>> WELCOME TO THE 115TH MEETING OF THE NATIONAL ADVISORY COUNCIL ON AGING. WE'LL OPEN WITH A REPORT FROM DR. RICHARD HODES, THE DIRECTOR'S STATUS REPORT. >> GOOD MORNING. IS FOR THOSE WHO HAVE BEEN ON COUNCIL FOR A WHILE, THIS IS FAMILIAR. FOR THOSE WHO ARE NEW, THIS IS A BRIEF PRESENTATION WHICH IS AN EFFORT FOR US TO UPDATE YOU ON SOME OF THE THINGS GOING ON AND INVITE ANY QUESTIONS OR DISCUSSIONS YOU'D LIKE TO HAVE NOW OR LATER I. FIRST THE NOTE VERY SADLY, SINCE OUR LAST COUNCIL MEETING, WE'VE LOST RICHARD SIZMAN, THERE WERE MULTIPLE TRIBUTESSSSS RICHARD WON'T BE REPLACED. JUST A COUPLE OF PICTURES THAT HAVE BEEN ABOUNDING IN RECENT DAYS AND WEEKS THAT SORT OF CAPTURE RICHARD. MANY OF YOU WILL HAVE SEEN THE PICTURE AT THE TOP LEFT ON THE ELEPHANT, THAT IS RICHARD WITH A BLACKBERRY IN HAND. ALWAYS IN TOUCH TIME DIFFERENCE THE STAFF HAS BEEN PHENOMENAL OVER THE PAST COUPLE OF DECADE, AND THE STAFF, I WOULD SAY, ALSO HAS DONE A REMARKABLE JOB WHILE GRIEVING AND KEEPING THE PROCESS VERY MUCH GOING AND VIBRANT, AS RICHARD WOULD HAVE WANTED, AND WITH THANKS TO JOHN HAGA, WHO'S BEEN I'D PIED AS THE ACT -- IDENTIFIED AS THE ACTING DIRECTOR AT THIS TIME. SOME OF THE USUALS. THIS IS A PORTRAYAL OF RECENT WRINKLES THAT EYE PEERS. APPEARS. THE CURVE OFS, THE UPPER SHOWS INCREASES FROM 2005, ALL SUBI SEQUESTER, A RECOVERY, INCREASES IN RECANTANT DOLLARS HAD INFLATION, YOU CAN SEE A PRECIP IT TUS LOW, AND EVEN THOUGH THERE IS AN INCREASE IN THE ACTUAL APPROPRIATION IN THE YEAR FOLLOWING SEQUESTER, YOU'LL SEE THAT IT DOESN'T QUITE GET US BACK, IN FACT, OH IT THE BUYING POWER OR CURRENT DOLLAR LEVEL OF PREVIOUS YEARS, AND THEN 2016 IS THE PRESIDENT'S PROPOSED BUDGET, NOT YET LAW, OF COURSE, AND YOU THISEE STILL SEE A 17% REDUCTION IN DOLLARS OR BUYING POWERS FOR RESEARCH IN THE PAST 10 YEARS. A COUPLE OF SLIDE JUST TO ILLUSTRATE T ASPECTS OF BUDGET IS THE SAME ILLUSTRATION IN CURRENT DOLLARS OF OUR BUDGETS FROM 2012 THROUGH THE PRESEN6 PROPOSAL. BUT WHAT YOU SEE IN THE BLUE PEAKS AT THE TOP IS THE COMPONENT OF THAT, WHICH HAS BEEN ALLOCATED BY CONGRESSIONAL LANGUAGE TO -- OR PRESIDENT'S BUDGET LANGUAGE TO ALZHEIMER'S RESEARCH. SO IT IS TARGETED TO THAT AREA OF RESEARCH IN IT PARTICULAR, AN YOU CAN SEE THAT IF ONE LOOKS AT THE RESEARCH OTHER THAN ALZHEIMER'S, WE'RE FAIRLY FLAT AGAIN WITH INFLATIONARY DECREASES, BUT WITH SOME VERY SUBSTANTIAL INCREASES IN THE APPROPRIATION TO ALZHEIMER'S RESEARCH, AND THIS IS A BIT OF A DIFFERENT WAY OF PORTRAYING WHAT'S HAPPENED IN THE LAST YEARS, SO THIS P THE CHANGE FM '14 TO '15, '15 TO THE PRESIDENT'S BUDGET. IT NO CHANGE IS A ZERO. THIS IS THE YEAR OF THE SSTER WHEN NIH AND NIA BOTH DROPPED ABOUT 5 1/2% IN THEIR BUDGET. 2013 TO '14 IS WHEN THERE WAS A PARTIAL RESTORATION OF THE LOST FROM SEQUESTER TO NIH, 12.6% INCREASE IN ALZHE.. SIMILAR, 2014 TO 1015, NIH WENT UP DUE IT TO THE $25 INCREMENT FOR ALZHEIMER'S RESEARCH, AND THE PRESIDENT'S BUDGET, 3.3% BUDGET INCREASE RECOMMENDED FOR THAT YEAR FOR NIH OVERALL, BUT ANOTHER $50 MILLIONERER TO ALZHEIMER UNIQUE SITUATION IN OUR HISTORY AND HISTORY OF MOST NIH INSTITUTES IN WHICH THERE IS A VERY SUBSTANTIAL AND GREEING GROWING ALLOCATION FOR A PARTICULAR TARGET OF ALZHEIMER'S DISEASE. SO HOW DOES HAD IT TRANSLATE INTO PAY LINES? ONE OF THE PARAMETERS WE LOOK AT REGULARLY FOR GENERAL PAY LINE, SO THIS IS NOT ACCOUNTING FOR THE ALLOCATED INCREASE FOR ALZHEIMER'S RESEARCH. FOR ALL APPLICATIONS UNDER $500,000, THE PAY LINE HERE IS EIGHTH PERCENTILE, WITH INCREASES HAD IN CONSIDERATION OF NEW INVESTIGATORS, 12TH PERCENTILE, EARLY STAGE INVESTIGATORS, 14TH PERCENTILE, FOR 5%, 9% AND 11% CORRESPONDINGLY. TO TOUCH BRIEFLY, THE REASON FOR THIS 8%, WHICH IS DECREASE FROM 11% THE LAST SEVERAL YEARS, ROBIN BARR HAS RELATED TO THE GROUP EARLIER IN OUR MEETINGS, BUT HAS BEEN ATTRIBUTABLE TO TWO FACTORS INTERRELATED. ONE, THE INCREASE IN THE NUMBER OF APPLICATIONS NIA HAS RECEIVED, THE INCREASE BEING FAR GREATER THAN THAT FOR NIH OVERALL, AND THE FACT THAT THOSE INCREASED APPLICATIONS HAVE DONE WELL IN REVIEW. SO OF COURSE IT'S QUITE AN YOUR HONOR FORTUNATE IRONY THAT AS WE ARE ATTRACTING MORE APPLICATIONS JUDGED BY PEER REVIEW TO DO WELL, FUNDING ENVELOPE IS NOT INCREASED AS -- HAVE GONE DOWN. FOR ALZHEIMER'S RESEARCH, THESE ARE ARE THE NUMBERS. NOW WITH THE INCREASED FUNDING THAT WE HAVE HAD, WE HAVE -- COM COME IN A N UNUSUAL -- EARLY IN THE ACTUAL FISCAL YEAR, ONLY HAD WE KNOWN THE BUDGET INCREASE WOULD BE COMING, AND BECAUSE WE'VE HAD, THEREFORE, TO PLAN FOR ALLOCATION, PLANNED IN ADVANCE THE EXECUTION REQUIRING SOME EXPEDITION. BUT WE'VE USED AS A MEANS OF FUNDING BY RFA RFAs PARTICULARLY TARGET AREAS, AWFUL OF THOSE ALL OF THOSE HAVE BEEN THROUGH THIS GROUP FOR ADVISORY INPUT, AT THIS STAGE OF THE YEAR, AND IT'S NOT OVER YET, THERE'S A POSSIBILITY THAT THIS PAY LINE MAY ACTUALLY BE ALTERED FURTHER LATER IN THE YEAR, BUT A COMPARABLE FIGURE TO THE 8% OVERALL FOR NONE ALZHEIMER'S RESEARCH IS 14TH PERCENTILE HERE, A VERY CONSIDERABLE DRCHES, DIFFERENCE, AND CORRESPONDING NUMBENUMBERS. IT IS AN ILLUSTRATION OF HOW MUCH DIFFERENCE IN TERMS OF PAY LINE AND TARGETED INITIATIVES CAN BE ACHIEVED WITH A SUBSTANTIAL INCREASE IN BUDGET, AND IN THIS CASE, RESTRICTED OH IT THE ALZHEIMER'S AREA, BUT A MOTIVATION FOR ALL TO THINK OF WHAT WE MIGHT BE ABLE TO DO IT ACROSS THE WHOLE SPECTRUM OF AGING RESEARCH WITH SIMILAR INCREASES. SO OH TO TALK ABOUT THE FUTURE AND IN PARTICULAR FOR ALZHEIMER'S FUNDING, IMPORTANT IS THE ALZHEIMER'S BYPASS IN 2015 APPROPRIATIONESSIONAL APPROPRIATION -- BUDGET EACH YEAR FOR ALZHEIMER'S RESEARCH. THE LANGUAGE AND INTENT IS FRAMED TO ASK WHAT RESOURCES WOULD BE NEEDED TO NIH IN ORDER TO ACHIEVE THE MILESTONES NECESSARY TO SUCCESSFULLY COMPLETE THE GOALS OF THE NATIONAL PLAN, FOR EXAMPLE, THE ASPIRATIONAL GOAL OF A 2025 DATE FOR SUCCESSFUL INTERVENTIONS TO PREVENT OR TREAT OR SLOW THE PROGRESS OF ALZHEIMER'S DISEASE. THIS HAS BEEN A PROCESS THAT WE HAVE ADDRESSED THROUGH A GREAT DEAL OF SCIENTIFIC INPUT, ACTUALLY FROM 2012 THROUGH 2015, SUPPLEMENTS, MEETINGS AND ADVISORY INPUT FROM ALL OF YOU, THAT HAS LED TO CAN -- IN PROCESS NOW BUT NEAR CULMINATION, AN INTEGRATED SET OF OBJECTIVES OR GOALS OR PRIORITIES. EACH OF THEM ATTACHED MILESTONES, AND THE PROCESS WILL CONTINUE BY ATTACHING DOLLAR FIGURES, ESTIMATES, COSTS NEEDED TO ACCOMPLISH THOSE MILES STONES. THIS WILL BE CONSTRUCTED INTO A BYPASS BUDGET, BYPASS MEETING THAT GOES DIRECTLY TO CONGRESS FOWITH AN OPPORTUNITY FOR COMMENT TO THE ALZHEIMER'S NATIONAL PLAN, BUT CANNOT BE CHANGED BY THEM, SO IT'S DIRECT IN IT RESPONSE TO CONGRESS SAYING, TELL US THIS IN YOUR PROFESSIONAL JUDGMENT, NIH, WHAT RESOURCES YOU THINK ARE NECESSARY TO ACCOMPLISH THE GOALS AND TELL US DIRECTLY WITHOUT ANY MODIFICATION. SO WE ANTICIPATE THAT IN IN SUMMER, LATE JULY IS THE TARGET DATE, WE'LL BE COMMUNICATING THIS BUDGET AND HAVE AN OPPORTUNITY TO SEE IT THEN. IT'S CONFIDENTIAL UNTIL THE TIME IT'S COMMUNICATED BUT AGAIN, WHEN IT LEAVES NIH, IT'S TO BE UNALTERED. WHAT THE OUTCOME WILL BE, WE'LL HAVE TO WAIT AND SEE. THERE ARE TWO BYPASS BUDGETS AT NIH LONG-STANDING, ONE FOR CANCER, ONE FOR OFFICE OF AIDS THE THIRD, COMING AT A VERY NEW AND DIFFERENT -- IN THE FUNDING FOR ALZHEIMER'S DISEASE RESEARCH. SO WE'LL LOOK FORWARD TO SHARING THE BUDGET PROCESS AND DOCUMENT WITH YOU, AND THEN, OF COURSE, WAITING FOR THE OUTCOME. THE I'M TABLE WE'RE SO -- FROM THAT MEETIN G PUT TOGETHER WITH THOSE PREEXISTENT INPUTS FROM EARLIER EXERCISES WERE COMPILED. THE NATIONAL PLAN TO WHICH THESE RECOMMENDATIONS ARE TIED, BECAUSE REMEMBER THE LANGUAGE SAYS WE HAVE TO INDICATE HOW MUCH IS NEEDED TO ACCOMPLISH THE GOALS OF THE PLAN, SO THE NEWEST PLAN WILL BE RELEASED SOON IN PROCESS, THAT'S A DEPARTMENT LEVEL PLAN, BUT WE'RE NOT WAITING FOR THAT OF COURSE. IN THE MEANTIME, WE'RE PUTTING TOGETHER THE BUDGET ESTIMATES OH IT ACCOMPLISH ALL THE MILESTONES, ALL THE OBJECT OFTIVES. JULY IS WHEN WE PROPOSE THAT THIS WILL BE PASSED ON FOR REVIEW BY THE DEPARTMENT SECRETARY EN ROUTE TO CONGRESS. JUST A FEW OTHER BITS OF UPDATE OR NEWS AND RESEARCH. THIS IS A PICTURE OF A VISIT OF BARBARA MIKULSKI TO NCATS, ALONG WITH FRANCIS COLLINS, AND IS REALLY MAYBE THE FIRST SUCCESS OF THE REPURPOSING PROGRAM. REPURPOSING PROGRAM THROUGH NCATS HAS BEEN ONE IN WHICH DRUGS HAVE ALREADY RECEIVED FDA APPROVAL, CAN BE REPURPOSED. IN THIS CASE, THE STORY IS OF A SARC KINASE MEMBER FIN INHIBITOR WHICH HAD BEEN DEVELOPED AS A CANCER DRUG AND THROUGH SOME VERY INTERESTING PRELIMINARY DATA, IT WAS SUGGESTED TO PLAY A ROLE IN SIGNALING THE TOXIC EFFECTS OF AMYLOID ON CELLS WITHIN THE CENTRAL NERVOUS SYSTEM IT. THAT'S THE RATIONALE FOR HAVING GONE THROUGH PLEA CLIN KOL AND SOME EARLY SAFETY PHASE 1 TESTING IN HUMANS EN ROUTE, SO IT'S REALLY THE FIRST IN AN IMPORTANT EXAMPLE OF WHICH PEOPLE ARE IMPRESSED WITH OF HOW IT MAY BE POSSIBLE TO BYPASS THE YEARS OF PRE-CLINICAL AND EARLY PHASE STUDY IN HUMANS IF ONE HAS AN AGENT WITH POTENTIAL EFFECTIVENESS TO SAVE MANY YEARS IN BRINGING IT TO TRIAL FOR EFFECTIVENESS. SO DON'T KNOW IF THIS WOULD BE WORKING OR NOT, BUT THIS IS AN EXAMPLE OF AN ACCELERATED PROCESS THAT IT NIH IS PAYING GREAT ATTENTION OH IT AND WE'RE DELIGHTED THAT WE WERE ABLE TO BE A PART OF THE FIRST EXAMPLE OF ITS SUCCESS HERE. WE'VE HEARD A LOT ABOUT PRECISION MEDICINE INITIATIVE ANNOUNCED BY THE PRESIDENT, AND WITH FUNDING IN HIS BUDGET FOR THIS INITIATIVE. THERE REALLY WERE TWO PARTS IT TO THE PRECISION MEDICINE INITIATIVE. THE FIRST IS CANCER RELATED, BASED ON THE FACT WITH A GREAT DEAL OF INFORMATION ON SEQUENCING OF INDIVIDUAL CANCERS, THE OPPORTUNITY TO INDIVIDUALIZE APPROACHES TO TREATMENT TARGETED TO EACH INDIVIDUAL CANCER, THEREFORE EACH INDIVIDUAL PATIENT IS THIS THIS T T UNDERWAY. MEDICINEOHORT ANALYZED WITH LARGE NUMBER OF PEOPLE OF THE APPROPRIATE PHENOTYPES AND OMICS GENOTYPES. WITH AN EYE TO UNDERSTANDING TARGETS FOR DISEASE PROCESSES AND FOR INTERVENTION. YOU'LL KNOW HERE, OVER A MILLION VOLUNTEERS, NUMEROUS EXISTING COHORTS, MAYBE NEW VOLUNTEERS, ALTHOUGH THIS PROCESS IS ON A SHORT TRACK, IT WILL BE MOVED ALONG IN THE NEXT MONTHS TO A REAL PLAN, IT'S STILL AT A REL TVTIVELY OPEN ANRELATIVELY OPEN AND EARLY STAGE IN DEVELOPING PRECISE PARAMETERS. A NUMBER OF US ARE ON ONE ADVISORY COMMITTEE OF NIH INSTITUTEORYORY COMMITTEE TO THE DIRECTOR COMMITTEE IN PARALLEL WORKING TO TRY TO PUT THIS TOGETHER.THTH INCREASINGLY MORE SO PLANNING IN FUNDS ALLOCATED PROPOSED IN 16 THIS COHORT. -- LARGE SCALE VENUE FOR RESEARCH FEBRUARY 11TH BY A MEETING OF THE G7 INTERNATIONAL GLOBAL COALITION TOWARDS ALZHEIMER'S DISEASE WHICH FURTHER EX-PLRED INTERNATIONAL ASPECTS OF THE RESEARCH PROGRAM. THERE ARE MORE THAN A THOUSAND PEOPLE INVOLVED, ABOUT 500 IN PERSON, ANOTHER 500 ONLINE. THE RECOMMENDATEEFINAFINALIZED AND, IN FAC T, WERE TO BE DISCUSSED AGAIN WITH YOU HERE FOR YOUR INPUT TO US, THESE BECOME FORMAL RECOMMENDATIONS ONLY WHEN THEY COME THROUGH YOU AS AN ADVISORY COUNCIL. THE OVERARCHING THEMES HERE, UNDERSTANDING ALL -- BROAD ENOUGH, BUT NOTE THAT IT DOES INCLUDE AN EMPHASIS ON BRAIN AGING IN ADDITION TO THE PATHOLOGY SPECIFIC TO ALZHEIMER'S DISEASE BECAUSE THE TWO ARE VERY MUCH RELATED. INTEGRATED DATA DRIVEN RESEARCH APPROACHES, WE'VE HEARD IN RECENT COUNCILS ABOUT SOME OF THE REMARKABLE PROGRESS OF RESEARCH ALREADY IN PROGRESS USING THESE NEW APPROACHES. COMPUTATIONAL TOOLS AND INFRASTRUCTURE TO ALLOW STORAGE AND ACCESS TO THE GROWING AMOUNT OF DATA. SPECIFIC RECOMMENDATIONS SUCH AS THE USE OF NEW TECHNOLOGIES, WEARABLE SENSORS AS WAYS OF ANALYZING BEHAVIORS OF RELATED PROGRESSION OF DEMENTIA, RELATED DISEASES, IN LESS INTRUSIVE AND PERHAPS MORE COMPREHENSIVE AND INFORMATIVE WAYS THAN SOME OF THE CONVENTIONAL TESTING TO WHICH WE ARE LIMITED BY OLDER TECHNOLOGIES. CLEARLY SUPPORT OF OPEN SCIENCE, BOTH BASIC AND TRANSLATIONAL, I WOULD APPLAUD THE EFFORTS OF INVESTIGATORS GLOBALLY IN THE AREA OF ALZHEIMER'S RESEARCH AS WELL IN THE REST OF AGING RESEARCH HAS BEEN VERY MUCH COMPLIANT EVEN ENTHUSIASTICALLY ABOUT THE SHARING OF DATA IS REMARKABLY DIFFERENT THAN IT WAS A NUMBER OF YEARS AGO, AND WE'VE TOUCHED UPON IT IN OUR CONVERSATIONS HERE AND WE'LL CONTINUE TO EMPHASIZE THIS ENORMOUSLY. THE WAY IN WHICH NIH CAN INFLUENCE ACADEMIC AND PUBLISHING INCENTIVES FOR COLLABORATION AND SO ON IS AN INTERESTING TOPIC. THIS IS NOT THE SOLE DOMAIN OF NIH BUT TO THE EXTENT BY WHICH OUR POLICIES, WE CAN ENCOURAGE THE RIGHT KIND OF RESEARCH THAT IS DRIVEN NOT BY NON-PRODUCTIVE OR COUNTERPRODUCTIVE CRITERIA FOR CAREER ADVANCEMENT, BUT IS CONSISTENT WITH WHAT'S NEEDED TO ADVANCE THE RESEARCH MISSION IS AN IMPORTANT BIT OF THOUGHT FOR US IN THESE NEXT YEARS. INVESTING IN THE NEW AND TRANSLATIONAL DATA SCIENCE WORKFORCE, AND FINALLY, AN EMPHASIS INCREASING ON ENGAGING CITIZENS, CAREGIVERS, PATIENTS AS PARTNERS IN RESEARCH, AND THIS WAS AN IMPORTANT PART OF THE THEME IT IN THE SUMMIT HELD IN FEBRUARY AS WELL. SO LET ME STOP THERE WITH A SURVEY OF SOME OF THE ISSUES THAT ARE BEFORE US AND ASK IF ANYONE WOULD LIKE TO RAISE ANY OF THESE POINTS FOR DISCUSSION OR QUESTION. ALL RIGHT. NOT YOUR ONLY OPPORTUNITY. >> WHILE PEOPLE ARE THINKING OR GETTING UP THE COURAGE TO ASK YOU A QUESTION, I'M REQUESTING TO IT REMIND YOGOING TOTELL YOU ABOUT FUTU RE MEETING DATES AND ALSO REMIND YOU THIS IS OUR LAST MEETING IN BUILDING 45, THE NATCHER BUILDING. IN SEPTEMBER, WITH WE WILL BE RETURNING TO BUILDING 31 IT AT THE OTHER SIDE OFF THE CAMPUS. WHICH THE MEETING ROOM IS ON THE SIXTH FLOOR. THE NEXT COUNCIL MEETING IS ON SEPTEMBER 16TH AND 17TH, AND THAT IS A WEDNESDAY/THURSDAY MEETING RATHER THAN A TUESDAY/WEDNESDAY MEETING, SO SEPTEMBER 16TH AND 17TH ON A WEDNESDAY AND A THURSDAY. IN JANUARY, WE GO BACK TO TUESDAY/WEDNESDAY MEETINGS, JANUARY 19TH AND 20TH, 2016, AND THEN ANOTHER EARLY MAY MEETING, MAY 10TH AND 11TH OF 2016. AND THEN A LATE SEPTEMBER MEETING IN 2016, SEPTEMBER 27TH AND. SO HEAR ALL GOING TO BE IN BUILDING 31. SEPTEMBER 16TH AND 17TH IS THE NEXT ONE. WEDNESDAY/THURSDAY MEETING, ALL OF THEM IN 2016 ARE TUESDAY/WEDNESDAY MEETINGS, JANUARY 19TH AND 20TH, MAY 10 AND 11, AND SEPTEMBER 27 AND 28. ALL RIGHT. YOU MAY STILL ASK QUESTIONS OF DR. HODES. >> LET ME ALSO SAY WE WILL BE PASSING AROUND THIS BOOK, A COLLECTION OF CLIPS, PARTICULAR NEWS ITEMS RELATED TO NIA-SUPPORTED RESEARCH SINCE WE'VE LAST MET, SO PLEASE HAVE A LOOK AND PASS IT AROUND. >> I'M GOING TO ASK FOR A MOTION OF CONSIDERATION FOR THE -- OH, JIM, GO AHEAD. >> SORRY, I JUST HAD A QUESTION FOR DR. HODES. ARE THERE PROJECTIONS FOR WHAT YOU FEEL THE PAY LINES MAY BE NEXT YEAR? I KNOW IT'S DIFFICULT TO COME UP WITH THAT, BUT DO YOU EXPECT THE PAY LINES WILL CONTINUE AT THEIR LOW LEVEL NEXT YEAR? >> JIM, YOU'RE RIGHT, IT'S EXTREMELY DIFFICULT. THE OVERWHELMING UNPREDICTABLE FEATURE OF COURSE WHAT OUR BUDGET WILL BE. SO WE CAN AND DO ROUTINELY A JOB OF CALCULATING BY THE TURNOVER OF GRANTS WHAT AMOUNTS OF MONEY WOULD BE AVAILABLE, BUT WITHOUT KNOWING WHAT OUR BUDGET IS, AND THE RANGE IS HUGE, WE REALLY CAN'T SAY. THE NIGHTMARE IS RETURN TO SEQUESTER, IN WHICH CASE IT WOULD BE DEVASTATING FOR US ALL AT NIH. MORE OPTIMISTIC WOULD BE AN INCREASE AND EVEN RECOGNITION OF NEEDS AND SPECIAL AREAS OF AGING RESEARCH. SO THE RANGE OF POSSIBLE BUDGETS IS SO LARGE THAT IT MAKES IT VERY DIFFICULT FOR US TO PREDICT. WE'RE POISED AND COULD DO A FAIR JOB OF ESTIMATING IF WE KNEW THE BUDGET. >> DR. SKINNER. >> MAY BE A BIT OF OPTIMISM. HAVE YOU HEARD ANYTHING ABOUT THE 21ST CENTURY CURES ACT, WHICH PROMISES AN EXTRA $10 BILLION FOR NIH. >> WE'VE HEARD A LOT ABOUT 21ST CENTURY CURES. AS YOU KNOW, THERE'S BEEN REVISIONS IN THIS PROPOSED LEGISLATION. I THOUGHT THIS WEEK -- WE HAVE YET ANOTHER -- I DON'T KNOW IF MELINDA IS HERE. IT HAS EVOLVED A GREAT DEAL, AND YOU'RE RIGHT, MELINDA, YOU CAN CORRECT ME IF WRONG, BUT A PART OF THE BUDGETARY LANGUAGE AND PROPOSAL IS AN INCREASE OF $2 BILLION PER YEAR TARGETED TO SPECIFIC AREAS. PRECISION MEDICINE BEING ONE, THE ADVANCEMENT OF NEW AND YOUNG INVESTIGATORS THE SECOND, AND THE THIRD, THE EVER POPULAR "OTHER." BUT THIS IS AT THE DISCRETION OF THE NIH DIRECTOR, AND JUST HOW THAT WOULD BE IMPLEMENTED, OF COURSE, WOULD TAKE SOME TIME AND DEVELOPMENT. SO MARK UP -- NEEDLESS TO SAY, IF THERE WERE TO BE THAT KIND OF AN INCREASE IN FUNDING ACROSS ALL OF NIH, THAT $2 BILLION WOULD RESTORE US TO PRESEQUESTER LEVELS AND THEN SOME, AND ENORMOUS ADVANTAGE ACROSS ALL OF NIH. YES. MELINDA, PLEASE COME TO THE MICROPHONE. >> I WOULD ALSO COMMENT THAT THE SENATE IS ALSO ON A MUCH SLOWER TIMELINE THAN THE HOUSE IN TERMS OF DEVELOPING THEIR VERSION OF THE 21ST SENT KREN CENTURY CURES. I DON'T KNOW IF THEY'LL HAVE ANY LEGISLATION MOVING UNTIL THE END OF THE YEAR. SO IT REMAINS TO BE SEEN IF WITH WE SEE ANYTHING COMPARABLE FROM THE SENATE. >> EMPA SIZE AGAIN RESPONSE TO YOUR QUESTION, JIM, THE RANGE FROM SEQUESTER TO POSSIBLE SUBSTANTIAL ADDITION OF THE NIH BUDGET IS SO LARGE, IT WOULD BE A SEVERAL FOLD INCREASE PROBABLY PROBABLY, OUT COME ABILITY TO FUND GRANTS. >> JUST A IT FOLLOW-UP QUESTION, I KNOW IT'S VERY DIFFICULT TO PREDICT WHAT THE FUNDING ENVELOPE WILL BE, BUT ARE THERE PLANS THAT ARE BEING DEVELOPED INTERNALLY TO MAKE SURE THAT SMALLER INVESTIGATOR ORIGINATED GRANTS GET SOME PRIORITY RELATIVE TO VERY LARGE GRANTS OR -- BECAUSE I'M SURE EVERYBODY IN THIS ROOM IS HEARING FROM THE COMMUNITY THE CONCERNS FROM SMALL INVESTIGATORS SPREAD AROUND THE COUNTRY, AND IN MY VIEW, I DON'T KNOW IF IT'S SHARED BY LEADERSHIP, BUT MANY OF THE GREATEST ADVANCES SEEM TO COME FROM SMALL INVESTIGATOR ORIGINATED GRANTS, THE THINGS THAT ARE REALLY SURPRISING AND TRANSFORMATIONAL TEND TO COME THROUGH. SO I WAS JUST WONDERING WHERE IF IN THE CONSTELLATION OF THINGS WHERE IF ONE THING OR ANOTHER IS GOING TO BE GIVEN PRIORITY, BROADLY WHETHER THERE ARE PLANS >> IT'S CERTAINLY AN IMPORTANT COMPONENT OF BALANCE WE PAY A GEAT DEAL OF ATTENTION TO. PROBABLY THE MOST EXPLICIT REFLECTION IS THAT THE FACT FOR SEVERAL YEARS, WE'VE HAD DIFFERENTIAL PAY LINES, SO FOR UNDER $500,000, THE PAY LINE HAS BEEN RUNNING ABOUT 3% DIFFERENT, WHICH IS A VERY SUBSTANTIAL PROPORTION OF GRANTS, THEREFORE, IN THE DIRECTION THAT YOU NOTED. IT'S INTENDED TO IT ENCOURAGE LSS EXPENSIVE RESEARCH APPLICATIONS WHEN THEY ARE APPROPRIATE OR AMENABLE TO THE KIND OF RESEARCH THAT'S BEING DONE, RECOGNIZING, OF COURSE, THERE'S SOME KIND OF RESEARCH THAT NEEDS TO BE DONE THAT, BY THEIR NAY IT TOUR, ARE EXPENSIVE AND WE HAVE TO MAKE SURE THAT WE BALANCE THEM APPROPRIATELY. BUT VERY MUCH RECOGNIZE WHAT YOU'VE SAID. THE FEAR THAT WE WILL BE COMPROMISING THE WORKFORCE BY DRIVING PEOPLE OUT OF THAT WORKFORCE IN A LARGELY IRREVERSIBLE WAY IS SOMETHING THAT HAUNTS US ALL. SO YES, THE NEW PROGRAMS, NEW AND YOUNG INVESTIGATORS, DIFFERENTIAL PAY LINES ARE AM THE MECHANISMS THAT WE'RE USING AND WILL CONTINUE TO USE TO GIVE REFLECTION TO IT THAT IMPORTANT ASPECT, SO I THINK WE SHARE COMPLETELY YOUR CONCERN AND INTEREST. >> ALL RIGHT. SO NOW I'LL ASK FOR A MOTION TO CONSIDER THE MINUTES FROM OUR J COUNCIL MEETING. THANK YOU. I SEE A SECOND AS WELL. ANY DISCUSSION OF THAT EXCITING DOCUMENT? HEARING NO DISCUSSION, ALL THOSE IN FAVOR OF APPROVING THE MINUTES? THANK YOU. ANY A ABSTENTIONS OR ANY OPPOSITION? THAT IS UNANIMOUS. THANK YOU. WE WILL NOW NEXT HAVE THE REPORT OF THE TASK FORCE ON MINORITY AGING RESEARCH, DR. CHARLES MUT MUTOGNE IS GOING TO GIVE THAT REPORT. >> AS YOU CAN SEE, I'M NOT ANNA MARIE. I DON'T HAVE A GREAT SPANISH ACCENT, BUT SHE TOLD ME THAT YOU WOULD BE BORED BY HEARING HER TWICE SO SHE HAS FORCED ME TO THE PODIUM. AGAIN I'D LIKE TO THANK THE TASK FORCE MEMBERS FOR THEIR PARTICIPATION. IF Y'ALL COULD WAVE, I'D APPRECIATE IT, LET EVERYBODY KNOW. A REAL STALWART IN KEEPING US ON TASK. WE HEARD FROM TWO PRESENTERS WHO DID IT EXCELLENT PRESENTATIONS, AND THEN WE ALSO HEARD UPDATES ON RECRUITMENT OF OLDER ADULTS CLINICAL TRIALS, AND OF COURSE A NEW CONCEPT CLEARANCE WHICH WAS VOTED ON BY THE COUNCIL. DR. KENNY GIBBS SPOKE ON THE SCIENCE OF WORKFORCE DIVERSITY, LOOKING AT CURRENT TRENDS AND POTENTIAL SOLUTIONS. REALLY EMPHASIZING THE NEED TO IT FOLLOW IT THE MISSION OF RESEARCH BY RECRUITING THE BEST SCIENTISTS INTO THE FIELD, AND HE REPORTED BASICALLY LOOKING AT ETHNICITY AND THE ISSUES RELATED TO THAT, THE REPRESENTATION OF WOMEN INITIALL WITH INITIAL NUMBER OF GRADUATES REALLY AT LEAST FOR WOMEN REPRESENTING NOTED SIMILARITIES OF POPULATION DEMOGRAPHICS, HOWEVER, GETTIN IN TO POST -- TENURED TRACK POSITIONS, BUT LOOKING AT UNDERREPRESENTED MINORITY, DRAMATIC DECLINE IN THE NUMBER OF UNREPRESENTED MAY NORTHS GOING ON INTO THESE POSITIONSMENT WHEN YOU LOOK AT IT IN TERMS OF CAREER INTEREST, HE FOUND IT WAS NOT EXPLAINED BY PUBLICATION RECORDS -- THINGS WE HAVE TYPICALLY THOUGHT ABOUT, REALLY DRIVEN BY PERSONAL VALUES, STRUCTURAL DYNAMICS SHAPING THEIR CAREER INTERESTS, AND THAT POLICY TO HELP RETAIN THESE INDIVIDUALS IN ACADEMICS NEED TO BE FOCUSED ON INSTITUTIONS, IN ADDITION TO TRAINEE DEVELOPMENT. HE SPOKE ABOUT THREE PROJECTS, ONE WAS FOCUS GROUP PROJECT WHERE THEY ACTUALLY SPOKE TO 38 CAREER INDIVIDUALS, 23 WOMEN AND 18 FROM UNDERREPRESENTED MINORITIES. THEY DID A NATIONAL SURVEY OF 1,890, RECENT SCM -- GRADUATES, AND DI A SERIE I DID A SERIES OF THESE INDIVIDUALS LACKING AT THEIR CAREER PATHWAYS. THEY ASSESSED WHETHER OR NOT THEY HAD INTEREST IN CAN -- POSITION, ARE YOU GOING -- TO TEACHING INTENSIVE UNIVERSITY, RESEARCH CAREER THAT WAS NON-ACADEMIC, MAINLY IN INDUSTRY INDUSTRY, OR A NON-RESEARCH CAREER, PARTICULARLY POLICY, PATENT LAW, BUSINESS, ET CETERA. THEY LOOKED AT THEIR GRADUATE POSTDOCTORAL TRAINING EXPERIENCES. THE CAREER GOALS AND KNOWLEDGE, AND SEVERAL TIME POINTS WHERE THEY WERE AT PH.D. ENTRY, COMPLETION, AND CURRENTLY IN INTERVIEWS. THE