>>WELCOME. I'M WIN ARIAS
SCIENTIST EMERITUS AT THE
NATIONAL INSTITUTES OF HEALTH.
THIS PROGRAM IS WORLDWIDE
DISTRIBUTED NOW IN 38 DIFFERENT
COUNTRIES. SO WE WELCOME ALL OF
YOU TO WHAT IS THE 11TH SESSION
AND 23RD YEAR OF DEMYSTIFYING
MEDICINE THIS IS REALLY A COURSE
IN BRIDGE BUILDING AND THE LOGO
IN THE UPPER RIGHT OF MY
POWERPOINT IS TO THOSE OF US IN
THE EASTERN PART OF THE UNITED
STATES, THE MOST FAMOUS BRIDGE
IN THE WORLD. BROOKLYN BRIDGE.
HERE IT IS UNDER CONSTRUCTION,
AND YES LIKE THE TWO INDIVIDUALS
ON THE CAT WALK EXCHANGING
VIEWS, EXCHANGING KNOWLEDGE, AND
SEEKING NEW COLLABORATIONS AND
EXPANSION OF OUR UNDERSTANDING
OF MAJOR HEALTH AND MEDICAL
PROBLEMS. KEEP IN MIND ONCE YOU
BUILD A BRIDGE LIFE IS NEVER THE
SAME ON EITHER SIDE. SO
DEMYSTIFYING MEDICINE IS A
COURSE IN BRIDGE BUILDING, IT
BRIDGES EXCITING DEVELOPMENTS IN
BIOLOGY AND ENGINEERING WITH
MEDICINE.
TODAY WE ARE GOING TO
HAVE A DISCUSSION OF A TOPIC
THAT WE ARE A ALL CONCERNED
WITH. THOSE OF US AT ANY AGE
PARTICULARLY THOSE WHO ARE
SLIGHTLY OLDER THAN YOUNGER. AND
THAT IS, WHAT IS AGING? IS AGING
A DISTINCT PROCESS, SOMETHING
THAT IS UNRELATED TO WHAT YOU
MIGHT CALL FRAILTY? OR ALL OF
THOSE CO-MORBID DISEASES
NEURODEGENERATIVE DISEASE, HEART
DISEASE, CANCER, ARE THEY PART
OF AGING? AND SPECIFICALLY
REGARDING NEURODEGENERATION, HOW
IS AGING RELATED THAT PROCESS?
WE WONDER WHETHER THERE'S
DISEASES OF PREMATURE AGING AND
IF SO CAN GENETIC STUDIES HELP
TO UNDERSTAND SOMETHING OF THE
BASIC PRONESS A TOPIC TO BE
DISCUSSED TODAY IS CAN AGING BE
DELAYED? CAN IT BE REVERSED? CAN
IT BE REGULATED? AND IF SO, HOW
THIS IS ONE OF THE BIG EXCITING
ASPECTS OF PANDORA'S BOX WHICH
HAS BEEN OPENED THE LAST SEVERAL
YEARS CREATING NEW IDEAS AND
SCIENTIFIC APPROACHES TO
UNDERSTANDING THE AGING PROCESS.
DOES THE AGING PROCESS ITSELF
AFFECT NEURODEGENERATION? HOW
ARE THESE RELATED? WHERE ARE WE
GOING TO BE THREE, FOUR, FIVE
YEARS FROM NOW? NEXT SLIDE
PLEASE. AGING HAS BEEN
CONSIDERED BY MANY PEOPLE ONE OF
MY FAVORITE THING IS A QUOTE
FROM THE FAMOUS AMERICAN
HUMORIST WILL ROGERS. YOU CAN
CERTAINLY SLOW THE AGING PROCESS
DOWN IF IT HAD TO WORK ITS WAY
THROUGH CONGRESS. SO TODAY, NEXT
SLIDE PLEASE, TODAY WE ARE
EXTREMELY FORTUNATE TO HAVE TWO
GLOBAL AUTHORITY IN THIS
EXCITING AREA OF AGING RESEARCH
AND ITS RELATIONSHIP TO
NEURODEGENERATION IN PARTICULAR.
