GOOD MORNING, EVERYBODY. THANKS FOR BEING HERE. MY NAME IS PHILIPPE (INDISCERNIBLE) DIVISION OF AGING BIOLOGY NATIONAL INSTITUTE OF AGING AND I'M HEAD OF THE TRANS-NIH GEROSCIENCE INTEREST GROUP IN CHARGE OF THIS MEETING. I WOULD LIKE TO WELCOME YOU TO THE FIRST EVER MEETING OF THE GEROSCIENCE SUBJECT WHICH IS A FIELD THAT SPANS THE BASIC BIOLOGY OF AGING AND DISEASES RELATED TO AGING OR CHRONIC DISEASES OF THE ELDERLY. I WOULD LIKE TO START BY THANKING ALL MY TRANS-NIH PARTNERS, THERE'S PLENTY OF INSTITUTES INVOLVED IN THIS EFFORT, A LOT OF PEOPLE PUT A LOT OF WORK INTO GETTING THIS TO WHERE WE ARE NOW. WE ALREADY HAVE -- THIS IS NOT THE END BUT THE BEGINNING OF WHAT WE'RE TRYING TO DO. I WOULD ALSO LIKE TO THANK OUR PARTNERS, THE ALLIANCE FOR AGING RESEARCH AND THE GEROSCIENCE RESEARCH OF AMERICA PREPARING ALL THAT'S SPECIALLY DURING THE GOVERNMENT SHUTDOWN SO THEY KEPT WORKING WHILE WE WERE HOME. OF COURSE I ALSO WANT TO THANK MANY CORPORATIONS WHAT YOU SEE IN THE SLIDE WHO PROVIDED THE FUND FOR THIS. I SHOULD STRESS NO FURTHER FUNDS HAVE BEEN USED FOR THIS ACTIVITY, THIS IS COMING FROM (INAUDIBLE) SO BIG THANK YOU TO THEM. BEFORE I START A COUPLE OF PRACTICAL THINGS I WANT TO BRING YOUR ATTENTION TO THE HASH TAG IN YOUR FOLDERS. THIS HASH TAG AGING SUMMIT. WE WANT YOU TO TWEET THOSE OF YOU OF THE AGE YOU KNOW HOW TO TWEET. WE P WANT AS MUCH SOCIAL ACTIVITY AS POSSIBLE, SOCIAL MEDIA, PRESS COVERAGE, ET CETERA AND THERE WILL BE PRESS AROUND IF THEY ASK YOU QUESTIONS, GET TO THOSE PEOPLE. ALSO ASKED TO LET EVERYBODY KNOW THE EVENT IS BEING RECORDED FOR FUTURE VIDEOCAST, NOT BEING VIDEOCAST LIVE BUT IT WILL BE POSTED AFTERWARDS SO EVERYBODY SHOULD KNOW THAT AND BE AWARE. WE HAVE A VERY FANTASTIC PROGRAM BUT ALSO VERY TIGHT PROGRAM, THIS IS GOING TO BE A LOT OF THINGS GOING ON IN A SHORT TIME SO WITHOUT FURTHER ADIEU I WOULD LIKE TO INTRODUCE FRANCIS COLLINS DIRECTOR OF NIH WHO WILL GIVE WELCOMING REMARKS. DR. COLLINS IS A PHYSICIAN GENETICIST WHO IS KNOWN FOR HIS DISCOVERIES OF DISEASE GENES AND LEADERSHIP OF THE HUMAN GENOME PROJECT. HE WAS A DIRECTOR OF THE NATIONAL HUMAN GENOME RESEARCH INSTITUTE AT THE NIH FROM 1993 TO 2008. HE'S -- HAS MANY ACCOLADES, ELECTED MEMBER OF THE INSTITUTE OF MEDICINE AND NATIONAL ACADEMY OF SCIENCES. MANY, MANY AWARDS SUCH AS THE PRESIDENTIAL MEDAL OF FREEDOM IN 2007. THE NATIONAL MEDAL OF SCIENCE IN 2009. IN 2010 HE WAS A CO-RECIPIENT OF THE NATIONAL CENTER ENTERPRISE BIOMEDICAL RESEARCH. I COULD GO ON AND ON WITH DR. FRANCIS COLLINS ACCOMPLISHMENTS BUT WE DON'T HAVE TIME FOR THAT SO DR. COLLINS. [APPLAUSE] >> THANK YOU, PHILIPPE. GOOD MORNING, EVERYONE. WONDERFUL TO HAVE A CHANCE TO ISSUE SOME WORDS OF WELCOME HERE AND WHAT I THINK IS GOING TO BE A REMARKABLE MEETING WITH THE SCIENTIFIC AGENDA THAT IS BROAD AND DEEP AND WILL I THINK PROVIDE A LOT OF INTERACTION, POSSIBILITIES BETWEEN PEOPLE WHO HAVE ATTENDED THIS MEETING. WE'RE GLAD GOVERNMENT IS OPEN SO WE CAN GATHER HERE IN THE NATCHER BUILDING IN THE KERSTCHTEIN AUDITORIUM INSTEAD OF HAVING TERRIBLE CONSEQUENCES OF THE MEETING LIKE THE FIRST HALF OF THE MEETINGS IN OCTOBER. WE HOPE THAT DEVASTATING EVENT NAMELY GOVERNMENT SHUTDOWN WILL NOT HAPPEN AGAIN FOR ANOTHER 100 YEARS. IF IT DOES, WE WILL BE PREPARED FOR IT NEXT TIME BUT I SURE HOPE WE DON'T HAVE TO BE. I DO WANT TO THANK THOSE WHO WORK SO HARD TO CREATE THIS POSSIBILITY OF THIS REMARKABLE MEETING. PHILIPPE ESPECIALLY BUT ALSO KEVIN (INDISCERNIBLE) AND RON (INDISCERNIBLE) PART OF THE LEADERSHIP EFFORT. MAYBE ASK FART OF THE TRANS-NIH GEROSCIENCE INTEREST GROUP TO STAND UP SO YOU CAN SEE WHO THEY ARE. THE FOLKS THAT CONTRIBUTED THEIR TIME AND EFFORT TO BUILD THIS REMARKABLE MEETING. [APPLAUSE] THANK YOU ALL. SO I THINK THE EXISTENCE OF THIS FOCUS ON GEROSCIENCE IS INDICATIVE OF THE WAY IN WHICH OUR IDEAS ABOUT HEALTH AND DISEASE HAVE BEEN EVOLVING OVER THE COURSE OF THE LAST DECADE OR SO. PERHAPS MORE TRADITIONALLY WE FOCUSED ON INDIVIDUAL DISEASE RISKS WHETHER CARDIOVASCULAR DISEASE OR CANCER, OR ALZHEIMERS BUT INCREASINGINGLY WE'RE DISCOVERING ON THE BASIS OF MOLECULAR INFORMATION, MORE CAREFUL STUDY IN THE PROCESS OF AGING, IT IS NOT A GOOD IDEA TO CONSIDER ISSUES IN ISOLATION BUT WE WOULD BE BETTER SERVEDDED IN GATINGERRINGS SUCH AS THIS TO APPRECIATE THE INTERACTIONS BETWEEN THOSE DISEASE RISKS. AND ALSO THE OTHER THING THAT I THINK WE'RE INCREASINGLY APPRECIATING IS THAT IT SERVES US WELL NOT ONLY TO FOCUS ON DISEASE BUT FOCUS ON HEALTH AND UNDERSTAND MORE ABOUT HEALTHY AGING AND HOW THAT CAN OCCUR AND WHY SOME INSTANCES IT DOESN'T BY CONTRAST. WE'LL ASK TO OUR UNDERSTANDING HOW TO IMPROVE THE HEALTH OF OUR NATION AND THE WORLD. CERTAINLY FOR ME COMING OUT OF THE FIELD OF GENOMICS ONE OF THE EXCITING AREAS THAT WE ARE ALL LOOKING FORWARD TO IS LEARNING MORE ABOUT WHAT IS IT THAT SEEMS TO ALLOW EXCEPTIONAL LONGEVITY. MUCH OF THAT IS GO TO BE ENVIRONMENTAL BUT SOME APPEARS TO BE HEREDITARY IF WE HAD COMPLETE DATA SETS WE DREAM OF, BOTH OF THOSE KINDS OF DATA PEOPLE WHO LIVE EXCEPTIONALLY LONG YEARS OF LIFE WHAT WOULD THAT TEACH US ABOUT THE WAYS WHICH WE CAN OFFER LONGEVITY TO GREATER NUMBERS OF INDIVIDUALS. WE'RE ON OUR PATH TOWARDS SEEING THAT ACHIEVEDDED. IN THE PAST NOTION OF NO CUSSING ON HEALTH IS A LITTLE LESS FOCUS ON EMPHASIS AN FOCUS ON DISEASE IS EMPHASIS. I THINK WE'RE SEEING A VERY APPROPRIATE BALANCING ACT NOW START TO APPEAR. FROM MY OWN PERSPECTIVE, LOTS TO LEARN ALSO BY STUDYING SPECIFIC EXAMPLES WHERE AGING SEEMS TO BE ACCELERATED, LAST YEAR WHEN I SPOKE TO THIS GROUP I HAD THE OPPORTUNITY TO TALK ABOUT RESEARCH GOING ON IN MY OWN LABORATORY ABOUT HUTCHINSON GILFORD PROGERIA, A MORE DRAMATIC FORM OF PREMATURE AGING WHERE THE LAB WAS ABLE TO DISCOVER TEN YEARS AGO IN JUST FOUR YEARS GET TO A THERAPEUTIC TRIAL. USING FAN SILL TRANSFERASE INHIBITORS. WHEN I SPOKE LAST YEAR WE HAD NOT SPOKE OF THAT, THE PUBLICATION CAME SHORTLY AFTER THAT SHOWING THERE DOES ATO BE BENEFIT IN THE PROGRESS OF CARDIOVASCULAR DISEASE. I DON'T KNOW HOW MANY HAD A CHANCE TO SEE THE HBO SPECIAL LAST WEEK, LIFE ACCORDING TO SAM, WHICH FOCUSED ON PROGERIA. NARRATED BY SAM BURNS ARC 17-YEAR-OLD BOY WITH THIS DISEASE WHO I HAVE KNOWN SINCE HE WAS THREE. REMARKABLE PIECE IN TERMS OF LAYING OUR CONSEQUENCES OF WHAT THIS DISEASE MEANS TO THIS BOY AND HIS PARENTS. BUT ALSO A VERY GOOD TEACHING EXERCISE ABOUT HOW RESEARCH HAPPENS, HOW YOU GO FROM A BASIC SCIENCE DISCOVERY TO AN IDEA ABOUT THERAPY, HOW YOU CONDUCT A CLINICAL TRIAL, SO ON, USEFUL THING TO POINT PEOPLE TO TRYING TO UNDERSTAND THE RESEARCH PROCESS. THERE WILL CERTAINLY BE AT THIS MEETING REFLECTIONS SOME MODELS TEACH US GENERAL PROPERTIES OF AGING. MIGHT NOT SURPRISE YOU WE ARE ENGAGED IN PROGERIA TESTING RAPAMYCIN IN A MOUSE MODEL OF THE DISEASE, THERE WILL BE LOTS OF RAPAMYCIN CONVERSATION QUITE SURE OVER THE COURSE OF THE NEXT DAY AND A HALF OF THIS MEETING BECAUSE OF POTENTIAL FOR SHOWING A PATH TOWARDS LONGEVITY THAT TEACHES ABOUT MTOR WAYS IT PLAYS A ROLE IN THIS PROCESS. I WANT TO ASK YOU ALSO TO PAY ATTENTION TO SOMETHING WE AT NIH PARTICULARLY CONCERNED ABOUT RIGHT NOW FEATURED IN A COVER STORY OF THE ECONOMIST LAST WEEK, REPRODUCIBILITY. IT HAS COME THE OUR ATTENTION WHEN YOU LOOK CAREFULLY WHAT HAPPENS AFTER A PRE-CLINICAL STUDY IS CONDUCTED THAT THEN LEADS TO THE POSSIBILITY OF MOVING INTO A CLINICAL TRIAL, THINGS DON'T ALL GO THE WAY YOU LIKE AND PUBLICATIONS SUGGESTED THAT A SUBSTANTIAL FRACTION OF PRE-CLINICAL STUDIES PARTICULARLY INVOLVING ANIMAL MODEL CAN'T BE REPRODUCED WHEN THE COMPANY THAT AIMS TO TRY TO MOVE THAT INTO HUMAN PATIENTS DOES THAT WORK AND FINDS THEY ARE UNABLE TO SHOW THIS RESULT CAN BE REPLICATEDNA DIFFERENT LABORATORY IN A DIFFERENCE WAY. THERE'S ALL KINDS OF TECHNICAL REASONS THAT MAY SOMETIMES HAPPEN BUT IT'S BECOME QUITE CLEAR WE THE BIOMEDICAL RESEARCH COMMUNITY NEED TO PAY CLOSE ATTENTION TO THIS ISSUE AND PERHAPS SOME OF THE RIGOR THAT OUGHT TO BE INCLUDED IN PRE-CLINICAL STUDIES HAS NOT ALWAYS BEEN THERE. I GIVE CREDIT TO THE NATIONAL INSTITUTE OF AGING IN TERMS OF THE WAY IN WHICH THEY FOCUSED ON THIS ISSUE AS FAR AS INTERVENTIONS THAT MIGHT ACTUALLY RESULT IN INCREASED LONGEVITY BECAUSE YOU CAN IMAGINE IN A MOUSE MODEL WHY THAT IS A CHALLENGE TO BE SURE YOU HAVE GOTTEN THE DATA RIGHT. AND HAVING SET UP A SYSTEM TO BE SURE THAT SUCH CLAIMS ARE TESTED IN A REPRODUCIBLE WAY HAS BEEN I THINK A GOOD EXAMPLE OF WHAT WE SHOULD BE DOING EVEN MORE OF. RAISE THIS AS AN ISSUE I THINK ALL OF US SHOULD BE LOOKING CLOSELY AT TO BE SURE IN THE PRESSURE, EXTREME PRESSURE NOW WITH BUDGETS SO TIGHT, TO DO RESEARCH AND GET THE RESULTS PUBLISHED, THAT THE APPROPRIATE ATTENTION IS PAID TO THE RIGOR OF THE STUDY AND THAT THE CONCLUSIONS CAN THEN BE BACKED UP AND REPLICATED AND IN ANOTHER LABORATORY. SOMETHING TO WATCH OVER. AGAIN, I WANT TO WELCOME YOU PRIMARILY, MY MAIN GOAL HERE, AND TO SET THE TABLE BRIEFLY WHAT I THINK WILL BE A REMARKABLE DAY AND A HALF OF REFLECTIONS ON WAYS IN WHICH THE STUDIES OF THE AGING PROCESS CAN INTERSECT WITH EACH OTHER, I HOPE ALL OF YOU WILL TAKE FULL ADVANTAGE OF THE OPPORTUNITIES TO MAKE NEW FRIENDS, DEVELOP COLLABORATIONS, THIS IS A FIELD GEROSCIENCE VERY MUCH IN WONDERFUL FERMENT AND BY BEING HERE YOU'RE PART OF THAT. I PERMLY AM DELIGHTED TO SEE THIS KIND OF OF INTERSECTION OCCURRING AND WISH YOU THE BEST MAKING THE MOST OF THIS REMARKABLE MEETING. THANK YOU VERY MUCH. [APPLAUSE] >> GOOD MORNING. MY NAME IS KEVIN HOWCROFT, PROGRAM DIRECTOR AT THE NATIONAL CANCER INSTITUTE AND CHAIR OF THE FUNDED PLANNING COMMITTEE. THIS OPENING SESSION WE HAVE THREE KEYNOTE PRESENTATION BY LEADERS IN GEROSCIENCE AND I'LL ASK THAT AUDIENCE MEMBERS WHO HAVE QUESTIONS TO APPROACH THE SPEAKERS DURING THE 30 MINUTE BREAK AFTER THE KEYNOTE SESSION OUT IN THE LOBBY AREA. OUR FIRST KEYNOTE ADDRESS IS BY DR. CHRIS MURRAY. DR. MURRAY IS A PHYSICIAN AND HEALTH ECONOMIST, HE EARNED MEDICAL DEGREE FROM HARVARD UNIVERSITY, Ph.D. IN INTERNATIONAL HEALTH ECONOMICS FROM OXFORD UNIVERSITY. CURRENTLY DR. MURRAY IS PROFESSOR OF GLOBAL HEALTH AND DIRECTOR OF THE INSTITUTE FOR HEALTH METRICS AND EVALUATION AT UNIVERSITY OF WASHINGTON. DR. MURRAY WILL PRESENT EFFORTS BY A CONSORTIA OF INVESTIGATORS AROUND THE WORLD THAT HE HAS LED TO QUANTIFY THE MAGNITUDE OF HEALTH LOSS DUE TO CHRONIC DISEASE. >> GOOD MORNING. I'M NOT SURE I QUALIFY AS A LEADER IN GEROSCIENCE BUT I WILL TELL YOU ABOUT THE GLOBAL BURDEN DISEASE STUDY WHICH I HOPE WILL BE SOMETHING LIGHTLY DIFFERENT FROM WHAT YOU'LL BE HEARING THE REST OF THIS IMPORTANT MEETING. LET ME TELL YOU ABOUT THE GLOBAL BURDEN OF DISEASE, 2010 STUDY AND SOME OF THE CONTINUED WORK OF THIS CONSORTIUM TO TRY TO UNDERSTAND PATTERNS OF HEALTH AROUND THE WORLD. WHAT IS THIS STUDY? IT DATES BACK TO THE EARLY 90s, A CONTINUATION OF BODY OF WORK INITIATED BY THE WORD BANK IN 1991 TO FILL A GAP IN INFORMATION ON EPIDEMIOLOGY OF DIFFERENT DISEASES AROUND THE WORLD. THE WAY WE LIKE TO THINK OF IT NOW IS THAT IT WAS A SYSTEMATIC SCIENTIFIC EFFORT TO ASSESS THE MAGNITUDE OF HEALTH LOSS AROUND THE WORLD. ON A COUNTRY SPECIFIC BASIS OVER TIME BY AGE AND BY SEX USING APPROACHES THAT AT LEAST FACILITATE COMPARISON. CURRENTLY WE COVER A MUTUALLY EXCLUSIVE AND COLLECTIVELY EXHAUSTIVE SET OF 291 DISEASES AN INJURIES FOR EACH DISEASE AND INJURY THERE'S OFTEN MORE THAN ONE CLINICAL SEQUELLA WE EXAMINE, WE TRACK OVER 1,000 CLINICAL OUTCOMES. AND WE ALSO LOOK AT 67 BEHAVIORS OR ENVIRONMENTAL EXPOSURES OR METABOLIC RISKS THAT EXPLAIN SOME OF THE PATTERNS OF DISEASE INJURY THAT WE SEE AROUND THE WORLD. THE STUDY IS LARGELY FUNDED BUT NOT EXCLUSIVELY FUNDED I BY THE BILL AND MELINDA GATES FOUNDATION LAST DECEMBER AND A LARGE NUMBER OF PAPERS COMING OUT FROM THIS CONSORTIUM INCLUDING OUR PAPER ON STROKE THAT WAS OUT OVER THE WEEKEND. SO WHAT I'M GOING TO REMEMBER IS WORK OF A LARGE BODY OF SCIENTISTS FROM AROUND THE WORLD, IN FACT, NEARLY 500 FROM OVER 300 INSTITUTIONS IN 50 COUNTRIES. THIS CONSORTIUM CONTINUES TO GROW AS I'LL MENTION AT THE END OF THE PRESENTATION. I WILL USE TERMINOLOGY WHICH MAY NOT BE FAMILIAR TO YOU. GIVE A BRIEF -- HEALTH LOSS, WE'RE ACTUALLY COMPARING THE STATE OF FUNCTIONAL HEALTH AND. LATION COMPARED TO SOME IDEAL WHICH IN OUR CASE IF EVERYBODY LIVES IN FULL HEALTH WITH A LIFE EXPECTANCY OF 86 YEARS THE NUMBER 86 IS PICKD BECAUSE THAT'S THE SYNTHETIC LIGHT TABLE BASED ON THE LOWEST OBSERVED AGE SPECIFIC DEATH RATES AROUND THE WORLD TODAY. THEN COMPUTE YEARS OF LIFE LOST AS THE NUMBER OF DEATH CHANGED BETWEEN THE LIFE EXPECTANCY BY USING THE LIFE EXPECTANCY IN THIS REFERENCE NORM. SO IF YOU DIE AT BIRTH YOU LOSS 86 YEARS F YOU DIE IN 08s YOU LOST A SMALLER NUMBER. WE ALSO COMPUTE THE NON-FATAL COMPONENT OF HEALTH WHICH WILL TURN OUT TO BE RATHER IMPORTANT AND THAT IS YEARS LIVEDDED WITH DISABILITY, YEARS LIVED WITH DISABILITY IS SIMPLE, THE PREVALENCE OF A THOUSAND PLUS SEQUELLAE TIMES A SEVERITY WEIGHT FOR EACH OUTCOME. THE SEVERITY WEIGHTS ARE BASED ON SURVEYS OF THE GENERAL POPULATION AROUND THE WORLD. IN REPRESENTATIVE COUNTRIES. QUITE LITERALLY PREVALENCE P TIMES SEVERITY WEIGH AND SOME ACROSS DIFFERENT DISEASES AND AND CONDITIONS AN OVERALL METRIC OF HEALTH DISABILITY ADJUSTED LIFE YEARS IS JUST THE MATHEMATIC SUM OF PREMATURE MORTALITY AND YEARS WITH DISABILITY. JUST TO NOTE THAT UNLIKE THE U.S. USE OF THE WORD DISABILITY IN THE GBD THE TERM DISABILITY ONLY REFERS TO ANY SHORT OR LONG TERM HEALTH LOSS. HERE IS A SCHEMATIC OF THE STUDY AND THE REASON THIS IS IMPORTANT IS TO HIGHLIGHT THAT THE APPROACH TO MEASUREMENT HERE IS PROTOCOLIZED. FOR EVERY TYPE OF DATA SOURCE WE CAN IDENTIFY THERE'S A PARTICULAR SET OF TESTS AROUND VALIDITY AND COMPARABILITY UNDERTAKEN AND THEN THERE'S ATOTALS TO FILL IN BOTH MISSING INFORMATION AS WELL AS INCONSISTENT INFORMATION USING A RANGE OF STATISTICAL METHODS. STUDY FALLS TO FOUR LARGE BLOCKS OF ANALYSIS. AROUND DEATH RATES TOP LEFT, ANALYSIS AROUND CAUSE OF DEATH TOP RIGHT, ANALYSIS AROUND A THOUSAND PLUS SEQUELLAE AND COMORBIDITIES OF THOSE THOUSAND PLUS SEQUELLAE. THEN THE ANALYSIS OF RISK FACTORS ON THE BOTTOM LEFT. BEHIND EACH BOX IS MORE DETAIL. AND FOR EACH TYPE OF DATA SOURCE THERE'S A SERIES OF BIASES THAT WE TRY TO IDENTIFY AND CORRECT FOR. I AM NOT GOING TO GO THROUGH EACH OF THESE STEPS BUT JUST TO HIGHLIGHT IF YOU'RE INTERESTED THERE IS A LOT OF DOCUMENTATION AVAILABLE ABOUT EACH COMPONENT HERE IN THIS PROCESS. ONE OF THE THINGS I THINK IS INTERESTING ABOUT WORK TO DATE HAS BEEN THE USE OF DATA VISUALIZATION TO HELP BOTH THE INVESTIGATORS IN THE STUDIED FEW PATTERNS OF DISEASE BUT ALSO TO LET OTHERS EXPLORE A LARGE DATABASE OF RESULTS. SO IN ALL THERE'S OVER 1 BILLION FINDINGS IF YOU THINK ABOUT METRICS OF AGE SEX DISEASE AND VARIOUS UNCERTAINTIES, AND WE CREATED A SERIES OF ONLINE TOOLS THAT YOU CAN ACCESS AT ANY POINT THAT I'M NOW GOING TO SHOW YOU SOME OF THE KEY RESULTS OF THE STUDY. LET ME SWITCH TO THOSE TOOLS. I I AM USING A VERSION OF THESE THAT IS NEAR A WEBSITE MIRRORED TO MY HARD DRIVE NOT KNOWING WHAT INTERNET ACCESS WE HAVE BUT EVERYTHING I'M GOING TO SHOW YOU IS AVAILABLE ONLINE. SO I WOULD LIKE TO START WITH BASIC PATTERNS AROUND THE WORLD. SYSTEM OF THESE ARE PROBABLY RELEVANT TO DISCUSSION HERE IN THIS CONFERENCE AROUND GEROSCIENCE. SO STARTING WITH THE MOST SIMPLE WAY THINKING ABOUT HEALTH, LOOKING AT DEATH, THIS DIAGRAM SHOWS DEATH RATE AT THE GLOBAL LEVEL OR DEATH NUMBERS AT THE GLOBAL LEVEL BY AGE. IN THE STUDY WE BREAK DOWN DEATH UNDER AGE 5 IN FOUR GROUPS EARLY NEONATAL, LATE NEONATAL, POST NEONATAL AND AGE 1 TO 4 AND FIVE YEAR AGE GROUPS OUT TO 80 PLUS. 80 PLUS A RATHER LARGE GROUP TO NOT TRACK IN MORE DETAIL, THAT'S ONE OF THE IMPORTANT LIMITATIONS WE SEE DATA AROUND THE WORLD, VERY OFTEN COUNTRIES ARE STILL NOT REPORTING DETAILED AGE. NEVERTHELESS FROM 1990 TO 2010, I'M GOING TO SHOW YOU THE CHANGE IN THE NUMBER OF DEATHS BUT THE DIAGRAM ALSO SHOW IT IS COMPOSITION OF DEATH AND MUTATION BY 21 BROAD CAUSE GROUPS. FOR EXAMPLE, YELLOW YEARS DIARRHEA PNEUMONIA, DARK BLUE CARDIOVASCULAR DISEASE, LIGHT BLUE CANCER, THE SALMON COLOR IS CHRONIC RESPIRATORY CONDITIONS, YOU CAN SEE SOME OF THE OTHER SMALLER AS WELL. FROM 1990 TO 2010 DUE TO BOTH CHANGE IN DEATH RATES AND DEMOGRAPHIC CHANGE, YOU GET PROFOUND SHIFT IN PATTERN OF GLOBAL MORTALITY. WITH A REDUCTION IN CHILD DEATH FROM 12 MILLION DOWN TO 7 MILLION AND A HUGE INCREASE IN NUMBER OF DEATH GLOBAL OVER AGE 80. TO DEMOGRAPHIC SHIFTS ARE VISIBLE EVEN AT THIS VERY MACRO VIEW AND WHEN WE LOOK AT COUNTRY SPECIFIC RESULTS, IN SOME PLACES THOSE SHIFTS ARE REALLY DRAMATICALLY MORE PROFOUND, PLACES LIKE BANGLADESH DUE TO MORTALITY THE AND FERTILITY CHANGE, IT'S QUITE EXTRAORDINARY. I MENTION WE USE MULTIPLE METRICS FOR OUTCOMES. HERE AT THE GLOBAL LEVEL, LET ME SHIFT FROM LOOKING AT DEATH TO YEARS OF LIFE LOST, THAT'S GOING TO MUTT MORE EMPHASIS ON DEATH AT YOUNG AGE IN YOUNG ADULTS, YOU'LL SEE THAT VISIBLY. LET ME CHANGE THE ACCESS HERE TO THE TO BE FOCUSED ON 2010. AND WE SEE A LOT OF PRE-MATURE YEARS LOST STILL DUE TO DEATH UNDER AGE 5. CONSIDERABLE PREMATURE DEATH IN TERMS OF YEARS OF LIFE LOST YOUNGER ADULT AGES FROM HIV TB ROAD TRAFFIC ACCIDENTS IN PURPLE, RANGE OF INJURIES, THEN OF COURSE PREMATURE MORTALITY FROM HEART DISEASE, KAREN, DIABETES IN GREEN AND RANGE OF OTHER CAUSES OVER AGE 60 AND ON INTO 80 PLUS. ONE OF THE MORE IMPORTANT INSIGHTS FROM THIS STUDY WHEN WE LOOK AT THE DISABILITY COMPONENT, PREVALENCE TIMES SEVERITY AND SOME ACROSS DISEASES WE SEE A COMPLETELY DIFFERENT AGE PATTERN AND DIFFERENT SET OF CAUSES THAT DOMINATE. THIS IS YEARS LIVED WITH DISABILITY AT THE GLOBAL LEVEL AGAIN, WHERE DOMINANT CAUSES OF YEARS LIVE WITH DISABILITY ARE THINGS LIKE MENTAL AND BEHAVIORAL DISORDERS. MUSCULOSKELETAL DISORDERS, GRAB BABB OF OTHER COMMUNICABLE HEARING, VISUAL LOSS CONGENITAL AND ANEMIA AND MALL KNEW FROM CHRONIC FROMTORY CONDITIONS. EVEN OLDER AGES FROM CARDIOVASCULAR DISEASE AND CANCER IS CARETIVELY SMALLER THAN THE CONTRIBUTION FROM MENTAL HEALTH MUSCULOSKELETAL DISORDERS AND VISION LOSS HEARING LOSS CATEGORY. P PUT ALL THISSING TO AND YOU GET COMPLEXITY WE KNOW AS AS PATTERNS OF HEALTH AROUND THE WORLD, MULTIPLE SIMULTANEOUS AGENDAS, PRE-MATURE DEATH AND CHILDREN AN PREMATURE MORTALITY, YOUNG ADULTS WITH DISABILITY AND AGENDA OF COURSE AROUND THE RANGE OF CONDITIONS AT OLDER AGES. SO THAT IS ONE WAY LOOKING AT THE RESULTS. I WANT TO SHOW YOU ANOTHER WAY, AGAIN USING THESE TOOLS TO UNDERSTAND RANGE OF PATTERNS WE SEE AROUND COUNTRIES IN THE WORLD. THIS IS AGE STANDARDIZED DEATH RATES FOR G-20 COUNTRIES. THAT GIVES A NICE RANGE OF COUNTRIES AROUND THE WORLD TO WHICH I ADDED HERE WITH WORST COUNTRIES IN THE WORLD WEST AFRICA. ND YOU CAN SEW IN 2010 ENORMOUS VARIATION IN AGE BY DEATH RATE, JAPAN AND THIS GROUP AT LOWEST, THE U.S. QUITE A BIT HIGHER THAN JAPAN IN TERMS OF AGE STANDARDIZED DEATH RATES BUT DRAMATICALLY LOWER THAN COUNTRIES LIKE INDONESIA, RUSSIA, INDIA OR SOUTH AFRICA. BUT WHEN WE SHIFT TO LOOKING AT YEARS OF LIFE LOST, YOU SEE IT EVEN BIGGER RANGE OF AGE STANDARDIZED RATES ACROSS COUNTRIES. WHEN WE SHIFT YEARS LOOKING AT DISABILITY WE SEE A RATHER INTERESTING FINDING WHILE THERE'S ENORMOUS VARIATION ACROSS COUNTRIES IN PREMATURE MORTALITY AND DEATH RATES, THERE IS MUCH LESS VARIATION ACROSS COUNTRIES IN AGE STANDARDIZED FACILITY RATES. IN FACT, WHAT WE'RE OBSERVING IS AS PREMATURE MORTALITY GOES DOWN, WE SEE MINIMAL CHANGE IN YEARS PREVALENCE DISABILITY. MAYBE 1919 TO TO 2010 IN MOST HIGH INCOME COUNTRIES A 5 OR 6% DECLINE. AND THE THE COMBINATION OF AGING OF THE POPULATION, THE CLEAR RELATIONSHIP WITH PREVALENCE OF DISABLE AGE MEAN IT IS VOLUME OF DISABILITY IN TERMS OF EXPERIENCE BY POPULATIONS GOES UP STEADILY. EVEN IF THE AGE STANDARDIZED RATES ARE VERY SLOWLY GOING DOWN. THAT IS SUCH A MARKED CONTRAST IN TRENDS OF MORTALITY BURDEN O DISEASE THE PROGRESSIVELY SHIFT TOWARDS DISABILITY AS A KEY FACTOR AND NOT PREMATURE MORTALITY. SO THERE'S A RANGE OF WAYS FOR US TO EXPLORE THESE PATTERNS. LET ME TRY ANOTHER VISUAL TOOL TO HELP US THINK ABOUT DISEASE PATTERNS AND TRANSITION. I'M NOW BACK IN 1990 SHOWING YOU A TREE MAP, IT'S A SQUARE PIE CHART. SO JUST LIKE A PIE CHART THE SIZE OF THE BOX IS THE SAME AS SIZE OF A WEDGE. THIS IS SHOWING VISUALLY THE 21 BROAD CAUSE GROUPS, THE NON-COMMUNICABLE CAUSES IN BLUE. COMMUNICABLE MA ATTORNEY NEONATAL CAUSES, THOSE MORE ASSOCIATED WITH POVERTY IN RED. AND INJURIES IN GREEN. AND GLOBALLY EPIDEMIOLOGICAL TRANSITION DRIVEN BY CHANGING DISEASE RATES MOSTLY AROUND MORTALITY, AND CHANGING DEMOGRAPHY MEANS FROM 1990 TO 2010 YOU HAVE THIS PROGRESSIVE SHIFT TOWARDS NON-COMMUNICABLE DISEASES AT THE GLOBAL LEVEL. IF WE LOOK BY COUNTRY THAT SHIFT IS MORE DRAMATIC IN MANY REGARDS. I'M GOING TO ADD A MAP ON THE BOTTOM. IF WE SHIFT TO LOOKING AT NON-COMMUNICABLE DISEASE IN THE BOTTOM FIGURE, AND SHIFT LOOKING AT THESE IN TERMS OF PERCENT WHAT WE SEE IS PERCENT OF BURREN MEASURED BY DISABILITY ADJUSTED LIFE YEARS DUE TO NON-COMMUNICABLE CAUSES. AS YOU EXPECT IN THE U.S., 85% OF THE BURDEN IS DUE TO NCDs. IN A PLACE LIKE CHINA IT'S NOT FAR BEHIND NOW. CHINA IS AN EXAMPLE OF A COUNTRY WHERE EPIDEMIOLOGICAL TRANSITION MOVEDDED AT AN EXTRAORDINARY PACE SO THE DISEASE PROFILE IN CHINA AS A COUNTRY PARTICULARLY CHINA IN THE EAST OF THE COUNTRY IS QUITE SIMILAR NOW TO THE UNITED STATES. INDIA, EPIDEMIOLOGICAL TRANSITION IS IN A HALFWAY POINT WITH ABOUT 45% BURDEN FROM NON-COMMUNICABLE DISEASES, 45% FROM COMMUNICABLE CAUSES AN INJURIES MAKING UP THE REST AND OF COURSE IN WEST AFRICA, WE STILL HAVE A DISEASE PATTERN THAT'S REALLY DOMINATED BY THE INFECTIOUS CAUSES OF CHILDHOOD MORTALITY OR YOUNG ADULT MORTALITY. MY TOOL IS NOT WAKING UP HERE. THAT'S THE RANGE OF EPIDEMIOLOGICAL TRANSITION. ANOTHER WAY TO SEE THAT AN GETS TO SOME OF THE GEROSCIENCE AGENDA IS WITH THESE ARROW DIAGRAMS WHERE WE CAN LOOK AT THE RANK LIST WITH UNCERTAINTY IN THE LITTLE BRACKETS CAUSES OR LEADING CAUSE OF PRE-MATURE MORTALITY DISABILITY IN 1990 CONNECTED TO THE CAUSES IN 2010. NCDs ARE BLUE, NEONATAL CAUSES OF RED AND INJURIES GREEN, AT THE GLOBAL SCALE YOU CAN SEE LOTS OF SHIFTS GOING ON. WITH ISCHEMIC HART DISEASE BEING NUMBER ONE CAUSE. PNEUMONIA NUMBER 2 AND STROKE 3, CLUSTER OF DIARRHEA, HIV AIDS MALARIA ON THE TOP BUT THEN LOW BACK PAIN, COPD IN THESE CAUSES. THIS RANGE LIST AT THE GLOBAL LEVEL REFLECTS BOTH RATES AND DEMOGRAPHYIES. SO THE CHANGES INCREASE OVER YEARS 30% ISCHEMIC HEART DISEASE IS CHANGING IN AGE STANDARDIZED RATES AND SHIFT TO OLDER AGES WE CAN SHIFT TO LOOKING AT AGE STANDARDIZED RATES AND P REMOVE THE EFFECTS OF DEMOGRAPHIC CHANGE, THERE WHAT YOU SEE IS ISCHEMIC HEART DISEASE THOUGH GOING UP GLOBALLY IN TERMS OF NUMBERS RATES ARE ACTUALLY GOING DOWN BY 18%. FROM 1990 TO 2010. PNEUMONIA GOING DOWN BY 50%, STROKE GOING DOWN BY 23%. THERE'S A HANDFUL OF THINGS WHERE THERE'S LITTLE CHANGE LOW BACK PAIN, SOME THINGS WITH INCREASES LIKE MALARIA OR ROGUE INJURY. MAJOR DEPRESSION, NO REAL CHANGE, DIABETES GOING UP BY 11% IN AGE STANDARDIZED RATES. AND THINGS LIKE SOME OTHER CAUSES WOULD GO LOWER IN THE RISK LIKE DEMENTIA. IF WE LOOK AT THE UNITED STATES, WHAT WE'RE GOING TO SEE IN TERMS OF AGE STANDARDIZED RATES, BIG INCREASES FOR DRUG USE DISORDERS AS EXAMPLE BIG INCREASE FOR ALCOHOL USE ALZHEIMERS AN LOWER IN THE CAUSE LIST SEE BIG INCREASES FOR PARKINSON'S AS WELL. SO THERE'S DETAIL ABOUT WHAT'S HAPPENING AROUND THE WORLD BY SPECIFIC CAUSES, THAT'S ACCESSIBLE AND SPEAKS TO BOTH SOME GENERAL PATTERNS WE OBSERVE IN THE WORLD AND REGIONAL SPECIFICITY THAT WE SEE IN THE DATA. ANOTHER IMPORTANT DIMENSION OF THE STUDY IS TO GO BEYOND THE ICD LIST OF DISEASES AN INJURIES AND LOOK AT SOME OF THE UNDERLYING EXPOSURES THAT MAY ACCOUNT FOR THE PATTERNS OF DISEASE THAT WE SEE AROUND THE WORLD. SO AGAIN USING THIS METRIC OF DISABILITY ADJUSTED LIFE YEARS I'M GOING TO CHANGE THE X AXIS PERCENT, HERE ARE THE LEADING RISK FACTORS GLOBALLY AND YOU GET A SENSE OF THE EPIDEMIOLOGICAL TRANSITION BACK TO 1990 THAT SHOWS IN THESE RISK FACTORS. BACK IN 1990, THE LEADING GLOBAL RISK WAS MALNUTRITION IN CHILDREN FOLLOWED BY DIET MORE GENERALLY IN TERMS OF CONTRIBUTION TO ADULTS. IN DOOR AIR POLLUTION NUMBER THREE, SMOKING NUMBER 4, HIGH BLOOD PRESSURE AND SUBOPTIMAL BREAST FEEDING. OVER THE 20 YEAR PERIOD YOU SEE BIG SHIFTS TOWARDS THE INDIVIDUAL BEHAVIORAL RISKS THAT UNDERLIE THE NCD PATTERNS WE SEE IN THE WORLD WITH NOW DIET HIGH BLOOD PRESSURE SMOKING AT THE TOP. HIGH BODY MASS INDEX COMING HERE IS THE 6TH RISK BUT IF WE LOOK AT DEVELOPED COUNTRIES, THE GROUPING WHAT WE SEE IS OBESITY ACTUALLY COMING IN AT NUMBER 4. SO THERE'S A LOT OF DETAIL ON THIS RISK TRANSITION. AND OPENS UP MANY OPPORTUNITIES FOR US TO UNDERSTAND WHERE ONE MIGHT INTERVENE ON RISK FACTORS TO HAVE BROAD EFFECTS ON HEALTH OUTCOMES. AND OUR FINDINGS MATCH SOME OF THE THINGS THAT FOR EXAMPLE CAME OUT OF THE IOM STUDY ON THE U.S., TOBACCO, OBESITY DO ACCOUNT FOR A SUBSTANTIAL FRACTION OF SOME OF THE VARIATION AN LIFE SPAN THAT WE OBSERVE ACROSS HIGH INCOME COUNTRIES AS AN EXAMPLE. SO LET ME SHOW YOU THE SPECIFIC RESULTS NOW FOR THE US. RELATED TO THE GLOBAL BURDEN OF DISEASE WORK IS OUR DRIVE TOWARDS SOME NATIONAL DETAIL AND THAT'S -- I'LL GIVE MORE UPDATE IN A MOMENT BACK TO POWERPOINT. I'LL SHOW YOU FININGS ON LIFE SPAN THAT COME FROM DRILLING DOWN IN SOME OF THE COUNTRIES WE EXAMINE, MAINLY THE UNITED STATES. HERE IS ANOTHER ONLINE TOOL. THIS REFLECTS ASSESSMENT OF LIFE EXPECTANCY BY LOCALITY IN THE UNITED STATES. MAINLY BY COUNTY. AND FOR THOSE INTERESTED THIS IS USING SOME SMALL AREA BASE YEN METHODS TO GENERATE FULL LIFE TABLES FOR EACH COUNTY OVER TIME FOR EACH YEAR. I'LL PLAY A MOVIE OF LIFE EXPECTANCY IN THE UNITED STATES FOR WOMEN FROM 1985 TO 2010, CHANGE IN LIFE EXPECTANCY OVER A GENERATION. GOOD NEWS IS PARTS OF THE NORTH UPPER MIDWEST, CALIFORNIA PARTS OF NEW ENGLAND ARE SEEING STEADY INCREASES FROM WOMEN, PARTS OF FLORIDA AS WELL. WHAT IS INTRIGUING FOR UNDERSTANDING LIFE SPAN IN THE UNITED STATES IS THAT AL L THOUGH THERE ARE COMMUNITIES WITH QUITE SUBSTANTIAL GAINS GENERATION UP TO SEVEN YEARS IMPROVEMENT FOR WOMEN. THERE IS ACTUALLY A WHOLE HOST OF POPULATIONS WHERE THERE'S LITTLE CHANGE OF WOMEN. IF I CHANGE THIS MAP TO LOOK AT CHANGE IN LIFE EXPECTANCY OVER THE 25 YEAR PERIOD, YOU SEE ALL THE PLACES IN RED AND DARKER YELLOW, NO CHANGE IN FEMALE LIFE SPAN. THERE ARE THESE POPULATION WITH SUBSTANTIAL INCREASES BUT THERE'S ALSO A HOST OF SOME 900 COUNTIES IN THE UNITED STATES WITH NO STATISTICALLY SIGNIFICANT IMPROVEMENT IN LIFE SPAN. CONNECTING THIS UP TO THE REST OF THE BURDEN OF DISEASE WORK, THE WORK IS TENTATIVELY COMPLETED, TRYING TO THOSE OUT DISEASES INJURIES RISK FACTORS THAT MIGHT ACCOUNT FOR THIS UNUSUAL HETEROGENEITY IN PROGRESS LIFE STATUS IN THE UNITED STATES. ON TO SOME OF THE OTHER ASPECTS OF THE STUDY AND WHERE WE ARE GOING IN THE FUTURE. SO SOMEWHAT TO OUR SURPRISE WHEN WE PUBLISH THESE RESULTS LAST DECEMBER WE WERE IMMEDIATELY APPROACHED BY THE UK GOVERNMENT, ASK IF WE CAN USE THE RESULTS FROM THE LOW BURDEN OF DISEASE TO BENCHMARK PROGRESS OF THE UK ON KEY OUTCOMES, SOME CANCER OUTCOMES, CARDIOVASCULAR DISEASE AN RANGE OF RISK FACTORS AROUND THE COUNTRIES IN WESTERN EUROPE, AND THE SURPRISING THING TO US WAS THAT WHY HADN'T THIS HAPPENED BEFORE AND IT COMES BACK TO FUNDAMENTAL YOU SHALL SHOE AROUND COMPARABILITY THAT AS REPORTED CAUSE OF DEATH IS HARD TO PREPARE BECAUSE OF NATIONAL VARIATION IN CODING PRACTICE. THERE'S TREMENDOUS AMOUNT OF WORK IN GLOBAL DISEASE STUDY TO HARMONIZE, STANDARDIZE CAUSE OF DEATH, CODING AN REPORTING. SO HAVING THIS SOMEWHAT CLEANED UP DATA SET FACILITATED FOR THEM THIS BENCHMARKING EXERCISE. THAT SPAWNED A SERIES OF BENCHMARKING EXERCISES THAT WE HADN'T ACTUALLY FORESEEN. SO THE UK ONE TURNED QUICKLY INTO A STUDY PUBLISHED IN THE LANSETT IN MARCH AND THAT WAS BOTH FROM OUR CONSORTIUM AN PEOPLE IN THE DEPARTMENT OF HEALTH AND UK, THAT THEN LED TO SOME IDENTIFICATION WHERE THE UK WAS DOING RATHER POORLY EVEN AREAS THEY INVESTD HEAVILY AND LED JEREMY HUNT SECRETARY OF STATE FOR HEALTH TO ISSUE A CALL TO ACTION THE DAY THE PAPER CAME OUT AND MORE INTERESTINGLY AN IMPORTANTLY FROM SCIENTIFIC POINT OF VIEW COMMITMENT TO MEASURE USING THE SAME DEFINITIONS AND APPROACHES, BURDEN OF DISEASE IN THE UK FOR 12 SUBNATIONAL UNITS, WALES, NORTHERN IRELAND, SCOTLAND AND NINE REGIONS OF ENGLAND. WORK UNDERWAY. A SIMILAR PROCESS HAPPENED IN CHINA WITH ANALYSIS OF BURDEN OF DISEASE RESULTS, PUBLICATION FROM THAT AND COMMITMENT BY THE GOVERNMENT, CDC AND SOME KEY SURVEILLANCE GROUPS IN CHINA AND INVESTIGATORS AT PEEKING UNIVERSITY MEDICAL COLLEGE COLLABORATE PRODUCING PROVINCIAL LEVEL AND COUNTY LEVEL WE BELIEVE ANALYSES OF HEALTH OUTCOMES IN CHINA. THAT'S EXCITING BECAUSE IT'S SUCH A LARGE PLACE, TURNS OUT TO BE BETTER DATA THAN WE KNEW ABOUT AND REALLY INTERESTING FOCAL PATTERNS OF DISEASE OUTCOMES THAT ARE STARTING TO EMERGE. WE HAD A SIMILAR ANALYSIS IN THE US. THE INVESTIGATORS PUTTING TO ANALYSIS OF THE STATE OF U.S. HEALTH USING THE DATABASE PUBLISHED IN JAMA. TIME AT THE WHITE HOUSE HOSTED BY MY SHELL OBAMA AND THERE WAS ALSO THE RELEASE OF THAT SUBNATIONAL RESULT AROUND COUNTY LIFE EXPECT P FANCY AT THIS EVENT AT THE WHITE HOUSE. SO THERE'S BEEN QUITE A BIT OF INTEREST IN FURTHER ANALYSIS WE HOPE SUBNATIONAL LEVEL USING SAME CASE DEFINITIONS APPROACHES FROM THE BURDEN OF DISEASE WORK. THIS DRIVE OR INTEREST IN SUBNATIONAL WORK IS CONTINUING TO GROW. SO THE GOVERNMENT OF MEXICO, NATIONAL INSTITUTE OF PUBLIC HEALTH MEXICO WILL PRODUCE SUBNATIONAL ASSESSMENTS FOR MEXICO, SAME FOR AUSTRALIA, INDONESIA AND SEVERAL OTHER COUNTRIES ARE STARTING TO DISCUSS SUCH AS INDIA, WHETHER THERE IS FEASIBLE. LET ME MOVE ON TO ENDING THIS PRESENTATION WITH WHERE THIS BODY OF WORK IS GOING. WE VIEW THE ANALYSIS SCIENTIFIC PUBLICATION AN ONLINE TOOLS AS A GLOBAL PUBLIC GOOD. AND WE'RE VERY HAPPY WE HAVE FUNDING FOR SOME OF THE CORE COSTS BILL AND MELINDA GATES FOUNDATION TO PRODUCE ANNUAL UPDATES OF THIS BODY OF WORK. THE FIRST WILL BE BRINGING THE ASSESSMENT THROUGH THE YEAR 2013 AND WILL BE PUBLISHED NEXT YEAR. THAT WILL INCLUDE THE SUBNATIONAL STUDIES FOR THE UK CHINA AND MEXICO. WE'RE ALSO EXPANDING THE SCOPE OF THIS ANALYSIS. ONE WILL BE ADDING A FORECASTING ELEMENT. WE HAD A SET OF FORECASTS THAT WERE PRODUCED IN THE 1990 ET CETERA FOR THE FIRST GLOBAL BURDEN OF DISEASE STUDY AT THE REGIONAL LEVEL AND WE WILL BE PRODUCING COUNTRY FORECASTS THAT WILL PROBABLY BE SOMETHING THAT WILL TAKE A COUPLE OF YEARS TO FINALIZE THE METHODS AND PRODUCE RESULTS SO LOOK FOR 2015 FOR THOSE FININGS. ONE OF THE EARLY RESULTS FROM THAT WORK IS THAT WE THINK LIFE SPANS WILL BE MUCH LONGER THAN WHAT FOR EXAMPLE THE SOCIAL SECURITY ADMINISTRATION IN THIS COUNTRY THINKS SO PROFOUND IMPLICATIONS FOR THE FINANCIAL VIABILITY OF THINGS LIKE SOCIAL SECURITY. PERHAPS NOT A SURPRISE BECAUSE HISTORICALLY UNDERESTIMATED PROGRESS IMPROVING LIFE SPAN IN LOW INCOME COUNTRIES. SECOND DIRECTION OF SCOPE IS TO TRACK HEALTH EXPENDITURE AT THE NATIONAL LEVEL FOR THE SAME DISEASE INJURY CATEGORIES. IT WILL BE INTERESTING EVENTUALLY TO BE ABLE TO LOOK AT CHANGE IN SPENDING VERSUS CHANGE IN OUTCOME AT DISEASE SPECIFIC LEVEL AND IDENTIFY WHERE THERE HAS BEEN QUOTE, VALUE FOR MONEY IN THE SENSE SPENDING ON OUTCOME LUKE DIABETES YOU HAVE SEEN THE GREATEST IMPROVEMENT. WE HOPE VERY MUCH TO CONTINUE THIS WORK THAT I MENTIONED ON COUNTY LEVEL OUTCOMES AND WE WOULD LIKE TO UNDERTAKE AND TRYING TO APPLY FOR FUNDING FROM A VARIETY OF SOURCES TO DO THE FULL BURDEN OF DISEASE ANALYSIS, LOCAL LEVEL IN THE UNITED STATES SO PART OF WORK WE HOPE WILL BE DONE AND SOMETHING PLANNED FOR THE FUTURE. ONE THING I WANT TO SHOW BEFORE CLOTHING, THOSE I KNOW HAVE IN THAT YOU ARE MIND THE QUESTION WHERE IS THE DATA FROM. SO I WANT TO POINT OUT THAT WE ARE TRYING RATHER CONSISTENTLY TO MAKE AVAILABLE RESULTS OF ANALYSIS BUT ALSO THE RAW DATA INTO IT. SO ONLINE YOU CAN LOOK UP MORTALITY DATA UNDERLYING PRIMARY MORTALITY DATA, HERE IS THE UNITED STATES, THIS IS VITAL REGISTRATION DATA, LOOK AT DIFFERENT AGE GROUP AND SEE THE RAW DATA. THAT'S USED IN THE ANALYSIS. BUT YOU CAN ALSO DO THAT FOR CAUSE OF DEATH DATA. SO ANOTHER TOOL ONLINE, LOOK AT CAUSE OF DEATH, YOU WILL SEE THE RAW DATA THAT'S AVAILABLE FOR EACH COUNTRY ON EACH CAUSE OF DEATH AND WE DON'T YET HAVE THESE TOOLS ONLINE FOR THE THOUSAND CLINICAL SEQUELLAE BUT NEXT MAY WE HOPE WE WILL BE ABLE TO PUT UP AVAILABLE VISUAL DATABASES LIKE THIS THAT SHOW YOU THE METADATA FOR EVERY STUDY THAT'S USED IN THIS ANALYSIS WHETHER PUBLISHED LITERATURE OR UNPUBLISHED ANALYSES GIVEN PERMISSION TO SHOW THEM. SO THANK YOU VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] >> GOOD MORNING. MY NAME IS VON COHINSKI, DIVISION -- AND WITH PHILIPPE CO-DIRECTOR OF THE GEROSCIENCE GROUP. THE NEXT KEYNOTE TALK IS ON BRIAN KENNEDY, BASIC RESEARCH ON AGING. DR. KENNEDY RECEIVED HIS Ph.D. IN BIOLOGY FROM THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY. WAS A FACULTY MEMBER DEPARTMENT OF BIOCHEMISTRY UNIVERSITY OF WASHINGTON AND CURRENTLY PRESIDENT AND CHIEF EXECUTIVE OFFICER OF THE BATCH INSTITUTE FOR AGING RESEARCH. DR. KENNEDY. -- THE BUCK INSTITUTE ON RESEARCH. DR. KENNEDY. >> IT'S A GREAT PRIVILEGE TO BE HERE TO GIVE THIS TALK. WHAT I'M GOING TO TRY TO DO TODAY IS SUM UP A LOT OF AGING RESEARCH AND GEROSCIENCE RESEARCH THAT'S GONE ON MANY LABS AROUND THE UNITED STATES AND THE WORLD. AND GIVE A BASELINE FEEL FOR WHERE WE ARE IN TERMS HOW AGING HAPPENS, WHAT WE THINK CAN BE DONE AND WHAT MIGHT HAPPEN IF WE DO THAT. LET ME JUMP INTO IT. THIS IS THE BUCK INSTITUTE. AND THESE ARE THE STATISTICS THAT I WANT TO START WITH. I COULDN'T USE DR. MURRAY'S DATA SO I'M GOING TO STICK TO ONE SLIDE HERE AND THE POINT IS THAT IN 2015, 2 BILLION OF THE 9 BILLION PEOPLE ON EARTH WILL BE OVER AGE 60. AND JUST A FEW YEARS FROM NOW MORE PEOPLE WILL BE OVER AGE 65 THAN UNDER 5. THE REASON I POINT THIS OUT IS THIS IS NOT JUST QUALITY OF LIFE O OR DISEASES OF OLD PEOPLE THIS IS A MAJOR ECONOMIC ISSUE FACING THE WORLD. IF THESE PEOPLE OVER 65 HAVE CHRONIC DISEASE CAN'T WORK AND HIGH HEALTHCARE COSTS THERE'S NOT GOING TO BE ENOUGH PEOPLE WORKING TO GENERATE A BIG ENOUGHMY TO PAY FOR THEM. SO WE HAVE A MAJOR ECONOMIC ISSUE ON OUR HANDS. WE'RE NOT THE ONLY ONES TO THINK ABOUT THAT. IN FACT, MANY GOVERNMENTS ARE THINKING ABOUT IT. AND THE WAY THEY THINK ABOUT IT IS INTERESTING. SO THEY'RE CONSIDERED HEALTHY AGING A LOT OF WORK IS FIGURING HOW THE CHANGE SOCIAL PROGRAMS AN SOCIAL POLICY TO ADAPT TO HAVING OLDER PEOPLE IN THE POPULATION. SO HOW DO WE DEAL WITH PERM INCOME AN DEPENDENCE. SOCIAL LEVEL FISCAL SUSTAINABILITY, ARE THEY TOO HIGH, TOO LOW, PEOPLE LIVING LONGER, CAN THEY AFOR IT, SHOULD WE CHANGE RETIREMENT AGE. YOU CAN GO DOWN THIS LIST. THE ONLY REASON I REALLY POINT THIS OUT IS THAT THE WORLD IS ALREADY THINKING ABOUT THIS PROBLEM. THOUGH NOT FROM PERSPECTIVE OF AGING RESEARCH. THE UNITED NEIGH OR WORLD HEALTH ORGANIZATION THEY'RE SUGGESTING WHAT COUNTRIES SHOULD DO TO TAKE CARE OF THE BURDEN OF OLDER POPULATIONS. EVERYTHING FROM REDUCING PENSION BENEFITS TO REDUCING HEALTHCARE COSTS, EXTENDING WORK LIVES AND DOWN THE LIST. NO COLUMN THAT SAYS KEEP PEOPLE HEALTHY LONGER OR DO SOMETHING ABOUT THE DISEASE OF AGINGING. SOMETHING LIKE EXTEND WORK LIFE PEOPLE ARE NOT HEALTHY AND NOT FUNCTIONING HIGHLY, IT WON'T HELP TO EXTEND RETIREMENT AGE AND MAKE PEOPLE WORK LONGER. PEOPLE COME ALL THE TIME, WE'RE SUCCESSFUL AND WORK LONGER WE HAVE TO WORK LONGER NO, YOU'RE GOING TO HAVE TO WORK LONGER AND WE HOPE WE CAN KEEP YOU HEALTHY WHILE DOING IT BECAUSE THOSE KINDS OF CHANGES WILL HAPPEN THROUGHOUT THE WORLD. THE 20 COUNTRIES RECENTLY SURVEYED, 13 WERE CURRENTLY THINKING ABOUT RAISING RETIREMENT AGE. SO BACK TO AGING THIS IS AN OVERSIMPLIFIED SLIDE BUT ILLUSTRATE IT IS POINT HOW THE WORLD CHANGED. THIS IS A ROUGH ESTIMATE OF LIFE EXPECTANCY OVER 10,000 YEARS ASIAN. YOU CAN SEE IT WAS HOLDING STEADY BASED ON THE DATA WE HAVE, AROUND 25, NOT AS ACCURATE AS YOUR DATA BUT DOING MY BEST, 25 YEARS OF AGE UNTIL RECENTLY WITHIN THE LAST 300 YEARS OVER 60 AND HIGHER THAN THAT IN MANY COUNTRIES. THAT'S TWO ISSUES AT HAND HERE, ONE IS WE HAVE NEVER LIVED IN A WORLD LICK THIS BEFORE, AND THE ENVIRONMENTAL CONDITIONS THAT WE HAVE NOW ARE NOTHING LIKE WHAT WE ADAPTED TO LIVE IN. SO A WORLD WHERE 20% PEOPLE ARE OVER AGE 65 WAS NOT ENVISIONED BY 4 BILLION YEARS OF EVOLUTION AN NEW WORLD WE HAVE TO FIGURE HOW TO ADJUST TO. WHY DID THIS HAPPEN? THEY STAY HEALTHY FOR WHILE. IF YOU PUT THEM IN THE WILD YOU'RE NOT FINDING 3-YEAR-OLD MICE YOU FIND MICE DYING AT 4, 5, 6 MONTHS, BARELY LONG ENOUGH TO PRODUCE PROGENY FOR THE NEXT GENERATION. THIS IS WHAT'S HAPPENED IN THE HUMAN POPULATION, WE HAVE GONE FROM LIVING IN THE WILD TO LIVING IN THE PROTECTED LABORATORY ENVIRONMENT. WHERE MOST OF US HAVE ENOUGH FOOD TO EAT, NOT DYING AS MUCH FROM INFECTIOUS DISEASE, CHILDBIRTH OR ANYTHING LIKE THAT. SO WE'RE LIVING LONGER IN A LAB NOW. ANOTHER WAY OF LOOKING AT THIS, FROM TOM KIRKLAND THINK ABOUT IT THIS WAY. WE HAVE A LIMITED AMOUNT OF RESOURCES TO DEVOTE TO LIVING. THE MAIN GOAL IS FAR RIGHT SIDE HERE, PROGENY. THAT'S FITNESS, THAT'S WHAT WE'RE SELECTED FOR. WE ALLOCATE THOSE RESOURCES TO MAXIMIZE FITNESS, MIGHT ALLOCATE