WELCOME TO THE WEDNESDAY
AFTERNOON LECTURE SERIES I'M
WITH THE NIA AND IT'S MY
PLEASURE TO INTRODUCE TODAY'S
LECTURE.
BEFORE I INTRODUCE HER PROPERLY
I WANT TO SAY TWO ANNOUNCEMENTS.
THE FIRST IS THE CODE FOR THE
CONTINUING MEDICAL EDUCATION
CREDITS IS 57685.
AND THE SECOND ONE IS THAT FOR
THOSE THAT ARE WATCHING YOU CAN
SUBMIT YOUR QUESTION TO THE
SPEAKER ANY TIME DURING THE
LECTURE.
SIMPLY CLICK ON THE BOTTOM THAT
SAYS SEND LIVE FEEDBACK WHICH IS
BELOW YOUR VIDEOCAST WINDOW.
TYPE IN YOUR MESSAGE AND WE WILL
RELAY YOUR QUESTION AT THE END
OF THE LECTURE.
LET'S GO BACK TO THE
INTRODUCTION.
DR. SUH IS A PROFESSOR CHARLES
AND MARIE ROBERTSON PREVENTION
IN REPRODUCTIVE SCIENCES AND
OBSTETRICS AND SERVED AS THE
DIRECTOR OF THE REPRODUCTIVE
AGING PROGRAM AT COLUMBIA
UNIVERSITY MEDICAL CENTER IN NEW
YORK.
DR. SUH IS AN EXPERT IN THE
FIELD OF EPIGENETICS AND
GENETICS.
HER RESEARCH HAS LIED IN THE
IDENTIFICATION OF EPIGENETIC
SEQUENCE VARIANTS LEAD TO THE
RISK OF AGE-RELATED DISEASES AND
FACTOR CONTRIBUTING TO THE
RESILIENCE AGAINST SUCH
DISEASES.
FOR EXAMPLE AS FOR THOSE IN S
CENTENARIANS AND LOOK AT RNA IN
HUMAN CODING AND LONGEVITY AND
THE EPIGENETIC CODES ASSOCIATED
WITH CELLULAR SENESCENCE.
HER CONTRIBUTION HAS BEEN
RECOGNIZED WIDELY THROUGH
SEVERAL ORGANIZATIONS.
SHE RECEIVED FOUNDATIONAL WORK
AND CURRENTLY IS THE MEMBER OF
THE ACADEMY OF HEALTH AND LIFE
RESEARCH.
IN ADDITION TO ALL HER RESEARCH,
SHE ALSO HAS ORGANIZED NUMEROUS
INTERNATIONAL SYMPOSIA AND
SERVED ON EDITORIAL BOARDS AND
HAS MORE THAN 100 PUBLICATIONS.
TODAY WE'RE VERY LUCKY BECAUSE
SHE'S GOING TO TALK ABOUT HER
LATEST DISCOVERY IN SCIENCE.
SHE IS LOOKING AT THE ROLE OF
AGING IN COVARIANTS IN AGING.
THIS IS A TOPIC THAT HAS BEEN
VERY INTERESTING IN THE FIELD OF
AGING.
BEFORE WE DIDN'T HEAR ABOUT THIS
BEFORE FIVE YEARS AGO WE NEVER
HEAR OF IT.
MOST RECENTLY, IT'S GAINED
IMPORTANCE BECAUSE THE COMMUNITY
HAS LEARNED THE SEX PLAYS A ROLE
IN THE AGING THE TITLE IS
MECHANISM OF AGING.
WELCOME DR. SUH.
>> THANK YOU FOR THE VERY KIND
INTRODUCTION.
CAN YOU HEAR ME OKAY?
I'D LIKE TO START BY THANKING
THE DIVISION OF AGING BIOLOGY
AND VIVIAN PEREZ FOR INVITING ME
TO VISIT AND TO GIVE A LECTURE
AT NIH TODAY.
I'VE BEEN ENJOYING IT VERY MUCH.
I OFTEN SAY I GREW UP WITH AGING
BIOLOGY SINCE I RECEIVED MY
FIRST RO1 IN 2004 AS A JUNIOR
FACULTY AND HAVE BEEN REALLY
GRATEFUL TO THE NATIONAL
INSTITUTES ON AGING AND NIH FOR
THEIR SUPPORT AND THE ITEMS SHA
SHAPED AND DEFINED MY CAREER.
THANK YOU SO VERY MUCH.
AS VIVIANIA INTRODUCED, MY LAB
HAS BEEN USING HUMAN GENETICS
AND FUNCTIONAL GENOMICS APPROACH
TO UNDERSTAND THE FUNDAMENTAL
MECHANISMS OF AGING AND
LONGEVITY.
TODAY I'D LIKE TO SHARE OUR VERY
RECENT WORK ON MECHANISMS OF
HUMAN OVARIAN AGING AND I HOPE
BY THE END OF MY TALK I WILL
CONVINCE YOU THAT BY TARGETING
OVARIAN AGING WE MAY BE ABLE TO
DELAY AGING IN THE OVARY THEREBY
MAKING WOMEN A LITTLE WILL --
DELAY IN AGING.
THIS AUDIENCE IS WELL VERSED IN
AGING BIOLOGY BUT JUST TO FRAME
MY TALK, I'D LIKE TO START WITH
A SIMPLE QUESTION, WHY STUDY
AGING?
SO, WE KNOW THAT AGING IS BY FAR
THE SINGLE LARGEST RISK FACTOR
FOR DISEASE AND SHOWN HERE IS
THE INCIDENCE RATE AT FUNCTIONAL
AGE AND YOU SEE INCIDENTS OF ALL
CHRONIC DISEASES INCREASE
DRAMATICALLY FROM MIDDLE AGE
ONWARDS FOR MEN AND WOMEN.
FOR EXAMPLE, JUST SIMPLY GETTING
OLD FROM AGE 50 TO 75 INCREASES
RISK FOR DISEASE BY A
HUNDREDFOLD WHICH DWARF TENFOLD
INCREASE IN RISK BY ALL KNOWN
RISK FACTORS COMBINED INCLUDING
BEING A FEMALE, HYPERTENSION,
SMOK
SMOKING, PHYSICAL INACTIVITY AND
THIS IS TRUE FOR ALL DISEASE,
KIDNEY DISEASE, CARDIOVASCULAR
DISEASE AND YOU NAME IT.
FOR THOSE WHO STUDY AGING
BIOLOGY, PROPOSE SINCE AGING IS
THE DRIVER OF THIS MAJOR CHRONIC
DISEASES BY TARGETING
FUNDAMENTAL MECHANISMS OF AGING
WE'LL BE ABLE TO DELAY THE ONSET
AND PROGRESSION OF MANY IF NOT
ALL AGE-RELATED CHRONIC
DISEASES.
AND THIS GERO SCIENCE HYPOTHESIS
HAS BEEN FORM LASTED BASED ON
MANY ELEGANT WORK AND NOW WE
LEARNED AGING IS NOT SIMPLY WEAR
AND TEAR, IT'S CONTROLLED BY
UNDERLYING BIOLOGY REGULATED BY
GENES AND PATHWAYS AND BY
TARGETING THIS EVE --
EVOLUTIONARY PATHWAY AND WE KNOW
A LOT ABOUT AGING BIOLOGY THAT
DRIVES AGING PROCESSES FROM
GENOMIC INSTABILITY
TO REGULATION, MITOCHONDRIAL
DYSFUNCTION AND CELLULAR
SENESCENCE.
THE DRUG THAT TARGETS THIS
FUNDAMENTAL PROCESS OF AGING
THEREBY ARE COLLECTIVELY CALLED
GERO PROTECTERS.
