>> GOOD AFTERNOON. AS PEOPLE ARE COMING IN, WE'LL START ON TIME TO NOT SHORTEN THE AVAILABLE TIME FOR THIS LECTURE. AS MANY OF YOU KNOW, THIS IS THE FLORENCE MAHONEY MEMORIAL LECTURE AS PART OF THE WEDNESDAY AFTERNOON SERIES AND I'LL REMIND PEOPLE VERY BRIEFLY THAT THIS WAS THE FLORENCE MAHONEY LECTURE UNTIL SHE PASSED AWAY AT THE AGE OF 103. IT HONORS HER BECAUSE SHE WAS AN ADVOCATE FOR NIH RESEARCH AND HER INTERACTIONS WITH INFLUENTIAL INDIVIDUALS IN HER FAMOUS GEORGETOWN TOWNHOUSE. THOSE OF YOU WHO KNOW THE AREA, THIS IS A VERY FAMOUS LANDMARK AND THE PICTURES OF HER INTERACTING WITH MANY FORMER INFLUENTIAL INDIVIDUALS LED TO THE FORMATION OF NIAS AS AN INSTITUTE ADD SHE SERVED ON COUNCILS. WHEN I WOULD MEET WITH HER PRIOR TO THESE LECTURES AND THE DETERMINATION OF THE SPEAKERS, SHE WAS ALWAYS VERY ADAMANT SHE WANTED SERIOUS SCIENCE. SHE WANTED TO KNOW WHAT IT WAS ALL ABOUT. AND SHE WAS THRILLED WITH TODAY'S SPEAKER, TOM RANDO. TOM WAS BORN IN BROOKLYN LIKE IT SEEMS MOST OF US WERE. HE DID HIS WORK AT HARVARD A YEAR AT MGH AND INTERNAL HOSPITAL AND MOVED TO THE WEST COAST WHERE HE DID HIS NEUROLOGIY TRAINING AT UCS. AND MOVED TO STANFORD WHERE HE HAS BEEN AS PROFESSOR AND DIRECTING THE GLENN PROGRAM IN BIOLOGY OF AGING RESEARCH THERE. HE HAS BEEN RECIPIENT OF MULTIPLE AWARDS AND HAD AN ENORMOUSLY PRESTIGIOUS CAREER IN PURSUING MECHANISMS OF AGING. THE TITLE OF HIS WORK INDICATES, IT CANNILY LOOKING AT ABILITIES TO MODIFY OR RESET THE AGING CLOCK. HE ELUCIDATED SO MUCH ABOUT THE NON-CELL AUTONOMOUS ASPECTS OF CELL AGES, THE BASEBALLSY TO INFLUENCE OF WHICH CELLS BEHAVE BY REGULATING THEIR ENVIRONMENT. HE APPLIED NEW TECHNIQUES AS HE WILL BE DESCRIBING TO US. WITHOUT TAKING ANYMORE FROM THE HOUR WE HAVE WITH HIM, IT'S A GREAT PLEASURE TO INTRODUCE TOM RANDO TO YOU. TOM? [ APPLAUSE ] >> THANK YOU VERY MUCH. IT'S A REAL HONOR TO BE HERE AND TO PAY TRIBUTE TO FLORENCE MAHONEY WHO I HEARD MANY WONDERFUL STORIES AND HER CONTRIBUTION TO THE RESEARCH AND BIOLOGY OF AGING AND THE FORMATION OF NIA. THANK YOU FOR COMING. I'LL BE TALKING TODAY ABOUT GENERAL OVERVIEW OF OUR INTERESTS IN THE BIOLOGY OF AGING WITH THIS PROVOCATIVE TITLE OF RESETTING THE AGING CLOCK AND I WILL SEE A GENERAL BACKGROUND AND THEN TALK ABOUT WORK WE HAVE DONE AS WELL AS WHERE WE ARE GOING IN TERMS OF OUR STUDIES. SO I ALSO LIKE TO START WITH OTHER PEOPLE'S VIEWS OF AGING FROM THERE VOTE QUOTE. I DON'T LIKE TO THINK OF AGING AS ROUGH BUT CHANGING. WITHOUT A DOUBT THERE IS A FUNCTION OF DECLINE WITH AGING. AND SO WHAT I'LL TALK ABOUT TODAY ARE THESE GENERAL QUESTIONS. CAN AGING BE SLOWED? CAN AGING BE ARRESTED AND FINALLY THE MAIN POINT IS, CAN AGING BE REVERSED WITH THE THOUGHT PROCESS THAT LED US FROM ONE TO THE OTHER TO ASK US, WHICH SOUNDS ALMOST A FANCIFUL QUESTION. SO THIS IS IS A STORE THEY STIMULATED LOT OF INTEREST IN HOW WE AGE. SHE IS THE WORLD RECORD HOLDER OF THE PERSON WHO HAS THE LONGEST LIFESPAN ON RECORD, 122 YEARS. SHE DIED MANY YEARS AGO. I NEVER HAD THE PLEASURE OF MEETING HER BUT SHE HAD A WONDERFUL LIFE STORY. THE QUESTION ARISES AS WE LOOK AT PEOPLE WHO ARE LIVING OLDER AND OLDER, WHY IS IT SOME OF US AGE MORE SLOWLY AND OTHERS AGE MORE RAPIDLY? SO I WANTED TO START OFF WITH A COUPLE OF GENERAL POINTS AND THE FIRST POINT I WANT TO MAKE IS THAT WE OFTEN TALK ABOUT AGING AND LONGEVITY IN THE SAME SENTENCE AND I THINK THIS IS A PROBLEM BECAUSE IT IS A DIFFERENT THING. AGING IS A PROCESS AND LONGEVITY IS A MEASURE. AGING RESEARCH HAS STEMMED FROM STUDIES OF LIFESPAN. BUT IN FACT, AGING AND LONGEVITY CAN BE ASSOCIATED. ONE CAN IMAGINE ONE COULD HAVE DEATH, THE END OF LONGEVITY WITHOUT AGING AND THEN I'LL TALK ABOUT THE IDEA OF AGING WITHOUT DEATH. BUT WHY IS LONGEVITY SUCH AN INTERESTING ENDPOINT IS BECAUSE IT'S VERY EASY TO MEASURE AND IT'S VERY RELIABLE. SO PRETTY MUCH YOU CAN COUNT ON AN ORGANISM DYING. SO THAT HASN'T BEEN A PROBLEM. BECAUSE IT'S SO EASY PEOPLE USED THAT AS AN ENDPOINT. SO IT HAS BEEN A PRODUCTIVE APPROACH TO THINKING ABOUT HOW LONG AN ORGANISM LIVES IN TERMS OF ITS RELATIONSHIP TO HOW IT AGES. BUT THIS OTHER FLIP SIDE IS YOU CAN IMAGINE DEATH ABOUT AGING. WHAT ABOUT AGING WITHOUT DEATH? THIS IS A MYTHICAL REPRESENTATION OF WHAT THAT MIGHT MEAN BUT ONCE YOU EXTRAPOLATE THAT INTO THE REAL WORLD, THIS SAY PICTURE WHO HAD THE MISFORTUNE OF GETTING INVOLVED WITH THE GOD WHOSE FELL IN LOVE WITH THE GOD EOSN A DISPUTE WITH ZEUS, SHE ASKED TO GIVE ONE WISH TO KEEP AS THE LOVER AND SHE ASKED TO GRANT MORTALITY. HE DIDN'T GRANT HIM ETUNNEL YOUTH. BUT HE CONTINUED TO AGE AND AGE AND HE TURNED ULTIMATELY INTO A LITTLE CRICKET IN THE CHIRPING AWAY AND BEGGING FOR DEATH. THAT IS AGING WITHOUT DEATH AND IT DOESN'T HAPPEN IN NATURE BUT ONE CAN IMAGINE LIFESPAN AS BEING INACCURATE MEASURE OF HOW WE AGE. SO CAN AGING BE SLOWED IS THE FIRST QUESTION? OF COURSE THERE ISASM EVIDENCE THAT IT CAN AND THE BEST EXAMPLE OF THIS THAT PEOPLE ARE FAMILIAR WITH IS THE IDEA OF CALORIC RESTRICTION. REDUCTION IN CALORIC IN TAKE AND CALORIES WHILE MAINTAINING ADEQUATE NUTRITION. HAD HAS BEEN SHOWN TO EXPAND LIFESPAN FROM YOUTH TO FLIES TO WORMS TO MICE. AND THIS IS ONE OF THE EARLY STUDIES OF MICE FROM RICK'S LAB SHOWING A LIFE CURVE OF WILDTYPE MICE SHOWN HERE AND THEN MICE OF INCREASINGLY REDUCED CALORIE IN TAKE SHOWING THEY LIVE LONGER TO THE POINT WHERE THE AVERAGE LIFESPAN OF CONTROL VERSUS FULLY RESTRICTED MICE IS EXTREMELY DIFFERENT WITH A MUCH LONGER LIFESPAN THAN THE CONTROL. SO IF ONE EXTRAPOLATES TO HUMANS, THIS MEANS HUMANS COULD LIVE TO 150-180 YEARS BY AN EQUIVALENT LEVEL OF CALORIC RESTRICTION. AND ONE ENGAGING IN CALORIC RESTRICTION IN WHICH YOU CAN SHARE YOUR AGONY OF CALORIC RESTRICTION WITH FELLOW MEMBERS OF SOCIETY BUT HAS YET TO BE PROVEN WHETHER THIS IS TRULY GOING TO WORK IN HUMANS ALTHOUGH THERE IS CERTAINLY CIRCUMSTANTIAL EVIDENCE THAT IT MIGHT BE ACHIEVED. BUT THERE IS SOMETHING ELSE IN TERMS OF THE IDEA OF SLOWING AGING THAT I THINK IS EMBEDDED IN HOW WE AGE AS A POPULATION. THIS IS JUST A LIFESPAN CURVE FOR HUMANS FROM THE U.S. SO PEOPLE BORN IN THE EARLY 20th CENTURY WHERE THERE IS VERY LITTLE INFANT MORTALITY. MOST PEOPLE SURVIVED SINCE THE AGE OF 50 OR 60 AT WHICH POINT PEOPLE START TO DIE AND FROM THESE YOU CAN EXTRAPOLATE WHAT THE NEW LIFESPAN IS AND THIS IS THE ACTUAL TABLES TELL US ABOUT WHAT DO LIFE EXPECTANCY IS OF ANY KIND OF COHORT. AND WHAT IS INTERESTING, IF ONE LOOKS AT THE MEAN LIFESPAN ACROSS A CENTURY, THEY START IN 1900, THE MEAN LIFESPAN IN DEVELOPED COUNTRIES WAS BETWEEN 40-60 AND IN THE SPACE OF JUST ABOUT 100 YEARS, THAT IS ALMOST DOUBLED. SO NOW THE MEAN LIFESPAN IS GETTING TO BE ABOUT OVER 80 IN THIS