THIS IS WIN ARIAS AND
WITH MY COLLEAGUE DAN KASTNER AT
THE NATIONAL INSTITUTES OF
HEALTH IN BETHESDA, MARYLAND
EMPLOY WE WELCOME YOU TO ANOTHER
EXCITING SESSION IN THE COURSE
CALLED DEMYSTIFYING MEDICINE
WHICH IS NOW IN ITS 22nd YEAR.
THIS IS A COURSE IN BRIDGE
BUILDING.
THE INTENT IS TO BRIDGE THE
EXCITING DEVELOP AMS IN BIOLOGY,
ENGINEERING AND COMPUTER SCIENCE
WITH MEDICINE.
IT IS NOT LAST WEEK'S RESEARCH
SEMINAR, NOR IS IT LAST WEEK'S
STRICTLY CLINICAL ROUNDS, IT
BRIDGES THESE 2 MAJOR
DISCIPLINES AS ILLUSTRATED IN
THE LOGO IN THE UPPER RIGHT OF
MY PRESENTATION OF THE BROOKLYN
BRIDGE AND WE WILL DISCUSS WHAT
THE 2 INDIVIDUALSOT CAT WALK ARE
CONSIDERING IN A MOMENT.
THE COURSE IS HELD ON FRIDAYS
FROM 3-5:00 P.M. EASTERN
STANDARD TIME FROM JANUARY TO
THE END OF MAY.
YOU CAN WATCH IT LIVE, YOU CAN
ALSO ACCESS IT ON AN NIH
VIDEOCAST WHICH IS INDICATED ON
MY SLIDE.
THE CME CREDIT CODE IS 58785.
AND MOST IMPORTANTLY, WE
ENCOURAGE YOU TO SUBMIT
QUESTIONS DURING THE
PRESENTATIONS AND THEY WILL BE
GIVEN TO THE SPEAKERS AND WILL
BE PART OF WHAT WE ALMOST ALWAYS
HAVE A VIGOROUS DISCUSSION AND
QUESTION AND ANSWER PERIOD AFTER
THE PRESENTATIONS.
AND YOU CAN SUBMIT YOUR
QUESTIONS BY CLICKINGOT SEND
LIVE FEEDBACK ON YOUR VIDEOCAST
DISPLAY.
NOW I BRING YOUR ATTENTION AT
ALL PREVIOUS SESSIONS FROM THE
VERY BEGINNING, ARE ARCHIVED AND
IT IS NOTED ON THE SLIDE.
IF YOU HAVE ANY OTHER QUESTIONS,
GET IN TOUCH WITH US.
THE OVERALL PURPOSE OF THE
PROGRAM IS TO BRIDGE SILOS AT
THE NIH -- TO CHANGE SILOS INTO
A BRIDGE.
MAY WE HAVE THE NEXT SLIDE.
PLEASE.
NEXT.
YEAH.
ALL RIGHT.
TODAY'S TOPIC IS AGING AND
YOU'LL SEE THE ACTUAL TITLE IN A
FEW MOMENTS AND I'VE LIST OFFICE
OF DIVERSITY THIS INTRODUCTORY
SLIDE, THE AGE OF AGING
THEORIES.
IT ACTUALLY GOES FROM GENESIS TO
GENES BECAUSE IN GENESIS STATED
THAT HIS DAYS SHALL BE 120 YEARS
WHICH WILL BE THE LIFE THAT
MOSES LED.
AND EVEN TODAY IN JEWISH
CIRCLES, IT IS SAID [SPEAKING
HEBREW ] MAY YOU LIVE TO BE 120
DAYS.
SO WITH THAT'S WHERE THE 120
DAYS -- 120 YEARS CAME FROM.
THERE WAS MUCH WRITTEN IN THE
ANCIENT TIMES MORE BY PHILOSOPHY
AND SOME OBSERVATION AND I THINK
IT REALLY WASN'T UNTIL THE
19th CENTURY WHEN
METCHNIKOFF TALKED ABOUT THESE
IDEAS WITH THE DISCOVERY OF THE
MICROBIOME AND THE DISCOVERY
THAT THE MICROBIOME COULD
PROLONG AGING AND IT DIDN'T WORK
TOO WELL FOR METCHNIKOFF WHO
DIED IN HIS 60S, I THINK.
BUT IT WAS IN THE 20th
CENTURY, WHEN A NUTRITIONIST
NAMED OSBORN, INTERESTING,
INTRODUCED THE IDEA THAT --
DIETARY RESTRICTION COULD
PROLONG LIFE TO, BUT MANY HAVE
DISCREDITED THAT, PARTICULARLY A
PROFESSOR FROM CAME BRIDGE WHO
LIVED TO BE NIX, AT ANY RATE,
THE IDEA OF PROLONGING LIFE IS
SUSTAINED UNTIL TODAY EMPLOY IN
THE MID20th CENTURY, LEONARD
HA YFLICK INTRODUCED IDEA OF
LIMITED DIVISION, THAT IS THE
CELL COULD ONLY DIVIDE
APPROXIMATELY 50 TIMES.
AND THIS CONCEPT HAS BEEN
RESURRECTED IN THE 21st SEBTRY
WITH THE DISCOVERY OF TELOMERES.
IN ABOUT THE 1980S, LEONARD
GUARENTE AND OTHERS, PRODUCED
THE INTERESTING CONCEPT THAT
PART OF A SIGNALING PATHWAY AND
ACTUALLY PROLONGED LONGEVITY AND
THE QUESTION HAS ALWAYS BEEN IN
MAMMALS AND EVEN SOMEWHAT
COMMERCIALIZED IT AND STRESSING
THE IDEA THAT AGING IN AN
EPIGENETIC PHENOMENA.
AND IT WAS SHOWN THAT ACTIVATION
OF PI3 KINASE, NAD,
ADMINISTRATION AND MET FORMIN
AND THE IDEA OF RESERVE TROL IN
RED WINE COULD BE A LIFE
PROLONGING EFFECTS.
BUT IN 1998, THE DISCOVERY THAT
TELOMERE SHORTENING LED TO
SENESCENCE APOPTOSIS AND EVEN
ONCOGENIC TRANSFORMATION WITH AN
ALTERED LIFE SPAN, INTRODUCED AN
ENTIRELY NEW ERA AND FOR THIS
BLACK BURN, RIDER AND OTHERS WON
THE NOBEL PRIZE IN 2009.
AROUND THAT TIME MANY
LABORATORIES PARTICULARLY THAT
OF DOCTORS AT ALBERT EINSTEIN
STUDYING PATIENTS WITH LONG LIFE
SPANS, LOOKING FOR LONG
LONGEVITY
GENES AND IT'S INTERESTING THAT
A LOT OF THESE STUDY VS BEEN LED
ASTRAY, ON PROBABLY MORE
INTERESTING 1S WHEN STORIES AGO
OF STORIES OF LONG LIVED HILL,
MOUNTAIN PEOPLE IN THE BALKANS,
HAD A LARGE COMSUMPTION OF
YOGURT, THAT THEY LIVED WAY
BEYOND 110 YEARS OLD.
OF COURSE, LATER IT TURNED OUT
THAT THE GENETICS OF THESE
FAMILIES WERE NOT QUITE AS
PRESENTED AND SO THIS QUESTION
WAS SORT OF UNDOUBTED.
THERE'S NO QUESTION THESE VERY
LARGE MEN WERE REALLY HEALTHY
LOOKING BUT WHETHER THEY WERE
REALLY THAT OLD WAS DEBATABLE
AND EVEN A 120 YEAR-OLD FRENCH
LADY WHO WAS RECENTLY DIED, AN
AMAZING STORY, HER QUESTION HAS
ALSO BEEN QUESTIONED THE
ACCURACY OF HER AGE.
THERE'S ALSO THE INTRIGUING
CONCEPT ADVANCED BY A FAMOUS
AMERICAN POET AND PHILOSOPHER
DR. OLIVER WENDLE HOLMES, IN HIS
POEM 1 HORSE SHAY, WHERE IT'S A
1 HORSE CARRIAGE WAS BUILT OUT
OF THE BEST OF ALL POSSIBLE
PARTS AND THEN THEY ALL FELL
APART AT THE SAME TIME AND THIS
HAS BEEN CALLED THE DEACON'S 1
HORSE SHAY SYNDROME?
IS THAT WHAT AGE SUGGEST ALL
ABOUT?
IS IT PREDICTABLE AND
ENVIRONMENTAL?
IS 120 YEAR SURVIVAL POSSIBLE IN
AND IT REALLY WORTH WHILE?
AND SO TODAY WE'RE GOING TO HEAR
FROM 2 EXPERTS ON HOW TO STUDY
AND MAYBE EVEN HOW TO MAKE
POLICY BASED ON THE RESULTS OF
SOME OF THESE STUDIES BECAUSE OF
THE BROAD IMPACT ON SOCIETY.
SO LET ME INTRODUCE OUR 2
SPEAKERS TODAY.
NEXT SLIDE.
OUR FIRST SPEAKER IS LUIGI
FIDUCCI, WHO IS THE DIRECTOR OF
THE NATIONAL
EN--STRATEGIESITUTES OF AGING.
LUIGI IS WORLD WIDE RENOWNED FOR
HIS LONG TIEWF NADEL STUDIES AS
REVEALING SUSCEPTIBILITY TO DEC
AND DISABILITY PARTICULARLY IN
ELDERLY PEOPLE.
HE TRAINED IN MEDICINE AND
EPIDEMIOLOGY IN FLORENCE WHERE
HE RECEIVED BOTH AN MD AND
Ph.D. DEGREES, CAME TO THE
NATIONAL INNSITUTES OF AGING IN
2002, AND IS THE SCIENTIFIC
DIRECTOR.
HE DOES MANY THINGS BUT IS BEST
KNOWN FOR LEADING THE NIA
LONGITUDINAL STUDY SECTION AND
CONDUCTING AGING STUDIES
INCLUDING SENTENARRIANS IN
SARDINNIA AND THE FAMOUS WOMEN'S
HEALTH AND AGING STUDY HERE.
LUIGI IS AN ADVOCATE FOR THE
HEALTHY LIFE SPAN CONCEPT, AN
IDEA THAT ALLOWS PEOPLE TO LIVE
HEALTHY INTO THEIR 90S AS OPPOSE
TO MERELY EXTENDING THEIR LIFE
EXPECTANCY.
OUR SECOND SPEAKER, NEXT SLIDE,
PLEASE.
P A YEL SEN, WITH THE STADTMAN
INVESTIGATOR AND RECEIVED HER
Ph.D. AT GRAD YAWD OFICAL
CUTTA UNIVERSITY IN BIOCHEMISTRY
AND MOLECULAR BIOLOGY AND THEN
DID A POST DOC WITH SHELLLY
BERGER AT THE EPIGENETICS
INSTITUTE OF UNIVERSITY OF
PENNSYLVANIA, DURING WHICH TIME
SHE IDENTIFIED NOVEL EPIGENETIC
REGULATORS OF AGING.
SHE HAS RECEIVED SEVERAL
FELLOWSHIPS DURING THE COURSE OF
HER CAREER.
SHE IS A STADTMAN INVESTIGATOR
AT THE NATIONAL INSTITUTES OF
ANALLING WHERE SHE LEADS A
FUNCTIONAL EPIGENOMICS UNIT IN
THE RNA-REGULATION SECTION OF
THAT INSTITUTE.
HER GOAL IS TO UNCOVER
EPIGENETIC MECHANISMS THAT DRIVE
AGING AND SHE USES A MOUSE MODEL
CAN COMBINES EXPERIMENTAL
COMPUTATIONAL AND GENOME SCALE
APPROACHES TO IDENTIFY NEW
EPIGENETIC TARGETS WHICH
HOPEFULLY WILL COUNTER THE
FUNCTIONAL DECLINE AND DISEASES
OF AGING.
SO THESE ARE OUR 2 INDIVIDUALS
ON OUR BRIDGE TODAY AND WE
WELCOME YOU BOTH AND PLEASE
SUBMIT YOUR QUESTIONS FROM THE
AUDIENCE AND LUIGI, IF YOU WOULD
PLEASE, BEGIN.
THANK YOU.
>> THANK YOU VERY MUCH FOR THE
WONDERFUL INTRODUCTION AND FOR
INVITING ME TO THIS FANTASTIC
PROGRAM AND ABOUT SPEAKING ABOUT
SOMETHING THAT I'M REALLY
PASSIONATE ABOUT AND IT'S JUST
NOT NOW, THAT WILL MAKE SENSE,
BUT YOU KNOW MANY, MANY YEARS
AGO, I WANTED TO STUDY AGING
WHICH I WAS 15 YEARS OF AGE AND
A LOT OF WHAT I PASSED FOR THE
AGE THAT WAS SHOWING AND STILL,
AN IMPORTANT ELEMENT OF AGING
HAS GROWN STUDILY OVER TIME.
IF I COULD HAVE MY FIRST TIME.
>> I'M SORRY DR. FERUCCI, I
THOUGHT
THOUGHT YOU WERE GOING TO SHARE.
>> I THOUGHT DIANEA WAS DOING
IT.
>> YOU ARE COMING ALONG, YEAH,
GOOD.
>> CAN YOU SEE IT.
>> YES, PERFECT.
>> VERY GOOD.
SO THE TALK THAT I'M GOING TO
GIVE IS VERY PROVOCATIVE, I
THINK.
THAT YOU KNOW WITH AGING
POPULATION WE TRULY NEED TO
CHANGE PERSPECTIVE ABOUT WHAT WE
THINK ABOUT HEALTH AND WHAT WE
THINK ABOUT HEALTHCARE.
NEXT.
SO FIRST OF ALL, WHY WE ARE
GAINING SO MUCH FROM AGING?
IT'S A RECENT PHENOMENA, IN
FACT.
IF YOU LOOK AT WHAT HAPPENED
BETWEEN THE 1500 AND MIDDLE OF
THE 1800S, LIFE EXPECTANCY
DURING THE WAR WAS VERY, VERY
LOW, 34 YEARS ON AVERAGE AND
DIDN'T CHANGE MUCH OVER TIME
UNTIL MAGIC HAPPENED AROUND THE
1860 AND WE SEE THAT THE
STARTING OF LIFE EXPECTANCY IS
AT THE SPEED THAT WAS HIGHER AND
HIGHER AND HIGHER.
IT'S QUESTIONABLE WHETHER, YOU
KNOW THEY INCREASE IN THE SPEED
OF LIFE EXPECTANCY IS CONTINUING
OR NOT.
ONE IMPORTANT EVALUATION HERE IS
THAT THE INCREASING LIFE
EXPECTANCY, SUCH A SHORT TIME,
NOT REALLY BE DUE TO GENETIC
CHANGES.
YOU KNOW GENETICS CHANGE WITH
THE EVOLUTION AND APPLY THROUGH
MULTIPLE GENERATIONS.
SO 1860-2023, IT'S REALLY A
GENETIC TIME.
SO THE MOST IMPORTANT CAUSES OF
INCREASING LONGEVITY AND IN
FACT, IT'S LARGELY DUE TO BETTER
NUTRITION, THE ABILITY OF CLEAN
WATER, CLEAN WATER, AND SEWER
AND UNDERSTAND, SOME PEOPLE SAY
LESS THAN 10% IS TO INCREASE.
NEXT SLIDE PLEASE.
OF COURSE, THE INCREASE IN LIFE
EXPECTANT DID NOT OCCUR
HOMOGENIUSLY ACROSS THE WORLD
AND IT WAS AFFECTING MOSTLY
EUROPE AND THE U.S. AT THE
BEGINNING AROUND THE 1800 AND
THEN THEY AFFECT MANY OTHER
COUNTRY, JAPAN, BRAZIL, AND
THEN, MORE RECENTLY, HAVE REALLY
EXPANDED AROUND THE WORLD AND IN
AFRICA ARE STILL LINGERING
BEHIND IN LIFE EXPECTANCY.
SO ALSO IN THIS POPULATION, LIFE
EXPECTANCY HAS BEEN INCREASING
VERY, VERY RAPID LOAMACYY AND IN
FACT, -- RAPIDLY AND IN FACT
BECAUSE OF THE SPEED OF
INCREASING LIFE EXPECTANCY IN
THIS COUNTRY, YOU KNOW THE AGING
OF THE POPULATION IS CREATING A
LOT OF PROBLEMS THAT OCCUR
WITHOUT THE NECESSARY TIME TO
ADAPT THE SOCIETY OF THESE
CHANGES.
NEXT SLIDE.
