GOOD AFTERNOON, WELCOME TO THE
AUDITORIUM
STEVE HORVATH GOT A PH.D. IN
MATHEMATICS,
AND HE REMAINED A MATHEMATICIAN
AND IN FACT, THE WAY HE
APPROACHED THE PROBLEM, HE WAS
NOT HAPPY ABOUT IT, SO HE ALSO
DECIDED THAT HE NEEDED A PH.D.
IN BIOSTATISTICS, AND HE GOT THE
BIOSTATISTICS PH.D. AT HARVARD,
WHERE HE WORKED ON FAMILY
STUDIES AND REALLY DEVELOPED
SOFTWARE THAT IS USED FOR
LINKAGE NOWADAYS.
HIS CLAIM TO FAME IS THE
DEVELOPMENT OF THE EPIGENETIC
CLOCK.
AND I WILL TAKE TWO MINUTES TO
DIVERSION.
MANY YEARS AGO, IN THE 80s,
WHEN I WAS STARTING TO COME AT
NIH, VISITING FROM ITALY, I
REMEMBER IN AN AFTERNOON I HAD A
MEETING WITH ANDREA -- ONE OF
THE PRINCIPAL INVESTIGATORS OF
THE WOMEN'S HEALTH INITIATIVE.
WE WERE DISCUSSING ABOUT THE
DREAMS FOR SOMEBODY WAS WORKING
ON THE AGING FIELD, AND WHAT SHE
WAS TELLING ME IS THAT WHAT WE
REALLY NEED IS THE ROBUST MY BYE
OWE MARKER OF BIOLOGICAL AGING
THAT WE COULD USE TO UNDERSTAND
WHY SOME PEOPLE TEND TO LOOK
LIKE THEY'RE AGING FASTER AND
SOME PEOPLE LOOK LIKE
THEY'RE AGING SLOWER
SLOWER.
 -- AS CLOSE AS WE ARE NOW TO
THAT DREAM, AND YOU WILL SEE
THAT TSH USING METHYLATION DATA
A BIOMARKER THAT AAPPROXIMATES
AGE VERY, VERY CLOSELY.
ALSO INDEPENDENT OF AGE, IS ABLE
TO PREDICT MORTALITY AND OTHER
HEALTH OUTCOMES.
I DON'T WANT TO STEAL MORE OF
HIS IDEAS AND RESULTS, BUTLY
JUST CONCLUDE TO SAY THAT WE
WORK TOGETHER ON SOME PROJECTS,
IT'S ALWAYS AN INCREDIBLE
PLEASURE TO DISCUSS WITH HIM,
HE'S VERY, VERY OPEN TO
DISCUSSION AND TO, YOU KNOW,
ADDRESS QUESTIONS, SO GIVEN
THESE PREMISES, PLEASE HELP ME
IN WELCOMING STEVEN HORVATH TO
OUR WEDNESDAY AFTERNOON LECTURE.
>> THANK YOU, LUIGI, FOR THE
VERY KIND AND GENEROUS
INTRODUCTION.
I ALSO WANT TO THANK DR. HODES
AND FRANCIS COLLINS FOR INVITING
ME.
IT'S A TREMENDOUS PRIVILEGE TO
STABBED IN FRONT OSTAND IN FRONT
OF YOU AN
D TO
DESCRIBE SOME OF THE LATEST WORK
WHICH I SUM UP BY THE EPIGENETIC
CLOCK.
AND WITHOUT GIVING YOU MUCH
DETAILS, THESE FIGURES
ILLUSTRATE PROPERTIES OF THE
CLOCK.
ON THE RIGHT-HAND SIDE, YOU
CEELSEELEONARDO DAVINCI THAT
DEPICT THE
PHYSICAL DIMENSIONS OF THE HUMAN
BODY.
NOW WE AIM TO DEVELOP CLOCKS
THAT ADD A TIME ACCESS TO THE
HUMAN BODY THAT TELL US WHAT
SHOULD BE THE AGE OF THE HEART
OF A 40-YEAR-OLD, OR WHAT SHOULD
BE THE AGE OF THE BREAST OF A
40-YEAR-OLD?
SO THIS EPIGENETIC CLOCK APPLIES
TO ALL TISSUES, ORGANS AND CELLS
THAT CONTAIN DNA.
WITH THE EXCEPTION OF SPERM.
AND ALTHOUGH IT'S BASED ON
METHYLATION LEVELS, THAT IN
PRINCIPLE COMPRISE HUNDREDS IF
NOT MILLIONS OF VARIABLES, THE
OUTPUT OF THE METHOD IS A
NUMBER, AN INTUITIVE NUMBER,
WHICH IS JUST THE AGE.
SO FOR EXAMPLE, FOR A MIDDLE
AGED MAN, I COULD SAY HIS HEART
IS 50 YEARS OLD, HIS LUNG IS 30
YEARS OLD AND SO ON.
THE LEFT PANEL SHOWS ANOTHER
PROPERTY OF THE EPIGENETIC CLOCK
WHICH IS THAT IT APPLIES TO THE
WHOLE LIFESPAN.
HERE I TALK, OF COURSE, TO AN
AUDIENCE OF AGING RESEARCHER,
HOWEVER, BE AWARE OF IT THAT THE
EPIGENETIC CLOCK ALSO APPLIES TO
DEVELOPMENT.
IT APPLIES TO PRENATAL SAMPLES.
HERE'S MY ONE MINUTE PITCH WHY
AGING RESEARCH MATTERS.
SO THIS IS AN ARTICLE FROM DANA
GOLDMAN AND JAY OLSHANSKI,  WHO
CALCULATED THAT IF WE CAN SLOW
DOWN BIOLOGICAL AGING BY AS
LITTLE AS 20%, THE U.S. WILL
SAVE $3 TRILLION IN MAJOR
ENTITLEMENT SPENDING OVER THE
NEXT 50 YEARS.
HUGE BENEFIT, IF WE CAN JUST
TWEAK THE AGING A LITTLE BIT.
COMPARE THAT TO DELAYING THE ON
SEPTEMBEONSET OF CANCER, WHICH
IS THE
BLUE CURVE.
AGAIN, A VERY WORTHWHILE GOAL,
BUT IF WE DELAY THE ONSET OF
CANCER BY 20%, WE ONLY SAVE LESS
THAN $5 BILLION.  SO THERE ARE
TREMENDOUS BENEFITS TO BE HAD IF
WE CAN SLOW BIOLOGICAL AGING.
NOW THERE IS GOOD NEWS.
IN PRINCIPLE, IT'S FAIRLY
STRAIGHTFORWARD TO FIND
INTERVENTIONS THAT SLOW HUMAN
AGING IF YOU HAVE A BIOMARKER.
SO HERE'S MY THREE-STEP APPROACH
FOR FINDING INTERVENTION FOR
HUMAN SUBJECTS.
STEP 1, DEVELOP A BIOMARKER OF
BIOLOGICAL AGE.
THAT'S, OF COURSE, THE TOPIC OF
THIS TALK.
STEP NUMBER 2, FIND
INTERVENTIONS THAT AFFECT THE
BIOMARKER, FOR EXAMPLE, IN A
DISH OR IN A MODEL.
AND WE CAN BRING TO BEAR ALL THE
THE -- -- IN STEP THREE, OF
COURSE, WE NEED TO CON DCT HUMAN
CLINICAL TRIALS.
AND AGAIN, IF YOU HAVE A
SUITABLE BIOMARKER THAT CAN BE
USED AT THE SURROGATE OUTCOME OF
AGING, YOU CAN SAVE
TREMENDOUSLY.
BECAUSE INSTEAD OF SHOWING THAT
AN INTERVENTION REDUCES
MORTALITY, AND YOU WOULD NEED TO
SHOW IT BY FOLLOWING PEOPLE FOR
MAYBE 10, 20 YEARS, IF INSTEAD
YOU CAN SAY THAT AN INTERVENTION
MOVES ITS BIOMARKER IN THESE
SUBJECTS, THEN POSSIBLY YOU CAN
SPEED THROUGH THE RECOVERY
PROCESS.
SO THERE IS OF COURSE A MAJOR
CHALLENGE, HOW DO WE DEFINE A
BIOMARKER OF BIOLOGICAL AGE?
AND THAT'S A CHALLENGING PROBLEM
FOR MANY REASONS, BUT ONE IS
THAT THERE'S NO CLEAR DEFINITION
OF WHAT IS BIOLOGICAL AGE.
SEEMINGLY EVERYBODY HAS THEIR
OWN DEFINITION.
AS A FORMER STATISTICIAN, I
WOULD CALL BIOLOGICAL AGE A LAY
AT THE PRESENT TIME VARIABLE.
THAT IS NOT WELL-DEFINED AND
THAT HAS TO BE DEFINED THROUGH
INDICES.
AND OF COURSE INTUITIVELY,
THERE'S ONE PROPERTY ABOUT
BIOLOGICAL AGE THAT WE CAN
REALLY LEVERAGE, AND THAT IS
BIOLOGICAL AGE WILL BE HIGHLY
CORRELATED WITH CHRONOLOGIC AGE.
AND WHY DO I KNOW IT?
WELL, BECAUSE THE WHOLE
INSURANCE INDUSTRY IS BUILT ON
THAT CONCEPT.
THE OLDER YOU ARE, THE HIGHER
YOUR PREMIUM.
AND SO, THEREFORE, TO THEN FIND
BIOMARKERS OF BIOLOGICAL AGE,
ONE CAN FOLLOW THIS PATH.
FIRST, YOU FIND MOLECULAR
BIOMARKERS THAT STRONGLY
CORRELATE WITH CHRONOLOGICAL
AGE.
