>> GOOD AFTERNOON, WE'LL GET STARTED. SO I OFTEN ANY ABOUT THE PROGRAM THAT'S COMING UP AND THOUGHTS THAT GO THROUGH MY MIND I OFTEN SHARE WITH YOU. I DON'T KNOW WHETHER MAYBE THAT'S A SIGN OF AGING. MAYBE. AT ANY RATE AT THINGS THAT WENT THROUGH MY MIND WERE WHY DO WE DIE. EVERYTHING, NOTHING SEEMS TO LIVE FOREVER, AT LEAST ON THIS EARTH AND SO THERE IS A NATURAL PROCESS WHERE EVERYTHING COME TO AN END. SO SHAKESPEARE DESCRIBED AS YOU LIKE IT ALL THE WORLD'S A STAGE. AND WHEN YOU GET DOWN TO THE LAST ACTD, IT' OCTOBER, IT'S ACT, IT'S CHI LDISH -- AS SOOISANS EVERYTHING. I LIKE WENDALL -- THAT'S A ONE HORSE THING THAT WAS BUILT TO LAST EVERY PART WAS PERFECT. AND THEN AT 100 YEARS, ALL AT ONCE AND NOTHING FIRST. JUST AS BUBBLES DO WHEN THEY BURST, ARE THE WHOLE THEN TURNED INTO DUST. WHAT A WAY TO GO. NOW IN BETWEEN ALL OF THAT FOR PROBABLY OF COURSE IS THE REALITY AND THAT'S WHAT ONE OF THE BIG SUBJECTS IS TODAY, WHAT IS AGING. WHAT DO WE KNOW ABOUT HOW IT ALL HAPPENS. AND THEN WHAT DO WE DO, DO WE DO ANYTHING THAT EXCEL RATES IT OR IS IT ALL WRITTEN SOMEWHERE IN OUR GENOME. DOES IT REALLY MAKE ANY DIFFERENCE IF YOU EAT A LOT AND IF YOU'RE SEDENTARY AND IF YOU SMOKE AND DO OTHER SORTS OF STUFF OR MORE IMPORTANTLY IF YOU DON'T DO THOSE THING IS THAT A PASSWORD FOR LIFE. MY IMPRESSION IS THOSE THING DON'T SEEM TO PROLONG LIFE BUT THEY CERTAINLY INFLUENCE DO IF YOU DON OVERDO IT. THIS IS MAJOR IMPORTANCE, GLOBAL IMPORTANCE, PEOPLE ARE LIVING LONGER, BEING CIRCUMSTANCE, THE DEMANDS ON THE HEALTH SYSTEMS. ALL OF THIS IS DRIVING AN INTENSE INTEREST IN BOTH THE SCIENCE OF AGING AS WELL AS THE PRACTICAL CAL TEASE OITIES OF IT FROM THE STANDPOINT OF PUBLIC HEALTH AND WHAT CAN WE DO TO DELAY, TO PREVENT, TO MAKE PEOPLE, QUOTE, HEALTHIER. IF ANYTHING. SO OUR SPEAKERS TODAY, THE FIRST WILL BE LUIGI FERRUCCI WHO IS, CAME TO THE NIH IN 19 -- IN 2002. NO, 1988 AS A VISITING SCIENTIST. SO HE IS A GRADUATE. HIS MEDICAL DEGREE IS FROM THE UNIVERSITY OF FERENZE AND HIS PH.D. FROM THE SAME INSTITUTION WHERE HE WAS ALREADY FOCUSED ON GERONTOLOGY AND PROBLEMS OF AGING. LUIGI IS THE DIRECTOR OF A LONG RANGE OF LONGITUDINAL STUDY POPULATION-BASED STUDY ON FACTORS THAT INFLUENCE AGING. AND WE PUT A LATE EDITION THAT HE SENT TODAY TO THE WEBSITE WHICH I WOULD URGE YOU ALL TO READ, WHICH IS A CHAPTER IN AN INTERNAL MEDICAL BOOK ON THIS WHOLE STORY OF AGING AS BEST AS WE UNDERSTAND IT. LUIGI IS THE SCIENTIFIC DWRERK OF THE NATIONAL -- DIRECTOR OF THE NATIONAL INSTITUTE OF AGING. NOW OUR SECOND SPEAKER IS TOREN FINKEL WHO IS A MEDICAL GRADUATE FROM HARVARD AND HIS PH.D. IS AS PART OF THE HAR HARVARD MIT HEALTH SCIENCES PROGRAM. HE'S A CARD ALL JILS BUT HE CAME TO THE NIH TO FINISH THAT TRAINING SEVERAL YEARS AGO HE'S FROM THE CHIEF OF THE MEDICINE BRANCH OF THAT INSTITUTE AND CHIEF ON THE CARDIOLOGY BRANCH. AND TOREN'S WORK WHICH IS ALSO SOME SLEPT REFERENCES ARE OSOME EXCELLENT REFERENCES ON THE WEBSITE AND I ENCOURAGE YOU TO READ THAT ABOUT THE MECHANISMS OF CELLULAR AGING. SO ENOUGH SAID. DR. FERRUCCI. >> CAN YOU HEAR ME. THANK YOU FOR THE WONDERFUL INTRODUCTION AND FOR THE HONOR TO SPEAK IN FRONT OF YOU. AND ABOUT THE TOPIC THAT I LOVE THE MOST, WHICH IS AGING. I WAS KIND OF STRUCK BY MY INTEREST ON AGING WHERE MANY YEARS AGO I WAS WORKING AS A WAITER IN ONE OF THE RED CROSS CHARITY DINNER AND TRYING NOT TO BREAK THEM AND THE PROFESSOR IN THE CORNER WAS PROFESSOR -- THAT WAS LOOKING AT ME. AND I WAS, YOU KNOW, 15 AND-A-HALF, REALLY A SMALL KID. AND I LOOK AND WHAT ARE YOU DOING HERE. I SAID WELL I REALLY WANT TO DO SOMETHING FOR THE OTHER. I REALLY WANT TO SERVE THE COMMUNITY. AND HE SAID THEN YOU'RE WASTING YOUR TIME HERE. IF YOU WANT TO REALLY DO SOMETHING THAT IS IMPORTANT, YOU NEED TO STUDY AGING. BECAUSE AGING, NOBODY'S LOOKING AT THIS. BUT IT'S GOING TO BE THE MOST IMPORTANT SOCIAL DEMOGRAPHIC PHENOMENA THAT'S GOING TO IMPACT ON THE LIVES OF INDIVIDUALS, FAMILIES. AND EVEN THE NATION THAT NOW THINK THAT THEY DON'T HAVE THE PROBLEM OF AGING BECAUSE THEIR MORTALITY IS VERY VERY HIGH EVENING AT A YOUNGER AGE ARE GOING TO BE AFFECTED BY AGING AS THE MOST IMPORTANT PHENOMENA THAT IS GOING TO IMPACT THE ECONOMY AND THE QUALITY OF LIFE. AND I THOUGHT OH MY GOD, THIS IS VERY VERY IMPORTANT THING BECAUSE NOBODY'S LOOKING INTO IT. SO I WANT TO STUDY AGING. AND THAT'S, YOU KNOW, THE END OF THE STUDY IS HERE. OVER MANY YEARS, MANY TRAGEDIES FORMATIONS -- TRANSFORMATIONS, I WILL SAY MANY LIVES I BECAME THE SCIENTIFIC DIRECTOR OF THE INSTITUTE OF AGING. ONE THING THAT I WANT YOU TO KNOW IS THAT IN MY PREVIOUS LIFE I WAS A -- I REALLY WAS THE HEAD OF A LARGE REHABILITATION HOSPITAL FOR OLDER PEOPLE WITH STROKE, MOSTLY THE STROKE. IT WAS DRIVEN BY A OPEN WHAT WHAT WE DO IN OUR RESEARCH MAY IMPACT THE LIVES OF OLDER INDIVIDUALS. I ALWAYS SAY THAT IN ORDER TO BE EFFICIENT, YOU NEED TO BE A SCIENTIST BECAUSE THE EFFICIENT PHASE IS FIGHT WITH NATURE. NATURE IS AGAINST THEM. ABLING IS THAGING IS THE DRIVING FORCE. THEY CAN CURE ONE DISEASE AND ANOTHER ONE COMES UP. THEY FIX SOMETHING AND THREE ANOTHER ONE COMING UP A FEW DAYS LATER. AND UNLESS THEY THINK THAT THERE'S A BETTER FUTURE, THERE IS SOMETHING THEY CAN DO BETTER THAN THAT IN THE YEAR TO COME IS VERY VERY DIFFICULT TO SURVIVE THE PRESSURE. SO I ALWAYS SAY IN ORDER TO BE -- YOU NEED TO BE A SCIENTIST SO THAT YOU CAN FIND THE WEAPONS TO COUNTERACT THE EFFECT OF AGING, GOING TO GROW MORE AND MORE AND MORE IN THE FUTURE. BUT THE REAL REASON WHY -- THIS IS WORKING? ONE OF THE REAL REASONS WHY I AM INTERESTED IN ABLING IS BECAUSE I'M INTERESTED IN THE QUALITY OF LIFE THAT DECLINES WITH AGING. THERE'S A SCHEMATIC RECONSTRUCTION OF OUR TRAJECTORY OF LIFE. YOU SEE THAT WHEN WE WERE BORN, OUR MOBILITY IS LIMITED BUT IT REALLY INCREASED TREMENDOUSLY OVER VERY FEW MONTHS. AND THEN IN THE FEW YEARS WE'RE ABLE TO RUN AND REALLY BE HIDING INTO THE ENVIRONMENT. THEN THE FEW DAYS OF OUR LIFE WHICH WE CAN CALL LEGAL AGE WHERE INTERCESSABLE VERY VARYS -- VARIOUS DECLINE IN OLD AGE. BUT IF EVERYBODY WAS GOING THROUGH THESE PHASES, IF EVERYBODY WAS EXACTLY FOLLOWING THIS PROJECT, THERE WAS REALLY NOTHING WE COULD DO ABOUT IT BECAUSE EVERYTHING WOULD BE FIXED. AND IT WOULD NOT BE THAT THEY WOULD GIVE UP THE HOPE OF IMPROVING THE FUTURE. BUT THAT'S NOT TRUE. WE KNOW THAT THIS TRAJECTORY HAS BEEN INCREDIBLE ORIGINAL NATED FOR IS OLD OLD PEOPLE THAT REACHED THE AGE OF 100 AND MORE OBTAINING INCREDIBLE MOBILITY. I ALWAYS REMEMBER, I REMEMBER THE FIRST STUDY I DID, I DID A STUDY OF -- IS VERY FAMOUS BECAUSE THERE'S A VERY STRANGE OF POPULATION THAT MAKES SENT CENTENARIANS. THERE WAS A MAN 105 THAT I CALLED ON THE TELEPHONE BECAUSE I NEEDED TO INTERVIEW HIM AND HE TOLD ME THAT HE COULDN'T BECAUSE HE HAD FOUR CHILDREN BUT THEY WERE WORKING AND BECAUSE THEY WERE WORKING THEY COULDN'T SHOP. SO HE HAD TO SHOP IN THE MORNING AND THE ONLY WAY TO INTERVIEW HIM WAS GOING WITH HIM CARRYING THE BAGS OVER THE STAIRS TO THESE FOUR FAMILY AND THE INTERVIEW CAME ACROSS. OF COURSE THE START OF THE EXCEPTION, THERE ARE MANY PEOPLE THAT EXPERIENCE A STRAIGHT IMPORTANT DECLINE OF THE PHYSICAL AND COGNITIVE FUNCTION WITH AGING AND DEVELOPED MANY COMMON DISEASE. AND SO WHAT WE WOULD LIKE TO DO IS TO BRING EVERYBODY TO THE VITALITY AND THE SKILL AND THE ENERGY OF THESE OLD MAN THAT COULD NOT INTERVIEW WITH ME BECAUSE HE WAS TOO BUSY. SO WE FIGURE IN YOUR MIND, THIS IS WHAT I'M GOING TO TALK TODAY. OKAY. IN 1995, WHEN I WAS WORKING WITH -- AT THE NATIONAL INSTITUTE OF AGING, WE DID A STUDY THAT IN PRINCIPLE WAS VERY SIMPLE. WE WERE MEASURING PHYSICAL LOWER EXTREMITY FOR FOUR MONTHS IN THE LARGE POPULATION. THE ESTABLISHED POPULATION FOR EPIDEMIOLOGICAL STUDY OF THEM. AND WE CREATED THE VERY VERY SIMPLE PERFORMANCE TEST WHICH I WANT TO SHOW YOU BECAUSE I'LL SHOW YOU IT CAN BE DONE WITH NO EXPECTATIONS, NO MONEY, VERY VERY CHEAP. SO YOU MAKE PEOPLE WALK FOR FOUR METERS AND YOU MEASURE THE WANTING SPEED. THEN YOU ASK THEM TO MAINTAIN THEIR BALANCE IN MORE CHALLENGING POSITION. THE FIRST POSITION IS SIDE BY SIDE LIKE THAT, THE SECOND POSITION WILL BE WITH THE NEAT, AND THE LAST ONE IS WITH THE FEET ON ONE LINE. AND BECAUSE OF OUR PHYSIOLOGY OF BALANCE, IS SUCH THAT WE'RE VERY GOOD TO MAINTAIN THE STABILITY IN THE -- POSITION BECAUSE OUR FEET ARE IN THIS DIRECTION. AS LONG AS -- THE DAYS OF SUPPORT OUR STUDIES IN THE LAST THING TREKION I DIRECTION IS NOT SO GOOD, SOME PEOPLE WILL FAIL. THE LAST ONE WAS RISING FROM THE CHAIR WITHOUT USING THEIR HANDS FIVE TIMES AND THEN WE WERE MEASURING HOW MUCH TIME WAS WE EXCITED TO DO THAT. VERY SIMPLE. FIVE MINUTES MUCH EVERYBODY CAN DO THAT. YOU HAVE THE