OUR FIRST SPEAKER, LUIGI PHRYGIA
IS A EPIDEMIOLOGIST AND RESEARCH
SCIENTIST WHO IS CURRENTLY
SCIENTIFIC DIRECTOR AT THE
NATIONAL INSTITUTE OF AGING. AT
THE NIH. LUIGI, FERRUCCI. PRIOR
TO COMING HERE HE WAS AT THE
UNIVERSITY OF FLORENCE ITALY,
WHERE HE RECEIVED BOTH M.D. AND
Ph.D. DEGREES, STUDYING AGING.
WHERE HE WAS ASSOCIATE PROFESSOR
OF BIOLOGY, HUMAN PHYSIOLOGY AND
AGING. AND CHIEF OF THE
GERIATRIC REHABILITATION AND
DIRECTOR OF THE LABORATORY OF
CLINICAL EPIDEMIOLOGY.LY YES
CAME TO THE NIH IN THE
LABORATORY OF -- LUIGI CAME TO
THE NIH IN THE LABORATORY OF
EPIDEMIOLOGY AND BIOLOGY AND
2011 BECAME SCIENTIFIC DIRECTOR
OF THE NATIONAL INSTITUTE OF
AGING. HIS WELL KNOWN FOR
EXTRAORDINARY LONGITUDINAL
STUDIES OF THE RISK FACTORS FOR
MOBILITY DISABILITY AGE
ASSOCIATED FRAILTY AND
MORBIDITY. HE FOCUSES ON THE
HALLMARKS OF AGING. WHAT CAUSES
DECREASE REGENERATIVE ABILITY
AND IMPAIRED SYNAPTIC
PLASTICITY? AND THE ROLE OF
INCREASE NEUROINFLAMMATION?
LUIGI WILL BE THE FIRST SPEAKER
AND FOLLOWING HIS TALK OUR
SECOND SPEAKER, NEXT SLIDE
PLEASE, WILL BE SAUL VILLEDA,
ASSOCIATE PROFESSOR OF ANATOMY
AT THE UNIVERSITY OF CALIFORNIA
AT SAN FRANCISCO. HE RECEIVED
HIS Ph.D. DEGREE AT STANFORD
IN NEUROSCIENCES. HIS RESEARCH
FOCUSES ON THE REVERSAL OF AGING
PARTICULARLY SYNAPTIC NEURAL
PLASTICITY AS WELL AS COGNITIVE
FUNCTION, PRIMARILY IN ANIMALS
WHICH ARE INFUSED WITH YOUTHFUL
FACTORS IN YOUNG BLOOD OR BLOOD
AFTER EXERCISE AND PRO AGING
FACTORS IN OLD BLOOD WHICH
APPEAR TO DRIVE PRE-MATURE
AGING. AT PRESENT HE HAS AN
ENDOWED CHAIR AT UCSF AND
RECEIVED A KECK AND GLENN AWARDS
FOR BIOLOGICAL MECHANISMS OF
AGING AS WELL AS NIH EARLY
INDEPENDENCE AWARDS. SAUL IS THE
ORGANIZER OF THE 2023 KEYSTONE
CONFERENCE SHORTLY COMING UP ON
THE MOLECULAR BASIS OF HEALTHY
AGING. SO WE ARE APPRECIATIVE TO
BOTH OF YOU AND LOOK FORWARD TO
AN EXCITING AFTERNOON OF YOUR
PRESENTATIONS AND OF DISCUSSION
OF THE QUESTIONS AT THE END OF
YOUR TALK. DR. FERRUCCI, WOULD
YOU PLEASE BEGIN.