COUNTRY. SO THAT'S AN EXTRAORDINARY EVENT. NOW A LOT OF THAT OF COURSE HAS TO DO WITH THE PREVENTION OF INFANT MORTALITY. A LOT MORE PEOPLE ARE REACHING THE AGE OF 50 OR 60 SO THEY COULD LIVE TO OLDER AGE AND SOMETHING ELSE HAPPENED AND I THINK WE DON'T REALLY UNDERSTAND THAT AND THAT IS THE IDEA THAT PEOPLE WHO ARE AGING NOW ARE MUCH YOUNGER THAN PEOPLE WHO ARE 80 A CENTURY AGO. AND WE DON'T REALLY HAVE ANY WAY TO QUANTIFY THAT BUT I'LL SHOW YOU ONE PIECE OF INFORMATION. HERE IS CHARLES DARWIN AS AN OLDER MAN. AN ADULT, AND THEN AS AN OLDER MAN. IF YOU LOOK AT THESE IMAGES AND WE TRY TO GUESS HOW OLD YOU THINK HE, IS YOU ARE PROBABLY THINKING IN TERMS OF TODAY'S LIFE EXPECTANCY. BUT IN FACT, THIS IS HIS AGE IN HIS PICTURES. I THINK YOU WOULD AGREE FOR A 64-YEAR-OLD PERSON TODAY, THIS PERSON LOOKS MUCH, MUCH OLDER. BIWAYS OF COMPARISON, I WOULD PRESENT ANOTHER ICONIC PERSON FROM OUR OWN GENERATION,SHIRE PERSON 45 YEARS OLD AND IN HER MID 60s. SO OF COURSE THIS IS JUST A SINGLE EXAMPLE. BUT THERE IS NO DOUBT THAT SOMETHING CHANGED IN HOW WE LIVE THAT LEADS US TO BE AS YOU'RE YOUNGER AT AN OLDER CHRONOLOGICAL AGE AND SOMETHING WE DON'T UNDERSTAND. SO CAN AGING BE ARRESTED? I THINK THERE IS A LOT OF GOOD EVIDENCE THAT THIS IDEA OF EXTENDING LIFESPAN BY SLOWING THE PROCESS BY WHICH YOU AGE EXISTS BUT CAN AGING BE ARRESTED? HOW DO WE THINK ABOUT THAT? ONE EXAMPLE OF THIS THAT I THINK IS VERY INTERESTING TO PONDER IS THE IDEA OF REALLY STOPPING THE AGING PROCESS THAT CURSE UNTILE IN NATURE. SO THIS IS A C ELEGANS AND THIS IS A WORM, GOES THROUGH THE EARLY STAGES OF LARVA DEVELOPMENT FOR A FEW DAYS AND THEN AS AN ADULT LIVES FOR 2-3 WEEKS. THAT'S THE NATURAL LIFESPAN, NATURAL CURVE OF THE AGE OF C ELEGANS. WHAT HAPPENS IN THE CASE OF SO-CALLED UNFAVORABLE ENVIRONMENT WHICH FOR EXAMPLE IS THE DEPRIVATION OF NUTRITION, THESE WORMS CAN ENTER A DO YOUER STATE, EXIST IN A STATE FOR SEVERAL MONTHS, MUCH, MUCH LONGER THAN ACTUALLY THE FULL LIFESPAN OF THE ORGANISM AND AFTERWARDS THEY CAN COME OUT OF THIS STATE AND THEN LIVE A NORMAL LIFE. SO WHAT IS THIS REALLY? IT REALLY IS A DISCONNECT BETWEEN THE PASSAGE OF TIME AND THE CHANGE WE CALL AGING. SO IT REALLY IS AN ARRESTING THE AGE PROCESS THAT OCCURS IN RESPONSE TO AN ENVIRONMENTAL STIMULUS. THERE ARE MANY SUCH EXAMPLES OF THESE OFTEN DURING DEVELOPMENT BUT THEY OCCUR AND THEY CAN LEAD TO A MUCH MORE EXTENDED LIFESPAN THAN WOULD BE IN THE ABSENCE OF THESE INTERVENTIONS. I PUT THIS OUT AS ANOTHER DRAMATIC EXAMPLE OF A DISCONNECT BETWEEN THE CHANGES THAT NATURALLY OCCUR AND THE PASSAGE OF TIME N THIS CASE, THIS IS A REPORT THAT CAME OUT SEVERAL YEARS AGO IN WHICH SOME -- FOUND FROM AN EXCAVATION THAT DATED THEM TO THE FIRST CENTURY BC. THEY WERE FOUND IN EXCAVATION AND ORIGINATE FRIDAY THAT TIME. THEY SOOT A DESK FOR SEVERAL DECK SPADES SOMEONE HAD THE IDEA, WHAT WOULD HAPPEN IF WE PLANNEDDED THEM. THEY PLANTED THEM AND THEY GREW PLANTS. SO THIS IS A BETTER CASE OF A REMARKABLE PRESERVATION OF BIOLOGICAL ACTIVITY IN WHAT I WOULD CONSIDER AN ARRESTED STATE. SO A DISCONNECT BETWEEN PASSAGE OF TIME AND CHANGES THAT NATURALLY OCCUR. SO, WITH THOSE KIND OF IDEAS, I'LL TURN TO THIS QUESTION OF CAN AGING BE REVERSED? THEY DIDN'T EMANATE FROM THESE QUESTIONS BUT DID FROM OUR OWN STUDIES. SO I'M GOING TO PRESENT TO YOU SOME OF OUR STUDIES IN AGE BUT THROUGH THE LENSE OF STEM CELL BIOLOGY. AND WE HAVE BEEN VERY INTERESTED IN STEM CELLS AND HOW THEY FUNCTION AND HOW THEY AGE AND HOW THEY EXIST IN THE CONTEXT OF AN AGING ORGANISM, ONE REASON OF WHICH I ILLUSTRATED HERE. ON THE ONE HAND CELLS THAT DIVIDE ARE CONSIDERED TO HAVE REP LA CAATIVE AGING AND THEY HAVE A LIMITED NUMBER OF TIMES THEY CAN DIVIDE. SO CELLS WILL DIVIDE AND AGE THAT WAY BUT THEN AT THE SAME TIME, CELLS ARE NOT DIVIDING. SO FOR EXAMPLE, IN THE BRAIN BUT UNDERGOES CHRONOLOGICAL AGING. SO A NEURON IN THE BRAIN OVER THE COURSE OF DECADES WILL SHOW CHANGES WITHOUT ANY CELL DIVISION. NOW STEM CELLS, PARTICULARLY STEM CELLS IN THE SOMATIC TISSUES, MANY OF THEM EXIST IN A QUIESCENCE STATE WHERE THEY EXHIBIT CHRONOLOGICAL AGING AND THEN ALSO IN RESPONSE OF STIMULI MAY UNDERGO CELL DIVISION. SO THEY MAY HAVE TWO WAYS OF AGING AND VERY INTERESTED IN TRYING TO DISSECT WHICH IS MOST IMPORTANT FOR THE KIND OF CHANGES WE SEE IN THE FUNCTIONAL STEM CELLS WITH AGE. SO ONE OF OUR MAIN AREAS OF INTEREST IS IN THE STEM CELLS THAT EXIST IN SKELETAL MUSCLE AND THIS IS AN EXAMPLE FOR STEM CELLS. SO HERE IS A SINGLE MULTI-NUCLEATED MUSCLE FIBER. MUSCLE CELLS ARE MANY NUCLEI IN ONE CYTOPLASM AND ASSOCIATED WITH THIS SINGLE MUSCLE FIBER IS A SINGLE CELL SHOWN HERE SO-CALLED SATELLITE CELL THAT REPRESENTS A STEM CELL COMPARTMENT OF SKELETAL MUSCLE. AND THESE ARE RARE CELLS. THEY CONSTITUTE A FEW% OF THE NUCLEAR CONTENT OF AN ADULT MUSCLE AND EXIST PRIMARILY IN THE QUIESCENCE STATE FOR THE DURATION OF OF A PERSON'S LIFE. SO WE THINK OF THE TURNOVER OF MUSCLES VERY, VERY LOW AND THEY MAY BE IN A QUIESCENCE STATE IN HUMANS FOR DECADES. IN RESPONSE TO A STIMULUS THEY CAN BE CALLED UPON AS RESERVE CELLS TO ENGAGE IN REMARKABLE TISSUE REPAIR AND REGENERATION AS DEMONSTRATED BACK HIRE. HERE IS A HISTOLOGICAL SECTION OF U.N. INJURED MUSCLE IN RESPONSE AN INJURY SHOWN HERE. THERE ARE A FEW OF STEM CELLS THAT WILL BE ACTIVATING AND WILL PROLIFERATE AND AMPLIFY A LOT AT WHICH POINT THEY DIFFERENTIATE AND INFUSE INTO SMALL MULTINUCLEATED CELLS WE REFER TO AS MYOTUBES HERE, AND THEN THESE WILL MATURE INTO MYOFIBERS OVER THE COURSE OF SEVERAL WEEKS. THIS IS A PROCESS THAT IS A REMARKABLE CAPACITY THAT IS A MARKER OF HOW THESE STEM CELLS CAN FUNCTION AND THESE CELLS ALSO SELF RENEW. SO REPEAT THIS PROCESS OVER AND OVER AGAIN AND MUSCLE WILL CONTINUE TO REGENERATE. SO I WITH RESPECTED TO DISCUSS ONE SIGNALING PATHWAY WE FOUND TO BE IMPORTANT IN THE STEM CELL LINEAGE THAT COMES INTO PLAY IN TERMS OF BIOLOGY OF AGING. SEVERAL YEARS AGO WE STARTED TO ASK THE QUESTION OF THESE SATELLITE CELLS, WHAT CONTROLS THE TRANSITION TO AN ACTIVATED STATE, A PROLIFERATIVE STATE AND THEN A DIFFERENTIATED STATE? ONE OF THE MATH WAYS WE FOUND TO BE IMPORTANT WAS THE NOTCH SIGNALING PATHWAY. WE FOUND IT IS HIGHLY INDUCED EARLY ON AND LEADS TO THE ACTIVATION OF CELLS IN A PROLIFERATION BUT THEN THAT SIGNALING PATHWAY MUST BE INHIBIT THE FOR THE CELLS TO GO ON TO A MORE DIFFERENTIATED STATE. THIS IS JUST AN ILLUSTRATION OF THAT SIGNALING PATHWAY. THE NOTCH SIGNALING PATHWAY IS A LIGAND RECEPTOR SIGNALING PATHWAY IN WHICH BOTH LIGAND AND RECEPTORS ARE TRANSMEMBRANE PROTEINS. SO THIS PATHWAY IS ACTIVATED WHEN A CELL BEARING THE LIGANDS IN WHICH THEY ARE DELTA AS ONE, INTERACT WITH A CELL