Genotoxic Stress Meets Mitochondria: Integrating Aging Mechanisms

Genotoxic Stress Meets Mitochondria: Integrating Aging Mechanisms


>>GOOD AFTERNOON AND WELCOME TO THE WALS LECTURE. JUST BRIEFLY FOR THOSE WHO NEVER HAD A CHANCE TO KNOW FLORENCE, SHE THROUGH OUT HER FULL LIFE OF 103 YEARS, WAS A STRONG ADVOCATE FOR NIH, FOR AGING RESEARCH, AMONG OTHERS FIELDS OF STUDY BUT ABOVE ALL SHE WAS A STRONG POETIC PONENT FOR WHAT SHE CALLED REAL RESEARCH, HARD RESEARCH AND RIGOROUS RESEARCH AND EVERY YEAR WHEN WE’RE PLANNING WITH HER WHO THE INVITED SPEAKER WOULD BE, SHE TOOK AN ACTIVE ROLE IN MAKING SURE THE SCIENCE WAS UP TO HER STANDARDS AND I KNOW SHE WOULD BE ABSOLUTELY DELIGHTED WITH THIS YR’S PRESENTATION BY DR. RON DEPINO. RON HAS PLAYED A UNIQUE ROLE IN THE CONVERGENCE OF OF SCIENCE AND EULOUSIDATING BASIC MECHANISM TO UNDERSTAND ALL THE MOOD TRANSLATION AND THE FIELD OF AGING, AND THE FIELD OF CANCER RESEARCH HAVE LONG ENJOYED WELL RECOGNIZED COMPLEMENTARITY AFTER ALL THE ESSENCE OF CANCER IS ONCA TRAINED GROWTH IN THE CASE OF AGING DIFFICULTIES THAT ARISE WITH AGING AND HAVE TO DO WITH DEFECTS AT THE TIME AND SO GROWTH AND PROLIFERATION AND COMMON AREAS OF METABOLISM AND COMMON CONCERNGENOMIC STABILITY AND RON IS UNIQUELY BEEN AT THE FOREFRONT OF RESEARCH IN THESE AREAS. HE BEGAN AND STAYED AT THE SCHOOL OF EINSTEIN AND DID TRAINING AT COLUMBIA AND AT HARVARD WHERE THERE WAS A FULL PROFESSOR SINCE 1998 UNTIL VERY RECEIPTLY SO MANY OF YOU WILL KNOW THAT AS OF SEPTEMBER 1, HE LEFT HARVARD, PROFESSORSh HIS ROLE WITH THE BELFOUR INSTITUTE THERE TO MOVE TO A GREATER LEVEL OF RESPONSIBILITY AS PRESIDENT OF MD ANDROGENNERSON WHERE HE WILL UNDOUBTEDLY BE ABLE TO MEET THE CHALLENGES AND CAPABILITY OF THAT AUGUST INSTITUTION. RON’S TAKEN A NUMBER OF PATHS, HE HAS WORKED ON SELMA TAB O LIMP AS THEY ARE WITH CANCER AND AGING, HE UNCOVERED A GREAT DEAL ABOUT THE MECHANISMINGSING OF GENES THAT ARE PROTECTIVE AND PROMOTING FOR CANCER, HE WAS AMONG THE PIE O NEARS WHO UNDERSTOOD THE RELEVANCE OF TELOMERES AFFECTING THE BIOLOGY THAT AGAIN AFFECTS THOSE TWO CONDITIONS AND MOST RECENTLY AND WHY IT’S EXCITING TO HAVE HIM HERE THIS YEAR, HE IS REALLY ELUCIDATED THE CONVERGENCE OF THE MECHANISMS OF TUMOR SUSEPTIBILITY OF TELOMERE LENGTH, OF TELOMERE DYSFUNCTION, WITH BASIC MECHANISMS OF METABOLIC AND PARTICULAR MITOCHONDRIA METABOLISM, AGAIN I’D EMPHASIZE A UNIQUE PRODUCT OF AN OPEN AND BRILLIANT MIND BROUGHT TOGETHER AREAS OF APPARENTLY TO MANY DISPARATE BIOLOGY UNTIL WHAT HE PRESENT SYSTEM A COMPELLING CASE FOR A NEW AND VERY IMPORTANT INTEGRATED VIEW OF THIS BIOLOGY. SO, RON, THANK YOU FOR BEING HERE, IT’S A GREAT PLEASURE TO INTRODUCE YOU TODAY. [ APPLAUSE ]>>RICHARD, THANK YOU VERY MUCH FOR THAT OVERLY KIND INTRODUCTION, I UNDERSTAND THIS IS BEING SIM SIMULCAST TO MD ANDERSON, HIGH, Y’ALL. I LEARNED THAT Y’ALL IS ACTUALLY SINGULAR. ALL Y’ALL IS PLURAL. SO I’M GETTING THERE. ANYWAY, IT’S JUST–IT’S SUCH A PRIVILEGE TO BE HERE AND THANKS AGAIN FOR THE EXTREMELY GENEROUS INTRODUCTION. I THINK THE SECRET TO MY SUCCESS HAS BEEN REALLY HAVING PHENOMENAL PEOPLE COME TO MY LAB AND LET THEM CUT LOOSE, ONE OF WHOM IS IN THE THIRD ROW THERE, JANE, ONE OF YOUR NEW STARS HERE. SO THIS IS JUST A WONDERFUL OPPORTUNITY TO CELEBRATE SOME OF THE REALLY COOL SCIENCE THAT’S BEEN GOING ON IN THE LAB AND COLLABORATORS THAT WE’VE BEEN BLESSED TO HAVE MAYBE TALKING ABOUT THE ROLE OF TELOMERES IN CANCER AND AGING AND WHAT GOT US INTROTHIS IS TRYING TO UNDERSTAND IT’S ROLE IN A VARIETY OF DIFFERENT BIOLOGICAL PROCESSES, CANCER, AGING, DEGENERATIVE DISEASES, BOTH DISEASES THAT ARE ACQUIRED LIKE LIVER CIRRHOSIS, LEADING CAUSE OF DEATH, SEVENTH WORLD WIDE AND PREMATURE AGING CONDITIONS SUCH AS WARNERS, BLOOM’S AND ALL THESE PROCESSES TELOMERE VS FIGURED PROMINENTLY. NOW WHAT GOT US INTERESTED IN THIS SPACE WAS TRYING TO UNDERSTAND THE INTIMATE LINK BETWEEN AGING AND CANCER. ADVANCING AGE IS BY FAR THE MOST IMPORTANT RISK PATHOR FOR THE DEVELOPMENT OF–FACTOR FOR THE DEVELOPMENT OF CANCER AND INTERESTINGLY IT’S NOT ALL CANCERS CANCERS IN AGED INDIVIDUALS TEND TO BE DOMINATED BY EPITHELIAL CANCERS AND THOSE CANCERS ALSO ARISE WITH RADICALLY ALTERED PROFILES THAT ARE CHARACTERIZED BY COMPLEX NONRECIPROCAL TRANSLOCATIONS AND COPY NUMBER ALTERATIONS. AND THIS IS JUST AN OLD RCGH TRACING OF A PAN KRIST AS CANCER AND SHOWING GAINS AND LOSSS AND WE NOW KNOW FROM THE GENOME PROJECT THAT THEREIN RESIDES ORCHGA GENES AND TUMOR SUPPRESSOR GENES. SO UNDERSTANDING THE MECHANISM THAT DRIVES THAT WHY IS AGE SUCH AS IMPORTANT RISK FACTOR? WHY DO THEY DEVELOP THE TYPES OF CANCERS THEY DO? WHY DO THOSE CANCER VS ALTERED GENOMES OR THINGS WE TRIED TO ANSWER AND THIS WAS FURTHER BROUGHT INTO FOCUS WHEN WE LOOKED AT THE MOUSE. WHICH INSTEAD OF DEVELOPING EPITHELIAL CANCERS HAD CANCERS THAT WERE MORE HEME AT O POETIC AND FOR THE MOST PART HAD AN ORDER OF MAGNITUDE LESS GENOME COMPLEXITYÑi TYPICALLY HOLD THE GAINS OR LOSSES BUT AT LEAST 10 FOLD LESS REGIONAL AMP MRI FIELD PLIFICATIONS AND DELETIONS AND WE FELT IF WE COULD UNDERSTAND THE CROSS SPECIES DIFFERENCE WE MIGHT ELUMINATE THE SIDE OF HUMAN BIOLOGY THAT IS ABOUT THIS EPITHELIAL DOMINANCE IN THE AGES. AND SO, FOR A NUMBER OF REASONS WE FELT THAT TELOMERES MIGHT BE AT LEAST ONE COMPONENT OF THAT TELOMERES ARE THE STRUCTURES THAT CAP THE ENDS OF CHROMOSOMES. THEY HELP TO MAINTAIN CHROMOSOMAL INTEGRITY. IN THEIR ABSENCE, TELOMERES, THE ENDS BECOME RECOMBINANT GENIC AND THEY ELICIT DNA DAMAGE SIGNALING, ET CETERA. IN HUMANS TELOMERES ARE SHORT, AND POLYMERASE ACTIVITY IS LOW AND IN THE MOUSE, TELOMERES TEND TO BE LONGER, ESPECIALLY INBRED MICE AND THEY HAVE MORE PERMISS CUE EXPRESSION OF TELEO MERACE, AND IN A SENSE, MICE DO NOT EXPERIENCE ONE EVENT IN CELL BIOLOGY WHICH IS TELOMERE BASED CRISIS. THAT IS CELLS DIVIDE IN THE ABSENCE OF TELEO MERACE, BECAUSE OF THE END REPLICATION OF TELEMERAISE AND YOU EVENTUALLY SIGNAL THE ESSENCE BIOERODED TELOMERES AND MICE DON’T EXPERIENCE TELOMERE BASED CRISIS. SO IF WE COULD ENGINEER MICE TO EXPERIENCE CRISIS, THEN WE MIGHT UNDERSTAND BETTER THE ROLE OF TELEO MERACE IN AGING AND CANCEROT ORGANISM MALLEVEL. AND SO TO DO THAT WE COLLABORATE WIDE CAROL BRIGHTER, MARIA THEN A POST DOC IN HER LAB HAD JUST CLONED THE GENE THAT ENCODES THE TEMPLATE FOR THE TELEO MERACE ENZYME, IT SERVES AS THE DENOY EDITION OF THE REPEATS THAT IS ALSO A CAD LIDDIC COMPONENT, A REVERSE TRANSCRIPT ACE, WE’LL KNOCK OUT THIS AND WE ALSO GENERATED KNOCK OUTS FOR THIS GENE AS OTHERS HAVE, LIKE LEAH HERRING TON AND FOR THE MOST FART THEY PHENOCOPY ONE ANOTHER WITH THE TELEO MERBEING THE CRITICAL ACTIVITY OF THE ENZYME: AND SO WHEN WE KNOCKED IT OUT, IN THIS CASE, IT’S HON O LEE AND IN