04:25:39,000 --> 04:25:41,240 PERSPECTIVE FOR VACCINES. BUT 5772 04:25:41,240 --> 04:25:43,840 A LOT OF HIGH QUALITY RESEARCH 5773 04:25:43,840 --> 04:25:44,440 HAS COME OUT AND CONTINUES TO 5774 04:25:44,440 --> 04:25:46,960 COME OUT TO INDICATE THAT ALL 5775 04:25:46,960 --> 04:25:49,960 OF THESE FACTORS AND 5776 04:25:49,960 --> 04:25:51,720 DEMOGRAPHIC FEATURES, 5777 04:25:51,720 --> 04:25:52,320 ESPECIALLY AGE WHICH WE WILL 5778 04:25:52,320 --> 04:25:55,280 FOCUS ON TODAY, CAN HAVE A BIG 5779 04:25:55,280 --> 04:25:55,680 IMPACT ON VACCINE 5780 04:25:55,680 --> 04:25:56,160 IMMUNOGENICITY AND EVEN 5781 04:25:56,160 --> 04:26:00,280 PROTECTION. 5782 04:26:00,280 --> 04:26:00,840 WITH THESE CONSIDERATIONS IN 5783 04:26:00,840 --> 04:26:01,480 MIND AND 2015 BOSTON CHILDREN'S 5784 04:26:01,480 --> 04:26:02,320 HOSPITAL CREATED THE POSITION 5785 04:26:02,320 --> 04:26:06,680 VACCINES PROGRAM, AN ACADEMIC 5786 04:26:06,680 --> 04:26:07,200 PROGRAM WITH ITS GOALS TO 5787 04:26:07,200 --> 04:26:07,880 DEVELOP VACCINES FOR VULNERABLE 5788 04:26:07,880 --> 04:26:17,800 POPULATIONS. WE HAVE A 5789 04:26:17,800 --> 04:26:18,440 PROCESSION VACCINES NETWORK OF 5790 04:26:18,440 --> 04:26:22,800 INDIVIDUALS ACROSS THE GLOBE. 5791 04:26:22,800 --> 04:26:23,320 THE SLIDE IS A LITTLE BIT 5792 04:26:23,320 --> 04:26:23,880 OUTDATED BECAUSE WE HAVE 5793 04:26:23,880 --> 04:26:24,480 SEVERAL HUNDRED COLLABORATORS 5794 04:26:24,480 --> 04:26:33,120 ACROSS THE GLOBE, SUMMONED THE 5795 04:26:33,120 --> 04:26:33,680 LEAD AND SOME IN SUPPORTIVE 5796 04:26:33,680 --> 04:26:34,240 ROLES. WE BRING CERTAIN MR. 5797 04:26:34,240 --> 04:26:34,760 TECHNICAL BIOINFORMATICS 5798 04:26:34,760 --> 04:26:35,400 ORGANIZATION LEGAL AND GRAPHIC 5799 04:26:35,400 --> 04:26:36,040 CAPABILITY FOR VACCINE PROJECT 5800 04:26:36,040 --> 04:26:37,840 AND FOR THOSE WHO DO TWITTER WE 5801 04:26:37,840 --> 04:26:45,960 ARE @PRECVACCINES. 5802 04:26:45,960 --> 04:26:46,400 SO WHAT DO WE MEAN BY 5803 04:26:46,400 --> 04:26:48,720 PRECISION VACCINES? AS WE KNOW 5804 04:26:48,720 --> 04:26:54,880 IN 2008 THE COUNCIL REFER TO 5805 04:26:54,880 --> 04:26:59,280 PRECISION VACCINE IS TAILORED 5806 04:26:59,280 --> 04:26:59,680 TO THE INDIVIDUAL 5807 04:26:59,680 --> 04:27:00,280 CHARACTERISTICS OF THE PATIENT 5808 04:27:00,280 --> 04:27:02,320 UNNECESSARILY MEANING SEPARATE 5809 04:27:02,320 --> 04:27:03,720 ROW FOR EACH INDIVIDUAL BUT 5810 04:27:03,720 --> 04:27:04,240 RATHER ABILITY TO DEFINE 5811 04:27:04,240 --> 04:27:05,720 SUBPOPULATIONS THAT MAY BENEFIT 5812 04:27:05,720 --> 04:27:14,280 IN THIS CONTEXT PRECISION 5813 04:27:14,280 --> 04:27:14,840 VACCINOLOGY IS INTO TAYLOR 5814 04:27:14,840 --> 04:27:15,400 IMMUNIZATION FOR VULNERABLE 5815 04:27:15,400 --> 04:27:15,960 POPULATIONS WITH THAT THE 5816 04:27:15,960 --> 04:27:16,520 COMMUNITY SUCH AS INFANTS, 5817 04:27:16,520 --> 04:27:17,120 ELDERS, AND IMMUNOCOMPROMISE 5818 04:27:17,120 --> 04:27:18,160 POPULATIONS. 5819 04:27:18,160 --> 04:27:18,640 THIS GRAPHIC IS MEANT TO 5820 04:27:18,640 --> 04:27:19,200 DEPICT SOME OF THE SEVERAL 5821 04:27:19,200 --> 04:27:19,680 APPROACHES WE TAKE IN 5822 04:27:19,680 --> 04:27:24,240 DEVELOPING PRECISION VACCINES. 5823 04:27:24,240 --> 04:27:25,960 WE TRY TO BASE OURSELVES IN 5824 04:27:25,960 --> 04:27:26,520 TARGETED CLINICAL TRIALS OF 5825 04:27:26,520 --> 04:27:27,240 DIVERSE POPULATIONS, INCLUDING 5826 04:27:27,240 --> 04:27:31,160 DIVERSE BY AGE. AND TYPICALLY 5827 04:27:31,160 --> 04:27:31,800 IT WE WILL ACQUIRE BIO SAMPLES 5828 04:27:31,800 --> 04:27:32,520 BEFORE AND AFTER IMMUNIZATION 5829 04:27:32,520 --> 04:27:34,040 THAT WE CAN THEN SUBJECT TO A 5830 04:27:34,040 --> 04:27:37,080 SMALL SAMPLE BIG DATA OF 5831 04:27:37,080 --> 04:27:38,640 STANDARD OPERATING PROCEDURE WE 5832 04:27:38,640 --> 04:27:41,760 HAVE DEVELOPED TO ALLOW US TO 5833 04:27:41,760 --> 04:27:49,520 EXTRACT MULTI-OHMIC 5834 04:27:49,520 --> 04:27:50,240 INFORMATION, TRANSCRIPTOMICS 5835 04:27:50,240 --> 04:27:53,200 EPIGENETIC ETC. WITH LESS THAN 5836 04:27:53,200 --> 04:27:56,720 HALF AN ML OF BLOOD, AND 5837 04:27:56,720 --> 04:27:58,160 UNDERSTANDING VACCINE INDUCED 5838 04:27:58,160 --> 04:27:58,880 CHANGES IN CELLULAR AND 5839 04:27:58,880 --> 04:28:02,840 MOLECULAR SIGNATURES. 5840 04:28:02,840 --> 04:28:03,400 AND MOST IMPORTANTLY WHETHER 5841 04:28:03,400 --> 04:28:04,880 THOSE EARLY EVENTS AFTER THE 5842 04:28:04,880 --> 04:28:07,080 VACCINE, AS MEASURED BY SYSTEMS 5843 04:28:07,080 --> 04:28:07,560 BIOLOGY, CORRELATE WITH 5844 04:28:07,560 --> 04:28:08,880 SOMETHING WE CARE ABOUT 5845 04:28:08,880 --> 04:28:10,200 CLINICALLY LIKE A PROTECTIVE 5846 04:28:10,200 --> 04:28:14,280 IMMUNE RESPONSE, AN ANTIBODY T 5847 04:28:14,280 --> 04:28:14,720 CELL OR OTHER IMMUNE 5848 04:28:14,720 --> 04:28:20,200 CORRELATIVE PROTECTION. 5849 04:28:20,200 --> 04:28:20,760 THAT IS A POWERFUL EXERCISE 5850 04:28:20,760 --> 04:28:21,280 BUT IT IS A HYPOTHESIS 5851 04:28:21,280 --> 04:28:21,880 GENERATING EXERCISE. IT IS AN 5852 04:28:21,880 --> 04:28:25,320 ASSOCIATION. WITHIN TRY TO GET 5853 04:28:25,320 --> 04:28:25,880 INSIGHT INTO MECHANISMS OF 5854 04:28:25,880 --> 04:28:28,600 ACTION IN DISTINCT POPULATIONS, 5855 04:28:28,600 --> 04:28:30,120 USING OUR HUMAN IN VITRO 5856 04:28:30,120 --> 04:28:30,760 MODELING, A PARTICULAR STRENGTH 5857 04:28:30,760 --> 04:28:34,160 OF OUR PROGRAM. 5858 04:28:34,160 --> 04:28:34,720 WE HAVE A RANGE OF HUMAN IN 5859 04:28:34,720 --> 04:28:35,320 VITRO PLATFORMS APPROXIMATELY 5860 04:28:35,320 --> 04:28:36,920 EIGHT OF THEM AS SIMPLE AS 5861 04:28:36,920 --> 04:28:40,880 WHOLE BLOOD ASSAYS TO MORE 5862 04:28:40,880 --> 04:28:41,520 SOPHISTICATED TISSUE-ENGINEERED 5863 04:28:41,520 --> 04:28:43,280 PLATFORMS, AND A NUMBER OF 5864 04:28:43,280 --> 04:28:46,720 FACULTY THAT DEVELOPED THESE. 5865 04:28:46,720 --> 04:28:47,280 THESE INDIVIDUAL SYSTEMS ARE 5866 04:28:47,280 --> 04:28:49,800 BASED ON HUMAN BLOOD DRAWS FROM 5867 04:28:49,800 --> 04:28:50,360 DIVERSE POPULATIONS. WE CAN 5868 04:28:50,360 --> 04:28:53,960 MODEL INFANT IMMUNE RESPONSES, 5869 04:28:53,960 --> 04:29:00,280 ELDER AND IMMUNOCOMPROMISED 5870 04:29:00,280 --> 04:29:05,520 COMORBID AND ADAPTATION TO 5871 04:29:05,520 --> 04:29:06,160 ADJUVANT AND ADJUVANT VACCINES 5872 04:29:06,160 --> 04:29:06,720 MANY TIMES CORRESPONDING TO 5873 04:29:06,720 --> 04:29:07,280 DIFFERENCES THAT HAVE BEEN 5874 04:29:07,280 --> 04:29:09,960 SHOWN IN VIVO. 5875 04:29:09,960 --> 04:29:10,480 SO THIS IN VITRO SYSTEM IS 5876 04:29:10,480 --> 04:29:11,760 VERY POWERFUL AND ALLOWS US TO 5877 04:29:11,760 --> 04:29:15,320 BENCHMARK NOVEL AGENTS, TO 5878 04:29:15,320 --> 04:29:17,520 LICENSE OR APPROVE VACCINES 5879 04:29:17,520 --> 04:29:18,080 THEREBY CONTEXTUALIZING THE 5880 04:29:18,080 --> 04:29:19,800 INFORMATION WE GENERATE AND 5881 04:29:19,800 --> 04:29:22,760 ALLOWING US TO SELECT LEADS 5882 04:29:22,760 --> 04:29:23,320 TARGETED TO A PARTICULAR 5883 04:29:23,320 --> 04:29:27,160 VULNERABLE POPULATION. AND THEN 5884 04:29:27,160 --> 04:29:27,760 CLOSE THE CYCLE OF INNOVATION 5885 04:29:27,760 --> 04:29:28,400 BY SELECTING APPROPRIATE ANIMAL 5886 04:29:28,400 --> 04:29:32,000 MODELS. 5887 04:29:32,000 --> 04:29:32,480 OF COURSE ADJUVANTS ARE 5888 04:29:32,480 --> 04:29:33,120 MOLECULES THAT BOOST AN IMMUNE 5889 04:29:33,120 --> 04:29:35,400 RESPONSE COMING FROM THE LACK 5890 04:29:35,400 --> 04:29:39,000 OF ADJUVAR TO HELP OR AID IN 5891 04:29:39,000 --> 04:29:39,600 THE TOP DEPICTION AND ANTIGEN 5892 04:29:39,600 --> 04:29:44,280 IN BLACK IS A TRIANGLE GIVEN 5893 04:29:44,280 --> 04:29:44,880 ALONE AND YOU CAN GET MODEST 5894 04:29:44,880 --> 04:29:45,480 ACTIVATION OF ANTIGEN PRESENT 5895 04:29:45,480 --> 04:29:52,800 CELLS AND MODEST IMMUNE 5896 04:29:52,800 --> 04:29:53,400 RESPONSES THAT WANE RAPIDLY, 5897 04:29:53,400 --> 04:29:54,120 REQUIRING RAPIDLY MULTIPLE 5898 04:29:54,120 --> 04:29:58,080 BOOSTER DOSES. 5899 04:29:58,080 --> 04:29:58,600 IN THE BOTTOM PICTURE THE 5900 04:29:58,600 --> 04:30:00,960 ADJUVANT IS ADDED, FOR EXAMPLE 5901 04:30:00,960 --> 04:30:01,560 ANTIGEN PRESENTING CELLS MAY 5902 04:30:01,560 --> 04:30:02,160 HAVE MORE PROFOUND ACTIVATION 5903 04:30:02,160 --> 04:30:05,240 AS THESE APCS, AND MORE 5904 04:30:05,240 --> 04:30:06,520 PROFOUND ACTIVATION OF 5905 04:30:06,520 --> 04:30:11,040 LYMPHOCYTES, B CELLS, ETC., AND 5906 04:30:11,040 --> 04:30:13,760 GET MORE HIGHER AND DURABLE 5907 04:30:13,760 --> 04:30:14,240 IMMUNOGENICITY. 5908 04:30:14,240 --> 04:30:14,800 NOW WHILE IT IS WELL KNOWN 5909 04:30:14,800 --> 04:30:21,440 THAT ACTIVATING PRRS CAN 5910 04:30:21,440 --> 04:30:22,000 ENHANCE NOT JUST INNATE BUT 5911 04:30:22,000 --> 04:30:27,720 ADAPTIVE IMMUNE RESPONSE, WHAT 5912 04:30:27,720 --> 04:30:28,320 HAS BEEN LESS APPRECIATED IS 5913 04:30:28,320 --> 04:30:38,160 THEIRS AND ONTOGENY TO HUMAN 5914 04:30:38,160 --> 04:30:38,720 NOTE RECEPTOR RESPONSES IN 5915 04:30:38,720 --> 04:30:39,360 OTHER WORDS A TYPE AND PATTERN 5916 04:30:39,360 --> 04:30:39,960 OF CYTOKINE PRODUCTION AFTER 5917 04:30:39,960 --> 04:30:44,240 STIMULATING. THIS GRAPHIC IS A 5918 04:30:44,240 --> 04:30:45,120 DEPICTION OF HER REVIEW THAT I 5919 04:30:45,120 --> 04:30:47,480 WROTE IN THE JOURNAL OF 5920 04:30:47,480 --> 04:30:48,080 COMMUNITY A FEW YEARS AGO ON 5921 04:30:48,080 --> 04:30:55,720 THE Y-AXIS IS THE CYTOKINE 5922 04:30:55,720 --> 04:30:57,760 INDUCTION AND THE X AXIS IS THE 5923 04:30:57,760 --> 04:30:58,360 INFORMATION FROM LABS ACROSS 5924 04:30:58,360 --> 04:30:59,120 THE WORLD SHOWING DIFFERENT 5925 04:30:59,120 --> 04:31:01,200 PATTERNS OF IMMUNE ACTIVATION 5926 04:31:01,200 --> 04:31:09,200 WITH IMPAIRED TH-1 ONE 5927 04:31:09,200 --> 04:31:09,800 RESPONSES AND LATER IN LIFE THE 5928 04:31:09,800 --> 04:31:10,360 PHENOMENON ALLUDED TO IS 5929 04:31:10,360 --> 04:31:10,960 INFORMATION DISCUSSED IN THIS 5930 04:31:10,960 --> 04:31:14,000 CONFERENCE OF LOW-LEVEL TONIC 5931 04:31:14,000 --> 04:31:14,880 ACTIVATION OF INNATE IMMUNITY 5932 04:31:14,880 --> 04:31:15,520 ASSOCIATED WITH THIS REGULATED 5933 04:31:15,520 --> 04:31:16,000 OR IMPAIRED RESPONSE 5934 04:31:16,000 --> 04:31:20,360 IMMUNIZATION OR INFECTION. 5935 04:31:20,360 --> 04:31:20,960 AND BECAUSE OUR TEAM IS REALLY 5936 04:31:20,960 --> 04:31:21,760 INTERESTED IN ADJUVANT 5937 04:31:21,760 --> 04:31:24,640 DISCOVERY AND DEVELOPMENT, I 5938 04:31:24,640 --> 04:31:28,080 WILL MENTION THE 2018 NIAD 5939 04:31:28,080 --> 04:31:28,720 STRATEGIC PLAN FOR RESEARCH ON 5940 04:31:28,720 --> 04:31:29,320 VACCINE ADJUVANT WHICH IS 5941 04:31:29,320 --> 04:31:32,600 PUBLICLY AVAILABLE. YOU CAN 5942 04:31:32,600 --> 04:31:33,240 GOOGLE IT AND IT IS A PDF. YOU 5943 04:31:33,240 --> 04:31:34,840 CAN SEE FROM THE COVER ART THAT 5944 04:31:34,840 --> 04:31:36,640 IT IS ANTICIPATED THAT ONE 5945 04:31:36,640 --> 04:31:41,560 MIGHT HAVE DIFFERENT DISTINCT 5946 04:31:41,560 --> 04:31:43,760 VACCINE FORMULATIONS, 5947 04:31:43,760 --> 04:31:44,240 ADJUVANTED VACCINE FROM 5948 04:31:44,240 --> 04:31:44,800 RELATIONS DEPENDING ON THE 5949 04:31:44,800 --> 04:31:47,440 TARGET POPULATION: INFANT, 5950 04:31:47,440 --> 04:31:49,480 ELDER, MALE-FEMALE, ETC. 5951 04:31:49,480 --> 04:31:56,120 OF COURSE WHEN THE CORONAVIRUS 5952 04:31:56,120 --> 04:31:56,680 PANDEMIC BROKE OUT IT WAS 5953 04:31:56,680 --> 04:31:57,240 RAPIDLY EVIDENT THAT ELDER 5954 04:31:57,240 --> 04:31:58,320 INDIVIDUALS WERE PARTICULARLY 5955 04:31:58,320 --> 04:31:59,200 SUSCEPTIBLE, AND ESPECIALLY 5956 04:31:59,200 --> 04:32:04,360 ELDERLY MEN, AND THAT BECAME A 5957 04:32:04,360 --> 04:32:05,800 FOCUS FOR US TO TRY TO 5958 04:32:05,800 --> 04:32:16,200 UNDERSTAND WHAT IS THE 5959 04:32:18,560 --> 04:32:19,080 LANDSCAPE OF ADJUVENTATION IN 5960 04:32:19,080 --> 04:32:19,720 HUMAN ELDERS AND WHAT IS KNOWN 5961 04:32:19,720 --> 04:32:23,280 AND NOT KNOWN? 5962 04:32:23,280 --> 04:32:23,800 SO THE RATIONALE FOR THE 5963 04:32:23,800 --> 04:32:27,200 VACCINE IN OLDER ADULTS IS THAT 5964 04:32:27,200 --> 04:32:27,760 IT CAN ENHANCE RESPONSE TO 5965 04:32:27,760 --> 04:32:28,320 VULNERABLE POPULATIONS AND 5966 04:32:28,320 --> 04:32:29,760 THERE IS A PLOT OF PROOF OF 5967 04:32:29,760 --> 04:32:31,320 CONCEPT INCLUDING YOUNG, THOSE 5968 04:32:31,320 --> 04:32:38,520 WITH COMORBIDITY AND OTHERS AND 5969 04:32:38,520 --> 04:32:39,160 CAN BROADEN EPITOPE SPECIFICITY 5970 04:32:39,160 --> 04:32:40,280 WHEN YOU HAVE VIRAL VARIANTS 5971 04:32:40,280 --> 04:32:48,560 SPECIFICALLY. 5972 04:32:48,560 --> 04:32:49,120 ADJUVANTED VACCINES AND THOSE 5973 04:32:49,120 --> 04:32:49,560 DEMONSTRATE TRANSIT 5974 04:32:49,560 --> 04:32:50,160 CIRCUMVENTION OF FEATURES OF 5975 04:32:50,160 --> 04:32:50,600 ELDER IMMUNITY ENABLE 5976 04:32:50,600 --> 04:32:51,080 GENERATION OF ROBUST 5977 04:32:51,080 --> 04:32:51,640 IMMUNOGENICITY. 5978 04:32:51,640 --> 04:32:56,760 WHAT IS THE LANDSCAPE? WHAT 5979 04:32:56,760 --> 04:32:57,400 ARE CURRENTLY USED VACCINES IN 5980 04:32:57,400 --> 04:33:02,040 OLDER ADULTS? MULTIPLE 5981 04:33:02,040 --> 04:33:02,640 ADJUVANTS HAVE BEEN INCLUDED. 5982 04:33:02,640 --> 04:33:08,840 OLDER ADULTS, ALUM IS THE MOST 5983 04:33:08,840 --> 04:33:09,360 COMMONLY USED ADJUVANT AN 5984 04:33:09,360 --> 04:33:13,400 EXAMPLE IS THE PNEUMOCOCCAL 5985 04:33:13,400 --> 04:33:16,600 CONJUGATE. AN OIL AND WATER 5986 04:33:16,600 --> 04:33:22,160 EMOTIONS INCLUDING MF59, THE 5987 04:33:22,160 --> 04:33:22,800 FLU VACCINE EFFECTIVE IN ELDERS 5988 04:33:22,800 --> 04:33:28,920 IS ADJUVANT WITH MF59. IN FACT 5989 04:33:28,920 --> 04:33:29,480 IT'S AUTHORIZATION AND USE 5990 04:33:29,480 --> 04:33:30,080 APPROVAL IN THE UNITED STATES 5991 04:33:30,080 --> 04:33:30,640 IS BASED ON HIS EFFICACY IN 5992 04:33:30,640 --> 04:33:39,400 ELDERS. 5993 04:33:39,400 --> 04:33:43,200 ADJUVANTATION SYSTEM OR AS03. 5994 04:33:43,200 --> 04:33:49,880 AND TLR AGONISTS ARE USED AND 5995 04:33:49,880 --> 04:33:50,360 AUTHORIZED AND APPROVED 5996 04:33:50,360 --> 04:34:00,160 VACCINES AND AS01B, WITH THE 5997 04:34:00,160 --> 04:34:10,680 SUPPONENT QS21, USED TO PROTECT 5998 04:34:13,440 --> 04:34:13,960 ELDERS AGAINST VARICELLA, 5999 04:34:13,960 --> 04:34:24,040 ZOSTER. 6000 04:34:24,040 --> 04:34:24,600 THE ADJUVENTATION SYSTEM IS 6001 04:34:24,600 --> 04:34:25,200 KEY TO THE HIGH ADVOCACY, IT 6002 04:34:25,200 --> 04:34:26,880 HAS A 95% VACCINE EFFICACY. 6003 04:34:26,880 --> 04:34:36,040 I SAW THE HEADLINES YESTERDAY 6004 04:34:36,040 --> 04:34:36,560 OF SENATOR FEINSTEIN WHO 6005 04:34:36,560 --> 04:34:37,160 SUFFERED FROM SHINGLES I HOPE 6006 04:34:37,160 --> 04:34:39,160 SHE IS RECUPERATING. 6007 04:34:39,160 --> 04:34:41,000 I WAS IN THE COMMITTEE THAT 6008 04:34:41,000 --> 04:34:41,640 HELPED APPROVE THAT VACCINE IN 6009 04:34:41,640 --> 04:34:46,240 TWO DOSES OF THE TLR9 6010 04:34:46,240 --> 04:34:47,600 ADJUVANTED VACCINE SHOWED 6011 04:34:47,600 --> 04:34:49,600 HIGHER IMMUNOGENICITY IN ELDERS 6012 04:34:49,600 --> 04:34:52,520 AND THREE DOSES OF THE 6013 04:34:52,520 --> 04:34:56,480 CONVENTIONAL ALUM-ADJUVENATED 6014 04:34:56,480 --> 04:34:57,040 VACCINE ON THE BASIS OF THE 6015 04:34:57,040 --> 04:34:57,560 EFFICACY DATA THAT WAS 6016 04:34:57,560 --> 04:35:00,200 APPROVED. 6017 04:35:00,200 --> 04:35:00,760 WE DID A LANDSCAPE ANALYSIS 6018 04:35:00,760 --> 04:35:01,360 HERE AT THE POSITION VACCINE 6019 04:35:01,360 --> 04:35:09,560 PROGRAM. WHEN I SAY WE, ETSURO 6020 04:35:09,560 --> 04:35:10,040 NANISH, A BRILLIANT AND 6021 04:35:10,040 --> 04:35:11,120 HARD-WORKING POSITION ON OUR 6022 04:35:11,120 --> 04:35:17,280 TEAM AND PARTNER WITH OUR -- 6023 04:35:17,280 --> 04:35:18,040 WITH THE USE OF ADJUVANT IN 6024 04:35:18,040 --> 04:35:20,640 OLDER ADULTS AND AGED ANIMALS 6025 04:35:20,640 --> 04:35:23,760 IN GLOBAL LITERATURE. AND WITH 6026 04:35:23,760 --> 04:35:25,160 STRUCTURED LITERATURE SEARCHES. 6027 04:35:25,160 --> 04:35:30,160 WE FOUND THAT IF YOU LOOK AT 6028 04:35:30,160 --> 04:35:31,080 PANEL A, THE GOOD NEWS IS THAT 6029 04:35:31,080 --> 04:35:31,720 THERE IS INCREASING INTEREST IN 6030 04:35:31,720 --> 04:35:34,200 THIS TOPIC. AS WE GO ACROSS 6031 04:35:34,200 --> 04:35:41,480 TIME ON THE X AXIS WE ARE 6032 04:35:41,480 --> 04:35:42,120 SEEING MORE PUBLISHED ARTICLES 6033 04:35:42,120 --> 04:35:42,720 IN HUMANS AND ANIMALS LOOKING 6034 04:35:42,720 --> 04:35:43,200 AT ADJUVANTS FOR AGED 6035 04:35:43,200 --> 04:35:43,640 INDIVIDUALS. 