MY LAB HAS BASEBEEN FOCUSSED ON
THESE DISCOVERIES BY ASKING
QUESTIONS, IS THIS THE SAME C
CONSERVED PATHWAYS TO HUMANS AND
THANKS TO THIS ENORMOUSLY LARGE
HUMAN DATA SET WE CAN DO REVERSE
TRANSLATIONAL GERO SCIENCE
APPROACH.
SO HUMANS, BY FAR THE BEST
PHENOTYPE SPECIES WHEN IT COMES
TO AGING RELATED DISEASE AND
CONDITIONS.
NOW THERE'S A LARGE DATA SET
FROM MULTI-OMICS AND HEALTH
RECORDS, WE CAN USE HUMAN AS A
DISCOVERY PLATFORM TO GENERATE
HYPOTHESIS AND TEST THAT IN
HUMAN CELLS AND MODEL ORGANISMS.
SO NOW, WHY STUDYING AGING IN
WOMEN?
AS VIVIANA INTRODUCED, WOMEN'S
HEALTH HAS RECEIVED LIMITED
ATTENTION SO HISTORICALLY THE
BIO MEDICAL RESEARCH HAD BEEN
FOCUSSED ON MALE BIOLOGY, STUDY
SUBJECTS INCLUDING ANIMALS AND
MAINLY MALE TO THE POINT WHERE
IN 2016, NIH MANDATED TO
INCLUSION OF BOTH SEXES IN ALL
RESEARCH.
AND UNDER THIS SEX BIOLOGICAL
VARIABLE POLICY.
SO AND OF COURSE THE FUNDING HAS
LAGGED BEHIND.
AS A CONSEQUENCE THE KNOWLEDGE
ABOUT HOW FEMALE SYSTEM WORKS
AND AGE IS LIMITED AND THE
KNOWLEDGE GAP HAS REALLY
PRACTICAL NEGATIVE CLINICAL
CONVERSATIONS AND OFTEN TIMES
IT'S MISDIAGNOSED OR DIAGNOSED
LATER.
THEY RESPOND LESS EFFECTIVELY TO
TREATMENT AND THEY SUFFER MORE
ADVERSE DRUG SIDE EFFECTS.
AND THERE'S MORE PUBLIC
ATTENTION CALLING FOR CHANGE.
AND WE ISSUED SPECIAL NOTICE IN
RESEARCH IN WOMEN'S HEALTH, SO
EXCITING.
SO FINALLY WHY ARE WE STUDYING
AGING IN THE OVARY?
AND IT DOES NOT ONLY INFLUENCE
REPRODUCTION BUT AFFECTS THE
WHOLE BODY THEREBY INFLUENCING
OVER ALL HEALTH IN WOMEN.
FIRST OF ALL, OVARY IS ONE OF
THE FIRST ORGAN TO AGE IN THE
HUMAN BODY.
SO AGING STARTS IN MIDDLE 30s
WITH DRAMATIC DECLINE IN
FUNCTION WHICH COMPLETELY STOPS
WITH MENOPAUSE AROUND AGE 51.
MALE REPRODUCTIVE FUNCTION
DECLINES AS WELL BUT RATHER
GRADUAL.
SO REPRODUCTIVE LONGEVITY OR
REPRODUCTIVE LIFE SPAN IS
DIFFERENT IN WOMEN COMPARED TO
MEN.
AND THE LIFE EXPECTANCY HAS
INCREASED DRAMATICALLY BUT THE
AGE OF NATURAL MENOPAUSE HAS
REMAINED LARGELY UNCHANGED.
WHAT THAT MEANS IS MORE AND MORE
WOMEN LIVE GREATER PROPORTION OF
THEIR LIVES IN POST MENOPAUSAL
STATE AND WE KNOW THIS IS BAD
BECAUSE MENOPAUSE COINCIDES WITH
VERY DELETERIOUS HEALTH OUTCOME
AND COGNITIVE, IMMUNE, BONE AND
CARDIOVASCULAR SYSTEMS.
AND MENOPAUSE ACCELERATED AGING
THERE'S A GENETIC COMPONENT IN
THIS MENOPAUSE INDUCED
ACCELERATED AGING CONSISTENT
WITH THE GENETIC LINK.
WOMEN WHO UNDER GO MENOPAUSE
LATER TEND TO LIVE LONGER THAN
WOMEN WHO UNDER GO MENOPAUSE
EARLIER.
SO ACTUALLY, FAMILY WITH HISTORY
OF EARLY MENOPAUSE HAS SIX TIMES
HIGHER RISK FOR THIS AND
BREEDERS OF WOMEN WITH LATER
MENOPAUSE HAVE A PROLONGEVITY
COMPARED COMPARED TO BREEDERS OF
WOMEN WITH EARLIER MENOPAUSE.
THIS SUGGESTS TO US THAT OVARY
DOES MUCH MORE THAN REPRODUCTION
AND REALLY INFLUENCES OVER ALL
HEALTH.
WHAT HAPPENS IF YOU REMOVE
OVARY, IT REDUCES THE RISK FOR
DEMENTIA AND CARDIOVASCULAR
DISEASE AND INCREASED RISK FOR
MORBIDITY AND ALL CAUSE
MORTALITY.
AND REPLACING OVARY FROM OLD
MICE TO YOUNG MICE IS ENOUGH TO
IMPROVE INSULIN SENSITIVITY AND
REDUCING INFLAMMATION.
FROM THE EYE OF THIS GEROSIN
SCIENTIST IT WAS CLEAR TO US
OVARY AND AGING CAN BE TARGETED
FOR GERO PROTECTION IN AGING.
WHAT'S THE UNDERLYING BIOLOGY WE
CAN TARGET?
UNFORTUNA
UNFORTUNATELY AND WHAT'S BEEN
DOCUMENTED IN HUMANS IS ENORMOUS
HETEROGENEITY IN AGING.
WHAT'S SHOWN IS NATURAL
MENOPAUSE IN THE U.K. BIO BANK
AND THE DISTRIBUTION.
SOME WOMEN UNDER GO MENOPAUSE IN
THEIR 30s AND SOME WOMEN
DEPENDS, LATE 50s.
YOU CAN PERFORM GENOME WIDE
ASSOCIATION STUDIES.
ONE OF THE LARGEST STUDIES
INVOLVES MORE THAN 200,000 WOMEN
IDENTIFIED IDENTIFIED 290 LOCI
ASSOCIATED WITH MENOPAUSE
TIMING.
WHEN IT DOES ANYTHING IT DOES IT
THROUGH REGULATORY CHANGES.
THE HUMAN GENOME HAS EXTENSIVE
LINKS TO EQUILIBRIUM.
IN THE LOCUS YOU FIND MANY IF
NOT VARIANTS ASSOCIATED WITH
MENOPAUSE TIMING AND REGULAR
ELEMENTS SUCH AS ENHANCER AND
PROMOTER, THEY TEND TO INTERACT
IN A DISTURBED WAY SO SOMETIMES
SKIPPING IN BETWEEN SO TO
IDENTIFY REAL CAUSAL CHANCE THAT
ARE UNDER INFLUENCED THE
REGULATORY VARIANT IS A PRIORITY
UNKNOWN AND REGULATORY ELEMENTS
THEY HAVE SELL TYPE SPECIFIC
FUNCTION.
SO TO IDENTIFY CAUSAL CELL TYPES
THAT ARE UNDER INFLUENCED OF
THIS CAUSAL VARIANT ARE UNKNOWN
LET ALONE THE MECHANISMS.