CHAIR, FOUR METERS AND NOTHING ELSE. WE DERIVE A SCORE USING THIS TEST THAT WAS GOING FROM ZERO TO 12. AND I'M NOT GOING TO GO INTO THE DETAIL HOW WE VALIDATED THAT. AND THEN WE MEASURED THAT IN THIS POPULATION OF PEOPLE WILL NOT BE ABLE. NOW HERE WE'RE GOING FROM 4 TO 12 BECAUSE WE ONLY SELECTED PEOPLE THAT WERE COMPLETING THE -- AND THE INITIAL SCORETH SCORE -- IN MOBILITY BEFORE BELOW THE ABILITY TO BE IN I INDEPENDENT IS NONE. BECAUSE IF YOU CAN'T WALK OR MOVE YOUR ARM IT'S VERY UNLIKELY YOU WILL BE INDEPENDENT. ALL THESE PEOPLE WERE INDEPENDENT. THEN WE WENT BACK NOW YEARS LATER TO SEE WHAT HAD HAPPENED TO THEM. AND THESE BARS, THESE ORANGE BARS GIVE YOU THE INCIDENCE RATE OF THE VISIBILITY TO TELL YOU IN VERY SIMPLE WORDS THIS IS THE PERCENTAGE OF THOSE WITH THE SCORE OF 4 THAT AFTER 4 THEY DEVELOP THIS AWE DISABILITY. THESE ARE PEOPLE THAT COULD NO LONGER LIVE ALONE. THESE ARE PEOPLE THAT NEEDED THE HELP OF ANOTHER PERSON TO BE AUTONOMOUS. SO IT'S NOT ALL DIFFERENT. THIS IS REALLY REALLY HUGE DIFFERENCE IN THE LIFE OF AN INDIVIDUAL. YOU CAN SEE THAT THERE WAS AN INCREDIBLE RELATIONSHIP BETWEEN THE -- AT THE TIME WHEN THEY'RE NOT DISABLED AND THE PROBABILITY FOR THEM TO BECOME DISABLED FOR YEARS LATER. WHILE THIS IS SUCH AN IMPORTANT STUDY THAT WE PUBLISHED THAT IN THE NEW ENGLAND JOURNAL OF MEDICINE. AND I COULD SAY THAT AFTER 1995, I SPENT MY ENTIRE RESEARCH TRYING TO UNDERSTAND WHY THIS LOWER PERFORMANCE IS SUCH A POWERFUL PREDICTOR OF EVERY IMPORTANT OUTCOME THAT WE SEE WITH AGING. FOR EXAMPLE MORTALITY. NURSING HOME ADDITION. THE ABILITY TO -- OKAY. I'M GOING TO SKIP A COUPLE SLIDES TO TELL YOU THESE MODELS WERE REFINED AND APPLIED IN A LARGE LARGE POPULATION. WE RECENTLY PARTNERSHIP THE EXACTLY SAME RESULTS OF 1995 WITH THIS TOWN OF A THOUSAND PEOPLE ACROSS 38,000 PEOPLE IN 2011. THIS IS IMPORTANT BECAUSE THIS WAS NOT RELATED TO MORTALITY. WE SHOW THAT YOUR SIMPLE SPEEDS OF THE FOUR METER WALK IS VERY STRONG. THAT CAN BE USED CLINICALLY TO MAKE ASSESSMENT AND DECISION-MAKING ABOUT OLDER INDIVIDUALS. I'M NOT GOING TO GO TO THAT. SO THIS IS THE MODEL THAT YOU KNOW FEW YEARS AGO I DEVELOPED THE STUDY OF AGING TO STUDY WHY MOBILITY WAS SO IMPORTANT IN THE EYES OF INDIVIDUALS. AND I IGNORE THIS LITTLE NAME, BUT YOU SEE THAT MODEL THAT IS MOBILITY WHICH IS THE NAME EVER MAIN OUTCOME FOR EVERYTHING ELSE. AND WE HAVE SEEN THE MOBILITY IS PREDICTIVE OF THAT OUTCOME MORE AND OVER ANY OTHER MEASURE WE KNOW IN MEDICINE. I CAN TELL YOU THAT IN MY ENTIRE STUDY, WALKING AT THE SPEED AT 0.8 METERS PER SECOND WHICH IS SOMETHING LIKE THAT, OKAY. IT WAS MORE PREDICTIVE OF MORTALITY -- SO HAVING, WALKING LOWERS THE METER OVERCOME AS PREDICTIVE VALUE THE DIAGNOSIS OF SOMEBODY -- SO WHY IS THAT. SO WE, IN ORDER TO UNDERSTAND MOBILITY, YOU COME TO WHAT MOBILITY IS AND WHAT IS REQUIRED FROM POSSIBILITY. SO THE FIRST THING TO DO IS YOU NEED THE MOTIVATION FOR MOBILITY WHICH IS CREATED IN THE CENTRAL NERVOUS SYSTEM. THE MOTIVATION IS TO BE WIRED INTO THE BRAIN THAT CREATES A MODERN PROGRAM, ANOTHER PROGRAM INTO THE GANGLIA. AND THEN WIRE THIS THROUGH THE SPINAL CORD AND THE NERVE TO THE FACTORS OF THIS PROGRAM. YOU WOULD REMOVE WHAT I WOULD SAY IS THE HARDWARE OF OUR BODY WHICH IS THE BONE AND THE JOINTS. AND IN ORDER TO DO THAT, YOU NEED TO HAVE ENERGY BECAUSE NOTHING MOVES WITHOUT ENERGY. YOU NEED TO PRODUCE AND DELIVER AND UTILIZE THE ENERGY AT THE RIGHT TIME IN THE RIO RIGHT PLACE. AND ALSO YOU NEED FEEDBACK FROM THEM BECAUSE YOU'RE NOW WALKING IN THE BACK AND IF THE RANGE IN FRONT OF YOU CHANGE, YOU DO NOT ADAPT TO THAT TERRAIN THAT IS CHANGING, YOU'RE GOING TO FOLD WITH ALL THFOLD -- FALL, WE ALL KNOW ABOUT FALL IN LATE LIFE. WHEN I WAS DOING THIS STUDY I REALIZE AND I'M GOING TO BE HERE SHOWING YOU THE DATA YOU HAVE TO BELIEVE ME, IS THAT THOSE WERE DECLINING WITH AGING INDEPENDENTLY. THERE'S HARMONY IN THE DECLINE. MY PROFESSOR AMOUN ANTHONY USED TO SAY MY -- AGE WITH THE SAME SPEED. SO WE HAVE AGING THAT IS HARMONIC ACROSS THE WHOLE SYSTEM. AND SO BECAUSE I WANT TO STUDY WHAT IS THIS UNDERLYING MECHANISM, THIS HARMONIC DECLINE IN AN ANATOMICAL INTEGRITY ACROSS THE SYSTEM, WE CREATED A NUMBER OF DOMAINS THAT I COULD -- AND THAT MOST OF THESE DOMAINS WILL BE MENTIONED AND DESCRIBED BY THE NEXT. I'M JUST GOING TO MENTION THAT OR MOMENTAHORMONAL CHANGING WITH AGING -- THE PHENOTYPE AND AUTONOMIC NERVOUS SYSTEM, THE PARA SYMPATHETIC AND THE SYMPATHETIC CHANGE WITH AGING. SO THAT FOR EXAMPLE IF YOU DO A VERY FAST MOVEMENT, ARE IT'S LIKELY THAT VERY OLD PEOPLE HAVE AN EGO BECAUSE THE READAPTATION OF THE SYSTEM IS LOW MANY TIMES AND INCOMPLETE. NUTRITION AND PHYSICAL ACTIVITY IS ALSO CHANGING. SO HOW DO WE STUDY THAT? HOW DO WE CONCEPTUALIZE ALL THESE MEASURES AND WE TRY TO PUT THEM TOGETHER IN WAYS THAT MAKE SENSE. LIKE TO GO THROUGH EACH ONE OF THESE LITTLE HORMONES AND SHOW YOU THE STUDY. BUT IN FACT, HOW DO ALL THESE STUDIES CAN BE CONCEPTUALIZED TOGETHER. SO THIS IS THE CHAPTER THAT I GAVE YOU THE LINK THAT YOU CAN LOOK TO BUT IT'S REALLY THE FINAL PRODUCT OF WHAT I'VE DONE ON THE STUDY OF AGING. SO THE IDEA HERE IS THAT AGING AFFECTS YOUR BODY TO FOUR MAIN FEEPHENOTYPES. AND THESE FOUR MAIN PHENOTYPES ARE CHANGES IN BODY COMPOSITION. WHEN I SAY CHANGE IN BODY COMPOSITION EVEN IF YOUR WEIGHT REMAINS THE SAME, THE COMPOSITION OF YOUR BODY IS GOING TO CHANGE. AND THE HEALTHY AND UNHEALTHY CHANGES I'M GOING TO GO TO THEM WITH YOU IN A FEW SECONDS. THEN YOU HAVE ENOUGH INTERESTING THINGS TO ME WHICH IS THE IMBALANCE BETWEEN HOW MUCH ENERGY YOU HAVE AVAILABLE AND HOW MUCH ENERGY YOU REALLY NEED TO BE ENJOYING EVERY OPPORTUNITY IN THE ENVIRONMENT. FAMILIES DON'T HAVE REGULATION WHICH I'M NOT GOING TO TALK ABOUT, ABOUT MY NEXT SPEAKER. AND IF WE HAVE TIME I ALSO WANT TO TALK ABOUT NARROW VISION. BUT BECAUSE OF THE TIME LIMB, I'M GOING TO TRY JUST TO FOCUS ON THESE TWO AND MAYBE SKIP YOU SOME OF MAY SLIDES. KEEPING ON TIME AND TELL ME WHEN I HAVE FIVE MINUTES LEFT BECAUSE I TEND TO TALK TOO MUCH. SO LET'S TALK ABOUT BODY COMPOSITION. THESE ARE I HOPE, OKAY, THESE ARE BAY DE WHAT THE STUDY OF THE AGING. THESE DATA, YOU KNOW, THESE LITTLE LINES ARE 58 YEARS OF DATA COLLECTED IN MORE THAN 3,000 INDIVIDUALS THAT HAVE COME EVERY TWO YEARS IN BALTIMORE AND THAT STAYED THERE AT EVERY VISIT FOR THREE DAYS. AND WHAT THEY COMPLAINED ABOUT IS THAT WE DON'T GIVE THEM ENOUGH TIME TO GO TO THE BATHROOM BECAUSE WE PRESS THEM CONSTANTLY AND WE COLLECT EVERY POSSIBLE PIECE OF DATA WE HAVE. SO THIS LONGITUDINAL PROJECT OF THE OVERALL TRAJECTORY. SO THIS ONE IS WASTE AND YOU SEE THAT ON OTHER AGE PEOPLE AND I'LL TALK TO MAN BUT WOMEN ARE VERY VERY SIMILAR HAVE INCREASED IN WEIGHT. AND THEN THERE IS AT SOME POINT AROUND THE AGE OF 70 TO 75 IS A DECLINE IN WEIGHT. THAT MANY PEOPLE INTERPRET AS THE RESULT OF DISEASE. NOT OF THE RESULT OF THE EFFECT OF AGING. AND MAN, THESE CHANGING WAYS IN MODIFICATION IN WAYS REALLY HIDE TWO LARGE COMPARTMENTS, THE LEAN MASS WHICH IS THE MUSCLE AND ORGANS THAT TEND TO INCREASE A LITTLE BIT UP TO THE AGE BETWEEN 30 AND 35. AND THEN DECLINE -- WAIT AROUND. AND THEN YOU HAVE THE FAT MASS THAT INCREASES AND THEN DECLINES ALMOST AT THE SAME TIME WHEN THE WASTE TENDS TO DECLINE. NOW THE DECLINE IS MISCHIEVOUS BECAUSE IT DOES NOT HAPPEN TO ALL THE FAT OF THE BODY. ONLY THE SUBCUTANEOUS FAT TENDS TO DECLINE WHILE THE ONE THAT IS ACCUMULATED HERE ALONG THE BELLY IS ADDITIONAL FAT. NEVER DECLINE WITH AGING AND WILL REMAIN ON AVERAGE ALWAYS THERE. AND THAT IS THE PROBLEM BECAUSE WE KNOW THAT THAT IS THE FACT THAT IS METABOLICALLY ACTIVE AND IS CREATING ALL THE PROBLEM. BUT I WANTED TO SHOW YOU THAT TWO CRITICAL MOMENTS IN LIFE OF BODY COMPOSITION. ONE AROUND THE AGE OF 40 WHEN THEY HAVE THOSE CHANGES, AND ONE AROUND THE AGE OF 70 WHERE YOU CAN SEE REALLY THE CHANGE THAT OCCUR IN A DOWNWARD DIRECTION. AND THIS IS SOMEWHAT DIFFERENT AGREEMENT WHERE THE DECLINE HERE SEEMS TO BE WIDELY ANTICIPATED AT THE AGE OF BETWEEN 65 AND 70. BUT LET'S LOOK AT EACH ONE OF THESE COMPARTMENTS. SO THIS IS THE PERCENTAGE OF PEOPLE THAT HAVE NO GREAT STRESS. WE MEASURE HOW MUCH YOU CAN SQUEEZE THE PLAN AND THEN REALLY NOT ENOUGH ABILITY TO SCREEN. AND THEN YOU CAN SEE THAT THE PERCENTAGE INCREASES WITH AGE. BUT IN THOSE WHO HAVE THE STRATEGIC DISEASE SUCH AS PULMONARY DISEASE, CHRONIC PULMONARY DISEASE. THE PREVIOUS LENLS O PREVIOUS PREVIOUS PRE VIOUS PREVALENCE OF SARCO PENIA. YOU CAN SEE THESE ARE LANG TO DOATODO -- LONGITUDINAL TRAJECTORY -- CONCEPT IS THAT ALTHOUGH WE THINK ABOUT THE PHENOTYPE OF AGING AS THE PHENOTYPE OF AGING, DISEASE AFFECTS THE FUNCTION AND THE QUALITY OF LIFE OF INDIVIDUALS