6036 04:35:43,640 --> 04:35:47,480 AND PANEL B, YOU SEE THAT MOST 6037 04:35:47,480 --> 04:35:48,120 STUDIES LOOK AT ONE OR AT MOST 6038 04:35:48,120 --> 04:35:49,840 TWO ADJUVANTS. VERY FEW STUDIES 6039 04:35:49,840 --> 04:35:53,120 COMPARE MULTIPLE ADJUVANTS. 6040 04:35:53,120 --> 04:35:53,680 THAT IS AN ISSUE BECAUSE WE 6041 04:35:53,680 --> 04:35:54,280 WANT TO UNDERSTAND HOW THE 6042 04:35:54,280 --> 04:35:56,120 ADJUVANTS COMPARED TO EACH 6043 04:35:56,120 --> 04:35:56,760 OTHER, ESPECIALLY AS A PIPELINE 6044 04:35:56,760 --> 04:35:59,480 OF ADJUVANTS IS GROWING. THAT 6045 04:35:59,480 --> 04:36:00,080 IS PART OF THE RATIONALE FOR 6046 04:36:00,080 --> 04:36:00,800 THE IN VITRO SYSTEMS AS WELL. 6047 04:36:00,800 --> 04:36:06,720 AND THEN IN PANEL C, THE 6048 04:36:06,720 --> 04:36:07,320 DIFFERENT ADJUVANTS EVALUATE 6049 04:36:07,320 --> 04:36:13,080 WHETHER IT IS ALUM, ETC. AND 6050 04:36:13,080 --> 04:36:13,720 YOU CAN SEE THE BREAKDOWN THERE 6051 04:36:13,720 --> 04:36:17,960 AND WE ALSO COMPARED ACROSS 6052 04:36:17,960 --> 04:36:18,560 PUBLISHED STUDIES TO SHOW THE 6053 04:36:18,560 --> 04:36:19,160 NON-ALUM ADJUVANT MAY BE MORE 6054 04:36:19,160 --> 04:36:21,680 EFFECTIVE THAN ALUM ADJUVANTS. 6055 04:36:21,680 --> 04:36:24,760 AND WE SEE IN PANEL C, ANIMAL 6056 04:36:24,760 --> 04:36:31,560 STUDIES AND IN PANELS A AND B 6057 04:36:31,560 --> 04:36:37,120 YOU CAN SEE MULTIPLE STUDIES, 6058 04:36:37,120 --> 04:36:42,000 THE STUDIES AS STATED ABOVE. IN 6059 04:36:42,000 --> 04:36:42,600 THE ANIMAL STUDY AND YOU SEE 6060 04:36:42,600 --> 04:36:44,800 THE ADJUVANT MAKES A BIG 6061 04:36:44,800 --> 04:36:45,400 DIFFERENCE VERSUS NEOADJUVANT 6062 04:36:45,400 --> 04:36:46,000 AND CAN MAKE THE AGED ANIMAL 6063 04:36:46,000 --> 04:36:46,640 LOOK LIKE A YOUNG ANIMAL WHEN 6064 04:36:46,640 --> 04:36:50,200 YOU ADD AN ADJUVANT. SO A LOT 6065 04:36:50,200 --> 04:36:50,760 OF INTERESTING DATA IN THIS 6066 04:36:50,760 --> 04:36:56,840 REVIEW ARTICLE BY NANISHI AND 6067 04:36:56,840 --> 04:37:02,440 CLINICAL INFECTIOUS DISEASES, 6068 04:37:02,440 --> 04:37:03,000 SUPPLEMENT TO THE PRECISION 6069 04:37:03,000 --> 04:37:09,760 VACCINES CONFERENCE.. 6070 04:37:09,760 --> 04:37:10,320 WE PARTNERED WITH TRYING TO 6071 04:37:10,320 --> 04:37:10,920 DEFINE WHETHER WE CAN DEVELOP 6072 04:37:10,920 --> 04:37:11,480 AN ADJUVANTED VACCINE THAT 6073 04:37:11,480 --> 04:37:12,080 COULD WORK WELL IN OLDER LIFE 6074 04:37:12,080 --> 04:37:19,560 AND WE PARTNERED WITH -- AND WE 6075 04:37:19,560 --> 04:37:23,800 OBTAINED BLOOD FROM ELDER 6076 04:37:23,800 --> 04:37:24,360 ADULTS IN THE BOSTON AREA 6077 04:37:24,360 --> 04:37:25,000 INCLUDING MY SYNAGOGUE WHO CAME 6078 04:37:25,000 --> 04:37:25,600 AT THE HEIGHT OF THE PANDEMIC 6079 04:37:25,600 --> 04:37:26,560 AND DONATED BLOOD FOR SCREENS. 6080 04:37:26,560 --> 04:37:27,200 THESE WERE INDIVIDUAL 65 YEARS 6081 04:37:27,200 --> 04:37:31,440 OF AGE AND OLDER. WE SCREEN IN 6082 04:37:31,440 --> 04:37:32,080 VITRO FOR MOLECULES THAT WOULD 6083 04:37:32,080 --> 04:37:37,920 BE EFFECTIVE AT ACTIVATING TH-1 6084 04:37:37,920 --> 04:37:38,520 TYPE IMMUNITY IMPORTANT FOR 6085 04:37:38,520 --> 04:37:39,120 ANTIVIRAL DEFENSE AND WE NOTICE 6086 04:37:39,120 --> 04:37:43,000 THE CPG WITH OR WITHOUT ALUM 6087 04:37:43,000 --> 04:37:43,640 WAS A SYSTEM THAT PARTICULARLY 6088 04:37:43,640 --> 04:37:44,200 ACTIVATED ELDER IMMUNITY IN 6089 04:37:44,200 --> 04:37:46,160 VITRO. 6090 04:37:46,160 --> 04:37:46,720 THIS ARTICLE WE PUBLISHED IN 6091 04:37:46,720 --> 04:37:47,360 SCIENCE TRANSLATIONAL MEDICINE 6092 04:37:47,360 --> 04:37:52,240 ABOUT AN ALUM HYDROXIDE, CPG 6093 04:37:52,240 --> 04:37:59,440 ADJUVANT AND ENHANCING 6094 04:37:59,440 --> 04:38:00,040 PROTECTION BY TWO RECEPTOR- 6095 04:38:00,040 --> 04:38:00,640 BINDING VACCINES AND AGED MICE 6096 04:38:00,640 --> 04:38:01,280 AND WE ACQUIRED AGED MICE WHICH 6097 04:38:01,280 --> 04:38:01,840 ARE EXPENSIVE AND ARE MORE 6098 04:38:01,840 --> 04:38:06,600 SUSCEPTIBLE ALSO TO CORONAVIRUS 6099 04:38:06,600 --> 04:38:07,200 AND DEMONSTRATED NOT JUST HI 6100 04:38:07,200 --> 04:38:07,680 IMMUNOGENICITY OF THE 6101 04:38:07,680 --> 04:38:09,360 ADJUVANTED PRODUCT BUT ALSO 6102 04:38:09,360 --> 04:38:13,040 PROTECTION. 6103 04:38:13,040 --> 04:38:13,480 THIS WORK LED TO AND 6104 04:38:13,480 --> 04:38:14,120 CONTRIBUTED TO THE INTELLECTUAL 6105 04:38:14,120 --> 04:38:19,160 BASIS FOR THE CORBID (PHONETIC) 6106 04:38:19,160 --> 04:38:20,760 VACCINE AUTHORIZED, NOW GIVEN 6107 04:38:20,760 --> 04:38:21,360 TO HUNDREDS OF MILLIONS OF 6108 04:38:21,360 --> 04:38:22,480 PEOPLE. 6109 04:38:22,480 --> 04:38:23,040 THIS IS SOME DATA FROM THAT 6110 04:38:23,040 --> 04:38:28,240 ARTICLE. YOU SEEING WITH THE 6111 04:38:28,240 --> 04:38:28,880 STAINING YOUNG VERSUS THE AGED 6112 04:38:28,880 --> 04:38:32,760 OF THE NODES, THE LYMPH NODES 6113 04:38:32,760 --> 04:38:33,400 AND AT THE BOTTOM RIGHT YOU CAN 6114 04:38:33,400 --> 04:38:39,760 SEE THE ALUMINUM HYDROXIDE TBD. 6115 04:38:39,760 --> 04:38:40,400 YOU SEE THAT IN AGED ANIMAL YOU 6116 04:38:40,400 --> 04:38:41,480 CAN GET ROBUST GENERATION OF 6117 04:38:41,480 --> 04:38:42,080 GERMINAL CENTERS WHEN YOU ADD 6118 04:38:42,080 --> 04:38:42,720 THE FULL ADJUVANT AGENT SYSTEM. 6119 04:38:42,720 --> 04:38:46,320 THE ALUM PLUS THE CPG, WHICH 6120 04:38:46,320 --> 04:38:50,920 YOU CANNOT GET UNDER THE GPS OR 6121 04:38:50,920 --> 04:38:51,520 ALUM CONDITIONS ALONE AND ON 6122 04:38:51,520 --> 04:38:52,120 THE RIGHT YOU CAN SEE SOME OF 6123 04:38:52,120 --> 04:38:56,040 THE IMMUNE CORRELATES WHETHER 6124 04:38:56,040 --> 04:39:00,680 GERMINAL CENTER B CELLS OR 6125 04:39:00,680 --> 04:39:11,240 (INDISCERNIBLE) -- AND SEE THE 6126 04:39:12,720 --> 04:39:13,240 EFFECT OF THE ADJUVANTATION 6127 04:39:13,240 --> 04:39:13,760 SYSTEM IN OTHER WORDS AND 6128 04:39:13,760 --> 04:39:14,480 PURPLE WHEN YOU COMBINE THEM 6129 04:39:14,480 --> 04:39:15,680 YOU GET THE MOST ROBUST 6130 04:39:15,680 --> 04:39:18,880 IMMUNOGENICITY. 6131 04:39:18,880 --> 04:39:19,480 ANOTHER THING IS WE WORK WITH 6132 04:39:19,480 --> 04:39:20,800 A COMPANY IN THE NOTHINGNESS 6133 04:39:20,800 --> 04:39:24,960 CALL THE LITEVAX AND THEY HAVE 6134 04:39:24,960 --> 04:39:25,560 A SOFTWARE ADVOCATE DEPICTED 6135 04:39:25,560 --> 04:39:31,400 THERE. IT INDUCES TH1 6136 04:39:31,400 --> 04:39:31,960 RESPONSES, IT SHOWS SYNERGY 6137 04:39:31,960 --> 04:39:34,760 WITH ONLY WATER TO INDUCE 6138 04:39:34,760 --> 04:39:38,160 (INDISCERNIBLE) AND ENHANCED 6139 04:39:38,160 --> 04:39:43,080 RBD NANO PARTICLE ANTIBODIES 6140 04:39:43,080 --> 04:39:43,680 AND TH1 IN T CELLS AND PROTECT 6141 04:39:43,680 --> 04:39:46,280 AGED ANIMALS PUBLISHED IN -- 6142 04:39:46,280 --> 04:39:51,160 MAGAZINE. 6143 04:39:51,160 --> 04:39:52,240 WE COMPARED HUNDREDS OF HUMAN 6144 04:39:52,240 --> 04:39:54,120 MOLECULES, COUNTER SCREEN 6145 04:39:54,120 --> 04:39:59,280 AGAINST ELDER PBNCS TO FIND 6146 04:39:59,280 --> 04:39:59,720 MOLECULES THAT WERE 6147 04:39:59,720 --> 04:40:00,280 PARTICULARLY EFFECTIVE IN 6148 04:40:00,280 --> 04:40:01,600 ACTIVATING VIRAL IMMUNITY AND 6149 04:40:01,600 --> 04:40:09,120 BYRON BROOK, HELPED US WITH THE 6150 04:40:09,120 --> 04:40:12,400 -- SMALL MOLECULE THAT HAS 6151 04:40:12,400 --> 04:40:13,040 GREATER ACTIVITY AGAINST ELDER 6152 04:40:13,040 --> 04:40:16,600 NUCLEAR CELLS AND ADULT HUMAN 6153 04:40:16,600 --> 04:40:19,880 PBMCS ON THE BOTTOM RIGHT WITH 6154 04:40:19,880 --> 04:40:20,520 TNF AS THE READER TO REDISCOVER 6155 04:40:20,520 --> 04:40:21,160 THE MARKET PARTICULARLY ACTIVE 6156 04:40:21,160 --> 04:40:22,720 IN ELDERS. NOW WE HAVE TO BE 6157 04:40:22,720 --> 04:40:24,280 WORKING ON THE MECHANISM OF 6158 04:40:24,280 --> 04:40:26,320 ACTION. WHY IS THIS MOLECULE 6159 04:40:26,320 --> 04:40:26,720 MORE ACTIVE? 6160 04:40:26,720 --> 04:40:29,320 TO CONCLUDE ADJUVANT TATIAN 6161 04:40:29,320 --> 04:40:29,800 VACCINES IS A PROMISING 6162 04:40:29,800 --> 04:40:37,600 APPROACH AND HAS 6163 04:40:37,600 --> 04:40:38,240 IMMUNOGENICITY, DURABILITY AND 6164 04:40:38,240 --> 04:40:44,240 PROTECTION. GROWING PIPELINE 6165 04:40:44,240 --> 04:40:47,720 OF CANDIDATE ADJUVANTS. 6166 04:40:47,720 --> 04:40:49,960 WE THINK OUR COLLABORATORS 6167 04:40:49,960 --> 04:40:56,200 AROUND THE GLOBE AND FOR NIA 6168 04:40:56,200 --> 04:40:56,800 THE GENEROUS SUPPORT AND YOU 6169 04:40:56,800 --> 04:40:57,360 ARE ALL INVITED TO OUR NEXT 6170 04:40:57,360 --> 04:40:57,920 PRECISION VACCINES PROGRAM 6171 04:40:57,920 --> 04:40:58,920 CONFERENCE IN ROME ON OCTOBER 5 6172 04:40:58,920 --> 04:41:04,440 AND 6. I'M HAPPY TO TAKE ANY 6173 04:41:04,440 --> 04:41:14,520 QUESTIONS. 6174 04:41:14,520 --> 04:41:20,400 >>QUESTIONS? 6175 04:41:20,400 --> 04:41:30,080 >>THANKS FOR THE TALK. YOU 6176 04:41:30,080 --> 04:41:30,600 GOING TO BE INCORPORATED 6177 04:41:30,600 --> 04:41:31,160 PRECLINICAL TESTING ON AGED 6178 04:41:31,160 --> 04:41:33,240 MICE AS PART OF YOUR PIPELINE 6179 04:41:33,240 --> 04:41:34,080 ROUTINELY? 6180 04:41:34,080 --> 04:41:34,640 >>I'M SORRY THE QUESTION IS, 6181 04:41:34,640 --> 04:41:35,320 CAN YOU REPEAT THE QUESTION? 6182 04:41:35,320 --> 04:41:42,160 >>SURE. WILL YOU BE INCLUDING 6183 04:41:42,160 --> 04:41:43,720 PRECLINICAL TESTING OF VACCINES 6184 04:41:43,720 --> 04:41:44,360 FOR ADJUVANT CANDIDATES IN AGED 6185 04:41:44,360 --> 04:41:46,320 MICE ROUTINELY? 6186 04:41:46,320 --> 04:41:48,920 >>I WILL NOT SAY ROUTINELY. I 6187 04:41:48,920 --> 04:41:49,480 WOULD SAY DEPENDING ON THE 6188 04:41:49,480 --> 04:41:50,040 DECISION WANT TO PROTECT 6189 04:41:50,040 --> 04:41:52,800 AGAINST. IF IT IS A DISEASE OF 6190 04:41:52,800 --> 04:41:56,480 PARTICULAR HITS ELDERS HARD, 6191 04:41:56,480 --> 04:41:57,080 THEN YES WE WOULD INCORPORATE 6192 04:41:57,080 --> 04:41:59,280 THAT BUT AN IMPORTANT APPROACH 6193 04:41:59,280 --> 04:41:59,880 WE TAKE IS WE FIRST PUT THINGS 6194 04:41:59,880 --> 04:42:05,200 INTO THE HUMAN IN VITRO SYSTEM. 6195 04:42:05,200 --> 04:42:05,840 SO WE PREFER NOT TO SPEND A LOT 6196 04:42:05,840 --> 04:42:06,440 OF TIME ON ANIMAL SYSTEMS IN 6197 04:42:06,440 --> 04:42:07,480 VIVO UNTIL WE CONFIRM THE 6198 04:42:07,480 --> 04:42:08,080 MOLECULES WE ARE STUDYING ARE 6199 04:42:08,080 --> 04:42:11,760 GOING TO BE ACTIVE, NOT JUST 6200 04:42:11,760 --> 04:42:12,360 TOWARDS HUMANS BUT ALSO HUMANS 6201 04:42:12,360 --> 04:42:14,160 OF THE TARGET POPULATION, 6202 04:42:14,160 --> 04:42:14,760 DEPENDING ON THE DISEASE ARE 6203 04:42:14,760 --> 04:42:15,360 VACCINE AND WHAT THE TARGET 6204 04:42:15,360 --> 04:42:20,400 WOULD BE, WHETHER INFANTS OR 6205 04:42:20,400 --> 04:42:21,000 ELDERS, WHETHER SOMEBODY WITH 6206 04:42:21,000 --> 04:42:21,560 CANCER OR OTHER COMORBID 6207 04:42:21,560 --> 04:42:23,800 CONDITIONS LIKE DIABETES. WE 6208 04:42:23,800 --> 04:42:24,360 BELIEVE IN TAILORING IT AND 6209 04:42:24,360 --> 04:42:24,840 THEN MOVING THROUGH THE 6210 04:42:24,840 --> 04:42:25,440 PIPELINE. 6211 04:42:25,440 --> 04:42:35,600 >>THANK YOU. 6212 04:42:47,400 --> 04:42:51,040 >>I WOULD ADD THERE IS GREAT 6213 04:42:51,040 --> 04:42:51,600 MECHANISTIC DATA PRESENTED 6214 04:42:51,600 --> 04:42:52,200 YESTERDAY AND TODAY WE HAVE A 6215 04:42:52,200 --> 04:42:52,800 LOT TO LEARN WE DISCOVER A 6216 04:42:52,800 --> 04:43:02,040 SMALL MOLECULE LIKE TBP 180 6217 04:43:02,040 --> 04:43:03,440 THAT WORKS WELL IN ELDERS WE 6218 04:43:03,440 --> 04:43:03,960 WELCOME COLLABORATION TO 6219 04:43:03,960 --> 04:43:04,520 UNDERSTAND THE MECHANISM OF 6220 04:43:04,520 --> 04:43:05,960 ACTION WHY A GIVEN MOLECULE 6221 04:43:05,960 --> 04:43:08,280 MIGHT WORK PARTICULARLY WELL 6222 04:43:08,280 --> 04:43:08,880 INACTIVATING INNATE IMMUNE 6223 04:43:08,880 --> 04:43:09,400 RESPONSES THROUGH PATTERN 6224 04:43:09,400 --> 04:43:11,240 RECOGNITION RECEPTORS IN ELDER, 6225 04:43:11,240 --> 04:43:16,920 MONONUCLEAR CELLS. THERE IS A 6226 04:43:16,920 --> 04:43:17,520 LOT OF MECHANISTIC WORK AHEAD 6227 04:43:17,520 --> 04:43:18,040 OF US AND WE ARE HAPPY TO 6228 04:43:18,040 --> 04:43:18,720 PARTNER WITH OTHER LABS TO SORT 6229 04:43:18,720 --> 04:43:21,560 THAT OUT. 6230 04:43:21,560 --> 04:43:22,120 >>THANK YOU VERY MUCH DOCTOR 6231 04:43:22,120 --> 04:43:24,400 LEVY. WE HAVE FIVE MINUTES 6232 04:43:24,400 --> 04:43:29,440 BREAK. WE WILL CONTINUE WITH 6233 04:43:29,440 --> 04:43:31,440 -- WE HAVE THREE MORE SPEAKERS. 6234 04:43:31,440 --> 04:43:56,840 >>THANK YOU DOCTOR LEVY. 6235 04:43:56,840 --> 04:43:57,440 >>GOOD AFTERNOON AND THANK YOU 6236 04:43:57,440 --> 04:44:01,760 FOR THE INVITATION. YESTERDAY 6237 04:44:01,760 --> 04:44:02,320 DURING HIS PRESENTATION I 6238 04:44:02,320 --> 04:44:05,680 INTRODUCE THE SUBJECT ON-- 6239 04:44:05,680 --> 04:44:08,600 IMMUNOLOGICAL RESILIENCE IN 6240 04:44:08,600 --> 04:44:18,920 THIS CASE COVID-19. 6241 04:44:21,720 --> 04:44:22,280 SO MARK IS NOT HERE BUT THE 6242 04:44:22,280 --> 04:44:22,880 INSPIRATION OF THE WORK BEGAN 6243 04:44:22,880 --> 04:44:33,440 FROM THE PAPER I WROTE IN 2006, 6244 04:44:35,760 --> 04:44:36,240 MOST OF THE ADVANCES CITED 6245 04:44:36,240 --> 04:44:36,800 INCORPORATING INTO STANDARD 6246 04:44:36,800 --> 04:44:37,400 MEDICAL PRACTICES SPECIALIZED 6247 04:44:37,400 --> 04:44:43,160 TO AN EXTENT (INDISCERNIBLE) 6248 04:44:43,160 --> 04:44:43,800 YOU MIGHT AND DON'T JUST THROW 6249 04:44:43,800 --> 04:44:44,760 YOU OUT BE OFFERED A WHITE CELL 6250 04:44:44,760 --> 04:44:49,520 BLOOD COUNT. ASK ABOUT BLOOD 6251 04:44:49,520 --> 04:44:50,160 LIPIDS YOU WILL BE GREETED WITH 6252 04:44:50,160 --> 04:44:54,280 WARM SMILES, MORALITY TALES 6253 04:44:54,280 --> 04:44:54,880 ABOUT GOOD AND BAD CHOLESTEROL, 6254 04:44:54,880 --> 04:45:00,960 AND HE GOES ON TO CONCLUDE THAT 6255 04:45:00,960 --> 04:45:01,560 ALTHOUGH THE MOUSE MODEL HAS 6256 04:45:01,560 --> 04:45:02,160 BEEN SPECTACULARLY SUCCESSFUL 6257 04:45:02,160 --> 04:45:04,680 IN ADVANCING OUR UNDERSTANDING 6258 04:45:04,680 --> 04:45:05,160 OF BASIC IMMUNOLOGICAL 6259 04:45:05,160 --> 04:45:08,560 MECHANISMS THIS RECORD IN 6260 04:45:08,560 --> 04:45:09,160 FORMULATING CLINICALLY USEFUL 6261 04:45:09,160 --> 04:45:09,640 PROTOCOLS IS MUCH LESS 6262 04:45:09,640 --> 04:45:15,120 IMPRESSIVE. 6263 04:45:15,120 --> 04:45:15,600 SO WE HAD IN THE MIDDLE 6264 04:45:15,600 --> 04:45:22,440 OVERACTIVE AND UNDERACTIVE. 6265 04:45:22,440 --> 04:45:23,080 AND WE HAVE THESE MARKERS THAT 6266 04:45:23,080 --> 04:45:23,640 ONE COULD POSSIBLY USE TO 6267 04:45:23,640 --> 04:45:27,480 DEFINE HEALTH. WE CAME UP WITH 6268 04:45:27,480 --> 04:45:29,200 THE CONCEPT OF IMMUNE 6269 04:45:29,200 --> 04:45:29,840 RESILIENCE, WHICH WE CATEGORIZE 6270 04:45:29,840 --> 04:45:31,960 NOW AS OPTIMAL, SUBOPTIMAL AND 6271 04:45:31,960 --> 04:45:32,520 NONOPTIMAL AND HOW WE CAN 6272 04:45:32,520 --> 04:45:36,720 MONITOR THEM. 6273 04:45:36,720 --> 04:45:37,280 I'M GOING TO DESCRIBE TO YOU 6274 04:45:37,280 --> 04:45:37,920 THE CONCEPT OF IMMUNE 6275 04:45:37,920 --> 04:45:41,320 RESILIENCE WHICH IS SEXUALLY 6276 04:45:41,320 --> 04:45:41,920 DIMORPHIC, MODIFIABLE TRADE 6277 04:45:41,920 --> 04:45:42,400 ASSOCIATE WITH SUPERIOR 6278 04:45:42,400 --> 04:45:45,040 IMMUNITY DEPENDENT HEALTH 6279 04:45:45,040 --> 04:45:48,280 OUTCOMES AND LONGEVITY. 6280 04:45:48,280 --> 04:45:48,880 SO THE MODEL SYSTEM AND GOING 6281 04:45:48,880 --> 04:45:50,720 TO SHOW YOU IS ABOUT LONGEVITY 6282 04:45:50,720 --> 04:45:55,920 BOTH YOUNG FEMALES HAVE 6283 04:45:55,920 --> 04:45:56,480 SURVIVAL ADVANTAGE BUT EVEN 6284 04:45:56,480 --> 04:45:57,080 AMONG YOUNG PEOPLE THERE IS A 6285 04:45:57,080 --> 04:45:58,160 WIDE VARIATION IN THE SURVIVAL 6286 04:45:58,160 --> 04:46:00,760 RATES AMONG YOUNG PEOPLE, 6287 04:46:00,760 --> 04:46:10,560 BETWEEN 40-66 AND AMONG THEM 6288 04:46:10,560 --> 04:46:11,720 THE SURVIVAL RATES ARE 6289 04:46:11,720 --> 04:46:12,600 DIFFERENCE. 6290 04:46:12,600 --> 04:46:16,960 THIS IS A NUN WHO SURVIVED 6291 04:46:16,960 --> 04:46:17,600 COVID, THE OLDEST LIVING PERSON 6292 04:46:17,600 --> 04:46:18,360 IN EUROPE AND SHE JUST GOT 6293 04:46:18,360 --> 04:46:20,400 COVID. AND UP THE STREET THERE 6294 04:46:20,400 --> 04:46:26,440 IS DOCTOR COSTA, CHIEF OF ICU 6295 04:46:26,440 --> 04:46:27,040 IN BALTIMORE WHO DIED A YOUNG 6296 04:46:27,040 --> 04:46:30,080 INDIVIDUAL AT OUR INSTITUTION. 