COLLABBUATION WITH MIRROR IMAGE RIA BLASTOWHO GENERATED THE MOUSE AND WENT ON TO CHARACTERIZE THE PHENOTYPE OF THE MOUSE AND WE SAW THAT IN THE FIRST GENERATION KNOCK OUTS THEY WERE PRETTY HEALTHY. THEY HAD LONG TELOMERES. SO WE CROSSED THEM THROUGH SUCCESSIVE GENERATIONS TO GET THEM DOWN TO A MORE HUMANIZED TELOMERE LEAPT AND BY THE THIRD–LENGTH AND BY THE THIRD GENERATION WITH PETER, SAW CYTOGENIC EVIDENCE OF LOSS OF TELOMERE FUNCTION. WE SAW THIS FUSION AND THERE’S NO DETECTABLE FUSIONS AND THEY RECOMBINED WITH THE HYPOTHESIS THAT WAS ESTABLISHED IN THE 30S AND CO INCIDENT WITH THE CYTOGENETIC EVIDENCE THAT TELOMERES ARE BECOMING DYSFUNCTIONAL, ANU LEE AND OTHERS WENT ON TO DEMONSTRATE THAT THESE ANIMAL VS A PREMATURE AGING CONDITION, A DIMINISHED CAPACITY TO HANDLE ACUTE AND CHRONIC STRESS, GUFF AS AGED INDIVIDUALS DO, THERE WAS ALSO WIDE SPREAD ORGAN ATROPHY ESPECIALLY SYSTEMS WITH HIGH PROLIFERATIVE WITH THE GI TRACT AND TESTES AND THE HEM AT O POETIC COMPARTMENT FOR EXAMPLE AND WE KNOW THAT WAS DUE TO THE COMPLETION OF RES DEBT STEM CELLS. LINDA CHEN INSPIRED BY THE WORK OF MIKE CASTIN WENT ON TO ASK THE QUESTION OF WHETHER OR NOT P53 MIGHT BE SENSING THIS DYSFUNCTION, MIKE TAUGHT US THAT DNA DAMAGE ACTIVATES P53 AND ACTIVATES IN TURN A CELLULAR CHECK POINT RESPONSE AND SO SHE ASKED WHETHER OR NOT, IF TELOMERES MIGHT BE AN ERODED DNA DAMAGED AND PERHAPS, P53 MIGHT SENSE IT, AND EXECUTE THESE CHECK POINT RESPONSES AND INDEED THAT TURNED OUT TO BE THE CASE SO SHE BROUGHT P53 THROUGH THE SUCCESSFUL GENERATIONS AND THIS IS JUST ONE EXAMPLE OF THE IMPACT ON AN ORGAN SIZE, THIS HAPPENS TO BE THE TESTES OR THE SIXTH GENERATION ANIMAL AND THIS IS A LITTER MATE THAT HAS P53 CONFIDENCE WHERE YOU SEE THE TUBE YULES DUE TO APOPTOTIC ELIMINATION OF THE GERM CELLS
CELLS AND HERE YOU HAVE RESTORED THE CELLULARITY OF THE THE TEST, THE LITTER MATE CONTROL WITH P53 DEFICIENCY AND ABOUT A 90% REDUCTION IN THE AMOUNT OF APOPTOSIS. SO NOW YOU HAVE A SITUATION IN THE ORGANISM WHERE YOU HAVE CELLS THAT ARE SURVIVING AND DIVIDING AT A TIME WHEN THE GENOME IS BECOMES UNSTABLE. WHICH WHATEE SAW WAS AN INCREASE IN CANCER AND THIS WAS A SURPRISE TO EVERYBODY IN THE FIELD BECAUSE AT THAT POINT, THE THINKING WAS, THAT TELEO MERACE WAS NEEDED FOR THE DEVELOPMENT OF CANCER AND IT TURNS OUT TO BE THEOPPOSITE. –THAT ENABLES ONE TO CREATE THE LARGE CHANGES NEEDED FOR THE DEVELOPMENT OF CANCER INITIATION. SO WHAT WAS MORE STRIKING IN THOSE STUDIES IS NOT ONLY DID WE SEE MORE CANCER BUT THE TUMOR SPECTRUM SHIFTED TOWARDS MORE HUMANIZED SPECTRUM DOMINATED BY EPITHELIAL CANCERS, THOSE CANCERS HAD ALTERED CYTOGENETIC PROFILES, NONRECIPROCAL TRANSLOCATIONS AND REGIONAL AMPLIFICATION DELETION AND SO ON. AND WE THINK THE BASES FOR THIS RELATES TO THAT FUSION FOR BREAKAGE CYCLE WHERE YOU HAVE OPPOSING ATTACHMENT OF THE CHROMOSOMES AND CELL DIVISION AND BREAKAGE OF CHROMOSOMES AS THEY MOVE TO OPPOSITE DAUGHTER CELLS. I SHOULD ALSO POINT OUT THAT THE GENETIC LUGGAGE THAT THE CELL CARRIES ON THE WAY TO CRISIS, DICTATES HOW CRISIS WILL BEHAVE EITHER TO PROMOTE OR SUPPRESS THE DEVELOPMENT OF CANCER. WE DID EXACTLY THE SAME SET OF STUDIES IN THE INC. RF MODEL, CANCER DEVELOPED FROM THE SARCOMAS BUT IT HAS AN INTACT DNA RESPONSE AND IT HAS NO CHANGE IN THE TUMOR SPECTRUM. SO THESE STUDIES TAUGHT US THAT THE COMBINATION OF TELOMERE DYSFUNCTION AND P53 ACTIVATION ALLOWS US TO ACQUIRE THE LARGE NUMBER OF CHANGES NEEDED FOR EPITHELIAL CARCINOGENESIS AND IN A SENSE MICE ARE PROTECT FRIDAY EPITHELIAL CARC NONAPOPTOTIC GENESIS BECAUSE THEY’RE MISS THANKSGIVING MUTATOR MECHANISM. –MISSING THIS MUTATOR MECHANISM. NOW WE ALSO COMPARED GENOMES. THIS WAS AN EARLY PLATFORM OF RCGH, BUT THE BOTTOM LINE IS THAT THERE WAS A 10 FOLD INCREASE IN THE AMOUNT OF AMPPLIFICATIONS, DELETIONS AND WE LOOKED ACROSS MULTIPLE TUMORS THAT WERE IN AMPPLIFICATIONS AND TARGETING ONCA GENES THAT WERE IMPORTANT IN THE PATHOGENESIS OF THAT CANCER. THIS HAPPENS TO BE COLON CANCER, WE SEE AMPLIFICATION OF KRASE MODEL, WE SAW AMPLIFICATION OF 33% OF SAMPLES FOR HERTWORKS NU, AND SO ON AND SO FORTH. AND THINK THAT TELOMERES ARE PARTICULARLY IMPORTANT IN PROVIDING US WITH THE EXPLANATION AS TO WHY AGE AND CANCER ARE INTIMATELY LINKED, CERTAINLY NOT THE ONLY MECHANISM BUT WE THINK IT’S AN IMPORTANT ONE, WHY YOU DEVELOPED TYPES OF CANCERS YOU DO AND HOW THOSE GENOMES ARE SHAPED. SO HAVE YOU A LIFETIME OF EPITHELI RENEWAL AND IT’S IMPORTANT TO APPRECIATE THAT YOU TURNOVER YOUR GI TRACT LINING EVERY WEEK. YOUR SKIN EVERY TWO WEEKS, YOU CREATE A TRILLION BLOOD CELLS PER DAY. THERE’S AN ENORMOUS AMOUNT OF RENEWAL THAT GOES OYOU WALK THIS TELOMERE PLANK, IF YOU DEACTIVATE P53, AND ALSO FURTHER ACCELERATE WITH CONDITIONS THAT ARE PROINFLAMMATORY CONDITIONS, HIGH ROTH CONDITIONS, ET CETERA THOSE WILL WILL FURTHER FUEL EROSION AND GENERATE CANCER PRONE CONDITIONS AND HAVE YOU THIS FUSION BRIDGE BREAKAGE AND JEFF WALL TAUGHT US THAT WHEN YOU BREAK CHROMOSOMES THAT PROVIDES AMPLIFICATION AND DELETION FROM THE BREAK. AND THAT CREATES AN OPPORTUNITY FOR ALL WHOLESALE DENOME CHANGES AT THE FRONT. THE THE BENIGN TRANSITION, THERE’S AN EXPLOSIVE SET OF GENES THAT OCCURS AND WE THINK THAT TELOMERE DYSFUNCTION PLAYS A MAJOR ROLE IN THE CARCINOGENESIS AND THAT ALLOWS YOU TO INITIATE THESE CANCERS. SO TELOMERE DYSFUNCTION IS IMPORTANT FOR CANCER INITIATION, BUT ONE OF THE THINGS WE NOTICE VERY EARLY ON IN THESE CANCERS IS THAT THEY HAD A VERY FEEBLE PROGRESSION PHENOTYPE. THEY’RE POORLY INVASIVE, NONMETASTATTIC, HARD TO ADAPT THE CULT AND YOU ARE PROPAGATE SO WE SPECULATED THAT PERHAPS WHILE THE DYSFUNCTION MIGHT BE IMPORTANT FOR INITIATION, TELEO MERACE MAY BE IMPORTANT FOR PROGRESSION. HOW IT’S PLAYING A ROLE IN PROGRESSION WAS UNCLEAR. WHETHER IT’S FURTHER TECH POINT RESPONSES THAT NEED TO BE OVERCOME OR WHETHER IT’S TOO MUCH GENOMIC INSTABILITY THAT’S UNHEALTHY FOR CANCER CELLS THAT NEEDS TO BE QUELLED. WE DIDN’T KNOW AND WE SPECULATE THE BUT THE EXPERIMENT HAD YET TO BE DONE TO ASSESS THE IMPACT OF THE TELEO MERACE OF REACTIVATION AFTER HAVING GONE THROUGH CRISIS. SO I’LL TELL YOU ABOUT TODAY, IS A SET OF EXPERIMENTS THAT WE’VE DONE WHERE WE’VE ENGINEERED A SYSTEM THAT ENABLES US TO ASK THE QUESTION OF WHAT IS THE ROLE OF TELEO MERACE IN CANCER PROGRESSION AND THIS IS AN INDUCIBLE SYSTEM SO IT ALSO AFFORDS THE OPPORTUNITY TO EXTINGUISH TELEO MERACE IN A FULLY FORMED TUMOR IN VIVO SO WE CAN ASSESS THE IMPACT OF TELEO MERACE EXTINCTION AND THE ADAPTIVE RESPONSES USING GENOME SCALE ANALYSIS. SO BEFORE I TELL YOU ABOUT THAT STUDY OF TELEO MERACE ACTIVATION AND EXTINCTION, I WANT TO JUST GO THROUGH A PUBLISHED SET OF DATA THAT WAS DONE BY A GIFTED POST DOC IN THE LAB TO UNDERSTAND THE TELEO