RESPONSE TO THE DEMOGRAPHICS DMOGRAPHICS, 25% WERE MALES FROM WELL REPRESENTED POPULATIONS. FEMALES FROM WELL REPRESENTED POPULATIONS WERE IN GREEN. FEMALES FROM UNDERREPRESENTED MINORITY POPULATIONS. IT REALLY REPRESENTED A LARGE SWATH OF ALL PH.D.s -- LOOKING AT THE FINDINGS FROM THE RESEARCH-INTENSIVE INSTITUTIONS, YOU CAN SEE THE DROP AS THEY START FROM PH.D. ENTRY TO PH.D. COMPLETION TO WHERE THEY ARE IN THEIR POSTDOC. MOST DRAMATICALLY, YOU SEE THE DROP FOR UNDERREPRESENTED MINORITY MALES, AS WELL AS UNDERREPRESENTED MINORITY FEMALES, WITH THAT GROUPING LOWER ON ALL ASPECTS. HOWEVER, WHEN YOU LOOK AT A FACT THAT THEY'RE AT TEACHING INTENSIVE INSTITUTION, YOU CAN SEE THERE'S LITTLE CHANGE. LOOKING AT THIS FOR RESEARCH IN NON-ACADEMIC ENVIRONMENTS, YOU CAN SEE THE DRAMATIC UPTICK FOR UNDERREPRESENTED MALES, AS WELL AS FOR UNDERREPRESENTED FEMALES. IT'S EVEN MORE DRAMA IT TICK FOR UNDERREPRESENTED FEMALES IN TERMS OF GOING INTO NON-RESEARCH CAREERS. SO YOU REALLY CAN SEE THE DRAMATIC LOSS OF UNDERREPRESENTED FEMALES AND THE -- AS THEY MOVE THROUGHOUT THE TRAJECTORIES FROM PH.D. TO POSTDOC. SOME OF THE REASONS THAT INFLUENCE THESE DECISIONS, FOR THE MEN, THEY TALKED ABOUT THE DIFFICULTY IN ACADEMIC JOB MARKET, THE DIFFICULTY GETTING GRANT FUNDING AND OBVIOUSLY THE LOW PAY FOR POSTDOC. FOR WOMEN, THEY TALK ABOUT LIFE BALANCE AND THE CLIMATE AND THE ENVIRONMENT. WHEN WE GET TO THE FOCUS GROUP DATA, YOU'LL SEE SOME CHANGES THERE. HERE'S SOME OF THE STATEMENTS. TALKING ABOUT THE LACK OF CONTROL THAT'S PERCEIVED BY THE MEN IN REGARDS TO SUCCESS IN THEIR CAREER. AND AGAIN, THIS ISSUE OF HAVING THE LOW PAY SCALE FOR POSTDOCS. FOR WOMEN, TH THEY TALK ABOUT WANTING TO HAVE A FAMILY, SEEING THEIR CHILDREN GROW UP AND NOT JUST GET HOME WHEN THEY'RE IN BED. THIS ONE GENERATED A LITTLE BIT OF CHUCKLES. THEY FELT THAT THEY COULD HOLD THEIR OWN WITH THEM, BUT THEY REALLY DIDN'T WANT TO WORK WITH THE FOLKS THAT THEY'RE SEEING IN THE FIELD. SO THEY REALLY TALK ABOUT THERE'S NO REASON WE WORK REALLY HARD WITH THESE PEOPLE THAT ARE OUR PEERS. I GUESS WE'RE TALKING ABOUT OURSELVES IN THAT. SO THOSE WERE SOME OF THE THINGS THAT WERE PRESENTED. I'M GOING TO SKIP THROUGH THIS SLIDE JUST TO TALK ABOUT THE CONCLUSIONS. THERE WAS A GENERAL TREND AWAY FROM FACTORY CAREERS, AND TOWARD NON-RESEARCH CAREERS. THERE WAS A DISPARATE INTEREST IN PH.D. COMPLETION, AGAIN RELATED TO THE ISSUE OF SOCIAL IDENTITY WHEN ACCOUNTING FOR STARTING INTEREST, PRODUCTIVITY, ACADEMIC INVESTMENT, RESEARCH ADVOCACY, THEY TALK ABOUT REALLY WANTING TO HAVE SOMETHING WHERE THEY CONTRIBUTED TO SOCIETY AS OPPOSED TO JUST A JOB. AND THEN OBVIOULY PERSONAL VALUES AND SYSTEMATIC DYNAMICS SHAPING THEIR CAREER INTEREST. ANY QUESTIONS ABOUT THAT BEFORE I MOVE ON TO THE NEXT PRESENTATION? ANYTHING I LEFT OUT FROM MY FELLOW TASK FORCE MEMBERS? OKAY. THE NEXT TALK WAS BY DR. JANET LUBE LOOKING AT PLURA -- I'M NOT GOING TO TALK ABOUT THE -- THIS IS A REAL RISK FOR A GERIATRICIAN, BY THE WAY, T WAY, TO GO DOWN THIS BASIC SCIENCE PATHWAY. BASICALLY THE POINT WAS THAT, YOU KNOW, HUMAN STEM CELLS HAVE ACALL RIGHA LOT OF POTENTIAL USES. THIS PARTICULAR RESEARCH WAS LOOKING MAINLY AT NEUROLOGICAL DISEASES AS WELL AS CARDIAC DISEASES, PARTICULARLY AROUND NEUROLOGIC ARCHITECTURE, AS WELL AS CARDIAC WHAT I WOULD CALL FUNCTION. THE REAL FOCUS WAS THE FACT THAT RIGHT NOW THE CUSTER ANALYSIS OF STEM CELLS REPRESENTING WORLDWIDE GENO TYPES TENDS TO FOCUS IN EUROPEAN AND MIDDLE EASTERN GROUPINGS, BUT THE THOUGHT WAS THAT HAVING A GREATER DIVERSITY FROM STEM CELL ORIGINS COULD MAYBE EXPLAIN SOME OF THE ISSUES RELATED TO HEALTH DISPARITIES. LOOKING AT THE MICRO ARCHITECTURE RELATED TO NEURON COMPLEXITY AND BRAIN DEVELOPMENT. HERE'S AN EXAMPLE OF GOING FROM ASTROCYTES IN NEURONS, MOVING FROM THAT PLURIPOTENT CELL, MOVING FORWARD ALL THE WAY TO ASTROCYTES AND INTO NEURONS. THE POINT OF THIS WAS, AGAIN, THE LENGTH OF TIME THAT YOU HAVE TO STUDY THESE CELLS AS THEY DEVELOP, BUT ALSO THE GENE EXPRESSION AS THEY MOVE FORWARD. AND I TOLD ANNA MARIA, IT IF I MADE MISTAKES, SHE'S GOING TO CLICK ON HER MIC AND CORRECT ME. THE ONE I LIKE AGAIN, I DISCOVERED THAT PRETTY PICTURES REALLY TELL A GREAT STORY. THIS IS LOOKING AT THE MATURATION FROM 21 DAYS TO 40 WITH IT DAYS THESE WERE FROM DIFFERENT ETHNIC GROUPS AND THE DEVELOPMENT OF THESE NEURONS FROM EARLY STEM CELLS ALL THE WAY TO NEURONS. THIS IS THE AFRICAN-AMERICAN GROUP, AND I GUESS THIS IS THE MAP TO EXPRESSION. YOU CAN SEE THERE'S A DIFFERENT BETWEEN THIS AFRICAN-AMERICAN STEM CELL LINE. THIS WAS A HISPANIC STEM CELL LINE. I FORGET WHAT THE F WAS. DO YOU REMEMBER? OH, SORRY. SO ASIAN, AFRICAN-AMERICAN, AND HISPANIC. I THINK THERE'S TWO HISPANIC STEM CELL LINES. AND AGAIN, THE DIFFERENCE IN HOW THEY DEVELOP OVER FROM THE PLURIPOTENTIAL LEVEL ALL THE WAY TO FULLY -- FULL MATURATION. AGAIN YOU CAN SEE THE DIFFERENCE IN THE PICTURES HERE BETWEEN THE ETHNIC GROUPS. AS THE CELLS DEVELOP. AGAIN, I LIKE THE PRETTY PICTURES. SHE ALSO TALKS ABOUT THIS IN TERMS OF HOME YES STAY TIS AND IMPLICATION, AGAIN, SPEAKING TO THE NEED TO FOLLOW THESE CELLS OVER A LONG PERIOD. SHE REALLY TALKED ABOUT HAVING DIFFERENTIAL STEM CELLS THAT STARTS FROM DIFFERENT ETHNIC POPULATIONS USING THE SOPHISTICATED NANOTECHNOLOGY CAN HELP US UNDERSTAND THE NEURAL CONNECTIVITY AND THE DISEASE DIFFERENTIATION AS THESE CELLS DEVELOP, AND SHE'D TALK A LOT ABOUT HER IT TECHNIQUES AND HOW THEY DEVELOP THESE CELLS. DOES THAT SUMMARIZE IT PRETTY GOOD? OKAY. THERE WAS A LOT OF DISCUSSION PROBABLY DRIVEN BY ME, I GUESS. THERE WAS DISCUSSION ABOUT WHAT DOES IT MEAN TO HAVE THIS KIND OF DIFFERENTIATION AT THE END OF A PLURIPOTENT STEM CELL, PARTICULARLY WHEN YOU HAVE SUCH HETEROGENEITY WITHIN ETHNIC GROUP. SO THERE WAS SOME DISCUSSION ABOUT WHAT THAT MEANS IN HOW THAT GETS TRANSLATED. INDIVIDUALS -- WE TALKED A LITTLE BIT ABOUT SPECIFIC SNIPS WITHIN THESE PLURIPOTENT CELLS THAT MAY HAVE DIFFERENTIAL DISEASE EXPRESSION AS IT MOVES THROUGH MATURATION AND DEVELOPMENT, AND AT THE END, THIS TYPE OF RESEARCH REALLY HAVING A NEED TO HAVE A DIVERSE GROUP OF TEAM MEMBERS TO TALK ABOUT AGAIN THE IMPACT OF THIS REALLY CELLULAR AND SUBCELLULAR LEVEL ANALYSIS, AND WHAT IT MEANS PARTICULARLY IF YOU'RE LOOKING AT HEALTH DIVERSITY IN DISPARATE HEALTH CONDITIONS. OBVIOUSLY WE TALK ABOUT OUR NEW CONCEPT CLEARANCE, AND AGAIN, SHOUT GOES OUT TO DR. HILL AND THE OFFICE. AS WE VOTED ON -- >> CHARLES, WE'LL DO THAT IN THE WORKING GROUP ON PROGRAMS. >> OKAY. AND THE NEW NAME. SO ANY QUESTIONS? >> DR. TILLIE. >> I WAS JUST GOING TO ASK, I WAS STRUCK STILL THINKING ABOUT YOUR FIRST PRESENTATION, AND I'M WONDERING, IT'S PRETTY CLEAR THAT SOME OF THE REASONS ARE THE ACADEMIC CULTURE AND THE ECONOMIC ASPECTS, BUT DID YOUR WORK DO ANYTHING OH TO -- OR NOT YOURS, WHOEVER'S WORK IT WAS, DID THEY DO ANYTHING TO LOOK AT POTENTIAL SOLUTIONS OR MAKE ANY RECOMMENDATIONS ABOUT HOW TO ADDRESS WHAT ARE SOME PRETTY DEEP SYSTEMIC ISSUES? >> WELL, I THINK YOU TALK ABOUT JUST THE FACT THAT IT WAS A DEEP SYSTEMIC ISSUE, I SHOULD HAVE PUT UP A SLIDE HERE SHOWING ECOLOGICAL DIAGRAM LOOKING AT HOW THE INDIVIDUALS EMBEDDED WITHIN THE CULTURE OF THE THE DIVISION, DEPARTMENT, INSTITUTION, INFLUENCES DRIVEN BY THE FUNDING STREAMS AS WELL AS JUST THE OVERALL RESEARCH ENVIRONMENT. ALL THOSE CONTRIBUTE TO HOW WELL A PERSON THINKS THAT THEIR CAREER CAN MOVE FORWARD IN RESEARCH. HE EMPHASIZES THIS CUTS ACROSS A LOT OF DIFFERENT AVENUES. ONE OF THE THINGS HE EMPHASIZED, ALTHOUGH THE APPROACH HAS TYPICALLY BEEN TO LOOK WITHIN THE INSTITUTE NECESSARILY NIH AND ACADEMIA FOR SOME OF THESE SOLUTIONS, THERE MAY BE REALLY STRUCTURAL ISSUES THAT NEED TO BE ADDRESSED AS WELL. SO IT OPENED UP A DISCUSSION ABOUT BROADER WAYS OF ADDRESSING THE PROBLEM. WE DIDN'T REALLY COME UP WITH A DEFINITIVE SET OF SOLUTIONS. >> ANY OTHER QUESTIONS FOR THE TASK FORCE REPORT? THANK YOU VERY MUCH. THE NEXT AGENDA ITEM IS REPORT OF COUNCILS OF NIH AND ANNA MARIA CUERVO IS OUR REPRESENTATIVE OH IT THAT AND WILL BE GIVING THE REPORT REPORT. >> SO WE HAVE THE MEETING IN GENERAL BUT BECAUSE IT WAS RIGHT AFTER OUR MEETING, I COULDN'T REPORT THERE. SO BASICALLY THIS IS KIND. AGENDA, OR AT LEAST THE KEY ITEMS I WOULD LIKE TO HIGHLIGHT. ONE IS REGARDING THE KNOWN HUMAN PRIMATES, AND I WILL PRESENT SOME OF THE HIGHLIGHTS OF THAT PROGRAM. THEN WE HAVE THE DEPUTY DIRECTOR'S UPDATE, SO I WILL FOCUS A LITTLE MORE ON HIS COMMENTS ON THE WORKFORCE, THEN WE DISCUSSED CHANGES IN THE EVALUATION OF THE PROGRAM AS WELL AS CHANGES IN THE OPERATING PROCEDURE, AND THEN JUST AN EXAMPLE OF ONE OF THESE COMMON FUNDS INITIATIVES. SO STARTING WITH KNOWN PRIMATES, COUNCIL OF COUNCILS CREATE OUR WORKFORCE TO DETERMINE THE NEED OF PRIMATES FOR RESESM, SO ANYTHING THAT INVOLVED PRIMATES IS GOING TO BE SECOND REVIEW BY THE COUNCIL, AND THEY ALSO HAVE BEEN OVERSEEING AT LEAST REPORTING TO COUNCIL OF COUNCILS ABOUT THE CENTRALIZED RESOURCES THAT ARE CURRENTLY AVAILABLE FOR RESEARCHING WITH NON-HUMAN PRIMATES. SO WE GO WITH THE REPORT OF THE ACTIVITIES OF THE PRIMATE CENTERS, SO THIS IS A NATIONAL RESOURCE TO PROVIDE INFRASTRUCTURE, AND ANIMALS AND -- THEY ALSO HAVE COLLABORATIONS WITH IT -- THAT DON'T HAVE THE ACCESS TO THOSE MODELS, AND THEN THEY ALSO HAVE A HOME BASE SO THERE ARE INVESTIGATORS THAT BELONG AND PHYSICALLY LOCATED IN THESE PRIMATE CENTERS. CURRENTLY THEY'RE SUPPORTED BY ABOUT 94 MILLION-DOLLARS, AND THIS IS HOW THEY DIVIDE, SO THERE ARE SEVEN LARGE CENTER ITS THAT GET ABOUT 23 MILLION, THEN THEY GET 6 SPECIALIZED CENTERS SPECIALIZING IN SINGLE SPECIES, AND SPECIFIC PATHOGEN FREEDOM COLONIES, AND THAT'S THE BREAKDOWN OF THE DOLLARS. AND THEN TO GIVE YOU AN IDEA WHO IS INVOLVED AND REGARDING BOTH THE ANIMALS AND THE PEOPLE, SO 60% OF THE STUDIES REALLY REVOLVE AROUND RHESUS MONKEYS, BUT FOR THE PERSONNEL, YOU HAVE THREA HUNDRED CORZINE TISES, THOSE ARCORE SCIENTIST,BUT IT'S WITH ABOUT 2,000 OF NEH THAT CAN HAVE ACCESS TO THOSE RESOURCES. AND AMONG THE DIFFERENT PROJECTS, ONE OF THE OF THE AREAS THAT THE USE OF NON-HUMAN PRIMATES HAVE BEEN PARTICULARLY IMPORTANT HAVE BEEN IN THE STUDY OF HIV AND AIDS. JUST TO GIVE YOU AN IDEA OF WHY THIS IS OF IMPORTANCE, SOME OF THE HIGHLIGHTS OF THE THINGS THEY'VE BEEN DOING IN AIDS RESEARCH THAT COULD HAVE NOT BEEN DONE IF PRIMATES WILL NOT HAVE BEEN USED. SO ONE OF THE -- YOU ARE VERY FAMILIAR WITH THIS, IT WAS ALL NEW FOR ME, THE ONE THAT RESEMBLES MORE AIDS, HE WAS DISCUSSING ABOUT -- BUT EVEN AT THE MOLECULAR LEVEL. SO THE IDEA IS TO UTILIZE THIS TO DEVELOP BETTER THEY WILL NOT BE ABLE TO IDENTIFY THESE WAYS AROUND OF THE VIRUS AND -- THE POSSIBILITIES. AND THEN HE MENTIONED THAT THIS IS NOT ONLY FOR HIV, BUT ALSO THIS IS KIND OF THE PROGRAMS THAT OVERALL THESE CENTERS ARE HAVING THAT INCLUDES VERY DIFFERENT TYPES OF INFECTIOUS DISORDERS AND EVEN CONCEPTS. SO FOR EXAMPLE, HE WAS TALKING ABOUT TUBERCULOSIS AND HOW WHEN THEY UTILIZE SOME OF THESE NEW VACCINES THAT THEY HAVE DEVELOPED IN THESE AN MAS, THEY CAN REALLY PROTECT NOT ONLY FROM THE -- BUT FROM THE SPREADING. SO THEY TALK ABOUT NUMBERS, LIKE 7- SO IN A WAY TO JUSTIFY THIS IS A UNIQUE RESOURCE AND THAT OF COURSE THERE IS A LOT OF ATTENTION PAID OF HOW ARE THESE ANIMALS USED BUT THEY ARE REALLY PAYING OFF FOR ALL THE EFFORT ON THAT. SO MOVING TO THE DEPUTY DIRECTOR UPDATE, THE DOLLARS AS RICHARD TOLD US -- OPPORTUNITIES, AND I GUESS CHOOSE OUT OF HIS COMMENTS ON THE WORKFORCE, BECAUSE WE TALK IN THE PREVIOUS MEETING WHEN WE REPORT ON THE MINORITY WORKFORCE, WE TALK ABOUT ALREADY DIVERSITY, BUT ONE OF THE SLIDES THAT HE SHOWED CAUGHT MY ATTENTION, HE WAS TALKING ABOUT HOW DIFFERENT COUNTRY, HOW SCIENCE IN DIFFERENT COUNTRIES AND HOW MONEY, PATENTS, PEOPLE, SO THEN HE CHOOSE THIS SLIDE THAT REFLECTS THE CHANGES IN THE WORKFORCE IN DIFFERENT COUNTRIES FROM '96 TO 2011, SO WHEN YOU COMPARE THE GREEN, '96, THIS IS 2011, SO YOU HAVE COUNTRIES LIKE CHINA, WE GROW AND IT'S GREAT, WE HAVE MORE PEOPLE INVOLVED IN SCIENCE, WITH BUT THEN IF THEY'RE HAVING COUNTRIES LIKE CHINA THAT ARE HAVING THIS REALLY, REALLY DRAMA IT TICK DRAMATIC GROW TH. ONE OF THE CONSEQUENCES OF THIS, HE PUT IT VERY BLUNT, WHICH IS SOMETHING WE SHOULD PROBABLY START THINKING ABOUT, MANY, MANY OF OUR TRAINEES AND POSTDOCS, WE HAVE A LOT OF INTERNATIONAL PEOPLE THAT WERE COMING FROM THESE COUNTRIES TO RECEIVE TRAINING, AND THAT CONTRIBUTE A LOT TO THE SCIENCE THAT WE ARE DOING IN THE STATES, SO WE MIGHT NOT HAVE THE LUXURY OF HAVING THESE ANYMORE BECAUSE THEY CAN COULD DO -- YOU KNOW, THEIR RESEARCH IN THEIR OWN COUNTRIES IS BLOOMING. SO ONE OF THE CONCLUSIONS IS WE HAVE TO SOMEHOW FREE LILY ENGAGE CITIZENS INTO THINKING ABOUT SCIENCE EARLY ON BECAUSE OUR WORKFORCE IS GOING TO CHANGE NATIONAES AND WE HAVE TO THINK IN ENGAGING MORE OF OUR OWN CITIZENS ON THAT. SO I THINK THIS IS SOMETHING IN THE LONG RUN THAT WE HAVE TO KEEP THINKING THAT THE EUROPEAN COMMUNITY -- BUT ASIA PROBABLY IS GOING TO TAKE A BIGGER DENT IN THE KIND OF FELLOWS THAT WE CAN HAVE IN OUR LABS AND FOR OUR RESEARCH. AND THEN JUST MOVING INTO THE COMMON FUND, THIS IS JUST TO UPDATE YOU ON SOME OF THE CHANGES THAT ARE CURRENTLY GOING, SO JUST TO REMIND YOU FOR NEW MEMBERS, THEY HAVE TO BE TRANSFORMATIVE SO THIS IS GOING TO HAVE A MAJOR IMPACT ON BIOMEDICAL RESEARCH, THAT THEY HAVE TO IMPACT TRANSNIH, SO THIS IS NOT SOMETHING THAT WILL BE ASSIGNED TO A SINGLE 16 TE AND IT HAS TO BE UNIQUE. THE WAY THAT NORMALLY THAT WORKS IS THAT THERE ARE TWO STAGES OR THREE STAGES, A STAGE OF STRATEGIC PLANNING, NORMALLY COUNCIL OF COUNCILS SEE THESE PROPOSALS, SO CONCEPT CLEARANCE SIMILAR TO THE ONES WE DO HERE, AND BASED ON THEIR RECOMMENDATIONS, FINAL PROPOSAL IS PREPARED AND IS PRESENTED TO THE DIRECTOR IT, TO FRANCIS CAN COLLINS. SO THIS WOULD BE THE FINAL PROPOSAL, THEN IT'S THE IMPLEMENTATION AND IT'S DONE INTO STAGES, SO YOU HAVE -- THEN IT MOVES TO OUTSIDE THE COMMON FUND AFTER THIS 10 YEARS. SO THERE HAS BEEN SOME CHANGES IN THE WAY THAT THE COUNCIL OF COUNCILS IS OPERATING, SO ONE OF THE FIRST THINGS IS THE REVIEW OF APPLICATION HAS YET CHANGED, THIS WAS APPROVIN APPROVED IN THE LAST MEETING. THE APPLICATION OF THE COMMON FUND ARE THESE HIGH RISK, HIGH REWARD APPLICATIONS THAT INCLUDE RESEARCH AWARDS, INDEPENDENT AWARD, NEW INNOVATOR AWARDS. THE 21ST ONES WERE ALREADY RECEIVING SECOND REVIEW AT THE LEVEL OF COUNCIL OF COUNCILS. BUT BECAUSE THESE ONES WERE CREATED BEFORE THE COUNCIL OF COUNCILS WAS CREATED, THEY WERE -- NOW THEY HAVE BEEN MOVED SO THE COUNCIL OF COUNCILS WILL DO THE SECOND REVIEW ON THOSE INITIATIVES SO IN CASE THAT YOU HAVE FACULTY APPLY, AT LEAST THEY HAVE AN IDEA OF HOW THE PROCESS IS GOING TO GO. SO THIS WAS ONE OF THE CHANGES. AND THEN THE OTHER CHANGE, AND I THINK THAT THIS WAS AN INTERESTING ONE, THEY PROPOSED AND IT WAS ACCEPTED A CHANGE IN THE WAY THAT THE CONCEPT CLEARANCE IS DONE FOR THE COMMON FUND PROGRAM, SO THE WAY IT WAS DONE BEFORE AS I MENTIONED -- PROVIDES A KIND OF A VERY -- TO HAVE AN IDEA OF WHAT IS GOING TO BE INTERESTING, THEN THOSE ARE DEVELOPED IN THE STAGES THAT I MENTIONED, AND THEN WE JUST DO ONLINE PREVOTE ABOUT WHICH ONES CAN MOVE FORWARD. SO IN A WAY, I THINK THAT THE PROBLEM THAT HAS BEEN HAPPENING WITH SAN JOSƒ'S PROGRAM IS THAT THE CENTERS DIDN'T FEEL THEY WERE ENGAGED ENOUGH, AND THE PROGRAM GOES OUT THERE AND NONE OF THE CENTERS IS PARTICULARLY INTERESTED, SO THEY SEEM TO FEEL THAT THERE WAS A DISCONNECTION BETWEEN THE COMMON FUND INITIATIVES AND THE -- CENTERS, SO THEY PROPOSED AND WE WERE ALL VERY ENTHUSIASTIC ABOUT THIS, THE IDEA OF CREATING A SMALL GROUP OF DIRECTORS FROM THE DIFFERENT CENTERS THAT ARE GOING TO ACT AS A FILTER. SO YOU GET ALREADY ENGAGED THE DIRECTORS. IT'S GOING TO BE VERY IMPORTANT BECAUSE THEY WILL HAVE AN IDEA OF WHETHER THIS IS -- IF THIS IS SOMETHING THAT WILL AFFECT THE CENTER SO THEY CAN ALREADY BE ON ALERT OF THIS, AND ALSO IT IS SOMETHING THAT THE CENTER IS ALREADY SUPPORTED AND IT DOESN'T NEED TO BE AT THE LEVEL OF THE COMMON FUND. SO ONE OF THE OF THE COMMENTS IS LIKE WHY A SUBSET OF DIRECTORS? SO I GUESS RICHARD CAN TELL US MORE THAN ANYBODY THAT THESE GUYS ARE BUSY GUYS, SO THEY WERE MENTIONING IT'S IMPOSSIBLE TO GET ALL THE DIRECTORS OF ALL THE CENTERS ENGAGED IN EACH OF THESE MEETINGS, BUT THE IDEA WOULD BE TO HAVE FAIR REPRESENTATION AND GAVE NOTICE IN ADVANCE SO THEY CAN TAKE A MUCH MORE ACTIVE ROLE, SO I THINK THAT WAS VERY ENTHUSIASTICALLY RECEIVED BY EVERYBODY. THE COMMON FUND HAS BEEN RUNNING NOW FOR A WHILE, SO THERE WAS THE COUNCIL OF COUNCIL ESTABLISHED A TASK FORCE TO EVALUATE HOW THE COMMON FUND WAS DOING, SO BASICALLY IT WAS A WORKING GROUP CREATED IN 2013 AND THE IDEA WAS TO EVALUATE THE PRINCIPLES TO EVALUATE THE COMMON FUND TO REVIEW AND ESPECIALLY TO ASSESS THE IMPACT THAT THESE NEW PROGRAMS ARE HAVING IN OUR BIOMEDICAL COMMUNITY AND ALSO PROVIDE RECOMMENDATIONS, LEARN FROM THEIR MISTAKES AND CAN WE MAXIMIZE THE SUCCESS BY LEARNING ABOUT THINGS THAT ARE GOING GREAT AND TRY TO IMPLEMENT THEM EVEN FASTER. SO THE WHOLE IDEA, THE RECOMMENDATION OF THESE EVALUATION -- ONE OF THEM WAS FOR THE STRATEGIC PLANNING AND THE OTHER FOR THE MANAGING -- MANAGEMENT OF THE PROGRAMS, SO THIS WILL HAPPEN BEFORE FRANCIS COLLINS -- BASICALLY. SO THEY CAME OUT WITH 47 RECOMMENDATIONS, I'M NOT REQUESTING TO GO THROUGH ALL OF THEM, BUT SOME OF THE RECOMMENDATIONS WERE INTO THE STRATEGIC PLANNING N A WAY, I THINK AS COUNCILMEMBERS, IT WAS VERY HELPFUL TO SEE THEY'RE REALLY THINKING VERY SERIOUSLY AND EVALUATING, BECAUSE THIS IS STILL RELATIVELY NEW PROGRAMS AND THERE CAN BE ROOM FOR IMPLEMENTATION. SO ONE OF THE THINGS THAT GOT IN THE STRATEGIC PLAN, THE RECOMMENDATION WAS TO ENGAGE A BROTHER GROUP OF STAKEHOLDERS. MANY ARE CONFUSED OF WHAT IS A COMMON FUND, GRANTEES ARE NOT TAKING ADVANTAGE OF SOME OF THESE INITIATIVES AND EVEN THE CENTERS ARE NOT PARTICIPATING. ALSO CLARIFYING THE CRITERIA AND ENGAGE AS I MENTION THE CENTER DIRECTORS AND AS SOON AS POSSIBLE IN THEIR PROGRAM. AND THEN FOR THE PROGRAM MANAGEMENT, THE IDEA AS I MENTIONED IS ALSO TO INCREASE COMMUNICATION OF PUBLICITY, MANY OF US WERE CONFUSED FOR A LONG TIME WITH THE COMMON FOUND, THINK THE COMMUNITY IN GENERAL NEEDS MORE INFORMATION, AN THEN TO CONTINUE TO EVALUATE THESE PROGRAMS TO CREATE SOME MECHANISM THAT WILL -- EVALUATION BEFORE THE FIVE YEARS ARE OVER, BECAUSE THERE ARE MISTAKES THAT COULD HAVE BEEN IDENTIFIED EARLIER THAT MIGHT HAVE MADE THIS PROGRAM MUCH MORE SUCCESSFUL. THEN AS I SAY, GET EVERYBODY FAMILIARIZED TO ORGANIZE MEETINGS WITH GRANTEES SO EVERYBODY IS ON TOP OF WHAT THE OTHER CENTERS ARE DOING, AND ALSO CREATE THIS MIDPOINT BEFORE THE FIVE YEARS ARE OVER AND THEN AFTER -- BEFORE THE 10 YEARS ARE OVER, JUST TO HAVE A LITTLE MORE CONTROL OF WHAT IS GOING AND THEY CAME OUT WITH WITH SOME VERY CREATIVE WAYS TO DO THAT AND MAINTAIN EVERYBY ENGAGED. SO AS I SAID, IT WAS GOOD THAT THEY WERE ALREADY -- THE STATUS -- AND THEN AN EXAMPLE FOR THOSE OF YOU WHO MIGHT HAVE NOT HEARD YET HOW THEY DEVELOPED THIS COMMON FUND INITIATIVE, SO THEY PRESENTED, ONE, THAT THEY'RE WORKING ON THAT IS RELATED TO THE -- THIS IS A -- IDENTIFY AREAS AS ALWAYS THAT -- THAT IS NOT ENOUGH EFFORT BUT THEY CAN BENEFIT TO MANY INSTITUTES. SO FOR EXAMPLE, WE KNOW OSH WE START TO KNOW A LOT ABOUT DNA MODIFICATION, WE KNOW A LOT ABOUT PROTEIN MODIFICATION, BUT WE DON'T KNOW A LOT ABOUT RNA MODIFICATION. THE MEANING OF THOSE MODIFICATIONS AND HOW THEY IMPACT RNA FUNCTION AND WHAT THEY DO, IT'S VERY LITTLE KNOWN. SO THIS IS JUST ONE OF THE MOD IF FIXES, THIS MC6A, SO THIS IS IT TO GIVE YOU AN IDEA HOW BEING AWARE THAT SOMETHING REQUIRES EVEN MORE TOOLS OR DIFFERENT WAYS TO EXPLORE CAN MAKE A BIG DIFFERENCE IN THE FIELD, SO THESE WERE THE PUBLICATIONS, FOR EXAMPLE, WITH THIS MODIFICATION, AND ALL OF A SUDDEN HERE, AN ANTIBODY WAS DEVELOPED OR TOOL WAS DEVELOPED TO STUDY THIS MODIFICATION. SO ALL THIS AVENUE HAD THE COMMUNITY ENGAGED IN A STUDY IN MORE DETAIL, YOU STARTED GOING AT THE MOLECULAR LEVEL AND IDENTIFYING MODIFIERS AND NOW YOU CAN MODIFY -- AND SEE WHAT IS GOING TO HAPPEN, AND THEN YOU HAVE THIS BUT THEY SHOW MORE THAN 20 DIFFERENT AREAS THAT GOT IMPACTED JUST BY LOOKING AT THIS PARTICULAR CHANGE. SO GOING FROM -- TO DOPAMINE RELEASE TO -- SO IT'S REALLY IMPACTING SEVERAL DISEASES THAT WERE ALSO RELATED. SO THE WHOLE IDEA WHEN THEY IDENTIFY A GAP WITH THIS, THE IDEA IS TO SEE IF WE ARE COVERING IT WELL ENOUGH, THERE ARE SOME PARTICULAR INSTITUTES THE THAT MIGHT BE COVERING IT BETTER, AND WHEN THEY ANALYZE THE PORTFOLIO IS THAT MOST OF THE MODIFICATIONS -- THE OTHER, NOBODY IS REALLY LOOKING AT THEM AT THE LEVEL OF DETAIL. THEN THEY CONSULT THE COMMUNITY, THEY REQUEST INFORMATION FROM AN EXPERT, AND THEN THEY CAME UP WITH WHAT DO THEY NEED SO BASICALLY IT'S CLEAR THAT THIS IS A FIELD OR THIS IS AN AREA THAT CAN IMPACT MANY DIFFERENT FIELDS BECAUSE OF ALL THE MANY DISEASES THAT COULDSESE THAT WILL REQUIRE DEVELOPMENT OF -- INITIAL FIVE YEARS, AND STUDY OF -- MORE FOR THERAPEUTICS AND DIAGNOSIS OF THE DISEASE THAT CAN BE RELATED. BUT THIS IS JUST TO GIVE YOU A FLAVOR OF HOW THIS CONCEPT CAME TO THE COUNCIL OF COUNCILS, THERE WAS FEEDBACK WITH ABOUT WHAT SHOULD BE DONE OR HOW TO DO IT, AND THEN THEY WILL HAVE ANOTHER STAGE IN WHICH THEY WILL DEVELOP BEFORE THEY PRESENT IT TO FRANCIS, BUT THAT'S THE TYPE OF TIME FRAME. AND THAT WAS THAT FOR THE MEETING. >> THANK YOU VERY MUCH DR QUESTIONER VO. DR. CUERVO. DR. MAYHUGH. >> WAS THERE ANY DISCUSSION ABOUT HOW TO SWITCH THE LOSS OF PEOPLE COMING IN TO THE WORKFORCE? >> YEAH, SO YOU MEAN INTERNATIONAL PEOPLE COMING? >> WELL, I MEAN EVEN U.S., THE YOUNG PEOPLE. CERTAINLY IN MOST OF THE COLLEGES, THEY GO INTO BIOCHEMISTRY AND THEY GO INTO THE SCIENCE, AND THEN ONCE THEY GRADUATE, THEY