WELCOME.
IT'S MY PLEASURE TO INTRODUCE
OUR SPEAKER TODAY.
I'M RICHARD HODES, HAPPY TO BE
WELCOMING YOU TO THE FLORENCE
MAHONEY LECTURE, THE TITLE OF
WHICH WILL BE TARGETING AGING,
LONGEVITY AND REJUVENATION.
VADIM GLADYSHEV IS THE SPEAKER.
A COUPLE ITEMS OF HISTORY.
ONE IS THE BACKGROUND BEHIND THE
NAMED LECTURER, FLORENCE
MAHONEY.
SO I HAD THE PLEASURE OF KNOWING
FLORENCE MAHONEY, SHE DIED IN
2002 AT THE AGE OF 103, AND SHE
WAS REALLY AN EXTRAORDINARY
PERSON WHO WAS LARGELY
RESPONSIBLE FOR THE FOUNDATION
OF NIA, ALSO SOME OTHER
INSTITUTES, SHE WAS GREAT
POLITICIAN AND SHE WOULD HOLD
COURT WITH INFLUENTIAL
POLITICIANS IN HER HOME IN
GEORGETOWN, WHERE A NUMBER OF
MOVIES HAVE BEEN FILMED AS WELL.
EXTRAORDINARY WOMAN.
AND WE WOULD MEET BEFORE THE
SELECTION OF A SPEAKER, SHE WAS
INSISTENT ON HARD SCIENCE, SHE
WANTED REAL HARD SCIENCE.
UP TO THE AGE OF 103, SHE WAS
SHARP ENOUGH TO BE DELIGHTED
TODAY BY THE CHOICE OF OUR
SPEAKER.
BEFORE WE GET STARTED, WON'T BE
ON SCREEN BUT THOSE INTERESTED
IN CME CREDIT, THE CODE IS
57682.
ON GOOD DAYS, THAT WOULD BE
DISPLAYED UP HERE, BUT I THINK
IT'S GOOD FOR SOME TIME
AFTERWARDS, IF YOU WANT TO COME
UP AND GET IT FROM US LATER, WE
CAN DO THAT.
IN ADDITION, DURING -- THOSE WHO
ARE JOINING BY VIDEOCAST, IF YOU
HAD QUESTIONS, YOU CAN ENTER
THEM UNDER THE LIVE FEEDBACK
ICON AND WE'LL COLLECT THOSE AND
THEY'LL BE READ OUT AND ANSWERED
IN THE DISCUSSION PERIOD.
FOR THOSE HERE IN PERSON, WE
HAVE MICROPHONES TO DO THAT
LIVE.
IT'S ALSO GOING TO BE -- THERE'S
ALSO GOING TO BE A RECEPTION
AFTER THE LECTURE, WANT TO MAKE
YOU ALL AWARE OF THAT WITH SOME
REASONABLY HEALTHY AND BALANCED
REFRESHMENTS.
SO TO INTRODUCE OUR SPEAKER
TODAY, VADIM GLADYSHEV IS
PROFESSOR OF MEDICINE AT
HARVARD, ALSO AN APPOINTMENT AT
THE BROAD INSTITUTE AND HE'S
BEEN A PIONEER IN THE AREA OF
REDOX BIOLOGY AND I'LL ELABORATE
ON THAT A BIT.
HE GOT HIS UNDERGRADUATE DEGREES
IN MOSCOW.
THEN HE CAME FOR POSTDOCTORAL
FELLOWSHIPS HERE ON CAMPUS.
SO HE KNOWS THE PLACE.
OR AT LEAST WHAT IT USED TO LOOK
LIKE.
THIS IS WITH NHLBI AND NCI, BUT
MORE TO THE POINT, HOW MANY OF
YOU NOTICED WHEN YOU WALK BY ALL
THE TIME THE EXHIBIT THAT'S
RIGHT UP THERE ON THE STADMAN
PATH.
EARL AND TERRY STADMAN, HIS
FIRST POSTDOC WAS IN THE STADMAN
LAB.
IF YOU GO UP THERE AND A LOOK AT
A FACE MASK ATTACHED TO A TANK,
HE'S GOT THE RECORD SECOND IN
PLACE FOR NUMBER OF HOURS SPENT
IN THERE.
THIS WAS TO BREATHE AIR IN A
SEALED NITROGEN ENVIRONMENT TO
LOOK AT MICROBES.
THIS WHOLE STORY IN HISTORY
COULDN'T BE MORE FITTING FOR OUR
SPEAKER TODAY.
HE'S TRANSFORMED THE FIELD,
WIDELY RECOGNIZED WITH HIS
CONTRIBUTIONS, NOW AN NIA
GRANTEE, FULL PROFESSOR, EUREKA
PIONEER AWARDS, HIS
CONTRIBUTIONS HAVE BEEN MANY.
SO WITHOUT FURTHER ADO WN AND WH
THAT HISTORICAL INTRODUCTION,
IT'S A GREAT PLEASURE TO WELCOME
HIM TO SPEAK HERE TODAY.
[APPLAUSE]
>> THANK YOU, DR. HODES.
IT'S A GREAT PLEASURE TO BE HERE
GIVING THIS MAHONEY LECTURE TO
YOU, AND THANK YOU, EVERYBODY,
FOR COMING, COMING HERE.
AS YOU MENTIONED I'VE BEEN HERE
AT NIH AND I HAVE MANY GOOD
MEMORIES ASSOCIATED WITH THIS
PLACE.
I'VE BEEN WORKING IN THE 90s
AS A POSTDOC.
AND I WAS WORKING WITH HATFIELD
IN BUILDING 37, HE'S JUST A
WONDERFUL HUMAN BEING, I JUST
YESTERDAY HAD DINNER WITH HIM,
HE IS LONG RETIRED BUT I HAVE
125 PAPERS TOGETHER WITH HIM.
AS DR. HODES MENTIONED, THERE IS
A STADMAN WAY, I ENCOURAGE YOU
AFTER THE LECTURE TO LOOK AT
THIS BECAUSE THERE'S REALLY A
LOT OF HISTORY IN THIS AMAZING
PLACE.
BUT RECENTLY, I'D BEEN --
ACTUALLY NOT RECENTLY, FOR MAYBE
EIGHT YEARS I'VE BEEN WORK ON
AGING AND OF COURSE I'M VERY
GRATEFUL FOR NIA FOR ALL THE
SUPPORT WHICH ALLOWED US TO
STUDY THIS.
BUT THE POINT IS ONCE YOU START
STUDYING AGING, IT'S HARD TO
STUDY ANYTHING ELSE.
IT'S JUST -- THE PROBLEM IS SO
IMPORTANT THAT NOTHING REALLY
COMPARES TO IT I THINK IN
BIOLOGY AND MEDICINE, BECAUSE
THE IDEA IS THAT MOST DISEASES
THAT MEDICINE STUDIES ARE AGING
DISEASES, AND IF YOU CAN TARGET
THE AGING PROCESS ITSELF, YOU
SEE ALL THIS AT ONCE, THIS IS
WHY IT'S SO APPEALING BUT ALSO
IT'S INCREDIBLY DIFFICULT TO DO.
THE FIRST QUESTION WE NEED TO
ASK IS ACTUALLY WHAT ARE WE
STUDYING ACTUALLY WHEN WE SAY
NATIONAL INSTITUTE ON AGING, BUT
WHAT IS AGING?
APPARENTLY, IT'S NOT EASY TO
DEFINE.
AND THERE IS DIFFERENCE OF
OPINION ON THAT TOPIC.
SOME PEOPLE THINK THAT AGING IS
LIKE INCREASED MORTALITY RATE,
INCREASED CHANCE OF DYING WITH
AGE.
SOME PEOPLE THINK IT'S DECREASED
LOSS OF FUNCTION OR SOME PEOPLE
THINK IT'S A PROCESS AFTER
DEVELOPMENT, OTHER PEOPLE THINK
IN TERMS OF THE BIOLOGICAL AGE
OR MAYBE DAMAGE ACCUMULATION.
THERE'S NO DOMINANT IDEA, SO IT
TURNS OUT THAT WHEN WE SAY
AGING, WE USE THE SAME WORD TO
MEAN DIFFERENT THINGS.
BUT TO ME, IT'S THE MOST
CRITICAL QUESTION I FEEL BECAUSE
ALL OTHER -- ALL EXPERIMENTS,
EXPERIMENTAL DESIGN IS BASED ON
THIS CONCEPTUAL UNDERSTANDING.
SO WE NEED TO THINK ABOUT THIS
PROCESS FIRST, AND THEN DESIGN
EXPERIMENTS.
AND IT DOESN'T HAPPEN OFTEN.
ANOTHER WAY TO ILLUSTRATE THIS,
YOU CAN STUDY AGING AT THE LEVEL
OF DYING, MORTALITY, BUT
MORTALITY IS CAUSED BY DISEASES,
WE CAN STUDY MORBIDITY, DISEASE
INCIDENCE, BUT THIS IS TYPICALLY
CAUSED BY FUNCTIONAL DECLINE.
FUNCTION NAT DECLFUNCTIONAL DECY
DAMAGE.
THERE'S NO CONSENSUS IN THE
FIELD THAT AGING STARTS HERE.
THESE LEITMAN 'FESS TA LATE MANF
THIS PROCESS.
I WAS TRAINED AS A BIOCHEMIST
AND I OFTEN THINK ABOUT EMG ENZS
THIS WAY.
SO LET'S CONSIDER AN ENZYME.
THERE MUST BE A GENE FOR THAT
ENZYME THAT CATALYZES THE
PROTEIN, CATALYZES SOME KIND OF
REACTION BUT THIS IS NOT
PERFECT.
IT'S COMPOSED OF ONLY 20 TYPES
OF AMINO ACIDS AND HAS A
FLEXIBLE STRUCTURE, SO THERE IS
NON-ZERO LIKELIHOOD IT SHALL
PRODUCE SOMETHING ELSE.
LET'S CALL IT DAMAGE.
SO AS A RESULT, WE HAVE A GENE
WHICH POSITIVE FUNCTION BUT AS A
RESULT OF THAT FUNCTION, WE HAVE
A NEGATIVE CONSEQUENCE IN THE
FORM OF DAMAGE.
AND IT APPLIES TO AN ENZYME.
NEGATIVE IS CUMULATIVE.
SO IF YOU USE THAT ENZYME EARLY
IN LIFE, UNAVOIDABLY YOU'LL HAVE
LATE DELETERIOUS CONSEQUENCES.
IF WE COULD EXTEND THIS CONCEPT
TO OTHER TYPES OF BIOLOGICAL
PROCESSES AND AS A RESULT DAMAGE
COULD WOMAN IN FORM OF ALL KINDS
OF ERRORS, IMBALANCE IN PROTEIN
COMPLEX, CELL COMPOSITION OF
ORGANS AND SO ON, ALL OTHER
KNOWN AND UNKNOWN FORMS OF
DAMAGE.
BUT THE WORD DAMAGE IS SOMEWHAT
LIMITING, BECAUSE PEOPLE
TYPICALLY THINK OF DAMAGE AS
LIKE MOLECULAR, SOME KIND OF
DAMAGING CHANGES.