MERCHECK POINT RESPONSE. AND THIS IS A NORMAL CELL. WE HAD SHOWN YEARS AGO THAT P53 IS IMPORTANT AS I MENTIONED AND THAT IT EXECUTES THE CLASSICAL CELLULAR CHECK POINT RESPONSES THAT LEADS TO ORGAN ATROPHY. WELL THAT MAKES A VERY–IT’S A GOOD EXPLANATION FOR TISSUES WITH HIGH PROLIFERATIVE HISTORIES, SUCH AS THE GI TRACT, BUT IT’S NOT A VERY GOOD EXPLANATION FOR THE KINDS OF OTHER PATHOLOGIES THAT WE’RE SEEING, THESE LATE GENERATION ANIMALS, WHICH WE SAW THINGS LIKE CARDIO MIRROR IMAGE OPERATING GLOBALLYATHY WHICH WAS FIRST DESCRIBED BY ANAVERSA AND BLASK O YEARS AGO. THIS IS AN ECHO CARDIOGRAM WITH LARGE DILATED LEFT VENTRICLES, VERY THIN WALLS, DECREASED FRACTIONAL SHORTENING AND SO ON, VERY THICK HEARTS. AND ALSO YOU SEE AN IMPAIRED METABOLIC PROFILE. THESE ANIMAL VS A VERY POOR RESPONSE TO FASTING SO THEY CAN’T MOUNT A ROBUST GLUCOGENIC RESPONSE SUGGESTING THAT SOMEHOW THE LIVER IS AFFECTED. AND THESE ARE NOT VERY HIGHLY PROLIFERATIVE TISSUES, SO HOW DO WE RATIONALIZE THESE PHENOTYPES IN THE CONTEXT OF TELOMERE DYSFUNCTION. SO, WE TOOK AN APPROACH THAT WAS UNBIASED AND WHAT ERGAN DID WAS TO LOOK AT MULTIPLE ORGAN SYSTEMS WITH DIFFERENT PROLIFERATIVE CAPACITY SUCH AS HEMEAT O POETIC STEM CELLS, THE LIVER WHICH IS RELL FIVELY QUIESCENT AND CAPACITY TO RENEW THE HEART AND WE LOOKED SENSE AT THE OTHER TISSUES AS WELL AND IN THE CONTE OF TELEO MERMERE DYSFUNCTION WE ASKED WHICH NETWORKS WERE PERTERBED IN THE NETWORK, THAT WAS A COMMON THEME AMONG ALL THESE TISSUES TO SEE IF WE HAD MISSED SOMETHING. SO WE SAW THE TYPICAL P53 CHECK POINT RESPONSES AND ET CETERA AND THE NETWORK BEING ACTIVATED AND APOPTOSIS AND SO ON, BUT ONE–ONE CONSISTENT OBSERVATION WAS THESE PATHWAYS THAT WERE INTIMATELY LINKED TO MITOCHONDRIAL BIOLOGY. THIS IS EVEN NOTICED YEARS AGO IN A YEAST STUDY AND THE ASSUMPTION WAS THAT THE INVESTIGATORS WERE NOT FEEDING THEIR YEAST WELL ENOUGH AND THAT THERE WAS SOMEHOW A PROBLEM AND EXPERIMENTAL PROBLEM AND THE FOCUS WAS ON OTHER PATHWAYS IN THE CONTEXT OF YEAST. BUT ESSENTIALLY THE SAME PROFILE WAS SECURED OVER A LARGE FILE O GENETIC DISTANCE AND IN MAMMAL SYSTEMS ACROSS MULTIPLE TISSUE AND COMPARTMENTS. IN ADDITION TO THE MITOCHONDRIAL DYSFUNCTION ON THE GENE LEVEL, THESE ARE MICROAWAY ANALYSIS, WE SAW THAT VIRTUALLY EVERY COMPLEX OF THE MITOCHONDRIA HAD REPRESSION OF GENES THAT ARE IMPORTANT FOR ETS FUNCTIONS AND THIS WAS CONFIRMED BY ERGAN BY RTPC R AND SO IT TOLD US AND IN SOME CASES WESTERN. IT TOLD US THAT TELOMERE DISFUNCTION IS LINKED TO MITOCHONDRIAL BIOLOGY AND A VARIETY OF DIFFERENT TISSUE CONTEXT. AND THAT GOT US THINKING. BECAUSE WE KNEW OF THE WORK OF LARRY DON HOUR AND P53, AND LARSON WITH PAUL G. AND BRUCE WITH PGCs THAT A LOT OF THESE ARE KNOCK OUTS OF THE GENETIC MODEL SYSTEM SYSTEM HAVE VERY COMMON PHENOTYPES OF THE GENERATION ACROSS THESE SYSTEMS. SO YOU HAVE DEFECTIVE MITOCHONDRIA DUE TO DNA SYNTHESIS AND PROOF READING
AND]/>YOU HAVE THE MASTER REGULATORS OF MIGHT O CONDRIIAL BEN GENESIS, THEY MAKE PGCs AND THEY MAKE THE REGULATING WORK, ALMOST ALL THE JEANS THAT ARE IMPORTANT FOR MITOCHONDRIAL BIOLOGY ARE VERY IMPORTANT FOROXIDATIVE EXPENSE AND IT’S GERM LINE P53 AND WE HAD SHOWN WHEN YOU ATTENUATE A LOT OF THESE PHENOTYPE SPECIALIZATION OF SPECIFIC ENDOTHELIAL YOU HAD A CONVERGENCE OF PHENOTYPES, AND THE QUESTION IS ARE THEY LINKED. SO THE FIRST THING THEY DID WAS TO LOOK AT PGCs AND WE FOUND, IN FACT THAT PGC ONE ALPHA, AND BETA, THE TWO KEY REGULATORS, OF MIGHT O KOBD RIA BIOLOGY AND THE GFOUR, LATE GENERATION WERE SIGNIFICANTLY DECREASED RELATIVE TO WILD-TYPE FOR THE GONEs AND THESE ARE JUST A FEW OF THE THE KEY TARGETS LIKE DNA SYNTHESIS IN THE MITOCHONDRIA THOSE WERE ALSO COORDINATELY REPRESSED SO THIS O TOLD US THAT TELEON MERE DISDISPUNKZ REPRESSING PGC AND POTENTIALLY CAUSING THE KINDS OF PROBLEMS THAT WE’RE SEEING, SO WE WANT TO ACTUALLY ASCERTAIN WHETHER OR NOT, MITOCHONDRIA WERE INFACT COMPROMISED. AND SO, REDUCING ABOUT SEVEN YEARS OF WORK TO ONE SLIDE, JUST SHOWING A FEW SNIPITS, THIS IS TRULY LIKE CENTER FUNERALLING DOWN A LOT OF DATA AND GIVENNING YOU THE PELLET ULTRA CENTER FUNERAL IS WHAT HE SAW WAS IN THE TISSUES WAS A MIGHT O CONDRIA DNA COPEY NUMBER, RELATIVE TO THE NUCLEAR DNA DECREASE IN THE GFORCE THAT AT THE LEVEL OF EM, THERE ARE TACTICALLY, HE WAS ABLE TO SHOW, THAT THERE ARE FEWER MITOCHONDRIA, THAT HE LOOKED AT ALL THE COMPLEX, JUST SHOWING YOU COMPLEX ONE AND COMPLEX FOUR WITH DECREASED IN THEIR ACTIVITY. THEY HAD A PROFOUND DECREASE IN THE ABILITY TO GENERATE ATP. AND A VERY SIGNIFICANT DECREASE IN DAY THREE RESPIRATION, AND RESPIRATION FOR THE OFFICKIANAD OS, THIS IS NOT JUST ON A WHOLE LIFE SAVER BUT THIS IS A PERMITOCHONDRIAL BASIS. SO HAVE YOU FEWER MITOCHONDRIA AND THE MITOCHONDRIA YOU DO HAVE ARE LESS FUNCTIONAL. SO THE QUESTION IS WHAT CONNECTS THE PGC IN AND OBVIOUS CANDIDATE WAS P53 WHICH TYPICALLY IS THOUGHT TO ACTIVATE GENES BUT ON OCCASION HAS BEEN SHOWN TO REPRESS GENES, IT’S QUITE POSSIBLE THERE WAS AN INTERMEDIATE STEP HERE BUT NEVERTHELESS WE LOOK AT P53 AND WE FIRST LOOKED AT THE GENETICS. WE WANTED TO ASCERTAIN WHETHER OR IN THE THERE WAS A REVERSAL IN THE TRANSCRIPT OHMIC IMPACT OF TELOMERE DYSFUNCTION ON THE PGC NETWORK AND SO WHAT WE SHOW HERE IS THE DECREASE IN MITOCHONDRIA DNA COPY NUMBER. THE WITH A RESCUE WHEN YOU HAVE P53 DEFICIENCY. WE HAVE A PARTIAL RESCUE, PGC ONE BETA COMPLETE RESCUE AND THE DOWN STREAM TARGETS A SIGNIFICANT RESCUE IN THESE VARIOUS TARGETS. SO AT LEAST AT THE MITOCHONDRIAL LEVEL AND THE TRANSCRIPT OHMIC LEVEL, WHEN YOU KNOCK OUT P53, YOU ALLEVIATE WHAT APPEARS TO BE REPRESSION ON PGC, I’M NOT GOING THROUGH ALL THE DATA BUT HE THEN DID INFILL COANALYSIS OF THE PROMOTERS. IDENTIFIED THREE EVOLUTIONARY CONSERVED BINDING ELMETROPOLITANS PREDICTED TO BIND P532, AND THE PGC-ONE BETA PROMOTER REGION, AND THIS IS THE POSITIVE ROLE OF CHIPPING P21 AND ALL THREE OF THESE IDENTIFIED FIFTH ELEMENTS WERE ABLE TO PULL DOWN WITH P53 ANTIBODY AND THE THE TWO THAT WERE IDENTIFIEDED IN THE PGC ONE BETA ALSO CAME DOWN IN THIS EXPERIMENT. AND THESE ARE JUST REPORTER ASSAYS THAT I WON’T GO THROUGH BUT ESSENTIALLY, IT SHOWS THAT WHEN YOU KNOCK OUT PC THREE, YOU ALLEVIATE THOSE IF YOU USE THOSE. SO AGAIN I’M NOT GOING THROUGH THE ENORMOUS AMOUNT THAT ERGAN DID BUT AT EACH STEP ALONG THE WAY HE SECURED GENETIC AND BIOCHEMICAL EVIDENCE FOR THIS CIRCUIT. FOR EXAMPLE, IN THE ANIMAL, HE USED ADENO VIRUS TURK, TO SEE IF HE COULD RESCUE THE METABOLIC DEFECT IN THE LIVER. AND WHEN YOU PUT TURK BACK IN, YOU RESCUE THE PGC, MET ON BOLETIC RISK AND THE COMPROMISE. SO THIS RULED OUT DEFECT IN THE GUT BECAUSE OF SOME OTHER ORGANIZATIONS NIGHS MALPROCESS, SO IT SHOWS CLEARLY AND ISOLATED HEPATOCYTES TO PROVE THE