AND THE OTHER THING I WANT TO
SAY, THAT WHY INITIALLY, THE
INCREASE IN LIFE EXPECTANCY WAS
DUE TO, YOU KNOW BETTER SURVIVAL
OF PEOPLE IN THE FIRST FEW YEARS
OF LIFE, YOU KNOW HIGH MORTALITY
IN THE FIRST YEAR OF LIFE WAS
VERY TYPICAL AROUND THE
BEGINNING OF THE 18th CENTURY.
YOU KNOW INCREASING LIFE
EXPECTANCY IS NOW OCCURRING IN
THOSE THAT ARE 70 YEARS AND
OLDER.
SO WE HAVE AN OLDER POPULATION
THAT IS LIVING LONGER AND
LONGER.
AND THE NEXT SLIDE, THE -- TO
SHOW A SLIDE THAT I'M VERY, VERY
FOND OF THAT WAS PUBLISHED BY
PROBABLY THE MOST DEMOGRAPHER IN
THE WORLD GENE P A PEL, AND
PAPAL TOOK ALL THE DIFFERENT
COUNTRIES IN THE WORLD THAT HAD
THE LONGEST LIFE EXPECTANCY AND
PLOTTED THEM OVER TIME AND
DISCOVERED AND SHOWED IN THIS
PAPER THAT PROBABLY BEEN SHOWN A
HUNDRED THOUSAND TIMES THAT THEY
WERE ALIENATED IN A PERFECT
LINE.
THESE WERE SHOW SHOCKING THAT
THEY WERE, YOU KNOW UNITED
NATIONS MEETINGS THAT DISCUSS
WHETHER THERE'S INCREASE IN LIFE
EXPECTANCY WAS GOING TO CONTINUE
TO SLOW DOWN AND OF COURSE YOU
SEE THOSE DASH RED LINES AND
PEOPLE THOUGHT THEY CANNOT
REALLY BE THINKING IT'S GOING TO
SLOW DOWN AND GO TO SENESCENCE,
AND OF COURSE, YOU KNOW, AS THE
DATA WILL SHOW, THIS IS NOT
TRUE, THE LIFE EXPECTANCY HAS
CONTINUED.
HOWEVER, IN MOST RECENT YEARS
THIS APPROACH HAS BEEN HIGHLY
CRITICIZED AND AS A RESULT FROM
THE FACT THAT, YOU KNOW IF YOU
SELECT ALL THIS POPULATION IN
THE WORLD, YOU CAN ARTIFICIALLY
CREATE THIS.
NEXT SLIDE.
OH, OKAY, I AM ITALIAN SO I HAVE
TO SAY THEY HAVE THE LONGEST
LIFE EXPECTANCY.
CAN YOU JUST GO TO THE NEXT 1
EMPLOY I WANT TO SKIP THIS 1.
CAN I GIVE YOU THE NEXT?
OKAY.
SO 1 OF THE -- YOU KNOW
INCREASING LIFE EXPECTANCY,
CERTAINLY SOMETHING WE HAVE
ACCOMPLISHED AND IT'S SOMETHING
WE NEED TO CELEBRATE.
HOWEVER, AS YOU INCREASE THE
TOTAL AMOUNT OF LIFE, THEY
INCREASE IN PART OF LIFE THAT'S
CHARACTERIZED BY DISEASE OF
DISABILITY, SOME PEOPLE SAY THAT
LIFE, YOU KNOW EXPAND AND THEN
THE BEGINNING.
SO THIS CREATED A LOT OF PROBLEM
BECAUSE THE OLDER POPULATION
MEANS AN ACCUMULATION OF
MORBIDITY.
GIVE ME THE NEXT SLIDE.
SO WHY THIS IS HAPPENING?
I THINK THIS IS PROBABLY THE
MOST IMPORTANT SLIDE OF MY
ENTIRE SHOW, SO A VERY CLEVER
DEMOGRAPHER SUGGESTED IN 2018
THAT THE INCREASING LIFE
EXPECTANCY IN THE WORLD WILL NOT
CONTINUE AND WILL SLOW DOWN
BECAUSE OF MORE AND MORE PEOPLE
WERE ENTERING INTO THE AREA OF
HIGH RISK OF FRAILTY AND
DISABILITY AND THESE ENTERING IN
THEIR AFFECTED DISABILITY ONLY
LEAD TO AN ARK KIEWMULATION OF
MORE AND MORE DISABILITY AND
FRAILTY.
THIS IS ONLY BECAUSE OF THE PACE
OF BIOLOGICAL AGE NOTHING OUR
BODY HAS NOT BEEN SLOWING DOWN.
AND SO AS MORE PEOPLE ENTER INTO
THE AREA OF DISABILITY, THEY
DEVELOP MORE IMMOBILITY AND THIS
IS MORE OF A CHALLENGE FOR THE
INDIVIDUAL AND THE SOCIETY.
THE OTHER PART OF THIS SLIDE,
PLEASE.
SO SUMMARIZING OF THIS SLOW DOWN
IN THE RISE OF LIFE EXPECTANCY
IS A PRODUCT OF OUR SUCCESS,
SHOULD NOT BE CONSIDERED
FAILURE, MORE PEOPLE LIVE BEYOND
OF AGE OF 70 AND ENTER INTO THE
OTHER HIGH RISK OF THIS.
SO OUR GOAL IS TO EXPAND THE
HEALTH EXPECTANT -- DISABILITY
LATE IN LIFE, SO THE OTHER PART
OF THIS LIFE, THERE'S
INFORMATION THAT SHOW WHAT WE
NEED TO DO.
WHAT WE NEED TO DO IS COMPRESS
THE AREA OF DISABILITY AND I
WILL ARGUE THAT LIVING TO 120 IS
NOT SOMETHING MANY PEOPLE WANT.
IF YOU ASK PEOPLE WHAT THEY
REALLY WANT, THEY WANT TO LIVE A
VERY SUCCESSFUL AND ENJOYABLE
LIFE, FOR MANY, MANY YEARS AND
THEN WHEN WE ARE SICK AND
DISABLE, THEY DON'T WANT TO STAY
SICK AND DISABLE FOR VERY LONG.
SO EXPANDING THE LIFE EXPECTANCY
FOR THE INDIVIDUAL FOR SOCIETY
IS MORE IMPORTANT THAN
INCREASING LIFE EXPECTANCY.
THE NEXT SLIDE.
AND IN FACT, YOU KNOW THE
PREDICTION APPEARED TO BE TRUE.
IN 2024, AT END OF 2024, THIS
PAPER WAS PUBLISHED IN NATURAL
AGING SHOWING THAT IN MANY, MANY
COUNTRIES THE RATE OF INCREASE
IN LIFE EXPECTANCY IS DECLINED
AND THIS IS THROUGH IN
PARTICULAR IN THE UNITED STATES
WHERE THE INCREASE IN LIFE
EXPECTANCE SESLOWING DOWN MORE
THAN ANY OTHER COUNTRY IN THE
WORLD.
NEXT SLIDE.
OKAY.
SO WHAT'S HAPPENING IS THAT
AGING, THESE AGING MAKE US LIVE
LONGER, BUT ALSO MAKE OUR LIFE
FOR DISEASE AND DISABILITY BE
LONG.
YOU KNOW I USED TO TALK TO MY
PATIENT WHEN I WAS A PRACTICING
GERIATRICIAN AND THEY USED TO
SAY WHEN YOU HAVE A DISEASE,
WHEN YOU ARE SUFFERING, IN PAIN,
YOUR TIME SEEMS LONGER AND
LONGER.
SO THOSE YEARS THAT PEOPLE LIVE
WITH DISEASES AND DISABILITY GO
SLOWLY AND SEEM TO BE INTERM
MINABLE.
SO THE NEXT SLIDE IS WHAT IS OUR
MISSION?
WHAT DO WE NEED TO DO?
WE NEED TO INCREASE LIFE
EXPECTANCY.
THE REASON WHY YOU SHOULD DO
THAT IS ALSO ECONOMICAL.
IF YOU LOOK AT THIS SLIDE THAT
WAS PUBLISHED NOT MANY YEARS
AGO, IS SHOWING THAT IF YOU LOOK
AT THE CURRENT HEALTH EXPANDER
PER CAPITA, COMPARE THAT WITH
THE DISABILITY, AND MOST
SURPRISINGLY, THE PEOPLE THAT
HAVE LONGER LIFE EXPECTANCY CAN
DISABILITY ARE IN THOSE
COUNTRIES, TO SPEND MORE MONEY
FOR HEALTHCARE.
SO SPENDING MORE MONEY WITH
HEALTHCARE IS ASSOCIATED
PROLONGING SELF.
AND ALTHOUGH IT'S NOT LOGICAL, I
WILL SHOW YOU THIS ABSOLUTELY
MAKES SENSE.
NEXT SLIDE.
WE WANT THE LIFE WE LOST.
HOW DO WE DO THAT?
NEXT SLIDE.
OKAY, MANAGING THAT, THIS IS A
PERSON AND THIS REPRESENT THE
LIFE OF THIS PERSON AND THEN THE
BLUE PART IS THE PART WHEN THEY
LIVE WITHOUT DEC AND DISABILITY
AND THEN AT SOME POINT IN THEIR
LIFE, THEY DEVELOP THE FIRST
DISEASE, SO SOMETIME BETWEEN
BIRTH AND FIRST DISEASE WE CAN
CALL THIS LIFE EXPECTANCY, OR
HEALTH EXPECTANCY, DEPENDING ON
THE DIFFERENT DEFINITION, AND
THEN AFTER THE FIRST DISEASE,
THIS PERSON WILL DEVELOP
ANOTHER, THEN ANOTHER 1, AND
THEN ANOTHER 1.
AND THEN SHOW ME THE NEXT PART
OF THIS SLIDE.
SO THERE'S ANOTHER HYPOTHETICAL
PERSON THAT HAS LONGER DISEASE
LIFE EXPECTANCY OR HEALTH
EXPECTANCY IN SPITE OF THESE
CONDITIONS, 1, 2, 3, DISEASE AND
AGAIN, WE HAVE 1 WITH -- SHOW ME
THE NEXT 1 -- WITH THE SLOWER,
WITH THE SHORTER LIFE EXPECTANCY
AND THE SAME ACCUMULATION OF
MOBILITY ALSO.
SHOW ME THE NEXT PART OF THIS
SLIDE.
THE PROBLEM IS THAT WE ONLY
INTERVENE BY HEALTHCARE AT THIS
POINT OF LIFE.
IN FACT, IN THE UNITED STATES,
WE SPEND 97.5% OF OUR HEALTHCARE
MONEY FOR PEOPLE THAT HAVE SOME
DISEASE AND DISABILITY AND ONLY
2.5% OF THAT MONEY BEFORE THAT
PERIOD.
BUT IN FACT, WHEN WE LOOK AT
PEOPLE WHO HAVE DISEASE, IT DOES
EXPAND WITH THE AGING OF THE
POPULATION AND THIS WILL
ACCUMULATE UNTIL IT WILL BREAK
THE BANK.
WE WILL NOT ALL BE ABLE TO
AFFORD THE HEALTHCARE, THE
BENEFIT OF THE HEALTHCARE THAT
WE HAVE NOW.
SO OUR GOAL IS TO EXPAND HEALTH
EXPECTANCY.
THE NEXT SLIDE.
ONE WAY TO DO THAT IS TO THINK
ABOUT THIS THRESHOLD, IT'S
ACCUMULATING IN OUR BODY, EVERY
YEAR I GO TO A DOCTOR AND THE
DOCTOR LOOK AT ME, AND VISIT ME
LOOK AT MY HEART AND MY LUNGS
AND THEY SAY, YOU'RE FINE,
YOU'RE OKAY AND THE PATHOLOGY
ACCUMULATING IN MY BODY, SO I
WANT TO KNOW WHAT'S GOING ON SO
THAT WHEN I CAN INTERVENE MUCH
EARLIER THAN, YOU KNOW WHEN I
FINALLY DEVELOP A DISEASE AND
SO, I THINK THE WAY I THINK --
NEXT SLIDE -- THAT IN FACT,
THESE ACCUMULATION OF THE
AUTOLOGY THAT HAVE THIS.
SO THE INDIVIDUALS THAT HAVE
FASTER PACE OF AGING AND HAVE
SHORTER LIFE EXPECTANCY WHILE
THE PEOPLE THAT HAVE THE SLOW
PACE OF AGING WILL HAVE A LONGER
HEALTH EXPECTANCY.
NOT ONLY THAT BUT THE PACE OF
AGING CAN BE MEASURED.
SO IF WE COULD MEASURE THE PACE
OF AGING, WE WILL BE ABLE TO
DETECT WHAT ARE INDIVIDUALS THAT
ARE AGING FASTER THAN OTHERS AND
INTERVENE TO SLOW DOWN THE PACE
OF AGING SO THAT WE CAN PREVENT
A NUMBER OF DISEASE ACCORDING TO
THE JOURNAL OF SCIENCE
HYPOTHESIS THAT ARE LINKED TO
THE CASE OF AGING.
THE NEXT SLIDE REALLY SUMMARIZE
THIS CONCEPT IN A SIMPLE WAY.
THE WAY WE DO NOW IS WE THINK OF
AGING ASSOCIATED WITH THE NUMBER
OF DISEASE, NEXT SLIDE, AND THEN
WHEN THIS DISEASE OCCURRED, WE
INTERVENE WITH FANTASTIC
MOMENTARIUM OF DRUGS AND
SURGICAL PROCEDURE THAT YOU KNOW
WE NEED TO BE HAPPY ABOUT
BECAUSE THEY DO IT FOR THESE
PEOPLE BUT WE DO VERY LITTLE TO
AVOID THIS DISEASE TO OCCUR AND
IF WE COULD -- WITH THE NEXT
SLIDE -- SLOW DOWN, GIVE ME THE
NEXT SLIDE.
SLOW DOWN THE PACE OF AGING,
THEN WE CAN PREVENT THEM, YOU
KNOW ALL 1 AT A TIME.
SO HOW DO WE EXPLORE THIS 1
SEPTORS?
THE WAY TO EXPLORE THIS CONCEPT
IS TO CONCEPTUALIZE AGING AS A
RATIO BETWEEN DAMAGE
ACCUMULATION AND RESILIENCE.
SO 1 OF THE MOST ACCEPTED THEORY
OF AGING IS THAT, YOU LEAN FROM
THE AREA OF DYNAMIC, WHERE EVERY
SYSTEM IS SUBJECT TO ANTHROPY,
SO ANTHROPY CAN DAMAGE AT THE
MOLECULAR LEVEL.
BUT THERE ARE A NUMBER OF
BIOLOGICAL MECHANISMS THAT HAVE
BEEN DEVELOPED EVOLUTIONARY AND
P A YEL WILL MORE ABOUT THIS
LATER.
AND THEN WITH AGING YOU HAVE AN
IMBALANCE THEN SO THAT YOU HAVE
DAMAGE ACCUMULATION AND CLOSE TO
THE END OF LIFE, YOUR ABILITY TO
DEAL WITH STRESS AND THEY HAVE
THE ISSUE OF RESILIENCY DO NOT
ALLOW YOU TO LIVE EVEN THE
NORMALLIEST OF LIFE AND THEN YOU
CAN TRANSLATE THIS CONCEPT INTO
SOMETHING WE CAN START
MEASURING.
THIS IS WHEN THE LOWER PART OF
MY SLIDE, YOU WILL SEE THAT OVER
THE GENETIC BACKGROUND, THERE IS
ACCUMULATION OF DAMAGE AND THE
MACROMOLAR LEVEL, THE CALORIES,
THE CARBOHYDRATES, THE DNA ARE
DAMAGED AND THEN THERE ARE A
NUMBER OF BEAUTIFULLY
CONCEPTUALIZED MECHANISMS THAT
REPAIR THEM OR SOMEWHAT PICK OUT
THOSE DAMAGED AND THAT
BIOLOGICAL DAMAGE TRANSLATE INTO
WHAT WE CALL THE PHENOTYPE.
AT SOME POINT WHEN THEY BECOME
SEVERELY LOW, THOSE CALL LOW,
PROBABLY ACCOUNT FOR VISUAL
ACUITY AND HEARING, AND THEN
ALSO STARTS IMMOBILITY AND
DISABILITY AND GAIT.
SO 1 OF THE 3 HERE AND THAT --
YOU KNOW THIS IS AN EXAMPLE AND
P A YEL WILL TALK MORE, I WILL
JUST SHOW 1.
THERE ARE ABOUT 10,000 DAMAGE OF
DNA EACH CELL, EVERY DAY AND
THIS COMPLEX NETWORK OF
MOLECULE, THEY REPAIR THE DNA
CONSTANT, THEY'RE CONTINUOUSLY
AND IF THEY DON'T, THERE IS
SEVERE CONSEQUENCE ON THE
HEALTH.
