>> GOOD AFTERNOON, MY NAME IS YOUNG OH, AND I AM WITH THE NHLBI, TODAY WE HAVE DR. JOANNE MURABITO, SHE IS FROM THE CLINICAL AT THE FRAMINGHAM HEART STUDY WHICH IS ONE OF THE LONGEST RUNNING PROGRAMS IN CARDIOVASCULAR DISEASE IN NHLBI AND HER RESEARCH HAS BEEN FOCUSED ON AGING AND WITH THE TRAITS AND PLANNING AND BEYOND. STATISTICALLY HER RESEARCH PROGRAM FOCUSES ON USING TOOLS OF EPIDEMIOLOGY AND GENETIC PLATFORMS TO BETTER UNDERSTAND AND AGE RELATED THINGS SHE LEDS SEVERAL CONSORTIA TO UNDERSTAND GENES FOR AGE-RELATED TRAITS AND AGE AND MENOPAUSE AND LONGEVITY. HER RESEARCH HAS DEMONSTRATED MULTIPLE LOCI, UNDERLYING WITH PRODUCTIVE AGING WHICH ARE ASSOCIATED WITH MANY DOWN STREAM AGING RELATED DISORD ORDERS SUCH AS OBESITY, DNA DAMAGE AND REPAIR AND IMMUNE FUNCTION. HER TITLE OF HER TALK TODAY IS AGING GENETIC FEIGNEE TYPES OVER THE COURSE OF POPULATION LIFE EXPECTANCY. WELCOME. >> WELL, THANK YOU FOR INVITING ME TO THIS SEMINAR, I WILL GIVE A BRIEF OVERVIEW OF THE FRAMINGHAM HEART STUDY I WILL FOCUS ON THE MAIN PART OF MY TALK ON THE INVESTIGATION OF PHENOTYPES, AND I WILL START WITH LONG INDIVIDUALS AND THEN I WILL BACK UP TO MIDLIFE, TO THE TIME OF MENOPAUSE AND THEN I WILL GO EARLY IN LIFE TO THE TIME OF MENARCHE. I WILL SPEND A BIT OF TIME ON THE USE OF OTHER OMICSS AND THEN I WILL TALK ABOUT A COLLABORATION WITH BASIC SCIENTISTS. SO THE FRAMINGHAM HEART STUDY IS A LONG STEWEDINAL STUDY FUNDED BY NHLBI, IT STARTED BACK IN 1948 WHEN THE ORIGINAL COHORT RECRUITED THERE WASSIFY THOUSAND 209 IN THE BEGINNING AND THEY'VE BEEN FOLLOWED EVERY TWO YEARS, THEY'VE UNDERGONE 32 EXAMINATIONS. IN THE EARLY 1970S THE CHILDREN OF THE ORIGINAL COHORT AND THEIR SPOUSES GROUPS WERE RECRUITED AND THEY'VE BEEN EXAMINED EVERY FOUR-EIGHT YEARS AND COMPLETED NINE EXAMS AS OF THIS YEAR IN 2014. THE GRANDCHILDREN OF THE ORIGINAL COHORT AND CHILDREN OF THE OFFSPRING STUDY WERE RECRUIT INDEED 2002. THEY'VE COMPLETED TWO EXAMS AS OF 2008 AND ARE UNDERGOING ACTIVE SURVEILLANCE. THE TOWN OF FRAMINGHAM LOOKED LIKE THIS BACK IN 1960 AND WAS COMPRISED OF WHITE INDIVIDUALS SO OUR THREE COHORTS HERE ARE PRIMARILY WHITE. THEREFORE IN 1995, WE RECRUITED THE OMNISTUDY WHICH REFLECTS THE DIVERSITY OF THE UNITED STATES AS IT IS TODAY AND IN 2002, WHEN WE RECRUITED THE THIRD GENERATION, WE RECRUITED THE SECOND GENERATION OF OMNIPARTICIPANTS. MY PRESENTATION TODAY IS GOING TO FOCUS ON THE ORIGINAL COHORT OFFSPRING AND THIRD GENERATION BECAUSE THAT'S WHERE WE HAVE THE DENSE GENOTYPING. UNTIL VERY RECENTLY WE DIDN'T HAVE GENO TYPING IN THE OMNI COHORT. THIS PICTURE IS FROM LIFE MAGAZINE IN THE MID1980S AND YOU CAN SEE THIS PARTICIPANT HERE AND HER DAUGHTER AND CAN YOU SEE THEM AGAIN HERE IN 2014 WHEN OUR CLINIC DIRECTOR WENT AT A HOME VISIT AT EXAM 32 AND I THINK THIS SPEAKS TO THE POWER OF THE FRAMINGHAM HEART STUDY. THESE PARTICIPANTS HAVE BEEN EXAMINED OVER THEIR COMPLETE ADULT LIFE COURSE. AND IF ANY OF YOU HAVE BEEN TO THIS TOWN, IT READS, THE TOWN THAT CHANGED AMERICA'S HEART, HOME OF THE FRAMINGHAM HEART STUDY. I BELIEVE THIS DATABASE CAN HELP US UNDERSTAND AGING AND HELP PEOPLE LIVE A LONG AND HEALTHY LIFE. SO FRAMINGHAM HEART STUDY PARTICIPANTS HAVE RICH CHARACTER BECAUSE IT PROVIDED THE BACKBONE ON TO WHICH MANY INVESTIGATORS HAVE RO-1s AND SO WE HAVE INFORMATION ON DEMENTIA AND STROKE AND OSTEOPOROSIS, OSTEOARTHRITIS, CANCER, DIABETES AND MANY OTHER DISEASES OF AGING. TODAY I'M GOING TO FOCUS ON LONGEVITY AND REPRODUCTIVE AGING. WE ALSO HAVE A RICH GENETIC AND GENOMIC DATABASE. OUR PARTICIPANTS HAVE INFORMATION ON EPIGENETICS, TRANSCRIPTOMICS, METABALOMICS. SO CAN WE DETECT NOVEL GENETIC VARIANTS ASSOCIATE WIDE LONGEVITY AND AGE-RELATED TRAITS AND MAY PROVIDE IMPORTANT INSIGHT INTO AGING BIOLOGY AND HELP US UNDERSTAND THE WIDE VARIATION IN AGING IN OLDER AMERICANS. AND CAN WE DO THIS BY USING GENETIC ASSOCIATION STUDIES IN HUMANS. THIS IS MOTIVATED BY ANIMAL STUDIES THAT IDENTIFIED GENES THAT WERE RELATED TO LIFE SPAN AND WE CAN SEE THIS IN HUMANS WITH THE GENE MUTATION WHICH HAS BEEN ASSOCIATED WITH MORTALITY, DECREASED HARDIO VASCULAR DISEASE AND IMPROVED COGNITION. HOWEVER IN HUMANS THIS REQUIRES LARGE STUDY COHORTS WITH INDEPENDENT STUDIES FOR REPLICATION. SO HOW DO WE DEFINE LONGEVITY AND MORE IMPORTANTLY COMPARISON GROUP WHEN WE'RE USING POPULATION BASED COHORTS? IN THINKING ABOUT THIS, I LOVE THIS HISTORICAL TIMELINE THAT THE U.S. CENSUS BURRO PUT OUT AND--BUREAU PUT OUT AND THIS IS A TIMELINE THAT A PERSON IN 1890 WOULD HAVE LIVED THROUGH IF THEY ACHIEVED SENTENARRIAN STATUS IN 1990 AND WOULD YOU SEE THAT THAT PERSON WOULD HAVE SURVIVED WORLD WAR ONE, FLU EPIDEMIC, START OF THE GREAT DEPRESSION AND THE START OF WORLD WAR II AND THIS SPEAKS TO THE IMPORTANCE OF