SAME THING. I’VE SHOWN THAT WHEN YOU KNOCK OUT PC THREE, YOU RESCUE THE REPRESSION AND INDEED THIS, IS JUST A PHENOTYPE SHOWING THAT YOU RESCUE THE CARDIAC FUNCTION IN THIS PARTICULAR EXPERIMENT WHEN YOU ARE A DEFICIENT FOR P53 AND SO THIS IS NOW IN A TELOMERE DYSFUNCTION, KNOCK OUT P53 AND YOU RESCUE THE IMPACT THAT YOU HAVE ON THE HEART. I JUST SHOWED YOU THE DIRECT TARGET DATA AND THE LAST THING HE DID WAS TO USE ADENO PGCONE IN THE ALPHA LIVER TO SHOW HE COULD RESCUE THE ECOGENESIS SO THIS IS A CLEAR CUT PATHWAY THAT HAS GENOMIC DATA THAT CLEARLY ESTABLISHED THIS AS A KEY PATHWAY IN THE RESPONSE TO TELOMERE DYSFUNCTION AND LOOKING AT HOW WE NOW THINK ABOUT THE AGING PROCESS AND RICHARD ALLUDED TO THIS, YOU KNOW, THERE’S–THERE’S THE THINKING THAT YOU HAVE YOU KNOW THESE DIFFERENT PROCESSES THAT SOME SOMEHOW ARE NOT THAT CONNECTED, GENOTOXIC STRESS THAT MIGHT CONTRIBUTE TO AGING BIOLOGY OR MIGHT O CONDRIAL DYSFUNCTION, ET CETERA THAT WOULD FURTHER FUEL COMPROMISE OF THE ORGANISM AS A FUNCTION OF AGE. I THINK THAT THEY CAN ALL BE INTEGRATED WITH SOME OF THE OBSERVATIONS THAT WE’VE MADE. FIRST AND FOREMOST WITH RESPECT OF TELOMERE DYSFUNCTION, P53 CONTINUES TO PLAY A VERY IMPORTANT ROLE BY DOING IT’S CLASSICAL FUNCTIONS OF ACTIVATING GENES THAT CAUSE APOPTOSIS AND ESSENCE AND CELL CYCLE ARREST. IN ADDITION, WE NOW KNOW THAT P53 DIRECTLY LINKED TO PGCs AND PGCs NOT ONLY REGULATE MITOCHONDRIA, BUT THEY DIRECTLY REGULATE MANY GENES THAT ARE INVOLVED INOXIDATIVE DEFENSE. AND THAT’S IMPORTANT BECAUSE WHEN YOU HAVE MITOCHONDRIA COMPROMISE LESS FLUX THROUGH ETS, YOU GENERATE MORE ROTH AND AT THE SAME TIME YOU ARE DECREASING YOUR ABILITY TO DEFEND AGAINST THE ROTH. SO IT’S A VERY STRATEGICALLY POOR THING FOR THE CELL TO DO TO REPRESS PGCs GIVEN ITS ROLE IN THESE TWO PROCESSES. MORE OVER WHEN WE THINK ABOUT ROTH ITSELF, ANY CONDITION THAT CREATES ROTH, IT’S PARTICULARLY INJUREIOUS OBVIOUSLY FOR THE GENOME BUT IN PARTICULAR FOR TELOMERES WHICH ARE G-RICH AND ROTH LOVES TO ATTACK G-RICH SEQUENCES SO YOU CAN IMAGINE THIS MIGHT CREATE A FEET-FORWARD LOOP. AND PROVIDE AN EXPLANATION FOR AN OBSERVATION THAT’S BEEN LONG SEEN WHICH IS THAT WE DO VERY WELL FOR DECADES AND THEN IN THAT LAST DECADE OF LIFE, THOSE LAST YEARS OF LIFE, YOU REALLY HAVE THIS ACCELERATED DECLINE IN YOUR PHYSIOLOGICAL RESERVE AND ROBUSTNESS AND CAPACITY TO RESPOND TO ACUTE AND CHRONIC STRESSES. YOU ONE COULD IMAGINE THAT THAT MIGHT RELATE TO THE FACT THAT OVER A LIFETIME, YOU ACCUMULATE DAMAGE, TELOMERES DON’T REPAIR THE DAMAGE, THEY SERVE AS A VEESER SORE, YOU EVENTUALLY TONICALLY SIGNAL TO P53, YOU START IN MOTION THIS KASICATE OF EVENTS INCREASE INTRA
INTRACELLULAR ROTH LEVELS THAT WOULD BE INJUREIOUS AND YOU CREATE MORE DAMAGE AND YOU CONTINUE THE CYCLE STILL FURTHER. SO, THIS IS A PATHWAY THAT AS WE LOOK AT FROM THE AGING STANDPOINT, IF YOU THINK ABOUT MANY OF THE GENETIC ELMEBTS IN AGING, GENETICALLY SUCH AS THE SER TUEINS AND COMPONENTS OF THE PITHREE PATHWAY, NOW WE KNOW THIS CORE PATHWAY, MANY THINGS DIRECTLY LINKED TO MODULATION OF FLUX THROUGH THAT PATHWAY. SO WE THINK THIS IS A CORE PATHWAY, VERY IMPORTANT PATHWAY FOR AGING CERTAINLY NOT THE ONLY ONE BUT A CRITICAL ONE. IF YOU JUST THINK ABOUT THE SERTUMOR SPECTRUMINS AND IF THEY MODIFY P53 AND PGC. THEY REPRESS P53 ACTIVITY AND THEY ACTIVATE HENS THEIR VERY GOOD POINTS OF INTERVENTION AND FROM THE STANDPOINT OF A-10IATEING THE AGING PROCESS AS THE PATH IS CONCERNED. SO THIS IS AN OPPORTUNITY FOR A FRAMEWORK FOR INTEGRATING A LOT OF THINGS ABOUT AGING MITOCHONDRIAL BIOLOGY AND GENOTOPPIC STRESS VIEWED THROUGH THE LENS OF THIS ACCESS. SO NOW LET ME, TELL YOU ABOUT THE RESPONSE OF CANCER CELLS TO FLIPPING THE SWITCH ON AND OFF. THIS IS A LOT OF WORK THAT A POST DOC IN THE LAB DID, MARY ELA, WHERE SHE KNOCKED IN THE ESTROGEN RECEPTOR INTO THE OPEN BREEDING FRAME OF THE TELEO MERACE REVERSE TRANSCRIPT ACE FOR THE REFUSION PROTEIN COMPLEXIAR. THIS IS RESPONSIVE TO TAMOXIFEN SUCH THAT WHEN YOU ADD TAMOXIFEN YOU RELEASE FROM HSP 90 AND YOU RENATURE THE PROTEIN AND COULD ACT ON A SUBSTRATE. THIS IS CHAMPIONED BY GERARD EVAN AND OTHERS, IT’S AN EFFECTIVE WAY OF REGULATING PROTEINS AT THE ENDOGENOUS LEVEL, FOR ACTIVITY IN THE CELL. AND THIS THEN WITH TAMOXIFEN ALLOWS THE TELEO MERACE TO ACT ON ITS ENDS AND IT WORKS LIKE A CHARM. I’M NOT GOING THROUGH ALL THE DATA BUT THIS IS A VEHICLE TREATED GFOUR, CELLS THAT CLEARLY, AND THIS IS AFTER A BIT OF TREATMENT WITH OHT, WHICH NOW RESTORES THE ENDS OF THE TELOMERES. SO GEN HUGH IN THE LAB WAS INTERESTED IN ASKING THE QUESTION IF HE COULD EXPLOIT THIS SYSTEM, TO TAGLE TELEO MERACE ON AND OFF IN THE SPECIFIC POINT AND DEVELOPMENT OF CANCER. AND HE TURNED TO THE ATM MODEL. THSHES IS AN ALLELE THAT WAS GENERATED BY FRED’S LAB, LYMPHOMA PRONE CONDITION, THEY GENERATE LYMPHOMAS AND MORE OR LESS BY A YEAR OF AGE AND HE CROSSED THAT ON TO THE TELEO MERACE KNOCK-IN TER, AND BROUGHT THAT THROUGH SUCCESS OF GENERATION AND I’LL TELL YOU ABOUT THE WHILED TYPES AND THE G-ONES ARE PRETTY SIMILAR. THEY HAVE RESERVE AND THE G-THREES AND G-FOURS IN THIS PARTICULAR EXPERIENCE HAVE SEVERE TELOMERE DYSFUNCTION. AND IT SHOWS AGAIN THE ATM KNOCK OUT–WHAT YOU SEE WHEN YOU HAVE TELOMERE DYSFUNCTION IS THAT THE ANIMALS LIVE LONGER AND THE REASON FOR THAT EVEN THOUGH IT’S ATM DEFICIENCY, YOU STILL HAVE AN INTACT P53 CHECK POINT RESPONSE AND CAROL HAS SHOWN THE SAME THING IN HER LAB SO WHAT YOU HAVE IS A–ELIMINATION OR DECREASE OF THE NUMBER OF CELLS THAT ARE ABLE TO BECOME MALIGNANT AND EVENTUALLY, KILL THE ANIMAL. SO YOU SEE A PROLONGATION OF SURVIVAL. AND HERE, WHAT YOU SEE IS G-ONE WITH OR WITHOUT OHT. SO THE PRESENCE OF ABSENCE OF TELEMERACE ACTIVITY HAS NO IMPACT ON THE KINETICS OF THE TUMOR AND THE SURVIVAL OF THE ANIMALS AND HERE WHAT YOU SEE SEE–AND WE SEE CANCER INITIATED IN THE THYMUS ALREADY AND YOU HAVE ACCELERATION HERE. SO SUGGESTING THAT IF YOU GO THROUGH CRISIS, AND THEN REACTIVATE TELEO MERACE THAT YOU HAVE NOW A MORE AGGRESSIVE CANCER. RELATIVE TO EVEN THOSE THAT HAD INTACT TELOMERES ALL ALONG. SO THIS PROCESS, THIS BI-PHASIC PROCESS COUPLED WITH ACTIVATION IS PROPROVIDING NEW BIOLOGICAL CAPABILITIES FOR THESE CANCER CELLS. AND THAT MANY LEVELS ARE OBVIOUS, YOU COULD SEE THAT THE CONTROL ANIMALS, THYMUS, CANCER BUT THESE ARE VERY AGGRESSIVE MALIGNANCIES, DEACTIVATED THE–THIS IS ONE OF MY FAVORITE PROTEINS 53 BPONE AND DECREASE ESSENCE 12 P53 SIGNALING AND AS I MENTIONED THESE ARE GREASES OF CANCERS AND THEY TAKE ON NEW BIOLOGICAL CAPABILITY WHERE WE HAVE FOR EXAMPLE AND THE LONG TEMO MERE ANIMALS, THEY NEVER GO TO BRAIN WHEREAS IN THE CONTEXT OF HAVING GONE THROUGH CRISIS AND REACTIVATING TELEO MERACE, WE SEE WIDE SPREAD AGGRESSIVE INVOLVEMENT