6297 04:46:30,080 --> 04:46:31,880 WHAT ARE THE IMMUNE FEATURES 6298 04:46:31,880 --> 04:46:32,480 THAT DETERMINE SUSCEPTIBILITY 6299 04:46:32,480 --> 04:46:34,160 RESISTANCE TO DEVELOP 6300 04:46:34,160 --> 04:46:34,800 PROGRESSIVE COVID-19 REGARDLESS 6301 04:46:34,800 --> 04:46:39,280 OF THE AGE? CAN THESE FEATURES 6302 04:46:39,280 --> 04:46:40,520 BE USED FOR PROGNOSTICATION. 6303 04:46:40,520 --> 04:46:48,360 NOT JUST IN COVID AND 6304 04:46:48,360 --> 04:46:50,960 SARS-COV-2, IT SHOWS THAT 47% 6305 04:46:50,960 --> 04:46:52,520 OF YOUNG PEOPLE AND 6306 04:46:52,520 --> 04:46:56,400 (INDISCERNIBLE). 6307 04:46:56,400 --> 04:46:56,960 ON THE OTHER HAND YOU ALSO 6308 04:46:56,960 --> 04:46:57,560 HAVE THE OTHER SPECTRUM WHERE 6309 04:46:57,560 --> 04:47:00,840 YOU HAVE LIKE SARS, PEOPLE GET 6310 04:47:00,840 --> 04:47:06,800 EXPOSED BUT NOT INFECTED. HERE 6311 04:47:06,800 --> 04:47:07,280 IS A WOMAN WHO HAS HAD 6312 04:47:07,280 --> 04:47:08,200 UNPROTECTED SEX WITH UP TO 2000 6313 04:47:08,200 --> 04:47:08,800 INFECTED MEN, AND REMAINS HIV 6314 04:47:08,800 --> 04:47:11,560 UNINFECTED. YOU HAVE SIMILAR 6315 04:47:11,560 --> 04:47:13,480 EXAMPLES OF OTHER VIRUSES WHICH 6316 04:47:13,480 --> 04:47:19,320 EVEN INSTEAD YOU PEOPLE BETWEEN 6317 04:47:19,320 --> 04:47:22,320 30-50% OF PEOPLE WHO EITHER 6318 04:47:22,320 --> 04:47:22,880 HAVE SEASONAL INFECTION OR 6319 04:47:22,880 --> 04:47:23,360 REMAIN UNAFFECTED OR A 6320 04:47:23,360 --> 04:47:28,040 SYMPTOMATIC. 6321 04:47:28,040 --> 04:47:28,600 SO MY VIEW IS THAT THERE ARE 6322 04:47:28,600 --> 04:47:32,000 INFLAMMATORY STRESSES THAT WE 6323 04:47:32,000 --> 04:47:32,520 EXPERIENCE, ALONG OTHER 6324 04:47:32,520 --> 04:47:37,800 CHALLENGES LIKE AGING, AND WE 6325 04:47:37,800 --> 04:47:38,360 CONVERT THAT TO LOW IMMUNO 6326 04:47:38,360 --> 04:47:40,960 COMPETENCE HIGH INFLAMMATION 6327 04:47:40,960 --> 04:47:41,480 STAGE, AND YOU SEE SOME 6328 04:47:41,480 --> 04:47:45,480 ABBREVIATIONS LIKE THAT. 6329 04:47:45,480 --> 04:47:46,040 THERE ARE INDIVIDUALS THAT 6330 04:47:46,040 --> 04:47:47,920 PRESERVE OR RAPIDLY RESTORE 6331 04:47:47,920 --> 04:47:50,440 HIGH IMMUNOCOMPETENT, LOW 6332 04:47:50,440 --> 04:47:50,960 INFLAMMATION STAGE AND I 6333 04:47:50,960 --> 04:47:51,600 DEFINED THIS AS OPTIMAL IMMUNE 6334 04:47:51,600 --> 04:47:58,960 RESILIENCE. AND I WILL SHOW YOU 6335 04:47:58,960 --> 04:47:59,560 THIS IS MORE IN FEMALES THAN IN 6336 04:47:59,560 --> 04:48:00,560 MALES WITH ASSOCIATED LONGER 6337 04:48:00,560 --> 04:48:05,200 LIFESPAN. 6338 04:48:05,200 --> 04:48:05,800 THIS IS AN UPCOMING PAPER THAT 6339 04:48:05,800 --> 04:48:06,440 SHOULD APPEAR PROBABLY IN ABOUT 6340 04:48:06,440 --> 04:48:14,040 TWO WEEKS FROM NOW. THE TITLE 6341 04:48:14,040 --> 04:48:14,640 IS IMMUNE RESILIENCY DESPITE 6342 04:48:14,640 --> 04:48:15,240 INFLAMMATORY STRESS PROMOTES 6343 04:48:15,240 --> 04:48:15,880 LONGEVITY AND FAVORABLE HEALTH 6344 04:48:15,880 --> 04:48:17,280 OUTCOMES INCLUDING RESISTANCE 6345 04:48:17,280 --> 04:48:18,320 TO INFECTION. 6346 04:48:18,320 --> 04:48:18,880 WE ALL KNOW THAT SOME PEOPLE 6347 04:48:18,880 --> 04:48:19,520 REMAIN HEALTHY THROUGHOUT LIFE 6348 04:48:19,520 --> 04:48:20,160 THAN OTHERS BUT WE DON'T REALLY 6349 04:48:20,160 --> 04:48:26,440 KNOW WHY. WE HYPOTHESIZE THE 6350 04:48:26,440 --> 04:48:27,040 DISADVANTAGES ATTRIBUTABLE IN 6351 04:48:27,040 --> 04:48:27,560 PART TO OPTIMAL IMMUNE 6352 04:48:27,560 --> 04:48:30,520 RESILIENCY DEFINED AS THE 6353 04:48:30,520 --> 04:48:31,040 CAPACITY TO PRESERVE AND 6354 04:48:31,040 --> 04:48:32,160 RAPIDLY RESTORE IMMUNE 6355 04:48:32,160 --> 04:48:34,160 FUNCTIONS THAT PROMOTE DISEASE 6356 04:48:34,160 --> 04:48:37,920 RESISTANCE I.E. IMMUNO 6357 04:48:37,920 --> 04:48:40,240 COMPETENCY AND CONTROL 6358 04:48:40,240 --> 04:48:40,840 INFLAMMATION, AND INFECTION 6359 04:48:40,840 --> 04:48:41,360 DISEASES AS WELL AS OTHER 6360 04:48:41,360 --> 04:48:42,120 CAUSES OF INFLAMMATORY STRESS. 6361 04:48:42,120 --> 04:48:45,240 OPTIMAL IR IS HIGH IMMUNO 6362 04:48:45,240 --> 04:48:49,680 COMPETENCY. WHAT WE ARE 6363 04:48:49,680 --> 04:48:50,280 INTERESTED TO UNDERSTAND IS 6364 04:48:50,280 --> 04:48:50,800 WHEN A PERSON EXPERIENCES 6365 04:48:50,800 --> 04:48:57,040 INFLAMMATORY STRESS, HI 6366 04:48:57,040 --> 04:48:58,240 INFORMATION HERE, AND THEN 6367 04:48:58,240 --> 04:48:58,840 DURING THE REPAIR PROCESS IT 6368 04:48:58,840 --> 04:48:59,440 GOES TO SOME SORT OF BASELINE 6369 04:48:59,440 --> 04:49:00,040 AND CURRENTLY THERE IS A DROP 6370 04:49:00,040 --> 04:49:01,800 IN IMMUNO COMPETENCY, AND THEN 6371 04:49:01,800 --> 04:49:06,000 HE GOES BACK TO SOME BASELINE. 6372 04:49:06,000 --> 04:49:06,520 HOWEVER DURING AN ACUTE 6373 04:49:06,520 --> 04:49:09,200 CHRONIC OR DURING AGING 6374 04:49:09,200 --> 04:49:09,720 OTHERWISE WE EXPERIENCE 6375 04:49:09,720 --> 04:49:10,520 MULTIPLE BOUTS OF THIS UP AND 6376 04:49:10,520 --> 04:49:11,120 DOWN CYCLE THAT I SHOWED YOU 6377 04:49:11,120 --> 04:49:13,400 HERE. SOME PEOPLE RESIST ANY 6378 04:49:13,400 --> 04:49:15,320 CHANGE. THOSE ARE THE ONES WHO 6379 04:49:15,320 --> 04:49:19,560 HAVE OPTIMAL IR, COMPARED TO 6380 04:49:19,560 --> 04:49:20,080 THOSE WHO HAVE A GRADUAL 6381 04:49:20,080 --> 04:49:20,680 INCREASE OR DEGRADATION FROM 6382 04:49:20,680 --> 04:49:22,600 THE STATE TO THE STATE VERSUS 6383 04:49:22,600 --> 04:49:24,880 THOSE WHO ARE IN THE EXTREME 6384 04:49:24,880 --> 04:49:30,120 STATE CALLED NONOPTIMAL. THOSE 6385 04:49:30,120 --> 04:49:30,640 WHO ARE HERE HAVE BETTER 6386 04:49:30,640 --> 04:49:31,320 COMMUNITY DEPENDENT MODELS. 6387 04:49:31,320 --> 04:49:35,160 THE CONCEPT IS WE 6388 04:49:35,160 --> 04:49:36,200 EXPRESS A LOT OF 6389 04:49:36,200 --> 04:49:46,720 (INDISCERNIBLE). DEPENDING 6390 04:49:49,240 --> 04:49:49,800 ON WHETHER WE REMAIN IN OPTIMAL 6391 04:49:49,800 --> 04:49:50,400 STATE OR SHIFT TO SUBOPTIMAL 6392 04:49:50,400 --> 04:49:50,960 AND AN OPTIMAL AND WITH THE 6393 04:49:50,960 --> 04:49:51,600 ADJUVANT STIMULATION EVAPORATES 6394 04:49:51,600 --> 04:49:52,240 IT CAN GO BACK TO THE STATE NOT 6395 04:49:52,240 --> 04:49:52,880 ALWAYS BUT IN MANY CASES. 6396 04:49:52,880 --> 04:49:59,960 AND IN THIS CASE, THIS IS 6397 04:49:59,960 --> 04:50:00,480 MOST COMMON IN FEMALES 6398 04:50:00,480 --> 04:50:01,040 ASSOCIATED WITH HIGH IMMUNO 6399 04:50:01,040 --> 04:50:01,680 CONFIDENCE LOW INFLAMMATION AND 6400 04:50:01,680 --> 04:50:02,160 SOME PEOPLE RESIST THIS 6401 04:50:02,160 --> 04:50:02,720 DEPRIVATION, AND THERE ARE 6402 04:50:02,720 --> 04:50:04,120 PEOPLE WHO ARE SUSCEPTIBLE. 6403 04:50:04,120 --> 04:50:05,600 WE DEVELOP MARKERS WHICH I 6404 04:50:05,600 --> 04:50:06,240 WILL DESCRIBE TO YOU ASSOCIATED 6405 04:50:06,240 --> 04:50:11,200 WITH OPTIMAL IR, IMMUNE HEALTH 6406 04:50:11,200 --> 04:50:11,720 GRADES AND SURVIVAL ARE 6407 04:50:11,720 --> 04:50:13,720 ASSOCIATED GENE SIGNATURES. WE 6408 04:50:13,720 --> 04:50:17,960 APPLY THEM SO THE SEVERAL 6409 04:50:17,960 --> 04:50:18,560 COHORT, ASSOCIATED WITH THESE 6410 04:50:18,560 --> 04:50:19,080 KINDS OF OUTCOMES AND WE 6411 04:50:19,080 --> 04:50:20,520 STARTED OVER 50,000 PEOPLE, 6412 04:50:20,520 --> 04:50:21,760 NONHUMAN PRIMATES AND MICE, 6413 04:50:21,760 --> 04:50:22,400 THAT WILL DESCRIBE THE STUDY TO 6414 04:50:22,400 --> 04:50:25,040 YOU. 6415 04:50:25,040 --> 04:50:25,640 WE DEVELOPED TWO METRICS ONE 6416 04:50:25,640 --> 04:50:31,080 IS WHAT WE CALL IMMUNE HEALTH 6417 04:50:31,080 --> 04:50:33,080 GATES DEFINED WITH THE CD8 CD4 6418 04:50:33,080 --> 04:50:35,000 PROFILE AND WE DEVELOP 6419 04:50:35,000 --> 04:50:35,640 TRANSCRIPTOMIC PROFILES AS WELL 6420 04:50:35,640 --> 04:50:39,800 AS ASSOCIATED MORTALITIES. 6421 04:50:39,800 --> 04:50:40,320 IN A LARGE STUDY IN IMMUNO 6422 04:50:40,320 --> 04:50:43,000 MEDICINE WE ESTABLISH THE 6423 04:50:43,000 --> 04:50:45,120 MEDIAN CD4 CONFIDENCE ABOUT 6424 04:50:45,120 --> 04:50:45,720 50,000 HIV-INFECTED WHICH IS 6425 04:50:45,720 --> 04:50:49,200 ABOUT 800, AND THEN WE USE THE 6426 04:50:49,200 --> 04:50:51,560 CD4 CD8 RATIO. GREAT ONE IS 6427 04:50:51,560 --> 04:50:56,000 THE BEST FOR PEOPLE HAVE BOTH 6428 04:50:56,000 --> 04:50:56,560 OF THESE CONDITIONS AND IS 6429 04:50:56,560 --> 04:50:58,440 ASSOCIATED WITH RESTRAINT CD8 6430 04:50:58,440 --> 04:51:02,080 CELLS WITH HIGHER LEVELS OF CD4 6431 04:51:02,080 --> 04:51:05,880 COUNTS. 6432 04:51:05,880 --> 04:51:06,440 OF THE OTHER HAND YOU HAVE 6433 04:51:06,440 --> 04:51:08,440 PEOPLE WITH LOWER CD4 COUNTS 6434 04:51:08,440 --> 04:51:12,640 BUT A HIGH RATIO WITH RESTRAINT 6435 04:51:12,640 --> 04:51:13,280 CD8 BUT LOWER CD4 COUNT AND ON 6436 04:51:13,280 --> 04:51:14,920 THE OTHER HAND YOU HAVE 6437 04:51:14,920 --> 04:51:15,440 INDIVIDUALS THAT HAVE AN 6438 04:51:15,440 --> 04:51:17,800 INVERTED PATIENT WITH HIGH 6439 04:51:17,800 --> 04:51:19,720 CD4S, INDIVIDUALS WITH CD8 6440 04:51:19,720 --> 04:51:22,280 EXPANSION, AND THOSE WITH 6441 04:51:22,280 --> 04:51:23,400 NEITHER WITH HIGH CDH AND LOW 6442 04:51:23,400 --> 04:51:28,160 CD 4 COUNTS. 6443 04:51:28,160 --> 04:51:28,760 THESE ARE ABOUT 3000 PEOPLE WE 6444 04:51:28,760 --> 04:51:33,000 HERE AT THE BOTTOM. SO THIS 6445 04:51:33,000 --> 04:51:36,840 GROUP OF PEOPLE WITH GRADE 1, 6446 04:51:36,840 --> 04:51:37,480 YOU CAN SEE HERE THEY HAVE 1100 6447 04:51:37,480 --> 04:51:41,880 CD4 CELLS; THIS GROUP GRADE III 6448 04:51:41,880 --> 04:51:48,440 HAS 900 CD4 CELLS, THIS IS 6449 04:51:48,440 --> 04:51:48,960 ASSOCIATED WITH LOWER CD8 6450 04:51:48,960 --> 04:51:49,600 COUNTS, AND THIS IS ASSOCIATED 6451 04:51:49,600 --> 04:51:51,120 WITH NEARLY TWICE THE AMOUNT. 6452 04:51:51,120 --> 04:51:53,280 AND THIS GROUP IN GRADE II AND 6453 04:51:53,280 --> 04:51:58,440 GRADE IV, THIS IS ASSOCIATED 6454 04:51:58,440 --> 04:51:59,000 WITH CDC EXPANSION COMPARED 6455 04:51:59,000 --> 04:51:59,720 THIS GROUP. 6456 04:51:59,720 --> 04:52:02,840 SO WE ARE GOING TO USE -- TO 6457 04:52:02,840 --> 04:52:08,400 DERIVE THESE GRADES. THIS IS 6458 04:52:08,400 --> 04:52:09,040 ABOUT 3000 PEOPLE FROM STARTING 6459 04:52:09,040 --> 04:52:16,480 A COHORT AGE 15 TO 90+ GREEN IS 6460 04:52:16,480 --> 04:52:27,040 GRADE III, BLACK IS GRADE IV. 6461 04:52:27,040 --> 04:52:27,560 THIS IS A GROUP OF YOUNG 6462 04:52:27,560 --> 04:52:28,000 INDIVIDUALS WHO HAD A 6463 04:52:28,000 --> 04:52:33,000 SUSCEPTIBILITY TO DEGRADE THE 6464 04:52:33,000 --> 04:52:33,600 IR, COMPARED TO THIS GROUP OF 6465 04:52:33,600 --> 04:52:34,200 PEOPLE WHO ARE OVER WHO DESPITE 6466 04:52:34,200 --> 04:52:36,440 THE ADVANCED STAGE MANAGED TO 6467 04:52:36,440 --> 04:52:45,280 PRESERVE IHG-1. 6468 04:52:45,280 --> 04:52:45,880 HERE YOU SEE THAT MORE FEMALES 6469 04:52:45,880 --> 04:52:46,480 THAN MALES PRESERVE THE BLUE 6470 04:52:46,480 --> 04:52:51,560 COLOR. WITHIN EACH AGE GROUP 6471 04:52:51,560 --> 04:52:52,200 YOU CAN SEE THERE IS THIS LEVEL 6472 04:52:52,200 --> 04:52:52,840 OF HETEROGENEITY, SO THE GRADES 6473 04:52:52,840 --> 04:52:57,360 THAT I WILL SHOW YOU IN A 6474 04:52:57,360 --> 04:52:57,920 MINUTE DIFFERENCE BY AGE OR 6475 04:52:57,920 --> 04:53:00,280 SOME OLDER PEOPLE ALSO HAVE 6476 04:53:00,280 --> 04:53:05,120 RESISTING IHD DEGRADATION. 6477 04:53:05,120 --> 04:53:05,720 I'M GOING TO USE THESE PROXIES 6478 04:53:05,720 --> 04:53:13,000 HERE FOR IMMUNOGENIC LOAD. THE 6479 04:53:13,000 --> 04:53:13,640 OTHER HERE ARE CHILDREN WHO ARE 6480 04:53:13,640 --> 04:53:15,480 FIVE YEARS OLD LOOKING AT -- 6481 04:53:15,480 --> 04:53:18,480 AND THE AMOUNT OF -- COUNTS IN 6482 04:53:18,480 --> 04:53:22,400 THE URINE FROM 99 TO MORE THAN 6483 04:53:22,400 --> 04:53:23,720 500, PROGRESSIVE DEGRADATION IN 6484 04:53:23,720 --> 04:53:30,400 THE IR, HAVING GRADE IV. 6485 04:53:30,400 --> 04:53:33,160 HERE ARE THE SAME SEX WORKERS 6486 04:53:33,160 --> 04:53:33,800 FROM NAIROBI. YOU CAN SEE THE 6487 04:53:33,800 --> 04:53:35,800 SEX ACTIVITY AND THERE IS A 6488 04:53:35,800 --> 04:53:36,480 DECREASE IN PROPORTION AND BLUE 6489 04:53:36,480 --> 04:53:40,360 OR THE (INDISCERNIBLE). 6490 04:53:40,360 --> 04:53:43,240 THIS IS HIV-POSITIVE PEOPLE. 6491 04:53:43,240 --> 04:53:46,800 THE CAPACITY AT THE PRESERVE-- 6492 04:53:46,800 --> 04:53:49,560 THE CLIENT AND THESE ARE AN 6493 04:53:49,560 --> 04:53:50,200 ELITE GROUP OF PEOPLE WHO WERE 6494 04:53:50,200 --> 04:53:51,560 THERAPY NAïVE WHO HAVE 6495 04:53:51,560 --> 04:53:52,120 LONG-TERM NON-PROGRESSION, 6496 04:53:52,120 --> 04:53:53,280 CONTINUES TO CONTROL THE VIRUS. 6497 04:53:53,280 --> 04:53:53,840 YOU CAN SEE THE PRESERVE A 6498 04:53:53,840 --> 04:53:55,640 FAIR AMOUNT OF (INDISCERNIBLE). 6499 04:53:55,640 --> 04:53:58,680 SO WE USED COVID IS AN 6500 04:53:58,680 --> 04:54:00,120 EXPERIMENT TO TEST THE CONCEPT 6501 04:54:00,120 --> 04:54:03,160 OF IR, BECAUSE WE COULD MONITOR 6502 04:54:03,160 --> 04:54:03,720 OF PATIENTS DAILY WITH HIS 6503 04:54:03,720 --> 04:54:05,800 GRADES. WE STARTED OVER 90,000 6504 04:54:05,800 --> 04:54:10,440 MEASURES OF BIOMARKERS. WILL 6505 04:54:10,440 --> 04:54:11,000 FOLLOW PEOPLE FROM THEIR 6506 04:54:11,000 --> 04:54:15,440 PRESENTATION TO MORE THAN 2.5 6507 04:54:15,440 --> 04:54:16,000 YEARS, AGE AND SEX MATCHED 6508 04:54:16,000 --> 04:54:20,280 THEM AND CONTROL THE EFFECTS OF 6509 04:54:20,280 --> 04:54:20,880 (INDISCERNIBLE), AND COMPARED 6510 04:54:20,880 --> 04:54:21,520 TO OTHER CONDITIONS SO WE HAVE 6511 04:54:21,520 --> 04:54:22,080 A LOT OF OUTCOMES WE COULD 6512 04:54:22,080 --> 04:54:23,040 EXAMINE. WE HAD A STANDARD OF 6513 04:54:23,040 --> 04:54:27,240 CARE PANEL OF SOME 7 OR 8 6514 04:54:27,240 --> 04:54:32,320 BIOMARKERS THAT WE EVALUATED 6515 04:54:32,320 --> 04:54:32,920 IN OUR PATIENTS EVERY DAY AND 6516 04:54:32,920 --> 04:54:33,560 THEN WE HAVE VIRAL LOAD IN GENE 6517 04:54:33,560 --> 04:54:35,040 EXPRESSION. WE ALSO DEVELOPED 6518 04:54:35,040 --> 04:54:36,920 A VACCINE COHORT. 6519 04:54:36,920 --> 04:54:39,880 THE BASIC THESIS IS THIS. 6520 04:54:39,880 --> 04:54:40,400 THIS IS A GROUP OF PEOPLE 6521 04:54:40,400 --> 04:54:42,640 NORMALLY PRESENT IN THE HUMAN 6522 04:54:42,640 --> 04:54:43,680 POPULATION, BLUE BEING GREAT 6523 04:54:43,680 --> 04:54:46,040 ONE, BROWN TWO, GREEN 3, BLACK 6524 04:54:46,040 --> 04:54:52,400 4. 6525 04:54:52,400 --> 04:54:52,960 THERE WILL BE PEOPLE WHO GO 6526 04:54:52,960 --> 04:54:53,520 FROM GRADE 1 TO GRADE 1 AND 6527 04:54:53,520 --> 04:54:54,160 THEY WILL DO WELL IN THOSE FROM 6528 04:54:54,160 --> 04:54:55,720 GRADE 1 TO BROWN OR 4 DO WORSE 6529 04:54:55,720 --> 04:55:00,080 AND GROUP 2 TO WORSE 4, ARE THE 6530 04:55:00,080 --> 04:55:03,720 ONES WHO DO WORSE. 6531 04:55:03,720 --> 04:55:04,280 TO QUANTIFY THIS BEFORE WE 6532 04:55:04,280 --> 04:55:06,040 SECULARIZE THIS GRADE 2 AND 6533 04:55:06,040 --> 04:55:09,320 GRADE 4 BASED ON THE CD4 6534 04:55:09,320 --> 04:55:13,080 COUNTS, WE HAVE 6535 04:55:13,080 --> 04:55:17,280 (INDISCERNIBLE), AND GRADE 4 6536 04:55:17,280 --> 04:55:19,440 SIMILAR FASHION. 6537 04:55:19,440 --> 04:55:19,960 AND THIS IS THE VACCINE 6538 04:55:19,960 --> 04:55:21,840 CONTROL COHORT. NOTED THAT 56% 6539 04:55:21,840 --> 04:55:24,080 OVER HERE. NONE OF THE PEOPLE 6540 04:55:24,080 --> 04:55:31,800 HAVE LESS THAN 200 HERE. THESE 6541 04:55:31,800 --> 04:55:32,400 ARE SOME OF THE OTHER CONTROL 6542 04:55:32,400 --> 04:55:33,160 COHORTS, WHEN PEOPLE GET COVID 6543 04:55:33,160 --> 04:55:34,320 THERE IS A MARKED SHIFT IN THE 6544 04:55:34,320 --> 04:55:34,920 DECLINE, AND A MASSIVE SHIFT 6545 04:55:34,920 --> 04:55:41,040 BETWEEN GRADES 2 C AND 4 C, AND 6546 04:55:41,040 --> 04:55:44,120 UPON RECOVERY THIS GOES AWAY. 6547 04:55:44,120 --> 04:55:46,360 IF YOU COMPARE IT TO ACUTE HIV, 6548 04:55:46,360 --> 04:55:46,920 BASICALLY YOU CAN SEE THAT 6549 04:55:46,920 --> 04:55:53,120 LESSON 200 IN THE GRADE 2 C 6550 04:55:53,120 --> 04:55:53,640 CATEGORY IN HIV-POSITIVE 6551 04:55:53,640 --> 04:55:56,800 PEOPLE, ALL APPEAR IN THE GRADE 6552 04:55:56,800 --> 04:55:57,320 4 CATEGORY AND FOUND THAT 6553 04:55:57,320 --> 04:56:05,960 APPROXIMATELY 18% OF COVID 6554 04:56:05,960 --> 04:56:06,600 PATIENT PRESENTED WITH AN ACUTE 6555 04:56:06,600 --> 04:56:09,040 AIDS LIKE DEFICIENCY, SAME 6556 04:56:09,040 --> 04:56:09,600 POLYMORPHISM PROGNOSTIC AND 6557 04:56:09,600 --> 04:56:10,200 ASSOCIATED WITH A STRONG RISK 6558 04:56:10,200 --> 04:56:15,240 FOR DEVELOPING SEVERE COVID. 