ADJUSTING FOR BIRTH COHORT AND COMPARISON GROUP WHEN WE'RE DESIGNING THE STUDIES OF LONGEVITY. SO THIS SLIDE SHOWS THE SENTARRIAN EXPERIENCE IN THE STUDY AND OUR CENTENARIAN WERE BORN FROM 1890-1913 AND WE HAVE 70 AND OUR COMPARISON GROUP WE RESTRICTED OUR PARTICIPANTS BORN IN THE SAME BIRTH YEARS. SO 14% OF OUR CENTENARIANS ARE MEN, ONE IN SEVEN WHEREAS 45 PERCENT OF THE COMPARISON GROUP ARE MEN AND YOU CAN SEE RATES FROM STUDY ENTRY IN 1948, THE CENTENARIANS LOOK DIFFERENT, THEY HAVE BETTER BLOOD PRESSURE PROFILE, THEY'RE LESS LIKELY TO BE SMOKERS. ONE OTHER THING THAT WE CAN DO THAT OTHER CENTENARIANS CAN'T DO IS WE CAN FOLLOW THESE PEOPLE OVER THEIR WHOLE ADULT LIFE COURSE. SO THIS IS JUST ONE CHARACTERISTIC, THIS IS BODY MASS INDEX AND CAN YOU SEE THIS IS FROM THEIR FIRST EXAM ALL THE WAY TO THEIR 28th EXAM. THE CENTENARIANS ARE SHOWN IN BLUE AND THE NONCENTENARRIANS ARE SHOWN IN RED AND THE LINE IS SHOWING UP WITH THE NONCENTENARRIANS PARTICIPANTS AND YOU CAN SEE THE NUMBERS DROP OFF AS THE EXAMS GO ON BECAUSE THE NONCENTENARRIANS ARE DYING AND I THINK IT'S INTERESTING THAT THE CENTENARIANS ARE INCREASING IN BODY MAX AND THIS IS DUE TO THE AGE RELATED MORBIDITY. NOW WE'RE JUST DIGGING INTO THIS DATA. SOPHISTICATEDY WE HAVE A LOT MORE WORK TO DO TO FIGURE OUT THESE TRENDS. THESE GRAPHS SHOW SURVIVAL FROM STUDY ENTER BY CENTENARIAN STATUS IN THE PARTS STUDY AND WE'RE SEEING PRETTY MUCH THE CENTENARIAN STUDIES HAVE SEEN, THE CENTENARIANS ARE SHOWN IN THE RED LINE AND THE NONRED CENTENARIANS IN THE BLUE LINE AND DELAY IN ONSET AND CARDIOVASCULAR DISEASE AND CANCER, DEMENTIA AND ANY OF THESE THREE TYPES OF DISEASES. SO THE CENTENARIANS CERTAINLY ARE A GOOD PHENOTYPE FOR DELAY AND AGE RELATED DISEASE BUT IN A POPULATION STUDY LIKE THE FRAMINGHAM HEART STUDY WE DON'T HAVE ENOUGH NUMBERS TO CONDUCT THE GENOME WIDE ASSOCIATION STUDY. SO WE NEED TO LOOK AT OTHER PHENOTYPES AND THE FIRST THING WE WANT TO DO IS CONDUCT A HERITABILITY STUDY TO LOOK AT THE CONTRIBUTION OF GENETICS TO DIFFERENT LONGEVITY PHENOTYPES SO FIRST WE LOOK AT AGE OF DEATH AS A CONTINUOUS TRAIT AND THE HERITABILITY WAS MODEST AT 22%. WE THEN LOOK AT HERITABILITY OF SURVIVAL TESTS, DIFFERENT AGES AND YOU CAN SEE THAT THE HERITABILITY INCREASED AND WAS MUCH MORE SUBSTANTIAL. SO NEXT WE CONDUCT A STUDY WITHIN THE CHARGE CONSORTIUM. WE HAD THE LONGITUDIAL COHORT STUDIES, THE AGES STUDY, CARDIO HEALTH STUDY, FRAMINGHAM AND ROTTER DAM AND HERE WE DEFINED SURVIVAL AS OVER 90 YEARS AND WE WERE ABLE TO ACCUMULATE LONG LIVED INDIVIDUALS WITH GENOTYPING. OUR COMPARISON GROUPS WERE DRAWN FROM EACH COHORT, HOWEVER WE WERE NOT ABLE TO GET VERY MUCH OVERLAP IN BIRTH COHORT EVEN DRAWING THE COMPARISON GROUP FROM THE SAME COHORTS. WE'VE LIMITED OUR COMPARISON GROUP TO PERSONS WHO DIED BETWEEN THE AGES OF 55 AND 80 SO THAT PEOPLE IN THE COMPARISON GROUP COULD NOT ACHIEVE LONGEVITY AND WE IDENTIFIED TWO INDEPENDENT COHORTS OF LONG LIVED INDIVIDUALS TO DO VALIDATION STUDIES. YOU CAN SEE IN THIS SLIDE THAT NONE OF OUR ASSOCIATIONS ACHIEVED GENOME WIDE SIGNIFICANCE. THE OBSERVED KEY VALUES ARE SHOWN ON THE X-AXIS AND EXPECTED ON THE Y-AXIS AND WE SEE NO DEVIATION. THE CHROMOSOMAL LOCATIONS ARE SHOWN IN THE MANHATTAN PLOT HERE AND THE P-VALUES AND THE GENOME WIDE EXPECTED THRESHOLD HERE. WE HAD 24 SNP ASSOCIATIONS THAT WERE SUGGESTED AND WE TOOK THESE ON TO OUR TWO INDEPENDENT COHORTS. IN THIS SLIDE WE SHOWED THE FORCED PLOT FOR THE STRONGEST ASSOCIATION FOR LONGEVITY WHICH WAS A SNP IN THE MNPP-ONE GENE HERE ARE OUR DISCOVERY COHORTS AND OUR TWO INDEPENDENT COHORTS AND THIS SNP WAS ASSOCIATE WIDE THE LOWER ODDS OF LONGEVITY. SO WHAT IS THE UNDERLYING BIOLOGY FOR THIS GENE? THIS GENE CODES A MULTIPLE ION CYTOSOL POLYPHOSPHATE IN THE COMPARTMENTALIZED TO ENDO PLAYSIC RETIC CUE LUM. THIS HAS NO OBVIOUS DEFECTS. TARGETED INVITRO IS ASSOCIATE WIDE SLOW PROLIFERATION. WE WEREN'T SURE HOW THIS GENE WAS WORKING TO CAUSE A DECREASE IN LONGEVITY. WE HAVE SENSE CONDUCTED AN EXPANDED GWAS LONGEVITY AND CHARGE WITH 13 COHORTS AND 6000 LONG LIVED INDIVIDUALS AND AGAIN DID NOT IDENTIFY ANY NOVEL GENES ASSOCIATE WIDE LONGEVITY. WE WERE ABLE TO CONFIRM THE ASSOCIATION WITH APOE AND FOSTER NURSED - -FOXO-THREE AND THOSE ARE KNOWN CANDIDATES. AT ABOUT THE SAME TIME OUR COLLEAGUES IN EUROPE CONDUCTED A GENOME WIDE ASSOCIATION STUDY IN PERSONS AGE 90 AND OLDER AND THEY ALSO IDENTIFIED E-LOCUST AND WE'RE ABLE TO IDENTIFY A SECOND LOCUST NEAR EVSONE WHICH WAS ASSOCIATED WITH THE INCREASED ODDS OF ACHIEVING LONGEVITY. THEY THEN CONDUCTED A PROSPECTIVE ANALYSIS AND AN INDEPENDENT SAMPLE AND THIS LOCUST APPEARED TO BE ASSOCIATED WITH DECREASED ALL-CAUSE MORTALITY AND THAT MORTALITY SEEMED TO BE ASSOCIATED WITH CARDIOVASCULAR