SO TO ADDRESS THIS CHALLENGE, WE
AND OTHERS HAVE BEEN INTEGRATING
HUMAN GENETIC DATA FROM GENOME
WIDE ASSOCIATION STUDIES TO
EPIGENOME AND EPIGENETIC DATA
SETS.
EVERY INCREASING NOWADAYS AND TO
MAP THEM IN DIFFERENT CELL TYPES
TO IDENTIFY CHANGES IN
TRANSCRIPTION FACTOR BINDING AND
LOOK AT ALSO EXPRESSION CHANGES
CALLED EQTL ANALYSIS AND PREDICT
CAUSAL VARIANTS AS WELL AS
CAUSAL GENES.
AND TO LOOK FOR CHROMATIN
ACCESSIBILITY, THERE ARE 220
HUMAN CELL TYPES DERIVED FROM 30
DIFFERENT HUMAN TISSUES BUT
UNTIL VERY RECENTLY, OVARY DATA
WASN'T AVAILABLE, WHICH IS
REALLY UNFORTUNATE BECAUSE
OVARIES IS A VERY COMPLEX ORGAN
TO MAINTAIN THIS OVARIAN
FUNCTION AND THERE ARE DIFFERENT
CELL TYPES.
FOR EXAMPLE, OVARY SPECIFIC CELL
TYPES ARE MAIN COMPONENTS OF
FOLLICLES THAT PROMOTE GROWTH
AND MATURATION AND THERE ARE
OTHER CELL TYPES SUCH AS STROMA
CELLS AND EPITHELIAL CELLS,
SMOOTH MUSCLE CELLS AND
LYMPHATIC AND BLOOD ORIGIN AND
IMMUNE CELLS.
TO UNDERSTAND THIS, THEY TOOK AN
IT SYSTEMIC APPROACH AND TOOK
OVARIES FROM YOUNG WOMEN IN
THEIR 20s AND REPRODUCTIVELY OLD
WOMEN IN THEIR 50s.
SO WE ARE TALKING ABOUT AGING
FROM 20 TO 50 AND PERFORMED
SIN
SINGLE NUC RNA SEQ AND
REGULATORY LANDSCAPE CHANGE AND
WE WERE HAPPY TO DETECT ALL
MAJOR CELL TYPES IN THE OVARY.
SO WITH THE DATA NOW YOU CAN
INTEGRATE THE MENOPAUSAL GWAS
AND VARIANTS AND WE FOUND THAT
THE MENOPAUSAL TIMING OF
VARIANTS ARE OCCUR IN REGULATORY
ELEMENTS THAT ARE ACTIVE IN NOT
JUST ONE CELL TYPE, ACROSS MANY
CELL TYPES IF NOT ALL CELL TYPES
IN THE OVARY.
AT THE VARIANT LEVEL, THEY HAVE
RATHER GLOBAL IMPACT.
WHEN YOU LOOK AT THE PREDICTED
TARGET JIN IT'S NEAREST FROM THE
VARIANTS THEY'RE INRICHED IN
JINS EXPRESSED NOT JUST IN ONE
CELL TYPE BUT ALL TYPES OF THE
OVARY.
FROM STROMA CELLS DOWN AND
ENDOTHELIAL CELLS DOWN TO
THICKER CELLS INDICATING THE
GLOBAL IMPACT.
IN COMPARISON, CHANNELS OF TWO
GWAS DATA FROM POLY CYSTIC OVARY
SYNDROME A HORMONAL DISORDER
FOUND IN REPRODUCTIVELY YOUNG
WOMEN AND HORMONE IS PRODUCED IN
GRANULOSA CELLS AND THEY'RE
ENRICHED IN GRANULOSA CELL
SPECIFICALLY.
WHAT ABOUT OVARIAN EPITHELIAL
CANCERS?
WHEN YOU TAKE GWAS DATA FROM
THAT CANCER THEY'RE ENRICHED IN
EPITHELIAL CELLS WITH THE CANCER
IS ORIGINATING.
SO THIS DATA CONVINCED US THAT
MENOPAUSE ASSOCIATED TIMING
VARIANTS HAVE GLOBAL IMPACT ON
THE REGULATORY NETWORK IN THE
OVARY ACROSS DIFFERENT CELL
TYPES.
SO USING THE DATA YOU CAN NOW
START IDENTIFYING POTENTIALLY
CAUSAL VARIANTS AND GENES.
I'LL SHARE WITH YOU A COUPLE
EXAMPLES.
WE FOUND A VARIANT NEAR A LOCUS
ASSOCIATED WITH LATER MENOPAUSE
AND IT OCCURS IN REGULATORY
ELEMENTS THAT'S ACTIVE IN ALL
THESE OVARIAN CELL TYPES FROM
STROMA CELLS, ENDOTHELIAL CELL
DOWN TO EPITHELIAL CELLS.
SO WE CALL IT PURATIVE CAUSAL
VARIANTS.
THIS LATER MENOPAUSE ASSOCIATED
VARIANTS WE IDENTIFY AS
POTENTIALLY CAUSAL, IS
CORRELATED WITH REDUCED
EXPRESSION OF HELB.
BUT WHEN THEY LOOK AT THE OTHER
TISSUES IN THE DATABASE IT WAS
SURPRISING THAT ALL THE TISSUES
THAT HAVE BEEN PROFILED, THIS IS
49 TISSUES SHOW THE SAME
PATTERN.
IN OTHER WORDS, OVARIAN AGING
ASSOCIATED VARIANTS HAS
IMPACT -- POTENTIAL IMPACT
ACROSS ALL TISSUE TYPE IN HUMAN
BODY.
SO OVARIES IS NOT EVEN NUMBER
ONE.
YOU CAN SEE MUSCLE FOR EXAMPLE,
SKELETAL MUSCLE, THE MAGNITUDE
OF DOWN REGULATION IS MUCH MORE
THAN WHAT IS FOUND IN OVARY.
YOU CAN SEE FROM MUSCLE TO BRAIN
TO HEART AND ALL THE TISSUES.
THIS LATER MENOPAUSAL VARIANT IS
COMPARED TO NON-RISK VARIANT.
WHAT I HAVE SHOWN YOU HERE IS
PREDICTION.
YOU INTEGRATE ALL THE RELEVANT
DATA AND PREDICT CAUSAL VARIANTS
AND CAUSAL GENES.
THE QUESTION IS, HOW DO WE BRING
THIS PREDICTION AND ASSOCIATION
TO EXPERIMENTAL VALIDATION TO
ESTABLISH CAUSALITY?
WE'VE BEEN THINKING VERY HARD
ABOUT THE BEST WAY TO APPROACH
THIS AND ANOTHER POSTDOC IN MY
LAB SPEARHEADED THIS APPROACH.
WHAT HE DOES IS HE TAKES HUMAN
PLURIPOTENT STEM CELL AND
ENGINEER THEM WITH CRISPR SO IT
CARRIES THE CAUSAL VARIANTS.
EVERYTHING ELSE IS THE SAME
EXCEPT FOR THE SINGLE
NUCLEOTIDE.
NOW YOU CAN DIFFERENTIATE THE
ENGINEERED CELLS TO MULTIPLE
CELL TYPES IN THE OVARY
INCLUDING GRANULOSA CELLS AND
ENDOTHELIAL CELLS AND SMOOTH
MUSCLE CELLS.
NOW, COMPARING TO ISO GENIC
CONTROL YOU CAN CONFORM THE REAL
CAUSAL VARIANT YOU PREDICT AND
CONFIRM THE DIRECTIONAL OUTCOME
AND ALSO MAGNITUDE, IN OTHER
WORDS, THE VARIANT DOESN'T MAKE
GENE EXPRESSION LESS OR MORE AND
OF COURSE FROM DIFFERENT CELL
TYPES YOU CAN CONFIRM THE CELL
TYPES SPECIFICITY AND REALLY
TREAT DOWN THE MECHANISMS
INCLUDING TRANSCRIPTION FACTORS
AND MEDIATE THIS CHANGE.