6559 04:56:15,240 --> 04:56:15,840 SO BASICALLY IN SUMMARY OF OUR 6560 04:56:15,840 --> 04:56:16,440 WORK WE FOUND THAT THOSE WHO 6561 04:56:16,440 --> 04:56:21,720 PRESENT GRADE 1, WHICH IS ABOUT 6562 04:56:21,720 --> 04:56:22,320 21% COMPARED TO THOSE WHO ARE 6563 04:56:22,320 --> 04:56:22,840 AGING ARE THE ELITE GROUP 6564 04:56:22,840 --> 04:56:23,400 COMPARED TO THE VULNERABLE 6565 04:56:23,400 --> 04:56:26,320 GROUP. THIS IS OPTIMAL IR VS. 6566 04:56:26,320 --> 04:56:29,560 NONOPTIMAL IR. THESE PEOPLE 6567 04:56:29,560 --> 04:56:30,160 HAVE THE SAME BUT THE REVERSE 6568 04:56:30,160 --> 04:56:40,640 AS WELL AS LOW NK SALES AND 6569 04:56:40,880 --> 04:56:45,520 INCREASED CRP AND - 6570 04:56:45,520 --> 04:56:46,120 ANTIBODIES-, WHEN WE LOOK BACK 6571 04:56:46,120 --> 04:56:46,720 AT THIS INDIVIDUAL WILL FIND 6572 04:56:46,720 --> 04:56:48,000 THAT INDIVIDUALS WHO CAME WITH 6573 04:56:48,000 --> 04:56:48,600 GOOD GRADES AFTER CONTROLLING 6574 04:56:48,600 --> 04:56:50,760 FOR AGE A LOWER PRE-EXISTING 6575 04:56:50,760 --> 04:56:51,360 COMORBIDITY COMPARED TO THIS 6576 04:56:51,360 --> 04:56:51,920 GROUP OF PEOPLE WITH HIGH 6577 04:56:51,920 --> 04:56:52,400 LEVELS OF PRE-EXISTING 6578 04:56:52,400 --> 04:56:53,360 COMORBIDITY. AND THIS PEOPLE 6579 04:56:53,360 --> 04:56:57,160 HAD GOOD OUTCOMES DURING ACUTE 6580 04:56:57,160 --> 04:57:05,440 AND POSTACUTE SEQUELAE, WHETHER 6581 04:57:05,440 --> 04:57:05,920 THESE PEOPLE HAD BETTER 6582 04:57:05,920 --> 04:57:06,520 OUTCOMES. BASICALLY IT TAKES 6583 04:57:06,520 --> 04:57:07,240 NEARLY 7 YEARS FOR PEOPLE TO 6584 04:57:07,240 --> 04:57:07,840 DEVELOP A LEVEL OF CD4 FOUND 6585 04:57:07,840 --> 04:57:11,280 THE PRESENTATION WITH COVID. 6586 04:57:11,280 --> 04:57:11,680 COVID IS HIGHLY 6587 04:57:11,680 --> 04:57:15,840 IMMUNOSUPPRESSIVE. 6588 04:57:15,840 --> 04:57:16,360 AND WE LOOK AT PEOPLE THAT 6589 04:57:16,360 --> 04:57:18,320 HAVE HIGH OR LOW COMORBIDITY WE 6590 04:57:18,320 --> 04:57:24,440 FIND A RESTRICTION OF 6591 04:57:24,440 --> 04:57:25,080 (INDISCERNIBLE), WHEREAS THOSE 6592 04:57:25,080 --> 04:57:25,520 WHO COME WITH HIGH 6593 04:57:25,520 --> 04:57:28,320 COMORBIDITIES AGAIN WITH THE 6594 04:57:28,320 --> 04:57:35,640 ELITE -- RESTRICTIVE AMOUNT OF 6595 04:57:35,640 --> 04:57:36,240 INFLAMMATION THAN PEOPLE COMING 6596 04:57:36,240 --> 04:57:36,880 WITH THE BAD VULNERABLE TRADE. 6597 04:57:36,880 --> 04:57:42,280 WE LOOK ACROSS AGE WE FOUND, 6598 04:57:42,280 --> 04:57:42,880 EVEN THOUGH THERE ARE CHANGES 6599 04:57:42,880 --> 04:57:43,480 OF AIDS ALWAYS THERE IS A GROUP 6600 04:57:43,480 --> 04:57:44,040 OF PEOPLE WHO MANAGED TO 6601 04:57:44,040 --> 04:57:44,640 PRESERVE GRADE 1 WILL DO THE 6602 04:57:44,640 --> 04:57:45,800 BEST. 6603 04:57:45,800 --> 04:57:46,320 AS AN EXAMPLE HERE IS THE 6604 04:57:46,320 --> 04:57:51,720 OVERALL COHORT. THERE IS A 6605 04:57:51,720 --> 04:57:52,240 SEXUAL DIMORPHISM THAT 6606 04:57:52,240 --> 04:57:52,880 REAPPEARS HERE; PEOPLE WHO ARE 6607 04:57:52,880 --> 04:57:56,520 NOT HOSPITALIZED IN GRADE 1 6608 04:57:56,520 --> 04:57:57,080 COMPARED TO THE REST OF THE 6609 04:57:57,080 --> 04:57:57,920 GROUPS THAT SURVIVOR WHO WERE 6610 04:57:57,920 --> 04:58:01,840 HOSPITALIZED, NOT SURVIVORS. 6611 04:58:01,840 --> 04:58:02,360 EVEN THOUGH THE RATE OF 6612 04:58:02,360 --> 04:58:02,960 HOSPITALIZATION INCREASES OF 6613 04:58:02,960 --> 04:58:07,400 RAGE, 35% IN THE 21-39 GROUP 6614 04:58:07,400 --> 04:58:12,480 AND 86% IN THE AGE 70 GROUP WE 6615 04:58:12,480 --> 04:58:19,200 FOUND THAT EACH GROUP -- YOU 6616 04:58:19,200 --> 04:58:19,800 CAN SEE MORE BLUE LESS BLUE, 6617 04:58:19,800 --> 04:58:21,320 MORE AND LESS. 6618 04:58:21,320 --> 04:58:27,200 ACROSS AGE GRADE ONE IS THE 6619 04:58:27,200 --> 04:58:32,320 BEST IN THIS IS A 30-YEAR-OLD 6620 04:58:32,320 --> 04:58:32,920 WITH -- PROBABILITY OF BEING 6621 04:58:32,920 --> 04:58:33,520 HOSPITALIZED ACROSS THE AGENT 6622 04:58:33,520 --> 04:58:37,200 DOES NOT MATTER. 6623 04:58:37,200 --> 04:58:37,600 SO THOSE ARE THE 6624 04:58:37,600 --> 04:58:40,360 (INDISCERNIBLE). YOU CAN 6625 04:58:40,360 --> 04:58:41,000 MEASURE WHATEVER YOU FEEL LIKE 6626 04:58:41,000 --> 04:58:44,960 IN THIS GROUP OF PEOPLE. THEY 6627 04:58:44,960 --> 04:58:45,560 ARE INDEPENDENT OF AGE, SEX, 6628 04:58:45,560 --> 04:58:50,080 BIOMARKER PROFILES. 6629 04:58:50,080 --> 04:58:50,680 THIS IS A PATTERN WHICH YOU 6630 04:58:50,680 --> 04:58:57,040 WILL FIND OF THE NON- IHG ONE 6631 04:58:57,040 --> 04:58:57,560 GREAT IT WHEN THE NORMAL 6632 04:58:57,560 --> 04:58:58,120 CONTROL POPULATION AND MORE 6633 04:58:58,120 --> 04:59:08,640 MALES PRESERVE THIS, NON-IHG 6634 04:59:10,200 --> 04:59:10,800 COMPARED THE FUMES AND THIS IS 6635 04:59:10,800 --> 04:59:11,400 SHIFTED LEFTWARDS FOR PEOPLE 6636 04:59:11,400 --> 04:59:17,480 WITH ACUTE COVID. 6637 04:59:17,480 --> 04:59:18,080 BIOMARKERS CAN GO UP WITH AGE 6638 04:59:18,080 --> 04:59:18,720 BUT THERE WILL LEAVE THIS GROUP 6639 04:59:18,720 --> 04:59:23,960 OF PEOPLE. THIS IS WHAT MY 6640 04:59:23,960 --> 04:59:24,520 MOOD LOOKS LIKE WHEN I WAS 6641 04:59:24,520 --> 04:59:25,120 MONITORING PATIENTS EVERY DAY 6642 04:59:25,120 --> 04:59:30,520 WITH THE GRADES. THE 6643 04:59:30,520 --> 04:59:31,120 NEUTRALIZING ANTIVIRAL TITERS 6644 04:59:31,120 --> 04:59:36,960 ACROSS PEOPLE OVER A PERIOD OF 6645 04:59:36,960 --> 04:59:37,560 TIME AND PEOPLE WHO PRESERVE 6646 04:59:37,560 --> 04:59:38,160 THE BEST GRADE IN THE STUDY 6647 04:59:38,160 --> 04:59:38,680 ABOUT THOSE WHO HAD GOOD 6648 04:59:38,680 --> 04:59:40,560 GRADES. 6649 04:59:40,560 --> 04:59:41,160 WHEN WE IDENTIFIED A CORE SET 6650 04:59:41,160 --> 04:59:43,480 OF SIGNATURES THAT -- AS WELL 6651 04:59:43,480 --> 04:59:46,480 AS HOSPITALIZATION, ETC., 6652 04:59:46,480 --> 04:59:47,200 RELATED TO B CELLS AS WELL AS 6653 04:59:47,200 --> 04:59:52,760 TO (INDISCERNIBLE). 6654 04:59:52,760 --> 04:59:53,320 IMPORTANT TO RECOGNIZE THAT 6655 04:59:53,320 --> 04:59:53,920 THE IMMUNE TRAITS ASSOCIATED 6656 04:59:53,920 --> 04:59:56,520 ARE CONTEXT DEPENDENT. THIS IS 6657 04:59:56,520 --> 04:59:58,720 4000 PEOPLE WITH 6658 04:59:58,720 --> 04:59:59,240 IMMUNOPHENOTYPE. WE CAN 6659 04:59:59,240 --> 05:00:00,280 CATEGORIZE THE IMMUNE TRADES 6660 05:00:00,280 --> 05:00:01,480 THAT CATEGORIZE ONLY TO THOSE 6661 05:00:01,480 --> 05:00:03,720 GRADES, ONLY TO AGE, RATES IN 6662 05:00:03,720 --> 05:00:05,240 NATURE NEITHER. I DON'T HAVE 6663 05:00:05,240 --> 05:00:09,200 TIME TO GO THROUGH THIS. 6664 05:00:09,200 --> 05:00:11,720 THE FINAL THING I WANT TO GO 6665 05:00:11,720 --> 05:00:12,280 THROUGH, AS WOMEN INCREASE 6666 05:00:12,280 --> 05:00:12,760 THEIR SEX ACTIVITY THE 6667 05:00:12,760 --> 05:00:14,560 PROPORTION OF BLUE GOES DOWN. 6668 05:00:14,560 --> 05:00:15,200 MOST OF THE RISK OF ACQUISITION 6669 05:00:15,200 --> 05:00:18,360 APPEARS IN THIS GROUP. WHEN 6670 05:00:18,360 --> 05:00:22,680 WOMEN STOP HAVING SEX, OR STOP 6671 05:00:22,680 --> 05:00:23,320 USING CONDOMS YOU CONSIDER OVER 6672 05:00:23,320 --> 05:00:33,200 TIME THEY ARE BACK TO NORMAL 6673 05:00:33,200 --> 05:00:33,760 AND EVEN AMONG PEOPLE WITH 6674 05:00:33,760 --> 05:00:34,360 AIDS, ALSO PRESERVE THE BEST 6675 05:00:34,360 --> 05:00:37,520 GRADE (INDISCERNIBLE). 6676 05:00:37,520 --> 05:00:39,720 WE IDENTIFIED A CORE SET OF 6677 05:00:39,720 --> 05:00:41,120 GENE SIGNATURES ASSOCIATED WITH 6678 05:00:41,120 --> 05:00:46,320 SECURITY IN THE COVID COHORT, 6679 05:00:46,320 --> 05:00:46,800 ASSOCIATED WITH HIGHER 6680 05:00:46,800 --> 05:00:47,360 EXPRESSION AND ASSOCIATIVE 6681 05:00:47,360 --> 05:00:51,640 MORTALITY AND THIS IS 6682 05:00:51,640 --> 05:00:52,200 ASSOCIATED WITH ASSOCIATIVE 6683 05:00:52,200 --> 05:00:52,800 SURVIVAL AND WE OVERLAID THIS 6684 05:00:52,800 --> 05:00:53,680 ON TOP OF THE FRAMINGHAM 6685 05:00:53,680 --> 05:00:54,240 COHORT, WE IDENTIFIED SOME 6686 05:00:54,240 --> 05:00:54,840 SIGNATURES COMMON TO BOTH SO 6687 05:00:54,840 --> 05:00:56,960 THIS RECORD SIGNATURE MEANS 6688 05:00:56,960 --> 05:00:59,840 ONLY PRESENT IN THE COVID 6689 05:00:59,840 --> 05:01:00,440 COHORT BUT THE SIGNATURES IN 6690 05:01:00,440 --> 05:01:03,560 GREEN OVER HERE FOR EXAMPLE, 6691 05:01:03,560 --> 05:01:05,040 HIGHER EXPRESSION OF THE 6692 05:01:05,040 --> 05:01:05,600 DEFENSE RESPONSE, BACTERIUM 6693 05:01:05,600 --> 05:01:06,120 SIGNATURE ASSOCIATED WITH 6694 05:01:06,120 --> 05:01:16,600 MORTALITY BOTH IN THE COVID 6695 05:01:17,040 --> 05:01:17,600 COHORT AND IN THE FARMING HAVE 6696 05:01:17,600 --> 05:01:18,160 COHORT AND PRE-IMMUNIZATION 6697 05:01:18,160 --> 05:01:18,760 RECEPTORS, HIGHER EXPRESSION 6698 05:01:18,760 --> 05:01:22,840 ASSOCIATED WITH SURVIVAL. 6699 05:01:22,840 --> 05:01:23,880 WE DEVELOPED THESE FINISHES 6700 05:01:23,880 --> 05:01:24,520 REMAIN ASSOCIATIVE SIGNATURES 6701 05:01:24,520 --> 05:01:25,080 ONE BY MARK DAVIS GROUP IN 6702 05:01:25,080 --> 05:01:34,160 ANOTHER RECENT IS SENMAYO AND 6703 05:01:34,160 --> 05:01:34,720 ANOTHER IS ESSENTIALLY JUST 6704 05:01:34,720 --> 05:01:35,360 CAME OUT FROM THE HARVARD GROUP 6705 05:01:35,360 --> 05:01:36,000 AND THE SIGNATURES BASICALLY-- 6706 05:01:36,000 --> 05:01:38,080 HERE IS A LONGEVITY SIGNATURE 6707 05:01:38,080 --> 05:01:40,400 FROM THE HARVARD IMMUNE ASSAY. 6708 05:01:40,400 --> 05:01:44,600 YOU CAN SEE THE MAS-1 CLUSTER 6709 05:01:44,600 --> 05:01:53,720 HERE AND THE (INDISCERNIBLE). 6710 05:01:53,720 --> 05:01:54,200 IF YOU HAVE HIGH IMMUNO 6711 05:01:54,200 --> 05:01:54,760 COMPETENCY SIGNATURE WOULD 6712 05:01:54,760 --> 05:01:55,760 LOWER INFORMATION PEOPLE LIVE 6713 05:01:55,760 --> 05:01:59,480 LONGER. THOSE WHO ARE 6714 05:01:59,480 --> 05:02:06,520 (INDISCERNIBLE) DIE QUICKLY. 6715 05:02:06,520 --> 05:02:09,040 PEOPLE WHO HAVE THEIR DOUBLE 6716 05:02:09,040 --> 05:02:09,680 GRADE, HI IMMUNO CONFIDENCE AND 6717 05:02:09,680 --> 05:02:10,800 NO INFORMATION PROFILE ARE THE 6718 05:02:10,800 --> 05:02:12,000 PEOPLE WHO GOT GREAT ONE. THIS 6719 05:02:12,000 --> 05:02:14,680 IS A CORE FROM SLE THIS IS 6720 05:02:14,680 --> 05:02:23,320 FROPM ACUTE COVID-19. 6721 05:02:23,320 --> 05:02:23,920 AS LONG AS THEY HAVE GREAT ONE 6722 05:02:23,920 --> 05:02:25,360 THEY HAD ENRICHED SURVIVAL 6723 05:02:25,360 --> 05:02:26,320 PROFILE. THE MORTALITY PROFILE 6724 05:02:26,320 --> 05:02:28,840 SIGNATURE (INDISCERNIBLE). 6725 05:02:28,840 --> 05:02:31,600 THE QUESTION ARISES, DOES IT 6726 05:02:31,600 --> 05:02:32,160 HAVE ANYTHING TO DO WITH 6727 05:02:32,160 --> 05:02:37,840 INFLUENZA? THIS IS A COHORT OF 6728 05:02:37,840 --> 05:02:38,480 NATURAL SEASONAL INFECTION AND 6729 05:02:38,480 --> 05:02:39,120 THIS IS A SAMPLE OF BLOOD A FEW 6730 05:02:39,120 --> 05:02:39,680 MONTHS BEFORE THEY HAD THE 6731 05:02:39,680 --> 05:02:40,280 SEASONAL FLU. AND THEN THEY 6732 05:02:40,280 --> 05:02:50,840 ZERO, 2, 6, 6, 21 DAYS. AND 6733 05:02:50,840 --> 05:02:51,480 YOU CAN SEE IS THAT NEARLY ALL 6734 05:02:51,480 --> 05:03:01,960 PEOPLE WHO DEVELOP ACUTE AND 6735 05:03:12,240 --> 05:03:12,840 YOU CAN SEE IS THAT NEARLY ALL 6736 05:03:12,840 --> 05:03:13,360 PEOPLE WHO DEVELOP ACUTE 6737 05:03:13,360 --> 05:03:13,960 RESPIRATORY INFECTION DURING 6738 05:03:13,960 --> 05:03:14,440 THE NATURAL SEASON ALL 6739 05:03:14,440 --> 05:03:15,080 DEVELOPED AS MORTALITY PROFILE 6740 05:03:15,080 --> 05:03:15,720 OVER TIME THEY WERE CONSTITUTED 6741 05:03:15,720 --> 05:03:17,080 (INDISCERNIBLE). 6742 05:03:17,080 --> 05:03:17,480 PEOPLE WHO WERE MORE 6743 05:03:17,480 --> 05:03:18,080 SYMPTOMATIC WE EXAMINED THE 6744 05:03:18,080 --> 05:03:22,520 GENE PROFILE HERE AND HERE. 6745 05:03:22,520 --> 05:03:23,120 THOSE WHO BECAME SYSTEMATIC 6746 05:03:23,120 --> 05:03:23,720 TURN ON THE MORTALITY PROFILE 6747 05:03:23,720 --> 05:03:26,920 AND THEY CAN SEE THE YELLOW 6748 05:03:26,920 --> 05:03:27,560 FROM HERE TO HERE AND THOSE WHO 6749 05:03:27,560 --> 05:03:28,160 ARE ASYMPTOMATIC YOU CAN SEE 6750 05:03:28,160 --> 05:03:29,280 THE INCREASE THE AMOUNT OF 6751 05:03:29,280 --> 05:03:29,760 BLUE, SO THEY REMAIN A 6752 05:03:29,760 --> 05:03:31,160 SYSTEMATIC SO THE SURVIVAL 6753 05:03:31,160 --> 05:03:33,840 PROFILE (INDISCERNIBLE) THIS IS 6754 05:03:33,840 --> 05:03:41,160 PURE INFLUENZA CHALLENGE COHORT. 6755 05:03:41,160 --> 05:03:41,720 YOU CAN SEE THAT THOSE WHO 6756 05:03:41,720 --> 05:03:42,360 WORK SYSTEMATIC ALL WERE IN THE 6757 05:03:42,360 --> 05:03:42,880 YELLOW AND THOSE WHO WERE 6758 05:03:42,880 --> 05:03:45,440 ASYMPTOMATIC WERE IN BLUE. 6759 05:03:45,440 --> 05:03:45,880 I DESCRIBED TO YOU A 6760 05:03:45,880 --> 05:03:46,480 MONITORING SYSTEM TO MEASURE 6761 05:03:46,480 --> 05:03:47,160 THE IMMUNOLOGICAL RESILIENCY OF 6762 05:03:47,160 --> 05:03:51,280 PEOPLE IN HERE OF PEOPLE DURING 6763 05:03:51,280 --> 05:03:52,480 40-50, YOU CAN SEE THIS GROUP 6764 05:03:52,480 --> 05:03:55,120 OF PEOPLE HERE SOME OF THEM, 6765 05:03:55,120 --> 05:04:02,240 25%, IN1 AND 45% ARE IN BLUE. 6766 05:04:02,240 --> 05:04:02,840 HE IS THE NUMBER GOES UP AND 6767 05:04:02,840 --> 05:04:03,440 YOU CAN SEE THE HETEROGENEITY 6768 05:04:03,440 --> 05:04:04,760 GO UP. 6769 05:04:04,760 --> 05:04:05,320 SO WHAT I WANT TO DESCRIBE 6770 05:04:05,320 --> 05:04:05,840 WITH YOU IS A PROCESS FOR 6771 05:04:05,840 --> 05:04:08,800 IMPLANTING STRESS UPPERS IN 6772 05:04:08,800 --> 05:04:09,400 VARIOUS CONDITIONS AND THOSE 6773 05:04:09,400 --> 05:04:10,000 WHO MANAGED TO PRESERVE THE 6774 05:04:10,000 --> 05:04:14,760 SUBOPTIMAL IR, BETTER IN MALES 6775 05:04:14,760 --> 05:04:15,240 AND FEMALES IN THIS IS 6776 05:04:15,240 --> 05:04:18,400 ASSOCIATED WITH GOOD OUTCOMES. 6777 05:04:18,400 --> 05:04:20,600 I WAS ASKED TO SAY SOMETHING 6778 05:04:20,600 --> 05:04:21,160 ABOUT CHALLENGES. THE FIRST 6779 05:04:21,160 --> 05:04:25,600 CHALLENGE OF COURSES ARE THERE 6780 05:04:25,600 --> 05:04:29,040 DISTINCT FORMS OF 6781 05:04:29,040 --> 05:04:38,120 IMMUNOSENESCENCE? WHAT IS AN 6782 05:04:38,120 --> 05:04:38,760 FROM TORY STRESS ASSOCIATED AGE 6783 05:04:38,760 --> 05:04:49,240 INDEPENDENT IMMUNOSENESCENCE. 6784 05:04:49,640 --> 05:04:50,240 AND THE OTHERS CHRONOLOGICALLY 6785 05:04:50,240 --> 05:04:55,040 IS DEPENDENT IMMUNOSENESENCE. 6786 05:04:55,040 --> 05:04:55,640 RESEARCH CHALLENGES IS THERE A 6787 05:04:55,640 --> 05:04:56,160 WAY TO RECONSTITUTE THE 6788 05:04:56,160 --> 05:04:58,000 RESILIENCE? THIS IS SOME OF THE 6789 05:04:58,000 --> 05:04:59,920 PEOPLE WHO DID THE WORK. VERY 6790 05:04:59,920 --> 05:05:10,480 BIG TEAM, NATHAN AND JUSTIN THE 6791 05:05:12,680 --> 05:05:13,240 BIOINFORMATICS AND I THANK YOU 6792 05:05:13,240 --> 05:05:23,440 VERY MUCH. 6793 05:05:24,360 --> 05:05:32,280 >> 6794 05:05:32,280 --> 05:05:36,920 WE CAN HAVE A VERY SHORT 6795 05:05:36,920 --> 05:05:47,400 QUESTION/ANSWER. >>>>WHAT 6796 05:06:56,920 --> 05:07:03,840 HAPPENS IN TERMS OF 6797 05:07:03,840 --> 05:07:07,200 (INDISCERNIBLE)? 6798 05:07:07,200 --> 05:07:07,680 I WANT TO START WITH THE 6799 05:07:07,680 --> 05:07:09,880 PARADOX. IT HAS BEEN KNOWN FOR 6800 05:07:09,880 --> 05:07:11,480 QUITE SOME TIME, MAYBE 10 YEARS 6801 05:07:11,480 --> 05:07:17,120 OR SO, THAT T-CELLS ARE LESS 6802 05:07:17,120 --> 05:07:22,080 RESPONSIVE TO (INDISCERNIBLE). 6803 05:07:22,080 --> 05:07:24,000 A NUMBER OF DIFFERENT REASONS. 6804 05:07:24,000 --> 05:07:25,840 ONE IS A HAVE IMPAIRED 6805 05:07:25,840 --> 05:07:26,520 (INDISCERNIBLE), YOU CAN SEE IN 6806 05:07:26,520 --> 05:07:36,960 THE UPPER -- IT ACHIEVES 6807 05:07:37,320 --> 05:07:42,360 (INDISCERNIBLE) -- 6808 05:07:42,360 --> 05:07:44,680 -- YOU WOULD EXPECT THE MEMORY 6809 05:07:44,680 --> 05:07:52,760 T-CELLS TO (INDISCERNIBLE). 6810 05:07:52,760 --> 05:07:53,160 IF YOU LOOK AT THE 6811 05:07:53,160 --> 05:07:56,640 CONSCRIPTION FACTOR, WE STARTED 6812 05:07:56,640 --> 05:07:59,200 THIS ABOUT FIVE YEARS AGO, AT 6813 05:07:59,200 --> 05:08:03,160 THE PEAK OF THE T-CELL 6814 05:08:03,160 --> 05:08:04,880 RESPONSE, THE PROFILE OF -- NOT 6815 05:08:04,880 --> 05:08:15,440 SURE WHY -- THE LOW EXPRESSION 6816 05:08:30,800 --> 05:08:36,120 OF THE -- YOU HAVE THE 6817 05:08:36,120 --> 05:08:36,760 PHENOTYPE OF THE RECEPTOR CELL 6818 05:08:36,760 --> 05:08:45,240 IN SPITE OF THE TCR. IT WAS 6819 05:08:45,240 --> 05:08:45,840 INTERESTING CAN YOU ACTUALLY 6820 05:08:45,840 --> 05:08:48,920 GET ACUTE RECEPTOR STIMULATION 6821 05:08:48,920 --> 05:08:49,520 WITH THE ABDOMINAL EFFECT OF 6822 05:08:49,520 --> 05:08:54,440 THE PHENOTYPE. AND IT PEAKED 6823 05:08:54,440 --> 05:08:57,080 IN THE FIRST 48 HOURS, IT 6824 05:08:57,080 --> 05:08:59,320 COMBINED WITH THE-- AND HERE IS 6825 05:08:59,320 --> 05:09:01,200 THE DATA AND THE 6826 05:09:01,200 --> 05:09:03,920 (INDISCERNIBLE). 