>> HELLO, EVERYBODY. THANKS FOR COMING TO COMING TO THIS TALK, SPONSORED BY -- GEROSCIENCE GROUP AT THE NIH. OUR SPEAKER IS WELL KNOWN GERONTOLOGIST, RICH MILLER, PROFESSOR OF PATHOLOGY AND DIRECTOR OF GERIATRICS CENTER AT UNIVERSITY OF MICHIGAN. LIKE WHAT IS IN THE SLIDES HE HAS M.D. AND Ph.D. AND I DIDN'T PUT THE M.D. IN THERE. LET'S NOT COMMENT ABOUT THAT. HE'S INTERESTED IN AGING MICE AND IN GENERAL, ABOUT (INDISCERNIBLE) HE'S GOING TO BE TALKING ABOUT. APART FROM HIS SCIENTIFIC INTERESTS WHICH IS THE REASON HE'S HERE, HE IS A VERY GOOD PHOTOGRAPHER, SPECIALIZING IN WILD LIFE, PRIMARILY BIRDS I THINK, THOUGH I HAVE SEEN SOME OTHER THINGS BUT REALLY GOOD PHOTOGRAPHY. YOU CAN SEE BY VISITING HIS WEBSITE ACTUALLY. HE'S PROLIFIC WRITER. IN SEVERAL THINGS. I WANT TO GIVE YOU AN IDEA ABOUT THE PERSON RICH IS -- RAID THE FEW LINES OF SOMETHING PUBLISHED A FEW YEARS AGO. IBG-1030. SO IBG-130, THE OLDEST LIVING MOUSE DIED PEACEFULLY IN HIS SLEEP NOVEMBER 15th, 2001 AT THE AGE OF 1450 DAYS, 11 DAYS SHY OF HIS FOURTH BIRTHDAY. BORN AND RAISED IN A SMALL PLASTIC CAGE IN ANN ARBOR, MICHIGAN ONE BORN TO PAIR. SO BASICALLY A FORMAL (INDISCERNIBLE) FOR A MOUSE. I WILL NOT COMMENT ABOUT WRITINGS LIKE THE FLIGHT PIGS THROUGH MIT TECH NOL REVIEWSM THOSE ARE THINGS YOU CAN FIND ON HIS WEBSITE, KIND OF FUN TO READ. WITHOUT MUCH MORE I'LL INTRODUCE RICH TO TALK ABOUT ANTI-AGING MEDICINES, THE BEGINNING OF THE END OF THE BEGINNING. RICH. >> THANK YOU. IT'S A GREAT HONOR TO BE A PARENTS PATE IN THIS IMPORTANT SERIES. I AND COLLEAGUES FELT FOR A LONG TIME THE QUICKEST CHEAPEST WAY OF CONQUERING ALZHEIMER'S DISEASE IS STUDYING BIOLOGY OF AGING. THE QUICKEST WAY OF CONQUERING CANCER IS STUDY BYE-BYOLOGY OF AGING AND QUICKEST AGAINST OSTEOPOROSIS, IMMUNE FAILURE AND SARCOPENIA IS STUDYING BIOLOGY OF AGING AND LINKS TO DISEASE. THAT'S THE UNDERLYING THEME OF THE WORK THAT I WANT TO PRESENT TODAY AND NOT COINCIDENTLY MY UNDERSTANDING THAT THIS IS A ORGANIZATIONAL IDEA BEHIND THE GEROSCIENCE INTEREST GROUP, A SPECTACULAR STEP FORWARD. I'M GOING TO TRY TO CONVINCE YOU IT IS NOT HARD TO SLOW AGING IN LAB ANIMALS. TEN TIMES LARGE THEARN CURE FOR CANCER AND THESE ANIMALS ARE ALIVE AND HEALTHY, NOT JUST ALIVE IN MOUSE NURSING HOMES BUT THEY ARE HEALTHIER THAN YOU ARE FOR A LONG PERIOD OF TIME. I'LL SPEND THE BULK OF THE TALK BY MUTATIONS, DRUGS, ME THIONEINE RESTRICTION AND ADOPTION PROGRAMS AND FOCUSING IN PARTICULAR ON THE NIA INTERVENTIONS TESTING PROGRAM WHICH I AND INTEFERL COLLEAGUES HAVE BEEN TRYING TO FIND DRUGS THAT EXTEND LONGEVITY AS THE FIRST STEP TOWARDS FINDING WAYS TO SLOW THE AGING PROCESS DOWN AND END WITH A SLIDE OR TWO ABOUT NEW KINDS OF OLD PEOPLE. THE DEFINITION USED FOR AGING THROUGHOUT TODAY'S TALK IS A PROCESS IN RED. PROGRESSIVELY CONVERTS HEALTHY YOUNG ADULTS INTO LESS HEALTHY OLDER ADULTS WITH PROGRESSIVELY INCREASING RISK OF INJURY ILLNESS AND DEATH. IF I TELL PEOPLE I ON AGING U THEY THINK I WORK ON OLD PEOPLE. THAT'S WRONG. I DON'T WORK ON OLD PEOPLE OR MICE. I'M INTERESTED IN WHAT HAPPENS WHEN YOU'RE OUR AGE, MORE OR LESS YOUNG PEOPLE, TO SLOW DOWN OR SPEED UP THE PROCESS WHICH WE BECOME OLD PEOPLE LIKE MY DAD. IT USED TO BE UNTHINKABLE THAT AGING COULD BE SLOWED BUT IT TURNS OUT THAT HAVING A SERIOUS IMPACT ON HEALTHY LIFE SPAN MUST INEVITABLY INVOLVE AGING RESEARCH BECAUSE THE PROBLEMS OF AGING CAN CANNOT BE CURED ONE DISEASE AT A TIME. THIS IS FROM THE U.S. STATISTICAL ABSTRACT IN 1997. THIS IS A LOG SCALE. SO THE RISK OF ALMOST ANY MAJOR DISEASES THAT OLE PEOPLE GETS DOUBLES ABOUT EVERY EIGHT YEARS, EVERY EIGHT YEARS YOUR RISK OF ANY ONE OF THESE THINGS DOUBLES AGAIN AND AGAIN AN AGAIN. SO IF WE WERE SUCCESSFUL, BY WE I MEAN YOU, SUCCESSFUL IN CURING CANCER SO NOBODY GOT CANCER AGAIN IT WOULDN'T HAVE MUCH EFFECT ON HEALTHY LIFE SPAN. P PEOPLE WOULD BUMP INTO THE HEART DISEASE LINE NEXT. EVEN IF HEART DISEASE AND CANCER WERE OBLITERATED THEY WILL BUMP INTO THE STROKE LINE NEXT. JAY (INDISCERNIBLE) PUBLISHED IN 1990, ON AVERAGE AMERICAN WOMAN 50 YEARS OLE WOULD HAVE ABOUT 31 YEARS LEFT OF REMAINING LIFE. SHE'D LIVE UNTIL AGE ROUGHLY 81. WHAT JAY CALCULATED WAS IF THERE WERE NO CANCERS AFTER AGE -- THE CANCER INSTITUTE WINS, THEY GO OUT OF BUSINESS, THERE'S NO CANCER ANY MORE, YOU HAVE JUST BOUGHT HER 2.6 YEARS OF ADDITIONAL LIFE. IF THE HEART ATTACK FOLKS WIN ALSO, YOU GET YOU'RE BUYING 2.7 YEARS ADDITIONAL LIFE. EVEN IF BOTH INSTITUTES GO OUT OF BUSINESS THERE'S NO MORE CANCER AND NO MORE HEART DISEASE, SHE HAS GOT A SIX YEAR LIFE SPAN EXTENSION. IT'S EASILY POSSIBLE, EXAMPLE AFTER EXAMPLE, IN LABORATORY ANIMALS TO SLOW THE AGE PROCESS TO LEAD TO A 40% INCREASE IN MEAN AN MAX LONGEVITY. IF THAT PROVED SOME DAY TRANSLATED TO HUMAN CLINICAL PRACTICE, THAT WOULD MAKE THE AVERAGE HEALTHY PERSON DIE AT AGE 110, 115, 120. THAT'S THE GOAL OF THE WORK I WANT TO PRESENT TODAY. THE FIRST ITEM ON THIS AGENDA IS CONVINCE YOU IT'S NOT HARD TO SLOW AGING EFFECT AS YOU HAVE SEEN TEN TIMES LARGER THAN CURE FOR CANCER AND THEY STAY HEALTHY A LISTENING TIME SO THE FAMOUS ONE THAT EVEN MY MOM HAS HEARD IS CALORIC RESTRICT, IT INCREASES MEAN AND MAXIMUM LIFE SPAN IN MICE. DONE BY 50 LABS, DOZENS OF STRAINS, OF MICE AND RATS AND MULTIPLE KINDS OF OTHER MAMMALS AN INVERTEBRATE ANIMALS. YOU GET THIS KIND OF EFFECT. HERE IS THE CONTROL GROUP, HALF DEAD, BY 800 DAYS THE LAST ONE CONDUCT IT IS BUCK AT 900 DAY, YOU GET EXTENSION OF MEAN AND MAXIMUM LONGEVITY BY ABOUT 30%, BEST CASE ABOUT 40%. THEY'RE NOT JUST ALIVE BUT SUFFERING. THEY ARE ALIVE AND HEALTHY. THIS ONE MANEUVER, THIS CALORIC RESTRICTION SLOWS CANCER, AR THROI AT THIS, MUSCLE STRENGTH IMMUNE DECLINE ABOUT 90% OF ANYTHING YOU COULD PUT ON THAT SLIDE. I'LL SHOW ONE EXAMPLE FROM ROGER (INDISCERNIBLE)'S WORK HE TOOK SOME RATS AND PUT ONE OF THOSE EXERCISE WHEELS INTO THE CAGE, LET THEM RUN IF THEY WANTED TO. THE CONTROL RATS RAN 1,000-METERS A NIGHT JUST AS WHEN WE BOUGHT A TREADMILL AFTER ABOUT SIX MONTHS THEY GOT TIRED. SIX OR 12 MONTHS LATER THEY WERE NO LONGER RUNNING MUCH AND ACTUALLY