AND YOU USE CHRONOLOGIC AGE
REALLY AS A PROXY OF BIOLOGICAL
AGE.
ONCE YOU HAVE THESE BIOMARKERS,
THEN YOU VALIDATE THEM IN
VARIOUS COHORT STUDIES TO SHOW
THAT THEY PREDICT OR RELATE TO
MANY AGE-RELATED PHENOTYPES.
SO I TALKED ABOUT BIOMARKERS OF
AGING, BUT YOU REMEMBER THAT I
ALSO TALK ABOUT THE EPIGENETIC
CLOCK, SO WHAT IS A CLOCK?
I HAVE A PERSONAL DEFINITION.
I CALL SOMETHING AN AGING CLAK
IF IT'S AN EXTREMELY ACCURATE
BIOMARC OF AGING.
FOR EXAMPLE, GRAY HAIR WOULD NOT
BE CALLED AN AGING CLOCK, IT'S
SIMPLY NOT ACCURATE ENOUGH.
HOWEVER, IN MY PERSONAL
DEFINITION, IF YOU HAVE AN
ESTIMATOR OF AGE THAT HAS A
CORRELATION OF .8, WITH THE TRUE
KROCHRONOLOGIC AGE IN SUBJECTS
THAT
ARE AGED BETWEEN ZERO AND 100,
IF THAT CAN BE ACHIEVED, I FEEL
COMFORTABLE THAT YOU CALL IT AN
AGING CLOCK.
IT'S WHY A CLOCK IS SIMPLY VERY
ACCURATE.
AND I DO WANT TO MENTION THAT
IT'S ABSOLUTELY CRITICAL TO
VALIDATE ALL CLAIMS AND
INDEPENDENT DATASETS, BECAUSE
IT'S VERY EASY TO COME UP WITH A
MULTIVARIATE MODEL IN ONE
TRAINING SET THAT IS VERY
ACCURATE, BUT IT SIMPLY DOESN'T
VALIDATE AN INDEPENDENT DATA.
SO IN PRINCIPLE, I'M COMING BACK
TO DEVELOPING BIOMARKERS OF
AGING.
WE HAVE WONDERFUL CANDIDATE
AGING CLOCK.
CLEARLY TELOMERE LENGTH MEASURES
A LOT IN HEALTH AND DISEASE.
THEN, OF COURSE, TRANSCRYPTOMIC
DATA, AND THE FOURTH TYPE, THE
DNA METHYLATION DATA OR
EPIGENETIC DATA ARE THE FOCUS OF
THIS TALK.
THE TRUTH IS I'M NOT AWARE OF
ANY BIOMARKER THAT MEETS MY
STRINGENT DEFINITION OF AN AGING
CLOCK APART FROM
METHYLATION-BASED BIOMARKERS,
AND THERE ARE SEVERAL OUT THERE.
SO LESS THAN THREE YEARS AGO, I
PUBLISHED A MULTI-TISSUE
BIOMARKER OF AGING, WHICH IS
BASED ON DNA METHYLATION LEVELS.
TOE TIME WHEN AT THE TIME I
PUBLISHED IT, 
IT
WAS NOT CLEAR WHETHER THIS
ACTUALLY CAPTURES BIOLOGICAL
AGE.
THE TALK TODAY IS VERY MUCH
ABOUT SHOWING THE PROPERTIES OF
THIS MULTI-TISSUE PREDICTER.
SO BEFORE I GO THERE, LET ME
REMIND YOU THAT WHAT IS DNA
METHYLATION?
SO DNA METHYLATION IS REALLY AN
EPIGENETIC MODIFICATION OF THE
DNA.
IT'S AN ADDITIONA AN ADDITION OF
THE METHY
L
GROUP OF ALL OF MY RESULTS WERE
BASED ON THE ILLUMINA ARRAY, THE
EPIGENETIC CLOCK IS ACTUALLY
PLATFORM INDEPENDENT.
YOU CAN APPLY IT TO THE LATEST
PLATFORM, THE EPIC CHIP, YOU CAN
APLAY TO THE OLDER PLATFORM, THE
INFINIUM 4050K AND THE
INFINIUM27K RATE.
THESE MARKERS ARE CALLED CPGs.
AND FOR EACH CPG, YOU GET A
NUMBER BETWEEN ZERO AND 1, AND
THIS NUMBER ROUGHLY CORRESPONDS
TO THE PROPORTIONAL CHROMOSOMES
THAT ARE METHYLATED AT THIS
LOCATION.
SO TO DEVELOP THE EPIGENETIC
CLOCK, I DOWNLOADED 82 PUBLICLY
AVAILABLE DNA METHYLATION
DATASETS THAT HAD BEEN DEPOSITED
IN GENE EXPRESSION OMNIBUS IN
THE CANCER GENOME AT LAS AND
OTHER VARIOUS DATA REPOSITORIES.
THEY WERE ALL IN REPOSITORIES
THAT WERE FUNDED SO PEOPLE WHO
WANTED TO PROVIDE OPEN ACCESS
AND COMPLETELY FREE ACCESS TO
THE DATA.
IN THE MANY OF THE DATASETS, THE
INVESTIGATORS WERE SO KIND TO
INCLUDE CLINICAL VARIABLES AND
DEMOGRAPHIC VARIABLES SUCH AS
CHRONIC LOGIC AGE.
SO YOU RETBRES A TRANSFORMED
VERSION OF CHRONOLOGIC AGE ON
ALL THE CPGs, AND YOU CAN USE
WHAT IS KNOWN AS AN ELASTIC NET
REGRESSION MODEL, AND THIS MODEL
AUTOMATICALLY TAKES THE BEST
COVARIANTS, THE BEST CPGs, FOR
PREDICTING THE OUTCOME.
AND THE RESULTING EPIGENETIC
CLOCK METHOD IS RATHER
STRAIGHTFORWARD.
SO YOU CAN IMPLEMENT IT IN THREE
STEPS.
FIRST, YOU WANT TO MEASURE THE
METHYLATION LEVELS OF 353
CPGs.
IN STEP NUMBER TWO, YOU FORM A
WEIGHTED AVERAGE OF THE CPG, AND
YOU GET A SINGLE NUMBER.
BUT THIS NUMBER IS NOT YET IN
UNITS OF YEARS.
SO NEXT, WE TRANSFORM THIS
NUMBER SO THAT IS AS THE UNIT
APPEARS, AND THE RESULT IS THEN
LITERALLY AN AGE ESTIMATE, A
NUMBER, AND THAT AGE ESTIMATE IS
IT REFERRED TO AS EPIGENETIC
AGE, SO FOR EXAMPLE, OR THE DNA
METHYLATION AGE.
SO WHAT MAKES THIS ALGORITHM SO
NOTEWORTHY IS THAT IT IS THE
IDENTICAL ALGORITHM FOR EVERY
TISSUE AND CELL TYPE.
NOWHERE DO I INPUT NOW YOU'RE
DEALING WITH BLOOD, NOW YOU'RE
DEALING WITH BRAIN TISSUE.
IT JUST RECOGNIZES IT
AUTOMATICALLY, AND THAT'S THE
SURPRISING THING.
IT'S SURPRISING BECAUSE CELL
TYPES HAVE VERY DIFFERENT
METHYLATION PATTERN.
A BLOOD CELL IS COMPLETELY
DIFFERENT FROM A NEURON WHEN YOU
LOOK AT METHYLATION LEVELS.
HOWEVER, THERE IS SOMETHING
INTRINSIC THAT'S REALLY
PRESERVED ACROSS ALL TISSUES AND
CELL TYPES.
SO LET ME GO BACK, SO REMEMBER
IN STEP NUMBER 2 OF THIS
ALGORITHM, YOU GET A WEIGHTED
AVERAGE.
IT'S A WEIGHTED AVERAGE OF THE
353 CPGs.
AND I WILL SHOW HOW THIS
WEIGHTED AVERAGE DEPENDS ON
CHRONOLOGIC AGE.
SO HERE THE Y AXIS SHOWS THE
WEIGHTED AVERAGE AND WHAT DO WE
SEE?
EACH IS A HUMAN SUBJECT.  SO
WHAT WE SEE IS THAT BETWEEN AGE
ZERO AND 20, THERE'S A SHARP
INCREASE IN THIS WEIGHTED
AVERAGE, AND AFTER AGE 20,
THERE'S AN ALMOST LINEAR
RELATIONSHIP.
AND SO I INTERPRET THIS BEHAVIOR
THEN AS SAYING THAT THE
EPIGENETIC CLOCK TAKES VERY
QUICKLY AS THE ORGANISM GROW,
BUT AFTER AGE 20, WHEN YOU'VE
REACHED ADULTHOOD, IT STARTS TO
TAKE ON A CONSTANT LEVEL.
SO THE EPIGENETIC CLOCK IS
EXTREMELY ACCURATE, AS ONE CAN
SEE FROM THE EVALUATIONS AND
TEST DATASETS, SO THE UPPER LEFT
PANEL SHOWS HOW CHRONOLOGIC AGE
CORRELATES WITH METHYLATION AGE
IN INDEPENDENT TEST DATA, AND
THERE THE CORRELATION IS .96.
THE OTHER PANELS REPORT FIND NGS
DIFFERENT TISSUE TYPES.
IN THE MIDDLE PANEL, IN PANEL H,
YOU SEE THE EXAMPLE OF BREAST
TISSUE, AND THE BLACK SOLID LINE
SHOWS THE AXIS Y EQUALS X, WHICH
INDICATES PERFECT CALIBRATION.
AND WHAT WE SEE IS THERE'S A
SYSTEMATIC SHIFT, SO THE CLOCK
ALWAYS OVERESTIMATES THE AGE OF
BREAST TISSUE.