I'LL GIVE YOU ONE EXAMPLE, THE
GENE THAT'S PREDICTED TO SHOW
REDUCED EXPRESSION IN MULTIPLE
TISSUE TYPE, IT'S NOT ALL TISSUE
TYPE THAT HAS BEEN PROFILED.
SO IN THIS CASE, FOR THE
REGULATORY VARIANT, THE BEST
APPROACH IS TO TAKE HETEROZYGOUS
CELL AND FIND A CODING VARIANT
AS A PROXY FOR REGULATORY
ACTIVITY.
WHEN YOU LOOK AT THE AABUNDANCE
-- ABUNDANCE OF PROXY MARKERS
YOU CAN REDUCE THEY WILL
REGULATORY CAPACITY.
THIS IS A CONTROLLED EXPERIMENT
WHEN YOU TAKE GENOMIC DNA AND
PERFORM PCR, HALF AND HALF.
WHEN YOU TAKE CB AND A FROM
DIFFERENTIATED CELLS THEN YOU
SEE LATER MENOPAUSE ASSOCIATED
VARIANT CAUSED REDUCE EXPRESSION
OF A HEALTHY GENE.
SO THIS IS NOW CONFIRMATION OF
THE PREDICTION.
AND ACROSS ALL CELL TYPES WE
HAVE TESTED AGAIN SHOWING GLOBAL
IMPACT.
WE WERE LUCKY TO HAVE PRIMARY
GRANULOSA CELLS AROUND THIS IS
COLUMBIA FERTILITY CENTER.
WE COULD GET FOUR CELLS,
HETEROZYGOUS CARRIER AND LOOK AT
REDUCED EXPRESSION AND HELB IS A
DNA HE LACASE AND IT'S A WAY OF
PREPARING DOUBLE-STRAND BREAK.
THIS IS ALSO INVOLVED IN MYOTIC
RECOMBINATION.
OUR STUDY DEMONSTRATING LATER
MENOPAUSE ASSOCIATED VARIANT
REDUCED EXPRESSION OF HELB GENE
SUCH THAT TO US, THE GENE
DEFICIENCY MAY IMPROVE OVARIAN
FUNCTION OR IMPROVE OVARIAN
RESERVE AND PRESERVE THE LIFE
SPAN.
TO TEST THAT HYPOTHESIS, WE HAVE
GENERATED HEALTHY KNOCKOUT MICE
IN COLLABORATION WITH COLUMBIA
AND WE ARE GOING TO TEST IF THIS
DEFICIENCY AS WE PREDICT
IMPROVES REPRODUCTIVE LIFE SPAN
AND OVARIAN RESERVE AND ALSO WE
ARE GOING TO TEST IF IT HAS ANY
IMPACT ON HEALTH SPAN IN PEOPLE.
IT'S GOING TO BE SPEARHEADED BY
SHWETA DIPALI IN THE LAB.
AND THE OTHER LOCUS WAS DETECTED
MORE THAN 10 YEARS AGO WITH MUCH
LESS INDIVIDUAL, I THINK 7,000
WOMEN.
AND IT WAS HAILED AS A LOCUS
ASSOCIATED WITH REPRODUCTIVE
AGING IN WOMEN.
THE QUESTION IS, IS BRCA1 THE
CAUSAL GENE?
AS I EXPLAINED THE LOCUS HAS
MANY VARIANTS AND MORE THAN 400
VARIANTS ARE ASSOCIATED WITH
LATER MENOPAUSE.
YOU CAN SEE THIS IS VCONTAINS M
GENES INCLUDING BRCA 1 SO HOW DO
WE KNOW IT'S THE CAUSAL GENE?
WHEN A POSTDOC IN THE LAB LOOKED
AT THE VARIANT FOUND IT'S
CORRELATED WITH EXPRESSION
CHANGES IN NBR2 GENE HAS NOTHING
TO DO WITH BRCA 1 OR ANY OTHER
GENES IN THIS LOCUS.
SO THE PURATIVE CAUSAL IS MBR2
NOT BRCA1.
SO TO CONFIRM THIS, HE PERFORMED
AGAIN EXPRESSIONAL ANALYSIS AND
CONTROL WHEN YOU TAKE GENOMIC
DNA AND YOU SEE CONTRIBUTION
FROM EACH ALLELE BUT WHEN YOU
TAKE CDNA FROM DIFFERENT CELL
TYPES, NOW IT'S IMMEDIATELY
CLEAR.
YOU DON'T EVEN NEED TO DO
STATISTICS THAT MBR2 IS THE GENE
THAT CHANGES AND MENOPAUSE
ASSOCIATED ALLELE CAUSE
REDUCTION IN EXPRESSION IN
BRC -- SORRY, NBR2.
SO THIS IS NOW CAUSAL GENES IN
THE LOCUS BUT WHAT ABOUT THE
CAUSAL VARIANT?
SO WE TOOK 400 VARIANTS THAT
LINKED IN THIS REGION AND
CONNECTED THEM IN REGULATORY
ELEMENTS THAT ARE ACTIVE IN
OVARIAN CELL TYPE THROUGH OUR
SIN
SINGLE NUC ATTACK SEQ AND FOUND
FIVE VARIANTS IN OVARY CELL
TYPES.
SO HOW DO WE TEST THIS?
SO WE DECIDED TO USE CRISPR
PERTURBATIONS AND DID
COMPRESSIONAL ANALYSIS AFTER THE
CRISPR SCREEN AND FOUND THIS
VARIANT IN THE DISTAL LOCUS
BETWEEN V8T IS AND R2 GENE IS
WHAT DYSREGULATE THE NBR2
EXPRESSION AND WE IDENTIFIED
CANDIDATE CAUSAL GENES AND
VARIANTS AND THROUGH THIS STEM
CELL DIFFERENTIATION PARADIGM
AND SPECIFIC EXPRESSION AND
CRISPR SCREEN WE PINPOINT CAUSAL
VARIANT.
OKAY, THESE ARE TWO LOCUS.
OH, I HAVE TO SAY THIS, SO NBR2
IS A LONG KNOWN CODING RNA
THAT'S PRIMATE SPECIFIC.
MICE DOESN'T HAVE IT.
IT'S INTERESTING HOW THE LONG
KNOWN VARIANT CONTRIBUTES TO
IMAGINATION OF OVARIAN AGING AND
MAG
MAGGIE KANE IN MY LAB IS LOOKING
TO HOW IT CONTRIBUTES TO OVARIAN
AGING IN HUMAN.
SO TWO LOCI.
IT TOOK US A WHILE.
BUT WHEN WE DID INSILICA
PREDICTION WE FOUND MORE THAN
100 POTENTIALLY CAUSAL VARIANTS
LINKED TO AGING NATURAL
MENOPAUSE.
HOW ARE WE GOING TO TEST IT?
ARE WE GOING TO TAKE OUR
FAVORITE GENE AND TEST THOSE OR
LOOK AT TARGETS?
SINCE WE PERFORMED THE HIGH
THROUGHPUT SCREEN TO IDENTIFY
CAUSAL GENES AND CAUSAL VARIANTS
IN ENDOGENOUS GENOMIC CONTESTS
BY USING SINGLE CELL CRISPR I
METHOD.
THIS IS A SIMPLIFIED SCHEMATIC.
