Rafael de Cabo

Transcription

>> I THINK WE'LL BEGIN. I JUST WANTED TO REMIND, SOMEBODY ASKED ME WHETHER THESE SESSIONS APPEAR IN THE NIH VIDEO ARCHIVE. INDEED THEY DO. IT TAKES ABOUT THREE DAYS OR FOUR DAYS FOR THEM TO LOG IT IN. AND THEN EVERYTHING IS THERE, ACTUALLY, FOR THE PAST TEN YEARS WORTH. SO YOU CAN CLICK ON EVERYTHING. IT'S INTERESTING, IT GOES AROUND THE WORLD AND SOME OF THE SESSIONS HAVE BEEN DOWNLOADED. THE RECORD IS 3600 TIMES. SO TODAY'S SUBJECT AS YOU KNOW IS AGING, WHICH INTERESTS ALL OF US, NO MATTER WHAT THE AGE IS. AND I JUST PUT A F THOUGHTS THAT CAME TO MY MIND IN THINKING ABOUT THIS AND I DON'T ÷ DWELL ON IT BECAUSE WE HAVE TWO VERY EXCITING SPEAKERS. BUT THE MORE YOU THINK ABOUT AGING, THE MORE COMPLICATED THE WHOLE BUSINESS COMES. I TRY TO ORGANIZE AT LEAST SOME OF THE COMPLEXITIES THAT WENT THROUGH MY MIND. I MEAN WE'RE SORT OF TOLD FROM WAY BACK THAT AN ANIMAL IS LIFE SPAN CORRELATES WITH THEIR BODY MASS, ELEPHANTS VERSUS MICE AND METABOLISM AND SOME SPECIES, THE GENDER WHERE IT SEEMS AS IF MORE OFTEN THE FEMALE LIVES LONGER THAN THE MALE. DO THESE GENERALITIES ACROSS THE BIOLOGICAL KINGDOM APPLY TO PRIMATES. CERTAINLY THE HUMAN LIFE SPAN GOING BACK IN HISTORY HAS INCREASED TREMENDOUSLY ASCRIBED TO WATER CONTROL NUTRITION, CONTROL OF INFECTIOUS AGENTS, ETCETERA ETCETERA. DRAMATICALLY INCREASE. IS THERE A LIMIT OR HAVE WE REACHED THE LIMIT. TO BE A HUNDRED YEARS OLD TODAY IS SOMETHING TO BE EXCITED ABOUT, BUT YOU KNOW, THEY DON'T HOIST THE FLAG. IT'S NOT THAT RARE. COME TO THINK OF IT, IT WASN'T SO RARE IN THE 17TH AND 18TH CENTURY EITHER, BUT MAYBE THERE WEREN'T AS MANY. BUT HAVE WE REACHED THE LIMIT. NOW IN THE 1950'S -- REMARKABLE HUMAN BEING, HE WAS IMPRESSED BY THE IDEA THAT -- DEPRIVATION INCREASED LONGEVITY IN ANIMALS AND HE WORKED WITH VETERINARIANS IN ENGLAND. IT'S ANOTHER CLASSICAL STUDIES IN A VARIETY OF FARM ANIMALS. SO HE DECIDED IF IT WAS GOOD FOR THEM, IT WOULD BE GOOD FOR HIM. AND HE SPENT THE LAST 30 ODD YEARS OF HIS LIFE EATING ONE MEAL A DAY AT NIGHT, AND HE WAS REALLY THIN AS A RAIL. HE WAS AMAZING. HIS MIND WAS ALERT, HE BICYCLED TEN MILES A DAY. HE WAS QUITE AN INTERESTING FELLOW. SOMEONE WORTH READING ABOUT AND ALSO IN TODAY'S WORLD PERHAPS TO EVEN GO BACK AND READ SOME OF HIS IDEAS WHICH ARE INCIDENTALLY ON THE WEBSITE. SO THEN COMES THE MODERN ERA WITH DISCOVERY OF SO-CALLED LONGEVITY GENES AND FACTORS, PARTICULARLY IN WORMS, YEAST AND THINGS WE'RE GOING TO HEAR ABOUT TODAY, THE -- ENERGY METABOLISM. THE METABOLIC SENSOR, AMPK, TELOMERES AND -- COMPOUNDS WHICH ACTIVATE THESE PROCESSES. ONE WILL HEAR QUITE A BIT OF -- A COMPOUND FROM RED WINE WHICH HAS ATTRACTED A LOT OF ATTENTION -- WHICH IS AN ANALOGUE OF AMT THAT ACTIVATES AMT KINASE. IT'S REALLY INTERESTING CONVERGENCE BECAUSE THESE THINGS HAVE BEEN DEMONSTRATED AND WE HEAR A GOOD BIT ABOUT THE EXPERIMENTAL SITUATIONS. R -- IS NOT CONTROLLED BYTE FDA. IF YOU WANT AN INTERESTING EXPERIMENT GROW ON THE INTERNET AND FIND OUT HOW MUCH YOU CAN SPEND. THE FOOTNOTE AT THE BOTTOM, THE NOTE IS WE CAN'T TELL YOU HOW MUCH YOU SHOULD BE TAKING BUT GO FOR IT ANYWAY AND SEND US A CHECK. THERE'S A LOT OF CONFUSION AND UNCERTAINTY AS TO THE RELEVANCE OF THIS IN HUMAN BIOLOGY. AT LEAST OF COURSE IN WORMS, THIS EXTRA EFFECT CALLED THE DOWER EFFECT WITH THE REDUCED GLUCOSE. THE WORM SORT OF SHUTS OFF, STAYS ALIVE, DOESN'T NEW VERY MUCH. AND CAN BE MAINTAINED IN THAT STATE FOR A LONG PERIOD OF TIME AND IT'S A REAL LONGEVITY FACTOR. IT'S BEEN COMPARED WHAT HAPPENS IN STAR TREK, SHIELDS UP OR SHIELDS DOWN. WHEN THE SHIELDS WERE UP THE SPACE SHIFT WERE PROTECTED FROM ALL THE OUTSIDE ENVIRONMENT BUT IT COULDN'T MOVE TO ESCAPE. BUT WHEN THE SHIELDS WERE DOWN, IT WAS VULNERABLE BUT IT COULD MOVE. AND IN A WAY, THIS SIMPLISTIC GENERALIZATION CERTAINLY A -- APPLIES TO THE DO YOU REMEMBER E -- DOWER EFFECT IN WORMS. YOU WILL HEAR ABOUT THAT POSSIBILITY TODAY. SO ONE OF THE QUESTIONS THAT COMES TO MIND IS IF WHAT WE DIE FROM THE ACCUMULATED EFFECTS OF SAY REACTIVE OXYGEN MEDIATED CHRONIC DISEASE, CENTRAL NERVOUS SYSTEM DISEASE, MAYBE PAR KINSON'S, ALZHEIMER'S AND SOME METABOLIC DISORDERS. THAT'S WHAT CAUSES THOSE THINGS, IS IT REASONABLE TO THINK THAT PREVENTION AND/OR TREATMENT OF THESE EVENTS WILL ACTUALLY PROLONG LIFE. AND IF IT DOES, WHAT WOULD BE THE QUALITY OF THE PROLONGED LIFE. THAT'S A LITTLE SPACEY TO CONSIDER BUT ONE WONDERS IF WE CAN DO THINGS THAT WILL AFFECT THE CARDIOVASCULAR SYSTEM TO THE EXCLUSION OF THE CENTRAL NERVOUS SYSTEM. WHAT ARE WE DOING. BUT THIS IS PHILOSOPHY, NOT SCIENCE. NOT PRACTICALLY IS THROUGH EXERCISE, DIET, WEIGHT CONTROL, AVOIDANCE OF SMOKING AND BAD HABITS. THEY MAKE LIFE HEALTHIER, BUT DO THEY PROLONG LIFE? ARE THEY EFFECTING AGING OR ARE THEY AFFECTING THESE SO-CALLED DEGENERATIVE PROCESSES. IF WE DIDN'T HAVE THE DEGENERATIVE PROCESSES, HOW WOULD WE DIE? LONG FELLOW YEARS AGO WROTE A HORRIBLE POEM CALLED THE DEACON'S ONE HORSE SHEA WHERE THE WAGON WAS BUILT, EVERY PART WAS PERFECT AND IT IS BUILT SO IT WOULD NEVER FALL APART. THERE WOULD BE NO POINT OF WEAKNESS. AND ONE DAY, THE WHOLE THING TURNED TO DUST. IS THAT WHAT HAPPENS WHEN EVERYTHING FAILED TOGETHER? WELL, I HOPE OUR SPEAKERS TODAY ARE GOING TO ANSWER THESE QUESTIONS. THE COMMENTS WERE JUST MEANT TO STIMULATE SOME INTEREST ON YOUR PART. SO AS ALWAYS, I ENCOURAGE YOU TO INTERRUPT, RAISE YOUR HAND, ASK QUESTIONS DURING AS WELL AS AFTER. SO WE'RE VERY FORTUNATE BECAUSE WE HAVE TWO SPEAKERS TODAY WHO ARE LEADERS IN THIS FIELD. AND SO THE FIRST SPEAKER IS GOING TO BE JAY CHUNG, WHO IS A SENIOR INVESTIGATOR IN THE LABORATORY OF OBESITY AND AGING RESEARCH HERE ON THIS CAMPUS AT NIH. SO JAY TRAINED AN ELECTRICAL ENGINEERING AND THEN BIOLOGY AT MIT AND GOT A PH.D. AT HARVARD IN GENETICS. HE TOOK TRAINING AND INTERNAL MEDICINE THIS BOSTON AND CAME HERE AS AN ENDOCRINE FELLOW, WHERE HE WORKED WITH GARY -- MOLECULAR SCIENTIST. HE MOVED TO THE HEART INSTITUTE IN 1994 AS AN INVESTIGATOR IN THE LABORATORY OF BIOCHEMICAL GENETICS. YOU WILL HEAR OF HIS INTEREST IN UNDERSTANDING HOW AGING AFFECTS OUR ABILITY TO BURN CALORIES AND PROCESSES THAT ARE INVOLVED IN WHAT HAPPENS IF WE INTERFERE WITH THEM. AND OUR SECOND SPEAKER IS RAFAEL DE CABO WHO IS IN THE NATIONAL INSTITUTE OF AGING. HE'S BASED IN BALTIMORE AND I'M SURE HE WOULD LOVE TO HAVE ANY OF YOU COME TO VISIT IF YOU ARE INTERESTED IN DOING SO. AND HE RECVED, HE'S FROM SPAIN ORIGINALLY AND MAINTAINS A VERY CLOSE LINK WITH COLLEAGUES IN SPAIN. HE'S TELLING ME HE'S BEEN TO SPAIN TWICE IN THE PAST THREE DAYS. NO, TWO WEEKS. AND SO HE GOT, RECEID HIS PH.D. IN NUTRITION AT DUKE, CAME TO THE NIH WHERE HE'S A SENIOR INVESTIGATOR IN THE LABORATORY OF EXPERIMENTAL GERONTOLOGY. MUCH OF HIS WORK HAS BEEN INVOLVED IN TRYING TO UNDERSTAND THE RELATIONSHIP BETWEEN METABOLISM, AGING AND ACTUALLY EXPERIMENTALLY TO TEST VARIOUS HYPOTHESES, DRUGS AND WHATNOT. NOT ONLY IN SMALL LABORATORY ANIMALS, BUT IN CHIMPANZEES WHICH YOU'LL HEAR ABOUT. SO WE WELCOME BOTH OF YOU AND THANK YOU VERY MUCH FOR COMING AND PERHAPS YOU'D LIKE TO BEGIN, JAY. >> THANKS FOR GIVING ME THIS OPPORTUNITY TO TALK A LITTLE BIT ABOUT VERY INTERESTING TOPIC THAT APPLIES TO EVERY SINGLE PERSON IN THE ORDER OF WHICH IS A RARE CASE FOR MOST TALKS. SO MY GROUP IS INTERESTED IN UNDERSTANDING THE LENGTH BETWEEN AGING PROCESS AND OBESITY. THAT'S HOW WE GOT INTERESTED IN THIS FIELD. AND WHAT I WOULD LIKE TO DO, SINCE THE TOPIC OF THIS TOPIC IS AGE, I WILL TALK MORE ABOUT PRACTICAL ISSUES, SOMETHING THATFECTS YOU AND ME DAILY AND WHAT WE CAN DO ABOUT IT. LET ME START BY TELLING YOU TO LITTLE BIT ABOUT WHAT YOU CANNOT CONTROL AND THAT'S YOUR GENES. IF YOU LOOK AT MORTALITY, AT DIFFERENT AGE SPAN, WHAT YOU SEE IS THAT MOST OF DEATHS THAT OCCUR IN MIDDLE AGE HAS VERY LITTLE GENETIC COMPONENT TO IT. THEY ARE ACTUALLY DETERMINED BY THINGS LIKE HABITS, YOUR LIFE-STYLE, YOUR BEHAVIOR. BUT AS YOU GO TOWARDS EXTREME LONGEVITY, GENETIC PLAYS MORE AND MORE IMPORTANT ROLE OF