AND LET'S MAKE A NOTE OF IT,
BECAUSE IT MIGHT SUGGEST THEN
THAT POSSIBLY FEMALE BREAST
TISSUE IS OLDER THAN THE REST OF
THE BODY.
THAT'S ONE INTERPRETATION.
ANOTHER INTERPRETATION IS THE
CLOCK SIMPLY ISN'T WELL
CALIBRATED HERE.
SO IN THIS APPLICATION, I
ANALYZED CADAVER, A FEMALE
CADAVER AND THE MALE CADAVER,
AND THE EPIGENETIC AGES OF
DIFFERENT BODY PARTS, AND THE
ONE BODY PART THAT AGAIN DIDN'T
FIT THE MOLD WAS THE FEMALE
BREAST TISSUE.
HERE IT HAD AN AGE ESTIMATE OF
67 YEARS, WHEREAS THE REST OF
THE BODY HAD AN AVERAGE AGE OF
44.
THAT'S, OF COURSE, JUST AN
ANECDOTE.
SO RECENTLY, WE REVISITED THAT
QUESTION ABOUT THE AGE OF BREAST
TISSUE, USING HEALTHY FEMALE
BREAST TISSUE SAMPLES FROM THE
KOMEN TISSUE BANK, AND FROM THE
VERY SAME WOMEN, WE ALSO HAD
BLOOD SAMPLES COLLECTED ON THE
VERY SAME DAY.
AND THE UPPER LEFT PANEL SHOWS
HOW METHYLATION AGE ON THE Y
AXIS RELATES TO CHRONOLOGIC AGE,
AND YOU SEE THE RED DOTS ARE
ALWAYS ABOVE THE BLACK DOTS, AND
THE BLACK DOTS ARE BLOOD -- WE
SEE BREAST TISSUE IS ALWAYS
OLDER THAN THE BLOOD TISSUE FROM
THE SAME WOMAN, WHICH IN CERTAIN
WAYS VALIDATES THIS FINDING.
SO TO ME, THAT'S INTERESTING
BECAUSE IT PROBABLY TEACHES ME
SOMETHING ABOUT THE EPIGENETIC
CLOCK.
I THINK HORMONE EXPOSURE SOMEHOW
RELATES TO EPIGENETIC AGING.
I WANT TO MOVE TO ANOTHER
APPLICATION WHERE WE ANALYZED
THE EFFECT OF OBESITY ON VARIOUS
HUMAN TISSUES.
THE UPPER PANEL SHOW THE
ACCURACY OF THE CLOCK IN LIVER
TISSUE SAMPLES, ADIPOSE TISSUE
SAMPLES, MUSCLE TISSUE SAMPLES
AND BLOOD SAMPLES.
AND YOU NOTICE I PUT A
REGRESSION LINE THROUGH THESE
POINTS.
AND LET'S THINK ABOUT THE
INTERPRETATION.
IF THERE'S A LIVER SAMPLE THAT
LIES ABOVE THE REGRESSION LINE,
THEN IT'S ESTIMATED TO BE OLDER
THAN IT SHOULD BE, AND IF THE
SAMPLE IS BELOW THE LINE, THEN
IT'S ESTIMATED TO BE YOUNGER
THAN IT SHOULD BE.
SO THE RESIDUALS OR THE DELTAS
TO THE REGRESSION LINE CAN BE
USED TO DEFINE A MEASURE OF WHAT
I CALL AGE ACCELERATION.
IF IT'S POSITIVE, YOUR LIVER IS
OLDER, IF IT'S NEGATIVE, IT'S
YOUNGER THAN IT SHOULD BE.
SO THIS MEASURE OF EPIGENETIC
AGE ACCELERATION CAN THEN BE
CORRELATED TO BODY MASS INDEX,
AND THAT'S DONE IN THE LOWER
PANEL.
AND WHAT DO WE SEE?
WE SEE A STRIKING CORRELATION IN
LIVER TISSUE, CORRELATION .42.
WHICH BY THE WAY HAS BEEN
VALIDATED IN INDEPENDENT DATA.
SO THE HIGHER YOUR BMI, THE
OLDER THE AGE OF YOUR LIVER.
IN CONTRAST, WE DON'T SEE SUCH A
DIFFERENCE IN ADIPOSE TISSUE, --
OR BLOOD.
THAT ALREADY TEACHES US
SOMETHING.
STRESS FACTORS THAT AI AGE YOU
PROBABLY WILL AGE NEW  YOU IN A
TISSUE-SPECIFIC MANNER.
WE REVISITED THIS USING MUCH
LARGER DATA FROM THE WOMEN'S
HEALTH INITIATIVE, AND BY NOW WE
DO SEE A CORRELATION BETWEEN
BODY MASS INDEX AND AGE
ACCELERATION IN BLOOD TISSUE,
BUT THE CORRELATION IS ONLY .1.
SO THE BIG QUESTION IS, OF
COURSE, DOES THE EPIGENETIC
CLOCK RELATE TO BIOLOGICAL AGE?
AGAIN, IT'S HARD TO DEFINE
BIOLOGIC AGE, BUT I THINK MOST
PEOPLE WOULD AGREE WITH THE
ROUGH BIOLOGIC DEFINITION OF
AGE, WHICH IS THAT WHATEVER
ESTIMATES YOU HAVE, IT SHOULD
PREDICT ALL-CAUSE MORTALITY,
EVEN AFTER YOU ADJUST FOR
CHRONOLOGIC AGE AND MANY OTHER
COVARIANTS.
THE SECOND CRITERION IS IT
SHOULD PROBABLY BE DECREASED IN
THE OFFSPRING OF CENTENARIANS.
IF YOU'RE SO LUCKY TO HAVE A
PARENT WHO LIVED UNTIL THE AGE
100, CHANCES ARE YOU INHERIT
GOOD AGING GENES.
AND, THEREFORE, THE EPIGENETIC
AGE OF YOUR BLOOD IS PROBABLY
YOUNGER THAN IT SHOULD BE.
THE THIRD CRITERION IS, OF
COURSE, AN ESTIMATE OF BIOLOGIC
AGE SHOULD REALLY RELATE TO MANY
AGE-RELATED DISEASES AND
MULTI-MORBIDITY, IDEALLY, IT
SHOULD PREDICT THEM.
AND THE EXCITING NOTION REALLY
THAT THE EPIGENETIC CLOCK
SATISFIES ALL OF THESE CRITERIA.
METHYLATION AGE SHOULD PREDICT
ALL CAUSE MORTALITY.
BY NOW THERE'S THREE
PUBLICATIONS OUT THERE WHERE
PEOPLE HAVE SHOWN EXACTLY THAT,
THE METHYLATION AGE OF BLOOD IS
PREDICTIVE OF HOW LONG YOU LIVE.
THE FIRST STUDY THAT SHOWED IT
WAS THE COLLABORATION WIT WHERE
WE
ANALYZED FOUR DIFFERENT COHORTS
AND SHOWED THAT THESE MEASURES
PREDICT MORTALITY.
BUT I WANT TO SHOW YOU SOME
UNPUBLISHED FINDINGS WHERE WE
REVISITED THIS QUESTION, AND IN
THIS STUDY, WE CARRIED OUT A
VERY COMPREHENSIVE
META-ANALYSIS.
WE ANALYZED 13 DIFFERENT
COHORTS.
FROM THE WOMEN'S HEALTH
INITIATIVE, NORMATIVE AGING
STUDY, MANY OTHERS.
WE ANALYZED OVER 13,000
SUBJECTS.
AND FOR EACH SUBJECT, WE HAD
METHYLATION LEVELS COLLECTED IN
THE PATH OF SAY 1990 AND WE HAD
MAYBE 10, 15 YEARS OF FOLLOW-UP
SO WE COULD ASSESS DOES THE
EPIGENETIC AGE ACCELERATION
PREDICT MORTALITY.
HERE ARE THE RESULTS.
SO THESE ARE META-ANALYSIS
PLOTS, AND EACH PANEL CORE
SPONTS TO A DIFFERENT MEASURE OF
AGE ACCELERATION.
I WON'T TORTURE YOU WITH THE
TECHNICAL DETAILS, BUT WE NOW
DISTINGUISH INTRINSIC AGE
ACCELERATION FROM SOMETHING
CALLED EXTRINSIC AGE
ACCELERATION.
ALL MEASURES WE CONSIDERED, ALL
MEASURES HAVE VERY SIGNIFICANT
PREDICTIVE ASSOCIATIONS WITH
MORTALITY.
P VALUES RANGE FROM 10 TO THE
MINUS 9 TO 10 TO THE MINUS 43 IN
THIS UNIVARIATE MODEL.
BUT WHAT ABOUT IF WE ADJUST FOR
CLINICAL VARIABLES?  WHAT ABOUT
IF WE ADJUST ALSO FOR BODY MASS
INDEX, EDUCATION, ALCOHOL,
SMOKING, PRIOR HISTORY OF
DIABETES, CANCER, HYPERTENSION,
PHYSICAL ACTIVITY?
AFTER WE ADJUST FOR ALL OF THESE
COVARIANTS, WE STILL END UP WITH
VERY SIGNIFICANT P VALUES
RANGING FROM 10 TO THE MINUS
4 TO 10 TO THE MINUS 19.
SO I FEEL VERY CONFIDENT THAT
THIS STUDY ESTABLISHES ONCE AND
FOR ALL THAT THE EPIGENETIC
CLOCK AT LEAST CAPTURES ASPECTS
OF BIOLOGIC AGE.
I MENTIONED TO YOU THE FINDING
IN OFFSPRING OF CENTENARIANS.