DON'T STAY IN IT. DO WE KNOW WHY? >> SO THAT GOES A LITTLE -- THE RED ARIT REALLY APPLIES TO EVERYBODY, SO THEY ALWAYS TALK ABOUT THIS FINAL -- YOU START WITH MANY, BY INCREASING ONLY THE NUMBER, IT'S NOT GOING TO BE ENOUGH, SO WE HAVE TO CREATE MECHANISM, YOU KNOW, THEY HAVE SOME MECHANISM IN PLACE TO TRY TO CREATE, LIKE, FOUR CENTERS THAT ARE GOING TO COORDINATE AND HAVE LIKE THIS UNDER -- COLLEGE KIDS TO GET INVOLVED, BUT I THINK WE NEED TO -- THERE WAS NO PARTICULAR DISCUSSION OTHER THAN WHAT WE DISCUSSED LAST TIME ABOUT HAD THESE EFFORTS OF MINORITY RETENTION AND RECRUITMENT. >> YES, DR. MAZILY A. >> REGARDING THE PRIMATE CENTERS, WAS THERE ANY DISCUSSION AS TO THE FUTURE OF THE PRIMATE CENTERS? I MEAN, WE KNOW THAT SOME MAJOR CENTERS LIKE THE NEW ENGLAND CENTER CLOSED AND THERE'S BEEN A LOT OF CHALLENGES TO CENTERS. I WAS WONDERING IF THERE WAS ANY DISCUSSION ABOUT THAT. >> YES, THERE WAS A COMMENT ABOUT SOME CENTERS CLOSING, AND I THINK EVERYBODY'S VERY AWARE OF HOW LIMITED THIS RESEARCH IS GOING TO BE, BUT I THINK THAT WAS THE REASON WHY THEY CREATE LIKE THIS CENTRALIZED PRIMATE CENTER. WE ASKED WHAT HAPPENED TO THE CENTES THAT ARE CLOSING, SO THE IDEA IS THAT WE HAVE TO -- YOU CANNOT DETERMINE OTHER STUDY, RIGHT, YOU HAVE TO SITUATE FOR THEN TO DIE NATURALLY, SO THOSE ANIMALS WERE MOVED THERE, BUT THE IDEA IS TO CENTRALIZE BECAUSE THEY SAY YOU WILL GET MUCH MORE EFFORT, BUT AT THE SAME TIME, WHEN YOU DO THAT, YOU'LL HAVE TO MAKE SURE EVERYBODY HAS ACCESS. SO THE NUMBERS LOOK GOOD, YOU HAVE 2,000 PEOPLE FROM OUTSIDE, ONE OF THE THINGS THAT WAS DISCUSSED IS THAT MAYBE THE LEVEL OF PUBLICITY THAT'S ABOUT THIS IS NOT GOOD OF ENOUGH, IT'S LIKE MANY PEOPLE THAT DON'T KNOW ABOUT THESE RESOURCES, SO IN A WAY THE SPEAKER WAS LIKE, WELL, I DON'T KNOW HOW MANY WE CAN ACCOMMODATE. SO YOU HAVE THIS BALANCE BETWEEN WHAT YOU SHOULD REALLY IT DO AND WHAT YOU CAN DO WITH THE MONEY YOU HAVE ALLOCATED, BUT AT LEAST THEY NEED TO PUBLICIZE BETTER AND CENTRALIZE. >> THANK YOU. WE DO NEED TO MOVE ON TO THE NEXT AGENDA ITEM, SO THANK YOU VERY MUCH. NEXT IS THE REPORT FROM THE COUNCIL OF PHYSICIAN SCIENCE WORKING GROUP. KEVIN HIGH IS GOING TO GIVE THAT REPORT FROM THE DESK HERE. >> THANK YOU. ON BEHALF OF OUR WORKING GROUP, I'M GOING TO GIVE WHAT WAS SUPPOSED TO BE A FINAL REPORT AND IS GOING TO BE A PEN ULTIMATE REPORT BECAUSE ONE OF THE STEPS WAS TO GET FEEDBACK WITH BY GROUPS AISKED B AFFECTED BY THIS, AND THROUGH THAT FEEDBACK, WE'RE GOING TO BE HAVING ANOTHER SET OF CONFERENCE CALLS AND REFINING OUR RECOMMENDATIONS. BUT JUST TO STATE THE WORKING GROUP TASK AND WHY WE WERE FORMED, THE NUMBER OF PH.D. APPLICATIONS FOR K AWARDS TO NIA IN THE LAST 10 YEARS HAS GONE UP BY 50%. AND THE NUMBER OF APPLICATIONS FOR K AWARDS FOR MDs AND MD-PH.D.s IN THAT SAME TIME FRAME HAS GONE DOWN BY 50%. SO THE TASK FOR FORCE WAS FORMED TO FIND OUT WHY THE THERE HAS BEEN SUCH A FALL AND HOW K A AWARDS WERE DOING IN IT JUMP STARTING CLINICAL CAREERS, AND THEN TO MAKE RECOMMENDATIONS TO THIS GROUP. WE HAD A SEER EAVES OF MEETINGS, A LOT OF DATA GATHERING AND A LOT OF HARD WORK BY NIA STAFF. A NUMBER OF DISCUSSIONS, A MEETING WITH DR. SHARI MILLS, CO-CHAIR OF THE NIH PHYSICIAN SCIENTIST WORKFORCE ADVISORY COMMITTEE. AND FOUND THAT THE K APPLICATIONS HAD GONE DOWN AS WE HAD SEEN, BUT PARTICULARLY THAT'S TRUE FOR KO #O8s. KO8s HAVE ALMOST DISAPPEARED. THEY WERE 50% OF ALL THE K AM CANCATIONS OF PHYSICIAN SCIENTISTS BACK IN 2002-2003, DROPPED OVER THE NEXT SEVERAL YEARS TO ABOUT 25% OF APPLICATIONS AND IN 2012, HAD GONE DOWN TO LESS THAN 5% OF ALL THE K APPLICATIONS FOR PHYSICIAN SCIENTISTS. TEY'VE REBOUNDED A LITTLE BIT BUT THEY REMAIN BELOW 10%. SO THE TASK FORCE THOUGHT THE MAJOR REASONS FOR THIS WERE THAT THERE'S A LOT OF UNCERTAINTY OF A GRANT FUNDED CAREER FOR YOUNG PHYSICIAN SCIENTISTS, THE AVERAGE SAL REA FOR THE SALARY HAD OUTPACE D THE COMPENSATION SUPPORTED BY A K AWARD, THAT THERE WAS DECREASED ABILITY FOR DEPARTMENTS AND INSTITUTIONS TO IT FILL THAT K GAP AND COST SHARE THE DIFFERENCE. THERE WAS A MUCH LOWER ABILITY FOR CLINICIANS TO PAY FOR MORE THAN 25% OF THEIR SALARY AND 25% OF THEIR TIME IN THE CLINIC BECAUSE THE MARGIN HS GONE DOWN THERE, AND THERE WERE A VARIETY OF OTHER MECHANISMS THAT MIGHT HAVE BEEN FILLING THE GAP. AND AS IT URNS OUT, THE DATA SUGGESTS THAT IN THE LAST FIVE YEARS OR SO, ONLY ABOUT 50% OF MDs WHO HAVE GOTTEN A FIRST RO1 HAVE 210 A K AWARD BEFORE THEY GOT A FIRST RO1. SO ABOUT HALF OF THEM GET AN R WITHOUT A PRIOR K. IT IF YOU LOOK AT THE AMOUNT TIME IT TAKES FOR SOMEONE TO GET TST R AWARD, IT'S AN AVERAGE OF 16 YEARS FROM DEGREE FOR THOSE WITH A K VERSUS A LITTLE OVER 18 YEARS FOR THOSE WITHOUT A CAN K. SO IT TAKES A LITTLE LONGER WITHOUT A K, BUT IMPORTANTLY, THAT'S ACTUALLY ABOUT A SEVEN-YEAR DIFFERENCE BECAUSE PEOPLE WITH A K USUALLY HAVE A FIVE-YEAR AWARD SO THEY'RE FUNDED FOR FIVE YEARS BEFORE THEY APLA APPLY FOR THAT, SO YOU WOULD THINK IF ALL THINGS WERE EQUAL, IT WOULD INCREASE IT BUT IT DECREASES IT QUITE DRAMATICALLY. SO WE THINK IT'S A STRONG MECHANISM THAT IS PROBABLY BEING UNDERUTILIZED. SO WE HAD FORMULATED ABOUT FIVE RECOMMENDATIONS AND GOT FEEDBACK ON THOSE OVER THE LAST SEVERAL WEEKS. THE FIRST WAS TO INCREASE THE DOLLAR AMOUNT FOR EACH K AWARD COMMENSURATE WITH COVERING THE SAME PERCENTAGE OF SALARY IN 2015 THAT WAS COVERED IN 1996, WHEN THE LAST INCREASE WAS MADE IN THIS AWARD. WE GOT A LOT OF MIXED FEEDBACK ABOUT THAT, HOWEVER. I THINK THERE'S A LOT OF CONCERN THAT THIS IS A FIXED PIE, AND IT IF YOU GIVE MORE DOLLARS, YOU'LL HAVE LESS AWARDS. T JUNIOR FACULTY WERE NOT AT ALL HAPPY ABOUT THAT. SENIOR FACULTY ALSO THOUGHT, AT LEAST GET THE FOOT IN THE DOOR AND GIVE THEM SOME DOLLARS. SO A LOT OF DISCUSSION WAS HAD, AND WE'LL TALK ABOUT IT IN OUR FINAL RECOMMENDATIONS, I BELIEVE, AN ALTERNATE STRATEGY WHICH MIGHT BE TO TARGET SOME RO3 PERHAPS THROUGH AN RFP -- THAT WOULD INCREASE THE AMOUNT OF DOLLARS FOR THEIR RESEARCH, WHICH ARE VERY MINIMAL IN THE CURRENT AWARD, AND ALLOW MORE OF THE K TOTAL FUNDING TO BE DEVOTED TO SALARY. THE SECOND RECOMMENDATION WAS A STEP-DOWN K THAT WOULD ALLOW LESS THAN 75% EFFORT CHARGED TO THE K AWARD AND ALLOW CONCOMITANT COFUNDING BY EITHER THEIR OWN GRANTS A THERE WAS A RESOUNDING POSITIVE RESPONSE TO THAT FROM THE JUNIOR FACULTY AND SOMEWHAT MIXED RESPONSE FROM SENIOR FACULTY, ALTHOUGH I THINK IN A VARIETY OF FORMS, PROBABLY THE MAJORITY AGREED THAT IN AN ERA OF TEAM SCIENCE, THAT WAS ACTUALLY NOT A DETRIMENT TO K AWARDEES BUT A POSITIVE, SO WITH WE WILL PROBABLY MODIFY THAT A LITTLE BIT AS WELL BUT GO FORWARD WITH THE GENERAL IDEA AND CONCEPT. THE THIRD WAS IT TO FOSTER CREATIVE WAYS TO FACILITATE CONTINUED K INITIATED RESEARCH PROGRAMS LIKE THE K99R00 WHICH HAS BEEN SO SUCCESSFUL FOR PH.D.s BUT DOESN'T REALLY FIT MDs VERY WELL, AND THERE'S BEEN A MOVEMENT NIH-WIDE IT TO MAKE IT MORE MD-FRIENDLY AND WE THINK THAT'S IMPORTANT TO DO AND THE FEEDBACK WE GOT FROM JUNIOR AND SENIOR FACULTY ECHOED THAT. THERE WAS A LOT OF DISCUSSION ABOUT CONTINUING EXPANSION OF PREK AWARDS SUCH AS GENERAL STAR AND BEASON WHICH HAVE BEEN SO UK SESUCCESSFUL. WE HEARD ABOUT IT AT THE PROGRAM REVIEW MONDAY, AND THE TASK FORCE SAID THOSE PROGRAMS WERE IMPORTANT TO KEEP MOVING FORWARD AND THE FEEDBACK WE GOT FROM JUNIOR AND SENIOR FACULTY ALSO ECHOED THAT. THEN THE FINAL RECOMMENDATION WAS TO INSTITUTE PERIODIC REPORTING TO THIS GROUP ON THESE MECHANISMS THIS IN THEIR SUCCESS, AND THERE WAS STRONG SUPPORT IN THE SCIENTIFIC COMMUNITY FOR THAT AS WELL. SO WE'RE GOING TO GO BACK AND REFINE THIS A LITTLE BIT MORE, THEN WE'LL TRY TO BRING FINAL RECOMMENDATIONS TO THE NEXT NACA MEETING. I WANT TO THANK AGAIN THE NIA STAFF FOR A LOT OF WORK ON THIS AND THE TASK FORCE MEMBERS WHO SPENT A LOT OF TIME. I'M HAPPY TO ENTERTAIN ANY A > DIFFERENT? >> THAT'S A GOOD QUESTION. NOT REALLY. THERE ARE -- THERE'S NOT A LOT OF DATA OUT THERE. NCI HAD IT DONE A PRETTY THOROUGH REVIEW OF THEIRS AND PUBLISHED IT A COUPLE YEARS AGO, AND IT'S SORT OF FLAT, IF I'M RECALLING THAT DATA CORRECTLY. BUT THE DATA WE HAD WAS NIA-SPECIFIC. WE DECIDED TO LOOK SPECIFICALLY AT THE AGING COMMUNITIMENT I THINK THERE ARE, AS WAS POINTED OUT YESTERDAY DURING OUR WORKING GROUP ON PROGRAM, THERE ARE OTHER INSTITUTES THAT HAVE A PAY AMOUNT IN THEIR K AWARD THAT'S QUITE A BIT HIGHER THAN THE NIA, BUT THE NIA HAS MECHANISMS THAT PAY LIKE A SUPER K, WHICH ARE MUCH HIGHER, SO THERE ARE DIFFERENT MECHANISMS IN DIFFERENT INSTITUTES,N TATA -- THE MD APPLICATIONS HAVE FALLEN SIMILAR TO THE K POOL OVERALL. >> ALL RIGHT, THANK YOU VERY MUCH, KEVIN. YOU ARE STILL ON, HOWEVER. THE NEXT AGENDA ITEM IS THE D.C. -- IT DGCG PROGRAM REVIEW PRELIMINARY REPORT, AND THAT'S YOURS. >> SORRY, YOU'VE GOT TO LISTEN TO ME AGAIN. SO ON MONDAY, WE HAD THE MEETING FOR THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY REVIEW. THE STAFF DID A FANTASTIC JOB PUTTING TOGETHER A VERY THOROUGH REPORT THAT WAS DISTRIBUTED TO COMMITTEE MEMBERS ABOUT 3 1/2 WEEKS BEFORE MEETING, WE HAD SEVERAL PHONE CALLS INCLUDING CAN DIVIDING UP THE REPORT INTO ASSIGNMENTS FOR WHO WOULD DIG IN VERY THOROUGHLY INTO EACH OF THE AREAS AND THE COMMITTEE DID A FABULOUS JOB, AND OBVIOUSLY TAKING THAT TASK SERIOUSLY, THERE WAS A LOT OF GOOD DISCUSSION OVER THE ENTIRE DAY, AND WE ARE IN THE MIDST OF FORMULATING OUR REPORT, BUT WE DID PUT TOGETHER WHAT WE THINK ARE FIVE GENERAL THEMES THAT WERE LIKELY TO COMMENT UPON IN THE FINAL REPORT. THE FIRST OF THESE IS TRANSLATION, THE TRANSLATIONAL EFTS IN THE DIVISION SHOULD TRY TO BE ACCELERATED AS MUCH AS POSSIBLE WHICH WILL REQUIRE CROSS NIA LAB CLAITIONS. THIS WAS EMPHASIZED IN THE MOST REASON IT DAB REPORT AS WELL, WE THINK THAT THEME IS IMPORTANT TO MOVE THROUGHOUT NIA, AND WE THINK GCG IS ONE THAT REALLY HAS INTERACTIONS WITH ALL THREE OF THE OTHER DIVISIONS IN NIA, AND TRANSLATION WOULD BE GREATLY ACCELERATED BY THAT. THAT COULD BE DONE WITH A VARIETY OF TRANSNIA COLLABORATIVE EFFORTS. SIMILAR TO ONE WE'RE GOING TO HEAR ABOUT IN THE CONCEPT FOR HEALTH DISPARITIES RESEARCH AND RESILIENCE A LITTLE BIT LATER ON. FROM MECHANISMS TO BRING TOGETHER DIRECTORS OF NIA SPONSORED CENTERS LIKE THE PEPPER CENTER, THE SHOCK CENTER, THE ALZHEIMER'S DISEASE, RIKMARS, ET CETERA. PERHAPS THROUGH A CONSORTIUM OR A MEETING THAT WOULD REALLY ADDRESS SPECIFIC THEMES THAT CROSS ALL FOUR NIA DIVISIONS, AND FINALLY DEVELOPING A MINIMAL PHENOTYPING DATASET BASED ON RESOURCE INTENSITY AND TIME AVAILABLE, SO IF YOU'RE COLLECTING COHORT STUDIES, STUDY VISITS AND HAVE MORE TIME, YOU CAN DEVELOP A MORE THOROUGH PHENOTYPING OF THEM BUT WE NEED TO HAVE CRITICAL EVEN SMALL AMONTS OF DATA THAT TAKE 10 TO 15 SECONDS IN A CLINIC VISIT AND CAN BE EMBEDDED IN AN EMR THAT WILL ALLOW PHENOTYPING OF AGING OUTCOMES TCOMES THAT ARE IMPORTANT AND ALLOW US TO HARNESS SOME OF THE NE RESEARCH METHODS THAT WE THINK DGCG IS LIKELY TO -- WE JUST TALKED A WHOLE LOT ABOUT TRAINING. THERE'S A VARIETY OF PROGRAMS AT DGCG TA ARE SUCCESSFUL BUT WE HAD OTHER THOUGHTS ABOUT EXPANDING ESPECIALLY BRINGING THEM NOT ONLY INTO AGING-RELATED SLOTS BUT A SCIENTIFIC COMMUNITY, BECAUSE WE THINK THE SUCCESS HAS NOT JUST BEEN BECAUSE THEY GOT THE MONEY, BUT BECAUSE THEY GOT A LOT OF PEERS AND A GROUP THAT THEY WORKED CLOSELY WITH AND STAYED IN TOUCH WITH AND BECAME PEER MENTORS. THE THIRD THEME WAS LEVERAGING PARTNERS. THERE'S A WHOLE VARIETY OF PARTNERS WE COULD LEVERAGE WITH, CTSAs, OTHER NIA-SPONSORED CENTERS ACROSS THEMATIC THEMES AS WAS MENTIONED, MODELING AFTER THE NIH JEER OWE SCIENCE INTEREST GROUP, D GCG COULD USE THAT MODEL TO BUILD A SIMILAR NETWORK, PROVIDING OPTIONS FOR TRANSLATION. DEVELOPING KNITTED COHORTS. IT'S VERY HARD TO KEEP COHORTS GOING OVER 35 OR 40 OR 50 YEARS. YOU DID HEAR ONE THAT'S GONE OVER 50 YEARS YESTERDAY. BUT I THINK MORE LIKELY LU HAVE TO KNIT COHORTS TOGETHER THAT ARE MAYBE CHILDHOOD, EARLY ADULTHOOD, MID LIFE AND LATER, AND HOW DO YOU AFFECT OR CONTROL FOR BIRTH COHORTS AND OTHER CHANGES ACROSS THOSE KNITTED COHORTS, AND THAT'S GOING TO BE AN IMPORTANT AREA OF EMPHASIS THAT WILL NEED TO BE LEVERAGED, INCLUDING, PERHAPS, WITH OUR EUROPEAN PARTNERS WHO ARE DOING SOME OF THOSE COHORT DEVELOPMENTS AS WELL. THE FOURTH THEME WAS TO DEVELOP ADDITIONAL STRENGTH IN NEW RESEARCH PARADIGMS SUCH AS OTHER OMICS. THERE'S BEEN A LOT OF GENOMICS BUT NOT MUCH EPIGENOMICS, METABOLOMICS, MICROBIOME, ET CETERA, SUPPORTED BY DGCG, AND MORE ESM MR BASED AND BIG DATA EMPHASIS OF RESEARCH FOR CLINICAL OUT COMES IS LIKELY TO BE A MAJOR MECHANISM AND PARTNERSHIP WITH PCORI IS LIKELY TO GROW FOR THIS GROUP OVER THE NEXT FIVE YEARS AND THERE'S SOME RECOMMENDATIONS WE'LL HAVE FOR EXPERTISE IN THAT AREA. THEN FINALLY, THE FIFTH THEME WAS REVIEW. THE REVIEW PROCESS FOR DGCG APPLICATIONS WE THINK SUFFER SUBSTANTIALLY -- ALL OF AGING APPLICATIONS SUFFER FROM THE ISSUE OF DIFFICULTY DEALING WITH COMPLEXITY. STUDY SECTIONS OFTEN DON'T LIKE COMPLEXITY. THEY LIKE SPECIFIC REDUCTIONISTIC VERY REFINED QUESTIONS. COMPLEXITY IS AGING. AND SO THE REVIEW PROCESS IS DIFFICULT FOR AGING IN GENERAL, BUT ESPECIALLY, WE WITH THINK, FOR DGCG, WHERE CLINICAL STUDIES OFTEN HAVE TO GO ABOVE THE $500,000 LIMIT AND THE PAY LINES GET EVEN SMALLER. WE'RE GOING TO HAVE SOME SUGGESTIONS ABOUT WAYS TO ADDRESS REVIEW, INCLUDING SOME WAYS THEY'VE ALREADY MOVED INHE CTAP GROUP -- >> MAKE A QUOTE FROM PHILIP BROTH WHEN HE SAID THAT AGING IS NOT A WAR, IT'S A MASSACRE. [LAUGHTER] >> AND ON THAT OBSERVATION, WITH WE WILL MOVE ON TO THE NEXT ADEN JEN DGENERAL DA ITEM. AT LEAST, KEVIN, YOU GET OTHERS TO SHARE THE RESPONSIBILITY THIS TIME. >> SO THE WORKING GROUP ON PROGRAM MET YESTERDAY, AND HAD RECOMMENDATIONS FROM PAST MEETINGS WHICH WERE PRESENTED. THE C TAP WAS PRESENTED BY SERGEI, WHICH WAS JUST A REPORT, AND THERE WERE NO SPECIFIC AGENERAL IT DA ITEMAGENDA ITEMS. NEIL, WERE YOU GOING TO PRESENT ANYTHING? WE'LL JUST MOVE AHEAD WITH THE FACT THAT THOSE RECOMMENDATIONS WERE SUPPORTED BY THE WORKING GROUP ON PROGRAM TO COME BEFORE COUNCIL, AND BE VOTED UPON AT THIS IT TIME. >> RIGHT. THE RECOMMENDATIONS WHICH YOU SAW IN YOUR MATERIALS, WE DISCUSSED THEM IN THE WORKING GROUP AND THERE WERE NO AMENDATIONS TO THE REPT THE REMENTSE RECOMMENDATIONS FROM THE SUMMIT. >> FIRST IS ON EXTENSION OF THE LOOKAHEAD STUDY. IT WAS PRESENTED BY DR. JUDAH HANNAH FROM DGCG AND STEVE CUMMINGS IS GOING TO GIVE US A BRIEF OUTLINE OF THAT. >> LOOK AHEAD HAS BEEN A VERY SUCCESSFUL RANDOMIZED TRIAL OF INTENSIVE LIFESTYLE MODIFICATIONS FOR THE TREATMENT OF DIABETES, AND IT HAS RESULTED IN SUSTAINED WEIGHT LOSS OVER THE LONG PERIOD OF FOLLOW HAD-UP. THERE'S AN OPPORTUNITY NOW TO, IN ITS EXTENSION, ADD MEASUREMENTS RELATED TO AGING SUCH AS WALKING SPEED, FUNCTIONAL PERFORMANCE LIKE SPBB MEASUREMENTS, SO THE REQUEST WAS MADE TO SUPPORT OR COFUND THAT AGING RELATED RESEARCH ALONG WITH NIDDK AND OTHER INSTITUTES TO SUSTAIN AND CONTINUE THE LOOKAHEAD STU CAN DI. THIS WAS CONSIDERED TO BE A TERRIFIC OPPORTUNITY FOR AGING RESEARCH, AND TO FOLLOW THE MODEL THAT WE HAVE RECOMMENDED FOR THE INCORPORATION OF AGING RESEARCH IN OTHER TRIALS OR STUDIES BY OTHER INSTITUTES OF DISEASES. AND SPECIFICALLY FOR THE ADDITION OF A IN M MINIMAL SET OF AGING-RELATED MEASUREMENTS WHICH COULD BE USED TO EXPAND THE REACH OF AGING RESEARCH TO DIABETES, DIABETE BEING AN IMPORTANT CONDITION THAT ACCELERATES AGING. SO THERE WAS A CONSENSUS OF THE PANEL OF OUR GROUP TO PROVIDE THAT COFUNDING TO EXTEND AGING RESEARCH INTO DIABETES AND TO MAKE AS WELL THAT DATASET AND SPECIMENS MORE BROADLY AVAILABLE TO THE AGING COMMUNITY FOR ITS USE. SO I THINK THAT THIS IS AN EXCITING OPPORTUNITY FOR BETTER UNDERSTANDING HOW DIABETES INFLUENCES THE PROCESS OF AGING. >> THANK YOU. FURTHER DISCUSSION? DR. TILLIE. >> I WAS JUST WONDERING, AMONG THOSE AGE MEASURES, IS THERE SOME KIND OF COGNITIVE -- I'M ASSUMING THERE IS. JUST ASKING. >> YES, THERE'S COGNITIVE ASSESSMENT. IN THE FIRST PHASE ACTUALLY, AS I RECALL, THE INTERVENTION DID NOT INFLUENCE COGNITION, COGNITIVE FUNCTION. I'M NOT SURE HOW BROAD THOSE MEASUREMENTS WERE, BUT OVER THE VERY LONGER TIME, THE SUSTAINED WEIGHT LOSS MIGHT INFLUENCE THAT SO I BELIEVE THE COGNITIVE MEASUREMENTS CONTINUE TO BE COLLECTED IN THAT. >> ACTUALLY I SPOKE TO JUDY AFTERWARDS, AND IT LOOKS LIKE THAT ONLY ABOUT 800 OF THE 5,000 PEOPLE GOT A COGNITIVE EVALUATION. THEY DID USE THE TOOLBOX, AND THERE IS SOME DISCUSSION ABOUT WHETHER THAT SHOULD BE DONE AGAIN, AND THERE ARE SEMPLE OF USEVERAL OFUS THAT THINK IT WOULD BE VERY IMPORTANT TO ADD TO THAT IN A MORE DETAIL FASHION THAT COULD BE WORKED OUT. >> OKAY. SO WITH WE HAVE TO VOTE ON THIS AS A COUNCIL. IS THERE A MOTION TO APPROVE THIS CONCEPT? SECOND? ANY FURTHER DISCUSSION? ALL THOSE IN FAVOR? ANY OPPOSED, ANY ABSTENTIONS? OKAY, THAT'S UNANIMOUS. THANK YOU. WE HAD A SECOND CONCEPT CLEARANCE PRESENTED BY DR. CARL HILL ENTITLED QX AGING RESEARCH ON STRESS AND RESILIENCE TO HELP ADDRESS HEALTH DISPARITIES IN THE UNITED STATES," AND ANNA MARIA. >> THIS INITIATIVE INITIATED IN 2011 WHEN THE WORK FOR THE STUDIES OF THE MINORITY ON AGING RESEARCH AS TO HAVE A FULL REVIEW OF THE MINORITY AGING RESEARCH WAS PERFORMED WITHIN THE LAST 10 YEARS. AND AS PART OF THAT REVIEW THAT WAS DIRECTED AT THAT MOMENT BY DR. -- IT BECAME CLEAR THAT THERE WERE HEALTH DID DISPARITIES IN PARTICULAR RELATED TO AGING THAT WERE NOT PROPERLY COVERED AND THAT ACTION WAS NEEDED TO REALLY KEEP THIS AS A MAIN GOAL FOR THE NEXT 10 YEARS. SO AS WE GO INTO 2014, THERE WAS FRAMEWORK APPROVED ALSO BY COUNCIL TRYING TO DELINEATE THE AREAS THAT WILL PRIORITIZE STUDIES OR RESEARCH TO ADDRESS THE DISPARITY IN AGING RESEARCH AND DISEASES OF AGING. AS A RESULT OF THAT, IT WAS IDENTIFIED THAT THERE WERE ACTIONS THAT CAN BE TAKEN IN EACH OF THE LEVELS, NEURAL, BIOLOGY, AND BY LOOKING AT THAT WONDERFUL TABLE, THERE WAS A COMMON THEME THAT CAME VERY CLEAR THAT WAS STRESSED, ONE OF THE COMMONALITIES OF ALL THE DIFFERENT WAYS IN WHICH WE CAN LOOK AT AGING SINCE THE ABILITY TO OR NOT RESPOND TO STRESS, AND MORE IMPORTANTLY RESILIENCE, SO WITH THAT, THE IDEA OF THIS INITIATIVE IS TO TRY TO SET ASIDE SOME MONEY TO REQUEST APPLICATION THAT WILL TRY TO ADDRESS DISPARITIES IN AGING, FOCUSING IN STRESS AND RESILIENCE. AND THE NEED FOR THE SETASIDE STARTS TO SHOW THE -- OF NIA FOR THIS VERY IMPORTANT MISSION, AND SECOND, BECAUSE YOU ARE GOING TO NEED REALLY SPECIALIZED EXPERTISE REVIEWING THOSE GRANTS, BECAUSE THE IDEA IS TO TRY TO GET PEOPLE FROM VERY DIFFERENT DISCIPLINES WORKING TOGETHER. SO THE INITIATIVE WAS VERY WELL RECEIVED, THERE WAS A LOT OF ENTHUSIASM BECAUSE IT'S ALSO A POSSIBILITY OF THE DIFFERENT DIVISIONS OF THE NIA WORKING TOGETHER, BECAUSE YOU ARE GOING TO BE LOOKING AT STRESS FROM VERY DIFFERENT ANGLES. IT ALSO WILL GIVE THE OPPORTUNITY OF INSTITUTIONS THAT THINK ABOUT DIVERSITY EVERY DAY TO COLLABORATE WITH IPS TEUTIONS THAT MIGHT HAVE MORE RESOURCES FOR OTHER TYPE OF RESEARCH THAT DON'T THINK ABOUT DIVERSITY EVERY DAY, SO THAT WILL BRING EXPERTISE TOGETHER AND IN THE LONG RUN, THE GAIN OF THIS PROGRAM CAN BE TREMENDOUS. SO IT WAS AS I SAY RECEIVED WITH A LOT OF ENTHUSIASM, DISCUSSION OF WHAT WAS GOING TO BE THE MECHANISM, AND I THINK THE FINAL CONCLUSION IS THE APPLICANTS WILL TELL -- THAT'S HOW THE NIA WILL TRY TO RESPOND TO THAT. BUT I THINK OVERALL IT WAS VERY ENTHUSIASTIC RESPONSE TO IT THIS VERY IMPORTANT PROGRAM. >> THANK YOU. ANY OTHER COMMENTS ABOUT THAT PRESENTATION? OKAY. DO I HAVE A MOTION TO APPROVE? A SECOND? THANK YOU. ANY FURTHER DISCUSSION? ALL IN FAVOR? ANY OPPOSED? ANY ABSTENTIONS? OKAY. THAT'S UNANIMOUS. THANK YOU VERY MUCH. THAT COMPLETES THE WORKING GROUP -- OH, NO, IT DOESN'T. OKAY. SORRY. IT'S THE LAST ONE ON THE LIST. >> NO, STATEMENT OF UNDERSTANDING IS STILL TO COME. WHAT WE NEED IS A MOTION TO APPROVE OF THE STATEMENT OF UNDERSTANDING AGAIN. WE DO THAT ANNUALLY. IF YOU REMEMBER THE WORKING GROUP YESTERDAY, I ASKED FOR ONE MINOR MODIFICATION IN THE STATEMENT OF UNDERSTANDING, TO DRAW UP A SENTENCE WHICH SAYS THAT IF WE INTEND TO REINSTATE FUNDS AND AIMS LEADING TO THE BASIS OF SCIENTIFIC MERIT, THEN THAT REQUIRES COUNCIL REVIEW TO DO IT. I'M DELETING THE SENTENCE NOT BECAUSE WE WANT TO DO THAT, WE DON'T, BUT IN FACT BECAUSE STUDY SECTIONS DON'T DO THAT ANYMORE. IN OTHER WORDS, STUDY SECTIONS NOW ARE SUPPOSED TO VOTE A SCORE ON AN APPLICATION BEFORE THEY CONSIDER THE BUDGET, AND, THEREFORE, THEY'RE NOT SUPPOSED TO CUT AIMS OUT IN ORDER TO IT GIVE IT A BETTER SCORE. THEREFORE, THAT IS NOT SUPPOSED TO HAPPEN. IT IF IT DOES HAPPEN, WHAT A COUNCIL SHOULD DO IS, IN FACT, NOT CONCUR WITH REVIEW, SEND IT BACK, IN OTHER WORDS. SO, THEREFORE, IT DOESN'T BELONG IN THE STATEMENT OF UNDERSTANDING, IT IS, IN FACT -- IF IT DOES HAPPEN, WE SHOULD NOT CONCUR WITH REVIEW BECAUSE REVIEW HAS MADE A MISTAKE AT THAT POINT, SO THAT'S WHY I'M ASKING THAT IT BE DELETED FROM THE STATEMENT OF UNDERSTANDING. SO WITH THAT LONG EXPLANATION, I'M ASKING FOR A MOTION TO IT APPROVE THE STATEMENT OF UNDERSTANDING AS MODIFIED. THANK YOU. A SECOND, I SEE. ANY OTHER COMMENTS OR DISCUSSION ON IT? ALL THOSE IN FAVOR, APPROVING? ANYONE OPPOSED, ANY ABSTENTIONS? ALL RIGHT. THANK YOUMENT BEFORE WE GO, I WILL JUST NOTE THAT WE ALSO PRESENTED A STA TIS IT TI CAL PACKAGE WITH WHICH IS AVALE IN THIS MEETING THAT HAS TWO TABLES IN IT THAT SHOW THE APPLICATIONS THAT WE RECEIVED FOR THIS COUNCIL ROUND AND ALSO SHOWS HOW WELL THE APPLICATIONS DID IN REVIEW, AND THE SECOND TABLE SHOWS, IN FACT, HOW APPLICATIONS DID IN IT REVIEW OVER THE LAST YEAR. ONE SLIGHTLY DIFFICULT THING TO IT UNDERSTAND IN THAT IS IN THE SECOND TABLE YOU'LL SEE FOR THIS COUNCIL ROUND, 12% OF OUR APPLICATIONS SCORED WITHIN THE TOP 10% OF APPLICATIONS THAT WERE PEER REVIEWED IN THE CSR. THAT