THE NEXT SLIDE.
BECAUSE OUR BODIES IS REDUNDANT,
THERE IS SOME RESILIENCE, SOME
RESEARCH, SO YOU CAN AFFORD SOME
BIOLOGICAL DAMAGE WITHOUT HAVING
PHENOTYPIC MANIFESTATION.
SO FOR EXAMPLE, YOU CAN HAVE A
LITTLE BIT OF ACCUMULATION OF
SOMATIC MUTATION WITHOUT ANY
MEASURABLE REDACTION OF THE
FUNCTION OF THE DIFFERENT
ORGANS.
AT SOME POINT THE ACCUMULATION,
AND OF COURSE PHENOTYPIC AGING
AND FUNCTIONAL AGING AND
BIOLOGICAL AGING AND THIS IS
IMPORTANT BECAUSE IN BIOLOGICAL
AGING OCCUR BEFORE PHENOTYPIC
AND FUNCTIONAL AGING OCCUR, IF
WE CAN DETECT THE DAMAGE AT THE
ABOUT I ONY LOGICAL LEVEL, WE
CAN INTERVENE EARLY AND AT THE
TIME WHEN THE INTERVENTION IS
MORE EFFECTIVE GIVE ME THE NEXT
SLIDE.
SO THE GLOBAL CHALLENGE FOR THIS
IS TO ACHIEVE LONGEVITY, THE
STATE IN WHICH GOOD HEALTH AND
BIOLOGICAL LIFE SPAN WITH
PHYSICAL CONJUGATE AND SOCIALLY,
WITH THE CROSS POPULATION EMPLOY
THE NEXT SLIDE REALLY PUT THIS
IN CONTEXT, WHAT ARE THE
ADVANTAGE OF THAT INDIVIDUAL
WILL LIVE A VERY STRONG AND YOU
KNOW ENJOYABLE LIFE.
THEY WILL BE INTERGENERATIONAL
SUPPORT, IN SOCIETY, THE ABILITY
AND THE SKILL WITH THE AGE, IT
WILL BE USEFUL FOR SOCIETY, THEY
WILL BE MORE SOCIAL BEHAVIOR,
WHILE THE COST OF INACTION IS TO
HAVE MORE PEOPLE LIVING IN POOR
HEALTH.
THE GDP WILL GO DOWN.
THERE WILL BE INCREASED BURDEN
ON MEDICAL AND SOCIAL CARE FOR
GOVERNMENT AND AT SOME POINT
THERE'S INCREASING FINANCIAL
BURDEN WILL GO INTO THE STRESS
OF INDIVIDUAL AND THE FAMILY.
THE NEXT SLIDE.
SO MAXIMIZING HEALTH, MINIMIZING
MOLECULAR DAMAGE.
NEXT SLIDE.
WITH THE NEXT SLIDE, I WANT TO
TELL YOU WHAT I TELL WHEN THE
NEWSPAPER INTERVIEW ME AND ASKS
THE QUESTION, WHAT IS THE MAGIC?
AND I ALWAYS SAY, THEY ALREADY
HAVE THE MAGIC, YOU KNOW,
CERTAIN BEHAVIOR, EFFECT, DURING
HEALTH EXPECTANCY.
SO BEING PHYSICALLY ACTIVE IS A
GIFT, AND THE MESSAGE WE GIVE TO
OUR OLDER PATIENTS IS WRONG, WE
SAY YOU NEED TO JOG AND PEOPLE
GET DISCOURAGED.
WHAT WE SHOULD TELL THEM IS
THAT, WALK AROUND THE BLOCK AND
THAT IS ALREADY MUCH, MUCH
BETTER THAN SEDENTARY.
WORK ON PREVENTION, TRY TO --
INCREDIBLY IMPORTANT FOR IT.
LEARN SOMETHING NEW, MAINTAIN
HEALTHY WEIGHT, USE YOUR BRAIN
TO LEARN SOMETHING THAT YOU
ENJOY, AVOID ALCOHOL, YOU KNOW I
THINK THAT IT'S CONTROVERSIAL
BUT I THINK YOU DRINK A GLASS OF
WINE PER WEEK, I DON'T THINK YOU
SHOULD BE CONCERNED VERY MUCH.
AND THEN, YOU KNOW HAVE THE
HEALTHY DIET, PROBABLY THE
MEDITERRANEAN DIET IS THE ONLY
DIET AND THEN USE YOUR BRAIN.
I THINK THAT FOLLOWING THIS VERY
SIMPLE SUGGESTION, WILL INCREASE
HEALTH EXPECTANCY AND CREATE A
BETTER MORE HEALTHY LIFE.
THE TRICK HERE IS TO UNDERSTAND
WHAT ARE THE TRANSDUCER OF THIS
MECHANISM.
YOU KNOW, WHY SLEEP IS AFFECTING
YOUR ABILITY TO DEVELOP CHRONIC
DISEASE?
WE DON'T KNOW THAT YET BUT IF WE
ANYHOW MORE, THE PROBLEM IS THAT
COULD BE AN INCREDIBLE POWERFUL
TARGET FOR INTERVENTION, THE
NEXT SLIDE.
SO I WILL SKIP THIS BECAUSE I'M
A LITTLE BIT LATE.
GIVE ME THE NEXT 1 PLEASE.
SO I WANT TO SUMMARIZE MY TALK
WITH A FEW THOUGHTS.
YOU KNOW WE ALWAYS TALK ABOUT
WHAT WE EAT, THE EXERCISE, BUT I
THINK THAT YOU KNOW THE
PSYCHOLOGICAL INTERVENTION THAT
CAN AFFECT THE HEALTH SPAN AND
HEALTHY LIFE ARE BECOMING
EXTREMELY IMPORTANT AND EMERGE
IN THE LITERATURE.
FOR EXAMPLE, IN THIS PAPER, YOU
KNOW NICOLETTI SHOWED THAT
INDIVIDUALS ARE LESS LIKELY TO
DEVELOP AN IMPAIRMENT, SO THAT
CAME TO THE BALTIMORE AGENCY FOR
AGING AND WENT TO THE BOXES, 40
YEARS BEFORE, FOUND THESE
INTERVIEWS AND LOOK AT WHAT
HAPPENED TO THESE PEOPLE AND SHE
FOUND THAT JUST HAVING A
POSITIVE BELIEF ABOUT THE AGING
PROCESS AS A POSITIVE EFFECT FOR
A LONG TIME IN THIS INDIVIDUAL.
THE NEXT SLIDE.
AND THEN, SHE ALSO FOUND THAT
THOSE WITH THE POSITIVE BELIEF,
HAD LESS TANG AND HE WILL
AMYLOID PLAQUES, SO IT'S NOT
JUST SOMETHING THAT SOFT
SCIENCE, IT'S REALLY, REALLY
SOMETHING THAT SEEMS TO BE VERY,
VERY HARD AND VERY, VERY WELL,
YOU KNOW DEFINED.
THE NEXT SLIDE.
SO ANOTHER THING WE DISCOVER IS
THAT, WE NEED TO THINK ABOUT
HEALTH WITH THE LIFETIME
PERSPECTIVE.
AND THIS TIME THE EXAMPLE SHOWS
THAT EXPERIENCING POOR ECONOMIC
CONDITION AT YOUTH, WHILE
LOOKING AT SOCIALIO ECONOMIC
STATE AS ADULT WAS ASSOCIATE
WIDE ACCELERATED AGING AND THAT
FADED OVER TIME BUT IT WAS VERY,
VERY EVIDENT DURING THE GREAT
DEPRESSION.
NEXT SLIDE.
OKAY, SO DURING MY LAST PHASE
SLIDE.
SO 1 THING THAT IS BECOMING
EVIDENT, THERE'S AN
AUTOMECHANISM THAT AFFECT AGING,
SO THAT YOU KNOW FOR EXAMPLE,
EXERCISE AND FRUIT AND VEGETABLE
COMSUMPTION WORK BECAUSE THEY
ARE IN FACT, VERY, VERY MILD
STRESS AND VERY, VERY MILD
STRESS IS GOOD FOR YOU BECAUSE
STIMULATE AND BUILD RESILIENCEY.
GIVE ME THE NEXT SLIDE.
EXAMPLE, I PUT HERE STRESSOR AND
THEN POSITIVE STRESSOR, HEALTHY
DIET, YOU KNOW SOME PHYSICALLY
ACTIVE, GOOD SLEEP, STIMULATING
JOB, NORMAL FAMILY, NORMAL
FINANCIAL STATUS, LIVING IN
NORMAL NEIGHBORHOOD, WHAT
HAPPENS TO THIS, THE REACTIVITY
TEND TO INCREASE AND GET
ACCUMULATING IN INDIVIDUALS AND
THIS MECHANISM ARE IMPORTANT TO
AFFECT THE CASE OF AGING,
REDUCING THEREFORE THE RISK OF
DISABILITY, CHRONIC DISEASE, AND
MORTALITY.
ON THE CONTRARY, IF YOU THINK
ABOUT THE NEGATIVE STRESSOR IN
THE NEXT SLIDE, THE NEGATIVE
STRESSOR DO EXACTLY THE
OPPOSITE, THEY CONSUME THE
ENERGY THAT IS ACCUMULATING, AND
IF YOU ARE USING THIS, YOU KNOW
ENERGY THAT IS ACCUMULATING
EARLY IN LIFE, THAT YOU DON'T
HAVE THE ENERGY LATER IN LIFE,
SO THERE IS AN ACCELERATED
DECLINE OF HEALTH AND
ACCELERATED AGING IN THE END OF
LIFE WHICH LEAD TO LONG PERIOD
OF DISEASE AND DISABILITY.
SO WE NEED TO START THINKING
ABOUT HOW WE WILL AGE AT THE AGE
OF 1.
YOU KNOW THE EXPERIENCE WE MAKE,
THE CHOICE WE MAKE OVER THE
ENTIRE LIFE SPAN ARE GOING TO
AFFECT THE QUALITY OF OUR AGING
AND THIS IS BECOMING VERY, VERY
EVIDENT AS THE EPIDEMIOLOGICAL
STUDY THAT'S SPANNED MANY, MANY
YEARS ARE BECOMING AVAILABLE.
NEXT SLIDE.
SO HELPFUL KEYS TO HAVING A LONG
LIFE, WILL BE THE HEALTH AGENDA
OF THE 21st CENTURY, I THINK
IF YOU CAN MAKE THE 20 YEAR, IF
YOU ARE INCREASING LIFE BY 20
YEAR MEANS WE'RE EXPANDING THE
PERIOD OF LIFE CHARACTERIZED BY
THIS ABILITY AND DISEASE, I
DON'T THINK THIS IS RELIABLE AND
BENEFICIAL GOAL.
THANK YOU VERY MUCH FOR
LISTENING TO MY PRESENTATION.
>> THANK YOU VERY MUCH.
SO NOW P A YEL WILL YOU CONTINUE
PLEASE?
I ASSUME YOU CAN SEE MY SLIDES
AND HEAR ME ALL RIGHT?
>> YES, PERFECT, THANK YOU.
>> OKAY, THANK YOU.
SO FIRST I WOULD LIKE TO THANK
THE ORGANIZERS FOR GIVING ME
THIS OPPORTUNITY AND I'M ALSO
INCREDIBLY GRATEFUL THAT YOU
KNOW I GET TO SHARE THE VIRTUAL
STAGE WITH LUIGI, SO LUIGI, JUST
GAVE YOU AN EPIDEMIOLOGICAL
PERSPECTIVE OF THIS PARTICULAR
QUESTION TODAY AND BEING AN
EXPERIMENTAL BIOLOGIST, I'M
GOING TO GIVE YOU SOME INSIGHT
INTO HOW, YOU KNOW, MAYBE
BIOLOGISTS VIEW THIS QUESTION.
SO THIS FIRST SLIDE IS GIF THAT
TRACES THE MEDIAN AGES ACROSS
ALL COUNTRIES OVER A SPAN OF
ABOUT A HUNDRED YEARS.
AND YOU CAN SEE THE COLORS
GETTING DARKER AS THE DECADES
PROGRESS WHICH ESSENTIALLY MEANS
THAT YOU KNOW, WE ARE GETTING
INTO THE DECADES WHERE WE HAVE A
LOT OF OLDER INDIVIDUALS AMONG
US AND THAT IS CONCERNING, NOT
ONLY BECAUSE YOU KNOW THERE'S
GOING TO BE A LOT OF
SOCIOECONOMIC PRESSURE BUT ALSO
BECAUSE THE QUALITY OF LIFE
HASN'T REALLY CHANGED MUCH IN
RECENT THEORIES AND WE WILL
CONTINUE -- IN SOME SORT OF
DISABILITY.
SO BEFORE I DIVE INTO THE
LECTURE, THE AGING BIOLOGY
LECTURE ITSELF, I WOULD LIKE TO
RECAP JUST VERY QUICKLY, A FEW
TIMES THAT LUIGI PROBABLY
ALREADY INTRODUCED SO, BUT I GO
THROUGH IT VERY QUICKLY, SO THE
FIRST 1 IS LIFE SPAN EXPECTANCY,
THE METRIC WE NORMALLY USE IS
LIFE SPAN EXPECTANCY AT BIRTH
AND YOU CAN THINK OF IT AS
SIMPLY THE AVERAGE LIFE SPAN OF
A POPULATION.
IT IS VERY MUCH DEPENDENT ON
YOUR GENETICS, WHAT YEAR YOU
WERE BORN, WHETHER YOU'RE MALE
OR FEMALE, SO FEMALES TEND TO
LIVE LONGER AS LUIGI SHOWED AND
THEN DEMOGRAPHIC FACTORS
INCLUDING WHETHER YOU'RE LIVING
IN A WEALTHY NATION OR NOT.
SADLY THOUGH, EVEN THOUGH THE
U.S. IS 1 OF THE WEALTHIEST
NATIONS IN THE PLANET, WE WILL
SEE THAT IN 2030 THE U.S. IS
EXPECTED TO TRAIL BEHIND A LOT
OF RICH NATIONS BY A LOT BECAUSE
MAIL LIFE SPAN IS AROUND 70 AND
FEMALE IS 83.
BUT BEYOND LIFE SPAN EXPECTANCY
THERE ARE A FEW KEY TERMS OF
MOST RELEVANCE DUE THAT IDENTIFY
PRESENTATIONS TODAY, IS MAXIMUM
LIFE SPAN, SO THIS IS THE
MAXIMUM TIME THAT A MEMBER OF A
POPULATION HAS BEEN OBSERVED TO
SURVIVE IN CASE OF A HUMAN
POPULATION, IT IS 122 YEARS, THE
FATE OF A FRENCH WOMAN, SO
BECAUSE SHE LIVED TO 122 YEARS,
KEY KIND OF GENETICALLY SAY THAT
MAXIMUM HUMAN LIFE SPAN IS 120
YEARS SO REALLY IT IS JUST FROM
RECORDS AND IF THOSE RECORDS ARE
AROUND THEN WE ARE PROBABLY OFF.
-- ARE WRONG, THEN WE ARE
PROBABLY OFF.
I DON'T THINK SHE DIDN'T LEAD
THE MOST HEALTHIEST OF
LIFESTYLES.
FROM WHAT I HEAR SHE SMOKED
UNTIL SHE WAS 117 YEARS OLD.
SHE DRANK A LOT OF WINE, SO
THAT'S WHY MOST PEOPLE BELIEVE
THAT SHE PROBABLY HAD SOME KIND
OF GENETIC ADVANTAGE.
SO SHE HAD MAYBE SOME LONGEVITY
VARIANTS THAT ALLOWED HER TO
PUSH THE LIMIT AND LIVE UP TO
122 YEARS.
SO FOR LESSER MORTALS LIKE US
WHO PROBABLY DON'T HAVE THAT
ADVANTAGE, WHAT CAN BE TO LIVE
BETTER LIVES AND LUIGI STRESSED
THIS TOWARDS THE END OF HIS
TALK, I THINK WHAT WE SHOULD
REALLY PLAN TO DO IS RATHER THAN
CHASE THE 120 YEAR-OLD DREAM WE
COULD PROBABLY EXTEND THE PERIOD
OF TIME THAT WE ARE HEALTHY
WHICH IS CALLED HEALTH SPAN.
SO THANKFULLY HELT SPAN IS
DETERMINED BY BOTH GENETICS AS
WELL AS ENVIRONMENTAL
INFLUENCES, SO EPIGENETICS.