6827 05:09:03,920 --> 05:09:06,440 WHAT THAT MEANS IS ESSENTIALLY 6828 05:09:06,440 --> 05:09:11,360 WE TRIED TO IDENTIFY ALL SITES 6829 05:09:11,360 --> 05:09:16,240 THAT ARE DIFFERENTIALLY -- -- 6830 05:09:16,240 --> 05:09:25,920 CLASS THEM INTO A TIME KLUSTER, 6831 05:09:25,920 --> 05:09:34,040 ARRANGED AST C1 THROUGH C6. 6832 05:09:34,040 --> 05:09:41,360 THIS IS A (INDISCERNIBLE) THIS 6833 05:09:41,360 --> 05:09:46,200 PARTICULAR CLUSTER. BOTH THE 6834 05:09:46,200 --> 05:09:47,560 OLD AND YOUNG LOOK SIMILAR. IN 6835 05:09:47,560 --> 05:09:51,960 SPITE OF THE TCR ADULATION THE 6836 05:09:51,960 --> 05:09:56,480 OLDER -- HAS (INDISCERNIBLE) -- 6837 05:09:56,480 --> 05:10:01,480 SO NOT FRAIL PEOPLE. THERE ARE 6838 05:10:01,480 --> 05:10:03,280 TINY DIFFERENCES. THERE IS 6839 05:10:03,280 --> 05:10:06,680 ONLY ONE CLUSTER WHICH APPEARS 6840 05:10:06,680 --> 05:10:07,320 TO BE IN YOUNG PEOPLE; DOES NOT 6841 05:10:07,320 --> 05:10:17,800 APPEAR TO BE IN OLDER PEOPLE. 6842 05:10:18,480 --> 05:10:19,040 THERE ARE SUBTLE CHANGES. IF 6843 05:10:19,040 --> 05:10:21,080 YOU LOOK AT THE DIFFERENT 6844 05:10:21,080 --> 05:10:22,840 MOTIFFS THROUGHOUT THE 6845 05:10:22,840 --> 05:10:33,360 ACTIVATION, YOU SEE THAT -- YOU 6846 05:10:36,800 --> 05:10:44,960 SEE THAT THERE ARE A NUMBER OF 6847 05:10:44,960 --> 05:10:45,520 DIFFERENT MOTIFFS THAT ARE 6848 05:10:45,520 --> 05:10:47,400 GETTING MORE ACCESSIBILITY. 6849 05:10:47,400 --> 05:10:50,200 CERTAINLY NOT THE CASE WHERE 6850 05:10:50,200 --> 05:10:53,200 YOU HAVE INCREASED MOTIF EXPECT 6851 05:10:53,200 --> 05:11:00,000 ABILITY IN THE YOUNG. A MOTIF 6852 05:11:00,000 --> 05:11:01,480 HERE IS RED OR BROWN COLOR AND 6853 05:11:01,480 --> 05:11:03,080 INTERMEDIATE IS YELLOW, 6854 05:11:03,080 --> 05:11:12,320 NON-ACCESSIBLE IS BLUE-COLLAR. 6855 05:11:12,320 --> 05:11:12,920 YOU SEE THAT PRETTY MUCH ALL 6856 05:11:12,920 --> 05:11:13,520 CHROMATIN OPENING HAPPENING IS 6857 05:11:13,520 --> 05:11:14,080 MORE PRONOUNCED IN OLDER 6858 05:11:14,080 --> 05:11:16,960 INDIVIDUALS. 6859 05:11:16,960 --> 05:11:22,240 SO IF YOU SEE ALL DIFFERENT 6860 05:11:22,240 --> 05:11:22,800 (INDISCERNIBLE), YOU HAVE A 6861 05:11:22,800 --> 05:11:25,080 FOCUS ON THE SLIDE THAT IS 6862 05:11:25,080 --> 05:11:25,600 DIFFERENTIALLY ACCESSIBLE 6863 05:11:25,600 --> 05:11:27,080 BETWEEN YOUNG AND OLD. YOU 6864 05:11:27,080 --> 05:11:30,200 ESSENTIALLY GET THE SAME STORY. 6865 05:11:30,200 --> 05:11:32,320 THIS IS PASSED IN 10 DIFFERENT 6866 05:11:32,320 --> 05:11:35,800 CLUSTERS. YOU CAN SEE THE 6867 05:11:35,800 --> 05:11:41,880 OPENING ACTIVATION. THE PLUS 6868 05:11:41,880 --> 05:11:45,440 AND DOWN, CLOSING ACTIVATION. 6869 05:11:45,440 --> 05:11:47,320 YOU SEE THE YOUNG PEOPLE ON THE 6870 05:11:47,320 --> 05:11:49,000 LEFT SIDE, DIFFERENT TIME 6871 05:11:49,000 --> 05:11:53,080 POINT, OPENING LEFT 6872 05:11:53,080 --> 05:11:54,160 (INDISCERNIBLE). 6873 05:11:54,160 --> 05:12:04,080 IN PARTICULAR FOR THE SECOND 6874 05:12:04,080 --> 05:12:04,640 CLUSTER, WHICH CONSTRICTION 6875 05:12:04,640 --> 05:12:05,200 MOTIFFS ARE NOT IN THIS 6876 05:12:05,200 --> 05:12:06,280 PARTICULAR CLUSTER, ARE STATED 6877 05:12:06,280 --> 05:12:07,920 ON THE LEFT SIDE. 6878 05:12:07,920 --> 05:12:15,720 YOU SEE THE ATF3 AND STAT, 6879 05:12:15,720 --> 05:12:19,200 MORE ACCESSIBLE IN OLD AGE. 6880 05:12:19,200 --> 05:12:21,040 YOU CAN CONFIRM IF YOU FOLLOW 6881 05:12:21,040 --> 05:12:25,320 IT UP WITH EXPRESSION DATA. WE 6882 05:12:25,320 --> 05:12:25,840 FOCUS ON THIS PARTICULAR 6883 05:12:25,840 --> 05:12:29,000 CLUSTER TOOL. AND LOOKED AT 6884 05:12:29,000 --> 05:12:31,480 THE DIFFERENT COMPONENTS AND 6885 05:12:31,480 --> 05:12:41,920 THE AVERAGE INCLUDED STAT5 OR 6886 05:12:41,920 --> 05:12:42,480 NPHGS, WE USE TWO DIFFERENT 6887 05:12:42,480 --> 05:12:52,960 LEVELS OF ACCUMULATION, LAW 6888 05:12:58,960 --> 05:12:59,320 ACCUMULATION, HIGH 6889 05:12:59,320 --> 05:12:59,920 RECOMMENDATION YOU SEE YOUNG 6890 05:12:59,920 --> 05:13:00,560 PEOPLE ON THE LEFT SIDE AND THE 6891 05:13:00,560 --> 05:13:05,640 OLDER PEOPLE IN THE RIGHT. 6892 05:13:05,640 --> 05:13:06,720 IF YOU LOOK AT THE RIGHT LOWER 6893 05:13:06,720 --> 05:13:12,240 CORNER, INHIBITED STAT 5 6894 05:13:12,240 --> 05:13:13,040 PHOSPHORYLATION, WE CAN 6895 05:13:13,040 --> 05:13:17,280 INCREASE IN (INDISCERNIBLE). 6896 05:13:17,280 --> 05:13:18,720 IF YOU FOLLOW THAT UP, 6897 05:13:18,720 --> 05:13:23,920 FOCUSING ON A FEW -- WITHIN THE 6898 05:13:23,920 --> 05:13:32,120 FIRST 24 HOURS, LOOKING AT 6899 05:13:32,120 --> 05:13:32,680 FEWER TRANSCRIPTION FACTOR 6900 05:13:32,680 --> 05:13:38,200 MOTIFFS THE UPPER ONE SHOW GENE 6901 05:13:38,200 --> 05:13:39,680 EXPRESSION IN THE LOW IS THE 6902 05:13:39,680 --> 05:13:50,240 STABILITY, (INDISCERNIBLE) MORE 6903 05:13:50,240 --> 05:13:53,960 ACCESSIBLE THE LAST CLUSTER. 6904 05:13:53,960 --> 05:13:54,560 IF YOU LOOK AT THE YOUNG SIDE 6905 05:13:54,560 --> 05:14:00,600 AGAIN YOU HAVE LESS EXPRESSION. 6906 05:14:00,600 --> 05:14:01,440 LESS ACCESSIBILITY 6907 05:14:01,440 --> 05:14:04,520 (INDISCERNIBLE). 6908 05:14:04,520 --> 05:14:08,160 PRDM1 -- FACTORS OF 6909 05:14:08,160 --> 05:14:11,360 DIFFERENTIATION. YOU CAN SEE 6910 05:14:11,360 --> 05:14:12,000 THE INFORMATION (INDISCERNIBLE) 6911 05:14:12,000 --> 05:14:19,480 -- AND IN ONE CLUSTER. AND 6912 05:14:19,480 --> 05:14:21,400 ACCESSIBILITY IS EVEN MORE, 6913 05:14:21,400 --> 05:14:26,560 MUCH MORE EVIDENT EARLY IN THE 6914 05:14:26,560 --> 05:14:28,960 T-CELL ACTIVATION CLUSTER. 6915 05:14:28,960 --> 05:14:29,480 THIS SUMMARIZES WHAT I 6916 05:14:29,480 --> 05:14:31,680 MENTIONED. 6917 05:14:31,680 --> 05:14:41,280 YOU HAVE REDUCED -- 6918 05:14:41,280 --> 05:14:45,040 PHOSPHORYLATION -- THE 6919 05:14:45,040 --> 05:14:46,320 PHOSPHORYLATION FACTOR IS 6920 05:14:46,320 --> 05:14:53,240 (INDISCERNIBLE). YOU CAN HAVE 6921 05:14:53,240 --> 05:14:53,840 OLDER NAïVE, YOU HAVE THE 6922 05:14:53,840 --> 05:14:58,360 EQUATION OF TWO RECEPTORS IN 6923 05:14:58,360 --> 05:14:59,000 THE REASON FOR THIS EXPRESSION 6924 05:14:59,000 --> 05:14:59,480 IS A LOTS OF DIFFERENT 6925 05:14:59,480 --> 05:15:05,080 (INDISCERNIBLE) AND IT HAS A 6926 05:15:05,080 --> 05:15:07,120 TRANSCRIPTION FACTOR DOMINATED 6927 05:15:07,120 --> 05:15:11,880 BY BATF AND IRF4. DIMINISHED 6928 05:15:11,880 --> 05:15:14,840 AND TRANSCRIPTION FACTORS LIKE 6929 05:15:14,840 --> 05:15:19,400 TCF 1 AND BACH2 IMPORTANT FOR 6930 05:15:19,400 --> 05:15:21,040 MEMORY DIFFERENTIATION. 6931 05:15:21,040 --> 05:15:25,280 T-CELLS IN OLDER DIFFERENTIATE 6932 05:15:25,280 --> 05:15:29,080 INTO -- CELLS, FAILURE TO 6933 05:15:29,080 --> 05:15:33,480 DIFFERENTIATE (INDISCERNIBLE). 6934 05:15:33,480 --> 05:15:38,320 I THINK I MENTIONED ALREADY IN 6935 05:15:38,320 --> 05:15:43,960 THE INITIAL SLIDE, THE FINAL 6936 05:15:43,960 --> 05:15:46,960 TRANSCRIPTION FACTORS. IT IS 6937 05:15:46,960 --> 05:15:49,120 ALSO IMPORTANT FOR MEMORY 6938 05:15:49,120 --> 05:15:54,880 DIFFERENTIATION. FOX01. 6939 05:15:54,880 --> 05:15:55,480 IS SLIGHTLY DIFFERENT TERMS OF 6940 05:15:55,480 --> 05:15:58,720 THE MECHANISM. FOX01 RAPIDLY 6941 05:15:58,720 --> 05:16:00,640 DEGRADES AFTER ACTIVATION. 6942 05:16:00,640 --> 05:16:10,560 ESSENTIALLY WITHIN 2-3 DAYS. 6943 05:16:10,560 --> 05:16:11,200 IT IS REALLY UNDETECTABLE. AND 6944 05:16:11,200 --> 05:16:11,920 THEN IT SLOWLY RECOVERS, 6945 05:16:11,920 --> 05:16:13,280 RECOVERS MORE IN YOUNG THAN IN 6946 05:16:13,280 --> 05:16:16,440 OLD PEOPLE. YOUNG PEOPLE ARE 6947 05:16:16,440 --> 05:16:17,080 MORE RESILIENT IF YOU THINK OF 6948 05:16:17,080 --> 05:16:19,200 THE LAST TALK. 6949 05:16:19,200 --> 05:16:21,080 THE REASON FOR THIS ONE IS 6950 05:16:21,080 --> 05:16:25,360 SUSTAINED (INDISCERNIBLE) AND 6951 05:16:25,360 --> 05:16:27,480 -- ACTIVATION ALSO 6952 05:16:27,480 --> 05:16:30,040 (INDISCERNIBLE) AND THEN IT'S 6953 05:16:30,040 --> 05:16:31,840 DEGRADED. 6954 05:16:31,840 --> 05:16:32,440 ONE OF THE INTERESTING PARTS 6955 05:16:32,440 --> 05:16:39,760 OF FOX01 IS IT EVENTUALLY 6956 05:16:39,760 --> 05:16:41,040 IMPAIRS LYSOSOMAL BIOGENESIS. 6957 05:16:41,040 --> 05:16:44,480 IN THE ABSENCE OF FOX01 YOU 6958 05:16:44,480 --> 05:16:48,480 CANNOT GENERATE NEW ISOZYMES. 6959 05:16:48,480 --> 05:16:51,560 A NUMBER OF DIFFERENT 6960 05:16:51,560 --> 05:17:01,520 TRANSCRIPTION FACTORS 6961 05:17:01,520 --> 05:17:02,120 (INDISCERNIBLE), MANY OF THE 6962 05:17:02,120 --> 05:17:03,040 ENZYMES THAT ARE IN LYSOSOME -- 6963 05:17:03,040 --> 05:17:08,880 IN THE ABSENCE OF FOX01 YOU 6964 05:17:08,880 --> 05:17:10,680 HAVE REDUCED EXPRESSION. AND 6965 05:17:10,680 --> 05:17:12,960 YOU CAN SEE ON THE LEFT SIDE, 6966 05:17:12,960 --> 05:17:15,080 YOU CAN SEE YOUNG AND OLD, OLD 6967 05:17:15,080 --> 05:17:21,320 IN BLUE, YOUNG IN RED, THE 6968 05:17:21,320 --> 05:17:28,480 EXPRESSION OF THESE ENZYMES IS 6969 05:17:28,480 --> 05:17:32,200 DECREASED. ALL LYSOSOME GENES 6970 05:17:32,200 --> 05:17:33,320 DISAPPEAR-- YOU SEE THAT PRETTY 6971 05:17:33,320 --> 05:17:36,240 MUCH THE EXPRESSION OF LYSOSOME 6972 05:17:36,240 --> 05:17:44,880 GENES (INDISCERNIBLE). 6973 05:17:44,880 --> 05:17:53,120 LYSOSOMES-- BASED ON -- IF YOU 6974 05:17:53,120 --> 05:18:02,440 FOUND A CERTAIN MECHANISM OF 6975 05:18:02,440 --> 05:18:03,080 HOW ACTUALLY LYSOSOMES GENESIS 6976 05:18:03,080 --> 05:18:05,040 HOW IT IS AFFECTED, THIS HAS TO 6977 05:18:05,040 --> 05:18:08,240 DO WITH TCF1, REDUCED 6978 05:18:08,240 --> 05:18:15,240 EXPRESSION IN OLDER INDIVIDUALS 6979 05:18:15,240 --> 05:18:15,840 AND TCF1 WE HAVE TRANSCRIPTION 6980 05:18:15,840 --> 05:18:16,520 FACTOR, IT IS VERY MUCH CONTEXT 6981 05:18:16,520 --> 05:18:18,240 DEPENDENT. MANY GENES ARE 6982 05:18:18,240 --> 05:18:27,960 REPRESSED BY TCF1 6983 05:18:27,960 --> 05:18:28,600 (INDISCERNIBLE), AS YOU CAN SEE 6984 05:18:28,600 --> 05:18:34,320 HERE IN THE PLOT, WHICH 6985 05:18:34,320 --> 05:18:36,040 COMPARES TCF1 POSITIVE COMPARED 6986 05:18:36,040 --> 05:18:38,840 TO NEGATIVE. TCF1 INDUCES THE 6987 05:18:38,840 --> 05:18:45,360 CELL (INDISCERNIBLE) -- 6988 05:18:45,360 --> 05:18:51,240 CONSCRIPTION FACTOR IS IN 1 -- 6989 05:18:51,240 --> 05:18:56,320 ESSENTIALLY REPRESSED BY 6990 05:18:56,320 --> 05:18:59,280 T-CELLS (INDISCERNIBLE). 6991 05:18:59,280 --> 05:18:59,800 WE WERE INTERESTED IN ONE 6992 05:18:59,800 --> 05:19:02,120 PARTICULAR GENE CALLED 6993 05:19:02,120 --> 05:19:06,920 (INDISCERNIBLE) ALSO THE FIRST 6994 05:19:06,920 --> 05:19:10,200 TCF1. 6995 05:19:10,200 --> 05:19:11,480 YOU CAN SEE ON THE RIGHT SIDE, 6996 05:19:11,480 --> 05:19:20,360 IF YOU SILENCED TCF1, IT'S 6997 05:19:20,360 --> 05:19:20,960 ABOUT 50% REGULATION ENDED UP 6998 05:19:20,960 --> 05:19:26,480 REGULATES AND YOU GET HERE. 6999 05:19:26,480 --> 05:19:27,120 THE ULTIMATE EXPRESSION IS THAT 7000 05:19:27,120 --> 05:19:29,920 IT INCREASES. 7001 05:19:29,920 --> 05:19:36,200 -- IS ONE OF THE DOMINANT 7002 05:19:36,200 --> 05:19:41,760 GENE THAT CAME UP, ESSENTIAL IN 7003 05:19:41,760 --> 05:19:42,360 THE FIRST SET AND ON THE LEFT 7004 05:19:42,360 --> 05:19:44,920 SIDE YOU SEE THE PLOT OF GENES 7005 05:19:44,920 --> 05:19:45,520 THAT ARE DOMINANTLY CHANGING 7006 05:19:45,520 --> 05:19:50,440 WITH AGE. THE SIZE OF THE -- 7007 05:19:50,440 --> 05:19:54,600 INDICATES ACCESSIBILITY. THE 7008 05:19:54,600 --> 05:19:55,240 COLOR INDICATES THE EXPRESSION 7009 05:19:55,240 --> 05:19:58,000 LEVEL. YOU SEE THE PRETTY MUCH 7010 05:19:58,000 --> 05:20:01,080 KISH (PHONETIC) HAS A 7011 05:20:01,080 --> 05:20:06,440 RELATIVELY LARGE SIZE. THE 7012 05:20:06,440 --> 05:20:10,280 KISH CHANGE AND THE DATA 7013 05:20:10,280 --> 05:20:14,000 PREDICTS THAT THE CHANGE IS 7014 05:20:14,000 --> 05:20:16,960 HIGHLY (INDISCERNIBLE) IN ALL 7015 05:20:16,960 --> 05:20:19,000 INDIVIDUALS. 7016 05:20:19,000 --> 05:20:28,960 WHAT KISH DOES IS THE MOLECULE 7017 05:20:28,960 --> 05:20:32,040 THE TARGETS OTHER MOLECULES. IT 7018 05:20:32,040 --> 05:20:34,720 FUNCTIONS AS A PLATFORM, ONE OF 7019 05:20:34,720 --> 05:20:36,960 THE MOLECULES THAT IS 7020 05:20:36,960 --> 05:20:46,720 (INDISCERNIBLE) WHY KISH IS 7021 05:20:46,720 --> 05:20:47,320 HGPS 1A. YOU CAN SEE THAT ON 7022 05:20:47,320 --> 05:20:50,960 THE LEFT SIDE. (INDISCERNIBLE). 7023 05:20:50,960 --> 05:20:53,080 COMPARED TO THE CONTROL. WHEN 7024 05:20:53,080 --> 05:20:59,360 YOU LOOK FOR ATPASE, LOOK FOR 7025 05:20:59,360 --> 05:21:00,840 THE EXPRESSION IN YOUNG VERSUS 7026 05:21:00,840 --> 05:21:09,080 OLD, AND YOU SEE IT EXPRESSED. 7027 05:21:09,080 --> 05:21:19,560 SO AGAIN ATPASE T 1 A, THIS IS 7028 05:21:27,200 --> 05:21:31,000 BASED ON OLD PEOPLE AND YOU SEE 7029 05:21:31,000 --> 05:21:38,880 -- -- IN THE ELECTRON 7030 05:21:38,880 --> 05:21:39,440 MICROSCOPY AND I SHOW ONE 7031 05:21:39,440 --> 05:21:49,800 PICTURE OF AMPHISOMES 7032 05:21:50,360 --> 05:21:50,960 (PHONETIC), GENERATING INFUSION 7033 05:21:50,960 --> 05:21:54,360 OF PHAGOSOMES. 7034 05:21:54,360 --> 05:21:55,400 YOU SEE A YOUNG EXPRESSION OF 7035 05:21:55,400 --> 05:22:00,200 THE (INDISCERNIBLE), IT IS 7036 05:22:00,200 --> 05:22:02,720 SILENCE ATPASE YOU HAVE MANY 7037 05:22:02,720 --> 05:22:07,720 MORE (INDISCERNIBLE). 7038 05:22:07,720 --> 05:22:08,240 IT SPITS OUT ALL DIFFERENT 7039 05:22:08,240 --> 05:22:08,880 THINGS INCLUDING MITOCHONDRIA 7040 05:22:08,880 --> 05:22:13,760 --. IF YOU LOOK OUT RESPONSES 7041 05:22:13,760 --> 05:22:18,680 WHAT WE SEE IS, IN THE POWER T 7042 05:22:18,680 --> 05:22:19,720 CELL RESPONSE, WE SEE AN 7043 05:22:19,720 --> 05:22:24,160 INCREASE THE CREATION OF 7044 05:22:24,160 --> 05:22:25,960 (INDISCERNIBLE) RDNA IN ALL 7045 05:22:25,960 --> 05:22:29,920 PEOPLE VERSUS YOUNG PEOPLE. 7046 05:22:29,920 --> 05:22:30,520 IF YOU LOOK AT THE PLOT ON THE 7047 05:22:30,520 --> 05:22:33,200 RIGHT SIDE TO SEE THE VARIANCE 7048 05:22:33,200 --> 05:22:35,280 IN YOUNG INDIVIDUALS. IT CAN 7049 05:22:35,280 --> 05:22:42,160 COME DOWN TO A DNA 7050 05:22:42,160 --> 05:22:42,800 (INDISCERNIBLE) WE SEE IN YOUNG 7051 05:22:42,800 --> 05:22:45,960 PEOPLE THE INCREASE -- OF 7052 05:22:45,960 --> 05:22:56,480 (INDISCERNIBLE). 7053 05:22:56,480 --> 05:22:56,960 WE FOLLOW IT UP WITH A 7054 05:22:56,960 --> 05:22:58,560 HEMOSTAT STATUS USING CD4 -- 7055 05:22:58,560 --> 05:23:04,400 WE SILENCED THE T-CELLS. IF 7056 05:23:04,400 --> 05:23:06,240 THERE IS A HUGE INFECTION, WE 7057 05:23:06,240 --> 05:23:08,480 WOULD SEE AN INCREASED IN 7058 05:23:08,480 --> 05:23:13,040 MITOCHONDRIAL DNA. THE 7059 05:23:13,040 --> 05:23:14,440 INCREASE IN MITOCHONDRIAL DNA, 7060 05:23:14,440 --> 05:23:16,160 SHOWS AN ACUTE INFECTION. WE 7061 05:23:16,160 --> 05:23:17,360 CAN SIGNIFICANTLY REDUCE THE 7062 05:23:17,360 --> 05:23:21,600 KISH. WE CAN ALSO 7063 05:23:21,600 --> 05:23:25,880 (INDISCERNIBLE) THE 7064 05:23:25,880 --> 05:23:26,520 (INDISCERNIBLE) AT THE TIME OF 7065 05:23:26,520 --> 05:23:27,000 THE PEAK OF THE IMMUNO 7066 05:23:27,000 --> 05:23:29,240 RESPONSE. YOU CAN SEE THAT THE 7067 05:23:29,240 --> 05:23:31,440 T-CELLS OF THE (INDISCERNIBLE) 7068 05:23:31,440 --> 05:23:37,280 ARE IN THE END, RESPONSIBLE FOR 7069 05:23:37,280 --> 05:23:39,520 THE SECRETION OF MITOCHONDRIA 7070 05:23:39,520 --> 05:23:45,760 DNA. 7071 05:23:45,760 --> 05:23:47,880 THE INCREASE OF MEDICAL DNA IS 7072 05:23:47,880 --> 05:23:48,640 A SYSTEMIC RESPONSE. YOU CAN 7073 05:23:48,640 --> 05:23:50,880 SEE THIS BECAUSE OF THE LEVELS 7074 05:23:50,880 --> 05:23:55,400 OF (INDISCERNIBLE). 7075 05:23:55,400 --> 05:24:05,360 THE SUMMARY OF MY LAST SLIDE, 7076 05:24:05,360 --> 05:24:06,000 I HAVE DISTINCT ACTIVATION THAT 7077 05:24:06,000 --> 05:24:09,160 LEADS TO (INDISCERNIBLE) WHICH 7078 05:24:09,160 --> 05:24:16,200 IMPAIRS CLASSICAL BIOGENESIS, 7079 05:24:16,200 --> 05:24:19,240 GENERATION OF MITOCHONDRIAL 7080 05:24:19,240 --> 05:24:19,880 BODIES AND INCREASED EXPRESSION 7081 05:24:19,880 --> 05:24:25,880 OF -- EXPRESSION, WHICH 7082 05:24:25,880 --> 05:24:27,960 DEGRADES THE EXISTING LYSOSOMES. 