BUT WE OFTEN USE THE WORD
DELETERIOME, THIS ENCOMPASSES
ALL NEGATIVE CHANGES AS A RESULT
OF LIFE.
YOU CAN THINK OF IN TERMS OF
CHEMISTRY AS A CUMULATIVE DAMAGE
AT ALL LEVELS OF BIOLOGICAL
ORGANIZATION, OR YOU CAN THINK
IN TERMS OF PHYSICS, LIKE
ENTROPY OR DISORDER.
SO IN THAT SENSE, TO ME, AGING
HAS A PHYSICAL NATURE.
IT COMES ULTIMATELY FROM
PHYSICS.
SO THEN A LIFE EVOLVED TO
COUNTERACT THAT INCREASE IN
ENTROPY AND THERE ARE VARIOUS
STRATEGIES TO DO IT.
ONE SIMPLY IS TO DILUTE THE
DAMAGE.
BECAUSE THERE ARE SO MANY
VARIETY OF DAMAGE FORMS, THE
MEANS OF PROTECTION ARE
OBVIOUSLY LIMITING, BUT CELLS
DON'T NEED TO KNOW THAT WHAT ARE
THE SPECIFIC DAMAGE FORMS IF
THEY CAN DILUTE IT?
SO FOR EXAMPLE, IN HERE, THERE
IS A CELL AND TWO BECOMES FOUR,
IT DIVIDES TWO AGAIN AND SO ON.
THAT'S ONE STRATEGY, TO DILUTE
ENTROPY.
ANOTHER STRATEGY IS GERMLINE,
FOR EXAMPLE.
SO WHEN THERE IS A SUCCESSION OF
ORGANISMS THROUGH GENERATIONS,
THAT'S ALSO A WAY TO DEAL WITH
THIS INCREASED ENTROPY.
AS A RESULT THE NATURE OF AGING
IS PHYSICAL, BUT COUNTERACTED
BIOLOGICALLY.
THROUGH LIFE.
AND SO WE HAVE THIS KIND OF
CONCEPT IN ALL OF OUR RESEARCH
AND THE ACTUAL RESEARCH IS
ORGANIZED LIKE THIS.
SO WE STUDY LONGEVITY, FOR
EXAMPLE, CELL TYPES, ACROSS
DIFFERENT MAMMALS, DIFFERENT
SPECIES HAVE DIFFERENT
LIFESPANS, IN FACT OVER 100 FOLD
DIFFERENCE IN LIFESPAN ACROSS
MAMMALS.
THIS IS US IN SO CALLED
SIGNATURES OF LONGEVITY, WHICH
ARE OMICS PATTERNS, TYPICALLY
OMICS, INDICATIVE OF THE SYSTEM
TO LIVE LONG.
THEY MAY NOT CHANGE WITH AGE B.
WE ALSO STUDY AGING, CHANGES
DURING AGING, AND HERE WE
QUANTIFIED THE AGING PROCESS
THROUGH BIOMARKERS OF AGING.
THIS MAY BE EPIGENETIC CLOCKS,
TRANSCRIPTOMIC CLOCKS, ORGANIZE
BEGAN SPECIFIC CLOCKS AND SO ON.
THESE ARE ACTIONABLE BIOMARKERS
OF AGING.
SO WE ACTUALLY NEED BOTH TO
STUDY THE AGING PROCESS.
AND THE THIRD COMPONENT IS
REJUVENATION.
THIS IS SOMETHING WE NEW IN THE
FIELD WHERE WE FIND THAT CELLS
OR SOMETIMES THE ENTIRE ORGANISM
CAN GO TO THE LOWER BIOLOGICAL
AGE, THE STATE OF LOWER
BIOLOGICAL AGE.
WE CALL IT REJUVENATION.
TRANSITION FROM AN OLDER STATE
TO A YOUNGER STATE.
I WOULD SAY THAT THE AGING
PROCESS ITSELF IS IRREVERSIBLE.
THERE IS NO WAY WITH ALL OF
THESE CHANGES THAT YOU COULD GO
THAT SAME ROAD BACK.
SO AGING IS IRREVERSIBLE, BUT
YOU COULD STILL TARGET AN
ORGANISM OR A CELL OR TISSUE
WHERE IT COULD GO TO A SLIGHTLY
LOWER BIOLOGICAL AGE.
SO THIS STRATEGY ALLOWS US TO
TARGET IN MOUSE MODELS PRIMARILY
AND DIETARY PHARMACOLOGICAL
GENETIC INTERVENTIONS.
AND I'LL GIVE A FEW EXAMPLES OF
HOW WE DO IT.
SO WE START WITH THE GENOMES, WE
ACTUALLY SEQUENCED MANY SPECIES.
THE FIRST ONE WAS THIS ONE, THIS
PAPER PUBLISHED ALREADY A LONG
TIME AGO, BUT I THINK IT WAS THE
FIRST PAPER WHERE GENOME WAS
SEQUENCED WITH THE GOAL OF
UNDERSTANDING LONGEVITY.
ANOTHER ONE IS CALLED -- THIS IS
ALSO A VERY AMAZING ANIMAL, ONE
OF THE SMALLEST MAMMALS BUT
LIVES MORE THAN 40 YEARS.
AND THIS IS THE LONGEST LIVED
MAMMAL CALLED BULLHEAD WHALE,
LIVES MORE THAN 200 YEARS.
WHAT WE FIND THROUGH THIS STUDY
IS THAT VARIOUS SPECIES DEVELOP
THEIR OWN WAY TO LIVE LONG.
SO THE ADAPTATIONS THAT THEY
DEVELOPED ARE NOT NECESSARILY
THE SAME ACROSS THIS LONG LIVED
SPECIES.
SO FOR THESE REASONS, WE ALSO
TRIED TO IDENTIFY COMMON CHANGES
ACROSS VARIOUS GROUPS OF
ANIMALS, AND OUR MAIN FOCUS IS
MAMMALS, SO IN THIS STUDY
PUBLISHED ALMOST TWO YEARS AGO
NOW, WE ACTUALLY ANALYZED 40
SPECIES OF MAMMALS.
THEY ARE SHOAP HERE.
IN THREE ORGANS LOOKING AT THE
GENE EXPRESSION CHANGES.
WE FIND SOME SHOW INCREASED OR
DECREASED EXPRESSION WITH THE
CHANGE IN LONGEVITY ACROSS
SPECIES.
WHAT'S INTERESTING, IF ONE GENE
GOES UP, TYPICALLY IT ALSO GOES
UP IN OTHER ORGANS.
IF IT GOES DOWN TYPICALLY IT
GOES DOWN TO OTHER ORGANS WHICH
INITIALLY WAS COUNTERINTUITIVE
ACTUALLY.
WHY WOULD IT GO SIMILARLY IN
DIFFERENT ORGANS?
BUT THE POINT IS THAT IN EACH
ORGAN, WE HAD ABOUT 500 GENES,
MAYBE 500 TO 1,000 GENES THAT
REPRESENT THESE LONGEVITY
SIGNATURES, WHICH AGAIN IS A
VERY USEFUL MEASURE FOR US,
MEASURE OF POTENTIAL TO LIVE
LONG.
YOU ALSO STUDY LONGEVITY ACROSS
INTERVENTIONS BECAUSE NOW WE
KNOW MANY WAYS TO EXTEND
LIFESPAN IN MODEL ORGANISMS.
I SHOW THIS SLIDE FROM THIS
PAPER PUBLISHED FIVE YEARS AGO,
AND HERE WE STUDY INTERVENTIONS
IN MICE THAT EXTEND LIFESPAN.
AND THE DATA IN THE FORM OF --
MATRIX AND GENE EXPRESSION DATA.
SO KIND OF RED MEANS THE GENE
EXPRESSION CHANGES ARE SIMILARLY
INDUCED BY DIFFERENT LONGEVITY
INTERVENTIONS.
AND BLUE IS KIND OF IN THE
NEGATIVE WAY.
SO YOU CAN SEE ONE CLUSTER, FOR
EXAMPLE, WE CALL IT CALORIE
RESTRICTION CLUSTER, SIMILAR TO
SOMETHING LIKE GROWTH HORMONE
RECEPTOR TO FG21 OR SOME GENETIC
MODELS AND SO ON.
BUT ANOTHER CLUSTER, ONE
COMPOUND CALLED RAPAMYCIN IS
WELL-KNOWN IT EXPANDS LIFESPAN
BUT INTERESTINGLY, IT INDUCES
CHANGES WHICH ARE QUITE
DIFFERENT FROM THE CHANGES
INDUCED BY CALORIE RESTRICTION
CLUSTER.
SO APPARENTLY THERE ARE MANY
WAYS TO MODIFY THE ORGANISM SO
THAT IT LIVES LONGER.
WE DON'T KNOW YET WHICH OF THESE
STRATEGIES MAY BE COMBINED AND
THIS IS CURRENTLY BEING STUDIED
ACTIVELY IN THE FIELD.
NOW WE HAVE THIS LONGEVITY
ACROSS SPECIES, LONGEVITY ACROSS
INTERVENTIONS, AND WE ALSO CAN
ADD ANOTHER DIMENSION WHICH IS
AGING CHANGES, AGING ITSELF.
NOW WE COULD ASK AT THE OMICS
LEVEL, HOW ARE THESE THREE
PATTERNS RELATED TO ONE ANOTHER?
AND THIS DATA SHOW HERE FROM A
PAPER THAT I HAVE -- REALLY
AMAZING RESEARCHER IN THE LAB
WHO DEVELOPED THIS STUDY.
AND I WILL WALK YOU THROUGH THIS
SLIDE.
IN BLUE ARE LONGEVITY CROSS
SPECIES, FOR EXAMPLE, BRAIN
ACROSS MAMMALS.
OR KIDNEY ACROSS MAMMALS AND SO
ON.
AND THE CHANGES CLUSTER WITH ONE
ANOTHER, SO AGAIN, CHANGES IN
DIFFERENT ORGANS ARE SIMILAR
THAT LEAD TO LONGEVITY OF THE
SPECIES.
AND THIS CLUSTER IS AGING, LIKE
AGING ACROSS MUSCLE OF MAMMALS,
BRAIN OF MAMMALS, DIFFERENT
TISSUES OF HUMAN, GLOBAL MEANS
DIFFERENT TISSUES AND SPECIES
AND SO ON.
THEY ALSO CLUSTER WITH ONE
ANOTHER.
AND THIS IS LONGEVITY ACROSS
INTERVENTIONS.
AGAIN, GROWTH HORMONE RECEPTOR,
CALORIE RESTRICTION, RAPAMYCIN,
SO ON.
THEY ALSO MOSTLY CLUSTER WITH
ONE ANOTHER, BUT THEY FORM THREE
DIFFERENT CLUSTERS, AND IF YOU
COMPARE THE CLUSTERS WHAT YOU
FIND IS QUITE STRIKING TO ME.
FIRST THERE IS A SLIGHT POSITIVE
CORRELATION BETWEEN LONGEVITY
ACROSS SPECIES AND AGING.
WHICH ON THE SURFACE MEANS THAT
LONGER LIVED SPECIES ARE OLDER.
THIS MAKES NO SENSE, WHY WOULD
LONGER LIVED SPECIES LIKE HUMANS
BE OLDER, FOR EXAMPLE, THAN
MICE?