BY IMPACTING ON THE PHENOTYPE OF AGING. SO IN A WAY, AGING AND PATHOLOGY OUR CO-MORBIDITY ARE ACTING TOGETHER ON THE LIFE OF THE INDIVIDUAL. AND I'M GOING TO SKIP SOME OF THEM. I'M NOT GOING TO SHOW YOU THIS. AND NOT EVEN THIS BECAUSE I WANT TO GO DIRECTLY TO IMAGES. BECAUSE IMAGES TELL YOU EVERYTHING. SO THESE ARE CT SCAN OF THE LEG OF THE THIGH THAT IS MEASURING THE LONGITUDINAL STUDY. THAT'S ONE OF THE MANY MEASURES WE DO. YOU CAN SEE THAT THESE, I SELECTED WOMEN WITH A BMI OF 30-32. SO BODY SIZE IS ALMOST THE SAME, OKAY. SO IF YOU LOOK AT 8-33 YEAR AGE 33 YEARS, MOST OF THE LEG IS MUSCLE. AND THE MUSCLE IS VERY TIGHT AND VERY DENSE. AND THERE'S A LITTLE BIT OF SUBCUTANEOUS THAT BUT REALLY JUST AN IDEA OF IT. IF YOU GO TO AGE 55, YOU SEE THAT THESE SUBCUTANEOUS PATH IS INCREASING AND THERE IS ACTUALLY FAT THAT IS TRYING TO INFILTRATE THE VALUE OF MUSCLE GROWTH. THEN YOU GO TO THE AGE OF 80 AND THE SUBCUTANEOUS FAT IS INCREASING AND THERE IS A COMPLETE FASCINATION OF THE MUSCLE GROUPS SO THAT IF YOU -- EVEN THE MUSCLE THAT IS HERE IS ACTUALLY LESS DENSE AND LESS STRUCTURALLY HOMOGENOUS THAN WHAT WE HAVE SEEN HERE. SO WE HAVE TWO PHENOMENAS HERE. ONE IS THE DECLINE IN THE QUANTITY OF THE MUSCLE AND ONE IS THE DECLINE OF THE QUALITY OF THE MUSCLE. AND I CAN TELL YOU THAT IT'S VERY CLEAR THAT IF YOU EXERCISE, THE DECLINE IN MUSCLE MASS DOES NOT CHANGE VERY MUCH BUT THE QUALITY OF MUSCLE THAT YOU RETAIN WHICH IS THE MOST IMPORTANT THING IS GOING TO INCLUDE TREMENDOUSLY. AND I'M NOT GOING TO SHOW YOU THIS, NOT GOOD BECAUSE I WANT TO GO TO ENERGY. I'LL TAKE TEN MINUTES TO THE ENERGY AND THEN I'LL STOP. OKAY. WE DO KNOW THAT ENERGY DECLINE WITH AGING. THIS IS THE 2005 SHOWING THAT THE MAXIMUM VO2, THE AMOUNT OF OXYGEN CONSEAMION WHESEAM CONSUMPTION, THA NKS TO DECLINE WITH AGING AND THERE'S -- DECLINE WITH AGING. BUT WE KNOW THAT. AND THESE ARE BEING HELD OFF BY THE CARDIOLOGISTS FOR VERY LONG TIME. THE PROBLEM IS THAT VERY RARELY IN LIFE YOU ACT AT THAT LEVEL, HOW MANY TIMES YOU DO SOMETHING THAT REQUIRES THAT YOU MAKE THE MAXIMAL EFFORT THAT YOU CAN. YOU MUST BE WORK THE MIDDLE LEVEL. YOU MAY WANT TO TAKE A BATH ONCE EVERY WEEK BUT MOST OF THE TIME YOU'RE VERY HAPPY DOING A NORMAL LIFE. SO WE NEED TO KNOW WHAT IS BELOW THE MAXIMUM LEVEL AND HOW WE CAN UTILIZE THAT ENERGY. OKAY. SO LET'S ASSUME THAT THIS IS THE ENERGY FOR THE DAY. SO IN THE MORNING, THE MAL MAILMAN COMES TO YOU AND HAVE THE BOX. HE GIVES THE BOX TO YOU AND THE BOX IS THE BOX OF ENERGY YOU ARE HAVE FOR THE DAY. YOU NEED TO MAKE WITH THAT BOX, YOU DON'T HAVE MORE ENERGY, THE ENERGY YOU'RE GOING TO GET IS IN THAT BOX. SHOULDN'T GET THAT ENERGY, IF YOU USE MORE ENERGY THAN YOU CAN, YOU'RE GOING TO DIE BECAUSE THERE'S NO ENERGY FOR YOU TO SURVIVE. SO MOST OF THIS ENERGY AND THIS IS NOT PROPORTIONAL IS GOING TO BE USED JUST TO STAY ALIVE IS 60% OF DAMAGE IS JUST TO STAY ALIVE. AND YOU KNOW WHEN I HEARD THAT, WHEN I READ THAT, I WAS STUNNED. I MEAN JUST TO SURVIVE WERE YOU GIVING TO THE SENSE OF. I SAWRT STARTED THINKING ABOUT THE RED BLOOD CELLS THAT YOU HAVE TO CHANGE EVERY DAY. THERE ARE 200 MILLION. YOU PROCESS, YOU KNOW, A COUPLE OF KILO IS BY THE BRAIN. SO OF COURSE YOU NEED A LOT OF ENERGY. AND ALL THE FLOW OF THE AND THE FLOW OF ION THAT GO IN THE CELL. SO YOU'RE LEFT WITH THIS. THE PROBLEM IS THAT IF YOU'RE HEALTHY, YOU ONLY NEED THIS. BUT IF YOU'RE NOT HEALTHY, FOR EXAMPLE YOU HAVE -- YOU ALSO NEED THE ENERGY TO FIGHT IT. SO YOUR REST METABOLIC CREATOR IS JUST AN ESTIMATE OF THE METABOLIC -- PROCESS THAT USES AN ENORMOUS AMOUNT OF ENERGY T SOMEONE ONCE TOLD THAT IN CHILDREN -- AND THAT'S WHY WHEN YOU HAVE A VERY SMALL CHILD EMBRACED, IT'S SO HARD BECAUSE THERE'S A REACTION OF PROTEIN SYNTHESIS. SO IF YOU'RE SICK, YOU NEED MORE OF THAT JUST TO STAY ALIVE, OKAY. AND THEN THESE SOME PARTS OF DAMAGE THAT YOU NEED TO STAY, JUST TO STAY ALIVE IN NORMAL, TO DRESS AND DRESS, GO TO THE RESTROOM AND DO THOUGH KIND OF THINGS. AND THEN FINALLY WITH THIS PART THAT CAN BE USED FOR THE FUN STUFF, YOU KNOW. GO TO THEM. THINGS THAT YOU LIKE TO DO. DRIVING IN THE MORNING, IN YOU DON'T LIKE DRIVING IN THE MORNING, YOU KNOW, JUST PREPARE OR WHATEVER YOU LIKE TO DO. THE PROBLEM IS THAT WE WILL NOW WHEN YOU AGE THE AMOUNT OF ENERGY THAT YOU NEED TO DO THE SAME TASK BECOME HIGHER AND HIGHER. SO YOU THINK THAT SOMEBODY THAT IS WASHING LIKE THAT, YOU KNOW, FOR ONE MINUTE WILL USE THE SAME ENERGY NO MATTER WHAT. THIS IS ACTUALLY NOT TRUE. WE KNOW THAT IN OLDER PEOPLE, THE AMOUNT OF ENERGY IS A LOT MORE. SO I WANT TO SHOW I WHY, JUST TO SHOW WHAT'S HAPPENING. WE HAVE AN UNBELIEVABLE MACHINE THAT IS ENERGETICALLY EFFICIENT FOR WALKING. THE MACHINE IS ENERGETICALLY EFFICIENT BECAUSE YOU HAVE A LOT OF STRATEGIES THAT ALLOW YOU TO WALK WITHOUT CHANGING THE BODY, THE CENTER OF GRAVITY. MOST OF THE ENERGY IN WALKING IS DUE TO UP AND DOWN OF THE CENTER OF GRAVITY. SO IF YOU WALK, YOU SEE THAT MY HEAD DOESN'T REALLY CHANGE. AND IT DOESN'T CHANGE BECAUSE PART OF THE WALK NOT DUE TO THE LEG BUT DUE TO THE ROTATION OF THE HIP AND THE ROTATION OF THE HIP DOESN'T NEED TO BE UP AND DOWN. THERE ARE A NUMBER OF OTHER PHYSIOLOGICAL STRATEGIES FOR THAT. LET'S SAY THAT MY BALANCE IS NO LONGER THE ONE THAT WAS BEFORE. AND IF IT'S NOT, THEN I NEED TO WALK WITH SUPPORT SO I DON'T FALL. SO WE HAVE THE LAWMPLEG BAS LARGE BASE OF SUPPORT. YOU SEE MY HEAD GOING UP AND DOWN. WE KNOW THAT MEASURABLY THE DECLINE OF EFFICIENCY WITH AGING. SO WHAT'S HAPPENING IS THAT THE BOX THAT IS COMING TO ME EVERY MORNING IS SMALLER AND SMALLER. THE AMOUNT OF ENERGY I NEED TO SURVIVE IS LARGER AND LARGER BECAUSE OF THE NEED TO FIGHT CHRONIC DISEASE. AND THE ENERGY I NEED TO DO, THE NORMAL THING FROM LIFE IS HIGHER AND HIGHER. AND FOR THE SAME STUFF VERY LITTLE IS LEFT. WHAT IS THE ILLUSION T SOLUTION TO THAT? WELL, THERE ARE A NUMBER OF SOLUTIONS AND I THINK I HAVE FINISHED MY TIME OR NOT. I CAN GO. FIVE MINUTES AND THEN I'LL -- ONE SOLUTION IS THAT I CAN GET A BIGGER BOX. CAN YOU TELL ME HOW TO GET A BIGGER BOX IN THE MORNING. I INCREASE MY FITNESS. THAT'S WHY PHYSICAL ACTIVITY WORKS SO WELL BECAUSE ALTHOUGH YOUR ENERGY NEEDS ARE INCREASING WITH AGING. IF YOU CAN GET A BETTER, A LARGE BOX IN THE MORNING, THERE'S A LOT MORE THAT YOU CAN DO. THE SECOND THING I CAN DO I CAN ACTUALLY INCREASE CHRONIC DISEASE IN WAYS THAT MINIMIZE THE ENERGY THAT I AM REQUIRED TO COUNTERACT THEM. BUT ARE WE MEASURING HOW HOUR CHRONIC INTERVENTURA FINANCIALS THE ESTIMATE. NO, WE'RE NOT BUT WE WILL, I'LL TELL YOU THAT THE ESTIMATE IS ONE OF THE FRONTIER OF THE NEW MEDICINE. ESPECIALLY WHEN YOU'RE TALKING ABOUT COMPLEX MATTERS. PEOPLE THAT ARE AFFECTED BY TEN DIFFERENT CHRONIC DISEASE. HOW ARE YOU NOGALES T -- THERE'S SO MUCH PARAMETERS, SO MUCH COMPLEXITY THERE. BUT YOU ARE ABLE TO REDUCE THE ENERGIES THAT REQUIRE TO KOWRMT ACT AND TO MAINTAIN HOMEOSTASIS THAT YOU KNOW HEAR DOING SOMETHING THAT IS RIGHT. AND SO YOU CAN, IT'S PART OF THOSE GLOBAL PARAMETERS THAT THE NEW FRONTIER OF MEDICINE IS LOOKING FOR. THE OTHER THING YOU CAN DO IS TRY TO UNDERSTAND WHY THERE IS LOSS OF EFFICIENCY. AND THERE WILL BE MY LAST LINE. I'M GOING TO KEEP THESE ... SO FAR I'VE TOLD YOU ABOUT THIS AND I'VE TOLD YOU ABOUT THIS. I TOLD YOU THAT THE CONSUMPTION AND THE WORK THAT IS GENERATED. I'LL TELL YOU THAT THE EFFICIENCY IS LEFT. SO I NEED TO CONSUME MORE OXYGEN IN ORDER TO DO THE SAME JOB. OKAY. NOW THERE ARE MANY POSSIBILITIES. ONE IS THAT TRANSPORTING THE OXYGEN TO THE PERIPHERY IS MORE EXPENSIVE. OR IT'S POSSIBLE THAT MIGHT MITOCHONDRIA -- SO I GET THE ENERGY AND THEY CANNOT USE IT PROPERLY. SO THEY WASTE. ALL THAT THE BIOMECHANICAL INSTITUTION, THE BIOMECHANICAL PATTERN ON MY BODY SO THEY CAN GENERATE THE WORK WITH VERY LITTLE ENERGY. THIS IS ACTUALLY TRUE. WE KNOW THAT IT'S TRUE AND WE STARTED IN BALTIMORE WITH A BIOECONOMICAL LAB. AND THILAB -- MECHANICAL LAB. THIS IS ONE RESULT IF YOU LOOK AT OXYGEN CONSUMPTION FOR WALKING TEN METERS, THE OXYGEN CONSUMPTION FOR WALKING TEN METERS IS PROPORTIONAL TO THE MAXIMUM RANGE OF MOTION. HOW MUCH YOU FLEX THE KNEE DOING IT. THERE ARE INDIVIDUALS WHERE THERE'S REALLY STRONG INEFFICIENCY THAT WE CAN DEVELOP THE ABILITY OF INTERVENTION THAT OPTIMIZE THE UTILIZATION OF ENERGY IN THE BIOMECHANICAL EFFICIENCY. I CAN TELL YOU THAT IN NORMAL PEOPLE, THIS HAS NEVER BEEN DONE BUT IN PEOPLE WITH STROKE AND STROKE REHABILITATION, THIS IS BECOMING POPULAR AND MORE AND MORE STANDING EFFICIENCY IS BECOMING THE WORD OF REFERENCE TO REALLY IMPROVE. SO THERE'S A LOT WE CAN DO. WE CAN UNDERSTAND HOW BETTER YOU CAN UTILIZE ENERGY, HOW BETTER TO EXERCISE. HOW BETTER EAT AND HOW THOSE DIFFERENT BEHAVIORS AFFECT OUR ABILITY TO MAINTAIN A GOOD BODY COMPOSITION, NOT TOO MUCH. THERE IS A CERTAIN AMOUNT OF MUSCLE THAT HAS ENOUGH BOX IN THE MORNING AND YOU EXERCISE AND WE GET BIGGER AND BIGGER. AND THEN YOU HAVE ENOUGH OF THAT ENERGY THAT YOU NEED TO ENJOY ANY CHANCE THAT LIKE YOU EVERY DAY. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> HOW YOU CAN MEASURE THE ENERGY -- >> WELL THAT'S ACTUALLY A VERY GOOD QUESTION. WE HAVE A PROXY AND THE PROXY IS A TREADMILL, MAXIMAL EXERCISE ON THE STUDY CAN BE A TUMOR MASS. OF COURSE THAT'S A VERY GOOD ONE BECAUSE THAT IS A PEAK TO EXERCISE YOU CAN MAINTAIN FOR ONE SECOND. THE IDEAL TEST WILL BE TO HAVE THE MAXIMUM ENERGY OF 24 HOURS. BUT LOTS OF PEOPLE THAT ARE WORKING ON THAT BUT STILL WE DON'T HAVE THAT TASK. >> SO WHICH OF THE EXERCISE MENTORS TELL YOU THAT YOU HAVE TO EXERCISE TO THE POINT OF PAIN. THAT MUSCLES REQUIRE INFLATION INFLATION -- INFLAMMATION FOR GROWTH TO BECOME STRONGER AND SO FORTH, IS THAT CORRECT. >> THAT'S TOTALLY INCORRECT. WE DO KNOW FROM EPIDEMIOLOGICAL STUDIES THAT EVEN WALKING FOR TEN MINUTES AROUND YOUR HOUSE COMPARED TO BEING A COUCH POTATO MAJOR A HUGE DIFFERENCE IN TERMS OF DISBAILITY I DISABILITY AND MORTALITY. SO IN FACT THE REDUCTION RISK OF JUST WATCHING TEN MINUTES BETWEEN NOT DOING NOTHING WALKING TEN MINUTES IS TEN TIMES HIGHER THAN THE INCREASE IN, THE IMPLEMENT YOU GET BY ACTUALLY RUNNING AN HOUR IN THE MORNING. YOU CAN STILL DO BETTER 2 IF YOU EXERCISE. YOU CAN RUN WHICH IS BETTER THAN WALKING TEN MINUTES. BUT THE DLIRCHLS I DIFFERENCE IS NOT AS LARGE AS THE SIMPLE GETTING OUT OF THE HOUSE AND WALKING. I THINK THIS IS AN IMPORTANT PUBLIC HEALTH MESSAGE. PEOPLE DON'T EXERCISE BECAUSE THEY'RE TOLD THEY NEED TO JOG. AND YOU KNOW IF I THINK ABOUT MY FATHER DIED IN 97 WAS SUCH A SMART PERSON AND HE'S ALWAYS TELLING ME HE HAS TO JOG IN THE MORNING. IT COULDN'T BE THERE BUT WHEN I ASKED HIM TO WALK TEN MINUTES AROUND THE HOUSE IT WAS ALWAYS DOING THAT. >> THAT'S SOME WHAT RIMNES REMINISCENT OF WINSTON CHURCHILL SAYING THE ONLY EXERCISE HE GOT WAS BEING A PALLBEARER FOR HIS FRIENDS. IF I COULD PURSUE IT FURTHER. THE ARGUMENT IF YOU EXERCISE A MUSCLE AND YOU REALLY DO IT TO THE POINT WHERE THERE IS SOME SMALL MYO FIBRIL DAMAGE AND WHATNOT. AND INFLAMMATION AND THEN THE ARGUMENT SAYS THAT AS A RESPONSE TO THAT ALL KINDS OF GROWTH FACTORS GET INCREASED AND THE MUSCLE GETS LONGER AND STRONGER. NOW IS THAT BAD PHYSIOLOGY. >> NO, NO, IT'S NOT BAD PHYSIOLOGY, IT'S ABSOLUTELY CORRECT. IN FACT YOU'RE NOT REALLY COUNT ACTING AGING. EVEN IN THE PEOPLE THAT EXERCISE FIVE TIMES A DAY, FIVE HOURS PER DAY, YOU SEE THAT THE -- IS HIGHER. BUT THE RATE OF DECLINE WITH AGING IN MUSCLE MASS AND MUSCLE STRENGTH IS EXACTLY THE SAME. SO WHAT YOU'RE DOING IS THAT YOU'RE CREATING LARGER RESERVES SO YOU DON'T CROSS THE THRESHOLD VIS-A-VIS MUCH LATER IN LIFE. SO IT'S A GOOD THING TO DO. I'M NOT SAYING THAT IS NOT A GOOD THING TO DO. BUT YOU KNOW, TO ME IT IS A TOLERANT FOR PEOPLE TO SAY WELL I CAN'T DO THAT. SO THE RESULT IS THAT THEY DO NOTHING. AND THAT'S WHERE IT'S REALLY WORRISOME BECAUSE THE EVIDENCE FOR THE GOOD EFFECT OF EXERCISE IS VERY VERY STRONG BUT STILL THE ONLY 10% OF THE PEOPLE OVER THE AGE OF 65 IN THIS COUNTRY, THEY DO ANY TYPE OF EXERCISE EVEN WALKING FOR EXERCISE. >> DANIELLE. -- DANIEL. >> GIVEN THE EVIDENCE OF THE BENEFITS OF WALKING, IF THERE HAS BEEN A STUDY OF THE LONG TERM EFFECTS OF WALKING CERTAIN DISTANCE VERSUS THOSE WHO ARE RUNNING. THEN THAT SORT OF TAKES INTO ACCOUNT LIKE JOINT OR BACK PAIN RUNNING ON HARD SURFACES AND SO FORTH. SO NOT MUST THE BENEFITS BUT -- >> WELL YOU KNOW, I DON'T THINK. YOU KNOW THE LIFE STUDY IS THE TRIAL THAT LOOKS AT THE EFFECT OF EXERCISE NOT WALKING ON THE DISABILITY AND MORTALITY. I DON'T THINK THE EFFECT OF WALKING AND THE EFFECT RUNNING I DON'T KNOW. I CAN TELL YOU LOOKING AT THE PHYSIOLOGICAL STUDIES, YOU KNOW, NO, SIR ARE ACTIVE AND CERTAINLY DO BETTER. THE DISTANCE WITH THOSE WHO WALKER HALF AN HOUR PER DAY IS SO MINIMAL THAT I ALWAYS WONDERED WHETHER THERE'S A RISK AND BENEFIT IS REALLY THERE OR NOT. I DON'T WANT TO FEEL ALL THE TIME FOR MY FRIENDS. I WANT TO LISTEN TO HIM. >> I JUST WANTED TO ASK YOU IF YOU COULD GO BACK TO THE IDEA THAT YOU MENTIONED REGARDING YOUNG CHILDREN THAT UNDERGO PROTEIN SYNTHESIS DURING SLEEP. OWE IF I GATHER IT'S A HYPER TERMIC REACTION AND THAT'S WHY THEIR BODY'S HOT. >> THEY NEED TO -- FIRST OF ALL -- >> -- LATER ON IN LIFE -- >> LET'S PUT THAT. IF YOU LOOK AT CHANGE OVER THE LAST SPAN, THE METABOLIC RATE IS MAXIMUM AT THE DAY ONE BECAUSE THEY'RE BUILDING. AND YOU KNOW WHEN THEY'RE BUILDING PROTEINS, THE ENERGY THEY REQUIRE TO DO JUST NOTHING BUT GROWING IS HUGE. SO YOU SEE THE MET BALL H METABOLIC RATE I S AT STAGE ONE. THEY GROW PROGRESSIVELY AFTER THE AGE OF 18 REMAIN STABLE FROM 18 TO 25. AND THEN SLOWLY DECLINE WITH PAGE, SLOWLY. PART OF THIS DECLINE IS DUE TO THE CHANGE IN BODY COMPOSITION SO THAT THE FAT MASS CONSUME LESS ENERGY THAN THE MUSCLE MASS. SO BECAUSE YOU'RE DECLINING IN MUSCLE MASS, YOU NEED LESS ENERGY. BUT NOT ALL OF THIS IS EXPLAINED BY THAT. WHAT IS INTERESTING, THE PEOPLE WERE SICK AND OLD GAUGE DO NOT DECLINE. SO THE DECLINE OF METABOLIC RATE IS A GOOD THING. YOU DO NOT DECLINE BECAUSE SOMEBODY'S STUCK IN THAT ENERGY TO DO SOMETHING ELSE. AND THERE'S SOMETHING PHYSIOLOGICALLY WRONG IN YOUR BODY. SO IT DOESN'T STAY THERE. IT'S THERE FOR PHYSIOLOGICAL PURPOSE. I DON'T KNOW THAT. IN OLDER INDIVIDUALS I DON'T KNOW IF IT'S TRUE. IN CHILDREN I KNOW THAT THERE IS A CYCLE AND THEY NEED TO DISBURSE THAT ENERGY BECAUSE THE PROTEIN ZIP THUSE SYNTHESIS IS A REACTION AND THAT'S WHY THEY NEED TO PROTECT THAT ENERGY. >> IT'S KNOWN THAT LIFE SPAN IS CACALORIE RESTRICTION. IT'S NOT THAT YOU HAVE LESS ENERGY IN THAT ENERGY BOX. >> DOESN'T REALLY. FIRST OF ALL, YOU KNOW, THE THINKING IS THAT PEOPLE THAT -- WELL LET'S GO BACK TO ANIMALS. PEOPLE ES MUCH MORE COMPLICATED. BUT IN ANIMALS, ONE OF THE THINGS YOU SEE IS MITOCHONDRIAL BIOGENESIS. YOU'LL SEE THEIR MITOCHONDRIA, THE MACHINE THAT ACTUALLY SYNTHESIZED ENERGY FROM THE FIELD INCREASE IN NUMBER AND IN QUALITY. SO RESTRICTION GIVES YOU FUEL BUT NOT ALL THE FUEL YOU GET IN YOUR BODY GETS USED AS ENERGY. MUSCLE GOES IN THE BELLY, GROWS IN THE FAT. SO AS LONG AS YOU HAVE ENOUGH ENERGY THAT MATCH YOUR ENERGY CONSUMPTION, YOU'RE NOT PRODUCING THE ENERGY DUE TO THE BODY. AND IN FACT THE EFFICIENCY OF USING THAT ENERGY MAY ACTUALLY BE BETTER. IT IS CERTAINLY TRUE. IN HUMANS THERE IS A STUDY, IT IS ALL OVER THE PLACE SO WE DON'T REALLY KNOW WHERE IT STARTED IN MIDDLE AGE IN HUMANS IS REALLY A GOOD THING FOR NOW. >> OKAY. THERE WILL BE TIME FOR MORE QUESTIONS. TOREN, WOULD YOU KERR CARRY ON. >> THE GOOD THING ABOUT THESE, I MUST SAY, I'VE ONLY BEEN WORKING FOR THE AGENCY 10 OR 15 YEARS BUT YOU GO TO MATTERS AND THE QUESTION CAME UP HERE SHOULD I DO THIS OR THAT. IT'S ALWAYS INTERESTING AND GOING TO THE IDEA OF HEALTHY LIVING. THE PERSON RECORDED THE LONGEST IS THIS WOMAN WHO LIVED TO 121. THIS IS REALLY SORT OF MORBID. BUT IF YOU HAVE A NICE APARTMENT, PEOPLE, WHILE YOU'RE ALIVE, PEOPLE CAN PAY YOU A LITTLE BIT OF MONEY WITH THE IDEA THAT WHEN YOU DIE. TWO PEOPLE DID THIS FOR HER. SHE OUTLIVED THESE TWO PEOPLE WHO GAVE HER MONTHLY MONEYS TO GET HER APARTMENT. AND THEY ALL LIVED A LONG LIFE BUT NOT AS LONG AS SHE DOES. ANYWAY SHE SMOKE AND DRANK UP UNTIL AGE 119. AT THE AGE OF 119 SHE WAS PRESSURED TO STOP SMOKING AND SHE PROMPTLY DIED TWO YEARS LATER. MY ADVICE IS IF YOU SMOKE AND DRINK AND YOU'RE 119, KEEP ON DOING IT. [LAUGHTER] SO I'M GOING TO TALK A LITTLE BIT ABOUT POTENTIA MOLECULAR MECHANISMS THAT MIGHT UNDERLIE AGING. I THINK IT MICELY SYNERGIZES WITH LUIGI TALK. THIS WILL GIVE YOU AN INTRODUCTION TO THE FIELD. I'LL GIVE YOU AN INDICATION SOME OF THE THING WE'RE DOING THAT RELATE TO THESE SORT OF GENERAL THEMES. HOPE THREE YOU COME AWAY WITH REALLY THE EXCITEMENT IN THE FIELD THAT SOMETHING AS COMPLEX AS AGING, IT SORT OF DEFIES SORT OF A REDUCTIONIST APPROACH. IT'S SORT OF FINALLY YIELDING TO SORT OF MOLECULAR TECHNIQUES TO TRY TO UNDER THESE BASIC MECHANISMS. >> I'M GOING TO START BY EMPHASIZING THE POINT LUIGI BROUGHT UP, THE INTIMATE RELATIONSHIP BETWEEN AGING AND THE DISEASE OF AGING. THIS IS THE U.S. POPULATION OF THE INCIDENT OF DISEASE, NEWER DEGENERATIVE DISEASE LIKE ALZHEIMER'S OR CARDIOVASCULAR DISEASE LIKE HEART ATTACK OR THE RATES OF CANCER. THERE IS A SORT OF UNIFORM RELATIONSHIP BETWEEN THE AGE OF THE INDIVIDUAL AND THE INCIDENCE OF THE GIVEN DISEASE. THIS EXPONENTIAL INCREASE. FOR INSTANCE FOR CANCER IF YOU'RE OVER THE