YOU CAN LOOK AT IT CONVERSELY,
MORE BIDDITY SPAN IS A STATE OF
BEING UNHEALTHY OR SYMPTOMATIC
WITH SOME DISEASE, SO THAT IS
ALSO OBVIOUSLY DETERMINED BY
GENETICS AND EPIGENETICS, SO
THEREFORE GIVEN THAT THAT 120,
YOU'RE FEELING IS A HARD 1 TO
BREAK, PERHAPS WE COULD FOCUS ON
EXPANDING OUR HEALTH SPAN AND
COMPRESSING MORBIDITY TO ACHIEVE
OPTIMUM LONGEVITY.
AND LONGEVITY IS JUST DESCRIBED
AS THE ABILITY TO LIVE A LONG
LIFE BEYOND THE SPECIES SPECIFIC
AVERAGE.
SO IF YOU LIVE BEYOND 79 OR 83
YEARS RIGHT NOW, I THINK YOU'VE
ACHIEVED SOME FORM OF LONGEVITY.
SO AM I SO ACTIVE IN PUSHING THE
120 CEILING?
AND THAT IS REALLY BASED ON
RECENT DATA.
THIS 1 IS A LITTLE OLD, THIS IS
PUBLISHED IN 2016 AND IN THESE 2
NICE FIGURES, THEY ESSENTIALLY
SHOWED THAT IMPROVEMENTS IN
SURVIVAL WITH AGE TEND TO
DECLINE AFTER A HUNDRED, SO YOU
CAN SEE THE PRECIPITOUS DROP AND
IN A RELATED FIGURE RIGHT HERE,
THEY ESSENTIALLY SAID THAT THE
MAXIMUM HUMAN LIFE SPAN HAS NOT
REALLY CHANGED MUCH FROM THE
1990S AND THE WOMAN DIED IN 1997
FROM WHAT I SAW, SO REALLY WE
HAVEN'T EXTENDED BEYOND THAT
MAXIMUM LIFE SPAN AND THEN A
MORE RECENT PAPER IN THIS LUIGI
HIGHLIGHTED AS WELL, IT WAS
SHOWING BY O'SHANSKI'S GROUP IS
THAT IMPROVEMENTS OVER LIFE
EXPECTANCY HAVE IN FACT DECLINED
AND I THINK WHAT THIS REALLY
MEAN SYSTEM EITHER WE ARE
GETTING SICKER, OR IT COULD EVEN
MEAN THAT YOU KNOW WE NEED SOME
RADICAL OUT OF THE BOX THINKING
ABOUT HOW TO PUSH YOU KNOW LIFE
SPAN EXPECTANCY FURTHER.
SO BASED ON THESE 2 STUDIES, I
THINK CHASING THAT 120 GOAL IS
DIFFICULT BUT MEAN WHILE WE CAN
FOCUS ON HEALTH SPAN EXTENSION
AND MORBIDITY COMPRESSION.
AND AS I MENTIONED BEFORE, THOSE
2 ARE REALLY DEPENDENT ON
GENETICS AND EPIGENETICS BUT
THEN WHAT IS THE RELEVANT
CONTRIBUTION TO THOSE 2
PARAMETERS.
SO THIS WAS SHOWN, THAT THIS WAS
INTERROGATED IN THIS STUDY BACK
IN 1990S, USING TWINS, SO HERE
THE SCIENTISTS JUST SIMPLY
PLOTTED LIFE SPAN OF TWIN 1
VERSUS TWIN 2 AND YOU CAN
IMAGINE IF GENETICS WAS THE SOLE
DETERMINANT THIS WOULD BE A
DISCIPLINARY NAG LINE.
BUT THAT IS NOT THE CASE EMPLOY
IT'S A CLOUD OF DATA AND
EPIDEMIOLOGISTS SUCH AS LUIGI
CAN DETERMINE WHAT'S CALLED A
HERITABILITY SCORE FROM THIS
KIND OF DATA DISTRIBUTION AND IT
TURNS OUT THAT THE HERITABILITY
SCORE HERE WAS .25.
WHICH ESSENTIALLY MEANS THAT
GENETIC CANS ONLY EXPLAIN 25% OF
LIFE SPAN IN TWINS SUGGESTING
THAT THE OVERWHELMING 75% IS
PROBABLY ENVIRONMENTAL
INFLUENCES.
BUT BEYOND THAT A MORE RECENT
PAPER LOOKEDDA THE RELATIONSHIP
BETWEEN THE DEVELOPMENT OF
GENETICS, THAT IT CONTRIBUTES 2%
WHEREAS YOUR EXPOSOME, IS ABOUT
17% AND THIS WAS A VERY RECENT
PAPER WHICH LOOKED AT THE I
THINK 500,000 INDIVIDUALS AND
USING THE HUMAN MORTALITY
DATABASE.
SO GIVEN -- GIVEN THESE SORT OF
CONTRIBUTIONS, I THINK, YOU KNOW
MAYBE WE CAN GET A LOT OF
INSIGHTS IF WE LOOK INTO GENETIC
MECHANISMS WHICH IS SOMETHING
THAT I AM GREATLY INTERESTED IN
BUT THAT DOESN'T MEAN THAT WE
SHOULDN'T BE LOOKING AT
GENETICS, RIGHT?
AND SOME PEOPLE HAVE BEEN
STUDYING GENE VARIANTS FROM
CENTENARIANS FOR EXAMPLE, AND
THEY'VE BEEN PUTTING THOSE CELLS
IN CULTURE AND SEE IF THOSE
CELLS HAVE INCREASED CELLULAR
STRESS RESISTANCE OR MAYBE SOME
OTHER ADVANTAGES, SUCH AS TUMOR
SUPPRESS AND SUCH SO THAT IS 1
WAY TO LOOK AT THE FUNCTION OF
THESE LONGEVITY GENE VARIANTS.
BUT ANOTHER WAY I WOULD TALK
ABOUT BRIEFLY IS THE COMPARITTOR
BIOLOGY, SO THIS IS THIS
INCREDIBLE POSITIVE CORRELATION
BETWEEN BODY MASS AND MAXIMUM
LIFE SPAN.
SO HERE, THIS IS A DIAGRAM THAT
ONLY SHOWS MAMMALS BUT EVEN
WITHIN MAMMALS, YOU CAN SEE THAT
YOU KNOW, ON THIS END OF THE
SPECTRUM, THE LONG LIFE SPAN
ANIMALS ARE ALL LARGE MAMMALS
SUCH AS THE BULL HEAD WHALE AND
HUMP BACK WHALE AND SO ON, AND
THEN ON THIS END OF THE SHORT
END OF THE SPECTRUM, YOU HAVE
THESE RODENTS LIKE SMALL MICE
AND RATS AND SUCH.
SO IF YOU NOTICE, HUMANS ARE
PRETTY MUCH AT THIS END OF THE
SPECTRUM, EVEN THOUGH WE ARE NOT
REALLY THAT LARGE OF AN ANIMAL.
SO THAT'S WHY I THINK AS HUMANS
MAYBE DUE TO OUR EVOLVED BRAINS
OR SOMETHING, WE MAY HAVE
ALREADY PUSHED THE LIMITS OF THE
LONGEVITY TO SOME EXTENT AND
THAT'S WHAT I BELIEVE, SO
COMPARATIVE BIOLOGIST THOUGH,
WHAT THEY DO IS THEY STUDY
WITHIN A PARTICULAR AND THEY
LOOK AT LIFE SPAN VARIATION
BETWEEN SPECIES WITHIN THAT
GROUP.
SO FOR EXAMPLE, A CURIOUS CASE
IS OF THE ORDER RODENTS, ON 1
END OF THE SPECTRUM LIKE MICE
AND RATS THAT LIVE MAYBE 5 YEARS
BUT ON THE OTHER END OF THE
SPECTRUM YOU HAVE THESE REALLY
STRANGE ANIMALS, THE BLIND MOLE
RAT AND THE NAKED MOLE RAT THAT
LIVE UP TO 20 OR 30 YEARS WHICH
IS INCREDIBLY LONG LIFE SPANS.
SO WHAT DO COMPARATIVE
BIOLOGISTS DO, IS THEY GO INTO
THESE ANIMALS AND THEY TRY TO
FIND OUT WHAT'S DIFFERENT IN THE
MOLECULAR COMPOSITION AS WELL AS
GENETIC COMPOSITION OF THESE
ANIMALS VERSUS THESE ANIMALS.
SO WHAT THEY FOUND WAS, AND THIS
IS JUST 1 EXAMPLE, BOTH NAKED
MOLE RAT AND BLIND MOLE RATS
HAVE THIS LONG OR THIS HIGH
MOLECULAR MASS, HYALLUREONIC
ACID, IS HELPS YOUR SKIN, JOINTS
AND HELPS TO RETAIN WATER, AND
WHAT THEY FOUND WAS THIS
PARTICULAR MOLECULE PREFERS
STRESS RESISTANCE TO THE CELLS
DERIVE FRIDAY THESE 2 KINDS OF
RATS AND THEN IN THE CASE OF THE
BLIND -- SORRY, THE NAKED MOLE
RAT, IF YOU HAVE THIS MOLECULE,
IT ALSO HELPS IN EARLY CONTACT
INHIBITION, SO IF YOU TAKE
FIBROBLASTS FROM THESE RATS, PUT
THEM IN A DISH, YOUR SOLES DON'T
GROW ON TOP OF EACH OTHER, SO AS
SOON AS THE NEIGHBORS TOUCH EACH
OTHER, THEY UNDERGO
PROLIFERATIVE ARREST.
SO THEY HAVE VERY POTENT EARLY
CONTACT INHIBITION IS THIS CAN
BE PART OF AS A CANCER
RESISTANCE MECHANISM, SO WITH
IMPROVED STRESS RESISTANCE,
CANCER RESISTANCE, THEY CAN
PERHAPS EXTEND THEIR LIFE SPANS,
BUT BEYOND THESE EXTREME
LONGEVITY CREATURES, YOU KNOW
WE'VE LEARNED A LOT FROM OUR
ARGUMENTS OVER THE YEARS AND I
MYSELF, I STARTED MY CAREER
LOOKING AND STUDYING YEAST.
SO HERE I'M SHOWING AGING AND
LONGEVITY STUDIES SO YEAST AND
WORMS AND FLIES HAVE CONTRIBUTED
A LOT TO OUR UNDERSTANDING OF
THE NUTRIENT SIGNALING LIKE THE
MTORE PATHWAY OR INSULIN
PATHWAY, SO THEN WE STARTED
GETTING MORE VERTEBRATE MODELS
OF AGING LIKE ZEBRAFISH AND THE
NEW KELLY FISH MODEL, AND THIS
KELLY FISH ONLY LIVES 6 MONTHS
SO VERY EASY TO DO LIFE SPAN
STUDIES ON, RODENTS OBVIOUSLY
HAVE CONTRIBUTED A LOT, AND
CONTINUE TO DO SO, RECENTLY, YOU
MAY HAVE HEARD OF THE AGING
PROJECT THAT WAS AT SOME POINT
FUNDED BY NIH, AND YOU KNOW
WE'VE LEARNED A LOT FROM THAT
PROJECT, AND YOU MAY HAVE
RECENTLY HEARD OF A PARTICULAR
MOLECULE BEING EVALUATED BY FDA
FOR MOLECULES TARGETING METADOLL
BOLLICI AND PRIMATES ARE CLOSE
TO HUMANS AND IF YOU WANT TO
STUDY HUMANS THEMSELVES, CAN YOU
STUDY HUMAN CELLS AND ORGANOIDS
AND MAYBE EVEN DIRECTLY LOOK AT
TISSUE BIOPSIES.
SO WHAT WE HAVE WE REALLY
LEARNED FROM ALL THOSE MODEL
SYSTEMS AND ORGANISMS.
WE HAVE LEARNED THAT THERE ARE
CERTAIN MOLECULAR PATTERNS THAT
EMERGE DURING AGE XG THESE HAVE
BEEN ORGANIZED INTO WHAT'S CALLS
FOR SPECULATIONED THE HALLMARKS
OF AGING AND THERE ARE 12 OF
THEM AND THEY ARE CATEGORIZED
INTO THESE 3 GROUPS.
IN BLUE ARE THE PRIMARY
HALLMARKS WHICH ARE THE MOST
UPSTREAM, MAYBE HER HAPPENS EVEN
CAUSAL CHANGES THAT OCCUR, MORE
CELLULAR RESPONSE TO THE PRIMARY
CHANGES AND FINALLY INTEGRATIVE
HALLMARK IS MORE OF A SYSTEMIC
RESPONSE TO THE PRIMARY AND
ANTAGONISTIC CHANGES.
NOW EVEN THOUGH THESE DIFFERENT
HALLMARKS IN THIS PICTURE LOOK
VERY DISCONNECTED FROM EACH
OTHER, THE TRUTH IS THEY ARE
VERY MUCH CONNECTED SO FOR
EXAMPLE, GENOMIC INSTABILITY CAN
AUSCELLULAR SENESCENCE RESPONSE,
AND THEN SENESCENT CELLS AND I
WILL TALK ABOUT THIS A LOT MORE,
THEY RELEASE A WHOLE LOT OF PRO
INFLAMMATORY CYTOKINES AND THAT
CAN CAUSE, YOU KNOW, CHRONIC
INFLAMMATION SYSTEMICALLY.
SIMILARLY ALL OTHER HALLMARKS
ARE IN SOME WAY CONNECTED TO
EACH OTHER FORM THANKSGIVING
REALLY COMPLEX NETWORK, WHICH I
THINK IS BOTH GOOD AND BAD.
IT IS BAD BECAUSE IT IS
IMPOSSIBLE ALMOST, TO DETERMINE
CAUSALITY.
YOU DON'T KNOW WHAT HAPPENS
FIRST, WHAT HAPPENS SECOND, BUT
IT IS GOOD BECAUSE IN CASE YOU
SOMEHOW DISCOVER AN INTERVENTION
THAT MOVES 1 OF THESE HIGH
MARKS, IT WILL LIKELY MOVE THE
OTHER HALLMARKS AS WELL IN THE
BENEFICIAL DIRECTION, SO WHICH
MEANS ESSENTIALLY THAT AGING
PERHAP SYSTEM TARGETABLE.
SO BECAUSE, YOU KNOW, WE DON'T
HAVE AS MUCH TIME TODAY, I WILL
QUICKLY, YOU KNOW DELVE A LITTLE
BIT DEEPER INTO 3 OF THESE
HALLMARKS, THE FIRST 1 WOULD BE
A PRIMARY 1, EPIGENETIC
ALTERATIONS AND THEN CELLULAR
SENESCENCE FROM THE CATEGORY AND
THEN CHRONIC INFLAMMATION FROM
THE INTEGRATIVE PATHWAY.
SO FIRST EPIGENETIC ALTERATIONS
AND AS I MENTIONED, THIS IS WHAT
I STUDY IN MY OWN LAB, SO WHEN I
WAS A POST DOC, WE YOU KNOW RAN
THIS REVIEW, ALMOST 10 YEARS
AGO, BUT WHAT WE DID WAS WE
COMBINED INFORMATION FROM
LITERATURE ACROSS MODEL
ORGANISMS TO BRING OUT CERTAIN
THEMEATIC CHANGES THAT ARE KNOWN
TO HAPPEN TO OUR EPIGENOME.
AND WHEN I TALK ABOUT EPIGENETIC
ALTERATIONS, I MEAN CHANGES IN
OUR NUCLEUS, IN THE CHROMATIN
COMPLEX, MADE UP OF HISTONE, SO
1 THING THAT HAPPENS WITH AGE IS
LOSS OF HISTONES AND THIS AS YOU
CAN IMAGINE OPENS UP OUR GENOME
AND FIRST DISCOVERED IN YEAST.
NEXT.
WE MAY HAVE IMBALANCE OF HISTONE
MODIFICATION, SO THERE ARE
CERTAIN MODIFICATIONS ON
HISTONES WHICH ARE ACTIVATING,
SOME ARE REPRESSIVE, IN VIEW,
THERE IS A BALANCE BETWEEN THE
2, BUT AS WE.