YOUR SURVIVAL. SO THIS IS ONE EVIDENCE OF THAT. THIS IS A STUDY WITH THE OKINAWA, AS YOU KNOW OKINAWAIANS HAVE THE LONGEST LIFE SPAN IN THE WORLD. WHAT THIS GRAPH SHOWS IF YOU ARE A CENTENARIAN, PROBABILITY THAT YOU WILL HAVE A SIBLING THAT LIVES TO 90 YEARS. IF YOU'RE A WOMAN IT'S CLOSE TO 50%. WITH YOU IF YOU ARE CONTROL FAMILY, IT'S ABOUT 4%. SO THERE'S A HUGE GENETIC COMPONENT TO LONGEVITY. OF COURSE MOST OF US WILL NEVER LIVE TO AGE 100. NOW SO THE THING THAT YOU CAN DO SOMETHING ABOUT AT LEAST IN THE LITERATURE, IS CALORIE RESTRICTION. YOU MAY HAVE HEARD A LOT ABOUT IT, 40% REDUCTION IN FOOD INTAKE EXTENDS LIFE SPAN IN PRACTICALLY ALL THE ORGANISMS THAT'S BEEN STUDIED. SO HERE'S ONE STUDY THAT'S PUBLISHED BY -- IN TWO DIFFERENT STRAINS OF MICE, B10 AND B6. AND IF YOU RESTRICT THE ANIMALS, OF COURSE THEIR WEIGHT DROPS AND THE SURVIVAL CURVE SHIFTS TO THE RIGHT. SO INDICATING THAT THEY LIVE LONGER. SO THIS IS A VERY WELL-KNOWN PHENOMENON. SO THE CONCLUSION HAS BEEN CALORIE RESTRICTION EXTENDS LIFE SPAN. I PUT A QUESTION MARK HERE BECAUSE THE WAY WE USUALLY DO THESE STUDIES IN ANIMAL MODELS IS WE HAVE THEM IN A CONDITION WE CALL AD LIBITUM GIVEN AS MUCH FOOD AS THEY'LL TAKE. EACH IS 2 PERCENT GLUCOSE, A LOT OF BACTERIA ON A PETRI DISH. FOR MICE IT'S UNLIMITED CHOW. NOW THE QUESTION IS, IS THIS NORMAL FOOD INTAKE, EVEN THOUGH THAT'S THE WAY WE'RE GROWING ANIMALS IN THE LAB. CERTAINLY IN NATURE WE DON'T FACE THIS KIND OF ABUNDANCE OF FOOD. NOW THIS IS OKAY IF OUR -- BUT WE KNOW FROM HUMAN STUDIES THE APPETITE IS VERY ELASTIC. THE MORE FOOD YOU PUT IN FRONT OF A PERSON, MORE HE OR SHE WILL EAT. SO BASICALLY WHAT WE'RE DOING WITH OUR ANIMAL MODEL IS, WE'RE DOING BUFFET, ALL YOU CAN EAT BUFFET CONSTANTLY. SO OVEREATING IS ADVANTAGEOUS FOR SURVIVAL IN THE CONDITION OF FEASTER FAMINE. OUR ANCESTORS LIVED IN THIS KIND OF CONDITION. SO WHEN YOU MAKE A BIG CATCH, YOU WILL FEAST FOR A WHILE AND YOU MAY GO FOR A LONG TIME OR YOU'RE STARVING. AND SO IT IS ADVANTAGEOUS TO BE ABLE TO OVEREAT. SO YOU CAN STORE UP THAT ENERGY IN THE FORM OF FAT SO THAT YOU CAN YOU CAN SURRIFE WHEN THERE'S NO FOOD. BASICALLY WE'RE LIVING IN THIS KIND OF ENVIRONMENT CONSTANTLY. AND WE'RE ALSO RAISING OUR ANIMALS IN THIS KIND OF ENVIRONMENT. SO THE BIG QUESTION DOES CALORIE RESTRICTION EXTEND LIFE SPAN OR DOES OVEREATING SHORTEN LIFE SPAN. AND THIS IS A SERIOUS QUESTION. ONE OF THE STUDIES THAT -- GROUP ALONG WITH DR. MADISON AS WELL AS THE STUDY DONE BY WISCONSIN GROUP WHERE THEY LOOKED AT CALORIE RESTRICTION IN RHESUS MONKEYS. CALORIE RESTRICTED MONKEYS IN THE -- STUDY AS WELL AS THE WISCONSIN STUDY, AS YOU CAN SEE CAL RERESTRICTION BRINGS DOWN THE BODY RATE IN MALE AND FEMALE MONKEY. BUT IF YOU LOOK AT THE VALUE RATE OF MONKEYS IN THE WILD, THEY MAY EVEN BE LOWER THAN THE CALORIE RESTRICTED ANIMALS IN THE LAB. SO THE ANIMALS LIVING IN THE WILD MAY BE LIVING UNDER WHAT WE CALL CALORIE RESTRICTIVE STATES IN THE LAB. THIS IS NOT JUST A SEMANTIC ISSUE, BECAUSE THERE ARE PEOPLE WHO BELONG TO THE CALORIE RESTRICTION, CUTTING CALORIES BY 20% OR SO. THE QUESTION IS WILL LEAN PEOPLE BENEFIT FROM CALORIE RESTRICTION. FROM 60-70% OF AMERICANS BEING OVERWEIGHT OR OBESE, YOU COULD ARGUE EATING LESS WOULD BE BENEFICIAL. BUT WHAT WOULD BE REALLY IMPORTANT AND COMPELLING IS WHETHER LEAN PEOPLE WILL BENEFIT FROM CALORIE RESTRICTION. SO HERE'S THE STUDY FROM THE WISCONSIN GROUP. AND THEY LOOKED AT CALORIE RESTRICTION AND THE TYPE OF DEATH. WHEN YOU LOOK AT OVERALL MORTALITY BETWEEN CONTROL GROUP AND CALORIE RESTRICTION GROUP, THREE NO STATISTIC RULE SIGNIFICANCE. HOWEVER, WHEN YOU REMOVE MORTALITY DUE TO COMPLICATIONS OF ANESTHESIA, GASTRIC BLOATING, ENDO ME TROASES. YOU GET A DIFFERENCES BETWEEN CALORIE RESTRICTED AND CONTROL GROUP. SO WHAT DOES THIS ALL MEAN? SO WHAT IS CLEAR IN HUMAN STUDIES IS THAT SUBCUTANEOUS FAT IS, HAS A PROTECTIVE ROLE FOR MANY DISEASES. WE DON'T REALLY APPRECIATE IN ANIMAL STUDIES. WE NORMALLY THINK OF AGING AND DEATH WITH A STRAIGHT LINE THROUGH IT, BUT IN MEDICINE, WHAT WE FIND IS TAKING MEAD -- WHICH LEADS TO SOME TYPE OF PHYSIOLOGICAL CRISES THAT ULTIMATELY KILL YOU. SO DEPENDING ON INTERVENTIONS AT VARIOUS STAGE, YOU CAN AFFECT THIS EQUATION. AND THE QUESTION IS WHETHER SUBCUTANEOUS FAT ACTUALLY PROTECTS AGAINST THIS PROGRESSION. GOING FROM AGING TO DEATH. AND TOO MUCH WEIGHT LOSS ESPECIALLY SOMEONE WHO IS LEAN, IF THEY WENT ON CALORIE RESTRICTION MAY CAUSE PROBLEMS IN OUR ABILITY TO HANDLE STRESS. THAT'S WHY YOU LOOK AT THOSE MUST NOT SKIS THAT ARE EXCLUDED -- MONKEYS THAT WERE EXCLUDED, THEY WERE ALL EXCLUDED BASED ON COMPLICATIONS DUE TO SOME TYPE OF STRESS, ANESTHESIA, ENDOMETRIOSIS, INJURIES, THOSE THINGS. SO THIS IS A WELL-KNOWN PARADOX IN MEDICINE CALLED OBESITY PARADOX. AND WHAT WE FIND IS PATIENTS WHO HAVE CHRONIC DISEASES, THIS SHOWS CHRONIC KIDNEY FAILURES, WHETHER IT'S CHRONIC HEART DISEASE, CHRONIC HEART FAILURE AND SO FORTH. WHAT YOU FIND IS THAT PEOPLE WHO ARE THE HEAVIEST HAVE THE LOWEST MORTALITY. COMPARED TO THE PEOPLE WHO ARE LIGHTER. IT'S POSSIBLE. WE DON'T KNOW WHAT THIS MEANS. IT'S POSSIBLE THAT PEOPLE WHO ARE LIGHTEST ARE THE THICKEST BUT WE CONSISTENTLY SEE THIS. AND THE OTHER BENEFICIAL EFFECTS OF ADIPOSITY IS BONE DENSITY AND HIP FRACTURE. NOW MORE THAN 300,000 HIP FRACTURES IN THE U.S. AND 20% OF PEOPLE WITH HIP FRACTURES DIES WITHIN ONE YEAR. AND IF YOU LOOK AT HIP FRACTURE ACCORDING TO THE BMI CALCULATED BY YOUR BODY WEIGHT IN KILOGRAMS, DIVIDED BY YOUR HEIGHT IN METERS SQUARED, YOU FIND AS YOU BECOME LESS THAN, WHEN YOU REACH LESS THAN 25BMI, HIP FRACTURE RATE RISES QUITE DRAMATICALLY. IF YOU CONTROL FOR BONE MASS DENSITY, IT STILL RISES A LITTLE BIT BUT NOT AS DEEPLY. THIS IS SOMETHING WE SEE IN ANIMAL MODELS AS WELL. BEING UNDER WEIGHT OR EVEN BEING NORMAL WEIGHT WHICH IS 20-25. YOU HAVE INCREASED HIP FRACTURE AND BEING HEAVIER IS PROTECTED. SO THE QUESTION IS WILL CALORIE RESTRICTION EXTEND YOUR LIFE SPAN. AND I THINK THAT DEPENDS ON YOUR ADIPOSITY, RISK FACTORS AND AGE. BECAUSE YOU MAY BE TRADING ONE WHO WILL BENEFIT HARM PROFILE WITH ANOTHER. SO YOU HAVE TO INDIVIDUALLY TAILOR TO THE BEST YOU CAN BASED ON YOUR RISK FACTORS. SO SINCE MY STUDY INVOLVES OBESITY, LET'S LOOK AT HOW WE GOT HERE. THE TERM OBESITY EPIDEMIC REALLY DIDN'T EXIST IN THE 70'S AND 80'S. IT REALLY TOOK OFF IN THE 80'S WHEN TOTAL FOOD SUPPLY AVAILABLE TO THE AMERICAN POPULATION DRAMATICALLY STARTED TO RISE. AND INDIVIDUAL FOOD INTAKE WENT UP BY SEVERAL HUNDRED CALORIES. OVER THIS TIME. SO YOU COULD ARGUE COMPARED TO NOW, PEOPLE LIVING IN THE 70'S WERE CALORIE RESTRICTED, EVEN THOUGH THEY WERE ALLOWED TO EAT AS MUCH AS THEY WANTED. AND THE OTHER ASPECT OF OBESITY IS THE WAY WE EAT OUT. IN THE 70'S, ABOUT 15% OF CALORIES AMERICANS ATE CAME FROM RESTAURANTS. NOW ABOUT 30% OF CALORIES WE EAT COME FROM RESTAURANTS. AND THIS IS AN ISSUE BECAUSE WHEN WE EAT OUT, WE CONSUME ABOUT 500 CALORIES MORE PER MEAL THAN WHEN WE EAT AT HOME. NOW YOU MAY HAVE HEARD OF THIS AD WHICH GAINED A LOT OF ATTENTION COMING OUT IN JANUARY ABOUT BENEFITS BEING OVERWEIGHT. THE CONCLUSIONS WAS BEING OVERWEIGHT MAY LEAD TO LONGER LIFE ACCORDING TO REVIEW OF MORE THAN 100 PEOPLE. SO MOST OF THE STUDIES SHOW A J CURVE WHEN YOU LOOK AT MORTALITY ON THE Y AXIS COMPARED TO BODY MASS INDEX. SO BMI GREATER THAN 25 IS OVERWEIGHT. BMI OF EQUAL TO GREATER OR 30 IS OBESE. IF YOU LOOK AT ALL SUBJECTS HEALTHY, WHAT YOU FIND IS -- ACTUALLY YOU CAN SEE IT BETTER IN MALES. BEING OVERWEIGHT ACTUALLY HAS VERY LOW MORTALITY. THAT'S WHAT THAT STUDY IS RECOVERING TO. AND THAT'S QUITE CONFUSING BECAUSE YOU THINK ALL THE EVIDENCE SUGGESTS BEING OVERWEIGHT IS NOT A GOOD THING. BUT WHEN YOU LOOK AT HEALTHY SUBJECTS WHO NEVER SMOKED, THE CURVE SHIFTS TO THE LEFT AND THE PEOPLE WITH THE LOWEST MORTALITY ARE THE PEOPLE WITH HEALTHY WEIGHT FROM NO LESS THAN BMI OF 20 TO ABOUT 25. SO WHY THIS CONFLICT? SO ONE OF THE POSSIBILITIES FOR WHEN YOU INCLUDE PEOPLE WITH DISEASES, IS THAT PEOPLE WHO