BUT OUR INTERPRETATION IS
ACTUALLY QUITE DIFFERENT.
SO WHEN ORGANISMS AGE, THEY
ACCUMULATE DAMAGE, BUT ALSO THIS
DAMAGE INDUCES ACTIVATION OF
PROTECTIVE SYSTEMS.
AND APPARENTLY, THESE PROTECTIVE
SYSTEMS ARE ALSO USED BY LONGER
LIVED SPECIES.
SO THEY ARE NOT OLDER, THEY'RE
JUST BETTER PROTECTED.
THERE IS NO CORRELATION BETWEEN
LONGEVITY ACROSS SPECIES AND
ACROSS INTERVENTIONS WE FIND IN
THE LAB.
SO WHATEVER WE DO IN THE LAB,
DIETARY, PHARMACOLOGICAL,
GENETIC INTERVENTIONS, THEY ARE
QUITE DIFFERENT FROM HOW NATURE
EXTENDS LIFESPAN.
TO ME THIS REPRESENTS AN
UNTAPPED POTENTIAL TO STUDY
LONGEVITY.
THE INFORMATION THAT WE COULD
GAIN FROM ANALYZING LONGEVITY
ACROSS SPECIES COULD BE USED
MAYBE IN THE FUTURE FOR RADICAL
CHANGES IN LIFESPAN, NOT
SOMETHING THAT WE FIND IN THE
LAB WHICH IS QUITE MARGINAL.
TYPICAL INTERVENTION OF MICE ON
ORDER OF 10 TO 20%.
WE NOW CONTINUE ACTIVELY WORKING
IN THIS DIRECTION TRYING TO
UNDERSTAND THESE PRINCIPLES OF
LIFESPAN CONTROL.
NOW I WILL GO TO THE NECK TOPIC,
BIOMARKERS OF AGING, AND TO ME,
THIS IS A TRUE REVOLUTION IN THE
FIELD.
THIS IS SOMETHING THAT HAPPENED
ABOUT 10 YEARS AGO AND THE FIRST
PERSON IS STEVE HORWATH, HE
CALLS IT AGING CLOCKS.
WE FOLLOWED ON THAT AND
DEVELOPED A MOUSE CLOCK.
THIS WAS ALREADY YEARS AGO.
WE SEQUENCE THE GENOME ABOUT 200
MICE OF DIFFERENT AGES AND OUT
OF MILLIONS OF CPG SITES,
IDENTIFIED A FEW LIKE IN THIS
PARTICULAR CASE, LIKE 90 CPG
SITES THAT CONSISTENTLY CHANGE
WITH AGE, INCREASE OR DECREASE
METHYLATION, AND TOGETHER, THEY
REPRESENT A MATHEMATICAL FORMULA
WITH EACH SITE HAS A PARTICULAR
WEIGHT IN THE MODEL WHERE YOU
COULD ACCURATELY PREDICT THE AGE
OF THE MICE.
THIS IS THE ACTUAL AGE OF MICE
IN MONTHS, AND THIS IS THE THE
PREDICTIONED AGE.
YOU CAN SEE THERE IS VERY GOOD
CORRESPONDENCE SO WE CAN
ACCURATELY PREDICT THE AGE OF
THE MICE.
THESE FOUR GROUPS OF MICE ARE
MICE THAT HAVE BEEN SUBJECTED TO
CALORIE RESTRICTION.
AT ANY AGE THESE MICE ARE
LITERALLY YOUNGER BASED ON THIS
CLOCK.
SO THIS CLOCK IS VERY USEFUL TO
IDENTIFY INTERVENTIONS LIKE
THIS.
SO FOR EXAMPLE, IF YOU WOULD
KNOW NOTHING ABOUT CALORIE
RESTRICTION, WHEN THE MICE ARE
10 MONTHS OLD, WE COULD MEASURE
AND SAY THIS ARE YOUNGER, MAYBE
THERE'S POTENTIAL TO EXTEND
LIFESPAN AND WE DON'T NEED TO
WAIT UNTIL MICE DIE.
THIS IS THAT TRACTION OF THE
BIOMARKERS IN HUMAN CLINICAL
TRIALS.
BECAUSE WE CAN LEARN OF THE
POTENTIAL OF CERTAIN PREVENTIONS
WITHOUT WAITING FOR LATE-LIFE
OUTCOMES.
AND ON THIS PART OF THE SLIDE,
IT SHOWS THAT EVEN IF WE
DEVELOPED A CLOCK BASED ON THE
BLOOD OF MICE AND APPLY THIS TO
CELLULAR PROGRAMMING WHERE WE
CAN INDUCE PLURIPOTENT STEM
CELLS, THE AGE ON THIS CLOCK
GOES TO ZERO.
SO OF COURSE EMBRYONIC CELLS
SHOULD BE YOUNG CELLS, BUT IT'S
REALLY NICE THAT EVEN SUCH A
CLOCK, LIKE A BLOOD CLOCK, SHOWS
THE AGE IS ZERO.
SO AGAIN, IT EXTENDS THE
APPLICATION OF THE CLOCKS.
BUT THEN THE QUESTION IS, WHAT
ARE THE BEST BIOMARKERS?
BECAUSE THE FIRST BIOMARKER THAT
WAS DEVELOPED WAS TRAINED ON
CHRONOLOGICAL AGE BUT IN FACT
YOU CAN MEASURE AGING IN
DIFFERENT WAYS.
YOU COULD, OF COURSE, MEASURE
BASED ON CHRONOLOGICAL AGE,
TRAIN THE MODEL CHRONOLOGICAL
AGE, YOU CAN TRAIN A CLOCK BASED
ON FUTURE MORTALITY AND THESE
ARE SO CALLED SECOND -- YOU CAN
TRAIN A CLOCK BASED ON THE RATE
OF CHANGE, THAT'S ANOTHER CLOCK,
YOU CAN BASICALLY MEASURE AGING
IN VERY DIFFERENT WAYS.
TO THIS DAY, IT'S STILL UNCLEAR
WHAT'S THE BEST WAY TO MEASURE
AND GOES BACK TO THE MAIN
PROBLEM THAT I POSED EARLY IN MY
TALK ON THE NATURE OF AGING.
BECAUSE WE VIEW AGING IN
DIFFERENT WAYS, AN THEREFORE, IT
CAN BE QUANTIFIED IN DIFFERENT
WAYS.
SO FOR THIS REASON, OUR LAB AND
MANY OTHER LABS STARTED A SO
CALL WOULD BIOMARKER OF AGING
CONSORTIUM, AND THIS IS AN
INSTRUCTOR IN THE LAB WHO
STARTED THIS WHOLE THING AND
KIND OF BROUGHT TOGETHER THE
COMMUNITY, AS WELL AS JC POGANIK
ALSO.
THIS IS THE FIRST PAPER OF THIS
GROUP, KIND OF POSITIONAL PAPER
WHERE WE DEFINED WHAT IS
BIOLOGICAL AGE, WHAT IS AGING,
WHAT'S THE INTERVENTION, YOU
KNOW, WHAT'S THE APPROACHES TO
ADDRESS THAT.
AND BECOME -- THE FIELD BECOMES
VERY POPULAR.
FOR EXAMPLE, WE HAD A CONFERENCE
LAST FALL AND THERE WAS 450
ATTENDEES FROM 30 COUNTRIES.
INITIALLY -- AND IT'S GROWING
EXPONENTIALLY, IT'S REALLY
AMAZING.
SO MUCH TALENT, SO MANY YOUNG
PEOPLE, PEOPLE ARE COMING FROM
ALL KINDS OF DISCIPLINES.
WE HAD A MEETING TOGETHER, A
CHALLENGE, A BIOMARKER CHALLENGE
WHERE ANYBODY COULD COMPETE,
FOUR, 500 PEOPLE FROM MASS
BRIGHAM GENERAL PATIENTS, GENE
METHYLATION, AND ASKED ANYBODY,
OKAY, TELL US WHAT'S THE AGE?
TELL US HOW LONG ARE THEY GOING
TO LIVE?
BECAUSE ABOUT 16% OF THESE
PEOPLE DIED, SAMPLES FROM 15
YEARS AGO.
THIS IS HOW IT WORKS.
THESE ARE THE THREE WINNERS,
THEY GO BY NICKNAMES.
AND THIS IS THE ACTUAL AGE OF
THE PATIENTS FROM OUR HOSPITAL
AND THIS IS -- SEE HOW WELL THEY
PREDICT?
THIS IS THE KNOWN CLOCKS, AND
IT'S ALL NEW CLOCKS FROM THAT
COMPETITION.
THEY ALL OUTCOMPETED THE
EXISTING CLOCKS.
IT'S REALLY AMAZING HOW, AGAIN,
RAPIDLY THINGS DEVELOPED.
, AND MEAN ABSOLUTE ERROR IS
ALMOST TWO YEARS NOW, AGE CAN BE
PREDICTED OF PEOPLE BASED ON THE
BLOOD ANALYSIS.
AND I WILL SHOW YOU A FEW
EXAMPLES OF HOW WE USE THE
CLOCKS CURRENTLY AND BIOMARKERS.
SO FOR EXAMPLE, IN THIS STUDY,
WHICH IS DONE BY JV POGANIK,
ALSO AN INSTRUCTOR IN THE LAB
AND ALSO HAS HIS OWN PROGRAM
WHERE WE STUDY HOW BIOLOGICAL
AGE CHANGES IN RESPONSE TO
STRESS.
AND HE DESCRIBED SEVERAL TYPES
OF STRESS, LIKE MAJOR SURGERY,
COVID-19, IN EACH SITUATION HE
FOUND UNDER STRESS, BIOLOGICAL
STRESS INCREASES, WE CANNOT SAY
IT GOES EXACTLY TO NORMAL BUT AT
LEAST IT'S DECREASED.
SO FOR EXAMPLE IN PREGNANCY, WE
FIND WOMEN ARE BIOLOGICALLY
OLDER IN THE THIRD TRIMESTER,
AND POSTPARTUM BIOLOGICAL AGE IS
DECREASED.
WHAT IS KNOWN ABOUT GESTATIONAL
DIABETES, HEART DISEASE,
MORTALITY CHANGE DURING THIS
PERIOD, WHICH IS ALSO INCREASED.
AND NOW WE HAVE MANY OTHER
MODELS THAT KIND OF SHOW THIS
CONSISTENT PATTERN.
ANOTHER EXAMPLE I'D LIKE TO SNOW
YOU LAST YEAR, THIS WAS LED BY
ALBERT INN, GRADUATE STUDENT,
DID HIS THESIS LAST WEEK, HE'S
NOW DR. YING.
HE DEVELOPED THE FIRST CAUSAL
CLOCK OF AGING.
WHEN AGING HAPPENS, THINGS
CHANGE, RIGHT?
AND DAMAGE IS ACCUMULATED BUT
ALSO AS I MENTIONED, PROTECTION
AGAINST DAMAGE ALSO CHANGES WITH
AGE.
AND WHEN WE BUILD CLOCKS,
TRAINED FOR LOGICAL AGE -- THE
RESPONSES ARE GOOD, BUT THEY
ALSO BECOME PART OF THE CLOCK.