MORTALITY, MAINLY THROAT MORTALITY. THIS GENE HAD BEEN ASSOCIATED WITH BLOOD PRESSURE AND GWAS OF BLOOD PRESSURE TRAITS AND THEY DID CONTROL FOR BLOOD PRESSURE AND STILL FOUND A DECREASE IN CARDIOVASCULAR AND STROKE MORTALITY SO THEY BELIEVED THAT THE BIOLOGIC FUNCTION IS INDEPENDENT OF LOWERING BLOOD PRESSURE. SO WHAT WENT WRONG IN OUR STUDIES. WHY DID WE HAVE SO FEW FINDINGS DESPITE SUCH LARGE SAMPLES OF LONG LIVED INDIVIDUALS. WAS OUR PHENOTYPE NOT EXTREME NOW ENOUGH. WE WEREN'T LOOKING AT CENTENARIANS, WE WERE LOOKING AT PEOPLE WHO ACHIEVED AGE 90 OR GREATER; IS THE PHENOTYPE JUST TWO HETEROGENEOUS, WE HAVE SEEN THESE PICTURES OF THIS CENTENARIAN WHOSE ABLE TO RUN A MARATHON OR THIS 104 YEAR-OLD WHO DOES A SPRINT OR THIS WOMAN WHO'S ABLE TO PLAY TABLE TENNIS BUT WE KNOW THAT THERE'S A RANGE OF HEALTH STATUS EVEN AMONG CENTENARIANS. SHOULD WE BE LOOKING AT OTHER AGING PHENOTYPES TO IDENTIFY AGING BIOLOGY IN OUR GWAS STUDIES. IS IT REALLY JUST RARE VARIANTS, THESE FEW ARE TAGGING COMMON VARIATION ACROSS THE GENOME. IS IT EPIGENETICS, IS IT THE ENVIRONMENT? I WOULD LIKE TO NOW FOCUS ON OTHER AGING PHENOTYPES EARLIER IN THE LIFE COURSE. SO CAN WE LEARN SOMETHING BY LIKING AT OVORRIAN AGING. BACK AT THE PREPRODUCTION MEET THANKSGIVING OCTOBER BIOMARKERS FOR OVARIAN AGING WERE LINKED TO RISK SCORES IN WOMEN AGE 25-45 AND FRAMING HALF RISK SCORE HAS BEEN ASSOCIATED WITH TENURE RISK FOR CARDIOVASCULAR DISEASE AND THESE WERE ALSO LINKED TO SHORTER TELOMERES. THIS LED DR. JOANNE MANSON AT THE SCHOOL OF HARVARD SCHOOL OF PUBLIC HEALTH TO RAISE THIS SAYING IT IS A VERY PROMISING HYPOTHESIS THAT REPRODUCTIVE AGING CAN SERVE AS A WINDOW INTO CARDIOVASCULAR HEALTH AND CELLULAR AGING PROCESS ITSELF. SO CAN WE USE AGE TO UNCOVER AGING BIOLOGY? WE CAN SEE HERE THAT THE TIMING OF AGE AT MENOPAUSE IS ASSOCIATE WIDE CARDIOVASCULAR DISEASE, OSTEOPOROSIS, AND A NUMBER OF CANCERS. DR. HARTGE, AT NCI SAID THAT THE GENETIC ASSOCIATIONS SHOULD PROVIDE INSIGHT INTO THE TIMING OF MENOPAUSE BUT MAY ALSO YIELDED BREAK THROUGHS IN THE UNDERSTANDING OF THE GENETIC VARIATION CONFERRING RISK OF BREAST CANCER CARDIOVASCULAR DISEASE AND OTHER HEALTH EVENTS OF LATER ADULTHOOD. AND WE'RE TALKING ABOUT NHLBI STUDIES AND HERE'S THE MESSENTERY STUDYING AND WE CAN SEE HERE THAT CLEARLY MENOPAUSE IS ASSOCIATE WIDE AGE-RELATED DISEASES. EARLY MENOPAUSE WAS ASSOCIATE WIDE CORONARY DISEASE AND STROKE COMPARED TO MENOPAUSE THAT OCCURRED LATER. EPIDEMIOLOGIC STUDIES, MENOPAUSE IS DEFINED AS THE ABSENCE OF MENSTRUAL PERIODS FOR ONE YEAR OR MORE. AND IN THIS HISTOGRAM WE SEE THE NORMAL RANGE OF AGE IN THE POPULATION AND IT NORMALLY OCCURS BETWEEN THE AGES OF 40 AND 60. AND MENOPAUSE THAT OCCURS BEFORE AGE 40 IS CONSIDERED PRIMARY OVARIAN INSUFFICIENCY AND WITH THE INCREASE IN LIFE EXPECTANCY IN THE POPULATION, WOMEN ARE SPENDING ABOUT ONE-THIRD OF THEIR YEARS IN THE POST MENOPAUSAL PERIOD. SO WHAT IF WE LOOK AT GENETIC CONTRIBUTION TO MENOPAUSAL TIMING. ESTIMATES OF HERITABILITY OF AGE AT NATURAL MENOPAUSE RANGE FROM 50-70%. THIS IS SUBSTANTIALLY HIGHER THAN THAT FOR LONGEVITY AND THIS MEANS THAT PERHAPS WE WOULD BE MUCH MORE SUCCESSFUL IN IDENTIFYING GENETIC VARIANCE FOR AGE AT MENOPAUSE. IN CONTRAST THE VARIATION IN AGE ASTERISKS MENOPAUSE AND DUE TO ENVIRONMENTAL CHAPTERS SUCH AS SMOKING, PARITY, SOCIOECONOMIC STATUS, DECADE OF BIRTH IS ONLY FIVE%. WE CAN ALSO LOOK AT THE FAMILY AGGREGATION OF MENOPAUSAL AGE AND HERE WE SEE THAT A WOMAN'S MOTHER HAD AN EARLY AGE AT MENOPAUSE. SHE HERSELF HAS SIX TIMES THE ODDS OF AN EARLY MENOPAUSE. SIMILARLY, A WOMAN HAS A MOTHER WITH A LATE MENOPAUSE, SHE HERSELF HAS SIX TIMES THE ODDS OF A LATE MENOPAUSE. SO MENOPAUSAL TIMING HAS HIGH AND SUBSTANTIAL HERITABILITY AND HIGH FAMILIAL AGGREGATION. SO WITHIN THE RESEARCH CONSORTIUM WE CONDUCTED A GWAS OF AGED NATURAL MENOPAUSE. PEOPLE WERE OF EUROPEAN ANCESTRY, CONSORTIUM IS INTERNATIONAL. WE DID STUDIES ACROSS THE UNITED STATES, EUROPE, AND AUSTRALIA, WE HAD 22 STUDIES IN THE DISCOVERY STAGE. HERE WE HAVE NOW OVER 38,000 WOMEN. WE HAD 21 STUDIES IN THE REPLICATION STAGE. WE DEFINED AGE OF NATURAL MENOPAUSE AS A QUANTITATIVE TRAIT BETWEEN 40 AND 60 YEARS. WE EXCLUDED WOMEN WITH SURGICAL MENOPAUSE. MENOPAUSE DUE TO CHEMO THERAPY OR RADIATION AND WE EXCLUDED WOMEN USING HORMONE REPLACEMENT THERAPY OR ORAL CONTRACEPTIVES. THE META-ANALYSIS RESULTS FOR AGE OF NATURAL MENOPAUSE ARE SHOWN IN THE PLOT HERE AND YOU SEE WE WERE ABLE TO REPLICATE FINDINGS ON CHROMOSOME 20, 19, FIVE, AND SIX. THESE HAD BEEN PREVIOUSLY REPORTED IN THE LITERATURE, THERE HAD ALSO BEEN A REPORT OF A GENE ON CHROMOSOME 13 WHICH WE WERE NOLL ABLE TO REPORT. SO WHAT IS KNOWN ABOUT THE BIOLOGY OF THESE GENES AND HOW MIGHT THEY BE LINKED