ARE OVERWEIGHT NATURALLY GET ON DOCTORS' RADARS MUCH MORE, ESPECIALLY IF YOU HAVE HYPOTENSION AND OTHER WEIGHT ASSOCIATED DISEASES. SO PEOPLE WHO ARE, WHO TEND TO BE OVERWEIGHT AND HAVE RISK FACTORS FOR DISEASE, THEY ARE MORE CLOSELY FOLLOWED BY PHYSICIAN WHICH GIVES YOU THIS POTENTIAL ARTIFACT. AND THE OTHER THING IS, PEOPLE WITH CERTAIN DISEASES DO LOSE WEIGHT. AND THEREFORE YOU ARE BIASING YOURSELF BY GOING TO A HEAVIER WEIGHT FOR PEOPLE WITH THAT UNDERLYING DISEASE. BUT THIS J-SHAPED COVER IS SEEN WITH -- THAT'S BEEN STUDIED. INTERESTINGLY THAT J-SHAPED CURVE FLATTENS OUT AS WE GET OLDER. AS YOU LOOK AT THE MORTALITY APPEARED WE GET OLDER, WHAT HAPPENS IS LESS AND LESS BMI HAS AN EFFECT ON YOUR MORTALITY. SO HERE IS PEOPLE OVER AGE OF 85. THE CURVE BASICALLY IS FLAT, UNLIKE PEOPLE IN THE YOUNGER AGE GROUP. WE DON'T KNOW WHETHER THIS IS AN EFFECT OF WHAT'S CALLED SURVIVORSHIP EFFECT. AND THAT IS PEOPLE WHO ARE UNHEALTHY AND OVERWEIGHT HAVE ALREADY DIED. AND WHAT'S LEFT ARE THE SUPER HEALTHY OVERWEIGHT AND OBESE PEOPLE. NOW, METABOLIC DISREGULATION ALSO AFFECTS OUR COGNITIVE DECLINE. IF YOU LOOK AT THE RISKS FOR ALL THESE PARAMETERS ON SCORING IN THE LOWEST QUARTILE OF A COGNITIVE TEST U WHAT YOU FIND IS BODY MASS INDEX BEING ELEVATED IN THE RISK FACTOR. ALONG WITH PERCENTAGE OF BODY FAT, FASTING INSULIN, INSENSITIVITY AND GLUCOSE LEVEL. IF YOU LOOK AT THE RISK FOR DEVELOPING ALZHEIMER'S IN THE 80'S, WHEN YOU REACH 80'S, BMI AND THE WAIST SIZE IN YOUR 40'S HAS A HUGE EFFECT. SO IF YOU LOOK AT PEOPLE WHO ARE OBESE AND HAS HIGH ABDOMINAL DIAMETER, THE THREE FOLD INCREASE PROBABILITY HOW FAR DEVELOPING ALZHEIMER'S DECADES LATER THAN PEOPLE WITH NORMAL BMI AND NORMAL ABDOMINAL DIAMETER. NOW AVERAGE AMERICANS GAIN ONE POUND A YEAR FROM AGE 20 TO AGE 50. SO WE ON AVERAGE GAIN ABOUT 30 POUNDS. SO ONE POUND OF FAT IS 3500 CALORIES. AND IF YOU DIVIDE THAT BY 365 DAYS THAT'S ABOUT 10 CALORIES A DAY. 10 CALORIES A DAY IS ONE GRAIN OF LIFESAVER THAT WE ARE LEAVING UNBURNED AS WE GAIN WEIGHT. AND IN FACT, AT AGE 50, WE EAT LESS THAN WE USED TO IN OUR 20'S. SO ALTHOUGH FOOD INTAKE IS THE MAIN DETERMINER OF BODY WEIGHT, IT'S NOT THE WHOLE STORY. WE ALSO EXERCISE LESS AS WE GET OLDER. NOW THAT'S ALSO NOT THE FULL STORY. THIS IS A STUDY DONE BY PAUL WILLIAMS ON SAN FRANCISCO RUNNING CLUB MEMBERS AND HE FOLLOWED PEOPLE FROM THEIR 20'S TO THEIR AGE 50 AND THEIR BODY WEIGHT AS THEY GET OLDER. AND HE STRATIFIED THEM ACCORDING TO HOW MUCH THEY RUN A WEEK. SO HERE THESE GUYS ARE RUNNING MORE THAN 64 KILOMETERS A WEEK. A YOU CAN IMAGINE PEOPLE WHO RUN MORE WEIGH THE LEAST AND PEOPLE WHO RUN LEAST WEIGH THE MOST. BUT BASICALLY THE SLOPE IS ABOUT THE SAME. AND THE WEIGH WE GAIN FAT IS DIFFERENT AT MIDDLE AGE THAN WE DO WHEN WE'RE YOUNG. WHEN CHILDREN GAIN WEIGHT, THEY ACCUMULATE FAT RATHER UNIFORMLY, SUBCUTANEOUS AS WELL AS THE ABDOMINAL DEPOT. HOWEVER WHEN ADULTS GAIN WEIGHT, WE GAIN WEIGHT PRIMARILY IN OUR ABDOMINAL DEPOT. SO THIS MAN HERE PROBABLY ALL 30 POUNDS OF HIS FAT IS IN HIS ABDOMEN. BECAUSE YOU LOOK AT THE REST OF HIS BODY, IT'S PERFECTLY LEAN. AND IT IS THIS ABDOMINAL OR WHAT WE CALL VISCERAL FAT THAT IS LINKED TO HYPERTENSION, HEART DISEASE STROKE, DIABETES, CANCER AND NEURODEGENERATIVE DISEASE COLLECTIVELY CONSUMES ABOUT 70% OF OUR TOTAL HEALTHCARE COSTS IN THE U.S. AND IT'S ABDOMINAL OR VISCERAL FAT THAT RELEASES INFLAMMATORY CYTOKINES INVADING VITAL ORGANS AND FAT. AND THERE ARE A NUMBER OF THINGS THAT CONTROL WHETHER THE, HOW WE ACCUMULATE ABDOMINAL VISCERAL. WHEN I TALK ABOUT VISCERAL OR ABDOMINAL FAT, I'M TALKING ABOUT FAT THAT'S INSIDE THIS RED STRIPE. THAT RED STRIPE IS WHAT WE CALL THE RECTUS ABDOMINIS MUSCLE. THE MUSCLE YOU HAD WHEN YOU WERE YOUNG, IT'S THE FAT UNDER THAT HE THAT. IT'S HANGING OFF YOUR SKIRT, OFF YOUR INTESTINES LIKE SKIRT. SO LIPO SUCTION CAN'T GET AT THAT FAT. SO ALTHOUGH LIPO SUCTION MAY MAKE YOU LOOK MORE ATTRACTIVE, IT'S NOT A GAME CHANGE FOR OUR METABOLIC PARAMETERS. AND THIS IS ANOTHER EVIDENCE OF THE PROTECTIVE EFFECT OF SUBQUEUE TAIN ANNUALS FAT. THIS IS AN IOWA WOMAN'S HEALTH STUDY AND THEY LOOKED AT THE ROLE OF WHERE THE FAT IS AND YOUR MORTALITY IN OLDER WOMEN. AND IN THE VERTICAL Y AXIS IS MORTALITY, AND BMI QUINTILE AND HIP TO WAIST RATIO WITHIN THE BODY CATEGORY. WHEN YOU FIND IS HIGHEST MORTALITY COMES FROM SKINNYIST WOMEN WITH THE HIGHEST HIP TO WAIST RATIO. LOWER MORTALITY IS WOMEN HERE WITH MODEST AMOUNT OF FAT WITH THE LOWER -- LOWEST HIP TO WAIST ISSUE. THAT IS AN INTERHEART STUDY WHERE THEY LOOKED AT HEART ATTACK RATES THROUGHOUT THE WORLD AND THEY DIVIDED THE RISK, THE ODDS RATIO ACCORDING TO THE BMI GROUP AND WITHIN EACH GRANT OF BMI THEY DIVIDED INTO QUARTILE OF HIP TO WAIST RATIO. AS YOU CAN SEE WITH INCREASING BMI THERE'S IN CREASING HEART ATTACK RATES, NOT SURPRISING. BUT THE SLOPE IS MUCH GREATER WITHIN EACH BODY WEIGHT GROUP, ACCORDING TO THE WAIST TO HIP RATIO. SO WHAT THIS TELLS YOU IS WHERE YOU HAVE THE FAT IS MUCH STRONGER DETERMINANT OF OVERALL MORTALITY THAN HOW MUCH YOU WEIGH UP TO CERTAIN POINT OBVIOUSLY. WE SAW A J-SHAPED CURVE ACCORDING TO MORTALITY AND BODY WEIGHT. BUT THAT'S NOT WHAT YOU SEE WHEN YOU LOOK AT MORTALITY RATE ACCORDING TO WAIST SIZE AND WAIST TO HIP RATIO. IT'S BASICALLY A LINE. SO YOU CAN NEVER HAVE SMALL ENOUGH WAIST TO HIP RATIO. IF YOU LOOK AT FOR MEN AND WOMEN, IT KEEPS ON DECREASING ACCORDING TO WAIST HIP RATIO AS WELL AS WASTE CIRCUMFERENCE SIZE. SO YOU DON'T WANT TO BE OBESE, YOU DON'T WANT TO BE OVERLY SKINNY. WHAT YOU WANT TO BE IS SOPHIA LOREN. YOU WANT TO HAVE VERY SMALL WASTE AND MODEST AMOUNT OF CUTANEOUS FAT. THIS IS FOR MEN AS WELL. OBVIOUSLY TWO DIFFERENT PROPORTIONS. NOW, THE OTHER FACTOR THAT CONTRIBUTES TO AGING IS EMOTIONAL. EMOTIONAL STRESS. IF YOU LOOK AT TELOMERE LINES THAT SOME PEOPLE SEE IT AS A BIOMARKER FOR AGING, AND LOOK AT THE CHRONICITY OF CARE GIVING YEARS, PEOPLE WHO ARE FAKING CARE OF ELDERLY OR SICK RELATIVES WHICH IS A TREMENDOUS SOURCE OF STRESS. WHAT YOU SEE IS WITH INCREASING AMOUNT OF STRESS, THE TELOMERES GET SHORTER. AND IF YOU LOOK AT THE PERSONALITY TRAITS OF CENTENARIANS, WHAT YOU FIND IS CENTENARIANS HAVE MORE THAN EXPECTED FREQUENCY OF PEOPLE WITH LOW NEURORAT -- THEY HAVE FEAR, ANXIETY, ARRANGE, SELF CONSCIOUSNESS. NOW YOU MAY HAVE SEEN THIS STUDY SO-CALLED U -- SHAPE OF HAPPINESS. WE START OUT LIFE WHEN WE'RE YOUNG, WE'RE VERY HAPPY. YOU THINK LIFE IS ALL SWELL AND EVERYTHING GOES WELL AND THEN YOU HIT MIDDLE AGE. HAPPINESS GOES DOWN, IT OCCURS AROUND AGE 50. AND IT STARTS TO RISE AGAIN. SO MAYBE THAT CENTENARIANS HAVING POSITIVE OUTLOOK IN LIFE MAY NOT BE, THAT MAY NOT BE A CAUSE BUT IT MAY BE AN EFFECT OF JUST BEING OLDER. THIS STUDY SUGGESTS OTHERWISE. THIS IS A STUDY WHERE THEY TOOK 7,000 STUDENTS ENTERING THE UNIVERSITY OF NORTH CAROLINA. THIS WAS IN THE 60'S, AND PERSONALITY INVENTORY. AND THEY FOLLOW THESE PEOPLE FOR 40 YEARS AND LOOKED AT DEATH RATES AND LOOKED AT DEATH RATES ACCORDING TO THEIR PEZ MISSAL SCORE. PEOPLE WHO HAD THE -- HAD THE HIGHEST MORTALITY RATE COMPARED TO PEOPLE WITH THE HIGHEST OPTIMISM SCORE. WHY IS THIS. PROAGING EFFECT OF CORTISOL. SO GLUCO-- IN HUMANS THE MAIN GLUCOCORTICOID IS CORTISOL. STRESS INCREASES CORTICOID CORTISOL LEVEL WHICH INCREASES MESENTERIC -- AS WELL AS ANGIOGENESIS TO ALLOW THIS EXPANSION OF FAT CELLS WHICH LEAD TO MACROPHAGE INFILTRATION AND INSULIN RESISTENT. ON TOP OF THAT -- THEY LEAD TO INCREASED BONE DENSITY, COGNITIVE LOSS AND COGNITIVE. MOST OF THE THINGS YOU ATTRIBUTE TO AGING, YOU CAN SEE IT REPEATED WITH ELEVATED CORTISOL LEVELS. NOW, WE KNOW WOMEN LIVE LONGER THAN MEN. LIFE EXPECTANCY OVER THE PAST THREE DECADES. AND YOU MAY HAVE NOTICED THAT MEN ARE CATCHING UP OVER THE YEARS. AND THE MAIN REASON FOR THE CLOSING OF THIS GAP IS DECREASED SMOKING IN MEN. SO SMOKING RELATED DEATHS DECREASED BY 64% IN MEN OVER THE PAST 30 YEARS. AND THE SMOKING RELATED DEATH MALE TO FEMALE RATIO DECREASED OVER THIS TIME. SO HOWEVER, IT'S PROBABLY THE