AND IF YOU RANDOMLY BUILD A
CLOCK AND IT HAPPENS TO BE BASED
ON THESE ADAPTIVE CHANGES, THIS
WILL BE VERY MISLEADING IF YOU
APPLY INTERVENTIONS.
-- DEVELOP CLOCK BASED ON
DAMAGING CHANGES AND ADAPTIVE
CHANGES.
AND WE CALL THEM DAMAGE CLOCK
AND ADAPTIVE CLOCK.
BOTH OF THEM CAN PREDICT CHANGES
WITH AGE, BUT WHEN WE APPLY
THESE CLOCKS TO INTERVENTIONS,
THEY SHOW RADICALLY DIFFERENT
CHANGES.
SO FOR EXAMPLE, HERE IS
REPROGRAMMING FROM MY BRO BLAST
CELLS AND DAMAGE CLOCK SHOWS
REJUVENATION, BUT ADAPT AGE DOES
NOT SHOW REJUVENATION, WHICH
MAKES SENSE.
WE TARGET ADAPTIVE CHANGES, THEY
MAY OR MAY NOT BE REJUVENATED.
SO AGAIN, IT SUGGESTS THAT
FURTHER WORK IS NEEDED IN ORDER
TO VERTICAL BIOMARKERS OF AGING.
IT'S A REVOLUTION, IT'S REALLY
AMAZING WHAT WE HAVE, BUT THE
MANY THINGS ARE STILL UNKNOWN,
AND WE NEED THE EFFORT OF THE
ENTIRE COMMUNITY TO DO IT.
ANOTHER EXAMPLE I'D LIKE TO
GIVE, HERE WE STRIVE TO
UNDERSTAND THE RELATIONSHIP OF
COREGULATED CHANGES AND
STOCHASTIC CHANGES.
DURING AGE SOMETHING, THERE ARE
STOCHASTIC CHANGES I EXPECTED.
MUTATIONS HERE AND THERE, THE
EPI MUTATION, SO ON, BY PRODUCT,
BUT ALSO SOME CHANGES MAY BE
KIND OF DETERM DETERMINISTIC.
WE CALL THEM REGULATORY.
AND HERE ASK A QUESTION, WHICH
ONE ACTUALLY WINS?
IF I LACK ATIF YOU LOOK AT THE L
STATE -- STOCHASTIC CHANGES LIKE
THIS, RANDOM CHANGES.
HE FOUND MANY CHANGES ARE
DETERMINISTIC.
LIKE REGULATORY DURING AGING.
BUT ALSO MANY ARE STOCHASTIC.
SO AGAIN, WE HAVE THIS
DEUMALITY, WHEN WE CAN TO THE
CLEARLY SEPARATE THE STOCHASTIC
NATURE.
BY THE WAY, HE HAS DONE IT BY
ANALYZING SINGLE CELL DNA
METHYLATION VERSUS BULK DNA
METHYLATION.
NOW I'D LIKE TO SWITCH TO
ANOTHER TYPE OF BY OWE MARKER,
TRANSCRIPTOMIC CLOCK.
AMAZING DATASET OF ALMOST 5,000
SAMPLES IN MICE AND RATS AND
LATER IN HUMANS AS WELL, THEY
PRESENT VARIOUS MODELS OF
SHORTER AND LONGER LIFE.
LIKE GENETIC MANIPULATION,
DIETARY, PHARMACOLOGICAL THAT
INCREASE LIFESPAN.
HE DEVELOPED A CLOCK, THIS IS A
CHRONOLOGICAL CLOCK BASED ON THE
TRANSCRIPTOME, AND YOU CAN SEE
IN BLUE IS TRAINING SET, IN RED
THE TEST SET.
YOU CAN SEE IT WORKS PRETTY
WELL.
IN PREDICTING CHRONOLOGICAL AGE.
IT'S A MULTI-TISSUE CLOCK BASED
ON THE RNA SEQ, AND BECAUSE
WE'VE HAD THIS LONGEVITY DATA,
HE WAS ABLE TO PREDICT ALSO
DEVELOPMENT OF A MORTALITY
CLOCK, WHICH QUANTIFIES TIME
UNTIL DEATH.
AND THIS MORTALITY -- YOU SEE
THERE'S VERY GOOD CORRESPONDENCE
ABOUT ACTUAL AND PREDICTIVE
MORTALITY.
AND THIS IS HOW JUST ONE
ILLUSTRATION OF THE USEFULNESS
OF THIS CLOCK.
WE APPLY THESE TO INTERVENTIONS
WHICH ARE ALREADY KNOWN TO
EXTEND LIFESPAN OR DECREASE
LIFESPAN, AND THIS IS CONTROL
AND THIS IS LIFESPAN EXTEND
INTERVENTIONS, THIS IS LIFESPAN
SHORTENING INTERVENTIONS.
YOU CAN SEE THE CLOCK CAN BE
USED TO DISTINGUISH THESE
INTERVENTIONS NICELY.
AND OF COURSE IN THE FUTURE, IT
MAY BE USED, YOU KNOW, WITH
OTHER INTERVENTIONS.
THIS STUDY IS STILL UNPUBLISHED,
CURRENTLY IN SUBMISSION, BUT WE
ARE VERY EXCITED ABOUT THIS
CLOCK AND WE KURNLY APPLY MANY
MODELS, I MENTIONED THIS IN A
FEW TALKS AND WE NOW HAVE
SEVERAL DOZEN COOPERATIONS ON
USING THIS CLOCK.
COLLABORATIONS.
THIS IS ILLUSTRATION OF THE
APPLICATION OF THIS CLOCK.
THESE ARE DISEASES IN MICE, LIKE
ALZHEIMER'S DISEASE MODEL, LIKE
A CHRONIC KIDNEY DISEASE,
ISCHEMIC STROKE AND SO ON.
BUT IN EACH CASE, WE FIND THAT
THE DISEASED TISSUE IN MICE
BASED ON THE TRANSCRIPTOMIC
CLOCK IS OLDER THAN THE CONTROL
SISH TEU.
SO IT'S INTERESTING THAT THIS
REALLY AMAZING RELATIONSHIP
BETWEEN DISEASES IN AGING, WHERE
LIKE DISEASE IS ASSOCIATED WITH
INCREASED BIOLOGICAL AGE IN THAT
PARTICULAR TISSUE.
NOW I'D LIKE TO TELL YOU A
LITTLE BIT ABOUT REJUVENATION.
SO WHY WE DISCUSS AGING, IT'S
REPRESENTED BY THIS WATER KIND
OF GOING FROM THE PIPE, AGING IN
THIS DIRECTION, AND IF YOU CAN
SLOW DOWN THIS PROCESS BY
INTERVENTIONS LIKE CALORIE
RESTRICTION, RAPAMYCIN AND SO
ON, BUT WHAT WE ALSO WOULD LIKE
TO DO, WE WOULD LIKE TO TAKE
WATER FROM HERE AND TAKE IT ALL
THE WAY TO HERE, WHICH MEANS
GOING FROM OLDEST STATE TO A
YOUNGER STATE.
IS THIS EVEN POSSIBLE?
IT'S STILL DEBATED IN THE FIELD
AND SOME PEOPLE THINK
REJUVENATION IS SIMPLY NOT
POSSIBLE.
BUT I THINK BY NOW WE HAVE A FEW
EXAMPLES.
AND THE ONE CLEAR EXAMPLE IS IPS
CELLS.
SO WHEN WE CONVERT SOMATIC CELLS
TO EMBRYONIC CELLS, LITERALLY WE
CONVERT THEM FROM OLDER CELLS TO
YOUNGER CELLS.
THEY'RE EMBRYONIC CELLS, THEY'RE
YOUNG CELLS.
ANOTHER EXAMPLE IN THIS STUDY
PUBLISHED IN AGING, NOW IS A
POSTDOC IN THE LAB AND CLOSE
COLLABORATION IS JEAN WYATT AT
DUKE.
WE USED A MODEL OF HETEROCHRONIC
PARABIODOSIS, WE FOLLOW WHAT
HAPPENS AFTER THREE MONTHS, THEN
THEY SEPARATE AND FOLD OASM THEM
NE THEY DIE.
WHAT WE FIND IS THAT AFTER THIS
PROCESS, THE OLD MOUSE IS
REJUVENATED AND IT LIVES LONGER
COMPARED TO CONTROL.
AT THE LEVEL OF EPIGENETIC CLOCK
SHOWN HERE, BUT ACTUALLY WE HAVE
OTHER CLOCKS AS WELL, WE FIND
THAT THESE MICE ARE LITERALLY
REJUVENATED.
THIS IS THE SITUATION THREE
MONTHS AFTER THEY ARE CONNECTED,
THIS SITUATION IS TWO MONTHS
AFTER THEY'VE BEEN DISCONNECTED.
IT REMAINS THERE.
SO THEY'RE STILL YOUNGER THAN
CONTROLS, AND OAFNTLY THEY LIVE
LONGER.
ALTHOUGH I SHOULD MENTION THAT
THE CHANGE IN BIOLOGICAL AGE IS
MUST STRONGER THAN THE EFFECT OF
LONGEVITY.
IT SEEMS LIKE THIS TIME THE
EFFECT DIMINISHES.
IT STILL REMAINS A LITTLE BIT IN
THAT THEY STILL LIVE LONGER, BUT
THE STRONGEST EFFECT IS REALLY
AT THE TIME WHEN THEY ARE
CONNECTED.
AND OVER TIME, AGAIN, IT
DECREASES.
BUT ANYWAY, THIS REPRESENTS
ANOTHER EXAMPLE OF REEF JEUF
NATION AND WE ALSO STUDY THIS ME
NAN NIS PARTICULARLY.
THE THIRD EXAMPLE I'D LIKE TO
SHOW IS ACTUALLY CURRENTLY THE
ONLY NATURAL PROCESS OF
REJUVENATION.
WE COVERED THIS A FEW YEARS AGO.
THIS WAS A CONCEPTUAL PAPER FOUR
YEARS AGO AND THEN WE HAD A FEW
EXPERIMENTAL PAPERS IN MICE
ITSELF AND SO ON.
AND THIS WAS DONE BY -- AND ALEX
TRAPP, AND LEADS INFORMATICS AT
A BIOTECH COMPANY.
WHAT WE FIND IS THAT WHEN -- AT
THE LEVEL OF THE ZYGOTE, WHICH
IS A FERTILIZED EGG, BIOLOGICAL
AGE IS VERY LOW, BUT IT'S NOT
ZERO.
AND INITIALLY, IT KIND OF STAYS
THE SAME AND THEN ABOUT IN THE
THIRD WEEK OF LIFE, IN HUMAN
LIFE, AND IN MICE OF COURSE IT'S
A LITTLE EARLIER, THERE IS A
REDUCTION IN BU BIOLOGICAL AGE.
THE LOWEST BIOLOGICAL AGE IS
FOUND HERE.
WE CALL IT GROUND ZERO.
AND FROM HERE, FROM THIS POINT,
WE COULD DETECT AN INCREASED
BIOLOGICAL AGE.