TO AGE AT MENOPAUSE AND AGING? SO MCM-EIGHT IS A MINICHROMOSOME MAINTENANCE COMPLEX COMPONENT EIGHT. IT'S A HIGHLY CONSERVED PROTEIN. IT'S BEEN PROVED TO BEALCY EXPRESSED IN THE HUMAN OVARIAN FOLLICLE, IT'S APPROVED FOR REPLICATION THE MCM-EIGHT AND NINE PROTEINS ARE RECRUITED TO DNA DAMAGE SITES. MCM-EIGHT AND NINE PROTEIN COMPLEX PLAYS A ROLE IN HOMOLOGOUS RECOMBINATION AND PROBABLY PLAYS A ROLE FOR MEIOSIS OR IN GERM CELL VIABILITY. INTERESTINGLY, UIMC-ONE IS MODERATELY EXPRESSED IN THE OVARY, THYMUS, HEART AND HIGHLY EXPRESSED IN THE TESTIS. THIS GENE IS REQUIRED FOR DNA DAMAGE RESISTANCE, CHECK POINT CONTROL AND DNA REPAIR. IT PLAYS A CENTRAL ROLE IN THE DNA DAMAGE RESPONSE BY RECRUITING BRCA ONE AND TWO TUMOR SUPPRESSORS TO DNA DAMAGE FOCI. SO THROUGH IDIDN'TIFYING THESE WE FOUND 13 NOVEL LOCI IN HORMONAL IMMUNE AND ADDITIONAL DNA REPAIR PATHWAYS. THESE TWO GENES ARE ASSOCIATED WITH PRIMARY OVARIAN INSUFFICIENCY. THIS GENE IS A PRIMARY BINDING PARTNER FOR FMRONE WHICH IS KNOWN TO BE ASSOCIATE WIDE FRAGILE X, THIS GENE IS A MITOCHONDRIAL DNA POLYMERASE, IN A MOUSE KNOCK OUT MODEL, IT'S KNOWN TO CAUSE PREMATURE AGING. THESE MICE HAVE PREMATURE KYPH OSIS, OSTEOPOROSIS AND HEART DEFECTS. THESE TWO GENES ARE INVOLVED IN THE IMMUNE SYSTEM. THIS FAMILY OF GENES ADDITIONALLY IS INVOLVED IN THE REPRODUCTIVE SYSTEM AND BEEN ASSOCIATED ALSO WITH PREMATURE OVARIAN INSUFFICIENCY, PRRC-TWOA ACTUALLY ON CHROMOSOME SIX LIES IN THE CELL COMPATIBILITY COMPLEX AND HAS BEEN ASSOCIATED WITH INSULIN DEPENDENT DIABETES. IT'S ASSOCIATE WIDE PANCREATIC BETA CELL OBSTRUCTION AND INFLAMMATION. MANY OF THE ADDITIONAL GENES ARE INVOLVED IN THE BETA PATHWAYS. WE THEN WENT ON TO DO SEVERAL TYPES OF PATHWAY ANALYSIS TO UNDERSTAND THE BIOLOGIC MECHANISM ASSOCIATED WITH OUR GWAS HITS AND WE IDENTIFIED NINE OF OUR CANDIDATE GENES, ASSOCIATED WITH THE DNA DAMAGE AND REPAIR AND REPLICATION PATHWAY. THESE GENES SEEM TO LIE IN MULTIPLE DIFFERENT DNA DAMAGE AND REPAIR PATHWAY MECHANISM. UIMC-ONE AND FAM175A IS IN THE PATCH REGENE, HELQ IS AN INTER-STRAND DNA CROSS LINK, REPAIR GENE AND FUNCTIONS IN THE GERM CELL MAINTENANCE AND TUMOR SUPPRESSION PATHWAY AND AS I STATED POLG IS IMPORTANT FOR THE MITOCHONDRIAL GENOME. SO WHAT IS THE BIOLOGIC MECHANISM THAT LINKS DNA DAMAGE AND REPAIR GENE IN MENOPAUSE. IT HAS BEEN SHOWN THAT DOUBLE STRANDED BREAKS IN DNA IN HUMAN OOCYTES, AT THE THERE'S DOUBLE STRAND BREAKS IN BOTH MICE AND HUMAN OOCYTES, THE BRACA-ONE, RAD 51, ATM, AND MRE 11 ARE EXPRESSION WITH AGE, THIS CAUSES APOPTOSIS, OOCYTE LOSS, DIMINISHED OVARIAN RESERVE AND WE THINK THIS IS THE UNDERLYING LINK TO MENOPAUSE. WE CONDUCTED INGENUITY PATHWAY ANALYSIS TO LOOK FOR BIOLOGIC PROCESSES. WE WAITED FOR MENOPAUSE TIMING GENES, THE TOP SIGNIFICANT NETWORKS ARE SHOWN IN THIS SLIDE, NETWORK ONE IS ASSOCIATE WIDE LIPID METABOLISM AND SMALL MOLECULE, BIOCHEMISTRY, THE GENE IN THE CENTRAL NODE IN THIS NETWORK WAS HNF A-FOUR, THIS IS THE GENE INVOLVED IN GLUE CONEOGENESIS AND PLAYS A ROLE IN DIABETES. OUR SECOND NETWORK, THE CELL CYCLE, CELL DEATH AND CANCER, ESR ONE WAS CENTRAL TO THIS NODE AND IMPLICATIONS ESTROGEN SIGNALING IN THIS NETWORK, OUR THIRD NET WORK WAS CELL DEATH, HEMEAT O LOGIC SYSTEM DEVELOPMENT AND CELLULAR DEVELOPMENT, GENES IN THIS NETWORK ARE TNF AND NF-kappaB SIGNALING AND OF COURSE OUR FOURTH NETWORK WITH DNA REPLICATION AND REPAIR. WE ALSO DID A SMALL SET ENRICHMENT ANALYSIS WHICH WAS IMPLEMENTED IN MAGENTA AND GOT COMPLIMENTARY PATHWAYS, EXODEOXYRIBONUCLEAS AND THIS PATHWAY WAS WARNER SYNDROME GENE WHICH IS A PREMATURE AGING SYNDROME GENE. WE SEE AGAIN NF-kappaB SIGNALING AND MIGHT O CONDKHIHIGHAL DISTONKS. WE NEXT CONDUCTED A VARIANT ANALYSIS OF MENOPAUSE AND MENARCHE, AND IDENTIFIED A NOVEL GENE ASSOCIATE WIDE MENOPAUSE, THE MH-16 AND THE GENE THAT IMPOSES ANOTHER DNA MISMATCHED REPAIR GENE TOIE KNOWLEDGE IT HAD NOT BEEN ASSOCIATE WIDE PREPRODUCTIVE AGING OR FUNCTION. IT'S ASSOCIATE WIDE ENDOMETRIAL CANCER, COLON CANCER AND FAMILIAL MISMATCH CANCER REPAIR SYNDROME AND IT ALSO FUNCTIONS IN THE BR CA-ONE RELATED PATHWAY. WE ARE CURRENTLY CONDUCTING EXPANDED MENOPAUSE GWAS AND NOW HAVE 69,000 WOMEN, WE IDIDN'TIFIED 64 SIGNALS AND GENOMIC REGION, THESE SIGNALS ARE ENRICH INDEED THE DNA DAMAGE RESPONSE AND 29 OF THE 64 REGIONS ARE IN THIS PATHWAY AND THEY APPEAR ACROSS ALL DIFFERENT TYPES OF DNA DAMAGE RESPONSE PATHWAY. 