YOU HAVE A CAUSAL VARIANT IN THE
MIDDLE THAT SITS IN THE
REGULATORY ELEMENT.
THERE ARE SIX SIX NEIGHBORING
GENES AND HOW DO YOU KNOW THE
CAUSAL VARIANT?
BY TARGETING CRISPR DCAS9 AND
YOU SEE GENE F IS DOWN REGULATED
BY THE CRISPR TARGETING.
BY COMBINING THIS WITH A SINGLE
CELL YOU CAN REALLY LOOK AT THE
DOWN STREAM TRANSCRIPTOMIC WIDE
NETWORK EFFECT.
SO TO BE ABLE TO DO THIS, THEY
SET UP THE STRONG DUAL REPRESSOR
SYSTEM LINKED TO DCAS9 DESIGN
GRNA THAT CAN BE SEQUENCED BY
10X AND THEN YOU CAN ANALYZE
EXPRESSION OF THE NEIGHBORING
GENES AS WELL AS TRANSCRIPTOME
WIDE CHANGES.
SO JINPING DID ALL 100 VARIANTS
AND IT WORKED BEAUTIFULLY.
THIS IS GRANULOSA CELL.
HE STARTED WITH THIS BECAUSE
THIS IS OVER SPECIFIC YOU CAN
SEE COMPARED TO NON-TARGETING
CONTROL YOU SEE HUGE REGULATED
GENES ABOUT 70 OF THEM AND MANY
SHOWDOWN REGULATION AS YOU WOULD
PREDICT FROM PERTURBATION.
THESE ARE THE TARGET GENES.
THE SIZE OF THE LETTER INDICATES
THE FREQUENCY OF THE DETECTION
AND YOU CAN APPRECIATE THE
FUNCTION OF THE GENES ARE REALLY
NOT KNOWN MUCH.
THAT MEANS WE HAVE A LOT TO DO.
I'LL PRESENT A COUPLE COUPLE
EXAMPLES WHEN WE TARGETED WITH
CRISPRI IT DOWN REGULATED
HEALTHY GENE AGAIN CONFIRM II
HELB AND WE LOOKED AT PLIO
TROPIC VARIANTS AND WHEN YOU
TARGET THE VARIANT IS THE
EXPRESSION IS SHOWN AND THE
PHOSPHO LIPID PROTEIN IS SEEN IN
SIGNAL TRANSACTION AND STUDIES
HAVE BEEN DONE AND ONE SHOWS
TATE CORRELATED WITH OVARIAN
CANCER.
EXPRESSION OF THE GENE IS
CORRELATED WITH BAD PROGNOSIS
AND MORE TUMOR GROWTH.
THE REASON WE'RE INTERESTED IN
THE GENE AND VARIANT IS WHEN YOU
TARGET THE VARIANT THEREBY
DECREASING THE EXPRESSION OF
THERE'S ENORMOUS TRANSCRIPTOME
WIDE IMPACT.
BY TARGETING HUNDREDS OF
VARIANTS WE TARGET GENES GOING
UP AND DOWN AND MORE THAN HALF
OR CLOSE TO HALF ARE DUE TO
TARGETING AND WHEN WE LOOK AT
THE GENES THEY'RE ENRICHED IN
THE HALLMARK OF AGING INCLUDING
MITOCHONDRIAL DYSFUNCTION AND
THIS IS OXIDATIVE
PHOSPHORYLATION AND APOPTOSIS
SIGNALLING.
SO THIS IS GOING TO BE ANOTHER
SET OF A STUDY WE DELVE INTO TO
UNDERSTAND THE UNDERLYING
MECHANISM OF CONTRIBUTION, THIS
GENE TO AGING IN OVARY IN HUMAN
IN WOMEN.
OKAY.
SO FINALLY WHAT ABOUT AGING
TRANSCRIPTOME.
IF WE PERFORMED A SINGLE NUC RNA
SEQ IN YOUNG VERSUS OLDER OVARY,
HOW DO THEY CHANGE?
CELL TYPES IN THE OVARY.
WE IDENTIFIED 3,000 GENES GOING
UP AND DOWN WITH AGE AND SURE
YOU CAN APPRECIATE WHEN YOU LOOK
AT THIS THE DIRECTIONAL CHANGE
IS THE SAME ACROSS DIFFERENT
CELL TYPES.
THERE'S COORDINATION.
THIS WAS QUITE STRIKING AND JIN
DECIDED TO LOOK AT THE EXTEND OF
COORDINATION SO HE COULD LOOK AT
PAIRWISE IN TERMS OF SIMILARITY
AND YOU CAN APPRECIATE THE
COORDINATION.
AND IT'S A COORDINATED MANNER.
TO SEE IF THIS IS OVARY SPECIFIC
OR GENERAL AGING PHENOMENON, JIN
ALSO LOOKED AT OTHER SINGLE CELL
DATA FROM OTHER HUMAN TISSUES
DURING AGING PROCESSES IN THE
SAME AGE.
INCLUDING ADIPOSE, BLOOD,
MARROW, BRAIN, LIVER, BRAINS AND
LUNG.
YOU CAN SEE COMPARED TO OVARY,
THERE'S LITTLE OR NO
COORDINATION.
THIS TRANSCRIPTOME WIDE
COORDINATED CHANGING IS A
STRIKING FEATURE OF OVARIAN
AGING.
ANOTHER FEATURE THAT WE THOUGHT
WAS INTERESTING IS THAT THIS
AGING TRANSCRIPT OME THAT
CHANGES WITH AGE IN DIFFERENT
CELL TYPES IN THE OVARY, THEY'RE
REALLY ENRICHED IN THE HALLMARKS
OF AGING AS WE KNOW IT.
THIS IS SOME OF THE EXAMPLES.
YOU CAN SEE MITOCHONDRIAL
DYSFUNCTION, DESENSING
SIGNALLING AND HOMEOSTASIS AND
GENOME INSTABILITY, CELLULAR
SENESCENCE AND TELOMERE
SHORTENING AND AGAIN YOU SEE THE
COORDINATED CHANGE ACROSS
DIFFERENT CELL TYPE.
WHAT CAUGHT OUR EYES WAS REALLY
NTOR SIGNALLING PATHWAY THAT'S
ACTIVATED IN THE OVARY ACROSS
MULTIPLE CELL TYPES.
SO USING THE HUMAN TISSUE DATA
FROM OTHER TISSUES WE COMPARED
AND LOOKED AT HOW SPECIFIC IS
THIS SO THE AGING TISSUES, AND
SO JIN MEASURED THE AMPLITUDE
INDEX AS WELL AS THE PREVALENCE
RATIO ACROSS DIFFERENT CELL
TYPES AND OVARY REALLY STOOD
OUT.
SO AT LEAST IN THIS AGE MTOR
SIGNALLING ACTIVATION IS TRULY
OVARY SPECIFIC.
AS YOU KNOW, MTOR SIGNALLING IS
A MAJOR CONTROL MECHANISM OF
AGING.
IT'S INHIBITOR, RAP RAPAMYCIN
IT INCREASES LIFE SPAN IN ALL
MOTOR ORGANISMS TESTED SO FAR.
SO VERY ROBUST GEROPROTECTOR.
AND THIS SIGNALLING IN ALL THE
OVARY SUGGESTS TO US THAT OVARY
CAN BE MAYBE A GEROTHERAPEUTIC
TARGET OF RAPAMYCIN.
AND THIS WAS ALSO IN LINE WITH
THE DATA FROM US AND RODENT
STUDIES IN MICE, RAPAMYCIN
TREATMENT INCREASED OVARIAN LIFE
SPAN AND FERTILITY AND EVEN
UNDER CHEMOTHERAPY TREATMENT
CONDITION.