BEARING ONE OF THE RECEPTORS THAT LEADS TO THE CLEAVAGE OF THE NOTCH AND THE INTRACELLULAR DOMAIN SHOULD TRANSLOCATE TO THE TRANSCRIPTAL ACTIVATOR. THIS IS THE MODEL WE HAVE BEEN WORKING ON IN TERMS OF UNDERSTANDING STEM CELL BIOLOGY. THIS LIGAND DEALT IS UP REGULATED IN RESPONSE TO INJURY IN THIS WHICH THE STEM CELLITS AND THAT ACTIVATES THE NOTCH RECEPTOR AND LEADS TO THEIR PROLIFERATIVE AMPLIFICATION. SO WRAPS WITH AGE? SO I SHOWED THIS PICTURE AS A WAY OF THINKING ABOUT THE REGENITIVE PROPERTIES OF TISSUES IN YOUNG AND OLDER MALES AND THIS IS PICASSO AND SON. A STORY FOR ANOTHER DAY. IF YOU LOOK AT THE TISSUES IN THIS YOUNG BOY, HE HAS REMARKABLE REGENITIVE TISSUES ACROSS ALL AREAS AND WILL LEAD TO RAPID REPAIR WITH ALMOST NO STAR FORMATION. WHEN ONE GETS OLDER, IF ONE INJURIES MUSCLE OR BONE, IT REPAIRS BUT LESS AFFECT AND I HAVE LESS GRAPHIC AND OFTEN OCCURS WITH A PROMINENT FORMATION OF SCAR. SO SOMETHING WOULD CHANGE OVER TIME IN TERMS OF TISSUE REGENITIVE PATHWAYS. THAT ILLUSTRATED THIS HERE FOR SKELETAL MUSCLE IN THE HOUSE -- US MONTH. THIS IS A YOUNG MOUSE AND AN OLD HOUSE AND A VERY OLD MOUSE CONSIST TONIGHT A 90 OR 100-YEAR-OLD HUMAN -- EQUIVALENT TO A -- SO IN THE YOUNG ANIMAL YOU SEE THESE NICE OR REGENERATING MYOTUBES AND CONNECTIVE TISSUE IN BETWEEN THEM AND AS THE ANIMALS GET OLDER AND WE DO THE SAME EXPERIMENT, WE SEE FEWER OF THESE MYOTUBES AND MORE CONNECTIVE TISSUE TO THE POINT AT THIS VERY OLD AGE IS VERY LITTLE REGENITIVE MYOGENESIS AND SCAR FORMATION T ILLUSTRATES THE DECLINING REGENITIVE CAPACITY THAT OCCURS IN LOTS OF TISSUES. SO WE BEGAN TO ASK, WHAT IS THE BASIS OF THIS? WHY IS IT THAT STEM CELLS ARE UNABLE TO REPAIR TISSUES IN THE VERY OLD ANIMALS AND HUMANS COMPARED TO VERY YOUNG ANIMALS AND HUMANS? IT TURNS OUT THAT IT IS NOT THE SIMPLE ANSWER. NOT THAT WE RUN OUT OF STEM CELLS. SO IN MOST CASINGS THERE ARE PLENTY OF STEM CELLS THAT EXIST IN THE TISSUE BUT THEY JUST DON'T SEEM TO FUNCTION PROPERLY. IF YOU COUNT THE NUMBER OF CELLS, THEY MAY DECLINE WITH AGE BUT NOT ENOUGH TO ACCOUNT FOR THIS PROFOUND DEFECT IN REGENITIVE CAPACITY. SO ONE OF THE FIRST EXPERIMENTS WE DID WAS TO ASK IF WE UNDERSTAND THE NOTCH SIGNALING PATHWAY IS IMPORTANT THAT WE LOOK AT THIS PATHWAY IN YOUNG OR OLD ANIMALS, DO WE SEE A DIFFERENCE? WHAT WE'RE ILLUSTRATING IS A RESPONSE TO INJURY. SHOWN BY THIS ORANGE THING HERE AND WE ARE LOOKING IN GREEN AT UP REGULATION OF NOTCHED LIGAND AND YOU SEE ADJAC TONIGHT THIS INJURY, THESE ARE THE MUSCLE FIBERS UP REGULATING THIS NOTCH LIGAND STIMULATING THE STEM CELLS TO ACTIVATE AND PROLIFERATE TO BEGIN TO MIGRATE INTO REPAIR. SO IF YOU LOOK AT OLD ANIMALS, WE SEE ALMOST NO UPREGULATION OF THIS NOTCH LIGAND DELTA. SO THE STEM CELLS ARE THERE BUT THEY ARE NOT GETTING THE SIGNAL THEY NEED TO ACTIVATE. SO THIS IS THE MODEL WE HAVE IN THE YOUNG. IF WE LOOK AT THE OLD WE SEE A FAILURE OF UP REGULATION OF DELTA SO FEWER OF THE CELLS ACTIVATE AND FEWER PRODUCE THESE DIFFERENTIATED MOLECULES. SO THIS ACCOUNTS FOR DECLINE IN REGENITIVE POTENTIAL. SO WE ASKED IF THAT IS THE CASE, IF THIS IS REALLY THE ONE OF THE PRIME DEFECTS, WHAT WOULD HAPPEN IF WE DIRECTLY STIMULATED THE NOTCH PATH WAY NOT RELYING ON UP REGULATION OF THIS ENDOGENOUS LIGAND? SO A EXPERIMENT WE DID WITH A POSTDOC IN MY LAB A DECADE AGO, THIS IS AN AREA OF INJURY AND A CONTROL ANIMAL WHICH PRODUCED AN INJURY AND REGENITIVE MYOGENESIS GOING ON HERE AND THE OLD ANIMAL, SO A LOT OF FIBROSIS. IF WE TAKE AN OLD ANIMAL AND CREATE AN INJURY AND INJECT AN ACTIVATOR OF THAT NOTCH PATHWAY, WE COULD GET REGENERATION THAT LOOKED JUST LIKE AN ADULT ANIMAL. SO THIS IS REALLY HIGHLY EFFECTIVE AND ROBUST FOR GENERATION. SO THIS IS A TURNING POINT EXPERIMENT. SO WE SAID THAT WE KNOW THE CELLS ARE THERE AND WE KNOW IF GIVEN THE RIGHT SIGNALS, EVEN IN OLD TISSUE, ONE CAN STIMULATE A STEM CELL IN OLD TISSUE TO REPAIR AS WELL AS A YOUNG STEM CELL. SO NOTHING IRREVERSIBLE THAT HAPPENED INTRINSICALLY IN THE STEM CELL THAT WOULD MAKE US UNABLE TO REPAIR TISSUE. SO IF THIS THE MODEL OF THE EFFECTIVE AGING, IF WE DIRECTLY ACTIVATE THE NOTCH PATHWAY, WE CAN RESTORE THAT YOUTHFUL REGENERATION TO AN OLD TISSUE. AND BUT WE ALSO ASKED THE QUESTION, OF THE CELLS THAT DO ACTIVATE IN RESPONSE TO THIS AGING ENVIRONMENT, DO THEY ACTIVATE NORMALLY? WE HAD EVIDENCE TO SAY NO BECAUSE WE BEGAN TO LOOK AT THE CELLS THAT EMERGE IN THE STATE OF INJURY TO AN OLD MUSCLE AND THEY SEEM TO BE NOT NEARLY THE SAME KIND OF RESPONSE THAT WE SEE IN THE YOUNG ANIMAL, NOT ONLY QUANTITATIVELY BUT ALSO QUALITATIVELY. SO WE CREATED QUITE A FEW MICE THAT ARE GENETICALLY LINEAGE TRACERS OF MUSCLE STEM CELLS. THIS IS INDUCIBLE CRE RECOMBINASE GENERATED BY KELLER AND PACK 7 IS A GENE EXPRESSED IN ADULT MUSCLE STEM CELLS. THIS IS A WAY OF TURNING ON THE GENE ONLY IN ADULT CELLS. WE CAN CROSS THAT WITH A REPORTER STRAIN WHICH EXPRESSES -- SO WHEN WE CROSS THOSE, WE MINISTER TAMOXIFEN AND THE STEM CELLS EXPRESS -- AT THAT POINT AND ONLY THOSE CELLS. AND WE GET OTHER MARKERS AS WELL SO WE CAN FOLLOW THE FATE OF MUSCLE STEM CELLS IN RESPONSE TO ENVIRONMENTAL STIMULI IN RESPONSE TO AGING. AND WHAT WE FOUND IS THAT IF WE LOOK AT THE PHENOTYPES THIS IS FROM A YOUNG OR OLD, WE SEE CELLS HERE THAT ARE POSITIVE DERIVED FROM BONA FIDE MUSCLE STEM CELLS. FROM THE YOUNG THEY EXPRESS THE MYOGENIC MARKERS AND PRETTY MUCH ALWAYS. BUT IN RESPONSE TO AGING OR IN THIS CASE RESPONSE TO OLD SERUM IN WHICH THE GROWN, MANY OF THE CELLS BEGIN TO EXPRESS THIS DIFFERENT MORPHOLOGY. THEY LOSE THESE MYOGENIC MARKERS AND THEY APPEAR TO ADOPT A MORE FIBROGENIC FOOD. THESE ARE TRUE MUSCLE STEM CELLS IN RESPONSE TO AGING, LOSE THEIR ABILITY TO RETAIN THE MYOGENIC LINEAGE AND BECOME MORE FIBROGENIC. THIS IS QUANTIFICATION OF THAT KIND OF PHENOMENON. WE RARELY SEE THESE PROGENY OF MUSCLE STEM CELLS IN YOUNG BUT WE SEE REALLY QUITE A HIGH PERCENTAGE OF CELLS FROM OLD ANIMALS THAT START OFF WITH MUSCLE STEM CELLS BUT THEN BECOME FIBROGENIC. SO IN ADDITION TO THE PROBLEM WITH NOTCH SIGNALING, LEADING TO IMPAIRMENT OF THE ACTIVATION, THERE IS SOMETHING THAT IS LEADING, SOME OF THESE CELLS TO DIVERGE AND BECOME MORE FIBROGENIC. SO THAT CLEARLY CONTRIBUTES TO THE FACT THAT WHEN MUSCLE, OLD MUSCLE IS INJURED, THERE IS LES MYOJENIC AND PERHAPS MORE FIBROSIS. SO OUR STUDIES HAVE LED US TO ASK THE QUESTION, IF THERE ARE DEFECTS IN NOTCH SIGNALING, CHANGING IN CELL FATE, CAN WE GONE TO UNDERSTAND WHAT IS REGULATING IN THOSE CHANGES AND CAN WE BEGIN TO UNDERSTAND THE SIGNALING DIFFERENT IN AN OLD MUSCLE STEM CELL COMPARED TO A YOUNG ONE? THESE WERE STUDIES DONE WITH A POSTDOC IN MY LAB LOOKING AT SO-CALLED TOP DOWN MICE WHICH