WE THINK AGING BEGINS RIGHT HERE
AT THE GROUND ZERO LEVEL AND
THIS IS IN DEVELOPMENT -- SO
AGAIN, WE OBSERVED THIS IN
MULTIPLE SITUATIONS, I MEAN,
THEY SEE THIS AT LEVEL OF
EPIGENETIC CLOCK, WE ALSO -- I
DIDN'T INCLUDE HERE BUT ALEX
ALSO DEVELOPED A SINGLE CELL
EPIGENETIC CLOCK, AND THAT'S
QUITE DIFFERENT.
IT ALSO SHOWS REJEUF RANGE OF
MOTION AND TRANSCRIPTOMIC --
EVEN CONCEPTUALLY W HE KNOW THAT
THE SPERM FROM OLDER MAN IS
OLDER THAN SPERM FROM YOUNGER
MACHINE?
SO THERE MUST BE A PROCESS OF
REJUVENATION SOMEWHERE BUT IT
WAS NOT KNOWN, BUT I THINK THIS
HAPPENS HERE.
MECHANISTICALLY, WE DON'T
UNDERSTAND, BUT WE ARE VERY
EXCITED ABOUT THIS FINDING, IT'S
A NATURAL PROCESS OF
REJUVENATION, APEESHES
UNIVERSALLY ACROSS MAMMALS AND
VERTEBRATES, AND IF YOU
UNDERSTAND MECHANISTICALLY,
PERHAPS IN THE FUTURE, YOU COULD
APPLY TO OTHER SYSTEMS INCLUDING
SOMATIC CELLS.
I WILL SHOW YOU A COUPLE OF
EXAMPLES OF HOW WE STUDY THIS.
THIS IS STRAN SCRIP TOE MIBG
CLOCK.
WE APPLY THIS AT THE SINGLE
LEVEL, SINT .5 -- YOU CAN SEE
THERE'S A NICE REDUCTION IN
BIOLOGICAL AGE.
THE QUESTION IS, OF COURSE, AT
THAT POINT THERE ARE MANY CELLS,
SO WHICH CELLS ARE REJUVENATED
AND WHICH ARE NOT?
AND WE COULD APPLY OUR CLOCK AND
YOU CAN SEE THAT ESSENTIALLY ALL
CELL TYPES ARE REJUVENATED.
THEY GO TO YOUNGER STATE AT THIS
POINT WITH THE EXCEPTION OF
EXTRA EMBRYONIC TISSUES.
SO WE HAVE A FEW EXAMPLES OF
CELLS WHICH LATER BECOME
PLACENTA WHICH ARE NOT
RECIPROCATED -- BUT NOT
REJUVENATED AS LIKE CELLS THAT
BECOME AN EMBRYO IT SELF TO
BECOME REJUVENATED.
AND NOW I'D LIKE TO TELL YOU A
LITTLE BIT ABOUT AN OMICS LEVEL
TO QUANTIFY BIOLOGICAL AGE BASED
ON PROTEOMICS, DONE BY A VERY
TALENTED POSTDOCTORAL FELLOW IN
THE LAB.
HE DEVELOPED A CLOCK THAT
PREDICTS BIOLOGICAL AGE BASED ON
THE PLASMA PROTEOME.
THIS IS AN ACTUAL AGE AND
PREDICTIVE AGE IN COLORS.
THIS IS THE CLOCK TRAINED ON
CHRONOLOGICAL AGE AND THIS IS A
CLOCK TRAINED ON TIME TO -- ALSO
WORKS REALLY WELL.
BUT WE'VE BEEN THINKING THAT WE
ALWAYS DISCUSS BIOLOGICAL AGE OF
INDIVIDUALS, LIKE WHEN WE LOOK
AT THE PERSON AND SAY OH, HOW
OLD IS THIS PERSON?
MAYBE 50 OR 30 OR 90.
BUT PEOPLE ARE COMPLEX ORGANISMS
AND THEIR CELLS AND TISSUES
MIGHT AGE WITH SLIGHTLY
DIFFERENT RATES.
SO WHAT WE REALLY NEED TO THICK
IS NOT JUST A BIOLOGICAL AGE OF
A PERSON, BUT BIOLOGICAL AGE OF
DIFFERENT TISSUES AND CELLS.
THAT'S THE PAPER WE PUBLISHED ON
THAT.
I WOULD MENTION THAT IT WAS --
ANOTHER POPE IF WE DEVELOP
THIS -- PIONEER THIS APPROACH
THE ORGAN-SPECIFIC AGING.
BASICALLY WHAT WE DID, THE STUDY
BIOBANK POPULATION, 40 TO 70
YEARS OLD, BUT 45,000 PEOPLE.
WE HAVE IDENTIFIED PROTEINS IN
PLASMA THAT COME FROM DIFFERENT
ORGANS.
LET'S SAY PROTEINS ARE MADE IN
THE BRAIN, BASED ON BE GENE
EXPRESSION AND WE DETECT THEM IN
PLASMA.
WE ENSURE THAT THESE ARE BRAIN
PROTEINS, AND IF YOU FOLLOW HOW
THEY CHANGE WITH AGE, WE COULD
BUILD A MODEL OF AGING OF THE
BRAIN AND BASED ON THESE PLASMA
PROTEINS, WHICH COULD BE EASILY
ACCESSIBLE BY -- WE CAN PREDICT
THE AGE OF THE BRAIN.
SO THIS WAY WE ARE ABLE TO
PREDICT THE -- BASED ON PROFILE.
THE CLOCK CHRONOLOGICAL AND ALSO
MORTALITY CLOCK, WE CAN ANALYZE
ORGAN -- YOU KNOW, USING THE
SAME INDIVIDUAL.
AND THESE ARE RESIDUALS WHICH
ARE SHOWN HERE FOR THIS OR GAB
AGING SO NOW WE HAVE CLOCK FOR
THE LIVER, BRAIN, ARTERY,
CONVENTIONAL -- YOU KNOW,
INTESTINAL CLOCK, KIDNEY CLOCK,
BASED ON THE PROFILE.
SO THEY'RE CORRELATED WITH ONE
ANOTHER, ALSO IN MORTALITY --
WHO HAS -- SO IT'S EXPECTED.
ORGANS SHOW CORRELATION.
BUT ALSO, THERE ARE SIGNIFICANT
DEVIATIONS, AND MAYBE 2% OF
PEOPLE, MAYBE THEY ARE OLDER IN
THE KIDNEY AND 2% MIGHT BE OLDER
IN THE BRAIN OR IN THE CART AND
SO ON.
SO IN FACT, WHEN WE APPLY OUR
ORGAN-SPECIFIC ASIAN MODELS, WE
FIND REALLY AMAZING
OBSERVATIONS.
FOR EXAMPLE, IF YOU TAKE A --
SPECIFIC MODEL, AND YOU LOOK AT
DISEASES, THE FIRST DISEASE
THAT'S PREDICTED BY THE LANT-YOU
SEE SOPD, OUR ORGAN-SPECIFIC
CLOCKS TRAINED ON MORTALITY PROO
PREDICT AGING-RELATED DISEASES
IN THESE PEOPLE.
NOW WE CAN RELATE THESE, PEOPLE
WITH NEN SHA.
BLUE IS YOUNG, RED IS OLD.
YOU CAN SEE IN MANY OF THE
TISSUES, THEY ARE QUITE YOUNG.
BUT THEY ARE OLD IN THE BRAIN.
LIKE PEOPLE WITH CPG, THEY'RE
OLD IN THE LUNG, AND SO ON.
AND WE ALSO HAVE THIS KIND OF
LARGE METABOLIC CLUSTER, WE
CANNOT -- THEY IB FLEUNS ONE
ANOTHER.
SO NOW THAT WE HAVE THESE ORGAN
SPECIFIC -- AGING IN THE ORGAN
RESULTS IN THE DISEASE IN THIS
ORGAN.
WE COULD INSTEAD OF LOOKING FOR
INTERVENTIONS, THAT EU UNIVERSAY
USED IN HUMANS, THAT TARGET
PARTICULAR ORGANS.
FOR EXAMPLE IF SOMEBODY IS OLD
IN THE BRAIN, MAYBE ALZHEIMER'S
DISEASE, FUTURE ALZHEIMER'S
DISEASE, WE NEED TO TARGET THE
BRAIN -- I THINK THERE WILL BE
NO -- NOTHING WORKS UNIVERSALLY
FOR EVERYBODY.
CALORIE RESTRICTION IS VERY
USEFUL BUT WE NEED TO KNOW WHO
CAN BENEFIT FROM IT, BECAUSE NOT
EVERYTHING -- LET'S LOOK AT THE
ASSOCIATION OF VARIOUS
ENVIRONMENTAL FACTORS.
THESE ORGAN-SPECIFIC AGING.
LIKE THIS ORGAN AGES AND -- BUT
WHICH ORGANS DO I AFFECT BY
SMOKING?
YOU FIND ACTUALLY MOST OF THE
ORGANS ARE AFFECTED.
LET'S LOOK AT DRINKING.
DRINKING IS LTION -- LYLE A
WHOA -- BUT THE EFFECT IS NOT AS
WITH THE CASE OF SMOKING.
KIDNEY, INTESTINAL AGE IS
INCREASED, ARTERIAL AGE IS NOT.
ACTUALLY IF ANYTHING, MIGHT BE
REJUVENATED BY ALCOHOL.
SO DEPENDING ON WHO AGES MORE IN
THE KIDNEY, INTESTINE, ARTERY,
ALCOHOL CONSUMPTION COULD HAVE
RADIALLY DIFFERENT EFFECT.
JUST ANOTHER EXAMPLE JUST TO
ILLUSTRATE THIS POINT.
LET'S CONSIDER ARTERIAL CLOCK.
AGAIN, PLASMA -- YOU TAKE
PROTEINS -- BY THE ARTERY AND WE
TELL THE AGE OF THE ARTERY PLACE
BACEED ON THE PLASMA PROTEOME.
WE LOOK AT ASSOCIATIONS, IN THIS
CASE, FOODS.
LIKE YOGURT AND WINE.
SO WINE FOR THE ARTERY SEEMS
GOOD.
YOE DPURT IS BAD.
YOGURT IS BAD.
BUT IF YOU LOOK AT INTESTINAL
AGING CLOCK, IT'S OPPOSITE.
SO NOW WINE IS BAD, YOGURT IS
GOOD.
SO TENDING ON AGE IS MORE IN ONE
ORGAN OR ANOTHER A DIFFERENT
INTERVENTION WOULD NEED TO BE
USED.
THE INTERVENTION NEEDS TO BE
PERSONALIZED.
SO WHAT CO DOES IT MEAN?
FIRST WE -- OF COURSE I TELL BUT
THE PROTEOMIC-BASED MEASURES,
BUT WE ARE TRYING TO DEVELOP
ADDITIONAL MEASURES OF
ORGAN-SPECIFIC AGING AND OF
COURSE NOT ONLY MY LAB BUT AN
EXCELLENT AREA OF RESEARCH.
WE NEED TO THINK OF TARGETING
ORGANIZE -- IF SOMEBODY AGES
MORE IN ONE PARTICULAR SYSTEM,
LET'S TART THAT BECAUSE THAT
SYSTEM WILL RESULT IN A DISEASE
ANTITHE PERSON WILL DIE FROM IT
MOST LIKELY.
NEED TO THINK OF PERSONALIZED
INTERVENTIONS.