ACTUALLY RELATES TO WHAT DR. HODES WAS TALKING ABOUT EARLIER, WHAT'S DRIVING THE FUNDING LINE. IT'S THAT OUR APPLICATIONS ARE COMPETING VERY SUCCESSFULLY AT THE MOMENT IN CSR REVIEW, DOING BETTER THAN AVERAGE. BETTER THAN THE OTHER IC APPLICATIONS THAT ARE COMING IN, AND THAT IS WHY WE'RE GETTING THAT 12% SCORING WITHIN THE TOP I 10% OF APPLICATIONS IN CSR, SO THAT IS JUST TO NOTE THAT. ALL RIGHT. THANK YOU. WE WILL NOW BREAK, AND DURING THE BREAK, PLEASE, SPEAKERS WHO ARE SPEAKING IN THE SECOND HALF, LOAD YOUR SLIDES DURING THE BREAK SO THAT WE DON'T HAVE ANY IPT RUPTIONS AT THAT TIME, 15-MINUTE BREAK. THANK YOU. WE'RE GOING TO MOVE TO THE HIGHLIGHTS. >> IT'S MY PLEASURE TO INTRODUCE ONE OF OUR NEWEST COUNCILMEMBERS, DR. ELIEZER MASLIAH. HE'S CURRENTLY PROFESSOR IN THE DEPARTMENT OF NEUROSCIENCES AND PATHOLOGY AT UNIVERSITY OF CALIFORNIA, SAN DIEGO, TALKING ABOUT HIS RESEARCH ON ALPHA SYNUCLEIN AS AN IMMUNOTHERAPY TARGET FOR ALZHEIMER'S DISEASE AND SIN NUCLEINOPATHYS OF THE AGING. >> THANK YOU VERY MUCH FOR IT INVITING ME TO BE HERE THIS MORNING, AND IT'S ALSO A PLEASURE TO BE PART OF THE COMMITTEE. SO SYNUCLEINOPATHYS REPRESS A PRETTY HETEROGENUS GROUP OF DISORDERS, THAT INCLUDES PARKINSON'S DISEASE, DEMENTIA WITH LEWY BODIES, MULTIPLE SYSTEMS ATROPHY BUT ALSO ALZHEIMER'S DISEASE, WHEN WE FIRST CLONE SYNUCLEIN FROM THE BRAIN OF PATIENTS IN THE EARLY 90s, ACTUALLY WE CLONE OFF SYNUCLEIN FROM THE PATIENTS WITH ALZHEIMER'S DISEASE AND WE IDENTIFIED THAT THESE SO CALLED KNACK DOMAIN OF ALPHA SYNUCLEIN, HIGHLY AMYLOIDOGENIC REGION WAS BOND -- AMYLOID MAKES IN PATIENTS WITH ALZHEIMER'S DISEASE AND WE ORIGINALLY THOUGHT IT WAS A MAJOR DRIVER OF THE PATHOGENESIS OF ALZHEIMER'S DISEASE, HOWEVER, LATER ON, A NUMBER OF INVESTIGATORS INCLUDING ROBERT HERE AT NIH DISCOVERED THAT NUMBER OF MUTATIONS AS WELL AS MULTIPLICATIONS OF ALPHA SYNUCLEIN WERE ASSOCIATED WITH FAMILIAL FORMS OF PARKINSON AND ALSO AS I MENTIONED WITH LEWY BODY DISEASE, AND THAT POLYMOREMORE OF MORPHISMS WERE ASSOCIATED BOTH WITH SPORADIC FORMS OF DEMENTIA WITH LEWY BODIES AS WELL AS WITH SOME MIXED VERSIONS OF ALZHEIMER'S DISEASE AND OTHER DEMENTIA. SO REALLY ALPHA SYNUCLEIN, IT'S A MOLECULE THAT PROBABLY PLAYS A ROLE IN A NUMBER OF NEURODEGENERATIVE DISORDERS, AND THAT MAKES A LOT OF SENSE BECAUSE ALPHA SYNUCLEIN, AS MANY OF YOU KNOW, IS 140 AMINO ACID MOLECULE THAT IS HIGHLY ABUNDANT IN MOST PRESYNAPTIC TERMINALS AND PLAYS AN IMPORTANT ROLE IN SYNAPTIC FUNCTION AND NEUROTRANSMITTER RELEASE, SO ANYTHING THAT AFFECTS PRIMARILY THE SYNAPSE LIKE IS THE CASE OF ALZHEIMER'S DISEASE, IN ONE WAY OR ANOTHER, IT'S GOING TO BE AFFECTING ALPHA SYNUCLEIN AND HOW ALPHA SYNUCLEIN REACTS WITH OTHER PROTEINS INVOLVED IN THE NEURODEGENERATIVE FROM SES IN ALZHEIMER'S DISEASE. IN THESE SLIDES THAT I BORROW FROM LEONARD MUKYE, I THINK THE EMERGING CONCEPT IN ALZHEIMER'S DISEASE IS THAT IT REALLY IS NOT A DISEASE OF ONE OR TWO PROTEINS, BUT IT IS REALLY A POLYPROTEINOPATHY WHERE BOTH, OF COURSE, OLIGOMERS ARE ACCUMULATING AND FORMING AT THE SYNAPTIC SIDE AND DAMAGING SNAPS, BUT ALSO ALPHA SYNUCLEIN IS PLAYING A ROLE IN THIS PATHOGENESIS, AND IT'S INTERACTING WITH OTHER PROTEINS INVOLVED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, INCLUDING APOE4 TAU AND SO ON. FOR EXAMPLE, THERE'S QUITE A BIT OF DATA IN THE LITERATURE SHOWING THAT ALF FA SYNUCLEIN AND TAU INTERACT, WE HAVE SHOWN BEFORE THAT A-BETA AND ALPHA SYNUCLEIN CAN INTERACT AND EVEN FORM HETERO-OLIGOMERS THAT WE FIND IN ALZHEIMER'S BRAINS, AND AS YOU ALL KNOW, ABOUT 75% OF ALL PATIENTS WITH PURE ALZHEIMER'S DISEASE ACTUALLY DISPLAY ALPHA SYNUCLEIN ACCUMULATION IN AREAS OF THE LYMPHIC SYSTEM, IT'S A PROTEIN THAT AS I MENTIONED PLAYS A ROLE IN AGING IT SELF BUT ALSO INCLUDING ALZHEIMER'S DISEASE. SO I THINK IN THIS CONTEXT THEN, ALPHA SYNUCLEIN MIGHT BE AN IMPORTANT TARGET FOR ALZHEIMER'S DISEASE AND A NOBLE TARGET FOR ALZHEIMER'S DISEASE AS WELL AS ALPHA SYNUCLEINOPATHY, SO ALPHA SYNUCLEIN MIGHT CHANGE THE PATHOGENESIS OF THE OUTCOME OF OTHER SYNUCLEINOPATHYS OF THE AGING INCLUDING ALZHEIMER'S DISEASE, SO WHEN ONE OF THE MAIN INTERESTS IN THE LAB THAT HAS BEEN SUPPORTED BY THE GRANT FROM NIA IS TO IT UNDERSTAND HOW TO MANIPULATE ALPHA SYNUCLEIN AND THERAPEUTICALLY AND WHAT IMPACT THAT WILL HAVE IN A DIVERSE NEURODEGENERATIVE DISORDERS OF THE AGING. FLOOB SO THE QUESTION THEN IS, WHAT TO MODIFY IN ALPHA SYNUCLEIN, SINCE FOR A LONG TIME, IT WAS BELIEVED THAT THE SYNAPTIC PROTEIN WAS PRIMARILY AN INTRACELLULAR CYTOPLASM PROTEIN, AND LIKEWISE, AS IF THE CASE WITH A BETA OR TAU, THE CONCEPT WITH ALPHA SYNUCLEIN WAS THAT TEMPLATED OLIGOMERIZATION OF ALPHA SYNUCLEIN INTO THESE GLOBULAR SPECIES THAT APPEAR TO LODGE IN THE MEMBRANE ARE THE PRIMARY DRIVER OF THE PATHOGENIC PROCESS AND THAT THE DEFIB LAR FORM OF ALPHA SYNUCLEIN FOUND, FOR EXAMPLE, IN LIEU E IN LEWY BODIES PLAYED A ROLE IN TOXICITY THAN RATHER THAN MIGHT BE ISOLATING THE MORE TOXIC SHE SHE'S. SPECIES. THE NEW CONCEPT THAT HAS ALSO EMERGED FROM THIS RESEARCH IS THIS ALPHA SYNUCLEIN THAT IS ACCUMULATING, MIGHT ALSO BE PROPAGATING FROM CELL TO CELL SO LIBERATED FROM THE NEURON, PROB GATE FROM CELL TO CELL AND CAUSING A CERTAIN DEGREE OF TOXICITY, AND FROM A THERAPEUTIC POINT OF VIEW, I THINK THIS IS INCREDIBLY IMPORTANT BECAUSE WE CAN TARGET THE MEMBRANE AS WELL AS THESE ALPHA SYNUCLEIN THAT IS PROPAGATING AND PROBABLY SOMEHOW AFFECT THE PATHOGENESIS OF THE DISEASE. SO NOW WHAT KIND OF EVIDENCE IS IN FAVOR THAT IF WE DIMINISH THAT ACCUMULATING OR THE PROPAGATING ALPHA SYNUCLEIN MIGHT BE BENEFICIAL. SO FOR EXAMPLE, A COUPLE OF YEARS AGO, WE DEVELOPED THIS TRANSGENIC ANIMAL MODEL THAT IS UNDER A REGULATABLE PROMOTER, WHERE ALPHA SYNUCLEIN IS CONCENTRATED PRIMARILY TO BE EXPRESSED IN THE OWE FACTORY BULB, NONETHELESS, WE HAVE PROPAGATION OF THAT THROUGH TRANSSYNAPTIC MECHANISMS INTO THE -- REGION AS WELL AS INTO THE HIPPOCAMPUS. INTERESTINGLY, NOT ONLY WE SEE PROPAGATION TO NEURONS, BUT WE ALSO SEE PROPAGATION TO -- CELLS, SO IN THIS PARTICULAR MODEL, WE CAN ASK THE QUESTION, WHAT ABOUT IF WE IT TURN OFF ALPHA SYNUCLEIN, WE LET IT PROPAGATE INTO THESE CELLS AND THESE ANIMALS ACTUALLY DEVELOP BEHAVIORAL DEFICIT, NOW WE TURN IT OFF FOR DIFFERENT PERIODS OF TIME, CAN WE REVERSE THE PROPAGATION OF THAT SYNUCLEIN AND CAN WE REVERSE THE DEFICITS IN THESE ANIMAL MODELS, AND IT SAYS YES, IN THIS PARTICULAR CASE, WE TURN OFF THAT ALPHA SYNUCLEIN FOR ONE MONTH, FOR THREE MONTHS, AND WE SEE WE CAN RESCUE -- SOME OF THE HYPERACTIVITY IN THOSE ANIMALS, AS WELL AS TO REVERSE SOME OF THE OF THE DEGENERATIVE PHENOTYPE ON THOSE ANIMALS. NOW WHAT ABOUT MODELS OF ALZHEIMER'S DISEASE, ALSO SEVERAL YEARS AGO, WE DEVELOPED THESE TRANSGENIC ANIMAL MODEL OF A BETA OVEREXPRESSIONING APP SO WE CROSS THESE ANIMALS WITH AN ALPHA SYNUCLEIN KNOCKOUT MICE, AND QUESTION IS WHAT HAPPENS, WE KNOCK DOWN ALPHA SYNUCLEIN, DOES THAT IN ANY WAY CHANGE THE PATHOGENESIS OF THE IT DISEASE? AND INTERESTINGLY, THE KEY FINDING HAS BEEN THAT THE DEGENERATION OF THE CHOLINERGIC SYSTEM, WHICH OCCURS IN OUR APP TRANSGENIC MICE, IS COMPLETELY PROTECTED BY KNOCKING OUT OFF-SITE KNEW CLEAN IN THOSE TRANGENIC ANIMALS. SO WE SEE LITTLE PROTECTION OF THE DEGENERATION OF OTHER CIRCUIT RIS LIKE, FOR EXAMPLE, THE DB HOWEVER, THE CHOLINERGIC SYSTEM, THESE ANIMALS DEVELOP HYPERACTIVITY IN THE OPEN FIELD, WE CAN COMPLETELY REVERSE THIS IERP ACTIVITY IN THE OPEN FIELD BY KNOCKING OUT ALPHA VIE KNEW CLEAN AND REVERSING THE CHOLINERGIC DEFICIT. SO IT APPEARS THAT TARGETING ALPHA SYNUCLEIN IN MODELS OF ENDOCRINOPATHY AS WELL AS ALZHEIMER'S DISEASE MIGHT HAVE BENEFICIAL EFFECTS AT TARGETING SPECIFIC CELLULAR POPULATION. SO THE QUESTION IS, WELL, HOW DO WE TARGET THAT ALPHA SYNUCLEIN AND WHAT DO WE TARGET? I THINK THERE ARE TWO BASIC CONCEPTS AS I MENTIONED BEFORE. ONE IS TO TARGET THE OLIGOMERIC SPECIES BY REDUCING THE AGGREGATION OR MODIFYING THE STATE OF AGGREGATION OF SYNUCLEIN, AND ALSO MORE IMPORTANTLY, BY INCREASING THE CLEARANCE OF ALPHA SYNUCLEIN AND AMONG THE MECHANISMS OF CLEARANCE, AUTO I AS DR. CUERVO HAS SHOWN IN SEVERAL PUBLICATIONS, WE HAVE WORKED ON THESE MECHANISMS, WITH PARTICULAR NEED TO DEVELOPING ANTIBODIES, BECAUSE ANTIBODIES HAVE THE ADVANTAGES OF POTENTIALLY TARGETING THE SPECIFIC OLIGOMERIC SPECIES, BUT ALSO VERY INTERESTINGLY, SINCE THIS CELL TO CELL OR PRE -- PROPAGATION OF ALPHA SYNUCLEIN MIGHT ALSO PLAY A ROLE IN THE PATHOGENESIS OF THE DISEASE, ANTIBODIES HAVE THE UNIQUE CAPACITY OF CAPTURING THIS PROPAGATING SPECIES AND HOPEFULLY HELPING CLEARANCE THROUGH MAYBE, FOR EXAMPLE, THE AUTOPHAGY PATHWAY. SO THERE ARE A NUMBER OF I YOU IMMUNOTHERAPY APPROACHES WE CAN TAKE. WHAT I'M GOING TO SHOW YOU IS PRIMARILY FOLK THAT WE HAVE FOCUSED ON UTILIZING ACTIVE AND PASSIVE IMMUNIZATION. THERE ARE OTHER DRUGS THAT HAVE ALSO CONSIDER CELLULAR IMMUNIZATION AND SOME INTERESTING PROGRESS HAVE DONE IN THAT REGARD, BUT AS I MENTIONED, I HAVE PRIMARILY FOCUSED ON -- AND AS I MENTIONED BEFORE, THE IDEA IS TO TARGET WITH SYNUCLEIN ANTIBODIES, THE SYNUCLEIN THAT ACCUMULATING IN THE MEMBRANE AND BECOMING NEUROTOXIC TO THE CELLS AS WELL AS THAT PROPAGATING FROM CELL TO CELL, SO THERE ARE A NUMBER OF DIFFERENT ADVANTAGES INCLUDING THE INCREASED CLEARANCE OF SYNUCLEIN, NOT ONLY THROUGH AUTO PHAGY BUT TO FAK PHASE MECHANISMS, PROMOTE -- PROTECTION, TARGET SPECIFIC SHE SHE'S AND HOPEFULLY ALSO THAT WILL SHOW REDUCED INFLAMMATION. WHEN WE FIRST STARTED TO DO THIS EXPERIMENT, ACTUALLY AT THAT TIME, WE DIDN'T KNOW MUCH ABOUT ALPHA SYNUCLEIN PROPAGATION SO THE RATIONALE FOR THESE EXPERIMENTS WAS NOT QUITE CLEAR BECAUSE AS I MENTIONED, SYNUCLEIN WAS KNOWN TO BE MOSTLY AN INTRACELLULAR SYNAPTIC PROTEIN. NONETHELESS, THIS WAS WORK THAT WE DID IN COLLABORATION WITH ELAN, WITH DALE, AND THAT TIME, WE TOOK BOTH YOUNG AND AGED OF SYNUCLEIN TRANSGENIC ANIMALS, AND A ACTIVELY IMMUNIZED THEM WITH ALPHA SYNUCLEIN PLUS CFA FOR EIGHT MONTHS, AND WE FOUND THAT ACTUALLY WE COULD SHOW A SIGNIFICANT DECREASE IN THE ACCUMULATION OF THE SYNAPTIC ALPHA SYNUCLEIN-INDUCED ANIMALS AS WELL AS IN THE -- THAT INTERESTINGLY, THERE WAS ASSOCIATED WITH AN INCREASE IN LYSOSOMOL ACTIVITY, AND TARGETING THAT ALPHA SYNUCLEIN INTO THE LYSOSOME FOR DEGRADATION. NOW SINCE AT THAT TIME THERE WERE SOME CONCERNS BECAUSE OF THE IMMUNOTHERAPY STUDIES IN ALZHEIMER'S DISEASE, SHOWING THAT ACTIVE IMMUNIZATION WITH ANTIGENS COULD BE POTENTIALLY PROBLEMATIC, WE STARTED A COLLABORATION WITH A COUNTRY THAT HAS A REALLY INTERESTING TECHNOLOGY. WHAT THEY HAVE IS THIS LIBRARY OF PEPTIDES THAT ANTIGEN IKLY MIMIC WHATEVER PROTEIN OR INTEREST YOU WANT, SO WE CLAB COLLABORATED WITH THEM AND WE IDENTIFIED WITH A SERIES WITHOUT REALLY ELICITING AUTOIMMUNE REACTION TO ALPHA SYNUCLEIN OR MASKING ANY KIND OF NONSPECIFIC REACTIVITY. SO WE CAME UP WITH A SERIES OF -- WE CALL THEM PD AFFITOPE, WE GENERATED AND CLONED THESE ANTIBODIES INTO MICE. WE LABELED THEM WITH ALEXA, INJECTED IT INTO THE TAIL VEIN OF OUR ALPHA SYNUCLEIN MICE AND SHOWED THAT THESE ANTIBODIES SPECIFICALLY TARGET ALPHA SYNUCLEIN AGGREGATE IN THE BRAINS OF THESE ANIMALS AND TRAFFIC INTO THE NERVOUS SYSTEM, AND WE DID THIS IN TWO COMPLETELY DIFFERENT MODELS, TWO COMPLETELY DIFFERENT SIDE. SO WE IMMUNIZE ACTIVELY WITH THIS AFFITOPE, OUR TWO DIFFERENT LINES OF TRANSGENIC MICE, SITE ONE AND THE PDGF, AND IN BOTH ANIMALS AGAIN IN BLIND FASHION MODE, TWO DID DIFFERENT SIDES, TOTALLY INDEPENDENT, DEMONSTRATED THAT WE CAN SIGNIFICANTLY REDUCE THE ACCUMULATION OF ALPHA SYNUCLEIN IN THOSE MICE, AND ALSO AMELIORATE THE DEFICITS IN THOSE TRANSGENIC ANIMALS. THAT WAS ASSOCIATED WITH A REDUCTION IN THE LOSS OF TH IN THE STRIATUM IN THE ANIMALS. WE IT DID NOT OBSERVE ANY OVERT NEURAL INFLAMMATION OR ASTROGLIOSIS OR BLOOD-BRAIN BARRIER DAMAGE, AND AS I MENTIONED, IT WAS ASSOCIATED WITH A RECOVERY BEHAVIOR. NOW, THESE ANTIBODIES APPEAR TO WORK IN IT INTERESTING WAYS, NOT ONLY THRAW CLEARING THE ALPHA SEE KNEW CLEAN THRAW NORMAL MECHANISMS, BUT WE ALSO FOUND IN THESE ANIMALS, MICRO GLIAL CELLS ACTUALLY CONTAINED ALPHA SYNUCLEIN AGGREGATE, AND WHAT WE FOUND, WE DID AN INFLAMMOSOME -- THERE WAS AN INCREASE ON FRAC FRACTILE -- RECEPTOR TO OFFSET THE ALPHA SYNUCLEIN WITH THE ANTIBO I --REQUIRED MALIGNANT -- OF THE AGING FOR WHICH THERE IS ABSOLUTELY NO THERAPEUTICS AVAILABLE AND PATIENTS ARE LEVEL DO PSM A-RESISTANT, MULTIPLE SYSTEMS ATROPHY, WE CALL THIS KIND OF LIKE THE EVIL SISTER OF PARKINSON DISEASE. SO WE TESTED THE SAME PD AFTER TOAP, WE HAVE A MODEL UNDER THE MYELIN BASIC PROMOTER, THE PRIME EE SITE WHERE IT IS ACCUMULATING IN PATIENTS WITH MSA. AND LIKEWISE IN A MODEL OF DLB AND PD, IN OUR -- WE SHOW SIMILAR IMPROVEMENTS THAT IS DECREASED ACCUMULATION OF ALPHA SYNUCLEIN AND BEHAVIORAL MODEL IMPROVEMENTS ON MODELS OF MSA, SO WE HAVE THREE DIFFERENT TRANSGENIC ANIMAL MODELS TESTED ON DIFFERENT SIDES SHOWING DIFFERENT BENEFICIAL RESULTS. THE QUESTION IS, WHAT HAPPENS IN MODELS OF ALZHEIMER'S DISEASE? SO I APOLOGIZE FOR THIS CLUTTER SLIDE, BUT WE TOOK MICE IN RED AND GREEN, CROSSED THEM, AND IMMUNIZED THEM EITHER WITH THE ISOTOPE THAT TARGETS ALPHA SYNUCLEIN OR THE TARGET THAT IDENTIFIES MAY BA BETA, WHAT ASPECT OF ALZHEIMER'S DISEASE DOES THE ALF SYNUCLEIN -- INTERESTINGLY, WITH THE EPITOPE IN OUR IT DOUBLE TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE AND AGING, WE SEE THAT THERE IS A NICE PROTECTION OF THE CHOLINERGIC DEGENERATION AND OF THE DOPE MANNER JIK GENERATION. IF WE IMMUNIZE THE ANIMALS WITH THE A BETA ISOTOPE VACCINE, WE HAVE REVERSE OF THE BEHAVIORAL DEFICITS THE IN THE WATERWAYS OF THESE TRANSGENIC ANIMALS. SO WHAT WE'RE TEST SOMETHING A COMBINED VACCINE WHERE WE HAVE BOTH THE A BETA AND THE ALPHA SYNUCLEIN. WHAT ILLUSTRATES IS THEY ARE TARGETING DIFFERENT NEURONAL POPULATION IN THE AGING NEURODEGENERATING BRAIN AND THAT THIS COULD BE MODULATED WITH DIFFERENT TYPES OF VACCINE. NOW, BECAUSE OF THE KNOWN COMPLICATIONS THAT I MENTIONED BEFORE AND BECAUSE WE ALSO WANTED TO DEVELOP PASSIVE IMMUNOTHERAPIES, WE CONTINUE TO COLLABORATE IN THIS CASE WITH ELAN PHARMACEUTICALS AT THAT TIME IN DEVELOPING ALSO PASSIVE IMMUNIZATION TARGETING ALPHA SINAI CLEAN, AND TSYNUCLEIN, WE GENERATED BODIES AGAINST THE -- AND FOUND THESE ANTIBODYS THAT WE CALL 94 THAT TARGET THIS REGION, 118 TO 226, IS THE MOST EFFECTIVE ANTIBODY TARGETING ALPHA SYNUCLEIN, WE CAN SEE THIS ANTIBODY LIKEWISE, TRAFFICKING AND NEURONS IN THE BRAIN. WE SEE THAT ACCUMULATE IN AUTO PHAGOSOMES, AND IT'S CLEAR AUTO AUTOPHAGY IN THESE MODELS. WE DEVELOPED THIS OTHER SYNUCLEIN ANIMAL MODEL THAT HAS A GFP TACK SO YOU CAN SEE IN GREEN IN THE BRAIN OF THESE TRANGENIC ANIMALS, SO WE TREATED WITH THESE TRANSGENIC MICE AND SHOW THAT WE CAN REVIEW THE ACCUMULATION OF ALPHA SYNUCLEIN IN THE BRAINS OF THESE ANIMALS. BUT WHAT IS MORE INTERESTING IS THAT THESE ANIMALS, BECAUSE OF THE GSP PROTEIN -- VERY NICELY IN GREEN AND ACTUALLY WE CAN SEEING A GATS OF ALPHA SIG SYNUCLEIN IN THE BEGAN GLEAN CELLS AND SHOW IN REALTIME LIFE WHEN WE IMMUNIZE THESE ANIMALS, THAT WE CAN REDUCE THE AK RANGE OF ACCUMULATION OF ALPHA SYNUCLEIN -- WE'RE TRYING TO DEVELOP THIS TECHNOLOGY NOW TO MONITOR IMMUNOTHERAPY IT IN THE A ANIMAL. IN THE MEANTIME, WE HAVE ALSO DEVED A NEW MODEL TO ASK THE QUESTION IF THIS PASSIVE IMMUNIZATION MIGHT BE TARGETING THE PROPAGATING ALPHA SYNUCLEIN GOING FROM CELL TO CELL. WE HAVE DEVELOPED TWO IT DIFFERENT MODELS. ONE OF THE MODELS INVOLVES ACTUALLY TRANSPLANTING NEURONAL STEM CELLS THAT ARE TACKED INTO THE BRAINS OF OUR TRANSGENERAL MINDS, AND THIS IS HOW WE IT DEMONSTRATED SOME YEARS AGO THE OFFICE OF SYNUCLEIN ACTUALLY TRANSFERRED. SO IF YOU IMMUNIZE THE ANIMALS, YOU CAN SHOW THAT WITH THESE ANTIBODYS THAT TARGETS SPECIFICALLY THE C TERMINALS, THERE IS A COMPLETE PROTECTION AGAINST THE PROPAGATION OF THESE ALPHA SYNUCLEIN. LIKEWISE, IN THE SECOND MO IT DELL, IF IT WE INJECT A LENGTHY VIRAL VECTOR EXPRESSING INTO OUR KNEW CLEAMICE, IMMUNIZING THESE ANIMALS WITH THE C-TERMINUS ANTIBODY ALSO PRESENTS THE TRANSSYNAPTIC PROPAGATION OF SYNUCLEIN IN THESE ANIMALS. IT TURNS OUT THAT THE CALPAIN CLEAVAGE TENDS TO PROPAGATE MORE EASILY AND TO BE MORE NEUROTOXIC AND PRO AGGREGATION, AND THE ANTIBODIES ACTUALLY ARE BLOCKED THAT CALPAIN CLEAVAGE SIDE AND -- IN THIS PRETTY SIMPLE EXPERIMENT, WE TOOK IT IN THE PRESENCE OF DIFFERENT ANTIBODIES AND SHOW THEM IN THE ANTIBODIES AND IN THE PRESENCE OF -- WE COMPLETELY PROPAGATE C KNEW CLEAN CLEAVAGE. THERE HAVE BEEN A NUMBER OF STUDIES PUBLISHED LATELY SHOWING THAT ACTUALLY ANTIBODIES AGAINST DIFFERENT DOMAINS OF ALPHA SYNUCLEIN REDUCE ACCUMULATION BOTH IN RODENT, RAT AND MOUSE MODELS AND MOST RECENTLY, VIRGINIA LEE USES HER ANTIBODY TO SHOW THAT SHE CAN BLOCK THE IT TEMPLATED PROPAGATION TO -- PROPAGATION OF ALPHA SINAI CLEAN CLEAN. SO THAT'S REGARDING THE C-TERMINUS -- BUT WHAT ABOUT THE MORE SPECIFIC SPECIES, LIKE FOR EXAMPLE, THIS -- THAT IS TOXIC FROM NEURON TO NEURON, PROPAGATE AND TEMPLATES, PROPAGATION, CAN WE SPECIFICALLY TARGET THAT TYPE OF ALPHA SYNUCLEIN? SO FOR THAT PURPOSE, WE TEAM UP WITH MAX -- WE CAME UP WITH A NUMBER OF SINGLE CHAIN ANTIBODIES THAT SPECIFICALLY TARGET OLIGOMERIC ALPHA SYNUCLEIN, TO BE EXPRESSED UNDER A LENGTHY VIRAL VECTOR WITH THE REASON TO DO THIS IS THAT SINGLE ANTIBODIES DON'T PENETRATE THE BRAIN AS WELL, SO WE WANTED TO ENHANCE THE PENETRATION AND ADDITIONALLY, WITH WE HAVE SHOWN BEFORE IT ACTUALLY ENHANCES THE PENETRATION THROUGH THE NERVOUS CYST IT TEM, I COULD SHOW IT HERE. THIS IS ACTUALLY THE SINGLE CHAIN ANTIBODY WITHOUT APOB, YOU CAN SEE THERE IS TREMENDOUS -- IN THE BRAIN, WITH APOB. VIA TRANSITE DOSES ENHANCE THE TRAFFICKING OF THE SINGLE CHAIN ANTIBODIES INTO THE BRAIN, AND LIKEWISE WHAT WE HAVE SHOWN IN THE OTHER TRANSGENIC MODEL, THESE MODELS USING THE SINGLE CHAIN ANTIBODY, WE ALSO WERE ABLE TO SHOW THE ACCUMULATION, WE CAN DECREASE THE OLIGOMER ACCUMULATION OF ALPHA SIGH FEW CLEAN AND THE RELATED DEFICIT. INTERESTINGLY THIS IN THIS SYSTEM WHAT WE HAVE IS THIS SINGLE CHAIN ANTIBODY RECOGNIZES THE PROPAGATING ALPHA SYNUCLEIN, THESE -- GOES INTO MICRO -- BODIES AND THIS IS TRAFFIC INTO THE LYSOSOME FOR AUTOPHAGIC DEGRADATION. SO WE SEE A LOT OF THE -- WITH A SINGLE GENE ANTIBODIES. WE CAN ACTUALLY PROC THIS PROCESS BY BLOCKING THE TRAFFIC OF MULTI-VERY VICK LAR BODIES WITH A MULTI-VIRAL VECTOR THAT BLOCKS THESE PROTEINS. SO I'M DOWN TO THE LAST SLIDE. NOW THESE CLINICAL TRIALS, BOTH THE ACTIVE IMMUNIZATION CLINICAL TRIAL WITH PASSIVE IMMUNIZATION THERAPY NOW HAVE A CHANCE TO CLINICAL TRIALS IN COLLABORATION W MICHAEL J. FOX, ACTUALLY CONDUCTED THESE PHASE ONE CLINICAL TRIALS, TWO DIFFERENT DOSES IN EIGHT PATIENTS PER GROUP AND SHOWED THAT THIS PASSIVE IMMUNIZATION THERAPY IS COMPLETELY SAFE, THERE WERE REALLY NO COMPLICATIONS, THEY DID IT BOTH IN HEALTHY INDIVIDUALS AS WELL AS IN PARKINSON'S PATIENTS, AND THEY DID ACTUALLY SOME SECONDARY OUT COME MEASURES ON THE PARKINSON PATIENTS AND THEY SHOWED THAT THEY COULD ISOLATE -- THEY ARE NOW CONDUCTING PHASE 2A CLINICAL TRIAL AND THEY ARE ALSO CONDUCTING IN EUROPE A CLINICAL TRIAL WITH THIS SAME FIT THAT WE DEVELOP IN PATIENTS WITH MSA. NOW, ABOUT POSSIBLE IMMUNIZATION, THESE ANTIBODY THAT WE DEVELOPED WITH ELAN CALLED 94 IS NOW BEING DEVELOPED BY, THEY HAVE ALREADY GONE TO A PHASE ONE CLINICAL TRIAL, THEY ROAR TON -- THIS IS A RANDOMIZED DOUBLE BLIND PL PLACEBO CONTROL, MULTIPLE DOSES. THEY SHOW IT WAS COMPLETELY SAFE, AND INTERESTINGLY, THEY MEASURE OFFSITE KNEW CLEAN, THE BPT OF THIS INDIVIDUAL, AND THEY SHOW A SIGNIFICANT REDUCTION IN ALPHA SYNUCLEIN IN THE PLASMA OF THESE INDIVIDUALS. I THINK SHOWING THAT THERE IS TARGET ENGAGEMENT AND AK OFTIVITY, AND NOW THEY ARE PLANNING A PHASE TWO. WE IN THE MEANTIME CONTINUE TO WORK ON THE SINGLE CHAIN ANTIBODIES, WE'RE REALLY PRETTY EXCITED ABOUT THESE SINGLE CHAIN ANTIBODIES TARGETING SPECIFIC SHE SEESSPECIES. THE COOL THING ABOUT THE SINGLE CHAIN ANTIBODIES IS YOU CAN ACTUALLY COMBINE THEM AND DO FOR EXAMPLE SINGLE CHAIN ANTIBODIES WHERE YOU CAN TARGET ALSO AT THE SAME TIME A-BETA AND TAU. THE BLOOD BRAIN BARRIER PENETRATES AND CURRENTLY TESTING IT IN OUR ANIMAL MODELS OF AGING AND ALZHEIMER'S DISEASE, AND I THINK THE IDEA WOULD BE TO TEST SOMETHING ALONG THESE LINES IN -- FOR CLINICAL MODELS OF ALZHEIMER'S DISEASE, BUT HOPEFULLY ALSO IN THE FUTURE IN PATIENTS. I THINK IT'S BETTER TO TARGET THESE MULTIPLE PROTEINS THAT ARE ACCUMULATING IN THE BRAIN WITH PARKINSON -- WITH ALLS DISEASE IT RATHEALZHEIMER'SDISEASE, RATHER THAN JU ST BAITING -- BUT I THINK THAT APPROACH COULD BE QUITE INTERESTING. SO I WANT TO CLOSE BY ACKNOWLEDGING - THANK -- THANK YOU. [APPLAUSE] >> QUESTIONS? DR. CUMMINGS. >> THAT'S REALLY TERRIFIC. >> THANK YOU. >> I'M LOOKING FOR OPPORTUNITIES FOR TRANSLATION BECAUSE I DEAL WITH LARGE HUMAN STUDIES SO A COUPLE OF THINGS THAT MOW ITING NOTHING ABOUT THIS MOLECULE, AND HOW IT MIGHT CIRCULATE, BUT CAN COULD IT BE DETECT ITED IN THE CIRCULATION IN A WAY THAT IS OF VALUE FOR HUMAN STUDIES OF THE ASSOCIATIONS? >> ACTUALLY BOTH IN CSF AND PLASMA, ALPHA SYNUCLEIN IS FOUND IN -- IN CSF ACTUALLY PROBABLY NEUROTOXIC OF THE SYNUCLEIN IS DETECTABLE AND THERE IS NOW SOME TECHNOLOGY TO DO THAT, SO IT COULD BE USED FOR MONITORING OF SYNUCLEIN. AT LEAST IN THE -- PILE, THE PASSIVE IMMUNIZATION TRIAL, THEY SHOW IMMUNOTHERAPY CONSERVATIVE REDUCTION OF ALPHA SYNUCLEIN IN THE PERIPHERY. >> GREAT, THAT'S A TERRIFIC OPPORTUNITY. BUT THEN ANOTHER -- SORRY, TWO MORE QUESTIONS. I LOVED THE ASSAY IN THE EYE. THAT'S REALLY CLEVER. WE HAVE SHOWN THERE ARE STRONG CORRELATIONS BETWEEN FUNCTIONAL TESTS IN THE EYE AND THE ONSET OF DEMENTIA, DECLINE IN COGNITIVE FUNCTION, AND OF COURSE THE HIGH IS READILY ACCESSIBLE TO INSPECTION IN HUMANS. IS IT POSSIBLE TO IMAGINE YOU MIGHT BE ABLE