SO WE SHOWED THAT PBMCs FROM
THE OFFSPRING OF ITALIAN
SUPERCREPT NAIRIANCENTENARIANS
OR
CENTENARIANS HAVE AN AGE
SIGNIFICANTLY YOUNGER OF THOSE
OF AGE MATCHED CONTROL.
HOWEVER, THIS FINDING WAS ONLY
IDENTIFIED IN AN ITALIAN
POPULATION, AND WE OF COURSE
HOPE THAT OTHERS WILL VALIDATE
IT IN OTHER POPULATIONS AS WELL.
TALKING ABOUT THIS ASPECT OF
CAPTURING MANY AGE-RELATED
PHENOTYPES, SO BY NOW, THERE'S
MANY PHENOTYPES HAVE BEEN LINKED
TO THE EPIGENETIC CLOCK, AND I
ARRANGE THEM HERE IN
ALPHABETICAL ORDER.
IF YOU DON'T MIND, I READ IT
THROUGH, AND THE OTHER CALL --
WHAT OTHER TISSUES IT HAS BEEN
LINKED.
SO FOR EXAMPLE, ALZHEIMER'S
DISEASE IS ASSOCIATED WITH
INCREASED EPIGENETIC AGING IN
PREFRONTAL CORTEX.
SIMILARLY, AMYLOID LOAD IS
RELATED, BODY MASS INDEX,
CALORIE RESTRICTION, CANCER,
CELL PATHOGEN, CENTENARIAN
STATUS, COGNITIVE PERFORMANCE,
DIET HAS A WEAK EFFECT, DOWN
SYNDROME HAS A STRONG EFFECT,
GESTATIONAL AGE, GRIP STRENGTH,
HAYFLICK LIMIT, SENESCENT CELLS
HAVE AN OLDER AGE.
HIV STATUS.
HUNTINGTON'S DISEASE, VARIOUS
LIPID LEVELS, FOR EXAMPLE, TRY
GLITRIGLYCERIDES, MENOPAUSE,
MORTALITY, NEWER PATHOLOGICAL
VARIABLES, OBESITY,
OSTEOARTHRITIS, PARKINSON'S
DISEASE AND SEX, MEN ARE
SLIGHTLY OLD NER WOMEN IN
CERTAIN TISSUE, BLOOD AND BRAIN,
FOR EXAMPLE.
SLEEP HAS A WEAK EFFECT, AND
FINALLY WALKING SPEED.
SO I WILL FLESH OUT THESE
RESULTS IN THE COMING SLIDES.
LET'S COME TO A DIFFERENT TOPIC.
WHAT ABOUT PROGERIOD SYNDROME.
HE RANKED SEGMENTAL PROGERIOD
SYNDROME ACCORDING TO VARIOUS
CRITERIA AND INTERESTINGLY, THE
ULTIMATE IS ACTUALLY DOWN
SYNDROME ACCORDING TO THIS
ANALYSIS, FOLLOWED BY WERNER
SYNDROME AND HUTCHINSON GILFORD
SYNDROME AND MANY OTHERS.
SO IN COLLABORATION I ANALYZED
BLOOD AND BRAIN TISSUE IN DOWN
SYNDROME SUBJECTS AND SURE
ENOUGH, WE FIND IN BOTH TISSUES,
THERE'S A SIGNIFICANT
ACCELERATED AGING EFFECT.
I'M VERY INTERESTED IN TESTING
OTHER POSTMORTEM TISSUES AS WELL
TO SEE TO WHAT EXTENT THIS
GENERALIZES TO OTHER TISSUES.
WHAT ABOUT HUTCHINSON'S PRO JEER
YA?
HERE I SHOW YOU SOME VERY
PRELIMINARY DATA WHERE WE IN
COLLABORATION WITH OTHERS
ANALYZED DERMAL FIBROBLASTS, THE
DOTS ARE COLORED BY PROGERIA
STATUS, SO RED AND MAGENTA ARE
PROGERIA, AND WHAT DO WE SEE?
WE BASICALLY SEE NOTHING.
OR I DON'T SEE ANYTHING.
I JUST DON'T SEE THAT PROGERIA
IS OLDER, YOU KNOW, THAN CONTROL
SAMPLES, AT LEAST IN THE DERMAL
FIBROBLASTS.
I'M NOT YET CONFIDENT ENOUGH IN
THIS FINDING, AND NOW WE
GENERATE A SECOND DATASET BUT I
JUST WANTED TO SHOW IT TO YOU.
THE GREAT -- IS OF COURSE
ALZHEIMER'S DISEASE.
WE HAVE RECENTLY SHOWN IN
COLLABORATION WITH MORGAN LE
VEEP, WHO ILEVINE, A POSTDOC,
AND DAVID
BENNETT, WE HAVE SHOWN THAT
EPIGENETIC AGE IN THE PREFRONTAL
CORTEX RELATES TO NEUROPATH
VARIABLES AND MORE.
AND THESE ARE 700 DORSO LATERA
LATERAL
SAMPLES FROM THE ROS STUDY AND
ALSO THE RUSH MEMORY AND AGING
PROJECT, AND WE THEN ANALYZED
EPIGENETIC AGE ACCELERATION IN
THE PREFRONTAL CORTEX AND
RELATED IT TO THESE NEUROPATH
VARIABLES AND IT RELATES TO ALL
OF THEM.
AMYLOID LOAD, NEURITIQUE PLAQUES
PLAQUES, NEUROFIBRILLARY
TANGLES, PHFTAU TANGLE.
WE FIND MUCH STRONGER
ASSOCIATION.
BUT THEY ARE THERE.
SO IT'S AN IMPORTANT PROOF OF
CONCEPT.
TO ME, IT SUGGESTS THAT, YES,
THE EPIGENETIC CLOCK MEASURES IN
CERTAIN WAYS THE BIOLOGIC AGE OF
THE BRAIN.
AND EVEN MORE EXCITINGLY, THE
EPIGENETIC AGE ACCELERATION ALSO
CORRELATES TO MEASURES OF
COGNITIVE FUNCTIONING THAT WERE
ASSESSED PREMORTEM OBVIOUSLY,
AND SO THERE ARE SIGNIFICANT --
WITH GLOBAL COGNITIVE
FUNCTIONING, EPISODIC MEMORY AND
SO ON.
SO THAT'S THE TOPIC AGING.
I WANT TO BRIEFLY MENTION
APPLICATIONS TO PRENATAL
SAMPLES, BECAUSE IT TEACHES US
SOMETHING ABOUT THE UNDERLYING
BIOLOGY.
SO HERE THEY ANALYZED 179
PRENATAL BRAIN SAMPLES, AND THEY
APPLIED THE EPIGENETIC CLOCK
ALGORITHM AND ON THE Y AXIS, YOU
SEAT MEASURE, AND YOTHE MEASURE
AND YOU NO
TICE IT'S
A NEGATIVE NUMBER THAT
INDICATION A PRENATAL SAMPLE.
SO ON THAT LEVEL, THE CLOCK
ALREADY WORKS.
BUT MORE IMPORTANTLY, THERE IS A
WEAK CORRELATION EVEN OF .15,
THAT SUGGESTS THAT ALREADY
GESTATIONAL AGE AND BRAIN
RELATED TO THE EPIGENETIC AGE,
AND I SHOULD MENTION THAT WE
REVISITED THESE ANALYSIS IN
BLOOD AND NOT YET DISCOVERED A
CORRELATION BETWEEN GESTATIONAL
AGE AND EPIGENETIC AGE IN BLOOD
TISSUE.
BLOOD MAY BE FOR WHATEVER REASON
MORE DIFFICULT.
SO WHY DO I HIGHLIGHT THIS
RESULT?
BECAUSE PEOPLE OFTEN THINK OF
EPIGENETIC AS A MEDIATOR OF
ENVIRONMENT ON THE ORGANISM,
RIGHT?
HOWEVER, EASY PAY IN MY WORD
PLAYS OF COURSE ANOTHER CRUCIAL
ROLE, WHICH IS DEVELOPMENT, IT
DISTINGUISHES CELL TYPES, AND IN
MY WORK, IT WAS VERY INTERESTING
THAT WE ALREADY SEE AN
APPLICATION IN PRENATAL SAMPLES
BECAUSE MAYBE WE CAN INTERPRET
THEN AGING AS A CONTINUATION OF
DEVELOPMENT, WHICH IS, OF
COURSE, AN OLD IDEA.
I WANTED TO REPORT AN ANALYSIS
OF A CURIOUS DISORDER, WHICH IS
KNOWN AS SYNDROME X AND
OCCASIONALLY SEE IT ON
TELEVISION.
SO THERE ARE CHILDREN WHO SIMPLY
NEVER DEVELOP.
THEY ALWAYS REMAIN TODDLERS.
THEY NEVER LEARN HOW TO WALK,
THEY NEVER LEARN HOW TO TALK.
YOU HAVE TO CHANGE THEIR DIAPER
UNTIL THEY'RE AGE 20 OR
WHENEVER.
SO HERE'S A GIRL FOR EXAMPLE WHO
AT AGE 2, 4 AND 6.
I WAS VERY INTERESTED IN
STUDYING WHETHER THESE CHILDREN
ARE IMMORTAL, WHETHER THEY NEVER
AGE.
AND SO I WORKED WITH RICHARD
WALKER ON THIS ANALYSIS OF BLOOD
SAMPLE FROM THESE CHILDREN, AND
THE FINDING WAS, THESE CHILDREN,
AT LEAST THEIR AGE -- THEIR
BLOOD AGE IS PERFECTLY NORMALLY.
SO ACCORDING TO THE BLOOD
ANALYSIS, THESE CHILDREN ARE
MORTAL.