THIS IS OUR MODEL.
LIFE AGAINS HERE, AGING BEGINS
HERE.
REMEMBER GROUND ZERO, THIRD WEEK
OF LIFE IN HUMANS?
THEN -- IN THIS PARTICULAR CASE,
JUST AN EXAMPLE, HEART AGES MORE
THAN OTHER ORGANS.
BUT THE HEART IS NOT SIMPLY
OLDER.
HEART INTERACTS WITH OTHER
ORGANS.
BECAUSE THERE IS A CROSSTALK.
SO OTHER ORGANS WHICH ARE
YOUNGER PULL IT BACK.
SO WITHOUT THESE ORGANS, IT WILL
BE EVEN OLDER, BUT NOW IT'S IN A
SLIGHTLY OLER BUT ALTERED STATE.
AND WE STILL DON'T KNOW EXACTLY
HOW TO DESCRIBE THAT KIND OF
SITUATION.
BUT WHAT I CAN TELL YOU IS THAT
TO US, BASICALLY WE THINK OF
DISEASES AS AGING.
SO TO ME THERE ARE NO DISEASE,
ALL WE HAVE IS AGING.
SO AGING HAPPENS, AND SOME
ORGANS, THEY ARE AGED MORE.
NOT NECESSARILY ORGANS OR
SYSTEMS, SOME PART OF THE ORGAN,
AND THAT STATE RECALL A DISEASE.
-- FROM THAT STATE, WE
CALL A DISEASE.
SO IT HIGHLIGHTS THE IMPORTANCE
OF THE AGING PROCESS IN ANY KIND
OF HEALTH-RELATED ISSUES.
SO I'D LIKE TO SUMMARIZE WHAT I
WAS TELLING YOU TODAY.
SO FIRST WE DISCUSSED A LITTLE
BIT ABOUT THE NATURE OF AGING,
AGING TO ME IS THE INCREASED
DELETERIOME, IT BEGINS AT
GASTRULATION, GROUND ZERO, NOT
ADAPTIVE.
IT HAS PHYSICAL INEVITABILITY,
MANIFESTS CHEMICALLY, MITIGATED
BIOLOGICALLY.
DISCUSSED ACROSS SPEES SHE
CELLS, DIFFERENCES BETWEEN
LONGEVITY AND KNOWN
INTERVENTIONS WHICH HIGHLIGHT,
AGAIN, INDICATES THE POTENTIAL
TO DEVELOP NEW CADICALLY LIFE
SAVING INTERVENTIONS, AND
GENOMES OF LONG LIVED SPECIES.
ALSO I DISCUSSED A LOT ABOUT
AGING BIOMARKERS AT THE LEVEL OF
BULK, SINGLE CELL, STOCHASTIC,
MULTI-TISSUE. ALSO I
HIGHLIGHTED REVERSIBLE CHANGES
IN THE PREDICTED BIOLOGICAL AGE
UPON SEVERE STRESS.
AND ALSO DISCUSSED BIOMARKER OF
AGING CONSORTIUM AND BIOMARKER
CHALLENGE, WHICH IS A COMMUNITY
EFFORT THAT WE SUPPORT.
ANOTHER TOPIC DISCUSSED WAS
REJUVENATION, AND EXAMPLE,
CELLULAR PROGRAMMING.
I DIDN'T MENTION CHEMICALS, BUT
LAST YEAR PUBLISHED A PAPER,
BEING ABLE TO REDUCE BIOLOGICAL
AGE.
ALSO THIS EXAMPLE OF YOU NATURE,
GROUND ZERO, AS WELL AS -- SOME
OF THE EXAMPLES WHERE BIOLOGICAL
AGE CAN BE REDUCED EVEN THOUGH
AGING -- THE AGING PROCESS IS
IRREVERSIBLE.
ALSO FINAL PART OF MY TALK WAS
ON ORGAN-SPECIFIC AGING.
I'VE TOLD BUT ORGAN AGING
MODELS, MORTALITY BASED MODELS
AND ASSOCIATION WITH DISEASES
AND DIETS, WHERE I THINK THAT
ACTUALLY RATED BIOLOGICAL AGE
SUBSYSTEM KIND OF -- AGING IS A
DISEASE, IS REPRESENTED BY
DISEASE AND, THEREFORE,
BIOLOGICAL AGE AS A MEASURE CAN
BE USED TO TARGET A PARTICULAR
PROCESS BEFORE IT HAPPENS,
PREEMPTIVELY.
SO DISEASES IN THAT CONTEXT CAN
BE VIEWED AS POCKETS OF
NON-AUTONOMOUS AGING.
ALL WE DO IS TRY TO UNDERSTAND
AGING, SO AGAIN THERE IS NO
CONSENSUS, BUT IT SUCH AN
IMPORTANT PROCESS BECAUSE IT
AFFECTS OUR HEALTH, LIKE IT
DEPENDS ON STUDYING AGING IN MY
MIND.
THAT'S THE MOST IMPORTANT
QUESTION.
AND THIS IS MY LAB.
THERE IS PEOPLE THAT HAVE BEEN
INVOLVED IN THIS WORK AS WELL AS
PREVIOUS MEMBERS.
WE HAVE MANY COLLABORATORS.
I WOULD LIKE PARTICULARLY TO
MENTION LUIGI FROM THE NIA,
WHO'S A GREAT COLLEAGUE, AND
WHAT HAPPENED YESTERDAY I HOPE
IS A MISTAKE.
AND OF COURSE OUR FUNDING, ALL
OF OUR FUNDING, MOST OF OUR
FUNDING IS FROM NIA, I AM
GRATEFUL FOR NIA AND NIH FOR
ALLOWING US TO DO THIS WORK.
WE ARE VERY PASSIONATE ABOUT IT,
HOPE TO CONTINUE MAKING PROGRESS
IN THE FIELD AS WELL AS OTHER
FUNDERS.
AND WITH THIS, I WOULD LIKE TO
YOTHANK YOU FOR YOUR ATTENTION.
[APPLAUSE]
>> THAT WAS A WONDERFUL TALK.
COULD YOU HAZARD A GUESS ON THAT
ORIGINAL SOURCE OF DAMAGE THAT
INITIATES THE AGING PROCESS?
WHAT DO YOU THINK ABOUT REACTIVE
OXYGEN SPECIES OR INFLAMMATION
AS UPSTREAM EVENT THAT DRIVES
ALL THIS -- ALL THE ORGANS?
>> MY OPINION IS THAT THERE IS
NO SINGLE CAUSE.
SO MUCH OF THE FIELD STUDIES OF
PARTICULAR DAMAGE TYPES, LIKE
YOU MENTIONED -- I COME FROM THE
REDOX BIOLOGY FIELD, THAT'S
MY -- 10 YEARS AGO I PUBLISHED A
PAPER WITH THE TITLE THE FREE
RADICAL -- WE SHOULD NOT LIMIT
OURSELVES TO INDIVIDUAL DAMAGE
TYPES.
SO THERE IS NO ONE MOST
IMPORTANT DAMAGE TYPE.
THE DAMAGE COMES FROM THE
TOTALITY OF BUY OJ THAT HAPP BIT
HAPPENS.
THE FUNCTION OF ITSELF,
GENETICALLY ENCODED TYPICALLY,
BUT ALSO NEGATIVE EFFECT WHICH
IS CUMULATIVE, AND IF YOU TRY TO
ISOLATE U ONE COMPONENT, IT WILL
BE MISLEADING.
SO IT'S A TOTALITY, THAT'S WHY
WE CALL IT THE DELETARIOME.
IT MAKES IT VERY DIFFICULT TO
STUDY BECAUSE WE TRAINED AS
REDUCTIONISTS, OTHERS FEATURED
ON THIS COMPONENT STUDY AND
EXPLAIN THE PROCESS BUT IT
DOESN'T WORK IN THE CASE OF
AGING, IN MY OPINION.
>> I HAVE TWO QUESTIONS.
THE FIRST, GOING BACK TO THE
BEGINNING OF YOUR TALK, WHAT'S
THE EVOLUTIONARY ADVANTAGE OF
LONG LIFE?
SO IF YOU WERE A SMALL RODENT,
LET'S SAY, THAT CAN MATE WHEN
YOU'RE A FEW WEEKS OR A FEW
MONTHS OLD, WHAT'S THE ADVANTAGE
OF LIVING TO THE AGE OF 40?
AND MY SECOND QUESTION HAS TO DO
WITH PARABIOSIS, SO I'VE BEEN
HEARING PEOPLE TALK ABOUT THIS
NOW FOR A NUMBER OF YEARS, SO
THERE MUST BE SOMETHING IN YOUNG
BLOOD THAT CAN BE USED TO
REVERSE AGING IN OLDER ANIMALS
OR OLDER PEOPLE, AND YET I
HAVEN'T HEARD ANYBODY TALK ABOUT
A SUBSTANCE, A CHEMICAL, A
PROTEIN, ANY YOUNG BLOOD THAT
HAS THAT EFFECT.
SO WHAT'S THE REASON FOR THAT?
>> OKAY, THANK YOU.
THAT'S GREAT QUESTIONS.
NOW I FORGOT THE FIRST QUESTION.
>> YES, THE EVOLUTIONARY --
>> ANIMALS ADAPT TO THE
ENVIRONMENT OF THE NICHE.
SOMETIMES IT'S BENEFICIAL TO
REPRODUCE VERY RAPIDLY LIKE IN
THE CASE OF MICE AND RATS, AND
SOMETIMES JUST -- THERE IS
ADVANTAGE TO LIVE LONGER AND
INVEST MORE INTO LIKE A FEW
PROGENY BUT KIND OF PROTECT THEM
REALLY WELL.
IT'S REALLY -- IT'S AN ADAPTIVE
PROCESS, BUT THE ADAPTATION IS
FOR THE FITNESS IN THEIR --
LONGEVITY COMES SEPARATE.
SO I'D LIKE TO MAKE THIS --
DISTINGUISH AGING FROM
LONGEVITY.
AGAIN I ALREADY TRIED IT A
COUPLE OF TIMES.
AGING TO ME IS A WASTE,
LONGEVITY IS ADAPTIVE.
AND PARABIOSIS.
YOU'RE RIGHT, SO THERE HAVE BEEN
MANY STUDIES AND WE STILL DON'T
UNDERSTAND MECHANISTICALLY HOW
IT HAPPENS, BECAUSE IT'S A
COMPLEX MODEL.
SO WHEN WE CONNECT THE MICE,
IT'S NOT SIMPLY LIKE
REJUVENATING FACTORS IN THE
BLOOD THAT GO TO THE OLD
ANIMALS.
BUT ALSO OLDER ANIMALS HAVE
ACCESS TO THE YOUNGER ORGANS.
IT'S VERY DIFFICULT TO SEPARATE
THIS.
TO ME IT'S LOCALLY
MULTIFACTORIAL PROCESS WHERE
MAYBE DAMAGE DELUSION, REMOVAL
OF DAMAGE FL THROUGH YOUNGER
ORGANS, ONCE YOU TRY TO
SEPARATE, ISOLATE, YOU LOSE THE
EFFECT.
SO IN OUR HANDS, WE CANNOT
RECAPITULATE THIS EFFECT BY
YOUNG BLOOD CELLS, FOR EXAMPLE.