TO SUSTAIN OR QUANTIFY IN SOME FASHIONS THE CONCENTRATION IN THE RED NA FOR HUMAN STUDIES? >> YEAH, I THINK THAT DEFINITELY IS A CHALLENGE, BUT I THINK IT'S DOABLE. A NUMBER OF GROUPS ARE DEVELOPING WORKING ON SYNUCLEIN LIGANDS THAT MIGHT BE FLUORESCENT OR AMENABLE TO OTHER WAYS TO LOOK INTO THE RETINA BUT CURRENTLY NONE OF THEM ARE AVAILABLE. BUT THAT'S THE WAY TO G >> SORRY FOR HOGGING THE MICROPHONE IN THE TIME BUT I'VE GOT ONE OTHER QUESTION. OF COURSE ONE OTHER THINGS THAT MAY BE VERY PROTECTIVE AGAINST DEMENTIA THAT STIMULATES AUTO PHAGY IS EXERCISE. HAVE YOU -- IS THERE SOME WAY TO AND HAVE YOU CONSIDERED EXERCISE STUDIES IN YOUR MOUSE MODEL? I DON'T MOW HOW THEY CAN BE DONE -- I'VE NEVER TRIED TO EXERCISE A MOUSE BUT COULD YOU SEE WHAT HAPPENS TO CON 16 PRAITION IN MICE? >> THAT'S ACTUALLY SOMETHING WE DID IN COLLABORATION WITH RUSTY GATES. INTERESTINGLY, WE DID NOT SEE A REDUCTION ON THE ACCUMULATION OF ALPHA SYNUCLEIN WITH EXERCISE. BUT WE DID SEE AN INCREASE IN NEUROGENESIS IN THE HIPPOCAMPUS IN THOSE ANIMALS, AND THAT INCREASE IN NEUROGENESIS WAS ASSOCIATED WITH IMPROVEMENTS ON INTERESTING OLFACTORY DEFICITS BECAUSE THESE ANIMALS HAVE OLFACTORY DEFICITS, SO THERE WASN'T AN INTERESTING EFFECT OF EXERCISE, BUT IT DEFINITELY IT'S ANOTHER THING TO LOOK INTO. >> THE PRESS MIGHT BE INTERESTED IN THE IDEA THAT EXERCISE IMPROVES YOUR ABILITY TO SMELL. >> YEP. >> DR. CUERVO. >> THIS WAS REALLY TERRIFIC. I WAS WONDERING, IT'S GREAT THAT YOU'RE GOING INTO SPEES SHE'S-SPECIFIC, HOW ARE YOU GOING ABOUT IDENTIFYING WHAT COULD BE THE TOXIC SPECIES VERSUS NOT IS ALWAYS THE QUESTION, AND THEN THE OTHER THING, THINKING, I COULDN'T BE HAPPIER, BUT THINKING ABOUT -- IT'S PART IT'S GOING TO BE BECAUSE OF THESE TOXIC PROTEINS SO IF YOU ELIMINATE IT, THAT'S ONE LESS PROBLEM, BUT EVENTUALLY DO YOU SEE A NEED FOR -- INTERVENTION THAT YOU MIGHT ALSO HAVE TO ENHANCE -- START NEEDING THEM FOR THE CLEARANCE? >> INSPIRED BY YOUR WORK, MY FAVORITE THING IS AUTO PHAGY, BUT YOU'RE ABSOLUTELY RIGHT, I THINK ONE NEEDS TO COMBINE WITH OTHER APPROACHES, EITHER INCREASING IN A REGULATED FEA SHON MICRO GLIAL -- ABSOLUTELY CRITICAL. AS TO THE SELECTION OF WHAT TOXIC SPECIES, I THINK -- I DON'T THINK WE KNOW BETTER THAN OTHER PEOPLE, BUT WE'VE BASICALLY BEEN USING PHAGE DISPLAY. WHAT MIKE HAS DONE I THINK IS REALLY INTERESTING, HE TOOK THE BRAINS FROM PATIENTS WITH COMBINED ALZHEIMER'S WITH PARKINSON DISEASE THAT WE PROVIDED HIM, AND LOOKED WITH THOSE SINGLE CHAIN ANTIBODIES TO THE SAME SPECIES THAT HE WAS TARGETING WITH A SINGLE CHAIN ANTIBODY IN PROTEIN THAT WAS DONE AGGREGATED RERECOMBINANT AND KIND OF LIKE SIMILAR SPECIES WERE RECOGNIZED, AND THAT PARTICULAR ANTIBODY WAS SELECTED BASED ON THAT CRITERIA THAT IT MIMIC OR MIRROR WHAT WE WOULD FIND IN BRAINS FROM IT PATIENTS, BUT THERE IS REALLY NO ABSOLUTE PROOF THAT THAT'S REALLY A TOXIC SPECIES. YOU'RE RIGHT. >> I'LL ACTUALLY ASK A QUESTION MYSELF. DO YOU KNOW THE AGE RANGE, ARE THERE ANY AGE LIMITATIONS OF THE PARTICIPANTS IN THE CLINICAL TRIALS THAT YOU MENTIONED? >> NO, NOT REALLY. I KNOW THAT THEY WERE HEALTHY INDIVIDUALS BUT I DON'T KNOW WHAT AGE RANGE. >> WHETHER THEY WERE SLIGHTLY MORE YOUNGER PARKINSON'S PATIENTS RATHER THAN OLDER PARKINSON'S PACE IS BECAUSE THERE IS A TREND TO EXCLUDE -- >> AS I RECALL THEY WERE OVER 50 BUT I DON'T REMEMBER EXACTLY WHAT AGES. >> ALL RIGHT. THANK YOU VERY MUCH, DR. M DR. MASLIAH. DR. HE VAN HADLEY WILL INTRODUCE DR. ANNE NEWMAN. >> ANNE GOT HER DEGREE FROM THE UNIVERSITY OF PITTSBURGH, CURRENTLY SHE'S CHAIR OF THE DEPARTMENT OF EPIDEMIOLOGY AT THE SCHOOL OF PUBLIC HEALTH AND ALSO HAS AN APPOINTMENT AT THE MEDICAL SCHOOL. SHE'S DONE EXTENSIVE IMPORTANT WORK ON AGING WITH THE CARDIOVASCULAR HEALTH STUDY, AND ALSO IN COLLABORATIONS WITH OTHER STUDIES, LEADING THE CHARGE CONSORTIUM IN COLLABORATIONS WITH PRAIMING HAM AND RECENTLY ALSO A LONG LIME FAMILY STUDY, AN NIA STUDY FOE KUTION ON LONG LIFE FAMILIES TO HEALTHY AGING. ANNE'S WORK IS NOTABLE FOR THE INNOVATIVE WAYS SHE'S USED EPIDEMIOLOGIC DATA TO ADDRESS IMPORTANT QUESTIONS. I THINK WE'RE GOING TO HEAR ABOUT SOME OF THOSE STUDIES IN HER TALK. >> I'LL TAKE A MOMENT TO FIND MY TALK. THANK YOU VERY MUCH. I'M PLEASED TO JOIN THE COUNCIL AND TO HAVE THE OPPORTUNITY TO SHARE WITH YOU SOME OF THE WORK THAT I'VE BEEN DOING OVER THE YEARS. IT'S BEEN A LITTLE BIT OF A JOKE BETWEEN HE VAN AN EVAN AND I THAT A LOT OF MY EARLY WORK WAS ACTUALLY FUNDED BY NHLBI. THERE WERE THREE GERIATRICIANS WORKING ON THE CARDIOVASCULAR HEALTH STUDY, MYSELF, LINDA FREED AND WOLF -- USED EARLY ON IN GERIATRIC MEDICINE EARLY ON TO UNDERSTAND FUNCTION. SO I BEGAN MY CAREER AS A CARDIOVASCULAR EPIDEMIOLOGIST, AND THAT REALLY FORMED MY VIEW OF WHAT WE CAN LEARN ABOUT AGING FROM LOOKING AT PREDOMINANTLY METHODS THAT USE IMAGING OR BLOOD MARKERS TO UNDERSTAND THE BURDEN OF DISEASE IN OLDER ADULTS. SO SOME OF MY EARLY WORK LOOKED AT WHETHER VASCULAR AGING EXPLAINED A LOT OF FUNCTIONAL DECLINE IN AGING AND HAVE BROADENED THAT TO LOOK AT MULTISYSTEM AGING. SO I USE THIS DEFINITION OF AIMING IN MAGING IN MY WORK, AND IT'S AN ELABORATION OF SEVERAL DEFINITIONS THAT I'VE LEARNED OVER THE YEARS, BUT I FOCUS ON CERTAIN ASPECTS OF DEFINING AGING. AND HOW WE CAN RELATE THAT TO DISEASE BURDEN. SO AGING IS THE ACCUMULATION OF DAMAGE AND REPAIR. I LIKE TO EMPHASIZE BOTH OF THOSE, BECAUSE IT'S DAMAGE AND REPAIR PROCESS THAT GIVES US THE PHENOTYPES, AND THIS OCCURS IN CELLS, TISSUES, ORGANS AND IN THE PERSON, WE CAN LOOK AT MEASURES AT ALL LEVELS BIEF LOGIC ORGANIZATION AND WE CAN DO THIS IN THE CONTEXT OF POPULATION STUDIES. THESE CHANGES OCCUR OVER TIME AND IN THE POPULATION STUDIES, WE HAVE FOLLOWED PEOPLE FOR 20 YEARS OR MORE, RESULTS IN A LOSS OF FUNCTION AND VULNERABILITY. WE'RE VERY GOOD AT MEASURING THE LOSS OF IT FUNCTION, NOT SO GOOD AT MEASURING THE VULNERABILITY, AND THAT'S AN IMPORTANT AREA OF DEVELOPMENTAL WORK IN CLINICAL STUDIES OF AGING. AGE SOMETHING STILL, IN HUMANS, AT LEAST, UNIVERSAL, DETRIMENTAL AND INEVITABLE, THOUGH THE PROMISE FROM RECENT WORK IN ANIMAL MODELS SUGGES THIS MAY CHANGE FOR HUMANS AS WELL. SO I DEVELOPED THIS MODEL, AND THIS ACTUALLY COMES FROM TEACH TEACHING GERIATRICIANS HOW TO THINK ABOUT DISEASE AND AGING AT THE SAME TIME, AND TO USE DATA FROM POPULATION STUDIES TO ANALYZE THESE VARIOUS RELATIONSHIPS. SO IN THIS MODEL, WE THINK ABOUT DISEASES AS BEING SELECTIVE AND PREVENTIBLE, AND THIS IS OVER IN THE UPPER RIGHT-HAND BOX, AND THAT IS DRIVEN BY MODIFIABLE RISK FACTORS. SO A LOT OF OF OUR WORK IN EPIDEMIOLOGY HAS FOCUSED ON IDENTIFYING MODIFIABLE RISK FACTORS THAT COULD BE THE TREATMENT TARGETS TO PREVENT DISEASES, WHICH ARE SELECTIVE, AND WE CAN PREVENT DISEASE. IT'S THESE DISEASES THAT HAVE BEEN SHOWN TO BE VERY IMPORTANT AS THEY ACCUMULATE IN LEADING TO DISABILITY AND VULNERABILITY TO MORTALITY AS WE AGE. BUT THERE'S BEEN A LOT OF NEW WORK SUGGESTING MAYBE WE CAN BETTER BEGIN TO UNDERSTAND THE INTRINSIC FACTORS RELATED TO AGING, AND GENETIC PREDISPOSITION. AND TO LINK THESE FACTORS AS WELL TO UNDERSTAND NOT JUST DISEASE BUT WHAT WE WOULD CALL AN AGING PHENOTYPE WHICH MIGHT BE VIEWED STILL AS UNIVERSAL AND INEVITABLE IN HUMANS. IN THIS MODEL, THIS ALLOWS FOR MODIFIABLE RISK FACTORS TO INFLUENCE INTRINSIC RISK FACTORS, AND FOR BOTH TOGETHER THROUGH ALTERED TISSUE FUNCTION, ORGAN FUNCTION, ULTIMATELY TO LEAD TO THE DISABILITY AND VULNERABILITY TO MORTALITY THAT IS PARTLY DISEASE-RELATED AND PARTLY AGING-RELATED. SO IT ALLOWS US TO LOOK AT BOTH AGING AND DISEASE AT THE SAME TIME IN HUMAN POPULATIONS. SO AS I SAID, A LOT OF EPIDEMIOLOGY HAS REALLY FOCUSED ON THIS SIDE OF THE EQUATION, PRESENTING DISEASE AND MODIFIABLE RISK FACTORS FOR DISEASE, AND THAT'S WHERE I BEGAN TO TRY TO UNDERSTAND RISK FACTORS FOR AGING. SO THIS IS FROM THE CARDIOVASCULAR STUDY WHERE WE LOOKED AT TOTAL AND COST-SPECIFIC MORTALITY, AND IN THIS PAPER, WE LOOKED AT ALMOST 80 DIFFERENT RISK FACTORS, AND WE LOOKED AT THEM ACROSS SPECIFIC CAUSES OF DEATH, LOOKING FOR COMMONALITIES IN UNDERLYING CAUSES OF DEATH. SO FOR EXAMPLE, IL6 WAS RELATED TO ALL OF THESE CAUSES OF DEATH THAT WE CATEGORIZED HERE. ONE OF THE THINGS THAT I THOUGHT WAS QUITE STRIKING ABOUT THIS WAS THAT WE -- IN THE STUDY, WE TEE FINED CAUSE OF DEATH BY ACTUALLY LOOKING AT THE MEDICAL RECORDS AND NOT THE DEATH CERTIFICATE, AND WE FOUND THAT WE COULD REALLY PINPOINT IN MANY PEOPLE A LEADING CAUSE IN THEIR CAUSE OF DEATH AND THEY WERE CATEGORIZED IN THIS WAY. WHAT'S SO STRIKING IS THAT FOR THE CANCER IT DEATHS OCCURRING IN THE STUDY, THEY WERE OCCURRING MUCH EARLIER THAN WHERE THE CARDIOVASCULAR DEATHS. WHAT THIS TELLS US IS THERE'S A PATTERN IN HUMAN AGING THAT I THINK WE'VE THOUGHT ABOUT FOR MANY YEARS AGO BEING MOSTLY DUE TO EXTERNAL TAC FACTORS. BUT EVEN CONTROLLING FOR ALL OF THE EXTERNAL RISK FACTORS FOR THESE CONDITIONS HA WE KNEW ABOUT, WE STILL SEE THIS PATTERN. THE CARDIOVASCULAR AGING OCCURS EARLIER THAN, SAY, DEMENTIA, AND IT TELLS US, I THINK, AS HUMANS AGE, THAT CERTAIN ORGAN SYSTEMS WE'RE TOLD ARE MORE SUSCEPTIBLE TO DAMAGE AND COMPLETE REPAIR AND THAT THIS IS SIMPLY A PATTERN OF ORGAN-SPECIFIC AGING THAT WE CAN SEE IT IN POPULATIONS. WE ALSO NOTICE ADD TREMENDOUS SPECIFICITY OF RISK, SO THEY -- WE SAW TREMENDOUS SPECIFICITY THAT THE CAROTID WALL -- SPECIFIC FOR PREDICTING CARDIOVASCULAR DEATH, THEY IT DD NOT PREDICT CANCER IT DEATH, INFECTIOUS DEATH. PULMONARY FUNCTION PREDICTED -- THIS WAS 10 TO 15 YEARS PRIOR TO DEATH, AND THE WAY I LOOKED AT THIS WAS THAT WE WERE, IN FACT, ABLE TO IDENTIFY AN INDIVIDUAL, WHAT WAS THEIR WEAKEST LINK THAT WOULD PREDICT THEIR CAUSE OF DEATH AND WE COULD SEE WHERE THEY WOULD EVENTUALLY END UP MANY, MANY YEARS BEFORE. NEVERTHELESS, AGE REMAINED AN INDEPENDENT RISK FACTOR AFTER CONSIDERING ALL OF THESE EXTERNAL AND PERHAPS SOME INTERNAL INTRINSIC AGING FACTORS. AND THIS BASICALLY SHOWS FOR EACH CAUSE OF DEATH THE STRENGTH OF HAZARDS RATIO FOR DEATH ACCOUNTING FOR EVERYTHING THAT WE KNEW WITH RISKS OF THREE FOLD AND, IN THE CASE OF DEMENTIA, 15 FOLD, EVEN AFTER ACCOUNTING FOR ALL OF THESE FACTORS. SO IT RAISES THE IMPORTANCE OF AGE ITSELF AND UNDERSTANDING WHY AGE REMAINS SO IMPORTANT. SO I WAS FORTUNATE TO BE FUNDED BY THE DGCG PROGRAM TO TAKE THE CARD YES VASCULAR HEALTH STUDY COHORT AND TO BEGIN TO LOOK AT AGING IN THAT COHORT BY CHARACTERIZING THE PEOPLE WHO DID THE BEST, THE LONG LIVED INDIVIDUALS. WE HAVE ACCUMULATED OVER 2,000 INDIVIDUALS WHO SURVIVE TO AGE 90 OR OLDER AND TO CHARACTERIZE AGE-RELATED CHANGES IN MULTIPLE SYSTEMS AND TO TRY TO UNDERSTAND THE CORRESPONDENCE BETWEEN SYSTEMS. THIS SHOWS THE TIMELINE FOR THE CARDIOVASCULAR HEALTH STUDY THAT BEGAN BEFORE 1992, BUT WE HAD A LARGE MINORITY COHORT RECRUITED THEM, SO WE STARTED THE BASELINE FOR THIS EVALUATION IN 1992, AND IN THIS EARLY PERIOD, WE HAD MANY REPEATED MEASURES OF ORGAN STRUCTURE AND FUNCTION AND PHYSICAL AND COGNITIVE FUNCTION, AS WELL AS SPECIMENS EVERY YEAR SO WE COULD BEGIN TO LINK AT THESE VARIOUS LEVELS OF BIOLOGIC ORGANIZATION THE RELATIONSHIP BETWEEN CHANGES AT THE BIOMARKER LEVEL TO THE BIOMARKERS OF ORGAN SYSTEMS STRUCTURE AND FUNCTION TO MEASURES OF COG OFTIVE AND PHYSICAL CHANGE. AND ULTIMATELY, TRY TO IT IDENTIFY WHAT ARE THE PATTERNS CHARACTERISTIC OF THOSE WHO LIVE THE LONGEST AND HAVE THE MOST ACTIVE LIFE EXPECTANCY. THE QUESTION WAS, DO HEALTHIER OLDER PEOPLE DELAY DECLINE IN MULTIPLE SYSTEMS? WE FOUND THAT WHEN WE LOOKED A AT THIS WITHIN THE CHS COHORT, THAT THERE'S A TREMENDOUS AMOUNT OF VARIABILITY IN INDIVIDUALS SORT OF LEADING HEALTH PROBLEMS. YES, MANY PEOPLE HAVE MULTIPLE, BUT THERE SEEMS TO SORT OF BE A WORSE SYSTEM FOR PEOPLE SO THAT WHEN WE LOOKED CROSS-SECTIONALLY, WE DIDN'T SEE A LOT OF CORRESPONDENCE BETWEEN SYSTEMS, AND IT'S THAT LACK OF CORRESPONDENCE DUE TO LOOKING AT THIS IN SUCH A NARROW WINDOW OF TIME, IF YOU LOOK ACROSS THE LIFESPAN, WE STILL SEE THE PATTERN THAT MOST EVERYTHING GETS WORSE AND WE BELIEVE THERE IS AN UNDERLYING SORT OF RATE OF AGING BEHIND ALL THAT, BUT LOOKING AT THESE INDIVIDUAL SYSTEMS, IT'S VERY DIFFICULT TO DISCERN. IT IT RAISES THE QUESTION WHETHER HUMAN AGING IS REALLY A COLLECTION OF INDEPENDENT SYSTEMS, SO WE SEE THESE INDEPENDENT TRAJECTORIES, AND WHAT I BELIEVE IS THAT THIS IS AGING, BUT BECAUSE THEY APPEAR TO BE FAIRLY INDEPENDENT, THIS, IN FACT, IS WHY WE CALL THEM DISEASES, BECAUSE WE RECOGNIZE THE INDEPENDENCE THEY HAVE FOR EACH OTHER AND WE CAN DEFINE THE UNDERLYING EXTERNAL RISK FACTORS, AGING FACTORS, AND CLINICAL IMPACT OF SYMPTOMS. SO I BELIEVE THAT THESE CHRONIC DISEASES OF AGING ARE STILL AGING PROCESSES AND THAT THERE IS POTENTIAL TO TREAT AWFUL THEM THROUGH INTERVENTIONS THAT TARGET THE UNDER ITLYING AGING PROCESS. THE CHANGES THAT WE'RE MEASURING IN MANY OF THESE COHORT WHEN THEY'RE OLDER APPEAR TO ME TO BE ADAPTIVE OR SECONDARY EFFECTS OF THE ACCUMULATION OF MULTIPLE CHRONIC DISEASES, AND THAT'S WHAT WE'RE LOOKING AT IN THIS GRANT. SO ONE OF THE THINGS WE DID TO TRY TO UNDERSTAND MULTISYSTEM AGING WAS TO LOOK ACROSS THESE SYSTEMS THAT WE HAD DETAILED MEASURES ON, AND CHS IS UNIQUE IN HAVING A LARGE SAMPLE OF INDIVIDUALS WHO HAVE VASCULAR MEASURES WHO HAVE BRAIN IMAGING, PULMONARY FUNCTION, MEASURES OF KIDNEY FUNCTION, AND WILL ARE SOME OTHER MEASURES AND SUBSETS THAT WERE POTENTIAL CANDIDATES, BUT NOT INCLUDED HERE. THESE WERE THE MEASURES THAT WERE THE MOST STRONGLY RELATED TO TOTAL MORTALITY IN THE COHORT AND THUS WERE CHOSEN TO TRY TO UNDERSTAND MULTISYSTEM AGING. WE DID A LOT OF COMPLEX ANALYSIS LOOKING AT CLUSTERING BETWEEN SYSTEMS TO SEE IF WE COULD IDENTIFY A UNIQUE GROUP OF INDIVIDUALS WHO WERE AGING SLOWLY IN ALL SYSTEMS, AND WE DID NOT FIND IT. SO CAME UP WITH THIS SCALE LOOKING AT TERTILES OF EACH ONE, SO IF YOU LOOK AT MEASURES OF SUBCLINICAL VASCULAR DISEASE, THEY TENDED TO BE LOOKED AT THIS IN THIS MORE STIM PE SIMPLE WAY. YOU END UP DEFINING INDIVIDUALS IN THE BEST TERTILE VERSUS THE WORST AND ADDING THAT UP ON A ZERO TO 10 SCALE, AND IT TURNS OUT THE BEST TERTILE FOR ALL OF THESE MEASURES IS WHAT YOU WOULD SEE IN A HEALTHY MIDDLE AGED NOT SICK POPULATION. SO THAT WE CAN TAKE THIS AS SORT OF AN AGE-FREE MEASURE OF AGING. AGE IS NOT INCLUDED IN HERE, THESE ARE NOT ADJUSTED FOR AGE, THEY'RE SIMPLY LOOKED AT IN THE COHORT AND CAN TELL US WHICH INDIVIDUALS, IF YOU HAVE A ZERO ON ALL OF THESE, YOU COULD BE BASICALLY AS WELL AS A HEALTHY MIDDLE AGED PERSON. SO WHEN WE DID THAT, WE GOT THE DISTRIBUTION ON THE RIGHT, WHICH IS BASICALLY WHAT YOU WOULD EXPECT TO SEE IF YOU CONSIDER THIS TO BE A NORMAL DISTRIBUTION OR RANDOM EFFECT, IS THAT THE DISTRIBUTION OF HAVING A 10, A ZERO TO A 10, BASICALLY A NORMAL DISTRIBUTION, VERY, VERY FEW INDIVIDUALS WERE ZERO ON THE SCALE. WE COMPARED THIS TO A COUNT OF CO-MORBIDITIES AND WHEN YOU DO THIS, YOU SEE THERE WERE A SUBSTANTIAL NUMBER OF INDIVIDUALS WHO WILL NO CHRONIC HEALTH CONDITIONS IN THESE DOMAINS, BUT AMONGST THOSE, YOU CAN SEE THAT THERE WOULD BE A LOT WHO WERE SORT OF USUAL HEALTHY AND VERY, VERY FEW WHO WERE REALLY TRULY SUPER HEALTHY. SO IT WAS THIS VERY SMALL GROUP THAT WAS VERY INTERESTING TO US BECAUSE THIS NOW PROVIDES THE OPPORTUNITY TO LOOK AT HEALTH AND PEOPLE AND NOT WAIT TO SEE IF THEY'RE LONG LIVED AND TO ACTUALLY IF GO BACK AND LOOK AT PEOPLE EARLIER IN THEIR OLD AGE SUPER HEALTHY. PEOPLE WHO HAD VERY LOW SCORES ON THIS INDEX HAD VERY, VERY LOW MORTALITY RATES, 7 PER THOUSAND IS VERY LOW FOR PEOPLE OVER 65, MEAN AGE 73 SHOWN THERE. WHEN YOU COMPARE THAT TO THE CO-MORBIDITY COUNT, YOU SEE THAT YOU HAVE A LOW RISK IN PEOPLE WITH ZERO CLINICAL HEALTH CONDITIONS, BUT THEN WE CAN FURTHER DISTRIBUTE THAT OUT AND FIND NOT ONLY HEALTHY PEOPLE BUT EXCEPTIONALLY HEALTHY PEOPLE. WE WERE ALSO VERY INTERESTED IN HOW THIS MIGHT EXPLAIN THAT AGE EFFECT, SO I HAD SHOWN YOU AGE REMAINS A VERY STRONG PREDICTER OF MULTIPLE CAUSES OF MORTALITY EVEN AFTER ADJUSTING FOR MANY RISK FACTORS. WHAT THIS GRAPH SHOWS YOU IS THE AFFECTED AGE, UNADJUSTED, AGE 85-PLUS, THERE IS A 7 TO 8 FOLD HIGHER RATE OF MORTALITY THAN AT 65, AND WHEN WE ACCOUNTED FOR THIS INDEX, WE EXPLAINED ABOUT 40% OF THAT RISK. THIS IS SOMETHING I'VE MADE A HOBBY OF DOING, IS LOOKING FOR HOW MUCH ANY MARKER CAN EXPLAIN CHRONOLOGICAL AGE AND PREET DICKPREDICTIONOF MORTALITY OR DISABILITY, AND 40% IS AS GOOD AS I'VE SEEN SO FAR SO IT'S SORT OF AN INTERNAL COMPETITION FOR ME TO SEE IF I CAN BEAT THAT OR IT IF ANYBODY ELSE WANTS TO TAKE ME UP ON THAT, WE CAN HAVE A LITTLE RACE ABOUT IT. INTERESTINGLY, THE INDEX PREDICTED MORTALITY AS WELL CEAD TO HEAD TO AGE, ACTUALLY PERFORMED A LITTLE BETTER IN THE CHS COHORT WITH THE AREA UNDER THE CURVE BEING A LITTLE LARGER FOR THE INDEX THAN CHRONOLOGIC AGE ITSELF. SO WE THOUGHT THAT WE HAD BASICALLY A GOOD MARKER OF UNDERSTANDING AGE, BUT WHEN WE WANTED TO TAKE THIS TO IT THE CONTEXT OF LOOKING AT POPULATION STUDIES INTERESTED IN LONGEVITY, WE FOUND THAT MANY OF THE OTHER COHORTS IT DID NOT HAVE THIS DETAILED LEVEL OF PHENOTYPING, SO WE DEVELOPED THIS ALTERNATE INDEX THAT WE CALLED THE HEALTHY AGING INDEX WHERE WE SUBSTITUTED MEASURES COMMONLY AVAILABLE IN MANY COHORT STUDIES AROUND THE WORLD AND USED SYSTOLIC BLOOD PRESSURE, MANY STUDIES HAVE PULMONARY FUNCTION THOUGH NOT ALL, WE USED A COGNITIVE TEST INSTEAD OF THE BRAIN MRI, DID HAVE KOREA A CREATININE AND CHS WHICH IS A STRONGER INDICATOR OF MORTALITY REFLECTING KIDNEY FUNCTION. WE LOOKED AT THE HERITABILITY OF THIS AND THE ABILITY IT TO PREDICT MORTALITY TO VALIDATE IT AS A POTENTIAL MEASURE IN IT GENETIC STUDIES. WE FOUND THAT THE HAD HAZARD RATIOS FOR MORTALITY WERE QUITE STRONG FOR THIS LEVEL OF INDECK, ABOUT THREE FOLD HIGHER, SO IT TELLS US THAT IT'S A PRETTY GOOD WAY TO SPREAD OUT THE POPULATION TO LOOK FOR THE SUPER HEALTHY AND DISTINGUISH THEM FROM PEOPLE WHO HAVE A HIGHER RISK OF MORTALITY. THEN IN THE LONG LIFE FAMILY STUDY, WE LOOKED AT THE HERITABILITY AND FOUND THAT THE HAIRHERITABILITY WAS ABOUT 30%. WE ALSO DEVELOPED MORTALITY WAITING TO TRY TO OPTIMIZE THE PREDICTION, THEN APPLY IT TO LONG LIFE FAMILY AND THE HERITABILITIES WERE SIMILAR, WE LOOKED AT THE UNDERLYING GENETICS OF THIS WITH BOTH THE WEIGHTED AND THE UNWEIGHTED. COMPONENTS, SO WE JUST PUBLISHED A GENOME-WIDE ASSOCIATION STUDY AND LINKAGE AND LONG LIFE FAMILY STU IT DI WHERE IT'S A RELATIVELY SMALL NUMBER OF PARTICIPANTS, THERE ARE ABOUT 5,000 IN THE STUDY, INCLUDING SPOUSE-CONTROLLED, SO THE LINK ARNLINGS OF COURSELINKAGE, OF COURSE, WAS LIMITED TO THE RELATED INDIVIDUALS. WE DID FIND SOME LOCI, AS YOU CAN SEE HERE, AND DIFFERED ACTUALLY IN MEN AND WOMEN AND THE GWAS ACTUALLY FOUND AN ASSOCIATION WITH A DIFFERENT SNIP IN DNF47 WHICH IS ON CME 8. SO WE SAW SOME POTENTIAL HERE THAT SUCH A PHENOTYPE CAN BE USEFUL FOR DEFINING HEALTHY AGING IN IT POPULATIONS AND FOR UNDERSTANDING THE BIOLOGIC UNDERPINNINGS, AND WE'VE PROCEEDED NOW WITH THE META-ANALYSIS IN 19,000 PARTICIPANTS FROM THE CHARGE CONSORTIUM, AND THIS INCLUDES THE HEALTH IN RETIREMENT SURVEY, THE RODDERDAM STUDY AND THE LARGE COHORTS ABLE TO LOOK AT THIS IN THEIR COHORTS CROSS-SECTIONALLY. WE ALSO HAVE LOOKED AT FRAILTY, LED BY LINDA FREED YEARS AGO, DEFINES PEOPLE AS FRAIL, BUT THE PEOPLE WHO ARE NOT FRAIL IS A LARGE PROPOROF THE POPULATION, AND AMONGST THOSE PEOPLE, WE WANTED TO KNOW WHO WERE THE SUPER NOT FRAIL, OR THE MOST ROBUST, WE WANTED TO KNOW WHICH PEOPLE WERE THE STRONGEST, THE FASTEST, AND THE FITTEST OF THE NOT FRAIL. WE TRIED SPREADING IT OUT IN A DIFFERENT WAY BY TAKING THE POSITIVE INDICATORS AND SCORING THEM ZERO TO FIVE, BUT YOU STILL END UP WITH THIS LARGE GROUP OF PEOPLE AND IT'S AMONGST THOSE WE THINK WE NEED TO SEPARATE OUT IT TO FIND THE SUPER HEALTHY, AND WHEN WE SCALED IT THE SAME WAY THAT WE HAD SCALED THIS OTHER INDEX, NOW YOU GET A NORMAL DISTRIBUTION, WHERE THESE ARE THE PEOPLE WHO ARE THE FASTEST AND THE STRONGEST AND THE FIT FITTEST. WHEN YOU DO THAT, IT'S VERY, VERY STRONGLY RELATED TO THIS ORGAN FUNCTION SCALE. SO IT'S A SCALING ISSUE. I THINK THAT WE CAN REMEDY. AND I THINK FRAILTY HAS HAD SOME DIFFICULTY IN TRANSLATING IT TO UNDERSTANDING ROW BUST HEALTH AND SUPER HEALTH BECAUSE OF THE SCALING ISSUE. SO I THINK THIS GIVES US THE OPPORTUNITY TO THINK ABOUT LOOKING AT INTRINSIC FACTORS THAT WE CAN NOW MEASURE THAT ARE RELATED TO AGING AND LOOK AT THIS SAME PATHWAY TO UNDERSTAND AGING. ONE OF THE THINGS WE DID WAS LOOK AT CIRCULATING BIOMARKERS AND ASK WHETHER THEY TRACK WITH EACH OTHER AS WELL AS WITH FUNCTION CHANGES OVER TIME, AGAIN, THIS IDEA OF LOOKING AT MULTISYSTEM AGING. AS WE FOUND WITH ORGAN SYSTEMS, WE FOUND WITH THESE BIOMARKERS THAT THE CORRELATIONS BETWEEN THEM OVER TIME WERE NOT VERY STRONG, CORRELATIONS LESS THAN .3, EVEN CORRELATIONS OF LESS THAN .1 NOW BECAUSE OF OUR SAMPLE SIZE, ALL OF THESE ARE STRONGLY ST STATISTICALLY SIGNIFICANT BUT THE ONLY ONE THAT'S REALLY SUBSTANTIALLY CORRELATED ARE TWO MARKERS IN THE SAME SYSTEM THAT W WE KNOW GO TOGETHER SO WE WOULD EXPECT THAT. THESE WERE MARKERS THAT WE HAD IN CHS AND WE'RE TRYING TO ADD MORE AS WELL AS MORE TO LONG LIFE FAMILY STUDY FOR MARKERS THAT ARE MORE DIRECTLY RELATED TO AGING. SO THEY WEREN'T STRONGLY RELATED TO EACH OTHER. THESE ARE CHANGE BY CHANGE ANALYSES, PU W BUT WE DID FIND THE MARKER OF ADRENAL A ANDROG. GEN MARKERS WERE RELATED TO GRIP STRENGTH OVER TIME AND CHANGE IN GAIT SPEED, SO WE CAN LOOK AT HOW THEE THINGS TRACK TOGETHER. SOME OF THEM TRACK TOGETHER MORE STRONGLY. NOW THAT WE'VE BEEN FOLLOWING PEOPLE FOR A REALLY LONG TIME, WE'VE BEEN ABLE TO MODEL THE TRAJECTORIES OF DECLINE IN FUNCTION WITH AGE. THIS IS SOMETHING I'M WORKING ON NOW WHERE WE DISTINGUISHED PEOPLE WHO REMAINED HEALTHY OVER THE TIME PERIOD. PEOPLE HAVE BEEN FOLLOWED WITH BY 20 YEARS, SO WE DON'T HAVE A WHOLE COHORTAT STARTED AT 