ARE REPORTER MICE THAT REPORT ON WNT SIGNALING IN A TISSUE. WHAT ANDY DID, THIS IS A WHOLE MUSCLE FROM THE MOUSE. HE PRODUCED A INJUR NEAN OLD ANIMAL AND FOUND THAT UNEXPECTANTLY THE INJUR -- INJURED AREA IN THE OLD ANIMAL HAD A DRAMATICALLY INCREASE AMOUNT EVER WINTER SIGNALING. HE WAS WONDERING IF THIS WNT SIGNALING ACTIVITY MIGHT RELATE TO OLD MUSCLE STEM CELLS F HE ADDED WNT, AND DRIVE THEM TOWARDS THE FIBROGENIC LINEAGE, IF HE BLOCKED WNT HE COULD MAINTAIN THEM A MYOGENIC LINEAGE. THIS IS IN VIVO DATA LOOKING AT REGENERATION IN YOUNG VERSUS OLD ANIMALS. NOW YOU SEE THE ORANGE COLOR IN THE FIBROSIS IN GREEN. YOU SEE WITH AGING, MANY FEWER FIBROSIS US BUT IF YOU INTRODUCE IT INTO A AGING AND INHIBITOR OF WNT SIGNALING WE GET MUCH LESS FIBROSIS. THIS IS MARKEDLY DECREASED BY BLOCKING WNT SIGNALING. SO WE HAD THIS EXPANDED MODEL THAT NOT ONLY SETHERE A BLOCK EARLY ON OF THIS NOTCH SIGNALING PATHWAY BUT WITH AGING INCREASE IN WNT SIGNALING ACTS ON THE STEM CELLS AND DRIVE THEM FOR THE NONMYOGENIC LIG I. LINEAGE. ANOTHER WAY IN WHICH AGED STEM CELLS ARE BEHAVING DIFFERENTLY FROM ADULT STEM CELLS. THESE ARE VERY INTERESTING PHENOTYPES OF AGING AND WE ARE TRYING TO UNDERSTAND WHAT IS IT ABOUT THIS AGING ENVIRONMENT? CAN WE BEGIN TO ASK THE QUESTION, WHAT CHANGES WITH AGE? IN THE ENVIRONMENT IN THE TISSUE THAT IS INSTRUCTING THE OLD STEM CELLS TO BEHAVE DIFFERENTLY. AND SO WE WANTED TO HAVE A SYSTEM IN WHICH WE COULD ARTIFICIALLY EXPERIMENTALLY MODULATE THE ENTIRE ENVIRONMENT OF A TISSUE WITHOUT INJECTING DRUGS OR INJECTING COMPOUNDS BUT WHERE THE SYSTEMIC ENVIRONMENT OF THAT TISSUE WILL BE CHANGED FROM A YOUNG TO OLD STATE AND WE TURN TO THIS TECHNIQUE THAT HAS BEEN AROUND FOR MANY, MANY YEARS, MANY, MANY DECADES AND THIS IS THE FIRST REPORT OF THIS KIND OF DRAFTING OF ANIMALS IN THE MID 19th CENTURY. AND HE WAS DOING A LOT OF DRAFTING OF BODY PARTS AND DIFFERENT PARTS OF ANIMALS FROM ONE TO ANOTHER AND HE TRIED TO GRAFT TWO ANIMALS TOGETHER. HE FOUND THEY DEVELOPED A SINGLE SHARED CIRCULATORY SYSTEM SO THE TISSUES OF ONE ANIMAL WERE CIRCULATING IN THE ENVIRONMENT OF THE OTHER ANIMAL. THIS HAS BEEN USED OVER THE YEARS TO STUDY ENDOCRINOLOGY AND WE RESURRECTED THIS STUDY OF AGING AND STEM CELL BIOLOGY. SO THIS IS A PHOTOGRAPH THAT ONE OF OUR COLLABORATORS SAW AND TOOK AS A PAINTING BY -- AND I DON'T THINK SHE WAS FAMILIAR WITH THE WRITING OF PAUL BURK BUT WHAT SHE PAINTED WAS HERSELF AS TWO PEOPLE. THIS WAS AFTER HER DIVORCE AND THIS SILENT MORNING AND HER HEART IS OPEN AND SHE IS BLEEDING BUT CONNECTED TO THE HAPPIER DAYS OF FRIEDA WHEN SHE WAS HAPPY WITH DIEGO. ANDED THE IDEA IS THAT ONE PART OF HER IS INFLUENCING THE OTHER PART OF HER. SO THIS ISN'T WHAT WE MODELED OUR EXPERIMENTS ON BUT WE DID FOLLOW ALONG THE WORK OF PAUL BURK TO CREATE THE SO-CALLED -- SO WE OPENED THE CELLS AND STITCHED THEM TOGETHER AND THEY DEVELOPED SPONTANEOUS -- WHEREBY THEY DEVELOPED A SINGLE SHARED CIRCULATORY SYSTEM. SO THE CONTROLLED EXPERIMENTS, SO A YOUNG ANIMAL CONNECTED TO A YOUNG ANIMAL OR AN OLD ANIMAL CONNECTED TO AN OLD ANIMAL. THE INTERESTING EXPERIMENT IS THE HETEROCHRONIC PAIR. YOUNG AND OLD CONNECTED. SO WE CREATE THESE PARABONDS AND LET THE PROCESS DEVELOP OVER MANY WEEKS AND WE LEAVE THEM THIS WAY FOR SEVERAL MONTHS. SO TISSUES OF ONE ANIMAL ARE EXPOSED AND CIRCULATING THE OTHER ANIMAL AND THE QUESTION IS, IN THIS OLD ANIMAL NOW EXPOSED TO THIS YOUTHFUL ANIMAL, IF WE INJUR THE MUSCLE OF THE OLD ANIMAL WHAT HAPPENS? ARE THERE INFLUENCES OF THE YOUNG ANIMAL ON THE OLD AND VICE VERSA? ARE THERE INFLUENCES OF THE OLD ANIMAL IN A NEUROGENITIVE CAPACITY TO THE YOUNG? WE ARE LOOKING AT REGENERATION AND INTERMEDIATE STAGES IN ISOCHRONIC PAIRS WHAT WE FIND IS THAT THEY REGENERATE JUST AS WELL IN YOUNG ANIMALS. HERE ARE EARLY FORMS OF INJURED AREA OF MUSCLE. IN THE OLD ISOCHRONIC PAIRS, HERE IS THE AREA OF INJURY AND YOU SEE REGENERATION ALONG THE BORDER AND A LOT OF FIBROSIS. AS WE TAKE THE HETEROCHRONIC PAIRS AND INJUR THE MUSCLE OF THE OLD MOUSE, WE SEE EXCELLENT REGENERATION. SO CLEARLY EXPOSURE OF ITS OWN TISSUE TO A YOUNG CIRCULATING ENVIRONMENT WAS PROFOUND ENOUGH TO REALLY REPROGRAM THESE OLD STEM CELLS TO BEHAVE LIKE YOUNG STEM CELLS MUCH IN THE WAY WE HAVE SEEN WITH EARLIER EXPERIMENTS. AND IF WE LOOK AT THE MOLECULAR CHARACTERISTICS, DELTA EXPRESSION, NOTCH LIGAND, IT'S HIGH AND YOUNG AND LOW AND OLD. IF WE LOOK AT THE HETEROCHRONIC PARABOND, IT'S INTERMEDIATE. SO IMPROVEMENTS IN THE OLD AND SUPPRESSION ON THE OTHER HAND IN THE EXPRESSION EVER DELTA IN THE YOUNG. AND BASICALLY THE CONCLUSION A LOT OF THESE STUDIES IS THAT WHENEVER WE LOOKED, THE OLD ANIMAL HAS BENEFITED AND THE YOUNG ANIMAL HAS SUFFERED FROM THIS PAIR. SO THIS IS LOOKING AT ENHANCEMENT OF THE AGED PHENOTYPE LOOKING AT AGED LIVER AND LOOKING AT PROLIFERATION OF HEPATOCYTES AND IT'S VERY LOW IN OLD ANIMALS OR ISOCHRONIC PAIRS BUT MARKEDLY ENHANCE IN HETEROCHRONIC PAIRS. IF WE LOOK AT NEUROGENESIS, WE ARE LOOKING AT THE BRAIN IN THE NEUROSTEM CELL COMPARTMENT LOOKING AT THE CORPORATION, NEUROGENESIS IS KNOWN TO PLANT PRECIPITOUSLY WITH AGE. WE CAN ENHANCE THAT SHOWN HERE IN THESE PROLIFERATING CELLS IN THE BRAIN. AND JUST LIKE WITH THE MUSCLE WHEN YOU LOOK AT THE MOLECULAR CHARACTERISTICS, NOT ONLY IS THERE ENHANCEMENT, BUT THE MOLECULAR CRITICS OF THE AGED CELLS ARE MORE LIKE THOSE OF THE YOUNG CELLS. HERE WE ARE LOOKING AT A COMPLEX THAT HAS BEEN SHOWN FROM A LAB AND ABSENT IN YOUNG ANIMALS BUT MARKEDLY INCREASED IN OLD ANIMALS SHOWN IN ISOCHRONIC PAIRS BUT IN HETEROCHRONIC PAIRS IN THE OLD ANIMAL IT'S REDUCED AND INCREASED IN THE YOUNG. SO A NORMALIZING BETWEEN YOUNG AND OLD. HETEROCHRONIC EFFECTS CLEARLY ARE HAVING BILATERAL EFFECTS. SO WHAT CAN MEDIATE THESE AGE-RELATED CHANGES IN THE STEM CELL FUNCTIONALITY? SO THIS IS A DIRECTION WE REALLY HAVE TAKEN NOW TO TRY TO IDENTIFY FACTORS THAT CHANGE WITH AGE, THAT ARE EFFECTED BY PARABIOSIS AND STEM CELL FUNCTION. SO THIS IS A PROJECT THAT IS DONE IN COLLABORATION WITH MY COLLEAGUE IN WHICH WE ARE LOOKING AT NEUROGENESIS AND NEUROGENESIS DECLINES DRAMATICALLY WITH AGE. AND THESE ARE PROLIFERATING NEUROSTEM CELLS IN THE OLD VERSUS THE YOUNG. BUT IN THE HETEROCHRONIC PAIRS IT'S INCREASED COMPARED TO THE OLD ISOCHRONIC PAIRS. SO WE LOOKED IN THE BLOOD OF YOUNG AND OLD ANIMALS AND LOOKED IN THE BLOOD OF THE PARABONDS AND IDENTIFIED THOSE FACTORS THAT BOTH CHANGES WITH THE PARABIOSIS AND INCREASE WITH AGE AND IN FACT, FOUND A RELATIVELY SMALL NUMBER OF PROTEINS AND CYTOKINES THAT FIT THIS KIND OF CRITERIA OF THE CHANGE WITH AGE AND EFFECTIVE PARABIOSIS. SO FOCUS ON A COUPLE OF THESE. I'LL TALK ABOUT CCL11 WHICH INCREASES