7083 05:24:27,960 --> 05:24:30,120 WE GET A LOT OF THESE 7084 05:24:30,120 --> 05:24:32,520 (INDISCERNIBLE) THAT LEAD TO 7085 05:24:32,520 --> 05:24:43,000 THE SECRETION OF EXOSOMES AND 7086 05:24:44,200 --> 05:24:48,760 MITOCHONDRIAL DNA. 7087 05:24:48,760 --> 05:24:49,280 I AM FOCUSING HERE ONLY ON 7088 05:24:49,280 --> 05:24:51,640 WHAT WE PLAN TO DO IN THE NEXT 7089 05:24:51,640 --> 05:25:02,080 -- -- WE KNOW THAT TCF1 7090 05:25:06,360 --> 05:25:06,920 ESSENTIAL FOR GENERATION OF TFH 7091 05:25:06,920 --> 05:25:07,560 AND LOG OF MEMORY CELLS AND FOR 7092 05:25:07,560 --> 05:25:10,040 FUNCTIONAL LYSOSOMES. 7093 05:25:10,040 --> 05:25:14,040 WE HAVE NETWORKS UPSTREAM AND 7094 05:25:14,040 --> 05:25:14,600 DOWNSTREAM IN HEALTHY OLDER 7095 05:25:14,600 --> 05:25:15,240 ADULTS AND WE ARE PLANNING TO 7096 05:25:15,240 --> 05:25:23,720 USE NEAT TECHNOLOGY, SEQUENCING 7097 05:25:23,720 --> 05:25:27,680 AND NUCLEOPROTEIN TO ATTACK THE 7098 05:25:27,680 --> 05:25:32,560 (INDISCERNIBLE). 7099 05:25:32,560 --> 05:25:39,720 OBVIOUSLY, MORE STUDIES ARE 7100 05:25:39,720 --> 05:25:48,440 DONE ON (INDISCERNIBLE). THE 7101 05:25:48,440 --> 05:25:49,040 ASPECT OF LYSOSOME DEFICIENCY 7102 05:25:49,040 --> 05:25:50,680 WE DO NOT KNOW IT YET BUT THAT 7103 05:25:50,680 --> 05:25:55,120 MEANS. OR LONG-TERM T-CELLS 7104 05:25:55,120 --> 05:25:58,560 (INDISCERNIBLE). 7105 05:25:58,560 --> 05:26:00,280 I WILL LET THE ACKNOWLEDGMENT 7106 05:26:00,280 --> 05:26:03,760 SPEAK FOR THEMSELVES. ALSO MY 7107 05:26:03,760 --> 05:26:14,200 LAB AND (INDISCERNIBLE). 7108 05:26:17,560 --> 05:26:18,160 >>AGAIN IF THERE IS ONE SHORT 7109 05:26:18,160 --> 05:26:18,800 QUESTION OR SOMETHING ONLINE -- 7110 05:26:18,800 --> 05:26:22,160 WE CAN -- ONE SHORT QUESTION IN 7111 05:26:22,160 --> 05:26:23,400 THE BACK. 7112 05:26:23,400 --> 05:26:29,320 >>YEAH, BEAUTIFUL. COULD YOU 7113 05:26:29,320 --> 05:26:29,920 CLARIFY IF YOU THINK THAT THE 7114 05:26:29,920 --> 05:26:40,480 ENHANCED AT 5 AGING IS BECAUSE 7115 05:26:40,720 --> 05:26:41,280 OF EXTRA CYTOKINES IMPLEMENTING 7116 05:26:41,280 --> 05:26:43,320 A RECEPTOR? 7117 05:26:43,320 --> 05:26:50,360 >>WE THINK IT IS AUTOPLAY. WE 7118 05:26:50,360 --> 05:26:54,600 FIND HELIOS IS IN HUMAN 7119 05:26:54,600 --> 05:26:55,200 T-CELLS, TRANSCRIPTION FACTOR 7120 05:26:55,200 --> 05:27:05,160 WE ONLY SEE IN TCF. HE WE LOSE 7121 05:27:05,160 --> 05:27:06,760 HELIOS IT STARTS TO 7122 05:27:06,760 --> 05:27:09,800 (INDISCERNIBLE). ALL HAVE SOME 7123 05:27:09,800 --> 05:27:17,200 LEVEL OF PHENOME EXPRESSION. 7124 05:27:17,200 --> 05:27:22,280 >>THANK YOU VERY MUCH. 7125 05:27:22,280 --> 05:27:23,720 >>POWERLESS PRESENTATIONS BY 7126 05:27:23,720 --> 05:27:31,560 DOCTOR -- IS THAT CLOSE ENOUGH? 7127 05:27:31,560 --> 05:27:32,120 FROM JOHNS HOPKINS AND I WILL 7128 05:27:32,120 --> 05:27:32,720 LET HER TAKE OVER. 7129 05:27:32,720 --> 05:27:37,640 >>IT'S 4 P.M. LAST LECTURE. 7130 05:27:37,640 --> 05:27:38,240 THANK YOU FOR THOSE WHO STUCK 7131 05:27:38,240 --> 05:27:41,560 WITH IT. I AM REALLY EXCITED 7132 05:27:41,560 --> 05:27:43,120 TO SHARE SOME OF OUR WORK WHICH 7133 05:27:43,120 --> 05:27:45,080 COMES FROM A DIFFERENT 7134 05:27:45,080 --> 05:27:45,600 PERSPECTIVE, BUT I THINK 7135 05:27:45,600 --> 05:27:46,760 CONNECTS A LOT OF THINGS THAT 7136 05:27:46,760 --> 05:27:48,320 WE HAVE HEARD. 7137 05:27:48,320 --> 05:27:52,520 SO, JUST TO GET SOME 7138 05:27:52,520 --> 05:27:52,960 BACKGROUND ABOUT THE 7139 05:27:52,960 --> 05:27:56,520 PERSPECTIVE I AM COMING FROM. I 7140 05:27:56,520 --> 05:27:57,160 WORK IN TISSUE ENGINEERING IS A 7141 05:27:57,160 --> 05:28:03,800 BIOMEDICAL ENGINEER, BUILDING 7142 05:28:03,800 --> 05:28:04,320 BIOMATERIALS TO HELP WITH 7143 05:28:04,320 --> 05:28:05,040 TISSUE REPAIR. AS A RESULT OF 7144 05:28:05,040 --> 05:28:06,800 OUR CLINICAL TRIAL, WE STARTED 7145 05:28:06,800 --> 05:28:07,360 TO REALIZE THAT THE IMMUNE 7146 05:28:07,360 --> 05:28:09,280 SYSTEM IS REALLY CRITICAL AND 7147 05:28:09,280 --> 05:28:09,840 BIOMATERIALS CAN BE A NICE 7148 05:28:09,840 --> 05:28:11,760 MODEL FOR DIFFERENT IMMUNO 7149 05:28:11,760 --> 05:28:12,320 ENVIRONMENT AND I WILL ALSO 7150 05:28:12,320 --> 05:28:16,440 SHOW YOU THE CHANGES IN AGING 7151 05:28:16,440 --> 05:28:17,080 AND THESE MODELS HAVE ALLOWED 7152 05:28:17,080 --> 05:28:19,520 US TO DEVELOP SOME BETTER 7153 05:28:19,520 --> 05:28:24,920 UNDERSTANDING OF 7154 05:28:24,920 --> 05:28:25,520 (INDISCERNIBLE) CELLS AND HOW 7155 05:28:25,520 --> 05:28:28,800 TO CONNECT WITH THE IMMUNE 7156 05:28:28,800 --> 05:28:29,320 SYSTEM. A GREAT QUESTION 7157 05:28:29,320 --> 05:28:32,800 EARLIER TODAY. 7158 05:28:32,800 --> 05:28:33,320 WE HEARD A LOT ABOUT THE 7159 05:28:33,320 --> 05:28:34,960 CONCEPT OF TISSUE REPAIR; A 7160 05:28:34,960 --> 05:28:35,880 FAIR AMOUNT IS KNOWN ABOUT 7161 05:28:35,880 --> 05:28:37,640 MYELOID CONTRIBUTIONS, 7162 05:28:37,640 --> 05:28:48,040 MACROPHAGES AND VARIOUS 7163 05:28:48,560 --> 05:28:52,480 GRANULAR (INDISCERNIBLE) WE 7164 05:28:52,480 --> 05:28:53,040 HAVE BEEN FOCUSING ON THE 7165 05:28:53,040 --> 05:28:53,640 ADAPTIVE IMMUNE RESPONSES IN 7166 05:28:53,640 --> 05:29:01,120 PARTICULAR T-CELLS, TH2, TH17. 7167 05:29:01,120 --> 05:29:01,760 I WILL DROP A NOTE THAT WHAT WE 7168 05:29:01,760 --> 05:29:05,200 HAVE SEEN WITH GAMMA DELTA 7169 05:29:05,200 --> 05:29:05,800 T-CELLS HAVE MADE INTERESTING 7170 05:29:05,800 --> 05:29:06,520 CHANGES IN AGING AND CONTRIBUTE 7171 05:29:06,520 --> 05:29:12,000 TO IL17 PRODUCTION AND -- 7172 05:29:12,000 --> 05:29:13,320 ENVIRONMENT. 7173 05:29:13,320 --> 05:29:13,840 AND ARE VERY RESPONSIVE TO 7174 05:29:13,840 --> 05:29:23,400 THINGS LIKE DIET AND INFECTION. 7175 05:29:23,400 --> 05:29:24,080 SO OUR PERSPECTIVE COMING FROM 7176 05:29:24,080 --> 05:29:29,080 DIFFERENT REPAIR, FIRST TRY TO 7177 05:29:29,080 --> 05:29:32,000 UNDERSTAND THE IMMUNE PHENOTYPE 7178 05:29:32,000 --> 05:29:32,520 AND THE COMMUNICATION AND 7179 05:29:32,520 --> 05:29:36,040 HEALING WOUND AND COMPARE THAT 7180 05:29:36,040 --> 05:29:36,640 TO ONE IN A NONHEALING WOUND 7181 05:29:36,640 --> 05:29:37,240 CHARACTERIZED BY FIBROSIS AND 7182 05:29:37,240 --> 05:29:40,360 CHRONIC INFORMATION. 7183 05:29:40,360 --> 05:29:40,960 UNDERSTANDING THOSE DIFFERENCES 7184 05:29:40,960 --> 05:29:41,520 WE CAN START TO REDIRECT 7185 05:29:41,520 --> 05:29:43,480 HEALING. 7186 05:29:43,480 --> 05:29:46,200 WE HAVE BEEN USING MODEL 7187 05:29:46,200 --> 05:29:49,720 SYMPTOMS, MUSCLE AS AN EXAMPLE 7188 05:29:49,720 --> 05:29:50,240 OF TISSUE THAT CAN REPAIR 7189 05:29:50,240 --> 05:30:00,680 PRETTY WELL.OPPOSED TO 7190 05:30:01,680 --> 05:30:02,240 CARTILAGE WHICH SWITCHES DOES 7191 05:30:02,240 --> 05:30:06,000 NOT REPAIR. AND WE HAVE 7192 05:30:06,000 --> 05:30:06,600 BIOMATERIALS THAT CAN MONITOR 7193 05:30:06,600 --> 05:30:14,320 EACH OF THOSE ENVIRONMENTS IN 7194 05:30:14,320 --> 05:30:14,960 THE BIOLOGICAL SCAFFOLDS ARE IN 7195 05:30:14,960 --> 05:30:15,480 THE CLINIC FOR WHEN IT IS 7196 05:30:15,480 --> 05:30:19,200 REPAIRED AND THE ROLE OF 7197 05:30:19,200 --> 05:30:19,840 MACROPHAGES IN THE RESPONSE AND 7198 05:30:19,840 --> 05:30:20,440 PROMOTING A POSITIVE HEALING 7199 05:30:20,440 --> 05:30:22,760 OUTCOME HAS BEEN DEMONSTRATED. 7200 05:30:22,760 --> 05:30:23,280 LOOK MORE AT THE ADAPTIVE 7201 05:30:23,280 --> 05:30:28,600 IMMUNE COMPONENT, KAILIN IS AN 7202 05:30:28,600 --> 05:30:32,800 INVESTIGATOR AT NIH LOOKED AT 7203 05:30:32,800 --> 05:30:33,440 (INDISCERNIBLE) PRODUCTION AND 7204 05:30:33,440 --> 05:30:33,960 HE WOULD LOOK AT POSSIBLE 7205 05:30:33,960 --> 05:30:34,600 CONNECTIONS WITH THE ADAPTIVE 7206 05:30:34,600 --> 05:30:38,160 IMMUNE SYSTEM, YOU WILL SEE IL4 7207 05:30:38,160 --> 05:30:38,760 IS AN IMPORTANT COMPONENT FOR 7208 05:30:38,760 --> 05:30:40,560 DIFFERENTIATION. 7209 05:30:40,560 --> 05:30:41,440 WHAT SHE FOUND WAS THAT YOU 7210 05:30:41,440 --> 05:30:49,040 HAVE SOME T-CELLS IN THE 7211 05:30:49,040 --> 05:30:52,080 BIOMATERIAL WOUND, IMPROVING 7212 05:30:52,080 --> 05:30:52,720 HEALING AND IMPACTS MACROPHAGE 7213 05:30:52,720 --> 05:31:02,040 BEHAVIOR. WE EVEN SEE LOCAL, 7214 05:31:02,040 --> 05:31:02,480 REGIONAL LYMPH NODES 7215 05:31:02,480 --> 05:31:07,800 (INDISCERNIBLE) AND INCREASING 7216 05:31:07,800 --> 05:31:12,480 RICTOR KNOCKOUT AND T-CELLS THE 7217 05:31:12,480 --> 05:31:13,080 DID NOT HAVE THE CAPACITY TO 7218 05:31:13,080 --> 05:31:13,760 UNDERGO DIFFERENTIATION AND WE 7219 05:31:13,760 --> 05:31:21,520 SEE FUNCTIONAL REPAIR. 7220 05:31:21,520 --> 05:31:22,080 IF YOU LOOK AT THE FIBROSIS 7221 05:31:22,080 --> 05:31:26,320 AND AND -- RESPONSE TO MATERIAL 7222 05:31:26,320 --> 05:31:28,840 AND TISSUE DAMAGE. THAT BRINGS 7223 05:31:28,840 --> 05:31:29,360 UP ALSO THE CONCEPT OF 7224 05:31:29,360 --> 05:31:32,280 FIBROSIS. FIBROSIS IS PRESENT 7225 05:31:32,280 --> 05:31:32,880 IN A LOT OF AGE-RELATED 7226 05:31:32,880 --> 05:31:40,000 DISEASES, IPF ARTHROSIS, 7227 05:31:40,000 --> 05:31:42,920 ARTHRITIS, FIBROIDS, NICE MODEL 7228 05:31:42,920 --> 05:31:45,120 FOR NONHEALING WOUNDS AND 7229 05:31:45,120 --> 05:31:46,760 CHRONIC INFORMATION, AND YOU 7230 05:31:46,760 --> 05:31:47,400 CAN SEE HOW FIBROSIS AND TISSUE 7231 05:31:47,400 --> 05:31:48,560 PROBABLY INCREASES WITH AGING. 7232 05:31:48,560 --> 05:31:56,400 FIBROSIS IS A NICE MODEL. 7233 05:31:56,400 --> 05:31:56,920 FIBROSIS HAPPENS AROUND 7234 05:31:56,920 --> 05:31:57,480 BIOMATERIAL IMPLANT EVEN IN 7235 05:31:57,480 --> 05:31:58,080 YOUNG ANIMALS AGAIN AND NICE 7236 05:31:58,080 --> 05:31:58,680 PLACE WHERE WE CAN ENGINEER 7237 05:31:58,680 --> 05:32:01,400 MODELS. 7238 05:32:01,400 --> 05:32:01,960 SO IN LOOKING AT THE IMMUNE 7239 05:32:01,960 --> 05:32:06,680 CELLS AROUND THE IMPLANT, 7240 05:32:06,680 --> 05:32:07,280 PEOPLE KNEW THAT MACROPHAGES 7241 05:32:07,280 --> 05:32:07,920 PLAY AN IMPORTANT ROLE IN THAT 7242 05:32:07,920 --> 05:32:10,600 FORM BY THE RESPONSE WE FOUND 7243 05:32:10,600 --> 05:32:11,120 T-CELLS FROM IMPLANTS IN 7244 05:32:11,120 --> 05:32:11,760 PATIENTS AND SO WE HAVE A LARGE 7245 05:32:11,760 --> 05:32:16,560 GROUP OF TISSUES FROM PATIENTS 7246 05:32:16,560 --> 05:32:19,600 UNDERGOING EITHER PERMANENT 7247 05:32:19,600 --> 05:32:20,080 IMPLANT EXCHANGE AND 7248 05:32:20,080 --> 05:32:22,800 RESPIRATORY CONSTRUCTION, OR 7249 05:32:22,800 --> 05:32:23,440 WITH AN ACE IMPLANT THAT NEEDED 7250 05:32:23,440 --> 05:32:24,320 TO BE REMOVED. 7251 05:32:24,320 --> 05:32:26,560 WHAT WE FOUND IN THE T-CELLS 7252 05:32:26,560 --> 05:32:30,960 IS THAT WE HAVE T4 T-CELLS 7253 05:32:30,960 --> 05:32:34,280 EXPRESSING IL17 AND ALSO GAMMA 7254 05:32:34,280 --> 05:32:38,200 DELTA T-CELLS EXPRESSING IL17, 7255 05:32:38,200 --> 05:32:38,840 A FAIR AMOUNT OF THOSE AND THAT 7256 05:32:38,840 --> 05:32:41,360 WAS RATHER UNEXPECTED. 7257 05:32:41,360 --> 05:32:42,040 AND WILL PUT THE FACT THAT 7258 05:32:42,040 --> 05:32:52,520 PRECLINICAL MODELS ALSO HAD 7259 05:32:53,960 --> 05:32:55,520 SOME PRE-(INDISCERNIBLE). IT 7260 05:32:55,520 --> 05:33:00,960 WILL LOOK ON THE LEFT, CD45.1 7261 05:33:00,960 --> 05:33:05,240 VS. CD45.2, THE .2 BEING FROM 7262 05:33:05,240 --> 05:33:09,200 THE OT2 MOUSE, YOU GET IMMUNE 7263 05:33:09,200 --> 05:33:11,280 ACTIVATION IN BOTH OF THEM BUT 7264 05:33:11,280 --> 05:33:15,040 ONLY TH 17 PRODUCTION IN THE 7265 05:33:15,040 --> 05:33:17,800 WILD TYPE NOT IN THE OT2. 7266 05:33:17,800 --> 05:33:23,920 SO IT WOULD DELIVER ANTI IL17 7267 05:33:23,920 --> 05:33:24,480 ANTIBODIES WE CAN REDUCE 7268 05:33:24,480 --> 05:33:25,120 FIBROSIS BUT THEN IT THERE IS A 7269 05:33:25,120 --> 05:33:30,640 CONNECTION BETWEEN IL17 AND 7270 05:33:30,640 --> 05:33:33,080 SENESCENTS. 7271 05:33:33,080 --> 05:33:36,800 IN KNOCKOUT ANIMALS WE SEE 7272 05:33:36,800 --> 05:33:39,400 REDUCED SENESCENCE. AROUND 7273 05:33:39,400 --> 05:33:40,640 CHEMICAL IMPLANTS WE ALSO SAW 7274 05:33:40,640 --> 05:33:45,440 SENESCENT CELLS IS LABELED BY 7275 05:33:45,440 --> 05:33:46,240 IL17 AND A POSITIVE CORRELATION 7276 05:33:46,240 --> 05:33:53,600 BETWEEN 6 AND IL17. 7277 05:33:53,600 --> 05:33:54,200 FIBERGLASS DIVERSITY HAS BEEN 7278 05:33:54,200 --> 05:33:59,120 THE RESEARCH TOPIC AND MANY 7279 05:33:59,120 --> 05:33:59,640 STUDIES DENY MENTIONING 7280 05:33:59,640 --> 05:34:00,200 FIBROBLAST BECAUSE THAT IS 7281 05:34:00,200 --> 05:34:03,080 PRIMARILY WHAT OUR SENESCENT 7282 05:34:03,080 --> 05:34:04,880 COME OUT TO. 7283 05:34:04,880 --> 05:34:05,280 WE HAD A BEAUTIFUL 7284 05:34:05,280 --> 05:34:07,320 INTRODUCTION OF SENESCENT THIS 7285 05:34:07,320 --> 05:34:11,080 MORNING SO WE ARE LOOKING AT 7286 05:34:11,080 --> 05:34:15,200 SENESCENCE FROM THE TISSUE 7287 05:34:15,200 --> 05:34:17,040 REPAIR FIBROSIS SIDE SO WE 7288 05:34:17,040 --> 05:34:27,480 LEARN THAT SENESCENCE IS A 7289 05:34:33,360 --> 05:34:33,920 NORMAL PART OF DEVELOPMENT IN A 7290 05:34:33,920 --> 05:34:34,520 NORMAL PART OF TISSUE REPAIR. 7291 05:34:34,520 --> 05:34:36,720 (INDISCERNIBLE). 7292 05:34:36,720 --> 05:34:43,400 SENESCENT CELLS WERE FOUND IN 7293 05:34:43,400 --> 05:34:43,880 CARTILAGE OF PATIENTS 7294 05:34:43,880 --> 05:34:44,800 UNDERGOING TOTAL KNEE IMPLANT, 7295 05:34:44,800 --> 05:34:47,600 QUITE A WHILE AGO. IT IS A 7296 05:34:47,600 --> 05:34:48,240 NICE EARLY TARGET AND YOU HEARD 7297 05:34:48,240 --> 05:34:55,840 ABOUT THE SASP WHICH INCLUDES A 7298 05:34:55,840 --> 05:34:56,440 NUMBER OF IMMUNE FACTORS THAT 7299 05:34:56,440 --> 05:34:56,920 WILL TELL YOU IS QUITE 7300 05:34:56,920 --> 05:35:07,320 IMPORTANT FOR T-CELL 7301 05:35:07,640 --> 05:35:08,200 DIFFERENTIATION AND UNEXPECTED 7302 05:35:08,200 --> 05:35:09,240 RESULT WAS INCREASED TISSUE 7303 05:35:09,240 --> 05:35:09,840 PRODUCTION FOR TISSUE REPAIR 7304 05:35:09,840 --> 05:35:14,040 AND THE SENESCENT CELLS FOR 7305 05:35:14,040 --> 05:35:14,640 SERVING AS A BREAK FOR TISSUE 7306 05:35:14,640 --> 05:35:15,480 REPAIR IN THAT ENVIRONMENT. 7307 05:35:15,480 --> 05:35:19,360 AND SOME BACKGROUND. IF YOU 7308 05:35:19,360 --> 05:35:19,920 HAVE A SHAM SURGERY OR YOU 7309 05:35:19,920 --> 05:35:22,240 DON'T GET AS MUCH SENESCENCE, 7310 05:35:22,240 --> 05:35:26,160 FOR CHRONIC SENESCENCE YOU HIRE 7311 05:35:26,160 --> 05:35:26,760 INFORMATION EARLY ON BUT THEN 7312 05:35:26,760 --> 05:35:29,640 HE GOES AWAY. AND THE ACL 7313 05:35:29,640 --> 05:35:34,320 TRANSACTION A LITTLE BIT LESS 7314 05:35:34,320 --> 05:35:34,880 SENESCENCE BUT THE STATES 7315 05:35:34,880 --> 05:35:35,480 CHRONIC AND THE INTENSITY AND 7316 05:35:35,480 --> 05:35:36,960 TIMING OF BOTH THE IMMUNE AND 7317 05:35:36,960 --> 05:35:37,480 SENESCENCE RESPONSE IS 7318 05:35:37,480 --> 05:35:39,080 CRITICAL. 7319 05:35:39,080 --> 05:35:39,600 IF WE LOOK AT THE FACTORS 7320 05:35:39,600 --> 05:35:46,600 PRODUCED BY THE T-CELLS, IL 1 7321 05:35:46,600 --> 05:35:51,920 BETA, IL6, WE ARE ARTIFICIALLY 7322 05:35:51,920 --> 05:35:55,120 INDUCED SENESCENCE AND WHAT WE 7323 05:35:55,120 --> 05:36:02,400 SAW WAS IN THE PRESENCE OF TH 7324 05:36:02,400 --> 05:36:06,240 BETA, (INDISCERNIBLE), WITHOUT 7325 05:36:06,240 --> 05:36:07,480 IT IS A NICE SWITCH TO 7326 05:36:07,480 --> 05:36:09,680 INTERFACE GAMMA. 7327 05:36:09,680 --> 05:36:10,240 AT THE SAME TIME WE CAN USE 7328 05:36:10,240 --> 05:36:16,280 ARTIFICIALLY USE T-CELL TO 7329 05:36:16,280 --> 05:36:16,880 INCREASE THE PHENOTYPE AND WE 7330 05:36:16,880 --> 05:36:17,640 SEE HEALTHY FIBROBLAST PRESSING 7331 05:36:17,640 --> 05:36:21,840 MARKERS OF SENESCENCE, IL6, 7332 05:36:21,840 --> 05:36:28,280 OTHER FACTORS. 7333 05:36:28,280 --> 05:36:28,880 WE CHARACTERIZE THIS A LITTLE 7334 05:36:28,880 --> 05:36:32,280 MORE AND INFLAMMATORY REDUCED 7335 05:36:32,280 --> 05:36:32,800 SENESCENCE, LOOKING AT 7336 05:36:32,800 --> 05:36:35,480 PERIMETER INFORMATION AND 7337 05:36:35,480 --> 05:36:36,120 SENESCENCE, WE THINK THIS IS A 7338 05:36:36,120 --> 05:36:38,520 MORE PHYSIOLOGICALLY RELEVANT 7339 05:36:38,520 --> 05:36:39,160 SENESCENCE WHEN YOU HAVE IMMUNE 7340 05:36:39,160 --> 05:36:40,440 ACTIVATION BUT WHAT IS A 7341 05:36:40,440 --> 05:36:43,000 SENESCENT CELL? 7342 05:36:43,000 --> 05:36:43,480 YOU HEARD THAT QUESTION 7343 05:36:43,480 --> 05:36:45,160 EARLIER TODAY. WE ARE QUITE 7344 05:36:45,160 --> 05:36:45,720 INTERESTED IN THE IMMUNE 7345 05:36:45,720 --> 05:36:56,240 FUNCTIONS OF SENESCENT CELLS IN 7346 05:36:57,560 --> 05:36:58,120 CONNECTION TO THE IMMUNE SYSTEM 7347 05:36:58,120 --> 05:36:59,760 SO WE USE THE FBR MODEL FROM ME 7348 05:36:59,760 --> 05:37:01,720 AND USE OUR FIBROSIS MODEL. 