GROWTH, MAINTENANCE OF OURSELVES GOOD FOR AGING. OUR MATERIALS ARE REPRODUCTION AND WE'LL CHOOSE HOW TO ALLOCATE THESE RESOURCES IF WE'RE SPECIES TO BEST OPTIMIZE FITNESS. WE'RE NOT OPTIMIZING FOR AGING. THAT'S TWOFOLD. ONE THING THAT EXPLAINS WHY THE AGES DISEASES OF AGING HAPPEN, AND COME AFTER REPRODUCTIVE YEARS END. WE'RE NOT SELECTED TO STAY HEALTHY DURING THAT WINDOW IN TIME BUT IT SUGGESTIONS THERE'S MALLIBILITY IN THE PROCESS, IT'S POSSIBLE TO CHANGE AGING RATES. WE KNOW THAT. THERE'S PLENTY OF LONG LIVED SPECIES OUT THERE. HERE IS A NAKED MOLE RAT THAT LIVES TO 30 YEARS OF AGE, TEN TIMES LONGER THAN MICE. WHICH IS THE SAME SIZE AS THE MOUSE, MORE OR LESS THE SAME METABOLISM, THERE'S THINGS SIMILARLY TO A MOUSE, 30 YEARS OF AGE, MANY MUCH LONGER LIVED SPECIES OUT THERE. SO NATURE CAN FIGURE OUT A WAY TO KEEP ANIMALS HEALTHY FOR A LONG PERIOD OF TIME IF OPTIMIZES FITNESS. SO I'M GOING TO COME TO THREE QUESTIONS TODAY. WHAT ARE THE MECHANISMS OF CAUSES OF AGING CAN WE SLOW IT AND WILL THAT IMPACT CHRONIC DISEASES OF AGING. THE FIRST ONE I'M GOING TO SPEND ONE SLIDE ON BECAUSE REALLY THIS IS WHAT YOU'RE GOING TO HEAR ABOUT OVER THE NEXT TWO DAYS. SO IT WOULD BE SILLY TO TELL YOU IN A 10,000-FOOT LEVEL WHAT YOU'LL HEAR GROUND LEVEL FOR MANY SCIENTISTS OVER THE NEXT COUPLE OF DAYS, I'LL POINT OUT WE DON'T KNOW IN DETAIL MOLECULAR MECHANISMS THAT DRIVE AGING PROCESS YET BUT IT'S PROBABLY SOME COMBINATION OF THESE. GROUPED TO THREE CATEGORIES. AVERAGE ACCUMULATION, REACTIVE OXYGEN SPECIES, DAMAGE TO MITOCHONDRIA, DNA DAMAGE OR PROTEIN MISFOLDING AND AGGREGATION WE KNOW WHAT HAPPENS WITH MULTIPLE TISSUES AN ORGANS OF THE GUY, WHAT DRIVES AGE RELATED DISEASE PROCESS THAT DISTRIBUTES DIRECTLY TO AGING. THERE'S ALSO A LARGE BODY OF RESEARCH THAT'S GONE ON SUGGESTING THAT LOTS OF HOMEOSTASIS IS IMPORTANT. WE SEE CHANGES IN EPIGENETIC REPROGRAMMINGPROGRAMMING WITH AGE, THAT'S A RELATIVELY NEW FINDING. ADULT STEM CELL POOLS ARE NOT ABLE TO REPLENISH DAMAGED TISSUE DURING THE AGE PROGRESSSIS, THIS IS SOMETHING OVER THE LAST TEN YEARS, EMERGED IN MAYBE A MAYBE FORCE DRIVING AGING. CHANGES IN IN METABOLISM, DRIVING AGE RELATED DISEASE LIKE DIABETES, CHANGES IN CELL SIGNALING PATHWAYS THAT OCCUR IN THE AGING PROCESS. FINALLY ANTAGONISTIC PLY OWE TROUGH BY, THESE ARE THINGS IMPORTANT FORFEITNESS PATHWAYS THAT YOU HAVE TO KEEP YOU HEALTHY BUT MAY HAVE A COST WHEN YOU GET OLDER. I PUT CELLS SENESCENCE IN HERE, YOU'LL HEAR A LOT ABOUT THAT. THE LOTS OF PROLIFERATIVE POTENTIAL CELLS HAVE IN CELL CULTURE AND ALSO IN YOUR BODY DURING AGING, IT'S A COMPLICATED STORY BUT ONE OF THE DRIVING FACTORS IN AGING, SHORTENING OF TELOMERES AND INFLAMMATION. ACUTE INFLAMMATION IN RESPONSE TO INJURY OR CRISIS IS IMPORTANT, CHRONIC INFORMATION SO MY GUESS IS SOME COMBINATION, SOME MORE IMPORTANT IN DIFFERENT TISSUES THAT ARE REALLY IN COMPILATION DRIVEING WHAT WE CALL AGING AND CONTRIBUTING TO AGE RELATED DISEASES. CAN WE SLOW THE RATE OF AGE SOMETHING WE'RE NOT THE FIRST TO THINK ABOUT THIS TURNS OUT. ONE EXAMPLE IS WHICH YOU KNOW CHIN WONG, A SUCCESSFUL EMPEROR, AT THE END OF THE STATES PERIOD HE UNIFIED CHINA, MANY GREAT SUCCESSES, HE DECIDED IMMORTALITY WOULD BE A GOOD THING FOR HIM AND HAD MANY OF HIS CHEMISTS AND DOCTORS WORKING ON HOW HE SHOULD STAY ALIVE FOREVER. AND THEY CHOSE MERCURY AND EVERY DAY HE TOOK MERCURY. ONE DAY THEY MADE A MISCALCULATION AND HE TOOK TOO MUCH MERCURY AND HE -- PUT IT THIS WAY, HE DIDN'T ACHIEVE IMMORTALITY. SO THAT WAS A LITTLE BIT OF AN UNSUCCESSFUL APPROACH. WE HAVE BEEN MORE SUCCESSFUL IN RESEN YEARS. AND THE START OF THIS IS REALLY DIETARY RESTRICTION. HERE IS ONE PIECE OF DATA, THIS IS NOW EIGHT DECADES OLD IN MICE AN RATS. AND REDUCING THE AM OF CALORIES FROM AN AD LIB DUMB DIET OR DIET THEY CAN HAVE AS MUCH AS THOUGHT DOWN TO LEVELS JUST ABOVE MALNUTRITION EXTEND LIFE IN RODENT, MICE, RATS AND ORGANISMS. THIS IS THE FIRST EVIDENCE I THINK THAT YOU CAN CHANGE AGING BUT IT'S ALSO EVIDENCE THAT THE ENVIRONMENT HAS A BIG IMPACT ON AGING. I WANT TO COME BACK TO THAT A COUPLE OF TIMES DURING THIS TALK. I ALSO WANT TO POINT OUT THE REAL STRENGTH OF THE AGING MODEL ORGANISMS OVER THREE DECADES OR SO THAT HAVE DRIVEN ADVANCES IN THE FIELD, WHAT'S HAPPENED IS TWO SPECIES WE FOCUSED ON, NON-VERY OPERATES LIKE YEAST, WORMS AND FLIES HERE, THEY AGE VERY QUICKLY, DO AGING STUDIES WITHIN TWO WEEKS TO TWO MONTHS. QUITE COST EFFECTIVE, YOU CAN HAVE BILLIONS OF WORMS IN YOUR LAB. YOU CAN DO NON-BIASED GENETIC STUDIES WHERE YOU CAN SURVEY THE WHOLE GENOME AND SAY WHICH MUTATIONS AFFECT AGING. WHEN THAT HAPPENS, YOU CAN FIND THESE GENES AND TEST THEM IN MORE COMPLICATED ORGANISMS LIKE MICE AN RATS AND PRIMATES AN EVEN HOPEFULLY HUMANS. THE PROBLEM HERE OF COURSE IS THEY AGE SLOWLY, THIS IS A FOUR DECADE EMPERIMENT. EXTREMELY EXPENSIVE. SO YOU CAN'T DO THOSE GENOME WIDE SURVEYS EASILY SO COMBINING THE TWO SETS OF SPECIES WE CAN GIVE ADVANTAGE. YOU CAN DEVELOP HYPOTHESES HERE IN SPECIESES THAT ARE EASY AND TEST THEM HERE WHERE WE HAVE A GOOD FEEL THERE'S CONSERVED FACTORS WITH HUMAN AGING. THREE PATHWAYS EMERGED THE MOST PROMINENT IN THE AGING FIELD. I WILL TAKE YOU THROUGH EACH BUT WHAT I WANT TO TELL YOU IS THAT IS A LIMITED SET, THERE'S PROBABLY MANY PATHWAYS TENS OF DIFFERENCE PATHWAYS AT LEAST THAT AFFECT AGING AND H HIGH HEIGHT THE ONES STUDIED THE MOST. THE IDEA LINKED TO AGING AND ALMOST ALL THE SPECIES WE STUDY, HERE IS FIRST DATA FROM CYNTHIA KIN I DON'T KNOW'S LAB, SHOWING MUTATION IN INSULIN RECEPTOR, DRAMATICALLY LIFE SPAN IN WORMS AN MULTIPLE POINTS IN THIS PATHWAY YOU CAN GET DRAMATIC CHANGES IN AGING. RELATED TO HUMAN AGING. THIS IS ONE PIECE OF DATA IN (INAUDIBLE) LAB WHERE THEY FOUND THEY'RE FUNCTIONALLY SIGNIFICANTNESS LYNN GROWTH FACTOR RECEPTOR MUTATIONS. THESE LONG LIVED POPULATIONS. SUBSET OF INDIVIDUALS HAVE MUTATIONS THAT HAVE REDUCED -- PRODUCED IGF RECEPTOR ACTIVITIES. SO CONSERVATION FROM WORMS TO HUMANS. THE PATHWAY SOMETHING REALLY EMERGED AS A DRIVING FACTOR IN MANY OF THE DISEASES OF AGING, WE PUBLISHED A FIRST PAPER IN YEAST A LONG TIME AGO NOW SHOWING MUTATIONS CAN EXTEND LIFE SPAN TESTED MORE DIRECTLY PROTEIN DEACETYLASE THAT YOU'LL HEAR ABOUT THIS THE NEXT TWO DAYS. THERE'S DATA IN WORMS AND A RANGE OF DATA HUMAN ORTHO LOG IS GOING TO AFFECT DISEASE PROCESSES ACROSS REALLY A WIDE RANGE OF TISSUES GEROSCIENCE. FINAL LYM I'M GOING TO TALK ABOUT THE TORE PATHWAY, MORE RECENT ENTRY BUT RELEVANT TO AGING, REDUCE TORE SIGNALING, AFFECTS AGING IN YEAST AN WORMS AN FLIES AN MICE. THEY'RE STARTING TO BEGIN TO BE SOME DATA P AND I THINK THIS IS SOMETHING THAT WE NEED TO FOCUS ON IN SOME DETAIL, ACTUALLY SOMETHING MY LAB WORKS ON TOO. I POINT OUT A COUPLE OF THINGS. FOR ONE, THIS IS A SIGNALING PATHWAY THAT'S KINASE HERE, TOR, THIS HIGHLY RESPONSIVE TO NUTRIENTS SO MAY FEED INTO THE DIETARY RESTRICTION RESPONSE. MORE CALORIES YOU HAVE THE HIGHER TOR SIGNALING YOU HAVE AND YOU DEVOTE YOUR EFFORTS TO GROWTH AND REPRODUCTION AS OPPOSED TO MAINTENANCE. IF YOU REDUCE TOR SIGNALING YOU TURN ON A NUMBER OF PATHWAYS THAT MAKE YOU STRESS RESISTANT AND LIKELY TO LIVE LONGER. SECOND THIS PATHWAY IS INTIMATELY CONNECTED TO INSULIN IGF SIGNALING SO TWO DIFFERENT PATHWAY BUS THEY MAY BE SIMILAR. THERE'S ALSO DATA THAT (INAUDIBLE) MAYBE REGULATING THIS PATHWAY. WHETHER WE LOOK AT THREE OVERLAPPING WAYS OF MODULATING, THERE'S AN OPEN QUESTION IN THE FIELD. SO ONE REASON I HIGHLIGHT THIS PATHWAY IS FROMs OOH A DRUG RAPAMYCIN THAT IS A SPECIFIC INHIBITOR OF TOR, THAT ALLOWED THE NATIONAL INSTITUTE OF AGING INTERVENTION TESTING PROGRAM TO TEST RAPAMYCIN AN MICE, SMALL MOLECULE CAN AFFECT AGING. THIS IS THE FIRST ONE THAT HAD A ROBUST EFFECT, THEY -- FOR REASONS I WON'T GO INTO GAVE THE MICE RAPAMYCIN AND 600 DAYS OF AGE, THAT'S RELATIVELY OLD FOR A MOUSE. AN CAUSED A 15% LIFE SPAN EXPANSION IN MALES AND 10% IN MALES. THERE'S A PICK TO THIS. FIRST IT'S DRIVEN A LOT OF RESEARCH IN BIOLOGY AN MEDICINE, SINCE THIS PAPER IN 2009, IF YOU JUST SEARCH RAPAMYCIN AN AGING, 430 PAPERS HAVE COME OUT GIVING YOU A FEEL FOR HOW IMPORTANT DISCOVERIES THAT SMALL MOLECULES LOVE THE AGING PROCESS. ARE THEY HEALTHY LONGER. I'LL SPEND TIME ON THAT. FIRST I'LL SHOW YOU MOVIES THAT RANDY STRONG AT UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER SAN ANTONIO. THESE ARE THE LAST TWO MICE FROM THE CONTROL GROUP AT 38 MONTHS OF AGE, INTERVENTION TESTING PROGRAM STUDY, NOT GROOMING WELL, NOT USING THE BACK LEGS AS WELL. THESE MICE THAT HAVE RAP MYSIN THEY HOOK LIKE YOUNGER MICE, THEY DON'T LOOK LIKE FOUR MONOOLD MICE, THIS IS NOT A PANACEA BUT THEY'RE DOING QUITE A LOT BETTER AT THE SAME TIME FRAME WITH THIS COMPOUND. IS THIS THE ONLY COMPOUND THAT WILL AFFECT AGE SOMETHING NO. TURNS OUT IN WORMS NOW, AND IN YEAST THEY'RE HUNDREDS OF GENES THAT IMPACT AGING. I EXPECT THAT'S THE CASE IN MAMMAL AS WELL. AS THE INTERVENTION TESTING PROGRAM GOES ON THEY'RE FINDING OTHER COMPOUNDS, THIS PAPER IS -- THERE'S A TYPO HERE, THIS PAPER IS PRESSED IN AGING AND IT SHOWS ANOTHER COMPOUND EXTEND LIFE SPAN CUT OFF MORE MALES THAN FEMALES RAPAMYCIN IN MALES, THIS DRUG OR MOLECULE HAS A MORE EFFECT IN MALES. QUITE ROBUST EXTENSION OF LIFE SPAN IN THE MALE INHIBITS DIGESTION OF POLYSACCHARIDES AN UP OF SUGARS FOR THE GU TRACK, TREAT DIABETICS AND IT PACT AGING NOT JUST DIABETES. THERE'S GOING TO BE A LOT OF THESE COMING OUT. SO THIS HAS POTENTIAL TO CHANGE HOW WE THINK ABOUT RESEARCH BECAUSE THE QUESTIONS GOING TO BE DO MOLECULES LIKE THIS IMPACT DISEASES OF AGING AND CAN THEY BE USED FOR PREVENTION OR THERAPY. WHERE DO WE STAND? CAN WE EXTEND LIFE SPAN AN HEALTH SPAN. I THINK THE ANSWER IS CLEARLY YES, FROM ENVIRONMENT OR GENETIC OR DRUGS IN THESE NON-VERTEBRATE SPECIES. IT'S CLEARLY YES IN MICE AT THIS POINT. AND PRIMATES WE HAVE LESS DATA. ANOTHER ONE THAT DIDN'T SHOW LIFE SPAN EXPENSION BUT HEALTH SPAN BENEFITS, I'M SURE GENETIC MUTATIONS AFFECT AGING AND PRIMATES THOUGH WE HAVEN'T IDENTIFIED YET. THERE HAVE BEEN NO STUDIES THAT I KNOW OF SMALL MOLECULES. THIS IS MY GRADUATE ADVISER. CAN WE DO ANYTHING TO HELP HIM. I WOULD ARGUE ENVIRONMENT, YES. EXERCISE AND NUTRITION ARE IMPACTING AGING. GENETICS FROM THE STUDIES AT LEAST IN THOSE LONG LIVED POPULATIONS GENERAL TUCK EVENTS IMPACT AGING AND MAYBE SOME OF THESE DRUGS WE'RE ALREADY TALKING ABOUT ALREADY TAKING, LIKE NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, STATINS, MAYBE THEY'RE ALREADY IMPACTING AGING TO A SMALL DEGREE. WE DON'T KNOW THAT YET. BUT WORTH AT LEAST PUTTING MAYBE HERE. SO THAT'S WHERE THE FIELD STANDS. IF YOU CAN IMPACT LONGEVITY WILL THAT CAUSE AN AFFECT, A BENEFICIAL AFFECT ON CHRONIC DISEASES OF AGING. SO FROM IS FROM PHILIPPE. LEADING CAUSES OF MORTALITY IN THE US. DATA NOT AS GOOD AS THE DATA YOU JUST HEARD, CARDIO VASCULAR DISEASE, STROKE, CANCER, LUNG DISEASES, ALL THESE THINGS HAVE ONE THING IN COMMON, THAT'S THE BIGGEST RISK FACTOR IS AGING. WE DON'T THINK ABOUT THAT WHEN WE THINK CARDIO VASCULAR DISEASE YOU HEAR CHOLESTEROL IS THE BIGGEST RISK FACTOR. BUT THERE'S A 20 FOLD INCREASE IN RATE OF CARDIOVASCULAR DISEASE AS YOU GET OLDER. WE CAN MAKE THIS ARGUMENT ABOUT A WHOLE RANGE OF DISEASES INCREASING PREVALENCE IN THE U.S. AND THROUGHOUT THE WORLD. THIS IS REALLY THE MANTRA OF OUR INSTITUTE IS HOW IS IT AGING ENABLES THESE DISEASES TO HAPPEN. OF COURSE, IT'S NOT THE ONLY RISK FACTOR. THERE'S MULTIPLE INDEPENDENT FACTORS DRIVING DISEASE BUT WE THINK THE MOST IMPORTANT COMMON ONE. WHEN YOU HAVE MUTATIONS THAT EXTEND LIFE SPAN THEY TEND TO PREVENT MANY OF THESE DISEASES IN THE ANIMAL MODELS. SO WE THINK IT'S A NOVEL APPROACH TO GO AFTER TO SAY WHAT IS IT ABOUT AGING THAT ENABLES DISEASE AND CAN WE DO SOMETHING ABOUT THAT. I WANT TO TOUCH A LITTLE BIT ON THE LINK BETWEEN DIFFERENT DISEASES, THIS IS DATA FROM A STUDY IN ENGLAND I THINK WHERE THEY LOOKED AT RELATIVE DISEASE RISK FOR PEOPLE WHO EXERCISE. THEY PUT PEOPLE IN DIFFERENT QUARTILES WHETHER THEY DON'T EXERCISE AT ALL OR EXERCISE A LOT. WHEN YOU EXERCISE IT REDUCES DEATH RISK OF DEATH FROM CARDIOVASCULAR DISEASE. THAT HAPPENS. IT WENT DOWN DRAMATICALLY BUT THE INTERESTING THING THEY FOUND IS THAT THE CONTROL GROUP WHO DIDN'T HAVE CARDIOVASCULAR DISEASE, THE RATE OF MORTALITY WHEN DOWN JUST AS DRAMATICALLY SUGGESTING THAT EXERCISE IS IMPACTING THE OTHER CHRONIC DISEASES OF AGING AS WELL. K LOOK AT HUNDREDS OF STUDIES, AND FIND THINGS YOU WANT -- THAT MAKE YOU WORRY ABOUT EACH INDIVIDUAL STUDY BUT WHEN YOU PUT THEM TOGETHER, IT'S CLEAR THE ENVIRONMENT -- HOW YOU BEHAVE IMPACT THE RATE WHICH YOU AGE. SO IF WE LOOK AT WHAT CAN BE ACHIEVED NOW, I WANT TO TAKE A STEP BACK. I ASK PEOPLE IN THE PUBLIC A LOT WHETHER THEY WANT TO LIVE LONGER. AND A LOT OF TIMES THEY SAY NO. I DON'T WANT TO DO THAT. THEY SAY WHY, WHY IS THAT? THEY SAY MY 80-YEAR-OLD GRANDMOTHER IS TAKING 25 PILL AS DAY, SHE'S SICK, IN PAIN, WHY DO I WANT TO LIVE LONGER LIKE THAT? WHAT THEY'RE IMAGINEING IS SOMETHING LIKE THIS IS GOING TO HAPPEN. THIS IS OPINION YOU'RE BORN, YOU'RE HEALTHY YOU DIE AT SOME POINT AND BEFORE THAT YOU HAVE ONSET OF MORBIDITY, WHICH IMPACT IT IS LIFE HOW YOU WANT TO LIVE IT AND PEOPLE IMAGINE MUTATIONS IN THE LIFE SPAN DO THIS, KEEPING YOU SICK LONGER BUT THAT'S NOT WHAT WHAT THEY'RE DOING AT LEAST I BELIEVE IN THE MOUSE STUDIES. THEY'RE KEEPING THEN MALLS HEALTHY LONGER AN THEY'RE STILL A PERIOD OF DECLINE. WHAT WE LIKE TO ACHIEVE IS THIS, WE HAVE REPRESS MORBIDITY, PEOPLE LIVE LONGER AND THEY HAVE A MUCH SHORTER PERIOD OF CHRONIC DISEASE OR MORBIDITY. I DON'T KNOW THIS IS ACHIEVABLE YET FROM THE GENERAL TICK STUDIES AN SMALL -- GENETIC STUDIES BUT WE HAVE GOTTEN TO THIS STAGE AT LEAST IN A MAMMAL WE HAVE SHOWN THIS CAN HAPPEN. IF YOU LOOK AT THE CHANGING DEMOGRAPHICS OF THE WORLD, THERE'S A HUGE ECONOMIC BENEFIT TO KEEPING PEOPLE HEALTHY LONGER RIGHT NOW EVEN IF STILL A PERIOD OF DECLINE AFTERWARDS. SO REASONABLE TO SAY THIS IS THE GOAL AND MAYBE HOPE WE CAN SOME DAY GET TO THIS. BUT YOU KNOW THE PROBLEM. THE PROBLEM IS THAT THE WORLD THINKS ABOUT DRUG DEVELOPMENT, PHARMACEUTICAL COMPANIES, TARGETD TREATING DISEASE. SO LOOK WHERE PHARMACEUTICAL COMPANIES FOCUS EFFORTS ON DISEASE TREATMENT, LESSER EXTENT BUT STILL DISEASE PREVENTION, THE IDEA OF GIVING A DRUG HEALTHY PERSON TO KEEP THEM HEALTHY LONGER RESONATED FOR REASONS INCLUDING REGULATORY BUT PROMISE OF AGING RESEARCH IS ALMOST I HAVE BEEN VERSE. WE THINK IT'S FEASIBLE TO KEEP PEOPLE HEALTHY LONGER LOOKING AT THESE PATHWAYS. USEFUL FOR DISEASE PREVENTION. IF YOU TALK ABOUT TREATMENT, WAITING UNTIL PEOPLE GET SICK WILL THESE IMPACT AGING TO ANYTHING OR NOT. THIS IS THE CHALLENGE WE HAVE TO SURMOUNT THINKING ABOUT TAKING THE RESEARCH WE'RE DOING AND HAVING IMPACT ON HUMAN POPULATION. HOW TO WORK WITH TWO INVERSE PYRAMIDS, WHAT LEVEL TO BRING BASIC RESEARCH FINDINGS THAT WE HAVE INTO A TRANSLATABLE FORM THAT IS USEFUL FOR HUMAN POPULATION. HERE IS T ANOTHER WAY TO THINK ABOUT IT. DOING BASIC AGING RESEARCH, IDENTIFYING THE PATHWAYS THAT AFFECT AGING. WILL I PREVENT DISEASE AN TREAT CHRONIC DISEASE SO I WANT TO SPEND A SLIDE OR TWO TALKING ABOUT EACH STARTING WITH PREVENTION. I'M GOING TO USE RAPAMYCIN AS A CASE STUDY BECAUSE WE KNOW THE MOST ABOUT IT. THIS IS A STUDY TOOK MICE AT 2 MONTHS OF AGE AND GAVE THEM RAPAMYCIN FOR THREE MONTHS AND DID A LOT OF TRANSP SCRIPTOMICS, METABALOMICS AN CARDIAC FUNCTION, IN MANY MEASURES LIKE EJECTION FRACTION OF THE HEART OR FRACTIONAL SHORTENING WHICH MEASURES LEV VENTRICULAR FUNCTION TO OUTPUT, HERE IS DECLINE IN FUNCTION AND CONTROL MICE IN THESE TWO GROUPS THEY GOT BETTER T. MICE AT 27 MONTHS WERE DOING BETTER THAN 24 MONTHS BEFORE THEY STARTED THE ASSAY. AND DRAMATICALLY SUPPRESSED LEFT VENTRICULAR HYPERTROPHY. THIS IS ONE STUDY BY MANY LABS THERE IS A LOT OF DATA LIKE THIS OUT THERE SUGGESTING IT'S BENEFICIAL FOR A RANGE OF CHRONIC DISEASES OF AGING NOT ALL, IT ACCELERATES OTHER DISEASES OF AGING LIKE CATARACTS. SO IT IS NOT PANACEA, MAY NOT BE THE RIG DRUG BUT ILLUSTRATES THE POINT SLOW AGING ARE LIKELY TO PREVENT A SUBSET OF DISEASES OF AGING. WHAT ABOUT TREATING CHRONIC DISEASE? THOSE WHO KNOW RAPAMYCIN KNOW IT WAS FOUND 40 YEARS AGO OR MORE AND BEEN TESTED OVER A RANGE OF DISEASE INDICATIONS. THERE'S ANIMAL MODELS, HUNTINGTON'S PARKINSON, SYSTEM RARE FORMS OF CARE, AT ONE POINT THERE WAS HOPE IT WOULD BE USEFUL IN KAREN THAN IT TURNED OUT TO BE BUT IT IS PROTECTIVE IN SOME KIDNEY KAREN, THERE'S DATA ON STROKE, QUITE A BIT OF ANIMAL RELATED DATA CARDIO VASCULAR DISEASE. IF YOU'RE INTERESTED IN TYPE 2 DIABETES, HAPPY TO TALK ABOUT IT. NOT GOING INTO IT TODAY SO IT BEHAVES LIKE SMALL MOLECULE BEHAVES. THERE'S A WIDE RANGE OF CLINICAL TRIALS WITH RAPAMYCIN. 2,000 ONGOING TRIALS WITH FIRST GENERATION ANALOG HAVE BEEN TESTED NOW ACROSS A RANGE OF DISEASE INDICATIONS. SOME HAVE BEEN EFFECTIVE, THERE'S SIDE EFFECTS OF RAPAMYCIN, WON'T GO INTO IT IN DETAIL BUT TO ILLUSTRATE PEOPLE USE THIS DRUG IN TREATMENT, IT IS EFFECTIVE IN SOME CASES AND NOT IN OTHERS. THIS IS WHAT'S HAPPENING FROM OUR RESEARCH AND OTHERS IN THE FIELD EVENTS DRIVING AGING ARE RELATED TO THE EVENTS DRIVING DISEASE. SO WHEN WE IDENTIFY THESE PATHWAYS IMPACTING THE RANGING PROCESS -- AGING PROCESS LIKE TOR, THERE'S ALSO THINGS THAT GO WRONG DURING DISEASE. SO MY CURRENT HYPOTHESIS IS THAT AGING IS ABOUT DAMAGE, IT'S ABOUT CHANGES IN SIGNALING, ALL KINDS OF EVENTS BEFORE CELL SENESCENCE, ONE THING THAT HAPPENS WHEN EVENTS GO WRONG, THEY CAUSE SECONDARY CONSEQUENCES. IF YOU LOOK ACROSS A WHOLE RANGE OF AGING, THE TOR PATHWAY IS TURNED UP. THE BENEFIT OF RAPAMYCIN MAYBE IT'S SUPPRESSING THAT, IT'S BLOCKING THAT SECONDARY CONSEQUENCE OF AGING. ANOTHER ENZYME IMPORTANT FOR AGING GOES DOWN IN MANY TISSUES WITH AGING. AND MOLECULE THAT ACTIVATES IT MAYBE SUPPRESSING THAT DECLINE. SO I THINK THE PATHWAYS ARE POINTING TO THINGS THAT ARE SECONDARY CONSEQUENCES OF DAMAGING EVENTS THAT CAUSE AGING BE OVERLAP DRAMATICALLY WITH EVENTS RELATED TO DISEASE. WE LOOKED AT TOR SIGNALING IN A RANGE OF DISEASE EVENT AS IT GOES UP. SO IT'S SIMILAR TO AGING, IT MAYBE POSSIBLE TO WORK BACKWARDS USING AGING TO IDENTIFY PATHWAYS AND WORK BACKWARDS TO FIGURE WHICH DISEASES WHICH THERAPIES THAT RESTORE THESE P&A WAYS MIGHT BE BENEFICIAL FOR IT. AS WELL AS PREVENTING IT BUT IT'S CERTAINLY A PROCESS THAT NEEDS TO BE STUDIED IN MORE DETAIL. SO WHAT YOU'RE GOING THE HEAR THE NEXT TWO DAYS ARE FOCUSED DISCUSSIONINGS AROUND MANY OF THE PATHWAYS THAT WE THINK ARE DRIVING AGING. I MENTIONED THEM, INFLAMMATION, THE STRESS AND ADAPTATION TO STRESS THAT OCCURS DURING THE AGING PROCESS OVER TIME. CHANGES IN EPIGENETIC, CHANGES IN METABOLISM, THE ONSET OF MACRO MOLECULAR DAMAGE WITH AGE, PROTEIN FOLDING PRO OWESTASIS AN STEM CELLS. I THINK THAT YOU'RE GOING TO HEAR COMPELLING CASES EACH OF THESE PROCESSES ARE CONTRIBUTING TO WHAT WE CALL AGING. THEY'RE ALSO DRIVING DIFFERENT DISEASES OF AGING, IT'S MY HOPE THAT HAVING THESE KIND OF DISCUSSIONS ARE REALLY GOING TO STIMULATE EVERYONE HERE TO THINK ABOUT THIS QUESTION AND WHAT IT IS ABOUT AGING THAT'S DRIVING DISEASE AND HOW IS THAT AN OPPORTUNITY TO LOOK AT THESE DISEASES FROM A NEW PERSPECTIVE AND DEVELOP NEW THERAPEUTIC CHANGES TO TREAT THEM. SO WITH THAT I WANT TO STOP AND THANK YOU FOR THE TIME AND TO GIVE THE TALK, HOPEFULLY I SET THE STAGE, THIS WILL BE A GREAT TWO DAY MEETING. THANK YOU. [APPLAUSE] >> I'M PHILIPPE -- THE LAST KEYNOTE SPEAKER THIS MORNING WILL BE DR. LINDA FRIED, THE DEAN OF THE MAILMAN SCHOOL OF PUBLIC HEALTH IN COLUMBIA, NEW YORK. ROCHE MEDICAL COLLEGE IN CHICAGO AND MASTERS IN PUBLIC HEALTH FROM JOHNS HOPKINS. HER THOUGHT ON FRAILTY AN RELATIONSHIP TO DISEASE IN THE ELDERLY. >> GOOD MORNING, IT'S A PLEASURE AND HONOR TO BE HERE TODAY. I WAS ASKED TO FRAME OUT A PARTICULAR PERHAPS SUBQUESTION OF WHAT BRIAN WAS TALKING ABOUT. I HOPE BY HONING IN ON FRAILTY AND RELATIONSHIPS TO DISEASE APPROXIMATE THE MR. ELLIS: DELI IT WILL EXEMPLIFY SOME OF WHAT WAS DISCUSSED. RECENTLY AN ARTICLE IN THE JOURNAL OF AMERICAN MEDICAL DIRECTORS ASSOCIATION PUBLISHED THE RESULTS OF A CONSENSUS CONFERENCE HELD LAST YEAR, DELEGATES FROM SIX MAJOR INTERNATIONAL EUROPEAN AND U.S. SOCIETIES WHICH AGREED THAT PHYSICAL FRAILTY SHOULD BE CONSIDERED AN IMPORTANT MEDICAL SYNDROME. TO FIND MEDICAL SIN CHROME WITH MEDICAL CAUSES CHARACTERIZED BY DIMINISHED STRENGTH ENDURANCE AND INDUCE PHYSIOLOGIC FUNCTION THAT INCREASES VULNERABILITY FOR DEVELOPING DEPENDENCY AND/OR DEATH. YOU CAN SAY THIS MORE CLOAK WALLY AS ONE OUR COLLEAGUES HAS DONE WE'RE TALKING A SYNDROME OF SHRINKING, SLOWING WEAKNESS WITH LOW ACTIVITY AND LOW ENERGY. WHAT I WOULD LIKE TO DO IS SUMMARIZE THE THINKING BEHIND THE STATEMENT, SHOW YOU SOME EVIDENCE AS TO WHAT IS EMERGING IN A SYNDROME WITH A NOW RECOGNIZABLE PHENOTYPE, WHAT IS EMERGING AS POTENTIAL UNDERLYING PHYSIOLOGY BIOLOGY AND CONCLUDE BY LINKING THAT TO A NUMBER OF QUESTIONS ABOUT CHRONIC DISEASE. SO START FROM A THEORY GERIATRIC MEDICINE THAT IN FACT FRAILTY HAS A CHARACTERISTIC PHENOTYPE WHICH CONSTITUTES ESSENTIALLY A VICIOUS CYCLE VERY MUCH IN APPEARANCE RELATED TO ENERGY DISREGULATION. SO SARCOPENIA. WE KNOW IS THE HALLMARK OF THE CLINICAL PRESENTATION OF PEOPLE WHO ARE FRAIL. AND WE KNOW MANY THINGS ABOUT PAIR WISE ASSOCIATIONS EVEN 15, 20 YEARS AGO WHEN I STARTED THINKING ABOUT THIS. WE KNOW THAT LOSS OF MUSCLE MASS WITH AGING PREDICTS DECLINES IN STRENGTH AND POWER AND EXERCISE TOLERANCE, ALL THIS PREDICTS SLOW WALKING SPEED AN MOTOR PERFORMANCE AND FURTHER DECLINES IN PHYSICAL ACTIVITY. WE KNOW THERE ARE A VARIETY OF STUDIES AT LEAST IN A SUBSET OF OLDER PEOPLE, THERE IS A MISMATCH BETWEEN THE LEVEL OF ACTIVITY AND THE LEVEL NUTRITION SUCH THAT EVEN IN THE LOW LEVEL PHYSICAL ACTIVITY IN SUBSET YOU SEE CHRONIC UNDERNUTRITION. THEN YOU SEE THE BEGINNING OF A VERY VICIOUS CYCLE. A QUESTION OF COURSE WITH MY OWN THINKING IS WHETHER THIS CLINICAL APPEARANCE WAS SOMEHOW RELATED TO ENERGY DISREGULATION ASSOCIATED WITH AGING. I'LL TRY AND SHOW YOU SOME EMERGING THOUGHTS ABOUT THAT. TO GET THERE WE HAVE TO START WITH SOMETHING THAT WAS STANDARDIZABLE AND WITH COLLEAGUES IN THE AUDIENCE, CERTAINLY ONE OF WHOM WILL BE SPEAKING TODAY, WE DEVELOPED A STANDARDIZED APPROACH OF SAYING THAT A SYNDROME, A CLINICAL SYNDROME HAS TO HAVE A CONSTELLATION OF SIGNS AN SYMPTOMS RECOGNIZABLE AND POINT TO A DISTINCT UNDERLYING PATHOPHYSIOLOGY. THE CYCLE I SHOWED YOU CAN BOIL DOWN TO THE FIVE MANIFESTATIONS, WE HYPOTHESIZED INITIALLY WE MIGHT BE ABLE TO IDENTIFY FOLLOWING THE DEFINITION OF SYNDROME. UNDERLYING PATHOPHYSIOLOGY,. WE HAVE GONE ON OVER THE YEARS TO PROVIDE MEASURES FOR THAT, AND BASED ON A HUGE AMOUNT OF VALIDATION STUDIES, IDENTIFIED PEOPLE WITH THREE, FOURER FIVE CRITERIAS BEING FRAIL WITH NONE OF THEM NON-FRAIL AND IDENTIFYING INTERMEDIATE WITH ONE TWO. SIMPLISTIC APPROACH BUT WITH A VERY I THINK REASONABLY WELL DEVELOPED UNDERLYING BIOLOGIC SET OF HYPOTHESES. WHAT HAVE WE LEARNED? WE LEARNED THAT IF YOU LOOK AT PEOPLE WITH 3, 4, 5 CRITERIA, CARDIOVASCULAR HEALTH STUDY, A MULTI-CENTER NATIONAL STUDY OF MEN AND WOMEN 65 AND OLDER THIS PREVENIENCE ARISES WITH INCREASING AGE, IT'S HIGHER IN WOMEN COMPARED TO MEN AND BY THE UPPER AGE GROUP IT IS OLDEST OLD, AT LEAST A QUARTER OF COMMUNITY DWELLING OLDER ADULTS MANIFEST THE TYPE OF FRAILTY. WE ALSO HAVE SHOWN THROUGH MANY STUDIES OF OUR OWN AND OTHERS THAT THIS IS A VERY HIGHLY VULNERABLE SUBSET CLINICALLY AT RISK FOR A HOST OF OUTCOMES. MORTALITY. FALLS. DISABILITY AND DEPENDENCY. DELAYED AND INCOMPLETE RECOVERY FROM ILLNESS. AND HIGHLY ELEVATED RISK OF ADVERSE OUTCOMES ASSOCIATED WITH HOSPITALIZATION AN SURGERY. NOTABLY, OUTCOMES THAT ASSOCIATE WITH CHRONIC DISEASES AS WELL. SO TO SUM ACROSS MANY STUDIES FRAILTY AS A PHENOTYPE OF AGING IS A MARKER OF ELEVATED VULNERABILITY FOR THESE OUTCOMES AND THERE'S A DOSE RESPONSE ASSOCIATION MORE MANIFESTATIONS OF FRAILTY THAT ARE PRESENT, THE GREATER THE LIKELIHOOD OF THOSE OUTCOMES. AND THE LOWER THE TIME FRAME TO EXPERIENCE. WE ALSO HAVE FOUND THIS IS A CHRONIC PROGRESSIVE PROCESS. 90% OF OLDER ADULTS BECOME FRAIL, THE INITIAL PRESENTATION SHOWN BY (INAUDIBLE) IS MUSCLE WEAKNESS SLOWING DOWN AND LOW PHYSICAL ACTIVITY AND ANY OF THESE MANIFESTATIONS PREDICT DEVELOPMENT OF THE REST OVER EVEN A THREE YEAR PERIOD. THERE IS COMPELLING EVIDENCE EARLY STAGES ARE MOST LIKELY RESPONSIVE TO INTERVENTION WHILE END STAGES APPEAR MUCH LESS SO. WHAT I WOULD LIKE TO SHOW YOU IS EMERGING EVIDENCE OF A DISTINCTIVE UNDERLYING BIOLOGY OF MULTI-SYSTEM AT THIS REGULATION THAT IS VERY TIGHTLY RELATED TO THE PHENOTYPE. FIRST I DIGRESS FOR THE STAKE OF THE CONFERENCE TO SAY ALSO STRONG EVIDENCE FOR MANY INVESTIGATORS THAT THE FRAILTY SYNDROME IS ASSOCIATED WITH A RANGE OF CHRONIC DISEASES CONSISTENTLY. CARDIO VASCULAR DISEASE, CLINICAL APPROXIMATE SUBCLINICAL, C OPD, ANEMIA, KAREN, ALL THINGS THE POOR SPEAKERS LIST OF PRIME SUSPECTS. PLUS HIV LATE LIFE DEPRESSION. AND THAT INFLAMMATORY DISEASES IN PARTICULAR, ARE TIGHTLY ASSOCIATED HERE IS ONE PIECE OF DATA FROM A STUDY BY ED KNEWMAN FROM THE CARDIOVASCULAR HEALTH STUDY LOOKING AT MEAN MAXIMUM INTERNAL CAROTID WALL THICKNESS, A SUBCLINICAL MEASURE OF CARDIO VASCULAR DISEASE, STRONGLY A HARKER OF PLAQUE, AND WHAT YOU CAN SEE IN THE LEFT HAND CROSS TEST THE PATCH BAR, AS YOU GO FROM -- LOOK AT PEOPLE WITH NO CLINICAL DIAGNOSIS OF CARDIOVASCULAR DISEASE AND THE MEAN WALL THICKNESS, THAT THE PROPORTION -- THE MEAN WALL THICKNESS INCREASES FROM NOT FRAIL TO INTERMEDIATE OR PRE-FRAIL TO FRAIL. SO THERE IS A ASSOCIATION WITH SUBCLINICAL DISEASE IN ABSENCE OF CLINICAL DISEASE AS WELL AS HERE IN THE RIGHT HAND BAR WITH -- IN THE GRAY BAR WITH CARDIOVASCULAR DISEASE I SHOULD SAY ALMOST NO ASSOCIATION. WHAT'S BELOW THE WEAR LINE? IF YOU HAVE A PRESENTATION THAT HAS CLINICAL SIGNIFICANCE IN TERMS OF PREDICTING VULNERABILITY FOR ADVERSE YOU COMES, IS THERE SPECIFICITY TO THE SYNDROME IN TERMS OF UNDERLYING PATHOPHYSIOLOGY AND HOW THAT RELATES TO CHRONIC DISEASE ITSELF. SO I'M GOING TO SUMMARIZE WHAT I'M QUICKLY GOING TO PRESENT WHICH IS THAT IN FACT MANY FIZZ QUO LOGIC SYSTEMS ARE UNDERSTOOD TO BE DISREGULATED IN THE PRESENCE OF THE FRAILTY PHENOTYPE, THE RELATIONSHIP BETWEEN THE NUMBERS OF SYSTEMS REGULATE AND LIKELIHOOD OF FRAILTY IS NON-LINEAR. AND THERE IS A STRONG EMERGING EVIDENCE THAT FRAILTY IS AN EMERGENT PROPERTY OF DISREGULATED COMPLEX SYSTEM. LET'S THINK TO START AT THAT TIME PHENOTYPE I PRESENTED BEFORE, UNDERSTANDING IS ASSOCIATED WITH VULNERABILITY FOR THESE ADVERSE OUTCOMES AND ASK SOME QUESTIONS ABOUT THE PHYSIOLOGIC DISREGULATION. AND HERE IS A SUMMARY OF THE SYSTEMS SHOWN ABNORMAL OR DISREGULATED IN ASORIATION WITH FRAILTY, STARTING WITH SARCOPENIA AS A HALLMARK OF FRAILTY. INFLAMMATION, DECREASED HEART RATE VARIABILITY, ALTERED CLOTTING PROCESS, ANEMIA, A NUMBER OF HORMONES INCLUDING THE IGF-1 ANDNESS LYNN RESISTANCE DR. KENNEDY WAS REFERRING TO. THE HOST OF MICRONUTRIENT PROTEIN AND ENERGY DEFICIENCY. ONE EXAMPLE FROM WORK BY JEREMY WALTON FROM THE CARDIOVASCULAR HEALTH STUDY SHOWS THAT LOOKING AT C REACTIVE PROTEIN AS A MARKER OF INFLAMMATION THE MEAN CRP LEVEL RISES IN ASSOCIATION GOING FROM LEFT TO RIGHT WITH FRAILTY STATUS, NOT FRAIL TO INTERMEDIATE TO FRAIL. HERE ANOTHER MARKER MEASURE OF INFLAMMATION, HIGH IL-6, PROPORTION IN A DIFFERENT STUDY POPULATION, WEALTH HEALTH AGING STUDY WITH HIGH IL-6 INCREASES IN A STEP WISE FASHION FROM GREEN NON-FRAIL TO YELLOW MILD FRAIL TO RED VERY FRAIL. LOW IGF-1 MIDDLE AND LOW DHES ON THE LEFT, PROCEED IN ASSOCIATION WITH FRAILTY IN THE SAME STEP WISE PARALLEL DOSE RESPONSE RELATIONSHIP. LOOKING AT NUTRIENT DEFICIENCY, WORK BY RICHARD SIMBA AS THE NUMBER OF MICRONUTRIENT DEFICIENCIES PRESENT RISE, SO DOES THE INCIDENCE OF FRAILTY. AND THIS IS IN TWO POPULATION BASED STUDIES, WOMEN'S HEALTH AND AGING STUDIES OF HIGHLY DISABLED AND NON-DISABLED OLDER WOMEN FROM AGE 70 TO 79. IF YOU LOOK WITHIN WHAT YOU MIGHT THINK A PHYSIOLOGIC MODULE OF SYSTEMS, HORMONAL SYSTEM, AND DO A COUNT OF NUMBER OF HORMONES AT ABNORMAL LEVELS IN OLDER WOMEN, IN ASSOCIATION WITH FRAILTY STATUS AND PARTICULARLY AT THE ORANGE AND THE RED, IT'S THOSE OR THE YELLOW AND RED YOU SEE THOSE WITH TWO SYSTEMS ABNORMAL, TWO HORMONES ABNORMAL LEVELS OR THREE OR MORE AT ABNORMAL LEVELS IN THE RED. AGAIN, INCREASE STEP WISE RELATIONSHIP WITH RISING FRAILTY STATUS. ROLL THAT TOGETHER ACROSS MODULES OF DITCH PHYSIOLOGIC SYSTEMS YOU FIND A SIMPLE COUNT OF THE NUMBER OF SYSTEM ABNORMAL IN ASSOCIATION WITH FRAILTY, AGAIN, THIS IS FROM THE WOMEN'S HEALTH AGING STUDIES 1 AND 2, YELLOW AND RED. AS THE NUMBER -- AS YOU GO FROM LEFT TO RIGHT FROM NON-FRAIL, TO FRAIL ON THE RIGHT HAND GROUP, THE PROPORTION WITH FOUR OR FIVE MORE SYSTEMS ABNORMAL RISES DRAMATICALLY IN THAT SAME SET OF ANALYSES, WE SHOWED IN FACT THAT COUNT OF THE NUMBER OF SYSTEMS ABNORMAL ACROSS IN MODULAR PHYSIOLOGIC SYSTEMS IS ASSOCIATED WITH PREVALENCE OF FRAILTY IN NON-LINEAR RELATION L SHIP. SUMMARIZING MANY STUDIES, WHAT WE'RE SEEING INCREASINGLY IS STRONG EVIDENCE THAT FOR THE DIVISION REGULATION OF THE NON-LINEAR COMPLEX ADAPTIVE SYSTEM THAT MAINTAINS A ROBUST HUMAN ORGANISM. NOT SURPRISING TO THIS AUDIENCE MOUNTING EVIDENCE BIOLOGIC CHANGES OF AGING PERHAPS AS DIVERSE RANGE OF THEM, LIKELY DRIVERS OF THIS MULTI-SYSTEM DISREGULATION AT THE PHYSIOLOGIC LEVEL. WHAT HAVE WE SEEN? IN THIS PICTURE MILLION SYSTEM DISREGULATION WE SEE A NUMBER OF MODULES, CONNECTED THROUGH THE PHYSIOLOGICAL NETWORK MUTUAL REGULATION AN REDUNDANCY, CONSISTENT WITH DYNAMICAL COMPLEX ADAPTIVE SYSTEM, THE RESULT COULD WELL BE THOUGHT B TO BE LOSS OF HOMEOSTATIC REGULATION AND UNDERLYING DECLINE IN RESERVES WITH WHICH OUR -- MAINTAIN REGULATION AN THIS APPEARANCE MAY WELL RELATE TO BOTH PHENOTYPE OF FRAILTY AND VULNERABILITY OF THE STRESSORS. NOW WHAT MIGHT BE GOING ON CONCEPTUALLY? OF COURSE WE HAVE BIOLOGIC CHANGES WITH AGING AT THE MOLECULAR GENETIC LEVEL. MANY CHANGES WE WILL BE DISCUSSING OVER THE NEXT THREE DAYS. OF COURSE THESE CHANGES WE KNOW DRIVE ALTERATIONS AT THE PHYSIOLOGIC LEVEL. THESE ALTERATIONS OF THE FIZZ CROW LOGIC LEVEL MULTI--- MUTUALLY REGULATE EACH OTHER. IN A TIGHT REDUNDANT COMPLEX NETWORK ESSENTIAL TO HOMEOSTASIS IF WE SAW DEPLETION OF THIS NETWORK WITHIN AN ACROSS CIRCLES, WE MAY -- WE OF COURSE MANY THE HEALTHY ORGANISM PERHAPSES YOUNGER ORGANISM KNOW WE RELY ON COMPENSATORY MECHANISMS IF ANYONE IS IT NOT FUNCTIONING ADEQUATELY. AND FEET FORWARD AND FEET BACKWARD LOOPS THAT ARE EXTREMELY TIGHTLY MAINTAINED IN A HEALTHY ORGANISM. THAT IS TRUE AT MANY LEVELS OF OUR FUNCTION. AND IF THESE COMPENSATORY MECHANISMS, IF THESE REGULATORY RELATIONSHIPS ARE DIMINISHED, WE COULD BE WELL THREATENING OUR ABILITY TO MAINTAIN HOMEOSTATIC RESERVES AND REGULATION. WHAT MIGHT THAT REFLECT FOR THE PERSON? THIS IS A WONDERFUL SLIDE FOR (INDISCERNIBLE) BUT IF YOU HAD A HUMAN BEING WHO WAS HOSPITALIZED , HOSPITALIZATION ILLNESS OR STRESSOR THEY'RE HEALTHY, THEY BOUNCE BACK QUICKLY, IF IN FACT THERE IS SOME DISREGULATION OF HOMEOSTATIC RESERVE, THE TIME TO BOUNCE BACK MAY WELL BE GREATER, IF IT PERCEIVE AN GETS WIDER AN WIDER THE TROUGH, THE PERSON IS IN GREAT TROUBLE IN TERMS OF BOUNCING BACK. PERHAPS FRAILTY IS EMERGENT PROPERTY OF COMPLEX ADAPTIVE SYSTEM, DO WE HAVE EVIDENCE OF THAT? I'LL SHOW YOU LITTLE BIT THEN MOVE TO CHRONIC DISEASES. HERE IS DATA LED BY ROBBIE (INAUDIBLE) MEAN DIRE PROFILE CORTISOL OVER 24 HOUR PERIOD IN THE OLDER WOMEN, IN THE WOMEN'S HEALTH AND AGING STUDY TOO AND SHOWED THAT IN THE NON-FRAIL YOU SAW INTACT VARIATION. IN THOSE WHO ARE FRAIL IN THE SOLID LINE IS ALL THE SAME FIRST THING IN THE MORNING SALIVARY COT SOL IN THOSE NON-FRAIL BUT DURING THE DAY A CONSISTENTLY HIGHER LEVEL OF CORTISOL OVER SEVEN MEASURES. BUT THAT'S IN STEADY STATE. WHAT WOULD HAPPEN? THEORETICALLY IN A COMPLEX DYNAMICAL SYSTEM YOU MIGHT SEE NOT MUCH DIFFERENCE IN THE STEADY STATE BUT IF IN FACT REGULATORY NETWORKS ARE COMPROMISED YOU MIGHT SEE LESS ABILITY IN A STRESS STATE TO RESPOND TO A STRESSOR IN PEOPLE WHO ARE FRAIL BY THIS DEFINITION. SO COUPLE OF EXPERIMENTS RECENTLY REPORTED. AND ONE IN PREPARATION. TO TRY AND TEST THIS HYPOTHESIS. CHALLENGE TESTS FRAIL, PRE-FRAIL, OLE, OLD WOMEN MIGHT REVEAL EVIDENCE AS TO DISREGULATED UNDERLYING BIOLOGY ASSOCIATED WITH THIS TEEN TYPE. AND I'M GOING TO SHOW A FEW EXAMPLES PARTICULARLY TARGETED TO HELPING US THINK ABOUT ENERGY DISREGULATION. AS I MENTION WOMEN'S HEALTH AND AGING STUDY 2 IS A PROSPECTIVE OBSERVE VISIONAL COHORT STUDY OF WOMEN 70 TO 79 YEARS OF AGE IN 1994, SELECTED TO BE REPRESENTATIVE OF THE TWO-THIRDS LEAST DISABLED. DATA I SHOW YOU ARE AT A POINT OF 15 YEARS OF FOLLOW-UP. AND THE STUDY WAS FUNDED AS ALL THE RESEARCH I'M SHOWING YOU BY THE NIH PRIMARILY THE NATIONAL INSTITUTE ON AGING. THE THEORY THAT WE ARE EVALUATING IN THESE CHALLENGE TESTS OF OLDS, OLD WOMEN WAS THE PHYSIOLOGIC DISREGULATION AND FAULTY WAS MORE NOTABLE THAN STRESS STATE AND MANIFESTED AS DELAYED EXAGGERATED OR PROLONG RESPONSES TO THE STRESSOR AND DELAYED RECOVERY TO BASELINE IN THE FRAIL COMPARE TO NON-FRAIL. WE ADMINISTERED EIGHT CHALLENGE TESTS OFFER TIME, I'M GOING TO MENTION SEVERAL VERY QUICKLY SO YOU CAN SEE THE PATTERNS ACROSS THE RESPONSES. THESE ARE SAFE CLINICALLY USED TESTS. GLUCOSE TOLERANCE TEST, ARCCT STIMULATION TEST, MAGNETE RESONANCE SPECTROSCOPY WITH ANTERIOR WITH 30 SECOND ISO METRIC FLEXION EXERCISE AND A SIMPLE FLU SHOT LOOKING AT ANTIBODY RESPONSE. HERE ARE A FEW FINDINGS. SOME OF THE HIGHLIGHTS. THIS IS THE RESULT OF A FLU SHOT CHALLENGE IN FRAIL AND NON-FRAIL OLDER ADULT THES. MEN AS WELL AS WOMEN IN THIS PARTICULAR SUBSTUDY. THIS WAS CONDUCTEDDED BY SEAN LANG. THE RATE AND PERCENT OF SERO CONVERSION IN RESPONSE TO INFLUENZA IMMUNIZATION CLINICALLY SIGNIFICANT RESPONSE FOUR FOLD OR HIGHER INCREASE IN TITERS WAS ALMOST NON-EXISTENT P IN THE FRAIL. OBSERVABLE H 3N 25% NO RESPONSE CLINICALLY SIGNIFICANT LEVEL FOR H 1N 1 OR -- IN THE FRAIL WHILE REASONABLE RESPONSE IN THE NON-FRAIL. HERE IS THE RESULT OF GLUCOSE TOLERANCE TEST BY RITA CULIANI AND RITA K COPOLA SHOWING THE NON-FASTING BLOOD GLUCOSE IN 85 TO 95-YEAR-OLD WOMEN WAS NO DIFFERENT BY -- REALLY NOT DIFFERENT BY FRAILTY STATUS WITH RED BEING FRAIL, GREEN PRE-FRAIL AND BLACK NON-FRAIL. BUT YOU CAN SEE BLOOD MEASURES OVER TIME SHOW AFTER 30 MINUTES THAT THE FRAIL ELEVATION IN MEAN GLUCOSE LEVEL WAS QUITE GREATER IN THE FRAIL COMPARED TO THE PRE-FRAIL AND NON-FRAIL. THAT THE TIME TO RECOVERY WAS WELL BEYOND WHAT WE THOUGHT TO MEASURE. SAME THINGEN THE RIGHT HAND SIDE IN TERMS OF MEAN LEVEL. PROLONGED ELEVATION, DELAYED RECOVERY. NOTABLY IN ADDITION TO THE FACT THIS IN THE FRAIL VERSUS NON-FRAIL THERE WAS NO DIFFERENCE IN THE FASTING GLUCOSE LEVEL, THE GLUCOSE LEVEL FOR THE FRAIL WERE ALMOST 70-MILLIGRAM PER DECALITER HIGHER, QUITE SIGNIFICANT AT THE 120 MINUTES. IN OTHER MEASURES WE FOUND PROFOUND HE WILL VISIONS IN GLUCOSE RAISING HORMONES AN LOWERING GLUCOSE LOWERING HORMONES IN THE SAME TESTING IN FRAIL COMPARED TO THE NON-FRAIL SO THE WHOLE SYSTEM APPEARS DISREGULATED. ALSO NOTABLE THINKING ABOUT DISEASE, THIS STUDY WAS DONE IN WOMEN WHO HAD NO CLINICAL HISTORY OF DIABETES. AND EXCLUDING THOSE WOMEN, IN THIS SUBSET OF OLD WOMEN WITH NO HISTORY CLINICAL DIABETES, ONLY 27% HAD A NORMAL FASTING GLUCOSE, NORMAL GTT. 48% PRE-DIABETES AND 25% UNDIAGNOSED DIABETES. MOST MOST DUE TO ABNORMAL GLUCOSE TOLERANCE TEST SO DISREGULATION ACROSS THIS WHOLE PATHWAY HORMONES REGULATING INSULIN RESISTANCE AND ENERGY METABOLISM AND IN THE TOP, POTENTIALLY DRIVING INFLAMMATION. FINAL STUDY, DONE BY ROBBIE BARGAIN, MAGNETIC RESONANCE SPECTROSCOPY EVALUATION OF THESE OLE, OLD WOMEN LOOKING AT THEIR TIBIA ANTERIOR AND CONDUCTING 30 SECOND ISOMETRIC EXERCISE IN THE SCANNER TO LOOK AT TIME TO RECOVERY PHOSPHOCREATININE. WHAT YOU CAN SEE IS THESE OLD WOMEN WHO WERE FRAIL, ON THE RIGHT, HAD MUCH DELAYED TIME TO RECOVERY OF PHOSPHOCREATININE OF WOMEN NOT FRAIL. THE ONLY OTHER STUDY I'M AWARE OF THAT LOOKED AT THIS WAS IL-10 FRAIL MICE COMPARED TO NORMAL AND A STUDY BY OCCY. IN STEADY STATE NOT UNDER STRESS CONDITIONS WHAT THEY FOUND WAS QUITE SUGGESTIVELY PARALLEL IN TERMS OF LOWER CREATININE LEVELS AT REST AND THE IL 10 MICE AND THEN ATP AS WELL. SUBMODULES, ITSELFS ARE DISREGULATEDDED, THERE'S EVIDENCE FOR PROBLEMATIC MUTUAL REGULATION THAT IN FACT THE PHENOTYPE EMERGES WHEN THE SEVERITY OF THIS IS PAST PERHAPS A CERTAIN THRESHOLD RELATED CLINICALLY TO A COMPROMISED ABILITY TO ADAPT TO STRESSORS. HIGH RISK ADVERSE CLINICAL OUTCOMES. IS THIS DUE TO THE INITIAL CORE HYPOTHESIS THIS WAS DRIVEN BY DISREGULATED ENERGETICS ASSOCIATED WITH AGING WHICH LEAD TO GENERALIZED PHENOMENA PHENOTYPE. THERE IS MOUNTING EVIDENCE TO SUPPORT THAT. I DON'T HAVE TIME TO SHOW IT. BUT CERTAINLY A SUBJECT FOR DISCUSSION AT THIS MEETING. LET'S THINK WHAT I SHOWED YOU IN CONCLUSION IN TERMS OF IMPLICATIONS FOR THE POTENTIAL RELATIONSHIPS OF FRAILTY BOTH PHENOTYPE AND BIOLOGIC PROCESS. IN CHRONIC DISEASES. THERE IS EVIDENCE THE FRAILTY SYNDROME MAYBE AGING SPECIFIC AND AGE RELATED BUT IT MAY ALSO BE A FINAL COMMON PATHWAY PARTICULARLY FOR CAT BOLLIC DISEASES KICKED OFF AT A CERTAIN LEVEL OF SEVERITY OF DISEASES. THIS IS A POTENTIAL MECHANISM FOR THE ASSOCIATION OF FRAILTY WITH CHRONIC DISEASE. A SECOND, THERE'S SOME EVIDENCE TO SUPPORT