THE FUNCTION EVER AGE AND WE ASKED, WHAT WOULD HAPPEN IF YOU EXPOSE A YOUNG ANIMAL TO CCL11 ALONE AS A MARKER OF AN AGING CYTOKINE? WE WERE DOING THIS BY USING NONINVASIVE IMAGING LOOKING AT NEUROJEN US? A LIVING MOUSE SHOWN BY THE LIGHT SIGNAL AND EMANATING FROM THE COMPARTMENT. IF WE ADMINISTER A VEHICLE ALONE THERE IS NO CHANG-UP TO DAY 4. BUT IF WE ADMINISTER CCL11 INTO THE VENTRICLE, THERE IS SUPPRESSION EVER NEUROGENESIS WESTERN A FEW DAYS. SO WE LOOKED AT BATTERY OF PROTEINS THAT EXIST AND CHANGE WITH AGE AND LOOK FOR ONES THAT ARE ENHANCING NEUROGENESIS AND OLD ANIMALS ARE SUPPRESSING NEUROGENESIS IN OLD ANIMALS. AND RECENTLY THIS IS WORK FROM TONY'S LAB, TAKING DIRECTLY -- INSTEAD OF DOING PARABIOSIS, TAKING PLASMA FROM YOUNG OR OLD ANIMALS AND DOING TRANSFUSIONS AND INJECTIONS OF PLASMA AND UP TO 8-10 INJECTIONS OF THE COUPLE OF WEEKS TO ASK IF WE CAN MIMIC THE EFFECTS OF PARABIOSIS BY DIRECT INJECTIONS OF PLASMA. AND SO WHAT THEY FOUND IS THAT IN FACT YOUNG PLASMA INJECTED OLD MICE ENHANCES NEUROGENESIS AND LEADS TO NOT ONLY IMPROVEMENT OF FUNCTION BUT BEHAVIORAL ACTIVITIES MEASURED BY A VARIETY OF BEHAVIORAL ASSAYS AND THIS IS JUST TWO GROUPS OF MICE IN THE TRAINING PERIOD. ONE OF WHICH RECEIVED OLD PLASMA AND WHAT WE ARE LOOKING AT IS THE NUMBER OF MISTAKES THEY MADE IN THIS TEST. SO IF THEY RECEIVED OLD PLASMA, THEY MID THIS MANY MISTAKE BUT IF THEY RECEIVED YOUNG PLASMA, THEY RECEIVED REDUCTION IN AREAS OF BEHAVIORAL ASSESSMENT AND A VARIETY OF OTHER BEHAVIORAL TESTS. SO IT IS SEEN AS IF THEY ARE BEGIN ING TO REDUCE THE COMPLEXITY OF THE EXPERIMENT TO SIMPLER BUT STILL COMPLEX IN VIVO EXPERIMENTS AND THEN TO DO THIS IN-VITRO BY ADMINISTERING TO CELLS AND TISSUE YOUNG AND OLD PLASMA AND ASKING WHAT COMPONENTS ARE THERE ARE EITHER SUPRESSING STEM CELL FUNCTION AS A FUNCTION OF AGE OR ENHANCING BY THE YOUNG. SO THIS LEADS TO THE QUESTION IS AGING REVERSIBLE? THIS IS A PAINTING FROM THE 16 CENTURY. AND THIS PAINTING IS RATHER BLEAK VIEW OF AGING BECAUSE IT IS A BLEAK LANDSCAPE WHERE OLDER WOMEN FOR SOME REASON ARE BEING CARVED AND EXAMINED AND THEY ENTER THE FOUNTAIN AND EMERGE AS YOUNG WOMEN AND LED INTO THE TENT WHERE THEY ARE CLOTHED AND THEN ENJOY LOVE AND LIFE AND LAUGHTER. THE QUESTION IS, IS THERE ANYTHING THAT REALLY IS A REVERSING THE PROCESS OF AGING? OUR QUESTION IS, WITH THIS INTERVENTION OF PARABIOSIS, ARE WE DRIVING YOUNG CELLS TO BECOME OLD AND OLD CELLS TO BECOME YOUNG OR IS IT MORE COMPLEX WHERE WE ARE CHANGING A YOUNG CELL OR YOUNG TISSUE TO BE DIFFERENT BUT NOT REALLY OLD IN THE SAME WAY AN OLD TISSUE TO BE DIFFERENT BUT NOT REALLY YOUNG. SO WE ARE REALLY ASKING, ARE WE REALLY WORKING ALONG THIS AGING AXIS IN THESE EXPERIMENTS? AND IS THE AGE ACTIVELY MAINTAINED AND REVERSIBLE? SO SEVERAL STUDIES HAVE COME OUT OVER THE YEARS. REALLY CONVINCED ME THAT WE'RE ON TO SOMETHING IN TERMS EVER THE AGING STATE BEING MAINTAINED AND REVERSIBLE AND THIS IS A FIGURE FROM A PAPER FROM SANG LOOKING AT SKIN AGE. HE FOUND THAT IF YOU LOOK AT OLD SKIN COMPARED TO THE YOUNG SKIN THERE IS NF-KAPPA B IN YOUNG SKIN. SO HE CREATED A YOUNG MOUSE WITH AN INHIBITOR IN AN OLD ANIMAL. WHAT HAPPENS IF NF CAPPA BE IS DRIVING SKIN AGING IS IT MAINTAINING THE PHENOTYPE OF OLD SKIN? WHAT WOULD HAPPEN IF WE BLOCKED IT? WHAT HE LOOKED SAT A COUPLE OF MARKERS AND THIS THE SO-CALLED ASSOCIATED DATA IN THE CELLS AND IN BLUE SHOWN HERE VERY HIGH IN OLD SKIN BUT IF YOU INDUCE WITH NF-KAPPA B INHIBITOR, REVERSE THE AMOUNT OF SIN ESSENCE YOU SEE BY THIS MARKER. ALSO A MARKER OF P16 SHOWN IN BROWN HERE IS REVERSED. SO THIS AGAIN SUGGESTS THAT HE WASN'T DELAYING AGE. HE WAS TAKING OLD TISSUE AND MAKING IT YOUNG AGAIN BY THESE CLINICAL MARKERS AND SHOWED ALSO THE SKIN FITNESS WAS ENHANCE THED IN THE MICE WHERE THE NF CAP B WAS INDUCED. THIS SAY PAPER FROM A LAB AT THE UNIVERSITY OF MICHIGAN WHICH AGAIN IS LOOKING AT THE IDEA NOT OF DELAYING AGING BUT REVERSING. SO WHAT SHE DID WAS ADMINISTERED RAPO MICE IN TO OLD MICE. IT'S BEING USED IN A LOT OF STUDIES TO SHOW OR TO TEST FOR AND HAS BEEN SHOWN TO DELAY AGING IN MICE. BUT THIS IS A QUESTION, WHAT IF YOU TAKE AN OLD MOUSE AND ADMINISTER RIPEO MICE IN FOR A SHORT PERIOD -- DO THEY BEHAVE LIKE YOUNG OR OLD STEM CELLS. AND THEY INCLUDED COMPETITIVE RECONSTITUTION ASSAYS AND IN ALL, THE YOUNG IS SHOWN IN LIGHT AND THE OLD IS SHOWN IN BLACK AND THE RAPPA MICE IN IS IN GRAY AND EACH CASE THERE IS A RESTORATION OR A REVERSAL OF AGING PROCESS TOWARDS A MORE YOUNG PHENOTYPE AS THIS AS SINGLE DRUG FOR A SHORT TIME CAN RESTORE AN OLD STEM CELL POPULATION. SO OUR HYPOTHESES HAS BEEN THAT IF THE AGING STATE IS EPIGENETIC STATE AND DRIVEN BY SKETCHES AND ACTIVELY MAINTAINED AND IT IS STABLE BUT REVERSIBLE. AND SO, A COROLLARY OF THIS IS THAT THE REJUVENATION THAT WE'RE SEEING IS REPROGRAMMED. SO I WANT TO FOCUS ON THIS IDEA OF REPROGRAMMING. IN THE IDEA OF AGING AND I WANTED TO DISCUSS IT IN THE SYSTEM THAT I THINK IT IS SOMETHING VERY, VERY FAMILIAR TO EVERYBODY IN THIS ROOM. AND IT'S PLURIPOTENCY. SO THIS REMARKABLE STORY OF INDUCED PLURIPOTENT STEM CELLS FOCUSING ON THE IDEA THAT ONE COULD TAKE A DIFFERENTIATED CELL AND UNDERGO DIFFERENTIATION BY A VARIETY OF FACT EXPOSE PRODUCE THESE PLURIPOTENT STEM CELLS WHICH COULD REDIFFERENTIATION THESE TISSUES. SO THIS HAS BEEN OBVIOUSLY A HUGE AND REMARKABLE SUCCESS IN UNDERSTANDING PLURIPOTENCY AND OTHER ASPECTS OF CELL BIOLOGY. BUT I WOULD ARGUE THERE IS SOMETHING INTERESTING GOING ON THAT HAS RECEIVED MUCH LESS ATTENTION AND THAT IS IN THE EXPERIMENTS THESE CELLS CANNOT ONLY DIFFERENTIATE BUT THEY ARE OLD N GENERAL THESE STUDIES ARE DONE BY ADULT ANIMALS SO THEY ARE NOT OLD OLE' BUT THEY ARE NOT USEFUL IN PLURIPOTENT CELLS. THEY ARE DULL CELLS THAT WHEN THEY ARE DIFFERENTIATED, THEY ARE REJUVENATED IN THE AIMING PROCESS HAS BEEN ACCEPTED. THESE ARE CELLS THAT ARE NOW ABLE TO GIVE RISE TO A GERMLINE AND ABLE TO GIVE RISE TO MEMBERS OF THE SPECIES. SO THESE CELLS THEN HAVE THE CAPACITY TO GIVE RISE TO A ORGANISM STARTING FROM ESSENTIALLY AN AGING -- AND THEN THESE CELLS CAN AGE AGAIN AND DIFFERENTIATE AND YOU DOCK THIS OVER AGAIN. IN THIS SENSE, TECHNOLOGY IS ABOUT RESETTING DIFFERENTIATION PROGRAMS AND THE AGING CLOCK. THIS IS SOMETHING THAT HAS BEEN KNOWN SINCE THE TIME OF THERAPY -- THE SAME THING HAPPENED IN THERAPEUTIC CLONING. THIS IS DOG AND SHEEP. MAMMALIAN CLONING. SO DOLLY WAS GENERATED BY AN ADULT THEREFORE A CELL WITH A SOMATIC CELL BY SOMATIC CELL NUCLEAR TRANSFER CREATING A SHEEP THAT COULD THEN GIVE RISE TO MORE SHEEP. SO THIS IS CLEARLY THE NOTION OF AN OLD CELL BECOMING A YOUNG CELL AND THEN THAT PROCESS OF AGING AND REJUVENATION