15 OF THESE REGIONS ARE LINKED TO BRCA-ONE. WE ARE COLLABORATING WITH THE BREAST CANCER ASSOCIATION CONSORTIUM AND HAVE DEVELOPED HOW THESE ARE RELATED TO BREAST CANCER, WE'RE BREAKING DOWN OUR RISK FOR AND THOSE GENES RELATED TO THE DNA DAMAGE RESPONSE VERSES THOSE THAT ARE NOT. WE'RE LOOKING FOR COLLABORATORS WITH ACCESS TO OTHER TYPES OF CANCERS THAT WE WOULD LIKE TO LOOK AT HOW THESE ARE ASSOCIATE WIDE OTHER ESTROGEN CANCERS AND HOW THESE GENES ARE NOT ONLY ASSOCIATED WITH CANCERS IN WOMEN BUT IN PARTICULAR PERHAPS PROSTATE CANCER. FOR THE FIRST TIME WE'RE ALSO SEEING GENE OVERLAP FOR MONOGENIC DISORDERS OF PUBERTY AND MENOPAUSE. SO THIS HAS NOT BEEN PUBLISHED YET. SO TO SUMMARIZE, WE HAVE IDENTIFIED GENES IN MENOPAUSE TIMING THAT ARE SIMILAR TO AGING, THE DNA DAMAGE RESPONSE AND NF-kappaB SIGNALING, LIPID TRAFFICKING AND MIGHT O CHOND RIIAL DYSFUNCTION, THESE PATHWAYS ARE ASSOCIATE WIDE GENETIC DISORDERS OF AGING SUCH AS LEARNER SYNDROME AND PROGERIA, AND WE BELIEVE WEES ARE BEGINNING TO UNRALPH THE EPIDEMIOLOGIC ASSOCIATION BETWEEN MENOPAUSE TIMING AND A NUMBER OF AGE RELATED DISEASES. WE CERTAINLY HAVE A LOT MORE WORK TO BE DONE BUT WE'RE CERTAINLY UNCOVERING SOME OF THE PATHWAYS HERE. AND WE BELIEVE THAT MENOPAUSE TIMING AND AGE AT MENOPAUSE IS A GOOD WAY TO GET AT THE BIOLOGY UNDERLYING AGING AND THE CONNECTION TO AGE RELATED DISEASES. SO WHAT IF WE LOOK A LITTLE EARLIER IN THE LIFE COURSE, WHAT TRIGGERS AND UNDERLIES PUBERTY, SCIENCE MANAGE VENE IN 2005 IDENTIFIED THIS AS ONE OF THE UNANSWERED QUESTIONS: WHAT DON'T WE KNOW? AND WHY MIGHT NHLBI HAVE INCLUDED THIS QUESTION AS ONE OF THE QUESTIONS IN ITS COHORTS. MANY PEOPLE DON'T KNOW THAT PUBERTY TIMING OR MENARCHE TIME SUGGEST ASSOCIATE WIDE MORTALITY AND IN TAKEN--THEY PARTICULAR CARDIOVASCULAR MORTALITY. THIS DATA IS FROM THE STUDY, BUT YOU CAN SEE HERE THAT TIMING OF MENARCHE IS ASSOCIATE WIDE ALL CAUSE MORTALITY, CARDIOVASCULAR MORTALITY AND CANCER MODEL CITIZEN MORTALITY AND THESE MORTALITY ASSOCIATIONS HOLD UP AFTER ADJUSTING FOR IMPORTANT CONFOUNDERS AND EVEN AFTER ADJUSTING FOR BODY MASS INDEX. THIS SLIDE SHOWS THE ASSOCIATION OF MENARCHE RELATED DISEASE TYPE TWO DIABETES. THE UNADJUSTED ASSOCIATIONS ARE SHOWN IN BLACK AND THE ASSOCIATIONS ADJUSTED FOR BMI ARE SHOWN IN THE WHITE CIRCLE AND YOU CAN SEE THAT WITH EARLIER MENARCHE, THE HAZARD FOR TWO TYPE DIABETES INCREASES AND IT PERSISTS AFTER ADJUSTMENTS FOR BODY MASS INDEX. SO AGAIN WE THINK THAT LOOKING AT THE TIMING OF MENARCHE MAY TELL US SOMETHING ABOUT THE BIOLOGY OF AGING AND THE ASSOCIATION WITH AGE RELATED DISEASES. AND OUR COHORT, MENARCHE AND THE AGE IS HIGHLY CORRELATED WITH THE R-SQUARED OF .8. THERE'S BEEN A CLEAR TEMPORAL DECLINE IN AGE OF MENARCHE, ACROSS BIRTH YEARS. THIS IS SEEN NOT ONLY IN THE UNITED STATES BUT IN CANADA AND EUROPE, SO WE'RE CAREFUL TO ADJUST FOR BIRTH YEAR IN ALL OF OUR GENOME WIDE ASSOCIATION STUDIES. THIS IS BELIEVED TO BE DUE TO IMPROVED NUTRITION. SO OUR FIRST GENOME WIDE ASSOCIATION STUDY WAS CONDUCTED IN ABOUT 17,000 WOMEN AND WE IDENTIFIED TWO LOCI INTO INFLUENCING AGE AT MENARCHE, AND AT THE SAME TIME THREE ADDITIONAL GROUPS IDENTIFIED THE SAME TO LOCI, WE WERE REALLY EXCITED TO SEE THIS ASSOCIATION WITH LYNN-28 B IT HA BEEN ASSOCIATE WIDE HEIGHT IN GWAS OF HEIGHT AND THE DIRECTION WAS CONSISTENT WITH THE EPIDEMIOLOGIC DATA SHOWING THAT GIRL WHO IS ENTERED PUBERTY EARLIER WERE SHORTER IN STATURE AS ADULTS. MORE IMPORTANTLY WHAT DO WE KNOW ABOUT THE BIOLOGY OF THIS GENE LYNN 28 B AND ITS HOMOLOGUE LYNN 28A ARE RNA BINDING PROTEINS THAT BLOCK SYNTHESIS OF MICRORNAs AND THEY CONTROL DEVELOPMENTAL TRANSITION SO THIS LOOKS BIOLOGICALLY RELEVANT TO OUR PUBERTY TRAIT. IMPORTANTLY TRANSGENIC MICE CAPITULATE THE HUMAN PHENOTYPE. THEY HAD DELAYED PUBERTY. AND INTERESTINGLY, THE LYNN 28, LET-SEVEN GLUCOSE METRICS TABOLATES AND IT DOES SO TO AN INDEPENDENT MANNER AND WE ALL KNOW THAT mTOR IS THE KEY AGING PATHWAY. AND THIS GROWTH PATHWAY IS LINKED TO METABOLIC DISEASE AND CANCER. SO AFTER THOSE FOUR PAPERS WERE PUBLISHED, WE ALL GOT TOGETHER AND COLLABORATED AND CONDUCTED AND EXPANDED GWAS OF AGE AT MENARCHY, AND THIS IS NINE TO 17, WE ADJUST FOR BIRTH YEAR, THE WOMEN ARE EUROPEAN ANCESTRY AND WE NOW HAD 87,000 WOMEN IN OUR DISCOVERY PHASE. SO WE CONFIRMED OUR FIRST TWO GENES. AND WE IDENTIFIED 32 ADDITIONAL GENES RELATED TO MENARCHE FINDING, THE TOP WAS AN ASSOCIATION WITH INHIBIT B, AND INHICKIN A IS PRODUCED IN THE OVALID AND RELIABLE SCHEKNOWN DO RISE AT THE TIME OF PUBERTY SCHETHIS ACTS ON THE HYPOTHAT WILL AMIC PITUITARYY ACCESS AND IT MADE PERFECT BIOLOGICAL SENSE AND THERE ARE TWO OTHER GENES HERE INVOLVED IN HORMONE PRODUCTION, TCF K-TWO HORMONES SUCH AS PRO INSULIN TO INSULIN AND MANY OF THESE GENES, THE GENES SHOWN IN RED ARE ASSOCIATE WIDE OBESITY AND ENERGY METABOLISM. SO WE WENT AHEAD AND LOOKED AT ALL THE SNPs AT THAT TIME. HERE ARE THE OBESITY GENES AND THE RELATED SNPs AND YOU CAN SEE THAT THE OBESITY SUSCEPTIBILITY ALLELE WAS THE SAME AS THE MENARCHE ALLELE WITH THE EXCEPTION OUR--SO WE HAD A COLLABORATOR LOOKING AT A