SO WE DON'T SEE REJUVENATION.
OF COURSE WE LOOK AT REJEUF
NEAREJUVENATION OF OTHER ORGANS.
IS LIVER REJUVENATED?
WE DON'T OBSERVE THIS EFFECT,
BUT ONCE WE GO INDIVIDUAL MODEL,
SOMEHOW WE LOSE THE EFFECT.
IT'S NOT AN EASY QUESTION.
>> OKAY, THANK YOU.
>> VADIM FIRST OF ALL THANK YOU
FOR A VERY STIMULATING LECTURE
AND IT'S LIKE THE MORE YOU KNOW,
YOU'RE OPENING A PANDORA BOX, SO
ALL KINDS OF INTERESTING THINGS
POP UP.
MY QUESTION IS VERY NARROW.
THERE HAS BEEN A LOT OF
ATTENTION IN THE LAST FEW YEARS
ON EXERCISE AS RESETTING
METABOLISM THAT COULD AFFECT
MANY O ORGANS.
HAVE YOU LOOKED AT SOME OF THE
EFFECTS OF EXERCISE IN YOUR
MODEL, AND IF IT RESETS SOME OF
THE AGING MECHANISM OF
INDIVIDUAL ORGANS WHICH WOULD BE
OF GREAT INTEREST?
>> YEAH, THAT'S A GREAT
QUESTION.
WE HAVEN'T STUDIED IT IN MY LAB,
EXERCISE, OF COURSE THERE ARE
MANY OTHER LABS WHO STUDY AND
THEY DO OBSERVE HEALTH BENEFITS
FROM EXERCISE.
OF COURSE IN HUMANS AND IN MICE.
I HAVEN'T SEEN ANYBODY LOOKING
AT ORGAN SPECIFIC.
ACTUALLY WE DID LOOK A LITTLE
BIT IN THE UK BIOBANK, WE CAN
ALSO PREDICT THE AGE BASED ON
LIKE IMAGING DATA, LIKE A DEXA
SCAN.
IN THIS PARTICULAR CASE, WE FIND
EXERCISE ACTUALLY -- AGING OF
THE BONE EVEN THOUGH IT
REJUVENATES -- HELPS TO SLOW
DOWN AGING OF INTERNAL ORGANS,
SO THERE IS A KIND OF
CONTRASTING -- BUT IT'S
PRELIMINARY DATA, IT'S NOT YET
PUBLISHED.
>> SO VADIM, TAKING OFF ON THIS
QUESTION, THERE ARE RESOURCES
AROUND, REAGENTS, SPECIMENS, FOR
EXAMPLE, FROM EXERCISE
INTERVENTIONS LIKE IN MOTRPAC.
WOULD THE ABILITY TO LOOK --
EVEN IF IT'S JUST SERUM, AT, FOR
EXAMPLE, EXOSOMES OR PARTICLES
WHICH CAN BE ATTRIBUTED TO
VARIOUS ORGANS AND TISSUES, IS
THIS POTENTIALLY A RICH SOURCE
OF INFORMATION ABOUT ORGAN
SPECIFIC -- WITH INTERVENTION,
THAT'S THERE FOR THE ANALYSIS?
>> YEAH, DEFINITELY.
YOU'RE RIGHT.
SO THESE METHODS -- IT'S VERY
NEW, SO JUST PUBLISHED, AND
LIMITED TO SOME DATASET LIKE IN
OUR CASE, IT'S A PROTEOMICS
BASED -- BUT YOU'RE RIGHT, SO
THESE ADDITIONAL APPROACH, WE
SHOULD BE ABLE TO GO
ORGAN-SPECIFIC, IN
ORGAN-SPECIFIC MANNER AND STUDY
ALL OF THESE EFFECTS INCLUDING
EXERCISE.
YOU'RE RIGHT.
>> HI.
SO I THOUGHT IT WAS REALLY
INTERESTING HOW CERTAIN
INVENTION LIKE CALORIC
RESTRICTION OR SENOLYTICS HAD A
DIFFERENT AGING SIGNATURE LIKE
AGING REVERSE SAL RATHER THAN
HOW YOU AGE, AND I WAS WONDERING
IF YOU'VE LOOKED AT HOW
REPROGRAMMING OR THAT
REJUVENATION DURING -- HOW THOSE
ASPECTS OF REDUCING AGING MIGHT
LOOK IN THAT CONTEXT.
>> WE ACTUALLY STUDIED THIS, BUT
WE DON'T HAVE INSIGHTS YET
BECAUSE WE WANT TO BETTER DEFINE
THIS REJUVENATION STATES, AND
LIKE IF YOU NOTICED IN MY TALK
LIKE IN THE CASE WHEN I WAS
TALKING ABOUT REVERSIBILITY IN
BIOLOGICAL AGE, I DIDN'T USE THE
WORD REJUVENATION BECAUSE LIKE
IN THIS CASE, ACTUALLY WE DON'T
KNOW.
IF WE ARTIFICIALLY INCREASE IT
AND THEN TO THE NORMAL STATE, IS
THIS REJUVENATION OR NOT?
I WAS REFERRING TO REJUVENATION
WHEN WE GO FROM THE NORMAL STATE
TO LIKE YOUNGER STATE.
THEN WE SAY REJUVENATION, BUT
BIOLOGICAL AGE FLUCTUATES, LIKE
SEALLY THROUGH STRESS, WHATEVER,
AND WE NEED TO BETTER UNDERSTAND
THOSE SITUATIONS.
BUT IT'S AN EXCELLENT QUESTION
AND HOPEFULLY IN THE FUTURE
WE'LL KNOW MORE ABOUT IT.
>> HI.
SO I THOUGHT THE MENTION OF
ORGAN-SPECIFIC AGING WAS SUPER
INTERESTING.
SO I UNDERSTAND YOU'VE DONE SOME
WORK ON HOW ORGANS AGE
ASYNCHRONOUSLY.
I WAS WONDERING IF YOU'VE DONOR
CONCEPTUALIZED INTERACTIVE
STUDIES, SO KIND OF
UNDERSTANDING HOW AGING OF LIKE
THE LUNGS WOULD CORRELATE WITH
AGING OF THE BRAIN OR AGING OF
THE PANCREAS, CORRELATING WITH
AGING OF THE EYE OR SKIN WITH
THE LIVER, ET CETERA.
YA, AGAIN, SO THIS IS ALL VERY
NEW AND IN ONE SLIDE I SHOWED
THAT THERE IS A CORRELATION, IF
YOU LOOK AT THE POPULATION
LEVEL, THERE IS CORRELATION IN
ONE ORGAN AGING -- ONE ORGAN,
AGING OF ANOTHER ORGAN IN
GENERAL BUT THERE'S OUTLIERS.
SOMETIMES IT'S DIFFICULT TO
RELATE, LIKE, VARIOUS ORGANS.
LIKE FOR EXAMPLE, IN THE
PLASMA -- ORGAN SPECIFIC -- WE
HAVE ACCESS TO MAYBE EIGHT OR
NINE ORGANS IN TISSUES.
SO FOR OTHERS, JUST NOT ENOUGH
DATA.
WE NEED BETTER DATASET.
BUT LIKE EYE, FOR EXAMPLE, WOULD
NOT BE PART OF IT.
SO WE TRY TO LOOK AT THE EYE
THROUGH NOT DEX KA SCAN --
IMAGING, AND ALSO -- BUT IT'S --
AGAIN, SO WE'RE WORKING ON IT,
BUT WE ARE NOT ABLE TO RELATE
YET TO INTERNAL ORGANS.
>> THANK YOU.
>> HI.
SO I WAS CURIOUS ABOUT YOUR
MODELS ON ORGAN-SPECIFIC AGING
AS WELL.
WHAT DID THE DATA LOOK LIKE THAT
YOU BUILT THOSE MODELS ON?
FOR EXAMPLE, HOW WERE YOU ABLE
TO BUILD A MODEL THAT COULD
PREDICT, FOR EXAMPLE, HOW YOE
IMYOGURTAFFECTS INTESTINAL AGIN?
>> THIS DATASET IN UK BIOBANK,
IT'S 50,000 PEOPLE AND THE
DATASET HAS ABOUT 3,000
PROTEINS, QUANTIFICATION OF
3,000 PR PROTEINS.
WE LOOK AT ORGAN-SPECIFIC
EXPRESSION OF GENES BASED ON
GENE EXPRESSION, BECAUSE WE
CANNOT LOOK AT THE PROTEINS,
PROTEIN, IF THEY ARE LIKE IN THE
ORGAN -- IN PLASMA, IT WOULD
BE -- BUT GENE EXPRESSION, IF
IT'S ONLY EXPRESSED IN ONE
PARTICULAR ORGAN AND DETECTED IN
PLASMA, WE CAN SAY OKAY, PROTEIN
COMES FROM THAT ORGAN.
SO NOW WE FOCUS ON ONLY THAT
SUBSET FOR PARTICULAR ORGAN, AND
SOMETIMES IT COULD BE LIKE 20 OR
50 OR HUNDRED PROTEINS WHICH ARE
UNIQUE TO A PARTICULAR ORGAN.
AND WE BUILT AGING BIOMARKERS
BASED ON THAT.
NOW IN PLASMA, WE CAN TELL THE
AGE AND BECAUSE WE HAVE OTHER
PROTEINS FOR OTHER ORGANS FOR
THE SAME PERSON, WE CAN TELL AGE
OF THE BRAIN, LIVER, KIDNEY, SO
ON, INTESTINAL, ARTERY, SO ON.
NOW THERE'S INFORMATION ABOUT
DIET FOR THESE PEOPLE.
NOT ONLY DIETS, BUT DRUGS, LIKE
PROFESSIONS, LIKE LIFESTYLES, WE
DO THIS, ALL OF THIS, AND WE CAN
FIND ASSOCIATIONS OF THIS KIND
OF LIFESTYLE CHANGES, WITH ORGAN
AGING.
SO YOU SEE?
>> SO ALL THE LIKE SORT OF
DIETARY DATA WAS SELF-REPORTED?
>> IT'S -- IN THIS PARTICULAR
CASE, IT'S SELF-REPORTED.
ALSO WE COULD QUANTIFY -- WE
COULD DO VARIOUS WAYS, BUT
SELF-REPORTED BUT ALSO WE
QUANTIFY THE TOTAL AMOUNT OF
CERTAIN TYPES OF FOOD BASED ON
THE KNOWN -- WHEN PEOPLE SAY
WHAT THEY EAT, WE COULD QUANTIFY
BASED ON CALORIES AT COMPONENTS
OF THE FOOD.
>> GOT IT, THANK YOU.
>> HI.
VERY INTERESTING.
SO A QUESTION, SO WHEN YOU
TALKED ABOUT THE DIFFERENT
ORGANS, DIFFERENT SPEED,
DIFFERENT PEOPLE AND DIFFERENT
INTERVENTIONS LIKE FOODS HAVING
DIFFERENT EFFECT, DOES YOUR BODY
TELL YOU WHAT TO EAT DEPENDING
ON THE SIGNALS THAT YOU GET FROM
YOUR ORGANS?