AGE OF 65, THE RATE OF CANCER IS TENFOLD HIGHER THAN IF YOU'RE UNDER THE AGE OF 65. SO IT DWARF AN DWARFS ANY OTHER RISK FARKS. SAME THING FOR CARDIAC DISEASE. WE TALK ABOUT HYPE HYPERTENSION AND SMOKING AND DIABETES. THEY'RE ALL IMPORTANT BUT AGAIN ABLE IS THE MAJOR RISK FACTOR. OBVIOUSLY THE REASON THAT WE DON'T TANK ABOUT IT A TALK BIT AS MUCH. YOU CAN TELL THE PERSON TO STOP SMOKING OR GIVE THEM BLOOD TO TREAT THEIR BLOOD PRESSURE BUT TELL THEM AS THEY'RE AGING THEY'RE IRAQING THEI AGE, THEY'RE IRAQING -- RUINING THEIR LIVES. IT'S HARD TO UNDERSTAND WHY IT'S SO IMPORTANT TO UNDERSTAND THE MOLECULAR MECHANISMS OF AGING. SO WE CAN'T AGAIN DO THESE IN PEOPLE BUT LET'S SAY YOU HAVE A MOUSE THAT HAS A SINGLE GENE MUTATION AND GENE EXIT CAUSE THE DISEASE. IT REALLY DOESN'T MATTER WHAT THE DISEASE IS. IT PRE DISPOSES IT TO ATHEROSCLEROSIS OR A SINGLE DISEASE WHERE A SINGLE MUTATION WOULD INCREASE RISK. IT'S IDENTICAL AND CARRIES THAT DISEASE EYE LEGAL BUT ALSO HAS ANOTHER MUTATION AND ANOTHER SINGLE GENE WIDE THAT EXTENDS LIFE. NONE OF THIS HAS REALLY BEEN TESTED BUT THE SIMPLE PREDICTION WOULD BE THAT THE INCIDENTS OF DISEASE IN STRAIN A WOULD BE HERE AND THE INCIDENCE OF THAT SAME DISEASE IN STRAIN B WOULD BE SHIFTED TO THE RIGHT, RIGHT. AGAIN, IT'S NOT EVER BEEN TESTED TO BE TRUE. INTUITIVELY YOU THINK THAT'S ONE THING THAT IS IN FACT TRUE. SO AGAIN EVERYBODY IS STUDYING DISEASE, COMING UP WITH THERAPIES TARGETING THE ACTIVITY AND FUNCTION OF GENE X AND THAT'S A VERY VALUABLE AND REASONABLE APPROACH. I WOULD JUST ARGUE IF YOU'RE THE PERSON WHO CARRIES DISEASE GENE X IS JUST AS HAPPY IF SOMEBODY COMES UP WITH A THERAPY THAT MIMIC THE EFFECT OF GENE Y AS LONG AS YOU GET SHIFTED TO THE RIGHT HERE, YOU DON'T REALLY CARE, RIGHT. AS LONG AS YOU CAN LIVE A HEALTHY LIFE WITH OR WITHOUT YOUR MUTATION. SO THE FACT IS IF YOU CAN UNDERSTAND THE MOLECULAR BASIS OF AGING, A LOT OF THOUGH DISEASES ON THAT FIRST SLIDE, ALZHEIMER'S, CANCER, NEURODEGENERATION, CARDIOVASCULAR DISEASE ALL GET SHIFTED TO THE RIGHT. NOT KNOWING ANYTHING ABOUT DISEASE GENES X OR I WON'T USE Y. X OR Z JUST BY TARGETING GENE Y AND EXTENDING THE SCALE. SLOWING DOWN THE SCALE THAT WE AGE SLOWS DOWN PRESUMABLY AGAIN NEVER BEEN TESTED. BUT PRESUMABLY SLOWS DOWN THE INCIDENT OF DISEASE AND IS INDEPENDENT OF SPECIFIC DISEASE. SO THE QUESTION IS WE RECOGNIZE WHAT AGING IS AND LUIGI HAS FINALLY PHENOTYPED IT BUT YOU CAN LOOK AT AS I SAY IT DOESN'T TAKE EINSTEIN TO LOOK AT THIS AND SAY THAT'S WHAT AGING IS AND LOOKS LIKE. THE QUESTION IS WHY DOES IT HAPPEN. THE REAL CONCEPTION ADVANCE IN THE FIELD FOR ME WAS GOING BACK AND REDUCING THE PROBLEM AND USING SIMPLE ORGANISMS TO TRY TO UNRAVEL THESE MECHANISMS. SO THE ORGANISM SUCH AS WORMS AND YEAST HAVE REALLY PROVIDED A BLUE PRINT THAT BEGINS TO ADDRESS I THINK A VERY COMPLEX PROBLEM LIKE AGING AND REDUCE IT TO SIMPLE, OH WELL, PRESUMABLY SINGLE GENES OR PATHWAYS TO STIMULATE LIFE SPAN. CYNTHIA -- AND A FEW OTHERS HAVE IDENTIFIED USING THIS HAVE IDENTIFIED SINGLE GENES THE RATE AN ORGANISM LIVES. AND THOSE MUTATIONS CAN SHIFT EITHER WHAT WOULD KNOW AS THE MEDIAN LIFE SPAN, THE POINT AT WHICH 50% OF THE COHORT DIED. AND AT THE SAME TIME ALSO SHIFT THE MAXIMUM LIFE SPAN. THAT IS THE TOTAL MAXIMUM LIFE THAT THE ORGANISM CAN LIFE. THAT'S NOT TO BE EVEN THOUGH LIFE SPAN HAS INCREASED OVER THE LAST SEVERAL CENTURIES, IT'S NOT BY IMPROVING PUBLIC HEALTH OR COMING DOWN WITH INFECT SHUTTLE DISEASE, ONE IS AFFECTING THIS MEDIAN LIFE SPAN. BUT THIS MAXIMUM LIFE SPAN IS THOUGHT TO BE A BIOLOGICAL DERLANT AND PROBABLY -- DETERMINANT AND PROBABLY ON THE ORDER OF 120 YEARS BASED ON THE FACT THAT NO ONE HAS EVER REALLY LIVED BEYOND THAT. OKAY. WHAT REGULATES THOSE PROCESSES. SIMPLE ORGANISMS, I'M A FEUJ FAN OF IT ALTHOUGH WE DON'T WORK IN THAT FIELD BUT I THINK IT REALLY HAS REVOLUTIONIZED HOW WE THINK ABOUT AGING. THERE ARE A NUMBER OF CAVEATS YOU HAVE TO THINK ABOUT AND INCORPORATE WHEN YOU START USING THOSE ORGANISMS. THIS IS AGING. WHEN PEOPLE TALK ABOUT THEY'RE STUDYING AGING AND YEAST WHAT THEY ACTUALLY ARE YOU DOING SO YOU MIGHT UNDERSTAND WHATEVER THEY GET OUT ALTHOUGH IMPORTANT AND INTERESTING YOU HAVE TO MAKE A LOT OF ASSUMPTIONS TO SAY THAT APPLIES TO US AS MORE COMPLEX ORGAN SMSZ LIKORGANISMS. PEOPLE TALK ABOUT LIFE SPAN HAVE A FLASH OF YEAST THAT WILL KEEP THEM THERE AND THEY'LL OCCASIONALLY TAKE OUT A YEAST AND ASK CAN THAT YEAST STILL GROW. CAN IT GO THROUGH THE CELL CYCLE. AND THEY WAIT AND WITH TIME EVENTUALLY THEY'LL TAKE OUT YEAST FROM THAT CULTURE AND IT NO LONGER CAN ENTER THE CELL CYCLE. THIS PERIOD OF TIME IS CALLED CHRONOLOGICAL AGING, OKAY. THE MOST POPULAR ALLEGE SA ASSAY THAT GIVES RISE FOR A SINGLE BUD. YOU PICK OFF THAT BUD THAT MOTHER CAN THEN GROW AND GIVE RISE TO ANOTHER BUD AND IT CAN KEEP ON DOING THIS FOR SUCCESS FIFTH GENERATIONS. EVENTUALLY THE MOTHER GOES EVENTUALLY IT CAN GIVE OFF THE BUD. SO THE NUMBER OF BUDS IT GIVES UP IS CALLED ITS REPLICATIVE LIFE SPAN. 30OR ON 40 TIMES IT CAN DO THAT. SO THAT'S REPLICATE OF CHRONOLOGICAL AGING. VERY DIFFERENT FROM WHAT WE WOULD CONSIDER AGING IN HUMANS. MUCH MORE COMPLEX. SAME THING IN WORMS. AN ADULT WORM, THERE IS NO CELL DIVISION. THERE'S A THOUSAND CELLS ONCE THE ANIMAL MUCHESZ. MUCHESZ -- MATURES. THERE'S NO CELL TENOR OVER. AS IMPORTANT AS THEY DISCOVERIES ARE, IT IS A HUGE LEAP BETWEEN AGING AND IN THIS CONTEXT AND AGING FOR US. SO THAT'S JUST A CAVEAT. OBVIOUSLY GETTING BIGGER AND FASTER AS WE AGE IS SOMETHING THAT WE ALL DO BUT WE DON'T GIVE IT IN THE CONTEXT OF GIVING OFF BUDS I WOULD SAY. OKAY. SO WITH THAT SAID GENETICS ARE NOT EVERYTHING AND AS HAS BEEN MENTIONED IT'S KNOWN FOR A LONG TIME ENVIRONMENTAL INFLUENCES CAN AFFECT LIFE SPANS AND THE MOST ROBUST ENVIRONMENTAL INFLUENCE AT LEAST SIMPLE ORGAN SUBPOENAS IS THE IDEA OF COLLOIDAL RESTRICTION. IF YOU LOWER THE AMOUNT OF FOOD THE ANIMAL IS ALLOWED TO EAT DOWN TO, AND THE EFFECTS ARE INCREASING AS THE FOOD IS REDUCED DOWN TO ABOUT 40% OF WHAT THE ANIMAL WOULD EAT NORMALLY. IF YOU RULES IT TO ABOUT 60% OF THAT, THAT IS A 40% REDUCTION, THAT'S ABOUT THE AMOUNT THAT THE ANIMALS NEED TO SUSTAIN LIFE ACTIVITY. AT THAT RATE, THERE'S A ROBUST INCREASE IN LIFE SPAN FOR ALMOST ALL ORGAN SMGZ ORGANISMS, FROM YEAST TO MA'AMAMMALS LIKE MICE AND YEAST. LUIGI MENTIONED THE AFFECTS IN MAN IS NOT AS CLEAR BUT THERE ARE SOME EXPERIMENTS NOW. THERE ARE LONG EXPEAMENTS AND THIS IS ACTUALLY AN EXPERIMENT THAT -- IS A SIGNIFICANT DECREASE PARTICULARLY IN PRIMATES IT LOOKS LIKE IN METABOLIC DISEASE AND CARDIOVASCULAR DISEASE BUT ALSO IN CANCERS AS WELL. OKAY. SO THAT LED THESE TWO CONCEPTS MERGED AND SO PEOPLE BEGAN TO ASK COULD WE IDENTIFY IN SIMPLE ORGANISMS THOSE GENETIC PATHWAYS THAT REGULATE THE EFFECTS, THE LIFE EXTENDING EFFECTS OF RESEARCHES. THE FIRST I THINK EXAMPLE CAME OUT OF LENGTHY' LENNY'S LAB. AGAIN THEY USED THAT ASSAY OF REPLICA OF LIFE SPAN LOOKING AT THE NUMBER OF BUDS THAT THE YEAST COULD PRODUCE AND HOW MANY GENERATIONS IT COULD DO IT. AND THEY TOOK WILD TYPE MICE AND THEY GREW THEM EITHER IN 2% GLUCOSE OR IN .5% GLUCOSE. AGAIN SO THAT'S THEIR MODEL. BEGIN. AGAIN THERE ARE MANY STEPS HERE. DIFFERENT FORM OF LIFE SPAN, DIFFERENT FORM OF WHAT WE COULD CONSIDER CHLORIC RESTRICTION FOR PEOPLE. UNDER THOSE CONDITIONS, WILD TYPE MICE ARE GROWN IN 2% VERSUS 5% AT A SIJT INCREAS -- SO LOWER GLUCOSE L ED TO LONGER LIFE SPAN. THEY LOOKED AT DELETION MUTANTS OF YEAST THAT COULD NO LONGER SUSTAIN THIS EFFECT. THAT IS THE LOWERING OF GLUCOSE NO LONGER PROVIDED LIFE SPAN EXTENSION. AND THEY ISOLATED A SINGLE GENETIC MUTATION IN A GENE CALLECALLED SERT 2 AND AGGRAVATED THE RESPONSE. THE IDEA THESE SERT 2 WHICH BELONGS TO THIS FAMILY OF PROTEINS WHICH I'LL TALK ABOUT BRIEFLY CALLED 8 SERT 2IANS. IF YOU DID A CONGRESS EXPERIMENT THAT IS NOT OVER SERT 2 IN YEAST OR IN WORMS, THEY SHOWED THEY COULD HAVE LONGER LIFE SPAN TO THESE ORGAN SMSZ. SO AGAIN OVEREXPRESSION OF A SINGLE GENE PRODUCEING A SINGLE INCREASE IN LIFE SMAWN. LIFE -- SPAN. WHAT ARE SERT 2 YUNTZIANS AS ENZYMES THAT ADD AS DEACETYLASE. YOU HAVE A SUBFRAT THAT HAS AN ACETYL GROUP ON IT AND YEAST TWO WHICH HAS THE FORM OR SERT S2 WHICH DEAWE SETTLE ACE THESE PROTEINS. BUT THEY DO SO IN A VERY UNUSUAL WAY FOR DEAWACETYLASES AND THAT IS THEY REQUIRE AS A COFACTOR, THE ENERGETIC INTERMEDIATE NAD. THEY'RE KNOWN AS NAD DEPENDENT DEACETYLASES. SO THE SUBSTRATE FOR SERT 2 DEAWE SETTLATION INCLUDES HISTONE BUT ALSO A VARIETY OF OTHER PROTEINS THAT HAVE BEEN IDEA WHERE MANY LABS. WE CAN RECOGNIZE THIS BY USING AN AMOUNT BY FOR INTERNAL AWE SETTLE LYSINE ROODZ DUES THAT'S SHOWN HERE. IF WE ADD TO THAT