CASE THAT MEN WILL NEVER COMPLETELY CLOSE THIS GAP. AND THAT HAS SOMETHING TO DO WITH TESTOSTERONE. AS YOU KNOW, MEN LOSE DECEMBER -- TESTOSTERONE LEVEL OVER THE YEARS. THIS IS ONE OF THE REASONS WHY VIAGRA IS A 5.3 BILLION DOLLAR INDUSTRY. NOW THEIR COMPANIES WHICH TOUT FOUNTAIN OF YOUTH BY SUPPLEMENTING AND RESTORING THE HORMONAL LEVELS IN OLDER MEN. SO THIS IS DR. JEFFREY -- HE'S A 70-YEAR-OLD GENTLEMAN WHO IS CHIEF MEDICAL OFFICER FOR THIS QUESTION. SO HE'S TAKING TESTOSTERONE GROWTH HORMONE SUPPLEMENTS AT $1500 PER MONTH. AS YOU CAN SEE HE LOST THE FAT AND GAINED IT BACK IN MUSCLE. ALTHOUGH THE HORMONE AFFECTS LIFE IT MAY NOT BE GOOD FOR LONGEVITY. THERE WAS A STUDY GAINED OUT OF INTEREST LAST YEAR, THEY STUDIED THE LIFE SPAN OF 81 EUNICHS AND THEIR LIFE SPAN WAS ABOUT 14-19 YEARS LONGER THAN NON-CASTERATED MEN OF SIMILAR SOCIO-ECONOMIC STATUS. THE MORE CONVINCING STUDY IS WITH RATS. IF YOU CASTRATE RATS COMPARED TO THE CONTROL RATS, THEY SHIFT TO THE RIGHT. IF YOU LOOK AT MAXIMUM LIFE SPAN, IT'S CLOSE TO CALORIE RESTRICTED RATS. THERE'S ALSO ETHNICITY ISSUE WHEN IT COMES TO WAKING. U.S. IS LEADING HERE AMONG DEVELOPED WORLDS. BMI GREATER THAN 30 IS THE OBESITY CUT OFF. THE COUNTRY IS THE LOWEST RATE JAPAN AND KOREA ON THE FAR LEFT. SO ALTHOUGH THE OBESITY RATE IN KOREA AND JAPAN IS TENFOLD LOWER, IF YOU LOOK AT THE TYPE 2 DIABETES RATE, IT'S ABOUT 30% LESS THAN AMERICANS. SO DISEASE THAT'S VERY VERY DEPENDENT ON OBESITY -- SO WHEN YOU LOOK AT THE DISEASE'S RISK, IT STARTS TO RISE AT BMI25 FOR CAUCASIANS. FOR ASIANS, IT SHIFTS TO THE LEFT BY ABOUT TWO TO THREE POINTS. SO IT STARTS TO RISE AT BMI ABOUT 20-23. WHICH IS CONSIDERED AS A VERY HEALTHY BODY WEIGHT FOR CAUCASIANS. AND IF YOU LOOK AT THE TOTAL BODY FAT MAKE UP, WHAT YOU FIND IS THE SAME BODY WEIGHT, ASIANS HAVE HIGHER CONTRIBUTION FROM FAT. SO US ASIANS ARE FATTER THAN WE LOOK. SO HOW DO YOU DELAY AGING, WHAT CAN WE DO. SO BASED ON KNOWN BIOCHEMICAL PATHWAYS, MTOR KINASE ACTIVATED BY FATTY ACIDS, AMINO ACIDS, GLUCOSE, TESTOSTERONE, THIS IS SHIN ALL THE THING THAT GO WITH ABUNDANCE OF FOOD, THEY ON THE ONE HAND LEAD TO GROWTH IN HYPER FUNCTION. IT MAKES YOU BIG AND STRONG. ON THE OTHER HAND, IT'S LINKED TO AGING AND DISEASE. SO IT'S MEANT TO LIVE A SHORT BUT VERY VIGOROUS LIFE. AND THIS IS A STUDY DONE BY HARRIS ET AL WHERE THEY LOOKED AT RAPAMYCIN WHICH IS AN MTOR KINASE INHIBITOR AND YOU CAN SEE THE SHIFT TO THE RIGHT IN MORTALITY SHOWN THAT RAPAMYCIN CAN INCREASE LIFE SPAN IN MICE. SO WHAT ARE THE PATHWAYS? NOW, RAPAMYCIN INHIBITS MTOR KINASE BUT THERE'S NO SUCH THING AS FREE LUNCH IN THIS BUSINESS. RAP MY SIST -- RAP MY SIST HAS SIDE EFFECTS. ANOTHER WAY OF INHIBITING MTOR IS BY KINASE CALLED AMPK. AMK ACTIVATED KINASE. AND AMPK IS INHIBITED BY AGING THAT IS ACTIVATED BY EXERCISE AND LOW ENERGY. AMPK ALSO INCREASES PATHOGENS, BASICALLY CLEANING OUT DAMAGE ORGANELLES. THAT'S BLOCKED BY MTOR. SO WE ARE INTERESTED IN COMPOUNDS THAT MAY BE ABLE TO ACTIVATE AMPK. NOW WHILE WE MAY BE INTERESTED IN DEVELOPING DRUGS FOR AGING, IF YOU GO TO THE FDA AND SAY I HAVE -- FOR AGING, I WANT TO DO A CLINICAL TRIAL. THEY'LL REJECT YOUR PROPOSAL BECAUSE THEY DO NOT CONSIDER AGING A DISEASE. YOU HAVE TO TARGET A DISEASE ASSOCIATED WITH AGING. SO TYPE 2 DIABETES, IT'S ASSOCIATION WITH OBESITY BUT IT IS EQUALLY POTENT RELATIONSHIP WITH AGING. SO DIAGNOSED TYPE 2 DIABETES INCREASES WITH AGING. UNDIAGNOSED TYPE 2 DIABETES AS WELL. AND THESE A HUGE POPULATION OF PEOPLE WITH WHAT'S CALLED GLUCOSE TOLERANCE, PREDIABETICS PEOPLE WHO WILL DEVELOP DIABETES IF YOU LIVE LONG ENOUGH. BY AGE 70, 40% OF THE PEOPLE ARE EITHER DIABETIC OR PREDIABETIC. SO WE GOT INTERESTED IN RESVERATROL, AT LEAST IN ANIMAL MODELS HAVE A NUMBER OF BENEFICIAL EFFECTS, INCLUDING PROTECTION AGAINST GLUCOSE INTOLERANCE, AS WELL AS A LOT OF OTHER BENEFITS LIKE BETA AMYLOID PRODUCTION WHICH IS IMPORTANT FOR ALZHEIMER'S, INFLAMMATION AND SO FORTH. NOW EARLY I TALKED ABOUT HIGH WASTE TO HIP RATIO BEING BAD. PEOPLE WITH ELEVATED RACE TO HIP RATIO WITH MITOCHONDRIA AND SKELETAL MUSCLE. AS YOU KNOW MITOCHONDRIA IS THE MAIN SITE FOR FAT BURNING. AND PEOPLE WHO ARE OBESE HAVE LESS 20% LESS MITOCHONDRIA AND SKELETAL MUSCLE. TYPE 2 DIABETICS HAVE 40% LESS AND THE OFF SPRINGS OF DIABETICS 30% LESS AND LEAN HEALTHY ELDERLY, PEOPLE IN THEIR 70, 70'S HAVE 40% LESS MITOCHONDRIA THAN PEOPLE IN THEIR 20'S. SO ONE OF THE THINGS RESVERATROL DOES IS TO INCREASE MITOCHONDRIAL CONTENT AND FUNCTION IN SKELETAL MUSCLE. AND WE FIND THAT AMP KINASE THAT I TALKED ABOUT EARLIER IS ESSENTIAL FOR RESVERATROL TO BE ABLE TO CONFER THIS BENEFIT. SO, WHAT WE WANTED TO DO WAS WE WANTED TO DISCOVER A NEW DIABETIC DRUG TARGET BY UNDERSTANDING THE MECHANISM OF RESVERATROL. RESVERATROL IS A NATURAL FOOD PRODUCT, AND ITS PROBLEM IS IT'S PROMISCUOUS. IT BINDS TO MANY PROTEINS, INHIBITS A LOT OF THINGS, WHICH MEANS IF YOU TAKE IT FOR THE DURATION OF YOUR LIFETIME, THERE ARE SIDE EFFECTS THAT YOU MAY NOT WANT. THAT HAS NOT BEEN STUDIED. SO WHAT WE WANTED TO DO WAS WHAT'S THE MAIN TARGET THAT'S CONFERRING THE ANTI-DIABETIC EFFECT. MAKING LONG STORY SHORT, WE GOT STARTED BECAUSE ALL OF THE THINGS THAT FASTING AND EXERCISE DOES IS TO INCREASE CYCLIC A AND P PRODUCTION IN OUR TISSUE. CYCLIC A AND P IS PRODUCED BY AWE DENY LACE AND PSYCH LACE, IT'S DEGRADED TO AMP BY -- SO WHAT WE REPORTED IN THIS PAPER IS RESVERATROL ACTIVATES A AND PK BY INHIBITING ONE OF 11 CALLED PDA4. NOW, IF THE STUDY IS TRUE, AND THIS WAS ALL DONE IN MICE, AND MICE ARE TERRIBLE MODELS FOR HUMAN DISEASE. AS YOU MAY KNOW, 95 TO 97% OF DRUGS THAT ENTER CLINICAL TRIAL FAIL. BECAUSE HUMANS ARE NOT LARGE MICE. MICE ARE GREAT FOR PUBLISHING PAPERS. SO THE BIG CAVEAT WITH ALL THESE STUDIES IS WHAT WE DISCOVERED IN MICE REALLY TRANSLATE INTO HUMANS. THAT'S REALLY THE IMPORTANT QUESTION. SO FORTUNATELY FOR US, THERE IS ONE TD INHIBITOR ON THE MARKET. IT'S CALLED -- IT'S ON THE MARKET FOR CHRONIC PULMONARY DISEASE, EMPHYSEMA. IT'S PD4 INHIBITORY IS 30 TIMES MORE IMPORTANT THAN RESVERATROL. AFTER WE PUBLISHED OUR PAPER, THE COMPANY THAT MAKES -- PUBLISHED INTERNAL DATA SHOWING THAT PDE4 INHIBITION SIGNIFICANTLY DECREASES HEMOGLOBIN -- COMPARED TO PLACEBO. HEMOGLOBIN -- IS AN INTEGRATED LOOK AT THE GLUCOSE OVER THE PAST THREE MONTHS. SO I'M NOW INITIATING A CLINICAL TRIAL, IN FACT I JUST PRESENTED THIS IN FRONT OF THE IRB, TO LOOK AT -- AS A THERAPY IN PREDIABETICS. NOW, WE KNOW EXERCISE, PHYSICAL ACTIVITY IS IMPORTANT FOR HEALTH. BUT WHEN WE TALK ABOUT PHYSICAL ACTIVITY, WE THINK ABOUT WORKING OUT, EXERCISE. WHICH WE DO 30-40 MINUTES, VERY SMALL SLICE OF OUR 24 HOUR TIME PERIOD. BUT IT'S BECOMING CLEAR THAT THE BENEFIT OF PHYSICAL ACTIVITY IS MUCH MORE COMPLICATED. MANY STUDIES ARE NOW SHOWING THAT IT'S NOT A LINEAR RELATIONSHIP. IF YOU LOOK AT MORTALITY, ACCORDING DO HOW MUCH YOU RUN A WEEK, IT'S A U-SHAPED CURVE. PEOPLE WHO RUN 20 TO, MORE THAN 25 MILES A WEEK HAVE ACTUALLY HIGHER MORTALITY RATE THAN PEOPLE WHO RUN MODEST AMOUNTS A WEEK. MAYBE SOME OF THIS EXCESS DEATH IS DUE TO OVER EXERTION AND THINGS LIKE HEART ATTACK WHICH WE'RE ALL FAMILIAR WITH. SO ANOTHER POSSIBILITY IS PEOPLE WHO EXERCISE INTENSELY ARE ALSO MORE TIRED. SO IF YOU LOOK AT THE ACTIVITY LEVEL THROUGHOUT THE DAY, THEY'RE LESS ACTIVE. SO HERE'S A STUDY THAT LOOKED AT MORTALITY AND NON-EXERCISE ACTIVITY LEVELS. SO TV WATCHING FOR MORE THAN FOUR HOURS COMPARED TO PEOPLE WHO WATCH TV FOR LESS THAN TWO HOURS A DAY. THEY HAVE ONE AND-A-HALF HIGHER ALL CAUSE MORTALITY. 