ALL DEAD BY 36 MONTHS OF AGE. THIS IS ARE CALORICALLY RESTRICTED. THEY'RE PUTTING IN 5K A NIGHT. NOT RAT ADJUSTED KILOMETERS. REAL KILOMETERS FROM HERE TO THE THE METRO STOP TO. THEY WERE RUNNING FIVE. THIS IS THE AGE -- THIS IS THE RAT EQUIVALENT AGE OF 80, 09 YEARS, THIS IS 120, 130 YEARS OF AGE. EVEN WHEN THE LAST OF THE CONTROL RATS DIED THESE GUYS ARE STILL CHURNING OUT ONE, ONE AND A HALF K PER NIESMGHT OTHER SLIDES MAKE THE SAME GENERAL POINT IN OTHER SYSTEMS. WE ALSO CAN DO THIS WITH MUTATIONSCH THIS IS A REGULAR MOUSE IN THIS ADORABLE SISTER IS YODA. I ASKED MY KID IF HE COULD TELL ME THE NAME -- THIS IS A DWARF MOUSE, THE OLDEST LIVING DWARF, HE SAID YODA, DAD SO THIS MOUSE WAS NAMED YODA. HE HAS A SINGLE GENE MOWATION, THE SNELL DWARF MOUSE THAT MESS IT IS PITUITARY WHEN THEY GROW SO THEY DON'T HAVE GROWTH MORE MOAN, NO IGF-1 AND THEY DON'T HAVE THYROID STIMULATING HORMONE, THEY DON'T HAVE PROLACTIN NOT ONLY ARE THEY ONE-THIRD NORMAL SIZE BUT THEY LIVE A LONG TIME, 40% LONGER. TAKES THEM ONE-THIRD OF THE MOUSE LIFE SPAN LONGER BEFORE THE FIRST ONES START TO GET SICK ENOUGH TO DIE. THESE TOO LIKE THE CALORIE RESTRICTED ONES HAVE USEFUL FUNCTION IN MULTIPLE SYSTEMS IN OLD AGE, THE DATA THAT CON INS VINCEED US THEY'RE AGING SLOWLY, WORK BY KEVIN FLURKY IN MY LAB, THIS IS A T HELPER STUDY, CONTROL MICE LOSE HELPER CELLS BUT NOT DWARFS. THEY LOSE KILLER CELLS BUT NOT DWARFS. THE TENDONS GET CROSS-LINKED, COSMETICS COMPANY WOULD BE VERY INTERESTED IN TRYING TO CURE. THE DWARF MICE CURE IT, THEY DON'T GET THE COLLAGEN CROSS LINKS. THEY'RE RHESUS TAN TO CAT ACT DEVELOPMENT AT EITHER AGE THE LEVEL OF CATARACTS IN THE NORMAL MICE ARE HIGHER THAN THOSE OF DWARF MICE. THEY'RE RESISTANT TO KIDNEY DISEASE. THIS AS STUDY OF BOB SIGNATURELER WHO LOOKED AT BASAL MEMBRANE DISEASE IN GLUE MER LUS. A LOT ARE FREE OF KIDNEY DISEASE AN NONE HAVE SERIOUS KIDNEY DISEASE, WHEREAS THE NOR MAT LITTER MATE CONTROLS ALMOST ALWAYS HAVE SOME. SOME ARE QUITE SERIOUS. THIS IS EVEN THOUGH THE NORMAL MICE, THEY'RE DYING 40 P% EARLIER THAN THE DWARF. THE DWARFS ARE HANGING OUT THERE, 40% LONGER AND EVEN SO, THEIR KIDNEYS LOOK GREAT. AT THE TIME OF THEIR NATURAL DEATH. THIS IS AN UNPUBLISHED STUDY FROM ROGER ALBAN WHAT WE WANTED TO KNOW, DOES THIS DWARF DO ANYTHING FOR HUNTINGTON'S DISEASE? YES. WE MADE A MOUSE THAT HAS THE DWARF GENE PLUS OR MINUS THE HUNTINGTON'S DISEASE SUSCEPTIBILITY GENE. HERE IS NORMAL MICE. THAT IS NONDWARF, IF THEY HAVE HUNTINGTON'S DISEASE THEY CAN'T STAY ON THE ROD VERY LONG. THE DWARF MICE, THEY'RE NOT ACROBAT, THEY WON'T WIN A GYMNAST MEDAL BUT THE HUNTINGTON DISEASE DOESN'T HURT THEM AT ALL. SIMILARLY, THERE HAS TO GO ACROSS A BALANCE BEAM THE HUNTINGTON'S NORMAL MICE ARE REALLY ROTTEN AT THAT. AND THEY TAKE FOREVER TO GET ACROSS THE BALANCE BEAM T. DWARF MICE HUNTINGTON DISEASE DOESN'T HURT THEM SO WE'RE LOOKING AT THE BRAINS OF THE MICE TESTING MECHANISTIC HYPOTHESES BUT EVEN BEHAVIORAL DATA AT THIS POINT MAKE A CLEAR CASE THE SPECTRUM OF ABNORMALITIES PRODUCES BEHAVIORAL ABNORMALITIES ARE BLUNNED BY THE DWAR DWARF. IT THE CALORIE RESTRICTED MICE AND OTHERS CHARACTERIZED ACTUALLY AGE SLOWLY. THIS GIVES US TWO CHALLENGES AS EXPERIMENTALISTS. WHAT CAUSES THE DECELERATION IN PARALLEL OF SO MANY DIFFERENT KINDS OF DISEASE AND SECONDLY, CAN WE LEARN ENOUGH FROM THAT MECHANISTIC STUDY TO DEVELOP DRUGS THAT WILL WORK IN MICE AND THEN EVENTUALLY GIVE CLUES AS TO THE DEVELOPMENT OF DRUGS THAT WILL POSTPONE ALL DISEASES OF AGING IN PARALLEL IN PEOPLE BY FUNDAMENTALLY ALTERING THE AGING PROCESS. THERE IS A STEADY SLOW INCREASE IN THE NUMBER OF MUTANTS WITH LIFE SPAN PROLONGATION EFFECTS. BILL SWINDELL POST-DOC IN MY LAB PUT THIS TOGETHER. MED LINE SEARCH BY THE TIME HE LEFT MY LAB FOR GREENER PASTURES THERE'S 21 PUBLISHED INDEPENDENT MUTATIONS OF MICE ALLEGED TO SLOW THE AGING PROCESS. THIS IS 21. I HAVE PUT A LITTLE GREEN HAPPY FACE NEXT TO ONES TWO LABS GOT IT TO WORK INDEPENDENTLY. SOMEBODY ELSE TRIED TO REPEAT IT AND COULDN'T. SO NOT ALL THESE REPORTS TURN OUT CORRECT. SOME MAY WORK ON ONE STRAIN BUT NOT ANOTHER STRAIN, SOME MAY WORK ON HIGH FAT DIET BUT NOT LOW FAT DIET. IT WILL TAKE A WHILE TO SORT THAT OUT. ONE PRINCIPLE YOU CAN SEE SOME HAVE SUBSTANTIAL, 25, 30, 40% INCREASE IN LONGEVITY. SO I'M GOING TO SPIND THE NEXT TEN MINUTES INTRODUCING YOU TO OTHER WAYS TO SLOW AGING, SOME FAIRLY NEW WAYS TO SLOW AGING. THIS IS A SAMPLER. IT GRIEVES KNOW HAVE TO DO THIS. FOR EACH ONE OF THESE NEXT SLIDES, I WISH I COULD SPEND TEN MINUTES TO TELL YOU WHAT WE HAVE DONE, WHAT OTHERS HAVE DONE. I'M GOING TO BE -- SHOW DISCIPLINE AND SHOW YOU ONE SLIDE ON EACH, NO MATTER HOW UNHAPPY THAT MAKE MESS. ONE IS ME THIONEINE RESTRICTED MICE. BOTH 30 MONTHS OF AGE, THIS HAD A REGULAR DIET AND THIS ONE HAD AMINO ACID AND ME THIONEINE CUT BACK TO LOWEST LEVEL IT WAS ALLOWED TO SURVIVE. YOU CAN SEE THIS GUY IS HAPPY AND HEALTHY AND DOING EXERCISE WITH PIECE OF CHALK AND THIS ONE IS THE LAST OF THE CONTROL GROUP TO SURVIVE. IF YOU START THIS WHEN THEY'RE BABIES IT'S NOT SO GOOD. SOME WHEN THEY'RE GROWING ME THIONEINE RESTRICTED DIETS ARE TOUGH SO WE STARTED AT ONE YEAR OF AGE. THESE ARE MICE WHICH LIVE TWO AND A HALF YEARS ON AVERAGE. YOU CAN SEE WHEN YOU DO THAT THE CURVE SEPARATE NICELY, YOU GET 13% INCREASE IN MEAN AND MAXIMAL LONGEVITY, IT'S SIGNIFICANT IF YOU CONSIDER THE WHOLE POPULATION AND ALSO IF YOU LOOK AT THE LAST 10% TO DIE, THE MAXIMUM LONGEVITY, THAT'S SIGNIFICANT AS WELL. WE WOULD REALLY LIKE TO KNOW HOW THAT WORKS. IS IT WORKING BY BLUNTING TRANSLATION? THAT WOULD GIVE A WHOLE CLUE TO SET OF DRUGS RELATED TRANSLATION WE SHOULD LOOK AT. OR IS IT WORKING BY MODULATING DNA METHYLATION? IF WE KNEW THAT LOOK AT WHAT KINDS OF METHYLATION EVENTS WERE ALTERED BY ME THIONEINE. IS IT MODULATING GLUTATHIONE LEVELS IN SPECIFIC ORGANS. ALL THIS IS PLAUSIBLE UNTIL WE CAN GET STUDY SECTION TO FUND WORK OR SOMEONE'S WORK IN THIS AREA, WE WON'T BE ABLE TO TAKE IT PAST THE LONGEVITY AND START TEASING OUT THE MECHANISM-J" WITH A GOAL TOWARDS