Q.OLDER THERE IS THIS
BALANCE AND THERE ARE
MANY STUDIES ON THIS:
PERHAPS THE BEST STUDY AND MAYBE
MOST OF YOU HAVE HEARD ABOUT
EPIGENETIC CLOCKS WHICH ARE
BASED ON DNA METHYLATION READ
OUTS ESSENTIALLY AND I WILL TALK
ABOUT THIS A BIT MORE AS WELL,
THEN WE HAVE CHROMATIN
REMODELING, NOT MUCH IS KNOWN
ABOUT IT BUT THESE ARE PROCESSES
AND IT DECLINES WITH AGE, WE
ALSO HAVE FOCAL AND
HETEROCHROMATIN FORMATION,
ESSENTIALLY THIS MEANS THERE ARE
ALTERATIONS IN THE 3D GENOME
THAT IS HOW THE GENOME FOLDS
WITHIN OUR NUCLEUS, AND ALL OF
THESE DIFFERENT EPIGENETIC
CHANGES ARE ACTUALLY TRIGGERED
BY 1 UPSTREAM PROCESS WHICH IS
THE BREAK DOWN OF THE NUCLEAR
LAMINA, SO YOU CAN THINK OF THE
LAMINA AS THIS NETWORK OF
PROTEINS ON THE PERIPHERY OF THE
NUCLEUS AND OUR GENOME ATTACHES,
CERTAIN PARTS OF OUR GENOME
ATTACHES TO THE NUCLEAR LAMINA,
AND THEY ATTACH BECAUSE THEY
WANT TO BE KEPT REPRESSED OR
CONDENSES AND YOU CAN IMAGINE IF
THE LAMINA BREAKS DOWN, THOSE
GENOMIC REGIONS CAN DETACH THEY
CAN BECOME DEPRESSED AND
ATTACHED TO CELLS AND ALL OF
THESE TOGETHER HAVE
TRANSCRIPTIONAL OUTCOMES THAT I
WILL DISCUSS.
SO, I THINK IF YOU WERE TO
SYNERGIZE ALL OF THESE
EPIGENETIC OLTERATIONS AND
PROPOSE 1 FUNDAMENTAL MODEL OF
EPIGENETIC OPERATIONS AND AGING,
I THINK THE MOST VIABLE 1 WOULD
BE THE LOSS OF HETEROCHROMATIN
MODEL IMAGING.
SO WHAT DO I MEAN BY THAT?
SO AS I TOLD YOU CERTAIN REGIONS
OF THE GENOME ARE CONSTITTATIVE
HETEROCHROMATIN AND BOUND TO THE
LAMINA, AND I JUST CALLED THEM
HETEROCHROMATIN FOR SIMPLICITY.
AND OTHER REGIONS OF OUR GENOME
WHICH ARE AWAY FROM THE NUCLEAR
LAMINA, AND ARE MOSTLY OPEN NOW
IN YOUTH, THERE'S A PERFECT
BALANCE BETWEEN THE 2, BUT WITH
AGE, WHAT HAPPENS IS THAT THE
HETEROCHROMATIN OPENS UP WHEREAS
IN THE U-CHROMATIN YOU CAN GET
OTHER CHANGES WHICH INCLUDES
SOME REGIONS OPENING AND SOME
CLOSING.
BUT THE MOST DELETEEROUS EFFECT
IS REALLY FROM THE
HETEROCHROMATIN OPENING AND WHY
IS THAT BECAUSE THE
HETEROCHROMATIN, THE
CONSTITTATIVE HETEROCHROMATIN
THEY HAVE CERTAIN VIRAL ELEMENTS
AND SO THIS IS A LONG TIME AGO
AND THESE ARE CALLED
RETROTRANSPOSON ELEMENTS AND
THESE NEED TO BE KEPT TO
REPRESSED AND SILENT.
SO IF THESE REGIONS NOW START
OPENING UP, YOU CAN IMAGINE THE
CONSEQUENCES, SO IN HIGHLIGHT 1
PAPER THAT STUDIED PRECISELY
THIS IS THIS WAS FROM JOHN'S
GROUP, PUBLISHED IN TWEBT 19 AND
THEY FOUND, THEY BASICALLY
LOOKED AT THIS 1 TYPE OF
TRANSPOSE ON, CALLED L1 OR 9-1,
RNA EXPRESSION WENT UP IN
SENESCENT CELL WHICH IS IS IN
GRAY HERE, THE YELLOW IS
PROLIFERATING CELLS OR LEAD
PASSAGE CELLS AND THE EXPRESSION
OF LINE 1 RESULT INDEED
EXPRESSION OF INTERFERON PATHWAY
GENES AND THIS WAS A LATE
SENESCENCE EVENT.
THROUGH OTHER EXPERIMENTS WE
DETERMINED WHICH WAS NOT REALLY
THE MRNA, ALTHOUGH THAT MAY
STILL CONTRIBUTE, IT WAS MOSTLY
THE L1 CDNA THAT CONTRIBUTED TO
THIS PROINFLAMMATORY INTERFERON
RESPONSE.
SO THEY DETERMINED IF YOU
SOMEHOW CAN TARGET THE REVERSE
TRANSCRIPT ACE THAT WAS
CONVERTING IT THROUGH THE CDNA,
CAN YOU PERHAPS MITIGATE SOME OF
THESE CHANGES.
SO HERE, THAT'S EXACTLY WHAT
THEY DID AND THEY DID IT IN
MICE, WHICH IS PUBLISHED IN A
HIGH IMPACT JOURNAL, SO, IN OLD
MICE, THEY SHOWED THE EXPRESSION
OF THESE ELEMENTS AND LOOKING AT
THE PROTEIN, AND IN THIS FIGURE,
THEY SHOWED IF YOU TREAT THE
ANIMALS WITH THE REVERSE
TRANSCRIPT ACE, YOU CAN GET
SIGNATURES 95 REDUCTIONS OF
SEVERAL MARKERS OF SENESCENCE
AND AGING PRIMARILY P16, P16 IS
A VERY WELL KNOWN MARKER AND
INTERFERON A AS WELL AS
INTERLEUKIN 6.
SO I THINK IT IS ALSO IMPORTANT
TO TALK ABOUT DNA METHYLATION
WHEN WE TALK ABOUT EPIGENETIC
ALTERATIONS.
THIS WAS PIONEERED BY STEVE
HARBACK PRIMARILY BUT ALSO MANY
OTHER PEOPLE, SO ESSENTIALLY
WHAT HE NOTICED WAS DNA
METHYLATION AT CERTAIN CPGs
WERE REALLY WELL CORRELATED TO
CHRONOLOGICAL AGE AND THEN HE
SORT OF MODELED VARIOUS CPGs
AND MADE A CLOCK OUT OF IT SUCH
THAT YOU COULD THEN TAKE A
SUBSET OF THOSE CPGs AND USE
IT TO ESTIMATE AGE IN OTHER
PEOPLE.
I THINK LUIGI KNOWS MORE ABOUT
PLOTS THAN I DO BUT VERY
RECENTLY AGAIN, STEVE HARVATH'S
GROUP DEVELOPED A MAMMALIAN
PLOT, SO THESE ARE LESS THAN A
THOUSAND CPGs BUT THIS PLOT
YOU CAN USE IT ACROSS MANY, MANY
DIFFERENT MAMMALIAN SPECIES, BUT
TO ME WHAT WAS MOST, AND THE
VERY FACT YOU CAN DEVELOP THESE
CLOCKS SUGGEST THAT THERE'S
PERHAPS A PSEUDOAGING PROGRAM
THAT IS PRESENT IN ALL MAMMALS
AND PERHAPS THAT'S WHAT WE NEED
TO TAP INTO.
SO THEN WE MOVE TO SENESCENCE,
SO SENESCENCE IS A STATE OF CELL
CYCLE ARREST.
SENESCENT CELLS HAVE A LOT OF
LYSOSOMES AND YOU CAN ADD SOME
CHROMOGENIC SUBSTRATE AND THESE
LYSOSOMES, THEY HAVE AN END ZYME
CALLED SENESCENCE WITH THE SO
THIS WAS THE TRADITIONAL RATE,
SENESCENT CELLS FOR SORT OF
FIRST ASSAYED BUT SINCE THEN
WE'VE COME TO KNOW A LOT MORE
ABOUT SENESCENT, IT'S NOT JUST
THE LIES STUDIES OF MULTIPLE
ENDOCRINAL CONTENT, BUT THERE
ARE MANY, MANY RPGHT FEATURES,
BUT PERHAPS 2 VERY IMPORTANT
FEATURES ARE THE RESISTANCE TO
APOP TOAZIS AND SENESCENT CELLS
DON'T DIE VERY EASILY, AND THEN
THE RELEASE OF A LOT OF
PROINFLAMMATORY PHENOTYPE.
BY TAPPING OR TARGETING THIS,
PEOPLE HAVE TARGETED CERTAIN
TYPES OF DRUGS FOR THERAPEUTICS
FOR EXAMPLE, 2 CLASS OF DRUGS,
CENOMORPH ICS AND THEY TARGET D
PREVENT THE FORMATION OF THESE.
SO NOW, THE QUESTION IS, YOU
KNOW IS CELLULAR SENESCENCE EVEN
RELEVANT IN PEOPLE.
SO I THINK THESE 2 PAPERS BY
DARREN'S GROUP BACK IN 2011 WHEN
HE FIRST POINTED OUT IT'S REALLY
A CRUCIAL ROLE IN VIVO, AND WHAT
THEY DID WAS, THIS IS A CLEVER
PHARMA CO GENETIC APPROACH AND I
WON'T GO THROUGH THIS TOO MUCH
BUT ESSENTIALLY JUST BY ADDING
THIS MOLECULE, YOU CAN INVOKE
APOPTOSIS IN THE CELLS, AND WHY
THE CELLS BECAUSE THIS CONCEPT
HERE IS DRIVEN BY THE P16
PROMOTER WHICH IS EXPRESSED IN
SENESCENCE AND WE CAN TALK ABOUT
WYOMING THEY MAY NOT BE
COMPLETELY TRUE.
ANYWAY, THIS IS A MECHANISM AND
IT IS IN A NATURAL AGING MODEL,
ADDITIONAL THE MOLECULE LOWERED
SEN ILLEGALSEN CESSENTS CAN
IMPROVE LIFE SPAN AS WELL AS
HEALTH SPAN.
SINCE THEN A LOT OF EFFORT HAS
BEEN DEDICATED TO FINDING THE
RIGHT SENESCENCE MARKERS ACROSS
DIFFERENT TISSUES BUT THAT HAS
PROVED TO BE QUITE DIFFICULT
BECAUSE SENESCENT MARKERS IN
PEOPLE ARE HIGHLY HETEROGENEOUS
AND IT GAVE BIRTH TO THE SENNET
CONSORTIUM FROM NIH THAT FIND
THIS IS PARTICULAR EFFORT IN
FINDING THE RIGHT SENESCENCE
MARKERS FOR DIFFERENT TISSUES.
FINALLY, AND WITH INFORMATION,
AGE IS A HALLMARK AND IT IS AT
THE CELLULAR LEVEL OR TISSUE OR
ORGAN LEVEL OR EVEN AT THE
SYSTEMIC LEVEL, 1 PAPER I WANT
TO HIGHLIGHT HERE IS FROM MATT
IN 2021 WHERE THE MAIN
TRANSGENIC MODEL MOUSE, IT'S NOT
A NATURAL AGING MODEL BUT THEY
WERE ABLE TO USE THIS MOUSE TO
SPECIFICALLY AGE THE IMMUNE
SYSTEM, AND THEN WE FOUND IF YOU
WILL SIMPLY HAVE AN AGED IMMUNE
SYSTEM, YOU CAN ACTUALLY AGE
YOUR OTHER ORGANS WHICH IS SHOWN
RIGHT HERE, MANY ORGANS AND DOWN
BELOW HERE, LIVER STAIN, AND
SENESCENT CELL MARKER AND AGED
CELL MARKER, AND IT IS HIGH NOT
ONLY IN OLD MICE BUT ALSO IN
OTHER MICE WITH AN AGED IMMUNE
SYSTEM.
AND ANOTHER EXAMPLE IS OF
COURSE, INCAS RELATED DISEASE
ALZHEIMERS, THIS IS MENTIONED
WHICH I THOUGHT WAS STRIKING,
USING THE AND SHOWING THESE 2
PEOPLE ARE HYMN THE SAME AGE BUT
YOU CAN SEE IT'S COMPLETELY, AND
THIS IS TARGETING THE ACTIVATION
WHICH IS A PROINFLAMMATORY
FEATURE.
SO FINALLY, I WON'T SPEND MUCH
TIME HERE SO WE CAN DISCUSS
THIS, BUT WE KNOW ALL THESE
DIFFERENT BIOMARKERS BUT ARE
THESE MOLECULAR CHANGES
REVERSIBLE, SO THERE IS SOME
EVIDENCE, SO I'LL POINT OUT 4
KIND OF INTERVENTIONS IF YOU
WILL IN ANIMALS, PARABIOSIS,
NUTRITIONAL INTERVENTION,
PHENOTHERAPY WHICH I TALKED
ABOUT A LITTLE BIT AND CELLULAR
REPROGRAMMING WHICH I THINK WE
ALLUDED TO DAVID SIN CLAIR'S
PAPER.
SO THESE HAVE SHOWN PROMISE BUT
THEY ARE NOT PERFECT OBVIOUSLY.
BUT IF YOU REALLY WANT TO
TRANSLATE THESE INTERVENTIONS TO
HUMANS, TELL BE DIFFICULT.
BUT THE VERY FACT THAT YOU KNOW
THERE ARE NEWS AROUND THE WORLD
WHERE THERE ARE A LOT OF
CENTENARIANS OR HIGH DENSITY OF
CENTENARIANS, YOU CAN SEE THAT
YOU KNOW THEY MUST BE DOING
SOMETHING AND HOPEFULLY IT'S NOT
JUST THE GENETICS THAT GETS THEM
THIS LONG LIFE SPAN, SO PERHAPS
WE CAN ADOPT SOME OF THE HABITS
AND LIFESTYLES AND IF YOU WANT
TO KNOW MORE, YOU CAN WATCH THIS
DOCUMENTARY, THANK YOU FOR
NETFLIX, AND SO WITH THAT, THANK
YOU VERY MUCH FOR YOUR
ATTENTION.
THESE ARE MY ACKNOWLEDGMENTS,
NIA HAS BEEN AN INCREDIBLE PLACE
TO BE DOING MY WORK AND I
COULDN'T HAVE ASKED TR MORE AND
I LOVE THE SUPPORT HERE AND I AM
HAPPY TO TAKE QUESTIONS.
>> OKAY, THANK YOU BOTH FOR
TAKING US ON 2 SOMEWHAT
DIFFERENT BUT HOPEFULLY AT LEAST
IN THE FUTURE OVERLAPPING I
HAVAGES I WONDER IF THEY HAVE
HEARD EACH OTHER'S PRESENTATION
AND I'M SURE NOT FOR THE FIRST
TIME BUT CONSIDERING THAT EACH
OF YOU ARE LOOKING AT THESE HUGE
PROBLEMS RELATED TO AGING FROM A
SOMEWHAT DIFFERENT PERSPECTIVE,
DO HAVE YOU QUESTIONS THAT YOU
WOULD LIKE TO ASK 1 ANOTHER TO
DISCUSS ANY OF THIS FURTHER?
PERHAPS LUIGI, DO YOU WANT TO GO
FIRST?
YOU HAVE ANY QUESTIONS YOU WISH
TO ASK P A YEL IN.
>> HAPPY TO DO THAT, YEAH, THAT
WAS A FANTASTIC PRESENTATION OF
AND COURSE, I HEARD SOME OF IT
BUT EVERY TIME I LISTEN TO YOU,
YOU KNOW I REALLY GET EXCITED.
ONE OF THE THINGS I WANTED TO
ASK YOU IS YOU KNOW, WE
MENTIONED IT, AND YOU KNOW,
BETWEEN MY PRESENTATION THAT ARE
A COUPLE OF MILLIONS HERE OF THE
EVOLUTIONARY CHANGES AND THE WAY
EVOLUTION WORKS IS THAT FIND THE
IMPERFECTION, EFFECT, AND THEN
CORRECT THEM SO THAT THE SPECIES
LIVE LONGER, AND SO THAT MEANS
THAT WHEN WE WORK ON ANIMAL
MODEL OR IN CELL MODEL, WE
REALLY NEED TO THINK ABOUT IS
THIS WHAT I'M FINDING HERE
ASSOCIATE WIDE AGING ALREADY
BEEN SOLVED FOR EVOLUTION AND
THE REASON I'M SAYING THAT IS
FOR EXAMPLE, YOU KNOW WHEN I DO
A LOT OF INSPECTION, IN EAST AND
IN C.ELEGANS, AND IT IS
INCREDIBLE LOAMACYY AFFECTING
AND THEN WHEN YOU GO UP OUT OF
THE GENETICALLY, THEN IN THE
PRIMATE, WE DON'T REALLY KNOW
AND IN HUMANS IT'S REALLY
QUESTIONABLE WHETHER IT WORKS OR
NOT.
SO I KNOW IT'S A VERY GENERAL
QUESTION, BUT IT'S SOMETHING
THAT IS CONSTANTLY IN MY MIND.
>> THANK YOU LUIGI, VERY THAT
VERY DEEP QUESTION, BUT I DON'T
KNOW IF I HAVE AN ANSWER.