THIS. THAT ACTUALLY THE CO-EXISTENCE OF FRAILTY AN CHRONIC DISEASE IN THE SAME PERSON IS ASSOCIATED WITH ELEVATED RISK FOR SHARED OUTCOMES LIKE DISABILITY LIKE MORTALITY, WE HAVE SEEN THAT IN STUDIES IN HIV AIDS, CONGESTIVE HEART FAILURE WHERE THE RISK OF DISABILITY AND MORTALITY ARE AT LEAST ADDITIVE BETWEEN THE CHRONIC DISEASE FRAILTY AND IN ADDITION VERY CLEAR PEOPLE HOSPITALIZED OR ADMITTED FOR SURGERY IF THEY GO IN FRAIL HAVE WORSE OUTCOMES THAN THOSE WHO DO NOT GO IN FRAIL. IN ADDITION THERE MAY WELL BE AS FRAN KENNEDY TALK ABOUT SHARED RISK FACTORS FOR FRAILTY AN CHRONIC DISEASE PARTICULARLY THINKING OFF THE CUFF, OFF THE BAT ABOUT INFLAMMATION AND INSULIN RESISTANCE. NICE FIGURE FROM FOLOLLO SUGGESTING IN TERMS OF CARDIOVASCULAR DISEASE MANY ASPECTS OF WHAT WILL BE DISCUSSING OVER THE NEXT FEW DAYS IN TERMS OF BIOLOGY OF AGING MAY WELL STIMULATE CHRONIC LOW GRADE INFLAMMATION WITH AGING WHICH IS CLEARLY A FRAILTY AND FOR EXAMPLE, CARDIOVASCULAR DISEASE SHARED YOU COMES. IN ADDITION THERE'S SHARED BEHAVIORAL PREDICTOR OF FRAILTY CHRONIC DISEASE, LOW FISCAL ACTIVITY, SMOKING, AND LOW POOR DIETARY INTAKE ARE ALL PREDICTORS OF FRAILTY, WE KNOW THAT AT THIS POINT. SAME PREDICTORS FOR MANY CHRONIC DISEASES. SO THE AGING RELATED CHANGES OF FRAILTY BOY LOGIC PHYSIOLOGIC CHANGES COULD WELL AS DR. KENNEDY SUGGESTS COULD BE DRIVING DISEASE DEVELOPMENT. ONE INTRIGUING QUESTION THAT IS WORTHYING I THINK IS WHERE DOES ACTUAL DISREGULATION END AND DISEASE BEGIN? THE DATA THAT I SHOWED YOU GLUCOSE DISREGULATION SUGGESTED IN WOMEN WHO DID NOT IN THESE OLD WOMEN WHO DIDN'T HAVE CLINICALLY KNOWN DIE BOW TEASE, ONLY 20% WERE NORMAL. IN TERMS OF RESPONSE TO ORAL GLUCOSE TOLERANCE TEST PARTICULARLY, IS THAT DISEASE? DISREGULATION OF AGING? SO WE HAVE RELATIONSHIPS OF FRAILTY WITH CLINICAL DISEASE WHICH SHOULD BE THOUGHT OF AS END ORGAN MANIFESTATIONS OF SHARED PROCESSES. WHETHER PHYSIOLOGIC LEVEL OR BIOLOGIC LEVEL. SO I WILL END IN A WAY SIMILAR TO WHERE DR. KENNEDY ENDED, THERE ARE MANY BIOLOGIC DRIVERS OF AGING THAT ALL OF YOU IN THE AUDIENCE WORK ON IS THERE ONE IN PARTICULAR DRIVING THIS PHENOMENON OF APRILTY OR A COMBINATION OF MULTIPLE BIOLOGIC DRIVERS STIMULATING THE MULTI-SYSTEM DISREGULATION WE SEE AT A PHYSIOLOGIC LEVEL. WE KNOW FRAILTY IS A CLINICAL SYNDROME AND PREDICTS TERRIBLE OUTCOMES IN THE SHORT TERM. THERE ARE MANY SYSTEMS DISREGULATED IN PARALLEL, MANY PHYSIOLOGIC SYSTEMS ASSOCIATED WITH FRAILTY AND THAT THE RISK, ASSOCIATION IS MONTHLYIA, THEN PERHAPS PHENOMENON OF COMPLEX SYSTEMS UNRAVELED IF YOU WILL AND THERE'S MOUNTING EVIDENCE OF UNDERLYING BIOLOGIC ALTERATIONS PREDICTING THIS PARTICULAR PHENOTYPE AND POSSIBLY THESE PHYSIOLOGIC DISREGULATIONS. THE RELATIONSHIP WITH DISEASE IS A QUESTION TO BE PURSUING AND I HOPE TODAY I HAVE BEEN ABLE TO SUGGEST SOME POTENTIAL MECHANISMS TO BE THINKING ABOUT IN TERMS OF THAT. OVERALL DOES THIS MATTER? I THINK THAT'S A RHETORICAL QUESTION GIVEN WE'RE HERE TO THINK ABOUT THESE ISSUES. BUT IF YOU THINK PARTICULARLY ABOUT APRILTY, THERE ARE A NUMBER OF ILLUMINATING INSIGHTS ABOUT OPPORTUNITIES TO FOCUS ON HEALTH SPAN AN PREVENTION AS DR. KENNEDY LAYED OUT COME PELLINGLY. IF YOU THINK ABOUT FRAILTY, IF I THINK AS THE EMERGING PROPERTY OF DISREGULATED COMPLEX SYSTEM, THAT WOULD CERTAINLY SUGGEST TO ME THAT THE OPPORTUNITIES FOR PREVENTION DO NOT CASUALLY LIE IN TWEAKING ONE OR ANOTHER ONE DISREGULATED ABNORMAL SYSTEM. THE DYNAMIC HAS TO BE THAT ARE ADDRESSED MUCH MORE BASIC OR MUCH MORE MILLION SYSTEM AND PHYSICAL ACTIVITY IS A PRIME EXAMPLE OF THAT. SO THANK YOU. I HOPE THAT THIS IS SET UP -- HAS SET UP DISCUSSIONS FOR THE DAY. I WANT TO POINT OUT ALL THE DATA I CAN SHOW YOU PEP FOR THE MOUSE DATA DATA FOR POPULATION BASED STUDIES WHERE I THINK PROVIDE IN THE FUTURE MUCH OF THE BASIC SCIENCE OF THESE KINDS OF VERY COMPLICATED QUESTIONS. THANK YOU. [APPLAUSE] >> ALL RIGHT. WE'RE GOING HAVE A 30 MINUTE BREAK NOW. WE'RE GOING TO RECONVENE, 9:45 I BELIEVE FOR THE INFORMATION SESSION SO GOOD MORNING AND WELCOME TO THIS SESSION ON INFLAMMATION, MY NAME IS ALLISON AUGUSTINE FROM THE NATIONAL INSTITUTE OF ALLERGIES AND INFECTIOUS DISEASES. DR. GRACE CHEN AND MYSELF, GRACE FROM THE NATIONAL EYE INSTITUTE WE CO-ORGANIZED IN SESSION WITH HELP OF OTHER COLLEAGUES FROM NIH, CLAUDE OWE -- JANICE ALAN FROM THE NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES. AND JUST AS A FOOTNOTE FOR GRACE HER NAME SUDS ACCIDENTLY LEFT OFF THE ORGANIZING COMMITTEE BUT SHE'S PART OF ORGANIZING COMMITTEE AND CO-LEAD. OUR CO-CHAIRS FOR THIS SESSION ON INFLAMMATION ARE CLAUDEIO FRANCESCHI AND JUDITH CAMPISI. HE'S FROM THE UNIVERSITY OF BOLOGNIA AND HE WILL GIVEN OVERVIEW OF THE TOPIC FOR THE SESSION. AND DR. KAMSIN IS PROFESSOR BUCK INSTITUTE FOR RESEARCH ON AGING AS WELL AS -- CAMPISI AD THE LAWRENCE BERKELEY WILL BENAL LABORATORY. DR. CAMPISI WILL DIRECT DISCUSSION FOLLOWING THE LAST SPEAKER APPROXIMATE WILL ALSO GIVE A SUMMARY OF THE SESSION. WITH THAT, HOPEFULLY WE -- OKAY. SO I WOULD LIKE TO INVITE DR. FRANCESCHI TO PLEASE COME UP AND GIVE THE INTRODUCTION. >> GREAT PLEASURE AND HONOR TO BE HERE AND I WOULD LIKE THE THANK ORGANIZERS AND HOW CAN I -- OKAY. THIS IS BUSY SLIDE BUT GIVES YOU THREE MESSAGES. FEST SOME YEARS AGO I PROPOSED A NAME (INAUDIBLE) FOR PURPOSES OF CHRONIC INFLAMMATION CHARACTERISTIC PERSISTENT STERILE, THAT IS CHARACTERISTIC OF AGING. PLEASE GIVE A LOOK TO THE SUBTITLE, EVOLUTIONARY PERSPECTIVE OF IMMUNE SENESCENCE BECAUSE THIS IS THE END RESULT OF MY STUDIES ON EVOLUTION OF NEW SYSTEM AND CENTRAL ROLE OF INNATE IMNINE AND MACROPHAGES. SECOND AS MANY PREVIOUS SPEAKERS MENTION INFLAMMATION AND I WILL USE THE EARLY INFLAMMATION FROM NOW ON, IS SHARED BY THE MOST IMPORTANT DISEASES OF AGING WHICH HAVE OR HAS GREAT INFLAMMATORY COMPONENT AND PATHOGENESIS. THE THIRD MESSAGE IS INFLAMMATION IS MULTI-SYSTEMIC INFLAMMATION AND SEVERAL ORGANS AND SYSTEMS CONTRIBUTE, THE GUT MICROBIOTA, THE IMMUNE SYSTEM OF COURSE, BUT ALSO THE LIVER, THE MUSCLES AND PROBABLY ALSO THE BRAIN AS IT WILL BE MENTIONED BY OTHER SPEAKERS. SO WE NEED A SYSTEMS BIOLOGY OR METHODS APPROACH TO DETECT INFLAMMATION. I WILL SUMMARIZE, THERE'S A LOT OF OPEN QUESTIONS YOU CAN IMAGINE BUT I WILL TRY TO SUMMARIZE SOME OF THE MOST IMPORTANT CHARACTERISTICS THAT JUDITH CAMPISI AND MYSELF IDENTIFY. INFLAMMATION IS TRIGGERED BY A VARIETY OF DANGEROUS SIGNALS EXOGENOUS LIKE CYTOMEGALO VIRUS OR HIV VIRUS, BACK TOREIA OF THE GUT MICROBIOTA AND ITS PRODUCT OR EBB DODGE MOUSE. THIS IS VERY -- ENDOGENOUS. SELF-DANGER SIGNALS, SENESCENCE CELLS THAT DO THIS EXPLORED THE (INAUDIBLE) AND THEY HAVE AN INFLAMMATORY PHENOTYPE. DYSFUNCTIONAL ORGANELLES SUCH AS MITOCHONDRIAIA, CELL CELL DEGREES BECAUSE EVERY DAY EVERY SECOND A LOT OF CELLS ARE DESTROYED. ALSO MODIFIED PROTEINS AND END GLYCAN AND DNA WHICH IS RECOGNIZED AS A BACK TIER YOU DNA. ADP REACTIVE OXYGEN SPECIES. THUS I THINK DISPOSAL PLAY A MAJOR ROLE IN TRIGGERING INNAMATION AND I PROPOSE TO YOU THIS NEW WORD, GARBAGING. WHICH SHOULD DELIVER THE MESSAGE. ALL ARE PRODUCED IN YOUNG HUMANS, SPECULATING THE HEALTH STATUS, THE PHYSIOLOGICAL HEALTH STATUS IS MAINTAINED ASSURED BY A PHYSIOLOGICAL INFLAMMATORY TONE AS IT WAS PREDICTED ABOUT A CENTURY AGO BY THE FAMOUS ENDOCRINOLOGIST (INDISCERNIBLE). AS AN ESSENTIAL INGREDIENT TO MAINTAIN BY BODY HOMEOSTASIS. WITHIN THIS PERSPECTIVE INFLOW PERSPECTIVE, INFLAMMATION INCREASE WITH AGE WITH INFLAMMATORY TONE FOSTERED BY INCREASING EXPOSURE TO EXOGENOUS DANGER AGENERALS AND INCREASED GENERATION OF ENDOGENOUS DANGER SIGNALS BECAUSE OF INCREASE NUMBER OF SINCEs SENT CELLS, INCREASE NUMBER OF CELL DEGREES, DAMAGE DYSFUNCTIONAL MITOCHONDRIAL ALTERED MOLECULES, AS I MENTIONED BEFORE. SO BUT TO INCREASE GENERATION OF ENDOGENOUS DANGER SIGNALS THERE IS A DECREASE GARBAGE DISPOSAL AND YOU WILL HEAR ABOUT DURING THIS DAY, INCLUDING DECREASE EFFICIENCY OF UBS PROTEOSOME UBIQUITIN PROTEOSOME SYSTEM, AUTOPHAGY AND MYTO HAVE GIVE AS OTHER PEOPLE WILL MENTION. FINALLY THERE ARE TWO MAJOR PLAYER, THE INCREASE ACTIVATION OF NF KAPPA B AN INFLAMMASOME. I WOULD LIKE TO PROPOSE TO YOU INFLAMMATION IS A FIRE AND THIS FIRE PROPAGATES IN THE BODY. SO I HAVE A PROPAGATING VIEW OF THE AGING PROCESS. THERE IS EVIDENCE THE AGING PHENOTYPE IS MAINTAINED BY CELL AUTONOMOUS MECHANISM RESPONSIBLE AGE MICROENVIRONMENT, THE NICHE AND THE MICROENVIRONMENT, ALL THE STUFF WHICH ARE FIBRIL LATING IN THE PLASMA OR BLOOD IN ANIMALS AND HUMANS SO INFLAMMATION CAN PROPAGATE FROM CELL TO CELL AND ORGAN TO ORGAN, AND THERE ARE DATA SUGGESTING EXSOMES CAN PROPAGATE MICRORNA, LOCAL INFLAMMATION TRIGGERS SUSTAIN AND FORCE EACH OTHER IN A VICIOUS CIRCLE SO DIFFICULT TO IDENTIFY WHICH CAME FIRST. IN THE CANCER FIELD PROPAGATION BY STANDARD CELLS, RESPONSE TO INFLAMMATION A WELL KNOWN AND CONCEPTUALIZED AS (INAUDIBLE) FORMATION. I WOULD LIKE TO GIVE SPECULATE THE TWO GIVEN THE IDEA HOW IMPORTANT CAN BE INNAMATION BECAUSE I I THINK THE EVOLUTION DOUBLING OF LIFE EXPECTANCY IN THE LAST 50 YEARS COULD BE A PART OF THE RESULT OF DECREASED RATE OF INFLAMMATION. DUE TO A LIFE LONG DECREASE PRODUCTION OF OR EXPOSURE TO GARBAGE AND SIGNALS BECAUSE OF ENVIRONMENT, SANITATION WHERE THERE ARE LESS MICROBE, LESS CELLULAR MOLECULAR DAMAGE PHYSICALLY AND I WOULD STRESS EMOTIONALLY STRESSFUL LIFESTYLE. WHICH CAN ALSO CAUSE INNAMATION. ALSO HAPPEN IN NEWBORN CHILDREN. IN THE LITERATURE DESCRIBED WHEN THE FETUS IS EXPOSED TO HIGH INFLAMMATORY ENVIRONMENT AND THERE CAN BE LONG TERM EFFECTS MAINLY DUE TO EPIGENETIC EFFECTS AND THERE IS A DECREASE INFLAMMATORY MEMORY. CONVERSELY IN POOR COUNTRIES THE RATE OF INFLAMMATION IS MUCH FASTER THAN THAT OF IN RICH COUNTRIES BY MUCH HIGHER AGE RELATED DISEASES. I THINK THAT THIS EXPLAIN THE DATA PRODUCED BY THE FIRST SPEAKER. GARBAGING AND INFLAMMATION CAN BE MEASURED THERAPEUTIC TARGETS BECAUSE OF THE IDENTIFICATION OF THE MAJOR SOURCES OF INFLAMMATION, THE LAST 20 YEARS, PAYED IF WAY FOR A VARIETY OF POSSIBLE INTERVENTIONS AIMED AT ELIMINATING OR NEUTRALIZING THE UNNECESSARY EXCESSIVE INFLAMMATORY STIMULI. WE CAN WORK ON THE GUT MICROBIOTA, WE CAN SLOW DOWN THE RATE OF INFLAMMATION AND ITS CAUSES AND WE CAN POSTPONE THE ONSET OF MEASURE AGE RELATED PHENOTYPES. THERE ARE SOME DATA THAT WILL BE SHOWN LATER ON IN THE SESSION. HAVE CONSEQUENCE OF ENTIRE BODY AND THERE WILL BE ALSO PRESENTATION OF INHIBITION OF INFLAMESOME ACTIVATION CAN BE ANOTHER MEASURE TARGET, THERE ARE OTHERS THAT I MENTION. I THINK THAT I FINISHED AND I THINK I CAN INTRODUCE IT'S A GREAT PLEASURE FOR ME BECAUSE WHEN I KNOW L UIGI FERRUCCI IN ITALY ON NATIONAL INSTITUTE OF AGING AND I HAVE SCIENTIFIC DIRECTOR OF THAT INSTITUTE AND LUIGI WAS A YOUNG PROMISING DOCTOR IN THIERIATRITION. NOW HE'S SCIENTIFIC DIRECTOR OF INTRAMURAL RESEARCH PROGRAM AT NIA SO IS A VERY PARTICULARLY PLEASED TO INTRODUCE YOU. [APPLAUSE] >> THANK YOU, CLAUDIO FOR THE INTRODICTION AND THE -- INTRODUCTION AND MEMORY OF THAT TIME. I'M GOING TO TRY TO GIVE YOU BRIEFLY AN INTRODUCTION ON PROINFLAMMATORY STATE OF AGING, WHAT CLAUDIO IS BEING NAMEDDED INFLAMMATION PHENOMENON. P I WANT TO START BY SAYING WHAT INFLAMMATION IS AND WHY WE'RE TALKING ABOUT INFLAMMATION NOW, WE'RE TALKING ABOUT SOMEWHAT OF A DIFFERENT INFLAMMATION. THIS IS WHAT IS HAPPENING IN A NORMAL INFLAMMATORY PROCESS WHICH IS ITS NATURE ACUTE PROCESS WHERE YOU HAVE A CODE, NORMAL INFLAMMATORY REACTION AS A RESPONSE TO ELIMINATE THIS INFECTION TRAUMA OR TOXIC ACTIVITY. AND THE INFLAMMATORY PROCESS IS WITNESSEDDED IN THE CIRCULATION BY LEVEL OF PROINFLAMMATORY MARKER. ONE OF THE MOST WELL KNOWN INFLAMMATORY MARKERS IS IL-6. AND INTERLEUKIN 6 WILL BE MENTIONED, PROBABLY BY ALL SPEAKERS THIS MORNING. RATER ON REACTION OF ACUTE PHASE C REACTIVE PROTEIN, C REACTIVE PROTEIN IS THE MOST KNOWN AND IS NOW ALSO USED IN CLINICAL PRACTICE BUT THIS REACTION IS MEANT TO ELIMINATE THIS DAMAGE AND WHEN THE PROCESS OF RESPONSE IS SUCCESSFUL THE LEVEL OF IL-6 AND CRT TENDS TO GO DOWN AND YOU HAVE A BEAUTIFUL (INAUDIBLE) AND ELIMINATION BECAUSE OF INFLAMMATION. WHAT IS HAPPENING WITH CROPPIC INNAMATION WHEN WE TALK ABOUT INFLAMMATORY, SO IL-6 GOES UP AT SOME POINT, WE DON'T UNDERSTAND WHEN THIS IS HAPPENING, BUT REMAIN INNOVATIVE FORKER A VERY, VERY LONG TIME AND THE CHRONICALLY ELIMINATED LEVEL OF INFLAMMATORY MARKERS IS EPIDEMIOLOGICALLY ASSOCIATED WITH A NUMBER OF BAD CONSEQUENCES. I'M GOING TO SHOW YOU DATA FROM ONE OF THE STUDIES SHOWING EVEN WHEN YOU SELECT VERY VERY HEALTHY POPULATION, THE LEVEL OF INFLAMMATORY MARKERS INCREASE WITH AGE. SO WILL IS SOMETHING THAT IS INTRINSICALLY CONNECTED TO EARLY AGING THAT UP REGULATE THE CHRONIC INFLAMMATORY PROCESS. THIS IS A HEALTHY POPULATION WITHOUT ANY CARDIOVASCULAR DISEASE, WITHOUT ANY CHRONIC INFLAMMATORY DISEASE SO THIS IS NOT CAUSED WHICH DISEASE BUT SOMETHING THAT WE DON'T REALLY UNDERSTAND. IS THAT INFLAMMATION, THIS CHRONIC ELIMINATION OF INFLAMMATORY MARKER IMPORTANT? INCREDIBLY IMPORTANT? NUMBER OF STUDIES THAT HAVE SHOWN, THIS IS ONE OF THE FIRST STUDIES SHOWING THAT IF YOU TAKE A POPULATION OF OLDER PEOPLE THAT HAVE ABSOLUTELY NO DISABILITY AND NO MOBILITY PROBLEM AND YOU MEASURE IL-6 OR OTHER INFLAMMATORY MARKERS, YOU SEE THAT BETWEEN THE DIFFERENT STUDIES, BETWEEN 2.5 AND 3.5 KEY PICO GRAM PER MILLILITER, THE RISK OF DEVELOPING DISABILITY INCREASES LINEARLY. THIS IS ONE OF THE MOST POWERFUL BIOMARKER PREDICTOR OF DISABILITY. I WANT TO STRESS THIS POINT BECAUSE I THINK IT'S VERY IMPORTANT IN TALKING AGING IN OLDER PEOPLE. THIS BEING SOMEBODY WHO IS ABLE TO DO EVERYTHING THEY CAN IN LIFE, WORKING OUT, SHOPPING, ENJOYING FULLY THEIR LIVES AN -- FULLY THEIR LIVES AND TRANSITION TO A CONDITION WHERE THEY NEED HELP JUST TO MOVE FROM THEIR BED. THERE IS NORMAL GAP IN QUALITY OF LIFE THAT GOES FROM BEING COMPLETELY MOBILE AND ADDING MOBILE DISSENT. WE HAVE NOW BIOMARKER THAT PREDICTS STRONGLY THIS, OVER AND BEYOND EVERYTHING WE KNOW WE HAVE USED SO FAR IN DISEASE. THE MECHANISM FOR CHRONIC LEVEL OF DIET -- INFLAMMATORY BIOMARKERS AND CONSEQUENCE OF ELIMINATING INFLAMMATORY BIOMARKERS HAS BEENIDENTIFIED BY IMMUNOLOGICAL L STUDIES BUT THE UNDERLYING MECHANISMS THAT CONNECT THE PHENOMENONS ARE SUITLY NOT KNOWN. I'M GOING TO TRY TO WALK YOU THROUGH A DICHOTOMY OF POSSIBLE INTERPRETATION. SO YOU START NORMALLY IN INFLAMMATORY REACTION WITH THE HARM -- SOME DAMAGE CELL, FROM CHEMICALS AND/OR PATHOGENS CLOSE THE GAP MA SHOWN THAT CLAUDIO WAS TALKING ABOUT THIS MORNING. IT'S A VERY BEAUTIFUL DEFINITION. WHAT'S HAPPENING IS THAT YOU'LL HAVE INFLAMMATORY RESPONSE, ATTEMPT TO REMOVE DAMAGED CELLS. WHEN THIS IS OCCURRING, ALL THE ENERGY, ALL THE ATTENTION IS DEDICATED TO THE REMOVAL OF THIS AGGRESSION. YOU HAVE TO -- INFLAMMATORY REACTION IS MEN TO FINE THIS AGGRESSION. DEDICATED ALL THE ENERGY, ALL THE SUPPLY TO THIS. IN FACT, THERE IS REALLY THE SHUTDOWN OF MEMBER VONNING MECHANISMS. FOR EXAMPLE, WE KNOW THERE IS REDUCED FOOT ABSORPTION DURING INFLAMMATION, THERE'S A STIMULATED AT THE LEVEL OF THE MUSCLE, THERE'S VERY, VERY LITTLE GROWING OF MUSCLE WITH DOWNING ARELATION AND LEVEL OF IDF-1 IN THE BONES OSTEOCLAST DOWN REGULATED OS OWE (INDISCERNIBLE) THE ENTIRE MUSCLE ACTIVITY IS PRODUCED BY IN PARTICULAR THE ACTIVITIES OF THE ERYTHROPOIETIN IS DOWN REGULATED SO EVEN THOUGH THE ERYTHROPOIETIN RISE TO THE BONE MARROW, DOES NOT STIMULATE PRODUCTION OF ERYTHROCYTE AT THE LEVEL THAT IS STIMULATION OF INHIBITION ON THE PHYSICAL ACTIVITY, AT THE LEVEL OF THE BRAIN IN ANIMAL MODEL DEMONSTRATED WHEN THERE IS CHRONIC INFROMMATION, ALL THE STIMULUS TO NEUROGENESIS INCLUDING EXERCISE, TEND TO BE LESS EFFECTIVE. SO ANYTHING THAT'S BUILT, EVERYTHING THAT REQUIRES USE OF ENERGY IS SHUT DOWN WHEN THERE IS THIS DEFENSE TO THIS ACUTE AGGRESSION. THIS ACTUALLY IN SOME WAY MAKES LOT OF SENSE BECAUSE WHEN SOMEBODY IS FINING YOU, WHAT YOU WANT TO DO IS TO WIN THE BATTLE. IF YOU WIN THE BATTLE, YOU HAVE TIME TO BUILD. YOU HAVE TIME TO REPAIR. YOU HAVE TIME TO MAINTAIN. IF YOU DONE WIN THE BATTLE YOU'LL BE DEAD SO IT DOESN'T MATTER WHETHER YOU HAVE DONE THOSE OR NOT. SO THE PROBLEM HERE IN NORMAL REACTION AS I WAS (INAUDIBLE) BEFORE WHEN THIS IS EFFECTIVE, YOU ELIMINATE CAUSE OF INFLAMMATION AND YOU HAVE SWITCH OF INFORMATION AND THEN YOU HAVE THE HEELING PROCESS. FURTHER WITH AGING WE NEVER GO TO THIS PART. I THINK THAT WE NEED TO HAVE TWO ALTERNATIVE HYPOTHESIS, EITHER WE NEVER REMOVE THE CAUSE OF INFLAMMATION, SO'S SOMETHING CONTINUING STIMULATING THE INFLAMMATORY RESPONSE THAT IS ALWAYS THERE. THE OTHER ALTERNATIVE IS THERE IS SOME INTRINSIC PROPERTY OF THE IMMUNE SYSTEM, FOR EXAMPLE, DISREGULATION OF NF CAP P PA B IS ONE OF THE POSSIBLE HYPOTHESIS, THAT MAINTAIN OXIDATIVE INFLAMMATION IN SPITE OF THE FACT THAT INFLAMMATION IS NO LONGER REQUIRED. THIS IS NOT TRIVIAL, IT'S INCREDIBLY IMPORTANT. IF INFLAMMATION IS FINDING SOMETHING DOWN REGULATING INFLAMMATION MAY NOT BE A GOOD IDEA. DISREGULATED OCCUR INTRINSICALLY IN THE IMMUNE SYSTEM THAT ACTING ON DISREGULATING AN DOWN REGULATING INFORMATION PHARMACO LOGICALLY DRIVE THE IDEA AND MAY HAVE GOOD CONSEQUENCES. I DOPE HAVE VERY MUCH TIME. I WAS JUST GOING TO GO WITH YOU CLUETHROUGH AN EXAMPLE HOW WHEN WE TALK ABOUT INFLAMMATION AND WE MAKE THE INFLAMMATION HIGH INFLAMMATORY MARKER THIS COULD BE AN EXCESSIVE SIMPLIFICATION. FOR EXAMPLE, IN THE MUSCLE, IF YOU HAVE MUSCLE DAMAGE, FIRST THING YOU DO HAVE IS THE INFILTRATION OF POLYMORPHISM NUCLEATES AND NUMBER OF PROCESS TO REMOVE THE DEGREES. WHEN THAT HAPPENS THEN YOU HAVE TO SWITCH THE IMMUNE SYSTEM IN THE REPAIR MODE. SO THE NEW SYSTEM DOES NOT ONLY FIGHT IMPORTANT TO FIGHT AGGRESSION BUT ALSO IMPORTANT TO REVEAL WHEN THE AGGRESSION HAD BEEN REMOVED. WE DON'T HAVE THAT NEW FACE OF INFLAMMATION WHERE THE DOWNING ARELATION OKAY CONSIDER AND NEW BUILDING PHASE OCCURS MAYBE VERY IMPORTANT METABOLIC PROCESS. THANK YOU VERY MUCH. [APPLAUSE] >> SO OUR NEXT SPEAKER IS JIM KIRKLAND. JIM GOT HIS M.D. AND Ph.D. FROM THE UNIVERSITY OF TORONTO. HE'S NOW PROFESSOR AT THE MAYO CLINIC AND HE'S DIRECTOR OF THE COGOOD CENTER FOR AGING RESEARCH AT THE MAYO. >> SO I WAS ASKED TO GIVE A TALK DATA FREE. BASICALLY WHAT I'M GOING TO DO IS ASK FIVE QUESTIONS, STEEL THE THUNDER FROM THE TALK BY SAYING THE ANSWERS TO THE QUESTIONS ARE EITHER YES OR BOTH. INTRODUCTORY SLIDES THERE. THE FIRST QUESTION IS THIS. CIRCULATING PROINFLAMMATORY MOLECULES ARE PREDUCKTORS OF AGE RELATED MORBIDITY BUT ARE THEY IMPORTANT DRIVERS OR MARKERS OF AGE RELATED DISEASE IN HUMANS. SO I'LL START BY SAYING BY SUMMARIZING THE PREVIOUS TALKS AND THAT'S THERE'S CHRONIC STERILE LOW GRADE INFLAMMATION THAT TENDS TO INCREASE IN MANY OLDER INDIVIDUALS TO CAN DIFFERENT EXTENT ASSOCIATED WITH MANY -- PRETTY WELL ALL MAJOR AGE RELATED CHRONIC DISEASE. IF THIS IS ASSOCIATED WITH OR MAY DRIVE OR BE DRIVEN BY CELLULAR SENESCENCE AND MACRO MOLECULAR DAMAGE, THESE ARE HIGH HI INTERRELATED. WE HAVE TO REMEMBER WE'RE NOT JUST DEALING WITH CYTOKINES IN THESE SITUATIONS. THERE ARE OTHER KINDS OF PROTEINS AND THERE ARE NON-PROTEIN ACTORS THAT MAYBE IMPORTANT AND ARE UNDERSTUDIED INCLUDING VARIOUS LIPID RELATED MOLECULES, CERAMIDES, AND OTHER NEUROLOGICAL MEDIATORS AND SOMETIMES WE'RE TALKING THINGS THAT MAY HAVE SYSTEMIC EFFECTS NOT JUST THROUGH GETTING INTO THE CIRCULATION BUT EFFECTS ON THE NERVOUS SYSTEM AFFERENT AND AFFRONT LOOPS SO THERE'S WORK THAT NEEDS TO BE DONE TO SORT SOME OF THESE THINGS OUT. NOW, WITH RESPECT TO THIS PARTICULAR QUESTION, ARE THEY IMPORTANT DRIVERS OR MARKERS IN MANY AGE RELATED DISEASE IN HUMAN? SIMPLE ANSWER IS YES IN MANY CASES. YES PLUS NO IN SOME CASES, AND NO IN OTHERS. SO THERE IS DIVERSITY. ONE THAT'S YES PLUS NO IS SITUATION WHERE THERE'S A DIVISION BETWEEN EFFECTS OF THE KINDS OF CONSEQUENCES. THAT'S MYELOFIBROSIS SO THIS DISEASE IS OFTEN ASSOCIATED WITH IL-6 PRODUCING TRANSLOCATION, SOMETIMES HALF THE TIME ASSOCIATED WITH HIGH CIRCULATING IL-6 LEVELS WITHOUT THE ELECTRONICS LOCATION. IT TURNS OUT FROM NICE WORK IF YOU USE JAG 1, 2 INHIBITORS TO BLOCK EFFECTS AND PRODUCTION OF IL-6 IN THESE PATIENTS IN A STUDY PUBLISHED IN NEW ENGLAND JURY ROOM YOU DO NOT AFFECT THE UNDERLYING DISEASE STATE MANIFEST BY TIME TO DEVELOPING LEUKEMIA OR CLONAL MYELOPROLIFERATION ASSAYS OF BONE MARROW BIOPSIES BUT TREMENDOUS EFFECTS ON CONSTITUTIONAL SYMPTOMS SO PATIENTS WHO HAVE A PROFOUND IL-6 SYNDROME, WITH THINGS DR. FRIED TALK ABOUT WITH WEIGH LOSS, CACHEXIA ANODIZE REAR DEPRESSION, AND DECREASE MOVEMENT AND COG MITIVE FUNCTION, THE REST OF IT, THOSE ARE DRAMATICALLY REVERSED BY GIVING JAG 1, 2 INHIBITORS BUT RATE OF PROGRESSION IS NOT AFFECT SOD THIS IS A YES AND NO SITUATION. OTHER PROCESSES INVOLVE PRODUCTION OF FACTORS THAT ADD LOCALLY IN LOCALIZED DISEASES THAT ARE AGE RELATED. IN ARTHRITIS FOR EXAMPLE, VARIOUS OTHER KINDS OF SITUATIONS, THERE CAN BE AUTOCRINE OR PARACRINE FACTORS NOT RELEASED IN CIRCULATION BUT IMPORTANT DRIVERS AN RELATED TO BOTH AGING PROCESSES APPROXIMATE THE DISEASES. AND MOST OF THESE DISEASES THERE IS ESCAPE TYPE CIRCULATION. SECOND QUESTION, DAMAGE MOLECULES OR CELLS, SINs SENT CELLS STIMULI FOR AGE RELATED INFLAMMATION. TO WHAT EXTENT DISTINCT COMPONENTS STIMULUS AFFECT PHENOTYPIC OUTCOMES OR AGE RELATED DISEASE. THE ANSWER TO LARGE EXTENT, SOME EXTEN OR NO EXTENT. SO THERE'S A LOT OF VARIATION. SOME OF THE EXPLANATION FOR THIS IS IS THE NATURE VARYS FROM INDUCER TO INDUCER SO IN THE KISS OF SECRETARY PHENOTYPE WHICH IS ONE THING THAT CAN UNLIE INFLAMMATION, PARTICULARLY IL-6 PRODUCTION, MOST CIRCULATING IL-6 ASSOCIATED WITH FRAILTY SYNDROME COMES FROM FAT TUSH SHOE. WE'LL TALK ABOUT THAT IN A MOMENT. BUT BUT IT APPEAR TO DIFFER AMONG CELL TYPES PROFOUNDLY. IL-6 A MAYOR MEDIATOR IS NOT INCREASED IN CORNEAL EPITHELIAL CELLS SO THERE ARE EXCEPTIONS AND DIFFERENCES AMONG THE TISSUES. WITH RESPECT TO FAT TISSUE, TAKE HUMAN FATS PROGENITORS FROM DIFFERENT REGIONS VERY POTENTIALLY CO-INFLAMMATORY CELL TYPE THERE ARE BASELINE CHARACTERISTICS DIFFERS SUBSTANTIALLY DEPENDING ON DEVELOPMENTAL GENE EXPRESSION PROFILES IN THESE RESONANT PROGENITORS AND DIFFERENT FAT -- SO YOU CAN TAKE FROM ABDOMINAL REGION, THIGH REGION APPROXIMATE AND THEY'RE TOTALLY DIFFERENCE FOR EXAMPLE WITH RESPECT TO GENE EXPRESSION THAT ENTERS THE ONES THAT WERE ELEMENTS. AND THESE DRIVE TO SOME EXTENT IN SOME STUDIES THAT ARE UNDERWAY, SOME ABOUT TO BE PUBLISHED, THE KIND OF INFLAMMATORY MEDIATOR EXPRESSION THAT VARIES FROM ORIGINATING DIFFERENT DEPOTS ACROSS THE BASELINE. WHEN YOU MAKE CELLS SINs SENT, SINs SENT, GIVEN THEY'RE DIFFERENT AT BASELINE THEIR S ASHS IS DIFFERENT. THEIR SAS IS DIFFERENT SO THERE APPEARS DIFFERENCES DEPENDING ON TISSUE INFLAMED AND INDUCTION THAT RESULTS IN DIFFERENCES WITH RESPECT TO PHENOTYPES. I TUCK MORE ABOUT MYELOFIBROSIS. THE THIRD QUESTION, DO STIMULUS SPECIFIC INFLAMMATORY MEDIATORS ACT PRIMARILY AT DISTANCE, RELATED SYSTEM UKLY OR ONLY LOCALLY? AND THE ANSWER IS BOTH. SO WITH RESPECT TO THIS QUESTION, A LOT OF CYTOKINES PRODUCED AND OTHER INFLAMMATORY MEDIATORS, HAVE BIPHASIC EFFECTS THAT DEPEP ON CONCENTRATION GRADIANTS AWAY FROM THE SOURCE OF INFLAMMATION. TNF ALPHA LOW CONCENTRATIONS CAN BE A VERY STRONG DRIVER OF PROLIFERATION OF A VARIETY OF DIFFERENCE CELL TYPES. HIGHER CELL TYPES INHIBITS PROLIFERATION AN DIFFERENTIATION AND CAUSES APOPTOSIS. SO THERE'S A CONCENTRATION DEPENDENCY AND A GRADIANT EFFECT THAT OCCURS THAT'S COMPLEX THAT WE DON'T COMPLETELY UNDERSTAND WITH RESPECT TO AGING PHENOMENA OR AGE-RELATED DISEASE. SOME MEDIATORS ARE DEGRADED LOCALLY, FOR EXAMPLE TNF ALPHA, OTHER VERSUS A PARACRINE EFFECT AND OTHERS ARE AUTOCRINE LIKE IL-1 ALPHA AND TECH NOT TO MAKE OUT OUTSIDE THE CELL. SO GIVEN SOME ARE STIMULUS SPECIFIC, SOME UP TO A GREATER EXTENT THAN OTHERS WITH RESPECT TO AGE RELATED DISEASE AND BIPHASIC EFFECTS AND THEY MAY OR MAY NOT ESCAPE TO CIRCULATION, YOU EXPECT THE ANSWER TO THIS QUESTION TO BE BOTH. NEXT QUESTION IS WHAT ARE ROLES OF LOCAL VERSUS SYSTEMIC PRODUCTION OF PROINFLAMMATORY CYTOKINES AND DRIVING PHENOTYPES AND PATHOLOGY ASSOCIATED WITH AGING. AGAIN, THE ANSWER IS BOTH CAN BE IMPORTANT DEPENDS ON DISEASE STATE YOU LOOK AT, DEPENDS ON PARTICULAR SIGHKINES AN INFLAMMATORY MEDIATORS INVOLVED. WE HAVE TO BEAR IN MIND THERE ARE INFLAMMATORY MEDIATORS LIKE CYTOKINES THAT TEN TO BE PRODUCED IN AGE RELATED PRO INFLAMMATORY STATES AN DISEASE PROINFLAMMATORY ACTIVATED STATES THAT ACT ON THE NERVOUS SYSTEM AS WELL. SOME INDUCERS GET INTO THE CIRCULATION AND LOW QUANTITIES BUT HAVE A MAJOR EFFECT ON ANOTHER ORGAN, THE LIVER WITH RESPECT TO PRODUCTION OF CRP, OR OTHER KINDS OF OUTCOMES THAT GET PRODUCED BY SMALL QUANTITIES OF LOCAL INFLAMMATORY FACTORS ESCAPING TO THE CIRCULATION DRIVING LIVER PRODUCTION. SOME FACTORS ALSO ACT LOCALLY WITH RESPECT TO STEM CELL AN PROGENITOR PROGENITOR NICHES. THE FINAL QUESTION IS S YOUNGER INDIVIDUAL, THIS IS A POTENTIALLY EXCITING, WE'LL HEAR MORE ABOUT THIS LATER. THERE ARE TGF RELATED FACTORS OTHER LOCAL FAP FACTORS THAT IN STUDIES AND OTHER EXPERIMENTS APPEAR TO BE PROTECTIVE IN SOME CASES ANTI-INFLAMMATORY APPROXIMATE PRODUCED BY YOUNGER INDIVIDUALS SO LONG RUN WE NEED MORE WORK TO UNDERSTAND THE ANSWERS TO THESE QUESTIONS. DIFFERENCE AMONG TISSUES CYTOKINE INFLAMMATORY MEDIATOR PRODUCTION. WE NEED TO KNOW -- WED WE NEED TO BERM WE'RE NOT JUST DEALING WITH CYTOKINES OR OTHER THINGS GOING ON AND MOST IMPORTANTLY WE NEED TO COME TO A MECHANISM BASED INTERVENTIONS SO IT DOES APPEAR THAT DOING THINGS LIKE ELIMINATING SENESCENCE CELLS WHICH APPEAR TO BE A MAJOR SOURCE OF IL-6 FROM FAT TISSUE REDUCE FRAILTY AND EXPERIMENTS THAT WERE DONE AT MAYOR. IT APPEARS THAT -- MAYO. RAPAMYCIN ACTS THROUGH MODULATE ING THIS PHENOTYPE, TRACK INHIBITORS THAT HAVE IMPACT ON CERTAIN AGE RELATED DISEASE OUTCOMES LIKE NUTRITIONAL STATE, FAT TISSUE GROWTH, SO FORTH. SO THERE MAYBE INTERVENTIONS COMING ALONG. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU. SO OUR NEXT SPEAKER IS JAYNA AMHATI PROFESSOR AT UNIVERSITY OF KENTUCKY WHO WILL TALK TO US ABOUT INFLAMMATION IN THE EYES. >> JAYAKRISHNA. I WAS ASKED TO SHARE MY THOUGHTS ON COMMONNALTIES AN DIFFERENCES IN INFLAMMATORY DRIVERS. OF CHRONIC DISEASE. SO I THOUGHT I WOULD DO SO BY FRAMING THE QUESTION IN THE CONTEXT OF FOUR GREAT DISEASES OF AGING. AND THIS AUDIENCE NO DOUBT IS FAMILIAR WITH AT LEAST THREE OF THEM. THERE'S TREMENDOUS HUMAN ECONOMIC TOLL EXACTED BY CONDITIONS LIKE ALZHEIMERS AN ATHEROSCLEROSIS AN ARTHRITIS ASSOCIATED WITH AGING. LESS WELL APPRECIATED IS THE EQUIVALENT TOLL BY CONDITION CALLED AGE RELATED MACULAR DEGENERATION, WORLDWIDE PREVALENCE TODAY EXCEEDS THAT OF ALL SOLID TUMORS COMBINED AND RIVALS THAT OF ALZHEIMER'S DISEASE. WHILE THESE CONDITIONS HAVE MULTI-FACETTED NEBULOUS ETIOLOGIES THEY'RE CHARACTERIZED BY AGE DEPENDENT DEGENERATIVE AND DESTRUCTIVE SET OF PROCESSES THAT RESULT OFTEN IN A COMMON HALLMARK, COMMON MOLECULAR HALLMARK, ACCUMULATION INADEQUATE ELIMINATION OF WHAT'S TERMD CELL DEBRIS. THESE TOXIC ACCUMULATIONS OVER TIME INITIATED INFLAMMATORY RESPONSE THAT AT THE OUTSET WITHIN QUITE BENEFICIAL PROMOTING HEALTH AND LONGEVITY OF TISSUE AN ORGANISM BUT AS YOU HEARD EARLIER TODAY FROM A VARIETY OF SPEAKERS FOR SET OF UNKNOWN REASONS INFLAMMATORY CASCADE IS OFTEN NOT TURNED OFF, AND PERSISTS. IN THAT CONTEXT IT TENDS TO BECOME DETRIMENTAL TO ANATOMY AND FUNCTION. CELLS DEBRIS TAKES MANY FORMS. IT CAN BE POLYPEPTIDE, LIPIDS, SUGARS, AND AS WE HAVE SHOWN RECENTLY THEY CAN BE NON-CODING OR REPETITIVE RNAs. DESPITE THE DIVERSITY OF THESE DEBRIS SUBSTANCES THEY OFTEN TEND TO RESULT IN SIMILAR FUNCTIONAL PATHOLOGIES. ONE REASON MIGHT BE THE DICOVERY OVER THE PAST FEW YEARS OF COMMON NODE CALLED INFLAMMASOME WHICH IS AN IMMUNE PLATFORM THAT INTEGRATE BIFORMING THESE VERY HETEROGENEOUS SIGNALS AND START TRANSDUCING A SET OF SIGNALS THAT INITIATE AND POTENTIATE CELLULAR DAMAGE DYSFUNCTION, CYTOKINE PRODUCTION FOR EXAMPLE P, RESULTING IN CELLULAR DYSFUNCTION AND DEATH. NOW T INFLAMMASOME WHICH THE INFLAMESOME BEST STUDIED EXAMPLE, CAN BE THOUGHT OF AS MOLECULAR MACHINE THAT TURNS OUT POWERFUL CYTOKINES LIKE INTERLEUKIN 1 BETA U IL-18, THIS PARTICULAR INFLAMESOME EMERGED IN REACCEPT YEARS, VERY ATTRACTIVE THERAPEUTIC TARGET IN A VARIETY OF THESE DISEASE STATES THAT WE'RE TALKING ABOUT TODAY. REALLY A CONVERGENT DATA SETS FROM MULTIPLE GROUPS HAVE IMPLICATED THE INALMOSTSOME IN A STARRING ROLE BOTH HUMAN TISSUES DERIVED FROM PATIENTS WITH THIS CONDITION AND IN STUDIES SHOWING THAT BLOCKING INMA'AMSOME OR MEDIATORS. CAN HAVE POWERFUL BENEFICIAL EFFECTS IN ANIMAL CONDITIONS. MIGHTY MITI 88 AND INTERLEUKIN AND SO ON. THERE'S DRAMATIC DIFFERENCES IN DISEASE STATES, ONE IN CELLULAR PHENOTYPE THAT DRIVES THESE CONDITIONS THAT CAN BE DRAMATICALLY DIFFERENT FOR EXAMPLE IN SOME IT'S DEGENERATION OF CELL AND TISSUE THAT DRIVE DYSFUNCTION. OTHER CONDITION YOU SEE THE COLUMN ON RIGHT IS CELLULAR PROLIFERATION THAT DOES THE DAMAGE. AND THE CELL ALREADY ACTORS CAN BE QUITE DIFFERENCE SO I THINK IT'S IMPORTANT TO CAPTURE SOME OF THESE REALLY NON-TRIVIAL SUBTLE DIFFERENCES. AS WE STUDY CONDITIONS. RECURRING THEME IN ALL THESE DISEASES IS OF COURSE IMMUNE DYSFUNCTION BUT THERE TOO, WHAT ARM OF IMMUNITY WE TALK ABOUT? CERTAIN STATES ADAPTIVE IMMUNITY IS IMPORTANT. INNATE IMMUNITY IS OFTEN THE DRIVER AND OTHER DISEASE STATES. AND P SO CALLED RESIDENT NEURAL IMMUNITY FUELS THE FIRE IN CONDITIONS LIKE ALZHEIMER'S OR AGE RELATED MACULAR DEGENERATION. THESE ARE NOT CRYSTAL CLEAR DISTINCTIONS, IT CAN BE OVERLAP PARTICULARLY DURING VARIOUS STAGES OF THE SAME DISEASE AND THE SAME INDIVIDUAL. ANGIOGENESIS OR BLOOD VESSEL GROWTH IS INCREASINGINGLY RECOGNIZED A KEY PATHOLOGICAL HALLMARK IN MANY OF THESE DISEASE STATES. MOST OFTEN PATHOLOGICAL DRIVING SPECIFICALLY CONDITION LIKE NEOVASCULAR FORM OF MACULAR DEGENERATION OR DEGENERATIVE ARTHRITIS. BUT HERE TOO, IN ATROPIC FORM OF MACULAR DEGENERATION, IT CAN BE ABSENCE OF INSUFFICIENCY OF BLOOD RESELLS IN THE CORE THAT SUPPLIES THE RETINA, THAT CAN FUEL THE FIRE, AS IT WERE. THERE'S CONFLICTING DATA SETS ABOUT ANGIOGENERALS IS AND PATHOLOGICAL IMPLICATIONS LIKE ATHEROSCLEROSIS. AS WE MOVE FORWARD TRYING TO UNDERSTAND AND CAPTURE VARIOUS INFLAMMATORY DRIVERS AND SUBSYSTEMS THAT REGULAR RATE CONTRIBUTION OF INFLAMMATION, I LIKE TO OBSERVE THE EYE EMERGED, PROVEN TO BECOME A SPECTACULAR PLATFORM FOR DISCOVERY AND INNOVATION IN TERMS OF INFLAMMATION AND AGING DISEASES. SO I THINK IT'S WELL KNOWN HA DECADE AGO THE FIRST STRONG DATA SETS FROM THE GWAS STUDY SHOW COMPLIMENT MACKTOR RANGE ASSOCIATED MACULAR DEGENERATION, CAME FROM THE PLATFORM STUDIED. NOW WE HAVE THE REALITY OF ARTIFICIAL SILICONE RETINAL VIEWING DEVICES FOR PATIENTS WITH END STAGE RETINAL DISEASES. THE EYE WAS ALSO THE FIRST PLACE WHERE INNOVATIVE THERAPEUTIC LIKE SMALL INTERFERON RNAs AND APT HERS WERE PRODUCEDDED AND IMPORTANTLY WHERE THE -- WERE INTRODUCED AND WHERE THE FIRST IMMUNOLOGICAL AND PROINFLAMMATORY ACTIVITIES OF THESE PARTICULAR DRUGS WERE DISCOVERED. ONE OF THE REASONS THE EYE EMERGE AS A PRIME PLATFORM TO TEST DEVICES AND DRUGS BECAUSE IT'S A NICELY COMPARTMENTALIZED SYSTEM THAT PERMITS ATTRACTIVE PHARMACOKINETICS AND ATTRACTIVE SELF-LIMITATION OF ADVERSE EFFECTS. THE EYE BEING ACCESSIBLE AND TRANSPARENT FOR STRUCTURE FROM UNPARALLEL VIEW OF PATHOLOGY EMOTION. SO WHAT YOU SEE HERE FOR EXAMPLE, IS CELLULAR DEBRIS ACCUMULATING IN THE CENTRAL RETINA OR A PERSON. FOLLOWED LONGITUDINALLY OVER TIME IN TERMS OF BLOOD VESSELS INVADING THE BLOOD VESSEL OF A PATIENT WITH MACULAR DEGENERATION. THE EYE THE IS THE FRONTIER FOR IMAGE TOOLS THAT PERMIT HISTOLOGICALLY APPROACHING RESOLUTION IMAGES OF THIS SELF-DEGREE BORROW AND EDEMA THAT RESULT FROM PRO-INFLAMMATORY CONDITIONS. THE EYE CAN TEACH A LOT ABOUT OCULAR DISEASE, BUT ALSO INFLAMMATORY CONDITIONS IN GENERAL. SO WOULD LICK THE LEAVE YOU WITH THAT THOUGHT. THANK YOU VERY MUCH. [APPLAUSE] >> OUR NEXT SPEAKER IS DEEP DIXIT, HE GOT HIS Ph.D. FROM THE UNIVERSITY OF HAHNOVER, NOW PROFESSOR AT YALE UNIVERSITY. >> GREAT. I TRAIN AT INTRAMURAL PROGRAM AT NATIONAL INSTITUTE ON AGING SO A GREAT HONOR TO BE HERE AT NIH TO SHARE THE STAGE WITH LEADERS. I WAS ASKED TO INITIATE A DISCUSSION TOPIC AGE ASSOCIATED -- ADAPTIVE OR BENEFICIAL OR PATHOGENIC. I DO NOT HAVE ANY ANSWERS PERHAPS MORE QUESTIONS AS WE MOVE FORWARD. POINT BEING INFLAMMATION HERE IS A MAJOR RISK FACTOR FOR SEVERAL CHRONIC DISEASES, AND ONE WOULD ARGUE IF ONE IS TO MORBIDITY AS DR. KENNEDY HE WILL GAPLY EXPLAINED IN THE BODY AGING PERHAPS SIMILAR RATE IF ONE IS TO UNDERSTAND THOSE PROCESSES U BUT IT'S CLEARLY NOT THE CASE SO I WILL TOUCH A LITTLE BIT ON THAT, ON THE ADAPTIVE IMMUNE SYSTEM AND INNATE IMMUNE SYSTEM. SO THIS IS PICTURE OF A YOUNG PILOT. MAGNETIC RESONANCE IMAGE OF SOMEBODY AROUND 24 YEARS OF AGE METABOLICALLY HEALTHY. IT'S ABOVE THE AORTIC ARCH AND THIS SUGGESTING THE MAJORITY OF THE SYSTEM IS FUNCTIONAL, AS MOST OF YOU KNOW, THYMUS IS CRITICAL FOR ESTABLISHING THE B CELL REPERTOIRE. THIS IS THE PLACE WHERE B CELL SPECIFICITY ARE CREATED. WHEN YOU'RE YOUNG YOU HAVE NAIVE T-CELLS AN THIS IS THE REASON WHY, THE CONSEQUENCE OF OVERALL IS THAT WE ARE -- REVIEW SYSTEM IS FUNCTIONING ADAPTIVE IMMUNE SYSTEM IS FUNCTIONING REALLY WELL. WHAT IS HAPPENING IS VERY POSITIVE BUT EXTREMELY CONSERVED THROUGHOUT THE -- THIS IS A PICTURE OF SOMEBODY WHO IS METABOLICALLY HEALTHY, WHAT YOU'RE LOOKING AT IS THIS WHITE MASS THAT YOU SIGH HYPERINTENSE REGION THAT IS BASICALLY A PILOT FULL OF LIPIDS. SO THIS IS A PERSON NOT OLD, IT IS NOT AN OLE PERSON. WHAT IS HAPPENING AS YOU GET OLDER, THE NUMBER OF B CELLS IN THE BODY DO NOT CHANGE T THE SYSTEM IS HIGHLY ADAPTIVE. AND AS WE HEARD TODAY, MOST OF US NEVER LOOK BEYOND AGE 40, 45, REACH YEAR 2000. AS WE GET OLDER THE FLAVOR CHANGES, AND THAT'S A HOMEOSTATIC EXPANSION OF EFFECTOR MEMORY T-CELLS, THE CELLS THAT HAVE SEEN THE ANTIGEN. AS A RESULT OF THAT, THERE'S RESTRICTION OF B CELL RECEPTOR REPERTOIRE DIVERSITY. WE HEARD FROM DR. FRIED HOW FREELY INDIVIDUALS ARE INTEGRATING INFLUENZA. THERE'S REASONS FOR THAT. ONE REASON IS THAT ADAPTIVE IMMUNE SYSTEM IS REGENERATING WITH AGE. THIS IS HAPPENING EARLY ON. SO THE QUESTION REMAINS, IS THE STAGE SET FOR US TO BE INFLUENCED AS GETTING OLDER? IS IT ADAPTIVE? BENEFICIAL? YOU DECIDE AS YOU HEARD FROM LUICSGI THE PHRASE HE COIND OF AGING, ALL OUR KNOWLEDGE COMES FROM HACAL HOST DEFENSE LITERATURE, INFORMATION IS REQUIRED FOR PROTECTION AGAINST INFECTION. SO NONE OF THE CLASSICAL SIGNSES OF INFLAMMATION EXIST IN AGING. FEVER, SWELLING PAIN. ALL THAT. LICK CHARLES JANEWAY CONCEPTUALIZED ININMATION, YOU HAVE TO BROKE DOWN THREE MAJOR COMPONENTS. TOUGH HAVE INDUCERS APPROXIMATE IMMUNE SENSORS AN MEDIATORS. INDUCERS WHICH CAN ALSO BE DANGER SIGNAL WHICH -- NOT VERY FAR FROM HERE NIAID COINED SO FOR THESE SIGNALS TO EXIST, YOU HAVE TO HAVE IMMUNE SENSORS. THE MOST IMPORTANT ARE MICROBES. INFECTION. BUT THERE ARE STERILE DANGER SIGNALS. AGING IS ASSOCIATED WITH THIS DAMAGE THAT CONTINUES. WE KNOW SEVERAL ARE ELEVATED WITH AGE. LUIGI HERE HAS SHOWN THAT WITH AGE, HE'S ONE OF THOSE -- SEVERAL ARE INCREASE WITH AGE, THERE'S SEVERAL, NON-MICROBIAL ORIGIN. FOR THESE TO BE PRESENT WE HAVE PATTERN RECOGNITION, TOLL LIKE RECEPTORS AND YOU HER FROM DR. DR. AMITY ABOUT TOLL LIKE RECEPTORS, THE INFLAMESOME. THEY CAN SENSE THE DANGER SIGNALS OR FACTORS THAT ARE PRESENT AS INDUCERS LEADING TO INFLAMMATORY RESPONSE AND ALL THESE MEDIATORS AN EFFECTORS IL-6, IL-18, THEY GET INDUCED IN THIS PROCESS. THEN THE QUESTION EMERGES HOW MUCH IS BENEFICIAL, INFLAMMATION IS EXTREMELY IMPORTANT BENEFICIAL RESPONSE TO INFECTION, GET INFLAMMATION, FOR SURVIVAL, AS WE HEARD WITH THE POSSIBILITY THE PROTECTION AGAINST INFECTION AN SURVIVAL THROUGH REPRODUCTIVE AGE PRIMARY FUNCTION. IN YOUNG INFECTION IMMUNE RESPONSE IS A HIGH ENERGY INTENSIVE EVENT. (INDISCERNIBLE) BUT WE RECOVER ARE FROM THOSE THINGS AND WE SURVIVE. IN OLDER INDIVIDUALS THERE'S NO -- THE MECHANISMS OF THESE PROCESSES ARE STILL FAIRLY UNKNOWN AND IT CONTRIBUTES TO EPISIS AND DEATH IN INDIVIDUALS. BUT CONCEPT OF INFLAMMATION COMES FROM CLASSICAL IMMUNOLOGICAL WORK WITH INFECTION. THIS IS PERHAPS DIFFERENT THAN WITH AGING. THIS IS JUST PART, THERE'S BUT DATA RIGHT NOW TO PROVE ANY OF THIS. WHAT WE DO KNOW IS THERE ARE CERTAIN METABOLIC CHANGES BECAUSE AS THEY INCREASE WITH AGE, -- COG MITIVE DYSFUNCTION PERHAPS HERE FROM INDUCTION FROM LATENT INFECTION FROM OBSERVATION IN THE GUT MICROBIOTA. THERE'S MORE AN MORE EVIDENCE EMERGING WITH THAT. AND THESE THINGS EVENTUALLY LEAD TO CHRONIC OVERINFLAMMATION. ALL IN THIS THINGS WE SEE, THIS IS ALL NICE AND GOOD BUT POINT REMAINS WE HAVE LITTLE CAUSALITY AND CUSS OF DATA IN THE FIELD HOW INFLAMMATION IS LINKED TO AGING. THAT'S FEW CLASSIC ANN INFLAMMATORIES THAT RESULTED IN LIFE EXPANSION OR THAT EFFECTIVE IN THIS SCENARIO. SO DR. AMITY ALREADY EXPLAINED THAT SUGGESTING THAT THREE INFLAMESOME IS IMPORTANT IN RANGING AND WHAT THIS PLEX DOES AS HE EXPLAINED, IT SENSES VARIOUS DANGER SIGNALS. THAT'S TWO INFLAMESOMES THAT RECENTLY EMERGED. THAT'S A NON-CANONCAL INFLAMMASOME CASPASE 11, IT'S TRIGGERED APPROXIMATE SENSES LPS INDEPENDENT OF TOLL LIKE RECEPTOR 4. SO THAT'S A LOT OF STUDIES THAT SUGGEST MAYBE METABOLIC ENDOTOX EMIA LEAKING FROM THE GUT AND CONTRIBUTING TO THE INFLAMMATION. SO WE LOOKED INTO THIS. SO DATA ARE FAIRLY CLEAR, IT