OCCURRING OVER AND OVER AGAIN. AND IT'S SO FIRMLY EMBEDDED THAT I DON'T THINK WE OFTEN THINK HOW COMMON IT IS REALLY NOT A SURPRISE IN FINDINGS BECAUSE WHEN YOU THINK OF ANY FERTALIZED EGG, YOU THINK OF A HUMAN FERTALIZED EGG THAT OCCURS BY THE FUSION OF TWO CELLS THAT ARE PERHAPS DECADES OLD IN TERMS OF SPERM AND EGG, FUSING TOGETHER AND FORMING A CELL THAT HAS AN AGE OF ZERO. THIS CELL STARTS THE AGING PROCESS OVER. SO WHATEVER THAT MAY BE, BY SOME SELECTION PROCESS, SOME PROTECTION OF GENOME, CLEARLY THERE IS SOMETHING THAT OCCURS WITH EVERY FERTILIZATION THAT IS THE BASIS OF THE ESSENCE OF METAZONE LIFE. SO THIS IS A THAT'LL HAS WHATEVER AGING ASPECT FOR PRESENCE OF THE SPERM IN THE EGG HAS BEEN ERASED AND THE CELL HAS NOW AN AGE OF ZERO. SO THE IDEA OF RESETTING IS CLEARLY AN INTEREST IN FUNDAMENTAL IMPORTANCE FOR THE BIOLOGY OF LIFE. SO THERE IS AN INTERESTING THING ABOUT THINKING OF THIS TECHNOLOGY, FERTILIZATION, NUCLEAR TRANSFER. THEY ALL OCCUR TOGETHER. DIFFERERENCEATION AND REJUVENATION OCCUR AS PART OF ALL OF THESE PROCESSES AND OUR QUESTION IS, CAN WE UNDOUBLE THIS? CAN WE TAKE CELLS THAT ARE OLD AND MAKE THEM YOUNG WITHOUT DIFFERENTIATING THEM? THAT'S WHAT WE THINK WE ARE DOING. WE ARE TAKING OLD MUSCLE CELLS AND MAKING YOUNG ONES. NOT MAKING THEM PLURIPOTENT CELLS BUT WE ARE ASKING, ARE WE MAKING THEM YOUNG CELLS? AND YOU SEE WITH THE CAPPA B AND RAPPA MICE IN TREATMENT. SO WHAT IS REJUVENATION WITH DEDIFFERENTIATION? HOW DO WE ASK THAT QUESTION? THESE ARE THE FUNDAMENTAL QUESTIONS WE ARE PURSUING IN THE LAB. CAN WE BEGIN TO ASK HOW SIMILAR ARE YOUNG CELLS TO REJUVENATE SELLS? ARE THEY THE SAME? ARE THEY DIFFERENT? ARE WE DRIVING WHAT IS OTHERWISE AN OLD CELL TO BECOME YOUNG? IN TERMS OF REJUVENATION? AND SECONDLY, HOW DO WE DIE FINE CELLULAR AGE AT THE MOLECULAR LEVEL? THIS GETS DOWN TO THE FUNDAMENTAL LEVEL OF HOW TO DEFINE AGE OF THE CELL? WE DON'T HAVE ANY MOLECULAR DEFINITION OF CELLULAR AGE AND IT WILL BE BY DOING THAT WE WILL KNOW FOR SURE IF WE ARE CONVERTING AN OLD CELL TO A I DON'T THINK SELL. SO I'LL PRESENT SOME OF THE RECENT STUDIES AND IN THE AFTERNOON IN TALKING ABOUT HOW WE ARE LOOK THE THIS AT THE TRANSCRIPTIONAL LEVEL. SO WE ARE ABLE TO PURIFY ON THESE MUSCLE STEM CELLS FLOW CYTOMETRY AND WE CAN LOOK AT TRANSCRIPTIONAL PROFILE ACROSS THE GENOME. IF WE COMPARE OLD CELLS TO YOUNG CELLS IN UNSUPERVISED CLUSTERS, FIRST OF ALL, THEY ARE SIMILAR. IT'S NOT AS IF THE TRANSCRIPTIONAL PROFILE OF THE CELL CHANGES DRAMATICALLY. THIS ARE INTERESTING DIFFERENCE BUS THEY ARE REMARKABLY SIMILAR. IF WE LOOK AT CELLS FROM -- THE YOUNG AND OLD CELLS ARE MORE SIMILAR TO EACH OTHER THAN THEY ARE TO YOUNG OR OLD CELLS. SO THIS IDEA THAT WE'RE CONVERGING SOMEWHERE BETWEEN SUPPORTED BY THIS TRANSCRIPTIONAL DATA AND IF WE LOOK AT THE AVERAGE EXPRESSION ACROSS THE WHOLE GENOME OF YOUNG CELLS, ALL THE TRANSCRIPTOME IN THE YOUNG CELLS VERSUS OLD CELLS, THEY ARE VERY HIGH LOW CORRELATED WITH A TIGHT CORRELATION. BUT IF WE LOOK AT THE PARABIOSIS CELLS, THERE IS EVEN MORE OF A STRICT CORRELATION BETWEEN STEM CELLS THAT HAVE BEEN ISOLATED FROM HETEROCHRONIC YOUNG AND OLD ANIMALS. THIS TRANSCRIPTIONAL PROFILE LOOKS AS IF IS IT FINDING SOME OF THE MEDIANS TO YOUNG AND OLD AND CELLS ARE REMARKABLY SIMILAR. IF WE DO PRINCIPAL COMPONENT ANALYSIS WE SEE THIS PHENOMENON. SO IF WE SEE THESE THREE GROUPS OF SAMPLES CLUSTERING TOGETHER FROM THE YOUNG AND CLUSTERING TO THE OLD, SO WE THINK OF THIS AS THE AGING AUXIN'S THIS COMPONENT WHERE THE YOUNG CELLS ARE POSITIONED HERE AND AGING IS HAPPENING. AND IF WE THEN LOOK AT THE PARABOPPED THEY ARE DISPLACED OFF THE AXIS BECAUSE WE THINK THE EFFECTS OF PARABIOSIS ITSELF. BUT THE DISPLACED POSITION IN THE MIDDLE OF THIS AXIS SO THE YOUNG PARABIOSIS AND THE OLD ARE FALLING IN THE MIDDLE OF THIS AGING AXIS. IN DEED IF WE LOOK AT GENES WE FIND THOSE GENES DOWN REGULATED WITH AGE ALMOST ALL OF THEM ARE REJUVENATED MEANING THEY ARE RETURNING MORE TOWARDS THE YOUTHFUL STATE AND GENES THAT ARE UP REGULATED WIT AGE MOST OF RE -- ARE REJUVENATED AND DOWN REGULATED TOWARDS THE YOUTHFUL STAGE. SO THE TRANSCRIPTIONAL APPEARANCE OF OLD CELLS SUBJECT TO THIS REALLY LOOKS LIKE THE REJUVENATION BY THIS CRITERIA. AND SO WE HAVE OBVIOUSLY DUG DOWN INTO THE TRANSCRIPTIONAL DIFFERENCES AND I'M GOING MENTION SO I WON'T TALK ABOUT THE DATE IN DETAIL. IF WE SEE DIFFERENCES EVEN THOUGH THE TRANSCRIPTOME IS SIMILAR, THERE ARE SOME INTERESTING DIFFERENCES. ONE EVER THEM WE SEE DIFFERENCES IN WNT GENES VERY INTERESTING IN LIGHT OF OUR FINDING OF WNT AS PROMOTING AGING PHENOTYPE AND THE SECOND IS IN TERMS OF CHROMATIN REMOLOGYING FACTORS AND I'LL TALK ABOUT THAT IN TERMS OF OUR CHROMATIN STUDIES. AND OUR COLLEAGUE IS LOOKING AT THE SAME KIND OF TRANSCRIPTIONAL ANALYSIS IN PARABY OXIS LOOKING AT THE BRAIN FROM CHRONIC AND ISOCHRONIC PAIRS AND THEY FOUND INTERESTING DIFFERENCE THAT IS OCCUR AND INTERESTING PATTERNS OF GENE EXPRESSION THAT OCCUR IN ISOCHROME TICK CREATE THESE KIND OF NETWORK DIAGRAMS AND TO LOOK FOR WHAT ARE THE KEY NODES THAT CHANGE IN PARABIOSIS THAT SUGGESTS THAT OLD CELLS BECOME YOUNG AND YOUNG CELL BECOME OLD AND THEY FOCUS IN ON THESE GENES THAT ARE KNOWN TO BE IMPORTANT TO REGULATE SYNAPTIC TOXICITY WITH AGE THAT MAY BE MORE OF A FEATURE OF DIFFERENTIATED NEURON ITSELF. IS IF WE ASK THIS QUESTION ABOUT WHAT ARE WE DOING WITH THESE INTERVENTIONS, IS IT REALLY MOVING ALONG THE AGING AXIS VERSUS JUST ALTERING THE PHENOTYPE OF THE CELLS, WE ARE BEGINNING TO FAVOR THE IDEA THAT WE REALLY ARE BEGINNING TO LOOK AT MOVEMENT ALONG THE AGING AXIS WITHOUT CHANGING THE DIFFERENTIATED STATE OF THE CELLS. SO I'LL END BY TALKING ABOUT OUR IDEAS OF LOOKING AT THE CHROMATIN STATE OF EACH CELL BECAUSE IN THE END WE THINK THAT UNDERSTANDING THE NATURE OF THE CHROMATIN PROFILE, THE EPIGENETIC PROFILE, IS GOING TO DEFINE WHAT IS ULTIMATELY A YOUNG AND OLD CELL. AND WE'LL DEFINE HOW A YOUNG CELL CAN BECOME AN OLD AND WE'LLOY YOUNG CELL AN OLD CELL MUCH IN THE WAY EPIGENETIC PROFILES DEFINED A PLURIPOTENT STATE TO THE DIFFERENTIATED STATE. SO WE WERE LOOKING AT BOTH HISTONE MODIFICATIONS AND DNA ISOLATION PATTERNS. I'LL TALK ABOUT OUR STUDIES IN THE HISTONE MODIFICATIONS. AND THE QUESTION IS, THERE IS A HISTONE CODE? WILL WE BE ABLE TO PULL OUT AND SAY AN OLD CELL HAS THIS PATTERN AND DISTRIBUTED IN THIS WAY ACROSS THE GENOME AND DIFFERENT FROM THE YOUNG CELL? CAN WE FIND THOSE HISTONE PATTERNS SHIFTING BETWEEN CELLS IN THESE MODELS? SO THIS IS JUST SOME CHIP-SEQ ANALYSIS LOOKING AT YOUNG STEM CELLS FIRST. SO TWO SPECIFIC MARKS, TRIMETHYLATION OF HISTONE 3 AND TRIMETHYLATION OF LYSINE 27. SO THESE ARE CONVENTIONALLY