MOUSE MODEL FOR PCS K-TWO WHICH AS I SAID IS A GENE THAT CLEAVES HORMONES TO HORMONES AND THIS GENE ACTUALLY CLEAVES PROINSULIN TO INSULIN AND HAS BEEN SHOWN IN HUMANS TO BE ASSOCIATED WITH DIABETES AND MI. AND THIS KNOCK OUT MOUSE MODEL, THE KNOCKOUT MICE HAD DELAYED FEMALE SEXUAL MATURATION COMPARED TO WILD-TYPE AND HETEROGENEOUS ROW ZYGOUS MICE. AND THEY ALSO HAD DECREASED IGF ONE COMPARED TO WILD-TYPE AND HETEROGENEOUS ROW ZYGOUS MICE. SO IT'S UNCLEAR WHETHER THIS GENE MAY ALSO BE OPERATING IN SOME WAY THROUGH IGF ONE WHICH IS ANOTHER KEY PATHWAY AND AGING BIOLOGY. SO JUST THIS PAST SUMMER, WE COMPLETED ANOTHER EXPANDED META-ANALYSIS OF MENARCHE NOW WITH 132,000 WOMEN WITH GENOME WIDE DATA AND AN ADDITIONAL 50,000 WOMEN WITHIN AN ARRAY AND WE NOW HAD 123 SNPs AND 106 GENOMIC LOCI AND THESE SNPs, THE MAJORITY OF THEM GENERALIZE TO OTHER PHENOTYPES IN BOTH BOYS AND GIRLS. AND WE NOTED THAT AMONG THESE 123 SNPs, THERE WERE SIX SIGNALS THAT LIE IN THESE ACROSS THE GENOME SO WE LOOK AT THESE 36S REGIONS AMONG 23 SNPs AND WE COMPARE THEM TO WHAT WAS PUBLISHED IN THE GWAS CATALOG AND IT LOOKED LIKE WE HAD AN ENRICHMENT. WE HAD 4.8% VERSES 1.7% IN THE GWAS CATALOG AND DEPARTURE FROM MENDELIAN INHERITANCE PER PUBERTY HAD NOT BEEN PREVIOUSLY SUSPECTED SO WE REACHED OUT TO OUR COLLEAGUES AT THE DECODE STUDY AND ASKED THEM IF THEY COULD DO A PARENT OF ORIGIN ANALYSIS SINCE THEY HAD INFORMATION ON GENEIOLOGY AND THIS IS THE RESULT OF THE PARENT OF ORIGIN SPECIFIC ALLELE ASSOCIATIONS IN THE DECODE STUDY, THE GRAY BARS ARE META-ANALYSIS RESULTS, THE RED BARS ARE THE MATERNAL ALLELES AND THE BLUE BARS ARE THE PATERNAL ALLELES. THE SNPs IN DLK ONE AND DECODE SHOW EVIDENCE FOR PATERNAL INHERITANCE, INTERESTINGLY, THIS GENE IS ASSOCIATED WITH FETAL IMPRINTING AND HAD BEEN ASSOCIATED WITH DELAYED PUBERTY IN THE LITERATURE. THE MKRN THREE GENE, THIS SNP ALSO WAS ASSOCIATE WIDE PATERNAL INHERITANCE ONLY IN THE DECODE STUDY AND PATERNAL DELETION IN THIS GENE IS ASSOCIATED WITH CRATER WILLIE SYNDROME AND HYPER GONADISM AND HYPOTHALAMIC OBESITY AND IT'S ALSO BEEN ASSOCIATE WIDE PUBERTY AND THIS SNP IS ASSOCIATE WIDE MATERNAL PUBERTY SCHEWE'RE NOT SURE WHAT THIS GENE IS IN SIMULATION TO MENARCHE. SO FOR THE FIRST TIME WE'RE SEEING PARENT OF ORINIGE EFFECT FOR PUBERTY PHENOTYPE. AND THAL SLIDE WE'RE LOOKING AT OTHER UNDERLYING BIOLOGIC AND SIGNALING GABBA TWO SIGNALING, A LOT OF EVIDENCE FOR OBESITY ENERGY HOMEOSTASIS AND GROWTH HORMONE SYNTHESIS, GENES RELATED TO LIPIDS AND THE GENE CIRCLED IN RED HAVE PREVIOUSLY BEEN ASSOCIATE WIDE MONOGENIC DISORDERS OF PUBERTY AND JUST TO SUMMARIZE HERE AGAIN WE'RE SEEING BIOLOGIC MECHANISM THAT UNDERLIE--THAT SEEM TO EXPLAIN THE UNDERLYING EPIDEMIOLOGIC ASSOCIATIONS BETWEEN MENARCHE TIMING AND DISEASES AND THIS MECHANISM SEEM TO CALIFORNIA BOTH IN BMI RELATED AND BMI INDEPENDENT SYSTEMS AND JUST TWO EXAMPLES THE LYNN 28 B, AND THE INSULIN SENSITIVITY PATHWAY THROUGH mTOR, AND THEN OXIDATIVE STRESS THROUGH THE GABBA B RECEPTOR SIGNALING. SO I HOPE I CONVINCED YOU THAT MENARCHE AND MENOPAUSAL TIMING MAY BE GOOD WAYS TO GET AT AGE RELYING DISEASES. SO I WOULD LIKE TO SWITCH IN MY REMAINING FEW MINUTES TO GENOMICS. THE FRAMINGHAM HEART STUDY HAS THIS SYSTEMS APPROACH TO BIOMARKERS RESEARCH OR THE PLAZA TO LOOK AT GENE EXPRESSION. WE HAVE 5700 OFFSPRING AND GENERATED THREE ACROSS TO WIDE AGE RANGE WITH GENE EXPRESSION DATA MEASURED IN WHOLE BLOOD WITH THE HUMAN AXON ARRAY AND THE CHARGE GENE EXPRESSION WORKING GROUP LED BY MY COLLEAGUE ANDREW JOHNSON HAS ASKED THE QUESTION CAN WE IDENTIFY GENES AND PATHWAYS THAT DIFFER IN THEIR EXPRESSION WITH AGE. AND THEY'VE IDENTIFIED 7000 PARTICIPANTS FROM SIX COHORTS IN THE DISCOVERY PHASE AND ANOTHER 8000 PARTICIPANTS FROM SEVEN COHORTS AND A REPLICATION PHASE AND IDENTIFIED 1500 GENES THAT DIFFERED IN EXPRESSION WITH AGE. THEY CONDUCTED A PATHWAY AND COEXPRESSION NETWORK ANALYSIS AND THEY IDENTIFIED A NUMBER OF GENES THAT WERE DOWN REGULATED WITH AGING AND WHAT I THINK IS PARTICULARLY INTERESTING IS MANY OF THESE PATHWAYS OVERLAP WITH THE PATHWAYS WE IDENTIFIED FOR MENOPAUSE AND MENARCHE TIMING SO IN THIS ONE CLUSTER HERE, WE SEE DNA REPLICATION OF ELONGATION AND REPAIR THERE ARE A COUPLE OF GENES THAT WE IDENTIFIED AND OUR MENOPAUSE TIMING OF GWAS. WE ALSO IDENTIFIED MIGHT O CHOND RIRIAL DYSFUNCTION IN OUR MENOPAUSE TIMING GWAS AND OF COURSE IMMUNE FUNCTION. THERE WERE ALSO GENES UPREGULATES IN A NUMBER WAYS THAT WERE IDENTIFIED SUCH AS ACTIN, CYTOSKELETON AND LIE SOLREGRESSION. WE ALSO USED IT TO MODEL VARYING AGE WITH LONGEVITY AGE WITH DIRECTION OF EFFECT RELATIVE TO FASTER AGING AND WE CAN SEE AS EXPECTED THAT FEMALE SEX IS LOWER COMPARED TO--IT'S SLOW ARE AND STRENGTH IS LOWER FOR AGING