OF MANY DIFFERENT ORGANISM SYSTEMS SUCH AS THE BRAIN, ET CETERA. SO I THINK THAT THIS IS ACQUIRING NEW GENOMIC EFFECTS THROUGH THIS MUTATIONAL MECHANISM THAT ENDOWS THESE CELLS WITH INCREASED BIOLOGICAL CAPABILITIES AND THAT’S CLEARLY THE CASE IN TERMS OF LOOKING AT THE GENOME NOMES WE SEE THE RED BARS ARE THE ONES THAT HAD TELOMERE DYSFUNCTION THAT HAD BEEN TREAT WIDE OHD AND THESE HAVE TELOMERE INTACT AND THEY’RE BOTH ATM DEFICIENT AND THESE LYMPHOMAS, THE RED BARS ARE THE ONES THAT HAD GONE THROUGH CRISE AND I GUESS REACTIVATED TELEO MERACE AND THEY ACQUIRE SIGNATURE EVENTS THAT LEAD TO AMPPLIFICATION OF ALL THE GENES WE KNOW TO BE IMPORTANT IN THE LYMPHOMA GENESIS SUCH AS SOME OF THEM LISTED HERE SUCH AS NOTCH, MYC THREE AND DELETIONS IN P-10 ET CETERA AND WE DON’T YET HAVE ENOUGH SAMPLES, THESE ARE VERY LIMITED SAMPLE SETS FOR US TO BE ABLE TO ASK WHAT MIGHT BE DIFFERENT IN THE TELOMERE INTACT VERSES THE ONES THAT HAVE GONE THROUGH CRISIS AND THEN TELEO MERACE AND WHAT’S INFERRING THE AGGRESSIVE BEHAVIOR IN THOSE CANCERS SO WE HAVE TO INCREASE THE NUMBERS HERE. SO THEN WE ASKED THE QUESTION HAVING ACTIVATED THESE TELEO MERS IN THE–TELOMERES IN THE SWIGS RESPONSE,S WHAT WOULD HAVE HAPPENED? AND IS THIS IS IMPORTANT BECAUSE IN CLINICAL TRIALS THERE ARE AGES THAT ARE DIRECTED AGAINST TELOMERES. SO WE TOOK ONE OF THESE LATE GENERATION CELL LINES, TUMORS I SHOULD SAY, THEY DIDN’T SAY PLASTIC, THEY DID PASSAGE IMMEDIATELY IN THE SUCCESSFUL GENERATIONS AND SUCCESS OF PATHOGENS AND THEY WERE LEFT ON, SO THIS IS TELEO MERACE, SO THAT’S THE CONTROL ARM. AND THEN ANOTHER ARM THAT WE REMOVED OHT AND PASSAGE AND THESE WERE TELEO MERACE OFF. AND I’LL TELL YOU THAT BASICALLY AROUND PTWO, PTHREE DEPENDING ON MULTIPLE DIFFERENT CELL LINE, DEPENDING ON THE CELL LINE, THEY START TO ENTER CRISIS AROUND HE AND THEN THEY REACQUIRE THEIR AGGRESSIVE TUMOR CAPABILITY. HAVING STILL TURNED OFF TELEO MERACE AND THEY HAVE INTERESTING ADAPTIVE RESPONSE. SO THIS IS P-ONE THE MEYER CURVE WITH OR WITHOUT OHD. NOT MUCH HAPPENS IN THIS PARTICULAR CELL LINE, YOU COULD SEE NOW, WHEN IN THE VEHICLE TREATED TELEO MERACE, OFF, THEY TART TO–THE MORE THE ANIMALS SURVIVE, THE CANCERS COME ON LATER AND YET, WE THEN REACQUIRE THE TUMOR GENIC CAPABILITY SO WHAT ARE THE AX AT THAT POINTIVE MECHANISMS. THIS IS JUST SHOWING YOU YOU HAVE PROGRESSIVE TELOMERE SHORTENING AND THEN ACQUISITION SUDDENLY OF LONGER TELOMERES WITH THE WIDER BASED SUGGESTING HETEROGENEITY IN TELOMERE LENGTH. SO WE ALSO SAW THAT AROUND PTWO, WE SAW ACTIVATION OF THE P53 CHECK POINT RESPONSE, 53 BP SIGNALING, INCREASED APOPTOSIS, INCREASED HTWO AX. NOW IT’S IMPORTANT TO APPRECIATE THAT YOU DON’T QUITE RESCUE ALL THE WAY WHEN YOU ADAPT. YOU DO RESCUE APOPTOSIS COMLITELY AND CELL CYCLE ARREST BUT WITH RESPECT TO GENOTOXIC STRESS AND SIGNALING, THERE STILL APPEARS TO BE,–YOU DON’T RETURN TO WILD-TYPE. SO THE ONGOING GENOTOXIC STRESS HERE AND IT’S IMPORTANT TO KEEP IN MIND. SO THIS IS A PATTERN THAT MIGHT BE CONSISTENT WITH ALL, THIS IS A TELEO MERACE INDEPENDENT RECOMBINATION MEDIATED MECHANISM DISCOVERED BY ROGER ADELL, THAT CAN MAINTAIN TELOMERES, ALBEIT INEFFICIENTLY. THE HALLMARK FEATURES OF HETEROGENEITY OF TELOMERE LENGTH OF EXTRA CHROMOSOMAL FRAGMENT AND ALL THE PML BODIES AND HIGHER LEVEL OF CHROMA SIDIC CHANGE. SO SOME OF THESE DATA IS HERE. THIS IS WHAT IT LOOKS LIKE WHEN YOU KEEP THE POLYMERASE IS ON, IT’S MAINTAINED AND AS YOU GO THROUGH THE THESE PASSAGES, YOU SEE THAT YOU START TO LOSE SIGNAL AND THEN SUDDENLY YOU REACQUIRE SIGNAL. YOU SEE INCREASED EXTRA CHROMOSOMAL FRAGMENTS THAT ARE QUANTIFIED HERE, INCREASED APBs QUANTIFIED HERE AND INCREASED CHROME TID EXCHANGE IN TELOMERES AS YOU CAN SEE HERE FROM THE DIFFERENT COLORED DOTS HERE AND THAT’S SIGNIFICANTLY INCREASED AS WELL. SO THOSE ARE CLASSIC FEATURES SO CLEARLY AT LEAST ONE ADAPTIVE MECHANISM IS WHAT WE WOULD HAVE EXPECTED WHICH IS THE ACQUISITION OF THIS RECOMBINATION MEDIATED OLD MECHANISM. WE WANTED TO ASK WHETHER OR NOT THERE WERE ADDITIONAL ADAPTIVE RESPONSES AND SO WE TOOK A GENOME WIDE APPROACH TO TRANSCRIPT OHMIC ANALYSIS OF THE CONTROLLED TELEO MERACE, VERSES THE TELEO MERACE OFF ALL CELLS AND THE PARENTAL CELLS. WE WENT THROUGH A SERIES OF CELLS WHERE WE FILTERED OUT THE OHT RESPONSIVE GENES AND I WON’T GO THROUGH THAT, BUT AGAIN WHAT WE SEE A COMMON THEME. THE NUMBER ONE NETWORK THAT GETS ACTIVATED ARE THINGS THAT ARE CONNECTED TO MITOCHONDRIA. THE THINGS THAT GET DOWN REGULATED ARE THICKS THAT ARE INVOLVED IN THE THE SIGNALING APOP TOESIS, THINGS OF THAT NATURE. BUT THE UPREGULATED ONES SEEM TO SUGGEST THAT WOVEN THE THINGS THAT THESE CELLS WANTED TO DO IN THE ABSENCE OF TELEO MERACE IS TO TRY TO SUPPORT MITOCHONDRIAL FUNCTION. AND IN ADDITION, THERE IS, YOU KNOW IN THE GENES THAT WERE UPREGULATED ROBUSTLY, IN THE OLD CELL, SO THIS IS TELEO MERACE, WILD-TYPE, FIRST PZERO PARENTAL, THESE ARE THE ONES THAT REMAIN TAME, SECOND BAR ON TELEO MERACE, AND THE LAST THIRD BAR ARE THE OLD CELLS THAT BROKE THROUGH AND YOU SEE THAT PGC ONE BETA, THE MASTER REGULATOR AND BIOGENESIS AND ALL OF–A LOT OF THESE GENES INVOLVED INOXIDATIVE DEFENSE ARE UPREGULATED AND ALSO THEY HAD HIGHER LEVELS OF ROTHS. INTERESTINGLY IN THESE TUMORS NOW WHAT’S GREAT ABOUT THE THE TELEO MERACE KNOCK OUT IS YOU GET AMPLIFICATIONS AND UNDER PRESSURE THEY SELECT FOR ONCA GENES AND TUMOR SUPPRESSOR GENES AND ARE THERE KNEW AMPPFICATIONS THAT OCCUR OR DELETIONS IN THESE TUMORS AND THE ONE THAT MARCHED NICELY WITH OVEREXPRESSION OF PGC WAS AMPLIFICATION OF PGC ONE BETA SO IT’S OVER EXPRESSEDDED AND THERE IS A GENETIC PRESSURE, TO AMPLIFY THIS LOC OUST. SO–LOC OUST. SO I DIDN’T MEAN WENT ON TO LOOK AT FUNCTION AND MITOCHONDRIAL FUNCTION, AND THE LOOK AT VICE CRISIS, MITOCHONDRIAL FUNCTION IS DECREASED AND THE MITOCHONDRIAL FUNCTION IS RESTORED BUT NOT TO WILD-TYPE LEVELS. AND WE SEE THAT ROTH LEVELS WHICH GO THROUGH THE ROOF IN THE CELLS GOING THROUGH CRISIS ARE SIGNIFICANTLY ALLEVIATED BUT AGAIN NOT COMLITELY SO IN THE CONTEXT OF ALL. SO WE ASKED THE QUESTION, IF THE CELLS ARE TRYING TO ADAPT BY MAINTAINING MITOCHONDRIA, IF YOU WERE TO KNOCK DOWN PGC ONE BETA TO PHYSIOLOGICAL LEVELS WHAT WOULD HAPPEN. SOOXIDATEIVE DEFENSE GENES SO WE DID THIS FOR SOD TWO AS WELL AS FOR PGC ONE BETA. AND WHEN YOU KNOCK IT OUT IN THE TELEO MERACE, POSITIVE CELLS, THEY DON’T QUITE DO AS WELL, BUT THERE IS NOT A SIGNIFICANT IMPACT AND THOSE ANIMALS ALL STILL DIE. HOWEVER, IF YOU KNOCK OUT IN THE ALL CELLS, PGC BETA KNOCKED DOWN I SHOULD SAY, WHAT YOU SEE IS A LOT OF THE ANIMALS BEING CURED OF THEIR DISEASE AND A SIGNIFICANT PROLONGATION IN THE ONSET OF TUMOR FORMATION AND THE SAME WAS TRUE FOR SOD. IF YOU DO THIS IN CELL CULTURE BASED