BUT I THINK YOU ARE RIGHT.
I KIND OF MADE MENTION OF IT,
WHEN I SHOWED THAT, YOU KNOW THE
HUMANS ARE PRETTY UP THERE IN
THAT MAXIMUM LIFE SPAN SPECTRUM,
AND I DO THINK THAT WE HAVE
ALREADY EVOLVED MECHANISMS TO
LIVE LONGER AND SOMETIMES AND
AGAIN, I DON'T HAVE AN ANSWER
PER SE BUT SOMETIMES I WONDER
WHETHER SOME OF THE CHANGES THAT
OCCUR IN HUMANS WITH AGE ARE
EVEN GOOD FOR US, I MEAN, ARE
THEY ADAPTIVE AND HELPING US TO
CURB CANCER OR OTHER NEURO-- OR
DEGENERATIVE DISEASES.
BUT I THINK THAT YOU KNOW, AS WE
GET OLDER WE CAN TAKE 1 OF 2
PATHS.
ONE PATH IS CANCER WHICH IS
EXTREMELY DELETERIOUS, BUT THE
ALTERNATIVE PATH IS DEGENERATION
AND I THINK WE'VE EVOLVED
MECHANISMS TOWARDS DEGENERATION
RATHER THAN CANCER BECAUSE
DEGENERATION AT LEAST HELPS US
TO LIVE A BIT LONGER.
AND BY CURBING THOSE MECHANISMS
IN HUMANS, I THINK WOULD ONLY
ENABLE CANCER, SO, I DON'T KNOW.
I THINK WE'VE ALREADY REACHED A
LIMIT IF YOU ASK ME.
>> THAT'S GREAT.
I THINK WE THINK A LIKE.
>> DO YOU HAVE ANY QUESTIONS FOR
ME?
>> YES.
>> YES, SO, I THINK 1 OF THE
QUESTIONS WAS REGARDING ADAPTIVE
CHAIRVELGS WHICH I THINK I
ALREADY ASKED YOU BUT I UPONNED
TO GET YOUR OPINION ON HOW TO
STUDY THESE MOLECULAR MECHANISMS
IN HUMANS GIVEN THE HUGE GENETIC
VARIABILITY AS A LAB SCIENTISTS,
I FIND IT INCREDIBLY DIFFICULT
TO WORK WITH HUMAN SAMPLES
BECAUSE I MEAN THE PROJECTED
NUMBER OF SAMPLES I WOULD HAVE
TO LOOK AT IN ORDER TO REALLY
DETERMINE IF SOMETHING IS
CAUSALLY AFFECTING AGING, THERE
WILL BE A HUGE AMOUNT.
SO I FEEL MORE SAFE, I DON'T
KNOW, TO STUDY, YOU KNOW MICE
MAYBE WITH A STABLE GENETIC
BACKGROUND SO THAT I KNOW THAT
THEY'RE STUDYING THE EPIGENETIC
EFFECTS SO I WAS WONDERING IF
YOU HAVE ANY THOUGHTS ON
STUDYING HUMANS IN THE LAB?
>> YOU KNOW I THINK THAT VERY
GREAT, NOW ABOUT WHAT YOU CAN DO
IN HUMANS IS MUCH LESS THAN CAN
YOU DO IN ANIMAL MODELS AND THE
TRADE-OFF IS THAT WHAT YOU FIND
IS LIKELY RELEVANT FOR HUMAN, SO
BECAUSE, YOU KNOW WE WORK REALLY
TO IMPROVE THE HEALTH OF HUMANS,
YOU GET SOMETHING THAT MAY BE
IMMEDIATELY TRANALATABLE AND
USEABLE.
AND YES, YOU'RE RIGHT, IT'S
QUITE CHALLENGING AS YOU KNOW,
YOU KNOW I DO 50 TO 60 MASSIVE
BIOPSIES A YEAR AND IT'S QUITE
CHALLENGING TO DO THAT BECAUSE
IT'S REALLY A SURGICAL PROCEDURE
AND SO THE NUMBER OF SAMPLES YOU
CAN GET IS SMALL.
BUT SOMETHING WE'RE LEARNING AND
HAS TO DO WITH WHAT YOU SAID
BEFORE IS THAT MANY OF THE
THINGS WE SEE CHANGING, ARE
REALLY ACTIVE AND RECEIVING
MECHANISMS.
YOU KNOW YOU TALKED ABOUT
INFLAMMATION AND I'M SURE THAT
INFLAMMATION BY ITSELF HAS A
NEGATIVE EFFECT ON SOME DISEASE
AND SOME VASCULAR EFFECTS,
HOWEVER, I ALSO THINK IF OUR
MISSION DOESN'T START THAT WAY,
IF THE MEASURE STARTS WITH THE
RESILIENCE MECHANISM SETS WITH
THE ACCUMULATION OF DAMAGE.
AND WHEN ACCUMULATION OF DAMAGE
OCCUR THOSE MOLECULES NO LONGER
CONSIDER ITSELF, THEY ARE
MOLECULE THAT MAYBE STRANDULES
AND THOSE MOLECULES BIGGER
INFLAMMATORY -- TRIGGER AN
INFLAMMATORY RESPONSE, SO THE
PRIMARY MODEL IS THIS DAMAGED
ACCUMULATION AND THEN LATER ON
WHEN YOU HAVE THE INFLAMMATION,
DOESN'T GO OFF, YOU HAVE THE
DEGENERATIVE DISEASE EMPLOY YOU
KNOW THAT WHEN YOU HAVE THE
INTEGRATED RESPONSE, PROTEIN
RESPONSE AND INFLAMMATION, BUT
ALSO YOU HAVE A COMPLETE BLOCK
OF PROTEIN SYNTHESIS, AND WHEN
YOU CAN, YOU KNOW MODIFY IT,
WHEN YOU CANNOT RECYCLE AND
REGENERATE YOUR PROTEIN, THE
PROTEIN ACCUMULATE DAMAGE AND
THAT IS 1 OF THE MECHANISMS THAT
WE THINK IS SOMETHING YOU KNOW
DEGENERATIVE DEC EMPLOY NOW THE
REAL ISSUE IS HOW DO WE
DISTINGUISH BETWEEN CAUSAL EVENT
AND RESILIENCE EVENT.
AND THAT'S NOT A STUPID QUESTION
BECAUSE WE DON'T WANT TO TOUCH
THE RESILIENCE EEIVET BECAUSE WE
WOULD BE REMOVING WHAT IS GOOD.
WE WANT TO IDENTIFY THE CAUSE OF
CHANGE SO THAT WE CAN INTERVENE
ON IT AND THE EPIDEMIOLOGIST
STARTED TO DO A LOT OF MEN
DEALIAN RANDOMIZATION ON THE
DISEASE WHERE BECAUSE YOU'RE
LOOKING AT GENETIC VARIABLE, THE
POINT, THE PHENOTYPE AND NOW
WITH THE AVAILABILITY FOR LARGE
POPULATION SUCH AS THE UK
BIOBANK, THEY ARE STARTING TO
DISTINGUISH BETWEEN WHO IS GOOD
AND WHAT IS BAD.
AND I HOPE THAT THESE, YOU KNOW
WORK WITH -- THIS WORK WILL
CONTINUE UNTIL, IT'S THE WHOLE
PROBLEM OF THE WORKING BIOME
BIOMARKER, WE NEVER KNOW WHETHER
THE BIOMARK, CODED THAT.
SO WHEN YOU LOOK AT BIOMARKER
THAT'S PREDICTIVE, IT DOESN'T
MATTER BUT WHEN YOU LOOK AT HINT
FOR TARGET FOR INTERVENTION,
THAT BECOMES ABSOLUTELY
IMPORTANT.
>> THANK YOU.
SO MAYBE IF I CAN NOW COUNTER
QUESTION AND I DON'T QUITE
REMEMBER, BUT MAYBE, A GROUP
ATTEMPTED SOMETHING LIKE THIS
AND THEY TRIED TO CORRELATE WITH
MORETALLITY INSTEAD OF LIFE SPAN
OR SOMETHING LIKE THAT?
SO BUT THEN ANYTHING THAT
AFFECTS MORTALITY IS CORRELATED
NEGATIVELY WITH LIFESTYLE,
RIGHT?
>> YES, YES, BUT, YOU KNOW -- I
KNOW THAT PAPER QUITE WELL, I
KNOW THE WORK QUITE WELL AND
THAT PAPER ACTUALLY DID NOT LOOK
AT THE BIOMARKER PREDICTER OF
MORTALITY.
THEY CREATED A GENETIC SCORE FOR
THAT BIOMARKER AND THEN THEY
LOOK AT WHETHER THOSE GENETIC
SCORE, THAT VARIABLE THAT ARE
REALLY GENETIC THAT DON'T CHANGE
OVER TIME PREDICTED MORTALITY OR
NOT, THAT PREDICT THE LEVEL OF
THAT BIOMARKER THAT PREDICT
MORTALITY BECAUSE THEN YOU
BECOME ALMOST INDEPENDENT FROM
ENVIRONMENTAL CHANGES SUCH AS
THOUGH THAT TRIGGER RESILIENT
RESPONSE, AND IF THAT IS TRUE,
IT'S 1 OF THE -- OF COURSE
NOTHING IS PERFECT, YOU KNOW MEN
DEALIAN RANDOMIZATION HAS ITS
OWN PROBLEMS SO I THINK THAT IS
A GOOD START AND WE NEED TO
REPLICATE AGAIN A LARGER
POPULATION AND I THINK THAT'S A
MATTER THAT WILL GROW IN THE
FUTURE.
>> THANK YOU.
>> WELL, FEEL FREE TO ASK
QUESTIONS OF EACH OTHER AS WE
PROCEED BUT WE HAVE A LARGE
NUMBER OF QUESTIONS THAT HAVE
BEEN SUBMITTED AND IT'S
INTERESTING, LOOKING AT THE
LIST, I THINK IT'S 2 PHENOMENA,
1 IS THE MULTIPLICITY OF IDEAS
AND THE OTHER IS MORE FROM LET'S
CALL IT THE CLINICAL ASPECT,
WHAT EXPOSURES MAKE AGING WORSE?
OR WHAT BENEFITS SPECIFICALLY
CAN HELP TO SOFTEN THE DECLINE.
AND IT'S INTERESTING THAT THE
QUESTIONS ALL REFLECT THIS
MULTIPLE DISCIPLINE, YOU GET THE
FEELING THAT WE'RE DEALING WITH
A HUGE COMPLEX PROBLEM IN WHICH
FORTUNATELY, DUE TO WORK LIKE
BOTH OF YOU, MUCH PROGRESS IS
BEING MADE EMPLOY SO LET'S GET
ON WITH SOME OF THE QUESTIONS
HERE THAT HAVE BEEN ASKED AND
LET ME SEE, OH YES, SO WILLIAM
CALLS TENSION TO A REPORT FROM
NASA THAT WAS PUBLISHED LAST
YEAR, STRESSING THE IMPORTANCE
OF MITOCHONDRIA AS SORT OF THE
HUB OF VARIOUS OMICS STUDIES OF
SPACE FLIGHT INJURY AND
POTENTIALLY LONGEVITY AND THERE
HAVE BEEN SEVERAL QUESTIONS
GOING BACK TO MITOCHONDRIA IN
PARTICULARLY MITOCHONDRIA
DYNAMICS.
PERHAPS EACH OF YOU WOULD LIKE
TO TAKE A TURN.
P A YEL, WHAT IS YOUR VIEW ABOUT
THAT?
>> GIVEN THE QUESTION, YOU KNOW,
I THINK, I DEFINE MYSELF
MITOCHONDRIA-CENTRIC SCIENTIST
BECAUSE I THINK THAT
MITOCHONDRIA ARE REALLY THE
CULPRIT OF WHAT'S HAPPENING WITH
AGING AND THE REASON IS THAT ALL
THOSE THAT THEY WERE TALKING
ABOUT, THE DNA REPAIR, THE PHOTO
STATIC MICANISM, ALL OF THEM
REQUIRE ENERGY, MASSIVE AMOUNT
OF ENERGY AND YOU KNOW, YOU
THINK ABOUT THE IMMUNE SYSTEM,
YOU KNOW THEY HAVE AN IMMUNE
RESPONSE, YOU NEED TO HAVE A LOT
OF, YOU KNOW PROTEIN SYNTHESIS,
AND PROTEIN SYNTHESIS IS
REQUIRING MASSIVE AMOUNTS OF
ENERGY.
SO UNLESS YOU HAVE GOOD
MITOCHONDRIA YOU DON'T HAVE
RESILIENCYS, AND SO YOU END UP
WITH ACCELERATED AGING AND IN
OUR WORK, WE DEMONSTRATED THAT
THE LOW MITOCHONDRIA FUNCTION
MEASURED BY MRI, WE USE THE MRI
SPECTROSCOPY TO DO THAT, IT'S
PREDICTIVE OF ACCELERATED
DECLINE BOTH IMMOBILITY AND
COGNITIVE FUNCTION.
I WILL FINISH BY SAYING IF YOU
LOOK AT 1 OF THE BIG GLOBAL
MEASURE OF VITALITY IN PEOPLE IS
FITNESS, HOW FIT YOU ARE.
AND IF YOU LOOK AT WHAT OTHER
PREDICTER OF FITNESS, 1 IS
CARDIAC FUNCTION AND THE OTHER 1
IS PERIPHERAL DELIVERY OF OXYGEN
AND AT THE BEGINNING, THEY
STARTED WITH THE DECLINE IN THE
ANALLING BUT THE EXTRACTION OF
OXYGEN IN THE PERIPHERY DOES
SUGGEST THAT THE PROBLEM IS THAT
THOSE MITOCHONDRIA CANNOT BE
UTILIZED, ALL THAT OXYGEN THAT
CAN BE PUT.
>> I CAN CHIME IN.
I WAS ACTUALLY GOING TO LET
LUIGI GO FIRST BECAUSE HE IS
INDEED THE MITOCHONDRIA EXPERT,
I TEND TO AT A WITHIN THE
NUCLEUS, BUT I CAN TELL YOU VERY
BRIEFLY THAT, YOU KNOW IN RECENT
WORK, VERY PRELIMINARY DATA, NOT
EVEN, YOU KNOW ESTABLISHED, BUT
THERE ARE CERTAIN REPORTS OF YOU
KNOW THIS METABOLIC SHIFT WITH
AGE, RIGHT IN SO YOU KNOW A
CHANGE FROM OFF STARTS IN THE
MITOCHONDRIA, THE MORE
MITOCHONDRIA BECOME DAMAGED, THE
MORE THE GLYCOLYSIS, THE
GLYCOLYSIS PRODUCES MAYBE ACETYL
TAKE AWAY WHICH IS LIPID
METABOLISM, WHICH IS ALSO
PROBABLY ACETALATES THE
EPIGENOME AND THEN ACTIVATES
CERTAIN PERHAPS PRO INFLAMMATORY
GENES, SO THIS IS A HYPOTHESIS
AT THIS STAGE AND ESPECIALLY AND
I THINK MACROPHAGE CLASS OF CELL
TYPES.
THIS METABOLIC SHIFT IS PRETTY
PROMINENT DURING AGING AND MAYBE
DRIVES SOME OF THE PHENOTYPES
THAT WE SEE AND 1 OTHER LITTLE
THING TO SAY IS THAT, YOU KNOW
BOTH LUIGI AND OUR GROUP WE
STUDY THE SKELETAL MUSCLE WHICH
IS REALLY RICH IN MITOCHONDRIA
AND IT'S ALMOST 40-50% OF OUR
BODY MASS AND SARCOPENIA, WHICH
IS A VERY NOTICEABLE EVENT AND
THAT CHANGES YOUR METABOLIC
OUTPUT COMPLETELY, AND THAT IS
ALSO BECAUSE ALL OF THE
MITOCHONDRIA, BASICALLY THE
TOTAL MITOCHONDRIA OUTPUT
OVERALL IS DEMINNISHING AND
YEAH, I WILL LEAVE IT AT THAT.
>> SO MAY I INQUIRE ABOUT THAT.
YOU RAISE ESSENTIA WILY THE
LDKAMP1 PATHWAY AS BEING
INCREASINGLY DOMINANT IN AGING
AND IT'S IN THAT AREA THAT
THINGS LIKE SURTOMBIN AND SOME
OF DAVID SIN CLAIR'S IDEAS COME
INTO THE PROCESS BECAUSE OF THE
LINK AS YOU POINT IN WITH
MITOCHONDRIA AND WITH OTHER
ORGANELLE METABOLISM.