PEOPLE HAVE LOOKED AT PRENATAL
AND EARLY LIFE INFLUENCES ON
EASEPIGENETIC AGE, IF YOU'RE
INTERESTED IN THAT.
I INVITE YOU TO READ THE PAPER
FROM ANDREW SIMPKIN AND OTHERS.
IN THIS PAPER, WE LOOKED AT MANY
FACTORS, BUT THE ONE FACTOR THAT
REALLY STOOD OUT TO ME WAS
GENDER.
BECAUSE BOYS WERE ALREADY OLDER
THAN GIRLS, ACCORDING TO THE
EPIGENETIC CLOCK.
SO THAT FEMALE ADVANTAGE STARTS
EARLY ON.
WE OF COURSE ARE ALL INTERESTED
IN INTERVENTIONS THAT AFFECT THE
EPIGENETIC CLOCK, SO I JUST WANT
TO GIVE YOU AN OVERVIEW OF WHAT
I LEARNED OVER THE LAST THREE
YEARS.
SO FIRST OF ALL CELL PASSAGING
OR POPULATION DOUBLING LEVEL IS
NOT THE SAME AS EPIGENETIC AGE.
THESE ARE DIFFERENT CONCEPTS,
HOWEVER, THEY ARE CORRELATED.
AND RECENTLY, THEY VALIDATED
THIS FINDING BY LOOKING AT
ENDOTHELIAL CELLS AND AGAIN THEY
FOUND REPLICATIVE SENESCENCE AND
ALSO SHOWED ONCOGENE-INDUCED
SENESCENCE ARE ACCOMPANIED BY
INCREASED ERG AGE.
EPIGENETIC AGE.
BUT THERE IS A THIRD WAY, AND
THAT'S RADIATION.
STRIKSTRIKINGLY, RADIATION DOES
NOT
INCREASE EPIGENETIC AGE AND I'LL
TALK ABOUT IT LATER.
HERE'S ANOTHER QUESTION PEOPLE
ASK, IS THERE A CERTAIN TIE ET
THAT WILL KEEP ME YOUNG.
MANY COLLABORATED FROM THE
WOMEN'S HEALTH INITIATIVE AND
ALSO IMPORTANTLY LUIGI AND BRIAN
CHEN AND TOSHIKO TAN A/K/A AND
OTHERS, WE POOLED OUR EFFORT TO
ASSESS WHAT DIETS AFFECT THE
EPIGENETIC AGE OF BLOOD.
LET ME ALREADY COME UP WITH THE
MAIN MESSAGE:  DIET HAS ONLY A
VERY WEAK EFFECT ON THE
EPIGENETIC AGE OF BLOOD.
SO WHATEVER I SHOW YOU, TAKE IT
WITH A GRAIN OF SALT.
YOU REALLY NEED THOUSANDS OF
SAMPLES TO DETECT THESE EFFECTS,
BUT HERE WE GO.
SO THIS SHOWS A PLOT WHERE ON
THE Y AXIS, I REPORT THE
PERCENTAGE OF PROTEIN IN THE
DIET AND ON THE X AXIS, I SHOW
THE PERCENTAGE OF CARBOHYDRATES.
AND RED MEANS HIGH INTRINSIC
EPIGENETIC AGE IN THE WOMEN'S
HEALTH INITIATIVE, AND WHAT WE
SEE IS THAT IN THE LOWER RIGHT
CORNER IS INCREASED AGING.
AND I WANTED TO CALL THIS LOWER
RIGHT-HAND CORNER THE COOKIE
DIET, LOTS OF SUGAR, UNTIL I DID
A GOOGLE SEARCH ON IT UNTIL I
LEARNED THERE IS SUCH A THING AS
THE COOKIE DIET SO I DIDN'T WANT
TO OFFEND ANYBODY, ANYWAY,
THAT'S ONE FINDING.
SO HERE IS A GRAPHIC OF THIS
STUDY, AND AS I MENTIONED
EARLIER, WE DID DISTINGUISH
INTRINSIC EPIGENETIC AGING FROM
EXTRINSIC AGING.
SO THE EXTRINSIC AGING MEASURE
WHICH INCIDENTALLY IS BASED ON
AN EPIGENETIC AGE ESTIMATED,
THIS MEASURE IS AFFECTED BY
ANYTHING YOU WOULD THINK OF.
IF YOU EAT A LOT OF FISH,
FRUITS, HIGH EDUCATION, IF YOU
EX-AREXERCISE, IT SLOWS THE
EXTRINSIC
AGING.
HIGH BMI, INSULIN LEVELS,
TRIGLYCERIDE LEVEL, HOMOCYSTEINE
LEVELS, INCREASE THE AGING
CLOCK.
AGAIN, WEAK EFFECT.
LET'S NOW COME TO AN
INTERVENTION THAT HAS A HUGE
EFFECT.
SO IF YOU TAKE A DERMAL
FIBROBLAST, FOR EXAMPLE, AND YOU
TURN IT INTO AN INDUCED FLEUR
PLURIPOTENT STEM CELL, THAT
RESETS THE EPIGENETIC AGE
COMPLETELY.
SO IPS CELLS HAVE A NEGATIVE
AGE, INDICATING A PRENATAL AGE,
OR AN AGE CLOSE TO ZERO.
AND THAT SIGNAL IS EXTREMELY
ROBUST.
I SEE IT IN EVERY CELL.
SIMILARLY, EMBRYONIC STEM CELLS
HAVE AN AGE THAT IS NEGATIVE OR
ZERO.
LET'S NOW COME TO INTERVENTIONS
THAT DO NOT AFFECT THE
EPIGENETIC CLOCK.
SO HERE IS AN UNPUBLISHED STUDY
BY ANDREW, CHRISTINE AND OTHERS,
WHERE ANDREW CONVERTED
FIBROBLASTS INTO NEURONS USING
WHAT IS KNOWN AS DIRECT
CONVERSION OR
TRANSDIFFERENTIATION.
SO THIS IS AN MICRO RNA BASED
METHOD FOR TURNING THE
FIBROBLAST OF AN ADULT INTO A
NEURON.
AND SO HE STARTED WITH THE
FIBROBLAST, ADDED CERTAIN MICRO
RNAs BY TRANSDUCING THEM AND
ENDED UP WITH THESE NEURONS, AND
THE LOWER PANEL SHOWS THE AGE
ESTIMATE BEFORE AND AFTER
CONVERSION.
THE X FACTOR SHOWS THE
METHYLATION AGE OF THE
FIBROBLAST BEFORE CONVERSION,
THE Y AXIS SHOWS THE AGE OF THE
RESULTING NEURON AFTER
CONVERSION.
AND WHAT DO WE SEE?
WE SEE A CORRELATION OF .91, YOU
KNOW, SO IN OTHER WORDS, THAT
PROCEDURE, MEDIATED DIRECT
CONVERSION, DOES NOT CHANGE THE
EPIGENETIC AGE.
DIFFERENT FROM WHAT IS OBSERVED
IN IPS CELL.
I WANTED TO FLESH OUT MY EARLIER
COMMENT THAT ANOTHER THING THAT
DOES NOT ACCELERATE EPIGENETIC
AGING IS RADIATION.
SO HERE RADIATED ENDOTHELIAL
CELLS OVER VARIOUS TIME POINTS
AND WE JUST NEVER SAW ANY CHANGE
IN EPIGENETIC AGE.
WHAT ABOUT WEIGHT LOSS?
SO WE HAD LIVER SAMPLE FROM
PEOPLE WHO UNDERWENT BARIATRIC
SURGERY, AND AS YOU KNOW,
BARIATRIC SURGERY DRASTICALLY
REDUCES THE WEIGHT, AND THE
UPPER PANEL SHOWS HOW THE BODY
MASS INDEX DECREASES UP TO NINE
MONTHS.
IN THE SAME SAMPLE, WE ASSESSED
THE METHYLATION AGE AND THERE
WAS NO DIFFERENCE IN THE NINE
MONTHS OF FOLLOW-UP.
SO THEREFORE THE DEPRESSING NEWS
IS THAT ONCE YOUR LIVER IS
ACCELERATED AGING DUE TO
OBESITY, PROBABLY AN
INTERVENTION WILL NOT RESET THE
AGE AT LEAST NOT IN THE SHORT
TERM.
YOU KNOW.
OF COURSE THAT NEEDS TO BE
REVISITED WITH MUCH LONGER
FOLLOW-UP STUDIES.
IN THE LOWER PANEL, I SHOW YOU
AN EXAMPLE WHERE I ANALYZED
PUBLICLY AVAILABLE DATA, WHERE
THE OFFICE CARRIED OUT A SIX
MONTH PHYSICAL EXERCISE
INTERVENTION, AND THEN MEASURED
METHYLATION LEVELS IN ADIPOSE
TISSUE AND AGAIN I SAW NO
DIFFERENCE.
SO IF YOU EXERCISE A LOT, IT
PROBABLY DOESN'T REJUVENATE YOUR
FAT TISSUE.
THAT'S THE MESSAGE.
BUT CLEARLY IT WOULD BE VERY
EXCITING TO REVISIT THAT NOW IN
OTHER TISSUES, MUSCLE TISSUE
WOULD BE AN OBVIOUS QUESTION.
ANOTHER NEGATIVE FINDING IS
REALLY RELATIONSHIP TO TELOMERE
LENGTH.
SO THERE IS NO RELATIONSHIP
BETWEEN TELOMERE LENGTH AND
EPIGENETIC AGE IN BLOOD OR
ADIPOSE TISSUE.
AFTER YOU CORRECT FOR
CHRONOLOGIC AGE, RIGHT?