FINDING DRUGS THAT CAN DO THE SAME THING WITHOUT MAKING THIS TERRIBLE LOW ME THIONEINE DIET. THE NEXT CANDY IN THE CHOCOLATE BOX IS THIS MODEL, A CAROTID LIVER MODEL WORK DONE BY JIM HARPER IN MY LAB. THE INTERVENTION IS THIS LITTLE THING HERE IT ONLY LASTED THREE WEEKS. THE CONTROL MICE IN BLUE ARE REGULAR MICE, BORN TO THEIR MOM, AND THEN MOM HAD TO NURSE EIGHT AT A TIME, THE MOM CAN NURSE 8 AT A TIME, NO BABY WITHOUT MILK OR GOT FRUSTRATED. THE CROWDED LITTER MICE IN RED, MOM GOT FOUR EXTRAS. SHE HAD TO TAKE CARE OF HER 8 AND FOUR MORE AT THE SAME TIME. SINCE MOM ONLY FEEDS 8 AT ONE TIME EACH PUCK IN THAT CROWDED LITTER HAD TO SPEND ONE-THIRD OF ITS TIME DURING THAT NURSING PERIOD WAITING FOR THE NEXT BROTHER AND SISTER TO MOVE AWAY SO IT CAN HAVE A CHANCE AT THE MILK. THEY ALSO ALL SURVIVED GREAT BUT THEY'RE A BIT SMALLER WHEN THEY'RE WEANED. THAT IS THE ENTIRE INTERVENTION. AT THE END OF THE THREE WEEK PERIOD THEY'RE BACK TO THE REGULAR MOUSE CAGE, NOTHING HAPPENS TO THEM. IN JIM'S PUBLICATION, 15, 20% DEPENNING MALE OR FEMALE INCREASE IN MEAN AND MAXIMAL LONGEVITY. MANAGE IS GOING ON IN THESE FIRST THREE WEEKS OF LIFE, SOMETHING THAT PRESUMABLY STAMPS AN EPIGENETIC PATTERN ON ONE OR MORE CELL TYPES THAT CAN BE READ OUT AT THE VERY END OF LIFE AS EXTENDED LONGEVITY. WE HAVE BEGUN TO LOOK AT GENE EXPRESSION PATTERNS. WE HAVE SHOWN IN WORK WE HAVE PUBLISHED THAT THE GENE EXPRESSION PATTERNS PRODUCED BY THIS THREE WEEKS OF EARLY INTERVENTION F YOU WAIT A FULL YEAR AND THEN LOOK AT THE GENE EXPRESSION PRA PATTERNS IN LIVER THEY'RE LIKE CALORIC RESTRICTION. SOMETHING MANY THE FIRST THREE PERIOD TRICKED THE MOUSE THINKING CALORIES ARE HARD TO GET AND IT TUNES UP ALL THE STRESS RESCISSION STANT MRNAs. WE'D LIKE TO KNOW HOW IT DOES THAT AND WHICH mRNA'S ARE IMPORTANT FOR SLOWING AGE AND DISEASE. THE THIRD SAMPLE I'LL SHOW YOU HAS TO DO WITH AN INTERESTING MUTANT. THE MUTANT IS MIF, MIGRATION INHIBITION FACTOR. HISTORICALLY WAS ONE OF THE FAMOUS CYTOKINES, PURIFIEDED AS PURE PROTEIN. 30 YEARS AGO PEOPLE DIDN'T KNOW THAT CYTOKINES COULD BE PURIFIED. THEY WERE THOUGHT TO BE SORT OF ANOMALOUS MIXTURES. WE GOT MIF KNOCKOUT MICE AT OHIO STATE, THIS WAS A SURVIVAL CURVE FOR THE AD LIB MICE AND THESE MICE DIFFER ONLY THAT THEY DO NOT EXPRESS MIF. THIS IS COOL IN A NUMBER OF WAYS. ONE IS MIF IS A PROINFLAMMATORY MOLECULE. SO THIS LENDS SOME WEIGHT TO THE NOTION THAT A LOT OF DISEASES YOU GET WHEN YOU GET OLD MAYBE EXACERBATED BY INFLAMMATION. WE SUSPECT THAT THE DAMPENING OF INFORMATION WE SEE IN THE KNOCK OUT MOUSE CONTRIBUTES TO THE LONGEVITY EFFECT. IT HAS IMMEDIATE HUMAN CORRELATE BECAUSE THE HUMAN POPULATION IS SEGREGATING FOR GENES THAT GIVE YOU MIF OR LESS. THE LOW MIF ALLELES ARE ASSOCIATED WITH RESISTANCE TO MANY DISEASES, ARLITIS, DIABETES AND SOME CANCER. THERE'S UNPUBLISHED DATA SAYING IF YOU'RE LUCKY ENOUGH TO GET THE LOW MIF ALLELE YOUR CHANCE TO BECOME A CENTENARIAN WILL ALSO INCREASE. IT'S LIKELY THAT WHAT WE'RE STUDYING IN THESE KNOCKOUT MICE IS GOING TO GIVE INFORMATION ABOUT GENETIC FACTORS TO PROTECT PEOPLE AGAINST MULTIPLE LATE LIFE DISEASE. THE OTHER POINT TO MAKE BEFORE LEAVING THE SLIDE IS THIS IS A REPORT OF A CYTOKINE WHERE THE KNOCK OUT EXTENDS LIFE. MOST TIME IN LIFE IN WORMS KNOCK OUT EXPRESSED IN CELLS YOU CAN'T MANIPULATE IN TERMS OF CLINICAL INTERVENTIONS. IF THE ONLY TIME THE GENE IS EXPRESSIONED IN BABIES AND THE FETUSES PITUITARY INTERVENTION THERE IS HOPELESS BUT THIS IS A CYTOKINE. SO IT'S EASY TO IMAGINE MOUSE AN HUMAN CLINICAL TRIALS BASED ON ANTI-MIF ANTIBODIES THAT INTERFERE WITH THE MIF RECEPTOR. IF IT BLOCKS MIF ACTION AT THE RIGHT CELLS RIGHT TIME RIGHT EXTENT IT'S POSSIBLE TO SEE THAT AS LEADING TO THE SAME SORTS OF LIFE SPAN EXTENSION THIS GENETIC KNOCK OUT PRODUCED FOR US. I'M GOING TO -- ONE THING I HAVEN'T TALKEDDED ABOUT YET IS THE DRUGS PART. THAT'S BECAUSE THE NEXT THE TEN MINUTES OR SO ARE FOCUSED ON INTERVENTIONS TESTING PROGRAM THE NIA HAS BEEN FUNDING WITH ONE YEAR INTERRUPTION THE LAST EIGHT YEARS. S THAT PROGRAM OUR LAB PLUS LABS OF DAVID HARRISON, JACK ON LABORATORY AND RANDY STROM UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER IN SAN ANTONIO. DO A PROTOCOL WE AGREE TO WITH NANCY NADON AND COORDINATING PERSON FROM THE NIA STAFF. ANYONE IN THE SCIENTIFIC COMMUNITY PROPOSING DRUGS AS AN ANNUAL DEADLINE, THE DEADLINE IS ANNOUNCEDDED, SO WE GET 10, 15, 20 SUGGESTIONÖ AS YEAR, A COMMUNE TOIF SCIENTISTS PICKS FIVE WE INCORPORATE INTO THE PROGRAM. MY ORIGINAL GUESS WAS PEST MISTIC. THE FIRST 20 EVALUATED, ONE MY WORK BUT WE HAVE FIVE WINNERS SO FAR, FIVE WINNERS IN THE SENSE THEY LEAD TO A STATISTICALLY SIGNIFICANT INCREASE IN AT LEAST MEAN MOUSE LONGEVITY. I TELL YOU ABOUT A FEW OF THESE TO GIVE YOU A FLAVOR HOW THIS RESEARCH IS GOING. THE LEAST EFFECTIVE OF THE ONES THAT WE HAVE LOOKED AT SO FAR ASK ASPIRIN, P VALUE OF .01 IN MALE MICE. INEFFECTIVE IN FEMALE MICE. THIS THIS LOOKS TRIVIAL, IF YOU LOOK AT CALORIE RESTRICTION DATA, A 40% LIFE SPAN BENEFIT, THAT'S NOT GOOD. I TAKE THE MOST OPTIMISTIC VIEWPOINT, THIS IS A SINGLE DOSE, LIKELY BY CHANCE WHICH PICKED THE RIGHT BEST DOSE, THE BEST DOSE IS PROBABLY THREEFOLD OR TENFOLD LOWER OR THREE FOAL OR TENFOLD HIGHER. I SUSPECT IF WE FINE TUNE THE DOSE WE MIGHT SEE A LARGER EFFECT THAN THAT. BUT I'LL POINT OUT THE EXTENT OF LIFE SPAN EXTENSION HERE IS ABOUT TWICE WHAT YOU WOULD GET IN PEOPLE BY A CURE FOR CANCER. IT'S NOT CHICKEN FEED. WE THINK WE KNOW WHY IT DOESN'T WORK IN FEMALES. THEY DEACETYLATE QUICKLY. THIS IS A TEST BY RANDY STRONG'S LAB LOOKING AT THE DEACETYLATION REACTION, IN FEMALES IT'S HIGH AND MALES LOW. SO THE ACTIVE ACETYL COMPOUND IS RAPIDLY CLEARED FROM THE FEMALES AND WE SUSPECT THAT'S WHY WE DIDN'T SEE A LIFE SPAN EFFECT. THE SECOND OF THE PUBLISHED AGENTS IS NDGA, NOR DI HYDRO WIRE ETIC ACID. IT'S A PRESCRIPTION DRUG IN EUROPE, A CREAM TO SPREAD ON ACNE LEAGUES, ANTI-INFLAMMATORY AN ANTIOXIDANT. SO FOR A VARIETY OF REASONS PEOPLE SUGGESTED AN ANTIOXIDANT ANTI-INFLAMMATORY AGENT MIGHT BE GOOD FOR YOU IF