REACTION NOTHING HAPPENS BUT THE PROTEIN ITSELF. -- HAS THE CATALYTIC ACTIVITY. AGAIN THESE ARE INDEPENDENT DEAWDEACETYLASES AND THIS CONNECTION WHICH IS AN ENERGETIC METABOLITE AND THE -- WHICH APPEAR TO REGULATE LIFE SPAN LED TO THESE VERY VERY, WELL INTERESTING OR SOMETIMES EMOTIONAL ARGUMENTS ABOUT HOW CERTAIN 2IANS MIGHT AFFECT LIFE SPANS. SO THIS IS JUST WHAT I WROTE FOR ONE SUCH THING A FEW YEARS BACK. AND THE ARGUMENT HAS BEEN THAT CHLORIC RESTRICTION ALTERS MA TAB INDIANAPOLISAL AND THAT -- METABOLISM AND THAT LEADS TO A RATIO WHETHER THIS HAPPEN OR NOT. THIS ACTIVATES THE CERTAIN 2 WHICH LEADS THE LIFE SPAN EXTENSION. SO SOMEHOW CONNECTING IN A SORT OF LINEAR FASHION THIS IDEA THAT NUTRIENT AVAILABILITY LEADS TO ALTERATIONS IN METABOLITE CONCENTRATIONS LIKE NAD THAT PROTEIN SYNTHESIS, THEY ACT ON A VARIETY OF SUBSTRATES THAT'S SOMEHOW REGULATE LIFE SPAN. OBVIOUSLY THIS IS NOT A VERY EASY STRATEGY TO ADOPT FOR LIVING LONG. SO PEOPLE SAY WELL IF THIS IS THE FINAL END RESULT, WE CAN GENERATE COMPOUNDS THAT MIGHT DO THIS DIRECTLY. SO DAVID SINCLAIRE AND OTHERS HAVE TRIED TO LOOK FOR ACTIVATORS OF SERT 2IAN AND THEY ARGUE INITIALLY THE COMPOUNDS LIKE RESVERATROL OR NATURALLY OCCURRING -- ONE COULD THEN CIRCUMVENT THIS SORT OF TEDIOUS NOTION OF CHLORIC RESTRICTION AND JUMP RIGHT HERE TO POLY FEAL AND IT'S HIGHLY ENRICHED IN RED WINE SO SOME PEOPLE THINK THAT'S A STRATEGY FOR LIVING LONGER WHICH I CAN'T DISAGREE WHY. AND THIS HAS NO BASIS IN FACT BUT PROBABLY HAVE SOME PEOPLE VERY WEALTHY. SO THE CERTAIN 2IAN IN YEAST IN MAMMALS THAT WE'VE BEEN INTERESTED ARE A LITTLE BIT MORE COMPLICATED THAN IN LOWER ORGANIZE SMSZ. THERE ARE SEVEN OF THESE MOLECULES THAT ARE CALLED SIRT1-7. SO SIRS1 ARE IN THE CREAS. THERE ARE SOME IN MITOCHONDRIA AND THERE'S ONE WHICH IS NOT, IT LOOKS LIKE IT'S BOTH CYTOPLASMIC AND NUCLEAR. AND SO A VARIETY OF WHAT ABOUT TREES HAVE BEEN INTERESTED IN TRYING TO UNDERSTAND WHETHER OR NOT THOSE SURTUNES APPEAR TO REGULATE LIFE SPANS IN MAMMALS AND THE LONG OR SHORT ANSWER TO THAT IS IT'S NOT CLEAR BUT THESE NO REAL CONVINCING EVIDENCE THAT THEY DO. SIR TOOSO A VARIETY OF GROUPS HAVE MADE MOUSE MODELS WHERE THESE INDIVIDUAL SURTUNES ARE HAVE MADE A NUMBER OF THESE MICE -- SIRTUINS. THE DELETION OF THESE VARIOUS SURTOONTSIR TOONTZ. SO NEITHER DELETION APPEAR TO HAVE A SIGNIFICANT LIFE EXTENDING EFFECT ALTHOUGH THERE ARE THINGS THAT WORK SO THAT MAY HAVE TO BE REVISED. SO THE ROLE OF SURTOONTZ THE BEST STUDY IS SIRT1 WHICH IS CLOSEST. IT HAS PROFOUND ROLES OF METABOLISM IN A VARIETY OF COMPARTMENTS IT'S PROBABLY BEST STUDY IN THE LIFER WHERE IT APPEARS TO REGULATE, BE INVOLVED IN -- BUT ALSO REGULAR LADLE THIS ISIOTHISINSULIN SECRETION AND OTHER SPECIFIC PROCESS. WE'VE ALSO BEEN INTERESTED AND SHOWN, TO GET BACK TO THIS IDEA OF MITOCHONDRIAL FUNCTION THAT MARIJUANA MENTIONED, SIRT1 REGULATES THE FUNCTION OF THIS TRANSCRIPTION REGULATOR WHICH IS INVOLVED IN SYNTHESIS OF NEW MITOCHONDRIA. WE'VE ALSO BEEN ABLE TO SHOW SIRT1 REGULAR LADLE THI REGULATES THIS OTH ER ONE. ONE POTENTIAL WAY SIRTUINS COULD BE INVOLVED IN LIFE SPAN WE THINK IS IN THE REGULATION OF MITOCHONDRIAL NUMBER AND FUNCTION. THAT IS IT COULD BE INVOLVED IN THE REGULATION OF PRODUCTION OF NEW MITOCHONDRIA AND REMOVAL OF DAMAGE MITOCHONDRIAL BUT THAT'S NOT BEEN ESTABLISHED IN VIVO YET. >> SO I WANT TO PUT SOME CAVEAT TO THE WORK ON SIRTUINS BECAUSE VERY REKRINLTL RECENTLY SEVERAL GROUPS AND ONE OF THEM PUBLISHING A STORY IN NATURE ARGUED THAT THE ORIGINATION BY THE LAB IS THAT SIRT2 WAS A LIFE SPAN IN YEAST. THEY CALLED INTO QUESTION THE MAGNITUDE OF THOSE EFFECTS AND SUGGESTED THE CORRECT CONTROLS WERE DONE THE ABILITY OF SIRT2 TO REGULATE LIFE SPAN WAS QUITE MODEST. SO THIS IS SOMEWHAT CONTROVERSIAL AT A TIME. IT'S STILL VERY CONTROVERSIAL AND VERETROL. SOME PEOPLE DON'T BELIEVE THEY ARE DIRECT OF SURTUNES BUT RATHER INDIRECT. IT'S UNCLEAR TO WHAT DEGREE SIRTUINS WHICH WAS PROBABLY ONE OF THE EARLY CANDIDATES AS AN IMPORTANT REGULATOR OF LIFE SPAN I THINK -- THERE ARE OTHER PATHWAYS THAT HAVE TAKEN THE SLACK IN TERMS OF WHETHER OR NOT THEY MAY BE IMPORTANT REGULATORS OF LIFE SPAN. SO ONE OF THEM, WE AND OTHERS ARE INTERESTED IF THIS PATHWAY MTOR. THIS IS A PATHWAY THAT HAS BEEN IMPLICATED IN REGULATING LIFE SPAN ABOVE LOWER ORGANISMS AND MAMMALS. AND TOR IS A KINASE THAT APPEARS TO BE DOWN STREAM OF NUTRIENTS AND GROWTH FACTORS AND A VARIETY OF PROCESSES THAT APPEAR TO AFFECT LIFE SPAN. AND THE GENERAL CONCLUSION FROM STUDIES IN BOTH LOWER ORGANISMS AND MAMMALS IS THAT LOWERING ACTIVITY IS ASSOCIATED WITH INCREASED LIFE SPAN AND INCREASING THE ACTIVITY IS ASSOCIATED WITH THE DECREASE IN LIFE SPAN. AND SO ONLY OF THAT EVIDENC SOME OF THAT E VIDENCE IS SHOWN HERE. THIS IS PROBABLY ONE OF THE EARLY DESCRIPTIONS SHOWING -- KNOCKING DOWN LED TO LIFE SPAN EXTENSION. AND AS I MENTION, MTOR IS A TARGET OF A SPECIFIC DRUG THAT WAS ISOLATED IN THE SOIL OF EASTER ISLAND AND THIS IS A VERY SPECIFIC INHIBITOR OF MTOR. AND THE REASON I BRING THAT UP IS BECAUSE VERY RECENTLY IN A VERY LARGE STUDY WITH REALLY HUNDREDS AND HUNDREDS OF MICE THAT WERE TREATED STARTING AT ROUGHLY MIDDLE AGE WITH EITHER CONTROL OR RAP MYOSIN THAT THERE WAS A SIGNIFICANT INCREASE IN MA MILLIAN LIFE SPAN IN THOSE MICE TREATED WITH RAP MYOSIN. PREDOMINANTLY IN MALES BUT MOTE IN FEMALES AND MALES RP MYOSIN GIVEN AT LATER AGE EXTANLDZ LYNCH SPAN. SO ACTIVITY IN MAMMALS CAN REGULATE LIFE SPAN. ACTUALLY WE'VE BEEN INTERESTED IN IT CREATING, I JUST WANT TO SHOW WAYS THIS CAN BE APPROACHED GENETICALLY. MY LAB HAS BEEN WORKING ON A MOUSE MODEL OF THIS GENERATED BY -- AT NYI ANCI BUT I WON'T GO THROUGH THE DETAILS. THE RESULTS OF MTOR IS LETHAL AND THIS IS BASICALLY A KNOCKING MOUSE THAT'S HYPO MORPHIC FOR MTOR AND IT LEADS TO A REDUCTION IN MTOR ACTIVITY TO ABOUT 30% OF WILD TYPE LEVELS WHICH IS ENOUGH TO PRODUCE A VIABLE OFFSPRING AS OPPOSED TO COMPLETE KNOCKOUT. SO THESE ARE ONGOING STUDIES THAT WE DON'T KNOW THE ANSWERS BUT AT LEAST AT TWO YEARS OF AGE, IT LOOKS LIKE THERE'S GOING TO BE A SIGNIFICANT INCREASE IN LIFE SPAN IN THOSE MICE WHICH HAVE GENETIC REDUCTION IN MTOR ACTIVITY IN THIS MOUSE CONSTRUCT. WE HAVE MICE THAT ARE SIGNIFICANTLY OLDER THAN WE'VE EVER SEEN CONTROLS GO WITH THE REDUCTION OF MTOR ACTIVITY. SO THIS LEADS TO A NUMBER OF WE THINK INTERESTING POSSIBILITIES BUT MOST IMPORTANT WHICH IS HOW DOES MTOR REGULATE LIFE SPAN IF IT IN FACT REGULATES AS IT APPEARS TO EITHER PHARMACOLOGICAL IN MTOR OR GENETIC INTERRUPTION OF MTOR ACTIVITY LEADS TO AN INCREASE IN LIFE SPAN. ONE OF THE AFFECTORS OF MTOR IS IMPORTANT FOR LIFE SPAN, TENSION. AND I REMEMBER POSSIBILITIES BECAUSE MTOR FAUST FORELAC FAUST PHOSPHORY LATES. ONE OF THE -- MTOR IS KAI IS THEY ALSO LIVE LONGER. THIS PATHWAY IS SOMETHING LUIGI SPOKE TO. THE PROTEIN SYNTHESIS AT LEAST. IF YOU RULES THAT A LITTL REDUCE THAT A LI TTLE BIT IN MICE THEY LIVE A LITTLE LONGER. THIS IS SOMETHING THAT MTOR REGULATES TOO WHICH IS THIS REMOVAL OF DAMAGED ORGANELLES AND PROTEINS. IT IS AN IMPORTANT REGULATOR OF THIS PATHWAY. INHIBITING TOR ACTIVATES -- AND ONE CAN IMAGINE IF ONE INCREASES THE FLUX THAT IS IF YOU GET RID OF DAMAGED ORGANELLES AND PROTEINS THAT MIGHT MAKE YOU LIVE LONGER OR LIVE HEALTHIER. SO ALL OF THESE ARE IMPORTANT POTENTIAL WAYS MTOR COULD REGULATE LIFE SPAN AND IT COULD BE VERY IMPORTANT THAT ONE COULD ESTABLISH MODELS WHERE TOR ACTIVITY IS REDUCED TO SEE WHICH OF THESE DOWN STREAM EFFECTORS ARE IMPORTANT FOR LIFE SPAN REGULATION. THE OTHER THING THAT'S REALLY COOL THAT COULD BE DONE IN THESE GENETIC MODELS IS THE QUESTION IS BECAUSE OF THE WAY THIS MODEL WALT OWAS MADE, WE CAN RESTORE ACTIVE KNEE TISSUE SPECIFIC FASHION. IN THE CURRENT MODEL MTOR IS REDUCED IN ALL TISSUE THROUGHOUT THE BODY. BUT WITH RECALL BENESS WE CAN PUT IT BOOK. WHERE DOES TOR REGULATE SPECIFIC SPAN. WHAT TISSUE IS REQUIRED FOR LIFE SPAN EXTENSION. I DON'T KNOW IF PEOPLE WANT TO TAKE A GUESS. WE DON'T KNOW THE ANSWER BUT DO YOU NEED TO REDUCE TOR IN THE BRAIN, DO YOU NEED TO RULES IT IN THE FAT, DO YOU NEED IT IN THE MUSCLE. WHERE OR DO YOU NEED IT EVERYWHERE TO GET THE LIFE SPAN EXTENSION. AND THAT'S SOMETHING YOU CAN'T DO FARM COLLAGEALLY BUT I THINK GENETICALLY ONE CAN DO THAT. FOR ME IT SEEMS LIKE, IT'S A VERY LONG EXPERIMENT UNFORTUNATELY IT TAKES THREE YEARS TO DO ALL THESE THING. BUT I THINK IT'S SORT OF INTERESTING TO SAY WHERE, WHAT BODY PART IS NECESSARY FOR THAT, THIS REDUCTION IN ACTIVITY. I THINK THAT MIGHT GIVE US A CLUE AS TO WHAT'S IMPORTANT. IT'S FUNNY BECAUSE I DON'T KNOW IF THEY WANT ME TO TELL YOU THIS. THE MIC MT ON R MICE ARE NORMAL BUT THEY'RE SMALLER