SO TOGETHER WITH OUR DATA, WE
NOW INITIATED CLINICAL TRIAL TO
TEST THE EFFICACY OF RAPAMYCIN
TO EXTEND FEMALE REPRODUCTIVE
LIFE SPAN IN HUMANS.
THE TRIAL IS CALLED VIBRANT
STUDY VALIDATING BENEFITS OF
RAPAMYCIN FOR REPRODUCTIVE AGING
TREATMENT IN COLLABORATION WITH
THE DIRECTOR OF COLUMBIA
FERTILITY CENTER.
AND THIS IS A SMALL COHORT 15
INDIVIDUALS, HALF PLACEBO, OF
COURSE.
WHEN THE CLINICAL TRIAL SITE
BECAME LIVE WE GOT E-MAILS FROM
200 WOMEN.
THEY REALLY WANTED TO
PARTICIPATE IN THIS TRIAL.
THE STUDY DESIGN THAT WE GIVE
LOW DOSE RAPAMYCIN, 5 MILLIGRAMS
PER WEEK.
THIS IS THE DOSE PEOPLE TAKE OFF
LABEL FOR GEROPROTECTIVE EFFECT
AND FOLLOW ADDITIONALLY FOR NINE
MONTHS.
DURING THE TREATMENT THEY HAVE
TO COME TO THE CLINIC EVERY
WEEK.
SO IT'S REALLY LIMITED TO THE
GREATER NEW YORK AREA FOR THAT
REASONS.
WE RECRUITED EVERYONE AND ALMOST
AT THE END OF THE FOLLOW-UP
STUDY.
IT'S ALL BRIALINDED.
WE DON'T KNOW THE RESULTS AROUND
THERE'S NO SIDE EFFECT OR
TOXICITY AND EVEN MENSTRUAL
CYCLE IS NOT ALTERED.
IT'S VERY SAFE.
THE PRIMARY OUTCOME OF THE TRIAL
IS OVARIAN RESEARCH.
WE'RE LOOKING AT MARKERS OF
OVARIAN RESERVE.
AT THE END WE ALSO WANT TO
COLLECT MULTI-OMIC BIOMARKER FOR
POTENTIAL MECHANISTIC INSIGHTS.
AS YOU CAN SEE THIS IS PILOT
PROOF OF CONCEPT STUDY.
NOW WE ARE PLANNING
MULTI-CENTERED TRIAL ACROSS THE
U.S.
THERE ARE SEVEN CENTERS
INTERESTED IN THE STUDY.
SO WE'RE QUITE EXCITED ABOUT
THIS TRIAL.
IT FORMED OUR BASIC SCIENCE
MECHANISTIC WORK.
OBVIOUSLY THE HUMAN TRIAL HAS
ALSO LIMITATIONS.
FOR EXAMPLE, WE CANNOT GET
TISSUES INCLUDING OVARY.
SO WE SAID, OH, MICE STUDY AND
THE HUMAN TRIAL EXACTLY AND THIS
IS TWO-MONTH RAPAMYCIN TREATMENT
FOLLOWED BY TWO MONTHS AND IN
THIS CASE WE CAN DO THOROUGH
COMPREHENSIVE ANALYSIS INCLUDING
TISSUES, OVARY IN THE LIVER.
THE LIVER -- THE REASON WHY WE
TOOK LIVER WAS BY THE END, I
KNOW IT WITH THE RECENT TALK THE
EPI GEN
EPIGEN
EPIGENETICS OF LIVER IS
IMPORTANT AND WE'RE DOING
EXTENSIVE MULTI-OMIC ANALYSIS
FROM SINGLE CELL TO EPIGENETIC
PROFILING, SPATIAL
TRANSCRIPTOMICS AND EPIGENETIC
AGE BY DEMETHYLATION.
THIS IS ONE OF THE LARGEST
COLLABO
COLLABORATIVE STUDIES WE'VE DONE
IN THE LAB.
I'M VERY EXCITED ABOUT MOUSE
RAPAMYCIN TRIAL.
SO WITH THAT I WOULD LIKE TO
SUMMARIZE MY TALK.
AS I SAY, THE OVARY DOES MUCH
MORE THAN REPRODUCTION AND
INCREASES LIFE SPAN IN WOMEN AND
BY INTEGRATING HUMAN GENETIC
DATA WITH EPIGENOME MULTI-OMIC
DATA SET WE COULD PREDICT CAUSAL
VARIANTS IN GENES AND CELL TYPE
AND WE VALIDATE USING STEM CELL
ENGINEERING AND DIFFERENTIATION
MODEL TO ESTABLISH THE CAUSALITY
AND USE THEM AS A TARGET.
AND OUR SINGLE CELL
TRANSCRIPTOMIC ANALYSIS CLEARLY
SHOWED THAT OVARY IS A MODEL OF
ACCELERATED AGING.
BUT INTERESTINGLY IT PROCEEDS
TRUE THE EVOLUTIONARY CONSERVED
PATHWAY OF AGING, WHAT WE CALL
HALLMARKS OF AGING.
THIS SUGGESTS TO US THAT KNOWN
GERO PROTECTERS THAT TARGET
HALLMARKS OF AGING CAN BE USED
TO DELAY AGING IN THE OVARY.
SO TO TEST THIS HYPOTHESIS WE
HAVE INITIATED A STUDY USING
RAPAMYCIN AS A PROOF OF
PRINCIPLE.
I'M SURE THERE WILL BE MANY MORE
THERAPEUTIC AGENTS WE CAN TEST
IN THE OVARY.
SO WITH THAT, I'D LIKE TO THANK
PEOPLE IN THE LAB.
I THINK I ACKNOWLEDGED ALMOST
EVERYONE AND ALSO WONDERFUL
COLLABORATOR
COLLABORATORS WITHOUT THEM THE
WORK WOULD NOT HAVE BEEN
POSSIBLE AND FUNDING FROM NIA.
THANK YOU FOR YOUR ATTENTION.
>> THANK YOU.
QUITE A FEW QUESTIONS ONLINE BUT
IF ANYONE HAS A QUESTION HERE
YOU KNOW WHERE THE MICS ARE.
I'LL START WITH THIS ONE BECAUSE
THIS JUST CAME IN.
WHAT IS THE AGE RANGE OF THE
WOMEN IN YOUR VIBRANT STUDY AND
THIS IS CUTE, DID THE MOUSE
VERSION CORRESPOND WITH THE
HUMAN AGE RANGE?
>> YES.
THE HUMAN -- WE WENT THROUGH
MANY DIFFERENT ROUNDS.
INITIALLY WE WANTED TO TARGET
WOMEN WHO HAD DIFFICULTY
INFERTILITY BUT THAT WAS VERY
DIFFICULT TO RECRUIT AND DECIDED
TO STICK TO NORMAL HEALTHY WOMEN
IN AGE RANGE 35 TO 45.
AND MOUSE AGE SORT OF ALIGNED
WITH THE AGE RANGE.
>> GREAT TALK.
IT'S VERY INTERESTING.
THANK YOU.
SO MY QUESTION IS REPRODUCTIVE
SYSTEM IS VERY SPECIAL.
IT'S VERY IMPORTANT FOR
EVOLUTION.
OVARY IS VERY PROTECTED BUT AGE
FASTER AND CEASE TO FUNCTION AT
A SPECIFIC AGE RANGE, RIGHT.
SO IS IT POSSIBLE OVARIAN AGING
LIKE GENERAL AGING AS OTHER
SYSTEM?