YOU'RE AGING. THEY'RE RIGHT. THE POOL DATA FROM ALL THREE LABSING TO IN THE MALE VERSUS FEMALES THE P VALUE IS CONVINCING. THERE'S A 12% LIFE SPAN INCREASE. WE'RE DOING THIS OVER AGAIN NOW AT MULTIPLE DOSES. WE -- ONCE WE HAVE A FIRST INITIAL RESULT OUR NEXT IMMEDIATE STEP IS TRY TO SEE IF WE CAN CONFIRM IT AND SEE WHETHER HIGHER OR LOWER DOSES WOULD BE BETTER AND THIS IS UNACCOMPLISHED DATA SHOWING THE DOSE WORKING BETTER THAN THE DOSE WE TRIED ORIGINAL LISM WE THINK WE KNOW WHY THIS WORKS IN MALES BUT NOT FEALS. IT'S A MATTER OF PHARMACOLOGY. THE FEMALE MICE AFTER EATING THE SAME AMOUNT OF FOOD WITH THE SAME AMOUNT OF DRUG, THE BLOOD LEVELS ARE MUCH LOWER IN THE FEMALES THAN THE MALES, WHETHER YOU USE THE DOSE WE TRIED ORIGINALLY OR HIGHER DOSE, DOESN'T MATTER. THE FEMALES APPARENTLY METABOLIZE THIS OR GET RID OF IT MORE RAPIDLY THAN THE MALES TO. SO THE RAPAMYCIN STUDY IS ONE I THINK HAS BEEN MOST EXCITING AND CERTAINLY THE ONE THAT HAS THE MOST PUBLICITY. WHEN YOU PUT MICE ON RAP RAPAMYCIN AT NINE MONTHS OF AGE YOU GET A DRAMATIC LIFE SPAN EXTENSION IN MEALS AND MORE DRAMATIC LIFE SPAN EXTENSION IN THE FEMALES. THE MAXIMUM LIFE SPAN IS INCREASED WITH P VALUE OF .0001 IN MEALS AND FEMALE MICE. EVEN IF YOU HAVE ONE-THIRD OF THE DATA TO WORK WITH, LOOKING AT ONLY THE JACKSON LAB DATA OR MICHIGAN DATA OR THE TEXAS DATA, YOU STILL GET HIGHLY SIGNIFICANT EFFECTS STARTING NINE MONTHS OF AGE. THIS SLIDE FROM THAT -- THE SECOND PAPER, YOU CAN SEE IT WORKS IN THE MALES, WORKS IN FEMALES, THE REASON WE DO IT AT 3 STUDIES IS THAT YOU SEE FROM ONE STUDY ONLY ONE LAB YOU DON'T KNOW IF IT'S A FLUKE. MAYBE THEY HAVE CHERRY PICKED THE DATA AND WE DON'T KNOW IF IT'S REPRODUCIBLE. BY DOING AT THREE LABORATORY MS. THE SAME PROPERTY COUGH WE BECOME MORE CONFIDENT BECAUSE IT WORKED IN TEXAS, WORKED IN MICHIGAN, WORKED IN BOTH MEALS AND FEALS, THIS LEADS US TO THE CONCLUSION IT'S A ROBUST REPRODUCIBLE EFFECT. SURPRISINGLY TO ME RAPAMYCIN WORKED, EVEN IF WE STARTED IT AT 20 MONTHS OF AGE, I THOUGHT FOR STUDY TO BE AN AUTHENTIC ANTI-AGING DRUG YOU HAD TO HAVE IT MOST OF YOUR LIFE. I THOUGHT THIS WOULD FAIL, THEY'RE ALREADY PRETTY OLD. NOT MANY DIED BUT THEY HAD SIGNS AN SYMPTOMS OF AGING THAT WOULDN'T WORK AT ALL. THAT WAS WRONG. STARTING AT 600 DAY, 20 MONTHS OF AGE WE GET A SIGNIFICANT EFFECT IN THE MALES AND A SIGNIFICANT EFFECT IN THE FEMALES. SOME ASPECTS OF AGING OR CANCER BIOLOGY INHIBIT ENOUGH BY RAPAMYCIN WHEN STARTED LATE YOU STILL GET A LIFE SPAN INCREASE. NOW, THIS IS PATHOLOGY FROM JAY WILKINSON. THEY ARE STILL DYING OF THE SAME THINGS THAT KILLED THEM IN THE CONTROL GROUP. MOST CONTROL MICE DIE OF CANCER, AND HE MANAGE OWE SARCOMA T MOST PROMINENT, ONES NOT DYING OF CANCER CARDIAC DISEASE IS PROMINENT. THE RAPAMYCIN ANIMALS SHOW THE SAME SPECTRUM, NOT WORK BIG SIMPLY ELIMINATING ONE CAUSE OF DEATH BUT IT'S SLOWING EVERYTHING DOWN SO WHETHER IT'S LYMPHOMA OR LUNG CANCER, SARCOMA THEY GET IT 20% LATER THAN IF THEY HAD BEEN THE MISFORTUNE TO BE IN THE CONTROL GROUP. SO THERE ARE TWO HYPOTHESES BOTH OF INTEREST HERE. THE FIRST HYPOTHESIS IS LIFE SPAN EFFECT WE'RE SEEING IS ANTI-CANCER EFFECT. IN HUMAN CLINICAL -- NOW HUMAN CLINICAL PRACTICE TO BLOCK CANCER GROWTH. COULD BE WE DISCOVERED A ABT KAREN DRUG. I DON'T GET PAID BY THE NATIONAL CANCER INSTITUTE. THAT'S A DISASTER. I DON'T WANT AN ANTI-CANCEL DRUG, I WANT A DRUG THAT SLOWS AGINGCH I WAS ROOTING FOR HYPOTHESIS SPEAK, LIFE SPAN EXTENDED BY ANTI-AGING EFFECT. WE THOUGHT THIS PLAUSIBLE TOO. INHIBITION OF TARGET OF RAPAMYCIN EXTENDS IN FLIES AND SO ANTI-AGING ALSO SEEMED PLAUSIBLE. WE TOOK MICE, PUT THEM ON RAP RAPAMYCIN AT MIDDLE DOSE, THE ONE I HAVE SHOWN SO FAR OR LOWER OR HIGHER DOSE AND TOOK SOME MICE IN THE CONTROL GROUP. WHEN THEY GOT TO BE 22 MONTHS WE EUTHANIZED A LOT. TEN MALES AND 20 FEMALES IN EACH GROUP AND GAVE TO PATHOLOGIST WHOSE DIDN'T KNOW WHICH IS WHICH AND SAID WHAT IS THE MOUSE GOT? THEY'RE NOT DYING OF ANY OF THIS STUFF, THEY'RE NOT OLD ENOUGH TO DIET BUT WHAT IS THE AGE SENSITIVE LESION? THERE WERE NINE AGE SENSITIVE LEAGUES THAT WERE SIGNIFICANTLY DIFFERENT BETWEEN THE OLD AND THE YOUNG MICE. OF THOSE FOUR SHOWEDDED HERE WE HAD A STATISTICALLY SIGNIFICANT EFFECT OF RAP MYSIS SO IT WAS BLOCKING LIVER DEGENERATION, BLOCKING CHANGES%/G IN–r THE HEART MUSCLE NUCLEIEE, BLOBBING CHANGING IN ENDOMEDIAL HYPERPLASIA. THIS IS WILL NOT KILL THE MICE, RARELY DOES THE MICE DIE OF THE TUMORS BUT NONETHELESS THEY GET THEM. THERE WERE FIVE OTHER LEAGUES ON THIS SLIDE AGING CAUSED A SIGNIFICANT INCREASE IN OCCURRENCE OF THAT LESION AND FOUR OF FIVE OVARIAN CYST, THYROID FOLLICLES AND NAYSANT LUNG TOW MORE WERE ALSO INHIBITED BY RAPAMYCIN BUT WITH FAIRLY SMALL NUMBERS OF MICE THESE WERE NOT STATISTICALLY SIGNIFICANT. ONE OF NINE LEAGUES, WHICH THERE WAS A BIG AGE EFFECT AND RAPAMYCIN DIDN'T DO NOTHING. DIDN'T INHIBIT THAT TO ANY EXTENT. AT THE SAME TIME DOGGING THIS WE TOOK TENDONS FROM THE MICE AN GAVE THEM TO SUE BROOKS AN GRADUATE STUDENT LAUREN WOODS WHO DID A TENDON STRETCH THING, THEY HAVE A MACHINE THAT STRETCHES THE DON AN LETS IT SNAP BACK. THEY CALCULATE SEVERAL VARIABLES THAT HAVE TO DO WITH HOW HARD IT SNAPS BACK WHEN YOU LET GO AND BOTH OF THOSE PARAMETERS TENDONS STRETCHING CHANGE WITH AGE, THIS ONE UP, THIS ONE GOES DOWN. THE RAPAMYCIN TENDONS LOOK GREAT, THE RAPAMYCIN TENDONS LOOKED CLOSER TO YOUNG MICE THAN OLD MICE. FOR IT SHALL SHIES -- FOR TISSUES LIKE LUNG, ENDOMETRIUM, EAZ WELL AS EXTRA CELLULAR MATERIALS LIKE -- THERE IS AN AGE INHIBITING EFFECT OF RAPAMYCIN. I DON'T VIEW THIS IN ANY SENSE AS A REASON TO GIVE RAPAMYCIN TO PEOPLE. I HOPE IF YOU'RE WRITING THIS UP FOR THE NIH REPORTER, THAT BECOMES A PART OF THE REPORT. THIS IS NOT A DRUG THAT ANY SANE PERSON WANTS TO TAKE OR LET ANY FRIENDS TAKE. I'M HOPEFUL OF COURSE STUDY OF RAPAMYCIN AND EFFECTS AND AGENTS IN THE SAME FAMILY MAY LEAD TO CLINICALLY USEFUL DRUGS THAT SLOW THE AGING PROCESS. LET ME SHOW YOU A REASON IT'S PROBABLY NOT A GREAT IDEA TO RUSH TO YOUR CATALOG TO BUY IT NOW. ONE THING, IT CAUSES