SYSTEMS IT’S AN IC 50 SHIFT OF ABOUT 10 FOLD. SO IT CLEARLY IS ANN IMPORTANT ADAPTIVE RESPONSE SO WHAT WE LEARNED OVER THE YEAR SYSTEM THAT TELOMERES PLAYING IMPORTANT ROLES IN APOPTOSIS AND ESSENCE AND MITOCHONDRIAL BIOLOGY THAT WHEN HAVE YOU DYSFUNCTION, YOU ACTIVATE APOPTOSIS IN ESSENCE AND COMP PROMISE MITOCHONDRIA BIOLOGY IN THE CONTEXT OF ALL, YOU ELIMINATE THESE CHECK POINT RESPONSES, GUIDED MOSTLY BY P53, AND YOU DO HAVE SOME RESTORATION OF MITOCHONDRIAL FUNCTION ANDOXIDATIVE DEFENSE BUT NOT AT SUFFICIENT LEVELS TO REALLY MAINTAIN ROBUST GROWTH AND DEVELOPMENT OF THESE CELLS AND THEY TRY TO MAINTAIN THIS ACCESS THROUGH UPREGULATION OF PGC ONE BETA. NOW ONE THING I DIDN’T MENTION IS THAT WE ALSO SAW AMPLIFICATION IN RECOMBINATION GENES, GENES INVOLVED IN HOMOLOGOUS RECOMBINATION, SO THE MRN COMPLEX IS VERY IMPORTANT FOR ALT AND ALSO THE FANCONI PROTEINS AND A FEW OF THOSE WERE UPREGULATED AND MRI WAS AMPLIFIED AND ONE OF THE FANC PROTEINS WERE ALSO AMPLIFIED. SO WHAT WE’VE LEARNED IS THAT TELEO MERACE PLAYS AN IMPORTANT ROLE IN AGING DISEASE AND THAT THIS FUNCTION ACTIVATES P53 WHICH ACTIVATES CELLULAR CHECK FORM RESPONSES OR REPRESSES PGC AND IMPACTS ON MIGHT
MITOCHONDRIAL BIOLOGY AND IN THE CONTEXT OF CANCER TELOMERE DYSFUNCTION IS IMPORTANT FOR CANCER INITIATION AND IN THE CONTEXT OF PC DEFICIENCY ENABLES YOU TO REQUIRE A LOT OF GENOME PROMOTING ALTERATIONS THAT ENABLE EPITHELIAL CARCINOGENESIS AND THAT TELEO MERACE ACTIVATION PLAYS A ROLE IN CANCER PROGRESS AND THE COMBINATION OF CRISIS AND ACTIVATION THAT ENABLES CELLS TO ACQUIRE MORE BIOLOGICAL CAPABILITIES FOR FULL MALIGNANT TRANSFORMATION. AND THAT ITS EXTINCTION CAN BE COUNTERED BY ADAPTIVE RESPONSES THAT INVOLVE RECOMBINATION BASED ALL AS WELL AS MITOCHONDRIAL IN THIS DEFENSE. SO IN THE LAST FEW MINUTES; I WANT TO DESCRIBE A ONE LAST SET OF EXPERIMENTS THAT DESCRIBE AND ATTEMPT TO ALSO EXEMPLOYED THIS INDUCIBLE SYSTEM TO UNDERSTAND WHETHER OR NOT PROCESSES OF AGING, THE DEGENERATIVE CONDITIONS CAN BE MODULATED. THERE’S A LOT OF ACTIVITY IN WHICH THE PATHWAYS THAT ARE KNOWN TO BE INTERNATIONAL CLASSIFICATION GRAIL TO THE AGING PROCESS OR BEING MODULATED PITHREE CAIN ACE PATHWAY AND SHOWING INTERESTING RESULTS IN TERMS OF LIFE SPAN REGULATION AND ATTENUATION OF AGE RELATED DISEASE AND SO WE’RE INTERESTED GIVEN THE PROMINENCE OF TELOMERES AND PRECIPITATING AGE RELATED DISEASE WHETHER OR NOT IT’S REGULATION EXPERIMENTALLY COULD ALLEVIATE SOME OF THE DEGENERATIVE CONDITIONS THAT I TALKED ABOUT. SO WHAT WE DID WAS FIRST OF ALL SHOW THAT THIS TURK ER INDUCIBLE SYSTEM RECAPITULATES THE PHENOTYPE OF THE CONVENTIONAL KNOCK OUT. IT IS IDENTICAL. IT SHOWS THE ANIMALS DIE SOONER AND ALL THE PATHOLOGICAL THAT WE SEE WITH THE CONVENTIONAL KNOCK OUT. I’M NOT GOING THROUGH THE DATA. TAKING FIBROBLASTS AND PUTTING THEM INTO CULTURE WITH OR WITHOUT CULTURE HAD IS THE WORK OF MARY, AND YOU SEE IN THE PRESENCE OF OHD, THE CULTURES TAKE OFF AND THEN THESE THAT ARE IN THE VEHICLE MAINTAIN A–UNDERGO A SIN ESTIMATE THADENT RESPONSE AND THEN IF YOU ADD OHT, THESE CULTURES THAT ARE SIGNIFICANTLY DECREASED IN THEIR PROLIFERATIVE CAPACITY HAVE THE ABILITY TO NOW REACQUIRE GROWTH AND YOU CAN SEE HERE THAT YOU DEACTIVATE SOME OF THE P53 CHECK POINT RESPONSES ON THE MOLECULAR LEVEL, P21 GOES DOWN AND NMDM GOES DOWN AND THESE CULTURES REALLY TAKE OFF. ON THE ORGANISM MALLEVEL ON THE GI TRACT, YOU SEE LOTS OF APOPTOSIS WHEN YOU HAVE THE DYSFUNCTION. IF YOU TREAT THE ANIMALS FOR ONE MONTH WITH OHT AND THEN ONE MONTH AFTER TERMINATION OF TREATMENT, YOU LOOK, SO ALL THE EXPERIMENTS I’LL TELL YOU ABOUT AFTER THAT ONE MONTH, WHAT YOU SEE IS AN ALLEVIATION OF THE APOPTOSIS. YOU ALSO SEE THAT TESTE EASE SIZE THAT GOES DOWN–TESTIS SIZE WHICH GOES DOWN, INCREASES, THIS IS A REMARKABLE RESULT THAT THESE ANIMALS THAT ARE LARGELY INFERTILE RESTORE FERTILITY AFTER OHD TREATMENT. SO THESE ARE THE PERIMETERS, IN A CLASSIC TELOMERE DYSFUNCTION. THIS IS AFTER A MONTH OF TREATMENT WITH OHT, RESTORE THE SINGULAR TESTIS. THE ORGAN SYSTEM WE FOCUSED ON MOST WAS THE BRAIN. BRAIN IS REALLY CENTRAL TO A LOT OF THE PROBLEMS THAT WE EXPERIENCE AS WE AGE. SO WE WANT TO UNDERSTAND THE IMPACT ON CNS. AND I THINK YOU CAN APPRECIATE THAT THESE BRAINS ARE MUCH SMALLER IN THE CONTEXT OF LATE GENERATION BUT IF YOU ADD OHT, THESE BRAINS CAN GO BACK TO NEAR NORMAL SIZE AND THIS IS JUST QUANTIFIED HERE. NOW, ONE OF THE MIN THEY THINKS THAT HAPPENED IN THE AGE, YOU GET DECREASED MILINATION AND ONE OF THE MAIN THINGS WE SAW WAS DECREASED OLIGO DENDRITIC CELL ROW SIGHTS AND POSITIVE CELLS AND THOSE CELLS THAT WERE THERE, WERE LESS MATURE, THEY HAD LESS ABILITY TO GENERATE MIRROR IMAGE LYNN. BUT AS SOON AS YOU ADD YOU SEE THIS IS THE CONTROLS OF THE THE TELOMERE INTACT THIS, IS THE LATE GENERATION LOOKS LIKE WITH THE POSITIVE AND THEN YOU ADD OHT AND THEN YOU SEE THAT THERE’S A DRAMATIC INCREASE IN THE NUMBER OF OLIG TWO POSITIVE CELLS AND IN ADDITION, YOU RESTORE THE GRATIOS, THE RATIO OF THE AMOUNT OF MYLINM SHEET WITH THE DIAMETER WHICH IS MORE OR LESS INSYNCH AND WHAT YOU SEE IS THAT THE G-RATIOS THAT IS THE MILEIN GETS MUCH THINNER IN THE CONTEXT OF GFOUR VEHICLE TREATED BUT OHT WE RESTORE MILEINATION IN THESE ANIMALS. SO WE LOOK IN VIVO AND WE WANT TO SHOW THAT PHARMACODYNAMICALLY WE’RE ACTUALLY RESTORING TELOMERES IN THE BRAIN, SO WE LOOKED AT THE CORPUS CO LOSS UMKC AND THE STRIATUM AND THE SUBVEPT RICKULAR ZONE AND IN EACH KAY WE SHOUGH THAT THEY INCREASE TO THE METHODS. WE’RE PARTICULARLY INTERESTED IN THE SVC BECAUSE THAT’S A REGION IN THE MOUSE BRAIN WHERE STEM CELLS RESIDE. WHERE NEW NEURONS ARE GENERATE INDEED THE SBC THOSE NEURONS GO OUT ROSTERLY TO GENERATE INTERNEURONS AND INNATE RESPONSES THROUGHOUT LIFE, AND FIRST THING WE DID WAS INVITO STUDIES WE TOOK OUT SBC NEUROSPHERES, AGAIN THE WE IN THIS CASE IS GH. PAIK AND JOSEPH, THERE’S SIGNIFICANT DNA DAMAGES SIGNALING IN THE GFOUR AND THE ADDITION OF OHT QUELLED THE DNA DAMAGING SIGNAL. WHEN WE TRY TO GENERATE SUCCESSIVE NEUROSPHERE CULTURES WE WERE VERY–ESSENTIALLY UNABLE TO GENERATE SECOND TERTIARY NEUROSPHERES AND YET, WHEN WE ADDED OHT WERE ABLE TO REGENERATE THE RENEWAL CAPACITY OF THESE NEUROSPHERE CULTURES. WE HAD SHOWN YEARS AGO THAT WHEN YOU HAD TELOMERE DYSFUNCTION, YOU SEE THE SIGNIFICANT IMPACT ON THE STEM CELLS TO GENERATE THE POSITIVE NEURONS AND HERE, WE SEE THAT IS IS SIGNIFICANTLY DECREASED RELATIVE TO CONTROLS AND THAT WE SEE KNOCK OUT PC-THREE YOU CAN RESTORE THAT AND IF YOU JUST ADD OHT, YOU CAN INCREASE THE NUMBER OF NEURONS YOU GET OUT OF THE NUROSPHERE CULTURES. WE THEN LOOKED IN VIVO IN THE BRAIN SUBVENTRICULAR ZONE SO YOU SEE PROLIFERATIVE ACTIVITY WHEN YOU HAVE TELOMERE DYSFUNCTION THAT IS SIGNIFICANTLY DECREASED AND YOU RESTORE PROLIFERATIVE ACTIVITY WHEN YOU ADD OHT. MARKERS OF STEM AND PROGENITOR CELLS ARE EXPRESSED IN THE SUBVENTRICULAR ZONE AND INTACT, DECREASE INDEED TELOMERE DYSFUNCTIONAL RESTORED WITH OHT. WE HAVE DX DOUBLE KORTON POSITIVE CELLS, TSE ARE MARKERS OF NEURONS AND WHAT YOU SEE IS A SIGNIFICANTLY DECREASED IN THE NUMBER OF NEW BORN NEURONS AND RESTORATION OF THE DOUBLE CORE POSITIVE CELLS WITH THE ARK DITION OF OHT. SO THE QUESTION IS, THESE NEW BORN NEURONS WHICH EVENTUALLY GO OUT TO THE OLFACTORY BULB ARE THEY REALLY GENERATING RENEWAL KACCT CAPACITY FOR THE BRAIN ON A PHYSIOLOGICAL LEVEL. AND AND TO DO THAT WHAT MARIELA DID, IN COLLABORATION WITH THE FLYER LAB WAS TO DO A WELL KNOWN TEST WHICH IS YOU BLOT EITHER WATER OR A NOXIOUS ODOR SUCH AS TWO-MBAND LOOK WHERE THE ANIMAL IS IN THE CAGE. SO THIS IS AN INNATE RESPONSE TO SPOILED FOOD OR PREED PREDATOR