65 AND WENT TO AGE 100, BUT THIS IS RATHER MODELING THE PEOPLE THAT WE HAD FROM 65 TO 85 AND THE PEOPLE WHO WE HAD FROM 85 TO 100, SO IT'S SORT OF A COMBINATION OF A CROSS-SECTIONAL AND LONGITUDINAL LOOK TETR AT THE TRAJECTORIES OF DECLINE. INTERESTINGLY, THE RATES OF DECLINE LATE IN LIFE WERE VERY SIMILAR IN PEOPLE REGARDLESS OF WHETHER THEY REMAINED FREE OF CLINICAL DISEASE OR NOT AND WERE QUITE STEEP LATER IN LIFE. NOW WE STARTED CHS HERE, AND YOU CAN SEE ACTUALLY A LITTLE BIT OF AN INCREASE WHICH I THINK IS A LEARNING EFFECT EARLY IN THE STUDY, BUT A PROBLEM WITH MANY OF OUR AGING MEASURES IS THAT WE DON'T SEE MUCH DECLINE UNTIL PEOPLE ARE IN THEIR 70s, SO IT'S A REAL CHALLENGE TO UNDERSTAND AGING BEFORE THEN. BUT WE THINK THAT PART OF THIS MIGHT BE DUE TO THE FACT THAT WE HAVEN'T ADEQUATELY ACCOUNTED FOR ALL OF THAT HUGE BURDEN OF SUBCLINICAL DISEASE THAT WE CAN MEASURE NON-INVASIVELY. A VERY SMALL PERCENTAGE OF INDIVIDUALS HAVE A CLINICAL EVENT BUT THE MAJORITY OF THEM HAVE AN EXTENSIVE SUBCLINICAL DISEASE. WE'VE BEEN ABLE TO LINK THESE TO TRAJECTORIES OF SOME OF THESE BIOMARKERS, AND HERE IN BOTH MEN AND WOMEN, YOU SEE THE BACKGROUND DECLINE IN GAIT SPEED, THEN YOU SEE INCREASES THAT TRACK WITH THEM IT IN IL IL6 AND ADIPONECTIY. MY TRAINING WAS IN CLINICAL GERIATRIC MEDICINE, AND THEN IN EPIDEMIOLOGY, AND I WOULD SAY BEGINNING WITH STEVE CUMMINGS' EFFORTS WITH THE LONGEVITY CONSORTIUM, I HAVE BEEN FASCINATED BY THE DEVELOPMENTS IN THE BIOLOGY OF AGING AND VERY INTERESTED IN HOW WE CAN UNDERSTAND THE AGING PROCESS BETTER BY COMBINING THESE. SO THE EPIDEMIOLOGY OF THE BIOLOGY OF AGING TRANSLATES BIOMARKERS OF BASIC AGING, BIOMARKERS TO HUMAN POPULATION, SO WE'RE ALWAYS TROLLING FOR THINGS THAT WE CAN MEASURE. IT POSITS THAT AGING CAN BE DISTINGUISHED FROM DISEASE USING THAT MODEL THAT I SHOWED YOU, WHERE WE UNDERSTAND THAT THEY COMINGLE AND WE DON'T REALLY TRY TO PULL THEM APART BUT RATHER TO LOOK AT BOTH AT THE SAME TIME. AND IT NOTES THAT AGING REMAINS A STRONG RISK FACTOR FOR MORE IT TALT AND DISABILITY EVEN AFTER ACCOUNTING FOR MULTI-MORBIDITY AND ATTEMPTS TO EXPLAIN WHY THAT IS. SO BY LINKING BIOMARKERS TO FUNCTION, LONGEVITY AND HEALTHY AGING IN UNIQUE POPULATIONS, I THINK WE'RE PART OF THE NEW WORLD OF TRANSLATIONAL GEROSCIENCE, WHICH HAS COME FROM THE BIOLOGY OF AGING AREA. SO THIS IS THE TRAJECTORY THAT WE SET OUT IN MANY OF THESE COHORT STUDIES TO MEASURE. WE'RE LOOKING AT HEALTH CONDITIONS, LOOKING AT MODIFIABLE RISK FACTORS FOR THEM, AND THIS IS THE ALL TOO TYPICAL PATTERN OF DECLINE THAT THERE'S SOME BACKGROUND DECLINE THAT'S ACCELERATED BY HEALTH EVENTS, AND I THINK MOST OF OUR EFFORTS HAVE BEEN TRYING TO STOP THESE HEALTH EVENTS, AND IT WE DO THAT, I THINK WE'LL STILL SEE THIS BACKGROUND RATE OF DECLINE, PERHAPS POSTPONED, THE ONSET OF FUNCTIONAL LIMITATIONS SOME, BUT WITH THE BIOLOGY OF AGING, I THINK THERE'S A GREAT DEAL OF PROMISE THAT WE COULD REALLY PUSH THIS IF WE ADDRESSED AGING ITSELF AND DELAY THE ONSET OF FUNCTIONAL LIMITATIONS UNTIL VERY LATE IN LIFE AND BASICALLY COMPRESS MORBIDITY WITH WHAT YOU SEE WITH THE RED BRACKET THERE WITH WHAT YOU SEE WITH THE GREEN BRACKET IN THE SHORT PERIOD AT THE END OF LIFE. WITH THE COHORT STUDIES THAT WE HAVE, WE CAN NOW DISTINGUISH PEOPLE WHO HAVE THESE TRAJECTORIES AND LOOK BACK HERE WITH STORED SPECIMENS FOR THE BIOMARKERS THAT HELP US TELL THESE PEOPLE APART THAT COULD BE TARGETS. SO IN SUMMARY, I THINK OF AGING AS SYSTEM FAILURE, THERE'S A PATTERN TO IT WITH AGING, CANCER, SALES FIRST, VASCULAR SYSTEM IMMUNE, THE NEUROLOGIC SYSTEM I THINK OF AS BEING INCREDIBLY PROTECTED AS WE GET OLDER, THAT WE'RE VERY, VERY FORTUNATE, I THINK, THAT IT IS SO WELL PROTECT ITED AND THAT FOR MOST PEOPLE, COGNITIVE FUNCTION IS THE LATER PROBLEM TO WORRY ABOUT AND NOT AN EARLIER PROBLEM TO WORRY ABOUT. BUT IT'S NOW BECOME THE MAY JR. REASON FOTHE MAJORREASON FOR DISABILITY FO R PEOPLE THAT LIVE A LONG TIME. THE IDEA OF THE WEAKEST LINK, I THINK THIS IS TRUE AND AS A IS THE RESULT OF EX-TRIN SIN AND INTRINSIC FACTORS THAT YES THERE IS UNDERLYING AGING BUT INDIVIDUALS CAN BE IDENTIIED BY WHAT THEIR UNIQUE TRAJECTORIES ARE GOING TO BE BY ORGAN SYSTEMS, AND THIS IS IMPORTANT FOR PERSONALIZED MEDICINE. WE DEVELOPED THIS HEALTHY AGING INDEX AND HAVE SHOWN THERE IS A LOW CORRELATION BETWEEN SYSTEMS, THAT WE NEED MULTIPLE BIOMARKERS TO IDENTIFY THOSE AT LOWEST RISK AND IT DOES APPEAR TO BE A USEFUL PHENOTYPE MANIFESTED EARLY IN OLD AGE THAT ALLOWS YOU US TO UNDERSTAND THE POTENTIAL FOR LONGEVITY, AND BIOMARKERS THAT ARE TARGETING AGING ITSELF AND IMPROVING OUR CHANCES FOR LONG TERM HEALTHY AGING. SO I'D LIKE TO ACKNOWLEDGE THE STAFF INVESTIGATORS AND STUDY PARTICIPANTS PARTICULARLY OF THESE TWO STUDIES, AS WELL AS THE LONG LIFE FAMILY STUDY, BUT A LOT OF WHAT I'VE LEARNED COMES FROM INTERACTING WITH INVESTIGATORS IN MULTIPLE STUDIES THAT I PARTICIPATE IN. I'M THE P.I. OF THE PITTSBURGH SITE FOR THE HEALTH AGING AND BODY COMPOSITION STUDY, WHICH IS FUNDED BY NIA, AND WE'VE CERTAINLY TRANSLATED A LOT BACK AND FORTH BETWEEN THOSE STU IT DIS. THE FUNDING IS FROM NIA FOR THE ALL-STARS GRANT AS WELL AS FOR THE LONG LIFE FAMILY STUDY AND ALSO ALSO SUPPORTED BY THE WONDERFUL ENVIRONMENT CREATED IN PITTSBURGH BY OUR FUNDING FOR THE PEPPER CENTER. CHS IT SELF IS FUNDED BY CSH. COURTS FROM THIS NATIONAL HEART, LUNG AND BLOOD INSTITUTE. SO THANK YOU. [APPLAUSE] >> QUESTIONS FOR DR. NEWMAN. EVAN, COULD YOU GO TO THE MICROPHONE, PLEASE. ONE THAT WORKS. >> THE HEALTHY INIT DEX FINDINGS YOU HAD, WHEN YOU HAVE A MULTICOMPONENT INDEX LIKE THAT, ONE OF THE QUESTIONS IS, IS A LINKAGE OR ASSOCIATION DRIVEN BY ONE OF THE COMPONENTS. I JUST WONDERED IF YOU'D LOOKED AT HOW TO LOOK AT WHETHER THE OF THE FIVE THINGS IN THE HEALTHY AGING INDEX, WHETHE THE RELATIONSHIP WAS PREDOMINANTLY DRIVEN BY ONE OR A FEW OF THOSE OR IF IT WAS KIND OF ACROSS THE BOARD. >> SO WE DIDN'T SEE THAT IN THE LONG LIFE FAMILY STUDY, BUT IN THE CHARGE CONSORTIUM, WE'RE SEEING POTENTIALLY, THOUGH, I DON'T HAVE THE RESULTS YET THAT GLUCOSE TOLERANCE MAY BE DRIVING A LOT OF IT. BUT IT IS ALSO POSSIBLE THAT MTABOLISM IS UNDER ITLYING ALL OF THIS AS WELL AS AN EXTREMELY IMPORTANT PATHWAY TO HEALTHY AGING AND LONGEVITY. >> DR. HIGH. >> THANKS, ANNA. I THINK IT'S REALLY GOO TO HAVE THIS TALK JUXTAPOSED WITH THE NEXT ONE, I THINK THEY'RE REALLY NICE, WHOLE ORGAN AND CELLULAR LOOK AT THIS. THE QUESTION I HAVE, WHEN I TRY TO EXPLAIN AGING TO SUBSPECIALISTS, WHICH IS WHERE I'VE SPENT MOST OF MY TIME, CHS AND HEALTH ABC, TO GET INTO THOSE, YOU HAD TO NOT HAVE THE PROBLEM, AND SO THEY'RE PRETTY HEALTHY COHORTS. HAVE YOU LOOKED AT YOUR PHYSIOLOGIC COHORTS IN AGING WITH A DOMINANT UNDER ITLYING DISEASE, LIKE HIV, LIKE RENAL DISEASE THAT'S MORE CHRONIC OR RHEUMATOID ARTHRITIS OR THAT KIND OF THING TO TRY TO TEASE OUT THE AGING IN THE PRESENCE OF ONE DOMINANT DISEASE? >> THAT'S A GREAT SUGG, KEVIN. I HAVEN'T. IN CHS AND HEALTH ABC, THEY WERE --CHS INCLUDED PEOPLE WITH PREVALENT CARDIOVASCULAR DISEASE. SO IN THAT CASE, IT'S THE SAME, WHETHER PEOPLE HAVE PREVALENT CARDIOVASCULAR DISEASE OR DO NOT. I THINK FOR THE DISEASES OF AGING LIKE COPD, KIDNEY FUNCTION, ET CETERA, KIDNEY DECLINE, IT PROBABLY WOULD HOLD UP. BECAUSE WHENEVER WE LOOK AT THESE POPULATIONS CLINICALLY, THEY ALL HAVE ALL OF THESE DISEASES IF YOU DO A NONINVASIVE TEST, AND THEY HAVE A SPECTRUM OF THEM. SO I THINK THAT IT WOULD. IF YOU TAKE IT BACK TO HIV, I'M NOT SO SURE. I THINK THAT IN HIV, THE VASCULAR CHANGES HAVE BEEN PREDOMINANT, THE IMMUNE FUNCTION CHANGES, I DON'T HAVE IN HERE, BUT I WOULD LOVE TO DO THAT WITH YOU IF YOU HAVE A COHORT THAT HAS THESE MEASURES. >> DR. BERNARD. >> AGAIN, THANK YOU, VERY NICE PRESENTATION. THERE'S BEEN A LOT OF DISCUSSION ABOUT HOW TO LOOK AT BIOMARKERS OF AGING IN ANIMAL MODELS THAT WOULD BE TRANSFERABLE TO HUMANS AND VICE VERSA. I WAS INTRIGUED BY YOUR SLIDES THAT TALKED ABOUT -- HOW TRANSFERRABLE ARE THE PARAMETERS THAT YOU LOOK AT IN YOUR HEALTHY AGING INDEX TO IT VARIOUS ANIMAL MODELS? >> I THINK THAT MOST OF THEM WOULD BE ACCEPTED SOME ANIMALS ARE NOT SUSCEPTIBLE TO THE SAME PATTERN OF DISEASES, SO IN THE MOUSE MODEL, THE IMMUNE AGING AND THE CANCER PREDOMINATE AND THE VASCULAR DOES NOT. SO BECAUSE DIFFERENT IN AN MA MODELS, THAT MODEL DOESN'T RECAPITUATE TO THE HUMAN, I THINK THAT'S WHERE VERY A LITTLE BIT OF A PROBLEM IN THE TRANSLATION. BUT NEVERTHELESS, THERE ARE ACCELERATED AGING IN ANIMAL MODELS WHERE THEY HAVE SOME OF THE FEATURES. SO YOU PROBABLY NEED TO HAVE A MODEL SPECIFIC SORT OF INDEX OF HOW THEY AGE BECAUSE THEY AGE DIFFERENT THAN HUMAN, I WOULD GUESS. I HAVEN'T TRIED THAT, BUT THAT SOUNDS LIKE FUN. >> DR. SKINNER FIRST, THEN DR. SIERRA. >> I REALLY LIKED YOUR EFFORTS TO PULL OUT THE CO-MORBIDITIES AND TO SEE SOMEHOW THE TRUE EFFECT OF AGING. THERE'S A CONTINUED DECLINE IN MORTALITY FOR THE 65 AND OVER POPULATION. ICAN YOU GET A SENSE OF HOW MUCH OF THAT IS BECAUSE OF THE DECLINE OF THE PREVALENCE OF CERTAIN DISEASES AND HOW MUCH IS PURE EFFECT THAT YOU CAN PULL OUT OF AFTER YOU ADJUST FOR ALL THE CO-MORBIDITY? >> FROM MY READING OF THE LITERATURE, I THINK MOST OF THAT IS -- ESPECIALLY MOST OF IT THAT'S OCCURRING AFTER AGE 65 IS CARDIOVASCULAR DISEASE PREVENTION AND CANCER SCREENING. SO I DON'T THINK WE HAVE EVIDENCE NOW THAT AGING ITSELF IS CHANGING, BUT RATHER THE EXTRINSIC FACTORS THAT ACCELERATE THE CHRONIC DISEASES OF AGING HAVE BEEN MITIGATED AND THIS IS WHAT HAS ALLOWED US TO DO SO MUCH BETTER AND MORE AND MORE PEOPLE ARE ARRIVING TO OLD AGE IN MUCH BETTER HEALTH EVERY GENERATION SO FAR. >> CONTINUING WITH A QUESTION THAT MARIE ASKED, IT IS TRUE THAT DISEASES THAT MICE GET, FOR EXAMPLE, ARE DIFFERENT FROM HUMANS. THAT IS LESS TRUE FOR OTHER SPECIES LIKE DOGS, FOR EXAMPLE, BUT LET'S STAY WITH MICE. BUT ARE YOU SURE THERE WAS NO CORRELATION DIRECTLY BETWEEN -- THAT EVERYTHING IS GOING DOWN, THAT IS TRUE FOR THE MOUSE AS WELL. SO THEY DO GET CARDIOVASCULAR DISEASE, IT'S JUST NOT -- SO THEY DON'T DIE OF THAT. BUT THEY DO GET CARDIOVASCULAR DISEASE, THEY DO GET OTHER DISEASES OF AGING JUST IF YOU LOOK AT THE OLD MOUSE, IT WILL GET MANY MULTI-MORBIDITIES JUST LIKE HUMANS. SO IT'S NOT SO DIFFICULT TO TRANSLATE, IT'S JUST THAT THE GRANULARITY IS SIGNIFICANT. >> YES. SO THE QUESTION THEN WOULD BE, WOULD YOU NEED TO DEVELOP A MODEL-SPECIFIC INDEX OF THE DECLINE IN MULTIPLE SYSTEMS, AND I THINK THAT YOU CAN. >> THAT'S EXACTLY WHAT WE ARE THINKING WE NEED TO DEVELOP. THAT'S EXACTLY WHERE WE'RE GOING. >> THANK YOU VERY MUCH, DR. NEWMAN. [APPLAUSE] >> I HEARD IN FIVE MINUTES THE LUNCHES WILL ARRIVE, IT IS TIME FOR BREAK. >> WE'RE GOING TO RESTART THE MEETING NOW, DR. RON WILL INTRODUCE A THIRD, DR. TOM RANDO DISPL. IT'S A SERIOUSLY GREAT PLEASURE TO INTRODUCE DR. RANDO, PROFESSOR OF NEUROLOGY AT STANFORD UNIVERSITY. HE'S HARVARD-EDUCATED, HE DID HIS INTERNSHIP AT MASS GENERAL HOSPITAL AND RESIDENCY AT UNIVERSITY OF CALIFORNIA-SAN FRANCISCO. HE DID HIS POST -- STARTED POSTDOC AT STANFORD IN 199 AT THE ONE. HE HAS BEEN THERE SINCE. HE IS ALSO AT THE VETERANS' ADMINISTRATION IN PALO ALTO, WHICH I LIKE TO CALL "THE VA AND THE PA." HE'S CHIEF OF SERVICE NEUROLOGY, DIRECTOR OF THE REHAB R & D CENTER, DEPUTY DIRECTOR OF THE STANFORD CENTER ON LONGEVITY, DIRECTOR OF THE GLEN LABORATORIES FOR THE BIOLOGY OF AGING. DESPITE ALL OF THESE MANY ADMINISTRATIVE DUTIES, IF YOU EVER SEND TOM AN EMAIL, YOU'LL GET AN AUTOMATIC RESPONSE THAT HE'S TRAVELING SOMEWHERE AND SIX HOURS LATER, YOU'LL GET THE ACTUAL RESPONSE FROM TOM. I DON'T KNOW HOW HE DOES IT. ON A PERSONAL NOTE, THOSE OF YOU WHO ARE INTERMEDIATE SKIERS, YOU'RE BETTER OFF GETTING ADVICE FROM TOM THAN YOU ARE FROM A SKI INSTRUCTOR. DR. RANDO. >> THANKS, RON. SO IT'S A GREAT HONOR AND PLEASURE TO SPEAK TO THE COUNCIL. ACTUALLY I GAVE ONE WITH OF THESE TALKS MANY, MANY YEARS AGO ON MY FIRST VISIT TO COUNCIL. IT WAS MY INTRODUCTION TO THE INNER WORKINGS OF THE NIH. NOW I'M A LITTLE MORE INSIGHTFUL ON HOW THINGS WORK AND IT'S A GREAT PLEASURE TO COME BACK NOW AND TALK ABOUT WORK THAT'S EVOLVED OVER THAT TIME. SO WHAT I'LL TALK ABOUT TODAY IS OUR WORK IN THE AREA OF BIOLOGY OF AGING, PARTICULARLY RELATING TO STEM CELL BIOLOGY. INTERESTINGLY, YOU'LL HEAR ECHOS OF BOTH OF THE TALKS FROM THIS MORNING, I THINK. AS RON MENTIONED, I'M A CLINICIAN, I OBVIOUSLY THINK ABOUT AGING OF INDIVIDUALS, BUT I WILL BE DIGGING WAY DOWN OH CELLULAR AGING TODAY, BUT KIND OF TRYING TO KEEP A BROAD PERSPECTIVE ON THIS AS WELL. SO I'M GOING TO INTRODUCE EPIGENETICS BECAUSE I KNOW NOT EVERYONE HERE LIVES AND BREATHS IT, JUST A VERY GENERAL SENSE OF WHAT IT IS AND HOW WE'LL TALK ABOUT IT. THIS IS KIND OF THE GENERAL DEFINITION OF EPIGENETICS, CELLULAR AND PHYSIOLOGIC TRAIT VARIATIONS THAT ARE NOT CAUSED BY CHANGES IN DNA SEQUENCE. THERE ARE MANY WAYS TO IT ILLUSTRATE THAT. I'VE SHOWN ONE HERE. SO YOU HAVE TWO CELLS IN A BODY, A NEURON AND A MUSCLE FIBER, EACH IF YOU TAKE THE DNA OUT, IT HAS EXACTLY THE SAME SEQUENCE, BUT FROM THE EXACT SAME CODE YOU GET TWO VASTLY DIFFERENT CELL TYPES. SO IT'S ONE OF THE GREAT MYSTERIES OF BIOLOGY AND THE EPIGENETIC, IT'S HOW THAT DNA SEQUENCE IS READ. SO WHAT WE'RE INTERESTED IN IS HOW YOU CAN CHANGE READING OF THE DNA TO IT GET VERY DIFFERENT FEE FOE TYPES, AND THIS IS THE OBLIGATORY WEDDINGTON'S LANDSCAPE IN EPIGENETICS, THE IDEA THAT YOU START WITH A CELL, AS IT DIFFERENTIATES, AS AN ORGANISM DEVELOPS, YOU DEVELOP ALL THESE DIFFERENT TISSUES FROM A SINGLE CELL. THIS BALL SORT OF ROLLS DOWN, IF IT ROLLS DOWN TO THIS, THE CELL BECOME AS BLOOD CELL, IF IT ROLLS DOWN HERE, IT'S A NEURON, IF IT ROLLS DOWN HERE, IT'S A HEART CELL, SO BASICALLY STARTING FROM THE SAME., AND DEPENDING ON HOW THE GENOME IS READ, YOU END UP WITH VERY, VERY DIFFERENT CELL OUTCOMES. BUT I'M GOING TO TALK ABOUT THIS IN TERMS OF AGING. AT LEAST THESE ARE IDEAS ON HOW WE MAY THINK ABOUT AGING AND HOW WE MAY, IN FACT, ALTER AGING IN CELLS AND TISSUES. SO WHAT WE'RE INTERESTED IN IS REALLY CHANGES IN AN INDIVIDUAL YOUNG MALE GOING TO AN OLDER MALE, OBVIOUSLY THERE'S MORE THAN JUST AGING BECAUSE THE PERSON HAS TO DEVELOP AND GROW, BUT THERE IS ONE THING I THINK THAT IS KIND OF MONO IT TONICALL CHANGING EVEN FROM A YOUNG TO IT OLD PERSON, AND THAT'S THE ABILITY OF TISSUES TO REPAIR THEMSELVES. FETUSES, EMBRYOS, NEWBORNS HAVE REMARKABLE REGENERATIVE CAPACITY. AND THAT REGENERATIVE CAPACITY IN RESPONSE TO AN INJURY OR EVEN HOMEOSTATIC MECHANISMS, DECLINING MONO TO NICKLY WITH AGE. WE'RE VERY INTERESTED IN THIS IDEA OF LOOKING AT HOW TISSUES REPAIR THEMSELVES WITH A FOCUS OF STEM CELL BIOLOGY AND HOW THAT CHANGES WITH AGE AND HOW THAT'S RELATED TO EPIGENETICS. SO THE IT TISSUE THAT I'LL TALK MOSTLY ABOUT TODAY IS SKELETAL MUSCLE, AND WE STUDY THE STEM CELLS IN SCREL TALL MUSCLE IP CREDIBLY POTENT IN TERMS OF REPAIRING MUSCLE WHEN IT'S INJURED. SO HERE'S A CROSS-SECTION OF NORMAL SKELETAL MUSCLE FROM A MOUSE, BUT THIS WOULD BE TRUE IN HUMANS AS WELL. AFTER A TOTAL DESTRUCTIVE INJURY FROM A TOXIN OR A CRUSH, YOU COMPLETELY DESTROY THAT ARCHITECTURE, BUT THE VERY FEW STEM CELLS PRESENT IN THIS TISSUE AT REST, THEY START TO ACTIVATE, PROLIFATE, THEY MAKE A LOT MORE CELLS, THEY ULTRAPATLY GIB TULTIMATELY BEGIN TO DIFFERENTIATE, THEY'LL GROW AND EXPAND AND MAKE NEW NUSS MUSSEL. MUSCLE. YOU CAN DO THIS OVER AND OAF AND MUSCLE CAN IT CONTINUE TO REPAIR IT SELF IN RESPONSE TO INJURY. BUT THAT CHANGES WITH AGE. WHAT I'VE ILLUSTRATED HERE IS FROM MICE OF DIFFERENT AGES. SO A YOUNG MOUSE, AN OLD MOUSE, EQUIVALENT TO A 70-YEAR-OLD HUMAN, AND A VERY OLD MOUSE, LIKE A 90 OR 100-YEAR-OLD HUMAN, LOOKING AT THIS REGENERATIVE PROCESS IN MUSCLE. YOU SEE THIS DECLINING REGENERATIVE POTENTIAL. SO HERE YOU SEE THESE NEW MUSCLE FIBERS BEING FORMED AFTER AN INJURY, IN A YOUNG MOUSE, FEWER FIBERS AND MORE OF THIS CONNECTIVE TISSUE OR SCARRING, WHICH IS ONE OF THE CHARACTERISTICS OF REGENERATIVE TISSUE IN OLD INDIVIDUALS, TO IT A VERY OLD ANIMAL WHERE THERE'S A LOT MORE SCAR TISSUE AND MUCH LESS MUSCLE. SO THIS IS CLEARLY A DECLINING REGENERATIVE POTENTIAL AND WE THINK THIS IS RELATED TO DECLINING FUNCTIONALITY IN STEM CELLS IN THIS TISSUE AS WELL AS OTHER TISSUES SMS MANY YEARS AGO, A POSTDOC IN MY LAB DID THIS EXPERIMENT THAT REALLY CHANGED THE WAY I THINK ABOUT THE BIOLOGY OF AGING THIS IS FAIRLY SIMPLE, PRODUCING A SINGLE SMALL INJURY TO MUSCLE WHICH IS SHOWN HERE IN AN OLD MOUSE. YOU SEE AGAIN THIS KIND OF IMPAIRED REGENERATION, A LOT OF SCARRING. BUT AT THE SAME TIME SHE PRODUCED THAT INJURY IN AN OLD ANIMAL, SHE INTRODUCE ADD MOLECULE THAT ACTIVATED THIS SIGNALING PATHWAY, THE NOTCH PATHWAY, SHE COULD GET ESSENTIALLY NORMAL REGENERATION, THE SAME AS WE SEE IN A YOUNG ANIMAL. SO THIS SAID TO US THAT IN AN OLD ANIMAL, THE STEM CELLS THAT ARE THERE, THE FACTORS THAT ARE THERE ARE CAPABLE IF GIVEN THE RIGHT SIGNALS TO REGENERATE JUST AS WELL AS A YOUNG ANIMAL. SO THAT REALLY SAID THAT THIS PROCESS THAT LOOKS IRREVERSIBLE AND INEVITABLE AT LEAST IS MAIL I CAN'MALEABLE, TO MAKE AN OLD TISSUE BEHAVE LIKE A YOUNG TISSUE. SO THAT STARTED US DOWN THIS LINE SAYING IT IF YOU CAN REVERT THIS AGE TO YOUNG, MAYBE THIS IS SOMETHING THAT IS TRULY EP YES EPIGENETICALLY ENCODED, TO ASK THIS IN A MORE GENERAL WAY, WE TOOK THIS APPROACH OF USING A WHOLE ANIMAL APPROACH TO IMPROVING OLD TISSUE REPAIR, AND WE REVISED THIS TECHNIQUE OF PARAA BIOSIS WHICH HAS BEEN AROUND FOR 150 YEARS TO LOOK AT AGING. IT HAD BEEN USED TO IT LOOK AT AGING OVER THE MANY, MANY DECADE BUT HADN'T BEEN USED SINCE THE EARLY 1970s, AND THE WAY THIS TECHNIQUE WORKS IS THIS. WE CONNECT COULD ANIMALS TOGETHER SO THEY SHARE A CIRCULATORY SYSTEM. ONE ANIMAL HAS BEEN EXPOSED TO THE CIRCULATING ENVIRONMENT OF THE OTHER ANIMAL. THESE ARE THE TWO CONTROL CONDITIONS SO AN OLD ANIMAL CONNECTED TO A YOUNG ANIMAL AND OLD TO IT OLD. ISOCHRONIC PAIRS. THE INTERESTING PAIRING, OLD ANIMAL CONNECTED TO A YOUNG ANIMAL, SO NOW YOU HAVE THIS OLD MOUSE BEING EXPOSED TO THE CIRCULATING ENVIRONMENT OF THE YOUNG ANIMAL UP TO, SAY, A COUPLE OF MONTHS. AND THE QUESTION IS NOW, WHAT IS THIS INFLUENCE OF THE YOUNG ON TOLD OR THE OLD ON THE YOUNG AFTER THESE MONTHS, HOW DO THESE CELLS NOW CHANGE IN RESPONSE TO THIS EXPOSURE. SO IF WE DO THIS PAIRING AND INJURE THE MUSCLE, THE YOUNG REGENERATE WELL, THE OLD REGENERATE POORLY, THIS IS A SCAR HERE. IF WE LOOK AT THESE HETEROCHRONIC PAIRS WHERE WE INJURE THE MUSCLE OF THE OLD ANIMAL, WE CAN SEE THE OLD ANIMAL REPAIRS AS WELL AS THE YOUNG ANIMAL. SO CLEARLY, AGAIN, BY EXPOSING OLD TISSUE TO THE YOUNG ENVIRONMENT, THEY CAN NOW REPAIR JUST AS WELL AS YOUNG. WE LOOKED AT SKIN, LIVER, INITIALLY AT BRAIN, AND THIS IS A PAPER WE DID IN COLLABORATION WITH TONY WEISS, A COLLEAGUE AT STANFORD, AGAIN LOOKING AT BRAIN REJUVENATION IN TERMS OF NEUROGENESIS AFTER HETEROCHRONIC PARABIOSIS. EACH OF THESE DOTS IS A NEW NEURON BEING FORMED THIS IS IN A YOUNG ANIMAL, MUCH LESS IN AN OLD ANIMAL, BUT THEN IN RESPONSE TO THIS HETEROCHRONIC PAIRING, WE SEE -- JUST BY EXPOSURE TO THE YOUNG ENVIRONMENT OF THE YOUNG MOUSE. THIS WAS FOLLOWED UP A COUPLE YEARS LATER BY THE STUDY IN WHICH WE'RE DOING ROUTINELY OF NOT DOING PARABIOSIS BUT ACTUALLY TRANSFERRING YOUNG PLASMA INTO OLD ANIMALS AND ASKING DO WE SEE THE SAME THING AS WITH THE HETEROCHRONIC PARABIOSIS AND THE ANSWER IS YES. IF WE PUT YOUNG PLASMA INTO -- WE CAN ENHANCE THE FUNCTION OF THESE OLD TISSUES, YOUNG PLASMA INTO OLD ANIMALS, WE CAN SUPPRESS THE FUNCTION OF THE YOUNG TISSUES. SO THERE REALLY SEEM TO BE THESE CIRCULATING FACTORS THAT ARE PRESENT IN BLOOD THAT ARE REMARKABLY INFLUENCING AND INTEGRATING IN A SENSE THE PROCESS OF AGING AT LEAST OF THESE STEM CELLS, AND THEN SOME DIFFERENTIATED TISSUE THAT WE'VE LOOKED AT. SO THIS HAS BEEN NOW REPEATED IN MANY TISSUES USING THIS HETEROCHRONIC PARABIOTIC PARADIGM, WE LOOKED AT LIVER, MUSCLE, BRAIN, SITES IN THE CNS, BETA CELLS IN THE PANCREAS, CARDIAC TISSUE, AND BRAIN VASCULATURE. SO AGAIN, THIS SEEMS TO BE QUITE A ROBUST I PHENOMENON THAT EXPOSING YOUNG ANIMALS TO AN OLD ENVIRONMENT CAN RESTORE A YOUTHFUL ENVIRONMENT TO THESE OLD TISSUES. SO WE AND OTHERS HAVE LOOKED FOR FACTORS IDENTIFYING THINGS THAT CHANGE WITH AGE THAT ACTUALLY MAY HAVE SOME OF THESE EITHER YOUTHFUL PROMOTING EFFECTS OR AGE PROMOTING EFFECTS. SOME OF THESE ARE LISTED HERE. IF I HAVE TIME AT THE IT END, I'LL TALK ABOUT SOME WORK WE'RE DOING AGAIN IN COLLABORATION WITH TONY LOOKING AT HOW EXERCISE AND HOW WE CAN LOOK THE AT FO FACTORS MAY ALSO RELATE TO THIS IDEA OF FACTORS THE IN THE BLOOD THAT INTEGRATE THE BIOLOGY OF AGING. SO THIS REALLY IS THE QUESTION WE'RE ASKING, IS AGING REVERSIBLE, ARE WE, IN FACT, MOVING OLD CELLS ALONG AN AGING AXIS OR ARE WE JUST ENHANCING THEIR FUNCTION? SO REALLY THIS GETS TO THE QUESTION OF CAN WE DEFINE AT A MOLECULAR LEVEL WHAT A CELLULAR AGE IS? BECAUSE ARE WE MOVING ALONG AN AGING AXIS OR ARE WE JUST CHANGING NATE TOUR OF THESE CELLS? THE ONLY WAY WE'LL KNOW THAT IS BY DEFINING CELLULAR AGE AT A MOLECULAR LEVEL. AND SO TO ANSWER THIS QUESTION, WE'VE BEEN THINKING A LOT ABOUT WHAT IT MEANS TO REJUVENATE A CELL. WE'VE KIND OF TAKEN A PAGE FROM A COUPLE DIFFERENT BOOKS. SO FIRST THE IPS FIELD, INDUCED PLURIPOTENCY FIELD, WHICH HAS REALLY REVOLUTIONIZED STEM CELL BIOLOGY. YOU TAKE A IT DIFFICULT RIN SHAITED CELL AND BY EXPOSING IT TO CERTAIN FACTORS GIST LIKE WE DO, YOU MAKE THAT CELL PLEUR OWE POTENT, SO YOU'VE KIND OF REVERTED ALL OF THE DIFFERENTIATION CHARACTERISTICS, YOU'VE ERASED THEM, NOW YOU HAVE A TOTALLY UNDIFFERENTIATED CELL THAT CAN REDIFFERENTIATE THAT CAN MAKE TISSUES, THAT CAN MAKE A MOUSE. THIS IS ENTIRELY EPIGENETIC. THE IT DNA IS NOT CHANGING. IT'S JUST CHANGING THE WAY THAT DNA IS READ TO GOING FROM A DIFFERENTIATED CELL TO A TOTALLY