CATARACTS AT LEAST IN MICE. THE MORE YOU GIVE THE WORSE THE CATARACTS. TRUE FOR MALES AN FEMALES AS WELL. MAYBE RAPAMYCIN OR DOSE SCHEDULE WHICH GIVES A LITTLE THEN TAKES IT AWAY, GIVE AS LITTLE THEN TAKES AWAY, OR DIRECTING SPECIFIC TARGET CELLS MAYBE THE GOOD STUFF WITHOUT THE CATARACTS BUT THAT REQUIRES REAL EVIDENCE. THE OTHER THING IT DOES THAT SOME CONSIDER A NEGATIVE SIDE EFFECT IS ACCELERATES TESTICULAR DEGENERATION SO OLD MICE, 15, 20% HAVE TESTICULAR DEGENERATION. OLD MICE WITH THE SMALLEST DOSE RAPAMYCIN MALE VERSUS 80 TO 90% -- 80 TO 100 HAVE TESTICULAR DEGENERATION. IF YOU CONSIDER THAT A NEGATIVE SIDE EFFECT YOU MIGHT NOT WANT TO TAKE RAPAMYCIN. SO THE SYNTHESIS OF THIS SET OF PROBLEMS, SET OF DATA IS SHOWN IN THIS SLIDE. I THINK RAPAMYCIN PROBABLY DOES EXTEND LIFE SPAN IN THESE MICE BY ANTITUMOR EFFECT, MOST DYING OF CANCER, WHETHER IT'S A SPECIFIC EFFECT ON THE CANCER OR WHETHER IT'S BOOSTING THE IMMUNE RESPONSE TO THE CANCER, RAPAMYCIN THAT SUPPRESSES IMMUNE RESPONSE AND BOOST IN MANY OTHER IMMUNE RESPONSES INCLUDING T-CELL IMMUNITY, COULD BE THEY'RE PROVING ANTI-CANCER DEFENSES. REGARDLESS HOW THAT SORTS OUT, I THINK THE DATA I HAVE SHOWN YOU, DEMONSTRATES THAT RAPAMYCIN ALSO SLOWS MANY OTHER ASPECTS OF AGING, MAY CAUSE SOME PROBLEMS OF ITS OWN BUT I THINK THE BULK OF THE EVIDENCE NOW IS IT IS SLOWING THE AGING PROCESS DOWN. I WILL TAKE ONE SIDE STEP INTO MECHANISTIC BIOLOGY. I THINK IT'S EXCITING BECAUSE I THINK IT GIVES US A CLUE HOW TO SCREEN FOR DRUGS THAT MIGHT WORK. IT IS INSPIRED BY A PAPER PUBLISHED BY GRETCHEN DARLINGTON FROM BAILOR. THEY FOUND IN A MUTANT MOUSE, THEY TURNED ON A LOT OF GENES IN THE LIVER THAT CAUSED DRUGS TO BE METABOLIZED. WHEN YOU TAKE A DRUG IT TURNS ON A SYSTEM OF GENES THAT IS SUPPOSED TO -- PROTEINS SUPPOSED TO CONJUGATE THAT DRUG AND EXCRETE IT. ALSO GOOD FOR TOXINS, IF YOU EAT SOMETHING BAD FOR YOU THE DRUG METABOLIZING OR XENOBIOTIC METABOLIZING ENZYMES. THEY PROTECT YOU AGAINST BAD STUFF THAT YOU HAVE EATEN OR THAT YOUR BODY MAKES. WHAT GR CHEN FOUND IS THESE MICE NOT ONLY HAVE PROTECTIVE ENZYMES BIBUT HIGH LEVELS OF BILE ACID IN THEIR BLOOD. IF YOU GAVE THEM CO-LICK ACID THEY CAN TURN THE GENES OFF. WITH THAT AS A STIMULUS WE LOOKED AT SEVERAL SLOW AGING MOUSES. YOU HAVE SEEN THE THE CROWDED LITTER MODEL SO THE CROWDED LITTER MODEL MICE WERE MADE, TOOK THREE WEEKS THEN WE WAIT ADIER TO GET OLDER AND THEN LOOKED AT THE ENZYMES OF THAT SET, THAT PROTECT YOU AGAINST DRUGS AND XENOBIOTICS. THE OPEN BARS CONTROL MICE AT 12 MONTHS, THE CLOSE BAR IS CAROTID, THIS IS WORK BY MIKE STEINBAUM WHO JUST FINISHED HIS DEGREE WITH ME. THERE IS SIGNIFICANT INCREASE TWOFOLD OR 8 FOLD INCREASE IN THESE CAROTID LITTER MICE IN SEVERAL GENES THAT ARE RELATED TO XENOBIOTIC METABOLISM. SOMETHING THAT HAPPENED AFTER BIRTH A YEAR LATER THEY REMEMBER THAT. THEY STILL HAVE GENES TURNED ON MORE OR LESS PERMANENTLY. TURNS OUT THAT THE SAME SET OF GENES IS PERMANENTLY TURNED ON ALSO BY CALORIC RESTRICTION. EACH DOT IN THE PLOT IS A DIFFERENT mRNA. YOU CAN SEE ONES TURNED ON BY THE CAROTID LITTER SYSTEM ARE ALSO TURNED BY LITTER RESTRICTION. CALORIC RESTRICTION IS A BIGGER BUMP, LIKE A THOUSAND FOLD INCREASE FOR THESE FOUR, FOR CAROTID LIVER IT'S 10 FOLD TO 100 FOLD INCREASE. MIKE FOUND GOOD CORRELATION. IF YOU'RE GENE TURNED ON BY CALORIC RESTRICTION, YOU'RE ALSO TURNED ON PERMANENTLY BY THIS THREE WEEKS OF EARLY LIFE CROWDING. THAT SAME SET OF GENES IN THE LIVER IS ALSO TURNED ON IN THE SNELL DWARF MICE, ALSO TURNED ON IN MICE THAT HAVE RAP RAPAMYCIN. S THAT DEVELOPMENTAL EFFECT, A GENETIC EFFECT OR DRUG EFFECT. ALL THINGS HAVE TWO THINGS IN COMMON, EXTEND LIVE SPAN, AND TURN ONSET OF XENOBIOTIC METABOLIZING ENZYMES SO THAT MAYBE A COINCIDENCE BUT GIVES A CLUE WHERE WE MIGHT WANT TO LOOK NEXT. THIS IS GRETCHEN DARLINGTON'S DATA, THESE ARE THE CROT THE DID LIVER NUMBERS, THE PAPERS FROM THE CO-LICK ACID TREATED MICE. BY TREATING THEM A FEW WEEKS, TURN TON P SAME SET OF GENES. QUITE LIKELY YOU COULD FIND DRUGS, WE HAVE FOUND DRUG, HALF A DOZEN DRUGS THAT TURN ON THE SET OF GENES IN THE LIVER IN A FEW WEEKS. THOSE ARE PLAUSIBLE CANDIDATES FOR DRUGS WE OUGHT TO EVALUATE FOR LIFE AND HEALTH SPAN EFFECTS. THIS IS THE TAKE HOME MESSAGE. YOU CAN TURN ON THE XENOBIOTIC METABOLIZING RNAs BY CHANGING DIET, WE HAVE DONE IT FOR AT LEAST FOUR MUTANTS, BY DEVELOPMENTAL MANIPULATION, RAPAMYCIN AND CHEMICALS THAT INDUCE THROUGH MOLECULE CALLED NERVE 2, THE BILE ACID IS GRETCHEN'S WORK AND WE HAVE DONE OXIDATION STRESS. WE DON'T KNOW IF THIS IS CAUSED. IT COULD BE THAT GETTING THESE THINGS UP IN THE LIVER HELPS THE MICE DELIVER ALL THE TIME. WE DON'T KNOW THAT. IT COULD BE SOMETHING ELSE PRODUCES LONGEVITY AND MAKES LIVER CHANGES. THAT'S PLAUSIBLE. WE WANT TO FIND OUT WHERE THE CAUSAL ARROWS RUN. BUT IT'S ALSO I THINK REGARDLESS OF HOW THIS ANSWER COMES OUT, THIS COULD BE A SCREEN FOR ANTI-AGING DRUGS, ONE THING WE'RE PURSUING NOW IS THE NOTION THAT IF YOU HAVE 20 MEMBERS OF A FAMILY AND WANT TO KNOW WHICH OF THE 20 YOU PUT INTO YOUR LIFE SPAN STUDY YOU MIGHT SCREEN FIRST FOR ABLE TO TURN ON GENES AND ONE THAT'S REALLY GOOD AT THAT DOSES THAT ARE NON-TOXIC MAY HAVE -- THIS MAYBE A SELLING POINT ACTUALLY INCORPORATING THAT IN AN EXPENSIVE LIFE SPAN STUDY. SO I'LL FINISH UP WITH TWO PRELIMINARY RESULTS. THIS IS NOT ONLY PRELIMINARY IN THE SENSE IT'S UNPUBLISHED BUT IN THE SENSE THAT WE DON'T YET HAVE ENOUGH OLD MICE TO KNOW HOW IT WILL COME OUT IN MAXIMUM LONGEVITY. THE FIRST OF THESE TWO DRUGS, THIS IS PART OF THE INTERVENTION TESTING PROGRAM, IT IS A PRESCRIPTION DRUG IN THE UNITED STATES, YOU CAN GIVE TO DIABETICS. THE MODE OF ACTION AS IT GOES IN THE CUT, STAYS IN THE GUT, NOT ABSORBED, IT BLOCKS ENZYMES THAT DIGESTS INTO POLYSACCHARIDES. SO WHEN YOU GIVE IT TO A DIABETIC PERSON IT WILL BLUNT THAT SPIKE. IF I EAT AN ICE CREAM CONE GLUCOSE SHOOTS UP AND COMES DOWN. IF I TAKE (INAUDIBLE) AND EAT THE ICE CREAM CONE, THAT PEAK LEVEL IS SUBSTANTIALLY BLUNTED. DAVID ALLISON AND DAN SMITH RECOMMENDED WE TRY THIS BECAUSE