CHRONOLOGIC AGE CONFOUNDS THE
TWO VARIABLES.
SO IF YOU HAVE PEOPLE OF THE
SAME AGE, THE BIRTH COHORT, AND
YOU JUST MEASURE THE TELOMERE
LENGTH AND EPIGENETIC AGE, YOU
WILL NOT SEE A RELATIONSHIP.
AND THERE IS A PUBLICATION FROM
A GERMAN GROUP WHO SHOW THAT
FRAILTY IS ASSOCIATED WITH THE
EPIGENETIC CLOCK BUT NOT WITH
TELOMERE LENGTH IN A LARGE
GERMAN COHORT.
MANY OTHERS REVISITED MORTALITY
PREDICTION AND THEY FOUND THAT
TELOMERE LENGTH AND EPIGENETIC
AGE INDEPENDENTLY PREDICTED
MORTALITY, WHICH IS EXCITING
NEWS, BECAUSE CLEARLY TELOMERE
LENGTH IS A VERY IMPORTANT
BIOMEDICAL, BIOMARKER, AND IT
JUST SHOWS THAT THESE MARKERS
COMPLEMENT EACH OTHER.
LET'S NOW TALK ABOUT ANOTHER
ANGLE OF GENETICS.
SO REMEMBER YOU HAVE A MEASURE
OF EPIGENETIC AGE ACCELERATION,
WHICH SL A NUMBER, AND YOU CAN
USE THAT QUANTITATIVE READOUT AS
A PHENOTYPE IN A QTL ANALYSIS TO
FIND SNPs THAT RELATE TO AGE
ACCELERATION.
AND WHY WOULD WE DO THAT?
FIRST, WE WANT TO UNDERSTAND THE
MECHANISM UNDERLYING THE
EPIGENETIC CLOCK, SO YOU WANT TO
FIND KEY GENES, BUT ALSO WE
CLEARLY WANT TO FIND AGING
GENES.
WE USE AGE ACCELERATION AS AN
ENDOPHENOTYPE FOR RELATED
PATHOLOGY.
HERE I WANT TO SHOW YOU RESULTS
WHERE WE ANALYZED THE CEREBELLAR
SAMPLES, AND WE FOUND GENETIC
VARIANTS NEAR TWO GENES
AFFECTING THE EPIGENETIC AGE OF
THE CEREBELLUM.
I WANT TO SHOW YOU A MANHATTAN
PLOT THAT THE GENETICISTS AMONG
YOU WILL RECOGNIZE.
SO HERE WE HAVE THE P VALUES
VERSUS CHROMOSOMAL LOCATIONS AND
WE FIND VERY SIGNIFICANT FIND
NGS TWO LOCATIONS.
BUT WHAT IS STRIKING ABOUT THIS
MANHATTAN PLOT IS THAT IT'S
ACTUALLY BASED ON ONLY 500
SAMPLES.
BECAUSE WHEN YOU TYPICALLY SEE
THESE TYPES OF MANHATTAN PLOTS,
THEY ARE BASED ON THOUSANDS IF
NOT TENS OF THOUSANDS OF
SAMPLES, BUT ARGUABLY IF YOU
HAVE A RIGHT ENDOPHENOTYPE, YOU
REALLY ENRICH THE SIGNAL AND YOU
GET AWAY WITH MUCH SMALLER
SAMPLE SIZES.
ONE OF THE GENES THAT'S
INTERESTING TO AGING RESEARCHERS
RESEARCHERS, IT'S A KEY
COMPONENT OF BOTH MTOR
COMPLEXES, WHICH, OF COURSE,
PLAY AN IMPORTANT ROLE IN MODEL
ORGANISM AGE.
SO I WANT TO PRESENT -- I SHOULD
SAY THESE STUDIES ARE ONGOING,
WE NOW ANALYZE MANY DIFFERENT
BRAIN REGIONS, WE ANALYZE BLOOD
SAMPLE, WE HAVE SOME EXCITING
HITS AND JUST STAY TUNED TO IT.
I WANT TO NOW SHIFT GEARS AND
PRESENT SOME APPLICATIONS.
SO HIV IS UNFORTUNATELY OFTEN
ACCOMPANIED BY AGE-RELATED
PHENOTYPES, AND SO WE WERE
INTERESTED IN TESTING WHETHER
HIV INFECTION ACCELERATES THE
AGE OF BLOOD AND ALSO BRAIN
TISSUE.
AND THE ANSWER IS IT REALLY
DOES, IN BOTH TISSUE, WE FOUND
SIGNIFICANT ACCELERATED AGE
BEING EFFECTS.
IT'S INTERESTING TO ME HOW THAT
COULD COME ABOUT.
WE LACK A ME CAN NIS TISH
MECHANISTIC
UNDERSTANDING BUT THE FINDING IS
CLEAR.
THIS IS ANOTHER APPLICATION IN
COLLABORATION WITH OTHERS WHERE
WE ANALYZE SUPERCENTENARIANS.
SO A SUPERCENTENARIAN IS A
PERSON WHO IS 110 YEARS OLD OR
OLD E AND IN THIS APPLICATION,
WE ANALYZED IN THE UPPER PANEL A
LADY WHO WAS 112 YEARS OLD, AND
WE ANALYZED 30 DIFFERENT PARTS
OF HER BODY.
ALL PARTS THAT I COULD THINK OF.
AND WE MEASURED THE EPIGENETIC
AGES.
AND THE ONE BODY PART THAT HAD
THE YOUNGEST AGE WAS THE
CEREBELLUM.
NOARND, BONE TISSUE AND BLOOD
WAS OLDER.
THAT'S ON THE RIGHT-HAND SIDE.
AND THIS FINDING OF THE YOUNG
CEREBELLUM WAS SUBSEQUENTLY
VALIDATED IN THE LOWER PANELS,
WHICH SHOW BRAIN OF OTHER
CENTENARIANS AND
SUPERCENTENARIANS, ALWAYS THE
CEREBELLUM IS THE YOUNGEST BRAIN
REGION.
FURTHER, WE ANALYZED HALF A KOZ
DATASETS WHERE WE ANALYZED
BRAINS FROM 80 YEARS OLD AND
AGAIN FIND IT.
SO I'M VERY CONFIDENT IN THAT
STATEMENT THAT THE CEREBELLUM
AGES SLOWLY ACCORDING TO THE
EPIGENETIC CLOCK.
AND OF COURSE THE QUESTION IS
WHY IS THAT THE CASE?
IT'S AN INTERESTING RESULT
BECAUSE IF WE CAN FIGURE OUT WHY
THE CEREBELLUM STAYS YOUNG,
MAYBE WE FIND A WAY TO KEEP THE
REST OF THE BRAIN YOUNG AS WELL.
I WANT TO SHIFT GEARS AGAIN AND
MENTION AN APPLICATION TO BREAST
CANCER.
TODAY I WON'T TALK MUCH ABOUT
CANCER, BUT I DO WANT TO MENTION
THAT BREAST CANCER TYPES HAVE
VERY DIFFERENT AGES.
YOU MAY HAVE HEARD OF LUMINAL
TYPE VERSUS BASAL TYPE, AND
LUMINAL CANCERS PRESENT WITH
CANCER TISSUES THAT HAVE
SIGNIFICANT POSITIVE AGE
ACCELERATION.
IN CONTRAST, THE BASAL TYPE, THE
TRIPLE NEGATIVE CANCER, IS
ACCOMPANIED WITH NEGATIVE AGE
ACCELERATION.
SO IN GENERAL, CANCER CAN BOTH
INCREASE THE METHYLATION AGE OF
THE AFFECTED TISSUE AND DECREASE
THE AGE.
SO THE EPIGENETIC CLOCK IS
BROKEN IN CANCER TISSUE.
I WANT TO ALSO MENTION ANOTHER
FINDING THAT'S COMING OUT SOON
BY MORGAN LEVINE AND OTHERS
WHERE WE EVALUATED THE EFFECT OF
MENOPAUSE ON EPIGENETIC AGING,
AND THE FINDING IS CLEAR.
SO WE LOOKED AT SEVERAL COHORTS,
WHI, PARKINSONS, AND WE FOUND
THAT WOMEN WHO ENTER MENOPAUSE
LATE, THEIR EPIGENETIC AGE IN
BLOOD IS YOUNGER.
SO DELAYED ONSET OF MENOPAUSE IS
ACCOMPANIED WITH LOWER AGING.
AND THAT HOLDS EVEN AFTER YOU
ADJUST FOR ALL SORTS OF
COVARIANTS.
I WANT TO MENTION SOME FUTURE
DIRECTIONS.
CLEARLY WE NEED TO EXTEND THE
EPIGENETIC CLOCK TO MODEL
ORGANISMS.
HERE I SHOW YOU AN ONGOING STUDY
UNPUBLISHED WHERE WE'RE NOW
BUILDING AN ER EPIGENETIC CLOCK
FOR
DOGS AND YOU CAN CLEARLY DO IT.
THAT'S IN BLOOD.
SO IN CONCLUSION, THEN, I FEEL
THAT THE EPIGENETIC CLOCK IS AN
ATTRACTIVE BIOMARC OF AGING,
IT'S HIGHLY ROBUST, I ALWAYS
TELL THE STORY THAT I COLLECTED
BLOOD TUBES IN LOS ANGELES AND
THEN THE PERSON WHO TRANSPORTED
THEM KEPT THEM
IN HIS CAR, AND THEY MELTED
BECAUSE HE DIDN'T HAVE AN AIR
CONDITIONERRER, SO WE ANALYZED
THE BLOOD SAMPLES FROM THE
COAGULATED BLOOD AND WE STILL
GOT PERFECT AGE ESTIMATES.