UNDIFFERENTIATED CELL. THE INTERESTING THING TO US IS THAT ACTUALLY IT TET, THERE'S A PROMINENT REJEUF RANGE OF MOTION RECURRING IN THIS PARADIGM THAT I WOULD SAY IS INTRINSIC TO THIS PROCESS OF EP GENETICS. SO YOU TAKE A CELL THAT'S NOT ONLY DIFFERENTIATED BUT IT HAS SOME AGE TO IT. HOWEVER YOU MEASURE THIS AGE, THIS IS OBTAINED FROM AN ADULT ANIMAL, YOU THEN CONVERT IT TO A CELL THAT WOULD BE EQUIVALENT TO A CELL THATS THAT AN AGE OF ZERO, A CELL THAT'S STARTING OVER AGAIN TO MAKE A NEW ANIMAL. YOU CAN DO THIS OVER AND OVER AND OVER AGAIN. SO CLEARLY, THERE'S A COUPLING BETWEEN THESE TWO PROCESSES, AND IT REALLY IS AN EPIGENETIC REJUVENATION. IN FACT, I WOULD ARGUE THAT THIS IS SO EMBEDDED IN OUR UNDERSTANDING OF BIOLOGY THAT WE REALLY DON'T PAY ATTENTION TO AN EPIGENETIC REJUVENATION HAPPENS ALL THE TIME. THIS IS A FERTILIZED EGG. OBVIOUSLY IF YOU THINK ABOUT THIS, YOU TAKE TWO CELLS THAT HAVE SOME AGE, HOWEVER YOU WANT TO MEASURE IT, SAY IN HUMANS, DECADES OLD, A SPERM AND AN EGG, TWO CELLS HIGHLY DID HAVE DIFFERENTIATED WITH SOME AGE, YOU GET FERTILIZATION, WHAT YOU GET IS A CELL THAT'S NOT ONLY TOTALLY UNDIFFERENTIATED, BUT A CELL THAT IS NOW STARTING OVER AGAIN IN TERMS OF THE BIOLOGY OF AGING. IT'S NOW, AGAIN, RESET THAT CLOCK BACK TO ZERO BECAUSE IT IF IT WEREN'T THE CASE, WITH EVERY GENERATION, OUR CHILDREN WOULD INHERIT SOME ASPECTS OF THE AGE OF OUR CELLS. THE AGE OF OUR SPERM AND EGGS. AND THAT DOESN'T HAPPEN. SO CLEARLY, IF IT WEREN'T POSSIBLE TO ERASE AGING MARKS, WE WOULDN'T HAVE THE ABILITY TO HAVE SUCCESSIVE GENERATIONS, WE WOULD ESSENTIALLY AGE OURSELVES INTO EXTINCTION. SO THIS IS SOMETHING THAT NATURALLY OCCURS AND OUR QUESTION IS WHETHER THE BIOLOGY WE'RE LOOKING AT IS SOMETHING LIKE THIS. ARE WE LOOKING AT SOMETHING THAT IS TRULY A REJUVENATION AT THE LEVEL OF THE EPIGENOME. SO CAN A CELL BE EPIGENETICALLY REPROGRAMMED TO A YOUNG CELL. SO I'M GOING TO SHOW A LITTLE BIT OF DATA, BUT WE'VE LOOKED AT THIS BY LOOKING AT BOTH THE MESSENGER RNAs THAT ARE PRODUCED IN OLD AND YOUNG CELLS AS WELL AS THE EPIGENOMES. THIS IS LOOKING AT ALL OF THE TRANSCRIPTS FROM A GROUP OF OLD CELLS, A GROUP OF YOUNG CELLS AND A GROUP OF CELLS THAT HAVE BEEN ISOLATED FROM THESE HETEROCHRONIC PARABONDS. -- MORE LIKE EACH OTHER BECAUSE THESE ARE CLUSTERED TOGETHER TO BE THE CELLS MORE SIMILAR TO ONE ANOTHER, THEY'RE MORE LIKE EACH OTHER THAN THEY ARE EITHER LIKE THE YOUNG OR OLD CELLS. SO THERE'S SOMETHING THAT'S CHANGING THESE CELLS THAT'S MAKING THEM MORE SIMILAR, AND I THINK THIS IS MORE CLEARLY SHOWN BY THIS PRINCIPLE COMPONENT ANALYSIS WHICH USES AN UNBUYS ASSED WAY TO SAY WHAT'UNBIASEDWAY -- YOUNG CELLS CLUSTER UP HERE, OLD CELLS CLUSTER DOWN HERE. SO CLEARLY WE LOOK AT THIS AS LIKE AN AGING ACCESS. THE YOUNG CELLS CLUSTER TOGETHER, THE OLD CELLS CLUSTER TOGETHER. WHEN WE LOOK AT THE CELLS FROM THE HETEROCHRONIC BARE A BONDS, THEY ALWAYS FALL INTERMEDIATE ON THIS AGING AXIS, RIGHT IN BETWEEN INTERESTINGLY, AND THEN DISPLACED OFF THIS AXIS BECAUSE OF THE EFFECTS OF THE EXPERIMENT ITSELF, SO WE SEE THIS DISPLACEMENT IF WE DO THIS KIND OF EXPERIMENT, BUT WE ALWAYS SEE THEM FALLING THIS WAY AS IF THE OLD CELLS ARE GUL -- IS THERE REALLY AN EPIGENETIC SIGNATURE? THIS IS WHAT WE WORK ON NOW. IS THERE REALLY SOME WAY THAT WE CAN TAKE AN OLD CELL, MEASURE SOMETHING IN THE EPIGENOME AND SAY, OKAY, THIS CELL IS REALLY MORE LIKE A YOUNG CELL AT A MOLECULAR LEVEL. I'LL PRESENT JUST A LITTLE BIT OF DATA WHICH IS RELATIVELY NEW DATA THAT WE'VE BEEN GETTING ON THIS. ONE IS TO LOOK AT METHYLATION OF DNA, BUT ANOTHER WAY IS TO LOOK AT MODIFICATION OF PRODUCING HISTONES, DNA IS WRAPPED AROUND THESE -- IT'S ALWAYS WRAPPED AROUND THESE PROTEIN COMPLEXES. AND WHAT'S KNOWN IS THAT THESE PROTEIN COMPLEXES UNDERGO MANY, MANY KINDS OF MODIFICATIONS. THE METHYLATION, ACETYLATION, PHOSPHORYLATION, AND THOSE CHANGES ARE WHAT REALLY -- DECIDE HOW THE GENOME IS READ. SO BY INDUCING A METHYLATION ON ONE AMINO ACID, AN ACETYLATION ON ANOTHER IN THESE HIS TOARNTION YOU CAN CHANGE THE SITUATION WHERE THE DNA IS SILENCED OR READ, AND THAT CAN REALLY BE -- IT'S A CRITICAL ISSUE IN DETERMINING HOW A CELL PHENOTYPE IS DETERMINED, AGAIN, WHETHER THAT CELL IS A LYMPHOCYTE OR A NEURON OR CARDIOMYOCYTE. SO WE'VE LOOKED AT A LOT OF THESE MODIFICATIONS ON HISTONES TO ASK, DO WE SEE DIFFERENCES IN THE EPIGENETIC STATE BETWEEN YOUNG AND HOLD CELLS, AND INDEED WE DO. I'M GOING TO SHOW YOU ONE, TRY METHYLATION OF LYSINE 27 ON HISTONE 3. SO A VERY SPECIFIC MARK BUT VERY WELL STUDIED TO BE SHOWN TO BE ASSOCIATED WITH REGIONS OF GENOME THAT ARE NOT EXPRESSED, SO A KIND OF REPRESSIVE MARK. WE LOOKED ACROSS THE WHOLE GENOME, LOOKING AT THE ENRICHMENT OF THIS MARK FROM EITHER YOUNG CELLS OR OLD CELLS, AND WHAT WE FIND IS THAT THIS REALLY IS A STRIKING CHARACTERISTIC OF OLD CELLS TO HAVE THIS HUGE INCREASE IN THIS OPPRESSIVE MARK ACROSS THE GENOME. SO IT REALLY SEEMS LIKE A -- WE LOOK AT THIS IN DIFFERENT WAYS -- QUITE A SPECIFIC MARK OF CELLULAR AGING IN THIS STEM CELL POPULATION. WE'VE ALSO LOOKED AT DNA METHYLATION, WE LOOK AT THE AMOUNT OF METHYLATION FROM MICE OF DIFFERENT AGES, WE SHOW A MONO TONIC CHANGE OF METHYLATION ACROSS THE GENOME, MOST OF THE REGIONS WE LOOKED AT ARE HYPERMETHYLATED, A FEW INTERESTING REGIONS ARE HYPOMETHYLATED, BUT MOST SEE A GRADUAL INCREASE OF METHYLASE. THIS COMPARISON OF REPRE SIEVE MARK I MENTIONED AND DNA METHYLATION, WHICH CAN BE EITHER REPRREPRESSIVE OR INDUCING OF EXPRESSION, WE SEE DIFFERENT PATTERNS WHETHER THAT REGION HAS A HIGH AMOUNT OF TRY METHYLATION OR A LOW AMOUNT OF TRIMETHYLATION IN ADDITION TO DNA METHYLATION. SO THE POINT IS THAT WE SEPA TERNS THAT EVOLVE DURING AGING THAT ARE VERY CLEARLY OCCURRING WITH AGING AND WHEN WE LOOK NOW AT OUR HETEROCHRONIC PARABONDS, WT WE'RE SEEING PRELIMINARILY THAT THESE ARE BEING REVERTED BACK TO A MORE YOUTHFUL STATE. SO THAT'S WHAT WE WERE HYPOTHESIZING AND ARE TRYING TO NOW UNDERSTAND WHICH CHANGES OCCURRING WITH AGE ARE FUNCTIONALLY IMPORTANT AND WHICH ONES ARE BEING REVERTED IF WE'RE COING THESE CELLS FROM A YOUNG STATE TO AN OLD STATE OR CONVERSELY. SO BACK TO KIND OF THINKING ABOUT THIS FROM AN EPIGENETIC POINT OF VIEW, OBVIOUSLY THIS IS GOING FROM AN UNDIFFERENTIATED TO DIFFERENTIATED STATE, ARE THERE ALSO EPIGENETIC PROCESSES MOVE DOWN THIS PATHWAY FROM A YOUNG STATE TO AN OLD STATE, AND JUST AS IPS TECHNOLOGY CAN MOVE THE CELLS BACKWARD ALONG THIS AXIS, WE'RE WONDERING WHETHER WE CAN ACTUALLY MOVE CELLS AND IT TISSUES BACKWARD ALONG THAT ACCESS. -- TO MAKE AN OLD CELL MORE LIKE A YOUNG CELL. WHAT WE'RE LOOKING AT IS STEM CELL BIOLOGY AND THE ABILITY TO REPAIR TISSUES AND OUR QUESTION IS, IF WE UNDERSTAND THESE EPIGENETIC STATES, CAN WE MAKE OLD CELLS BEHAVE MORE LIKE YOUNG CELLS IN THE SETTING OF TISSUE INJURY. SO THIS IS NOT ABOUT LIVING LONGER OR REJUVENATING INDIVIDUALS, BUT CAN YOU TAKE SOMEONE WHO HAS HAD A SKIN INCISION THAT'S NOT HEALING AND INDUCE THE STEM CELLS IN THAT TISSUE IN A TEMPORAL AND SPAISHT SPECIFICALLY WAY TO NOW REPAIR WELL, OR A BONE FRACTURE, NATISH EU IN AN AGING INDIVIDUAL WHICH RELIES ON STEM CELL FOR REGENERATION AND REPAIRS POORLY, CAN WE REJUVENATE THAT STEM CELL FUNCTION AND CAN WE ENHANCE TISSUE REPAIR IN AN OLD INDIVIDUAL TO MAKE THAT AS EFFECTIVE AS A YOUNG INDIVIDUAL? A FEW MORE MINUTES, TURN NOW TO ANOTHER SUBJECT THAT IS RELATED AND ACTUALLY RELATES TO IT A QUESTION THAT STEVE ASKED EARLIER DURING THE TALK EARLIER TODAY, AND THAT; WE KNOW THERE ARE A LOT OF HEALTH BENEFITS OF EXERCISE BUT CAN WE THINK OF THESE BENEFITS ALSO IN THE CONTEXT OF THIS IDEA THAT THERE ARE FACTORS IN THE BLOOD THAT CHANGE WITH EXERCISE, SO WE THINK OF THIS VERY MUCH THE SAME WAY WE THINK OF AGING, WE'RE LOOKING AT SYSTEMIC INTEGRATION OF TISSUE HEALTH, IN THIS KAY, WAYWAY,WHY IS EXERCISE BENEFICIAL FOR SO MANY DIFFERENT TISSUES. FUNDED BY IT DAB AND DN HERE, SO IT'S WITH TONY, MY COLLEAGUE, TO STUDY THIS IDEA OF EXERCISE FACTORS AND HOW THAT AFFECTS DIFFERENT TISSUES BUT IN PARTICULAR, THE BRAIN, WHICH IS WHAT I'LL TALK ABOUT TODAY. SO THE IDEA HERE IS THAT YOU HAVE MUSCLE, WHICH IS OBVIOUSLY IMPORTANT FOR MOVEMENT, BUT IS ALSO INCREASINGLY BECOMING RECOGNIZED AS AN ENDOCRINE TISSUE, SO THERE ARE FACTORS MADE IN MUSCLE, SECRETED, THAT APPEAR TO HAVE A VERY PRO HEALTH EFFECT, KIND OF ANTI-INFLAMMATORY EFFECT, AND THEN THEY'RE TERMED MYOKINES, SO AS OPPOSED TO OR IN CONTRAST TO ADIPOKINES INDUCED FROM FLAT. SO THE QUESTION IS IS EXERCISING MUSCLE INTRODUCING PROTEINS THAT ARE BEING SECRETED THAT ARE CIRCULATING AND HAVING BENEFICIAL EFFECTS. WHAT WE'RE PARTICULARLY ASKING IS WHETHER THAT HAPPENS IN TERMS OF THE BENEFICIAL EFFECTS WE SEE ON NEUROGENESIS AS WELL AS COGNITIVE FUNCTION. SO AGAIN, WE'RE DOING THIS IN COLLABORATION WITH TONY LOOKING AT LEARNING AND MEMORY, NEUROGENESIS AS WELL AS BRAIN IFLINFLAMMATION IN RESPONSE TO EXERCISE. THIS IS ALL AT THIS POINT BEING DONE WITH MICE, BUT WE HAVE OTHER STUDIES BEING DONE WITH HUMANS AS WELL, AND WE'LL LOOK AT THIS AND SEE IF THIS IS TRUE. THE LESS EXERCISE, MORE EXERCISED MICE, DIFFERENT READOUTS CORRELATING THAT IN PARTICULAR WITH FACTORS THAT WE FIND IN BLOOD. SO THIS IS JUST THE EXPERIMENTAL SETUP, SO KEVIN -- WHO ASKED CAN YOU EXERCISE MICE? STEVE ASKED. SO YOU CAN DEFINITELY EXERCISE MICE, NOT ONLY CAN YOU EX-ARE EXERCISE THEM, BUT THEY'RE NOCTURNAL, THEY WILL RUN AT NIGHT, THEY WILL RUN KILOMETERS AT NIGHT, A SINGLE MOUSE. WE HAVE THEM ON COMPUTERIZED WHEELS SO WE CAN ACTUALLY TRACK HOW MUCH EACH INDIVIDUAL MOUSE RUNS. I WANTED TO THROW IN THIS ONE POINT, PEOPLE HAVE ARGUED FOR A LONG TIME WHETHER THIS IS A SUL THING THAT MICE RUN BECAUSE THEY'RE UNDER STRESS AND THEY SEE THIS WHEEL, BUT IN FACT, WHAT THIS GROUP DID, I THINK FROM THE NETHERLANDS, THEY PUT A WHEEL IN THE WILD. AND MICE CAME TO THE WHEEL AT NIGHT AND RAN ON THE WHEEL. [LAUGHTER] SO I FIGURED SOMETHING LIKE GOLD'S GYM OR SOMETHING MUST LOVE THIS, THEY'LL SAY THIS IS REVOLUTIONARY, PEOPLE WANT TO RUN ON TREAD MILLS. BUT IT WAS TRULY AMAZING, THESE MICE WOULD COME AND THEY'D RUN AND RUN AND RUN ON THESE WHEELS. SO WE THINK OUR MICE ARE RUNNING BECAUSE THEY ENJOY IT. SO THIS IS -- ELISSA MENTIONED THIS EARLIER, IF YOU EXERCISE MICE, YOU INDUCE NEUROGENESIS IN THE HIPPOCAMPUS, SO WE'VE SHOWN THAT HERE. WWE'VE BEEN LOOKING MORE QUANTITATIVELY, WE SEE THIS DOSE-RESPONSE CURVE THAT THE MORE EXERCISE, THE MORE NEUROGENESIS THEY GET, AND WE THEN TAKE THE BLOOD FROM THESE ECK EXERCISED MICE AND WE LOOK AT WHAT THE PROTEIN PATTERN IS. SO WE USE CUSTOMIZED PROTEIN ARRAYS, LOOKING AT HUNDREDS OF PROTEINS AND ASKING HOW DO THEY CHANGE IN RESPONSE TO EXERCISE AND CAN WE CORRELATE THE CHANGES IN LEVELS IN THE BLOOD WITH CHANGES IN NEUROGENESIS IN PARTICULAR. SO AGAIN, THIS IS ALL VERY RECENT DATA, SO WE'RE JUST PICKING OUT PROTEINS THAT CHANGE, THESE ARE THE CONTROLS, THESE ARE THE EXERCISE MICE, SOME GO UP, SOME GO DOWN, AND WE'RE LOOKING AT THE ONES THAT CHANGE IN EITHER DIRECTION THAT MAY ENHANCE OR MAY BE CORRELATED WITH CHANGES IN NEUROGENESIS. SO WE'RE LOOKING FOR KIND OF THIS INTERSECTION FOR THOSE PROTEINS THAT ARE BOTH EXERCISE-RESPONSIVE AND RELATED TO NEUROGENESIS. AND THEN WE CAN NOW DID BAC GO BACK AND PICK SOME OF OUR TOP HITS AND INTRODUCE THEM INTO OLD MICE AND ASK ARE WE ENHANCING NEUROGENESIS BY THE ADMINISTRATON OF SINGLE FACTORS. SO SORT OF LIKE WHAT WE DO WITH THE PARABIOSIS, WE LOOK FOR INDIVIDUAL FACTORS THAT CHANGE AND ASK, ARE THEY AGING PACK TORES OR PRO YOUTHFUL FACTORS N OUR CASE, WE'RE LOOKING FOR EXERCISE FACTORS, BUT I THINK THERE'S GOING TO BE A STRONG OVERLAP BY FACTORS WE SEE INCREASING WITH EXERCISE, ENHANCING FUNCTION IN THE OLD TISSUE AND WHAT WE SEE IN THE SETTING OF THESE PARABIOTIC PAIRINGS, WE SEE A LOT OF THE SAME PROTEINS POP UP IN THESE TWO ANALYSES. SO WE'RE COMING BACK NOW AND LOOKING NOT ONLY AT NEUROGENESIS BUT DOING A LOT OF STUDIES OF LEARNING AND MEMORY SO BRAL TEST, THEN LOOKING AT OTHER MARKERS OF BRAIN INFLAMMATION, AT THE SAME TIME WE'RE LOOKING AT OTHER TISSUES, OBVIOUSLY AT MUSCLE, THE ABILITY OF MUSCLE FACTORS TO ACTUALLY IMPROVE MUSCLE FUNCTION, WITH WHICH IT SEEMS TO DO, AND THEN WE'RE LOOKING ALSO AT ITS EFFECTS ON ADIPOSE IT TISSUE AS WELL AS OTHER TISSUES IN THE BODY. SO I'LL END THERE ACKNOWLEDGING THE PEOPLE IN MY GROUP. I MENTIONED MY CLOSE COLLABORATION WITH TONY, ANOTHER CONTACT AT STANFORD LOOKING CLOSELY AT EP HE GENETICS AND AGE AGING SHE LOOKS AT NEURAL STEM CELLS IN PARTICULAR. I CERTAINLY WANT TO ACKNOWLEDGE THE FUNDING FROM THE NATIONAL ITE ON AGING, FUNDED ACTUALLY ALL OF THIS WORK. WE'VE GOTTEN ALSO FUNDING FOR SOME OF THIS WORK IN THE GLEN FOUNDATION AND THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE. SO WITH THAT, I'LL STOP AND TAKE ANY QUESTIONS. >> THE SUPPOSE THE FIRST THING WAS WERE MICE THE ONLY THING TO EXERCISE ON THAT WHEEL. >> ACTUALLY, NO. THERE WERE FROGS -- ABOUT FIVE OR SIX DIFFERENT SPECIES -- FROGS CAME AND JUMPED ON THE WHEEL. THEY WERE COMPETING AT TIMES, RUNNING ON THE SAME WHEEL. >> QUESTIONS FOR DR. RANDO. DR. HEIN. >> THANKS, TOM. AS ALWAYS, THAT WAS IT REALLY GOOD. I SHOULD PROBABLY KNOW THE ANSWER TO THIS, BUT IN DIETARY RESTRICTION, I'VE DONE VERY FEW OF THOSE STUDIES BUT I'VE DONE A FEW, AND THOSE MICE ARE RUNNING EVERYWHERE. THEY ARE REALLY LOOKING FOR FOOD FOOD. HAS ANYBODY EVERY STOPPED THEM FROM RUNNING AROUND TO SEE IF DIETARY RESTRICTION ACTUALLY WORKS INDEPENDENT OF THE ACTIVITY THAT YOU SEE? >> SO NO ONE HAS EVER STOPPED THEM FROM RUNNING, BUT THEY DO SEEM TO BE INDEPENDENT. THAT IS, IF YOU LOOK AT THE EFFECTIVE DIETARY RESTRICTION, IT DEPENDS ON THE READOUT, BUT CORRELATED WITH THE AMOUNT OF INCREASED ACTIVITY, IT'S NOT ONLY THE INCREASED ACTIVITY. FOR EXAMPLE, AS ANOTHER EXAMPLE, YOU CAN GET MICE TO DO THAT SAME ACTIVITY AND NOT SEE THE BENEFITS OF CALORIC RESTRICTION. SO IN BOTH WAYS, IT'S NOT ONLY INCREASED ACTIVITY BUT YOU'RE ABSOLUTELY RIGHT, THEY MOVE AROUND MORE, THEY'RE HUNGRY. >> DR. CUERVO. >> HI, TOM, REALLY SPECTACULAR. SO WHEN YOU GUYS STUDY EPIGENETICS AND YOU WANT TO SEE WHAT'S HAPPENING AND YOU ARE SHOWING THESE MODELS, HOW DO YOU GUYS GO ABOUT DIFFERENTIATING WHAT IS REACTIVE? I MEAN, WHAT CHANGES IN THE GENOME ARE REACTIVE TO WHATEVER HAPPENED TO FROM WHAT ARE PRIMARIES? IS THERE ANY WAY TO DO THAT? >> THAT'S A CRITICAL QUESTION. THE WHOLE FIELD OF EPIGENETICS IS A BIT PLAGUED BY THAT -- ITS CORRELATION. SO YOU SEE CHANGES WITH WHATEVER, DIFFERENTIATION, AGE. NOW, IF YOU CAN INTERVENE AND REVERT THEM, AGAIN, YOU'LL STILL SEE THIS CORRELATION. I THINK THE FIELD IS EVOLVING TO THE POINT NOW WHERE -- AND WE'RE STARTING TO DO THIS, WE'LL ONLY KNOW THIS WHEN WE CAN MODIFY THE EPIGENOME IN A LOCUS-SPECIFIC WAY AND ASK IF THAT ADDS TO THE EFFECT DOWNSTREAM. YOU'RE USING ENZYME -- 9 BUT YOU LINK IT TO BASICALLY RECRUITING A COMPLEX THAT WILL MODIFY THE CHROMATIN AT A LOCUS. THEN YOU CAN SAY SOMETHING EXACTLY WHAT YOU'RE ASKING, THAT THERE'S A CAUSE AND EFFECT RELATIONSHIP, BUT IF YOU DEMETHYLATE THIS LYSINE OR THESE LYSINES IN THIS AREA, YOU SEE INCREASED GREEN GENE EXPRESSION AND A CHANGE IN PHENOTYPE. AT THIS POINT, YOU'RE RIGHT, IT'S ENTIRELY CORRELATIVE, AND CERTAINLY FOR THE AGING STUDIES, IT IS, BUT AT LEAST WE HAVE AN IDEA OF HOW TO GET AT THIS EXPERIMENTALLY. >> AND THEN ONE MORE QUESTION. FOR THE -- CIRCULATING FACTORS, BECAUSE EVERY ORGAN US A SAY IS GOING TO BE DIFFERENT, IS THERE GOING TO BE AN INTERACTION BETWEEN LOW CAN CUSS-SECRETED FACTORS AND -- SO EVERY ORGAN IS GOING TO HAVE AN IMPACT AND IS THERE A WAY TO MEASURE THAT? I KNOW THEY PUT THE NEEDLE SO THEY CAN KNOW WHAT ARE THE LOCAL FACTOR, BUT IS THAT SOMETHING THAT CAN BE DONE IN TISSUES? >> IT CAN BE DONE. WE ACTUALLY PROPOSED TO DO THAT AS PART OF THIS STUDY, TO DO A LOCAL MICRO DIALYSIS. IT'S STILL PRETTY INVASIVE, SO THIS NEVER IS GOOD, DRAWING BLOOD AND MEASURING WHAT'S IN THE BLOOD, BECAUSE YOU'RE INJURING THE TISSUE A LITTLE BIT, BUT WE'RE TRYING TO ASK THAT QUESTION, IS WHAT WE SEE SYSTEMICALLY, IS IT REFLECTED IN ANYTHING WE SEE LOCALLY OR IS IT DIFFERENT AND ARE THEY THE SAME OR DIFFERENT FACTORS. THERE ARE CERTAINLY FACTORS WE'RE NEVER GOING TO PICK UP IN THE BLOOD, SO THAT'S OUR OTHER HOPE TO LOOK AT THAT. I'M NOT CONVINCED THAT'S GOING TO BE SO EASY TO DO JUST BECAUSE LIKE I SAID, WE'D LIKE A MUCH LESS INVASIVE WAY TO ASK, WHAT'S CHANGING IN THE LOCAL ENVIRONMENT OF THE STEM CELL WITHOUT HAVING TO STICK A NEEDLE OR SOMETHING INTO THE TISSUE. >> DR. CUMMINGS. >> AGAIN FROM MY IGNORANCE, I UNDERSTAND THAT MANY OF THEM DIE OF CANCER, THAT'S CORRECT? SO I'M WONDERING IF YOU CARRIED OUT THESE EXPERIMENTS LONG ENOUGH AFTER PLASMA INFUSIONS OR CONNECTIONS TO SEE IF IT REDUCES BOTH -- I MEAN, IMPROVES LONGEVITY BUT ALSO DECREASES THE RISK OF GETTING CANCER. >> SO MICE DO DIE OF CANCER BUT A LOT OF THEM ARE BLOOD-RELATED CANCERS, SO THEY'RE NOT SO MUCH SOLID CANCERS. WE HAVEN'T DONE IT. THE PEOPLE HAD DONE, AGAIN, BACK IN THE 50s AND 70s, EXPERIMENTS LOOKING AT LONGEVITY BUT THEY WERE DONE WITH RATS AND THERE WERE VERY FEW PAIRS SO IT WAS VERY POORLY POWERED. THEY LOOKED AT SOME PATHOLOGIES AND DIDN'T SEE TOO MUCH, SO I GUESS THE QUESTION IS -- AND WE'VE THOUGHT A LOT ABOUT THIS BECAUSE IN A WAY, WHEN I BROUGHT THE IDEA BACK TO WHY WE THINK OF THIS THERAPEUTICALLY IN TERMS OF TISSUE REPAIR AND NOT IN TERMS OF TREATING DISEASES, IT'S BECAUSE ONE CAN THINK OF THIS EITHER WAY, THAT GIVING YOUTHFUL FACTORS TO AN OLD PERSON MIGHT PROMOTE CANCER. I MEAN, THERE MIGHT BE A REASON WHY WE HAVE GROWTH-SUPPRESSIVE ACTIVITY WITH AGE. AND SO IT MIGHT PREVENT CANCER, BUT IT MIGHT MAKE THINGS WORSE. SO WE DON'T KNOW YET. AND WE HAVEN'T SET UP COHORTS TO TEST THIS BECAUSE IT IS A CHALLENGE TO GIVE THESE BLOOD INFUSIONS, LET ALONE THE PARABOW CYST, REPEATEDLY FOR A LONG TIME BUT IT'S AN IMPORTANT QUESTION, CERTAINLY THINKING OF GIVING ANY OF THESE FACTORS THERAPEUTICALLY FOR ANYTHING OTHER THAN A SHORT-TERM TREATMENT, THAT WOULD BE THE MAJOR QUESTION, IS IT GOING TO MAKE THINGS BETTER OR WORSE IN TERMS OF CANCER. >> >> ALONG SORT OF A RELATED LINE, I BELIEVE THERE IS EVIDENCE THAT AN ORGAN TRANSPLANT AND IN BONE NARROW TRANSPLANT, THAT THE AGE OF THE DONOR BEING YOUNGER PREDICTS BETTER OUTCOMES. I'M WONDERING IT IF WHAT YOU'RE DOING IS BEING TRANSLATED IN THAT SENSE IN THOSE FIELDS, IN THE TRANSPLANT FIELD AND BEING LOOKED AT IN TERMS OF THE AING AGE EFFECT. >> I GUESS I CAN ONLY SPEAK TO ONE THING AND THAT IS BLOOD TRANSFUSIONS. SO I DON'T THINK -- AGAIN, I'M NOT SURE WHETHER YOU'RE ASKING WHETHER PEOPLE ARE LOOKING TO DONATE YOUNGER ORGANS OR JUST WHETHER THIS IS A HOST-DONOR INTERACTION. SO WHAT WE DON'T KNOW IS WHETHER BLOOD TRANSFUSIONS FROM YOUNGER INDIVIDUALS VERSUS OLDER INDIVIDUALS MAKES ANY DIFFERENCE BECAUSE THE BLOOD IS DE-IDENTIFIED IN TERMS OF AGE. SO YOU CAN'T GO IN AND ASK FOR YOUNG AGE BLOOD. BUT TONY HAS ACTUALLY STARTED A COMPANY, ACTUALLY HAS A CLINICAL TRIAL IT GOING TO GIVE YOUNG PLASMA TO PATIENTS WITH EARLY ONSET ALZHEIMER'S DISEASE. SO DIRECTLY -- I KNOW. IT'S A HIGH -- IT'S A HIGH BAR IF IT'S GOING TO WORK, BUT IT'S JUST -- IT'S A SMALL STUDY TO GIVE YOUNG PLASMA AND SEE IF IT HAS ANY EFFECT IN TERMS OF PROGRESSION OF PATIENTS WITH EARLY ALZHEIMER'S DISEASE. TO YOUR QUESTION ABOUT SOLID ORGAN TRANSPLANT, I DON'T KNOW ANYTHING ABOUT THAT IN TERMS OF WHETHER THERE'S ANYTHING ONGOING. PEOPLE ALWAYS ASSUME THAT YOUNGER ORGANS ARE HEALTHIER, BUT I DON'T THINK THAT CHANGES THE AVAILABILITY, AND THAT SENDS ME OBVIOUSLY TO THE CUTOFF FOR DONOR AGE. >> WE'RE GOING TO HAVE TO STOP QUESTIONS THERE AND THANK YOU VERY MUCH, DR. RANDO. AND FOR OUR NEXT AND LAST TALK, DR. LIZ NIELSEN WILL INTRODUCE DR. ELISSA EPEL. >> SO IT'S MY PLEASURE TO INTRODUCE DR. HELY IS ELISSA EP EL. SHE RECEIVED A B.A. FROM PSYCHOLOGY FROM STANFORD UNIVERSITY AND PH.D. IN CLINICAL AND HEALTH PSYCHOLOGY FROM YALE. FOR THE PAST 15 YEARS, SHE STUDIED STRESS IN THE LAB AND IN THE FIELD WITH THE GOAL OF UNDERSTANDING THE COMPLEX RELATIONSHIPS BETWEEN MIND, BEHAVIOR AND BIOLOGY AND HOW STRESS MECHANISMS AFFECT HEALTHY AGING. HER RESEARCH GROUP EXAMINES THE PHYSIOLOGICAL IMPRINTS OF STRESS SUCH AS ALTERED INFLAMMATORY IMMUNE FUNCTION, THE CELLULAR MECHANISMS UNDERLYING VASCULAR HEALTH AND ADIPOSITY, AND AT THE CELLULAR LEVEL, CELLUL STRESS AND CELL AGING. SHE COLLABORATES WIDELY WITH COLLEAGUES IN BOTH CLINICAL AND LAGE SCALE STUDIES TO EXAMINE HOW PSYCHOLOGICAL, BEHAVIORAL, DEMOGRAPHIC AND SOCIAL FACTORS IMPACT CELLULAR AGING, AND SHE'S BEEN INVOLVED IN ADDING TELL MERE MEASURES TO SEVERAL POPULATION BASED STUDIES. CURRENTLY SHE IS LEADING A NEW NIA SUPPORTED STRESS MEASUREMENT NETWORK WHICH IS TRYING TO FORGE STRONGER LINKS BETWEEN LAB SCIENCE AND EPIDEMIOLOGICAL RESEARCH ON STRESS BY IMPROVING THE APPROACHES TO STRESS MEASUREMENT FOR POPULATION BASED STUDIES, BOTH NATIONALLY AND INTERNATIONALLY. FINALLY, SHE'S BEEN A CONSULTANT IN THE DI VIG O DIVISION OF AGING BIOLOGY ON SETTING THE SCIENTIFIC AGENDA FOR THE NEXT FIVE YEARS ON THE INTERPLAY BETWEEN BEHAVIOR AND BIOLOGY IN SHAPING HEALTH, HEALTH SPAN AND DISEASE. SO IT'S MY PLEASURE TO INTERELISSA EPEL. WHO IS SPEAKING ON PSYCHOLOGICAL STRESS, PHYSIOLOGICAL STRESS AND CELLULAR AGING MECHANISMS. >> IT' IT'S A PLEASURE TO BE HERE SPEAKING TO ALL OF YOU. SO BECAUSE THIS IS PROBABLY THE FIRST COUNCIL MEETING WITHOUT RICHARD, I WANTED TO JUST TAKE A MOMENT TO ACKNOWLEDGE RICHARD SUZMAN, WHOSE MISSION LIVES ON IN NIA AND MANY OF US. LIZ NIELSEN INTRODUCED HIM TO ME ABOUT 10 YEARS AGO, WHEN OUR FIRST SMALL PAPER CAME OUT LINKING PSYCHOLOGICAL STRESS TO SHORTER TELOMERES. BACK THEN, RICHARD HAD A VISION THAT THIS MIGHT BE HELPFUL IN LARGE SCALE POPULATION BASED STUDIES TO UNDERSTAND THE LANDSCAPE AND FABRIC OF HEALTH