THEY THOUGHT THIS MIGHT BE A FORM OF CALORIC RESTRICTION. MICE ON THIS MIGHT NOT GET THE SAME INTAKE AS BUDDIES ON THE CONTROL DIET, MAYBE A FAR COLOGIC WAY OF MIMICKING RESTRICTION. THEY WERE HALF RIGHT. SO THE WEIGHT CURVE I LEFT OUT, THE WEIGHT CURVE SUGGESTS THEY ARE RIGHT. THE WEIGHT CURVE SHOW WHENCE YOU PUT MICE ON THIS THEY LOSE 10% OF BODY WEIGHT. MALES LOOSE IT, FEMALES LOSE IT SO IT RESTRICTS ABILITY TO ABSORB CALORIES AND MAINTAIN THEIR BODY WEIGHT BUT THE LONGEVITY DATA SHOW THAT WE GET A BIG DRAMATIC EFFECT LIMITED TO MALES ONLY. EFFECT IN MALES IS AS GOOD AS RAPAMYCIN SO FAR IN TERMS OF WHAT IT'S DOING TO THE MEDIUM LONGEVITY, 20, 22% INCREASE IN MEDIAN LONGEVITY. THE MALE EFFECT IT TURNS OUT THIS IS ONCE THEY GET TWO MONTHS FURTHER THERE IS A FEMALE, SLIDE IS ABOUT 3% CHANGE, ALL THE DATA ARE IN, IT WILL OR WILL NOT BE AT THE LEVEL OF STATISTICAL SIGNIFICANCE. WE DON'T KNOW THAT. BUT SEEMS VERY LIKELY TO US THAT WHEN THE DATA ARE IN, THE LAST 20 OF THE MICE ARE DEAD, WILL HAVE A LARGE EFFECT ON MEAN AND IMMEDIATE -- MAXIMAL LONGEVITY IN MICE. WE WOULD LIKE TO KNOW HOW THAT'S WORKING, WE WOULD LIKE TO KNOW IF INDEED IT'S MATTER OF CHANGING THE DYNAMICS OF GLUCOSE BLOOD LEVELS, WHY THAT'S GOOD FOR MALES AND NO EFFECT ON FEMALES, I'S A MYSTERY AND GIVE US WAYS TO ASSESS, WE CAN LOOK AT MALE AND FEMALE MICE IF WE HAVE A HYPOTHESIS, WHAT'S CHANGING IS HYPOTHALAMIC RESPONSES TO FEEDING. WE CAN TEST THAT IN BOTH MALES AND FEMALES IF WE SEE A BIG EFFECT OF CAR BOASE ONLY IN THE MALES AND THAT WE WANT TO FOCUS IN ON THAT HYPOTHALAMIC EFFECT CAUSATIVE IN THE LIFE SPAN EXTENSION. THE SECOND UNPUBLISHED AGENTS IS 17 ALPHA ESTRADIOL. THIS IS NOT THE FAMOUS ESTRADIOL. THE FAMOUS STRA DIAL IS 17 BETA ESTRADIOL, THAT'S WHAT MAKES WOMEN DIFFERENT FROM MEN, THROUGH THE ESTROGEN VEP TORES, WELL KNOWN TO EVERYBODY IN THIS AUDIENCE. 17 ALPHA ESTRADIOL IS A TUMOR WITH ONE CHIRAL CHANGE, IT DOESN'T GO THROUGH THE ESTROGEN RECEPTOR, 90% LESS EFFECTIVE HAHN THE FAMOUS BETA ESTRADIOL BUT THERE ARE EFFECTS THAT ESTROGEN CAN ESTABLISH IN MICE THAT ARE ESTROGEN RECEPTOR INDEPENDENT. MANY ARE CNS EFFECTS SO JIM SIMILAR KINS RECOMMENDED WE TEST THIS. HE THOUGHT IF WE GAVE THIS TO MICE, WE MIGHT DO THINGS THAT MAKE FEMALE HUMANS AN FEMALE MICE LIVE LONGER THAN MALES. WITHOUT TURNING THE MALE MICE INTO FEMALE MICE. IMAGINE NO GUY WOULD WANT TO -- INCREASE LIFE PAN BY 7% SO HE PROPOSES THIS AS A WAY TO DO THE GOOD STUFF ESTROGENS DO WITHOUT THE GIRLY NONSENSE. IN FACT THAT'S WHAT WE SEE. SO THE 17 ALPHA ESTRADIOL GIVEN TO THE MALES IS GIVING A NICE LIFE SPAN EFFECT, NOT AS GOOD AS ACAR BOASE BUT STILL QUITE GOOD. HIGHLY SIGNIFICANT INTERIM ANALYSIS AT THIS STAGE AND FEMALES NO EFFECT WHATSOEVER. WE CAN GUESS WHAT WE'RE DOING IS PRODUCING IN MALES THE GOOD STUFF THAT THE FEMALE MICE ALREADY HAVE IF THEIR -- AS THEIR NATURAL BIRTHRIGHT. THAT'S A HYPOTHESIS. WE NEED TO OPERATIONALIZE THAT, TEST IT, EVALUATE SPECIFICALLY IF THERE ARE GOOD THINGS HAPPENING IN THESE MALE MICE, TREAT WITH 17 ALPHA ESTRADIOL, WE OUGHT TO SEE THEM MALE, FEMALE DIFFERENCES AN INFLUENCE BY THE 17 ALPHA ESTRADIOL ONLY IN MALES. WE THINK AGAIN HYPOTHESIS, THE BRAIN IS THE PLACE TO LOOK. A LOT OF WORK THAT JIM SIMILAR KINS HAS DONE ON 17 ALPHA ESTRADIOL SHOWS POTENT CNS EFFECTS IN TERMS OF MIMIC THE EFFECTS OF ESTROGEN IN THE BRAIN. SO I'LL FINISH WITH COUPLE OF ADVERTISEMENTS. THE VIEW FROM 10,000-METERS. THIS IS WHY IF YOU'RE NOT DOING THE BIOLOGY OF AGING DROWP WHAT YOU'RE DOING AND BECOME A BIOGERONTOLOGIST. SO I HAVE TRIED TO CONVINCE YOU THAT IT IS NOT THAT HARD TO SLOW AGING AT LEAST IN LABORATORYJf„ ANIMALS. BY DRUGS DO IT, MUTATIONS DO IT, TWO KINDS OF DIETS, EARLY LIFE CROWDING. I SAY THIS TO ME IT SEEMS OBVIOUS. THERE ARE VERY STRONG, DOZENS OF LABS HAVE SHOWN THIS, REALLY TRUE, IN MY PERSONAL VIEW THE MAIN REASON AGING RESEARCH HAS NOT TAKEN OFF, NOT BECOME THE MAIN THING NIH DOES, YOUR PRESIDENT, PRESIDENT ACTUALLY OBAMA TOO, WE'RE GOING TO CURE ALZHEIMER'S YOU GET A PLOT OF APPLAUSE, PEOPLE ARE ENTHUSIASTIC ABOUT THAT. IF THE SAME PRESIDENT OR ANY TT PRESIDENT SAYS WE'RE GOING TO SLOW THE AGING RATE MY ADMINISTRATION IS GOING TO DEVOTE ENERGY TO SLOWING THE AGING RATE YOU GET A CHUCKLE. CRAZY, RIGHT? YOU CAN'T SLOW THE AGING RATE SO THEY'RE WRONG. PEEP WHOM ARE CHUCKLING AT THAT ARE WRONG BECAUSE YOU CAN SLOW THE AGING RATE. THE FACT YOU CAN SLOW THE AGING RATE AND POSTPONE A VAST RANGE OF AGE SENSITIVE DISEASES SUGGESTS TO ME THAT THE SMART WAY TO DO MEDICAL RESEARCH IS TO FOCUS ON AGING AND IT LINKS TO THESE GENES. THE EFFECT IN THESE LAB ANIMALS IS NON-TRIVIAL IN THE SENSE IT'S TEN TIMES LARGER PERCENTAGE WISE THAN A CURE FOR HUMAN CANCER. I HAVE SHOWN YOU A LITTLE BIT OF EVIDENCE, THERE IS A TON BUT I HAVE SHOWN ONE OR TWO SLIDES TO SHOW THEY'RE NOT JUST ALIVE BUT HEALTHY TOO. WHEN I TELL -- MY WIFE IS AN ENGLISH PROFESSOR I TELL MY STORY AT DINNER PARTIES THAT I DO AINGING RESEARCH THEY YELL AT ME WE DON'T WANT THE WORLD TO FILL UP WITH SICK OLD PEOPLE. I EXPLAIN THE KIND OF STUFF WE'RE TRYING TO DO IS THE SAME STUFF ANY MEDICAL RESEARCHER IS TRYING TO DO, POSTPONE THE DISEASES, KEEP PEOPLE THEY HEALTHY PRODUCTIVE AND HAPPY WITH THEIR LIVES A LONGER PERIOD OF TIME. WE'RE NOT TRYING TO CREATE A CADRE OF PEOPLE WHO LOOK LIKE TODAY'S SICK, 110-YEAR-OLD PEOPLE AND KEEP THEM IN NURSING HOMES DEMENTEDDED AND UNHAPPY FOR A LONG PERIOD OF TIME. WE WANT TO POSTPONE THAT PERIOD AND KEEP THEM HEALTHY FOR A LONG PERIOD OF TIME THAT'S NOT SCIENCE FICTION. ALL THE EVIDENCE FROM THESE ANTI-AGING MANIPULATIONS IN ANIMAL MODELS SUGGEST THAT'S WHAT YOU GET. MY TAKE HOME MESSAGE IS IT MIGHT BE NICE TO FIGURE HOW THESE WORK AND USE THAT INFORMATION TO SEEK SAFE AND EFFECTIVE DRUGS THAT SLOW THE AGING PROCESS. IF YOU TOOK SERIOUSLY, YOU WOULD DEVOTE THE REST OF YOUR LIVES TO A NEW PARADIGM FOR MEDICAL RESEARCH. MOST RESEARCH FUNDING WHETHER THE UNIVERSITY OF MICHIGAN OR NIH OR ANYWHERE IN THE WORLD, IS ORGANIZED BY DISEASE OR ORGAN SYSTEM. IF YOU ASK ONE OF MY COLLEAGUE