Genotoxic Stress Meets Mitochondria: Integrating Aging Mechanisms


Uploaded by nihvcast on 20.09.2011

Transcript:
>> 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 ]