DISPARITIES, AND ENLIGHTEN SOME OF THE PATHWAYS THERE. SO I'M GOING TO SHOW YOU SOME DATA THAT I THINK BEARS THAT OUT. AND IT'S BEEN -- SINCE THEN, IT'S BEEN REALLY INCREDIBLE AND ENRICHING TO BE INVOLVED IN MANY NIA INITIATIVES IN GERO SCIENCE ON STRESS, STRESS MEASUREMENT, EARLY TRAUMA, SO THANK YOU SO MUCH. IT'S GREAT TO BE HERE. SO I'M GOING TO START WITH DEFINITIONS. WHAT IS STRESS? WE SIT IN ROOMS AND WE ARGUE ABOUT WHAT STRESS IS, SO IT'S REALLY EXCITING TO DEVELOP A TAXONOMY OF STRESS, BUT AT THE VERY BASIC LEVEL, HERE IT IS. WE HAVE GOOD STRESS AND BAD STRESS. AND I'D LIKE TO SAY I THINK RICHARD SUSSMAN EMBODIED THAT STATE OF CHALLENGED STRESS, BUT WHAT I'M TALKING ABOUT IS THREAT STRESS, MORE THAT GAZELLE. SO HOW CAN CELL AGING HEALTH HELP US UNDERSTAND DISPARITIES IN AGING AND DISEASE. I'M GOING TO BE TALKING ABOUT TELL MERE LENGTHS AND OTHER -- WE ALWAYS SHOW THIS FAMOUS PICTURE OF TELOMERES, THE YELLOW DOTS THAT PROTECT THE CHROMOSOMES. THIS WAS A PICTURE TAKEN BY RICHARD HODES. SO WHERE DOES THIS RESEARCH STAND IN IT'S EXCITING TO IT BE IN THE AGE OF RESEARCH MEDICINE WHERE WE'RE GETTING THIS KEEP UNDERSTANDING OF THESE LEVELS OF OMICS ALL THE WAY UP TO THE SYSTEMS PHYSIOLOGY AND ORGAN SYSTEMS. AND THIS IS GOING TO TAKE US FAR IN UNDERSTANDING, PREVENTING AND CURING DISEASES. THERE ARE FEW OTHER LAYERS THAT WE CAN ADD TO THIS THAT WILL BE HELPFUL. WE DO KNOW WHEN WE LOOK AT A CAUSES OF DEATH, ABOUT 50% OF CAUSES OF DISEASES ARE DUE TO HEALTH BEHAVIORS AND RISKY BEHAVIOR. STEPPING BACK FROM THAT, WE KNOW THAT IT'S THE SOCIAL STRUCTURE A SOCIAL ENVIRONMENT RELATIONSHIPS THAT ACTUALLY ARE THE CAUSES OF THE CAUSES THAT PROMOTE BEHAVIOR AND SHAPE BEHAVIOR. SO HERE ARE SOME OTHER LAYERS FROM SOCIAL DOWN TO INDIVIDUAL. IT'S THE INTERACTIONS BETWEEN THESE TWO PYRAMID INS THAT I THINK WILL BE ESPECIALLY FRUITFUL IN UNDERSTANDING AND PREVENTING AGING TRAJECTORIES. SO TODAY I'M GOING TO BE TALKING ABOUT A LINK BETWEEN EXTREME PSYCHOLOGICAL STRESS AT THE INDIVIDUAL LEVEL, THAT'S SOCIALLY DETERMINED, SUCH AS BEING A CAREGIVER, AND CELLULAR AGING PROCESSES. I'LL BRIEFLY MENTION WHY CELLULAR AGING AND SOME EXAMPLES. MOSTLY I'LL BE FOE KUTION O FOCUSING ON OU R NIH STUDY OF THE CAREGIVERS AND CELLULAR AGING MECHANISMS MOST LIKELY LINKED TO STRESS PROCESSES, AND I'LL ALSO MENTION OUR STUDY WHERE WE LOOKED AT TELOMERES, AND WE'RE REALLY EXCITED ABOUT HAVING THE ABILITY TO IT USE THIS GRANT TO ALSO STUDY OTHER EMERGING CELLULAR AGING MARKERS THAT ARE ALSO TIGHTLY RELATED. SO WE BENEFIT FROM THIS MODEL OF AL STATIC LOAD, HELPS US UNDERSTAND HOW THE SLOW WEAR AND TEAR OF AGING HAS A CUMULATIVE TOLL ON REGULATORY SYSTEMS. THIS HAS BEEN -- INSTEAD OF HOMEOSTASIS, WE HAVE THIS ALLO ST. TASIS, UP AND DOWN FLUCTUATION THAT OVER TIME CAN CAUSE DAMAGE, HIDDEN IN THE BODY, AS WE CAN MEASURE THE LOAD. IT'S BEEN TRADITIONALLY MEASURED AS RISK FACTORS LIKE THE METABOLIC SYNDROME AS WELL AS STRESS HORMONES. THIS IS HELPFUL BUT REALLY WE CAN ONLY DO THIS IN OLDER PEOPLE WHEN WE'VE ACCUMULATED SOME DAMAGE AND WE'RE RIGHT ON THE DISEASE PROCESS. YOU MEASURE HIGH BLOOD PRESSURE THAT SEEMS ELEVATED, YOU'RE ON THE PATH TO HYPERTENSION. SO THERE IS SOME KIND OF REDUNDANCY, AND WE WANT TO BE ABLE TO MEASURE BIOLOGICAL AGING AT BIRTH. THE PROCESS OF AGING THAT IS THE NOT CONFOUNDED BY DISEASE. SO I'VE TURNED TO LOOKING AT CELLULAR AGING AT THE PHYSIOLOGICAL LEVEL, MORE OF A CELLULAR VIEW OF ALOE STATIC LOAD, WHICH IS SENSITIVE, WE CAN CATCH AGING AS IT IT OCCURS AT THE CELLULAR LEVEL BEFORE DISEASE ACCUMULATES AND MONITOR IT. SO ALL OF THIS IS IN CLAB WAITION WITH ELIZABETH BLACKBURN. YOU CAN SEE THIS IS THE REPEAT SEQUENCE OF DNA AND IT'S NOT FULLY REPLICATED AS OUR CELLS DIVIDE AND AS THEY'RE DAMAGED BOF THE LIMITS OF THE POLYMERASES. BUT AT THE END, YOU SEE THAT BIG YELLOW GLOB. THAT IS THE ENZYME PROTEIN COMPONENT OF ENZYME TELOMERASE WHICH ALSO HAS A REVERSE TRAN DESCRIPTIVE ELEMENT THAT CAN ADD BACK THE BASE PAIRS. SO IT'S THIS XINJIANG SYSTEM THAT WE'VE BEEN STUDYING AND THEY APPEAR TO BE VERY SENSITIVE TO OUR DAILY STRESS. WHEN THE TELOMERE GETS TOO SHORT, THE CELL BECOMES SENESCENT AND IT BECOMES PRO INFLAMMATORY IN THE IMMUNE CELLS. AND IT CAN ALSO SEND SIGNALS THROUGH PCGA1 TO MITOCHONDRIA AND IMPAIR MITOCHONDRIAL GROWTH. [INAUDIBLE] WE MEASURED THIS IN A SAMPLE OF YOUNG HEALTHY MOTHERS CARING FOR CHILDREN WITH DIVERSE CHRONIC ILLNESSES, AND HEALTHY YOUNG LOW STRESS MOTHERS, THE BIGGER CHALLENGE IS FINDING THE LOW STRESS MOTHERS, ONCE YOU FIND A CAREGIVER THERE, ALMOST ALWAYS HIGH STRESS. SO WHAT YOU CAN SEE ON THE TOP PANEL IS THE TELOMERES WERE SIGNIFICANTLY SHORTER IN THE HIGHEST PERCEIVED STRESS CATEGORY, THERE ARE ABOUT 500 -- SHORTER, THE AT THE LOM RACE -- 50% SHORTER, THEY HAD SIGNIFICANTLY HIGHER LEVELS OF STRESS. SO NOW LET'S FAST FORWARD 10 YEARS, WHAT HAVE WE LEARNED SINCE THEN THAT HAS BEEN ACCUMULATION OF STUDIES FROM SAMPLES OF 4,000 TO 40 SHOWING THAT THIS RELATIONSHIP THE LONGER YOU'VE BEEN A CAREGIVER, TE SHOR SHORTER THE TELOMERE. VARIOUS TYPES OF TRAUMA, EARLY TRAUMA, LIVING WITH DOMESTIC VIOLENCE, LIVING IN UNSAFE NEIGHBORHOODS, ALL OF THESE ASSOCIATED WITH SHORTER TELOMERES. ALSO EMERGING LITERATURE ON PSYCHIATRIC CONDITIONS, IN PARTICULAR, MAJOR DEPRESSION. SO THAT'S GENERATION ONE OF THIS STORY. BUT REALLY, WE WANT TO DIG DEEPER AND UNDERSTAND THE MECHANISM. I JUST WANTED TO POINT OUT THAT THERE ARE ALSO MANY ANIMAL STUDIES IN THIS, AND BIRDS ARE PARTICULARLY USEFUL MODEL BECAUSE TELOMERES ARE PRETTY GOOD PREDICTERS OF LONGEVITY IN BIRD, NOT SO MUCH IN MICE, WHO HAVE HUGE LONG TELOMERES. SO YOU CAN SEE DIFFERENT TYPES OF STRESS, SOCIAL STATUS, SOCIAL ISOLATION ARE BOTH PREDICTIVE OF MORE RAPID TELOMERE SHORTENING AND SHORTENED MORTALITY IN BIRDS. SO WE HAD THE OPPORTUNITY THROUGH NIA TO CHARACTERIZE TELOMERE LENGTH IN 8,000 PEOPLE IN A COHORT AND LOOK AT HEALTH DETERMINANTS AND MORTALITY, SO THIS IS THE FIRST DEMONSTRATION IN A POPULATION BASED SAMPLE IN THE UNITED STATES, LOWER EDUCATION WAS ASSOCIATED WITH SIGNIFICANTLY GREATER TELOMERE SHORTNESS. SMOKING, BMI, OTHER FACTORS, TELOMERES WERE PREDICK ITTIVE OF MORTALITY AND WE'RE ALSO LOOKING AT BEHAVIORAL CORRELATES. SODA CONSUMPTION IS RELATED TO SHORTER TELOMERES. IT'S CLEARLY A MEASURE SENSITIVE TO ALL SORTS OF STIMULI, NOT JUST STRESS. HOW WELL CAN OUR PREDICTIVE MODEL BE WHEN WE CHARACTERIZE ALL THE EXPOSOME FACTORS THAT WE CAN. SO THIS IS NOW PUBLIC AND MANY PEOPLE ARE LOOKING AT TELOMERES IN N HANES IN DIFFERENT CONTEXTS SO WE'LL LEARN A LOT MORE. THE STEERING WHIT EE FOR THE HEALTH AND RETIERM TIERM RETIREMENT STUDY LOOKED AT 5,000 PEOPLE. WE PEEKED INTO THAT DATASET TO LOOK AT LIFE STRESS. WE KNOW IT'S CUMULATIVE, IT THERE'S BIOLOGICAL EMBEDDING EARLY ON IN LIFE, WHICH APPEARS TO HAVE A BIG EFFECT ON ADULT HEALTH. SO EARLY ADVERSITY SEEMS TO MATTER A LOT. SO WE QUANTIFIED ALL THE STRESS MEASURES IN HRS AND MADE A COMPOSITE CUMULATIVE CHILDHOOD ADVERSITY AND CUMULATIVE ADULT ADVERSITY. AND WHAT YOU CAN SEE IS THAT TOGETHER, THEY DO PREDICT TELOMERE SHORTNESS IN OLDER ADULTS. BUT WHEN THEY'RE IN THE SAME MODEL TOGETHER, WHAT'S CARRYING THE WEIGHT? CUMULATIVE CHILDHOOD ADVERSITY AS AN INDEPENDENT AND STRONGER PREDICTER. SO THAT IS A SIGNAL WE WERE GETTING FROM A LOT OF STUDIES THAT WE NEED TO ALSO MEASURE, EVEN IF IT'S RETROSPECTIVE, EARLY LIFE EXPERIENCE TO UNDERSTAND LIFESPANS, HEALTH AND LONGEVITY. SO NOW LET ME GO TO GENERATION Q. WE HAD THE OPPORTUNITY TO LOOK AT A LARGER SAMPLE OF ALMOST 200 WOMEN, HALF WHO HAD A CHILD WITH AUTISM SPECTRUM DISORDER, VERY STRESSFUL CONDITION. WE'VE BEEN STUDYING THE MOTHERS, THE HUSBANDS, AND THE CHILDREN OF IT IN TERMS OF DAILY STRESS IN TELOMERES OVER SEVERAL YEARS. AT THE VERY END OF THE STUDY, WE ARE DOING A STRESS REDUCTION INTERVENTION TO SEE WHETHER WE CAN IMPACT TELOMERES THROUGH REDUCING THEIR DAILY STRESS. SO WHICH CELL IS REALLY CARRYING THE DAMAGE HERE? WE KNOW FROM THE WORK OF RITA EFFROS THAT CHRONOLOGICAL AGE LEADS TO AN IMMUNE SENESCENT PROFILE CHARACTERIZED BY CD8 AGING. SO THE CD8 CELLS SHOW REPUBLICTIVE SENESCENCE SOONER THAN ANY OTHER CELLS. SO THE QUESTION BECOMES WHETHER PSYCHOLOGICAL STRESS IS MIMICKING OR ACCELERATING THE EFFECT OF CHRONOLOGICAL AGING ON THE IMMUNE SYSTEM. SO OF THE CELL TYPES, WE SORTED CELLS IN THIS LARGE SAMPLE. WE REALLY FOCUSED ON CD828 MINUS CELLS, AND WE MEASURE AT THE LOM RAISE -- IN THESE DIFFERENT CELL TYPES TO REALLY GET A CLOSE LOOK AT PHENOTYPES OF IMMUNE AGING IN THIS HIGH STRESS SAMPLE. WE FOUND THAT CHRONIC STRESS DOES MIMIC CHRONOAL AGING IN THIS HEALTHY YOUNG SAMPLE. SO IT WASN'T ACTUALLY IN TELOMERE LENGTH, IT WAS IN THE AT THE LOM RACE ACTIVITY. WE CALL IT THE STAGE STUDY. I'LL FIRST SHOW YOU THE BASELINE DATA. OF COURSE IT'S HIGHER IN B CELLS, RICHARD SHOWED THAT LONG AGO, AND IT IS -- TENDS TO BE LOWER IN THE CD8 CELLS, BUT WHAT WE FOUND IS IT WAS VERY SIMILAR ACROSS CELL TYPES IN THE HIGH -- THE CELLS THAT TEND TO GO PRESENESCENT EARLY, SO THIS WAS EXACTLY THE SIGNATURE WE THOUGHT WE'D FIND AND THIS PARTICULAR MEASURE IS ASSOCIATED WITH ALL OF OUR -- OUR MOST SENSITIVE MEASURES OF STRESSFUL -- DAILY STRESS. WE'RE REALLY GOING DEEP TO UNDERSTAND WHAT THE PHENOTYPE OF CHRONIC STRESS LOOKS LIKE IN A DAY, AND I'LL SHOW YOU QUICKLY SOME DATA THAT LINKS THIS MEASURE TO CHRONIC STRESS. FIRST I WANT TO TELL YOU ABOUT SOME EXCITING NEW FINDINGS. WE'VE USED THE OPPORTUNITY OF HAVING THESE WELL CHARACTERIZED TWO GROUPS TO TEST OUT WHETHER WE CAN DETECT A SYSTEM OF CELLULAR AGING, NOT JUST TELOMERES. TELOMERES ARE IMPORTANT, BUT AS YOU KNOW, THEY HAVE THEIR LIMITATIONS WHICH WE CAN TALK ABOUT TOO IN THE DISCUSSION. WE DO THINK OF THEM AS ONE OF THE DRIVERS OF POOR MITOCHONDRIAL HEALTH. RHONDA AND COLLEAGUES HAVE SHOWN THAT IN TERMS OF SIGNAL AND PATHWAYS. SO MY COLLEAGUE POSTDOC MARTIN TICARD, WHO WILL BE AT COLUMBIA SOON, HAS BEEN VERY INTERESTED FOR YEARS IN WHETHER MITOCHONDRIAL HEALTH IS ASSOCIATED WITH CHRONIC STRESS, AND THAT'S PART OF THE AGING SYNDROME WE SEE. SO TO LOOK AT THIS QUESTION, WE NEED TO MEASURE THE MITOCHONDRIAL ENZYMES, FUNCTIONAL HEALTH. MITOCHONDRIA AND CONTROL FOR HOW MANY PEOPLE HAVE. THE COPY NUMBER, THE ENZYME, SO WITH SOME VERY SENSITIVE CAREFUL ASSAY, HE HAS CHARACTERIZED POSITIVE MITOCHONDRIAL HEALTH. SO LET ME SHOW YOU WHAT WE'VE FOUND WITH THIS MEASURE. WHEN WE COMPARE THE HIGH AND LOW STRESS WOMEN ON MY TO MITOCHONDRIAL HEALTH, YOU SEE SIGNIFICANTLY WORSE MITOCHONDRIAL HEALTH IN THE HIGH STRESS WOMEN WITH THE SAME NUMBER OF MITOCHONDRIA, SO THAT MEANS THEY'RE IN AN ENERGY DEFICIENT STATE WITH THE SAME MATERIAL THEY'RE NOT PRODUCING AS MUCH ATP. WE'RE NOW GOING TO ROOK AT HOW LOOK AT HOW THIS RELATES TO OTHER HEALTH PHENOTYPES, BUT WHEN WE LOOK AT POSITIVE NEGATIVE AFFECT, IT WAS -- WAS STRONGLY CORRELATED WITH THESE MITOCHONDRIAL ENZYMES, SO HIGHER POSITIVE AFFECT, HIGHER MITOCHONDRIAL HEALTH. AT UCSF, COLLABORATING, WE LOOKED AT CLOSSO, FOUND ASSOCIATED WITH BETTER COGNITIVE AGING, SO HIGHER KLOTHO -- IN MEES, IT'S RELATED TO LONGEVITY. IN HUMANS, THE ACTUAL LEVEL OF KLOTHO IN THEIR BLOOD IS ASSOCIATED WITH BETTER FUNCTIONING, BETTER COGNITION. SO MY COLLEAGUES LOOKED AT KLO IT THO IN STRESSED WOMEN AND FOUND SIG TAN -- WE SHOULDN'T SEE TOO MUCH DEFINE IN ENCLOSE THOUGH IN THIS PERIOD. YOU CAN SEE THAT KLOTHO IS STABLE OVER THESE TWO DECADE IN THE LOW STRESS WOMEN, AND IS DROPPING SIGNIFICANTLY IN THE HIGH STRESS WOMEN. SO CHRONIC STRESS APPEARS TO BE AK SET RATING THE AGE-RELATED DECLINE THAT WE TYPICALLY SEE IN A 60-YEAR-OLD. BACK TO IT STRESS. LET ME MAKE SOME POINTS ABOUT STRESS MEASUREMENT. SO TRY TO ANSWER THIS QUESTION. HOW STRESSED HAVE YOU FELT OVER THE PAST DECADE? THIS IS A TERRIBLE QUESTION. BUT I SHOULDN'T SAY THAT BECAUSE IT IS USED IN SOME STUDIES, BUT WITH NO VALIDITY. SO WE KNOW IT'S THROUGH MEASUREMENT STUDIES AND THROUGH STUDIES OF MOOD, ET CETERA, WE CAN BARELY RECALL WHAT WE DID LAST WEEK OR HOW WE FELT YESTERDAY. SO THESE MEASURES OF SELF-REPORT ARE INEVITABLY FLAWED ARNTIOND WE CAN ACCESS BIG TICKET ITEMS LIKE IT DID YOU STUFFER CHILD ABUSE, AND WE HAVE QUESTIONNAIRES THAT SOMEONE ACTUALLY GET RET TROA SPECULATIVE MAJOR STRESSORS. WE ASK ASK IF YOU'RE A CAREGIVER. THAT'S NOT TOO HARD. BUT TO ACTUALLY GET YOUR PSYCHOLOGICAL EXPERIENCE ON A DAILY BASIS IS MORE WORK BUT IT'S ABSOLUTELY CRITICAL TO UNDERSTAND HUMAN HEALTH ON AGING. IN OUR -- WE'VE BEEN TRYING TO IMPROVE STRESS MEASUREMENT, THESE ARE JUST SOME OF THE OP VEES WAYS WE WANT TO MEASURE EXPOSURES AND RESPONSES. WE'VE GOT THOSE SLEDGE HAMMER ITEMS, TRAUMATIC STRESS, CHRONIC STRESS, LIFE EVENTS, THEN THERE'S DAILY STRESS, WHICH WE THINK OF AS A SMALL EFFECT BUT WHAT I'M GOING TO SHOW YOU SUGGESTS THAT IT'S THROUGH DAILY STRESS. THAT STRESS IS PROPAGATED THROUGH TIME AND AFFECTS OUR IF PHYSIOLOGPHYSIOLOGY WITH THE LARGEST DOSE THAT WE HAVE, WITH WHICH IS ON A DAILY BASIS. IT'S PROBABLY SHAPING EMOTION REGULATION PATHWAYS THROUGH THE LIFETIME. WHEN PEOPLE EXPERIENCE EARLY TRAUMA. LET ME SHOW YOU WHAT WE'VE LEARNED ABOUT OUR CAREGIVERS ON A DAILY BASIS. WHAT IS KROJ STRESS? WE SAY YOU'RE A CAREGIVER, YOU'RE UNDER CHRONIC STRESS. WHAT DOES IT LOOK LIKE IN THE MOMENT WHEN THEY WAKE UP? IT ARE THEY STARTED OFF WITH A CLEAN SLATE OR ARE THEY ALREADY JUMPING INTO THIS PSYCHOLOGICAL PROCESSES THAT PROMOTE CHRONIC AROUSAL. PARTS PATIENT OF THE DAY'S EVENTS, THEN WHEN THE EVENT HAPPENS, IT'S NOT OVER, THEN THERE'S A SLOW RECOVERY AND RUMINATION, KEEPING THE EVENT ALIVE, KEEPING PHYSIOLOGY VIGILANT. SO THAT'S WHAT WE'VE BEEN MEASURING ON A DAILY BASIS. WE KNOW THAT ANTICIPATION OF A STRESSOR IS CRITICAL AND THAT WE'RE OFTEN IN A PAR TIS PA TRI STATE. WE MEASURE HOW ARE YOU GOING TO DO WHEN YOU HAVE TO GIVE A SPEECH IN FRONT OF THESE TWO STONEY FACED INTERVIEWERS. SOME PEOPLE SCORE HIGHER ON THE THREAT SCALE, SOME PEOPLE SCORE HIGHER ON THE POSITIVE CHALLENGE, LET ME TAKE IT ON, GIVE ME THIS CHALLENGE. SO THESE TWO PROFILES ARE ACTUALLY PREDICTIVE OF HOW THEY ACTUALLY DO, AT LEAST HOW THEIR BODY RESPONDS. SO THE GREATEST ARE -- CORTISOL REACTIVITY, IMMUNE REACTIVITY IT, AUTONOMIC REACTIVITY IT, TOTAL PERIPHERAL RESISTANCE, AND THEY'RE ASSOCIATED WITH SHORTER TELOMERE LENGTH. TELOMERE LENGTH DOESN'T CHANGE OVERNIGHT, IT CHANGES OVER YEARS, SO THIS IS PROBABLY REPRESENTATIVE OF A CHRONIC STATE. SO WE'VE MEASURED THIS IN OUR DAILY DIARY STUDY OVER SEVEN DAYS. FOUR TIMES OVER TWO YEARS IN OUR CAREGIVER. SO I'M GOING TO SHOW YOU THE BASELINE. JUST ASK YOURSELF THIS FIRST QUESTION, HOW MUCH ARE YOU LOOKING FORWARD TO OR DREADING TODAY' EVENT? WHEN YOU WOKE UP AND KNEW YOU WERE COMING TO COUP TODAY, WHAT WAS YOUR APPRAISAL? SO CAREGIVERS SCORE IN THIS THREAT APPRAISAL MODE FROM THE MOMENT OF WAKING UP. WE MEASURE THOSE APPRAISAL, THEY'RE SIGNIFICANTLY HIGHER ON WORRYING, FEELING OVERWHELMED, FEELING THE DAYS ARE UNPREDICTABLE. IN TERMS OF BEING ASSOCIATED WITH CELL AGING, IT'S THE AT THE LOM RAISE AND -- THAT'S SIGNIFICANTLY CORRELATED HIGHER WITH POSITIVE FEELINGS OF LOOKING FORWARD TO THE DAY AND IT'S SIGNIFICANTLY LOWER WITH THESE THREAT APPRAISALS. WE FIND THE SAME THING WITH RESPONSE TO DAILY THREAT AND RUMINATION. SO BASICALLY WE THINK CHRONIC STRESS IS A HYPERRESPONSIVITY SYNDROME THAT WE CAN TAP INTO AND MEASURE IN A DAY. THERE'S A QUESTION OF CAN WE REVERSE THIS? WELL, THE PHARMACOLOGICAL MEANS ARE GOING TO BE CRITICAL. WE KNOW THE CELLULAR AGING MECHANISMS. IF YOU DON'T STOP THE MOTOR WHERE IT STARTS, WHICH IS THE PERCEPTION, THEN WE'RE NOWHERE, WE'RE GOING TO KEEP GENERATING STRESS AND IT'S GOING TO OVERRIDE ANY PURE PHARMICOLOGICAL INTERVENTION. I COULD TALK WITH ABOUT THAT IF I HAD MORE TIME. SO WE'RE USING THE NATIONAL NETWORK TO DEVELOP SOME VALIDATED STRESS MEASURES THAT SPAN FROM EARLY ADVERSITY TO DAILY OR MOMENTARY STRESS, AND WE'RE PARTNERING WITH THE NIA'S GROABL STUDIES OF AGING AND WE SO FAR HAVE HAD A GOOD RESPONSE. THEY DON'T HAVE MANY STRESS MEASURES, SO THIS IDEA OF UNDERSTANDING HEALTH DISPARITIES IN CROSS COUNTRY COMPARISONS WITH REALLY WELL VALIDATED MEASURES OF LIFESPAN STRESS IS EXCITING. AND THIS WAS ONE OF RICHARD'S -- I'LL JUST SAY THAT CELLULAR RESISTANCE IS STRESS, AN ADAPTATION AND STRESS RESISTANCE IS VERY EXCITING MODEL IN THE DIVISION OF AGING BIOLOGY, WHAT WE'RE LEARNING ABOUT A UNIVERSAL MECHANISM THAT MAY BE DRIVING CELLULAR AGING AND THERE'S TREMENDOUS POTENTIAL TO LOOK AT THIS WITH HUMANS AND COLLABORATE WITH ANIMAL RESEARCHERS. AND I WILL STOP THERE AND JUST SAY THAT IT'S EXCITING TO BE IN AN ERA WHERE WE CAN REALLY MEASURE STRESS WELL AND MEASURE CELLULAR AGING WELL. WE NEED TO DO BOTH OF THOSE BETTER, WE NEED TO COLLABORATE TO DO TRANSLAL GERO SCIENCE. I LOVE THAT TERM, ANNE. FROM ANIMALS TO HUMANS, SO THAT'S A LOT OF THE DIALOGUE HAPPENING HERE AT NIA THROUGH DAB AND BSR. AND THESE LINKS CAN HELP US UNDERSTAND BOTH HEALTH DISPARITIES BUT ALSO HELP US WITH PREVENTION THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH, DR. EPEL. DR. CUMMINGS? >> TERRIFIC WORK OVER THE LAST -- I'M OVER HERE. TERRIFIC WORK OVER THE LAST DECADE. SOME OF THE CONCERNS ABOUT MEASURING TELOMERES IN PERIPHERAL BLOOD HAD TO DO WITH DIFFERENCES IN THE DIFFERENTIAL THAT YOU MIGHT SEE SO THAT STRESS, IN FACT, MIGHT BE ASSOCIATED WITH MORE PMNs, MORE CELLS THAT HAVE HIGHER TURNOVER AND PRESUMABLY SHORTER TELOMERES, AND SO DO YOU HAVE EVIDENCE THAT, IN FACT, WHAT YOU'RE MEASURING IS SOMETHING OTHER THAN THE STRESS RESPONSE OF CHANGES IN -- POPULATIONS? >> IT'S A GREAT QUESTION. INEVITABLY, WE HAVE A MOVING TARGET. WE'RE MEASURING CELLS AND CELL DISTRIBUTION. SUBPOPULATIONS ARE CHANGING. IN OUR CLINICAL STUDIES, WHICH TEND TO BE SMALL, ALWAYS DO PHENOTYPING. WE'RE DOING A BREAKDOWN NOT JUST WITH CBC BUT LOOKING AT THE NUMBER OF CELL TYPES. IN THE LARGE POPULATION BASED STUDIES OVER TIME, THAT'S AN INEVITABLE PROBLEM. SOME PEOPLE ARE OF MOVING TOWARDS BUCCAL CELLS, IN CHILDREN IT LOOKS LIKE BUCCAL CELLS ARE SHORTER OVER YEARS LONGITUDINALLY WITH ADVERSITY AND EXPOSURE TO -- AND VIOLENCE, ET CETERA. SO THERE IS -- THERE ARE PROBLEMS WITH MEASURES OF TELOMERES WITH THE PCR METHOD AND THE FIELD IS A LITTLE BIT OF -- THERE'S A LOT OF NULL FINDINGS AND IF YOU LOOK AT THE METHODS AND YOU LOOK AT THE COEFFICIENT OF VARIATION FOR THE ACCURACY OF THEIR PCR MEASURE, YOU WOULD BE SHOCKED THE AT SOME OF WHAT SHOULD BE PUBLISHED. SO THERE ARE PROBLEMS WITH MEASUREMENT AND THERE ARE ALSO PROBLEMS WITH HAVING A A MOVING TARGET. SO TLT, THE OVERALL MEASURED DOES -- DESPITE THIS PROBLEM, IT DOES SEEM TO BE A PRETTY RELIABLE PREDICTER OF DISEASE. WHAT HE SHOWED YOU WASN'T RELATED TO -- IT WA IT WAS AT THE IT WAS T ELOMERASE. WHAT WE'D LIKE TO DO IS JUST MEASURE THE CD28 MINUS CELLS IN THESE LARGE STUDIES. >> DR. RANDO. >> REALLY INTERESTING WORK, LISSA. I WAS INTRIGUED BY THE TELOMERASE DATA. HOW ARE YOU THINKING ABOUT THAT IN TERMS OF IT BEING KIND OF PRIMARY VERSUS SECONDARY TO WHAT YOU SEE AT THE TELOMERE? IT SEEMS LIKE YOU WOULD ALMOST EXPECT THE OPPOSIE. >> RYE. SO A COUPLE THINGS. SO THROM RACE, IF WE'RE ABLE TO MEASURE IT WELL -- WE CAN'T MEASURE IT IN LARGE STUDIES BECAUSE IT'S NOT A HIGH THROUGH PUT MEASURE. IT'S A COUNTER REGULATORY DEFENSE MEG NISM TO DEFEND THE GENOME. WE ARE FINDING SMALLER CHANGES IN CD828 MINUS TELOMERE LENGTH OVER TIME WHICH WE WOULD HAVE MISSED IT IT WE WERE JUST GOING TORE WHAT 99% OF THE STUDIES DO. SO WE ARE ABLE TO DETECT CD8 CHANGES IN THE HIGH STRESS POPULATION BOTH WITH THE TELOMERE LENGTH TO A LESSER DEGREE, PARTICULARLY WITH THE TELOMERES ACTIVITY. SO WE USED TO THINK OF IT AS THE MAIN DRIVER OF TELOMERE LENGTH BUT THERE ARE MANY OTHER FACTORS ON TELOMERE LENGTH AND THEY'RE IMPORTANT. >> DR. NEWMAN. >> I WAS VERY INTERESTED IN YOUR CHARACTERIZATION OF STRESS VERSUS CHALLENGE BEING SOMEWHAT IN THE EYE OF THE BEHOLDER AND RECIPIENT OF THE EXTERNAL STIMULUS. IT'S ALWAYS SEEMED TO ME THAT OLDER PEOPLE NEED SOME STRESS OR CHALLENGE, THAT THEY'RE CALLED UPON TO MAINTAIN A I HAOER LEVEL OF PHYSIOLOGIC FUNCTION AND INTEGRITY OF HEALTH IF THEY HAVE MORE CHALLENGE IN THEIR LIFE. I'M WONDERING IF YOU THINK ABOUT THIS AS ALL BEING BAD OR IS THERE A SWEET SPOT OF SORT OF AN IDEAL A STIMULATION THAT WE NEED TO IT KEEP OUR SYSTEMS PRIMED TO RESPOND. >> IT'S A GREAT QUESTION. AND I ABSOLUTELY THINK THAT WE SHOULDN'T JUST TALK ABOUT STRESS AS A WHOLE BECAUSE STRESS IS CRITICAL TO IT ENGAGING WITH LIFE AND IT'S THE CHALLENGED STRESS THAT'S CRITICAL FOR HEALTHY AGING. SO THERE IS SOME DOWN SIZE AND SOME STRESS BEING INVOLVED IN THESE LOW INCOME SCHOOLS, BUT OVERYOU A, IT LOOKS LIKE THE QUALITATIVE AND HEALTH DATA FROM THE EXPERIENCE CORE SHOWS THAT THEY'RE IMPROVING IN THEIR HEALTH THROUGH -- IN PART THROUGH CHALLENGED STRESS, SO CHALLENGE STRESS IS PROBABLY PROMOTING CELLULAR RESISTANCE. WE DON'T HAVE DATA FOR THAT BUT IT IS ACTIVATING COUNTER REGULATORY RESPONSES, REPAIR MECHANISMS AT THE RIGHT DOSE RATHER THAN THE TOXIC DOSE. SO I THINK OF IT AS HORM OESIS. GORDON AND I HAVE WROTE A PAPER WITHOUT MUCH DATA SUGGESTING THAT HEALTHY AGING SHOULD -- PART OF THAT IS THE RIGHT LEVEL OF MANAGEABLE STRESS AND ENGAGEMENT. >> THANK YOU VERY MUCH, DR. EPEL. [APPLAUSE] >> AND I THINK IT'S FAIR TO SAY THAT WE'VE ALL ENJOYED SUFFICIENT CHALLENGE STRESS FOR THIS MEETING. AND WE'RE RED REDI TO READY DO ADJOURN. >> I'D LIKE TO THANK COUNCIL FOR ALL OF THE DUTY AND ACTIVITIES. ONCE AGAIN, THIS LAST COUPLE OF HOURS OF AN OPPORTUNITY TO HEAR ABOUT SOME OF THE EXCITING SIGH FOR SOME OF US, MAYBE ALL OF US, A GREAT REWARD AND INSPIRATION KEEP GOING, SO IT'S A GOOD POINT TO END, AND WE'LL BE SEEING YOU IN BETWEEN, BUT IF NOT, FOR OUR NT COUNCIL MEETING. WE DON'T HAVE A GAVEL HERE IN THIS BUILDING, BUT WE'RE ADJOURNED NONETHELESS. THANK YOU.