WHAT IS DO YOU DO, THEY SAY I STUDY BONE OR CANCER OR LUNG DISEASE OR I STUDY INFECTIOUS DISEASES. BUT AGING IS THE MAJOR RISK FACTOR FOR NEARLY ALL THE COMMON DISEASES THAT ADULTS GET ONCE THEY GET TO THE POINT WHERE THEY HAVE AN ASSISTANT PROFESSORSHIP AND ABOVE. SLOWING THE AGING IN RODENTS SLOWS MULTIPLE DISEASES IN PARALLEL TOGETHER. SO MY MIND IMPLICATION IS IF WE CAN DEVELOP DRUGS THAT SLOW AGING IN PEOPLE, IF THE DRUGS ARE PRACTICAL AND ACCEPTABLE AND DIDN'T PRODUCE SIDE EFFECTS, THAT THEY WOULD SLOW MULTIPLE DISEASES AT THE SAME TIME JUST AS EVERYTHING THAT WE HAVE LOOKED AT SO FAR IN THE MOUSE SYSTEM DOES. I THINK THAT WILL REQUIRE THAT CANCER EXPERTS TO WORK WITH THE AGING EXPERTS TO LEARN WHAT IT IS ABOUT AGING THAT MAKES CANCER HAPPEN, IT WOULD REQUIRE THE BRAIN EXPERTS TO WORK WITH AGING EXPERTS LEARN HOW IT IS AGING SLOWS DOWN OR SPEEDS UP AGING OF THE BRAIN. FROM THAT PERSPECTIVE IT'S MY BELIEF, NOT SELF-SERVING BELIEF WOULD REVOLUTIONIZE RESEARCH IN MEDICAL FIELDS TO MAKE IT MORE EFFECTIVE AND QUICKER. BIOGERONTOLOGY IS NOT GERIATRIC MEDICINE F. YOU'RE SICK AND OLD, I WOULD URGE YOU TO FIND A GERIATRICIAN. IF YOU ARE YOUNG, AND STAY YOUNG A LONG TIME DON'T CALL YOUR GERIATRICIAN, YOU CALL THE BIOGERONTOLOGIST. NOT TO TREAT YOU WHEN YOU'RE SICK BUT TO KEEP YOU YOUNG AND HEALTHY. THIS IS A PICTURE OF A NORMAL AVERAGE PERSON AGE 70, BELIEVE IT OR NOT AT AGE 70. AND THE GOAL OF THE RESEARCH THAT I'M TRYING TO PROMOTE, TRYING TO ADVERTISE FOR IS TO GET A SYSTEM OF PREVENTIVE MEDICINES IN PLACE SO A NORMAL PERSON AT AGE 114 WILL LOOK ABOUT LIKE THAT. IN A REGIME OF -- THAT IS ACTUALLY INFORMED BY ANTI-AGING MEDICINES SOME WILL GET SICK AND DIE WHEN THEY'RE 70, 80, 90, 100, 110, 120, 130, 140. WE'RE NOT GOING TO CURE DISEASE, NOT PUT PHYSICIANS OUT OF BUSINESS BUT WE WANT TO GIVE THEM A 30 YEAR VACATION. WE WANT THEM TO HAVE 30 YEARS TO REST AND RELAX AND THEN GET BACK INTO BUSINESS WHEN PEOPLE REACH THE AGES OF 100 TO 110 WHEN THEY START TO GET SICK. SO THAT'S THE END OF THE MATERIAL I WANTED TO PRESENT. THIS IS MY LAB ACTUALLY STUDIES STRESS RESISTANCE IN MICE SO THIS IS A SLIDE I USE AS PART OF MY STRESS RESISTANCE TALK BUT IT'S ALSO APPROPRIATE SLIDE TO LEAVE UP THERE FOR QUESTION AND ANSWER PERIOD WHICH I WOULD BE DELIGHTED IF WE HAVE TIME TO ENTERTAIN NOW. [APPLAUSE] >> ARE THERE QUESTIONS? LIGHTS ARE IN MY EYES SO YOU MAY HAVE TO BE AGGRESSIVE AND SAY SOMETHING. YEAH. (OFF MIC) >> THE EVIDENCE ACTUALLY THOUGH NOT GOOD, THE EVIDENCE IS TO THE OPPOSITE. TURNS OUT WHEN YOU LOOK AT MICE OR DWARF MICE DYING AT THE END OF THE LIFE SPAN HAY MORE OFTEN THAN CONTROL GROUP DON'T HAVE ANY SIGNS OF MAJOR DISEASE. PRESUMABLY A METABOLIC ABNORMALITY OR CARDIAC ARRHYTHMIA HARD TO SPOT. I SHOWED YOU THAT IN THE GLAMELULAR DISEASE. THE SNELL DWARF TREATED MICE, THOUGH OLDER KIDNEYS LOOKED BETTER . THAT'S PHENOMENON THAT THE OLDER ANIMALS DO NOT HAVE A RAPID ONSET OF DEATH WITH MAJOR DISEASES HAPPEN HAPPENING TO THEM BUT MANY DISEASES ARE LESS PROMINENT IN THE SLOW AGING MICE EVEN AT ADVANCED AGE. >> YOU HAVE HAD A CHANCE TO LOOK AT BRAIN OF THE AGED MICE? IS THERE ANY (INAUDIBLE) FOR THE PROGRAM THE TEARS RELATED TO THOSE DEGENERATION? >> WELL, THERE'S SEVERAL INTERESTING FRAG MEANTERS ON THAT. FOR INSTANCE, WHEN THEY GET OLDER THEY DON'T SHOW DEFICITS IN MEMORY. THESE TRUE FOR THE GROWTH HORMONE RECEPTOR MICE SO COGNITIVE FUNCTION IS PRESERVED IN GENETIC AS WELL AS CALORIE RESTRICTED MICECH PEOPLE LOOK AT THE BRAINS OF THE MICE AND THE STUDY I THINK IS MOST EXCITING HAS THE TO DO WITH LOCAL PRODUCTION OF GROWTH HORMONE IGF-1. VERY LOW SERUM GROWTH HORMONE IGF-1. THAT'S WHY THEY OTHER DWARFS. THEIR BRAINS HAVE A LOT. IN FACT WHEN REGULAR GET OLD THE GROWTH HORMONE GOES AWAY IN THE BRAINS BUT STAYED UP IN THE DWARF MICE SO SOMEHOW THE BRAINS OF THESE MICE NOTICED NOT ENOUGH GROWTH HORMONE IGF-1 IN SERUM, I ASSUME, LEAVES ON THE BRAIN SPECIFIC PRODUCTION OF THOSE HORMONES LOCALLY PRODUCED FOR LONGER PERIOD OF TIME THAT HAS BEEN SHOWN THAT LEADS TO PRESERVATION OF STEM CELL TURN OVER WITHIN THE CNS. A REASON THAT THAT HELPS PRESERVE COGNITIVE FUNCTION. THERE'S NOT NEARLY ENOUGH DETAILED ANALYSIS. WE'RE GOING TO DO IT WITH THIS HUNTINGTON DISEASE MODEL WE HAVE SHOWN WITH ROGER ALBIN THAT HUNTINGTON'S DISEASE GOES MORE SLOWLY ON A SNELL DWARF BACKGROUND THAN CONTROLS. SO WHAT THEY'RE GOING TO DO NOW IS LOOK FOR INSTANCE AT ACCUMULATION OF THE HUNTINGTON PROTEIN, THE PRELIMINARY EVIDENCE'S NOT HOW IT WORKS. THE SNELL DWARF MICE DON'T HAVE DELAY IN ACCUMULATION OF HUNTINGTON AGGREGATES. SO THEN THEY'LL GO DOWNSTREAM. WHAT IS THE HUNTINGTON AGGREGATE CAUSE? THAT'S WHAT IS DELAYING THE SYMPTOMTOLOGY. THERE'S WORK TO BE DONE CONSTRUCTING NEW MODELS IN WHICH SLOW AGING ANIMALS WHETHER DRUGGED ANIMALS, MUTANT ANIMALS OR CROWDED LITTER ANIMALS, ARE EVALUATEDDED FOR SPONTANEOUS DISEASE OR IN THE CASE OF COMPOUND MUTANT WITH HUNTINGTON ALZ HIGH MERS OR HEART ATTACKS TO SEE WHAT ASPECTS ARE SLOWED DOWN BY SLOWING THE AGING PROCESS. >> NOW WE HAVE THE MOST GENOME DATABASE SO YOU COULD LOOK AT ALL THE ISSUES OF AGING I'M LOOKING AT (INAUDIBLE) NOWS GENOME FROM 111 TO 180 DAYS. I'M LOOKING AT THE (INAUDIBLE) CELLS WHERE THEY SHED 10% OF THE OUTER SEGMENTS EVERY DAY BECAUSE OF THE CHEMICAL EFFECTS. SO I WILL LOOK AT THE HEAT SHOCK GENES, DID YOU HAVE A SPECIFIC GENE WITH RESPECT TO AINGING EFFECTS ON DRUG ENTERVINGS? >> TWO ASPECTS OF THAT QUESTION. ONE IS SEPARATING POLYMORPHISMS THAT DO OR DON'T PRE-DISPOSE YOU TO AGING. THAT'S LOVELY STUFF BUT I DON'T THINK THAT'S RELEVANT TO ANTI-AGING MECHANISMS PER SE. BY DEFINITION ALMOST ALL ARE GOING TO BE RELATED TO THE EFFECTS OF AGING ON ONE SPECIFIC ASPECT, BONE OR BRAIN AGING OR MUSCLE AGING OR WHATEVER, YOU TALK GENE EXPRESSION DATA, THOSE CAN PROVIDE AMONG OTHER THINGS USEFUL BIOMARKERS HOW FAST THE AGING PROs IS GOING. SO IN HUNTINGTON DISEASE MODEL FOR INSTANCE WE WILL LOOK FOR GENES EXPRESSION MODIFIED BY HUNTINGTON DISEASE BUT NOT MODIFIED BY HUNTINGTON DISEASE IN THE SNELL MODEL. THAT