WHEREAS CARDIOVASCULAR RISK FACTORS ARE FASTER IN AGING. AND I WILL END ABOUT SLIDES WITH COLLABORATIONS ABOUT BASIC SCIENTISTS, WE ARE FORTUNATE TO HAVE A COLLABORATION WITH THE LAB, NATHAN SHOCK CENTER WITH THE BASIC BIOLOGY LAST AND WE'RE ALSO DOING THE C.ELEGANS LIFE SPAN SCREENS AND TAKE THOSE ON TO THE MOUSE MODEL. WE ALSO HAVE A COLLABORATION WITH THE NEALY LABORATORY AT THE GARZA MEDICAL INSTITUTE IN AUSTRALIA, AND THE NEALY LABORATORY HAS THE GWAS RESULT FROM THE LONGEVITY SCREEN AS WELL AS THE EXPRESSION SCREEN. AND DR. NEELY IS LOOKING AT TISSUE SPECIFIC BRAIN AND HEART AS WELL AS WHOLE BODY AND TRIES AND HE'S DOING NORMAL CHILD, AND CALORIE RESTRICTED DIET. SO WE ONLY HAVE RESULTS AT THIS POINT FOR THE RNAi AND C-ELEGANS AND SO I WILL WET YOUR APPETITE JUST A LITTLE BIT. WE DID THESE DR. SUTPH IN DID THESE TESTS AT 16-DEGREES, 25-DEGREE WITH C.ELEGANS AND THESE SHOW CHANGE COMPARED TO EMPTY VECTOR. THE BARS SHOW DIFFERENT GENES AND THE BLUE BARS SHOW SIGNIFICANT CHANGE IN LIFE SPAN, THE BLACK BAR SHOWS NO CHANGE IN LIFE SPAN AND THE GRAY IS JUST RANDOMLY SELECTED GENES SO CAN YOU SEE THAT THESE CHARGE GOONS ARE SHOWING LIFE LIKE EFFECTS IN AN ANIMAL MODEL. SO WHERE DO WE PLAN TO GO FROM HERE? WE WOULD LIKE TO EXTEND OUR ASSOCIATION STUDIES FOR THESE LIFE TRAITS TO RARE VARIANTS WE HAVE GENOME CHIPPING AND WE HAVE EXOME SEQUENCING AND NHLBI AND HAS ANNOUNCED WHOLE GENOME SEQUENCING SO WE WOULD LIKE TO GET ANALYSIS FUNDING TO LOOK AT THESE PROMISING GENES WITH THOSE ADDITIONAL RESOURCES WE PLAN TO CHARGE THESE AGE GENE EXPRESSION ANALYSIS AND WE WOULD LIKE TO USE SOME ADDITIONAL TOOLS TO IDENTIFY THE MOST PROMISING RESULTS, AMONG THE 1600 GENES, THAT CHANGE EXPRESSION WITH AGE SO THAT WE COULD TAKE THE MOST PROMISING GENES ON TO ANIMAL MODELS. WE PLAN TO LOOK AT MICRO RNAs AND DNA METHYLATION FOR THOSE GENES. SO, IN CONCLUSION UNLIKE ANIMAL MODELS AND HUMAN GENETIC ASSOCIATION STUDIES IT TAKES MORE THAN A VILLAGE. I THINK I SHOWED YOU THAT WE HAVE 10 FIST NOT HUNDREDS OF THOUSANDS OF PARTICIPANTS IN THESE HUMAN GENETIC ASSOCIATION STUDIES, THE PROPRODUCTIVE AGING TYPES HAVE IDENTIFIED NOVEL GENES AND IMPORTANT BIOLOGIC PATHWAYS LINKING THESE TIME AND TRAITS TO AGE RELATED DISEASES AND WE CAN ONLY IDENTIFY ASSOCIATIONS. WE NEED COLLABORATION WITH BASIC SCIENTISTS TO UNDERSTAND FUNCTIONAL RELEVANCE AND ULTIMATELY TO IDENTIFY PROMISING INTERVENTION. THESE SEMINARS ARE VERY IMPORTANT SOPHISTICATED THAT WE HAVE MORE OPPORTUNITIES AMONG CROSS TALKS AMONG POPULATION SCIENTISTS AND BASIC SCIENTISTS. AND FINALLY I WOULD LIKE TO END BY ACKNOWLEDGING MY FUNDING FORCES AND TO ACKNOWLEDGE ALL MY COLLABORATORS BOTH AT FRAMINGHAM, THE CHARGE AGING AND LONGEVITY WORKING GROUP, THE CHARGE GENE EXPRESSION WORKING GROUP, THE JACKSON LAB, THE FRAMING HAPPEN CVD PROJECT AND MY GRANDMOTHER WILL BE 101 NEXT WEEK. THANK YOU VERY MUCH. [ APPLAUSE ] >> WELL THAT'S A LOT OF INFORMATION HERE, THAT'S A QUITE STIMULATING TALK SO THERE ARE LOTS OF THINGS THAT HAPPEN DURING PUKE ARTY MENARCHE BEING ONE OF THEM WHICH APPLIES TO ROUGHLY HALF THE POPULATION, WHAT ABOUT THE BOYS? >> SO I PROBABLY SKIPPED OVER THIS VERY QUICKLY BUT WE DID TEST OUR MENARCHE IN THE GENES WITH THE BOYS WITH THE TANNER STAGE PHENOTYPE AND THE MAJORITY OF THOSE ACTUALLY GENERALIZED SO OUR COLLABORATORS IN THE U. K. HAVE ACCESS TO SOME STUDIES WITH BOYS. SO IN THE SHIFT OF AGE OF MENARCHE AND IT BECOMING A BIMODAL DISTRIBUTION OR IS THERE ENOUGH OF A SPREAD YOU COULD SEE BECAUSE IF THE WHOLE POPULATION IS SHIFTING, THAT WOULD SUGGEST EVERYBODY'S SUSCEPTIBLE ALTHOUGH SOME MAY BE MORE, BUT IF IT'S BECOMING BIMODAL IN TERMS OF--WHICH I GUESS IT ISN'T-- >> IT'S DEFINITELY NOT NWELL THAT SHOOTS THAT HYPOTHESIS. >> SURE, I DID MY PHENOTYPES WERE FEMALE-RELATED. THAT'S WHY IT'S IMPORTANT. I'M HOPING WE CAN FIND SOME INVESTIGATORS PERHAPS AT NCI WHO HAVE LARGER CANCER DATABASES. WE WOULD LOVE TO TEST OUR MENOPAUSE GENES MAYBE EVEN IN PROSTATE CANCER CASES AND OTHER--IN ADDITION TO BREAST CANCER, PERHAPS OVARIAN CANCER AND MAYBE EVEN LUNG CANCER. >> I THINK IT WAS VERY INTERESTING ABOUT THE LIFE COURSE AND PHENOTYPES WITH THE AGES AND I WAS GOING TO ASK, IN TERMS OF THE VARIANCE YOU SEEM RELATED TO AGE OF MENOPAUSE WHAT KIND OF FINDINGS YOU HAD OR THINKING OF LOOKING FOR IN TERMS OF OTHER RELATED PHENOTYPES NOT ONLY TO [INDISCERNIBLE]. BUT JUST OTHER [INDISCERNIBLE] EFFECT ALL THOSE OTHER KIND OF BENCHMARKS OR MORBIDITY AND OVER THE LAST [INDISCERNIBLE]. >> SO THAT WAS A POWER PACKED LECTURE, THE MOST DENSE OR CONCENTRATED I REMEMBER HEARING--I DON'T KNOW HOW YOU WERE ABLE TO DO THAT, BUT I HAD THE SAME QUESTION RON DID, THE BOYS, WHAT ABOUT THE BOYS, BUT WHAT ABOUT THE BOYS AT THE OTHER END OF THE