2.3 FOLD HIGHER CARDIOVASCULAR DISEASE MORTALITY. THAT'S INDEPENDENT OF YOUR BODY WEIGHT BECAUSE YOU THINK OH THOSE PEOPLE ARE HEAVIER. YOU CONTROL FOR BODY WEIGHT, AGE, EVEN HOW MUCH THEY EXERCISE. THIS RATIO STILL STANDS. SO WHEN WE THINK OF PEOPLE WATCHING TV FOR MORE THAN FOUR HOURS WE THINK OF THE PROVERB -- PROVERBIAL HOW MUCH POTATO. BUT IT'S NOT ABOUT TV WATCHING. IT'S HOW WE WATCH TV. WE WATCH TV SITTING DOWN. IN FACT PEOPLE WHO ARE INACTIVE ARE NOT JUST PEOPLE LIKE HIM BUT IT'S ALSO US. EXCEPT WE'RE LOOKING AT A DIFFERENT TYPE OF SCREEN. AND REMEMBER, IN THE BIGGEST EVIDENCE FOR THE DAMAGING EFFECTS OF LACK OF PHYSICAL ACTIVITY IS THAT 25% OF THE PEOPLE DIE WITHIN ONE YEAR OF HIP FRACTURE. THEY ARE NOT DYING OF HIP FRACTURE, THEY'RE DYING OF INACTIVITY DUE TO HIP FRACTURE THAT LEADS TO ALL SORTS OF PROBLEMS. SO ONE POSSIBILITY, SOMETHING WE COULD DO IS HAVE WHAT'S CALLED A WALKSTATION AT N IT H. SO YOU CAN BUY THIS WALK STATION. IT'S A TREADMILL WITH A DESKTOP WORKING STATION ON TOP OF IT. SO YOU WALK AT ONE MILE, TWO MILES PER HOUR. VERY SLOW PACE. SO THAT WE DON'T SIT IN FRONT OF A COMPUTER FOR HOURS. SO LET ME CLOSE WITH A TAKE AWAY BY TELLING YOU A LITTLE BIT ABOUT MY GRANDMOTHER. WE JUST CELEBRATED HER HUNDREDTH BIRTHDAY THIS WEEKENED. THIS IS A PICTURE OF HER WITH HUNDRED OF HER GREAT GRAND DAUGHTERS. THIS ISN'T EXPERIMENT WITH N EQUALS 1 BUT FROM MY OBSERVATION OF HER LIFE, SHE LED A VERY PURPOSE AND RESPONSIBLY GIVEN LIFE. SHE GETS UP IN THE MORNING, SHE HAS THINGS THAT SHE NEEDS TO ACCOMPLISH. IT'S NOT LIKE LIVING FOR THE SAKE OF LIVING. THERE ARE THINGS SHE NEEDS TO ACCOMPLISH. SHE HAS CONSTANT ACTIVITY. HER MASS WAS HER VEGETABLE GARDEN. SHE BASICALLY CONVERTED ALL OF MY PARENTS YARD INTO HER VEGETABLE GARDEN, MUCH TO THE CHAGRIN OF MY PARENTS. AND SHE'LL BE OUT THERE ALL DAY WORKING IN THE GARDEN UNTIL HER MID 90'S. ALSO NOTICE SHE HAD LOW INTAKE OF MEAT MOST OF HER LIVE TIME. AND SHE'S SURROUNDING BY LOVING RELATIONSHIPS AND COMMUNITY. EARLIER I TALKED ABOUT THE MENTAL ASPECTS OF STRESS. AND THIS IS ALSO SEEN WITH OTHER STUDIES LOOKING AT LONGEVITY AND EXTREME LONG LIFE SPAN. SO THESE MAY BE BENEFICIAL ALTHOUGH THEY MAY NOT GUARANTEE YOU LIVE TO A HUNDRED. THANK YOU. I'LL STOP THERE. [APPLAUSE] >> HOW MUCH DOES INFLAMMATION ENTER INTO THE ADVERSE SITUATIONS YOU DISCUSS SUCH AS OVERWEIGHT AND LACK OF EXERCISE AND DIET. >> TO EACH COMPONENT. IN FACT, DUE TO GENE EXPRESSION ANALYSIS, IN OLD ANIMALS COMPARED TO YOUNG ANIMALS, THE BIGGEST AND MOST STRIKING INCREASE COMES FROM INFLAMMATORY PATHWAYS. SO IN FACT, SOME PEOPLE CONSIDER DIABETES AS A DISEASE OF INFLAMMATION. AND THEY HAVE SALICYLATE AND IMPROVE YOUR GLUCOSE. I WOULD SAY IT DOES PLAY A SIGNIFICANT ROLE. >> THE OTHER THING I'LL POINT OUT WHILE EXPERIMENTS CARRIED OUT ON MICE PARTICULARLY AT THE NIH ARE NOT PREDICTED, THEY'RE ALMOST ALL DONE ON YOUNG MICE RATHER THAN OLD ANIMALS, WHICH HAVE MORE OF THE DISEASE THAN THE YOUNG PEOPLE. SO IT'S JUST SORT OF CRAZY THE WAY WE'RE DOING THINGS. >> YOU MADE REFERENCE TO BMI FOR CAUCASIANS VERSUS ASIANS SHOULD BE TREATED DIFFERENTLY. IN THE PICTURE OF YOUR $1500 A MONTH DOCTOR WHO IS ONE TIME FAT, ONE TIME VERY MUSCULATURE HE MAY HAVE A HIGHER BMI IN HIS MUSCULATURE STAGE THAN HIS FAT STAGE IF YOU LOOK AT THE PICTURE. THERE'S BEEN A LOT OF DATA THAT SHOWS LOOKING AT BMI AS A SINGLE NUMBER VERSUS PUTTING IN AGE, OBVIOUSLY GENDER. BUT BONE FRAME MUSCULATURE IN ALL OF THESE OTHER ASPECTS GIVE DIFFERENT SORT OF RESULTS. THAT TREATS OPTIMAL 25. HAVE YOU SEEN DATA WHEN YOU BREAK THE BMI DOWN TO MUCH MORE OF ITS COMPONENT PARTS. >> WELL SO FOR THAT OU HAVE TO GO LOOK AT RISK FACTORS, PARTICULARLY DISEASES. SO WHEN YOU LOOK AT DIABETES OR ATHEROSCLEROSIS. CLOSE CORRELATION WITH WAIST TO HIP RATIO AND THE FAT CONTENT. THAT'S VERY WELL ESTABLISHED. YOUR POINT IS WELL TAKEN BUT BMI IS A VERY CRUDE NUMBER. IT MAY HAVE BEEN IL30 BUT IT'S ALL MUSCLE. IT'S DIFFICULT TO DO POPULATION STUDIES WHERE THEY'RE LOOKING AT TENS OF THOUSANDS OF PEOPLE AND GET ACCURATE MEASUREMENT. SO RACE TO HIP RATIO IS ABOUT AS FINE AND REFINED REGIMEN AS YOU CAN DO IN THAT TYPE OF STUDY. >> THANK YOU FOR AN INTERESTING LECTURE. YOU SHOWED THAT THE -- RELATIONSHIP, CO-RELATION BETWEEN LIFE SPAN AND -- EMOTIONAL STRESS. I'M JUST CURIOUS WHAT YOU THINK ABOUT THE RELATIONSHIP BETWEEN NUTRITION, EMOTIONAL STRESS AND LIFE SPAN. >> CALORIE RESTRICTION AND EMOTIONAL STRESS. >> ACTUALLY, BASED ON SOME EVIOUS -- EXTENDED LIFE SPAN EVEN THOUGH NOW [INDISCERNIBLE] IT MEANS ACTUALLY EMOTIONAL STRESS IS INCREASE. SO I'M JUST CURIOUS ABOUT THIS. >> SO THE QUESTION WAS, I GUESS CALORIE RESTRICTION ITSELF IS A FORMAL EMOTIONAL STRESS. SO MAYBE PERHAPS YOU ARE CANCELING THE BENEFIT OF CALORIE REVICTION WITH MORE EMOTIONAL STRESS. WELL FIRST OF LL CALORIE RESTRICTION FROM A PHYSICIAN'S STANDPOINT BASICALLY NEVER WORKS BECAUSE NO ONE CAN STAY ON IT. YOU LOOK AT THE INVESTIGATORS WHO STUDY CALORIE RESTRICTIONS, YOU KNOW THEY ARE NOT CALORIE RESTRICTIONS THEMSELVES. SO THE HUMAN, IF YOU LOOK AT TELOMERE, ACCORDING TO BMI, PEOPLE WHO RE OVERWEIGHT HAVE -- BUT NO ONE'S DONE THAT TYPE OF STUDY THAT YOU'RE SUGGESTING FOR LONG ENOUGH TIME TO MAKE A DIFFERENCE. BUT YOU KNOW, TELOMERE I THINK IS NOT NECESSARILY GOOD MARKER OF AGING BECAUSE IF YOU LOOK AT THE TELOMERE LENGTH IN TISSUES LIKE BRAIN AND HEARTED, THEY DON'T REALLY SHORTEN. IT'S RAPIDLY PROLIFERATING TISSUE LIKE BONE MARROW CELLS AND INTESTINAL EPITHELIUM AND SO FORTH. >> CAN YOU EXPAND A LITTLE BIT ON THE ROLE OF GLUCOCORTICOID, IF THERE ANY RELATIONSHIP TO THE ACTION OF THE RESVERATROL SPECIFICALLY. >> I DON'T KNOW. WE HAVEN'T LOOKED. BUT GLUCOCORTICOID LEVELS GO UP WHEN WE CALORIE RESTRICT OURSELVES. BECAUSE ONE OF THE FUNCTIS OF GLUCO CORTICOID IS TO INCREASE GLUCOSE PRODUCTION WHICH IS GOOD IF YOU'RE STARVING. IT'S NOT GOOD IF YOU'RE PREDIABEC. >>IT'S INTERESTING ON THE INTERNET, THEY HAVE A PICTURE OF THE OLDEST VERIFIED INDIVIDUAL WHO IS A JAPANESE GENTLEMAN OF 115 YEARS OF AGE W IS SITTING WORKING IN HIS GARDEN WITH HIS GREAT GRANDDAUGHTER. YOU MIGHT TAKE A LOOK AT IT. >> THANK YOU. >> ALL RIGHT. WELL, WE HAVE TIME AFTERWARDS FOR MORE QUESTION AND DISCUSSION. THANK YOU VERY MUCH, JAY. NOW DR. DE CABO, IF YOU WANT TO CONTINUE. >> THANK YOU EVERYBODY FOR BEING HERE. THANK YOU FOR THE INVITATION TOSPEAK AT TH IS FANTASTIC SERIES. I WILL GIVE YOU A LITTLE DIFFERENT PERSPECTIVE ON -- RESTRICTION AND AGING. WE'RE GOING TO TRY TO SEE HOW AND WHAT WE'RE DOING -- TRYING TO UNDERSTAND SOME OF THE BASIC PRINCIPLES BEHIND CALORIE RESTRICTION, WHY AS JAY MENTIONED IN SOME CASES CALORIE RESTRICTION MAY NOT WORK IN WHAT CASES OR WHAT CONTEXT CALORIE RESTRICTION MIGHT WORK. WHEN I WAS INVITED -- I DECIDED TO ADD A LITTLE THING. THAT'S WHAT WE DO IN THE LABORATORY AND I'M GOING TO TRY TO FOCUS, SELECT THE OTHER VIEW OF THESE PARTICULAR FIELDS FROM MY OWN PERSPECTIVE AND THE PERSPECTIVE OF MY LAB. SO THE FIRST THING IS WHAT IS AGING. SO IF WE GO AROUND THE ROOM AND I ASK YOU WHAT IS AGING, EACH ONE OF YOU IS GOING TO HAVE A PERSONAL PERSPECTIVE AND A PERSONAL OPINION WHAT AGING IS. IF WE ASK WHAT ARE MECHANISMS BEHIND AGING, AS YOU HEAR FROM JAY HE HAS HIS OWN OPINION OR IF I ASK -- SO I THINK THE MECHANISM BEHIND AGING ARE VERY PRE, YOU ARE PRE DISPOSE TO THINK WHAT SOME OF THE MECHANISMS ARE. WE HAVE INFORMATION AND WE UNDERSTAND CARDIOVASCULAR DISEASE AND SUCH. I'M ASKING NOW THE QUESTION CAN WE WITH A MANIPULATE THE PROCESS OF HOW WE MANIPULATE. THIS QUESTION HAS BEEN POSTED FOR CENTURIES, NOT SOMETHING WE JUST STARTED WASTING OUR TIME ON IT. THE CENTER IS TRYING TO FIND THE FOUNTAIN OF YOUTH OR HOW TO PRESERVE FUNCTION OVER TIME. THIS IS A PICTURE OF MY FAMILY, MY GRANDMOTHER, MY MOM, MY SISTER AND MY NIECE. SHE'S NOW 17. THE POINT OF THIS PICTURE IS THAT THESE NOW INDIVIDUALS SHARE AN ABUNDANCE OF GENETIC INFORMATION. THEY HAVE BEEN GROWN AND RAISED IN THE SAME AREA OF SOUTHERN SPAIN. THEY HAVE A GOOD MEDITERRANEAN DIET -- AND THE PROGRESSION THEY ARE GOING TO WORK THROUGH THOSE DISEASES IS NOT GOING TO BE EXACTLY THE SAME. WHAT IT'S TELLING US IS BEHIND THE AGING PROCESS OR PROCESSES, THERE'S MANY FACTORS THAT CONVEY AND DETERMINE WHAT YOUR PARTICULAR AGING PROCESS IS GOING TO BE FOR A GIVEN ORGANISM. ONE THING THAT'S VERY CLEAR IS THAT AS TIME GOES BY, THE WORLD IS AGING VERY RAPIDLY. THE IMPACT OF AGING WE HAVE ON OUR SOCIETY IS GOING TO BE TREMENDOUS. IF YOU LOOK AT