GIVES CLUES TO THE PATHWAYS BUT WHETHER THAT'S OFTEN TWO, THREE, FOUR, FIVE CAUSAL STEPS AWAY DIFFERENT CELL TYPES, THE REAL EFFECT SON STEM CELLS. GETTING FROM TRANSCRIPTOME ANALYSIS, WITH MULTIPLE INTERVENTIONS, TO CAUSAL MODELS IS TRICKY I THINK. >> THREE QUESTIONS, ONE, ARE YOU WITHIN THE INTERVENTIONS GROUP STARTING TO LOOK AT COMBINATION INTERVENTION? >> YES, IN AN INTERESTING WAY. RAPAMYCIN WHICH EXTENDS LIFE SPAN AND SLOWS AGING HAS A NEGATIVE EFFECT, IT MAKES YOU MORE INSULIN RESISTANT. SO WE HAVE A COMBINATION STUDY WHICH THE RAPAMYCIN TREATED MICE GET METAPHOR MAN AND OUR GUESS IS WE HAVE NO DATA SO OUR GUESS IS THE INSULIN RESISTANCE PRODUCED BY RAPAMYCIN IS MUTED BY HAVING METAPHORMAN ON BOARD AT THE SAME TIME. SO WE HOPE TO EXTEND LIFE SPAN MORE WITH THAT COMBINATION. THERE IS ALSO STUDY JUST BEGUN WITH A PROPRIETARY CALLED PROTANDEM, A PICTURE OF BOTANICAL PRODUCTS THAT INDUCE NERVE TWO, A STRESS RESPONSE ELEMENT. THE IDEA OF PEOPLE WHO SUGGESTED THIS IF YOU GAVE AT HIGH ENOUGH DOSE TO BE TESTED MIGHT HAVE NEGATIVE SIDE EFFECTS BUT IF YOU GIVE FIVE WITH DIFFERENT NEGATIVE SIDE EFFECTS, FAIRLY LOW LEVELS THE IDEA WAS YOU WOULDN'T HAVE SERIOUS SIDE EFFECTS AND GET A BOOST, WHERE WHR THAT'S TRUE OR FALSE WE'LL KNOW WITH THE LIFE SPAN DATA. >> SPEAKING AMONG NEGATIVE ASPECTS OF RAPAMYCIN WOULD IT BE POSSIBLE SOME OF THE AGE INHIBITOR EFFECTS ARE CAUSED BY DECREASED TESTOSTERONE LEVEL? >> I THINK THAT'S POSSIBLE. >> LASTLY -- >> LET ME JUST -- YES, BUT WORKS BETTER IN FEMALES. IN THE FEMALES PROBABLY NOT GOOD TO INDUCE TESTOSTERONE N MALES IT'S POSSIBLE LOWERING TESTOSTERONE WOULD BE GOOD FOR YOU BUT FEMALES PROBABLY NOT. >> FEMALES HAVE TESTOSTERONE S TOO. TUMOR SUPPRESSOR GENES WERE HOT BUTTON TOPICS FOR AGING RESEARCH WHETHER FACILITATE AGING OR COULD HAVE AGE INHIBIT TORE EFFECTS BUT A LOT OF ARGUMENTS DO TO CANCER INHIBITION. BUT THE ROLE OF TUMOR SUPPRESSION GENES LEADING TO CELL SENESCENCE LEADING TO PHENOTYPES, WONDERING WHERE YOU SIT ON THAT NOW. >> I'M HOPING (INAUDIBLE) ISN'T IN THE ROOM BECAUSE I HAVE A DIFFERENCE OF OPINION. I DON'T THINK THE SENESCENCE STORY IN PARTICULAR THE NOTION OF LEADING TO CELL SENESCENCE IS WAY OF PRODUCING AGING, I DON'T FIND THAT MYSELF TERRIBLY CONVINCING. IN PARTICULAR THE EVIDENCE HAS COME FROM PREMATURE AGING MICE, SOMEONE HAS A MOUSE, A DEFECT THAT CAUSES A LOT OF CELLULAR DAMAGE, INCLUDING SENESCENCE, THE MICE GET SICK AND DIES, THAT IS SOMETIMES PREMATURE AGING, THERE'S A CONTROVERSY, I'M LESS CONVINCED THAN OTHERS THAT THOSE ARE USEFUL FOR STUDYING WHAT HAPPENS IN AGING AMONG THOSE OF US NOT PRO GERIOID. >> THANK YOU. >> YOU MENTION THE POTENTIAL ROLE OF INFLAMMATION IN TERMS OF PROCESSES AND THE DATA ON MACROPHAGE INHIBITION MIGRATION FACTOR. IN THIS MODEL I WONDER WITH THE VARIOUS INTERVENTIONS, ARE THERE CHANGES POSSIBLY IN TERMS OF INTESTINAL PERMIBILITY TO ENDOTOXIN? ARE THERE DIFFERENCES IN TERMS OF CIRCULATING LEVELS OF ENDOTOXIN IN THIS AGAIN, MODELS YOU DISCUSSEDDED? >> I DON'T HAVE DATA AND I DON'T HAVE AN OPINION BUT WELL WORTH EVALUATING THAT. SOME OF THE AGENTS CLEARLY HAVE AN EFFECT LOCALIZED TO THE GUT WHICH MIGHT HAVE SOME EFFECT LATE IN LIFE OR EVEN EARLY IN LIFE ENDOTOXIN PERMIBILITY. THERE'S ALSO A BEAUTIFUL PAPER FROM OMAR UMA AND DAVID SABATINI. CALORIC RESTRICTION INCREASES STEM CELL HEALTH IN THE GUT BUT NOT THROUGH DIRECT EFFECT IN STEM CELLS. IT'S INFLUENCING THE CELLS THAT NURTURE AND SUPPORT STEM CELLS. THEY FOUND THIS IS TOR MEDIATE SOD IN THEIR HANDS THE CALORIC RESTRICTION HAS EFFECT DEPENDING ON TARGET OF RAPAMYCIN IN THE INTESTINAL CELLS THAT THEN INCREASE STEM CELL BIOLOGY AND PROVE STEM CELL SELF-REGULATION. IT'S POSSIBLE THAT SOME OF THE RAPAMYCIN EFFECTS WE HAVE BEEN SEEING HERE, WHETHER INTESTINAL OR OTHER STEM CELLS, MIGHT BE MEDIATEDDED BY MODULATION OF STEM CELL NICHES IN WAYS THAT PROMOTE STEM CELL VIABILITY IN OLD AGE. WE ARE BEGINNING A COLLABORATION WITH OMAR UMA AND DAVID SABATINI, WE'RE SENDING GI TISSUE FROM THE MICE, THE RAP MYSIS MICE AND THE ESTRADIOL MICE SO THEY CAN SEE THE EFFECTS THEY HAVE ALREADY NOTED IN CALORIC RESTRICTION ANIMALS ARE ALSO SEEN IN THE DRUG INDUCED MODELS FOR SLOW AGING EXTENDED LIFE SPAN, WHETHER THAT IS RELATED TO LPS PERMIBILITY AND PROTECTIVE PROPERTIES OF GUT WE DON'T HAVE ANY DATA YET. >> THANK YOU. >> RELATED TO A PREVIOUS QUESTION. WE KNOW INFLAMMATION IS BAD WHEN YOU HAVE AN EXCESS OF IT BUT IT IS GOOD USUALLY WHEN YOU'RE CHALLENGED BY THE ENVIRONMENT. IF YOU TEST YOUR MICE IN BACTERIAL VIRAL CHALLENGE MODEL, LIKE CL ELONGATION, HOW IS SURVIVAL IN -- >> SO THERE'S NOT NEARLY ENOUGH DATA YET TO GIVE A GOOD STRONG COMPREHENSIVE ANSWER TO THAT. IF YOU TAKE A CALORICALLY RESTRICTED ANIMAL, THOSE THAT HAVE BEEN STUDIED, THEY HAVE FEW IMMUNE CELLS. THEIR (INAUDIBLE) IS 1/8 NORMAL SIZE OF THE SPLEEN. IN THERE'S SO FEW IF YOU CHALLENGE -- IF YOU GIVE THE ANIMAL AN INFECTIOUS CHALLENGE THAT REQUIRES THAT THEY RAPIDLY MOBILIZE ENERGY THEY HAVE NO FAT STORES. THEY CAN'T DO THAT. THEY'RE MORE SUSCEPTIBLE TO DEATH INDUCED BY WIDE RANGE OF PATHOGEN T. SO IT COULD BE, THIS IS I GUESS COULD BE THE OPTIMAL APPROACH WOULD BE TO EXPOSE ANIMALS TO ONE OF THESE DRUGS OR DIETARY INTERVENTIONS FOR A PERIOD OF TIME AND TAKE THEM OFF THAT. THAT MIGHT LEAVE THEM WITH A PEPPIER IMMUNE SYSTEM, BETTER DEFERENCE AND MORE ABILITY TO MUSTER ENERGY RESERVE AND IMMUNE RESPONSE WHEN NECESSARY. THERE'S A LITTLE EVIDENCE FOR THAT FROM (INAUDIBLE) AT UNIVERSITY OF WASHINGTON SEATTLE. IF YOU HAVE A COLOR RESTRICTED -- CALORIE’8 WOUND THE WOUND DOESN'T HEAL BECAUSE SO LITTLE ENERGY. BUTCAL I RESTRICTION MOST OF LIVES AND LET THEM EAT WHAT THEY WANT, PUT THEM ON A DIET NORMAL FOR FEW WEEKS, WOUND HEALING IS TERRIFIC, MUCH BETTER THAN OLD ANIMALS SO THIS IS CONSISTENT WITH THE NOTION THAT THEY -- THE AGE PROCESS IS SLOWED AND THEY ARE USEFUL BUT SOME ASPECTS OF RESPONSE TO WOUNDING OR POTENTIALLY INFLAMMATORY STIMULI REQUIRE RAPID MOBILIZATION OF RESTRICTION THAT CALORIC RESTRICTION MAKES IMPOSSIBLE. >> THANK YOU. >> THANK YOU.