WHERE THE ANIMAL WITH THE NOXIOUS ODOR WILL WILL GO TO GET AS FAR, A WAY FROM THE ANIMAL AS POSSIBLE. IT’S NOT A LEARNED RESPONSE. SO THE ANIMAL WITH WATER WERE TRAINED THROUGHOUT THE CAGE. IF THEY’RE WILD-TYPE THEY WILL WILL GO TO ONE SIDE. AND IF THEY’RE KNOCK OUT, THEY TEND TO GO INTO ALL QUADRANTS ALTHOUGH THEY TEND–THEY HAVE SOME FUNCTION, THEY DO TEND TO STAY AWAY FROM THE NOXIOUS ODOR AND THIS IS JUST QUANTIFIED AT LOWER DOSES. YOU SEE THAT THERE’S VERY POOR DISCRIMINATION THAT THE TELEO MERACE SUFFICIENT ANIMAL VS WITH VEHICLE CONTROL. THESE ARE THE WILD-TYPE ANIMALS, GZERO, TELOMERE INTACT AND WITH THE ADDITION OF OHT TO THE COHORT, WE NOW RESTORE THE ABILITY DISCRIMINATE THESE NOXIOUS ODORS SO THESE NEW BORN NEURONS ARE GENERATED SO THEY’RE MIGRATING OUT THEY GENERATE THE NEURONS AND RESTORE THIS INNATE PHYSIOLOGICAL FUNCTION. THE LAST SLIDE IS JUST LIFE SPAN OF THESE ANIMALS, SIGNIFICANTLY DECREASED IF YOU JUST TREAT THEM WITH VEHICLES, JUST ONE PULSE FOR ONE MONTH IS ABLE TO SUG95 CANTILY RESTORE THE ROBUSTNESS OF THESE ANIMALS AND THEY LIVE A BIT LONGER. NOT TO THE LEVELING OF THE WILD-TYPE ANIMALS THOUGH, AND ONE THING WE CAN DISCUSS IS THE CANCER SPECTRUM OF THESE ANIMALS. THEY DID NOT DEVELOP AN INCREASE IN CANCER. SO, JUST TO SUMMARIZE, I DIDN’T SHOW YOU DATA BUT TELOMERES PLAY VERY IMPORTANT RATE LIMITING ROLES IN THE PATHOGENESIS OF PREMATURE AGING CONDITIONS IF YOU KNOCK OUT WORKERS IN THE MOUSE, YOU GET NO PHENOTYPE. IF YOU LAYER ON TOP, LIMITING TELOMERES IN THE MOUSE, YOU THEN PRECIPITATE CLASSIC FEATURES OF WARNERS, THIS IS TELLING US THAT TELOMERES ARE RATE LIMITING PATHOGENETIC ELEMENTS IN THOSE AND OTHER DISEASES. IN THE CONTEXT OF NORMAL AGING, I THINK IT REMAINS TO BE DETERMINED WHETHER OR NOT TELOMERES ARE PLAYING AN IMPORTANT ROLE IS IF WE WERE TO REPAIR TELOMERES WHETHER OR NOT THAT WOULD IMPACT A NORMAL BIOLOGICAL AGING. BUT IN THE EXPERIMENT THAT WE DID DO, WHAT IT DOES TEACH US IS THEW THERE IS A POINT OF RETURN FOR TISSUES THAT ARE IN A VERY SEVERE STATE OF DEGENERATION. OR CALLED THE TESTIS AND HOW ATROPIC IT WAS. TISSUES EVEN IN A VERY SEVERE STATE OF DEGENERATION RETAIN A REMARKABLE CAPACITY OF TO RENEW THEMSELVES. SO AS WE UNDERSTAND THE CIRCUITRY OF AGING, WHICH I CONSIDER TO BE A DISEASE AND PHARMACOLOGICALLY MANIPULATE THOSE PATHWAYS IN A WAY THAT’S SAFE, BUT APPROPRIATE FOR AGE RELATED PATHOLOGY, WE HAVE A CHANCE OF IMPACTING ON NORMAL AGING, BUT EVEN IF WE DIDN’T GO AS FAR AS TO REALLY IMPACT ON JUST THE NORMAL AGING PROCESS ALONE, IT’S PRETTY WELL ESTABLISHED AT THIS POINT THAT TELOMERES, CORRELATE WITH AGE RELATED DISEASES. OVER THE AGE OF 60, IS A VERY SIGNIFICANT INCREASE IN ALZHEIMERIMEERS CARDIO MYOPATHY AND DIABETES CANCER IF YOU HAVE SHORTER TELOMERES SO THIS IS TELLS US THIS AT LEAST PART OF THE PROCESS ON A POPULATION WIDE LEVEL AND THE REASON WHY THIS IS IMPORTANT TO APPRECIATE IS THE IMPACT OF THE GREAT DISEASES THAT WE’RE GOING TO BE FACING. AND WHEN I WAS BORN IN 1955, THE AVERAGE LIFE EXPECTANCY IN CHINA WAS 42 AND TODAY IT’S 74. AFTER THE AGE OF 60 FOR ALZHEIMERS, HAVE YOU A NEAR DOUBLING EVERY FIVE YEARS OF THE INCIDENCE OF ALZHEIMERS SO OVER 40% OF INDIVIDUALS BY THE AGE OF 85 HAVE DEMENTIA, HAVE ALZHEIMERS ALZHEIMERS AND BY THE YEAR 2025, THERE ARE GOING TO BE ONE PUBLICITY TWO BILLION INDIVIDUALS OVER THE AGE OF 60. SO OUR WORLD IS CAREENING TOWARDS AN ENORMOUS CHALLENGE BECAUSE OF THE CHANGING DEMOGRAPHICS. I THINK WHAT’S GOING TO DOMINATE SOCIETAL ISSUES AND POLITICS WILL BE THE AGING POPULATION. THAT WILL BE THE GREAT CHALLENGE WE WILL FACE IN THE CENTURY AND YOU KNOW WHILE MANAGING HEALTHCARE IS VERY IMPORTANT, OPTIMIZING HAVING BETTER EVIDENCE BASED STRATEGIES TO QUELL AND MANAGE PATIENTS IN THESE, THERE IS ONLY ONE ANSWER AND IT’S SCIENCE. WE HAVE TO FIGURE OUT THE PATHOGENESIS OF AGING AND HOW AGING RELATES TO THESE GREAT DISEASES BECAUSE IF WE DO NOT, WE HAVE A NONSUSTAINABLE SITUATION AND 2025, THAT’S ONLY 14 YEARS FROM NOW WE’LL HAVE OVER A BILLION PEOPLE THAT WILL BE ACQUIRING THESE DISEASES. SO I HOPE THAT OUR ELECTED OFFICIALS THINK BEYOND THE ELECTION CYCLE AND SUPPORT SCIENCE TO THE LEVEL THAT HUMANITY DESERVES AND THIS GREAT CAMPUS, THE GREAT STATE OF TEXAS, AND THE THE REST OF THE WORLD CAN MAKE A DIFFERENCE IF THE WIND IS PUT IN OUR SAILS. SO LET ME JUST THANK YOU FOR THE PEOPLE THAT DID THE WORK. WE HAVE JAN HU, WHO DID THE ER CANCER STUDY, MARY JOE KELLOFF, AGENCY ON AGING AND WE HAVE A PHENOMENAL BODY OF WORK THAT LINK THIS IS GENOTOXIC EXPRESS TO AGING WE ARE REALLY–THESE ARE PEOPLE ON THE LEFT HERE ARE INDIVIDUALS THAT REALLY WERE, YOU KNOW ON THE NINA, THE SANTA MARIA AND THE PINTA, TRYING TO FIGURE OUT WHETHER OR NOT TELOMERES ARE IMPORTANT. AND ALL OF OUR COLLABORATORS AND AND JUST REALLY GRATEFUL FOR ALL THEÑi GIFTS COLLEAGUES I HAD A CHANCE TO INTERACT WITH AT DANA FAVREER AND HARVARD MEDICAL SCHOOL. IT’S A PHENOMENAL ENVIRONMENT. GREAT TRAINING, IT’S JUST GREAT GREIGS. TREMENDOUS AMOUNT OF TALENT AND I’M JUST INSPIRED BY THE LEVEL OF SCIENCE AND THE WORK AND THE CHANCE TO DO GREAT GOOD AT M. D. ANDERSON. 18,000 PEOPLE, ENORMOUS AMOUNT OF RESOURCES, A SINGULAR FOCUS ON CANCER, THERE’S A REAL CHANCE THAT WE TOGETHER COULD DO GREAT THINGS AND REALLY DO WHAT PEOPLE ARE EXPECTING US TO DO WHICH IS TO BEND THE CURVE ON THESE DISEASES IF NOT CURE THEM. THANK YOU VERY MUCH. [ APPLAUSE ] F THAT WAS GREAT. PEOPLE WANT TO USE THE MICROPHONES FOR QUESTIONS. LET ME START WITH ONE AS INTRIGUING AS IT IS THAT THE DNA LINKS TO MITOCHONDRIAL METABOLISM TO YOUR CLOSING CHALLENGES OF USING THIS INFORMATION TO IDENTIFY INTERVENTIONS TO MODIFY AGING TO THE GOOD, THEICAL SENCH TO INCREASE THE COMPLEXITY OF THE SYSTEMS AND THAT PROTEIN COMPLEX BATIONS IN THE PRO DICKED OUTCOMES ARE NOT SO SIMPLE. YOU WANT TO COMMENT IS WHAT YOU SAY TO THAT?