THIS DATA, YOU CAN SEE THAT BY 2015, THE AMOUNT OF PEOPLE INCREASE AND THE AMOUNT OF PEOPLE OVER THE AGE OF 65 IS GOING TO BE TREMENDOUS. YOU LOOK AT THE PEOPLE THAT ARE GOING TO PASS A HUNDRED YEARS WILL INCREASE BY 400%. SO CLEARLY AGING PROCESS OR PROCESSES ARE MALLEABLE. AS WE ARE IMPROVING OUR NUTRITION AND OUR DEVELOPMENT, I THINK THAT WE'RE MOVING THE CURVE. THIS IS CLEAR THAT THE ONLY, THAT AGING IS ALSO THE MAJOR RISK FACTOR FOR ALL THESE DISEASES. THESE ARE ALL THE TOP DISEASES THAT KILL THE WESTERN SOCIETY. THE ONLY THING YOU NEED TO DO TO GET ONE OF THESE DISEASES, AS YOU LOOK IN THIS CURVE IS TO GET OLD ENOUGH. AS YOU AGE, THE INCIDENCE INCREASES EXPONENTIALLY. AND YOU GET TO THE 80'S, LIKELY YOU'RE GOING TO HAVE ONE TWO OR MULTIPLE DISEASES OF WHICH DISEASE YOU'RE GOING TO DIE IS GOING TO BE DEPENDING ON MANY THINGS WITH GENETICS, NUTRITION AND ENVIRONMENT. SO THE QUESTION IS CAN WE STOP AGING. THE QUICK ANSWER IS NO. THERE'S NO, RIGHT NOW WE CANNOT STOP THE AGING PROCESSING. BUT WE CAN DEFINITELY MANIPULATE IT. WE GO TO HISTORICAL DATA AND THIS IS DATA COLLECTED AND HIGHLIGHTING HOW YOU CAN SQUARE THE SURVIVAL CURVE. THIS DATA STARTS IN ABOUT 1500'S AND HOW YOU HAVE A VERY HIGH MORTALITY AND THEN THE CURVE KIND OF FLATTENS OUT. THERE ARE PLENTY OF PEOPLE NOT AS MANY AS NOW THAT THEY REACH AGE OF 100 OR MORE. WHAT HAS HAPPENED OVER THE LAST CENTURY. THIS IS OVER A HUNDRED YEARS OF HISTORY, IS THAT OUR INCREASES IN MEAN LIFE SPAN, THE AVERAGE LIFE SPAN OF THE POPULATION, INCREASES TREMENDOUSLY. EVEN FROM THE 1900'S TO TODAY, WE HAVE BEEN PAYABLE TO -- THE AVERAGE LIFE SPAN SUBSTANTIALLY 25 TO 50% IN SOME CASES. WHAT WE HAVE NOT BEEN ABLE TO MOVE MUCH IS THE MAXIMUM LIFE OF THE INDIVIDUAL. THE RECORD STANDS AT 122 YEARS GIVE OR TAKE A FEW MONTHS. SO IN DEVELOP TREE ANIMALS WE ARE ACHIEVING IN A HUNDRED YEARS IS INDUCING CALORIC RESEARCH. YOU RESTRICT THE ANIMALS 40% WHAT THEY CAN EAT AND YOU SEE THIS SHIFT IN THE CURVE WHERE YOU SEE INCREASES IN BOTH MAXIMAL LIFETIME. THESE ARE NOT JUST ASSOCIATED WITH OVERALL DISEASE. THEY HAVE AN EFFECT ON MOST EVERY SINGLE DISEASE THAT THESE PARTICULAR MICE DIE OFF. WHAT IS REPRESENTED HERE ARE TUMORS. THE ONSET OF A SPONTANEOUS TUMORS -- OF CONTROL ANIMALS. AND YOU CAN SEE THAT THEY START MUCH EARLIER -- POSTPONED BY WOULD THE NUMBER OF TUMOR ANIMALS THAT INCREASE TREMENDOUSLY. THIS IS NOT ONLY IN TUMORS THAT IF YOU LOOK FOR EXAMPLE AT OLDER TISSUES LIKE FOR EXAMPLE MUSCLE THAT IS VERY ESSENTIAL FOR DAILY LIFE ON FUNCTION DISEASE, THE MUSCLE FROM THE -- AND THIS IS THE SAME MATCH ON FELLOW RESEARCH. YOU CAN SEE THAT THE TISSUE EVEN THE STRUCTURE ON THE FUNCTION IS PRESERVED THROUGHOUT AGING. I MENTIONED TUMORS, AND THIS IS NOT JUST A SPONTANEOUS TUMOR BUT IF YOU INDUCE THEM EITHER CHEMICALLY OR INJECT -- THE TUMOR EITHER DO NOT DEVELOP OR IS MUCH MUCH LOWER. SO WHY IS THE STUDY CALORIC RESTRICTION. IT'S THE MOST CONSISTENT INTERVENTION OF ALL AGING DISEASES SINGLE LIFE SPAN IN ALMOST, THIS IS AN ALMOST UNDER AND/OR ALL SPECIES TESTED. IF WE'RE ABLE TO UNDERSTAND HOW CALORIE RESTRICTION WORKS, THAT WILL DEFINITELY PRODUCE LEADS FOR UNDERSTANDING HOW THE PROCESSES ARE UNDER GOING. AND THEN IT WILL ENABLE US YOU WILL SEE LATER TO DEVELOP TARGETS FOR INTER INTERVENTION THAT WILL LEAD SURVIVAL IN HUMAN POPULATION. WHAT IS THE ISSUE WITH CALORIE RESTRICTION. THIS SLIDE WAS IN 2000 FOR MARK LANE, MY MENTOR AND TODAY. SO IF YOU ASK ANYONE WHAT IS THE MECHANISM BEHIND CALORIE RESTRICTION THEY WILL TELL YOU SOMETHING LIKE THIS. YOU HAVE THE ANIMALS LIKE A BLACK BOX WHEN SOMETHING HAPPENS. THEN YOU HAVE PROCESSES -- TODAY WE HAVE A LITTLE MORE KNOWLEDGE OF WHAT IS HAPPENING HERE BUT WE DO NOT HAVE A MECHANISM OF MULTIPLE MECHANISMS FOLLOW RESTRICTION. SO WHAT DOES IT DO? SO PICK YOUR BATTLE. EVERYTHING THAT YOU MEASURE IS AFFECTED BY THIS INTERVENTION. THIS IS A VERY STRONG AND POWERFUL INTERVENTION THAT AFFECTS FROM THE BRAIN TO THE TAIL ARE MOST ABSOLUTELY EVERY SINGLE PROCESS IN A ORGANISM. IT IS THOSE DEPENDENTS. IF YOU DO 10, 20, 40 AND SUCH YOU WILL GET INCREASES IN SOME OF THESE ASPECTS AND DECREASES IN OTHERS. SO IN MY LAB, OUR WORKING HYPOTHESES IS BASED ON HOW AN ANIMAL, AN ORGANISM OR CELL IS ABLE TO DETECT THESE CHANGES IN ENERGY AND THE WAY THAT THE ENERGY GETS MANIPULATED AND USED THROUGH THE CELL OR THE ORGANISM AND HOW THOSE CHANGES EFFECT LONGEVITY. I KNOW YOU HAVE THE EXAMPLE OF HOW WE THINK ABOUT THINGS. SO HERE'S A PICTURE OF JUST THE CELLS, MEMBRANE CYTOSOL, NUCLEI. AND BASICALLY CONTINUOUSLY EVERY CELL IS SENSING AND BEING DIRECTED BY NUTRIENTS UNDER STRESS OR GROWTH FACTORS THAT HAS INFORMATION ABOUT THE STATUS OF THE ENERGY THAT'S AVAILABLE. THIS IN TURN AS SOON AS IT'S READ AND PROCESSES THE MEMBRANE WE HAVE SENSORS THAT GET ARLTD AT THE RESPONSE OF MANY OF THESE METABOLIC INPUTS AND THIS CHANGES THE RATIO. AGAIN THESE ARE JUST CHOICES -- AND OTHERS. THESE SENSORS -- IN THESE RATIOS ARE THEN READ BY MASTER REGULATORS THAT TURN ON SUBSCRIPTION FACTORS AND ACTIVATORS THAT GO INTO THE NEW -- NUCLEI AND ADAPT AND CHANGE THE METABOLISM TO ADAPT TO THE ENVIRONMENT. YOU GET AN INCREASING METABOLIC -- THAT YOU WILL SEE WITH FELLOW RESTRICTION, METABOLIC OUTPUTS. YOU GET INCREASES IN HEALTH SPAN AND AGING. I'M SEPARATING THOSE TWO AND YOU'LL SEE WHY LATER ON. IF YOU GET THESE TWO HAPPENING AT THE SAME TIME, THEN YOU SEE, YOU SHOULD SEE CHANGES IN LONGEVITY. SO OUR OVERALL WORKING HYPOTHESES IS THAT INTERVENTION THAT -- ENERGY WILL LEAD AND WILL HAVE A POSITIVE IMPACT IN -- AND THAT SHOULD IMPROVE THE HEALTH SPAN. SO WHEN I START WORKING ON THIS, I WAS TOLD ONLY ON THAT CALORIE RESTRICTION WORKS. I WAS TOLD -- REGARDLESS OF THE -- OR REGARDLESS OF THE ORGANISM. OVER THE PAST 12 YEARS -- AND THROUGH PAPERS THAT HAVE BEEN PUBLISHED SINCE THEN, I REALIZE IT'S NOT AS STRONG AS WE THOUGHT. I'M GOING TO WALK YOU THROUGH SOME OF THESE THINGS THAT THEY ARE CLEAR EXAMPLES OF THE RECENT LITERATURE. FOR EXAMPLE, WHAT IS THE EFFECT OF GENETIC BACKGROUND AND SEX AND THE EFFECT -- DOES IT WORK FOR ALL. SO FIRST I'LL TALK TO YOU ABOUT THE -- STRENGTH AND THEN I'LL TELL YOU ABOUT THE -- AND GENETIC MANIPULATION THAT EFFECTS THE EFFECT OF CALORIE RESTRICTION. SO YOU THINK OF THE -- THESE ARE ANIMALS PRODUCED THROUGH MULTIPLE -- YOU GET AND YOU PUT THEM ON 20% CALORIE RESTRICTION. THIS IS VERY IMPORTANT, 40% CALORIE RESTRICTION. YOU GET THE DIFFERENCE BETWEEN CR AD LIBITUM LIFE SPAN TO RESPOND POSSIBLY TO CALORIE RESTRICTION. ABOUT ONE THIRD DO NOT RESPOND AT ALL. ANOTHER ONE THIRD ACTUALLY HAVE A NEGATIVE IMPACT OF CR. BOTH IN MALES AND FEMALES. YOU REPEAT THIS EXPERIMENT IN A ANOTHER LAB -- AND THE SAME THING ABOUT ONE THIRD DISTRIBUTION OF RESPONDENT, NO RESPONDENT AND THE OTHER RESPONDERS. YOU REALIZE SOME OF THEM HAVE A NEGATIVE EFFECT OF CALORIE RESTRICTION. WHAT WAS HAPPENING AS JAY MENTIONED EARLY 40% IS PROBABLY WAY TOO MUCH FOR THAT PARTICULAR GENETIC MIX BACKGROUND. IF WE LOOK AT ANOTHER STRAIN DBA2'S THAT'S BEEN MANY YEARS AGO AND MORE RECENTLY -- YOU SEE THAT DBA2 TYPICALLY IS A STRAIN OF MICE THAT DO NOT RESPOND WELL TO CALORIE RESTRICTION. THESE ARE MALE AND YOU CAN SEE THERE'S A MORTALITY AND THEY NEVER CROSS THE LIFE SPAN THE CONTROL ANIMALS. A NEGATIVE EFFECT IS REPORTED TOWARD CALORIE RESTRICTION. USING THIS PARTICULAR, I WANTED TO ADD THE QUESTION. IS THERE AN OPTIMAL CR PERCENTAGE THAT I CAN USE TO ACTUALLY MAKE IT LIVE LONGER. IT DOESN'T MATTER THE TYPE OF SEX THAT THE ANIMAL IS FROM. SO THIS IS UNPUBLISHED DATA. BUT YOU CAN SEE DBA2 MALES AND FEMALES. WE DID EITHER 40% CR OR 20% CR IN BOTH MALES AND FEMALES. WHAT YOU CAN SEE IS BASICALLY WE PRETTY MUCH REPRODUCE WHAT'S BEEN REPORTED AT THE MORTALITY OF 40% CR. BUT THERE'S AN INCREASE OF A MAXIMAL LIFE SPAN THAT IS VERY INTERESTED WHEN WE REDUCE THE AMOUNT OF CR UP TO 20% FOR MALES, THERE IS AN EARLY MORTALITY AND THEY'RE GOING TO LIVE LONGER. SO IF YOU ARE DBA2 MALE, MAYBE 10% IS EVEN BETTER. YOU NEED TO