IF THAT'S THE CASE, RIGHT, SO
GET GEROPROTECTOR BASED ON AGING
OF OTHER ORGANS WOULD NOT WORK,
CAN YOU COMMENT ON THAT?
>> YEAH, THAT'S A VERY
INTERESTING QUESTION.
ACTUALLY, I WAS REALLY PUZZLED
BY OUR RESULTS.
AND I WAS TRAINED IN AGING
BIOLOGY -- PROGRAMMED AGING.
>> AS IT A TOOL CANDIDATE CAN
YOU IDENTIFY FOR THE GWAS AND
OTHER AGING GENES, RIGHT.
IT MAKES ME THINK THE
POSSIBILITY.
>> SO, I CALLED UP A COUPLE
EVOLUTIONARY BIOLOGISTS AND IS
IT REALLY PROGRAMMED?
TO ME IT LOOKS LIKE IT.
AND OF COURSE THERE'S NO CLEAR
ANSWER.
BUT I THINK IT'S POSSIBLE.
THERE ARE HYPOTHESIS WHY HUMANS
HAVE MENOPAUSE AND OVARIAN AGES
SO MUCH RAPIDLY AND THIS IS
SOMETHING I WOULD LEAVE TO
EVOLUTIONARY BIOLOGISTS BUT ONE
THING I'D LIKE TO SAY IS WHEN
YOU'RE AGING PROCESS IS SO
COMPRESSED IN A RAPIDLY AGING
ORGAN LIKE OVARY -- YOU SEE THIS
ENORMOUS COORDINATION AS IF
THERE'S A SIGNAL COMING SAYING,
LET'S AGE NOW.
AND THEN YOU GO THROUGH VERY
RAPIDLY.
SO I THINK WHEN WE ARE TALKING
ABOUT TRANSLATION OF GE
GEROTHERAPEUTICS WE DON'T HAVE A
GOOD WAY FORWARD -- RAPID, I'M
SORRY.
I THINK THE OVARY COULD BE A
GOOD EXAMPLE AND IF RAPAMYCIN WE
CAN USE THE OVARY AS A RAPID
TEST SYSTEM TO TEST
GEROTHERAPEUTICS.
>> THANK YOU.
>> SO, IT'S REALLY FASCINATING
STUDIES ESPECIALLY THE
CONNECTION LINKED TO ENCODING OF
THE GENE EXPRESSIONS.
SO MY QUESTION IS SIMPLE.
TWO QUESTIONS.
SO ONE IS PROBABLY THE
REGULATING GENE ITSELF IS NOT
SPECIFICALLY EXPRESSED IN THE
OVARY.
PROBABLY LIKE THE HELB OR THE
NBR1 AND EXPRESSED AND ONE
QUESTION IS THE WHAT YOU
DISCOVERED CLUSTERED IN THE
SYSTEMS OR CLUSTERS TO THE
IDENTIFIED GENE IS REGULATED IN
PATHWAYS.
THAT'S MY FIRST QUESTION.
THE SECOND QUESTION IS JUST
LINKED TO THE PREVIOUS MENTION
THE GENE IS PROBABLY NOT JUST
EXPRESSED IN OVARY BUT ALSO
OTHER TISSUES.
SO WITH THE OTHER LIVER OR
MUSCLE, THE GENE EXPRESSION
CHANGES ALSO HAS A BENEFICIAL
FOR THE FITNESS OF THE SPECIFIC
TISSUES RATHER THAN THE OVARIES.
>> YEAH, TWO VERY IMPORTANT
QUESTION.
SO THE FIRST QUESTION SO WHEN
THIS MENOPAUSE GWAS CAME OUT, IT
WAS A BIG SURPRISE BECAUSE WHEN
WE LOOK AT THE POTENTIAL CAUSAL
GENES THERE ARE REALLY
SIGNIFICANT ENRICHED IN DNA
DAMAGE RESPONSE AND REPAIR.
WHICH, PERSONALLY I HAVE NEVER
SEEN.
THIS IS THE ONLY TRAIT THAT SO
DRAMATICALLY SHOW ENRICHMENT OF
THE MAJOR GENOME STABILITY
MECHANISM.
SO I THINK BUT THEY'RE NOT
CLUSTERED.
THEY'RE ALL OVER THE GENOME.
SOMEHOW THERE'S SOME SELECTION
GOING ON DURING AGING PROCESSES
IN THE OVARY THAT ARE OVER
REPRESENTED IN THE GWAS.
THAT'S NUMBER ONE.
NUMBER TWO, ABOUT THE
IMPLICATION.
>> NOT ONLY FOR THE OVARY BUT
OTHER TISSUES MIGHT BE AFFECTED
BY THE CHANGE OF GENE
EXPRESSION.
>> I DIDN'T MENTION -- I FORGOT.
THANK YOU FOR BRINGING THAT UP.
WE STARTED WITH THE GRANULOSA
CELLS.
THE CRISPR SCREEN AND IDENTIFIED
TARGET GENES AND VARIANTS.
WE EXPECT TO SEE THE GLOBAL
VARIANTS AND CELL TYPE SPECIFIC
VARIANT IN GENES.
MUST BE, RIGHT?
SO THIS SOMETHING WE TRIED TO
TEASE OUT.
ALL THE PREDICTIONS THROUGH THE
INTEGRATION SIGNALS AGAIN IT'S A
PREDICTION.
WE REALLY DON'T KNOW IF THIS IS
REALLY HAPPENING IN THE OVARY
AND CELL TYPE.
THAT'S SOMETHING THAT WE'RE
GOING AFTER.
SO, MY PREDICTION, YES, IT WILL
HAVE GLOBAL INFLUENCE BUT WE'LL
ALSO FIND CELL TYPE SPECIFIC
VARIANTS ESPECIALLY FOLLICULAR
CELLS LIKE GRANULOSA CELLS.
>> THANK YOU.
>> VERY NICE TALK.
I HAVE TWO QUESTIONS.
FIRST IS THE SYNCHRONIZATION
ACROSS THE CELL TYPE TO THE
OVARY IS PARTICULAR BECAUSE WHEN
YOU WANT TO TEST THE AGING OF
THE ISSUE IT TYPICALLY FIND
DIFFERENT MARKERS.
HAVE YOU CHECKED OTHER AGING
MARKERS IN THE CELL TYPES AND DO
YOU HAVE SOMETHING TO COMMENT
ABOUT WHY DO YOU THINK YOU HAVE
THIS SYNCHRONY AMONG THE CELLS?
>> THAT'S A VERY INTERESTING
QUESTION.
AGAIN, AS I SAID TO MAX'S
QUESTION, AS IF SOMETHING IS
VERY EXPRESSED AND THE SIGNAL
MAKES AGE VERY FAST.
WE DON'T KNOW.
SOME OTHER MARKERS WE LOOK ARE
PURATIVE CELL SENESCENCE
MARKERS.
WE SAW P21 EXPRESSION LEVEL
INCREASED QUITE SIGNIFICANTLY
WITH AGE IN THIS SETTING.
AND WE SEE SOME SYNCHRONY
CLEARLY SENESCENCE IS ONE OF
THEM.
I THINK THERE'S MORE DISCOVERED.
>> AND FOR GALS LISTENING, HOW
EARLY IS EARLY MENOPAUSE?
>> EARLY MENOPAUSE?
I THINK AGE 40 IS EXTREME EARLY
MENOPAUSE.
45, EARLY AND THEN 50, 51 IS
NORMAL RANGE.
>> OKAY.
LET ME SNEAK IN ONE QUESTION
FROM ONLINE.
GREAT TALK, EXPLANATION MARK.