TO MARK GENES THAT ARE ACTIVELY TRANSCRIBED VERSUS GENES THAT ARE REPRESSED. AND THEN INTERESTINGLY, BIVALIANT DOMAINS ARE GENES THAT EXPRESS BOTH OF THESE MARKERS AND IN THE PLURIPOTENT STEM CELLS ARE CAPABLE EVER BEING ACTIVATED. IN YOUNG STEM CELLS WE LOOK AT THE HISTONE CODE, THE VAST MA JORITY OF GENES ARE MARKED BY K4 TRIMETHYLATION. VERY, VERY FEW CELLS ARE MARKED BY ONLY K27 TRIMETHYLATION. SO THEN MOSTLY ACT IIVE, AND VERY, VERY FEW ARE REPRESSED BUT STILL QUITE A FEW GENES EXPRESS BIVALIANT DOMAIN. WE HAVE BEEN LOOKING AT THESE DOMAINS AND WHAT GENES SHOW THEM AND IT IS INTERESTING BECAUSE WE LOOK AT THE ANALYSIS OF THE PATHWAYS THAT ARE ENCODED BY THESE GENES. THEY ARE PATHWAY THAT IS YOU WOULD NOT HAVE PREDICTED TO BE OCCURRING IN MUSCLE STEM CELLS. WE ARE BEGINNING TO UNDERSTAND THAT PERHAPS SOMATIC STEM CELLS BIVALIANT IN EMBYRONIC STEM CELLS. BUT AS WE GET BACK TO THESE GENES AND TARGETS WE ARE INTERESTED IN. IF WE LOOK AT TWO OF OUR FAVORITE PATHWAYS SO THE NOTCH TARGET GENES AND WNT TARGET GENES, WHAT IS INTERESTING IN YOUNG MUSCLE STEM CELLS IS NOTCH TARGET GENE ARE ALL MARKED BY K4 TRIMETHYLATION BUT NOT BY K27. SO INDICATIVE OF ACTIVE GENE TRANSCRIPTION WHEREAS ALL THE WNT TARGET GENES ARE BIVALIANT. HAVE K4 AND K27 TRIMETHYLATION. WE DON'T UNDERSTAND THIS YET BUT IT'S AN INTERESTING SIGNATURE THAT WE WILL NOT HAVE PREDICT FRIDAY WHAT WE BEEN NOTCH SIGNALING IN YOUNG STEM CELLS. SO THEN IF WE COMPARE YOUNG STEM CELLS TO OLD STEM CELLS, HISTONE PATTERNS OF EPIGENETIC PATTERNS ARE VERY INTERESTING AND UNEXPECTED. HERE WE ARE LOOKING AT A ACTIVE MARK K4 TRIMETHYLATION LOOKING AT YOUNG STEM CELLS SEEN IN YELLOW AND OLD STEM CELLS IN BLUE, JUST LOOKING AT THE DISTRIBUTION OF THE MARKS ABOUT THE TRANSCRIPTION START SITE OF ALL THE GENES IN THE GENOME. WE SEE THAT THE ENRICHMENT FOR K4 TRIMETHYLATION IS HIGHER IN THE YOUNG THAN OLD. BUT WHAT IS INTERESTING WE LOOK AT THE SUPPRESSIVE MARK, THERE SAY LOT OF ENRICHMENT IN OLD AND ALMOST NONE INDEPENDENT YOUNG. SO THE YOUNG STEM CELLS APPEAR TO HAVE A REAL GIRTH OF ENRICHMENT OF H3K27 TRIMETHYLATION. WHEREAS WITH AGE, THERE SAY MARKED ENRICHMENT OF THIS REPRESSIVE MARK ACROSS THE GENOME IN STEM CELLS. AND THIS IS JUST ANOTHER WAY TO LOOK AT THIS. SO NOW WE ARE LOOKING AT TRANSCRIPTION STARTS HERE 5 PRIME AND 3 PRIME. YOUNG STEM CELLS ARE HIGHLY ENRICHED IN THIS ACTIVATING MARK. BUT IF YOU LOOK AT THE REPRESSIVE MARK, ALMOST COMPLETELY ASKING ACROSS THE GENOME FOR GENES IN YOUNG STEM CELLS BUT HIGHLY ENRICHED ACROSS THE GENOME IN OLD STEM CELLS. SO THIS IS THE KIND OF DATA THAT WE'RE GETTING. WE ARE DOING CHIP SEEK ANALYSIS AND OTHER TRANSCRIPTIONAL ANALYSIS TRYING TO LOOK AT PATHWAYS AND GENES TO UNDERSTAND WHAT MIGHT BE THE IMPORTANT PATTERNS EMERGING NOT ONLY IN THESE STEM CELLS BUT IN OTHERS. SO TO LOOK AT NEUROSTEM CELLS YOUNG AND OLD AND DO WE FIND THAT SOME OF THE THINGS WE ARE FINDING ARE SHARED BETWEEN STEM CELLS AS A FUNCTION OF AGE? THEREBY TRYING TO COME UP WITH WHAT IS TRULY EPIGENETIC SIGNATURE OF STEM CELL AGING AND THEN OBVIOUSLY THE NEXT STEP WILL BE TO UNDERSTAND HOW THE MODIFICATIONS ARE OCCURRING AND ARE THESE MODIFICATIONS WHAT WE ARE CONTROLLING AS INCH VENING WITH HETEROPRIMERS OR OTHER REJUVENATING INTERVENTIONS? SO I WANT TO END BY RETURNING TO THE YOUTH AND ASK THERE QUESTION, WHAT ARE WE DOING HERE? AND ARE WE LEARNING SOMETHING ABOUT THE NATURE OF AGE? I THINK WE ARE. WE ARE SETTING UP FOR SOMETHING THAT OCCURS NATURALLY. BUT IT DOES RAISE THE QUESTION OF, HOW WE THINK ABOUT THE AGED STATE AND HOW WE THINK ABOUT IT BEING ALTERED IN A WAY TO MAKE CELLS MORE YOUTHFUL. NOT TALKING HERE ABOUT TRYING TO MAKE ENTIRE ORGANISM MORE YOUTHFUL BUT AN APPLICATION WHEREBY ANY OLD INDIVIDUAL IF YOU COULD ADMINISTER TREATMENT AT A TIME OF AN INJURY, TO MAKE THOSE STEM CELLS MORE YOUTHFUL AND MORE ACTIVE DURING THE STATE OF REGENERATION, NOT IN ANY CHRONIC WAY AND NOT DISTRIBUTE THROUGHOUT THE BODY, BUT IN A TEMP LEEWAY, ONE COULD ENHANCE TISSUE REPAIR AND EN FANS FUNCTIONALITY IN OLDER INDIVIDUALS BY MODULATING THE CHROMATIN STATE AND THE TRANSCRIPTIONAL STATE OF THE STEM CELLS. SO I WANT TO END BY ACKNOWLEDGING A LOT OF PEOPLE IN THE LAB WHO DID THIS WORK AND REALLY IS THE WORK OF MANY, MANY PEOPLE IN PARTICULAR A LOT OF THE WORK ON EPIGENETICS IS DONE BY TOM CHUNG AND MY POSTDOCS IN THE LAB DOING THIS WORK STARTING WITH TRANSCRIPTIONAL PROFILING AND EPIGENETICS AND A LOT OF OTHER STUDENTS AND LABS. I WANT TO ACKNOWLEDGE MY FORMER COLLEAGUES WHO REALLY LED US UP TO THESE STUDIES IN TERMS OF UNDERSTANDING THE BIOLOGY OF AGING AND THESE PARABIOTIC STUDIES AND THE SIGNALING PATHWAYS CONTROL THEM. STAMFORD IS INTERESTED IN STUDYING THESE TOGETHER AND WORKS MOSTLY IN THE BRAIN AND LOOKING AT THE TRANSCRIPTOME EPIGENOME AND THE PROTEOME WHICH IS ONE OF TONY'S AREAS OF EXPERTISE, UNDERSTAND COMING PROTEINS ARE CHANGING IN THE SYSTEMIC ENVIRONMENT THAT ARE INFLUENCING STEM CELL FUNCTION AND MY COLLEAGUES ANNE AND STEVE AND DIFFERENT KINDS OF TRANSCRIPTIONAL CHANGES THAT OCCUR AND WHAT INFLUENCES AND HOW THAT CONTROLS STEMCELL AGING ACROSS DIFFERENT TISSUES AND I WANT TO ACKNOWLEDGE THE AMAZING SUPPORT I HAD FROM THE NIH NIA. IT'S BEEN GREAT WORKING WITH THE NIA IN THE PROGRAM OFFICERS AND THE PEOPLE IN THE INSTITUTION. IT'S BEEN A GREAT INTERACTION AND WE ARE VERY GRATEFUL. WE HAVE NICE SUPPORT FROM THE GLENN FOUNDATION AND THE AMERICAN FEDERATION OF AGING RESEARCH AND THE DEPARTMENT OF VETERAN'S AFFAIRS HAS ALSO CONTRIBUTED. WITH THAT I'LL STOP AND I'LL BE HAPPY TO TAKE ANY QUESTIONS. THANK YOU. [ APPLAUSE ] >> THANK YOU. I WILL ASK PEOPLE TO COME UP TO THE MICROPHONES WITH QUESTIONS. LET ME ASK ONE QUESTION ABOUT YOUR INTERPRETATION OF THE SOME OF THE PARABIOTIC EXPERIMENTS. ONE COULD LOOK AT EXPERIMENTS IN WHICH YOU REVERSED THE AGE-RELATED DEFECTS IN MUSCLE STEM CELLS OR NEURONS AS INDICATION THAT THERE ARE SELECTED TISSUE THAT IS HAVE SUFFERED AS A RESULT OF AGE INTRINSICALLY AND THEN OTHERS THAT HAVE NOT SO THAT MUSCLE STEM CELLS AND NUR ONLY CELLS WERE PRESERVED AND IT'S DEFECTS ELSEWHERE SO THAT RESPONSIVENESS TO DELTA LIGAND IS AGO BUT DELTA LIGAND IS MISSING. SO THAT INTERPRETATION IS SELECTIVE LOSSES AND ONE CAN REPLACE THEM. THE ALTERNATIVE IS THAT THERE ARE PERVASIVE CHANGES IN ALL THESE CELLS AND IT'S THE NET EFFECT IN THE ENVIRONMENT AND THE MORE COMPLEX SYSTEMS WAY THAT RESULT IN VE VERSABILITY. CAN YOU COMMENT ON THE ABILITY TO DISTINGUISH BETWEEN THOSE TWO? >> SO WE HAVEN'T REALLY TRIED FORMALLY BUT I WOULD SAY THAT ANECDOTALLY WHEN WE LOOKED AT FUNCTIONALITY OF CELLS YOUNG AND OLD CELLS, I JUST THOUGHT WE HAD SEEN EXAMPLES OF CELLS