WHAT IS YOUR VIEW ABOUT THAT
FROM A BIOLOGICAL STANDPOINT?
AND PERHAPS EVEN FROM A CLINICAL
PERSPECTIVE WHICH LUIGI MAY WANT
TO COMMENT UPON, THAT'S BEING
PROMOTED IN CERTAIN PARTS OF THE
WORLD.
SO P A YEL, WHAT IS YOUR VIEW?
>> I THINK MORE STUFF FOR VIABLE
ISHT VENTIONS OUT THERE, SO FAR
THAT GAINED A LOT OF PRESS,
THERE'S OBVIOUSLY THE RAPOMICE O
SIN AND mTOR, INTAKE
INHIBITOR, CALORIC RESTRICTION,
ALL OF THESE ARE VERY
INTRICATELY INTERCONNECT WIDE
EACH OTHER AND ULTIMATELY, I
THINK THEY ALL IMPINGE ON
WHETHER -- ON ENERGY PRODUCTION,
RIGHT IN SO THE mTOR PATHWAY,
IF YOU HAVE NUTRIENT EXCESS FOR
EXAMPLE, THAT IS ACTIVE AND
TRANSLATIONAL RESEARCH PROMOTES
AUTOPHAGE EXPE THAT IS BIND, BUT
THE NUTRIENT DEPRIVATION LIKE
CALORIC INSTRIKS, IT INHIBITS
THE MTORE PATHWAY AND THAT'S
SOMEHOW GOOD.
SO MY UNDERSTANDING OF THE
COMPLEXITY OF THE PATHWAYS IS
NOT VERY GOOD BUT ALL I CAN SAY
IS MAYBE THE UNDERLYING MESSAGES
WE SHOULD LIMIT TRANSLATION AND
FUTILE ENERGY UTILIZATION IN OUR
BODY AND THAT COULD HAVE SOME
LONGEVITY BENEFITS.
>> SO LET'S LOOK AT THE SPECIFIC
QUESTIONS THAT HAVE BEEN ASKED
AND MAYBE SO WE CAN COVER MORE
IF WE COULD KEEP OUR RESPONSES
SOMEWHAT AS BRIEF AS REASONABLE
EMPLOY SO SEVERAL PEOPLE HAVE
ASKED ABOUT THE RELATIONSHIP
BETWEEN AGING AND COSMIC
BACKGROUND SO THEY PARTICULARLY
REFER TO DROSOPHILA EXPERIMENTS
WHICH WE'VE DONE MANY YEARS AGO
AND ALSO CONCERNED FOR EXAMPLE
IN NASA ABOUT PEOPLE BEING OUT
IN SPACE TOO LONG.
IS THERE SOLID EVIDENCE
FORCOSMIC BACKGROUND RADIATION
HAVING AN EFFECT?
LUIGI WANT TO COMMENT?
>> I KNOW NOTHING ABOUT IT TO BE
HONEST.
I AM ABSOLUTELY COMPLETELY
UNAWARE SO I AM NOT THE RIGHT
PERSON TO ADDRESS.
P A YEL, DO YOU KNOW ANYTHING
ABOUT IT?
>> ALMOST NOTHING BUT I READ IN
THE PRESS, THAT YOU KNOW THE
TELOMERES BECAME SHORTER,
ASTRONAUTS WHO CAME TO SPACE AND
THEIR TELOMERES BECAME SHORTER
EMPLOY I CAN IMAGINE THAT COSMIC
RADIATION MAY CAUSE SOME LEVEL
OF DAMAGE, PERHAPS ACCELERATED
TELOMERE SHORTENING, BUT THERE'S
NO EVIDENT, I THINK, NUMBERS,
NOT MANY PEOPLE HAVE BEEN
STUDIED THIS WAY BUT I DON'T
KNOW WHERE THAT CAN -- THOSE
KIND OF TRANSIENT DAMAGES CAN BE
REPAIRED EASILY OR NOT ONCE THEY
COME BACK TO EARTH.
SO HOW THAT HAS AN EFFECT ON
LIFE SPAN OR DEVELOPMENT OF
CANCER, I DON'T KNOW.
RESPIRATORY.
>> SO IF I MAY, I WOULD LIKE TO
GO BACK TO THE MITOCHONDRIA FOR
A SECOND, FOR A MOMENT.
AND YOU KNOW THE ONLY PATIENTS
IN HUMAN IS CALORIE, THE CALORIE
STUDY PUT PEOPLE ON 25%, AND
THEY WERE UNABLE TO DO IT, BUT
THEY REACHED 14% AND WE STUDIED
THOSE MASSIVE BIOPSY FROM PEOPLE
THAT WERE UNCHARACTERISTIC FOR 2
YEAR ANDS IN CONTROLS AND WHAT
WAS INTERESTING IS THAT YOU KNOW
OF COURSE WE'RE LOSING WEIGHT,
YOU LOSE MUSCLE MASS BUT THE
FOLDS DPENERATED BY THAT MASS
DID NOT CHANGE.
WHICH MEANS THAT THAT MUSCLE WAS
MUCH MORE EFFECTIVE IN
GENERATING FOLD, AND THEN WE
LOOK AT GENE EXPRESSION IN THOSE
MUSCLE AND WHAT WE FIND THAT IS,
YOU KNOW OVERREGULATED,
OVEREXPRESSED, SILT1, Foxp3,
AND PGC1 ALPHA WHICH IS THE
MASTER REGULATOR OF MITOCHONDRIA
BIOGENESIS.
SO I THINK THAT, THAT IS
EVIDENCE IN HUMANS THAT
SUGGESTING THAT 1 OF THE, YOU
KNOW INTERVENTION THAT IS
SUPPOSED TO BE REYOU'VEINATING
AND IN THAT CASE, REALLY HAD
POSITIVE EFFECT ON MUSCLE WAS
MEDIATED BY THE EXPECTED, YOU
KNOW TRANSCRIPTION FACTOR AND
MOLECULE.
SO I THINK THERE'S SOMETHING
IMPORTANT THERE AND I WILL TELL
YOU 1 MORE THING, THAT WITH THIS
WE DISCOVERED IS THAT OF COURSE
IF YOU EXERCISE YOU HAVE MORE
MUSCLE THAT, IS NOT SURPRISING,
YOU KNOW YOU CONTRACT THE
MUSCLE, AND YOUR MUSCLE ADAPT,
BY CREATING MORE ENERGY BUT YOU
ALSO HAVE MORE MITOCHONDRIA IN
THE SKIN, IN YOUR IMMUNE CELLS,
IN THE FIBROBLASTS, SO THAT
EFFECT ON MITOCHONDRIA IS NOT
LIMITED TO THE MUSCLE, NOW, WE
DON'T KNOW WHAT THIS MECHANISM
BY WHICH THE EXERCISE INCREASE
THE MITOCHONDRIA YOU KNOW
PRESENT IN THESE OTHER TISSUE,
PERSISTENTLY THE MITOCHONDRIA
ISSUE ARE TALKING TOGETHER.
>> VERY GOOD.
WELL, LET'S MOVE ON.
WE HAVE HERE --
>> MAY I MAKE A QUICK COMMENT
HERE IF YOU DON'T MIND?
>> YEAH.
>> YEAH, SO I JUST WANTED TO
TELL LUIGI, THAT NEARBY STUDIES
THE TRIALS, MET FORMIN TRIALS
AND ALSO I HEARD HIM TALK AND
THERE WAS A PANEL DISCUSSION
WHERE HE MENTIONED THAT MET
FORMIN, SOME PEOPLE SAY THAT IT
DEACTIVATES THE TOR PATHWAY SO
YOU DON'T GET MUCH MUSCLE MASS
AND IT'S BAD BUT I THINK HE MADE
THE POINT THAT THE MET FORMIN
TREATED MUSCLE IS ABOUT THE
SAME, SO I WANTED TO PROVIDE IT.
>> YES, LET'S CONSIDER SOME OF
THE OTHER QUESTIONS THAT HAVE
BEEN ASKED HERE.
ALL RIGHT, WE HAVE AN
INTERESTING QUESTION HERE, THIS
IS ABOUT HYDRA, HYDRA, ABLE TO
LIVE FOREVER BECAUSE THEY LIVE
THROUGH STEM CELLS WHICH
REGENERATE THROUGH DUPLICATION
OR CLONING.
SO THESE ANIMALS DON'T
DETERIORATE AS THEY GET OLDER
BUT THEY DIE UNDER NATURAL
CONDITIONS PREDOMINANTLY ATORS
AND SO FORTH AND SO ON.
THEY KEEP GOING, ALMOST FOREVER,
DO YOU SEE ANY RELATIONSHIP
BETWEEN THIS AND MAMMALIAN
PHYSIOLOGY?
IT'S A BIT WAY OUT, BUT MAYBE
HAVE YOU SOME BRIEF THOUGHTS
ABOUT THAT.
I GUESS WE COULD EXPAND IT
BECAUSE PEOPLE HAVE ASKED ABOUT
OTHER SPECIES, TOO, CERTAIN
SHARKS, CLAMS, DIFFERENT SPECIES
HAVE DIFFERENT -- AS YOU POINT
OUT DIFFERENT LIVE SPANS AND
DIFFERENT ADAPTATIONS SO IN
BRIEF IS THAT DUE TO COMPLETELY
DIFFERENT EVOLUTIONARY CHANGES?
IS THERE SOME LINEAR
RELATIONSHIP TO PROCESSES IN
MAMMALS?
>> WELL AS A HUMAN SCIENTIST, I
DON'T KNOW VERY MUCH ABOUT IT
BUT I TRY AND PARTICIPATED
AROUND THE TABLE WITH HUMAN
SCIENTISTS AND BASIC SCIENCE,
SCIENTISTS THAT WERE DISCUSSING
WHETHER HY DRA, LIVE FOREVER OR
NOT.
AND THE DISCUSSION FOCUS ON, YOU
KNOW WHAT IS AN INDIVIDUAL.
ARE WE THINKING ABOUT YOU KNOW
BECAUSE HYDRA LIVE FOREVER BUT
THE CELL THAT EITHER HAS YOU
KNOW 4 WEEKS LATER, ARE NOT THE
SAME CELLS THAT THE HYDRA HAD
BEFORE.
SO THE REGENERATION THAT IS --
DOES NOT IMPLY THE PARTITIONING
AND I WILL ARGUE, IF YOU CAN
THINK ABOUT MORTALITY OR NOT,
BECAUSE YOU CAN THINK THAT THE
HUMANS LIVE FOREVER BECAUSE THEY
HAVE GENESIS, AND THEY ARE USING
TO CREATE THEIR CHILDREN, AND
THEIR CHILDREN START FROM THE
SAME CELL OF THE OTHER
INDIVIDUAL.
THE FACT THAT THEY ARE
PHYSICALLY SEPARATED FROM THE
MOTHER AND THE FATHER, YOU KNOW
MAY NOT BE SO IMPORTANT AND SO
THE SAME PHENOMENON CAN OCCUR
WITHIN THE SAME INDIVIDUAL
WITHOUT SEPARATION OF WHAT WE
CALL INDIVIDUAL, SO I'M NOT SURE
THIS IS BIOLOGICAL BUT I THINK
THAT WAS THE CONE OF THE
DISCUSSION, AT SOME POINT IT
GENERATED A LITTLE BIT BECAUSE
WANE CAME INTO IT, SO IT BECAME
MORE CONFUSED.
>> LUIGI, WHILE YOU'RE
COMMENTING, WE HAVE A QUESTION
IN HERE, YOU USED THE PHRASE I
KIND OF DIFFERENTIATED WHAT YOU
CALLED THE BIOLOGICAL LIFE SPAN
AS DISTINGUISHED FROM LIFE
EXPECTANCY.
WHAT DO YOU HAVE IN MIEBD WHEN
YOU REFER TO THE BIOLOGICAL LIFE
SPAN?
LUIGI?
ARE YOU ON?
>> HE'S UNFORTUNATELY MUTED FOR
A SECOND.
HE'S TRYING TO UNMUTE NOKAY, --
>> OKAY, I AM HERE.
I DON'T TALK ABOUT BIOLOGICAL
LIFE SPAN, I TALK ABOUT
BIOLOGICAL AGING AND WHEN I
THINK ABOUT BIOLOGICAL AGING, I
AM THINKING ABOUT THE ARK
KIEWMULATION OF ORGANELLE DAMAGE
SPECIFICALLY AND WE CAN DEMON
TRAIT THAT THAT MICROMOLECULAR
CHANGES OCCUR EVEN YOU KNOW IN
THE FIRST YEAR OF LIFE, SO
THEY'RE THERE, THEY'RE NOT
EVIDENT PHENOTYPICALLY BECAUSE
THEY DEVELOPMENT PROGRAM THAT IS
INSCRIBING OUR DNA IS INCREDIBLY
POWERFUL, REDUNDANT AND FULL OF
CHECK POINTS THAT MAKE IT SO
EVIDENT THAT WE HIDE EVERYTHING
UNDERNEATH BUT STEVE HORVATH,
SHOW THAT THE CHANGE IN
METHYLATION THAT CHARACTERIZE
AGING OCCUR EVEN FASTER IN THE
FIRST YEAR OF LIFE.
AND SO WHEN I TALK ABOUT
BIOLOGICAL AGING, I'M THINKING
ABOUT, YOU KNOW, THAT BALANCE
BETWEEN MACROMOLECULAR DAMAGE
AND RESILIENCE.
>> ALL RIGHT, WHILE YOU'RE ON
LUIGI, WHAT IS YOUR VIEW ABOUT
CALORIC RESTRICTION AND AGING.
TAKING ALL OF THE EXISTING DATA,
SOME OF ITS CONFUSION, PEOPLE
WANT SPECIFIC ADVICE AS BOTH THE
SCIENTISTS AND ALSO A SCIENTIFIC
CLINICIAN, WHAT DO YOU ADVISE
PEOPLE ON THAT SUBJECT.
>> IT'S A HARD QUESTION.
YOU KNOW I THINK THAT, YOU KNOW,
IF YOU LOOK AT THE
EPIDEMIOLOGICAL STUDIES, I'LL
START WITH THERE, WILL TELL YOU
THAT THE PEOPLE THAT LIVE
LONGER, ARE THOSE INDIVIDUALS
THAT DO NOT CHANGE, MINIMAL
CHANGE WAYS ACROSS THE LINE ANDS
NOW THOSE PEOPLE, THE DECLINING
WEIGHT, GAINING WEIGHT, THOSE
ARE BOTH OF HIGHER MORTALITY.
THE SWEET SPOT FOR LOWER
MORTALITY IS NOT BELOW A BMI OF
25, IT'S A BMI OF 26-27, SO
SLIGHTLY OVERWEIGHT.
NOW IT'S DIFFICULT TO KNOW
WHETHER THAT IS A BIAS DUE TO
THE FACT THAT THE PEOPLE THAT
GET SICK, YOU KNOW LOSE WEIGHT,
EVEN IN STUDIES LIKE THE UK BY O
BANK WHICH ARE HUGE, FAMILIAR
WITH PEOPLE, WE COULD NOT
DISTINGUISH MORTALITY BETWEEN
THE PEOPLE WITH THE BMI WITH 25
AND THE BMI OF 26.
YOU KNOW 26 IS BETTER AND THERE
WE HAD THE HUGE AMOUNT OF
CONFOUNDING VARIABLE THAT WE
COULD USE, FOR A VERY, VERY
LARGE DATABASE.
SO I THINK THAT YOU KNOW
MAINTAINING WEIGHT IS THE MOST
IMPORTANT NOW AND WE GO TO
SHAPE, IF WE TALK ABOUT PEOPLE
THAT ARE SERIOUSLY OVERWEIGHT OR
OBESE, THERE'S ABSOLUTELY NO
DOUBT THAT LOSING WEIGHT IS GOOD
FOR YOU.
I MEAN THAT'S BEEN DEMONSTRATED
HUNDREDS OF TIMES YOU NEED TO DO
IT PROPERLY, UNDER MEDICAL
CONTROL, YOU HAVE TO MAKE SURE
YOU HAVE THE ESSENTIAL PROTEIN
AND VITAMINS BUT LOSING WEIGHT
IS ASSOCIATE WIDE DRASTIC
REDUCTION OF INFLAMMATION, IS
ASSOCIATE WIDE REDUCTION OF THE
CARDIOVASCULAR MORTALITY AS AN
EFFECT ON THE RISK OF CERTAIN
CANCER, AND NOT ALL CANCER BUT
CERTAIN CANCER.
NOW THE REAL ISSUE IS, IF YOU
ARE NORMAL WEIGHT OR SLIGHTLY
OVERWEIGHT, THIS CALORIC
RESTRICTION GOING TO BE
EFFECTIVE?