I COULD TELL YOU LOTS OF THESE
STORIES.
SO METHYLATION LEVELS ARE
SURPRISINGLY ROBUST.
IT'S A VERY ACCURATE MEASURE OF
TISSUE AGE, IT'S ASSOCIATED WITH
MANY AGE-RELATED CONDITIONS,
IT'S PROGNOSTIC OF MORTALITY,
AND IT ALLOWS YOU TO CONTRAST
THE AGES OF DIFFERENT TISSUES.
SO I FEEL MOST STUDY THRAS
LOOK -- SUCH AS TELOMERE LENGTH
COULD BE REVISITED, BUT I DO
WANT TO MENTION THAT IT WILL BE
IMPORTANT TO LOOK AT TISSUES
BEYOND JUST BLOOD.
FOR EXAMPLE, SOME OF THE MOST
STRIKING FINDINGS CAN BE FOUND
IN BUCCAL EPITHELIUM AS OPPOSED
TO BLOOD.
SO REMEMBER THE FINDING FOR
OBESITY, STRONG EFFECT IN LIVER
BUT NOT IN OTHER TISSUE.
FINALLY, I MENTIONED THERE IS
PRFREE USER-FRIENDLY SOFTWARE ON
MY WEBPAGE SO I INVITE YOU TO
TRY THAT OUT.
I WANT TO ACKNOWLEDGE THE ABOVE
ALL
THE NATIONAL INSTITUTE ON AGING
AND NIH FOR ALL THE WONDERFUL
SUPPORT FOR CREATING WONDERFUL
DATA REPOSITORIES, I WANT TO
THANK THE MANY RESEARCHERS WHO
ANSWERED MY EMAILS AND FREELY
SHARED THEIR METHYLATION DATA IN
THESE PUBLIC REFOS TRIES.
I THINK I ALREADY MENTIONED MANY
OF THESE PEOPLE DURING MY TALK.
SO THANK YOU VERY MUCH.
[APPLAUSE]
QUESTIONS?
>> THANK YOU FOR YOUR WONDERFUL
AND CHALLENGING PRESENTATION.
THIS IS OPEN TO QUESTIONS.
>> THANK YOU.
MY QUESTION IS ABOUT ESLs --
WHEN YOU DIFFERENTIATE THEM IN
VITRO, DO THEY UNDERGO VERY
RAPID AGING OR IS THE AGING
PURELY CHRONOLOGICAL?
>> ALL RIGHT.
SO LET'S -- LET ME MENTION AN
UNPUBLISHED FINDING THAT I HOPE
ANSWER YOUR QUESTION.
SO WHEN YOU TAKE SAY AN IPSL AND
YOU TURN IT INTO -- YOU
DIFFERENTIATE IT INTO A NEURAL
PRECURSOR IN VARIOUS STAGES,
VERY IMPORTANT QUESTION IS, IS
THAT ACCOMPANIED WITH INCREASES
IN EPIGENETIC AGE?
SO I ANALYZED SUCH A DATASET AND
THE ANSWER IS YES.
IT IS STATISTICALLY VERY
SIGNIFICANT.
IN ACTUAL UNITS, IT'S PROBABLY
NOT THAT MUCH, AN INCREASE OF, I
DON'T KNOW, SEVERAL MONTHS, BUT
NO DOUBT IT WAS ASSOCIATED.
>> I HAVE TWO QUESTIONS.
YOU SAID THAT DIFFERENT -- MAY
HAVE DIFFERENT BIOLOGICAL AGE.
SO THE HEART MAY BE 50, THE
LIVER MAY BE 30, SO WE ONE IT IS
ACTUALLY THE AGE?
IS IT THE SCORE, IS IT A
FORMULA, WHICH ONE IS THE AGE?
>> THAT'S A VERY GOOD QUESTION.
LET ME GIVE YOU MY OPINION.
I THINK IF YOU HAVE A PERFECTLY
HEALTHY PERSON, COMING BACK TO
THE TRUE -- THE IDEAL HUMAN
BODY, I THINK ALL PARTS HAVE THE
IDENTICAL AGE, YOU KNOW?
IT'S CALIBRATED CHRONOLOGIC AGE,
ALL PARTS MOVE AT THE SAME
SPEED.
BUT VARIOUS STRESS FAK, TO
FACTOR,
INTERNAL OR GENETIC, WILL THEN
LEAD TO DIVERGENCES, SO AGAIN,
IF EURO BEES YOU'RE OBESE, YOUR
LIVER WILL
BE OLDER THAN THE OTHER PARTS OF
YOUR BODY BUT MAY BE UNAFFECTED.
PEOPLE OFTEN ASK ME, DOES
SMOKING ACCELERATE AGING?
THE ANSWER IS NOT IN BLOOD.
CERTAINLY YOUR BLOOD IS YOUNG,
YOU KNOW, BUT I DON'T KNOW
WHETHER SMOKING ACCELERATES THE
AGE OF YOUR LUNG TISSUE OR THE
HEART, YOU KNOW.
SO IN ANY EVENT, COMING TO YOUR
QUESTION, WHAT IS THE ONE
SUMMARY MEASURE OF THE BODY
THEN, AND I MEAN, AS A
MATHEMATICIAN, I WOULD ANSWER
FOCUS ON THE WEAKEST LINK,
RIGHT, YOU TAKE THE MINIMUM.
IF YOUR HEART IS 20 YEARS OLDER
THAN IT SHOULD BE, YOU WILL
PROBABLY BE IN TROUBLE.
BY THE WAY, THESE STATEMENTS
NEED TO BE TAKEN WITH A GRAIN OF
SALT BECAUSE WE HAVE NOT YET
VALIDATED THAT THE EPIGENETIC
AGE OF HEART TISSUE HAS ANY
CLINICAL RELEVANCE.
CLEARLY THAT'S A VERY IMPORTANT
RESEARCH DIRECTION TO UNDERSTAND
TO WHAT EXTENT THE EAS
EPIGENETIC
AGES OF DIFFERENT ORGANS RELATE
TO PATHOLOGY.
>> UNDERSTAND.
AND BEING A NUTRITIONIST AND
ONCE EXPLAINED THAT NUTRITION IS
NOT AS IMPORTANT, HOW COME YOU
KEEP MENTIONING THE GRAIN OF
SALT?
[LAUGHTER]
>> TAKE EVERYTHING WITH A GRAIN
OF SALT.
>> I HAVE A SECOND QUESTION.
SO MY SECOND QUESTION IS, I'M
VERY INTERESTED IN GAS
MICROBIOTA AND GAS MICROBIOME.
MICROBIOTA CHANGES WITH THE AGE.
>> YES.
>> HAVE YOU LOOKED INTO A
POSSIBILITY OF MODULATING OR IT
IS A SPOBILITY I POSSIBILITY IN
YOUR OPINI
ON
OF MODULATING THE AGING PROCESS
THROUGH MODULATING THE
MICROBIOME?
>> I THINK IT'S A SUPER
INTERESTING QUESTION.
I JUST DON'T HAVE ANY DATA THAT
WOULD LINK THE COMPOSITION OF
THE MICROBIOME TO EPIGENETIC
AGING.
BUT FOR ALL THE REASONS YOU
MENTIONED, I THINK IT'S AN
IMPORTANT QUESTION.
>> THANK YOU.
>> IN YOUR EPIGENETIC
METHYLATION ANALYSIS OF THE
PRENATAL BRAIN, I'M ASSUMING YOU
GOT THAT FROM AUTOPSY MATERIAL?
>> YES.
>> OKAY.
IF YOU'RE GETTING IT FROM
AUTOPSY MATERIAL, MY EXPERIENCE
IS THAT MOST OF THOSE ARE GOING
TO BE FROM ABORTIONS.
IF THEY'RE FROM ABORTIONS, IT'S
A HUGELY HETEROGENEOUS GROUP.
IT COULD BE A VASCULAR INSULT,
IT COULD BE SOME KIND OF
CHROMOSOMAL THING, SO THAT WOULD
KIND OF EXPLAIN THAT AWAY.
IF YOU HAD THE GOOD LUCK TO
RECEIVE MONO ZYGOTIC TWINS OR
TRIPLETS OR EVEN QUINN IT UP
LETS, THAT WOULD CERTAINLY GIVE
YOU A BETTER ANSWER TO WHAT
YOU'RE LOOKING AT.
YOU COULD KIND OF CORRELATE
THOSE.
THE OTHER QUESTION IS, IN TERMS
OF -- YOU SEEM TO HAVE SKIPPED
PLACENTA, WHICH WOULD SEEM TO BE
THE BEST CONTROL TISSUE OF THEM
ALL.
IT'S HUMAN, IT LIVES FOR 8 TO
9 MONTHS, AND YOU COULD SAY,
GEE, OUR EPIGENETIC METHYLATION
REALLY WORKS OR IT DOESN'T.
>> THANKS FOR THROWIN DRAWING MY
ATTENTION TO IT.
SO I CERTAINLY EVALUATED
PLACENTA, AND IT TURNS OUT THAT
THE EPIGENETIC AGE OF PLACENTAL
SAMPLES IS BASICALLY ZERO OR
NEGATIVE, MEANING AGAIN, VERY
YOUNG.
SO THE EPIGENETIC CLOCK -- WHAT
IS THE TRUE AGE OF PLACENTA.
DO YOU TAKE THE CHRONOLOGIC AGE
OF THE MODEL OR DO YOU TAKE THE
GESTATIONAL AGE OF THE
CHILD.