GO -- NOW YOU ARE DBA2 FEMALE IS EVEN BETTER NEWS BECAUSE YOU DO NOT REGISTER DAILY MORTALITY EITHER WITH 20% OR 40% BUT CLEARLY YOU DO NOT NEED TO GO ALL THE WAY TO 40% TO GET EXACTLY THE SAME BENEFICIAL EFFECT OF CALORIE RESTRICTION IN TERMS OF LIFE SPAN. SO SEX AND PERCENTAGE OF CALORIE RESTRICTION ARE PLAYING A GAME TO TRY TO FIGURE OUT HOW THEY INTERACT. YOU GO BACK TO THE LITERATURE AND LOOK CAREFULLY THROUGH IT. THE ABUNDANCE OF LITERATURE ON THE -- CR. THERE WAS A TALLY THAT WAS DONE -- THESE ARE USING ABOUT 2000 ANIMALS. WHAT WAS VERY INTERESTING ABOUT THIS, AND THIS WAS SORT OF LIKE -- IN THE LITERATURE IS THAT USING -- THESE ARE IN THE SAME TYPE OF MICE. YOU PUT THEM ON DIFFERENT DIET THAT'S NOT USED ANYMORE OR THE NIH THIRD ONE AND THE ANIMALS JUST BY CHANGING THE DIET COMPOSITION. -- YOU HAVE INCREASE OF MAXIMUM LIFETIME UNDER LIMITED CONDITIONS. SO THE ROLE PLAYS AN IMPORTANT ROLE FOR LIFETIME. NOW THE INTERESTING THING IS WHEN YOU PUT THESE ANIMALS ON CALORIE RESTRICTION YOU GET LIKE A MAXIMIZED RESPONSE. REGARDLESS OF WHAT YOUR GUIDE WAS YOU DO SELECT MAXIMUM OF THE TOTAL SURVIVAL. YOU DO GET THE MAXIMAL LIFE SPAN. THE PROPORTION OF IT IS VERY DIFFERENT. SO YOU AT NIH IN THIS PARTICULAR STATEMENT YOU GET 16% LIFE SPAN INCREASE. IF YOU ARE -- YOU GET A 40% LIFE SPAN INCREASE. TO THE POINT OF JAY THAT DIET IS VERY IMPORTANT IN THE CONTEXT. SO JAY MENTIONED THIS STUDY. AND THIS IS THE IN OUR OPINION THERE IS EVIDENCE IN THE RHESUS MONKEY THAT SOME OF THE -- HAVE VERY IMPORTANT IMPACT ON THE OUTCOMES OF SURVIVAL AND CALORIE RESTRICTIONS. IT SHOWS THAT THE MONKEYS LIVE LONGER IN CR. IF YOU LOOK AT MORTALITY THERE'S NOT -- SEPARATE THE SENSOR -- AND YOU DO GET MORTALITY INCREASE IF YOU DO NOT HAVE THOUGH DISEASES. WE JUST PUBLISHED RECENTLY THAT -- ABSOLUTELY NO DIFFERENCES BETWEEN THE MALES AND FEMALES IN TERMS OF SURVIVAL. SO WE DO NOT GET AN OVERALL MORTALITY EFFECT BUT IF WE LOOK AT THE ONSET OF THIS REGARDLESS OF THE EFFECT ON SURVIVAL, WE DO SEE A SHIFT TO THE RIGHT. SO THE DISEASES THAT THE MONKEYS, DYING OF OCCUR LATER IN LIFE. SO IN THIS STUDY, AND WE'RE WORKING VERY CLOSELY TO TRY TO ELUCIDATE WHAT ARE THE DIFFERENCE. WE'RE COMPARING DIET COMPOSITION, SHARING ISSUES AND TRY TO ELUCIDATE WHAT ARE THE KEY MECHANISMS BETWEEN THESE OBVIOUS DIFFERENCES. YOU CAN SEE THE DIET COMPOSITION IS VERY VERY DIFFERENT. WISCONSIN HAS FORMULATED LIKE CLOSE FORMULATION DIET SO THEY CONTROL EXACTLY EVERY SINGLE MECHANISM. WE WENT TO A FORMAL APPROACH. SO THAT ENTAILS FOR SEASONAL CHANGES IN LIKE WEEKS AND THINGS LIKE THAT. AND WE ALSO HAVE A DIFFERENCE IN THE WAY THAT WE WERE FEEDING THE ANIMALS, RESPONDING TO THE ANIMALS ONCE A DAY. WE DID TWICE A DAY. AND THEN WE HAVE CONTROL -- EVALUATE EFFECT AS JAY MENTIONED THERE'S A BIG DIFFERENCE BETWEEN THE TWO STUDIES IN TERMS OF THE -- AND HOW CALORIE RESTRICTION IMPACTED. THEN THE GENETIC VERSION OF MONKEYS COME FROM TWO DIFFERENT BACKGROUNDS. AND THE AGE OF ONSET. ONE SINGLE AGE OF ONSET AND THEY HAVE -- AGE OF ONSET AND WE HAD THREE DIFFERENT ON SETS. WE HAD VERY YOUNG, ADULT AND LATE ADULT OF ONSET. THIS IS ONE OF THESE REGULATORS OF METABOLISM THAT WE THINK PLAYS A ROLE IN CONTROLLING THESE METABOLIC. SO WHAT WE DID IS IN COLLABORATION -- WE TOOK A HOMOZYGOUS ANIMALS OR WILD TYPE AND PUT THEM UNDER CONDITIONS -- YOU CAN SEE HERE CLEARLY IS THAT WHEN YOU DO NOT HAVE ANY SINGLE COPY OF -- REGARDLESS IF YOU ARE IN CR OR NOT, YOUR LIFE SPAN IS SHORTER. IF YOU HAVE ANIMALS THAT HAVE A HEALTHY DIET OF THE HETEROZYGOUS FOR SIRT1 AND YOU HAVE THE -- WOULD BE RIGHT THERE. BUT REGARDLESS IF YOU HAVE ONE COPY OR TWO COPIES OF SIRT1 YOU DO SEE EFFECT OF CALORIE RESTRICTION. AT LEAST SOME OF THE EFFECT OF CR -- THE SAME IS THE CASE WITH -- THAT WE POSITION ABOUT FOUR YEARS AGO. AND WE'RE NOW TRYING TO ELUCIDATE EXACTLY THE KEY DIFFERENCES BETWEEN THE DIFFERENT GENOTYPES AND THE RESPONSE FOR SURVIVAL. SO TO SUMMARIZE THIS PART OF THE TALK, IT IS VERY CLEAR THAT CC REMAINS THE MOST ROBUST INTERVENTION TO EXTEND MEAN AND MAX LIFE SPAN. WHEN YOU SEE ANIMALS, IT'S NOT AS SIMPLE AS YOU THINK. SO THERE ARE MANY THINGS YOU NEED TO CONSIDER BEFORE WE DO THIS KIND OF INTERVENTION. SO I GIVE YOU EVIDENCE THAT THE GENETIC BACKGROUND OR GENETIC MAKE UP IS VERY IMPORTANT FOR THE OUTCOMES OF THESE INTERVENTIONS. THE DIET COMPOSITION SEEMS TO BE PLAYING A VERY KEY ROLE IN THIS AND THERE ARE SPECIFIC GENES AND PATHWAYS THAT DO AFFECT THE OUTCOMES OF CALORIE RESTRICTION. SO WHERE DO WE GO FROM HERE, HOW DO WE TRY TO USE SOME OF THIS INFORMATION TO MOVE FORWARD. SO IT IS VERY IMPORTANT THAT WE NEED TO MOVE BEYOND CR. WE CAN USE CR AS A TOOL TO UNVEIL SOME MECHANISMS AS I WILL SHOW YOU IN A SECOND. BUT WE NEED TO TRY TO DO THESE TRANSLATIONS. WE NEED TO GO FROM TESTING CULTURE TO MICE TO MONKEYS TO HUMANS. SO WE'VE BEEN LOOKING AT THINGS THAT WILL MIMIC THE EFFECT OF CALORIE RESTRICTION THAT WOULD TIE THE ABSOLUTE NEED OF THE CALORIC INTAKE. SO WHAT WILL BE THE FUTURES. YOU HAVE TO HAVE A POSITIVE IMPACT IN THE GLUCOREGULATORY FUNCTION, STRESS PROTECTION AND PRE-- IMIMYOU CAN GET TO THE VERY END OF YOUR LIFE AND THEN ONE DAY YOU JUST DROP DEAD. [LAUGHTER] SO IF YOU PUT THAT IN A MOST SERIOUS THING IS BASICALLY IT WILL BE THE TOTAL COMPRESSION OF MOBILITY. SO WHAT WE WILL SEE IS IF WE'RE ABLE TO DO A CR MIMETIC, IT WILL BE THE ONSET AND PROGRESSION OF DISEASES WILL MOVE TO THE RIGHT SIDE AND YOU WILL GET A CURVE OF SOMETHING LOOKING LIKE THIS. THE WAY WE'RE DOING IT IN OUR LAB IS WE USE CELLS TO SCREEN FOR COMPOUNDS THAT INCREASE THE STRESS AND METABOLIC STRESSES THAN POSITIVE HITS. WE NORMALLY MOVE THEM TO MICE AND WE TEST THEM THROUGHOUT THE LIFE SPAN. THEN HITS THAT WE GET IN MICE AND RATS MOVE TO MONKEYS AND FROM MONKEYS WE CAN MOVE TO HUMAN. AND THROUGHOUT THE WHOLE PROCESS WE TRY TO FOLLOW THE SAME TYPE OF PATHWAYS THAT GO AROUND THE CLOCK. SO ONE THING THAT IS VERY IMPORTANT IS THAT IN THE PAST, MOST LONGEVITY STUDIES THAT WERE DONE IN ANIMALS WERE -- SO BASICALLY DID AN INTERVENTION, STARTED WHATEVER AGE STARTED AND THEN YOU LET THEM DIE WITHOUT DOING MANY MEASUREMENTS THROUGHOUT LIFETIME. AND THAT GIVES YOU A VERY GOOD IDEA ABOUT THE M PATHOLOGY AND THE EFFECT OF INTERVENTION IN MAXIMAL LIFE SPAN THAT DID NOT TELL YOU ANYTHING ABOUT THE PROCESS ITSELF. IN THE LAST FEW YEARS WE HAVE ADVANCED TREMENDOUSLY IN THE TECHNOLOGY THAT WE CAN DO A LOT OF INTERVENTIONS THAT WILL PROVIDE US A VERY GOOD VIEW OF HOW IS PROCESSES LIKE GLUCOSE, INFLAMMATION, THINGS THAT YOU CAN MEASURE REPEATEDLY THROUGHOUT A LIFETIME CAN BE ASSESSED. THIS IS WHAT WE DO TO TEST INTERVENTION FOR -- SO WE APPLY INTERVENTION WHAT ABOUT GENETIC, NUTRITIONAL AND ENVIRONMENTAL. AND THROUGHOUT THE LIFE SPAN OF THIS ANIMAL, WE MEASURE A NUMBER OF THINGS AND TO TRY TO ASSESS HOW WELL THESE ANIMALS ARE AGING. WHAT WE DO ALSO IS TRY TO CHECK THE CHANGES IN THE SHAPE, SO YOU MOVE THIS CURVE UPWARDS THAT INCREASE IN HEALTH SPAN. YOU MOVE IT TO THE RIGHT AND THIS IS INCREASING HEALTH SPANS. WHAT IS IMPORTANT IS TO TRY TO INDUCE A STRESS TEST BECAUSE AS SOMEBODY MENTIONED ALL ANIMALS IN OUR COLONIES WE LEAD HAPPY HEALTHY LIVES BECAUSE THEY HAVE NO PATHOGEN AND NO STRESS. SO OFTEN WHEN YOU'RE TRYING TO DO AN INTERVENTION TO SEE AN ORGANISM YOU EITHER STRESS THEM YOU OFTEN DO NOT SEE THE INTERVENTION. WE HAVE CHOSEN IN MY LAB HAS BEEN IMPLEMENTATION OF A HIGH FAT, HIGH SUGAR DIET TO CUT SOME OF THESE INTERVENTIONS ALSO MOARLT FIDE AT THE CURVE. WE USE CALORIE RESTRICTION THAT'S LIKE A POSITIVE CONTROL. THROUGHOUT THE WHOLE ENTIRE LIFETIME, WE MEASURE SEVERAL TIMES ALL THESE ASPECTS OF NORMAL AND HEALTHY AGING. SO THROUGH RESEARCH WE HAVE UNVEILED A NUMBER OF TARGETS FOR MIMETICS. YOU HAVE THE PATHWAY AND M FOREAND A NUMBER OF THINGS THAT WE KNOW THROUGHOUT THE EVOLUTION TO HAVE IMPACT IN HEALTH AND LONGEVITY. BASED ON THESE ELUCIDATION, WE HAVE BEEN ABLE TO IDENTIFY THINGS LIKE CR, ALSO CR MOLECULES THAT INDUCES AN INCREASING SURVIVAL WHILE