NOW, LOSING WEIGHT IS VERY
DIFFICULT, VERY, VERY FEW PEOPLE
ARE EFFECTIVE AND WITH THE
NORMAL WAY WE DO WITH THE DIET,
IF YOU LOOK AT PEOPLE FOR A LONG
TIME ALMOST ALL OF THEM OVER
TIME REGAIN WHAT THEY LOST AND
THIS HAS BEEN DUE TO THE FACT
THAT WHEN YOU LOSE WEIGHT, YOUR
ORGANIZATIONSISM ADAPT, AND YOU
ADAPT BY REDUCING RESTING
METABOLIC RATE.
SO YOU LOSE THAT EFFECT AND SO
WHAT IS NOW MORE THINKING IS THE
MORE EFFICIENT WAY OF DOING
CALORIC RESTRICTION IS
INTERMITTENT FASTING, SO THE
INTERMITTENT FASTING CAN BE DONE
IN MANY WAYS, 2 DAYS A WEEK, 1
DAY A WEEK, REDUCING INTAKE FOR
6 TIMES THE CALORIE 2 DAYS A
WEEK, MANY, MANY MECHANISMS, OR
EVEN AND SOON TO BE 1 OF THE
MOST SUCCESSFUL NOT EATING FOR
14 HOUR FOR DAY AND EATING ONLY
IN THE REMAINING HOURS.
THAT SEEMED TO BE QUITE
EFFECTIVE ESPECIALLY IF YOU DO
RESTRICTION IN THE MORNING.
NOW, THOSE HAVE SHOWN THAT THESE
PEOPLE ARE ABLE TO MAINTAIN THIS
CHARACTERISTIC AND SHOWED THE
LOSING OF THE WEIGHT FOR A VERY
LONG TIME.
I RECENTLY HAD A DISCUSSION AT
THE MEETING OF THE DIETITIANS
WHEN I INTRODUCED THE AGING AND
SOME OF THEM TOLD ME THAT ALL
THEIR LIFE, THERE HAVE BEEN SO
MUCH DISAPPOINTED WITH THE
NORNLAL DIET BECAUSE PEOPLE LOSE
WEIGHT AND A YEAR LATER IT'S
OBVIOUS THEY HAVE REGAINED
WEIGHT.
BUT WE START THE FASTING, THEY
ARE SEEING SOMETHING DIFFERENT.
OF KOWRGS IT REQUIRE ALSO A LOT
OF SELF-CONTROL, BUT PEOPLE SEEM
TO BE ABLE TO DO IT SO I THINK
THERE'S SOMETHING THERE.
AND THERE IS A LOT OF TRIALS
COMING UP.
YOU KNOW THERE WAS 1 FAIRLY
RECENTLY IN THE NEW ENGLAND
JOURNAL OF MEDICINE SHOWING THE
EFFECTS.
>> SO I ASSUME WE WILL HEAR A
LOT AT SOME POINT IN THE FUTURE,
NOT NOW, ABOUT THE GLUE CO
GONZALEZ ANTAGGISTIC DRUGS WHICH
HAVE MULTIPLE EFFECTS AND BY THE
WAY WE'RE HAVING A SESSION IN
DEMYSTIFYING MEDICINE WITH 1 OF
THE DISCOVERERS OF THAT LATER IN
THE YEAR.
SO HERE'S ANOTHER QUESTION.
NOW, YES, P A YEL, THIS IS AN
IMPORTANT PROBABLY 1 OF THE MOST
SIGNIFICANT QUESTIONS.
THERE ARE REALLY 3 OF THEM AND I
DON'T KNOW HOW YOU CAN ANSWER IT
IN A SHORT PERIOD OF TIME BUT
TRY.
THIS IS REGARDING EPIGENETICS IN
A CAUSAL PATHWAY OF AGING.
DO YOU SEE IT PRIMARILY AS A
CAUSE, A MARKER OF WHETHER
UNDERLYING PROCESSES OR AN
EFFECT OF AGING ITSELF?
ADDITIONALLY HOW SIGNIFICANT IS
ITSELF CONTRIBUTION REGARDING
OTHER AGING MECHANISMS AND I
MIGHT THROW IN THE TELOMERE
CONTRIBUTION, AND LASTLY WOULD
YOU SAY THAT THE GENERATION IS
PART OF EPIGENETIC TARGET FOR
THERAPY?
YOU CAN'T ANSWER ALL OF THOSE
QUESTIONS BUT PLEASE DO YOUR
BEST IN A SHORT PERIOD OF TIME.
THANK YOU.
>> YEAH, SURE.
I THINK THERE'S QUESTIONS FROM
MIN Q, SHE'S ALSO HERE AT THE
NIH, SO OBVIOUSLY A VERY HARD
QUESTION, I THINK THAT AT THIS
POINT, IT IS VERY HARD TO
DISTINGUISH WHAT EPIGENETIC
CHANGES OCCURRED FIRST AND THEN
WHAT EPIGENETIC CHANGES OCCURRED
SECOND.
SO TO ESTABLISH CAUSALITY, THE
WAY WE DO IT IN THE LAB IS YOU
KNOW VERY SIMPLY, KNOCK DOWN AN
IMPORTANT FACTOR, SEE IF THAT
AFFECTS ALL OTHER DOWN STREAM
KNOWN PHENOTYPES OF AGING OR
OVEREXPRESSED, SAY THE OPPOSITE
EFFECT BUT THAT'S ALL PRETTY
MUCH WHAT WE CAN DO NOW
EXPERIMENTALLY TO GET AT
CAUSALITY.
NOW WHETHER -- HOW SIGNIFICANT
IS THE CONTRIBUTION RELATIVE TO
OTHER AGING MECHANISMS, AS I
SHOWED IN MY HALLMARKS OF AGING
SLIDE, EVERY HALLMARK IS
CONNECTED TO EVERY OTHER
HALLMARK, BUT I PERSONALLY THINK
THAT EPIGENETIC ALERATIONS ARE
PRETTY FUNDAMENTAL BECAUSE
THAT'S WHERE YOU KNOW YOU CHANGE
THAT, AND YOU KNOW, YOU CAN HAVE
WIDE SPREAD EFFECTS THROUGH GENE
REGULATION.
SO I WOULD SEE IF YOU REALLY
IDENTIFY CAUSAL TRANSCRIPTION
FACTOR, YOU SHOULD BE ABLE TO --
YOU SHOULD BE ABLE TO YOU KNOW
MITIGATE SOME OF THOSE PROBLEMS
BUT YEAH, IT'S A VERY DIFFICULT
QUESTION.
>> IT'S A GREAT ANSWER FOR A
VERY COMPLEX AND IMPORTANT
PROBLEM WHICH NEEDS MORE
SCIENCE, RIGHT?
>> YES.
>> LUIGI IS THERE ANY CONNECTION
BETWEEN LIFE EXPECTANCY AND
REPRODUCTIVE AGE SPAN IN THAT'S
A QUESTION THAT AMEET ASKS, AND
THEN PRIMARILY CONCERNED BY THE
FACT THAT PUBERTY IS COMING TO
KIDS EARLIER NOW, THAN IT USED
TO BE WHICH DOES THIS HAVE ANY
POTENTIAL IMPACT ON LIFE SPAN OR
HEALTH SPAN, WHAT DO YOU THINK?
>> NOT MY STRONG KNOWLEDGE BUT I
READ OF COURSE ABOUT THIS
CONTROVERSIAL AND THERE ARE
DIFFERENCES OF OPINION, BUT I
THINK THAT 1 LINE OF THE SEARCH
SEEMS TO BE VERY INTERESTING,
THE FACT THAT THE ANTICIPATION
OF PUBERTY SEEMED TO BE DUE TO
ENVIRONMENTAL EXPOSURE AND
DELIVER SOME EEIVETS AND OTHERS
SEEM TO BE ASSOCIATED WITH
ANTICIPATED PUBERTY IN SOME PART
OF THE WORLD WHETHER THE
PRODUCTIVE AGE IS ASSOCIATE WIDE
LONGEVITY.
I REALLY DON'T KNOW.
BUT WOMEN THAT HAVE MULTIPLE
CHILDREN THAT ARE NOT KNOWN TO
PRIOR, AND LONGER, THAT WE KNOW.
YEAH, SO CHRISTOPHER SAYS WITH
ADEQUATE NUTRITION?
THAT'S A VERY, VERY INTERESTING.
YOU KNOW LIFE CAUSE STUDIES HAVE
SHOWN THAT GAINING WEIGHT
THROUGH PRIOR TO PUBERTY IS A
GOOD THING, IF YOU GAIN WEIGHT
PRIOR TO PUBERTY THAT IS
PREDICTIVE OF HEALTH LATE OR IN
LIFE.
BY GAINING WEIGHT AFTER PUBERTY,
SEEMS TO BE ASSOCIATED WITH BAD
OUT COME.
WHAT IS THE MECHANISM THERE.
I DON'T KNOW.
AND IT'S MUCH STRONGER IN WOMEN
THAN IN MEN, BUT IN WOMEN, THE
EFFECT IS REALLY POWERFUL.
>> THAT'S VERY, VERY
INTERESTING.
LET ME AND SEE.
THERE WERE SOME VERY INTERESTING
QUESTIONS HERE WHICH SOMEHOW I
HAVE.
-- AH, YES.
YOU REFERRED TO AGING PRETTY
MUCH AS A DISEASE OF CELLULAR
DAMAGE OF LIMITATION OF CELLULAR
RENEWAL AND REFERRED TO THE
APOPTOTIC CYCLE AND OTHERS AS
BEING ACCENTUATED IN THE AGING
PROCESS SO IF THAT'S CENTRAL, IS
THAT THE MAJOR LOCUST AT WHICH
BIOLOGICAL AGING BEGINS AND IF
SO --
>> FIRST OF ALL I THINK
BIOLOGICAL AGING STARTS
IMMEDIATELY.
I THINK THAT WE CANNOT ESCAPE
YOU KNOW THE CENTRAL DYNAMIC,
IT'S THERE.
AND SO I THINK THAT YOU KNOW I
DIDN'T HAVE THE TIME TO EXPLAIN
BEFORE BUT THINK ABOUT AGING
SOMETHING THAT IN THE OFF SENSE
OF ANYTHING CONTRASTING IT, WILL
OCCUR VERY RAPIDLY, YOU KNOW YOU
HAVE DAMAGE AND THIS DAMAGE IS
SO STRONG THAT AT SOME POINT,
IT'S NOT BY CHANCE THAT MASTER
PROGERIATRICKIZATIONIAS ARE
ASSOCIATED WITH THE EFFECT OF
DNA REPAIR BECAUSE THE DNA, THE
ONLY PART OF THE CELL THAT YOU
CANNOT EXCHANGE.
IT'S NOT THAT YOU'RE LIMITED IN
YOUR DNA, YOUR SYNTHESIS,
PROTEIN, CAN YOU DO THAT,
ALLEVIATE, YOU CAN DO THAT, THE
DNA IS THERE FOREVER UNTIL THE
CELL DIES, AND SO I THINK THAT
THE PRINCIPAL IS THAT AGING IS
ANOTHER PHYSICAL PHENOMENON, AND
THE QUESTION IS HOW WE CAN SLOW
IT DOWN AND NATURAL POURED SO
MUCH EFFORT IN SLOWING IT DOWN
THAT IT'S ABLE TO CREATE HUMAN
THAT LIVE 100 YEARS, THAT IS
BECAUSE OF THAT, BECAUSE OF
THOSE MECHANISMS -- AND I WANT
TO POINT THE EXAMPLE FROM THIS,
IF WE COULD ENHANCE THE EFFECT
OF THOSE MECHANISMS, THAT WOULD
BE THE MOST POWERFUL MEDICAL
APPROACH TO HEALTH THAT WE CAN
THINK OF.
AND SO, I DON'T THINK AGING IS A
DISEASE.
I THINK THAT AGING IS ENOUGH OF
A PHENOMENON AND WE FIGHT
CONSTANTLY DURING OUR ENTIRE
LIFEY TO SLOW DOWN, THAT'S THE
WAY TO THINK ABOUT IT.
>> ALL RIGHT, P A YEL, DO YOU
WANT TO COMMENT ABOUT THAT?
WHAT IS YOUR CONCEPT OF AGING?
>> I WOULD AGREE WITH LUIGI.
I DON'T THINK AGING IS A
DISEASE.
AGING, MY NAIVE IDEA OF AGE
SUGGEST THAT IT'S A NATURAL
PROCESS LIKE LUIGI SAID AND IN
FACT, I ALMOST THINK OF IT AS
BENEFICIAL, BENEFICIAL TO
PREVENT CANCER AND THAT'S -- BUT
UNFORTUNATELY SOME SIDE EFFECTS
COULD BE, YOU KNOW THE ONSET OF
DEGENERATIVE DISEASES AS I
MENTIONED SO I REALLY THINK IT
IS A BALANCE OF PREVENTING
CANCER AND MAINTAINING FUNCTION
AND THE ONLY WAY TO DO THAT IS
UNFORTUNATELY GO DOWN THE
DEGENERATIVE ROUTE AND
THEREFORE, I DON'T THINK AGING
ITSELF IS A DISEASE, IT MAKES
THE CELLS MAYBE GET DISEASE AT
SOME POINT OR BE ASSOCIATED WITH
A DISEASE STATE.
>> SO YES, LET ME THROW IN JUST
A BRIEF COMMENT HERE, SOMEWHERE
IN DISCUSSION OF AGING AND A LOT
OF THINGS, ATTENTION IS DIRECTED
TO CELLULAR TURNOVER, TO
ORGANELLE TURNOVER, BUT EVERY
MEMBRANE, EVERY STRUCTURE WITHIN
THE CELL CONSISTS OF HUGE
NUMBERS OF PROTEINS, LIPIDS AND
SO FORTH EACH 1 OF WHICH HAS ITS
OWN INDEPENDENT RATE OF
DEGRADATION AND PARTICULARLY,
AND SYNTHESIS AND DEGRADATION,
SO ALTHOUGH LIKE THE MEMBRANE
LOOKS INTACT, IN FACT, ALL OF
ITS COMPONENTS INDIVIDUALLY ARE
RAPIDLY TURNING OVER, THERE'S A
WHOLE DIMENSION OF DYNAMICS THAT
IS NOT -- THAT IS ONLY SEEN WHEN
YOU BEGIN TO SEE HIGH RESOLUTION
MICROSCOPY FOR EXAMPLE.
SO I'M CURIOUS, AT ANY POINT IN
THE CONSIDERATION OF AGING IS
THIS LEVEL OF DYNAMICS
CONSIDERED?
PEOPLE WHO ARE DOING SUPER
RESOLUTION MICROSCOPY OF
MOLECULES CONCERNED WITH THE
AGING PROCESS?
>> WELL, AS FARs I KNOW, WE
KNOW LITTLE ABOUT THAT BUT 1
STUDY THAT THE NIA IS DOING IS
LOOKING AT THE HALF LIFE OF
PROTEIN, WHETHER THE HALF LIFE
OF PROTEIN CHANGE WITH AGING AND
WE DO THAT BY, YOU KNOW,
STUDYING HUMANS, HEAVY WATER,
AND THEY TAKE THE HEAVY WATER
FOR A CERTAIN PERIOD OF TIME.
OF COURSE, THAT DID MARK THE
SAMPLE TO SIPGHTICIZE AND THEN
YOU DO A SECOND SAMPLE AND YOU
ASSUME THAT THE SYNTH SCIZZ AND
DEGRADATION SHOULD BE IN THE
EQUILL LIP RIBIUM BECAUSE THEY
REMAIN CONSTANT AND YOU CAN
UNDERSTAND WHAT IS THE HALF LIFE
OF THE PROTEIN AND YOU STUDYING
YOU CAN IMAGINE WOULD REQUIRE
TIME BECAUSE IT REQUIRE A LONG
PERIOD OF FINDING THE HEAVY
WATER AND SO, WE WILL KNOW THE
RESULT BUT WE DON'T KNOW THOSE
YET.
>> ALL RIGHT, WELL, LISTEN,
WE'VE RUN OUT OF TIME BUT I WANT
TO THANK ON BEHALF OF ALL THE
PEOPLE WATCHING, AND WE ARE
AROUND THE WORLD, I AM TOLD AT
LAST, SO, THANK YOU AGAIN AND WE
LOOK FORWARD TO FURTHER
DISCUSSIONS BECAUSE ALL OF US
ARE AGING NTHANK YOU VERY MUCH.
IT'S BEEN A PLEASURE REALLY TO
BE HERE WITH YOU, ALL OF YOU.
>> THANK YOU.
YES.
>> SO WE'RE OFF.