IS PRIMARILY CANONCAL INFLAMMASOME, THESE THREE COMPONENT PARTS THAT GET ASSEMBLED WHEN YOU SIGH THESE DANGER SIGNALS LEADING TO ACTIVATION OF CASPASE 1 IN AGING AT LEAST IN MOUSE MODELS. THE NON-CANONCAL INFLAMESOME, CASPASE 11 INFLAMMASOME THAT SENSES LBS WHICH COULD BE IMPORTANT IN METABOLIC ENDOTOXEMIA IS NOT ENGAGED. WHAT THAT DOES IS YOU GET ACTIVATION OF CASPASE 1, SO IL-1 BETA IS MACROPHAGE IN A PROFORM SO THESE ARE RELEASED PROVIDED EL-1 BETA, CLEAVES THOSE THINGS. WE LOOK DOWNSTREAM WHICH IS IMPORTANT BECAUSE THERAPEUTICALLY IT IS AN IMPORTANT QUESTION. THE DATA SUGGESTS WHEN YOU ABLATE THE ANNE FLAMSOME YOU CAN ATTENUATE COMPONENT SEVERAL PARTS THAT ARE ASSOCIATED WITH INFLAMMATION, BONE LOSS BUT ADIPOSE TISSUE INFLAMMATION, GLUCOSE INTOLERANCE AND FRAILTY. SO THIS IS FIRST CAUSAL EVIDENCE IN MY VIEW THAT WE CAN SHOW THAT THIS ACTIVATION OF COMPLEX CAN LEAD TO SEVERAL INFLAMMATION ASSOCIATED CONDITIONS. IMPORTANT POTENTIALLY FOR THERAPEUTICS IS IF IF YOU BLOCK IL-1 BETA IN MICE ONLY PARTIAL DOWNSTREAM EFFECTS ARE AFFECTED. SO THE U YOU BLOCK IL-1 BETA YOU GET PARTIAL IMPROVEMENT IN CNS INFLAMMATION, COGNITIVE DECLINE. I'LL LEAVE IT AT THAT, WE'LL PROBABLY HAVE A GOOD LONGER DISCUSSION AFTER THIS. THANK YOU. [APPLAUSE] >> LAST BUT NOT LEAST IS RUSS TRACY, Ph.D. PROFESSOR UNIVERSITY OF VERMONT AND SEVERAL TRANSLATIONAL UNITS WITHIN THE UNIVERSITY. I WAS ASKED TO ADDRESS A PARTICULAR QUESTION, INTERVENTIONS THAT CAN OPEN DYNAMICS THAT CAN LIMIT CHRONIC DISEASE, ANSWER IS YES. THERE ARE MANY WAYS TO THINK ABOUT THIS. SO I HAVE CHOSEN TO TAKE ONE APPROACH. MIGHT BE DUE TO SOME OF YOU. WORK RESEASONLY AND HIV POSITIVE COMMUNITIES, THIS COMPETING MEETING IN BALTIMORE THIS SAME HOUR ON HIV AND AGING WHICH PUSHES THE NOTION THAT HIV IS ACTUALLY ACCELERATED AGING. AND SOME OF THIS CONCEPTS MAY PROVE USEFUL TO US IN THINKING INTERVENTIONS SO THAT'S MY GOAL TODAY. SO THE VIRUS KILLS CD4 CELLS WHERE THEY LIVE. THEY DON'T LIVE IN BLOOD PARTICULARLY, THEY LIVE IN LYMPHOID TISSUE SO IT KILLS THEM IN PLACES LIKE THE THYMUS AND THE THE SPLEEN AND BONE MARROW AND LYMPH NODES. AND IN GUT ASSOCIATED LYMPHOID TISSUE WHICH BREAKS DOWN BARRIER FUNCTION LEADING TO MICROBIAL TRANSLOCATION. SO OFF SIGNIFICANT PROBLEM OFF THE BAT. MICROBIAL PRODUCTS IN EXCESS OF AMOUNTS INTO THE BLOODSTREAM AND OTHER PLACES, THAT PLUS WHAT LOOKS LIKE AN ANTIVIRAL INTERFERON MEDIATED RESPONSE IN THE LIVER. CAUSES PROTEIN SYNTHESIS TO DECLINE THAT LEADS TO CHANGES IN COAGULATION FACTORS. WHICH LEADS TO IN ESSENCE A PRO CO-INGING A LANT STATE. SO YOU HAVE -- COAGULANT STATE. SO YOU HAVE LPS AND CHANGE IN COAGULATION LEADING TO A COAGULANT STATE. WHEN WE THINK ABOUT INFLAMMATION WE DON'T LIMIT IT TO INNATE ADAPTIVE IMMUNITY, WE INCLUDE COAGULATION IN THE TRIAD. MANY OTHER COMPONENTS THAT'S BEEN POINTED OUT BY SPEAKERS TODAY, THOSE ARE THREE WE TEND TO THINK ABOUT AND MAKE MEASURES OF WHEN WE DO STUDIES OF INFLAMMATION. SO WE CAN THINK OF INTERACTIONS OF THESE PATHWAYS. TALK ABOUT HOW THINGS LICK TISSUE FACTOR EXPRESSION AND LEADING TO HYPERCOAGULATION LEADS TO CARDIOVASCULAR DISEASE, SAME CAN BE TRUE BACK THE OTHER WAY, TALKING ABOUT MICROBIAL TRANSLOCATION LEADING TO CHANGES IN LIVER FUNCTION, SAME CAN BE TRUE BACK THE OTHER WAY TO A CERTAIN EXTENT. VARIETY OF NOSH YEAHTORS AND OTHER RISK FACTORS LEADING TO AGE ASSOCIATED DISEASESSEN ONE WE STUDIED THE MOST, CARDIOVASCULAR DISEASE. THAT'S THE OVERARCHING DESIGN. TRIED TO SUMMARIZE IN A SLIDE LIKE THIS. A POSITION WE AND OTHERS TALK ABOUT FOR 20 YEARS NON-IMMUNE STIMULATORS, WOUND HEALING FREQUENTLY LIKE ALCOHOLIC LIVER DAMAGE OR SMOKE RELATED LUNG DAMAGE ARE INFLAMMATORY CONDITIONS THAT HEAD TO CHANGES IN INNATE IMMUNITY AN COAGULATION. BOTH CAN CONTRIBUTE TO SOMETHING LIKE ATHEROSCLEROTIC PROGRESSION AND IF THERE'S ENOUGH OF THAT, DEVELOPMENT, THAT CAN BECOME STIMULATOR SO EROSION OF PLAQUE LEADS TO COAGULATION SYSTEM WHICH LEADS TO MORE INFLAMMATION AN STIMULATION. SO YOU GET INTO THE CYCLE IMMUNE STIMULATORS THAT'S WHERE THE HIV WORK LED US TO CONTEMPLATE ABOUT THIS. TH-1 CELLS ASSOCIATED WITH INCREASED ATHEROSCLEROSIS FOR EXAMPLE, THAT KIND OF CHANGE IN TERMS OF SPECIFIC IMMUNE FUNCTIONS BIASING AND HELPER FUNCTION IS OF INTEREST TO US BUT TODAY'S DISCUSSION, ALL THIS ACTIVITY WHETHER VIRALLY DRIVEN BACTERIALLY DRIVEN OR AUTOIMMUNE DRIVEN, TAKE AZYGOSES DONE NICE BY DR. D IT AND BECOMING INCREASINGLY IMMUNOSENESCENCE. WE HAVE BEEN EXPLORING THATTEN CREASING IMMUNOSENESCENCE LEADS TO INCREASED INFLAMMATION BECAUSE YOU GET MORE EFFECTOR MEMORY CELL FUNCTION BUG ALSO YOU'RE LOSING THE ABILITY TO DEAL WITH INVASION, APPROPRIATELY, SO INCREASING BURDEN ON INNATE IMMUNITY. INFECTIOUS DISEASE BURDEN BECAUSE YOU'RE INEFFICIENT IN MOVING AND INCREASE CANCER RISK DUE TO LOSS OF IMMUNE SURVEILLANCE OBVIOUS TO THE HIV COMMUNITY, AND WE HOPE TO BE EXPLORING MORE IN NON-HIV OLDER POPULATIONS. THAT'S OUR OVER ARCHING DESIGN. THINK ABOUT INTERVENTIONS THEN, SOME KEY IDEAS COME UP, SUBSTITUTE ALL CRIME DISEASE FOR ATHEROSCLEROSIS, WE HAVE A PAPER PUBLICATION, LOW NAIVE CELLS, NOT ONLY PREDICT ATHEROSCLEROSIS IN HEALTHY POPULATIONS THEY PREDICT TYPE 2 DIABETES AS WELL THROUGH THE SAME MECHANISM THAT IT'S INCREASING INFLAMMATION DUE TO INEFFICIENT ADAPTIVE IMMUNITY. QUESTION QUESTIONS TO CONSIDER, IF YOU THINK INTERVENTIONS IN THAT OVERALL CONTEXT, WHEN TO INTERVENE, EARLY VERSUS LATE. IT MAYBE DIFFERENT FOR BEHAVIORAL MODIFICATION VERSUS PHARMACO THERAPY. LINDA FRIED TALKED EXERCISES ALMOST ALWAYS BEING A GOOD THING. STOPPING SMOKING IS ALWAYS A GOOD THING. LOSING SOME WEIGHT. SO THESE ARE EFFECTIVE INTERVENTIONS WE HAVE KNOWN FOR 50 TO 100 YEARS IN SOME CASES CAN AFFECT HEALTH. WE NOW KNOW IT CAN EFFECT HEALTH THROUGH SYSTEMS WE'RE DISCUSSING SO WE HAVE INFORMATION ABOUT IT. MANY POWERFUL APP INFLAMMATORY THERAPIES THAT HAVE LONG TERM COST KENS WHICH WE'LL HAVE A TOUGH TIME KNOWING BECAUSE RANDOMIZE CONTROL TRIALS AREN'T FUNDABLE, WE NEED TO DO 40, 50 YEARS, NO ONE WILL ALLOW US TO DO THAT. AT THE END OF THE DAY WE USE BIOMARKERS IN PHASE 2, 3 TYPE STUDIES TO ASSESS LONG TERM FUNCTION MIGHT BE. THAT'S WITHIN APPROACH TO DO THIS SORT OF WORK, THERE SHOULD BE MORE APPROACHES LIKE THAT. IT SEEMS LIKE INTERESTINGLY THESE POWERFUL THERAPIES MAYBE BETTER TOLERATED IN YOUNG THAN IN OLD. ANTITNF THERAPY, A WONDERFUL ADDITION O THE ARMAMENTARIUM IN JURY ROOM ARTHRITIS, INNUMBERTORY BOWEL DISEASE, OLDER FOLKS WITH HEART FAILURE, PART OF PROBLEM IS TNF SIGNALING AND APOPTOTIC AND CARD YES MYOCYTES AND THEY FAIL WITH CLINICAL TRIALS. WE CAN ARGUE ABOUT DOSES AN APPROACHES, REGIMENS BUT IT'S MUCH BETTER TOLERATED IN YOUNG PEOPLE THAN OLD PEOPLE SO WE'LL HAVE QUESTIONS TO ANSWER, AS WE APPROACH THAT I WON'T BELABOR IT BUT THE SAME SYSTEM THAT CAUSED P PATHOPHYSIOLOGY WE NEED FOR NORMAL PHYSIOLOGY. HOW DO WE INTERVENE AND KEEP IT FUNCTIONAL AND ACTIVE BEHAVIORAL MODIFICATION, TRYING IN THE NEXT SLIDE GIVE A STRUCTURE TO HOW WE THINK ABOUT INTERVENTIONS. BEHAVIOR AND PHARMACO THERAPY SO THERE'S ONE THAT WILL REDUCE PROINFLAMMATORY RISK FACTORS STOP SMOKEING IS A GREAT ONE. HOW ABOUT CYCLOVEER FOR CMV INFECTION, THIS IS AN PERFORM USER UPPER OF ADAPTIVE -- APPROACHING COMMON UBIQUITOUS INFECTION THAT AFFECTS MANY, MANY PEOPLE LOOKING AT THE AGE OF FOLKS IN THIS ROOM, 50 TO 60% OF THE POPULATION IS SERE ROW POSITIVE IS CHEWING UP 3% IN N HAYNES, VERY NICE STUDY SHOWING A 3% OF T-CELLS, ALL THINGS T CELLS WORK ON, 3% TARGETED PEPTIDES, THIS IS A TEARER USE OF IMMUNE LANDSCAPE AND SOMETHING WE MAY TRY TO DO SOMETHING ABOUT. BEHAVIORAL MODIFICATION EXERCISE IS A GREAT ONE. PHARMACO THERAPY TO REDUCE RESPONSE, SO ITKINE INTERVENTIONS EVERYBODY IN THIS ROM CANAL TO THE SLIDE, LARGE -- ADD NUMBERS TO THE SLIDE, I OFFER NO EVIDENCE, I HAVE A COMPREHENSIVE LIST, THIS IS THE ONE, THE WAY AGAIN OF MAYBE STRUCTURING THE THINKING THAT WE HAVE FOUND USEFUL IN RECENT REVIEW ARTICLE, I TOOK OUT THE HIV SPECIFIC PART OF THIS BUT THE REST I THINK IS REASONABLE. GETTING RID OF EXCESS CO-PATHOGEN BURDEN MIGHT BE ONE APREACH MICROBE IDEAL TRANSLOCATION INCREASES LPS IN PLASMA DOES GO UP WITH AGE. BACTERIAL TRANSLOCATION AND THERE'S SOME OTHERS THAT MAY PLAY ROLE BEING ABLE TO SEQUESTER IT AN COPE IT FROM TRANSLOCATING. IF YOU HAVE T-CELL FUNCTION THERE'S POSSIBILITIES FOR INCREASING THAT FUNCTIONALITY WITHOUT ACTUALLY INCREASING NUMBER OF T-CELLS, THE ONES THAT HAVE LYMPHOID TISSUE FIBROSIS IS A PROBLEM. OTHERS THAT MIGHT BE INTERESTING TO EXPLORE. MORE SYSTEMIC CHRONIC INFROMMATION. LOTS OF POTENTIAL CANDIDATES. WON'T GO THROUGH ALL OF THAT. HYPERCOAGULATION, WE UNSUCCESSFULLY TRIED TO ARGUE FOR BIG TRAN TRIAL LOW DOSE BIG TRAN TRIAL IN HIV POSITIVE PEOPLE, ANTI-INFLAMMATORY DRUG IT CALMS DOWN THE COAGULATION SYSTEM, PLAYING ON INTERACTIONS OF SYSTEMS AND MAYBE INTEREST IN THAT. CELLULAR AGING, ATTACKING METABOLIC DISREGULATION. WE HEARD SOMETHING ABOUT THAT. AND I'LL STOP THERE. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> THANK YOU TO ALL SPEAKERS. NOW WE'RE GOING TO HAVE AN OPEN QUESTION-AND-ANSWER PERIOD. WE'LL WELCOME QUESTIONS FROM THE AUDIENCE. I'LL VERY BRIEFLY SUMMARIZE SOME OF THE MAIN POINTS OF THE SESSION. FIRST BEING INFLAMMATION REALLY IS THE GLUTAHOLDS TOGETHER BASIC AGING PROCESSES THAT OCCUR AND THE DISEASES OF AGING, THIS IS THE MAIN FOCUS OF THIS ENTIRE SUMMIT HOW TO UNDERSTAND HUH AGING IMPACTS MULTIPLE DISEASES THAT ARE -- WE CALL CHECK TVLY THE DISEASE OF AGING AND SEEMS THAT INFLAMMATION IS ONE OF THESE GLUES. IT IS NOT GOING TO BE A SIMPLE PROBLEM TO SOLVE BECAUSE WE NEED INFLAMMATORY RESPONSE TO SURVIVE. SO WE HAVE TO THINK ABOUT CLEVER WAYS OF DAMPINGENING THE PATHOPHYSIOLOGICAL FUNCTION AND MAINTAINING THE NORMAL ESSENTIAL FOR FIGHTING OFF INFECTION. AND FOR DEALING WITH TRAUMA. WHAT WE'LL DO NOW IS OPEN THE QUESTION AND ANSWER PERIOD UP TO THE AUDIENCE, PLEASE USE THE MICROPHONES IN THE AISLES TO ADDRESS YOUR QUESTIONS TO THE PANEL AND PLEASE STATE YOUR NAME AND YOUR ORIGIN SO THE AUDIENCE CAN NO WHO YOU ARE. -- WE HAVE A QUESTION. YES. GO AHEAD. >> THIS IS FOR DR. TRACY, I'M KNOWLEDGE FOUNDATION. I CAME FROM MY MOTHER. [LAUGHTER] I'M VERY INTERESTED IN THE HYPERCOAGULATION, PERHAPS WELL KNOWN TO EVERYONE IN THE AUDIENCE BUT NOT TO ME, YOUR SLIDE MENTIONED ALCOHOL INSULT AND INJURY, SUBCLINICAL. COULD YOU TALK ABOUT THAT A LITTLE BIT AND HOW MUCH IT CONTRIBUTES TO THE OVERALL CHRONIC ELEMENT OF INFLAMMATION? >> I THINK MANY INSULT, MANY MENTIONED THIS MORNING. TYPE A PERSONALITY. AND THAT SORT OF THINK CONTRIBUTES AS WELL. H THAT'S LOTS OF CHOICES AROUND THOSE. I THINK IT WAS MENTIONED THIS MORNING, ECHO WE DOPE KNOW HONESTLY FROM AN AMOUNT STANDPOINT HOW MUCH. YOU CAN FIND ASSOCIATIONS OF SUCH THINGS WITH POOR OUTCOMES EVEN WHEN WE TRY TO CONTROL FOR ALL THE OTHER ONES. MY BELIEF IT'S NOT INSIGNIFICANT, CERTAINLY IN OUR HYPOTHESIS IT'S NOT INCISION CAN AND SOMETHING WE'RE PURSUING RAPIDLY IN AS MANY VENUES AS WE CAN. TALK ABOUT COAGULATION SUPER BRIEFLY. D DIMER IS A BIOMARKER MANY FAMILIAR WITH, YOU GET WHEN YOU MAKE A FIBRIN AND LIGHT THE FIBRIN WITH PLASMA SOME YOU GET A SPECIFIC MARKER HOW MUCH THROMBIN YOU GENERATED, HOW MANY FINE GENERATE AND HOW MUCH FIBROLYSING YOU HAVE DONE. THAT'S A MARKER NEVER ZERO ON ANYONE. WE'RE ALWAYS DOING SOME OF THIS AND IT INCREASES WITH AGE. THE AGE RELATED -- IT'S VERY STRONG PREDICTOR OF GOOD OUTCOMES IN OLDER PEOPLE IN THE CARDIOVASCULAR RISK FACTOR LINDA CAUSED ABOUT, ALL CAUSE MORTALITY, NOT JUST CLOT BASED MORTALITY, THAT'S ALSO TRUE IN HIV POPULATIONS. SO THERE'S SOMETHING THAT IS SIGNALING THAT THIS INCREASING COAGULATION SIGNALING IN BOTH THE ELDERLY AND OTHER CONFIRMED AND POPULATIONS THAT WE DON'T COMPLETELY UNDERSTAND BUT WE THINK IT'S TIED TO THE BROAD SYSTEM THAT THESE GUYS GAVE YOU WONDERFUL SLIDES ABOUT. THIS MORNING TO LOTS OF FACES AN SIGNALS ACROSS A WIDE RANGE OF PHYSIOLOGY. >> ADD LIKE TO ADD A LITTLE BIT, BECAUSE SOME YEARS AGO WE STARTED THE STUDY OF CENTENARIANS AND ONE MAJOR OBSERVATION WAS ALL THE MAJOR COAGULATION FACTORS ARE INCREASED IN THE CENTENARIANS BUT THEY ARE FREE OF MOST OF THE RELATED DISEASES. SO WE CALLED THE PARADOX, BUT IT MEANS WE DIDN'T UNDERSTAND WHAT WAS GOING ON. BUT I WOULD LIKE TO DRAW YOUR ATTENTION THAT PROBABLY IMPORTANT NOT ONLY TO LOOK AT THE CLASSICAL FACTORS BUT TO SOME OTHER PROTECTIVE FACTORS WHICH DESPITE INCREASE OF CLASSICAL COAGULATION MARKERS PROTECT THESE PEOPLE WHICH ARE A MODEL OF EXTREME LONGEVITY. >> TRY TO KEEP YOUR COMMENTS SHORT BECAUSE I SEE WE HAVE A LINE OF PEOPLE. >> I'LL POINT OUT THE AMOUNT OF THE COAGULATION FACTORS IS LESS PERFORM THAN THE BALANCE. INTERFERON MEDIATED GLOBAL PROTEIN SYNTHETIC DROPS BY HEPATOCYTES LEADS THE LOWER LEVEL COAGULATION FACTORS THAT LEADS TO IMBALANCE BETWEEN PRO AN ANTI-CO-ING A LAPS THAT MAKES YOU PRO COAGULANT. THAT'S WHAT WE HAVE BEEN MODELING TO PROVE AND MAYBE SOMETHING OF INTEREST FROM THE SENNARYIANS. >> (INDISCERNIBLE) FROM THE (INDISCERNIBLE) ON AGING. I WOULD LIKE TO CONGRATULATE THE ORGANIZERS FOR THE EXCITING SESSION. I WOULD LIKE TO DRAW YOUR ATTENTION TO A CELL TYPE WHICH IS OMNI PRESENT WHICH IS PRESENT IN EACH ORGAN AFFECTED BY INFLAMMATION. THIS IS THE VASCULAR MICROVASCULAR ENDOTHELIAL CELL. YOU HAVE FIVE KILOGRAM IN YOUR BODY. AND ALTERATION OF THE CELL TYPE, NAMELY PRO-INFLAMMATORY PHENOTYPE SHIFT GENE EXPRESSION PROFILE IN CELL TYPE. ALL THE ORGANS AFFECTED BY AGE RELATED INFLAMMATORY DISEASES. ANY COMMENT ON THAT? >> YES. THERE IS -- THERE ARE SOME MICRORNAs WHICH ARE SPECIFIC -- WE DID SOME STUDIES ON UVEK AND SHOWED MEAN 146A WHICH IS HIGHLY INCREASED WHEN BECOMES SENESCENCE AND I THINK YOU DID THE SAME TYPE OF OBSERVATION. YOU ARE RIGHT. ENDOTHELIAL CELLS ARE VERY IMPORTANT TARGET. >> ALSO ON ENDOTHELIAL CELLS SEEM MORE SUSCEPTIBLE TO SENESCENCE THAN ORIEL TYPES MORE READILY AND WHEN YOU LOOK THEY TEND TO BLOOD VESSELS. >> >> I'M SORRY. NOT 'ALLY GOOD MODEL AGING RESEARCH BECAUSE (INAUDIBLE) ENDOTHELIAL CELLS. IF YOU LOOK AT ENDOTHELIAL CELLS (INDISCERNIBLE) YOU SEE THE (INAUDIBLE) PROFILE. >> WE STUDIED NOT ONLY -- BUT THE PRECURSORS IN THE BLOOD. >> YES. >> I'M FROM STANFORD UNIVERSITY. I HAVE A QUESTION O THE GENERAL, WE HEARD ABOUT INFLAMMATION. INHIBITING INFORMATION CAN BE GOOD OR BAD AND MAYBE THERAPY CAN BE A LITTLE BIT DRAMATIC IF IT ALSO HELPS FIGHT DISEASE AND INFECTIOUS DISEASE, SO WHAT -- WE DIDN'T HEAR A LOT ABOUT IS WHAT ARE MOLECULAR MECHANISMS WHICH INFLAMMATION CAN BE MATERIAL DELETERIOUS, SINs SENT, OXIDATIVE DAMAGE, PROTEIN MEMBRANE, PERHAPS BIGGER AVENUES TO TARGET PARTS OF INFLAMMATION WITHOUT LEAVING ELDER THROUGH PEOPLE WITHOUT IMMUNE RESPONSE OR PROTECTIVE RESPONSE. >> DURING INFLAMMATION THE WHOLE IDEA OF CALLING THE IMSYSTEM TO SITE OF THE WOUND OR TRAUMA IS TO FIGHT OFF A PATHOGEN, TO KILL. SO THE CELLS THAT RESPOND ARE DESIGNEDDED TO MAKE TOXIC PRODUCTS THAT CAN BE DAMAGING TO SURROUNDING TISSUE WITH KILLING INVADING PATHOGEN. SO I DON'T KNOW, SOMEBODY HAS SOME IDEAS HOW TO TARGET THOSE PRODUCT OR KEEP THEM MORE SPECIFIC FOR PATHOGEN AS OPPOSED TO CELLULAR TARGET? >> ELIMINATE SENESCENCE CELLS PERIODICALLY WHILE HEALTHY. >> THE IF THEY ARE THE MAIN SOURCE. >> BUT IT DOES APPEAR AT LEAST IN MOUSE MODELS THAT THEY CONTRIBUTE SUBSTANTIALLY. >> ONE OF THE ADVANTAGES IN THE EYE IS THAT OPERATIVE SYSTEMS ARE SLIGHTLY DIFFERENT IN CONTRAST TO THE KINDS OF DISEASES THAT AND EARS IN THIS PAM. IT'S AMTURE CELLS NON-CELLS IN THE EYE DOING DAMAGE SO IN THE CONTEXT OF AGE RELATED MACULAR DEGENERATION, IT IS NOT INVADING MACROPHAGES NEUTRAPHILS OR ANYTHING THAT ARE DOING THE DAMAGE. RETINAL PIG. EPITHELIAL CELLS ASSUMING AMTURE ROLE OF INFLAMMATORY CELL TRANSDUCEING SIGNAL. AS WELL AS FROM A CONFINED NATURE AS WELL AS A CELLULAR PERSPECTIVE YOU CAN TARGET DOWNSTREAM INTERLEUKINS OR MITI 88 THAT WOULDN'T HAVE AN OVERALL DETRIMENTAL EFFECT BY BLOCKING THE ORGAN'S ABILITY TO COMBAT INFECTION. HOW DO YOU THE PRESERVE THE PHASIC NATURE OF INFLAMMATION? YOU HAVE INFLAMMATORY RESPONSE, DO NOT FORGET THE REPAIR PART OF IN THE EFFECTIVE TISSUES SO HOW DO WE AFFECT INFLAMMATION WITHOUT KILL ALSO THOSE RESPONSES. THE PROVINCE UNDERSTANDING IS THE MECHANISM SOMETHING THAT IS INTRINSIC WILL DOWN REGULATED OR DISREGULATED IN IMMUNE SYSTEM AND WE NEED TO FIND THAT MECHANISM OR IS THE IMMUNE SYSTEM RESPONDING TO SOMETHING THAT DOWN REGULAR LAYER TO RESPONSE IS GOING TO HAVE A CONSEQUENCE. WE UNDERSTAND THAT DUALISTIC HYPOTHESIS IT IS DIFFICULT TO KNOW WHAT IS THE BEST INTERVENTION. >> TALK ABSENTNARYIANS, THEY ARE PEOPLE WHO LIVE VERY LONG AND SUCCESSFUL CENTENARIANS ARE INFLAMED. THEY HAVE HIGH LEVEL IL-6 AND OTHER INFLAMMATORY COMPOUNDS. THIS IS ANOTHER PARADOX. BUT THEY HAVE ALSO A LOT OF ANTI-INMA'AMTORY COMPOUNDS AROUND. THERE ISEN CREASE CORTISOL, TGF BETA. IL-10, AD POENECTIN IS VERY HIGH. IS THE BALANCE BETWEEN INFLAMMATORY AN ANTI-INFLAMMATORY COMPOUNDS WHICH MATTERS FOR -- TO HAVE A PATHOLOGICAL PHENOTYPE. >> PERSONALIZED MEDICINE. YES. >> (INAUDIBLE) UNIVERSITY OF ARIZONA. WE HER GREAT IDEAS, A LOT OF INTERESTING INTERVENTION, SOME CORRELATIONS WHICH ARE TANTALIZING ABOUT PREDICTORS. WHAT WE ARE NOT QUITE SO CLOSE TO IS QUANTIFYING THE PRECISE SOURCE INFLAMMATION IN THE BODY UNDERSTANDING THE RELATIVE RELATIONS OF WHAT WERE BETWEEN SOME OF THESE POSSIBLE SOURCES, IN TERMS OF CELLS PRODUCING IL-6, ONE OF THE QUESTIONS -- AND I WOULD LIKE TO HEAR FROM THE PANEL WHAT YOU THINK, WHERE WE STAND IN TERMS OF QUANTIFYING AND HOW WE MOVE FORWARD, A GRAND CHALLENGE. SPECIFICALLY I WOULD LIKE TO HEAR FROM THE (INAUDIBLE) ON THE PANEL, WHERE HOW MANY SAS CELLS DO WE HAVE AROUND AND YOU TAKE AWAY WHO ELSE IS PRODUCING IL-6? OTHER CELLS MAKING IL-6 AND WHAT ARE RELATIVE BALANCES AND GETTING TO THE GRIPS OF WHAT'S THAT AND WHAT'S MICROBIOTA INDUCED. IN THE LAST SPEAKER TALK IF WE TAKE AWAY THE MEMORY CELL ARE INNATE PRODUCING, A LITTLE BIT MORE DISCUSSION ALONG THOSE LINES. >> I THINK THE ANSWER TO YOUR QUESTION IS WE HAVE THE TOOLS TO DO EXPERIMENTS YOU SUGGEST. YOU CAN ELIMINATE SENESCENCE CELLS AND ASK WHAT'S LEV. EFFECTOR T-CELLS AND ASK WHAT'S LEFT. THOSE ARE NOT BEEN DONE BUT THEY'RE IMPORTANT QUESTIONS AND WE'RE ON THE CUSP OF UNDERSTANDING WHAT THE CONTRIBUTIONS ARE OF EACH. >> AT LEAST IN FAT TISSUE IT APPEARS MOST OF THE IL-6, MOST THAT RHODENS HAVE, COMES FROM THE FRACTION OF FAT TISSUE. WHEN BOTH OVERWHELPING BOLT OF IL-6 IS CONCENTRATED WITHIN THE SENESCENCE CELL ACTION, INCREASED MARKER WITH GFP, THAT WAS IN THE INTACT PAPER. >> I WOULD LICK TO ADD TWO FACTS. ONE WHEN WE ADD GENE EXPRESSION IN HUMANS WE DON SEE IL-6 RECEIVE THE BLOCK FROM CELLS, THAT IS ONE THING WE CAN SAY. IF YOU LOOK AT IL-6 NOT PASS LINE AS EVERYBODY DOES BUT THE AREA UNDER THE CURVE OF IL-6 DURING THE DAY THERE IS ABSOLUTELY NO CORRELATION WITHIN THE BASELINE LEVEL AND ADD UNDER THE CURVE DURING THE DAY WITH LARGE VOLUME ABILITY. SO YES, THEY MAY BE INDUCTION OF IL-6 BUT SHOULD BE INDUCIBLE MECHANISM TO CREATE THE VARIABILITY OF THE EXPOSURE TO IL-6. THAT'S WHY I THINK THAT SENESCENCE IS ONE PART. BUT DOESN'T EXPLAIN ALL OF IT. >> QUICK COMMENT REGARDING POTENTIAL SOURCES. WE ARE NOT THERE YET TO HAVE THE ANSWER AT THIS POINT IN TIME. ONE THING THAT IS SOMETIMES LOST LIKE JIM WAS MENTIONING IF YOU LOOK AT THE VASCULAR FRACTION OF ADIPOSE TISSUES ATIPCYTES AND CELLS IN THE BODY, CLOSE TO 70% OF THOSE CELLS ARE HEMATOPOIETIC ORIGIN. ALMOST EVERY ITSELF IS PRESENT THERE. THERE ARE PRO INFLAMMATORY CELLS AND REGULATORY CELLS AND CONTEXT OF AGING, WE TO NOT HAVE AT THIS POINT IN TIME SOLID DATA TO CONCLUDE EITHER WAY. I HOPE AS NEW DATA EMERGE WE'LL BE IN BETTER POSITION TO ANSWER THOSE QUESTIONS. >> WE ARE PUBLISHING A PAPER WE SHOW MITOCHONDRIAL DNA CIRCULATING MITOCHONDRIAL DNA IS INCREASING WITH AGE. IT'S FUNCTIONAL. SO IT'S PRO INFLAMMATORY. THESE ARE SOURCES OF GARBAGE THAT WE HAVE NOT LOOK PROPERLY. >> WE KEEP ADDING CONCEPTS WITHOUT BEING ABLE TO QUANTIFIBLY SAY THIS ONE IS REALLY IMPORTANT OPPOSED TO THIS ONE VERY MINOR. SO THAT'S A FRUSTRATING PART. ABOUT IT. >> JUST A QUICK THOUGHT ON SENESCENCE CELLS. I DON'T KNOW MUCH ABOUT NON-LIPOLYMPHOCYTES SENESCENCE CELLS BUT LYMPHOCYTES YOU GET CD 28 NEGATIVE CELLS AS CLONE REACTIVATES OVER AN OVER, SOMETHING OCCURRING WITH THE NORMAL FATE OF THOSE CELLS GETS AVOIDED BY A FEW SO THEY DON'T APOPTOSE OUT, THEY DON'T BECOME MEMORY CELLS. THEY BECOME SENESCENCE CELLS. >> I DON'T KNOW IN THIS CASE IF YOU LOOK AT THOSE CELLS, LOOK AT 28 NEGATIVE CELLS IN VIVO, PLENTY TURN OVER THOUGH T-CELL SPECIFIC STIMULUS THEY H NOT DIVIDE IN VITRO, LISTEN THE TURN OVER IN VIVO. SO CALLING THEM SENESCENCE IS DANGEROUS AND DIFFICULT IN THE ABSENCE OF PRECISEBLY LIVE DEFINING. >> AGREED. SO CALL THEM CD 28 NEGATIVE CELLS. PRODUCE MOST SIMILAR TO OTHER TYPES OF SINs SENT CELLS SEEM TO BE PRODUCING SO THE QUESTION THEN IS WHAT CAUSES REACTIVATION OF THE SAME CLONES AND CELLS OVER AND OVER AND THAT'S WHERE WE GET TO SOMETHING LIKE CMV OR HIV OR OTHER HERPES VIRUS REACTIVATING VIRUSES THAT >> WHICH IS ANOTHER PLACE WE CAN'T REALLY -- >> GO HAY HEAD. >> RICHARD FLANAGAN, UNIVERSITY OF BRIE TON. I THINK IT WAS A LOVELY SESSION THAT COVERED A LOT OF GROUND. I WOULD LIKE SOMETHING THAT I THINK IS QUICK FROM THE PANEL. OF THE TWO BROAD APPROACHES COMING THROUGH OF REMOVING SENESCENCE CELLS OR MODULATING INFLAMMATORY MILIEU CONTRIBUTING TO, WIDOW THE PANEL THINK IS MOST LIKELY SUCCESSFUL OVER MEDIUM TIME FRAME? I SEEM TO BE ONE OF THE FIRST ACCIDENTAL SASPOLOGICSSTS, MY LAB REPORTED THE OBSERVE RATION THAT IL-6 DOESN'T GO UP WITH SINs KERATINCYTES, YOU NEED IL-6 RESPONSE TO CLEAR BACTERIAL KERATITIS. SO YOU CAN SEE ADVANTAGES AN DISADVANTAGES ANTI-INFLAMMATORY IN THAT ARGUMENT WHEN IT'S BODY WIDE. IT IS OBVIOUSLY MORE DIFFICULT TO ACHIEVE SHORT TIME FRAME. IF YOU HAVE TO DO ONE WHICH WOULD YOU PLAN FOR? FROM WHICH FACTOR WOULD YOU TARGET IN THE CIRCULATION? >> WHICH FACTOR WOULD YOU TARGET? >> WOULD YOU TRY -- SO WOULD YOU TRY TO USE GENERAL ANTIINFLAMMATORY APPROACH OR GO AFTER SENESCENCE CELLS >> I DON'T THINK GENERAL ANTI-INFLAMMATORY ARE AS GLOBAL AS YOU LIKE TO THINK THEY ARE. JIM HAS SOME IDEAS ON THIS. I WOULD SAY TARGETING SINCE ESSENCE CELLS, WE'RE NOT THERE YET TO DO PHARMACO LOGICALLY BUT CERTAINLY CAN BE DUNGEON TICKLY NOW AND WE CAN TEST WHETHER IT'S EFFICACIOUS. >> THERE ARE EMERGING PHARMACOLOGIC APPROACHES TO SEE HOW IT ALL WORKS OUT. >> ONE OF THE -- >> GENERAL INFLAMMATORY MARKERS ANTI-INFLAMMATORY DRUGS WAS NOT THE AM OF CIRCULATING (INAUDIBLE) THAT AT LEAST DOESN'T WORK. >> YOU MENTIONED SENESCENCER TINCYTES, IN TERMS OF IMMUNE PRIVILEGE BUT ONE THING WE HAVE LEARNED FROM HALF DOZEN ONGOING COMPLETED ANTI-COMPLIMENT TRIALS IN MACULAR DEGENERATION IS THESE CONTRARY TO EXPECTATION DON'T DEVELOP ANY LOCAL OR SYSTEMIC INFECTIONS, NOT PROF LAXD FOR IT. SAME THING WITH A LOT OF INTRICACIES, CORTICAL STEROID INJECTION. TYPICALLY PEOPLE DON'T. SO AT LEAST IN THE CONTEXT OF THE EYE MAYBE QUITE LUCKY IN TERMS OF BEING ABLE TO USE THESE WITHOUT FEAR OF LOSING THE ABILITY TO COMBAT INFECTION. >> I'M DR. (INAUDIBLE). THE QUESTION DR. TRACY, YOUR INVENTORY LECTURE YOU MENTIONED ONE OF THE WAYS TO IMPROVE IMMUNITY IS THYMIC REPLACEMENT. WOULD YOU PLEASE EXPAND ON THAT. WHAT RECOMMENDATIONS DO YOU HAVE? >> MY MAJOR RECOMMENDATION IS DONE TRY IT TOMORROW. THERE ARE CLEARLY EFFORTS IN THE PAST ON GOING NOW LOOKING PROGENITOR CELL REPLACEMENT FOR EXAMPLE, WHAT YOU TRY TO DO IN A PANCREAS WITH BETA CELL REPLACEMENT, TRY TO DO IT ON THYMUS IF YOU CAN FIGURE OUT HOW TO DO IT SO I HOPE TO -- I PREFACE MY COMMENT, IT'S SORT OF STILL SCIENCE FICTION AT LEAST TO MY KNOWLEDGE ABOUT IT. BUT IT'S GETTING AWAY FROM SCIENCE FICTION, NOT AS SCIENCE FICTION. >> THE WHOLE CONTINGENCY OF BRIGHT PEOPLE STUDYING THYMUS AND LOOKING AT HOW VARIOUS MECHANISMS ARE RESPONSIBLE FOR DEGENERATION OF THYMUS THAT HAPPENS THERE ARE PROBLEMS IN PROGENITORS FROM BONE MARROW, THERE ARE PROBLEMS IN THE STROMA. I THINK WHOLE SESSION NEEDS TO BE TO DO IT POINT BEING THERE'S AT THIS PIN IN TIME NO EVIDENCE IN HUMANS, THERE'S SOME DATA IN MOUSE MODEL SUGGESTING CERTAIN GROWTH FACTORS ARE EFFICACIOUS. FOR EXAMPLE, KGF OR FGF-7 WHICH IS ACTUALLY IN TRIALS IN HUMANS IS ACCIDENTALLY FOUND TO INCREASE B CELL PRODUCTION FROM THYMUS BECAUSE IT REBUILDS THE EPITHELIUM. SO PATIENTS THAT UNDERGO MUCOUSITIS AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION, IF YOU GIVING ANISTS YOU -- IT SHUTS OFF EGX IN MICE, IT'S SHOWN EF KASHA IN REBUILDING THE THYMUS AND RICHARD BOIL AS SHOWN DATA SO LOOK ONLINE, IT -- >> SUMMARY COMMENTS OF THE GERMAN THYMUS SOCIETY. EUROPEAN FRIENDS MAYBE KNOW ANYTHING ABOUT THAT? >> CHAIRMAN THYMUS SOCIETY. >> ANYONE? NO, SORRY. >> THE QUESTION BASED ONEROUS'S PRESENTATION ABOUT INFLAMMATION AN COAGULATION. CENTENARIANS ARE PRO CO-INGING AABLE SO IT -- NOT SOMEHOW THEY LIVE A LONG TIME BUT NOT ACTIVATING THE COAGULATION CASCADE BUT FROM EPIDEMIOLOGICAL POINT OF VIEW HAVE YOU LOOKED AT CROSS TALK BETWEEN SYSTEMS, ELEVATED AND PRO COYING A LANT ACTIVITY WITH A MULTI-REGRESSION MODEL, CAN YOU PREDICT WHO GETS AGE RELATED DEGENERATIVE CONDITIONS AN WHO ISN'T? ALONG THOSE LINES, THE NATURAL EXPERIMENT PRO COAGULABLE DO THEY HAVE AGE RELATED DEGENERATIVE CONDITIONS? >> >> VERY LITTLE STUDIES THAT CHECK INFORMATION ON THAT CALCULATION. AND INFLAMMATORY MARKERS. A FEW STUDIES THAT HAVE DONE IT HAVE SHOWN ASSOCIATION WITH CARD QUO VASCULAR DISEASE AND BOTH COAGULATION CONTRIBUTEND PENDENTLY OF PREDICTION. THERE IS NO CHANGE OVER TIME IN INFLAMMATORY MARKET THAT I KNOW ABOUT. SO THAT IS (INAUDIBLE). I DON'T KNOW WHETHER -- >> SO THERE'S BEEN A LOT OF EPIDEMIOLOGIC EXPLORE RATION OF BOTH SIDES YOU DISCUSS. AS LUIGI SAYS THE LEVEL AND THE RATE OF INCREASE OF COAGULATION FACTORS SYSTEMIC INFLAMMATORY MEDIATORS PREDICT BAD OUTCOMES. THE REDICTION TAKES AN INTERESTING TURN, IN YOUNGER PEOPLE, MIDDLE AGED PREDICTION IS PRIMARILY AROUND CARDIOVASCULAR DISEASE. WHAT CAN BE ASSESSED IN POPULATIONS, FREQUENTLY ENOUGH FOR US TO SEE BUT THE ELDERLY PREDICTION CHANGES FROM CARDIOVASCULAR DISEASE TO ALL CAUSE MORTALITY, ELDERLY POPULATION. AS IS D DIMER, A COAGULATION MARKER AS I MENTIONED BEFORE. MOLECULAR LEVEL THERE'S CROSS TALK THAT'S WELL DOCUMENTED, VARIETY OF FOLKS SHOW MANY ENZYMES PARTICIPATE NOT ONLY IN SECRETION CREASE OF CYTOKINES FIBROUS MEDIATION, JUST HAS A PAPER SHOWING THAT THROMBIN SIGNALING THROUGH RECEPTOR IS CRITICAL FOR PROPER ANTIVIRAL INTERFERON RESPONSE. SO UP REGULATION OF VIRAL INFECTION MAY NOT BE A BAD EPIPHENON NONTHAT LEADS TO BLOOD CLOTS IN H 1N 1 PEOPLE FOR EXAMPLE. SO YOU HAVE INCREASED THROMBIN TO GENERATE APPROPRIATE INTERFERON RESPONSE. INTERESTING TIME AS WE LOOK AT THIS. >> ALL CAUSE MORTALITY IN FACTOR 5 A LOT IN PATIENT? HAS IT INCREASED? DOES ANYBODY KNOW? >> WE HAVE LOOKED AT IT IN ELDERLY POPULATION. I THINK WE HAVE LOOKED AT IT MAINLY AROUND BLOOD CLOTTING. BUT THE ARGUMENT WOULD BE YEAH, YOU NEED A FEEDBACK LOOP TO GET TO INFLAMMATION FOR ALL CAUSE TALK AND -- WHEREAS GOING UP FOR SIMILAR REASON BOTH SIDES FEEDBACK IS IMPORTANT BUT YOU'RE GETTING INDEPENDENT INCREASES THAT WOULD BE POWERFUL. >> (INAUDIBLE) DRUG DISCOVERY FOUNDATION. MY QUESTION IS ABOUT MODELS TO PRODUCE EFFICACY. THERE WAS A HIGH PROFILE PAPER USED TO DEVELOP DRUGS FOR MORE ACUTE CHRONIC ACUTE INFLAMMATION LIKE SEPSIS FOR EXAMPLE HAVE NOT BEEN PREDICTIVE OF CLINICAL EFFICACY IN PEOPLE. SO WHEN IT COMES TO SYSTEMIC THERE'S SEVERAL ASPECTS OF MY QUESTION, IS THERE EVIDENCE ANIMAL MODELS ARE MORE PREDICTIVE? TWO, DO YOU THINK STRATEGIES MAYBE TO PROTECT AGAINST THE KIND OF THING BY USINGING A DIVERSITY OF ANIMAL MODELS RATHER THAN STICKING WITH JUST A COUPLE OF ANIMAL MODELS? AND THREE, WHETHER OR NOT THERE MIGHT BE A PURCHASE FOR TESTING THE ANIMAL MODELS AND FOR EXAMPLE GENE EXPRESSION PATTERNS FOR SIMILARITIES TO HUMANS? >> SO WE -- I THINK I AGREE WITH YOU NOT ENOUGH ATTENTION IS PAID TO ON HUMAN MOUSE RAT OR HUMAN ANIMAL MODEL DIFFERENCES. ON THE OTHER HAND I WOULD SAY THAT PARTICULAR EXAMPLE WAS SPECIFIC EXAMPLE WHERE THERE WAS THE EVIDENCE MOUSE MODEL AND THAT WAS LARGELY IGNORED. BUT I THINK FOR THE MOST PART I WOULD SAY WHAT WE DO NEED IS TO PAY MUCH MORE ATTENTION TO WHEN THE MOUSE FAILS AND WHEN IT DOES NOT AND THERE ARE AT LEAST IN CERTAIN ASPECTS OF HUMAN DISEASE FAIRLY SUCCESSFUL INTERVENTIONS IN THE MOUTH THE MORE WE UNDERSTAND DIFFERENCE IT IS MORE WE CAN HUMANIZE THE MOUSE TO MAKE IT A BEAR MODEL FOR PEOPLE. THE PROBLEM WITH ANIMAL MODELS IS THEY'RE BIG, EXPENSIVE AND IF THEY'RE LONG LIVE THEY'D EAR ALSO EXPENSIVE. >> TRUE SO EVEN SHORT LIVED ANIMAL MODELS WONDER IF CHOOSING DIVERSITY, MAKING SURE EFFECTS ACROSS THEM IF THAT ALSO INCREASES TRANSMISSIBILITY. >> EXACTLY. RICH MILLER TALK ABOUT MIXING OF GENERAL IT CAN BACKGROUNDS NOT DEALINGING WITH IDIOSYNCRATIC GENETIC BACKGROUNDS. ANYONE ELSE L CARE TO COMMENT? >> THE PROBLEM IS IN MOST EXPERIMENT THAT I KNOW, FOR EXAMPLE, THE GUT MICROBIOTA OF MICE IS NOT ASSESSED PROPERLY. SO THIS IS A MEASURE OF VARIABLES BECAUSE IT CAN VARY, WE WERE DISCUSSING WITH RICHARD AT SIX O'CLOCK SO WE WERE NOT PARTICULARLY -- BUT THE PROBLEM IS THERE. SO THERE ARE A LOT OF VARIATION BETWEEN LABORATORIES AND I THINK TO CONTROL FOR THE GUT MICROBIOTA AND AFFECT OF DIET CAN BE A MEASURE TARGET TO STANDARDIZE. >> JUST TO ADD GUT MICROBIOTA ANIMAL MODEL. WE HEARD FROM THE MORNING FROM DR. FRANCIS COLLINS, IMPORTANCE OF STUDIES REPEATABLE ACROSS LABORATORIES. ONE OF THE PROBLEMS WITH REGARD TO GUT MICROBIOTA IS THAT MOUSE MODELS WE INCREASE THIS AND THAT, IT IS VERY IMPORTANT MANY PEOPLE STILL COMPARE THEIR KNOCK OUT WITH WILD TYPE THAT DO NOT COME FROM THE PROCESS. SOMETIMES THEY COME FROM DIFFERENCE FACILITY, I HAVE SEEN PAPERS LIKE THAT. THIS IS PLEATLY WRONG. IT SHOULDN'T BE DONE. THERE'S SO MANY INFLUENCES TO THAT. DIET IS ONE. ANOTHER MAJOR ONE IS THE WATER. IF YOU ARE IN A FACILITY IN NEWHAVEN, YOU GET THE CITY WATER WHICH IS CHLORINATED BUT MANY CITIES ARE HYPERCHLORINATED YOU CAN IMAGINE DOING AN AGING STUDY YOU ARE GETTING MICE HYPERCHLORINATED WATER OVER TWO YEARS, THEN THE BIOFILMS THAT DEVELOP ON THOSE PLACES, YOU'RE LOOKING AT A POINT AN ARTIFICIAL SYSTEM AND SOMETIMES THOSE THINGS ARE LEADING TO DISCREPANCIES IN THE LITERATURE. >> MAIN ISSUE HOW TO MAKE THE MOUSE WORK, ANIMAL MODELS MORE HUMAN LIKE AND THEN THE OTHER PROBLEM IS VARIABILITY. I THINK WE NEED TO MOVE ON. WE STILL HAVE A FEW PEOPLE. >> MY NAME IS (INAUDIBLE) FROM (INDISCERNIBLE) I WOULD LIKE TO KNOW YOUR OPINION ABOUT ROLE THAT EXSOMES COULD PLAY DURING THE INFLAMMATION AND ALSO IN THE AGING CONTEXT. THANKS. >> THIS IS A HOT TOPIC. MOST OF IT WENT WELL, I BELIEVE PART OF WHAT WE'RE MEASURING IS BLOOD, IN REALITY IN EXSOMES OR IN VESICALES. SO WE HAVE TO LOOK AT WHAT WE HAVE PUB ESTABLISHED TO KNOW THE STAFF THAT WE MEASURED IN THE BLOOD SUCH MOST PROBABLY REGULATED BY EXSOMESSER OTHER STUFF. SO WE NEED A NEW TYPE EXPERIMENT WHERE WE ISOLATE WITH PROPER TECHNIQUE. THE EXSOMES AND WE DO EXPERIMENTAL WORK WHERE WE CAN USE EXSOME FOR ALL ANIMALS MANY EFFECT ON YOUNG CELLS AN VICE VERSA. IN THE FIELD OF CANCER THERE IS A LOT OF LITERATURE, THIS IS A HOT TOPIC FOR EVERYBODY. VERY QUICKLY. IT'S A VERY IMPORTANT POINT. >> DEAN JONES FROM EMORY UNIVERSITY. FABULOUS PRESENTATION AND DISCUSSION. THE QUESTION I HAVE RELATES TO THIS UNAFFORDABLE 40 YEAR EXPERIMENT. THE REALITY IS EACH AN EVERY ONE IS A 40 YEAR OR MORE EXPERIMENT. WE ARE UNCONTROLLED ALL SORTS OF VARIABLE ASPECTS BUT YET OUR HEALTHCARE SYSTEMS WHETHER IT BE MAYO OR KEISER PERMANENTE OR OTHERS WILL IN FACT BE FOLLOWING US FOR OUR LIFETIME. SO OUR QUESTION IS, DO YOU HAVE ANY SUGGESTIONS ON MEASUREMENT, AFFORDABLE MEASUREMENTS THAT COULD BE MADE TODAY THAT WOULD BE POTENTIALLY USEFUL 20 YEARS OR 40 YEARS DOWN THE ROAD FOR US TO ADDRESS HEALTH ISSUES. >> VERY INTERESTING QUESTION. CERTAINLY TIMELY BECAUSE THERE ARE A NUMBER OF COUNTRIES THAT ACTUAL HI CREATE A LARGE COHORT. THEY WILL FOLLOW OVER TIME TO TRY TO MAKE DISCOVERIES INSTEAD OF TARGETS EXPERIMENT BY LOOKING AT LARGE POPULATION AND MINING DATA. SO WHAT ARE THE ESSENTIAL MEASURES WE CAN DO? I SUSPECT THAT I ALREADY-6 AT THIS POINT CLINICAL STUDIES BUT CERTAINLY BE READY TO BE STUDIED IN LARGE POPULATIONS TO SEE WHETHER CHANGE IN INFLAMMATORY MARKERS ASSOCIATE WITH -- EVEN IF ONE WE LOOK AT THE GENERAL POPULATION AND THAT WILL BE AN IMPORTANT IDEA. ONE PROBLEM WITH THAT APPROACH IS WE'RE DISCOVERING THOSE STATIC MEASURES WE USE ARE REALLY REVEALING A LITTLE PART OF THE EXPOSURE TO THE RISK FACTOR SO THERE'S SOME LIMITED VALUES OF DOING THOSE MEASURES, CERTAINLY MY SUGGESTION WILL BE I ALREADY-6 IS READY FOR THAT. >> ANY OTHER SUGGESTIONS? QUICKLY. >> TIMING. >> THE ASSESSMENT OF IMMUNE SYSTEM IS ONE OF MOST IMPORTANT THINGS WE CAN DO. AND THERE'S A VARIETY OF MEASURES THAT WE CAN ADD BUT THAT WOULD HAVE TO BE WORKED OUT. BUT IF WE CAN GET A SIMPLE ASSESSMENT PROVOCATIVE IN SOME WAY THAT'S E CITY DO AND SIMPLE, TIE INTO A FLU VACCINATION BUT IN A CAREFUL CONTROLLED WAY, SOMETHING LIKE THAT, THAT CAN BUILD UP THE INFORMATION ON POPULATIONS OVER TIME. THAT MIGHT BE A USEFUL THING TO DO. >> BRIEF COMMENT. I KNOW THE WORD BIOMARKER IS NOT POPULAR IN THE STATES BUT IN EUROPE WE DID HUGE STUDY CALLED -- WE TESTED MORE THAN 300 POTENTIAL BIOMARKERS FROM 35 TO 75. AND ALSO JUST COMING OUT SO I THINK CERTAINLY BIOMARKERS TO CHECK. SO I THINK IN THIS SENSE EUROPE AND U.S. COULD MAKE SOMETHING LIKE THIS, EVENT LIKE THIS ON BIOMARKERS. BUT I THINK THE FAILURE THAT I KNOW IN PREVIOUS STUDIES HERE IN U.S. HAS DELETERIOUS LONG TERM EFFECTS. >> A LITTLE PREMATURE. YES. >> NICK MUSY FROM THE BAR (INAUDIBLE) INSTITUTE IN SAN ANTONIO. WE HAVE BEEN INTERESTED IN LOOKING AT THAT TIME ROLE OF THE MICROBIOME ON INFLAMMATION AND THE CONTEXT OF AGING. AND OTHER DISEASES. WE HAVE BEEN LOOKING AT THE ROLE OF METABOLIC ENDOTOXEMIA AND OTHER BACTERIAL PRODUCTS. ONE LIMITATION IS THERE'S NO STANDARDIZATION HOW TO MEASURE ENDOTOXINS AND BLOOD. BEFORE THE FIELD CAN MOVE FORWARD SPECIFIC TOPIC SOMETHING HAS TO BE DONE IN ORDER TO STANDARDIZE MEASURE OF ENDOTOXINS IN THE BLOOD, NIH OR CDC CAN PUT TOGETHER IN THE WORKING GROUP AND SOLVE THAT PROBLEM. >> YES JEFF KELLY FROM SCRIPPS SO I WORK ON AGE ASSOCIATED FAMILIAL AGGREGATION DISEASE UNLIKE ALZHEIMERS AFFECT PERIPHERAL AND AUTONOMIC NERVOUS SYSTEM AS WELL AS THE HEART. I SAID THERE'S GENETIC PHARMACOLOGIC EVIDENCE THAT AGGREGATION DRIVES THESE DISEASES BUT IF YOU TALK TO THE PHYSICIANS WHO TREAT THESE PATIENTS, THE COMMON OBSERVATION IS THAT A PATIENT HAS -- THOUGH THEY CARRY THESE MUTATIONS THEIR WHOLE LIFE THEY HAVE AN INFLAMMATORY EVENT THAT SEEMS TO INITIATE THE DISEASE. THEN I WOULD LOVE TO GET --'S HARD TO THINK ABOUT HOW TO THINK ABOUT THIS. THAT'S MY QUESTION. HOW DOES ONE THINK ABOUT THIS INITIATING INFLAMMATORY EVENT THAT TRANSFORMS THIS CARRIER TO A DISEASE SUBJECT. >> THERE'S ENTIRE SESSION ON PROTEOSTASIS AGGRAVATED PROTEIN. >> I'M A SPEAKER IN THAT SESSION. I'M ALMOST CERTAIN >> WE ALSO SAID THERE IS INFLAMMATORY EVENT THAT GENERALIZE INFLAMMATION START THAT PROCESS OF INFLAMMATION OR CHRONIC INFLAMMATION OR PROINFLAMMATORY STANDARDIZATION WE DESCRIBE FROM POINT OF VIEW. THERE ARE ANIMAL MODELS THAT ARE QUITE INTEREST FROM THIS PROSPECTIVE, TAUPE THINK THERE'S ANY STUDY IN HUMANS. FOR EXAMPLE IF YOU CREATE INFLAMMATION JOIN IN THE MOUSE, IN A YOUNG MOUSE YOU HAVE NO REACTIVITY OF LEVEL OF RANGE ASTROCYTE AND MICROGLIA. THERE IS SOME SORT OF IT BECOMES A PHENOMENON. >> INNAMATION IS THE FIRE. >> I -- >> I THINK THE -- >> I THINK THE NIH IS WORRIED WE'RE GOING TO BECOME CALORICALLY RESTRICTED IF WE DON'T BREAK FOR LUNCH. I'M GETTING SIGNALS FOR THE LAST FIVE MINUTES. ARLEN DO YOU KNOW TO SAY SOMETHING? >> THIS IS SOMETHING BRIAN BROUGHT UP RELATED TO QUESTION ON MOUSE MODELS. AND ONE OF THE THINGS THAT -- IN OTHER WORDS JUDY WAS TALKING HUMANIZING THE MICE. CERTAINLY WE HAVE DONE THAT WITH CANCER, ALS, OTHER DISEASES. THE PROBLEM IS THOSE MICE ALWAYS GET THE DISEASE WHEN THEY'RE VERY YOUNG, SO THEY'RE LOOKING AT A -- IT WOULD BE LIKE LOOKING AT CANCER IN TEENAGERS WHEN YOU'RE DOING, THE SAME WITH ALZHEIMER'S -- INNAMATION HAS A DIFFERENT EFFECT IN YOUNG ANIMALS VERSUS OLE ANIMALS SO YOU WOULD EXPECT WHEN YOU'RE INDUCING ATHEROSCLEROSIS OR ALZHEIMERS OR WHATEVER IT IS, YOU WOULD HAVE A DIFFERENT PHENOTYPE AND MAYBE DIFFERENT THERAPIES WORK IN YOUNG ANIMAL, NOT OLD ANIMAL. >> I GUESS IT'S VOLUNTARILY THOSE WHO WANT TO CALORICALLY RESTRICT AND THOSE WHETHER WANT THE EAT. >> I'M (INAUDIBLE) FROM NCI. I WANT TO THANK THE CO-CHAIRS, PANELISTS AND THE AUDIENCE FOR THE ENGAGING FIRST SECTION FOR THIS MEETING. WE ARE BREAKING FOR LUNCH, IT'S UP STAIRS IN THE CAFETERIA, IF YOU ALREADY HAVE PURCHASED A TICKET YOU GET THEIR LUNCH THERE AND THERE'S ALSO FOOD TO BE PURCHASED UPSTAIRS. WE'LL START PROMPTLY AT 1 P.M. ON THE SECOND SESSION OF ADAPTATION TO STRESS. GOOD AFTERNOON. WELCOME TO THIS AFTERNOON'S SESSION ON ADAPTATION TO STRESS. I'M JULIA ROLAND, I HAVE THE PRIVILEGE OF DIRECTING THE CANCER SURVIVORSHIP WITHIN THE CANCER CONTROL POPULATION SCIENCES AT THAT TIME NATIONAL CANCER INSTITUTE. I HAVE BEEN JOINED BY -- TO PLAN THIS SPECIAL SESSION BY MYs SERUMMED NIH COLLEAGUES DR. GEORGE NEEDRY FROM THE NATIONAL CENTER FOR COMPLIMENTARY ALTERNATIVE