>>YOU LOOK AT M-TOR, SUPPRESSIVE ATTENUATE SIGNALING AND YOU GET RESPONSES AT THE ORGANIZATIONS NIGHS MALLEVEL. YOU HAVE TO UNDERSTAND THE DETAILS OF HOW THESE THINGS ARE REGULATED. ALL RIGHT? IT’S THE CONTEXT AND IT’S EXACTLY WHERE TO INTERVENE. IMAGINE IF YOU WERE TO DO AN AGONIST FOR PGC THAT YOU WOULD HAVE PROBLEMS WITH, YOU KNOW THE GLUE COGENESIS AND SO ON, THAT MIGHT NOT BE USEFUL IF YOU OVEREXPRESS IT TOO MUCH, YOU MIGHT GET MIGHT O CONDRIIAL PROLIFERATION, SO YOU NEED TO UNDERSTAND THE TARGET, YOU KNOW ONE THING THAT I THINK WOULD BE INTERESTING TO CONSIDER WOULD BE IF YOU ACCOUNTED REAWAKEN TELEO MERACE BECAUSE IT IS AN IMPORTANT ELEMENT, EARLY ENOUGH IN LIFE, BEFORE YOU GET INTO THE INITIATED CANCER STAGE, ONE COULD IMAGINE THAT WOULD BE HELPFUL ORE ENHANCE WAYS TO DNA REPAIR ACTIVITY SO SOMETHING SOMEWHAT WOULD MODIFY SIGNALING FLUX IN THE PATHWAY AND WE THINK IN THOSE TERMS BUT WE DON’T TEND TO THINK OF IT WITH THE P53 PGC ACCESS, SO NOW THAT WE HAVE THE ACCESS WE CAN THINK ARE THERE MODIFIERS THAT CAN HAVE THE RIGHT KIND OF SIGNALING ATTENUATION SO THAT WE CAN DAMPEN THE RESPONSE SO WE CAN MAKE MORE MITOCHONDRIA AND MAKE MORE BETTER FOR INCREASEOXIDATIVE DEFENSE. SO SO I THINK THE SER TUMOR
TUMOR–SERTUIN
S, THAT ARE A GOOD SHOWING OF THAT. CAN YOU REGULATE PGC AS WELL. THOSE ARE THE THINGS IF WE THINK ABOUT AND SET THINGS UP ARE IMPORTANT. THE CHALLENGE THERE IS THAT AND THIS IS, I THINK A KEY POINT THAT WE’VE LEARNED IS THAT COACH BASED SYSTEMS ARE NOT GOOD SYSTEMS IN WHICH TO STUDY THIS ACCESS. THIS IS AN IMPORTANT POINT BECAUSE WE’RE GROWING OURSELVES IN SNICKERS BARS CONDITIONS, HYPEROXIC STATE AND THEY’RE NOT AS DEPENDENT ON MITOCHONDRIA, THEY’RE VERY GLIET COLITIC AND YOU DON’T SEE SO MUCH DEPENDENCE ON MITOCHONDRIA. SO AS A RESULT IF YOU’RE STUDYING MITOCHONDRIA OR AGING, YOU MAY NOT GET THE FULL SORRY SO I THINK NOT TO SAY THAT THEY’RE NOT USEFUL THAT MODEL SYSTEM, ALL MODEL SYSTEMS OF THE DISADVANTAGES BUT IF YOU’RE LOOKING FOR SCREENS, YOU GOTTA KNOW WHAT IT IS TO LOOK FOR AND WHAT CONTEXT THE STUDY THAT COULD HAVE BEEN SO YOU CAN GET THE RIGHT ANSWER.>>THANK YOU SO MUCH, VERY ELEGANT WORK YOU DID THIS THEIR AND THAT SEVEN YEAR LENGTH SCALE IS ABOUT WHERE WE’RE AT SO THAT’S ENCOURAGING. SO MY QUESTION IS WITH THE FEWER MITOCHONDRIA YOU OBSERVE, IF YOU COULD COMMENT, IS IT AN ISSUE OF OF TO BE SIMPLISTIC, POOR SYNTHESIS OF THE MITOCHONDRIA OR HIGHER DEPLETION? ARE YOU SEEING ANYTHING THAT IS SHOWING SOMETHING LIKE IS THAT.>>IT’S A VERY, VERY, GOOD QUESTION, WE HAVEN’T LOOKED. WE’RE VERY INTERESTED IN LOOKING AT MIGHT O CONDRIRIAL RECYCLING AND SO ON, WE JUST DON’T–WE DON’T KNOW. BUT IT’S VERY IMPORTANT. PFAMILIES IS DECREASED SO THAT’S ONE ASPECT OF IT. BUT WE CAN’T SAY BUT WE DO KNOW MINIMALLY ON A PERMITOCHONDRIAL BASIS, THEY’RE NOT WORKING WELL BUT I THINK THERE’S INTERESTING BIOLOGY OVER A LARGE GENETIC BUSINESS THAT RELATES TO HOW MITOCHONDRIA ARE MAINTAINED IN THIS THE MOOD AND SO ON, THAT WE SHOULD LOOK AT BUT WE HAVEN’T.>>VERY, VERY, INTERESTING, LECTURE. MY INTEREST IS THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION, AGING AND CANCER. THE PLASTICS OF THE TELEO MERACE ASSOCIATION WITH APOPTOSIS AND IT’S REVERSAL THAT YOU MENTIONED, INCLUDE THE MUTASE FROM MITOCHONDRIA, SEEKING ALL THE NEED THAT THERE IS AN INBALLANCE BETWEEN THE BALANCE THAT SHOULD BE TO KEEP IMMUNE SURVEILLANCE OF THE TISSUE, MAINTAINING IMMUNE BALANCE AND IT’S AN IMBALANCE BETWEEN APOPTOSIS AND WOUND HEALING PROCESSES OR GROWTH ARRESTING AND GROWTH PROMOTING EVENTS THAT IS GOING ON IN A NORMAL HEALTHY TISSUE.>>YEAH, I AGREE. SO I THINK THESE ARE PROCESSES THAT ARE IMPORTANT AND HELP TO MAINTAIN TISSUE HOMEOSTASIS. AND JUST LOOKING AT IT THROUGH THE LENSES OF TELOMERE BIOLOGY. NOT TO SAY THERE AREN’T IMPORTANT PROCESSES THAT DRIVE THE AGING PROCESS THAT YOU MENTIONED AND I AGREE. I THINK THAT THERE ARE ALSO OPPORTUNITIES TO ASK WHETHER OR NOT THEIR INTERACTIONS BETWEEN THOSE PROCESSES AND INFLAMMATION WHICH IS PARTICULARLY ROSS GENERATING IS AN EXAMPLE OR THE INJURY REPAIR WHERE YOU WOULD HAVE MORE CELL TURNOVER. THINK ABOUT CROHN’S DISEASE, INFLAMMATORY BOWEL DISEASE, HAVE YOU THE OPPORTUNITY TO CREATE MORE DAMAGE ON TELOMERES AND SO ON, RIGHT, SO YOU CAN THINK ABOUT THOSE THINGS BEING QUITE INTERACTIVE, AND ACTUALLY FUELING ONÑi EACH OTHER AND WE SHOULD SHOWN ON EACH OTHER, LIVER CIRRHOSIS WHEN YOU ENGINEER MICE WHEN HAVE YOU MICE WITH LONG TELETELOMERES AND YOU INJURY THE LIVER, YOU DON’T GET SIROTTIC LIVERS, AS SOON AS YOU GET TYOU GET STAGE FOUR CIRRHOSIS AND WHEN YOU HAVE LIMIT THE TELOMERE SYSTEM THAT THE APOPTOTIC CELLS, THE THE LIPID PEROXIDES FROM DYING CELL MEMBRANES ACTIVATE STELLATE CELLS THAT CAUSE THIS FIB ROTTIC REACTION. SO HAVE YOU THIS LENGTH BETWEEN INFLAMMA TORPRO SEASES WHERE DNA DAMAGE COULD CREATE INFLAMMATION AND VICE VERSA WHERE INFLAMMATION CAN CREATE A HIGH ROTH STATE.>>THANK YOU.>>HAVE YOU HAD THE OPPORTUNITY TO INVESTIGATE TELOMERE AND PROTECTION PROTEINS AND DO YOU THINK THEY MIGHT PLAY A ROLE IN FUTURE TRANSLATIONAL WORK?>>WE HAVEN’T AND I THINK THE SHELTERING COMPLEX PLAYING AN IMPORTANT ROLE IN MAINTAINING TELOMERE BIOLOGY. EXTREMELY IMPORTANT. I THINK MOST PEOPLE THINK OF TELOMERES IN TERMS OF ATTRITION, THAT’S NOT THE CASE. IT’S REALLY ABOUT MAINTAINING THE INTEGRITY OF THE TELOMERE AS A CAP WHICH COULD RELATE TO THE AMOUNT OF DAMAGE, REGULATE THE T-LOOP AS IT RELATES TO THE SHELTERING COMPLEX AND ALL OF THOSE THINGS COULD BE MODULATED IN AGING AND IN RESPONSES TO TELOMERE DYSFUNCTION THAT COULD BE JUST AS IMPORTANT AS ATTRITION BUT WE HAVEN’T LOOKED.>>VERY GOOD TALK. I WAS JUST WONDERING, YOU KNOW MAMMALIAN MIGHTY KOAND RIA ABOUT 15 PROTEINS CONTAINED–1500 PROTEINS IN THE MITOCHONDRIA, 95% OF THE MITOCHONDRIA PROTEIN ARE ENCODED BY NUCLEUS GENES SO I WAS WONDERING HAVE YOU SEEN THE MITOCHONDRIA PROFILE OF THIS MITOCHONDRIA INFLUXION FLUX OF PROTEIN WHICH IS ENCODED BY NATURE.>>WELL, CERTAINLY THE PROTEINS BUT ONLY A FEW BY WESTERN BLOTTING. CERTAINLY THE THE PROTEINS ENCODED, THESE ARE THE VAST MAJORITY THAT WE SAW THAT WERE OPPRESSED AND WE HAVE THE LEVEL AND WHERE WE LOOKED PROTEIN WAS ALSO DAMAGED. SO, THE NUCLEAR ENCODED NETWORK THAT PGCs REGULATED IS DOWN ACROSS THE BOARD AND WE DIDN’T CATALOG EVERY SINGLE PROTEIN AND I HAVE STOCK EXCHANGE SAY I DIDN’T CAREFULLY LOOK AT THE LIST OF ALL PROTEINS FOR MITOCHONDRIA, BE PGC DEPENDENT WE HAVEN’T LOOKED AT IT.>>WE SRO TO LET EVERYONE KNOW WHILE WE HAVE A CHANCE TO SPEAK WITH RON FURTHER IF YOU’LL JOIN US FOR A RECEPTION OUT THIS WAY IN THE LIBRARY. THANK YOU AGAIN, RON. WE LOOK FORWARD TO SPEAKING WITH YOU INFORMALLY. [ APPLAUSE ]

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