THAT HAVE PRESERVED FUNCTIONALITY ACROSS THE AGING SPECTRUM. I THINK THAT IS THE IMPLICATION. SO THAT WOULD BE THE FIRST THING. WE HAVEN'T FOUND THAT. IT DOESN'T MEAN IT DOESN'T EXIST. AND I THINK THAT WHAT IS UNIFYING THEORY OF WHAT WE HAVE FOUND IS THAT REALLY IT IS A SYSTEMIC -- THAT IS INFLUENCING THE TISSUES ACROSS THE BODY AND THAT CAN BE MODIFIED SYSTEMICALLY IN EVERY TISSUE. SO WE ALSO HAVE NOT FOUND ANY TISSUE THAT IS IS NOT RESPONSIVE TO CHANGE. SO WHILE FORMERLY WE HAVEN'T EXCLUDED, I THINK MOST OF OUR DATA SUPPORTS THE LATTER INTERPRETATION. >> GLAD TO HEAR THERE IS SOME EXCITING FEATURES AND EPIGENETICS FOR REVERSING THE POSSIBILITY. I AM THINKING AT MY AGE OF 71 WITH 7 BILLION PEOPLE, THEY WILL HAVE A GRACEFUL ENVY. AND SO, WE HARDLY -- APOPTOSIS. BUT IT HAPPENS TO THE LEAVES NOT THE WHOLE TREE. SO WILL YOU FIND SOME SWITCH THAT IS HELP US TO RESERVE THIS PLANET SO THE YOUNGER GENERATION CAN ENJOY BETTER? >> YOU'RE ASKING HAVE WE FOUND THE -- I MISSED A COUPLE OF WORDS. HAVE WE FOUND -- >> THE ELDERLY PEOPLE LIKE US, TO -- IN A GRACEFUL WAY. LIKING NOT ROTTING. >> AGAIN, I THINK THE MAIN FOCUS OF THE WORK AT FLEET MY POINT OF VIEW AND ANY KIND OF TRANSLATIONAL APPLICATION IS ABOUT HEALTH CARE. NOT LIFESPAN. IT'S NOT TO MAKE PEOPLE LIVE LONGER IT'S TO PRESERVE FUNCTIONALITY TO ENHANCE PRESERVATION OF ACTIVITY AND GRACEFUL EXIT AS YOU SAY IN A WAY THAT WE COULD DO TISSUE BY TISSUE RATHER THAN SYSTEMICALLY. I DON'T FINISH THAT ADDRESSES YOUR QUESTION -- I DON'T KNOW IF -- >> [ OFF MIC ] >> WE'LL TRY. >> I HAVE A QUESTION ABOUT THE HETEROCHRONIC PARABIOSIS EXPERIMENT. YOU ARE CITING A LOT OF DIFFERENCES FOUND IN THE OLD POPULATION WITH THE DEGENERATIVE POTENTIAL IN THE AGED ANIMAL. DID YOU DO THE OPPOSITE AND LOOK AT THE YOUNG ANIMAL AND SEE IF THE OLD MILL YOU NEGATIVELY EFFECTED REGENITIVE REPLICATION IS THIS. >> YES. I THINK I PROBABLY BREEDS BY THAT IN PART BECAUSE OUR INITIAL INTEREST IS PERHAPS THE MOST EXCITING, THE IDEA OF REVERSING AGING. BUT WITHOUT IT, THERE IS NO FREE LUNCH. SO EVERY EXPERIMENT WE DID IN WHICH WE HAVE DONE WITH HETEROPARABIOSIS, INDICATES THE OLD MILL YOU SUPRESSES STEM CELL FUNCTION IN THE YOUNG ANIMAL AT EVERY LEVEL. SO THE ONE PIECE OF DATA I SHOWED IS WE FOUND THIS ONE AT CCL11 THAT INCREASES AGE. IF WE ADMINISTER THAT CHROMATIN LET ALONE THE WHOLE PARABIOTIC PARADIGM TO THE YOUNG ANIMAL, IT SUPRESSING NEUROSTEM CELL FUNCTION. WE STARTED OFF BEING INTERESTED IN THE REJUVENATING FACTORS AND THEN BECAME MORE INTERESTED BECAUSE IT SEEMED TO BE SO -- MAYBE MORE DOMINANT IN AGING FACTORS. SO I THINK THAT DOMINANT INFLUENCE IS THE AGING INFLUENCE AND IT IS MORE DIFFICULT TO REVERSE THE AGING THAN IT IS FOR MOST OF THE AGING IN THE YOUNG. BUT ABSOLUTELY. AND EVER SINCE YOU LOOKED AT THE INFLUENCE OF THE OLD ON THE YOUNG WERE THE SUPPRESSIVE ONE. >> THANK YOU. >> TELL ME, ONE FURTHER QUESTION ABOUT THE IMPACTS OF PARABIOSIS IN EITHER DIRECTION. AND THE LIKELIHOOD THAT THEY'LL BE MEDIATED BY ONE OR A SMALL NUMBER OF FACTORS VERSUS MANY. IF I REMEMBER CORRECTLY, IN ONE OF THE QUESTIONS I'M LOOKING AT BRAIN FUNCTION AND IDENTIFYING A NUMBER OF CANDIDATE MOLECULES, YOU'RE ABLE WITH AN ANTIBODY TO ONE, REPRODUCE SOME OF THE SYSTEMIC EFFECTS. THAT'S MANIPULATING ONE FACTOR, I REMEMBER THAT WAS IN THE WRONG DIRECTION. THAT WAS DECREASING FUNCTION. AND IN REGARD TO COMMENTS YOU JUST MADE, THEREFORE LIKELY BE EASIER TO FIND ANYONE OF MANY THINGS THAT WILL MAKE THINGS WORSE BUT WILL IT BE MORE CHALLENGING TO FIND ONE, A SMALL NUMBER OF FACTORS THAT WILL MAKE THINGSET? >> I DON'T KNOW -- I PREDICT THAT IS TRUE. BUT I THINK WHAT MAY BE INTERESTING IS THAT WHY WOULD ONE FACTOR DO THIS? SO YOU FIRST HAVE THIS EXPERIENCE AND EVERYONE WAS ASKING TO BE FOUND THE FACTOR AND MY RESPONSE IS, THERE IS NO WAY THIS WILL BE A FACTOR. AND YET SO I THINK THIS IS REALLY AN INTERACTIVE NETWORK IN WHICH WE INTERVENE IN ONE AREA WE CAN DISTURB THE NETWORK GENERAL TOW CREATE A MORE YOUTHFUL OR MORE AGE ED PHENOTYPE. THE REAL QUESTION IS ENDURANCE. WE DON'T REALLY THAN HERE. IF WE CREATE A MORE YOUTHFUL PHENOTYPE IN STEM CELL DOES IT PLAST HAVE WE CREATED A PERMANENT -- I I DON'T THINK WE HAVE THAT. SO I THINK WHAT WE ARE DOING IS TWEAKING THE SYSTEM AND HAVE NOT YET REACHED A EN COURAGE OF PERMS R. PERMANENT YOUTH FULLNESS AGED STATE AND I THINK TO YOUR QUESTION, IT IS MORE DIFFICULT TO VEY PERMANENT YOUTHFUL STATE THAN A PERMANENT -- EVEN IF WE DO IT WITH ONE OR A FEW FACTORS. >> SO CONSISTENT. SO ONE LAST QUESTION, ONLY TOW SAY AFTER THIS WE'LL HAVE A CHANCE FOR THOSE WHO WOULD LIKE TO SPEAK WITH TOM FURTHER, THERE IS A RECEPTION AFTERWARDS IT WILL INCLUDE REFRESHMENTS AND THE GOVERNMENT CANNOT PROVIDE AND THIS WILL BE IN THE LIBRARY OUT AT THE CORRIDOR. SO ONE LAST QUESTION. >> THANK YOU VERY MUCH FOR A VERY PROVOCATIVE AND INTRIGUING WEDNESDAY AFTERNOON. I WAS INTRIGUED BY THE PICTURES OF DARWIN. DO YOU HAVE ANY OTHER EVIDENCE THAT PEOPLE WERE AGING FASTER IN THE 19th CENTURY THAN JUST THAT PICTURE? IF YOU GAVE HIM A SHAVE, HE WOULDN'T LOOK THAT BAD. AND HE ALSO DID HAVE A CHRONIC DISEASE. IT'S HARD TO DEL BUT HE PROBABLE HE SOME KIND OF CHRONIC DISEASE THAT HE ENCOUNTERED IN THE TRAVELS OF THE AMAZON. >> YES. SO IT MAY BE UNFAIR. I'LL PICK ONE EXAMPLE THAT IS PICK TOREALLY ELUSTATIVE. I THINK THE DATA ARE THE TABLES AND THE INSURANCE COMPANIES WILL TELL YOU THAT YOUR CHANCES OF DYING AT THE AGE OF 60 NOW ARE VASTLY LOWER THAN THEY WERE A CENTURY AGO AND THIS IS TRUE OVER THE DECADES. NOW, YOU KNOW, I WAS JUST TREATING DISEASE AGING DIFFERENTLY OR ARE PEOPLE REACHING THE AGE HEALTHIER AND MORE FIT THAN THEY WERE? SO I THINK THAT IS THE PREPONDERANCE. >> HOW COULD THAT BE? >> THAT'S A GOOD QUESTION. >> WE HAVE 47,000 KINDS OF CHEMNALS OUR BODIES NOW THAT OUR GRANDPARENTS NEVER HAD. >> THAT'S WHY I SAY, IT REMAINS UNEXPLAINED. WE ARE NOT ONLY KEEPING PEOPLE ALIVE LONGER BY PREVENTING CHRONIC DISEASE. MORE AND MORE PEOPLE ARE LIVING TO OLD AGE HEALTHIER, NOT JUST -- SO I THINK IT'S ONE OF THESE MYSTERIES OF DOES IT HAVE TO DO WITH SOMEHOW HOW WE ARE VACCINATED AND NUTRITION? ALL THE THINGS THAT MIGHT HAVE CHANGED AND BEEN INITIAL INFANT MORTALITY OR HAVING LONGER EFFECTS ON HEALTH. I'M JUST SPECULATING. BUT THAT I DON'T THINK IT'S SO OUTRAGEOUS TO THINK THAT THAT IS TRUE. BECAUSE CLEARLY THERE ARE PLACES IN THE WORLD NOW WHERE THE AVERAGE LIFESPAN IS 45. AND THAT TOO. I MEAN IF YOU LOOK AT THE PEOPLE THEY ARE NOT LIVING OR NOT VERY LIVING TO 100. SO ALSO EARLIER DEATH IN OLDER AGE. >> AND MAYBE NIH PLAYED A IMPORTANT ROLE. THERE YOU GO. THANK YOU VERY MUCH. WE LOOK FORWARD TO THE RECEPTION FOR THOSE WHO CAN MAKE IT.