MEDICINE FOLLOW SHIP MEMBERS OF THE GEROSCIENCE INTEREST GROUP. CO-CHAIRS FOR THIS SESSION AS YOU CAN SEE ARE DR.S ELISSA EPEL AND GORDON LITHGOW. IF WE READ EVERYBODY'S BIOS WE WOULD BE HERE ALL AFTERNOON AND PROBABLY THROUGH THE WEEKEND. THESE ARE REALLY BRIEF INTRODUCTIONS. APOLOGIES FOR THAT BUT THAT KEEPS US MOVING. DR. EPEL IS PROFESSOR DEPARTMENT OF PSYCHIATRY UNIVERSITY OF CALIFORNIA SAN FRANCISCO AND A LEADER OF THE NEW ECSF -- UCSF CENTER ON OBESITY STUDY AND TREATMENT AND DR. LITHGOW IS ENTERRESEARCH CONSORTIUM AT GEROSCIENCE AT THE BUCK INSTITUTE FOR RESEARCH ON AGING. I I WOULD ALSO POINT OUT IT'S DR. LITHGOW WHO DEVELOPED GEROSCIENCE, IN WIKIPEDIA FOR OUR INTEREST GROUP. HIGH DIRECT THE DISCUSSION WHICH FOLLOW IT IS LAST SPEAKER IN THIS SESSION, PROVIDING A SUMMARY OF THE SESSION INCLUDING REMARKS. AND WE WILL GET STARTED WITH DR. EPEL WHO WILL GIVE THE OPENING TOPIC OVERVIEW PRESENTATION. DR. E PEP. >> THANK YOU SO MUCH. THANK YOU. VERY HAPPY TO BE HERE. SO NOW FOR SOMETHING A LITTLE BIT DIFFERENT. GOING TO GIVE YOU A BRIEF INTRODUCTION TO THE GOOD AND BAD OF STRESS. THIS IS GOING TO BE DIFFERENT BECAUSE WE'LL BE SWITCHING BETWEEN MODEL -- BETWEEN WORMS ABOUT PEOPLE SO YOU HAVE TO LISTEN CAREFULLY SO YOU DON'T MAKE THE WRONG CONCLUSIONS. WHEN YOU THINK AND WHAT REGULATES AGING BUYINGOLOGY, WE KNOW HOW IMPORTANT IT IS TO STUDY AGENING CONTEXT TO KNOW THAT GENES UNFOLD IN ENVIRONMENTS, IN DIFFERENT RATES. STRESS HAS COME TO THE FOREFRONT AS A FACTOR THAT CAN ALTER THE RATE OF AGING. IT CAN MAKE SOME PEOPLE AGE FASTER IN CAT YEARS. OR MAYBE IT CAN SLOW DOWN AGING. SO LET ME TELL YOU FIRST ABOUT A DRAMATIC SOLID FINDING IN THE BASIC SCIENCE OF AGING. SO WHEN MODEL ORGANISMS ARE EXPOSED TO ADVERSITY, SHORT BURST, WHEN THERE'S TIME TO RECOVER, THEY DEVELOP STRESS RESPONSE WHICH IS OFTEN CHARACTERIZED BY INCREASES IN THESE HEAT SHOCK FACTORS, HEAT SHOCK PROTEINS. AND THIS PROMOTES STRESS RESISTANCE, MULTI-PLEX STRESS RESISTANCE. THE ORGANISM IS NOW ABLE TO RECOVER MORE QUICKLY FROM ALL DIFFERENT TYPES OF STRESSORS. AND THIS IS SOMEHOW TIED TO LONGEVITY SO THIS IS REALLY THE QUESTION IF WE CAN UNDERSTAND MORE HOW STRESS RESISTANCE MIGHT PROMOTE LONGEVITY AND HARNESS IT. IN OTHER WORDS, WHAT DOESN'T KILL YOU CAN MAKE YOU STRONGER. IN THESE SPECIFIC MODELS. SO LET ME SUMMARIZE THIS IN A LITTLE MORE DETAIL. AND IF I -- IF THERE ARE INACCURACIES DON'T BLAME GORDON WHO PROVIVIDDED THE SLIDES. A RANGE OVERSEES ORS, ANTIBIOTICS, HEAT SHOCK, NUTRITIONAL FLUCTUATIONS, OXIDATIVE STRESS, ALL DO ANOTHERRER THE RATE OF AGING WITH A HERMETIC STRESS OR SHORT TERM STRESS YOU CAN SEE MORE OF A LONGEVITY PHENOTYPE AND WITH WHAT WHEN HE W CALL TOXIC STRESS WHICH MEANS THE STRESS RESPONSE OVERWHELMING THE REPAIRTIVE PROCESS YOU SEE DAMAGE AND EARLY DEATH. SO THERE ARE SEVERAL PATHWAYS THAT ARE GOOD CANDIDATE PATHWAYS TO HELP UNDERSTAND THE STRESS RESISTANCE MODEL, INSULIN LIKE GROWTH FACTORS, CHANGES OR IMPROVEMENTS IN INTRACELLULAR DAMAGE AND REPAIR SIGNALING, GETTING THE GARBAGE OUT AND METABOLIC CONTROL. SO WE DEFINITELY NEED TO UNDERSTAND HOW THIS WORKS MORE IN THESE BASIC ORGANISMS ABOUT HOW THIS IS TIE TIED TO LONGEVITY BUT WE ALSO AT THE SAME TIME NEED TO BE LOOKING AT THIS IN A TRANSLATIONAL WAY AND ASK HOW THIS RELATES TO HUMAN AGING SO WE KNOW THAT STRESS RESISTANCE IN BASIC RESEARCH IS TIED TO DIFFERENT PATHWAYS OF AGING AND WE NEED TO EXPLORE EXACTLY HOW. THEN I'M GOING -- THE BIG QUESTION FOR OUR SYMPOSIUM TODAY IS HOW DOES THIS RELATE TO HUMANS? SO WE CAN TAKE HUMAN CELLS OUT AND LOOK IN VITRO AND YES THERE'S HERMYSIS, THEY RESPOND TO FZ QUO LOGICAL STRESSORS BUT FOR HUMANS STRESS IS A VERY IMPORTANT WORD BECAUSE WE ARE -- WE ARE BOMBARDED BY COMMON DAILY STRESSORS AS WELL AS SEVERE TRAUMA, THAT LEAVE IMPRINTS ON OUR HEALTH. SO STEPPING BACK AND THINKING ABOUT STRESS IS SO IMPORTANT, WOULDN'T WE SEE THAT IN EPIDEMIOLOGICAL DATA. ONE OF THE MOST CONSISTENT P FINDINGS ABOUT HUMAN DISEASE OF AGING, ALL DISEASE NOT JUST ONE DISEASE, IS PEOPLE WITH LOWER INCOMES AND LOWER EDUCATION DEVELOP THESE DISEASE EARLY. THIS IS ROBUST, ACROSS DISEASES, THIS IS WHAT SOME PEOPLE THINK IS PREMATURE AGING. AND SO THE COMMON THEORY, ONE OF THE COMMON MODELS FOR UNDERSTANDING IS THROUGH STRESS PATHWAYS. THE PSYCHOLOGICAL BURDEN OF CHRONIC FINANCIAL STRAIN COPING EVERY DAY WITHOUT RESOURCES, ET CETERA, LEADING TO ACCELERATED AGING. SO THIS MIGHT BE THIS IDEA THIS YES IS CAN PSYCHOLOGICAL STRESS LEAD TO ACCELERATED BIOLOGICAL AGING THAT MIGHT SEEM A VAST CANYON OR A HUGE LEAP, IF YOU'RE NOT FAMILIAR WITH THE STRESS LITERATURE SO LET ME GIVE BRIEF BACKGROUND. WHAT DO WE KNOW ABOUT PSYCHOLOGICAL STRESS IN HUMAN? A TREMENDOUS NUMBER OF BOTH RESPONSE AND REGULATORY SYSTEMS AS WELL AS WHAT WE KNOW MOST ABOUT IS IMMUNESIS STANCE, WE KNOW STRESS LOCK TERM STRESS LEADS TO IMMUNE SUPPRESSION. YOU'RE GOING TO HEAR ABOUT ONE OF THE MOST ELEGANT MODELS IN A MINUTE BY -- WE ALSO KNOW UNDER ACUTE STRESS WE RELEASE INFLAMMATION. LET ME SAY THAT AGAIN. STRESS CAUSES AN INCREASE IN INFLAMMATION. AN HOUR LATER IT DOESN'T GO DOWN QUICKLY. CHRONIC STRESS CAUSES SYSTEMIC SUS L INCREASES IN INNAMATION BEYOND AGING. WE KNOW THIS WITH CAREGIVERS AN DEPRESSION. SO I CAN'T EMPHASIZE ENOUGH, STRESS AND AGEING AGEING IS NOT SUCH A MYSTERY AT LEAST IN TERMS OF INFLAMMATORY PATHWAY. YOU'RE GOING TO HEAR ABOUT ANOTHER NEW EMERGING MODEL HOW STRESS GETS UNDER THE SKIN. WE CALL IT SOCIAL SIGNAL TRANSDUCTION DEVELOPED BY STEVE COLE AND A MODEL REPLICATEED IN MANY HUMAN MODELS OF STRESS. THIS IS AN ELEGANT WAY OF UNDERSTANDING HOW THE STRESS RESPONSE TURNS INTO SIGNALS THAT CREATE A PATTERN OF GENE EXPRESSION THAT LOOKS I THINK YOU'LL AGREE PRO AGING. SO I WILL END THERE AND LET OUR SPEAKERS FILL IN THE DETAILS. BUT MY POINT IS THAT STRESS HAS AFFECTS FROM MOLECULAR TO SYSTEMIC PHYSIOLOGICAL MEASURE FEW BUT ALSO INTERGENERATIONAL EFFECTS. TO E RALEIGH UNDERSTAND HUMAN AGING WE DONE START WITH A BLANK SLATE, WE ARE BORN WITH PROGRAM FOR CERTAIN RATES OF AGING FROM ANIMAL MODELS AS WELL AS HUMAN COHORT STUDIES. THERE ARE PRE-NATAL PROGRAMS THAT ARE PROFOUND. WE'LL HEAR MORE ABOUT GOOD AND BAD STRESS FROM ONE STRESS -- WHEN STRESS IS LINKED TO DISEASE PROCESS VERSUS MORE A SAL TEAR RESPONSE. THEN HEAR FROM GRETCHEN HOW WE CAN USE EXPERIMENTAL MODELS TO REALLY UNDERSTAND THE STRESS RESISTANCE MORE DOWN TO THE CELLULAR MOLECULAR LEVEL. WE'RE HERE FROM RICHARD MILLER HOW WE CAN -- WHAT WE ALL WANT TO KNOW HOW TO HARNESS STRESS RESISTANCE OUR DEEP UNDERSTANDING TO SLOW AGING AND THAT'S REAL AGING. I ASSUME INDEPENDENT OF DISEASE. HOW EXERCISE AFFECTS DISEASE PHYSIOLOGY AND POSSIBLY STRESS AND LASTLY HOW STRESS AFFECTS THE GENE EXPRESSION PROFILES. SO FOR FIRST HEAR FROM (INAUDIBLE) SAN P FORD UNIVERSITY AND HAS BEEN STRESSING OUT RATS. [APPLAUSE] >> I WANT TO BEGIN BY THANKING THE ORGANIZERS FOR PUTTING TOGETHER A FANTASTIC MEETING AS WELL AS MY SESSION CHAIRS FORGIVING ME A CHANCE TO SHARE SOME THOUGHTS WITH YOU. YOU ALL OF COURSE FOR BEING HERE. HERE IS A POSTER THE NATIONAL LIBRARY OF MEDICINE THAT SAYS STRESS IS A LOADED GUN. IF LEFT UP TREATED IT CAN KILL YOU JUST AS SURELY AS A BULLET. IT SAYS DON'T WAIT FOR THE GUN TO GO OFF, GET HELP TODAY. NATIONAL LIBRARY OF MEDICINE CONVENIENTLY LOCATEDDED ACROSS THE STREET FROM HERE. WE WANT TO CONSIDER WHILE THIS SITUATION CAN BE TRUE, KEEP IN MIND MOTHER NATURE GAVE US A STRESS RESPONSE TO HELP US SURVIVE NOT THE KILL US. SO WHEN WE TALK STRESS, WE MEAN A CONSTELLATION OF EVENTS THAT BEGINS WITH A STRESSOR, THE STIMULUS OR STRESSOR THAT PRECIPITATES A REACTION IN THE BRAIN, THIS IS YOUR STRESS PERCEPTION THAT RESULTS IN THE ACTIVATION OF FIGHT OR FLIGHT SYSTEM IN THE BODY. THIS IS YOUR BIOLOGICAL STRESS RESPONSE. IN ORDER FOR STRESS TO HAVE ANY KIND OF EFFECT ON BRAIN, BODY OR CELL, YOU ABSOLUTELY NEED THE BIOLOGICAL STRESS RESPONSE P WITHOUT WHICH IT DOESN'T MATTER WHAT'S GOING ON STRESS WISE. WE FIND IT VERY USEFUL TO DEFINE STRESS INTO TWO BROAD CATEGORIES SO WE DEFINE SHORT TERM OR ACUTE STRESS AS STRESSES THAT LAST MINUTES TO HOURS IN DURATION. WE DEFINE LONG TERM OR CHRONIC STRESS AS THAT WHICH LASTS FOR WEEKS TO MONTHS TO YEARS IN DURATION. SO IF A PREDATOR WALKED INTO THIS ROOM, A CHEETAH OR A LION AND ROARED, IT WOULD STIMULATE A FIGHT OR FLIGHT RESPONSE IN MOST OF US AS WE FIGURE OUT HOW TO HELP OURSELVES AN HELP OTHERS GET OUT OF HARM'S WAY. THE RESPONSE CONSISTS AMONG OTHERS OF INCREASED HEART RATE, INCREASED HORMONE LIKE ADRENALINE OR CORTISOL AND CYTOKINES RECENTLY DISCOVERED RELEASED IN THE BLOODSTREAM, ELISSA ALLUDED TO THIS UNDER PSYCH PSYCHOLOGICAL STRESSFUL SOLUTIONS. BUT SOMETHING LIKE I'M DOING NOW, GIVING A TALK IN THIS CHARGE TIME DEPENDENT SITUATION ALSO ACTIVATES A SIMILAR BIOLOGICAL RESPONSE, I WAS SURPRISED TO SEE ELISSA HAD FIGHT OR FLIGHT GOING TOO. ELISSA LOVES RUN, SHE DOES IT REALLY WELL BUT EVERY TIME SHE DOES IT, GUESS WHAT THE SAME BIOLOGICAL RESPONSE IS ACTIVATED. GETTING MORE EXOTIC THAN THAT, INTENSELY EXCITATORY STIMULI SO THERE'S APPROACHING SOMEONE FOR A FIRST KISS, ESPECIALLY THE PERSON DOING THE APPROACHING IS ROMANTICALLY CHALLENGED, ALSO WILL ACTIVATE THE STRESS RESPONSE. IN FACT, SCORES IS ONE OF THE SEXUAL INTERCOURSE IS ONE OF THE MOST POTENT ABOUT VISITORS. MOTHER NATURE HAS GIVEN US THIS RESPONSE. IT'S ACTIVATED WHEN WE'RE UNDER PROTECTION, WHERE WE NEED TO PERFORM AND INSTANCES THAT MIGHT INVOLVE PLEASURE. SO HOW DOES THE IMMUNE SYSTEM REACT DURING SHORT TERM STRESS? I WILL SUMMARIZE MANY YEARS WORTH OF WORK IN THIS ONE SLIDE. ESSENTIALLY THE IMMUNE CELLS ARE LIKE THE BODY SOLDIERS THAT RESIDE IN THE BODY'S BARE RACS FOR EXAMPLE, ORGANS LIKE THE SPLEEN OR BODY'S BLOOD VESSELS. VERY EARLY ON WITHIN TWO TO 15 MINUTES OF STRESS RESPONSE YOU HAVE A LARGE SCALE MOBILIZATION OF SOLDIERS OR IMMUNE CELLS SO THEY LEAVE BARE RACS SUCH OUT AND ENTER THE BLOOD VESSELS OF THE BODY AND THIS IS REGISTERED AS INCREASE IN ABSOLUTE NUMBERS OF CELLS L IN THE BLOODSTREAM EARLY ON DURING STRESS SO THIS IS BASELINE, THAT NUMBER INCREASES WITHIN 2 TO 15 MINUTES, AS STRESS RESPONSE PROGRESSES YOU HAVE DECREASE, BELOW BASELINE AND THIS DECREASE IN THE BLOODSTREAM, CHUTE NUMBERS OF CELLS IN THE BLOODSTREAM DOES NOT REPRESENT A NET LOSS OR DESTRUCTION OF CELLS FROM THE BODY BUT A REDISTRIBUTION. THE STRESS RESPONSE IS SENDING THE BODY SOLDIERS FROM THE BOULEVARDS ON TO POTENTIAL BATTLEFIELDS WHERE THEY'RE MAYBE TROUBLE SUCH AS WOUNDING OR PATHOGEN ENTRY. A GREAT EXAMPLE OF POTENTIAL BATTLEFIELDS IS THE SKIN. SO WITH THE STRESS RESPONSE HAS INCREASED NUMBERS OF DEPEND TENDERS IN SITES OF -- DEFENDERS IN SITES OF POTENTIAL TROUBLE. THE RESPONSE ALSO DOES IS INCREASES THE FIRE POWER OF THESE IMMUNE CELLS SO IF INDEED WILL IS AN IMMUNOLOGICAL CHALLENGE OR ACTIVATION THAT TAKES PLACE, THE IMMUNE CELLS THAT ARE THERE ARE BETTER ABLE TO PERFORM THEIR FUNCTION. IF THERE IS A SITE OF ONGOING INFLAMMATION AND FIGHT OR FLIGHT STRESS RESPONSE IS SUPER IMPOSEDDED UNDER THOSE CONDITIONS THIS RESPONSE ALSO DIRECTS GREATER IMMUNE CELL TRAFFIC TO THE SITE OF INFLAMMATION. SO THEN THE QUESTION IS, IS IMMUNE CELLS RUSHED TO THE SKIN DURING STRESS, DOES THIS ENHANCE SKIN IMMUNE FUNCTION? WHAT DOES THIS MEAN FUNCTIONALLY, THERE ARE MANY, MANY DIFFERENCE STUDIES WE IN OUR GROUP AND OTHERS HAVE DONE AND THE ANSWER IS YES. I'LL GIVE A FEW EXAMPLES. IF YOU COUPLE THIS ADAPTIVE IMMUNOLOGICAL FLIGHT OR FIGHT RESPONSE DURING SURGERY, SOME PATIENTS MOUNT THIS ADAPTIVE RESPONSE DURING SURGERY, OTHER PATIENTS IN THIS CASE HUMANS DO NOT. WHAT YOU FIND IS PATIENTS WHO DO MOUNT THE ADAPTIVE RESPONSE SHOW GREATER POSSUMINGCAL RECOVERY. THIS IS A STUDY THAT ELISSA AND I DIDDING TO WITH OUR COLLEAGUES AT YALE. IF YOU COUPLE THE FLIGHT OR FIGHT IMMUNE SITE LOGICAL RESPONSE WITH VACCINATION YOU SIGNIFICANTLY ENHANCE INNATE AS WELL AS ADAPTIVE IMMUNE RESPONSES SO WE DID THE PRE-CLINICAL WORK AND OTHERS INDEPENDENTLY IN ONE SINGLE STEP REPLICATED OUR WORK IN HUMANS SO COUPLE EXERCISE WITH VACCINE OR PSYCH LOGICAL STRESSOR WITH THE VACCINE, THAT COUPLING ENHANCES THE VACCINE RESPONSE. PRE-CLINICALLY THEY HAVE BEEN REPLICATED AND LAST BIT IS PRE-CLINICAL. WE HAVE UV INDUCED SQUAMOUS CELL CARCINOMA A INLAYINGSIC MODEL FOR REGRESSION OF TUMORS. IF DURING THE TIME COURSE OF TUMOR DEVELOPMENT WE PULSE THE SYSTEM WITH THE FIGHT OR FLIGHT STRESS RESPONSE, GENERATING IMMUNE RESPONSE, YOU SIGNIFICANTLY ENHANCE ANTITUMOR IMMUNITY AND INDO YOU UNDERSTAND TUMOR REGRESSION. SO WHAT ARE MECHANISMS OF STRESS INDUCED IMMUNOENHANCEMENT? YOU HAVE LEUKOSITE TRAFFIC AND INFILTRATION, GENE EXPRESSION, I'M GOING TO RAPIDLY SUMMARIZE THERE ARE PUBLICATIONS I CAN REFER YOU TO. WE HAVE INCREASE MACROPHAGE AND DENDRITIC CELL ACTIVATION AND DRAINING LYMPH NODES, MEMORY T-CELL FORMATION IN SITUATIONS WHERE ADAPTIVE COMMUNITY IS COUPLED WITH A STRESSOR. YOU ALL THESE CHANGES ARE DRIVEN BY THE PRINCIPLE STRESS FREE HORMONE EF NEFF PRINT NOR EF NEFF PRINT CORTISOL. SHORT TERM STRESS NOT ONLY ENHANCES IMMUNE FUNCTION BUT ALSO COGNITIVE PERFORMANCE. WHETHER OR NOT THIS HAPPENS DEPENDS ON GENOTYPE. SO THE GENES HAVE A VARIANT MORE EFFICIENT CLEARING DOPAMINE FROM THE PRE-FRONTAL CORTEX, OTHERS ARE NOT. DEPENDING WHAT THAT DOES, YOU HAVE DIFFERENT LEVELS OF PERFORMANCE UNDER STRESS CONDITIONS OR NOT. BUT IF YOU HAVE A GENE LESS EFFECTIVE THROUGH TRAINING, YOU COULD HARNESS IT TO HARNESS YOUR PROTECTIVE FIGHT OR FLIGHT RESPONSE FOR PERFORMANCE IN THIS CASE MENTAL PERFORMANCE. ANXIETY UNDER TEST CONDITIONS CAN ENABLE YOU TO DO BETTER AND CHALLENGE VERSUS STRESS STATEMENT IN TERMS OF WHAT A PERSON FINDS THEMSELVES IN IS A DETERMINANT HOW THIS CAN AFFECT COGNITIVE AND PHYSICAL PERFORMANCE. WHAT ABOUT BAD STRESS? HOW DOES ADAPTIVE SYSTEM FIGHT OR FLIGHT SYSTEM BECOME MALADAPTIVE? IT IS IN THE TRANSITION FROM ACUTE SHORT TERM RESPONSES WITH SHUTDOWN TO LONG TERM OR CHRONIC STRESS. SHORT TERM STRESS FROM MINUTE TO HOURS CAN BE BENEFICIAL, LONG TERM STRESS HAS NUMEROUS DELETERIOUS EFFECTSEN BRAIN AN BODY. SO KNOWN TO INCREASE SUSCEPTIBLE TO ENVIRONMENT BACTERIAL INFECTION, SOME TYPES OF CANCER, INCREASE SUSCEPTIBILITY TO FREE INFLAMMATORY AND WOUND DISEASE, SUPPRESS WOULDN'T HEELING AND VACCINE GENERATED RESPONSES AN INCREASE DEPRESSION AN MENTAL HEALTH DISORDERS. WHAT ARE THE MECHANISMS THAT MEDIATE THE DELETERIOUS EFFECTS OF CHRONIC STRESS? AGING IN THIS CASE. CIRCADIAN RHYTHM DISRUPTION IS A ONE. YOU HAVE SUPPRESSION OF BASELINE IMMUNE CELL NUMBERS. YOU HAVE DECREASE IN FIGHT OR FLIGHT RESPONSE STIMULATED BY STRESS IN THE CHRONIC STRESS BACKGROUND. YOU HAVE LEUKOCYTE TELOMERE SO THIS IS WORK ELISSA DID SO THAT SUGGESTS INCREASE IN IMMUNOLOGICAL SENESCENCE AN MAYBE BIOSENESCENCE AND OTHER CELL TYPES. SUPPRESSION OF PROTECTIVE CELL MEDIATED IMMUNE RESPONSES BUT AT THE SAME TIME YOU HAVE ENHANCEMENT OF LOW GRADE CHRONIC INFLAMMATION, THE KIND WE HEARD ABOUT IN THE SESSION BEFORE LUNCH AND IN SOME CASES ENHANCEMENT OF TYPE 2 CYTOKINES AND THEIR ACTIONS. INCREASES IN OXIDATIVE STRESS AND ALL THIS IN SOME CASES CAN BE COMPOUNDEDDED BY INCREASE IN HEALTH AVERSIVE BEHAVIOR ESPECIALLY THE PART OF HUMANS. SO THEREFORE, THERE ARE MANY BENEFITS OF MINIMIZING BAD STRESS RESPONSES AND OPTIMIZING GOOD STRESS RESPONSES, WE PUT TOGETHER THE CONCEPT OF STRESS SPECTRUM TO FIGURE HOW ALL -- OR CONCEPTUALIZE HOW THIS MIGHT COME TOGETHER. SO ONE END OF THE SPECTRUM YOU HAVE GOOD STRESS, FIGHT OR FLIGHT STRESS RESPONSE. THE OTHER END OF THE SPECTRUM YOU HAVE BAD STRESS, DEPRESSION, STRESS RELATED DISORDER, AND IN BETWEEN YOU HAVE THIS ZONE OF LOW OR NO STRESS. SO THIS IS YOUR RESTING ZONE. WHAT YOU WANT IS TO MINIMIZE BAD STRESS, MAXIMIZE YOUR ZONE OF LOW OR NO STRESS, AND OPTIMIZE FIGHT OR FLIGHT STRESS RESPONSE. HOW DO YOU GET THERE? DIFFERENT MECHANISMS BUT SLEEP NUTRITION AN EXERCISE APPEAR THE PRINCIPLE THREE. THEN THERE'S THINGS LIKE GIVING AND RECEIVING SOCIAL SUPPORT. LIVING A COMPASSIONATE LIFESTYLE, TRAINING IN SOME CASES. COGNITIVE REAPPRAISAL SO A GENUINE GRATITUDE FOR WHATEVER YOUR CIRCUMSTANCES ARE. THEN THEY MAYBE INDIVIDUALIZED PROGRAMS, THIS CASE WHATEVER FLOATS YOUR BOAT. MEDITATION, YOGA, WALKING, HIKING, GARDEN PHOTOGRAPHY, ART FISHING SO ON. WHATEVER WORKS YOU WOULD KNOW IT. THE POINT IS YOUR PSYCHOLOGICAL AND P PHYSIOLOGICAL RESILIENCE MECHANISMS HELP YOU STAY ON THIS SIDE OF THE STRESS SPECTRUM, IT'S GOOD FOR IMMUNITY AND COGNITIVE PERFORMANCE AND OVERALL HEALTH SO HARNESS GOOD STRESS TO PROMOTE HEALTH AND WELL BEING, REDUCE OR ELIMINATE BAD STRESS AS MUCH AS POSSIBLE AND MAXIMIZE THE ZONE OF HEALTH, HEALING AND RESILIENCE. BIG THANK YOU TO MY COLLABORATOR, STUDENTS AS WELL AS FUNDING AGENCIES. THANK YOU. [APPLAUSE] >> SO NOW I WOULD LIKE TO INTRODUCE -- HEAR FROM GRETCHEN DARLINGTON FROM BAILOR COLLEGE OF MEDICINE WHO HAS DONE SEMINOLE WORK IN MODELS OF AGING THROUGH THE IGS PATHWAY. THANK YOU, GRETCHEN. >> THANK YOU, ELISSA. >> WE WERE ASKED TO CONSIDER WHAT WE KNOW, WHAT WE THINK WE KNOW AND WHAT WE WOULD LIKE TO GO WAS THE LAST CATEGORY BEING MAJOR ONE OF COURSE. WE CERTAINLY KNOW THESE TWO MODELS, LABORATORY BASED MODELS, OF DELAYED AGING. FROM THESE MODELS WE LEARNED A GREAT DEAL ABOUT THE BASIC MECHANISMS OF AGING AND ALTHOUGH WE HAVE MUCH LESS INFORMATION ABOUT STRESS MEK ANYMORE WE HAVE GREAT POTENTIAL FOR EXPERIMENTATION INTO THE IMPACT OF STRESS IN THESE PARTICULAR MODELS. I THINK YOU HAVE SEEN SOMETHING SIMILAR TO THIS, BOTH NUTRIENT RESTRICTIONS AND GROWTH HORMONE SIGNALING DEFICIENCY WORK IN TERMS OF EXTENDING LIFE SPAN IN ALL THESE SPECIES. THE STRATEGY THAT THE COMMUNITY AND BASIC MECHANISMS OF AGING HAS USED HAS BEEN A VERY POWERFUL ONE. BROAD SCREENS ARE DONE IN LOWER ORGANISMS TO IDENTIFY GENES THAT IMPACT AGING, THAT GETS TRANSLATED TO THE MOUSE WHICH I WOULD SUGGEST COMES BETWEEN WORMS AND HUMANS. AND THE ABILITY TO CREATE GENETIC MUTATIONS WITH POINT MUTATIONS SURGICAL PRECISION IN THE MOUTH TO TEST THEM IN A TISSUE SPECIFIC MANNER AND TO ARLEN'S POINT TO BE ABLE TO TURN THINGS ON OR OFF AT VARY YOU STAGES IN LIFE WITH MOUSE MODELS I THINK HAS BEEN A POWERFUL CERTAINLY MOUTH EXPERIMENTS ARE MORE EXPENSIVE THAN THOSE IN LOWER ORGANISMS BUT I THINK THEY GIVE AN OPPORTUNITY TO SIGH MUCH MORE IN TERMS OF DETAIL OF THE BASIC MECHANISMS, SO BRIAN SHOWED YOU EARLIER A TYPICAL SURVIVAL CURVE UNDER NUTRIENT RESTRICTION IN THE MOUTH. THE GREATER THE RESTRICTION THE LONGER THE MAXIMUM LIFE SPAN, IN ESSENCE IF YOU'RE A MOUSE THE LESS YOU EAT THE LONGER YOU LIVE, UP TO A POINT THEN YOU FALL INTO MALNUTRITION. THE INTERESTING IMPORTANT OBSERVATION IS THERE IS A CORRESPONDING DELAY IN THE ONSET OF MORTALITY AND MORBIDITY DURING THIS PERIOD IS REDUCED BY NUTRIENT RESTRICTION. DURING THAT PERIOD WE HAVE REDUCED INCIDENCE OF AGE ASSOCIATED DISORDERS INCLUDING CANCER, CARDIO VASCULAR AND KIDNEY DISEASE, CATARACTS, THERE'S A HOST OF OTHER CHARACTERISTICS OF FUNCTIONAL DECLINE IN AGING THAT ARE IMPROVED DURING THIS PERIOD UNDER NUTRIENT RESTRICTION. THEN TURNING TO THE GENETIC MODEL, GROWTH HORMONE SIGNALING DEFICIENCY, YOU CAN SEE THE HOMOLOGY OF MANY OF THE GENES IMMEDIATELY DOWNSTREAM FROM THE INSULIN LIKE PEPTIDES AND THEIR RECEPTORS. MUTATIONS -- MUTATIONS HAVE BEEN MADE IN ALL OF THESE GENES, IN THE MOUSE AND THEY EXTEND LIFE SPAN TO VARYING DEGREES, QUITE CONSIDERABLE DIFFERENCES DEPENDING ON THE GENE THAT HAS BEEN MUTATED. WITH THE GROWTH HORMONE DEFICIENCY ITSELF BEING ONE OF THE MORE POTENT MEDIATORS OF LIFE SPAN EXTENSION. AT THIS POINT THERE HAVE BEEN 25 OR 30 GENETIC MUTATIONS THAT HAVE BEEN CREATED GENERATED IN ORDER TO STUDY ACTIVITY IN DELAYING AGING. HERE ARE TWO EXAMPLES OF SINGLE GENE MUTATIONS THAT LEAD TO EXTENDED LIFE SPAN AND THERE'S REDUCTION IN TUMOR BURDEN. COGNITION IS RETAINED UNTIL LATER AGES, AND MUSCLE LOSS FOR EXAMPLE IS DELAYED. THESE MODELS DO NOT REPRESENT A MODEL OF FRAILTY. THE ANIMALS MUTANT ANIMALS ARE NOT DECREEPED, NOT HIDING IN THE CORNER OF THE CAGE WAITING TO MEET THEIR MAKER. THEY ARE QUITE ACTIVE. HERE THEY ARE TRYING ON HALLOWEEN COSTUMES LOOKING FORWARD TO THE TREATS BECAUSE THESE ANIMALS CAN EAT AS MUCH AS THEY WANT AND STILL LIVE A LONGER AND HEALTHIER LIFE. THE NIA IS NOT PARTICULARLY INTERESTED IN MAKING MICE LIVE LONGER SO I'LL TRY TO GIVE YOU FILL IN A BIT SAW BUT SUPERFICIAL SUMMARY WHAT IS KNOWN IN NON-HUMAN PRIMATES AND EVEN IN THE HUMAN POPULATION. BRIAN'S SLIDE THIS MORNING INDICATED THAT EXTENDED LONGEVITY IN PRIMATES WAS A BIG MAYBE. THERE HAVE BEEN TWO INDEPENDENT ONGOING STUDIES THEY'RE CONTINUING ON LONG TERM CALORIE RESTRICTION AND ALTHOUGH INCREASED MAXIMUM LIFE SPAN NOT PROJECTED IN ONE OF THE STUDIES AS IN THE OTHER, BOTH HAVE SHOWN A VERY SIGNIFICANT DECREASE IN THE ONSET OF CANCER. THERE WAS A TREND FOR THE ONSET OF AGE RELATED DISORDERS, OTHER AGE RELATED DISORDERS TO BE DELAYED MORE SO IN ONE STUDY THAN ANOTHER. SO AT THIS POINT WHETHER AND HOW CALORIE RESTRICTION MAY WORK NON-HUMAN PRIMATES IS WHAT OPEN BUT BEING OPTISTIC WITH THE STUDIES BETTER DEFINITION OF THE -- AND REVIEW OF STUDY DESIGN, WE WILL BE ABLE TO SAY THAT NUTRIENT RESTRICTION IS WORKING SIMILARLY IN MANY RESPECTS TO WHAT WE HAVE SEEN IN THE MOUSE. NUTRIENT RESTRICTION IN HUMANS, VERY DIFFICULT TO CARRY OUT. THERE HAVE BEEN SHORT TERM STUDIES, 6 TO 12 MONTHS CARRIED OUT IN OVERWEIGHT INDIVIDUALS AND THEN INDIVIDUALS WHO HAD HAD LONGER TERM CALORIC RESTRICTION SELF-IMPOSED ALSO EXAMINED. BOTH INSTANCES THERE WAS IMPROVEMENT IN COMMON RISK FACTORS FOR CARDIOVASCULAR DISEASE, GLUCOSE TOLERANCE AN UNDERSTAND LYNN ACTION WAS IMPROVED. AND REDUCTION IN WEIGHT AND FAT MASS AS YOU MIGHT IMAGINE. HOWEVER, IN THE INDIVIDUALS WITH LONGER TERM CALORIC RESTRICTION, BONE DENSITY AND MUSCLE MASS WERE LOWER. AND FEELING HUNDREDRY SURPRISE SURPRISE. WHAT ABOUT GROWTH SIGNAL SOMETHING WE HAVE NO INFORMATION IN NON-HUMAN PRIMATES. IN HUMANS ALL PHYSICIANS IN THIS ROOM KNOW THAT GROWTH HORMONE DEFICIENCY CAN BE A SERIOUS MEDICAL PROBLEM PARTICULARLY IN INFANCY. HOWEVER THERE HAVE BEEN INTERESTING STUDIES OF GENETIC VARIANTS IN GENETIC ISOLATE POPULATIONS. YOU HER THIS MORNING ABOUT THE IGF-1 RECEPTOR VARIANTS AND INCREASED INCIDENCE OF THAT VARIANT IN THE CENTENARIAN POPULATION. THERE'S ANOTHER EXAMPLE WHICH WAS CARRIED OUT IN A POPULATION THERE WAS INCREASED INCIDENCE IN HORMONE GROWTH RECEPTOR. IN THAT POPULATION AFFECTED INDIVIDUALS IS EXTREMELY LOW AROUND 1%. WHEREAS IN CONTROL IT WAS AS HIGH AS 17% AND MANY OF THOSE CANCERS WERE LISTED AS THE CUSS OF DEATH. THE PREVALENCE OF DIABETES WAS MARKETTEDLY DIFFERENT, 5 TO 6% INCIDENCE IN THE RELATED POPULATION BUT NOT A SINGLE CASE AMONG AFFECTED INDIVIDUALS. SO IN CATEGORY OF WHAT WE KNOW OF INDIVIDUAL GENES SHOWN TO IMPACT AGING, WE THINK WE KNOW A FEW MAJOR DOWNSTREAM TARGETS, THESE WERE OPERATING IN EMERGENCY METABOLISM AND DETOXIFICATION. I HAVE LISTED FIVE PATHWAY INSTEAD OF THREE, THESE PROBABLY ARTIFICIAL, THESE ENTERACT AND OVERLAP. SOME HAVE BEEN SHOWN BY GENETIC ANALYSIS TO EXTENT LIFE SPAN, OTHERS HAVE HIGH ASSOCIATION WITH LIFE SPAN EXTENSION SUCH AS ANTIBIOTIC METABOLISM. SO WHAT WOULD WE LIKE TO KNOW? NUTRIENT RESTRICTION AND GROWTH HORMONE DEFICIENCY IS PROTECTIVE AGAINST MANY STRESSES. ACTIVE SAY SOME STUDIES WERE DONE IN THE MOUTH BUT MOSTLY ACUTE NATURE. WE HAVE LITTLE TO NO INFORMATION ABOUT PSYCHOLOGICAL STRESS AND WITH THE INCREASING SOPHISTICATION OF BEHAVIORAL STUDIES IN THE MOUSE, THAT'S AN OPPORTUNITY CHRONIC EXPOSURE OPPOSED TO ACUTE EXPOSURE. CONVERSELY WHAT AN EXAMINATION OF AGING HUMAN POPULATIONS WITH AND WITHOUT STRESSORS REVEAL? AND WHAT I WAS THINKING HERE WAS SOMETHING DR. FRIED TALKED ABOUT THIS MORNING, LOOK AT THE BASIC PATHWAYS WE KNOW TO BE IMPORTANT IN EXTENSION OF LIFE SPAN AND EXTENSION OF HEALTH SPAN. AND WHAT IS HAPPENED AT THAT LEVEL IN VARIOUS POPULATIONS. WE NEED BETTER READ OUTS FOR THAT. IN THE FUTURE. FINALLY, THE - QUESTION WHICH WE ALL ARE ASKING IS, ARE THESE CRITICAL MOLECULAR CHANGES DRUGGABLE? AND I THINK THE DETAILED ANALYSIS BASIC PATHWAYS IN THE MOUSE WILL GIVE US POINTS OF INTERVENTION OF CALORIC RESTRICTION AND GROWTH HORMONE SIGNALING DEFICIENCY. THE NEXT SPEAKER WILL ADDRESS THE PROGRESS IN THAT AREA. I YIELD THE FLOOR TO DR. MILLER. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> RICHARD MILLER UNIVERSITY OF MICHIGAN WHO MADE SEMINOLE DISCOVERIES LINKING STRESS RESISTANCE TO AGING. THANK YOU, RICHARD. >> MY GOAL TODAY IS TO HELP GET TO THIS SITUATION, IT'S NOW ROUTINELY EASY IN MICE TO DO THIS, NOT YET POSSIBLE IN PEOPLE BUT WOULD LIKE TO SEE THAT CHANGE. THIS IS NORMAL PERSON AT AGE 70. IF WE CAN ACCOMPLISH IN PEOPLE WHAT IS ROUTINE IN LIFE THIS IS WHAT A NORMAL PERSON LOOKS LIKE AT AGE 114. THINGS I WOULD LIKE YOU TO UNDERSTAND, THE THINGS I WOULD LIKE YOU TO BUILD INTO YOUR BEANS YOUR PHILOSOPHY IS THAT IT'S NOT HA HARD TO SLOW AGING IN LAB ANIMALS AND THE EFFECT IS TEN TIMES LARGER THAN A CURE FOR CANCER. WHEN YOU DO THIS YOU GET ANIMALS NOT JUST ALIVE A LONG TIME, THEY'RE HEALTHY FOR A LONG TIME AND IT'S MY PERSONAL BELIEF, I HOPE THIS IS 23409 TOO CONTROVERSIAL IT MIGHT BE NICE TO FIGURE HOW THESE THINGS WORK AND SEEK SAFE EFFECTIVE DRUGS THAT SLOW AGING IN PEOPLE. I MR. TALK NUTRITION, DIET, GENES AND THEN TALK ABOUT DRUGS. P THIS IS THE NUTRITION SLIDE. THERE ARE AT LEAST THREE DIFFERENT WAYS, SOME PARTIALLY OVERLAPPING TO DO THIS IN RATS AND MICE, CALORIE RESTRICTION, GRETCHEN MENTIONED MOST HAVE HEARD THIS ME THIONEINE RESTRICTION WORKS SINCE 1993 IN RATS, YOU GET AN EFFECT AS BIG AS CALORIE RESTRICTION. THERE'S A WINDOW OF VULNERABILITY IN FIRST THREE WEEKS OF LIFE IF YOU LIMIT NUTRITION THREE WEEKS YOU GET A LONG TERM PERMANENT SLOWING DOWN OF THE AGING PROCESS. I WON'T GO INTO DETAILS OF THAT BECAUSE IT'S NOT THAT KIND OF A SESSION BUT I WANT TO EMPHASIZE THESE ANIMALS ARE NOT JUST ALIVE, THEY ARE HEALTHY. THEY SLOW CANCER ARTHRITIS, KIDNEY DISEASE, ALL ON THIS SLIDE AND MANY MORE, I HAVE A FANTASY TO TALK TO DR. COLLINS SAYING WE HAVE SECRET TRICK THAT REDUCES CANCER INCIDENCE RATES BY 90%, IT HAS A SIDE EFFECT. IT ALSO SLOWS ARTHRITIS AND ANOTHER ONE SLOWS MEMORY LOSS AND LOSS OF MUSCLE STRENGTH, ET CETERA, ET CETERA, WHY AREN'T WE SPENDING A LOT OF OUR EFFORTS ON STUDYING THIS? THE ONE SLIDELY GRANT MIST TO SHOW YOU FROM ROGER MCCARTER. PUT APPROXIMATE EXERCISE WHEEL IN THE CAGE OF ANIMALS IF TSAI ARE CONTROL ANIMALS THEY LOSE INTEREST IN ABOUT SIX MONTHS IF THEY ARE CALORIC RESTRICTED THEY ARE RUNNING FIVE KILOMETERS A DAY AT AN AGE AL CONTROLS ARE DEAD. SO THESE ANIMALS ARE VIGOROUS, QUITE HEALTHY. JAY (INAUDIBLE) PUBLISHED IN THIS SCIENCE IN 1990. A 50-YEAR-OLD WOMAN HAS 31 YEARS OF AVERAGE LIFE SPAN REMAINING, SHE'LL DIE AT 81. I'M IN FAVOR OF CURE FOR CANCER, THAT WOULD BE NICE OR CURE FOR HEART DISEASE BUT IT MUST BE ADMITTED THEY DON'T GET HOUR VERY MUCH, THEY GET 2.6 AND 2.7 EXTRA YEARS RESPECT THETIVELY T. RED BAR WE GET RUE TENLY BY CALORIC RESTRICTION ME THIONEINE RESTRICTION IN RATS AND MUTATIONS. THIS SYSTEM WOULD BE ONE THAT YOU WOULD WANT TO LEARN HOW THAT WORKS. NICE THING ABOUT MUTANTS IS THEY ARE POINTERS TO NEW DRUGS BECAUSE MUTANTS, WHAT THEY CODE FOR, NOT TOO HARD TO IMAGINE WAYS TO ACCOMPLISH PHARMACO LOGICALLY WHAT THAT MUTATION HAS ESTABLISHED FOR YOU. THIS IS A DWARF MOUSE, WHEN THE LAST CONTROL MOUSE IS DEAD, HUMAN EQUIVALENT OF 100 OR 110 WE STILL HAVE 80% ALIVE AND HEALTHY. I WON'T GIVE YOU THE LONG LIST OF MUTANTS THAT CAN DO THIS. YOU CAN SEE THE NUMBER OF PUBLICATIONS ON INDIVIDUAL MUTANTS THAT EXTEND MOUSE LONGEVITY CONTINUES TO GO UP LINEARLY. AS GRETCHEN MENTIONED WELL OVER 30. I WILL POINT OUT SOME OF THEM SHOULD RING LITTLE BELLS WHERE TO LOOK FOR DRUGS. ONE I'M FOND OF BECAUSE WE HAD INFLAMMATION SESSION IS MYTH, A PROINFLAMMATORY CYTOKINE MIGRATION INHIBITION FACTOR, KNOCK IT OUT IN THE MOUSE YOU GET 15, 20% LIFE SPAN INCREASE. AND THERE ARE PHARMACOLOGICAL COMPANIES SPENDING MORE THAN MY BUDGET FIGURING OUT HOW TO DESIGN DRUGS TO BLOCK INFECTIVITY. PAP A KNOCK OUT MUTANT HAS SIMILAR ADVANTAGES. AND THESE MICE SLOW CANCER, ARTHRITIS, ET CETERA, ET CETERA, ET CETERA. I HAD A SLIDE HERE WHICH PHILIPPE INSISTED YOU COULD NOT SHOW YOU, IN WHICH ROGER HAS DOCUMENTED DWARF MUTATION SLOWS HUNTINGTON DISEASE BUT IF YOU WANT THE ASK A QUESTION ABOUT IT LATER WITH WE CAN TALK SOME. WE'RE ALSO WORKING ON DRUGS SO RAPMYCIN MENTIONED ALREADY SEVERAL TIMES BY INTERVENTIONS TESTING PROGRAM THAT THE NIA FUNDS. WE HAD AN AGING CELL, SHOWING NDGA HAVE POTENT EFFECTS. THE EFFECT IS JUST AS GOOD AS RAPAMYCIN. SOME HAVE MECHANISMS THAT ARE EASILY GOING TO BE INVESTIGATABLE IN PRIMATE AS WELL AS IN HUMANS. ALL FOUR DRUGS ARE AVAILABLE IN EUROPE OR IN AMERICA. THE OTHER THING I WANT TO SAY GIVEN THE LIMITED TIME FRAME IS THEY HAVE INTERESTING SPECIFIC EFFECTS. IT HAS A HUGE EFFECT IN MALE MICE THOUGH SIGNIFICANT BENEFIT IN MALE MICE IT'S A SMALL BENEFIT, IT'S -- FOR REASONS WE'RE JUST WORKING OUT THE BENEFIT SEEMS BIGGER IN FEMALES. THIS GIVES LOTS OF IDEA HOUSE THEY MIGHT BE WORKING IN WAYS TO ADJUST THE STRENGTH OF THE RESPONSE. I THINK THE WORK THAT IS BEING FUNDED NOW TO LOOK AT DRUGS THAT SLOW THE AGING PROCESS IS THIS KIND OF A TOOL KIT. 50 TO 100 YEARS FROM NOW WE'LL HAVE A TOOL KIT LIKE THIS, WON'T BE DUMPING SOMETHING AS CRUDE AS RAPAMYCIN TO A BATCH OF MICE BUT WE WILL HAVE TAILORED DRUGS AIMED AT SPECIFIC CELL TYPES AND INTERVALS IN THE LIFE SPAN, BE ABLE TO DO SOMETHING REFINED AND HOPEFULLY MORE EFFECTIVE WITH MUCH HIGHER BENEFIT TO COST RATIO. I WANT TO DISCRIMINATE BETWEEN FATS ON THIS SLIDE AND WHAT I SUSPECT MAYBE TRUE ON NEXT SLIDE T. FIRST FACT TO MENTION IS IN THE WORMS, GORDON LITHGOW WAS THE FIRST TO NOTICE THIS. THEY REDUCE OXIDATION IN HEAVY METALS AN DNA OX DATING AGENTS THAT'S REALLY IMPORTANT BECAUSE THE IMPLICATION IS IT IS THE STRESS RESISTANCE THAT LEADS TO THE LONGEVITY EFFECT. THOSE WORM WITH HIGH STRESS PROTEIN, TOM JOHNSON'S GROUP SHOWED THIS LIVE LONGER AND SHOWN BY MARK AT A TIMER AND OTHERS IF YOU TAKE AN INDIVIDUAL WORM HEAT IT UP FOR TEN MINUTE, THAT ALSO GIVES A LIFE SPAN BENEFIT SO ALL THESE PUT TOGETHER SUGGEST IN THE WORMS THAT AUGMENTING THE STRESS RESISTANCE PATHWAY LEADS TO LONG TERM HE EFFECTS BENEFICIAL EFFECTS ON LONGEVITY. GETTING THIS IN MA KNOWN DECADES NOW THAT CALORIC RESTRICTED MICE ARE RESISTANT TO TOXINS THEY MIGHT EAT AND CELLS FROM MANY SLOW AGING MICE ARE RESISTANT TO TOXINS GIVING YOU A MALLABLE SYSTEM TO EVALUATE. SO THE GUESS IS THAT THE LINKS BETWEEN STRESS AGING AND STUFF THAT COMES IN QUOTATION MARKS MEANING IT MIGHT BE IGF-1 THOSE VERY EARLY PRIOR TO SPLIT BETWEEN WORMS, FLIES AND MAMMALS. SO YOU CAN STUDY THEM IN FLIES AND P WORMS AND HAVE A GOOD GUESS IT MAY WORK IN MAMMALS. THE OTHER KEY IMPLICATION IS MULTIPLE STRESSES ARE OPT SAME CONTROL. WE HAVE SEEN SLIDE AFTER SLIDE ALREADY WHERE THERE ARE FIVE TO TEN TO 20 STRESS PATHWAYS OR INFLAMMATORY PATHWAYS ARE BAD THINGS. THE POINT OF THIS STUDY IS THEY MAY HAVE A SINGLE THAT TURNS UP AND DOWN TOGETHER RELATED TO STRESS BIOLOGY. NOT PSYCHOLOGICAL STRESS OR ABOUT MY NEXT GRANT REVIEW, I'M TALKING THE KIND OF STRESS THAT AFFECTS CELLS. I WOULD LIKE TO KNOW WHICH CELLS FROM LONG LIVED STRESSES ARE IMPORTANT FOR THIS. THE VASCULAR ENDOTHELIAL CELL L? BRAIN CELL? PART OF THE IMMUNE SYSTEM? LIVER? THE ANSWERS TO THAT WILL BE VERY IMPORTANT. EASY TO WORK RELATIVELY EASY TO WORK OUT IN WORMS AND WILL BE REALLY IMPORTANT FOLLOWING THE LEAD OF WORM BIOLOGIST TO GET THAT KIND OF INFORMATION IN MAMMALS. I PARTICULARLY LIKE TO KNOW WHETHER DRUGS THAT INCREASE LIFE SPAN DO SO BY MEANS OF STRESS RESISTANCE AND CONVERSELY IF WE FOUND DRUGS WOULD MAYBE A GOOD BET TO INCREASE HEALTHY LIFE SPAN. NOW THAT WE HAVE THIS PANOPLY OF TOOLS SOME DIET SOME DRUGS AND MUTATIONS THAT LEAD TO EXTENNED LONGEVITY, PUTS US FOR THE FIRST TIME WE HAVE GUESSES, PEOPLE SUGGESTED HEAT SHOCK PROTEINS, I THINK IGF 4. XENOBIOTIC MARKERS. NOW HAVE THE TOOLS TO TEST THE GUESS AN TRY TO IDENTIFY MOLECULAR CELLULAR PATH WAYS THAT ARE ALWAYS OR ALMOST ALWAYS SLOWED DOWN IN A SLOW AGING MAMMAL. USE THOSE TO FOCUS OUR ATTENTION TRYING TO DEVELOP DRUGS THAT EFFECTIVELY SLOW AGING ENOUGH TO PRESERVE HEALTH FOR 100 OR 110 OR 120 OR MORE. THAT'S THE MATERIAL I WANT TO PRESENT AND I'M GRATEFUL FOR THE I WERE VISITATION TO COME IN AND TALK TO YOU TODAY. [APPLAUSE] >> NOW WEE ERGOING TO HEAR FROM NATHAN LEBRASSEUR FROM THE MAYO CLINIC WHO WILL TALK ABOUT EXERCISE AND WE'RE ALL GOING TO GET UP AND RUN OUT OF AFTER THIS. >> THANK YOU VERY MUCH, ABSOLUTE PLEASURE FOR BEING HERE, I FEEL UP STAGED BY THE FACT WE NOW ARE THINKING ABOUT CHEETAHS AND SEX INSTEAD OF Q. IT'S AND GLAM MARCH OF EXERCISE BUT I WILL GIVE MY TALK. I WANT TO MAKE A FEW IMPORTANT POINTS. WE TALK ROLE EXERCISING STRESS AND STRESS RELATED DISEASE BUT IT'S IMPORTANT TO RECOGNIZE EXERCISE IS A ROBUST MULTI-FACTORIAL STRESS COMPOSDED OF MECHANICAL NEURAL AND HORMONAL STIMULI STARTING TO APPRECIATE AND UNDERSTAND HOW THEY WORK. THE SECOND IMPORTANT PART -- POINT I WANT TO MAKE IS STRESS OF EXERCISE MEDIATE ADAPTATIONS NOT SKELETAL MUSCLE AND CARDIOVASCULAR SYSTEM, SIMPLE MINED RECOGNIZING THESE SYSTEMS HAVE ROBUST ADAPTATIONS TO EXERCISE BUT ORGANS SUCH AS BRAIN, PANCREAS AND LIVER ADIPOSE TISSUE, BONE ADAPT TO EXERCISE SO HERE WE LOOK AT AN INTERVENTION WITH A MULTITUDE OF EFFECTS. FINALLY IT'S IMPORTANT TO NOTE THE ADAPTATIONS IN THESE DIFFERENT ORGAN SYSTEMS TO EXERCISE MAKE THEM RESILIENT P TO A HOST OF AGE RELATED DISEASE AND INCREASE RESILIENCY OR LOWERS SENSITIVITY TO A HOST OF STRESSES. HAVING SAID THAT I CHANGE THE TONE OF MY TALK TO EXERCISING TO AGING, BELIEVE THE HYPE BUT WOULD REMISNOT TO MENTION THE OBVIOUS ALLUDED TO BY MORNING SPEAKERS DR. FRIED AND MURRAY AS WELL AS DR. KENNEDY IN TERMS TO HAVE WHAT WE'RE FACING TODAY IS NOT A PROBLEM OF TOO MUCH EXERCISE OR HOW TO ADMINISTER EXERCISE BUT REALLY THIS INCREDIBLE CHALLENGE TO HEALTH AND WELL BEING OF PHYSICAL INACTIVITY. I WOULD PROPOSE TO YOU WE NEED TO VIEW SITTING AS THIS GENERATION'S SMOKING. SITTING IS CLEARLY THE MOST PROMINENT ROBUST RISK FACTORS FOR A HOST OF CHRONOLOGICAL CONDITIONS. TODAY PHYSICAL ACTIVITY HAS BEEN RELATIVELY ENGINEERED OUT OF LIFE WHEN WE THINK ABOUT IT, THE MOST ROBUST THING WE DO DURING THE DAY IS TRANSFER FROM OUR IPAD TO OUR iPHONE TO OUR IMACK AND THINGS OF THAT NATURE SO WE HAVE BEEN VERY EFFECTIVE ENGINEERING PHYSICAL ACTIVITY OUT OF LIFE, AND JUST TO TELL THE STORY T AND POWER OF PHYSICAL INACTIVITY IT WAS TIME TO GIVE A CASE STUDY SO I'LL TELL YOU MY BUDDY BOB 56 YEARS OLD. GREAT GUY BUT SPENDS LOT OF TIME ANOTHER WORK AND AT HOME SITTING AND BEING SEDENTARY. WHAT I MOON BY SEDENTARY IS NOT JUST LACK OF MODERATE OR VIGOROUS PHYSICAL ACTIVITY BUT THE FACT THAT HE HAS VERY LOW OR NO HABITUAL PHYSICAL ACTIVITY. THE PROBLEM WITH THAT IT'S OFTEN COUPLED WITH POOR NUTRITIONAL HABITS. ONE THREAT TO SOCIETY MORE THAN THAT IS NUTRIENT EXCESS IN QUALITY AND QUANTITY OF FOODS WE'RE CONSUMING. THESE ARE LEADING TO THIS OVERWHELMING EPIDEMIC OF OBESITY IN THE UNITED STATES WHICH IS LINKED TO INFLAMMATION IN A HOST OF CHRONIC DISEASES THAT HAVE BEEN TALKED ABOUT EARLIER TODAY. THE PROBLEM WITH OBESITY IS NOT SO MUCH BODY WEIGHT BUT THE FACT THESE LIPIDS ARE SPILLING OVER TO OR ORGANS SUCH AS LIVER AND SKI TALL MUSCLE CREATING TOXIC INTERMEDIATES THAT ARE DAMAGING ORGANS. BOB IS NOTICING THROUGH HIS REGULAR PHYSICIAN FEW SITS LDL TO HLDL RATIO NOT IN THE RIGHT DIRECTION, BLOOD PRESSURE RISING AN INFLAMMATORY STATE IS ALSO INCREASING BOB IS AT HOST FROM CHRONIC CONDITIONS ALLUDED TO AND IN PARTICULAR CARDIOVASCULAR DISEASE CANCER AND COGNITIVE IMPAIRMENT. NOT SO GOOD ABOUT TAKING IT AND THERE'S SIDE EFFECTS BETA BLOCKER IS TIRED AN DEPRESSED. AND ON TOP OF THAT AS WE HEARD EARLIER THE STRESS OF LIFE IS ADDING TO THESE THINGS AND IS QUITE SHOCKING. BEAUTIFULLY DISPLAYED BY -- HOW PSYCHOLOGICAL STRESS DRIVES THESE THINGS TRIGGERS AN MECHANISMS IN OUR BODY THAT OTHER FORM OF PHYSICAL STRESS DRIVE. BECAUSE OF BOB'S STATE OF HEALTH HE'S PARTICULARLY PRONE TO THE NEGATIVE EFFECTS OF STRESS AND HE MOUNTS INFLAMMATORY OXIDATIVE STRESS RESPONSES IN MULTIPLE ORGANS BECAUSE OF IT AND THESE PERPETUATE THE CYCLE SO WHEN WE LOOK AT THIS MESS BOB IS IN IN THIS VICIOUS CYCLE AND TRY TO IDENTIFY ONE QUICK FIX, TO ME WHAT REALLY IS A RESOUNDING POSSIBILITY IS THE FACT WE NEED TO ADDRESS SEDENTARY LIFESTYLE. BOB IS ASKING, AM I JUST AGENING IS THIS A FEATURE OF AGING IN TERMS OF SIDE EFFECTS THAT WE'RE DISPLAYING ON THIS SCREEN. AS A SCIENTIST WE ASKED THIS MORNING MANY TIMES IS THIS REALLY MODEL ACCELERATED AGING? THESE ARE IMPORTANT QUESTIONS TO ASK. SO BOB HAD A BIT OF COME TO JESUS MOMENT FIGURATIVELY, NOT LITERALLY, DON'T MEAN TO OFFEND ANYBODY AND SAID HE WOULD CHANGE PHYSICAL ACTIVITY LEVELS BY INCREASING HABITUAL PHYSICAL ACTIVITY AND INCREASING MODERATE PHYSICAL ACTIVITY INTO HIS DAILY LIFE. BOB FOUND A NUMBER OF POSITIVE EFFECTS, A RECENT REPORT HIGHLIGHTED IN NEW YORK TIMES THAT THOSE WHO ARE TAKING PART IN REGULAR INTERVAL EXERCISE TRAINING HAVE IMPROVEMENTS IN TERMS OF ENERGY INTAKE, LOWER QUANTITY IMPROVED QUALITY, HE SEES IMPROVEMENT IN BODY COMPOSITION BUT I WOULD ARGUE THAT BODY WEIGHT SHOULD BE NOT PRIMARY METRIC FOR IMPROVEMENTS IN HEALTH BUT IF WE WERE TO DO MORE ANALYSIS OF BOB WE SEE HIS ORGAN HEALTH IS IMPROVED IN TERMS OF