SO FAR I COULD NOT FIND ANY --
THERE'S CERTAINLY NO
RELATIONSHIP BETWEEN THE
PLACENTAL AGE BASED ON THE
EPIGENETIC CLOCK AND THE
CHRONOLOGIC AGE OF THE MOTHER
THAT I KNOW.
WHEN I APPLI THE ALGORITHM TO
THE PLA SET TA PLACENTA, IT'S
AGE ZERO.
>> THANK YOU.
>> THANKS VERY MUCH FOR
SPEAKING.
I'M NOT A -- MY QUESTION IS, DID
YOU SAY BOTTOM LINE THAT
GENETICS IS THE LIFESPAN -- YOU
CAN HAVE PARENTS THAT LIVE TO BE
ELDERLY, IN THEIR 90s, WHAT'S
THE PERCENTAGE OF CHANCE YOU
HAVE?
>> THERE'S NO DOUBT THAT THE AGE
OF YOUR PARENTS IS A VERY
SIGNIFICANT PREDICTER OF HOW
LONG YOU WILL LIVE.
I DON'T HAVE THE EXACT NUMBERS,
BUT CAN SOMEONE HELP ME?
I WANT TO SAY HERITABILITY 40%
MAYBE?
30% -- LUIGI HAS VERY OLD
PARENTS SO HE'S BLESSED.
BUT YEAH, I CANNOT ANSWER BEYOND
THAT.
BUT YES, GENETICS MATTERS A LOT.
>> WHAT PERCENT DID YOU SAY?
>> 30%.
>> THAT'S ALL?
>> YEAH.
AND ALSO THE DISSH WELL -- WELL,
I THINK
IT'S A LOT, BECAUSE THINK ABOUT
IT, IF YOU HAVE THE PERFECT
GENES, HOWEVER, YOU SMOKE AND
HAVE POOR LIFESTYLE CHOICE, YOU
KNOW, THAT WILL DO YOU IN.
ALSO THE EPIGENETIC AGE
ACCELERATION ALSO IS QUITE
GENETIC, MAYBE 40% OF THE
VARIATION IS UNDER GENETIC
INFLUENCE.
>> I HAVE ANOTHER QUESTION.
WHAT ABOUT TELOMERE GENE, THAT
AGING GENE?
>> SO TEL TELOMERE LENGTH
SHORTENS
AS WE AGE, THAT'S A VERY WELL
STUDIED MOLECULAR -- IN CERTAIN
WAYS, AFTER YOUR TELOMERES
BECOME SHORT, IT TRIGGERS
CELLULAR SENESCENCE, BUT
INTERESTINGLY, SHORTENING VEILY
NOT RELATED TO THE EPIGENETIC
CLOCK, WHICH IS EXCITING BECAUSE
AFTER 20 YEARS OF RESEARCH, WE
KNOW TELOMERE SHORTENING IS NOT
THE ROOT CAUSE OF AGING.
IT'S A CONTRIBUTOR TO AGING.
BUT ARGUABLY WE ARE OPEN FOR NEW
IDEAS TO FIND NOVEL MECHANISMS.
>> THANK YOU.
>> THANK YOU.
>> YOU TRIED IONIZING RADIATION
AND FOUND THAT THAT DOES NOT
ACCELERATE.
>> YES.
>> SO WHICH MEANS DOUBLE
STRANDED DNA BREAKS ARE NOT THE
DRIVING FORCE.
>> YES.
>> HOW ABOUT ROS OXIDATIVE
STRESS?
>> I DON'T THINK I HAVE -- I
CAN'T THINK OF A STUDY RIGHT NOW
THAT INVESTIGATED IT.
BUT IT'S CLEARLY AN EXCITING
QUESTION.
I HAVE CERTAINLY EVIDENCE THAT
MITOCHONDRIA PLAY A ROLE, YOU
KNOW, SO IN THIS OBESITY PAPER,
WE HAVE METHYLATION LEVELS FROM
LIVER SAMPLES BUT WE ALSO ARE
TRAN SCRIP TOE MIC DATA FROM THE
VERY SAME LIVER, SO WE COULD
CORRELATE GENE TRANSCRIPTS THAT
RELATE TO THE AGE OF THE LIVER,
AND SURE ENOUGH, NUCLEAR
MITOCHONDRIAL GENES REALLY
POPPED UP.
SO MEANING IF YOU EXPRESS
NUCLEAR MITOCHONDRIAL GENES,
THEN THE CORRESPONDING LIVER
SAMPLES ARE YOUNGER THAN
EXPECTED.
>> THIS YOU CHECKED
MITOCHONDRIAL DNA CONTENT AND
HOW IT CORRELATES WITH
EPIGENETIC AGING?
>> NO, NOT YET.
BUT IT'S ON MY TO-DO LIST, WAY
UP ON MY TO-DO LIST, BUT MAYBE
OTHERS CAN LOOK AT IT.
I THINK IT'S A VERY PROMISING
HYPOTHESIS THAT THERE IS A
RELATIONSHIP.
>> BECAUSE WE LOSE MITOCHONDRIAL
COPY NUMBER AS WE --
>> YES, BUT MANY OTHER
PROPERTIES OF MITOCHONDRIA,
VARIOUS WAYS OF -- THEIR HEALTH,
IT WOULD BE VERY EXCITING.
>> DR. HORVATH, THANK YOU VERY
MUCH FOR A VERY INTERESTING
TALK.
>> THANK YOU.
>> I WANT TO RETURN TO THE
BEGINNING OF IT, WHERE YOU
DESCRIBED THE DEVELOPMENT OF THE
EPIGENETIC CLOCK AND MENTIONED
THAT THE METHYLATION IS AFFECTED
BY DOZENS OF FACTORS, ALMOST
ANYTHING CAN HAPPEN, SMOKING,
ANY EXOGENOUS INFLUENCE, AND YET
YOU WERE ABLE TO EXTRACT A
STABLE BIOMARKER, AND I'M
WONDERING IF YOU HAVE THOUGHT
ABOUT WHAT IT IS IN THE
BIOMARKER OR WHAT IT MIGHT TELL
YOU ABOUT THE BIOLOGY OF
METHYLATION.
ARE THERE CERTAIN POSITIONS THAT
ARE AGE-RELATED PRESUMABLY AND
OTHERS WHICH ARE JUST HIGHLY
VARIABLE AND LABILE?
>> JUST TO TELL THERE YOU IS A
VAST LITERATURE ON STUDYING THE
EFFECT OF AGE ON METHYLATION
LEVELS IN VARIOUS TISSUES.
OVERALL, SIGNIFICANT
TISSUE-SPECIFIC EFFECT.
SO FOR EXAMPLE, CPGs HAVE
CORRELATED AGE AND BLOOD WILL IN
GENERAL BE DIFFERENT FROM CPG
THATHAT CORRELATES WITH AGE IN
MUSCLE TISSUE.
HOWEVER, THE STRIKING AND
SURPRISING THING IS ACTUALLY YOU
CAN IDENTIFY A SUBSET OF CPGs
THAT ARE -- ENCODE SOME SORT OF
A UNIVERSAL PROGRAM THAT IS
TISSUE-INDEPENDENT.
BUT COMING TO YOUR QUESTION, I
THINK IN ORDER TO LEARN THE
BIOLOGY UNDERNEATH IT, ONE
SHOULD NOT LOOK AT MY 353 CPG,
BECAUSE THEY ARE JUST
REPRESENTATIVES OF A GLOBAL IF
PHENOMENON.
SO AGE AFFECTS PROBABLY HUNDREDS
OF THOUSANDS OF CPGs, YOU
KNOW, AND SO -- AND PEOPLE HAVE
CERTAINLY CHARACTERIZED WHICH
CPGs GET HYPERMETHYLATED AS WE
AGE.
THESE ARE CPGs THAT TEND TO BE
LOCATED IN CPG ISLANDS AND
PROMOTERS, WHEREAS CPGs THAT
TEND TO LOSE METHYLATION TEND TO
BE LOCATED IN OUTSIDE OF CPG
ISLANDS.
THE OTHER KEY ITEM IS WHAT WE
AND MANY OTHERS HAVE FOUND
BEFORE IT WAS THAT REGIONS THAT
ARE KNOWN AS POLYCON GROUP
TARGETS, THESE REGIONS TEND TO
GET HYPERMETHYLATED WITH AGE.
IN MY OPINION, THAT'S ONE OF THE
UNDERLYING CAUSES WHY SUCH AN
AGING CLOCK IS POSSIBLE, BECAUSE
THAT'S PROPERTY REALLY PRESERVED
ACROSS MANY TISSUE.
THIS POLYCAN CON PROTEIN PLAY A
VERY IMPORTANT ROLE IN
MAINTAINING -- OF THE STEM CELLS
AND WHEREVER THEY BIND, THESE
REGIONS ALSO GET
HYPERMETHYLATED.
SO THAT'S SOME ANSWER, BUT WE'RE
ONLY AT THE BEGINNING.
I THINK IT'S ONE OF THE GRAND
CHALLENGES, REALLY, TO
UNDERSTAND THE EXACT MECHANISM
OF THIS AGING CLOCK.
THIS CLOCK WAS FOUND BY A
MACHINE LEARNING ALGORITHM WHICH
LED TO AN EXTREMELY ACCURATE
CLOCK, BUT THIS CAME TO THE
EXPENSE -- MANY OTHERS AND I
WORK ON IT CERTAINLY TO KIND OF
DISSECT THE UNDERLYING
MECHANISM.
>> WELL, THANK YOU VERY MUCH FOR
STAYING AND FOR A GREAT
PRESENTATION.
FR YOU WANT TO JOIN US AT THE
NIH LIBRARY FOR A RECEPTION AND
YOU CAN CONTINUE YOUR
CONVERSATION WITH STEVE HORVATH.