7349 05:37:01,720 --> 05:37:02,200 IN THE PRECLINICAL MODEL 7350 05:37:02,200 --> 05:37:07,680 INDUCING FIBROSIS AND 6 AND TD 7351 05:37:07,680 --> 05:37:15,880 TOMATO. WE LOOK FOR -- 7352 05:37:15,880 --> 05:37:16,960 INDUCTION, NOT IN THE EARLY 7353 05:37:16,960 --> 05:37:18,040 IMPLEMENTATION, MORE OF THE 7354 05:37:18,040 --> 05:37:20,560 CHRONIC SENESCENCE. 7355 05:37:20,560 --> 05:37:21,600 AND AS YOU SAW EARLIER I 7356 05:37:21,600 --> 05:37:23,280 THINK, VERY SMALL NUMBERS. 7357 05:37:23,280 --> 05:37:27,080 SENESCENT CELLS ARE INTERESTING 7358 05:37:27,080 --> 05:37:27,720 BECAUSE THEY ARE REALLY LOW IN 7359 05:37:27,720 --> 05:37:28,360 NUMBER BUT THEY SEEM TO HAVE A 7360 05:37:28,360 --> 05:37:28,960 BIG EFFECT, AT LEAST WHEN YOU 7361 05:37:28,960 --> 05:37:30,240 CLEAR THEM. 7362 05:37:30,240 --> 05:37:36,880 IT'S ONLY A SMALL PERCENTAGE, 7363 05:37:36,880 --> 05:37:37,520 .09%, USING A LARGE FLOW PANEL 7364 05:37:37,520 --> 05:37:38,720 YOU CAN SEE THAT MOST OF THOSE 7365 05:37:38,720 --> 05:37:41,280 SENESCENT CELLS IN THIS YOUNG 7366 05:37:41,280 --> 05:37:45,200 ANIMAL FIBROSIS IMPLANT MODEL 7367 05:37:45,200 --> 05:37:50,160 WERE CD 45 NEGATIVE, CD 49 7368 05:37:50,160 --> 05:37:53,120 POSITIVE AND WE HAVE SOME 7369 05:37:53,120 --> 05:37:56,320 MYELOID CELLS, PRIMARILY 7370 05:37:56,320 --> 05:37:58,160 (INDISCERNIBLE) CELLS IN THE 7371 05:37:58,160 --> 05:37:59,760 ANIMAL VALIDATED WITH TISSUE 7372 05:37:59,760 --> 05:38:04,120 AND THE (INDISCERNIBLE) ITSELF. 7373 05:38:04,120 --> 05:38:10,720 WE SORTED OUT THOSE TD TOMATO 7374 05:38:10,720 --> 05:38:15,960 POSITIVE, TC 15 POSITIVE, AND 7375 05:38:15,960 --> 05:38:19,360 WE DID BOTH SEQUENCING ON THIS 7376 05:38:19,360 --> 05:38:23,200 AND HAVE A SENESCENCE SIGNATURE 7377 05:38:23,200 --> 05:38:29,040 AND WHILE THE SIGNATURE IS 7378 05:38:29,040 --> 05:38:30,040 DETERMINED BY THAT EXPRESSION, 7379 05:38:30,040 --> 05:38:30,680 WE'VE GOT GREATER THAN 1000 IS 7380 05:38:30,680 --> 05:38:33,760 GOING UP AND DOWN. YOU CAN USE 7381 05:38:33,760 --> 05:38:34,360 THIS TO COMPARE TO OTHER DATA 7382 05:38:34,360 --> 05:38:34,960 SETS AND FIND CELLS THAT MAY 7383 05:38:34,960 --> 05:38:41,440 NOT BE T 16 POSITIVE EXPRESSING 7384 05:38:41,440 --> 05:38:43,440 SOME OF THESE MARKERS SO, WHAT 7385 05:38:43,440 --> 05:38:46,440 ARE THE INTERESTING PATHWAYS? 7386 05:38:46,440 --> 05:38:47,040 WE SAW THINGS THAT RELATE TO 7387 05:38:47,040 --> 05:38:47,880 ENDOTHELIAL MIGRATION. YOU CAN 7388 05:38:47,880 --> 05:38:48,440 SEE THE PICTURES AND THE 7389 05:38:48,440 --> 05:38:51,480 CONNECTION TO (INDISCERNIBLE), 7390 05:38:51,480 --> 05:38:52,080 MAKE SENSE WITH TISSUE REPAIR 7391 05:38:52,080 --> 05:38:54,480 AND TISSUE DEVELOPMENT. AND IN 7392 05:38:54,480 --> 05:38:59,480 THE DIFFERENTIATION, WITHOUT 7393 05:38:59,480 --> 05:39:00,120 THIS LITTLE STRAIN WONDERING IF 7394 05:39:00,120 --> 05:39:00,680 WE HAD LIGAMENT OR TENDON 7395 05:39:00,680 --> 05:39:05,640 CONTAMINATION BUT NO IT WAS IN 7396 05:39:05,640 --> 05:39:06,280 THE FIBROSIS REGION WITH A LOT 7397 05:39:06,280 --> 05:39:06,760 OF PROTEINS AND GLYCAN 7398 05:39:06,760 --> 05:39:07,400 ASSOCIATED WITH CARTILAGE WERE 7399 05:39:07,400 --> 05:39:09,280 IN THE FIBROSIS REGION. 7400 05:39:09,280 --> 05:39:13,600 SO WHICH OF THE SAME CD 49 7401 05:39:13,600 --> 05:39:14,240 POPULATION AND THE SINGLE CELL 7402 05:39:14,240 --> 05:39:24,760 WE DO NOT SEE T 16 VERY HIGH, 7403 05:39:35,800 --> 05:39:36,320 BUT WE HAD TO TRANSFER THE 7404 05:39:36,320 --> 05:39:36,880 LEARNING APPROACH AND APPLY 7405 05:39:36,880 --> 05:39:37,520 THAT TO THE SINGLE DATA SET TO 7406 05:39:37,520 --> 05:39:38,000 SEE WHICH CELLS GREATER 7407 05:39:38,000 --> 05:39:38,680 SIMILARITY TO THE SENESCENT 7408 05:39:38,680 --> 05:39:40,920 CELLS. 7409 05:39:40,920 --> 05:39:48,120 AS YOU MIGHT GUESS FROM THE -- 7410 05:39:48,120 --> 05:39:48,640 CONNECTION WE RENAMED THE 7411 05:39:48,640 --> 05:39:49,240 CARTILAGE POPULATION FIBROTIC 7412 05:39:49,240 --> 05:39:49,760 BUT THERE IS A COMMON 7413 05:39:49,760 --> 05:39:50,360 PROGENITOR CELL THAT WE SEE 7414 05:39:50,360 --> 05:39:51,320 THROUGH THE RED CELLS, AND THE 7415 05:39:51,320 --> 05:40:01,160 FIBROTIC AND PERICYTE. 7416 05:40:01,160 --> 05:40:01,720 WE CAN ALSO PREDICT FACTORS 7417 05:40:01,720 --> 05:40:06,520 RELATED TO ANGIOGENESIS, 7418 05:40:06,520 --> 05:40:07,120 COLLAGEN PRODUCTION AND ALSO 7419 05:40:07,120 --> 05:40:11,760 INTERESTING THINGS LIKE GDF 15 7420 05:40:11,760 --> 05:40:12,360 WHICH COMES UP IN A LOT OF 7421 05:40:12,360 --> 05:40:16,760 FRAILTY STUDIES IN THE SERUM. 7422 05:40:16,760 --> 05:40:17,360 AND ALSO APPLIED CLINICAL SETS 7423 05:40:17,360 --> 05:40:18,000 AROUND ONE OF THOSE IMPLANTS, 7424 05:40:18,000 --> 05:40:22,000 YOU CAN SEE P15 -POSITIVE CELLS 7425 05:40:22,000 --> 05:40:26,240 IN PURPLE AROUND THE BLOOD 7426 05:40:26,240 --> 05:40:26,760 VESSEL LOOKING MORE LIKE 7427 05:40:26,760 --> 05:40:27,400 PARASITES AND MORE STRESSED OUT 7428 05:40:27,400 --> 05:40:32,080 FIBER PLASTIC LIKE P16 POSITIVE 7429 05:40:32,080 --> 05:40:32,640 AND YOU CAN SEE THE GENES 7430 05:40:32,640 --> 05:40:36,080 DRIVING SIMILARITY, WHICH ONES 7431 05:40:36,080 --> 05:40:36,680 WERE IN THE CLUSTERS AND WERE 7432 05:40:36,680 --> 05:40:40,720 IN THE SENESCENCE SIGNATURE AND 7433 05:40:40,720 --> 05:40:41,720 NOW WORKING WITH NEW METHODS TO 7434 05:40:41,720 --> 05:40:45,560 DO THE TRANSFER LEARNING USING 7435 05:40:45,560 --> 05:40:47,360 PROJECT R SO WE CAN START 7436 05:40:47,360 --> 05:40:47,920 LOOKING AT THE DIFFERENTIAL 7437 05:40:47,920 --> 05:40:52,240 EXPRESSION BETWEEN SENESCENCE 7438 05:40:52,240 --> 05:40:57,080 CELLS AND NON-SENESCENCE CELLS 7439 05:40:57,080 --> 05:40:57,720 IN EACH CLUSTER AND WE CAN PICK 7440 05:40:57,720 --> 05:41:00,520 OUT THE SENESCENCE CELLS, AND 7441 05:41:00,520 --> 05:41:08,600 WE THOUGHT RPF WAS INTERESTING 7442 05:41:08,600 --> 05:41:09,120 BECAUSE IT SUGGESTED THAT 7443 05:41:09,120 --> 05:41:17,720 CERTAIN EPITHELIAL CELLS WERE 7444 05:41:17,720 --> 05:41:18,360 SENESCENCE, EVEN THOUGH WE DID 7445 05:41:18,360 --> 05:41:18,960 NOT HAVE EPITHELIAL CELLS IN 7446 05:41:18,960 --> 05:41:29,200 ORIGINAL THE SIGNATURE. 7447 05:41:29,200 --> 05:41:30,000 AND THIS IS IN THE 7448 05:41:30,000 --> 05:41:33,280 GEREOSCIENCE PAPER. THIS IS BY 7449 05:41:33,280 --> 05:41:33,880 ONE OF OUR COLLABORATIVE WHO 7450 05:41:33,880 --> 05:41:35,720 HAS BEEN COMPARING THE VARIOUS 7451 05:41:35,720 --> 05:41:37,560 SENESCENCE SIGNATURES-- 7452 05:41:37,560 --> 05:41:38,320 APOLOGIES THAT IT IS HARD TO 7453 05:41:38,320 --> 05:41:48,720 READ, THE FPR -- AND 7454 05:41:51,920 --> 05:41:52,480 ESSENTIALLY WE ARE GETTING THE 7455 05:41:52,480 --> 05:42:02,720 REALLY HIGH CORRELATION IN THE 7456 05:42:02,720 --> 05:42:03,280 FBR-DERIVED SIGNATURES WHEN 7457 05:42:03,280 --> 05:42:03,840 COMPARING IT TO THE OTHER 7458 05:42:03,840 --> 05:42:05,840 METHODS. 7459 05:42:05,840 --> 05:42:08,720 AS YOU COMPARE THE INDIVIDUAL 7460 05:42:08,720 --> 05:42:10,200 SIGNATURES PLEASE FEEL FREE TO 7461 05:42:10,200 --> 05:42:12,880 USE (INDISCERNIBLE). 7462 05:42:12,880 --> 05:42:13,400 I'M GOING TO END WITH WHAT 7463 05:42:13,400 --> 05:42:19,600 GOES ON WITH AGING. JIN HAN IS 7464 05:42:19,600 --> 05:42:20,160 HERE A SENIOR FELLOW IN THE 7465 05:42:20,160 --> 05:42:25,800 LABORATORY IN THE BACK OF YOUR 7466 05:42:25,800 --> 05:42:26,360 QUITE INTERESTED IN WHAT 7467 05:42:26,360 --> 05:42:26,960 HAPPENS TO THE RESPONSE WITH 7468 05:42:26,960 --> 05:42:27,520 THERAPIES AND HEALING WITH 7469 05:42:27,520 --> 05:42:30,440 AGING. AND AGAIN THE 7470 05:42:30,440 --> 05:42:39,640 COLLABORATOR BEEN HEALTH GROWTH 7471 05:42:39,640 --> 05:42:44,680 (CORRECTION) BEN HATHGROVE 7472 05:42:44,680 --> 05:42:50,200 (PHONETIC) A FEW YEARS AGO. 7473 05:42:50,200 --> 05:42:50,760 IF YOU PUT THE SAME MATERIAL 7474 05:42:50,760 --> 05:42:58,640 TO PROMOTE TISSUE REPAIR IN AN 7475 05:42:58,640 --> 05:42:59,240 OLD ANIMAL YOU SEE A LOT MORE 7476 05:42:59,240 --> 05:42:59,800 FIBROSIS AND EPIGENESIS IN 7477 05:42:59,800 --> 05:43:00,360 THOSE OLDER ANIMALS AND WE 7478 05:43:00,360 --> 05:43:10,200 DON'T SUPER HAPPENING. IN 7479 05:43:10,200 --> 05:43:10,720 MUSCLE YOU WANT TO SEE 7480 05:43:10,720 --> 05:43:17,600 ESSENTIAL LOCATED NUCLEI. 7481 05:43:17,600 --> 05:43:18,200 WHAT HE FOUND WAS INTERESTING 7482 05:43:18,200 --> 05:43:18,760 DIFFERENCES BETWEEN A LYMPH 7483 05:43:18,760 --> 05:43:23,160 NODE AND FLAME, PRODUCE NUMBERS 7484 05:43:23,160 --> 05:43:23,800 BETWEEN AVON OLD AND INCREASED 7485 05:43:23,800 --> 05:43:25,840 RECEPTOR CELLS, AND THAT IS 7486 05:43:25,840 --> 05:43:30,120 DIFFERENT IN DIFFERENT PLACES. 7487 05:43:30,120 --> 05:43:30,680 T CELLS IN THE OLDER ANIMAL 7488 05:43:30,680 --> 05:43:33,600 SWITCHING TO IL17 EXPRESSION 7489 05:43:33,600 --> 05:43:37,200 AND CD4 T-CELLS WE GET MORE 7490 05:43:37,200 --> 05:43:39,600 DIFFERENT GAMMA IL17. 7491 05:43:39,600 --> 05:43:45,240 WE SEE INCREASED IL17 IN OLDER 7492 05:43:45,240 --> 05:43:45,840 ANIMALS. WE PUT IN INJURY AND 7493 05:43:45,840 --> 05:43:46,720 IMPLANTS WE SEE INCREASES IN 7494 05:43:46,720 --> 05:43:53,080 IL17 A AND F, AND IF WE LOOK 7495 05:43:53,080 --> 05:43:54,520 LITTLE BIT FURTHER IN THE 7496 05:43:54,520 --> 05:44:00,280 TRAINING LYMPH NODES, T 17 CAN 7497 05:44:00,280 --> 05:44:05,000 REDUCE MMPS AND VARIOUS 7498 05:44:05,000 --> 05:44:11,160 (INDISCERNIBLE), WE DON'T SEE 7499 05:44:11,160 --> 05:44:11,760 DIFFERENCES BETWEEN YOUNG AND 7500 05:44:11,760 --> 05:44:15,000 OLD AT BASELINE BUT THERE ARE 7501 05:44:15,000 --> 05:44:15,600 SEVERAL CHANGES IN THE IMPLANT 7502 05:44:15,600 --> 05:44:16,720 THAT IS IMPEDING THE RESPONSE. 7503 05:44:16,720 --> 05:44:22,480 IL4 DECREASES IN THE IMPLANT 7504 05:44:22,480 --> 05:44:23,080 DOESN'T IN THE TISSUE AND IN 7505 05:44:23,080 --> 05:44:23,600 ADDITION YOU ALSO HAVE 7506 05:44:23,600 --> 05:44:24,880 INCREASED IL17. 7507 05:44:24,880 --> 05:44:35,320 LAST FEW SLIDES. T-CELLS-SNC 7508 05:44:36,600 --> 05:44:38,640 COMMUNICATION. 7509 05:44:38,640 --> 05:44:39,160 IN THE BOTTOM WE HAVE THE 7510 05:44:39,160 --> 05:44:42,440 CLUSTERS ENRICHED IN THE 7511 05:44:42,440 --> 05:44:46,400 SENESCENT SPACE AND IN THE 7512 05:44:46,400 --> 05:44:50,520 SENESCENCE SIGNATURE AND THIS 7513 05:44:50,520 --> 05:44:52,320 MGP FIBROBLAST IS IMPORTANT. 7514 05:44:52,320 --> 05:44:58,080 THAT MGP FIB IN READ INDICATE 7515 05:44:58,080 --> 05:44:58,680 IF YOU THINK YOU LOOK AT THE 7516 05:44:58,680 --> 05:45:01,280 OLD ANIMAL. T-CELLS ARE DOING A 7517 05:45:01,280 --> 05:45:03,800 LOT MORE HERE, A LOT MORE 7518 05:45:03,800 --> 05:45:05,920 RECEPTORS COMMUNICATING IN A 7519 05:45:05,920 --> 05:45:11,160 T-CELL AND LOOK AT THOSE 7520 05:45:11,160 --> 05:45:11,800 SENESCENCE IN THE OLDER ANIMALS 7521 05:45:11,800 --> 05:45:12,400 THAT THEY ARE COMMUNICATING A 7522 05:45:12,400 --> 05:45:18,960 LOT MORE. SO AGAIN THE T-CELLS 7523 05:45:18,960 --> 05:45:21,080 SENESCENCE COMMUNICATION IS 7524 05:45:21,080 --> 05:45:21,680 IMPORTANT. LAST TWO SLIDES I 7525 05:45:21,680 --> 05:45:31,880 PROMISE. 7526 05:45:32,400 --> 05:45:33,080 THERE WERE FEWER NAïVE IN OLD. 7527 05:45:33,080 --> 05:45:34,080 YOU GET INCREASE 7528 05:45:34,080 --> 05:45:36,080 DIFFERENTIATION OF THE OLDER 7529 05:45:36,080 --> 05:45:36,840 SALES AND INCREASED PRESS STAR 7530 05:45:36,840 --> 05:45:47,360 3 ON YOUR Q (CORRECTION) TH 17 7531 05:45:52,120 --> 05:45:56,600 DIFFERENTIATION IN ORDER CELLS. 7532 05:45:56,600 --> 05:45:57,240 WE HAVE ALL THESE MARKERS THAT 7533 05:45:57,240 --> 05:46:00,400 ONE OF EXPRESSING DIFFERENTLY. 7534 05:46:00,400 --> 05:46:01,040 A LOT OF THINGS WERE RELATED TO 7535 05:46:01,040 --> 05:46:01,640 VASCULAR DYSFUNCTION IN OLDER 7536 05:46:01,640 --> 05:46:06,080 ANIMALS IN THE T-CELLS ARE 7537 05:46:06,080 --> 05:46:06,720 TRYING TO REPAIR THE DISRUPTED 7538 05:46:06,720 --> 05:46:08,000 VASCULATURE IN AGING. 7539 05:46:08,000 --> 05:46:10,040 T-CELLS ARE DIFFERENT IN OLDER 7540 05:46:10,040 --> 05:46:13,480 ANIMALS TOO. YOU LOOK AT THE 7541 05:46:13,480 --> 05:46:15,880 SIGNATURE AND THE PHENOTYPE, IS 7542 05:46:15,880 --> 05:46:18,320 DIFFERENT IN THE YOUNG AND OLD 7543 05:46:18,320 --> 05:46:22,520 AND FACTORS A DIFFERENT. METRIC 7544 05:46:22,520 --> 05:46:29,080 MODELS BEING EXPRESSED, AND THE 7545 05:46:29,080 --> 05:46:29,600 (INDISCERNIBLE) DIFFERENT 7546 05:46:29,600 --> 05:46:30,160 EXPRESSION AND AGAIN THE 7547 05:46:30,160 --> 05:46:36,040 T-CELLS AND SENESCENT CELLS ARE 7548 05:46:36,040 --> 05:46:37,240 DIFFERENT. 7549 05:46:37,240 --> 05:46:38,560 JIM WAS ABLE TO RESCUE IT BY 7550 05:46:38,560 --> 05:46:39,680 AN INHIBITOR. HE CAN INCREASE 7551 05:46:39,680 --> 05:46:42,160 THE TISSUE REPAIR, DECREASE THE 7552 05:46:42,160 --> 05:46:48,040 IL17, PROMOTE THE IL4 PHENOTYPE 7553 05:46:48,040 --> 05:46:49,040 AND DECREASE FIBROSIS, 7554 05:46:49,040 --> 05:46:51,520 DECREASED EPIGENESIS WITH A 7555 05:46:51,520 --> 05:46:52,120 COMBINATION THERAPY TARGETING 7556 05:46:52,120 --> 05:47:02,640 THE IMMUNE HEPATORY FACTORS IN 7557 05:47:03,000 --> 05:47:03,440 BLOCKING RESPONSES TO 7558 05:47:03,440 --> 05:47:05,640 PROGENITOR MATERIAL. 7559 05:47:05,640 --> 05:47:08,120 IN THIS IS TIGHTLY INTEGRATED. 7560 05:47:08,120 --> 05:47:12,080 SENESCENT CELLS TIGHTLY 7561 05:47:12,080 --> 05:47:12,600 INTEGRATE WITH THE IMMUNE 7562 05:47:12,600 --> 05:47:16,560 SYSTEM. SNCS PLAY A ROLE IN 7563 05:47:16,560 --> 05:47:17,200 REGULATED TISSUE REPAIR PROCESS 7564 05:47:17,200 --> 05:47:19,040 CORRELATING IMMUNE CELLS, 7565 05:47:19,040 --> 05:47:19,520 MATRIX PRODUCTION AND 7566 05:47:19,520 --> 05:47:20,840 REGULARIZATION. 7567 05:47:20,840 --> 05:47:26,640 AGING IS A CHRONIC, NONHEALING 7568 05:47:26,640 --> 05:47:27,280 WOUND IMPEDED WITH AGE SO THAT 7569 05:47:27,280 --> 05:47:27,920 IS ANOTHER PERSPECTIVE TO THINK 7570 05:47:27,920 --> 05:47:29,560 ABOUT. 7571 05:47:29,560 --> 05:47:30,160 THANK YOU FOR YOUR TIME AND 7572 05:47:30,160 --> 05:47:30,960 THANK YOU FOR STICKING AROUND 7573 05:47:30,960 --> 05:47:34,800 TO THE LAST LIVE TALK. I LOOK 7574 05:47:34,800 --> 05:47:36,040 FORWARD TO CONNECTING WITH 7575 05:47:36,040 --> 05:47:37,600 PEOPLE LATER BY EMAIL OR 7576 05:47:37,600 --> 05:47:43,440 WHATEVER. 7577 05:47:43,440 --> 05:47:45,200 >>SO WE CAN AGAIN HAVE ONE 7578 05:47:45,200 --> 05:47:46,040 QUESTION. AND THEN WE WILL GO 7579 05:47:46,040 --> 05:47:47,480 ON TO OUR GAPS AND KNOWLEDGE 7580 05:47:47,480 --> 05:47:50,880 SESSION. ONE QUESTION. 7581 05:47:50,880 --> 05:47:52,680 >>REAL QUICK. SO REALLY 7582 05:47:52,680 --> 05:47:58,960 WONDERFUL TALK. WITH THIS DATA, 7583 05:47:58,960 --> 05:47:59,920 COULD YOU TELL IF THE CONNECTED 7584 05:47:59,920 --> 05:48:00,560 MY FIBROBLAST IN THE CARTILAGE 7585 05:48:00,560 --> 05:48:04,040 WERE THEY COMING FROM 7586 05:48:04,040 --> 05:48:04,680 SENESCENCE RESIDENT FIBROBLAST 7587 05:48:04,680 --> 05:48:08,040 OR GAINING SENESCENCE AS THEY 7588 05:48:08,040 --> 05:48:10,600 WERE DIFFERENTIATING? 7589 05:48:10,600 --> 05:48:14,000 >>I DON'T THINK WE HAVE THAT-- 7590 05:48:14,000 --> 05:48:15,880 WE HAVE NOT DONE THE STUDIES TO 7591 05:48:15,880 --> 05:48:21,520 SHOW THAT. I THINK, WELL, 7592 05:48:21,520 --> 05:48:27,760 REALLY IT IS THE SENESCENCE 7593 05:48:27,760 --> 05:48:28,320 SIGNALING SO THAT THERE IS 7594 05:48:28,320 --> 05:48:33,520 SOMETHING WRONG WE ALSO SEE 7595 05:48:33,520 --> 05:48:35,400 MECHANO RESPONSES, GENES COMING 7596 05:48:35,400 --> 05:48:36,200 UP. ARE THEY DIFFERENTIATING 7597 05:48:36,200 --> 05:48:41,160 INTO SENESCENT CELLS? THAT IS A 7598 05:48:41,160 --> 05:48:42,120 GREAT QUESTION. BUT THE 7599 05:48:42,120 --> 05:48:42,680 FIBROBLAST IS ONLY A SMALL 7600 05:48:42,680 --> 05:48:43,840 PERCENTAGE. THAT IS A GREAT 7601 05:48:43,840 --> 05:48:48,200 QUESTION. I DON'T HAVE AN 7602 05:48:48,200 --> 05:48:48,800 ANSWER AND I WOULD LOVE TO DO 7603 05:48:48,800 --> 05:48:49,840 SOME TRACKING STUDIES IF THERE 7604 05:48:49,840 --> 05:48:53,640 IS A WAY TO DO THAT. 7605 05:48:53,640 --> 05:48:54,200 >>THANK YOU VERY MUCH TO ALL 7606 05:48:54,200 --> 05:48:56,280 OF THE SPEAKERS. AND WE WOULD 7607 05:48:56,280 --> 05:48:59,520 LIKE TO HAVE THE SPEAKERS WERE 7608 05:48:59,520 --> 05:49:07,000 STILL HERE FROM THE SESSION, 7609 05:49:07,000 --> 05:49:07,600 COME UP FOR OUR NEXT SESSION 7610 05:49:07,600 --> 05:49:08,760 THAT IS UNDER BONNIE'S 7611 05:49:08,760 --> 05:49:17,920 JURISDICTION. THE GAPS. 7612 05:49:17,920 --> 05:49:19,520 >>SO THERE ARE FOUR OF YOU 7613 05:49:19,520 --> 05:49:24,400 HERE. THANK YOU FOR JOINING US 7614 05:49:24,400 --> 05:49:29,160 FOR THE GAPS. PERHAPS IN THE 7615 05:49:29,160 --> 05:49:33,800 FIELD DISCUSSION. SOME OF YOU 7616 05:49:33,800 --> 05:49:35,920 HAVE ACTUALLY LIFTED SOME OF 7617 05:49:35,920 --> 05:49:36,560 YOUR GAPS THAT YOU THOUGHT WERE 7618 05:49:36,560 --> 05:49:37,120 IMPORTANT TO PUT FORWARD TO 7619 05:49:37,120 --> 05:49:38,240 DISCUSS. BUT I WOULD GIVE YOU 7620 05:49:38,240 --> 05:49:42,760 THE OPTION OF DOING THAT AGAIN. 