COMPOSITION AND QUALITY. BOB IS WITNESSING LOWER RISK FACTORS INCLUDING GLUCOSE AND LIPID LEVELS, BLOOD PRESSURE IS IMPROVING LOWER INFLAMMATION AND HE'S AVOIDING THE CONDITIONS THAT WE WERE CONCERNED ABOUT AGE RELATED CONDITIONS INCLUDING CARDIOVASCULAR DISEASE CANCER, MILD COGNITIVE IMPAIRMENT. AS A RESULT OF HIS IMPROVED HEALTH HE CAN TAKE FEW MEDICATIONS, LESS SIDE EFFECTS AND WHAT'S STRIKING TO ME AND I WOULDN'T HAVE APPRECIATED THIS IF I WASN'T GOING TO GIVE THIS TALK IS THE FACT HE'S MORE TOLL RENT OF EVERY DAY LIFE STRESSORS. WHETHER THE SANDWICH GENERATION TAKING CARE OF HIS KIDS AS WELL AS PARENTS OR THE FINANCIAL STRESSES OF LIFE OR WORK LIFE BALANCE HE'S MORE TOLERANT FOR THOSE STRESSORS. EXERCISE IS SHOWING A POWERFUL AFFECT HERE. WE'RE PHASED WITH WHETHER OR NOT EXERCISE IS GOOD FOR YOU AND HOW WHO AND WHAT BENEFITS FROM EXERCISE. THERE'S A NUMBER OF INTERESTING QUESTIONS AND ONE IS HOW IS EXERCISE WORKING? THERE'S A NUMBER OF DIFFERENT REPORTS THAT CAME OUT RECENTLY THAT DEMONSTRATE THAT EXERCISE IS CLEARLY AFFECTING THE BASIC MECHANISMS OF WHY WE AGE. MARK RECENTLY PUBLISHED A BEAUTIFUL PAPER IN PNAS SHOWING THAT IN THE MOUSE EXERCISE IS ABLE TO COMPLETELY PREVENT ALL THE CONDITIONS OF AGING THAT THIS MOUSE EXPERIENCES BY GENERATING NEW MITOCHONDRIA, IMPROVING FUNCTION AND DNA ABUNDANCE. IF ADDITION TO THAT, EXERCISE SEEMS TO DRIVE HERMYSIS AND OX DAYTIVE STRESS SO WE'RE GUILTY OF IT'S A LITTLE BIT OF SOMETHING IS GOOD MORE MUST BE BETTER AND ALLOW SOMETHING BAD LESS SHOULD BE GOOD. IN THIS CURVE WE YIELD OXIDATIVE STRESS TO MEDIATE EFFECTS OF EXERCISE AND CAUSE POSITIVE EFFECTS ON NUMBER OF ADAPTATIONS TO EXERCISE. WE SHOWED NICELY EXERCISE IS A ROBUST AUTOPHAGY RESTORING PROTEIN HOMEOSTASIS. THERE'S A VOLUME OF WORK SHOWING THE ROLE OF EXERCISE ON INDUCING HEAT SHOCK PROTEINS AN RESTORING PROTEOSTASIS, AFFECTING THE RIBOSOME. RESEN WORK IN OUR GROUP INTERESTED IN ROLE OF EXERCISE ON THE ABUNDANCE ACCUMULATION OF SENESCENCE CELLS AS WE AGE AND DIFFERENT DIETARY INTERVENTIONS. THAT'S PROMISE BUG PRELIMINARY. THE ROLE OF EXERCISE AND INFLAMMATION IS QUITE CONTROVERSIAL. THERE'S CLEAR DATA IN LARGE EPIDEMIOLOGICAL STUDIES THOSE PHYSICALLY ACTIVE AND ROWER LEVELS, THE DATA ON IL-6 AND ALPHA RECEPTORS IS LESS CLEAR BUT SOMEWHAT PROMISING IN PART THESE ARE BECAUSE CONFUSION IS DUE TO THE FACT THAT THE RIGHT STUDY VERSUS NOT QUITE DONE QUITE YET. THE OTHER INTERESTING AREA WE'RE PARTICULARLY INTERESTED AS A NUMBER OF OTHER LABS CONCEPT, HOW DOES MUSCLE COMMUNICATE WITH MUSCLES AN TISSUES. THERE IS A GROWING LIST OF MUSCLE SECRETED PROTEINS THAT IMPACT THE HEALTH OF BONE, LIVER AND THE BRAIN AND THESE ARE EXCITING AREAS FOR INVESTIGATION. BUT WE'RE STILL STUCK WITH THE BASIC QUESTION AS WELL ABOUT WHO BENEFITS FROM EXERCISE, PART WE'D LIKE TO ARGUE WE NEED TO BE ACTIVE FROM CRADLE TO GRAVE. THERE'S ARGUMENTS FOR THAT. BUT ALSO THIS QUESTION ABOUT PREVENTING AGE RELATED CHANGES IN DIFFERENT CELLULAR PROCESSES VERSUS TREATING DERANGEMENTS CELLULAR PROCESSES WHERE IS EXERCISE MOST EFFECTIVE. WE THINK ONE AREA PARTICULARLY INTERESTING IN LATE LIFE IS CONTEXT OF FRAILTY. SO CAN WE USE REHABILITATION STRATEGIES TO IMPROVE RESILIENCY SUCH AS SURGERIES IN OLDER PERSONS AND HOW EFFECTIVE IS THAT. ANOTHER COMMENT PREVENTION VERSUS TREATMENT. THE WORK BY MARK (INAUDIBLE) NEEDS TO BE HIGHLIGHTED HOWEVER THAT WAS A STORY IN -- WHETHER OR NOT IF IT WAS INTRODUCED LATER IN LIFE EFFECTIVE PREVENTING AGE RELATED CONDITIONS NOT YET KNOWN. FINALLY WHAT DO WE NEED TO DO, WHAT IS ACTIVE ENOUGH? WE DONE QUITE UNDERSTAND WHAT THE CRITICAL THRESHOLD IS IN TERMS OF DEGRATION, INTENSITY AN FREQUENCY OF EXERCISE. IT'S HABITUAL PHYSICAL ACTIVITY GOOD ENOUGH? IF BOB PARKS FURTHER AWAY AT WORK AND USE IT IS STAIRS, IS THAT SUFFICIENT TO RACH HIS SYSTEM AND IMPROVE RESILIENCY AND LOWER SENSITIVITY TO A HHS 06 STRESSORS? WE'RE STILL WORKING HARD IN THIS SPACE. EXERCISE HAS A STIGMA TO IT SO WE RYE TO USE THE TERMS PHYSICAL ACTIVITY MORE. TRYING TO UNDERSTAND THE ROLE PHYSICAL ACTIVITY PLAYS IN AGING, HOW EFFECTIVE IS EXERCISE AS INTERVENTION TO PREVENT. HOPEFULLY AT A POINT WE WILL COME UP WITH STRATEGIES, PIE IN THE SKY BUT HARNESS SOME EFFECT OF EXERCISE, WE OWN GET THEM ALL BUT IT'S POSSIBLE TO CAPTURE SOME IN THAT FORM. AND HOPEFULLY HAVE A POWERFUL IMPACT ON HOST OF AGE RELATED CONDITIONS. SO WITH THAT, I SAY GO BOB GO. LOOK FORWARD TO YOUR QUESTIONS DURING THE DISCUSSION. [APPLAUSE] >> THANK YOU VERY MUCH. NATHAN. LAST WE'LL HEAR FROM STEVE COLE UCLA STUDIED IN VITRO MODELS POPULATION BIOLOGY SHOWING HOW PSYCHOLOGICAL SOCIAL STRESS AFFECTS PATTERNS OF GENE EXPRESSION. THANKS. >> SO AS YOU'RE ALL AWARE, WE IN AMERICA EXCEL AT LEADING OUR LIVEs EFFICIENTLY. WE GET THEM OVER WITH 5% FASTER THAN ANY COMPARABLE NATION THAT HAS A SIMILAR SOCIAL AND ECONOMIC COMPOSITION. #WE DO THAT NOT BECAUSE #WE ARE TURNING OURSELVES OVER FAST TORE THESE OTHER FOLKS OR REACHING OUR LIMIT SOONER. WHAT WE DO IS EXCEL AT CHRONIC ILLNESSES THAT YOU HEARD ABOUT EARLIER TODAY, ATHEROSCLEROSIS, NEURODEGENERATIVE DISEASES, METASTATIC CANCER ARE THE MAJOR ARCHITECTS OF OUR RELATIVE WHAT YOU MIGHT CALL EFFICIENCY IN LIFE SPAN. THIS IS NOT PARTICULARLY NEW, IT'S BEEN GOING ON DECADES, PROBABLY SOMETHING ABOUT AMERICAN CIRCUMSTANCES THAT CONTRIBUTE TO THIS. WHAT IS NEW, YOU'RE ALL INTIMATELY FAMILIAR WITH IS OUR ABILITY AS SCIENTISTS TO UNDERSTAND THE MOLECULAR MECHANISMS OF THESE DYNAMICS PARTICULARLY IN THE LAST MAYBE 15 YEARS OR SO WITH THE HUMAN GENOME SEQUENCING AND THE SUBSEQUENT INFRASTRUCTURE THAT'S GIVEN US. WE NOW FOR JUST ABOUT ANY HIGHLY PREVALENT DISEASE CAN SHOW YOU A PORTRAIT LIKE THIS DESCRIBING WHAT WE KNOW ABOUT THE PARTICULAR GENES THAT ORGANIZE TOGETHER IN PROGRAMS TO CARRY OUT THE PRODUCTION OF DISEASE, USUALLY NOT ON PURPOSE, USUALLY THESE ARE INADVERTENT WELL MEANING RESPONSES THE PROGRAM IS CARRIED OUT BY EVOLUTION DESCRIBED EARLIER, WORTH -- STRANGE NEW WORLD NOT SO PRODUCTIVE. BUT NUMBERS, IF IF DEATH WERE MOLECULAR BIOLOGIST HE WOULD HAVE A FAIRLY NICE RECIPE FOR HOW TO GENERATE DISEASE IN A RELATIVELY GENERIC WAY, KIND OF INDEPENDENT OF THE SPECIFIC DISEASE, AND ACROSS A WIDE VARIETY OF DIFFERENT TISSUE SYSTEMS SO BIOLOGIST WOULD CALL IN FORCE RECIPE FOR A DISEASE OFTEN SAY UP REGULATE EXPRESSION OF GENES INVOLVED IN INFLAMMATION AS WE HEARD ABOUT TODAY. AND LET'S AT THE SAME TIME PUSH DOWN THE EXPRESSION OF THE GENES THAT ACTUALLY CARRY OUT THE PUPPED MENTAL FIZZ QUO LOGICAL PROCESSES OF THE CELLS AN TISSUES AND SO IN THIS PARTICULAR CASE OF HEAT FROM A LUKECYTE GENE EXPRESSION PROFILE WE MIGHT FOR EXAMPLE SEE ORDERING IN PRODUCTION OF GENES, EXPRESSION OF GENES INVOLVED IN ADAPTIVE IMMUNE RESPONSE OR I BELIEVENATE IMMUNE RESPONSES. SO WE HAVE A FAIRLY CLEAR PORTRAIT OF THESE DYNAMICS AND WE CAN ASK HOW THIS KIND OF ARCHITECTURE OF DISEASE INTERCEPTS WITH THE ARCHITECTURE OF HUMAN GENOME RESPONSE TO ENVIRONMENTAL CONDITIONS. THAT'S WHAT I'M SHOWING YOU IN THAT HEAT PLOT THOUGH I I HAVE SHOWN AS RECIPE FOR DISEASE IT'S A REPRESENTATION OF DATA FROM BASICALLY TRANSCRIPTOMES FROM THE LEUKOCYTE SAMPLE FROM PEOPLE THAT CONFRONT THE MOST ROBES EPIDEMIOLOGIC RISK FACTORS WE HAVE FOR ALL CAUSE MORTALITY. IF THIS RISK FACTOR WERE THE KINDS PHYSICAL CHEMICAL INSULT THAT OUR INTUITIONS OFTEN THREATEN US MOST WITH LIKE BENZENE IN BRING DRINKING WATER OR SMOG IN THE AIR OR RAY DON IN HALLWAYS, THIS PARTICULAR PROFILE TRANSCRIPTIONAL RESPONSE TO ENVIRONMENTSAL STRESS WOULDN'T BE PARTICULARLY SURPRISING. BUT WHAT IS MORE SURPRISING THE THIS PARTICULAR TRANSCRIPTIONAL RESPONSE WAS STRUCTURED PRIMARILY BY THE EXTENT WHICH PEOPLE IN THE FIRST FEW ROLES FEEL DISCONNECTED FROM THE REST OF HUMANITY SO SO IT'S LONELINESS THAT'S THE RISK FACTOR IN THIS STUDY, AND WHY LONELY PEOPLE SHOULD TURN ON INFLAMMATORY GENES AN SUPPRESSING ANTIBODY MEDIATING GENES AND INNATE ANTIVIRAL RESPONSES, A LITTLE BIT OF A PUZZLE, WE'LL TALK ABOUT THAT IN A MOMENT BUT I DON'T WANT TO LEAVE YOU WITH THE IMPRESSION THIS IS A TERRIBLY SPECIFIC OR QUIRKY PUZZLE WE SEE SIMILAR TRANSCRIPTOMIC RESPONSES ACROSS DIFFERENT TYPES OF TISSUE ENVIRONMENTS IN RESPONSE TO A WIDE VARIETY OF DIFFERENT ADVERSE PSYCHOLOGICAL AND SOCIAL CONDITIONS. SO THIS SEEMS TO BE SOMETHING A GENERIC TRANSCRIPTIONAL RESPONSE TO ADVERSITY. WE UNDERSTAND WITHOUT TOO MUCH DETAIL IN THE LIMITED TIME HERE CONCEPTUALLY QUITE WELL HOW THIS HAPPENS. WE KNOW FIRST THESE EFFECTS ARE CAUSAL, THIS ISN'T AN EFFECTIVE DISEASE ON GENE EXPRESSION PROFILES AND SOCIAL BEHAVIOR AS A CONSEQUENCE. WE KNOW THAT BECAUSE WE CAN RANDOMIZE ANIMALS TO DIFFERENT SOCIAL EXPERIENCES AND START TO SEE THE PRODUCTION OF THESE DIFFERENT GENE EXPRESSION PROFILES AND THE REMODELING OF TISSUE IN WAYS THAT FACILITATE DISEASE. WE ALSO KNOW CONCEPTUALLY THAT THE REASON THESE DIFFERENT TYPES OF ADVERSITY CAN PUSH THESE CONSERVE GENE EXPRESSION PROFILES IS PREDOCUMENT ANYONELY BECAUSE THEY ALL HAVE THE CAPACITY TO EVOKE RESPONSES IN THE CENTRAL NERVOUS SYSTEM THROUGH WHAT YOU MIGHT CALL GENERIC STRESS CIRCUITRY, ACTIVATING CENTRAL NERVOUS SYSTEM STRUCTURES THAT PROGRAM BASICALLY OUR RESPONSES IN A WIDE VARIETY OF IT SHALL SHOE SYSTEMS VIA EXACTLY THE KINDS OF NEURAL EFFECTER MOLECULES TALKED ABOUT EARLIER, CATECHOLAMINES FROM THE NERVOUS SYSTEM, GLUCO COTTOIDS FROM THE SYSTEM AXIS, THEY ENGAGE RECEPTORS THAT IN TURN ACTIVATE OR SOMETIMES REPRESS TRANSCRIPTION FACTORS AND ULTIMATELY THE ORCHESTRATORS OF THESE CHANGES IN GENE EXPRESSION. WE ALSO UNDERSTAND A FAIR AMOUNT, THE PARTICULARS. NOT JUST THAT GENERIC STORY I TOLD YOU ABOUT THERE, BUT WHAT HAPPENED IN RESPONSE TO WHAT PARTICULAR KINDS OF PSYCHOLOGICAL OR SOCIAL EXPOSURE. FOR INSTANCE, IN PEOPLE CHRONIC ADVERSITY IN GENERAL THEY CAN OVERCOME BUT ARE JUST FEELING CHALLENGED OFTEN SHOW REPETITIVE LONG TERM CHRONIC ACT VISION OF SYMPATHETIC NERVOUS SYSTEM RELEASING CATECHOLAMINES IN A VARIETY OF TISSUE ENVIRONMENTS WHICH REACT WITH ADRENERGIC RECEPTORS ON THE SURFACE OF CELLS AND THEY HAVE A PARTICULAR STEREOTYPE IMPACT ON THE HUMAN TRANSCRIPTOME. FOR EXAMPLE FROM THE IMMUNE CELLS THEY TEND TO UP-REGULATE THE TRANSCRIPTION OF PROINFLAMMATORY GENES WHILE SIMULTANEOUSLY PULLING DOWN TRANSCRIPTION OF GENES INVOLVED IN ANTIBODY PRODUCTION AND TYPE 1 INTERFERON RESPONSES. IF YOU ARE SEVERE OVERWHELMING THREAT FOR PERIOD OF TIME YOU MAY GET A DIFFERENT RESPONSE INVOLVING GLUCOCORTICOID WHICH HAVE A DIFFERENT IMPACT ON THE GENOME. IT SUPPRESSES BOTH PROINFLAMMATORY GENE EXPRESSION AN ADAPTIVE IMMUNE RESPONSES SO DIFFERENT TYPES OF ADVERSE EXPERIENCE HAVE DIFFERENT BIOCHEMICAL REPRESENTATIONS IN THE BOY THE AND EVOKE DIFFERENT TRANSCRIPTIONAL RESPONSES. WE KNOW THESE EFFECT ALSO AREN'T LIMITED TO JUST CHANGING TRANSCRIPTION FROM EXISTING PORTFOLIO OF CELLS, YOU CAN ACTUALLY CALL FORTH DIFFERENT CELLS FROM THE BODY AS A FUNCTION OF THIS, IF IT IS PROTRACTED ENOUGH AS THEY BECOME A LIFESTYLE OF THREAT AND ADVERSITY SO THE WAY ADVERSE ENVIRONMENTS CALL FORTH FOR INSTANCE MORE MYELOID LINEAGE CELLS FROM THE HEMATOPOIETIC SYSTEM IS BY VIA THE NERVOUS SYSTEM ABILITY TO EVOKE SYMPATHETIC NERVOUS SYSTEM SIGNALING AND INNERVATION OF HEMATOPOIETIC STEM CELL NICHES BY THE SYMPATHETIC NERVOUS SYSTEM IN THE BONE MARROW YOU END ONE A PROGRAM THAT ADVISES THEM TO LIGHTEN UP ON THE PRODUCTION OF LYMPHOID LINEAGE IMMUNE CELL AND PUMP OUT MORE MYELOID LINEAGE IMMUNE CELL SO YOU HAVE NEUTRAPHILS AND MONOCYTES AN SUBSEQUENTLY MACROPHAGES AN TISSUE, DENDRITIC CELLS CIRCULATING THROUGH THE BODY THAT INTERACT WITH TISSUE DAMAGE INITIATED ELSEWHERE IN THE BODY TO ACCELERATE THESE DISEASE PROCESSES. FOLLOWED OVER TIME AS THEY METASTASIZE OVER THE REST OF THE BODY. IF WE ADD STRESS TO THIS SYSTEM, RELATIVELY MODEST AMOUNTS OF STRESS FOR NOT TERRIFICALLY LONG PERIODS OF TIME YOU CAN HAVE A MOUSE THAT GENERATES SOMEWHERE ON THE ORDER OF ABOUT 10 TO 30 FOLD MORE DISTANT METASTASIS AS FUNCTION OF THAT EXPERIENCED ADVERSITY. NO DIFFERENCE IN THE GROWTH OF THE PRIMARY TUMOR IN THIS BREAST CANCER MODEL YOU CAN SEE AND THAT QUADRANT THERE SO IT'S NOT LIKE THE STRESS IS GIVING YOU CANCER, THIS IS A CASE THE CANCER COMES FROM BEING ALIVE, FROM MAKING A COPYING MISTAKE IN DNA OR WHAT ARE OTHER WAYS THE INITIATE, THIS STRESS BASICALLY PUMPS MYELOID LINEAGE CELLS INTO THE PRIMARY TUMOR AND KICKS OFF A VARIETY OF DIFFERENT PROGRAMS THAT ESSENTIALLY ALLOW THE TUMOR CELLS TO ESCAPE AND COLONIZE THIS TISSUE. WE KNOW THIS IS MEDIATED BY MYELOID CELL BECAUSE WE CAN BLOCK DYNAMICS WITH DRUGS THAT BLUE BLOCK FOR INSTANCE COLONY STIMULATING FACTOR ONE, ALSO BLOCK AT LEVEL OF FIGHT OR FLIGHT THAT BLOCK ENGAGE. MENT OF ADRENERGIC RECEPTORS. THAT'S ONE EXAMPLE HOW YOU CAN EVOKE DISEASE FROM WHAT IS OTHERWISE A KIND OF PROTECTIVE AND REASONABLE RESPONSE FROM THE BONE MARROW, IF YOU'RE CONFRONTING LONG TERM ADVERSITY UP REGULATE THE CELLS THAT SHOULD BE DEFENDING YOU AGAINST TISSUE INJURY BACTERIAL INFECTIONS ASSOCIATED WITH THAT, BUT INADVERTENTLY YOU HAVE CONTROLLING A BUNCH OF CELLS IN THE BRAIN FACILITATE NEURODEGENERATION AND THE VASCULATURE CONTRIBUTE TO ATHEROSCLEROSIS AN LUNGS AGGREGATE YOUR INFECTIONS THERE. POLARIZE YOUR RESPONSES TO ALL KINDS OF DISEASES. THIS IS A SITUATION ACQUIRED WISDOM OF THE HUMAN GENOME SAYS YOU SHOULD CHANGE GENE EXPRESSION PROFILE IN RESPONSE TO A CERTAIN EXPERIENCE OF LIFE THAT MADE SENSE WHEN THERE WAS A GOOD BINDING BETWEEN THE DIFFERENT TYPES OF PATHOGENS WE CONFRONTED AND THE EXPERIENCES WE HAVE IN DAILY EXPERIENCE. THAT IS NOT SO MUCH THE CASE ANY MORE, SO NOW WE HAVE BODIES THAT ADAPT TO ADVERSITY BY CHANGING OUR STRUCTURE IN THE SAME WAY THE TREE IS ADAPTED TO A FORCE CONSTANTLY PUSHING ON IT AND THEREFORE BECOMES VULNERABLE TO GRAVITY OUR GENOMES HAVE ADAPTED TO A WORLD THAT SEES THIS ASSOCIATION BETWEEN EXPERIENCE AND MICROBES AN CHANGES AS A RESULT AND HOOKED THOSE UP TO NON-PHYSICAL STRESSOR. THAT'S ONE EXAMPLE HOW THE HUMAN GENOME RESPONSE TO STRESS CAN REGULATE AGING. [APPLAUSE] >> GREAT SET OF TALKS. 20 YEARS AGO WHEN IT BECAME APPARENT LONGEVITY MUTANTS WERE RESISTANT TO MULTIPLE STRESSES I THOUGHT IT WOULD BE A GOOD IDEA TO GO TO STRESS CONFERENCE AND FINE OUT WHAT STRESS WAS. AND I WANDERED FROM ROOM TO ROOM. ONE ROOM THERE WAS A TALK ABOUT HEAT SHOCK INDUCTION OF MOLECULAR GENES IN E. COLI. IN THE VERY NEXT ROOM THERE WAS A TALK ABOUT HEALTH OUTCOMES AS A RESULT OF THIS PSYCHOSOCIAL STRESSES OF THE (INDISCERNIBLE) I HAD NO IDEA WHY PEOPLE WERE AT THE SAME CONFERENCE. ABSOLUTELY NO IDEA. NO IDEA WHETHER THEY TALKED TO EACH OTHER WENT TO SESSIONS OR NOT. 20 YEARS LATER, I THINK WE'RE BEGINNING TO SEE SIGNS OF THAT MIGHT HAVE BEEN A GOOD IDEA. CONNECTIONS BETWEEN STRESS AND AGING WERE WORKING ON HOW MOLECULAR MECHANISMS ARE UNCOVERED, YOU WILL HEAR MORE TOMORROW. THE MECHANISM THE CONNECTIONS BETWEEN PSYCHOSOCIAL STRESS AND AGE RELATED DISEASE NOW OPEN UP THE POSSIBILITY WE ARE LOOK AT SOME CONTINUUM. (OFF MIC) >> SO WONDERFUL SESSION. ALSO I THINK IN REFERENCE TO THE MORNING SESSIONS I WOULD LIKE TO ASK THE QUESTION TO ALL THE PANELISTS ABOUT CROSS SPECIES COMPARISONS AN CONTRASTS. WE HAVE HEARD SEEMS TO BE HONEST CONSERVATION OF THE GENETIC BASIS OF HEALTH EXTENSION AND LIFE EXTENSION ACROSS FROM WORMS AND ALSO TYPES OF STIMULUS THAT EVOKE THAT EXTENSION AND LIFE EXTENSION BUT THE MAGNITUDE OF THE RISK SO FAR IS VERY MUCH LESS, PROPORTION OF LIFE SPAN IN LONGER LIVED SPECIES, OVER SPECIES THAT HAVE THREE ORDERS OF MAGNITUDE DIFFERENCE WE HAVE LESS THAN ONE ORDER MAGNITUDE ABSOLUTE EXTENSION, 6 OR 8 MONTHS IN WORKS AND 6 OR 8 YEARS IN HUMANS. SO SEEMS TO ME WE NEED TO CONSIDER THE POSSIBILITY THAT THOUGH THE MASTER CONTROL GENES THAT ARE GIVING US ANY KIND OF RESPONSE IN SPECIES CONSERVEDDED, NEVERTHELESS THE DOWNSTREAM EFFECTER PATHWAY THAT ACTUALLY DETERMINE THE MAG DID OF THAT RESPONSE, ARE SIMPLY LESS -- MORPHINE IN LONG LIVED SPECIES DUE TO LESS SELECTION FOR THEM OR SOMETHING. I'M WONDERING WHETHER THE PANELISTS HAVE ANY IDEA AS TO HOW WE MIGHT ACTUALLY TEST THAT HYPOTHESIS AND THERE BY TEST PLAUSIBILITY OF THE IDEA THAT RICH MENTIONED OF ACTUALLY GETTING THE SAME PROPORTION OF INCREASE LIFE SPAN IN HUMANS THAT WE CAN ROUTINELY DO IN MICE. >> SURE. DOGS TEST THE DRUG IN DOGS. PET DOGS, FIVE YEARS FIVE-YEAR-OLD DOGS YOU KNOW WHETHER THEY WORK OR NOT, THEY APPRECIATE THE FREE BED CARE, IF THE DOGS LIVE A LONG TIME THEY'LL BE HAPPY. YOU CHECK THE DOG OF A YEAR, IF IT'S SICK YOU STOP THE DRUG. NO PROBLEM. >> I WANT TO CHALLENGE THE PREMISE OF THE QUESTION. WE HAD THE OPPORTUNITY TO LOOK AT MANY ALLELES AND MANY EXPERIMENTS. THAT OPPORTUNITY HASN'T BEEN TRUE FOR THE RODENT STUDY, SO MAYBE THERE ARE MOUSE MUTANTS OUT THERE P IF WE HAD THE MONEY FOR IT. MY NAME IS (INDISCERNIBLE) FROM NIDA. NATIONAL INSTITUTE OF DRUG ABUSE. I HAVE QUESTION OF OBESITY. I WAS A FORMER FOOD ADDICT MYSELF. GROWING DISPROPORTIONATELY. EXTENSION OF LIFE IS ONE THING. IMPORTANT THING IS QUALITY OF LIFE MUST BE ADDRESSED MORE TO MY MIND THAN THE LONGEVITY OF LIFE. ANYBODY EXPRESS ON IT? >> I WOULD LIKE TO EXPRESS AN OPINION ON THAT. OVER AND OVER PEOPLE HAVE BEEN TALKING QUALITY OF LIFE AND QUANTITY OF LIFE AS THOUGH THEY WERE ON A SEESAW THAT YOU GOT ONE BY GIVING UP THE OTHER. BUT ALL THE EVIDENCE SO FAR POINTS IN EXACTLY THE OPPOSITE DIRECTION. ALL THE INTERVENTIONS THAT WE HAVE IN MICE AT LEAST SO FAR. INCREASE QUANTITY OF LIFE DO THAT BY POSTPONING VAST RANGE OF DISEASES AND AREAS OF DISABILITY AND DYSFUNCTION AS IS PERFECTLY LOGICAL THAT'S HOW YOU INCREASE LIFE SPAN BY INCREASING THE AMOUNT OF TIME INDIVIDUALS ARE HEALTHY. THE TEMPTING IDEA IS ONE OR THE OTHER IS AGAINST THE EVIDENCE AND DOESN'T MAKE A POWERFUL CASE EITHER. >> KEVIN (INAUDIBLE) FROM NAAIRP. I HAVE A QUESTION THAT'S A PECULIAR QUESTION THAT COULD HAVE BEEN ASKED IN THIS MORNING'S SESSION RELATED TO WHAT YOU SAID JUST NOW, MORE AND MORE IN THE WORK THAT I DO, I DO GENOMICS AND OTHER STUFF, WE HAVE 25,000 WORDS FOR GENES AND WE HAVE 10,000 WORDS FOR LINKS NOW AND MICRORNAs BUT WE HAVE FEW PHENOTYPIC DESCRIPTORS FOR THESE GENERAL TERMS LIKE STRESS OR INFLAMMATION IT WOULD BE USEFUL TO HAVE AN ONTOLOGY, A SPECIFIC ONTOLOGY OR HIERARCHICAL ONTOLOGY OF TYPES OF STRESS OR TYPES OF INFLAMMATION. SO WHEN IT GETS TO TITLE OF PAPER AND YOU SEARCH FOR THOSE PAPERS, YOU CAN SPECIFY WHAT THEY'RE TALKING ABOUT. IT WOULD BE USEFUL TO SPECIFY PHENOTYPIC WORDS. >> COULDN'T AGREE MORE. THERE'S AN INITIATIVE OUT OF NIA FOR MORE SCIENTIFIC ONTOLOGY OF STRESS. THE WORD STRESS DOESN'T MEAN ANYTHING ALONE, IT'S A CATCH ALL TERM SO WE MIGHT THINK HEAT SHOCK INDUCED LONGEVITY IS RELEVANT PSYCHOLOGICAL STRESS AN UNLESS WE BREAK DOWN STRESS AND HAVE ONTOLOGY WE CAN'T TALK AND COMPARE BUT I JUST WANT TO POINT OUT THAT THAT'S THE -- I THINK YOU PROBABLY SEE NOW AFTER HEARING SOME OF THE TALKS THAT PSYCHOLOGICAL STRESS IS ONLY ONE TINY PIECE OF THE PHENOMENA, BIOLOGICAL STRESS FOLLOWS PSYCHOLOGICAL STRESS AN EFFECTS THE CELLS SO I HOPE THAT POINT WAS MADE. AND -- OKAY. >> I WANTED TO ADD THAT IDEALLY WE'D LIKE TO HAVE A DEFINITION OF STRESS THAT YOU CAN POINT TO VARIOUS MOLECULAR CHANGES. AND KIND OF MY HOPE AND THE POINT OF MY TALK WAS IF WE CAN GO BACK TO MAYOR PATHWAY THAT WE KNOW EXTEND LIFE SPAN AND HEALTH SPAN AND ASK WHETHER DEPRESSED INDIVIDUALS HAVE A CHANGE THAT IMPACT MTOR AND SO FORTH. THAT WILL GET A BETTER DEFINITION WHAT STRESS MEANS UNDER EACH CIRCUMSTANCE. >> DO YOU THINK WE NEED ONTOLOGY WHEN WE HAVE GENE EXPRESSION PROFILES? >> PROBABLY DO THOUGH I HAVE TO AGREE THE WORD STRESS MEANS SO MANY THINGS IT'S MORE UNVISITATION CONFUSION THAN AN OPPORTUNITY FOR CLARITY. OFTEN WE STRIVE TO ERADICATE THAT TERM FROM OUR PAPER NOT BECAUSE WE DON'T BELIEVE IN THE PHENOMENA PRECISELY PHARMACOLOGY TO SAY ADRENERGIC SIGNALING. THAT'S PROBABLY WHAT IT MEANS IN ECOLOGY OF HUMAN LIFE BUT AS A SCIENTIFIC TERM IT MEAN SOTS MANY THINGS THAT IT STARTS TO MEAN ALMOST NOTHING. >> FRIEND FROM NIDDK, (INAUDIBLE) OUR FRIEND FROM THE PH.D.DK NHLB LOOK AT THIS PROGRAM WONDERING WHERE IS OXIDATIVE STRESS IN THIS PROGRAM. I WANT TO BRITT UP BECAUSE MAYBE WE HAVE BETTER VIEW OF WHAT IT MEANS IN OUR FIELD CERTAINLY IT IS ALREADY IMPORTANT IN THEIR FIELD BUT EXERCISE IS ONE OF THOSE EXAMPLES THAT IF ANYTHING YOU'RE GOING TO INDUCE HUGE OXIDATIVE STRESS YET OUTCOMES ARE GOOD. COULD WE TALK A SECOND ON OXIDATIVE STRESS NOT THAT YOU TALK ABOUT IT BUT MAYBE THAT'S THE OPPORTUNITY TO GET SOMETHING ABOUT THAT. >> THAT LAST SLIDE IN TERMS OF STIMULI RELATED TO EXERCISE. CLEARLY EXERCISE IS A ROBUST ACTIVATOR OF OXIDATIVE STRESS AND OXIDATIVE STRESS IS NECESSARY TO MEDIATE THAT EXERCISE CONFERS. THERE IS A CASE WE ASSUME OXIDATIVE STRESS DAMAGING AGENT NEED TO BE WIPED OUT FROM THE SYSTEM BUT CLEARLY PLAYS AN IMPORTANT ROLE IN MEDIATING THE AFFECT AFFECTS OF EXERCISE. WHAT HAPPENS IS WE NOT ONLY INDUCE OXIDATIVE STRESS BUT ALSO INDUCE THE SYSTEM AND REGULATORY NETWORKS THAT COUNTER ACT IT SO OXIDATIVE STRESS, THE TEMPORAL NATURE IN RIDES AND STRESSORS ASSOCIATED WITH EXERCISE POORLY REGULATE IN A WAY THAT THEY GO AWAY AND STRESSORS ARE CHRONIC WHETHER PSYCHOLOGICAL OR PHYSICAL, THAT'S WHEN IT'S DAMAGING. >> SIMILAR IN INVERTEBRATES WHERE OXIDATIVE STRESS LEADS TO LONGEVITY, LARGER LEADS TO PREMATURE DEATH. IT'S A MIXED BAG RIGHT NOW BASED ON GENETIC THE MODIFICATIONS OF STRESS RESPONSE ENZYMES AN REGULATORS GOING ON. WHEN WE START THAT'S THE CHEMISTRY WE'RE GOING TO BE TALKING ABOUT. >> ONE COMMENT BRIEFLY. THE WORK STUDIES, NOW MUCH MORE SLOWLY THE MOUSE CELL STUDIES, ARGUE THESE CAN BE UNDER COORDINATED CONTROL. MUTANTS THAT LEAD TO AUGMENTED RESISTANCE TO OX DAYTIVE STRESS LEAD TO RESISTANCE TO A WIDE RANGE OF STRESSORS, HOW THAT WORKS IS GOING TO BE A VERY IMPORTANT CUTTING EDGE KIND OF INTERVENTION SCIENCE. >> SO I WANT TO FOLLOW-UP ON -- RAISING CAUTION NOT TO REDUCTIONIZE STRESS TOO MUCH, I THINK SOME SYSTEMS OUGHT TO BE STUDIES MULTI-FACTORIAL PHYSIOLOGIC SYSTEMS SO SOMETIMES REDUCE STRESS TO ADRENERGIC RECEPTOR BECAUSE IT'S CONVENIENT TO STUDY IT THAT WAY. BUT YOU'RE IGNORING EVERYTHING ELSE THAT GOES ON WHEN ORGANISMS IS STRESSED. ONE DISTINCTION WOULD BE AN ORGANIZE IN THIS MALL STRESS AND CELLULAR LEVEL STRESS AN DEFINE IT, THAT'S WHAT WE DO IN OUR PAPERS, AND THE DIFFERENCE WE HAVE FOUND IN TERMS OF THE DURATION OF THE BIOLOGICAL STRESS RESPONSE IS CRITICAL, BUT WHEN YOU LOOK AT THAT WAY SHORT VERSUS LONG TERM YOU SEE BREAK UP OF DIFFERENT EFFECTS OF THE STRESSOR. WHILE WE NEED DISCUSSION OF CLARIFICATION, IT'S TOO EASY TO SAY IT'S NEBULOUS MIGHT HARM US IN THE LONG RUN NOT ENABLING US TO STUDY IN ITS ENTIRETY WE NEED TO DO TO GET TO THE BOTTOM OF IT. >> RON KOHINSKI FROM NIA, BASED ON DR. (INAUDIBLE) SLIDE ON THE BARE RACS BOULEVARDS BATTLEFIELDS SO INCREASE IN CELL NUMBER WITH DURATION OF STRESS AND THEN A FALL OFF. AT SOME POINT THE SYSTEM RESETS. SO WITH AGING DO BARE RACS GET DEPLETED SO YOU WOULD HAVE LOWER AMPLITUDE? WHAT ABOUT ABILITY TO RESET THE BASELINE? >> THANKS FOR THE QUESTION. IN TERMS OF SHORT TERM RESPONSE ITSELF WITHIN THREE HOURS AFTER CESSATION OF STRESSOR, EVERYTHING IS BACK NORMAL. CELL COMPOSITION MAYBE DIFFERENT AND WE NEED ABOUT 24 HOURS TO COME BACK TO NORMAL BUT EVERYTHING ELSE RETURNS TO BASELINE. SUCCESSFUL AGING BUT NORMAL RESPONSE TO WEAR AN TEAR THE BARE RACS ARE GETTING DEPLETED AND THEY MAYBE GETTING REPLENISHED LEUKOSITES LIKE IT IS ONES MORE ABLE TO PROTECT YOU. TWO THINGS OVERALL CELL NUMBERS MAY COME DOWN, THE PROPORTIONS MAY CHANGE SO THE PROINFLAMMATORY CELL TYPES MIGHT INCREASE RELATIVE TO THE MORE PROTECTIVE ONES. IN TERMS OF RESETTING THE BASELINE, IN AN AGING SITUATION I DON'T KNOW. >> FOLLOW-UP DATA BEHIND THAT COME FROM WHICH ORGANISMS? >> THANK YOU FOR ASKING THAT. BARE RACS TO BOULEVARDS TO BATTLEFIELD RESPONSE THAT I SHOWED YOU EVOLUTIONNARILY COP SERVED FROM REP UNTILLIAN TO -- REP UNTILLIAN TO REPTILES TO MAMMALS FROM MOUSE TO PERSON, VERY, VERY CLEARLY AND REPRODUCIBLY, THAT'S WHY PRE-CLINICAL FINDINGS IN ONE STEP WE AND OTHERS WERE ABLE TO TAKE TO THE CLINIC. NOTHING IN BETWEEN LAB TO CLINIC. >> I HAVE BEEN ASKED BY NIH TO NOT ALLOW ANY MORE THAN ONE FOLLOW-UP COMMENT. I'M SORRY. THEY MADE THE RULES. Q. ON AGING. MY QUESTION IS, I'M ALWAYS IMPRESSED BY DIVERSITY OF ACTION GROWTH HORMONE IGF-1. WE HEARD DURING THE MORNING TALK THAT FACTORS ARE IMPORTANT FOR IMMUNE FUNCTION SKELETAL MUSCLE MASS YET DECREASE IN HORMONE AND UGF-1 SHOWN TO INCREASE THE LIFE SPAN. SO THERE'S TWO PARTS, I DO IT AT ONCE. FIRST IS ARE THERE OPPORTUNITIES FOR WINDOW OF TIME WHEN DEFICIENCY OR EXCESS OF GROWTH HORMONE MAYBE HAVING THESE EFFECTS, THAT'S ONE. AND PART TWO, ARE WE VIGILANT ENOUGH ABOUT THE ANIMAL MODELS THAT WE ACTUALLY USE? WE ALL KNOW THAT A LOT OF THE CHANGES WE MAKE, WE CREATE ANIMALS NOT ABLE TO LIVE OUTSIDE A TWO BY TWO BOX, THEY ARE NOT VIABLE. SO ARE THEY GOOD MODELS OF AGING OR NOT? >> GOOD POINT. THE ANIMALS ARE IN A PROTECTIVE ENVIRONMENT AS BRIAN DESCRIBE IN THE MORNING AND THEY WOULDN'T SURVIVE TEN MINUTES. HOWEVER, I THINK THE EVOLUTIONARY CONSERVATION WOULD STRONGLY SUGGESTION WE FINE IMPORTANT BENEFITS IN THE HUMAN POPULATION FROM MODULATING THE DOWNSTREAM TARGETS AND PERHAPS RELATIVELY FAR UP IN THE PATHWAY, PERHAPS ALL THE WAY TO RECEPTORS THAT HAVE PARTIAL ACTIVITY. YOUR QUESTION ABOUT TIMING IS AN INTERESTING ONE. I SEE ALL SUSPECT THESE INTERVENTIONS HAVE BEEN LIFE LONG IT MAY NOT HAVE APPLICATION BUT WE CAN TEST THAT, TURN ON AND OFF AND BEGIN TO UNDERSTAND WHAT'S OUR WINDOW OF OPPORTUNITY. >> STEWART KING FROM STANFORD UNIVERSITY. TWO QUESTIONS ABOUT LONELINESS. DO YOU FINE PERSON TO PERSON VULNERABILITY IN THE LONELINESS GENES? EVER FIND A PERSON THAT DOESN'T MIND BEING ALONE? >> IF THAT'S YOUR ONE QUESTION, THE ANSWER IS YES. THERE ARE WHAT WE WOULD CALL INTROVERTS PEOPLE PERFECTLY HAPPY BEING ALONE AND IF YOU PUT THEY WILL WITH OTHER PEOPLE THEY WOULD BE EVERY BIT AS STRESSED OR AUTO NONICALLY ACTIVATED OR THREATENED, WHATEVER YOU WANT TO CALL IT AS AN EXTROVERT ISOLATED. >> SON THE HEAT MAP THEY LOOKED UNSTRESSED. >> IN THE HEAT MAP THEY WEREN'T THERE BECAUSE THEY TAIL SAMPLED PEOPLE THAT SCORED ON MEASURES OF LONELINESS WHICH ACTUALLY HAVE ONLY A MODEST INPUT ON HOW MANY PEOPLE YOU HAVE CONTACT WITH BUT A HEAVY INPUT ON YOUR PSYCHOLOGICAL EXPERIENCE OF THAT. SO BASICALLY SAY SOMETHING LIKE I DON'T -- I THINK YOU CAN'T TRUST ANYBODY IN THE WORLD. THE FINGERPRINT OF A LONELY PERSON. THAT'S DIFFERENT FROM SOMEBODY SAYING I'M ON MY OWN BUT EVERYTHING IS FINE. >> ONE FOLLOW-UP. I GET MY FOLLOW UP. >> I THOUGHT YOU HAD IT. >> HOW IS LONELINESS -- WHAT HAPPENS TO LONELINESS AND AGE SOMETHING DO THE LONLY GENES GO UP DURING AGING AND IF YOU'RE YOUNG GUY AND YOU EAR AGING BUZZ -- WHAT HAPPENS DURING AGING FOR LONELINESS? >> AT THE GENOMIC LEVEL THESE FOR INSTANCE SCRIPTOMES LOOK SIMILAR. A YOUNG LONELY PERSON HAS A FOR INSTANCE SCRIPTOME LOOKS MOTHER LIKE OLD PERSON WITH PROINFLAMMATORY SIGNALING, A LITTLE LESS ADAPTIVE RESPONSE SIGNALING AT LEAST THROUGH THE EYES OF THE GLUE CO-SITE, MAYBE DIFFERENCE IN THE BRAIN THAT'S DIFFERENT QUESTION. WHAT WE DON'T KNOW IS WHETHER THOSE ARE INCIDENTALLY THE SAME THING OR WHETHER -- THERE ARE CERTAINLY VERY CLEAR PROFOUND TREND TOWARD GREATER EXPERIENCE OF LONELINESS IN THE LIVES OF OLDER PEOPLE SO PROFOUND EPIDEMIOLOGIC ISSUE THAT RANKS HIGHLY IN THE NATIONAL INSTITUTE OF AGING BEHAVIORAL SCIENCE PORTFOLIO UNDERSTANDING LONELINESS AN AFFECT ON BIOLOGY. SO THEY'RE DEFINITELY RELATED SOMEHOW, WHETHER INTRINSICALLY CAUSALLY CONNECTED IS TO BE DETERMINED QUESTION. >> CAN I JUST ADD THAT IN TERMS OF FACTORS THAT PREDICT MORTALITY, THERE'S META ANALYSES ON SOCIAL ISOLATION, THAT'S DIFFERENT THAN LONELINESS BUT PEOPLE ARE MORE SOCIALLY ISOLATED TEND TO HAVE EARLIER MORTALITY AND EFFECT IS AS LARGE AS OTHER FACTORS SUCH AS SMOKING. >> PEOPLE MAKING COMMENTS AND ASK QUESTIONS KEEP THEM CRISP. >> (INAUDIBLE) FROM THE (INAUDIBLE) INSTITUTE. THE QUESTION IS STRESS INHERITED BY EPIGENETIC FACTORS ALONE? >> YES. THIS AREA IS INCREDIBLY COMPLEX AN THERE ARE MIND BLOWING STUDIES IN PROGRESS, IN ANIMALS AND HUMANS LOOKING AT THAT TIME EPIGENETICS OF TRANSMISSION OF DEPRESSION AND STRESS DURING PREGNANCY TO PLACENTAL CHANGES AND BABY CHANGES AND THE TELOMERE IS THERE AS WELL, MOMS MORE ANXIOUS HAVE BABIES WITH CORED BLOOD WITH SHORTER TELOMERES. >> AND THERE'S EVIDENCE FROM OTHERS THAT LONGEVITY ITSELF CAN BE -- GO THROUGH MULTIPLE GENERATIONS PROBABLY THROUGH EPIGENETIC MECHANISM. >> GOOD AFTERNOON, IAN KRAMER FROM THE LEAGUE COALITION. I WANT TO THANK THE PANEL, THIS IS BEEN ILLUMINATING FOR THE ONE NON-SCIENTIST IN THE ROOM BUT I THINK IT HAS AGED ME TREMENDOUSLY. I HAVE A QUESTION, A TWO PART QUESTION RELATED TO DIFFERENTIATION BETWEEN YOUNG ONSET ALZHEIMERS AN MORE TYPICAL AGE ONSET. WHAT'S THE LITERATURE LOOKING AT STRESS AND TO THE EXTENT YOU CAN COMMENT ON THE MORNING TOPIC INFLAMMATION WHERE THE DIFFERENTIATION MAYBE BETWEEN TYPICAL AGE ONSET AND NORMAL ONSET. AND LONELINESS ONSET, YOUNG ONSET OR TYPICAL AGE ONSET BUT BEGAN TO EXPERIENCE SEVERE ISOLATION AN LONELINESS DUE TO SOCIAL STIGMA OF THE DISEASE AS WELL AS THE LIFESTYLE LIMITING FACTORS OF THE DISEASE, CAN YOU COMMENT OUR THAT AFFECT IT IS TRAJECTORY OF THE SYMPTOMOLOGY OF THE DISEASE? >> IT MAKES SENSE AS A LOGICAL RESULT, WE DON'T HAVE EMPIRICAL DATA WHETHER OR NOT THAT IS TRUE BUT IT SEEMS LIKE A REASONABLE GUESS. PART OF THE BIOLOGICAL PHENOMENOLOGY MAKES IT SEEM A REASONABLE ASSUMPTION THAT THAT MIGHT BE THE CASE, COMES FROM SOME TERRIFYING STUDIES THAT JOHN SHARON'S GROUP AT OHIO STATE DOES RUNNING MODELS OF SOCIAL STRESS, PUMPS OUT MYELOID LINEAGE CELLS, LOOK IN THE BRAIN OF ANIMALS AFTERWARDS AND THE GFP POSITIVE ONCE UPON A TIME MONOCYTES DIFFERENTIATING MACROPHAGES AND DENDRITIC CELLS TAKE UP RESIDENCE IN THE BRAIN. THEY COME UP WITH INSTRUCTION PRIMED FOR INFLAMMATORY INSTRUCTIONS SO THEY'RE NEWLY IMPLANTED TIME BOMBS, THEY'RE NOT GOING TO GUARANTEE TROUBLE BUT IF THEY GO TO ENVIRONMENT INITIATED DISEASE PROCESS SUCH AS EARLY STAGE DYNAMICS AND ALZHEIMERS THEY MAY AMPLIFY THEM AS I SHOWED IN THE CASE OF INITIATED CANCER CELL, WHERE IT'S PRIMARY UNLESS IT GETS MONOCYTES TO FREE METASTASIS FOR THEIR DIRTY DEEDS AND DISTANCE COLONIZATION. >> >> PETER NATHANIAL, I'M PLEASED LITERALLY THE LAST FIVE MINUTES TRANSCRIPTIONAL PASSAGE BECAUSE I WORK IN FIELD OF DEVELOPMENTAL PROGRAMMING AND EPIGENETICS AND SAW EARLY ON FROM CRADLE TO GRAVE BUT WE HAVE TO CHANGENA FROM THE WOMB TO THE TOMB. BECAUSE IN MY BEGINNING IS MY END, IT'S SO CLEAR FROM THE DEVELOPMENTAL STUDIES IN ANIMALS, FOUR EXAMPLES YOU'RE BORN WITH SMALLER MUZZLE MASS, YOU RESET YOUR PEPTIDE THERMOSTAT IN YOUR NUCLEUS, YOU'VE GOT DIFFERENT SPINES ON YOUR HIPPOCAMPAL NEURONS AND AFTER ADDRESSING ONE THING THAT'S GOING THROUGH THIS AFTERNOON T YOU ALSO COMPLETELY RESET YOUR PITUITARY ADRENAL AXIS. SO MY QUESTION, MY INTEREST WHAT THE PILOTING ABOUT THIS, BECAUSE I DON'T THINK IT'S TOUCHED ON TOO MUCH, IS THAT THIS DIFFERS IN ANIMALS BETWEEN MALE AND FEMALE OFFSPRING. I DON'T THINK YOU GET A PAPER PUBLISHED IN THAT FIELD UNLESS YOU STUDY BOTH. MY QUESTION, WHAT CAN YOU LEARN FROM THIS, WHAT IS THE SIGNIFICANCE, THE DEVELOPMENTAL PROGRAMMING FROM THEWOMAN TO THE TOMB -- WOMB TO THE TOMB AND MY BEINGING IS THE END IS SO DIFFERENT IN THE MALE AND THE FEMALE, WHAT CAN WE LEARN ABOUT THAT FOR THE PROCESSES THAT LEAD TO AGE SOMETHING >> EXTREMELY BROAD QUESTION. I'LL PUT TWO (INAUDIBLE) DATA IN FRONT OF YOU. THE CHANGES IN HYPOTHALAMIC NEURONS INDUCED BY IGF 11 LEVELS WITHIN THE FIRST THREE WEEKS OF LIFE ARE DRAMATIC BUT THE OPPOSITE OF THAT WHICH IS SEEN IN A SESSION LIKE A MUTATION THAT SITUATION THAT MODULATES, YOU GET OPPOSITE DIRECTIONS. SOME OF THE DRUGS THAT THE ITP IS TESTING HAVE DIFFERENCIAL EFFECTS IN MALE AND FEMALE MICE AND SEEING HOW THE DRUGS ENTERACT WITH THE SEXUALLY DIMORPHIC HORMONE LEVELS, CHANGES IN XENOBIOTIC ENZYMES IN THE LIVER AS WELL AS WITH SYMPATHETIC NERVOUS SYSTEM EVALUATE IN TERMS OF HOW ANTI-AGING MANIPULATIONS OF CNS AND NEURAL HUMORAL RESPONSES, IT'S A FERTILE AREA FOR INVESTIGATION BUT NOT MUCH IS KNOWN YET. ARLEN RICHARDSON SAN ANTONIO. THE QUESTION WOULD BE TO GORDON AND RICH. . YOU POINTED OUT NICELY THE FACT THAT ALMOST ALL, MAYBE ALL EXTENSIONS ARE ASSOCIATED WITH INCREASE RESISTANCE TO STRESS. ON THE OTHER HAND THERE ARE STUDIESK GET RESISTANCE TO STRESS NOT JUST OXIDATIVE STRESS WHICH WE DID BUT I REMEMBER WHEN TOM WAS TALKING THE NEMATODES HE WAS SAYING THAT WHILE YOU WOULD SEE THE LONG LIFE MUTANTS HAD RESISTANCE TO STRESS, NOT ALL STRESS RESISTANCE MODELS HAD INCREASED LIFE SPAN, HOW DO YOU SEE THAT APPARENT DICHOTOMY OR WOULD YOU EXPLAIN THAT? >> THE CORRELATION ISN'T QUITE -- THERE ARE MANY MUTATIONS, THERE'S OVER 500 MUTATIONS IN C ELEGANS THAT EXTEND LIFE SPAN. MANY OF THOSE MUTATIONS ARE NOT SHOWN TO BE STRESS RESISTANT. AT LEAST IN YOUNG ANIMALS. SO THAT THERE'S A DERTH OF DATA ON OLDER ANIMALS, MIDDLE AGE ANIMALS AND WHETHER STRESS RESISTANCE COMES ABOUT BUT FOR YOUNG ANIMALS THE CORRELATION ISN'T P 100% COMPLETE. WHAT I THINK MIGHT BE BETTER IS WHEN WE DRILL DOWN INTO MOLECULAR MARKERS OF STRESS RESISTANCE OR STRESS RESPONSE, FOR EXAMPLE, IF YOU LOOK AT PROTEINS THAT BECOME I WERE SOLUBLE DURING NORMAL AGING THERE'S A STRONG CORRELATION SO FAR OF MOLECULES THAT SLOW AGING TEND TO ALWAYS ALSO SLOW PROTEIN AGGREGATION AS WELL. >> HOW WOULD EXPLAIN THAT YOU CAN GET STRESS RESISTANCE AND NOT LIFE SPAN? >> I THINK ARLEN, THAT THE -- OVERSIMPLIFICATIONS -- I WOULD NEVER SAY ALL THE SLOW FORMS OF AGENING MICE LEAD TO RESISTANCE TO ALL STRESSES. THE EVIDENCE IS STRONG. THAT IS MUCH TOO SIMPLE. THE CHALLENGE IS GOING TO BE TO FOSTER SPECIFIC CELLS RESISTANT TO SPECIFIC CLASSES OF STRESS. PEOPLE SAID LIKELY PROTEIN FOLDING OR MODULATION OF HORMONAL BALANCE, THERE ARE A VARIETY OF MOLECULAR AND CELLULAR HYPOTHESES THAT NEED TO BE TESTED. THE WORM DATA POINTS US IN A LOT OF INTERESTING DIRECTIONS BUT IT'S NOT GOING TO MAP ONE TO ONE WITH ALL OF THEM INTERESTING MORE COMPLICATED STUFF IN PEOPLE LIKE US. >> FOLLOWING THE LAST RESPONSE, I WOULD LIKE TO KNOW IF AMONG DIFFERENCE BETWEEN MOUSE STRAINS IF THERE ARE DIFFERENCES IN COPING WITH EMOTIONAL STRESS? IF THIS CORRELATE WITH RESISTANCE TO MORE CLASSICAL STRESSORS LIKE MECHANICAL -- LIKE SAY HEAT STRESS OR REACTIVE OXYGEN SPECIES. AND THE SECOND QUESTION IS I REMEMBER PROHIBITION OF LIFE SPAN IN P-66 SHEIK MICE BUT THEY WERE SHOWN TO BE RESISTANT TO MANY STRESSORS BUT THEN WHEN THEY WERE PUT IN A WILD TYPE ENVIRONMENT THEY WERE ALL DEAD BECAUSE THEY WERE VERY SENSITIVE TO COLD. SO I WONDER IF THERE ARE SUCH TYPE OF TRADE OFF BETWEEN RESISTANCE TO ONE STRESSORS AND BEING MUCH MORE WEAK IN RESPONSE TO OTHER TYPE OF STRESSORS BECAUSE WHAT NATURE DID DURING EVOLUTION WAS TO MAKE A COMPROMISE IN THE WILD ENVIRONMENT BETWEEN RESISTANCE TO DIFFERENT TYPE OF STRESSORS AND THE ANIMAL MODEL THAT ARE PRODUCED IN THE LAB ARE MONSTERS IN THIS SENSE. >> THANK YOU. >> I'LL PRESENT THE FIRST PART. YOU GET THE SECOND. I LOVE THE FIRST QUESTION ASKING ABOUT STRESS RESISTANCE IN FOR EXAMPLE RHODEN MODELS, PSYCHOLOGICAL RESISTANT TO STRESS AND DOES THAT ALSO LEAD TO MULTI-PLEX STRESSORS, CELLULAR STRESSORS AND MODELS WE TEST IN A MORE STANDARDIZED EASY WAY. I LOVE THAT QUESTION BECAUSE THAT'S THE TYPE OF QUESTION THAT WILL -- WE LEAD THAT WILL BRIDGE THE GAP SO THIS IDEA THAT PSYCHOLOGICAL STRESS IS PROAGING AND WE SEE THESE PHYSIOLOGICAL EXAMPLES BUT DON'T KNOW HOW THAT COMPARES TO THE STRESSORS IN ITS MODEL ORGANISMS IS EMPIRICAL QUESTION WE GET SO MUCH BANG FOR BUCK TO ADDRESS. SO THE QUICK ANSWER IS YES, THERE ARE STRESS RESISTANT GENOTYPES, TEN FAVORITE CANDIDATE GENES THAT LOOK LIKE THEY LEAD PEOPLE TO BE MAYBE LESS VULNERABLE TO DEPRESSION UNDER STRESS AND THERE'S ALSO THE IDEA THE STRESS GENES LEAD ANIMALS TO BE MORE OPEN TO THE ENVIRONMENT PERIOD WHETHER AVERSIVE OR SUPPORTIVE SO THRIVE MORE IN ENVIRONMENT AND HAVE MORE STRESS VULNERABILITY AND DISEASE AND MORE ADVERSITY. >> THERE ARE AMONG MOUSE STRAINS LIKE DIFFERENCES IN STRESS SUSCEPTIBILITY OR RESISTANCE AND IN RAT STRAINS. I DON'T KNOW SPECIFICALLY HOW THEY'RE WITHIN THE STRAIN DIFFERENCES TO DIFFERENT TYPES OF STRESSORS LIKE YOU ASKED, COLD VERSUS SOMETHING ELSE. THERE ARE OTHER VULNERABILITIES THAT ARE COMING IN, SO EXAMPLE THE LUIS RAT IS STRESS HYPORESPONSIVE, SINGLE STRESSOR, REPEATED STRESSOR SO YOU CAN SAY STRESS RESISTANT, MOUNTS A LOWER SPREES RESPONSE COMPARED TO THE SPRADALY RAT, THE FISSURE RAT IS STRESS HYPERRESPONSIVE, SO WITH STRESS IT MAYBE AS MOUSE MUCH GREATER STRESS RESPONSE. DISEASE WISE THE FISHER RAT IS MORE SUSCEPTIBLE TO TUMORS AND CANCER LIKE DISEASE, THERE'S A MODEL FOR THAT BUT THE LUIS RAT MORE RHESUS TAN TO THOSE KINDS OF DISEASES THE MORE SUSCEPTIBLE TO AUTOIMMUNE AND PROINFLAMMATORY DISEASE. SO THE TRADE OFF MAY COME NOT ONLY ACROSS STRESS STRESSORS BUT ALSO ACROSS DISEASES. WITHIN THE SAME STRAIN IF IT'S A WILD TYPE STRAIN, TUMOR MODEL IS DELIBERATELY MADE IN WILD TYPE TO KEEP IT AS IN AN OUTBREAD STRAIN, TO GIVE IT CLOSER TO THE HUMAN GENETIC VARIANTS, WHAT YOU SEE IS WITHIN THAT THERE'S A SPECTRUM OF RESPONSIVITY RESISTANCE AND SUSCEPTIBILITY STRESSORS AND PHENOTYPING A MOUSE BASED ON ANXIETY CHARACTERISTICS AT BASELINE BEFORE YOU DO ANYTHING TO