IN THE UNDERLYING DNA SEQUENCES
HARBORING THE OVARY AGING
ASSOCIATED VARIANTS, HAVE YOU
FOUND AN ENRICHMENT OF CERTAIN
TF BINDING MOTIFS.
THESE TFs MAY BE CANDIDATED FOR
MEDIATING THE CHANGE OF THE
CAUSAL GENE EXPRESSION.
>> WE DID.
YES.
IT'S PUBLISHED.
IT'S IN OUR NATURE AGING PAPER
WHICH JUST CAME OUT.
CVP DELTA.
WE THINK IT'S A MASTER REGULATOR
OF OVARIAN AGING ACROSS
DIFFERENT CELL TYPES.
THAT'S QUITE STRIKING ACTUALLY.
DUE TO THE INTEREST OF TIME I
DIDN'T TALK ABOUT IT BUT THE
AUDIENCE CAN FIND THE PAPER.
IT'S VERY INTERESTING.
>> SO, MY QUESTION IS ON THE IPS
CELLS.
DIFFERENTIATED INTO OVARIAN CELL
TYPES.
I'M TRYING TO CHALLENGE AN
INITIATIVE ON MICROPHYSIOLOGY
SYSTEM.
I'M THINKING FOR DEVELOPING AND
USING OVARY AS A TESTING
PLATFORM FOR GEROTHERAPEUTICS,
WOULDN'T IT BE NICE IF YOU COULD
BUILD SOME SMALL MICROPHYSIOLOGY
SYSTEMS.
>> PLEASE SIGN ME IN.
WE CAN PROVIDE OVARIAN CELL
TYPES.
IT TOOK US A WHILE TO ESTABLISH
DIFFERENTIATION BUT YES, PLEASE.
THERE'S A POSTDOC THAT DEVELOPED
ORGANOIDS.
WE'RE NOW TRYING TO DEVELOP
HUMAN ORGANOIDS BY ADDING CELL
TYPES.
THAT WOULD BE REALLY COOL.
>> THAT WAS MY QUESTION.
ARE YOU WORKING ON THE ORGANOIDS
OR ARE YOU THINKING TO LITERALLY
ENGINEER THREE DIMENSIONAL
MODELS?
>> THAT WAS A POSTDOCTORAL AWARD
APPLICATION.
SO WE ARE USING ORGANOIDS FIRST.
>> OKAY.
TO SCREEN KNOWN NEUROPROTECTERS
AND PRIORITIZE AND THEN GO.
THAT WAS THE WHOLE PLAN.
>> THANK YOU.
>> A QUESTION ABOUT THE
RAPAMYCIN STUDY.
PRESUMABLY IN PREPARATION YOU
DID SURVEY THE PUBLISHED
CLINICAL LITERATURE ON USE OF
RAPAMYCIN.
WAS THERE SUFFICIENT DATA THERE
TO BE ABLE TO LOOK TO SEE FROM
THE NATURAL HISTORY MEDICAL
RECORDS INVOLVED IN THOSE
STUDIES WHETHER THERE WAS HINT
OR CLUE OF AFFECTS OF MENOPAUSE
?
>> WE TRIED HARD TO FIND
INFORMATION BUT THUS FAR THE
RAPAMYCIN TAKERS ARE OLDER
INDIVIDUALS MOSTLY 60 PLUS.
WE COULD FIND ONE WOMAN 50.
YOUNGER WOMEN ARE IN TRIAL.
NO ONE SUFFERED FROM ANYTHING
NOT EVEN MOUTH SORE.
MAYBE BECAUSE YOUNG PEOPLE ARE
MORE RESILIENT.
>> MAYBE I CAN SNEAK IN ONE MORE
QUESTION.
WHAT HAPPENS WHEN YOUR OVARIES
ARE SURGICALLY REMOVED?
>> I HAD A SLIDE MAYBE THE
PERSON MISSED IT.
IF YOU SURGICALLY REMOVE OVARY,
THIS IS SURGICALLY INDUCED
MENOPAUSE, IT'S NOT GOOD AND
THEY HAVE A SHORTER LIFE SPAN
AND HAVE A HIGHER RISK FOR
AGE-RELATED DISEASES.
NOWADAYS AT THE TIME OF
HYSTERECTOMY THEY TRY TO SAVE
THE OVARY BECAUSE IF YOU
CONSERVE OVARY, THEY TEND TO
LIVE LONGER AND SUFFER LESS WITH
AGE-RELATED DISEASE COMPARED TO
COMPLETELY OVA ECTOMIZED WOMEN.
>> MY QUESTION IS RELATED TO
PREVIOUS QUESTIONS.
FOR THOSE AS YOU MENTIONED,
THOSE ALSO HAVE THE OVARY
REMOVED HAVE A LONGER REDUCED
MORTALITY.
DOES TREATMENT WITH THE
GEROPROTECTERS HELP REDUCE THEIR
MORTALITY?
>> NO ONE HAS EVER TESTED BUT
THAT'S A VERY GOOD WAY TO START.
SO WE'VE BEEN THINKING A LOT
ABOUT HOW TO EXPAND OUR VIBRANT
STUDIES.
NOW WE START WITH YOUNG HEALTHY
WOMEN BUT WOMEN WITH DIFFICULTY
GETTING PREGNANT OR OVARIAN
INSUFFICIENCY WILL HAVE
IMMEDIATE BENEFIT IF IT WORKS.
WE'VE BEEN TALKING ABOUT THIS
WITH POI PATIENTS.
>> I'M SURE THERE'S AN OBVIOUS
ANSWER TO THIS BUT THE NEGATIVE
EFFECTS OF SURGICAL REMOVAL
DESPITE EFFORTS OF HORMONE
REPLACEMENT, DO YOU HAVE ANY
IDEA WHAT THE SYSTEMIC EFFECTS
ARE BEYOND THE MEASURABLE HOE
MOAN CHANGES?
>> -- HORMONE CHANGES.
>> I CAN TELL YOU TWO STORIES.
NUMBER ONE, BASED ON OUR STUDY,
I MEAN ACROSS ALL THE CELL TYPES
IN THE OVARY, IT'S NOT JUST
STROMAL CELLS AND EVERYONE SHOWS
THE SAME.
THE OVARY INTERACTED WITH THE
SOMA AND INFLUENCE EACH OTHER.
YOU CAN REJUVENATE OLD LOCI WITH
A YOUNGER ONE AND A GROUP IN
SINGAPORE RECONSTITUTE THE OLD
WITH THE YOUNG FOLLICLES AND
SHOW THEY REGENERATE.
IF YOU REPLACE OLD OVARY WITH
YOUNG OVARY IT'S BENEFICIAL.
THOUGH THE SAMPLE SIZE WAS TOO
LITTLE.
I CANNOT MAKE CONCLUSION OF IT
BUT THE EFFECT WAS DRAMATIC.
BEFORE TRANSPLANTATION, THEY
REMOVED FOLLICLES THAT PRODUCE
HORMONE.
THERE'S A CHEMICAL THAT REMOVES
FOLLICLES.
NOW YOU HAVE A YOUNG OVARY
WITHOUT HORMONE WAS ENOUGH TO
EXTEND THE LIFE SPAN.
LOOKS EVEN BETTER.
THE COMPARTMENT HAVE LONGEVITY
EFFECTS.
AND SOMA DOES A LOT TO THE
HEALTH OF THE OVARY.
>> OKAY.
I'M GOING TO REPEAT OUR CME
CODE, 57685.
REMIND PEOPLE THERE'S A
RECEPTION JUST OUTSIDE THE DOORS
HERE AND MAYBE THANK OUR SPEAKER
ONE MORE TIME.
>> THANK YOU SO MUCH.