SPECTRUM. YOU SAID ONLY 14% OF YOUR CENTENARIANS WERE MEN. WHERE ARE THE MEN? WHY ARE THEY DYING SO FAST RELATIVE TO WOMEN? >> SO IT TURNS OUT THAT THERE'S A PORTION OF MEN IN OUR CENTENARIANS GROUP SIMILAR TO WHAT THE U.S. CENSUS BUREAU REPORTS FOR ALL OF THE UNITED STATES, SO THAT'S NOT DIFFERENT AND WE KNOW THAT WOMEN LIVE LONGER THAN MEN. I DON'T KNOW IF ANYONE ELSE--DR. LEE OR--WANTS TO COMMENT ON THAT WITH THE LONG LIFE FAMILY STUDY BUT THAT REALLY REFLECT WHAT IS' HAPPENING IN THE UNITED STATES. >> BUT THE ONES THAT DON'T, MAYBE THEY HAVE AN EARLIER MENARCHE? >> YEAH, RIGHT. BUT I THINK WHAT WE CAN REALLY DO AT FRAMINGHAM, WHICH OTHER CENTENARIAN STUDIES CAN'T DO BECAUSE THEY ENROLL THEIR CENTENARIANS LATE IN LIFE. MOST OF THOSE STUDIES ENROLL PEOPLE AT AGE 90 WHERE WE HAVE THE LIFE COURSE EFFECT AND WE'RE JUST DIGGING INTO THAT DATA AND I SHOWED THE BMI OVER THE 28 EXAMS JUST AS AN EXAMPLE TO WET PEOPLE'S APPETITE BUT WE'RE REALLY QUITE EXCITED NOW THAT WE HAVE STUDIED THE COHORT LONG ENOUGH AND HAVE 70 PEOPLE TO ACTUALLY LOOK AT. >> AND ONE MORE QUESTION, YOU HAD IGF A COUPLE TIMES AND YOU KNOW THAT ONLY ONE% OF PREIGF ONE IS IN CIRCULATION, IT'S ALWAYS BOUND TO IGPT-THREE AND BOUND TO COUPLE OTHER PROTEINS BECAUSE IT'S SO TOXIC AND IF YOU LET IT LOSE, TELL CAUSE CANCER ALL OVER THE PLACE. AND THERE IS A STUDY IN DENMARK THAT SHOWS THE SINGLE MOST IMPORTANT RISK FACTOR FOR PREDICTING BREAST CANCER LATER IN WOMEN IN LIFE IS HEIGHT AT AGE 14 WHICH ARE THE GIRLS THAT DIDN'T CONTROL IGF AS WELL, MAYBE. >> RIGHT SO I TRIED TO HIGHLIGHT UNDERLYING PATHWAYS WE KNOW HAVE BEEN FOUND IN AGING LIKE mTOR AND IGF ONE, BUT CLEARLY WE'RE SEEING OTHER PATHWAYS AS WELL. THE IMMUNE SYSTEM WITH THE NF CAPPA B AND OUR BIOLOGIC PROCESSES AND THE DNA DAMAGE AND PREPARE PATHWAY FOR MENOPAUSE WHICH CLEARLY HAS BEEN LINKED TO CANCER. THERE'S SOME DATA LINK TAG PATHWAY TO CARDIOVASCULAR DISEASE SO CLEARLY WE'RE UNDERSTANDING HOW THESE RATES ARE LINKED TO LATER LIFE DISEASES IN WOMEN AND MAYBE WE CAN HELP US UNDERSTAND HOW THEY'RE LINKED IN MEN AS WELL BECAUSE I'M SURE THESE PATHWAYS ARE RELEVANT TO BOTH SEXES. >> THANKS VERY MUCH, ENJOYED IT. >> THANK YOU. >> SORRY. OVER HERE. SO THE CO-EXPRESSION NETWORK THAT YOU PUT IN, THAT WAS BASED ON GENE EXPRESSION? >> THAT WAS THE CHARGE GENE EXPRESSION DATA, YES. >> OKAY SORRY, GO AHEAD. SO I GUESS THE QUESTION IS, SO FAR YOU'VE SHOWN MUTATION DAT WITH THE GWAS, GENE EXPRESSION DATA HAVE YOU VENTURED INTO OTHER OMICs, DATA AS WELL, SUCH AS METHYLATION, IT WOULD BE INTERESTING TO SEE THAT. >> WE HAVE METHYLATION DATA, WE HAVE NOT DONE THAT JUST YET BUT WE'RE PLANNING TO DO THAT. >> AND SORT OF THE LAST QUESTION IS THE CO-EXPRESSION NETWORKS ARE NICE BUT IT DOESN'T REALLY--IT DEFINITELY TELLS YOU SORT OF WHICH GENES BELONG TO WHICH PATHWAYS OR MORE SPECIFICALLY GENE ONTOLOGY IS MORE FUNCTIONS AND STUFF, BUT ESPECIALLY IF YOU DO HAVE GENE EXPRESSION DATA HAVE YOU BEEN LOOKING AT MORE TRADITIONAL GENE NETWORKS, EITHER LITERATURE, BASE NETWORKS THAT SHOW CAUSALITY OF DNA ACTIVATES OR INHIBITS GENE B OR LOOK AT SOME OF THE DATA RECONSTRUCTION METHODS THAT LOOK AT GENE EXPRESSION AND RECONSTRUCT THE GENE NETWORK BASED ON THE GENE EXPRESSION. SO ARE THERE PARTICULAR METHODS YOU'RE THINKING? >> SO ACTUALLY AT THE UNIVERSITY, JIM COLLINS AND JIM GARDENER DEVELOPED CLR WHICH IS A METHOD WHERE IF HAVE YOU GENE EXPRESSION DATA YOU CAN BIND OR PREDICT WHAT THE NETWORK WAS TO GENERATE THAT AND THAT WOULD DEFINITELY HOPE YOU FIND TRANSCRIPTION FACTORS AND MORE REGULATORY METHODS OF THAT, RATHER THAN JUST LOOKING AT A CO EXPRESSION NETWORK, WHICH IS USEFUL BUT I THINK YOU COULD FIND MORE USES WITH THE GENE EXPRESSION DATA THAT A MORE RICH GENE NETWORK. >> OKAY, GREAT, THANK YOU. >> SURE. >> SO CONSIDERING THE NUMBER OF HITS YOU ARE GETTING FROM THE GWAS, I WANT TO CONGRATULATE YOU ON THE OOH PROACH OF COLLABORATIVE WEAR, AND LOOKING AT THEIR FUNCTION IN C.ELEGANS AND IN THAT STUDY, YOU DID OR RON DID THE EXPERIMENT AT TWO DIFFERENT TEMPERATURES AND WHAT WAS THE CORRELATION BETWEEN IT IS GENES THAT EFFECT AT ONE TEMPERATURE OR THE OTHER. IN OTHER WORDS DO THE GENES INCREASE OR DECREASE LONGEVITY ARE THE SAME. ARE THEY THE TEMPERATURES OR WHAT? >> THERE WAS SOME CROSS OVER BETWEEN THE TWO TEMPERATURES, BUT CLEARICALLY THERE WERE MORE GENES EXPECTING LIFE SPAN AT THE 25-DEGREE TEMPERATURE. >> BUT YOU SAID THERE WERE SOME AT FIVE%, 10%, 50%. >> I HAVE TO LOOK IT UP FOR YOU. BUT I CAN GET BACK TO YOU WITH THAT NUMBER. AND WE'RE ALSO SEEING SOME VALIDATION IN THE PLUGS OF THE SAME GENES. SO DR. NE, LY HAS THE SAME GENES THAT DR. CRISTHAN'S LAB HAS AND SO WE'RE LOOKING AT TWO OTHER ORGANS AND THEN WE WILL TAKE IT TO THE MOUSE. [ APPLAUSE ]