IT'S BEEN DONE UNDER A HIGH FAT AND HIGH SUGAR DIET -- ALSO HELPS THE IMPACT UNDER HIGH FAT CONDITIONS AND AS JAY MENTIONED RAPAMYCIN. SO WE'RE NOW BEING ABLE TO SPECIFICALLY TARGET SOME OF THESE PATHWAYS AND WE ARE STARTING TO GET THE FIRST GLIMPSES AT AFFECTING IN A NON-GENETIC WAY THE SURVIVAL -- ONE VERY IMPORTANT QUESTION IS ARE THESE JOBS EFFECTS -- WITH IMPROVEMENTS IN HEALTH AND SURVIVAL. THIS IS A VERY KEY ASPECT OF OUR RESEARCH. SO THIS IS PART OF OUR PAPER -- WHERE WE SHOWED THAT RESVERATROL UNDER NORMAL CONDITIONS DID NOT HAVE AN EFFECT ON OTHER SURVIVAL BUT IT DOES HAVE A TREMENDOUS EFFECT IN THE HEALTH OF THE ANIMALS. WHY? PROBABLY BECAUSE THE EFFECT IT WAS HAVING A HEALTH WERE THINGS THAT THE ANIMALS IN THE LAB DO NOT DIE OFF CARDIOVASCULAR DISEASE, CATARACTS, MUSCLE FUNCTION. THIS IS THE LAST TIME WE CAN SEE THAT UNDER STANDARD CONDITION THAT'S ABSOLUTELY NO EFFECT OF -- BUT YOU SEE THE HIGH DOSE -- CATARACTS OR INCREASES IN BONE HEALTH. YOU PUT THEM ON A HIGH FAT DIET YOU DO SEE SHIFTS IN THE CURVE FROM THE HIGH FAT DIET SO THE ANIMALS WERE TREATED WITH HIGH FAT DIET AND THE DRUG THEY DID HAVE THE SAME LIFE SPAN AS THE ANIMALS. IF YOU LOOK DEEPER IN, IF YOU LOOK AT THING LIKE CARDIOVASCULAR DISEASE, YOU DON'T SEE THAT UNDER NORMAL CONDITIONS BOTH NORMAL CONDITIONS MUSCLE AND HIGH FAT DIET IT'S A VERY CRUCIAL EFFECT IN THE VASCULATURE OF THESE ANIMALS. SO IT PRESERVES THE CARDIOVASCULAR FUNCTION MUCH HEALTHIER AND LONGER. SO BASICALLY A LOT OF THESE INTERVENTIONS WERE BEING ABLE TO ILLUSTRATE THAT TWO THINGS. ONE, THAT WE CAN EXTEND -- THAT WE'VE BEEN ABLE TO IDENTIFY MOLECULES AND TARGETS OF THESE MOLECULES LIKE THE -- OR MTOR. AND THAT THESE INTERVENTIONS DO NOT ONLY -- SO YOU CAN HAVE HUGE IMPACTS IN HEALTH WITHOUT HAVING HUGE IMPACTS IN SURVIVAL. AND YOU REMEMBER ONE OF THE FIRST CURVE THAT I SHOWED YOU IN THE HUMAN POPULATION IS BASICALLY WHAT WE'RE DOING IS REPEATING THE HISTORY. WE ARE ABLE TO MOVE THE CURVE TO THE RIGHT INCREASING THE HEALTH BUT NOT REALLY ABLE TO MOVE THE MAXIMAL LIFE SPAN OF THE POPULATION. SO I WOULD LIKE TO THANK EVERYBODY IN MY LAB AND GROUP HAVE BEEN COLLABORATED THE LAST FEW YEARS. AND I WILL TAKE ANY QUESTIONS THAT YOU MAY HAVE. THANK YOU. [APPLAUSE] >> READ THE PAPERS IN THE OBITUARY SECTIONS, FAMOUS PEOPLE MOSTLY. NONE OF THEM DIE OF OLD AGE, THEY ALL DIE OF SOMETHING, MOSTLY PNEUMONIA OR AFTER SOM INJURY. IN THE LABORATORY YOUR ANIMALS PROTECTED FROM INFECTION. WHAT DO THEY DIE OF WHEN THEY FALL OFF. WHICH ANIMALS, THE MICE OR THE MONKEYS. >> IT'S DIFFERENT. >> [INDISCERNIBLE] SO -- WHY THE CURVE DOESN'T COME OUT WHOLE AT ONCE. THESE ARE VERY GENETIC HOMOGENEOUS ANIMALS SPEAKING LIFE IN THE SAME CAGE WITH THE SAME FOOD WITH THE SAME ENVIRONMENT. EVEN WITH THAT HOMOGENEOUS GENETICS YOU HAVE THIS DIFFERENCES OF LIKE ABOUT A YEAR BETWEEN THE FIRST -- DO THEY DIE OFF IN MICE. SO IN MICE DEPENDING ON THE STRAIN BUT MOST MICE DO DIE OF CANCER. IN THESE PARTICULAR -- THEY DIE OF A LOT OF LYMPHOMA. AND IT'S ABOUT 60-40% OF DEFINITE THEY ALL HAVE CANCER. THEY HAVE A NUMBER OF OTHER DISEASES. SO IT'S VERY RANDOM THAT YOU SEE LIKE A STROKE OR HEART DISEASE OR ANYTHING LIKE THAT IN THIS PARTICULAR UNLESS YOU HAVE A HIGH THAT DIET. IN THE MONKEYS THEY ARE NOT IN A TOTAL SPF CONDITIONS SO THEY DO DIE OF HEART DISEASE, ABES AND CANCER. >> DOES FLUCTUATING WEIGHT HAVE ANY ROLE TO PLAY HERE. I UNDERSTAND IN FEAST OR FAMINE WEIGHT GOES UP AND DOWN. >> THAT'S A GREAT QUESTION. THERE'S ANOTHER WAY OF DOING REAL CALORIE RESTRICTION CALLED EVERY OTHER DAY FEEDING. YOU CAN BASICALLY SEE THE ANIMAL AS SOON AS YOU WANT ONE DAY AND THEN THE NEXT DAY. IN THOSE ANIMALS YOU GET UP AND DOWN WEIGHTS. THE DIFFERENCE IN BODY WEIGHT IT CAN BE AS BIG AS FIVE GRAMS TO THE -- IN THOSE ANIMALS LIFE SPAN EXTENSION AS YOU SEE WITH HISTORY 40% CALORIE RESTRICTION. >> [INDISCERNIBLE] >> CORRECT. >> SO -- WOULD WANT TO SAY SOMETHING ABOUT THE PROPOSED MECHANISMS BY WHICH IS PHARMACOLOGIC INTERVENTIONS. >> I THINK EACH ONE -- SO MOST OF THE PHARMACOINTERVENTIONS WE'VE BEEN TESTING SO FAR IN THE AGING APPROACH -- ARE TARGETED THE PATHWAY. THEY ARE SO FAR ONLY INTERVENTIONS THAT HAVE BEEN TESTED IN HETEROGENETIC MICE -- WE STILL ARE A FAR SHOT TO ACTUAL CLINIC AND PRACTICE. BUT THE BASICS ARE INTERVENTIONS OR MOLECULE THEY ARE MOTIVATING THE WAY ENERGY GETS HANDLE EITHER THROUGH INCREASED MITOCHONDRIAL, DECREASED -- THOSE ARE HAVING A POSITIVE IMPACT BOTH IN HEALTH AND LOEVITY, OKAY. >> I AGREE. I THINK WHAT WE'RE FINDING IS THAT BOTH RESVERATROL AND THE COMPOUNDS THAT WAS TALKED ABOUT, THEY BOTH ACTIVATE -- SO WE THINK IT'S GOING THROUGH THAT PATHWAY THAT MIMICS FASTING OR EXERCISE. SO I THINK THERE'S AN OVERLAP THERE. >> [INDISCERNIBLE] [INDISCERNIBLE] >> ALL THESE PATHWAYS ARE MERGED IN THE WAY THAT ENERGY GETS HUMBLE IN THE CELL BOTH EITHER THE -- AS JAY MENTIONED THERE'S A COMPONENT OF HUNGER THAT IS VERY IMPORTANT -- THAT THE WAY THAT THE ENERGY GETS SENT AND GETS TRANSFERRED TO A CELL AND USED IN THE CELL IS CRUCIAL AND CRITICAL FOR THE OVERALL HEALTH OF THE CELL AND THEN BY DEFAULT THE ORGAN AND ORGANISM. IF WE ARE ABLE TO OPTIMIZE THE ENERGY USAGE AND HOW WELL THAT ENERGY IS PROCESSED THROUGH WITHOUT ANY -- I THINK WE HAVE A POSSIBLE IMPACT ON HEALTH AND SURVIVAL. >> -- WHEN YOU AFFECT ONE YOU'RE GOING TO AFFECT THE OTHER. >> WHAT DO YOU THINK ABOUT THE [INDISCERNIBLE] [INDISCERNIBLE] >> SOMEONE DID A VERY INTERESTING STUDY. THEY CONTROLLED BODY TEMPERATURE OF MOUSE -- IN THEHYPOTHALAMUS. WHEN YOU FOOL YOUR BODY INTO THINKING THAT YOUR TEMPERATURE IS HIGH, YOUR BODY EQUALS THE TEMPERATURE. SO WHEN YOU DO THAT AND LOWER THE BODY TEMPERATURE BY GENETIC MEANS YOU ACTUALLY LIVE LONGER. SO METABOLIC RATE ACTIVITY, ALL THOSE THINGS INCREASE BODY TEMPERATURE. PERHAPS IT'S RELATED TO THAT. >> I HAVE A DIFFERENT TAKE ON THAT ONE -- TO RESPOND TO STRESS PARTICULARLY THE ABILITY -- LOWER SPECIALS LIKE THE -- TO GO THROUGH STRESSFUL SITUATION. AS THE COMPLEXITY OF THE ORGANISM GOT HIGHER AND HIGHER AND HIGHER WE LOST THE ABILITY TO BASICAL BECOME -- AN SIT IN THE CORNER AND WAIT. SO WE DEVELOPED MECHANISMS MUCH MORE ADVANCE -- AND ALLOW US TO BASICALLY TO BE PROTECTED TO LONGER PERIOD OF TIMES WITHOUT HAVING TO DO THESE LITHURGY EFFECTS. I THINK THAT CR IS PROBABLY ONE OF THESE, YOU KNOW, STRESS RESISTENT MECHANISMS THAT HAS BEEN PRESERVED AND THE ONLY WAY WE CAN CALL UPON IT IS TO DECREASE IN ENERGY. >> [INDISCERNIBLE] >> I THINK IT STARTED FROM CALIFORNIA AS YOU WOULD THINK. SO ANYWAY, THEY ARE ADVOCATING ABOUT 30% DECREASE. SO AVERAGE CALORIE INTAKE IS 1800 CALORIES I BELIEVE FOR MEN. THEY'RE EVEN ON "60 MINUTES" I BELIEVE. AND YOU KNOW, THE BENEFITS ARE THINGS LIKE DECREASED CHOLESTEROL AND BLOOD PRESSURE AND SO FORTH. BUT THAT'S NOT SURPRISING. WHEN YOU LOSE WEIGHT YOU WILL DROP ALL THOSE THING. THE BIG QUESTION IS IF YOU'RE NOT AT RISK FOR THOSE METABOLIC DISEASE, IN THE FACE OF POSSIBLE OTHER NEGATIVE EFFECTS, WHETHER THOSE PEOPLE ARE ALL BENEFITED. SO I THINK THAT'S THE BIG QUESTION. >> [INDISCERNIBLE] >> THE SAME THING THAT IF YOU DO -- THEY DO HAVE LIFE SPAN EXTENSION. SO JAY MENTIONED EARLIER THAT -- THERE ARE MANY STUDIES THAT HAVE GONE BACK AND FORTH ABOUT CONTROLLING CALORIC INTAKE SO YOU'RE NOT COMPARING AN OBESE MOUSE TO A LEAN MOUSE. EVEN WHEN YOU DO 15% CR -- SO YOU ARE RESTRICTING THEM LIKE A FEAT PHENOTYPE YOU STILL HAVE THE BENEFICIAL EFFECT OF CR. SO CR IS NOT JUST FIXING THE PROBLEM THAT OBESITY HAS EVEN IN LEAN CONDITIONS YOU DO HAVE LIFE SPAN EXTENSION AND YOU HAVE THE BENEFICIAL EFFECT ASSOCIATED WITH DECREASE -- THERE WAS ALSO A QUESTION EARLIER ABOUT CORTICOSTEROIDS. WE KNOW -- IT'S BEEN DEMONSTRATED THAT AT LEAST THE ANTI-TUMOR EFFECTS OF CALORIE RESTRICTION -- ANIMALS AND YOU USE TUMOR ANIMALS ON CR WILL GET THE SAME NUMBER OF TUMORS IF THEY DO NOT HAVE THE ABILITY TO PRODUCE INCREASE CORTICOSTEROIDS. -- THE TUMOR SYSTEM AND CR -- PAPER PUBLISHING THAT. >> THANK YOU VERY VERY MUCH.