THAN THE WILD TYPE. WE ACTUALLY HAVE MADE. WE RESTORED TOR BACK IN FAT ALONE AND THE MICE, EVEN THOUGH TOR IS NOW RULES THE IN EVERY TISSUE EXCEPT FAT, SIMPLY RESTORING TOR TO WILD TYPE LEVELS IN FAT PRODUCES A NORMAL SIZE MICE NOW. SO THAT SUGGESTS THAT TOR THE LEVEL OF TOR ACTIVITY IN THE FAT SENDS SOME SIGNAL TO THE BODY TO SAY WHETHER OR NOT THE REST OF THE BODY SHOULD GROW OR NOT WHICH IS SORT OF INTERESTING BECAUSE IT SORT OF MAKES SENSE IF YOU HAVE FAT BASICALLY. IF YOU DON'T HAVE ANY FAT YOU PROBABLY SHOULDN'T GET BIGGER. IF YOU HAVE FAT, THE BODY MUST BE SAYING OKAY THE REST OF YOU CAN GROW NOW. AND THERE MUST BE SOMETHING THAT FAT IS RELEASING THAT TELLS THE BODY TO DO THAT. AND SO WE'RE VERY INTERESTED IN THAT. AND I DON'T KNOW, MAYBE THAT'S THE SAME SIGNAL THAT TELLS THE BODY TO GROW ALSO TELLS THE BODY HOW TO LIVE. SO I THINK FAT'S A GOOD CHOICE. I THINK THE BRAIN'S A GOOD CHOICE, I'LL LET YOU KNOW IN THREE YEARS. IN THE MEANTIME DON'T EAT THAT MUCH. [LAUGHTER] LET ME SKIP OVER ALL THIS BECAUSE, SO THIS IS THIS IDEA OF CELLULAR SENESCENCE AS A WAY OF TRYING TO UNDERSTAND ABLING MECHANISMS. I WON'T GO THROUGH IT BECAUSE TIME IS WHAT IT. THAT'S A SHAME. IT'S LIKE YOUR LIFE FLASHING BEFORE YOU. SO LET ME JUST END WITH THIS IDEA. IS THIS A UNIFORM THEORY. SO WE'VE GOTTEN VARIOUS GENETIC PATHWAYS, THE MTOR. IT'S ALL PROGRESS THAT WE NOW HAVE SORT OF TARGETS WE CAN GO AFTER AND POTENTIAL DOWN STREAM EFFECTORS THAT MAY REGULATE LIFE SPAN BUT IT'S A LITTLE UNSETTLING BECAUSE THE QUESTION IS WHY ARE WE AGING. WHAT IS THE SORT OF UNIFIED MECHANISM. I MEAN IF SIRTUINS CONTRIBUTES SOMETHING, IF TOR CONTRIBUTES SOMETHING THERE MUST BE SOME SORT OF UNIFIED MECHANISM BOY WHICH WE AGE. IN A WAY AGING IS SO STEREOTYPICAL. IT DOESN'T SEEM A RANDOM THING. SO ONE SORT OF UNIFIED THEORY THAT'S THE OLDEST OUT THERE IS THE FREE RADICAL THEORY OF AGING. IT WAS PROPOSED BOY THIS GENTLEMAN, THIS IS A PICTURE OF HIM WHEN HE WAS 27. NO. [LAUGHTER] HE'S ACTUALLY LIKE IN HIS LATE 890'S NOW. HE PROPOSED THIS THEORY IN 1956. HE WAS LIKE IN THE MANHATTAN PROJECT INTERESTED IN RADIATION BIOLOGY. AND HE LIKED THIS IDEA OF FREE RADICALS AND CAME UP WITH THIS IDEA THAT THE CELL CONSUMED OXYGEN. THEY DIDN'T REALLY KNOW, THEY THOUGHT IT WAS THE MITOCHONDRIA AT THE TIME. AND THE MITOCHONDRIA REDUCED THESE FREE RADICALS THAT WILL RANDOMLY DAMAGE DNA AND PROTEINS AND SO LIPIDS. AND SO HE PROPOSED THIS, IT'S A TWO-PAGE PAPER. THERE'S NO DATA. IT'S JUST A THEORETICAL ARGUMENT THAT THIS COULD CONTRIBUTE TO AGING. HE'S STILL ALIVE AND HIS THEORY IS STILL THAT, JUST A THEORY. THERE IS SOME EVIDENCE TO SUPPORT IT BUT THERE'S A LOT OF EVIDENCE AGAINST IT. SO AGAIN WITH MOUSE MAWCIALTIONS ONE CAN BEGIN TO MAKE FOR PREDICTIONS. SO HERE'S AGAIN A MOUSE MODEL OF WILD TYPE MILES AND THIS IS A MOUSE HAT HAS ONE ALLELE OF MANGANESE SOME D DELETED IT CLEARLY MAKES MORE MITOCHONDRIAL OBSTINANCE IN THE WILD TYPE MICE. YOU CAN SEE THESE PEOPLE STUDIED 70 MILD TYPE MICE AND 69 WILD TYPE AND 70SOD HETEROZYGOUS, CLEARLY HIGH LEVELS HERE, LOWER HERE. NO DIFFERENT THAN LIFE SPAN. ACTUALLY A DIFFERENCE IN CANCER BUT NO DIFFERENCE IN LIFE SPAN. SO THAT CERTAINLY DOESN'T SUPPORT THAT CONCEPT THAT OR SIMPLE INTERPRETATION OF THE FREE RADICAL THEORY. WE ALSO HAVE A LITTLE BIT OF A BONE TO PICK OVER IT BECAUSE WE SHOWED MANY YEARS AGO THAT IT'S NOT SARCASTIC RANDOM DAMAGING AGENTS THEY CAN BE REDUCED BY IN THIS CASE, THIS IS ACTIVATION OF CELLS WITH A GROWTH FACTOR IN TERMS OF PDGF AND WE MEASURE THE HYDROGEN PEROXIDE IN THESE CELLS. THERE'S THIS HUGE BURST THAT OCCURS AFTER PDGF STIMULATION. THIS IS NOT BAD FOR THE CELL. IN FACT THIS IS HOW THE CELL RESPONDS TO PDF AND NEEDS TO MAKE ROS IN ORDER TO RESPOND TO PDGF. SO ACCIDENTS ARE RANDOMLY MADE OR PURPOSELY OR ARTIFACTS ARE BAD OR JUST SARCASTIC AGAIN DIDN'T MAKE COMPLETE SENSE TO US. AND WE STRUGGLED WITH THIS IDEA IF OUR OXIDANTS ARE IMPORTANT FOR AGING, DO THEY WORK THROUGH THIS RANDOM PATHWAY AS HARMON SUGGESTED OR DO THEY WORK THROUGH SPECIFIC PATHWAYS OR ARE THEY UNIMPORTANT FOR AGING. I JUST WANT TO CLOSE AND SAY THAT THIS IDEA IS CONSTANTLY GETTING REFINED AND ONE OF THOSE SORT OF MORE INTERESTING NUANCES TO THIS THEORY CAME RECENTLY OUT OF THE WORK OF RON DEPINO'S GROUP -- AND HE HAD A PAPER IN HE -- SUGGESTING THAT IN MICE WHICH HAD A TELOMERE TRANSITION THAT LEAD TO AN INCREASE IN P53 ACTIVATION WHICH LOOKS LIKE IT INHIBITS THIS FACTOR WHICH I BRIEFLY TALKED ABOUT WHICH IS INVOLVED IN MITOCHONDRIAL GENERATION AND ROS HOMEOSTASIS. AND SO THE PINO GROUP WAS ABLE TO MOCK SORT OF AN UPDATED VERSION OF THE THREE ARTICLE THEORIES SUGGESTING THAT TELOMERE AND OUR MITOCHONDRIAL FUNCTION WERE LINKED ALL TOGETHER. AND WHETHER OR NOT THAT TRULY IS IMPORTANT IN AGING I THINK WILL PROBABLY NEED ANOTHER 50 YEARS TO SORT OF FIGURE OUT AS WELL. SO I DON'T KNOW IF I HAVE ANY ANSWERS TO YOU WHY THIS OCCURS. I THINK IT'S CLEARLY THE USE OF SIMPLE ORGANISM HAVE BEEN INCREDIBLY IMPORTANT TO ELUCIDATE CERTAIN PATHWAYS THAT APPEAR TO BE AT LEAST CANDIDATES FOR THE AGING PROCESS. I THINK WE'VE MADE THROUGH THE USE OF THOSE MODELS AND MOUSE MODELS I THINK WE'RE BEGINNING TO TREAT WHAT I THINK WAS A VERY DIFFICULT PROBLEM IN THIS SORT OF REDUCTION EIST APPROACH. THERE'S A LOT OF QUESTIONS ABOUT NO UNIFYING HYPOTHESES THAT CAN TELL US EXACTLY WHY WE AGE OR WHAT REGULATES THE RATE OF AGING. LET ME JUST THANK SOME OF THE MEMBERS OF MY LAB AND I'LL BE HAPPY TO TAKE ANY QUESTIONS. >> THANK YOU VERY MUCH. [APPLAUSE] >> THAT WAS MARVELOUS. SO OKAY. >> WHAT ABOUT INFLAMMATION EXAMINANDWAYS TO REDUCE. HOW IMPORTANT IS THAT. >> LUIGI IS PROBABLY A BETTER, I MEAN I THINK LUIGI'S DATA FROM HIS LONGITUDINAL STUDIES SUGGEST THAT YOU KNOW THE LEVELS OF INFLAMMATORY CYTOKINES IN PATIENTS IN PEOPLE'S SERUM IS A VERY GOOD PREDICTOR OF MORTALITY. SO I THINK THE QUESTION IS WHY ARE THESE INFLAMMATORY MEDIATORS UP AND WHAT IS THE BIOLOGICAL BASIS FOR WHY IO6 OR IO8, ANY IO GOES UP AS WE AGE. I DON'T THINK THERE'S A GREAT ANSWER TO THAT. THERE'S SOME INTRIGUING DATA SUGGESTING THINGS LIKE DNA DAMAGE AND INFLAMMATION MIGHT BE RELATED OR THINGS LIKE -- AND FLAWTION MAY BE RELATED. BUT THE EXACT REASONS OF WHAT THAT BIOMARKER OR MAYBE MORE DESCRAWRNG THASTRONGER THAN A BIOMARK. WHY IT GOES UP IS UNCLEAR. BUT CLEARLY THE VERY STRONG PREDICTORS OF MORTALITY AND AGING. SO THERE MUST BE SOMETHING THERE. >> [INDISCERNIBLE] >> NO, NO, NO, GO. >> >> THERE ARE WAYS TO MODULATE THE INFLAMMATION. THE WAY WE MODULATE THE INFLAMMATION NOW IS WE SHOOT ON THE FLAMMATION THEN WE TURN IT DOWN IN ORDER TO AVOID PAIN AND TO AVOID LARGE OVERT INFLAMMATORY DISEASE. HERE THE INFLAMMATION IS IN MY CHRONIC REGULATION IS MORE A SELECTIVE WAY. THE AGENTS THAT CAN DO THAT ARE JUST COMING OUT NOW. >> W -- I TRIED ASPIRIN AND IT CAUSES BLEEDING SO I CAN'T TOLERATE IT SO I AM USING [INDISCERNIBLE] I HAVE A GOOD QUALITY OF LIFE. >> IN LADY LIVED TO 120 SHE LED A GREAT QUALITY OF LIFE. SHE WROAD A BICYCLE. SHE WAS MOKIN SMOKING AND DRINKING. I WANT HER LIFE WITH OR WITHOUT IBUPROFEN. >> HOW ABOUT TURL TURTLES HOW DO THEY DIFFER FROM OTHER ANIMALS FOR EXAMPLE. >> I DON'T KNOW THAT MUCH ABOUT TURTLES. DO THEY LIVE LONG? >> 120 YEARS. >> OH, I DON'T KNOW. THERE'S A LOT OF -- >> [INDISCERNIBLE] >> RIGHT. SO THERE'S LIKE THESE NAKED MORATS THAT ARE VERY SIMILAR TO OTHER RODENTS BUT THEY LIVE 40 YEARS AND PEOPLE ARE NOW TRYING TO SEQUENCE THEIR DNA AND TRYING TO FIGURE OUT THE SECRET. I DON'T KNOW IF ANY OF THOSE APPROACHES THAT I KNOW OF HAVE BEEN ANYBODY'S COME UP WITH THE MAGIC BULLET THERE. >> WELL YOU KNOW, IF YOU LOOK AT METABOLIC RATE OF, SO THERE ARE SOME OUTLAYERS. GENERALLY IF YOU LOOK AT LIFE SPAN AND METABOLIC RATE THERE'S A PRETTY GOOD LINEAR CORRELATION. AND SOME OF THESE PIECES THAT LIVE LONGER FALL OFF THAT CORRELATION. SO WE FALL OFF THAT CORRELATION A LITTLE BIT. BIRDS FALL OFF THAT CORRELATION. SO I DON'T KNOW ABOUT TURTLES, I HAVE TO GO BACK AND LOOK. BUT IT'S JUST A CORRELATION SO IT'S A LITTLE HARD TO INFER MECHANISM. >> A QUESTION TO BOTH OF YOU IN A WAY. I WONDER IF THE STUDIES THAT HAVE GONE IN SOME OF THE OLDER POPULATIONS, PEOPLE WHO LIVE TO THE AGES OF 100, ARE THERE ANY EITHER ISOFORMS OR SIRTUINS OR ACTIVITY OF SIRTUINS HAVE BEEN FOUND TO BE DIFFERENT FROM THE REST OF THE POPULATIONSES? >> SO THE SIRTUINS THE DATA IS PRETTY WEAK. THERE IS SOME REPORT OF ONE POLYMORPHISM OF SIRT3 THAT IS ENRICHED ALONG PEOPLE. FOR THE MOST PART I DON'T KNOW OF ANY OTHER GENETIC DATA. THROUGHS A FELLOW UP IN EINSTEIN WHO HAS DONE A LOT OF THIS WORK WHERE HE'S LOOKED AT THE POPULATION OF CENTENARIAN AND LOOKING FOR GENES INRICHARD