FOR EXAMPLE, LIKE YOUR ARTERY IS
AGING FASTER AND YOU HAVE A
CRAVING FOR WHITE WINE, OR YOUR
INTESTINE AND THEN -- THAT'S WHY
YOU LIKE THE YOGURT DURING THESE
FEW YEARS FOR EXAMPLE AND THEN
DON'T ANYMORE.
>> IT MAY BE, IT MAY BE THE
CASE.
WE HAVEN'T STUDIES THIS.
IT WOULD BE VERY INTERESTING TO
TEST, I AGREE.
IT'S AN IMPORTANT QUESTION.
>> I THOUGHT IT WAS VERY
INTERESTING OF HOW YOU DESCRIBED
CELL DIVISION AS DELUSION OF DIF
DAMAGE.
DO YOU THINK THE SAME CONCEPT AT
A MACROSCOPIC LEVEL, WHERE IT'S
DILUTING DAMAGED PRODUCTS IN THE
BLOOD, AND THEN AS A FOLLOW-UP
TO THAT, DO YOU EVER TEST
WHETHER THE YOUNG MICE AFTER
PARABIOSIS LIVE FOR A SHORT
AMOUNT OF TIME?
>> SO MECHANISTICALLY WE DON'T
FULLY UNDERSTAND BUT I THINK
DAMAGE DILUTION IS DEFINITELY
ONE OF THE FACTORS IN CHANGING
THE BIOLOGICAL AGE.
IN TERMS OF THE OLD MICE, WE
ACTUALLY DO HAVE THE DATA,
PUBLISHED A PAPER ON THAT AND WE
FOUND THAT AFTER THREE MONTHS,
YOUNGER MICE, THEY DR. MATICALLY
INCREASE THEIR BIOLOGICAL AGE,
ALMOST DOUBLE.
TWO MONTHS LAY TE THE BIOLOGICAL
AGE GOES BACK TO ALMOST MORE
MALL.
SO IT SEEMS LIKE UNDER STRESS,
THEY ARE NOT ABLE TO DEAL WITH
ALL THIS DAMAGE THAT COMES FROM
THE OLDER MICE, BUT AFTER THE
MICE ARE SEPARATED, SLOWLY, THEY
ARE ABLE TO RECOVER AND KIND OF
REMOVE THAT DAMAGE.
AND THEREFORE BIOLOGICAL AGE IS
DECREASED.
THE ACCURACY OF THE CLOCKS IS
INSUFFICIENT WHETHER THEY'RE
EXACTLY THE SAME AS NORMAL OR
SLIGHTLY ABOVE, THIS, WE ARE NOT
SURE WITH YOU IT DEFI BUT IT DES
REVERSIBILITY.
>> THANK YOU.
>> THANK YOU FOR A FASCINATING
TALK.
TREMENDOUS BODY OF WORK.
>> THANK YOU.
>> MY QUESTION HAS TO DO WITH
PHYSIOLOGIC STRESS-RELATED
CHANGES.
IN AGING.
YOU MENTIONED AS AN EXAMPLE
PREGNANCY, THEN THERE'S A
REVERSAL IN THE POSTPARTUM
PERIOD.
AND MY QUESTION IS, IS IT AN
UNMECHANISTIC EXPLANATION FOR
THIS REVERSAL IN THE POSTPARTUM
PERIOD?
THE SECOND RELATED QUESTION IS
YOU MAP THE PATTERN OF AGING OF
DIFFERENT O ORGAN, AND MY QUESTN
IS WE HAVE AN ORGAN THAT HAS A
TIMETABLE THAT IS THE PLACENTA.
DO YOU KNOW IF THERE IS AGING OF
THE PLACENTA?
>> LET ME GO FIRST WITH THE
PLACENTA BECAUSE EVENTUALLY WE
DID TEST IT BECAUSE I WAS
THINKING PLACENTA EXACTLY AS YOU
SAY HAS A PARTICULAR TIME SPAN,
AND THEREFORE MIGHT BE OLDER.
BUT WHEN WE TESTED, WE STILL
FIND IT YOUNG.
SOMEHOW IT AGES BUT DOESN'T AGE
AS I THOUGHT IT WOULD AGE.
IT WOULD AGE MORE LIKE THAN THE
EMBRYO, BUT ITS AGE IS ABOUT THE
SAME FOR SOME REASON.
>> SO IT MAY BE THAT THERE IS A
PROCESS THAT IS NOT MEASURABLE
WITH THE TOOLS THAT WE HAVE.
>> IT'S POSSIBLE.
>> BUT PERHAPS IT'S THE WAY THE
QUESTION IS FRAMED.
THIS PHYSIOLOGIC PREGNANCY AND
COMPLICATED PREGNANCY AND IN THE
CONTEXT OF COMPLICATION, LET'S
SAY, PREMATURITY OR
PREECLAMPSIA, WOULD THAT
AFFECT --
>> THIS PREMATURE KIND OF
PREGNANCY, WE HAVE A PROJECT ON
THAT, WE STUDY THIS, WE DON'T
HAVE DATA YET, BUT THAT'S
EXACTLY WHAT -- LIKE EARLY LIFE
ADVERSITY BASICALLY WE CALL
EARLY LIFE ADVERSITY, HOW IT
AFFECTS BIOLOGICAL AGE.
BUT IN TERMS OF REVERSIBLE
CHANGES DURING PREGNANCY, I
THINK DAMAGE DILUTION IS AN EASY
KIND OF WAY TO EXPLAIN IT, AND
THERE'S A HUGE STRESS IN
PREGNANCY ON WOMEN, THEY'RE NOT
ABLE TO DEAL WITH ALL OF THE
DAMAGE THAT IS GENERATED BUT
POSTPARTUM DAMAGE CAN BE SLOWLY
REMOVED.
BUT SOMETIMES I'M GETTING A
QUESTION WHETHER WHEN THEY
RECOVER, THE AGE WILL BE EVEN
LOWER THAN NORMAL.
AND THE REASON IS BECAUSE OF THE
PARABIOSIS WITH THE FETUS.
THAT'S ALSO A VERY INTERESTING
QUESTION.
AFTER WE PUBLISHED OUR PAPER
ABOUT A YEARING A, THERE WAS
ANOTHER PAPER PUBLISHED LATER
ALSO IN CELL METABOLISM, THEY
FOUND THAT THERE MIGHT BE A
REDUCTION EVEN MORE SIGNIFICANT,
OUR -- IN THEIR CASE IT WAS A
BETTER DATASET AND THEY FOUND
ALSO THAT WOMEN WHO BREAST-FED
THEIR BABIES, THEY ALSO
RECOVERED FASTER.
SO IT'S INTERESTING.
SO IT -- IT NEEDS TO BE
REPRODUCED BY OTHER LABS BUT IT
SEEMS LIKE AT LEAST IN THE CASE
OF REVERSAL OF CHANGES DURING
PREGNANCY, THE TWO LABS HAVE
SIMILAR DATA.
>> MAYBE ONE MORE, DR. HODES,
AND THEN WE'LL FINISH UP OVER
HERE.
SHE WAS THERE FIRST.
>> THANKS FOR THE TALK.
AND MY QUESTION IS, THE AGING
COMMUNITY SEEMS TO USE THAT
DEVIATION FROM TRUE PREDICTION
AS A MEASURE OF REJUVENATION,
LIKE, IF WE'RE PREDICTING WITH
LESS ACCURACY, PREDICTING
YOUNGER.
SO MY QUESTION, EVEN WITH -- IF
YOU HAVE A CAUSAL CLOCK AND YOU
INCORPORATE SMR, HOW DO YOU KNOW
IF THERE'S REALLY RELEVANT
BIOLOGICAL CONTEXT IN
REJUVENATION?
>> IT'S A VERY GOOD QUESTION.
SO THE CONCEPT OF BIOMARKERS OF
AGING IS VERY NEW, RIGHT?
AND IT'S POSSIBLE THAT IF YOU
JUST USE ONE INDIVIDUAL
BIOMARKER, IT MIGHT HAVE
MISLEADING EFFECT.
SO IN ANY OF THE STUDIES THAT
DEFINED, THERE IS ALL THIS -- WE
CANNOT BE 100% SURE, THAT'S
TRUE.
BUT FOR EXAMPLE, IN THE CASE OF
LIKE -- IN -- REJUVENATION,
THAT'S WHY I MENTIONED WE HAVE
DIFFERENT TYPES OF CLOCK,
COMPLETELY DIFFERENT, LIKE
TRANSCRIPTOMIC CLOCK -- THEY ALL
SHOW THE SAME.
AND CONCEPTUALLY WE EXPECT TO
SEE THAT AS WELL.
SO THEN WE SAY OKAY, I FEEL
QUITE CONFIDENT THERE IS
EMBRYONIC REJUVENATION.
ALSO FOR PARABIOSIS, WE USE ALL
KINDS OF BIOMARKERS, WE OBSERVE
CONSISTENT EFFECTS SO WE ARE
QUITE CONFIDENT.
IN MANY OTHER CASES, WE ARE
QUITE UNSURE.
IF YOU LOOK N IN THE LITERATURE,
IS IT REJUVENATION, SLOWING OF
AGING OR -- A PARTICULAR
BIOMARKER.
>> HOW DO I RECONCILE IN TERMS
OF SOME SENESCENT CELLS IN AGING
IN DISEASE AND CANCER, THEY
START TO HAVE THE STEMNESS
FACTOR AND IT SEEMS TO PREDICT
YOUNGER, BUT THEY ARE STILL
INCREASING --
> INCREASING
EMBRYONIC STEM CELL MARKERS.
>> EMBRYONIC STEM CELL MARKERS
OF -- IN SENESCENT CELLS?
>> I MIGHT BE WRONG.
IN CANCER CELLS.
>> ON CANCER, I CANNOT BE SURE.
I JUST KNOW SOMETIMES IN THE
CANCERS, WE OBSERVE REDUCTION IN
BIOLOGICAL AGE, MAYBE BECAUSE
CELLS DIVIDE A LOT AND THEY DO
DAMAGE SOMETIMES, INCREASE
BIOLOGICAL AGE, SO THERE'S A LOT
OF HETEROGENEITY IN THE CANCER.
BUT I HAVEN'T SEEN DATA WHICH
WOULD SHOW THAT SENESCENT CELLS
ARE YOUNGER.
I JUST HAVEN'T SEEN IT.
I'VE SEEN THAT SENESCENT CELLS
ARE OLDER, BUT MAYBE I MISSED
SOMETHING.
>> THANK YOU.
>> THANK YOU FIRST FOR A
FANTASTIC LECTURE.
OVER TIME AND NO ONE'S LEAVING.
APOLOGIES TO THOSE WHO WERE
ONLINE AND HAVE THEIR QUESTIONS
WITHOUT TIME, WE'LL SEE WHAT WE
CAN DO ABOUT IT.
AND JUST FOR THOSE THAT DIDN'T
GET THE CME CODE BEFOREHAND,
THERE IT IS, 57682, STILL GOOD,
YOU CAN ENTER IT NOW, AND YES,
PLEASE JOIN US UP AT STADMAN WAY
FOR THE RECEPTION TO FOLLOW.
THANKS SO MUCH.
GREAT TALK.
>> THANK YOU VERY MUCH.
[APPLAUSE]