7621 05:49:42,760 --> 05:49:46,360 I THINK WE CAN START WITH -- 7622 05:49:46,360 --> 05:49:48,240 PERHAPS, AND GO DOWN THE LINE. 7623 05:49:48,240 --> 05:49:50,800 THANK YOU SO MUCH. ANYTHING 7624 05:49:50,800 --> 05:49:54,040 THAT YOU WANT TO SAY ABOUT GAPS? 7625 05:49:54,040 --> 05:49:54,640 >>I THINK THE BIGGEST GAP IS 7626 05:49:54,640 --> 05:49:56,840 CONSIDERING AGE AS A CATEGORY 7627 05:49:56,840 --> 05:49:59,280 TO ONLY DO RESEARCH. VERY 7628 05:49:59,280 --> 05:50:03,720 IMPORTANT IN GETTING PEOPLE. 7629 05:50:03,720 --> 05:50:04,280 BECAUSE THE YOUNG PEOPLE I 7630 05:50:04,280 --> 05:50:06,760 SHOWED YOU TODAY WILL HAVE GENE 7631 05:50:06,760 --> 05:50:08,280 PROFILES THAT TRACK SURVIVAL OR 7632 05:50:08,280 --> 05:50:15,160 MORTALITY. SO IF YOU HAVE A 7633 05:50:15,160 --> 05:50:15,760 POPULATION OF SAY-- I DID NOT 7634 05:50:15,760 --> 05:50:22,680 SHOW THE WHOLE DATA SETS-- BUT 7635 05:50:22,680 --> 05:50:23,280 MAYBE 20-YEAR-OLD PEOPLE HAVE 7636 05:50:23,280 --> 05:50:23,880 TISSUE FOUND IN ABUNDANCE IN 7637 05:50:23,880 --> 05:50:28,320 ALL PEOPLE. CHARACTERIZING 7638 05:50:28,320 --> 05:50:28,880 PEOPLE WITH DIFFERENT RISK 7639 05:50:28,880 --> 05:50:32,280 PROFILES. (INDISCERNIBLE). 7640 05:50:32,280 --> 05:50:32,880 SO I DID NOT HAVE TIME TO SHOW 7641 05:50:32,880 --> 05:50:35,560 YOU. IF YOU ACTUALLY COMPARE 7642 05:50:35,560 --> 05:50:38,560 OLDER PEOPLE WHO HAVE THE SAME 7643 05:50:38,560 --> 05:50:41,320 GRADE AS A YOUNG PEOPLE, THERE 7644 05:50:41,320 --> 05:50:43,320 IMMUNE PROFILES ARE SHARED, AND 7645 05:50:43,320 --> 05:50:43,920 THEY ARE DISTINCT FROM THOSE 7646 05:50:43,920 --> 05:50:49,920 THAT ARE OLDER. 7647 05:50:49,920 --> 05:50:50,480 AND SAME WITH A IF I TOOK A 7648 05:50:50,480 --> 05:50:53,080 GENERAL PERSON WHO HAS A 7649 05:50:53,080 --> 05:50:53,600 DEGRADED IMMUNOLOGICAL 7650 05:50:53,600 --> 05:50:54,200 RESILIENCE AND WE GIVE THEM THE 7651 05:50:54,200 --> 05:50:55,360 FLU VACCINE ARE NOT RESPONSIVE. 7652 05:50:55,360 --> 05:50:56,320 THAT COULD HELP IN TAKING CARE 7653 05:50:56,320 --> 05:51:01,280 OF THE (INDISCERNIBLE) MEMORY. 7654 05:51:01,280 --> 05:51:01,840 THIS IS A LARGE STUDY AND 7655 05:51:01,840 --> 05:51:02,440 YOU'RE WELCOME TO READ IT WHEN 7656 05:51:02,440 --> 05:51:03,760 IT COMES OUT, BUT HE GETS TO 7657 05:51:03,760 --> 05:51:06,160 THE IDEA THAT IF YOU CONTROL 7658 05:51:06,160 --> 05:51:07,720 FOR THE HETEROGENEITY, THERE 7659 05:51:07,720 --> 05:51:10,920 ARE TWO PROCESSES GOING ON IN 7660 05:51:10,920 --> 05:51:12,080 THE CONTROL FOR THOSE PROCESSES 7661 05:51:12,080 --> 05:51:12,720 YOU MIGHT GET GREATER 7662 05:51:12,720 --> 05:51:16,040 DISTINCTION. WHY DO CLINICAL 7663 05:51:16,040 --> 05:51:19,760 TRIALS FAIL? THING ONCOLOGISTS 7664 05:51:19,760 --> 05:51:22,760 ARE VERY SMART. ONCOLOGIST ARE 7665 05:51:22,760 --> 05:51:23,360 WAY AHEAD OF US IN THE CONTROL 7666 05:51:23,360 --> 05:51:23,960 FOR HETEROGENEITY AND GENE 7667 05:51:23,960 --> 05:51:26,840 SIGNATURES. AND THEY TARGET 7668 05:51:26,840 --> 05:51:27,400 THE POPULATION IN THE SAME 7669 05:51:27,400 --> 05:51:31,760 THING HOLDS TRUE HERE. 7670 05:51:31,760 --> 05:51:32,280 IF YOU FOR EXAMPLE HAVE A 7671 05:51:32,280 --> 05:51:32,840 CLINICAL TRIAL WITH A SMALL 7672 05:51:32,840 --> 05:51:40,520 STUDY EVEN, AND YOU ARE IN 7673 05:51:40,520 --> 05:51:41,080 BALANCE FOR PEOPLE WHO HAVE 7674 05:51:41,080 --> 05:51:43,600 DIFFERENT LEVELS OF GREATER 7675 05:51:43,600 --> 05:51:44,640 IMMUNE SURVIVAL MORTALITY 7676 05:51:44,640 --> 05:51:46,720 SIGNATURES WOULD BE 7677 05:51:46,720 --> 05:51:50,320 (INDISCERNIBLE). YOU CAN 7678 05:51:50,320 --> 05:51:50,920 CONTROL HETEROGENEITY AND WE 7679 05:51:50,920 --> 05:51:53,560 NEED TO CONTROL IT. 7680 05:51:53,560 --> 05:51:55,200 >>OKAY JUST MAKE SURE THAT 7681 05:51:55,200 --> 05:51:57,920 EVERYBODY CAN HEAR YOU. THANK 7682 05:51:57,920 --> 05:52:00,080 YOU. 7683 05:52:00,080 --> 05:52:03,200 >>THANKS. I THINK ONE OF THE 7684 05:52:03,200 --> 05:52:05,920 GAPS IS MOVING FUNDAMENTAL 7685 05:52:05,920 --> 05:52:06,720 KNOWLEDGE AND TO SPUR MENTAL 7686 05:52:06,720 --> 05:52:17,280 MEDICINE TRIALS. AND HAVING 7687 05:52:17,280 --> 05:52:22,240 REALLY GOOD PRECLINICAL MODELS. 7688 05:52:22,240 --> 05:52:23,920 WE TALKED A LOT ABOUT THE 7689 05:52:23,920 --> 05:52:24,480 STRENGTHS AND WEAKNESSES OF 7690 05:52:24,480 --> 05:52:25,880 VARIOUS MODELS INCLUDING USING 7691 05:52:25,880 --> 05:52:28,600 ANIMALS AS MODELS. 7692 05:52:28,600 --> 05:52:29,200 I THINK WE NEED TO EMBRACE THE 7693 05:52:29,200 --> 05:52:33,080 FACT THAT AGING IS COMPLEX. WE 7694 05:52:33,080 --> 05:52:35,240 NEED ALL THE MODELS WE CAN GET. 7695 05:52:35,240 --> 05:52:39,000 AS LONG AS WE UNDERSTAND THE 7696 05:52:39,000 --> 05:52:39,560 LIMITATIONS, BUT ALSO THE 7697 05:52:39,560 --> 05:52:43,160 STRENGTHS. THAT I THINK WE 7698 05:52:43,160 --> 05:52:43,800 SHOULD BE USING EVERY SYSTEM WE 7699 05:52:43,800 --> 05:52:49,120 HAVE. 7700 05:52:49,120 --> 05:52:51,560 >>SO I THINK THERE IS GREAT 7701 05:52:51,560 --> 05:52:52,080 OPPORTUNITY IN BRINGING 7702 05:52:52,080 --> 05:52:52,680 TOGETHER THE COMMUNITIES THAT 7703 05:52:52,680 --> 05:52:54,200 WE HAVE HERE. VERY DIFFERENT 7704 05:52:54,200 --> 05:52:57,680 PERSPECTIVES. THERE'S A LOT OF 7705 05:52:57,680 --> 05:52:58,960 I WOULD SAY LOW HANGING FRUIT 7706 05:52:58,960 --> 05:53:05,960 CONNECTING THE TOPICS HERE. 7707 05:53:05,960 --> 05:53:06,440 SO WE HAVE BEEN WORKING 7708 05:53:06,440 --> 05:53:09,200 PREVIOUSLY ON MAPPING VARIOUS 7709 05:53:09,200 --> 05:53:10,840 ENVIRONMENTS, IN HEALING AND 7710 05:53:10,840 --> 05:53:21,400 NONHEALING WOUNDS, NOT REALLY 7711 05:53:21,400 --> 05:53:22,000 SHIFTING TO WHAT TRANSLATION 7712 05:53:22,000 --> 05:53:24,200 DOES ADDRESSING THE GAP IN 7713 05:53:24,200 --> 05:53:24,800 PRECLINICAL AND CLINICAL AND 7714 05:53:24,800 --> 05:53:27,120 AGING IS A BIG ONE. 7715 05:53:27,120 --> 05:53:27,760 HETEROGENEITY, YOU HAVE GREAT 7716 05:53:27,760 --> 05:53:28,400 MINDS IN THE SAME CONDITION AND 7717 05:53:28,400 --> 05:53:29,240 THEY HAVE HETEROGENEITY. 7718 05:53:29,240 --> 05:53:34,160 (INDISCERNIBLE). 7719 05:53:34,160 --> 05:53:38,040 BUT OTHER THINGS BEING, LIKE 7720 05:53:38,040 --> 05:53:40,320 HISTORY OF INFECTIONS IMPACTING 7721 05:53:40,320 --> 05:53:40,920 RESPONSES, COMORBIDITIES, AND 7722 05:53:40,920 --> 05:53:41,520 IT IS INTERESTING HOW YOU CAN 7723 05:53:41,520 --> 05:53:43,680 SEE LOCALLY AGE ENVIRONMENTS 7724 05:53:43,680 --> 05:53:46,280 EVEN IN A YOUNG SAY ANIMAL 7725 05:53:46,280 --> 05:53:46,840 MODEL BUT YOU CAN IMAGINE 7726 05:53:46,840 --> 05:53:47,440 ANOTHER SYSTEMS THAT YOU HAVE 7727 05:53:47,440 --> 05:53:50,360 THESE LOCAL ENVIRONMENTS THAT 7728 05:53:50,360 --> 05:53:50,960 MIGHT BE AGED INFLUENCING IN 7729 05:53:50,960 --> 05:53:52,800 OTHER THINGS. 7730 05:53:52,800 --> 05:53:54,800 AS AN EXAMPLE, I THINK CANCER 7731 05:53:54,800 --> 05:53:56,520 PEOPLE ARE SMART TOO. I AGREE 7732 05:53:56,520 --> 05:53:59,160 WITH YOU ON THAT. WE PUT 7733 05:53:59,160 --> 05:54:02,600 DIFFERENT TYPES OF WOUNDS WITH 7734 05:54:02,600 --> 05:54:03,320 TUMORS IN OTHER PARTS OF THE 7735 05:54:03,320 --> 05:54:11,360 BODY. ONE TYPE OF ONE WILL 7736 05:54:11,360 --> 05:54:12,000 INCREASE TUMOR GROWTH, INCREASE 7737 05:54:12,000 --> 05:54:14,520 RESPONSE AND ANOTHER TYPE WILL 7738 05:54:14,520 --> 05:54:15,040 INCREASE TUMOR GROWTH AND 7739 05:54:15,040 --> 05:54:24,640 DECREASE THERAPEUTIC RESPONSE.A 7740 05:54:24,640 --> 05:54:25,200 SIMPLE SYSTEM SHOWING HOW 7741 05:54:25,200 --> 05:54:25,760 COMORBIDITIES ARE DIFFERENT 7742 05:54:25,760 --> 05:54:26,320 THINGS GOING ON CAN CHANGE 7743 05:54:26,320 --> 05:54:26,960 RESPONSE AND ALSO THE NEED FOR 7744 05:54:26,960 --> 05:54:29,000 ACCOMMODATION THERAPIES. FOR 7745 05:54:29,000 --> 05:54:29,640 VARIOUS REASONS THAT HAVE BEEN 7746 05:54:29,640 --> 05:54:30,200 HARD TO INTEGRATE THAT INTO 7747 05:54:30,200 --> 05:54:31,680 OTHER FIELDS. I THINK THAT IS 7748 05:54:31,680 --> 05:54:37,720 A GOOD PLACE TO START. 7749 05:54:37,720 --> 05:54:39,920 >>I AGREE WITH WHAT HAS BEEN 7750 05:54:39,920 --> 05:54:45,320 SAID. WITH THE HUMAN STUDIES IN 7751 05:54:45,320 --> 05:54:50,600 THE CONTEXT OF AGE EMBRACING 7752 05:54:50,600 --> 05:54:51,120 HETEROGENEITY, AND USING 7753 05:54:51,120 --> 05:54:51,760 APPROPRIATE STATISTICAL METHOD 7754 05:54:51,760 --> 05:54:53,360 TO TRY TO GET TO SOME OF THAT 7755 05:54:53,360 --> 05:54:57,040 HETEROGENEITY, THE COVARIANTS, 7756 05:54:57,040 --> 05:55:01,080 NOT USING T-TESTS OF THINGS 7757 05:55:01,080 --> 05:55:02,120 LIKE THIS TO A BETTER MODEL OF 7758 05:55:02,120 --> 05:55:02,720 HETEROGENEITY IS IMPORTANT AS 7759 05:55:02,720 --> 05:55:05,920 YOU MOVE FORWARD. 7760 05:55:05,920 --> 05:55:07,600 THE POINT THAT I MADE AT THE 7761 05:55:07,600 --> 05:55:09,280 WERE, AND HE CERTAINLY 7762 05:55:09,280 --> 05:55:15,160 MOTIVATED BY SOME OF THE STUFF 7763 05:55:15,160 --> 05:55:18,760 WE ARE DOING WITH COOL BIOLOGY, 7764 05:55:18,760 --> 05:55:20,240 AIMING TOWARDS QUESTIONS OF 7765 05:55:20,240 --> 05:55:20,760 VACCINE RESPONSE AT THE 7766 05:55:20,760 --> 05:55:25,360 FOREFRONT NOW. BECAUSE WE SEE, 7767 05:55:25,360 --> 05:55:26,680 IT IS ACCEPTED EVEN IN THE 7768 05:55:26,680 --> 05:55:29,640 POPULAR PRESS, YOU WILL SAY 7769 05:55:29,640 --> 05:55:36,160 OH! OLDER ADULTS LOSE TITERS TO 7770 05:55:36,160 --> 05:55:36,720 NEUTRALIZING ANTIBODIES AND 7771 05:55:36,720 --> 05:55:37,360 THIS IS SOMETHING YOU WILL SEE 7772 05:55:37,360 --> 05:55:41,320 ON CNN AND SOMETHING LIKE THIS. 7773 05:55:41,320 --> 05:55:41,920 WHAT DO WE DO ABOUT THIS? 7774 05:55:41,920 --> 05:55:51,720 THERE IS AN URGENT NEED TO 7775 05:55:51,720 --> 05:55:52,200 UNDERSTAND, IS THERE A 7776 05:55:52,200 --> 05:55:53,720 DIFFERENCE BETWEEN MAGNITUDE, 7777 05:55:53,720 --> 05:55:59,360 INTENSITY OF RESPONSE? IS THERE 7778 05:55:59,360 --> 05:55:59,880 A DIFFERENCE BETWEEN THE 7779 05:55:59,880 --> 05:56:04,000 DURATION OF THE RESPONSE? DO 7780 05:56:04,000 --> 05:56:04,600 YOU HAVE ANY DIFFERENCE ABOUT 7781 05:56:04,600 --> 05:56:06,480 THE PERSISTENCE OF ANTIGENS? IS 7782 05:56:06,480 --> 05:56:07,080 THERE SOMETHING WE CAN DO TO 7783 05:56:07,080 --> 05:56:12,680 CHANGE THAT? SO THAT WE HAVE 7784 05:56:12,680 --> 05:56:18,120 LONGER (INDISCERNIBLE) T-CELLS 7785 05:56:18,120 --> 05:56:18,680 RESPONSES THAT WILL PROTECT 7786 05:56:18,680 --> 05:56:19,280 PEOPLE AGAINST GETTING REALLY 7787 05:56:19,280 --> 05:56:24,720 SICK. BUT A LOT OF THE UPTAKE 7788 05:56:24,720 --> 05:56:26,800 AND CONTROVERSIES THAT VACCINES 7789 05:56:26,800 --> 05:56:27,400 DON'T WORK AS WELL FOR THE 7790 05:56:27,400 --> 05:56:28,960 ACQUISITION OF INFECTION. WHAT 7791 05:56:28,960 --> 05:56:32,480 CAN YOU DO TO GET IT THAT? 7792 05:56:32,480 --> 05:56:33,040 THE QUESTION ALWAYS WONDERED 7793 05:56:33,040 --> 05:56:34,560 ABOUT IS, HOW DO WE COME UP 7794 05:56:34,560 --> 05:56:39,280 WITH NEW ADJUVANTS? SHOULD WE 7795 05:56:39,280 --> 05:56:39,880 DECLARE VICTORY THAT WE HAVE 7796 05:56:39,880 --> 05:56:40,880 SOME THAT WORK REALLY WELL? IS 7797 05:56:40,880 --> 05:56:51,440 IT THAT ASO 3D IS JUST REACTIVE 7798 05:56:56,360 --> 05:56:56,920 GENETICS BUT WE DON'T WANT TO 7799 05:56:56,920 --> 05:56:57,520 USE IT WITH EVERYBODY BECAUSE 7800 05:56:57,520 --> 05:56:58,080 THEY WILL GET SORE ARM AND 7801 05:56:58,080 --> 05:56:59,520 COMPLAINS. SO IT IS NOT 7802 05:56:59,520 --> 05:57:03,080 ONE-SIZE-FITS-ALL. 7803 05:57:03,080 --> 05:57:04,800 >>ARE THERE ANY OTHER COMMENTS 7804 05:57:04,800 --> 05:57:05,440 FROM PEOPLE THAT ARE STILL OUT 7805 05:57:05,440 --> 05:57:07,160 THERE? 7806 05:57:07,160 --> 05:57:16,480 SO -- YES? 7807 05:57:16,480 --> 05:57:17,120 >>THIS MORNING WE HAD A VERY 7808 05:57:17,120 --> 05:57:18,920 INTENSIVE PRESENTATION OF THE 7809 05:57:18,920 --> 05:57:23,440 RESTRICTION OF (INDISCERNIBLE). 7810 05:57:23,440 --> 05:57:26,040 ANOTHER IMPORTANT PRIMARY 7811 05:57:26,040 --> 05:57:34,480 (INDISCERNIBLE) BONE MARROW. 7812 05:57:34,480 --> 05:57:35,440 WE DID NOT DISCUSS 7813 05:57:35,440 --> 05:57:38,000 (INDISCERNIBLE) AND IMMUNE 7814 05:57:38,000 --> 05:57:41,240 DEGRADATION. DOES ANYBODY HAVE 7815 05:57:41,240 --> 05:57:43,400 ANY INSIGHT OR COMMENT? 7816 05:57:43,400 --> 05:57:47,640 >>WELL, GIVEN THAT I'M A B 7817 05:57:47,640 --> 05:57:49,160 CELL PERSON I'M GOING TO MAKE 7818 05:57:49,160 --> 05:57:53,680 SOME COMMENT BUT NOT TOO LONG. 7819 05:57:53,680 --> 05:57:54,280 BASICALLY THE BONE MARROW AND 7820 05:57:54,280 --> 05:57:55,240 THE GENERATION OF CELLS, IT IS 7821 05:57:55,240 --> 05:57:57,920 AFFECTED BY AGE. AND REALLY I 7822 05:57:57,920 --> 05:58:00,080 WOULD LIKE TO POINT OUT AT 7823 05:58:00,080 --> 05:58:01,360 LEAST THAT THERE ARE TWO 7824 05:58:01,360 --> 05:58:02,000 POSSIBILITIES OF LOOKING AT THE 7825 05:58:02,000 --> 05:58:05,280 PROBLEM. ONE PROBLEM IS, WHAT 7826 05:58:05,280 --> 05:58:09,680 IS CAUSING THAT? 7827 05:58:09,680 --> 05:58:10,280 FOR EXAMPLE THE BONE PROBABLY 7828 05:58:10,280 --> 05:58:10,880 HAS SOMETHING TO DO WITH BONE 7829 05:58:10,880 --> 05:58:11,960 MARROW FOR EXAMPLE. FOR ALL OF 7830 05:58:11,960 --> 05:58:15,600 OUR SYSTEMS. WHAT IS CAUSING 7831 05:58:15,600 --> 05:58:18,400 THAT? WHAT IS DOWNSTREAM? WHAT 7832 05:58:18,400 --> 05:58:20,520 IS UPSTREAM AND WHAT IS 7833 05:58:20,520 --> 05:58:20,960 DOWNSTREAM? 7834 05:58:20,960 --> 05:58:21,480 THE MORE WE CAN GET THE 7835 05:58:21,480 --> 05:58:23,320 DETAILS OF THAT WITH REGARDS TO 7836 05:58:23,320 --> 05:58:26,640 WHATEVER WE ARE TAKING ABOUT OR 7837 05:58:26,640 --> 05:58:28,520 WORKING ON AND WE HAVE HAD A 7838 05:58:28,520 --> 05:58:33,040 WONDERFUL COMPILATION OF REALLY 7839 05:58:33,040 --> 05:58:33,680 WONDERFUL INTEGRATION OF TOPICS 7840 05:58:33,680 --> 05:58:36,000 HERE. I DON'T HAVE TOO MUCH 7841 05:58:36,000 --> 05:58:40,400 MORE TO SAY. BUT I WILL OPEN IT 7842 05:58:40,400 --> 05:58:44,200 UP AGAIN IF THERE'S ANYBODY 7843 05:58:44,200 --> 05:58:44,760 ELSE THAT IS SOMETHING ELSE 7844 05:58:44,760 --> 05:58:45,400 THAT WOULD LIKE TO SAY BEFORE I 7845 05:58:45,400 --> 05:58:48,520 SAY MY FINAL REMARKS. 7846 05:58:48,520 --> 05:58:49,080 IS ANYONE ELSE IT WOULD LIKE 7847 05:58:49,080 --> 05:58:50,640 TO ADD SOMETHING WITH REGARDS 7848 05:58:50,640 --> 05:58:53,080 TO THIS TOPIC? WHICH IS 7849 05:58:53,080 --> 05:58:56,680 BASICALLY GAPS IN THE FIELD OR 7850 05:58:56,680 --> 05:58:57,280 ANYTHING ELSE THAT YOU WOULD 7851 05:58:57,280 --> 05:59:00,920 LIKE TO SAY? AND IF NOT, I 7852 05:59:00,920 --> 05:59:02,800 WOULD LIKE TO SAY THANK YOU TO 7853 05:59:02,800 --> 05:59:11,760 MERCY AND TO -- AND TO --, 7854 05:59:11,760 --> 05:59:16,000 BECAUSE THEY HAVE ORGANIZED, 7855 05:59:16,000 --> 05:59:16,600 AND SOME OF US HAVE HELPED A 7856 05:59:16,600 --> 05:59:19,880 LITTLE TINY BIT, MYSELF AND LIZ 7857 05:59:19,880 --> 05:59:23,240 AND OTHERS IN THE ORGANIZATION. 7858 05:59:23,240 --> 05:59:23,840 I REALLY WANT TO SAY I THOUGHT 7859 05:59:23,840 --> 05:59:25,800 THIS WAS A WONDERFUL WAY TO GET 7860 05:59:25,800 --> 05:59:28,960 TOGETHER. WAS REALLY EXCITED 7861 05:59:28,960 --> 05:59:31,640 ABOUT EVERYBODY'S TALK. I 7862 05:59:31,640 --> 05:59:35,480 THINK YOU ALL DID A GREAT JOB. 7863 05:59:35,480 --> 05:59:36,040 ANY NO ONE ELSE HAS ANYTHING 7864 05:59:36,040 --> 05:59:38,600 TO SAY I WILL SAY PLEASE HAVE A 7865 05:59:38,600 --> 05:59:41,040 SAFE TRIP EITHER TO THE NEXT 7866 05:59:41,040 --> 05:59:41,680 MEETING OR AT HOME OR WHEREVER 7867 05:59:41,680 --> 05:59:43,240 YOU ARE GOING. AND THANK YOU 7868 05:59:43,240 --> 00:00:00,000 EVERYONE.