VERSUS NON-SEN NON-CENTENARIANS. A LOT OF THEM HAVE TO DO WITH METABOLISM AND OTHER THINGS. I MEAN THE ISSUE AND IT GOES BACK TO THIS CONCEPT OF AGING. AGAIN, THE SIMPLE ORGANISMS ARE VERY HELPFUL BUT WE DON'T REALLY KNOW, I DON'T PARTICULARLY KNOW WHAT WURMINGZ DI WORMS DIE OF BASICALLY. IT'S CONCEIVABLE FOR US AND YOU KNOW THIS FROM STRAINS OF MICE. CERTAIN STRAINS OF MICE HAVE CERTAIN DISEASES THAT KILL THEM BASICALLY, RIGHT? I MEAN SO CERTAIN STRAINS IT WILL BE KIDNEY DISEASE, IT WILL BE LYMPHOMAS. IF YOU'RE STUDYING THAT ORGANISM AND YOU HAVE A GENE THAT AFFECTS THAT DISEASE PROLINGS, YOU WILL SEE A LIFE SPAN EXTENSION. IN PEOPLE, IF YOU TREAT. IF YOU PUT PEOPLE ON STATIN, THEY'RE GOING TO LIVE LONGER, RIGHT. I MEAN, YOU KNOW, SO I MEAN I GET THE ISSUE, WITH A I'M TRYING TO SAY IS THAT GENES THAT ARE ENRICHED IN CENTENARIANS MIGHT ROW TECPROTECT US AGAINST CERTAIN COMMON DISEASES THAT NORMALLY WOULD KILL US. AND THAT IS SORT OF WHAT WE WANT BUT ON THE OTHER HAND IS THAT THE INTRINSIC WAY OF AGING OR IS THAT RATE LIMITING DISEASES. AND SO ARE THAT'S WHY THAT TYPE OF ANALYSIS IS A LITTLE DIFFICULT TO INTERPRET SOMETIMES. >> SO WITH CALORIC RESTRICTION THERE ARE SOME GROUPS THAT SAY THE CONTROL GROUPS ARE OVERFED IN THE FIRST PLACE, IS THAT THEN DISPUTED? >> IT'S A VALID CRITICISM BECAUSE THE STRAINS THAT MICE THAT WE HAVE IN THE LAB, THEY ARE THERE BECAUSE THEY REPRODUCE -- THEY'RE NOT WHAT YOU'D FIND IN THE WILD. SO I THINK THAT IS A VALID CRITICISM IN THE RODENT EXPERIMENT. I DON'T THINK IT'S AS MUCH IN THE PRIMATE EXPERIMENTS WHERE THEY'RE DOING CHIMP'S BECAUSE THERE ISN'T THAT TYPE OF LABORATORY STRAIN. AND PEOPLE, YOU KNOW, WE LITERALLY DON'T KNOW THE EFFECT. WE CAN'T DO A CONTROLLED EXPERIMENT. ALL OF THESE EXPERIMENTS, ALL THE THINGS THAT HAVE BEEN DONE HAVING PEOPLE WHO HAVE SELECTED THEMSELVES TO CHLORICALLY RESTRICT. THERE'S A TRIAL? THE STUFF THAT'S BEEN PUBLISHED HAVE BEEN PEOPLE WHO HAVE SELECTED AND THEY HAVE LOWER THAN EXPECTED RATES OF HYPERTENSION AND CARDIOVASCULAR DISEASE FOR THEIR AGE. BUT I DON'T KNOW. >> I AGREE WITH YOU -- FOR NOT EATING. YOU ARE A VERY PECULIAR PERSON BECAUSE I WILL NEVER DO THAT. I DON'T KNOW ABOUT YOU. SO THERE IS A TRIAL, A STUDY THAT CALCULATE THE AMOUNT OF ENERGY REQUIRED TO SURVIVE. REDUCE THAT BY 25%. SO THESE PEOPLE ARE 25%, I THINK 20 OR 25% CALORIC RESTRICTED. AND SOME OF THE DATA THE FIRST PHASE OF THE STUDY'S BEEN PUBLISHED WITH, YOU KNOW, VERY LITTLE RESULTS. I THINK EVERYBODY WAS THINKING THAT THE -- WILL BE LOWER AND THE RESISTANCE WOULD BE LOWER AND THE ONLY THING THAT THEY REALLY SEEMS TO BE WORKING IS THAT, YOU KNOW, ARE THE MITOCHONDRIAL SEEMS TO BE HIGHER WITH PGC ONE ALPHA OVER THE STRESS. BUT YOU KNOW, WE'RE WAITING FOR MORE DATA FROM THAT STUDY. >> [INDISCERNIBLE] YES, YES. THE SIRTUINS ARE LIKE EVERYTHING IN SCIENCE, THEY HAD A GOLDEN PERIOD AND NEER READJUSTING NOW. >> SO HAS THE INTE INTESTINAL ENTERED -- FOR LIFE SPAN STUDIES. >> YOU KNOW, I DON'T, ALL THE STUDIES ON LIFE SPAN ARE DONE IN CLEAN FACILITIES. I DON'T KNOW IF PEOPLE HAVE LOOKED AT THAT. I MEAN I DON'T KNOW. NOTHING THAT I KNOW OF. WE'RE HERE TO LOOK AT COMPOSITION BUT NOT FLORA COMPOSITION. BUT CERTAINLY THERE ARE THINGS LIKE FOR INSTANCE WE'RE INTERESTED IN -- WHICH LOOKS LIKE IN LOWER ORGANISMS REGULATES LIFE SPAN. I KNOW THAT -- HAD A PAPER, THEY HAD A -- DEFECT THAT HAD NO PHENOTYPE BUT THE INTESTINAL FLORA DOES HAVE IT. YOU WOULD THINK IT WOULD BE IMPORTANT. >> I HAVE ANOTHER QUICK QUESTION. IS THE OBSERVATIONS YOU'VE MADE WITH THE FACT, DOES THAT BEAR SOME RESEMBLANCE TO THE DO YOU REMEMBER EFFECT WITH YEAST AND WORMS? >> YES. I THINK THAT SO WHEN IT'S REFERRING TO WORMS, IF YOU, THE WORM IS DEVELOPING, IF YOU HAVE A HARSH ENVIRONMENTAL CONDITION FOR FOOD THAT THE ANIMAL WILL GO INTO THE PHASE WHICH IS SORT OF A SUSPENDED ANIMATION. SO IT RECOGNIZES SOMEHOW THAT THERE'S NOT ENOUGH FOOD AND RATHER THAN BE BORN AND THEN REQUIRE A LOT OF ENERGY AND NUTRIENTS IT DECIDES TO STOP. A LOT OF GENES THAT REGULATE THAT PHASE LOOK LIKE THEY ALSO REGULATE LIFE SPAN. SO THAT THERE'S THIS INTRIGUING MOTION ALL OF THESE SORT OF THINGS THAT SOMEHOW IF THERE'S FOOD AROUND, THE BODY SAYS OKAY, LET'S GO AT IT, LET'S GO AHEAD AND BE MERRY AND IF THERE'S NO FOOD AROUND, YOU SAY WAIT A MINUTE THERE'S NO FOOD AND LET'S STOP WHAT WE'RE DOING HERE AND NOT STIR UP ANY TROUBLE. AND SOMETHING, SOME WAY, IF YOU CAN MIMIC THAT, LET'S STOP WHAT WE'RE DOING HERE AND NOT STIR UP ANY TROUBLE. THOSE TYPES OF THINGS APPEAR TO CORRELATE WITH LONG LIFE, RIGHT. BUT THAT'S THE SORT OF VARIES THE GERIATRIC. >> IT'S INTERESTING HERE BECAUSE THEY ALSO CORRELATE WITH RESISTANCE. >> RIGHT, BASICALLY YOU'RE SAYING THINGS ARE TOUGH, I'M GOING TO JUST HUNKER DOWN HERE, I'M GOING TO PROTECT MYSELF AND I'M NOT GOING TO CAUSE ANY TROUBLE, RIGHT. IT'S LIKE JUNIOR HIGH SCHOOL. >> I FORGOT WHO IT WAS BUT SOMEBODY SAID IT WAS LIKE STAR TREK WHERE YOU CAN, WHEN RT SPACESHIP HAS YEALZ UP, IT'S NOT VULNERABLE. YOU LOWER THE SMEALDZ OR SOMETHING BUT YOU'RE -- SHIELDS OR SOMETHING BUT YOU'RE VULNERABLE TO THE OTHER PERSON. I THINK THERE IS SIMILARITIES. >> THERE IS A GENERIC FEELING THAT UNDER HARSH CONDITIONS YOU ACTIVATE THESE STRESS RESISTANT PATHWAYS THAT PROTECT YOU UNDER THOSE CONDITIONS AND IF YOU CAN KEEP SOME MODICUM OF THOSE PATHWAYS ACTIVATED, THEN YOU'LL LIVE LONGER. MAYBE NOT BETTER BUT LIVE LONGER. >> ONE LAST QUESTION. I HOPE SOMEBODY ELSE WILL ASK. WE HAVE A LITTLE TIME IF YOU WISH. SO I WANT TO ASK YOU ABOUT WOMEN. ITALIANS ALWAYS HAVE SOMETHING TO SAY ABOUT WOMEN. WHEN YOU LOOK AT THE LIFE SPAN. WHEN YOU LOOK AT THE LIFE SPAN IN OUR SOCIETY AND LIFE SPAN STATISTICS, THEN DISAPPEARS TEN YEARS BEFORE WOMEN END UP. THAT'S A GENERALIZATION. BUT WHAT'S THE REASON DO WE REALLY UNDERSTAND THE REASON FOR THAT. IS THIS TRUE LONG JEFFITY IN WOMEN IS MUCH HIGHER THAN IN MAN. IF YOU LOOKS AT SENT FLAIRNS, 4.3 SENS CENTENARIAN WOMEN FOR EVERY CENTENARIAN MAN. SOMEBODY SAID THE DREAM OF MAN IS ONLY FULFILLED WHEN THEY BECOME 100. BUT IT'S NEVER BEEN ALWAYS TRUE. IT'S NOT ALWAYS BEEN TRUE. IT'S A THOUSAND YEARS AGO WAS NOT LIKE THAT. SO WE SEE THAT THERE IS ENVIRONMENTAL FACTOR. IT REALLY MAKES LITTLE SENSE BECAUSE IN FACT WOMEN GET MORE DISEASE AND MORE DISABILITY BUT LIVE A LONGER LIFE. SO THERE IS SOME SORT OF OF A SITUATION WHAT WE CULL HELL AND WHAT WE CALL SURVIVAL. MY INTRODUCTION IS THAT WOMEN ARE TOUGH AND HAVE THE ABILITY TO -- THE DISEASE MUCH LARGER THAN MEN. >> BY THE WAY, IF YOU GO TO THE -- >> I'M NOT GOING TO TOUCH THAT QUESTION. >> IF YOU GO HE TO THE INTERNET AND YOU LOOK UP AGING GRACEFULLY, WHAT YOU GET ARE PICTURES OF PREFER FAMOUS FRENCH WOMEN WHO LOOK ENTIRELY STERILE ISSUE IN THEIR -- STYLISH. COUPLE MORE QUESTIONS. ANYBODY WHO HASN'T ASKED. SCOTT. >> ACROSS THE WORLD THERE ARE A NUMBER OF ZONES A LOT OF PEOPLE LIVE TO RIP OLD AGE ONE IN THE U.S. HAS THERE BEEN ANY LOOK TO SEE -- THE PEOPLE IN BLUE ZONES TO THOSE SURROUNDING PEOPLE WHO AREN'T PARTAKING IN THAT EXTRA EFFORT. >> I DO KNOW, ACTUALLY TO TELL YOU THE SMALL STUDY, THE ORIGIN OF THE NAME BLUE ZONE, IT'S BECAUSE OF ME. BECAUSE WHEN WE WERE WORKING ON THE CENTENARIAN -- IT WAS AN AREA, THE EAST AREA OF THE ISLAND WHERE THERE IS SPECIFICALLY IN THE EYE CONCENTRATION OF CENTENARIANS, IT'S TEN TIMES HIGHER. SENAND THE PECULIAR THING IT'S THE ONLY PLACE IN THE WORLD WHERE THERE'S AS MANY CENTENARIAN MEN AS WOMEN. IT'S ONE TO ONE. AND NO WHERE ELSE IN THE WORLD IS LIKE THAT. SO WE WERE WORKING ON THIS TABLE AND WE WERE ADJUSTING THE -- THIS WAS CAP DHOOFERRE CAPTURED GUY NEWSPA PERS AND NOW THAT IS WHAT WE USE IN THE FIRST -- CENTENARIANS. >> ONE THING I WANTED TO SAY ABOUT THE ENERGY WHICH I THINK THAT SENSING ENERGY CONSUMPTION AND GENERATION IS REALLY SO MUCH AGING AND IS REALLY PUZZLING. THERE'S ONE STUDY THAT'S BEEN DONE A FEW YEARS AGO. YOU KNOW THE YOUNG WOMEN THAT START TO EXERCISE TO PREPARE FOR MARATHONS MOST OF THE TIME HAPPEN, AND THIS IS DUE TO THE FACT THAT THAT'S HALF MASS DECLINED TREMENDOUSLY AND THEY ARE BASICALLY LEADING THE MASS IF NOTHING ELSE. WELL, IN ORDER TO RECONSTITUTE, YOU CAN DO TWO THINGS. YOU CAN STOP EXERCISING AND FEED THEM BUT YOU ALSO GIVE THEM -- SO THE BRAIN SENSE THAT THERE IS FACT AND THERE IS ENERGY BECAUSE THEY HAVE THE -- AND SO IT'S TRUE, THERE IS SOME WAY THE BRAIN IS ABLE TO DETECT THAT THERE IS ENERGY AVAILABLE. AND SO THAT SIGNAL CAN ACTUALLY BE CREATED. SO I THINK THAT THIS PART OF THE STUDY IS SO IMPORTANT THAT IT'S GOING TO BE PREGNANT WITH RESULTS FOR THE FUTURE. >> WELL LISTEN, I WANTED TO ON BEHALF OF EVERYONE THANK YOU VERY MUCH. IT'S VERY EXCITING.