IT AND THEN THROUGH TUMOR MODEL THAT BASELINE PHENOTYPE PREDICTS MORE TUMORS UNDERLINE SUSCEPTIBILITY AND CONNECTED TO THE STRESS REACTIVITY. SO THERE'S THOSE MODELS AVAILABLE. >> ONE MINUTE PER QUESTION. >> MY NAME IS (INDISCERNIBLE) FROM THE COLUMBIA AGING CENTER. AND ACTUALLY IT FOLLOWS UP NICELY FROM THIS RECENT EXCHANGE. I WAS TRIGGERED ON THE EFFECTS OF PHYSICAL EXERCISE AND I WAS TRIGGED BY COMPARING IT WITH THE WORK THAT WE HAVE DONE AND WE FOUND SIGNIFICANT MODERATIONS DEPENDING ON GENE POLYMORPHISMS IN THE REACTION TO PHYSICAL EXERCISE. MY MORE GENERAL QUESTION LEADS ON TO THAT, ON THE STAGE AND SIGNS OF AGING WHERE WE HAVE A CRUDE -- ACCRUED A LOT OF KNOWLEDGE AND DETAIL AT VARIOUS LEVELS OF THE CAUSAL CHAIN THAT WOULD NOW ALLOW US TO BIND THIS TOGETHER TO A MORE PERSONALIZED VERSION OF AGING BECAUSE IF WE WANT TO TAKE THE NEXT STEP I THINK WE AGREE IT'S NOT ONE SIZE FITS ALL. IF WE DO NOT INVEST IN BUILDING THESE VERY COMPLEX MODELS NOT SURE HOW WE WILL GET THERE. SORRY (INAUDIBLE). >> ANYONE WANT TO COMMENT? >> I THINK IT'S A GREAT POINT AND INTERESTING FROM THE CLINICAL PERSPECTIVE, INDIVIDUALIZED MEDICINE DEVELOP ESTABLISHED PROTOCOLS TO TREAT EVERY CONDITION SO IT HAS TO BE HEALTHY BALANCE IN TERMS OF EXERCISE FEWER NON-RESPONDERS SO WE'RE COMFORTABLE WITH TAKING A BLANKET -- >> I MEAN THE GENE PROTOTYPE IS JUST ONE VARIABLE WE HAD ANXIETY AND EFFECTS OF BIOGRAPHIES, IT'S AN ENDLESS COMPLEXITY I THINK WE NEED TO HAVE AN EYE ON. >> THIS IS (INDISCERNIBLE) UNIVERSITY OF PARIS INSTITUTE. I WOULD GO BACK TO UNIVERSAL MECHANISMS, I PREFER. THE QUESTION TO RICHARD, WORK WITH DRUG RESISTANCE, I REMINDED LINDA BECOME A COUPLE OF YEARS AGO BEFORE GETTING HER PRIZE FOR RECEPTORS WRITING A PAPER ON NATURE ORION PNAS MAYBE, IN WHICH SHE PROPOSED 30% LIFE SPAN ENHANCEMENT OF C ELEGANS, HAVING BEEN TREATED WITH -- WHICH IS A HUMAN ANTIDEPRESSANT, THE TIME IT WASN'T YET ON THE MARKET, HAS BEEN SUBSTITUTED BY ANOTHER MOLECULE WHO IS CALLED (INAUDIBLE). BUT THE MOST IMPORTANT THING IS THAT THIS MOLECULE WAS (INAUDIBLE) WHICH IS USED NOW TO TREAT (INAUDIBLE) SO MY QUESTION IS WOULD YOU ACCEPT TO TRAIN STRESS RESISTANCE AGAINST RELAXATION OR OVER RELAXATION IN (INAUDIBLE)? >> I DON'T THINK WE HAVE GOOD IDEA HOW TO PRIORITIZE THE AMONG SUGGESTIONS FOR DRUGS THAT NEED TO BE TESTED IN MAMMALS FOR LIFE SPAN AND HEALTH IMPROVING CAPABILITIES. THE NIA HAS JUST BEGUN TO FUND WORK IN WORMS SCREENED FOR A VARIETY OF CELLULAR PROPERTIES. WE HOPE AT MICHIGAN TO DO THE SAME THING, WORMS AND FLIES AND CELLULAR STRESS RESISTANCE. OUR HOPE AS IMMUNITY IS CHEAPER SIMPLER SCREENING SYSTEMS DO A GOOD JOB FINDING DRUGS THAT HAVE A BETTER THAN AVERAGE CHANCE AT HAVING BENEFITS TO HEALTH IN MICE AN RATS AND MAYBE PEOPLE. THAT'S MY INTUITION AND I'LL BE HAPPY TO FIND OUT TEN YEARS FROM NOW WHETHER THAT INTUITION IS CONFIRMED BY DATA BUT SO FAR WE DON'T HAVE A GOOD WAY DOING IT BEHIND PROFESSIONAL GUESSES. >> THIS IS MORE A COMMENT FOR YOU, GORDON. SO WHEN YOU HAVE A ALICE IN WONDER LAND MOMENT, RICK NOR,MOTO NORTHWESTERN. ALICE IN WONDER LAND MOMENT BUDAPEST AND YOU WANDERED BETWEEN A MEETING ON STRESS AN HEAT SHOCK, SOME REMEMBER (INDISCERNIBLE) AT INTRAMURAL AT NIA. NOT SURE THIS A STRESS SOME CAN TELL ME SINCE YOU WORK WITH MICE BUT SHE NOTICED NAIVE MICE IN THE SAME ROOM WITH THE OTHER MICE GETTING THEIR HEADS WILL BED OFF WERE ACTIVATING HSV 70 IN THE ADRENAL CORTEX AND VASCULAR ENDOTHELIAL. SHE THEN TEAMS WITH ANOTHER LAB, OURS, IT'S A FULL HEAT SHOCK RESPONSE, FULL ACTIVATION OF HEAT SHOCK FACTOR. SO IF A HOUSE WATCHING ANOTHER MOUSE GETTING ITS HEAD LOCKED OFF IS AN EMOTIONAL STRESS, WE HAVE THE FULL LINK. THAT MOUSE WAS ACTIVATING HEAT SHOCK, CHAPERONES AN VERY SPECIFIC TISSUE PROBABLY TO REMODEL THE VASCULAR ENDOTHELIAL TO ALLOW THAT MASSIVE FLUX OF BLOOD TO GO THROUGH AND SAY GET THE HELL OUT OF HERE. >> I'M JAY SEIGAL, PRIVATE DEMOGRAPHIC CONSULTANT. MY COMMENT IS ADDRESSED TO DR. MILLER AND IT SAID AN INCIDENTAL THING THAT APPEARED TON SCREEN IN ONE OF YOUR COMMENTS RELATING TO THE FACT THAT YOU COULD POTENTIALLY ELIMINATE BOTH HEART DISEASE AND CANCER. SEEMS TO ME GIVEN COMPETING RISKS BETWEEN THESE DISEASES THAT THIS IS AN IMPOSSIBLE DREAM, WHILE YOU MAY HOPE TO REDUCE THESE DISEASES BY SLOWING AGING, THERE HAS TO BE A GRADUAL SLOWING OFF OF THIS UNLESS YOU APSALM MORTALITY. IN FACT WE KNOW IN RECENT DECADES FINALLY THERE HAS BEEN SOME SIGNIFICANT REDUCTION IN CANCER BUT WE NOTICE SIMULTANEOUSLY CARDIOVASCULAR DISEASE, THAT GROUP OF DISEASES SLOWED OFF THAT DESCRIBE. SO JUST A COMMENT. >> THE COMMENT IS THAT -- WAS HYPOTHETICAL SITUATION. THE POINT OF THE SLIDE WAS NOT TO SAY THAT COMPLETE ABOLITION FOR CANCER WAS A LIKELY THING. TO POINT OUT DEMOGRAPHIC IMPLICATION OF ASSUMING THAT NO ONE EVER DIED OF CANCER WAS FAIRLY SMALL COMPARED TO THE AM OF LIFE SPAN EXTENSION ONE GETS IN LABORATORY ANIMALS BY SLOWING THE AGING PROCESS BY DIET OR NOW BY DRUGS OR GENES. JUST A WAY OF TRYING TO POINT OUT THAT INTERVENTIONS IN AGING ARE LIKELY TO HAVE VERY POWERFUL EFFECT ON PUBLIC HEALTH AND WELL BEING BECAUSE IF THEY WORK IN PEOPLE THEY SLOW DOWN MULTIPLE CAUSE OF DISEASE. >> GEORGE MARTIN UNIVERSITY OF WASHINGTON. I WOULD LIKE TO GET SOME FEEDBACK FROM THE PANEL ABOUT -- POTENTIAL ADDITIONAL VARIABLE THAT MIGHT CONTRIBUTE TO THIS INTERESTING HETEROGENEITY OF HUMANS IN TERMS OF REACTION OF STRESS AND VARIOUS ANIMAL MODEL, THAT'S THE MICROBIOME, THE BIGGEST NERVE ENDINGS IN THE GI TRACK ARE TALKING TO THE CENTRAL NERVOUS SYSTEM. THERE WAS A PAPER A YEAR OR TWO AGO FROM CANADIAN GROUP WHERE THEY CHANGEDDED THE MICROBIOME USING SPECIES OF BACTERIA THAT IS QUITE A CAUSE OF WHAT WE EAT IN OUR YOGURT. THEY HAD (INAUDIBLE) FOR ANXIETY AN THESE MICE BECAME VERY LAID BACK EQUIVALENT TO WHAT THEY CAN GIVE WITH THE VALIUM TYPE DRUG. SO HAS INTERESTING IMPLICATIONS LIKE EQUAL TRANSPLANTS FOR EATING A LOT OF YOGURT. SO THAT MIGHT BE ONE POTENTIAL SINCE THERE'S SO MUCH OF THE MICROBIOME SUPPORT CONTRIBUTION WHAT'S GOING ON IN PHENOTYPES, ANY OF YOUR COLLEAGUES INTERESTED IN THAT? DO YOU KNOW IF ANYTHING IS HAPPENING IN THAT AREA? >> ALL OUR COLLEAGUES ARE INTERESTED IN THAT. BUT THE PROBLEM IS ANALYTICAL. 15 YEARS AGO ONE WAS CONFRONTED BY 5,000 GENE CHANGES AND IT TAKES BIOINFORMATICS A WHILE TO MAKE SENSE. MANY LABORATORIES PRODUCE THIS AS BACTERIAL SPECIES AN E VALUE WAIT CORRELATION WITH DIETARY OTHER OUTPUTS GETTING MEANING OUT OF THAT FINDING CORRELATIONS THAT ARE ROBUST ACROSS DIFFERENT ENVIRONMENTS, DIFFERENT STRAINS OF MICE, DIETARY CHANGES. I THINK IT'S VERY IMPORTANT BUT I DON'T THINK IT'S SOMETHING THAT'S CURRENTLY ROUTINE. >> PERHAPS YOU CAN LOOK AT ONE MICROBE AT A TIME. LAST QUESTION. >> JOE (INAUDIBLE) FROM HEALTH EXTENSION IN CALIFORNIA, SO I SPENT YESTERDAY LABORATORY ANIMAL CONFERENCE DOWN THE ROAD AND GOT A LOOK ALSO LOOKING AT A NUMBER OF VARIOUS RESEARCH FACILITIES TO LEARN MORE ABOUT MAMMAL STUDIES IN PARTICULAR. THIS IS A QUESTION ABOUT THE RELATIONSHIP BETWEEN USING MAMMALS AND STRESS STUDIES SO FANTASTIC TALK YESTERDAY BY JOE GARNER AT STANFORD WHO ARGUED QUITE PERSUASIVELY THE PRESENT MODE OF STUDIES FOR RODENTS ARE PRETTY MUCH ALL STRESSED. AND IN PARTICULAR HE POINTED TO A STUDY, A NUMBER OF STUDIES HE WAS POINTING TO, ONE WHERE ANIMALS HAD ADDED TO THE NORMAL STANDARD OF CARE THAT IS PREVALENT ACROSS THE INDUSTRY USEFUL ENRICHMENT IN THE ANIMAL WORLD THEY CALL IT. THEY HAD MASSIVELY DIFFERENT FIZZ QUO LOGICAL OUTCOMES, IN THIS PARTICULAR CASE LOOKING AT A BUNCH OF CANCERS AND THIS IS NOT JUST ONE SPECIFIC MODEL. SUPER VULNERABLE BUT A GENERAL STUDY. THEY HAD A LOT OF INCREASEDRY SUSTAINS TO THESE DISEASES. SO I'M WONDERING HAS ANYBODY DONE ANY LIFE SPAN STUDIES IN RODENTS COMPARING NORMAL STANDARD OF CARE AND EXTREMELY ENRICHED, NOT WHERE YOU DROP IN EGG CARTON BUT YOU HAVE THINGS MEANINGFUL TO THE RODENT? >> I THINK THE IDEA AS TO WHETHER ANTI-AGING MANIPULATIONS ARE ROBUST ACROSS STAGES AN ENVIRONMENT AND DIET AND PSYCHOLOGICAL SITUATION VERY IMPORTANT MY OWN INTUITION IS STRONGEST THINGS WILL PROVE TO WORK QUITE WELL REGARDLESS OF THAT. JIM NELSON HAS DONE A NICE STUDY HE TOOK NICE GROUP HOUSED WHICH I COMPARED -- FOR MOUSE SEX TREATMENTLY STRESSFUL AND GOT DIFFERENTS IN WEIGHT AND DIFFERENCES IN FOOT CONSUMPTION BUT THE CALORIC RESTRICTION REGIME WORKED QUITE WELL TO EXTEND LIFE SPAN IN CIRCUMSTANCES. SIMILARLY FOR DWARF MICE WHEN THEY'RE GROUP HOUSED OR HOUSED WITH BIG MICE OR SMALL MICE. SO THE GENERAL POINT ENVIRONMENTAL CHANGES COULD MODIFY THE EFFECTS OF ANTI-AGING MANEUVERS IS PERFECTLY VALID BUT SO FAR THE BIG STRONG ONES ARE RHESUS TAN EVALUATING FROM THAT PERSPECTIVE TO ANY PERTURBATIONS. >> THAT'S SAYING IF YOU START WITH GROUP HOUSE MICE AND MAKE THEM EVEN MORE STRESSED BY PUTTING THEM SINGLY HOUSED THAT DOESN'T MAKE THAT MUCH DIFFERENCE BUT DOESN'T NECESSARILY ADDRESS THE POSSIBILITY OF MAKING THEM COMFORTABLE. >> I WAS AGREEING WITH YOU. >> THANK YOU. [LAUGHTER] >> REALLY QUICK COMMENT THAT IT'S -- WE CLEARLY NEED MORE MONEY AND FUNDS TO STUDY MECHANISMS IN ISOLATION IN CONTROL CONDITIONS AN MODEL ORGANISMS BUT WE'RE NEVER GOING TO UNDERSTAND AGEING IF WE DON'T ALSO IN PARALLEL REMEMBER THERE'S A BRAIN ATTACHED, THAT THE BRAIN AND BODY ARE NOT SEPARATE. SO I MEAN, YOU HAVE EXAMPLE OF THE MICROBIOME BUT THERE'S TREMENDOUS EXAMPLES INFLAMMATION ALSO CAUSES DEPRESSION OF THE BIDIRECTIONALTY THAT THIS IS THE CENTRAL REGULARLYTOR IN HUMANS IS GOING TO CONTROL NOT DIRECT STRESS RESPONSE THAT WE HAVE BEEN TALKING ABOUT BUT BEHAVIOR. SO HUMAN AGING IN EPIDEMIOLOGICAL STUDIES IS REALLY NICE TO THINK WE CAN DO CALORIC RESTRICTION BUT PEOPLE ARE THAT WOULD MEAN WE CONTEND WITH BEHAVIOR AND WE KNOW THAT BEHAVIOR CHANGE IS ONE O OUR BIGGEST CHALLENGES TO PUBLIC HEALTH AND GETTING PEOPLE TO FOR EXAMPLE NOT DO STRESS EATING OF COMFORT FOOD WHICH CAUSES A TREMENDOUS AMOUNT OF METABOLIC SYNDROMES THAT WE HAVE. SO POINT IS YOU CAN BRING STRESS MODELS TO RODENT STUDIES LIKE YOU JUST READ A RHODEN JUNK FOOD YOU SEE NO EFFECT IN THREE WEEKS ON METABOLIC SYNDROME, IF YOU ADD STRESS YOU HAVE A FULL BLOWN METABOLIC SYNDROME. SO IT'S IMPORTANT TO LOOK AT INTERACTIONS WHEN POSSIBLE. WHEN IT COMES DOWN TO USING EPINEPHRINE AND BIOLOGICAL STRESS TO HELP US UNDERSTAND WHAT'S HAPPENING. THAT MAKES THOSE MODELS MORE RELEVANT TO THE HUMAN CONDITION. >> THANKS FOR YOUR QUESTIONS AND YOUR COMMENTS. [APPLAUSE] >> I WANT TO SAY ONE OF THE GREAT PLEASURES OF BEING A FEDERAL EMPLOYEE AT NIH EMPLOYEE IS YOU GET TO INVITE REALLY BRILLIANT THINKERS AND SCIENTISTS AND COME AND SPEAK AND THEY ALL AGREE EVEN IF IT MEANS LEAVING COSTUMES AT HOME AND WE KNOW FROM DR. -- Q. GRETCHEN'S WORK THE MICE ARE PLAYING WHILE WE'RE HERE WORKING. SO WE THANK THEM FOR THAT AND FOR YOUR APPLAUSE FOR A WONDERFUL -- OUR WONDERFUL CHAIRS FOR THIS PARTICULAR SESSION, TERRIFIC PANELISTS AND YOU FOR PARTICIPATING IN THIS AND I WOULD ASK YOU THAT WE'RE GOING TO TAKE A BREAK NOW BUT AS MANY OF THE QUESTIONS HAVE COME UP TO THE NEXT THING IS WE'RE GOING TO START VERY PROMPTLY OUR EPIGENETICS AND REGULATORY RNA SESSION VERY PROMPTLY, THAT WILL BEGIN AT 3:15 SO THANK FOR THIS OUTSTANDING PANEL. SEE YOU AT 3:15. MY NAME IS JOHN BURCH FROM THE CENTER FOR SCIENTIFIC REVIEW AT NIH. MY CO ORGANIZER FOR THIS SESSION IS KEVIN HOCROFT WHO YOU MET THIS MORNING, HE'S ALSO A MAIN ORGANIZER FROM THE NATIONAL CARE INSTITUTE. WE BOTH -- CANCER INSTITUTE AND WE'RE BOTH MEMBERS OF THE GEROSCIENTIST GROUP. OUR CO-SHARES ON EPIGENETICS AN REGULATORY RNA ARE SHELLEY BERGER AND ANN BRUNET. DR. BERGER IS IN THE DEPARTMENT OF CELL AND DEVELOPMENTAL BIOLOGY AT THE PEARLMAN SCHOOL OF MEDICINE UNIVERSITY OF PENNSYLVANIA. SHE WILL GIVE AN INTRODUCTORY OVERVIEW OF THE TOPIC FOR THIS SESSION. DR. BRUNET IS ASSOCIATE PROFESSOR DEPARTMENT OF GENETICS AT STANFORD UNIVERSITY AND SHE WILL BE DIRECTING THE DISCUSSION WHICH WILL FOLLOW THE LAST SPEAKER. SHE ALSO WILL BE GIVING A SUMMARY OF THE SESSION. SO WITHOUT FURTHER ADIEU, SHELLEY, PLEASE. >> OKAY. SO THAT'S ME. SHELLEY BERGER. PLEASED TO BE HERE, THANKS VERY MUCH FOR INCLUDING A SECTION ON EPIWREN TICK IN THE MEETING. ON BEHALF OF THE ANN BRUNER AND MYSELF WE WANT TO WELCOME YOU TO SESSION 4. I WANT TO POINT OUT BRIAN BROUGHT THIS UP EARLIER, AGING IS ENDLESSLY FASCINATING TO HUMANS, ALL THROUGH HISTORY, LEONARDO DA VINCI DEPICTED AN AGING COURSE IN HUMANS. DRAWING. SO WHY DO WE BELIEVE IN SPEAKERS IN THIS SESSION, WHY DO WE BELIEVE EPIGENETICS HAS A BASIS IN AGE RELATED DISEASE? MUCH AS THE OTHER SPEAKERS HAVE DISCUSSED, ALL OF OUR SLIDES ARE PRETTY MUCH WHAT YOU HAVE SEEN THROUGH THE COURSE OF THE DAY, BUT WE'RE GOING TO DISCUSS IT FROM REVIEW OF EPIGENETICS AND CHROMATIN BIOLOGY. SO THERE'S TWO REASONS, IF WE LOOK AT AGING AND DISEASE IN HUMANS. ONE IS THERE IS THIS VERY PROFOUND ASSOCIATION OF HUMAN DETEE YOUR RATION DISEASE WITH AGE. THIS BIFURCATION AT MID LIFE. AND THE SECOND REASON DISCUSSED EARLIER TODAY IS THAT THE EXPECTED LIFE SPAN OF HUMANS HAS INCREASED TWOFOLD IN OVER THE LAST CENTURY. THESE SORTS -- THIS SORT OF PLASTICITY OF -- STRONGLY SUGGESTS THAT AGING AND AGING RELATE DISEASE CUB DUE IN PART TO EPIGENETIC ALTERATIONS. SO THIS IS THE BASIS OF THE QUESTIONS AND DISCUSSION THAT WE'RE GOING TO HAVE IN THE NEXT COUPLE OF HOURS. SO OUR POINT OF VIEW, OF COURSE YOU ALREADY HEARD A LOT OF EPIGENETIC ISSUES HAVING TO DO WITH EPIGENETICS ALREADY AS THE DAY HAS GONE ON THERE ARE MANY EPIGENERAL TECH REGULATORS. WHAT WE'RE INTERESTED IN ARE EPIGENETIC REGULATORS AT THE LEVEL OF CHROMATIN, AT THE LEVEL OF THE PACKAGING OF THE GENOME INTO THIS POLYMER OF HISTONES PLUS DNA. THE FIELD AS A WHOLE, CHROMATIN FIELD IN THE EPINETIC FIELD IS VERY INTERESTED IN THIS ISSUE THAT YOU SEE HERE REALLY EVERYTHING CAN BE REDUCED TO THIS ISSUE OF THE INTERCONVERGE OF REPRESSED CLOSED CHROMATIN, OPEN ACTIVE CHROMATIN OVER OUR GENOMES. THE ASPECTS THAT WE'RE GOING TO DISCUSS TODAY THEN ARE THREE TYPES OF REGULATORY MECHANISMS THAT ARE EPIGENETIC WORKING AT THE LEVEL OF CHROMATIN. ONE IS TRANSCRIPTION FACTOR NETWORKS, THE SECOND IS DNA AND HISTONE MODIFICATION AND THIRD NON-CODING RNAs SO YOU SEE OVER NEXT FIVE TALKS ASPECTS OF EACH OF THESE REGULATORY MECHANISMS. NOW, WHAT THE VIEW IS -- ONE OF THE VIEWS ONE THAT ACTUALLY MY LAB IS -- FAVORS AND OTHERS IN THE FIELD IS THAT YOUNG CELLS, PARTS OF THE GENOME THAT HAVE TO BE CHROMATIC ARE IN THAT STATE IN YOUNG CELLS, PARTICULAR I REPETITIVE AREAS TELOMERES AND OTHER AREAS OF THE GENOME, THROUGH THE COURSE OF AGING THE CHROMATIN BEGINS TO OPEN, AREAS OF THE CHROMATIN THAT ARE NOT SUPPOSEDDED TO BE OPEN BECOME OPEN. THIS THEN LEADS TO VARIOUS EVENTS THAT ARE NOT GOOD, MUTATIONS AND ALSO TRANSCRIPTION THAT OCCURS IN AN UP REGULATION OF TRANSCRIPTION. SO JUST AS OTHERS HAVE DISCUSSED OVER THE COURSE OF THE DAY, THESE EVENTS CAN BE MODELED IN YEAST SACRO MYSEIZE CEREVISIAE BUDDING YEAST AND TO HUMANS THEMSELVES OF COURSE. WHY DO WE THINK, WHAT ARE EXPLANATIONS, MOLECULAR EXPLANATIONS THAT SUGGEST HUMANS -- EPIGENETIC CHANGES OCCUR WITH HUMAN AGING? SO THE STUDIES IN MONOZYGOTIC TWINS FROM YOUNG TWINS TO OLD TWINS HAVE SHOWN AT LEVEL OF DNA METHYLATION, THAT YOUNG TWINS, 3-YEAR-OLD TWINS WHEN YOU LOOK AT THEIR DNA METHYLATION, USING THIS DEPICTION YOU SEE IT'S ALL YELLOW, THE TWO TWINS HAVE A GREAT CONCORDANCE IN THEIR DNA METHYLATION PROFILES OVER THESE CHROMOSOME REGIONS. HOWEVER, AS MONOZYGOTIC TWINS AGE YOU CAN SEE THE GREEN AND RED FEATURES THAT THERE'S A DIVERGENCE OF DNA METHYLATION SIGNATURES ACROSS THE ENTIRE GENOME. SO THAT, THESE -- THIS AND MUST HAVE MORE EVIDENCE YOU'RE ABOUT TO SEE SUGGESTS THAT BOTH GENETIC AND NON-GENETIC FACTORS ARE INVOLVED IN AGING AND IN FACT THAT THE PACE OF AGING CAN BE DETERMINED BY THESE NON-GENETIC FACTORS. LEADING TO THIS QUESTION, PERHAPS EPIGENETIC MODIFICATIONS THAT AFFECT CHROMATIN STATES MEDIATE THE SLOWING AND REVERSE -- COULD MEDIAD SLOWING AND REVERSIBILITY OF AGING, INDEED MANY MOLECULES THAT SPEAKERS YOU'RE GOING TO HEAR TODAY THIS AFTERNOON ARE FOCUSED ON ARE ENZYMES THAT REGULATE THESE PATHWAYS AND ENZYMES OF COURSE ARE WONDERFUL POTENTIAL DRUGGABLE TARGETS SO THAT LEADS TO A GREAT FASCINATION WITH THIS AREA. EXTREME EXAMPLE LONGEVITY CORRELATING WITH EPIGENETICS IS IN THE SOCIAL ANIMALS THE NAKED MOLE RAT WAS SHOWN EARLIER, AND SOCIAL INSERTS ARE OTHER EXAMPLES OF REMARKABLE PLASTICITY OF THE EPIGENOME WITH RESPECT TO LONGEVITY. WORKERS FEMALE L IN SOCIAL INSECTS ARE WORKERS OR QUEEN. AND THE WORKERS HAVE A SHORTER LIFE SPAN, QUEEN IS LONGER LIFE SPAN. IF YOU WONDER ABOUT MALES THEY HAVE A TINY LIFE SPAN. THEY DON'T CARRY OUT ANY OF THE WORK, GO FIGURE. SO THE REMARKABLE THING IS THAT IN THE SOCIAL INSECTS ONE OF THE SPECIESES THAT WE STUDY IN MY LABORATORY, YOU CAN INTERCONVERT A WORKER INTO A QUEEN AND THIS SHORTER -- THIS SHORTER LIFE SPAN OF THE WORKER IS AN EPIGENETICALLY INHERITED AS THE WORKER OF -- BECOMES REPRODUCTIVE AND TAKES ON THE ROLE OF THE QUEEN. ALL RIGHT. SO FINALLY, AGAIN, A SLIDE YOU HAVE SEEN OVER AN OVER AGAIN, THIS -- THE DITEAR RESTRICTION DELAYS THAT RESULT IN EXTENSION OF LIFE SPAN IN MANY OF THE MODEL ORGANISMS THAT WE HAVE BEEN DISCUSSING TODAY. KEY POINT IN THIS SESSION IS SOME OF THE KEY GENETIC REGULATORS OF DIETARY -- THAT AFFECT DIETARY RESTRICTION ARE EPIGENETIC REGULATORS SO YOU'LL HEAR ABOUT THAT TODAY, AGAIN THIS EVENING. SO OUR PANELISTS THIS AFTERNOON ARE DAVID SINCLAIR FROM HARVARD, WHO WILL TALK EPIGENETIC CHANGES DURING AGING AND METABOLIC DISEASES AND CAN THESE -- ARE THESE PREVENTABLE? STEWART KIM FROM STANFORD WILL TALK ABOUT EPIGENETIC CLOCK TO DETERMINE RATE OF AGING. LEEWAY SI FROM MIT WILL TALK COGNITIVE AGING AND NEURODEGENERATION. PETER ADAMS CAME FROM SCOTLAND FOR US, HE'S GOING TO DISCUSS AGE DEPENDENT COURTROOM TIN CHANGES CAUSING THE -- COULD THEY BE AT THE ROOT OF THE AGE DEPENDENCY OF CANCER AND JUAN CARLOS BELMONTE WILL TALK CELLULAR MODELS FOR PREMATURE AGING, DO THEY PROVIDE A BASIS FOR A CURE. SO WITH NO FURTHER DELAY, AGE DEPENDENT DELAY WE'LL GO ON TO OUR FIRST SPEAKER, DAVID. [APPLAUSE] >> OKAY. THANKS, SHELLEY. IS THIS MIC WORKING OKAY? >> HELLO. THERE WE GO. GREAT. THANK YOU, SHELLEY FOR INTRODUCING A SESSION AND FOR INVITING ME. THANKS PHILIPPE AND EVERYONE ELSE FOR MAKING THIS POSSIBLE POSSIBLE. THIS IS ONE OF MOST INTERESTING AND BROAD MEETINGS, I THINK YOU'LL AGREE THIS IS A LAND MARK MEETING, I'M GRATEFUL TO BE PART OF IT. THANKS AGAIN. WHAT I WANT TO WANT TO DO IN THE SHORT TIME IS HAVE TWO PARTS OF THE TALK. FIRST IS ABOUT NEW IDEAS IN THE EPIGENETIC REGULATION OF AGING THAT WOULD BE INTERESTING TO TELL YOU ABOUT, THE SECOND HALF IS ABOUT SMALL MOLECULES THAT MODULATE EPIGENETIC SYSTEMS IN ANIMALS AND END WITH PROMISING BUT PRELIMINARY DATA IN HUMAN STUDIES TOWARDS THE ULTIMATE GOAL WE HAVE HEARD ABOUT TODAY USING THE KNOWLEDGE ABOUT AGING AND DEFENSES AND HERMYSIS TO HAVE IMPACT ON SOCIETY AND GET US TOWARDS THAT FUTURE, THAT ORIGINAL HELD OUT AS A PROMISED LISTENED TO US. I'M HOPING IF WE GO QUICKLY WE WON'T HAVE TO WAIT MORE THAN 100 YEARS TO SEE THAT. THAT WOULD BE TOO LATE FOR EVERYONE IN THIS ROOM UNFORTUNATELY. SO WHAT I WANT TO GET INTO REALLY IS FIRST PART, AN IDEA THAT'S BUILT ON MANY YEARS OF OBSERVATION BUT I THINK FINALLY COMING TOGETHER TO GIVE US A UNITED THEORY HOW EPIGENETICS AND AGING COME TOGETHER. WHEN BRIAN KENNEDY GAVE A TALK THIS MORNING, I POINTED OUT THERE ARE THREE MAJOR AREAS OF MECHANISMS OF AGING, HE GROUPED TO DNA DAMAGE, EPIGENETIC REGULATION AND WHAT HE TURNED ANTAGONISTIC PLY OWE TROUGH BY WHICH IS SENESCENCE CELLS AND INFLAMMATION. WHAT I LIKED ABOUT THE SLIDE IS THE SET UP FOR WHAT I'M ABOUT TO TELL YOU, A NEW IDEA THAT MAY UNITE ALL THREE OF THOSE AREAS. NOW WHERE THIS STARTED, REALLY FOR ME, REMARKABLE PUBLICATION CAME FROM A YANK IN THE LAB, A NEIGHBOR FROM HARVARD MED SCHOOL PUT OUT PAPER THAT SHOWED IN THE AGING BRAIN YOU CAN SEE THAT THERE AS YOU GO THROUGH AGING, AGES OF PEOPLE WHO DONATED BRAINS OF SCIENCE, FAIRLY PREDICTABLE CHANGES THAT OCCUR DURING AGING. THIS IS A BRAIN BUT WE KNOW FROM OTHER PEOPLE'S WORK AS WELL THAT IT'S TRUE FOR OTHER ORGANS. SO WE KNOW FOR SURE THAT THERE IS A GENE EXPRESSION CHANGES TO AGING. QUESTION IS, DO WE HAVE ANYTHING TO DO WITH AGE SOMETHING AND IF SO CAN WE DO SOMETHING ABOUT IT. THE THREE QUESTIONS TO ADDRESS IN THIS TALK ARE THE FOLLOWING. WHY DO THESE GENE EXPRESSION CHANGES HAPPEN IN THE FIRST PLACE? DO THEY UNDERLIE ASPECTS OF AGING,? ARE THEY FUNDAMENTAL OR JUST ASSOCIATED EVENT? IF SO, ARE THEY REVERSIBLE? AND I THINK THE TERM REVERSIBLE IS WORTH EMPHASIZING HERE BECAUSE UNLIKE MUTATIONS WHICH ARGUABLY ARE EXTREMELY DIFFICULT TO REVERSE WHAT WE'RE TALKING ABOUT HERE IF EPIGENETICS TAKES OFF IN THE WAY IT SEEMS TO BE IT OFFERS A WONDERFUL CHANCE TO INTERVENE IN AGING, NOT JUST SLOW DOWN THIS PROCESS BUT ACTUALLY RAPIDLY REVERSE IT AND WHAT I HOPE TO TELL YOU PART OF THE TALK IS THAT YOU -- ONCE YOU UNDERSTAND ASPECT OF WHAT'S GOING ON AT THE CELLULAR LEVEL AND MOLECULAR LEVEL YOU CAN'T RAPIDLY REVERSE AGING, DOESN'T SEEM TO BE THAT DIFFICULT AT LEAST ASPECT OF AGING. WE'RE NOT GOING TO HAVE OLD PEOPLE SUDDENLY LOOK 20 YEARS OLD BUT I THINK THAT CERTAIN ASPECTS SUCH AS MET BOLL UK AGING DIABETES ARE RAPIDLY REVERSIBLE ANIMAL MODELS SO FAR. SO THIS IS THE IDEA THAT I WANT TO PUT FORWARD, BASED ON MANY PEOPLE'S WORK AND ORIGINALLY PUT FORWARD IN PART IN A THEORY CALLED THE HETERO CHROMATIN HYPOTHESIS OF AGING. THE IDEA IS THAT WHEN WE'RE YOUNG, WHEN ORGANISMS ARE YOUNG WITH EPIGENETIC PROFILE, AN GENE EXPRESSION PROFILE THAT IS USEFUL, THIS FUNCTIONS VERY WELL, THIS IS OPTIMAL, MICRORNA THAT COULD BE PROTEIN CODING GENES, THEY CAN BROADCAST BE NON-CODING COMPETITIVE GENES THAT REACH STABILIZATION. WHAT THE EVIDENCE IS POINTING TO MORE AND MORE, YOU'LL HEAR MORE ABOUT THIS TODAY IS WHAT'S GOING ON IS A RESHUFFLING OF EPIGENETIC REGULATORS ACROSS THE GENOME AS WE AGE. FOR INSTANCE I'M SHOWING YOU HDAC NERD COMPLEX HERE THAT ARE KNOWN TO REDISTRIBUTE DURING AGING. THE FIRST CLUES TO THIS CAME FROM YEAST. BRIAN KENNEDY MENTIONED WHEN WE'RE WORKING ON YEAST THAT MANY YEARS AGO AT THE TIME THE IDEA WAS THE DNA DAMAGE WAS THE MAJOR CAUSE OF AGING, SO WHEN BRIAN AND OTHERS WERE LOOKING FOR GENES THAT REGULATED AGING IN YEAST CELLS WE'RE EXPECTING TO FIND A DNA REPAIR FACTOR, WHAT POPPED OUT WAS THE SERTUIN FAMILY, THEY SHOWED WERE INVOLVED IN EPIGENETIC REGULATION. THIS WAS A REMARKABLE BREAK THROUGH AND WE FINE OURSELVES TODAY STILL STUDYING THIS POSSIBILITY IN MAMMALS. WHAT I WANT TO ADD TO THAT HYPOTHESIS THAT SEEMS TO BE CONFIRMED THE LAST FEW YEARS, IS THESE FACTORS ARE REDISTRIBUTING IN RESPONSE TO DNA DOUBLE STRAND BREAKS. WE AND OTHERS FOUND THAT A SINGLE DNA BREAK IN A CHROMOSOME IN A YEAST OR MAMMALIAN CELL CAUSES A LARGE RESHUFFLING OF CHROMATIN FACTORS INCLUDING SERT 1 AND 6 AND PUBLISHED WORK ON HDAC 1 AS WELL. SO WHAT WE THINK IS GOING ON PERHAPS AS WE GET OLDER THAT WE ARE ACCUMULATING MORE AN MORE DNA BREAKS AND THE CELL OVERCOMPENSATING TRYING TO REPAIR THEM AND THE RESET BUTTON BACK TO ORIGINAL STATE IS DEFECTIVE, COULD BE CHROMATIN LEAVES SCARS AND WE'LL HEAR LATER ABOUT THESE, EASIER THAN MANY OTHERS HAVE NOW SHOWN THERE ARE SCARS LEFT ON CHROMOSOMES AFTER DNA DAMAGE. WHAT WE ALSO ARE VERY INTERESTED IN IS HOW WE CAN PREINVENTORY THEM FROM OVERCOMPENSATING. WHEN I SAY OVERCOMPENSATING YOU MIGHT SAY WHY ARE YOU CALLING OVERCOMPENSATING? THE IDEA IS THAT -- THIS GETS TO THE THINK PART, ANTAGONISTIC PLEOTROPHY IS HELPFUL WHEN YOU HAVE DNA DAMAGE THEY MOVE FROM TRANSCRIPTION SITES HERE AND GO AND ALTER THE CHROME TIP, THEY HELP REPAIR THEN BOOK WHERE THEY CAME FROM. THE REASON THE CELL DOES THIS IS THESE FACTORS ARE INVOLVED IN BOTH PROCESSES, IT'S IMPORTANT TO UNRUFFLE CHROMATIN AN CHANGE TRANSCRIPTION IN THIS AREA. BUT ALSO ON YEAST WORK THE GENES THAT ARE D REPRESSED DURING THIS PROCESS ARE TYPICALLY INVOLVED IN DNA REPAIR APPROXIMATE STRESS RESPONSE SO WHAT WE THINK IS THAT THIS IS A SHORT TERM TRANSIENT PROCESS IN A YOUNG ANIMAL, YOUNG CELL, AND THAT THE GENE EXPRESSION THAT COMES ON IS HELPFUL IN THE SHORE TERM. BUT AS YOU GET OLDER THIS PROGRAM BECOMES CHRONICALLY ACTIVATED SO HAVING A LIVER GENOME IN YOUR BRAIN WHICH WE SEE IS PROBABLY NOT A GOOD THING. SO ONE THING WE HAVE BEEN WORKING ON WHICH I'LL TELL YOU ABOUT IS TRYING THE ACTIVATE AND MODULATE FACTORS TO SEE IF WE CAN DELAY THE PROCESS OF AGING OR ACCELERATE IT. POSSIBLY REVERSE THE AGING PROCESS. SO ONE OTHER THING I WANTED TO MENTION, AN EMERGING IDEA IN THE FIELD, THIS COMES FROM LARGE AM OF WORK NOW MOSTLY C ELEGANS IS THE ROLE OF MITOCHONDRIA IN AGING. AND THE ABILITY OF MITOCHONDRIA TO CONTROL THE SECRETION OF LONGEVITY FACTORS WHAT'S ALSO INTERESTING IN EPIGENETIC REGULATION IS THERE'S ONE IDEA THAT HOLDS SOME WAY THAT IS PERHAPS AS WE GET OLDER THE TWO GENOMES IN OUR CELLS, THE NUCLEAR AND MITOCHONDRIAL GENOMES DON'T COMMUNICATE AS WELL AS THEY SHOULD. IT'S LIKE A NEWLY MARRIED COUPLE, WHEN YOU'RE YOUNG YOU'RE COMMUNICATING REALLY WELL AND BY THE END OF THE RELATIONSHIP YOU'RE NOT TALKING TO EACH OTHER VERY MUCH, I'M NOT TALKING FROM EXPERIENCE AT LEAST NOT YET. BUT IN A CELL THIS SEEMS TO BE HAPPENING. WHAT WE AND OTHERS ARE SEEING IS THAT IN ALL MUSCLE, IN MICE AS A GOOD EXAMPLE, THE ABILITY OF THIS PROTEIN TO COMMUNICATE WITH THE MITOCHONDRIAL GENOME THESE CIRCLES GOES DOWN BUT THE GOOD NEWS IS THAT ONCE YOU UNDERSTAND WHAT'S GOING ON HERE YOU CAN REVERSE WITHIN A COUPLE OF DAYS SO YOU CAN TAKE A TWO-YEAR-OLD MOUSE PHYSIOLOGY BACK THE SIX MONTH OLD RAPIDLY. THE IDEA IS PERHAPS TO FIND MOLECULES THAT COULD DELAY OR REVERSE THIS. , 31 WHICH I'LL TALK ABOUT IN THE LAST FEW SLIDES SEEMS TO BE INVOLVED THIS THIS PROCESS AND WE'RE GOING TO TARGET WITH SMALL MOLECULES AND SEE IF WE CAN DELAY OR REVERSE DISEASE OF AGING. SOME SAW MY SLIDES AND ASKED ME WHAT THE HECK IS THIS? THIS IS A MOLD AT PRODUCES ENZYME CALLED PPO-1, A DNA RESTRICTION ENZYME THAT CUTS RARELY IN MA NAILIAN GENOMES. IN THE MOUSE PREDICTED TO CUT ABOUT 15 TIMES. SO WHAT WE HAVE DONE IS CROSSED THIS MODEL WITH A MOUSE, SO WE HAVE THE ABILITY TO INDUCE CUTTING RARE CUTTING IN THE GENOME AT NON-CODING REGIONS AND ASK IS THIS HYPOTHESIS THAT DNA CAUSES CAUSES REDISTRIBUTION AND CHANGES DURING AGE AGING. IS THAT THE STRIGGER? AND SECOND QUESTION, IS IT A CAUSE OF AGING? AND IF IF NOTHING HAPPENS, MY HYPOTHESIS MIGHT NOT BE CORRECT. IF SOMETHING HAPPENS THE MICE WILL GET PREMATURELY OLE THEN WE HAVE SOMETHING TO STUDY SO WE DID THAT AND P CAN INDUCE WITH THE DRUG FOR DAYS OR WEEKS AND HOW LONG WE INDUCE THE CUTS WE GOAD GET STRONGER AND STRONGER AGING PHENOTYPE WHICH THIS IS THE FIRST SNAP SHOT ON iPHONE, SO THAT'S THE MOUSE. WHAT I WANT TO SHOW YOU THIS IS EVIDENCE THAT EPIGENERAL IT CAN CHANGES ARE UNDERLYING THE AGING PROCESS THOUGH WE NEED TO CHARACTERIZE THE MOUSE. SO IN THE LAST MINUTE I'LL TELL YOU ABOUT -- SORRY. SO THESE ARE MOLECULES THAT ACTIVATE CERTAIN ONES. IF YOU GIVE THEM TO A HUMAN DISEASE WE CAN TREAT DISEASE CALLED PSORIASIS, YOU CAN SEE THIS PATIENT RESPONDED WELL AND SO THIS ACTIVATE MOLECULE WORKS EFFECTIVELY IN THE MOUSE. AND THIS IS IN MOUSE STUDIES FOR LONGEVITY AND RESULTS LOOK PROMISING. THANKS FOR HAVING MAINE [APPLAUSE] STEWART KIM FROM STANFORD UNIVERSITY HE WORKS IN C ELEGANCE AN HUMANS AND INTERESTED IN TRANSCRIPTIONAL NETWORKS AND HOW THEY MODIFY GENE EXPRESSION CHANGES DURING THE AGING PROCESS IN BOTH ORGANISMS. STEWART. >> THANK YOU, ANN, SHELLEY FORGIVING ME THIS PRIVILEGE TO COME TALK TO YOU TODAY AND ORGANIZE, THIS HAS BEEN FANTASTIC AND INSPIRING. SO I'LL TALK TO YOU ABOUT EPIWREN TICK CLOCK THAT MAYBE WORKING IN WORMS AND IN PEOPLE. HERE IS THE IDEA. WE'D LIKE TO KNOW WHAT IS CAUSING THIS. SO HERE IS US AGING ABOUT 60 YEARS AND HERE IS A WORM AGING IN TWO WEEKS. TELL YOU FIRST A STORY HERE THEN HERE AND THE IDEA IS TO FIGURE WHAT'S DIFFERENT BETWEEN THESE TWO STATES AND FIGURE OUT WHAT CAUSES THOSE DIFFERENCES. AND I CAME FROM THE FIELD OF GENOMICS IN SYSTEMS BIOLOGY BUT I THINK MAYBE POSSIBLE IS TO TRY TO DEFINE AT MOLECULAR LEVEL WHAT IS DEVIL BETWEEN YOUNG AND OLD AND RIGHT NOW USING RNAs AND WE'RE DEFINED 1200 OR SO RNAs OF CHANGE. I CAN TELL YOU THAT WAS ALSO LOOKING AT PROTEINS THAT ARE DIFFERENT BETWEEN YOUNG AND OLD. TURN OVER RATES BETWEEN EVERY PROTEIN YOUNG AN OLD. GORDON AND CYNTHIA KIN I DON'T KNOW'S LAB ARE LOOK AT PROTEINS AGGREGATING BETWEEN YOUNG AND OLD AND WHAT'S DIFFERENCE FROM THE YOUNG STATE AT MOLECULAR LEVEL, NEXT STEP TO FIGURE WHY DOES THAT HAPPEN. WHAT ARE THE UPSTREAM REGULARLYTORS THAT CAUSE GENES TO START HERE AND THESE GENES TO GO DOWN AND THESE UP. SO THE APPROACH WE TOOK WAS TO USE DATA FROM THE CODE PROJECT. MY LAB WAS ONE THAT PARTICIPATED IN THE MODERN CO-PROJECT. WE SCREENED TRANSCRIPTION FACTORS FOR CHIP SEEK AND MY LAB TOOK AND LOOK AT TRANSCRIPTION FACTORS THAT TEND TO BIND TO AGE REGULATED GENES, THE TRANSCRIPTION FACTOR THIS BINDS THE THAT COULD BE A REGULATOR. THAT'S HOW WE GOT TO THIS GENE. SO THIS SLIDE IS WRONG. BUT L-2 STARTS OFF HIGH IF THE GADA TRANSCRIPTION FACTORS STARTS OFF HIGH, IT BINDS TO THE GENES AND THEN GOES LOW AS THE WORM GETS OLDER, AS IT GOES LOWER IT'S CAUSING THESE GENES TO TURN OFF, THAT'S CAUSING ONE TO GET OLDER. ONE THING THAT IS SURPRISING FROM THESE RESULTS IS A (INAUDIBLE) FAMOUS GENE BECAUSE OF DEVELOPMENTAL ROLES. THIS IS THE MASTER REGULATOR OF INTESTINAL FUNCTION SO WHAT THIS WAS REALLY QUITE SURPRISING TO US BECAUSE ALREADY BY MIDDLE AGE, THE WORM IS VERY LOW LEVELS OF THIS MASTER REGULATOR FOR P INTESTINAL FUNCTION, THIS MADE NO SENSE. THIS WORM THEN BEFORE THIS OVERT SIGN OF DAMAGE IS DOOMED BECAUSE INTESTIN IS REPROGRAMMED. IT'S LOSING HE CAN PRESENTATION OF THE NECESSARY INTESTINAL GENES, ACTUALLY TURNING ON NEURONAL GENES SO IN THE WORM SOMETHING BIZARRE IS HAPPENING, IS THAT THE INTESTIN IS BECOMING REPROGRAMMED FAIRLY EARLY IN LIFE. WE COULD SHOW SOME OF THAT BY TAKING A YOUNG WORM AND TURNING IT OFF PREMATURELY. WHEN YOU TURN OFF THE GENES EARLY, EARLY REGULATOR GENE EARLY THE RESPONSE IS OLD WORM, OLDER THAN AN OLD WORM. OPPOSITE IS TRUE TOO. YOU CAN TURN ON THE L-2 IN THE OLD AGE, REJUVENATING THE WORM. TAKE AN OLD WORM AND BY TURNING ON THIS TRANSCRIPTION FACTOR WE CAN RESET THE GENES TO A HIGHER STATE THAT -- FOR THIS ONE LOOKS YOUNGER, THIS ONE OLDER. BECAUSE OF THIS WE THINK THAT WE ARE -- THIS IS EVIDENCE THAT WE'RE TALKING AGING ITSELF. THIS WORM LIVES LONGER. THIS WORM DIES FASTER: AND THIS TYPE OF DATA THEN MAKES YOU THINK THAT WE'RE NOT JUST THINKING THE WORM LIVES LONGER WE'RE RESETTING IT O THE YOUNGER STATE AND THEN IT LIVES LONGER SO WE'RE TALKING AGING ITSELF. LET ME SWITCH TOPICS AND WE HAVE DONE BASICALLY THE SAME THING BUT FOR KIDNEY, HERE IS THE KIDNEY GROWING OLD, THESE GENES GOING UP, THESE ARE GOING DOWN, WE ACCESS THE ENCODE DATA AND LOOK THROUGH 140 TRANSCRIPTION FACTORS IN ENCODE TO FIND TRANSCRIPTION FACTOR THAT SEEMS TO BE REGULATING THIS PATTERN OF GENE EXPRESSION. HERE IS WHERE TO DO THAT, TAKING IN, THIS IS AN UNBIASED VIEW SO I'M NOT ACTUALLY MAKING A GUESS AN ONLY TESTING MY GUESS, I'M SAYING WHICH OF THE 140 MAKE IT IS MOST SENSE. THERE THE BIG WINNER WAS A TRANSCRIPTION FACTOR CALLED STAT 3. STAT 3 THEN STARTS OFF AT A INACTIVE STATE AND THEN AS THE KIDNEY GETS OLDER BECOMES MORE ACTIVE. BINDING TO THE AGE REGULATED GENES IN THE KIDNEY AND THEN IT CHANGES EXPRESSION OF THOSE GENES. WE CAN ALSO SHOW THAT BY TURNING DOWN STAT 3, WE CAN REJUVENATE THE TRANSCRIPTOME BUT TURNING UP CAUSE PREMATURE AGING OF THE TRANSCRIPTOME SAME IN WORMS. THAT WE CAN EXPLAIN SOME MOLECULAR CHANGES BETWEEN YOUNG AND OLE FOR THE KIDNEY. SOME STUFF HAS CHANGED HOW I THINK ABOUT AGING AND DOING THE THIS STUFF SO I THOUGHT I WOULD TELL YOU ABOUT THE THINGS ONE THING WE FOUND IS THAT A LOT OF STUFF WE FOUND REPROGRAMMING OF TISSUE AND THAT THE YOUNG INTESTINE AND THE OLD INTESTIN ARE FUNDAMENTALLY DIFFERENT. THE INTESTINAL DIFFERENTIATION GENES ARE OFF, NEURAL GENES ARE ON. ED IN KIDNEY THERE'S STAT 3 A POWERFUL TRANSCRIPTION FACTOR. SO THE OLD STATE IS NOT SIMPLY THE YOUNG STATE DAMAGE BECAUSE THE WHOLE TRANSCRIPTOME HAS CHANGED. WE CAN GET HANDS ON REGULATORY MOLECULES, WE CAN CHANGE NOT JUST ONE PROTEIN AT A TIME WE CAN AFFECT HUNDREDS OF PROTEINS BY TURNING UP OR DOWN THE NODES CAUSE HIM AGE REGULATED CHANGE. BECAUSE WE CAN SWITCH TO TRANSCRIPTOME FROM THE OLD STATE TYPE THE YOUNG STATE I THINK THAT'S EVIDENCE THAT WE HAVE MOLECULAR MEANS TO REJUVENATION. SO MAYBE POSSIBLE TO BY RESETTING THE REGULATORY FACTORS IN GENERAL EPIGENETIC AGING TO RESET THE EPIGENOME FROM THE OLD STATE TO THE YOUNG STATE. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU, STEWART. SO OUR NEXT SPEAKER NECESSARY SESSION IS LI-HUEI TSAI FROM THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY, ALSO HEAD OF THE PCOU CENTER AT MIT AND WORKS ON MOUSE MODEL FOR DISEASE IN TO HUMANS AND SHE'S VERY INTERESTED IN THE ROLE OF EPIGENETIC REGULATORS IN PARTICULAR HISTONE DEACETYLASES AND OTHERS IN THIS PROCESS. THANK YOU. >> THANK YOU, ANN. GOOD AFTERNOON, EVERYBODY. SO TODAY I WOULD LIKE TO DISCUSS WITH YOU I THINK A FASCINATING RELATIONSHIP OF NEURONAL ACTIVITY IN THE NERVOUS SYSTEM, THE EPIGENETIC LANDSCAPE AND CONNECTIVE FUNCTION -- COG MITIVE FUNCTION. SO NEURONAL ACTIVITY IN THE NERVOUS SYSTEM GIVES RISE TO EVERYTHING WE KNOW OF OURSELVES AND ABOUT THE WORLD. UNFORTUNATELY OVER THE COURSE OF NORMAL AGING, AND DURING DEGENERATIVE DISEASE NORMAL IS REDUCED ROBBING US OF NORMAL COGNITION MEMORY AND I DID PEP DENSE FOR INSTANCE. TODAY I REALLY WANT TO ARGUE FOR A MODEL WHERE THERE IS A GRADUAL DOWNWARD SLOPE OF NEURONAL DIMMING. AND I WANT TO ARGUE THAT THIS IS A DRIVING FORCE FOR NEURODEGENERATION. SO THAT'S -- LET'S TEST THE IDEA LOOKING AT EXISTING DATA ABOUT A VERY DEVASTATING DISEASE WHICH IS THE MOST COMMON CAUSE FOR DEMENTIA, ALZHEIMER'S DISEASE. SO ALZHEIMER'S DISEASE PRESENCE WITH A STEREO TYPICAL -- PRESENTS WITH A STEREO TYPICAL PATTERN OF BETA AMYLOID PLAQUE PATHOLOGY. IN CERTAIN PARTS OF THE BRAIN. THIS PART OF THE BRAIN NEURAL CIRCUITS HAPPEN TO BE CIRCUITS THAT MEDIA HIGHER ORDER MEMORY AND COGNITION FUNCTION. SO DURING ALZHEIMER'S DISEASE THIS IS THE PARTICULAR CIRCUITS THAT SHOW GRADUAL REDUCED NEURONAL ACTIVITY SO DATA GENERATES BY HUMAN FMRI IMAGING STUDIES PARTICULARLY FROM RANDY BACONER. AND THESE ARE MORE AUTOMATICALLY THESE ARE THE CIRCUMSTANCES THAT EVENTUALLY DISPLAY NEURODEGENERATION, NEUROAL AND EVENTUALLY ATROPHY OF THE BRAIN. A LARGE BODY OF LITERATURE IN NEUROBIOLOGICAL STUDIES ALSO SHOW BETA AMYLOID PEPTIDES THEY CAN REDUCE GLUTE MACE INACTIVE TRANSMISSION, REDUCE SYNAPTIC DENSITY, REDUCE PROBINGSISTY IMPAIR COGNITIVE FUNCTION SO WHEN YOU PUT ALL THIS TOGETHER SYMPTOMS NEUROSCIENCE AND NEUROBIOLOGICAL STUDY IT IS PICTURE EMERGES TO ME THE BETHE AMYLOID PEPTIDE DEPOSITION IN CERTAIN PART OF THE BRAIN LEADS TO REDUCE NEURONAL ACTIVITY AND THIS TRIGGER FURTHER CASCADE OF EVENTS LEADING TO NEURODEGENERATION. SO AT THE MOLECULAR LEVEL SO WE COMPILED A LOT OF PUBLISHED DATA FROM GENE EXPRESSION PROFILING STUDIES IN NORMAL BRAIN AND IN ALZHEIMER'S DISEASE BRAINS. WE COMPARE DATA ALTOGETHER ABOUT CLOSER TO 200 NORMAL AND ALZHEIMER'S DISEASE SUBJECTS, THEY'RE QUITE CONSISTENT WITH EACH OTHER. AND SHOW A COMMON TREND DIFFERENCES IN GENE EXPRESSION. NOT SURPRISINGLY ONE SEES A HUGE REDUCTION OF GENES INVOLVED IN SYNAPTIC TRANSMISSION, SYNAPTIC NEURONAL FUNCTIONS. AND YOU HAVE HEARD A LOT THIS MORNING VERY PROFOUND INFORMTORY -- INFLAMMATORY RESPONSE GENE STRESS RESPONSE GENES, THEY ASSOCIATE WITH AGING AND ALSO TREMENDOUSLY CONSPICUOUSLY WITH ALZHEIMER'S DISEASE VERY CONSPICUOUSLY UP REGULATED. ALSO POINT OUT THIS P POPPED ANSWER OF INCREASE IMMUNE RESPONSE GENE EXPRESSION IS CONSISTENT WITH A LOT OF THE RECENT GENOME WIDE ASSOCIATION STUDIES ALZHEIMER DISEASE WHERE QUITE A LARGE NUMBER OF GENES INVOLVING IMMUNE RESPONSE INFLAMMATION DISREGULATION CONTRIBUTE TO INCREASE RISK OF ALZHEIMER'S DISEASE. HOW ABOUT AT THE EPIGENETIC LEVEL. THE LARGE SCALE GENOME WIDE SO FAR HAS NOT BEEN PUBLISHED IN HUMAN SUBJECTS YET. HERE I'M SHOWING YOU A STUDY IN ANIMAL MODEL OF ALZHEIMER'S DISEASE THIS MODEL REALLY PRETTY NICE HI RECAPITULATE ALZHEIMER DISEASE PHENOTYPE WITH PROFOUND NEURONAL LOSS AND IMPAIRED COGNITIVE FUNCTION. SO LOOK AT GENE I'M SORRY PRESENTATION PROFILES REALLY THIS RECAPITULATE HUMAN GENE EXPRESSION PROFILES THAT I SHOW YOU. SO THERE'S REDUCED EXPRESSION OF SYNAPTIC TRANSMISSION GENES AN HUGE INCREASE INFLAMMATORY AND STRESS RESPONSE GENES. THIS IS A COMPLICATED PROFILE GENOMIC RESULTS CARRY OUT IN TWO DIFFERENT STAGES OF MOUSE MODEL. EARLY STAGE PRE-SYMPTOMATIC THERE'S NO NEURONAL LOSS OR SYMPTOMS AND LATER STAGE PROFOUND LOSS AND COGNITIVE IMPAIRMENT. SO THERE ARE EPIGENERAL IT CAN OR CHROMATIN ACTIVATION MARKS AND SILENCING MARK PERFORMED HERE SO THIS IS BASICALLY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY DEEP SEQUENCING. SO I WANT TO POINT OUT THE EPIGENETIC CHANGES REALLY CONSISTENT WITH GENE EXPRESSION CHANGES IN TERMS OF ACTIVATION MARK IN THOSE GENES INVOLVED IN SYNAPTIC TRANSMISSION AN THOSE ARE INCREASED IN THE GENES INVOLVING INFLAMMATORY RESPONSE, SIMILARLY THE SILENCING MARK SHOW A CONVERSE PROFILE. THERE'S SOMETHING HERE STRIKING THAT I WANT TO POINT OUT. REMEMBER EARLY STAGE, THIS IS ASYMPTOMATIC IN A MOUSE. BUT ONE CAN SEE SIGNIFICANT CHANGES IN THE EPIGENETIC LANDSCAPE PROFILE BUT I THINK THE INTERPRETATION HERE IS THAT EVEN WITH THESE CHANGE IT IS EPIGENETIC LANDSCAPE STILL MAINTAINS A CERTAIN PLASTICITY, THEREFORE WHEN ONE SEARCHES ANIMALS TO BEHAVIOR TRAINING THESE ANIMALS ARE CAPABLE OF RESPONDING TO THE STIMULATION AND INDUCE GENE EXPRESSION TO SUPPORT LEARNING MEMORY FUNCTION. BUT SOME STAGE WHEN CHANGES GO FURTHER AND EVENTUALLY LOCK INTO INACTIVE STATE, AT THIS POINT PHYSIOLOGICAL SIMULATION WITH TRIGGER PROPER RESPONSE TO SUPPORT LEARNING OR MEMORY. SO IN TERMS OF RECENT EFFORT IN MODULATING THE CHROMATIN LANDSCAPE TO ACHIEVE BENEFICIAL EFFECTS, I THINK THERE ARE A FEW STUDIES FROM MY LABORATORY AND OTHER GROUPS SHOWING THAT MANIPULATING ESPECIALLY INHIBITION OF ENZYMES CAN BE BENEFICIAL. MY LABORATORY ALSO AND OTHERS SHOW THAT HISTONE DEACETYLASE TWO INHIBITS EXPRESSION OF GENES INVOLVING LEARNING AND MEMORIES AND TOXICITY AND SO ON. SO THIS TREATMENT HAS BEEN SHOWN IN NUMEROUS ALZHEIMER'S MODEL TO RECOVER COGNITIVE FUNCTION. HERE I'M SHOWING YOU GENE EXPRESSION PROFILE FOLLOWING I FOUND THIS DATA IS VERY COMPELLING. GENE EXPRESSION OF CONTROL MICE WITH NEURODEGENERATION, ANIMAL DISEASE MODEL WITHOUT TREATMENT AND ALZHEIMER'S MODEL WITH TREATMENT. SER E OWE TYPICAL ALZHEIMER'S CHANGES, FUNCTIONING GENES NOW EXPRESSION IS RECOVERED WHICH IS NOT SURPRISING. WHAT'S SURPRISING ARE THIS GROUP OF GENES. EXPRESSION TREMENDOUSLY INCREASED IN MODELS BUT FOLLOWING TREATMENT THEY SHOW A MUCH REDUCED EXPRESSION PATTERN SHOW A PATTERN SIMILAR TO THE CONTROL MICE THAN THE ALZHEIMER'S MICE. THIS SUGGESTIONS THAT THOUGH THE EPIGENETIC LANDSCAPE IS LOCKED IN THE STATE MODULATING THE CHROMATIN LANDSCAPE STILL HAS CAPACITY TO REVERT THE CHROMATIN INACTIVE STATE. SO IN CONCLUSION I WANT TO EXPLAIN AGAIN THAT I WOULD LIKE TO HAVE FOR AN ACTIVITY MODEL OF ALZHEIMER'S PATHOLOGY, I WOULD LIKE TO PROPOSE AMYLOID DEPOSITION IN CERTAIN BRAIN RIDGES LEAD TO REDUCED NEURONAL ACTIVITY AND THIS INDUCE CASCADE OF EVENTS INVOLVING DISREGULATION AN TRANSCRIPTIONAL DISREGULATION LEADING TO COGNITIVE DECLINE. I ALSO SHOW YOU PROMISING EVIDENCE THAT EVEN WHEN CHROMATIN IS LOCK IN INACTIVE STATE MODULATING CHROMATIN MODIFYING ENZYMES CAN POTENTIAL TO REVERT IS THE THE PATHOLOGY. SO MODELING PERSPECTIVE, CAN LEAD TO DECREASE IN TOXICITY GENES AND INCREASE INFLAMMATION AND TRESS RESPONSE. WE CAN DISCUSS LATER BUT I FEEL LIKE THERE'S TWO CLASSES OF GENES ALMOST HAVE THIS RECIPROCAL RELATIONSHIP. AND I ALSO SHOW YOU THAT ONCE THE EPIGENETIC LANDSCAPE IS LOCKED IN INACTIVE STATE PHYSIOLOGICAL SIMULATION ARE UNLIKELY TO REIGNITE NEURONAL FUNCTION NECESSARY FOR COGNITION. BUT PHARMACOLOGICAL MODULATORS OF CHROMATIN MODIFYING ENZYMES RESTORE ACTIVE CHROMATIN LANDSCAPE AND RECOVER COGNITIVE FUNCTION. I THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> PETER IS A PROPOSING A NEW MODEL THAT CANCER IS AN EPIGENETIC DISEASE AND NOT JUST A DISEASE OF GENETIC -- PETER THANK YOU. >> THANK YOU FOR THE INVITATION TO SPEAK AND ORGANIZING THE FANTASTIC MEETING. HOW DO I -- OKAY. SO I'M GOING TO TALK ABOUT CANCER AND AGING AND SPECIFICALLY I'M GOING TO ASK THE QUESTION WHY DOES CANCER INCREASE WITH AGE. AS YOU ALL KNOW THE INCIDENCE OF MANY CANCERS INCREASES WITH AGE, IN FACT MANY OR MOST CANCERS AGE IS THE BIGGEST SINGLE RISK FACTOR FOR CANCER. WE ALSO HEARD TODAY THE LINK BETWEEN AGING AND CANCER IS FURTHER UNDERSCORED BY DEMONSTRATION VARIOUS MANIPULATIONS WITH DIETARY SMALL MOLECULE OR GENETIC, THOSE INTUBATIONS WHICH EXPAND LIFE SPAN WILL THE CRITICAL QUESTION IS WHY DOES CANCER INCREASE WITH AGE. IT'S TRUE TO SAY, WITHIN THE CANCER FIELD ITSELF THERE IS A GENERAL ASSUMPTION THAT CANCER INCREASES WITH AGE BECAUSE CANCER -- GROWTH OF THE CANCER IS A MULTI-STEP PROCESS THAT DEPENDS UPON MULTIPLE GENETIC AND P GENETIC ALTERATIONS. SO THAT'S A LONG HISTORY FOR THIS. GOING BACK TO THE 1950s FROM EPITEAM LOGICAL MODELING DATA FROM RICHARD DOLLEN AND CARL -- TO HYPOTHESIS DEMONSTRATION OF ONCOGENE COOPERATION BY BOB WINEBERG IN RODENT AND HUMAN CELLS GENETIC PARADIGM IN COLON CANCER ESTABLISHED BY BURT VOGELSTEEN AND CO-O WORKERS, WHOLE GENOME EFFORTS HAVE UNCOVERED HUNDREDS OR THOUSANDS OF GENETIC GENETIC ALTERATIONS IN CANCER. AS I SAY THIS MODEL HAS BEEN EXTENNED TO INCLUDE EPIGENETICS BECAUSE IT'S KNOWN FOR EXAMPLE EPIGENETIC SILENCING OF TUMOR SUPPRESSER SUCH AS APC CAN CONTRIBUTE -- CAN DRIVE INACTIVATION OF THOSE TUMOR SUPPRESSERS INSTEAD OF GENETIC MUTATION. BUT I THINK WHAT WE NEED TO REMEMBER IS JUST BECAUSE CANCER IS A MULTI-STEP PROCESS DOESN'T MEAN IT TAKES 50, 60, 70 YEARS TO ACCUMULATE AND THE CANCER TO MANIFEST ITSELF, THAT WASN'T AUTOMATICALLY FOLLOWED. AFTER THE FACT CLOSER TO THE IDEA IT WAS QUITE GOOD EVIDENCE THAT IT'S MORE COMPLICATED THAN THAT. SO FOR EXAMPLE, THERE ARE CANCERS THAT HAVE A LARGE NUMBER OF GENETIC ALTERATIONS THAT PEAK INCIDENCE IS MUCH EARLIER. SO FOR EXAMPLE OSTEOSARCOMA HAS A COMPLEX GENOME AND CONSIDERS YOUNG ADULTS AND ADOLESCENTS. PEOPLE SUCH AS YOUNG VIC HERE IN THE AUDIENCE ACTUALLY MEASURED MUTATION RATES WITHIN DEVELOPMENT AND GROWTH OF YOUNG ORGANISMS AND INTO AGING. AND WHAT THESE STUDIES TEND TO SHOW IS RATE OF ACCUMULATION OF MUTATIONS IS HIGH DURING DEVELOPMENT AND EARLY GROWTH AS YOU MIGHT EXPECT BECAUSE THAT'S WHEN SELF-PROLIFERATION GOING ON BUT IF YOU LOOK IN ADULTS, THIS IS MOUSE AGING HERE OBVIOUSLY. IN ADULTS THE RATE OF ACCUMULATION OF MUTATIONS IS VARIABLE BETWEEN TISSUE. BUT ACTUALLY QUITE OFTEN RELATIVELY SLOW. SO THE GRAY LIGHT HERE, THIS IS THE BIGGER -- SHOWS THE SURVIVAL OF THESE MICE WHICH APPROXIMATES TO THE I'M SORRY DENSE INVERSE OF CANCER THIS IN THESE MICE BECAUSE THEY DIE OF CANCER SO WHAT YOU CAN SEE IS THE CANCER INCIDENCE INCREASES EXPONENTIALLY IN LATE LIFE BUT ACCUMULATION OF MUTATIONS IS SLOW TO OUR LIFE. SO THERE'S NOT A CLEAR RELATIONSHIP BETWEEN ACCUMULATION OF MUTATIONS AND THE ONSET OF CANCER. FINALLY, BACK TO THE VOGELSTEIN MODEL, TURNS OUT IT TAKES ABOUT TEN YEARS TO GO THROUGH THAT ENTIRE SEQUENCE FROM ADENOMA TO A CARCINOMA. THAT MODEL DOESN'T TELL US WHY THE AVERAGE AGE OF DIAGNOSIS OF A CANCER P -- OF A COLON CANCER IS 72 AND WHY WE DON'T SCREEN FOR COLON CANCER BEFORE AGE 50. SO WE DON'T KNOW WHAT'S GOING ON IN THAT FIRST 50 YEARS. PUTTING THIS TOGETHER WE SHOULD THINK ABOUT REVISED MODEL. THIS ISN'T MY MODEL, THIS IS A SYNTHESIS OF OTHER IDEAS WHICH ARE ALREADY OUT THERE, I THINK NEED TO BE THOUGHT ABOUT MORE WITHIN THE FIELD. THAT IS THE IDEA THAT IN YOUNG NORMAL TISSUES WE HAVE A CERTAIN NUMBER OF MUTATIONS ONCO GENIC MUTATIONS BUT THOSE ONCO GENIC MUTATIONS ARE WELL TOLERATED BY THE TISSUE. AS WE AGE ADDITIONAL MUTATIONS ACCUMULATE, THE DEVELOPMENT OF THE CANCER IS DRIVEN BY THE INTERACTION OF THESE MUTATIONS WITH OTHER CHANGES TO ASPECT OF MOLECULAR CELL AND TISSUE BIOLOGY, BUT KEY THING ABOUT THESE CHANGES, THESE ARE ESSENTIALLY PROGRESSIVE AGE ASSOCIATED CHANGES TO ASPECTS OF CELL AND TISSUE BIOLOGY WHICH ARE QUITE PLASTIC. SO THAT REFERRED TO EPIGENETICS, METABOLISM, THE IMMUNE SYSTEM, INFLAMMATION, STEM CELL NICHES, PRETTY MUCH ANYTHING YOU CAN THINK OF APART FROM DNA SEQUENCE. SO EPIGENETICS IS A VERY GOOD EXAMPLE OF THIS. BECAUSE WE KNOW IN YOUNG NORMAL TISSUES MOST CPG ISLANDS ARE UNMETHYLATED STATE. IN A CANCER MANY CPG ISLANDS ARE METHYLATED, THEY THOUGHT THAT METHYLATION CONTRIBUTES TO SILENCING OF TUMOR SUPPRESSER GENES OR PROGRESSION OF CANCER. WE KNOW FROM THE WORK OF (INAUDIBLE) THAT THIS TRANSITION FROM UNMETHYLATED TO METHYLATED CAN BE PROGRESSIVE THROUGH AGE. SO IF YOU LOOK AT HISTOLOGICALLY FORMAL TISSUES YOU CAN SEE INTERMEDIATE STATES OF METHYLASE SUGGESTING THIS IS A PROGRESSIVE PROCESS. ESSENTIALLY A SHIFT IN A DYNAMIC EQUILIBRIUM OF THESE PROCESSES. SO WHY IS THIS IMPORTANT? FIRST OF ALL, WHAT WE'RE FINDING FROM TARGETED THERAPIES IN CANCER, MOST OF THESE TARGETED THERAPIES ARE DIRECTED TOWARDS THE DOMINANT GENETIC ALTERATIONS WITHIN THOSE CANCERS THAT MELANOMA IS DIRECTED TOWARDS THE ACTIVATED BRAF ONCOGENE. MOST TARGETED THERAPIES IN ADVANCE CANCER HAVE A RELATIVELY MODEST BENEFIT FOR THE PATIENTS. I AND I THINK OTHERS BELIEVE TO BEAT CANCER WHAT WE HAVE TO DO IS TO DO RISK ASSESSMENTED, EARLY DETECTION, AND CHEMOMOW PREVENTION IN YOUNG TO MIDDLE AGED ADULTS. AT THE MOMENT WE DON'T KNOW HOW TO DO THIS. SO IN TERMS OF WHAT I WOULD CONSIDER A WAY FORWARD, WE NEED TO CONTINUE MAPPING AGE ASSOCIATED CHANGES IN THESE DIVERSE ASPECTS OF MOLECULAR CELLULAR AND TISSUE STRUCTURES AND ORGANIZATION. THOSE CHANGES NEED TO BE MODELED, AGE ASSOCIATED CHANGES NEED TO BE MODELED IN VITRO AND IN VIVO MODELS OF CELL TRANSFORMATION AND TUMORIGENESIS. WE NEED INHIBITORS TO THESE CHANGES. AND THOSE INHIBITORS NEED TO BE TESTED IN MOUSE MODELS THAT ARE DESIGNED TO RECAPITULATE THE AGE DEPENDENCE OF CANCER, WE HEARD MOUSE MODELS ALREADY TODAY. THE PROBLEMS WITH SOME OF THEM, AND I THINK IN THE CANCER FEEL THIS IS A PARTICULAR PROBLEM. SO MANY MOUSE MODELS USED IN THE CANCER FIELD ARE DOING NOW GOOD JOB REKA RECAPITULATING THE GENETICS OF HUMAN CANCER BUT POOR JOB OF RECAPITULATING THE AGE DEPENDENCE OF HUMAN CANCER AND VARIOUS REASONS REASONS WE CAN DISCUSS. IT'S NOT SIMPLY BECAUSE THE MOUSE ONLY GETS TWO OR THREE YEARS IN A HUMAN, MUCH LONGER THAN THAT. MORE FUNDAMENTAL PROBLEM. SO WITH THAT, I'M DONE. [APPLAUSE] >> THANK YOU, PETER. NEXT APPROXIMATE LAST SPEAKER IS JUAN CARLOS IZPISUA BELMONTE FROM THE SALK INSTITUTE AND JUAN CARLOS WILL TALK TO US ABOUT USING IPS AND REPROGRAMMING TO MODEL AGING AND AGE RELATED DISEASE AND WAYS THAT EPIGENETIC CHANGES CAN BE USED IN THAT CONTEXT. >> FIRST I WOULD LIKE TO THANK THE ORGANIZERS AND THEIR KIND INVITATION, IT'S AN HONOR AND PRIVILEGE TO BE HERE. I WAS ASKED TO DISCUSS HOW CELL REPROGRAMMING COULD GIVE INSIGHTS INTO (INAUDIBLE) WITH PARTICULAR FOCUS OF EPIGENETIC SESSION OF THIS AFTERNOON. THE REPROGRAMMING OF CELL THAT IS ADDING THESE FOUR FACTORS OF ANY SOMATIC CELL OBTAINING PLURIPOTENT CELL IF IN FACT EPIGENETIC REJUVENATION EXPERIMENT YOU SEE GLOBAL MANIPULATION OPENING OF THE CHROMATIN, REGULATION OF RNA AND OTHERS. BUT WHAT THIS EMPERIMENT ALLOW US IS FROM THIS PLURIPOTENT CELL THAT WE HAVE GENERATED, TO DIFFERENTIATE THE TO ANY OF THE CELL TYPES THAT WE HAVE BEEN DISCUSSED TODAY HERE THAT COULD BE THE TARGET AND RE-ESTABLISH THESE TISSUE SPECIFIC EPIGENETIC MARKS. AGING MARKS. ANY OF THE EXPERIMENT THAT FIRST EXPERIMENT WOULD GO FORWARDS. WHAT YOU WOULD DO IS TO IDENTIFY A PARTICULAR GENE THAT IS INVOLVED IN ANY OF THE DIFFERENT FACTORS. CREATE TWO DIFFERENCE SETS. ONE IN THE ABSENCE OF THAT GENE AND THE OTHER ONE EXACTLY THE SAME ONE, PERFECT THE ISOGENIC LINE WHILE YOU HAVE CORRECTED THESE MUTATED GENES. FROM THERE, FROM THESE TWO PLURIPOTENT CELLS, THEN DIFFERENTIATE TWO DIFFERENCE CELL TYPES. TWO EXAMPLES OF THESE EXPERIMENTAL DATA, THIS ONE HERE. HUTCHINSON (INAUDIBLE) SYNDROME. THIS IS A MUTATION ON LAMIN A AND ONE OF THE CHARACTERISTICS OF THESE MUTATION AS YOU CAN SEE IN THE MIDDLE PANEL IS AL L TEAR RATION IN THE NUCLEAR ENVELOPE. THIS ALTERATION IN THE NUCLEAR ENVELOPE WILL HAVE TRAUMATIC CONSEQUENCES FOR AGING OF THESE KIDS. ONCE THE GENE IS CORRECTED, THEN WE HAVE PERFECT SITUATION WHERE WE CAN STUDY DIFFERENTIATION, HOW THESE PHENOTYPE DEVELOP. THESE ALSO, HERE IS ANOTHER EXAMPLE, HELPS TO UNCOVER NOVEL HALLMARKS OF DISEASE RELATED TO AGING. PARKINSON IS A DISEASE THAT CERTAIN CORRELATES WITH AGING THE GENE MORE OFTEN EFFECTED THAT HAPPENS AS WELL TO CORRELATE WITH ALTERATIONS IN THE NUCLEAR ENVELOPE. THESE PHENOTYPE NOT PREVIOUSLY KNOWN OBTAINED THROUGH THESE TECHNOLOGY CERTAINLY REFLECT WHAT IS HAPPENING IN VIVO. YOU CAN SEE THE RIGHT, HERE TO THIS SIDE YOU CAN SEE BRAIN AFFECTED WITH PARKINSON, YOU CAN SEE HOW THE ALTERATION IN THE NUCLEAR MORPHOLOGY IS CLEARLY DISPLAYED COMPARED TO THE CONTROL. SO WHAT THESE MODELS GIVE US IS NOT JUST NOVEL FEATURES AND HALLMARKS OF THE DISEASE BUT AFTER LOOKING AT THESE AND OTHER MODELS LIKE FOR INSTANCE THE WARNER SYNDROME MODEL THE CONCLUSION THAT WE CAN EXTRAPOLATE FROM ALL THESE PROGERIA MODEL DISEASE AGING ASSOCIATED MODELS, IS THAT THEY PRESENT THE EPIGENOMIC CHANGES THAT ARE CHARACTERISTIC OF CHROMOSOMEAL STRUCTURE WHAT (INAUDIBLE) TOLD YOU AT THE BEGINNING, CHARACTERISTIC OF THE AGING PROCESS. HELP US BETTER UNDERSTAND THE DISEASE PERHAPS TO INTRODUCE AND CHALLENGE THE CELLS DIFFERENTIATE AND AGE WITH CHEMICAL COMPOUNDS AND EVENTUALLY THEY CAN PASS CELL THERAPY AND RENEW NATION. IT IS CLEAR THE GENETIC FACTORS, AND I SHOW YOU A COUPLE OF EXAMPLES, THE ROLE OF THIS FACTORS CAN BE ADDRESSED IN THIS MODEL. BUT WHAT ABOUT THE ROLE OF EPIGENETICS? FOR THAT THERE IS ONE TOOL WE NEED TO DEVELOP AND THAT IS TOOL OF EPIGENOME BECAUSE THIS WAS TO REALLY MAKESHIFTING OF THESE WHOLE GENOME EXPRESSION PROGRAM PERHAPS BETTER UNDERSTAND PHYSIOLOGIC AGING. ONE OF THE PROBLEMS THAT THE FIELD HAS IS THE DIFFERENTIATION OF PARTICULAR CELL TYPES. WHY THAT IS A PROBLEM. THIS IS A PROBLEM BECAUSE WE DO NOT HAVE ANY PROPERTY PROTOCOL IN THE FIELD THAT LEAD TO A CELL AND THIS IS VERY IMPORTANT AS YOU CAN IMAGINE IN AGING. WE CAN REALLY NOT TRY TO ATTACK A PROBLEM, WE CAN GO AFTER AGING BUT WE CANNOT ATTACK STUDY CHRONOLOGICAL AGING AND WILL HAVE PROTOCOLS THAT LEAD TO (INDISCERNIBLE) CELLS. ANOTHER PROBLEM CELLS ARE NOT ORGANIZED STRUCTURE, THEY ARE NOT ORGANS. CERTAINLY CONCLUSIONS WE OBTAIN FROM CELLS CANNOT BE IMMEDIATELY EXTRAPOLATED. FUTURE DIRECTIONS, NEAR TERM NOWTURE DIRECTIONS AND A QUESTION I THINK THIS FIELD FACES IN ORDER TO HAVE INSIGHTS INTO THE FIELD OF AGING, I HAVE SUMMARIZED THEN IN THREE QUESTIONS. ONE OF THEM TO TRY TO KNOW WHETHER CAUSE A CONSEQUENCE OF THE AGING PROCESS, PERHAPS IT CAN BE FELT BY THE DERIVATION OF ALL YOUNG INDIVIDUALS AND AFTER ANALYZING OF THESE EPIGENOMIC RECAPITULATION PERFORM EPIGENOME EDITING OF THESE CELLS. THE OTHER ONE TO DEVELOP PROTOCOLS FOR DIFFERENTIATION OF POST MITOTIC POPULATION. THEY GIVE US STUDIES CELLULAR DIVISION, CHRONOLOGICAL AGING. AND THE THIRD ONE, IS A QUESTION THAT FITS PROBABLY NOT ENOUGH. TO STUDY WHETHER ORGAN MODEL IN THE LAST FEW MONTHS DIFFERENT LABORATORIES CAN DEVELOP 3-D PROTOCOLS FOR THE GENERATION OF MANY ORGANS IN VITRO. BRAIN, LIVER AND WE REACCEPTLY DEVELOP PROTOCOL FOR GENE. THIS IS ALL WHAT I WANTED TO SAY. THANK YOU. [APPLAUSE] >> CAN EVERYONE COME UP FROM THE PANEL. PEOPLE ARE TAKING THEIR PLACE I WILL DO A BRIEF SUMMARY OF THE SESSION. SO I DID THE TWO KEY CONCEPTS THAT ARE BROUGHT ABOUT BY THIS EPIGENETIC AND AGING SESSIONS, ONE IS THE POSSIBILITY, THE CONCEPT THAT EPIGENETIC CHANGES ARE LONG RANGE LONG LASTING TYPE OF CHANGES AND THE OTHER KEY CONCEPT THAT EPIGENETIC CHANGES THIS AMAZING CAPACITY OF BEING REVERSIBLE AND THIS BRINGS THE NOTION OF REJUVENATION OF THE REVERSAL OF ALREADY OLD DISEASED ORGANISMS. SO IN SUMMARY, IT E CLEAR NOW THERE ARE EPIGENETIC CHANGES TO THE GENOME DURING AGING PROCESS, IT IS COLOR FROM THE TOOLS THAT ONE CAN MANIPULATE THE ENZYME OR TRANSCRIPTION FACTORS THAT DO IMPOSE THOSE CHANGES ON THE GENOME ACCESSIBILITY AND THE GENE EXPRESSION AND THOSE CHANGES CAN HAVE SOME IMPACT ON REVERSAL OF SOME HALLMARKS OF AGING AND SOME DISEASE, THIS IS ALSO INTERESTING THAT CANCER COULD BE A DISEASE THAT'S EPIGENETIC, THERE ARE TWO REFLYINGS IN THE FIELD THAT TOUCH ON EPIGENETICS THAT ARE INTERESTING FOR THE FUTURE, ONE IS THE CAPACITY TO MODEL SOME HE CANTIVE AGING AN AGING OF DISEASE WITH CELLULAR MODELS AND WE HAVE SEEN THAT. AND THE OTHER ONE THAT YOU HAVE SEEN IN MANY OF THE SLIDES WITH THOSE LARGE SCALE BETA IS THE REVOLUTION IN THE GENOME TECHNOLOGIES WHETHER IT'S RNA SEEK, MICROARRAYS, CHROMATIN PRECIPITATION. THIS IS THE FIRST TIME EVER CAPACITY TO LOOK AT CHANGES IN THE GENOME AT VERY FINE RESOLUTION WHICH FINALLY EMPOWERS US TO UNDERSTAND AND MANIPULATE MORE SPECIFICALLY THOSE CHANGES. SO THAT'S FOR THE SUMMARY. IN TERMS OF CHALLENGE I WILL LEAVE THAT TO THE QUESTIONS BUT THEY WILL POSE A FEW CHALLENGES IN TERMS OF FIRST DRUGS THAT CAN MANIPULATE EPIGENETICS, ARE THEY GOING TO BE SAFE, ARE THEY EFFECTIVE AGAINST DISEASES. SOME OF THEM ALREADY EXCITING BECAUSE CANCER AND THE NEURODEGENERATIVE DISEASES ARE ALMOST AN ANTAGONISTIC OF ONE ANOTHER ANOTHER. ONE WONDERS WHETHER DRUGS DESIGNED FOR ONE DISEASE SAY CANCER MIGHT HAVE A DEGENERATIVE EFFECT AND VICE VERSA. SO WHEN YOU THINK ABOUT THIS AND THE CHALLENGES. THAT'S FOR THE DISEASE ASPECT. THEN FOR THE PREVENTION ASPECT VERY INTERESTING TO SEE ALL THESE OTHER PANELS, INTERESTING TO THINK ABOUT EPIGENETIC UNDERLYING SCENES IF IT IS IT COULD BE AN UNDERLYING THEME THAT COULD BE PREVENTED PERHAPS BY BOTH INTERVENTIONS THAT HAVE BEEN MENTIONED HAVE BEEN MENTIONED WITH HEALTH SUCH ADS DIETARY RESTRICTION, EXERCISE LOWERING THE STRESS LEVELS. SO COULD THEY HAVE IMPACT IN RESETTING EPIGENETIC CHANGES AND LONG LASTING EFFECT FROM EARLY DEVELOPMENT TO LATER AND EVEN PASSED ON UPON GENERATION IN TRANSGENERATIONAL EPIGENETIC ASPECT. SO THAT'S THE CHALLENGE. NOW I WILL OPEN THE SESSION TO THE PANEL FOR QUESTIONS. >> HI, DONNA LOVE FROM NIDDK, THIS QUESTION IS FOR STEWART KIM, I HAVE CURIOUS ABOUT YOUR MICROARRAY STUDIES. HAVE YOU DONE TISSUE SPECIFIC ANALYSIS, DO YOU FIND ANY TISSUE DRIVING THE AGING PROCESS MORE THAN OTHERS AND THEN I WANTED TO GIVE YOU A CHANCE TO EXPAND ON THE OLD YOUNG PLUS STRESS. >> SO FIRST THE WORK I SHOWED WITH THE HUMAN KIDNEY, AND WE COULD DO IN THAT PAPER WE DID THE CORTEX AND THE MEDULLA. WE HAVE ALSO DONE A FAIR NUMBER OF MOUSE STUDIES. WITH KEVIN BECKER LOOKED AT 17 TISSUES IN THE MOUSE. WE DID THE GAME OF WHICH TISSUE WAS AGING THE FASTEST. WE TRIED TO FIGURE OUT WHICH WERE AGING IN SYNCHRONY. SO AMONG THE DIFFERENT MICE WE COULD ADD IS THE MOUSE BE THE OLDEST HEART THE SAME MOUSE WITH THE OLDEST BRAIN KIND OF THING. >> I'M GUESSING IN C ELEGANS. >> WE HAVE TECHNOLOGY TO DO TISSUE SPECIFIC EXPRESSION IN C ELEGANS. ONE WAY IS WE CAN EXPRESS AN RNA BINDING PROTEIN THAT GRABS THE RNA ONLY IN TISSUE EXPRESSED IN IMMUNOPRECIPITATED SEQUENCE. BUT IN THE WORK I SHOWED THERE YOU CAN DO AN INFORMATICS STUDY ON THAT AND SAY OF THE 1200 GENE, WHAT TISSUE DID THEY COME FROM. AND IF YOU DO THAT, MOST ARE INTESTINE SO THAT'S BIG WINNER IN TERMS OF WHAT'S CHANGING BETWEEN YOUNG ADULT WORMS. ANOTHER ONE THAT CHANGES IS THE SKIN. SOMETHING THAT DOESN'T CHANGE LIKE NOT ONE GENE DO WE FIND DIFFERENT ARE NEURONAL GENES. SO WE WOULD LOVE TO TRY TO GET AN ANGLE IN TO NEURONAL AGE BUT WORMS ARE WELL PRESERVED FOR NEURONAL AGING. MONICA DRISCLE'S LAB MADE INROADS TO NEURONAL AGING AND C ELEGANCE BUT IF YOU ASK WHAT'S CHANGING MOLECULARLY THERE'S NOT MUCH CHANGING. >> (INDISCERNIBLE) FROM THE (INAUDIBLE) INSTITUTE. ALL DAY TODAY I HEARD WONDERFUL PRESENTATIONS ABOUT CHEMISTRY. AND VERY LITTLE ABOUT PHYSIC. QUESTION IS HOW IMPORTANT IS VOLTAGE? IS IT AN EPIGENETIC FACTOR? VOLTAGE. ELECTROMAGNETISM. >> ARE YOU TALKING CHANGES IN CHARGE? >> VOLTAGE. THE CELLS HAVE -- >> SO THESE MODIFICATIONS WE'RE TALKING ABOUT SUCH AS ACETYLATION CHANGES THE CHARGE IN THE DNA CHROMATIN POLYMER SO THERE'S DEFINITELY CHANGES IN CHARGE THAT LEAD TO CHANGES IN STRUCTURE IN THE CHROMATIN SO I THINK THERE ARE CHANGE -- >> DOES THE VOLTAGE DROP WHEN YOU HAVE CHANGE? >> VOLTAGE DROP. >> IN NEURONAL CELLS FOR EXAMPLE IS THIS >> EVERYWHERE. NEURAL CELL ESPECIALLY. >> THAT'S THE WHOLE POINT. IF WE WANT TO TALK ABOUT LIKE THE EXCITABILITY OF NERVE CELLS DURING AGING PRECISELY ALZHEIMERS DISEASE, IT REALLY IS VERY TREMENDOUSLY REDUCED. AND EVEN WHEN P YOU USE ELECTROOR -- THAT'S TO TRY TO EXCITE THE CELLS, THEY NO LONGER RESPOND PROPERLY. SO I THINK THAT IS PRIMARY PROBLEM. CONNECTIVITY IMPAIRMENT. >> WE KNOW ONE OF THE PROTEIN IS ACTIVE HIGH VOLTAGE GOES BACK TO NORMAL OR TWO QUIET STAGE IT DROPS VOLTAGE TO CONJUGATE. IF YOU HAVE VOLTAGE TO BEGIN WITH LOWER TO LOWER VOLTAGE STATE AND PROMOTE EPIGENETIC DISEASE. >> TAKE ANOTHER QUESTION THEN. >> JOSH MIDDLEDORF, EVOLUTIONARY BIOLOGY FROM PHILADELPHIA. I HAVE A CONCEPTUAL IDEA TO INTRODUCE. A THEME I HEAR IN THIS SESSION THAT'S SO EXCITING IS THAT NOT ONLY ARE THERE CHANGES CLEARLY DIFFERENTIATING YOUNG BUT FROM OLD BUT THERE ARE CONSISTENT PATTERNS THAT EVERYBODY HAS THE SAME GENES TURNED ON AND TURNED OFF AS THEY GET OLDER, THIS IS REALLY SURPRISING FROM EVOLUTIONNARY PERSPECTIVE WHY EVOLUTION PUT UP WITH THESE GENE EXPRESSION CHANGES THAT ARE SELF-DESTRUCTIVE. WE KNOW THAT GENE EXPRESSION IS TIGHTLY UNDEREVOLUTIONNARY CONTROL THAT EVOLUTION CARES AS LOT ABOUT WHAT GENES ARE EXPRESSED WHEN AND WHERE. SO I WANT TO INTRODUCE A CONCEPT THAT PEOPLE WHO AREN'T IN THE FIELD MAY NOT BE FAMILIAR, THERE'S A RESOLUTION GOING ON IN THE EVOLUTIONARY BIOLOGY FIELD FROM THE SELFISH GENE IDEA WHICH IS PREDOMINATED THE LAST 50, 60 YEARS, TO A MORE COMMUNAL IDEA THAT OFTEN WHAT'S GOOD FOR THE IMMUNITY CAN EVOLVE EVEN WHEN IT'S BAD FOR THE INDIVIDUAL. MY SUGGEST IS PERHAPS WHAT WE SEE IN GENE EXPRESSION CHANGES IS A RESULT OF EVOLUTION AT THE GROUP LEVEL, AGING IS BAD FOR THE INDIVIDUAL DESTROYS INDIVIDUAL SICKNESS BUT AGING IS NECESSARY AT THE GROUP LEVEL TO PRESERVE FOR EXAMPLE, POPULATION HOMEOSTASIS, AGING LEVELS OUT THE DEATH RATE, MAYBE THIS IS -- THE DEEP MEANING BEHIND THE EPIGENETIC CHANGES THAT WE SEE. >> I DON'T KNOW ABOUT AGING AT THE GROUP LEVEL BUT YOU MENTION EARLIER SOME MECHANISM CREATED TO DESTRUCT THE CELLS. I WOULD LIKE TO ARGUE DIFFERENTLY. SO REMEMBER THIS MORNING PIPELINE KENNEDY'S TALK, IT'S BECAUSE OF THE MEDICAL L ADVANCES AND PEOPLE LIVE LONGER AND LONGER. SO IN TIME PEOPLE ONLY HAVE A VERY LIMITED LIFE SPAN. SO WHEN I TALK ABOUT REDUCED NEURONAL ACTIVITY, I ACTUALLY BELIEVE THAT THIS PROCESS OPERATES SAY DURING NERVOUS SYSTEM DEVELOPMENT. DURING DEVELOPMENT THE SYSTEM HAS THE USE EXUBERANT PROCESSES AN SYNAPSES AND SO ON. AND YOU HAVE TOO MUCH GOOD THING THAT CAN BE BAD FOR YOU AS WELL. SO THERE IS A MECHANISM TO ELIMINATE CERTAIN SYNAPSES OR NEURONAL PROCESSES, DENDRITE AND SO ON POPULATION IS LOWER THAN THE SYSTEM ESPECIALLY LOOK THERE AND PUBLICATION, THAT WHEN CERTAIN SYNAPSES SHOW LOWER ACTIVITY THE IMMUNE SYSTEM MICROGLIA GETS ACTIVATED AND THEY WILL PREFERENTIALLY ATTACK THE SYNAPSES AND ELIMINATE THOSE SYNAPSES AND THAT'S A VERY IMPORTANT NORMAL PROCESS FOR PROPER BRAIN DEVELOPMENT. MY HYPOTHESIS IS THAT THIS SYSTEM IS MALL ADAPTED DURING AGING DOING NEURODEGENERATIVE DISEASE THAT SYSTEMIC REDUCTION OF EXCITABILITY DUE TO BETA AMYLOID ACCUMULATION OR OXIDATIVE STRESS, SO ON, THIS SYSTEM GETS ACTIVATED AGAIN AND THAT BECOMES DETRIMENTAL. SO I WOULD STOP HERE AND SEE >> SO MAYBE AN ANSWER AND THEN WE MOVE TO THE NEXT QUESTION. >> SO WILLIAMS AND OTHERS HAVE GONE TO THIS IN DEPTH AND THERE IS A BIG REVOLUTION IN TERMS OF GROUP SELECTION FOR LONGEVITY. I THINK THAT WOULD BE DISCUSSION OVER SOME BEERS LATER. BUT IN GENERAL IN OUR FIELD AT LEAST IN OUR CIRCLE THERE IS NOT A BELIEF YET THAT CERTAINLY FOR HUMANS THAT FOR ANY LARGER LIFE FORMS GROUP SELECTION WITHIN INDIVIDUALS. THAT SAID YOU RAISE AN IMPORTANT POINT WITHIN AN INDIVIDUAL, CELLS WITHIN OUR BODY ARE ACTING COMMUNALLY BECAUSE THEY NEED TO ALL SURVIVING TO AND PERHAPS THE CHANGES HERE ARE ADAPTIVE AND BENEFICIAL TO THE ORGANISM BUT NOT SO MUCH FOR THEMSELVES. SENESCENCE PROGRAM WE HAVE HEARD ABOUT IS A GOOD EXAMPLE OF THAT, THE CELLS WILL ARREST THEMSELVES TO BENEFIT THE REST OF THE ORGANISM BUT THERE ARE ALWAYS TRADE OFFS TO THAT AS WELL >> I COULD FOLLOW-UP WITH THAT, IT'S EXACTLY LIKE THIS ON THE ORGANISMAL LEVEL THAT INDIVIDUALS HAVE VERY SHORT LIFE SPAN, MALES LIVE THREE MONTHS, WORKERS LIVE TWO YEARS AND QUEENS LIVE TEN YEARS, SO THERE'S THIS HUGE DISPARITY. SO AGAIN FOR THE GOOD OF THE COLONY, THE INDIVIDUALS CARRYING OUT DIFFERENT TASKS LIVE DIFFERENT LIFE SPANS SO I AGREE WITH DAVID'S POINT OF VIEW. >> SEEMS OPPOSITE OF WHAT DAVID JUST SAID BUT I AGREE. >> THE INDIVIDUALS IN -- YOU HAVE TO THINK OF THE COLONY THE SAME AS AN -- AS ONE SOMA. IN THAT CASE EACH INDIVIDUAL CAST IS SACRIFICING ITS LIFE SPAN FOR THE GOOD OF THE SOMA. QUESTIONS >> (INDISCERNIBLE) JOHN HAWKINS, I HAVE A QUESTION FOR DEBBIE AND I KNOW THAT TIME LIMITATION SO GIVEN (INDISCERNIBLE) MY QUESTION IS DO YOU SEE AGING DEPENDENT INCREASE OR DECREASE (INAUDIBLE) LOCATION? DISTRIBUTION BETWEEN YOUNG AND OLD? THESE ARE -- YES. THIS IS FOR DAVID. ARE >> THE HDAC IS BETTER FOR LI-HUEI ANSWER THIS SPECIFICALLY. >> OKAY. >> SO THERE ARE QUITE A FEW PAPERS PUBLISHED ABOUT THAT DISTRIBUTION. IT'S HISTONE DEACETYLASE SO IT FUNCTIONS IN THE NUCLEUS. IT HAS A NUCLEAR SUBSTRATES. BUT DURING AGING AND TOXICITY SITUATION, SEEMS TO REDISTRIBUTE TO THE CYTOPLASM. SO THIS SEEMS TO REPRESENT LOSS OF FUNCTION. SO IN OTHER WORDS, (INAUDIBLE) ACTIVITY IS DOWN REGULATED. >> SO BECAUSE HDAC INHIBITOR IS -- NOT A VERY SPECIFIC HOW DO YOU ADDRESS SPECIFICITY? >> IT'S A VERY GOOD QUESTION. RIGHT NOW ALL THE AVAILABLE SMALL MOLECULE INHIBITORS CANNOT DIFFERENTIATE (INDISCERNIBLE) SO CLEARLY MORE CHEMISTRY NEEDS TO BE DONE TO ACHIEVE MORE SELECTIVITY. INHIBITORS. >> THANK YOU. >> MY QUESTION FOR LI-HUEI. IN YOUR MOUSE STUDY, SEEMEDDED LIKE THE TRANSCRIPTIONAL CHANGE IS GRADUAL. THAT IN THE END YOU END UP WITH UP REGULATION OF INFLAMMATORY GENES AND DOWN REGULATION OF NEUROGENESIS TYPE OF GENE. MY QUESTION IS THAT IF YOU REALLY PROMOTE -- PROVOKE AMYLOID THEN THAT SEEMED TO BE A BIT LATE ON THE -- I WONDER IF YOU ACTUALLY -- CONSIDER THE POSSIBLY THAT IT'S ACTUALLY THE GLIAL CELLS SOMEHOW HAVE GONE HAYWIRE AND BECOME INFLAMMATORY AND THEN DESTROYED THE NEURONS. SO ONE QUESTION THEN FOLLOWING THAT IS HAVE WE ANALYZE GENE EXPRESSION DID YOU SEPARATE GLIA AND NEURON/AND WHAT DO THEY LOOK LIKE IF YOU SEPARATE? >> GREAT QUESTION. SO RIGHT NOW I THINK FOR THE EPIGENOMIC EPIGENETIC STUDIES IN THE FIELD, THE MOST IMPORTANT TASK FOR EVERYBODY IS TO DO CELL TYPE SPECIFIC ANALYSIS. THIS IS NOT EASY TO DO IT IN THE BRAIN. IN MOUSE PROBABLY ONE CAN USE GENETIC MARKERS WITH GFP AND CELL TYPE SPECIFIC PROMOTER AND THOSE CELLS, IT REPRESENTS A VERY TALL ORDER TO ISOLATE SPECIFIC CELL TYPES. WHAT I THINK ONE WAY THAT POSSIBLY CAN GET AROUND THIS DILEMMA IS WHAT DR. (INAUDIBLE) PRESENT THEY ACTUALLY USE INDUCE PLURIPOTENT STEM CELL MODEL. THERE YOU CAN TRY TO INDUCE THE CELL TO A PURE NEURONAL POPULATION, THIS IS A PURE GLIAL CELL POPULATION AND USING ANALYSIS SEPARATELY. LOOKING AT PROFILING RIGHT NOW, I WILL BET MY MONEY THAT MOST OF THE DOWN REGULATED GENES REPRESENT NEURONAL GENES. MOST OF THE UP REGULATED GENES REPRESENT GLIAL GENES SUCH AS MICROGLIA OR ASTROCYTES BUT THAT NEEDS TO BE VALIDATED WITH BETTER MODELS. FOR THE FIELD TO BELIEVER DRIVER OF DIMERS IS GLIAL MORE SO THAN THE NEURONS? >> THAT DEPENDS ON WHAT'S YOUR DEFINITION OF DRIVER. IF YOU TALK -- THERE HAS IT CAN A TRIGGER. >> THE TRIGGER IS PROBABLY INFLAMMATION CON VEALED SOMETHING INTRINSIC HAPPENING TO THE GLIAL CELLS. AND THEN THAT SETS OFF. >> I HAVE TWO QUESTIONS. WE DID IN OUR LAB RECENTLY TWO GENOME WIDE STUDIES ON DNA METHYLATION IN CENTENARIANS AND THEIR OFFSPRING. AND IN DOWN SYNDROME AS A MODEL OF ACCELERATED AGING THEIR MOTHER AND UNAFFECTED SIBS. APPARENTLY THE EPIGENETIC CHANGES CLUSTER IN FAMILIES. SO THE QUESTION IS, ARE THE EPIGENERAL TUCK CHANGES WHICH OCCURS DURING AGING ARE GENETICALLY CONTROLLED SECOND QUESTION IS, IN DOWN'S SYNDROME FOR EXAMPLE, OF COURSE THE CHROMOSOME 21 IS DEEPLY AFFECTED BUT THERE ARE MANY OTHERS CHROMOSOME WHICH ARE ALSO AFFECTED NOT ALL THE SAME WAY. SO WE WONDER IF GROUP ARCHITECTURE OF THE CHROMATIN WHICH MATTERS TO UNDERSTAND WHAT IS GOING ON ON THIS EPIGENETIC CHANGES WITH AGE. >> PETER YOU WANT TO COMMENT ON THAT? >> COMMENT ON THE FIRST PART EXTENT TO WHICH THE EPIGENETIC CHANGES ARE GENETICALLY DETERMINED AND I GUESS THEREFORE HOW THEY MIGHT DIFFER BETWEEN INDIVIDUALS DEPENDING UPON THE GENETIC MAKEUP OF THE INDIVIDUAL. SNPS AND WHAT HAVE YOU. I THINK IT'S A VERY GOOD QUESTION, NOT SURE WE REALLY KNOW THE ANSWER AT THIS PIPE. MY GUESS IS THAT THERE IS A GENETIC DETERMINE NATION TO SOME EXTENT BUT I THINK ONE OF THE THINGS WE KNOW ABOUT ABOUT CHROMATIN IS IT'S INHERENTLY A QUITE PLASTIC DYNAMIC STOCHASTIC STRUCTURE. SO FOR EXAMPLE BACK TO THE PHENOMENON OF AFFECT VERY DIVISION AND IT FLIES. IT HAS A STOW CHASTISETY ABOUT IT. SO THE GENETIC PERHAPS PRE-DETERMINATION VERSUS THE INHERENTLY STOCHASTIC BEHAVIOR OF THE CHROMATIN PLAY OFF EACH OTHER, AS WELL I GUESS ENVIRONMENTAL INFLUENCES COMING IN AS WELL. ALL THAT IS GOING TO FEED TO THE END POINT. I DON'T THINK WE KNOW THE RELATIVE CONTRIBUTIONS OF THOSE THREE FACTORS AT THIS POINT. THAT'S THE MAJOR QUESTION. >> THERE ARE RECENT PAPERS FROM THE LAST ISSUE OF SCIENCE WHERE PEOPLE LOOK AT MIKE SCHNEIDER JENNIFER PRITCHARD, SNPS AND HOW THEY INFLUENCE CHROMATIN CHANGES AND THERE'S A LINK BETWEEN LOW GENOME AND CHANGES TO THE CHROMATIN O THAT OCCURS TO EXACTLY WHAT YOU'RE TALKING ABOUT, THAT'S EXCITING. >> IF CHROMATIN IS AFFECTING ARE DIFFERENTLY AFFECTED. >> IT'S AN AREAND THE OFFSPRING. >> (INDISCERNIBLE) MAYBE THEY CORRESPOND TO THE SAME LOCI EXCITING. >> I WAS GOING TO ASK QUESTION IN A MINUTE BUT DISCUSSION IS RAISING ANOTHER QUESTION TO CLARIFY STARTING WITH JOSH'S DISCUSSION. SO IF IT'S DETERMINATIVE ADAPTIVE SO IT'S LIKE DETERMINATIVE SEQUENTIAL GENE ACTION AND DEVELOPMENT, AS YOU GO ON INTO AN ADULT LIFE, CERTAINLY THE STOCHASTIC -- THE CHANGES YOU FIND IN NEOPALACE.S, PETER, YOU'RE SILENCING TUMOR SUPPRESSER, MUST BE STOCHASTIC BASICALLY. AND THEN YOU HAVE LOTS OF EVIDENCE OF EPIGENETIC DRIFT. (INAUDIBLE) HAS GIVEN US A GOOD INFORMATION ABOUT DRIFT POST REPLICATIVE CELLS SO CLARIFY MAKE SURE THAT WHAT JOSH IS SAYING EVERYBODY GETS THE SAME GENES ON, SAME GENES OFF, MY NOTION IS THAT THERE'S TREMENDOUS VARIATION AND A LOT OF STO CAST USTY. FILL US IN ON THAT AND THE COGNITIVE STORY. >> THE DATA IS WHAT IT IS. YOU CAN JUST LOOK AT THE TISSUES BETWEEN YOUNG AND OLD YOU SEE REPRODUCIBLE CHANGES IN GENE EXPRESSION. SO >> THIS IS BEYOND THE FORCE OF NATURAL SELECTION. WE ARE WATCHING EVENTS HAPPEN BEYOND THE FORCE, THEY HAPPEN TO BE REPRODUCIBLE. SEEMS LIKE CANCER IS NOT AN EVOLVED PROGRAM. OUT'S GOT TRANSCRIPTION FACTORS, RESULTS ARE PRODUCIBLE CHANGES. P-53 RESULTS IN REPRODUCIBLE CHANGES IN CANCER BUT THAT'S NOT HOW THEY EVOLVE, THEY EVOLVE FOR POSITIVE ROLES DURING DEVELOPMENT AND EVERYTHING WE TALKED ABOUT HAS A POSITIVE ROLE, SOMETIMES DURING YOUNG ADULTHOOD AND WE'RE WATCHING WHAT HAPPENS AND BRIAN SHOWED, I THINK WE AGREE WE'RE TALK ABOUT THE 80-YEAR-OLDS AND OLD WORMS, THEY'RE NOT OBVIOUSLY HAVING JUST LIKE CANCER IS AN EVOLVED PROPERTY. WE CAN STUDY IT AS SOMETHING THAT HAPPENS REPRODUCIBLY. JUST LIKE THE WINEBERG PATHWAY AND VOGELSTEEN PATHWAY, NOT STOCHASTIC, IT'S NOT A BUNCH OF THINGS THAT HAPPENS WILLIE NILLY, BECAUSE IT DIDN'T EVOLVE, IT IS -- P-53 IS EVOLVED MECHANISM THAT HAPPENS. AND IT HAPPENS TO JUST BE ONE OF THE WAYS YOU GET TO GET CANCER BUT IT IS REPRODUCIBLE IN CANCER SO POSSIBLE TO BELIEVE ONE OF THE IDEAS IS THAT WHEN AGING YOU SEE REPRODUCIBLE THINGS HAPPEN. BUT NOT BECAUSE IT EVOLVED. >> SO JUAN DOESN'T SCREAM, SPEAKING OF HIS WORK HE'S ABLE TO SHOW SINGLE CELL LEVEL THAT THERE IS GREAT VARIABILITY WITHIN A TUSH SHOE BETWEEN INDIVIDUAL CELLS. AND WHAT I THINK MIDDLE GROUND WILL TURN OUT TO BE, THE LARGER AMOUNTS OF CELLS EVANS OUT YOU CAN SEE DEFINITE WHAT LOOKS LIKE A PROGRAM, PROBABLY IS NOT BUT IN MY TALK, I HAVE IT ON SLIDES IF ANYBODY IS INTERESTED, BUT WHAT I WAS TRYING TO GET ACROSS WAS THE IDEA RANDOM EVENTS SUCH AS RANDOMLY PLACED DNA BREAKS GIVE RISE TO PROGRAM OR REPRODUCIBLE EFFECT BECAUSE THE CELLS RESPOND TO THAT RANDOM DAMAGE. SO I HOPE THAT HELPS. >> ANOTHER QUESTION MAYBE. >> REALLY QUICKLY, I ALSO WANTED TO ASK ABOUT THE HISTOLOGY OF YOUR MICE WITH AD MODEL. DO YOU STILL SEE GLIOSIS OR MICROGLIA THAT IS ACTIVATED, CAN YOU MEASURE SYNAPTIC DENSITY. SYNAPTIC DENSITY COME UP COME BACK. >> USUALLY DECREASE IT DOES DECREASE? >> IN THE MODELS. >> WITH HDAC INHIBITOR, IS IT COME BACK? >> THAT'S COOL. YEAH. >> YES. >> QUICKLY TELL ME COGNITIVE ASSAYS. >> REALLY MAINLY IN MOUSE THE EASIEST TO DO IS HIPPOCAMPUS DEPENDENT COGNITIVE FUNCTION, ACQUIRE A FEW TESTS, CAN DO SPATIAL MEMORY, ASSAYS ASSOCIATIVE MEMORY, OBJECT RECOGNITION, OBJECT LOCATION SO THERE'S QUITE A FEW. YEAH. >> OKAY. >> THANK YOU. >> (INAUDIBLE) PHILADELPHIA. MY QUESTION IS TRIGGERED BY PETER'S TALK, HIS ANALYSIS OF THE EXPONENTIAL RISE IN CANCER WITH AGE. IT MADE ME WONDER ABOUT A THRESHOLD AFFECT WITHIN CHROMATIN, CHROMATIN EPIGENETIC REMODELING HAVE A THRESHOLD EFFECT SUCH THAT LARGE REGIONS OF THE GENOME ARE REMODELED RAPIDLY SUCH AS DURING IPS DEDIFFERENTIATION PROCESS. IF SO, HAVE IMPLICATION FOR AGING, SO UP THAT TRIGGER, THAT'S CREATING A PROPAGATION WAVE OF CHANGES THAT MAY HAVE IMPRIACATIONS IN LATE LIFE OF DISEASES. >> THAT'S A REALLY INTERESTING POINT WHICH I HADN'T THOUGHT ABOUT BUT I THINK JUST THINKING ABOUT THE BIOCHEMISTRY OF CHROMATIN IT SEEMS ENTIRELY FEEDSABLE. WE KNOW CHROMATIN STRUCTURES HETERO CHROMATIN IN PARTICULAR IS MAINTAINED THROUGH POSITIVE FEEDBACK. DYNAMIC STRUCTURE AND MAINTAINED THROUGH A SYSTEM OF POSITIVE FEEDBACKS. SO I CAN MARGE IF IT STARTS TO COLLAPSE IT WILL GET THE POSITIVE FEEDBACK ALSO COLLAPSE SO YOU CAN CROSS THE THRESHOLD EFFECT WHEN HELL IS LET LOOSE, THAT MIGHT BE CONTRIBUTING TO THE RAPID RISE WITH AGE WHEN PERHAPS THAT INTRACELLULAR THRESHOLD OF CHROMATIN STRUCTURE OR ANY OTHER STRUCTURE IN THIS IS CROSSED. WE COULD BE TALKING ABOUT STRUCTURES WITHIN METABOLIC NETWORKS AS WELL. >> RIGHT. >> GORDON WILL BELIEVE BUCK INSTITUTE. PETER I WANTED TO HEAR YOUR CONCERNS WITH MOUSE MODELS AGE RELATED COMPONENT OF CANCER. EPIGENETICS ISSUE? DOES IT ALSO THREATEN OTHER DISEASES IN TERMS OF THEIR MODELING? >> I HAVEN'T THOUGHT SO MUCH ABOUT OTHER DISEASES SO I'LL LET OTHERS COMMENT BUT MY CONCERN ABOUT THE MOUSE MODELS THAT ARE COMMONLY USED IN CANCER IS SEVERAL. FIRST WE KNOW WITH RESPECT TO CANCER MOUSE CELLS L AND HUMAN CELLS FUNDAMENTALLY QUITE DIFFERENT WHICH IS WHY BOB WINEBERG TRANSFORMED MOUSE CELLS IN 1983 TOOK ANOTHER 15 YEARS TO DO THE SAME EXPERIMENT WITH HUMAN CELLS, JUST FUNDAMENTALLY MORE DIFFICULT TO DO IT. THERE'S VARIOUS REASONS FOR THAT WE CAN GO INTO BUT THIS OTHER PROBLEM SPECIFICALLY WITH THE WAY THE MODELS ARE SET UP AS WELL, FOR EXAMPLE, BASIC PRINCIPLES OF HUMAN CANCER BIOLOGY, A CLONAL DISEASE, IT COMES FROM A MUTATION SINGLE CELL THAT EVOLVES, THE VAST MAJORITY OF MOUSE MODELS OF CANCER OUT THERE, PANCREATIC CANCER, THEY HAVE A TISSUE SPECIFIC CRE WHICH ACTIVATES AN ONCOGENE IN EVERY CELL IN THE TISSUE. YOU NEEDILY LOST WHAT IS THE BIGGEST DETERMINE FANTASTIC THE INITIAL ONCO GENIC EVENT WITHIN A CELL IN A TISSUE IS HANDLED BY THE TISSUE. BECAUSE YOU HAVE INTRODUCED THE MUTATION IN EVERY CELL IN THE TISSUE ALL AT ONCE. CATASTROPHIC THING THAT RARELY IF EVER HAPPENS THIS A HUMAN TISSUE. THE OTHER THING IS THE WAY THE MIND SET OF THE INVESTIGATORS. WE NEED INVESTIGATORS, RESULTS, THIS IS ARGUABLY DRIVEN BY THE DRUG INDUSTRY, PEOPLE WANT RESULTS AS QUICK AS POSSIBLE PUT THE DRUGS TO THE MASSES AS QUICK ADS POSSIBLE SO THEY CAN GET TO THE CLINIC IS QUICK AS POSSIBLE. SO THE EMPHASIS IS PAST MODELS THAT GIVE YOU A RESULT QUICKLY. SO RESULTS OF CANCER OUT THERE WILL DEVELOP CANCER WITHIN WEEKS OR MONTHS. THAT'S GENERALLY CONSIDERED TO BE A GOOD THING WITHIN THE FIELD BUZZ YOU GET YOUR DATA QUICKER. PEOPLE WILL SPEED MODELS UP BY GIVING DSS TOCOLON CANCER MODELS OR INFLAMMATORY AGENTS TO PANCREATIC CANCER MODELS. SO THERE'S NOT REALLY A MIND SET WITHIN THE CANCER FIELD OF TRYING TO RECAPITULATE THAT AGE DEPENDENCE. >> JOE (INAUDIBLE) FROM HEALTH EXTENSION IN CALIFORNIA. SO AGING AND EPIGENETICS, PROBABLY THE MOST EXCITING THING I SAW SO FAR THIS YEAR ON THAT WAS GREG CANON'S PAPER FROM UCSD AND (INAUDIBLE) DOWN THERE WHERE HE FOUND A -- HE FOUND THE BEST BIOMARKER FOR AGING I HAVE EVER SEEN AND HAS A CORRELATION R OF .96 BETWEEN AGE OF HUMAN BEINGS AND SOMETHING YOU CAN MEASURE IN THEIR BLOOD. I DON'T THINK WE HAVE SEEN ANYTHING THAT GOOD LOOKING AT METHYLATION. INTERESTING THINGS YOU SAW IN THERE SEEMINGLY MEN AGE FASTER THAN WOMEN. SO IF YOU USE THE SAME CREATING THE FUTURES FOR HIS COMPONENT ANALYSIS, THEN ON THE SAME CO-ORDINANTS YOU WILL SEE A DIFFERENT SLOPE FOR WOMEN AN MEN WHICH I THOUGHT WAS INTERESTING AND I WONDER YOU GUYS SADDENING LIKE THAT. ALSO DIFFERENT TISSUES. >> I COMPLETELY AGREE WITH YOU THAT'S AN INCREDIBLE RESULT. IT'S THE DNA METHYLATION IN CASE YOU DON'T KNOW THE DNA METHYLATION STATE AND LYMPHOCYTE FROM PEOPLE, THERE'S TRAY IDEKER AND OTHERS DEVELOPED AN ALGORITHM THAT CAN PREDICT AGE OF THE PERSON WITH THIS CORRELATION OF .96. I TALKED TO TRAY LAST WOKE AND SAY HE AGREES THIS IS MAGIC BUT HE DIDN'T SAY HE KNEW WHY IT WORKED BUT THAT KIND OF INCREDIBLE LINK SAID L SOMETHI IMPORTANT IS GOING ON. I THINK THAT WOULD BE AN AMAZING RESULT AND I THINK SHOULD BE FOLLOWED UP. >> WE PUBLISHED A PAPER IN AGING CELL SHOWING THAT THERE IS AN INCREASE METHYLATION OF THE LL-2 GENES AND OTHER COUPLE OF GENES AND THE CORRELATION WITH AGE IN 500 PEOPLE IS .99. SO IT IS PUBLISHED. >> SO WHAT THE IS THE MECHANISM? >> SO WE'LL CLOSE THIS SESSION. THANK YOU, VERY MUCH FOR YOUR TIME. [APPLAUSE]