>> SO FIRST OF ALL,
LET ME THANK THE ORGANIZERS AND
ESPECIALLY DR. ARIAS TO -- FOR
INVITING ME THIS REALLY
IMPORTANT CONVERSATION THAT IS
FOCUSED ON WHAT I THINK IS NOT
ONLY ONE VERY, VERY IMPORTANT
ISSUE FOR SOCIETY BUT MY PASSION
FOREVER. I WANTED TO STUDY AGING
SINCE I WAS A TEENAGER AND I'M
NO LONGER A TEENAGER YOU CAN SEE
FROM THE COLOR OF MY HAIRS BUT
IT IS ABSOLUTELY STILL THERE. I
WILL START BY SAYING THAT I HAVE
NO FINANCIAL CONFLICT TO
DISCLOSE OF ANY TYPE. THEN I'M
GOING TO TELL YOU WHAT I THINK
IS OUR LEARNING OBJECTIVE FOR MY
PRESENTATION TODAY. I WANT TO
SHOW YOU SLOWING DOWN OF THE
AGING HAS POTENTIAL TO IMPROVE
GLOBAL HEALTH EXPECTANCY. THAT
IS VERY IMPORTANT IN THIS WAR,
WHERE AGES IS PROBABLY THE MOST
IMPORTANT FORCE THAT IS CHANGING
OUR ENTIRE SOCIETY FROM FAMILY
TO ECONOMY TO HEALTHCARE AND
OTHER CHARACTERISTICS. SO THIS
IS AN INTRODUCTORY SLIDE FROM MY
TALK TO THAT TELL US WHERE WE
ARE. THIS IS A SLIDE THAT COME
FROM PAPER THAT WAS WRITTEN BY
JIM LAPEL AND HIS GROUP, HE'S
BEEN CERTAINLY THE MOST
IMPORTANT AGING DEMOGRAPHER IN
THE WORLD, FOR VERY LONG TIME,
HE JUST DIED VERY RECENTLY
DURING THE PANDEMIC IN 2020. AND
WHAT IS THE BIG TAKE HERE IN
THIS LITTLE BALL OF DIFFERENT
COLORS? THE NATURE WITH THE
LONGEST LIFE EXPECTANCY. OVER
TIME JIM SELECTED THOSE
COUNTRIES THAT HAD THE LARGEST
LIFE EXPECT STAIN, STARTED FROM
YOU SEE THE BLUE THAT WAS
AUSTRALIA, THEN NORWAY THEN NEW
ZEALAND THEN SWEDEN THEN YOU CAN
SEE THAT ICELAND CAME UP, THEN
FOR LONG TIME THE OLD AGE NATION
HAVE BEEN JAPAN. WHAT IS REALLY
AMAZING TO ME IN THIS SLIDE IS
THAT IF YOU LOOK AT OVER TIME
THEY INCREASE IN LIFE
EXPECTANCY, ALMOST LINEAR
INCREASE WITH AGE. AND WHEN
PEOPLE LOOK AT THIS SLIDE IN
2000 WHEN THE FIRST SUBMISSION
OF THIS PAPER, EVERYBODY SAID IN
IS A PHENOMENON THAT HAS TO SLOW
DOWN AT CERTAIN POINT. IN FACT,
DIFFERENT ORGANIZATION INCLUDES
UNITED NATION AND MILLION
INDUSTRIAL STENOGRAPHERS AND
EPIDEMIOLOGISTS MADE A NUMBER OF
PROJECTION. THE PROJECTION ARE
ILLUSTRATED HERE BY THIS DASHED
LINE. OF COURSE NATURE HAS A WAY
TO BE MUCH STRONGER AND MUCH
MORE CONVINCING THAN ANY
DEMOGRAPHER OR EPIDEMIOLOGIST.
IN SPITE OF THE PRODUCTION, LIFE
EXPECTANCY TEND TO INCREASE
LINEARLY OVER TIME. AND DOESN'T
REALLY HAVE SHOWN, AT LEAST SO
FAR HAVE REALLY SHOWN NO SLOWING
DOWN, NO MODIFICATION OVER TIME
WHY THIS IS IMPORTANT? BECAUSE
WHY WE NEED TO CELEBRATE THE
INCREASING LIFE EXPECTANCY, WE
NEED TO -- WE ARE ABLE TO LIVE
LONGER. THIS IS SUCCESS OF
HUMANS AND THE SAME TIME THE
INCREASE IN LIFE IS NOT
OCCURRING ON THE LEVEL OF THE
GOOD LIFE, THE LIFE THAT IS
CHARACTERIZED BY HEALTH AND JOY
AND EVERYTHING THAT LIFE HAS TO
OFFER BUT ALSO FROM THE LAST
POINT OF LIFE, LIFE THAT IS
CHARACTERIZED BY MULTI-MORBIDITY
AND DISABILITY. AND INTERESTING
PART YOU PROBABLY NEVER REALLY
THOUGHT ABOUT, FEWER PEOPLE MAY
HAVE IS THAT THE MOST SPENT IN
HEALTHCARE, THE LONGEST IS
(INAUDIBLE) OF LIFE EXPECTANCY.
ISN'T THAT -- THE MORE
HEALTHCARE WE TAUGHT INTO GRACE
THE LONGER THE DISABLED LIFE
EXPECTANCY. THAT IS AN IMPORTANT
PART OF OUR CONVERSATION TODAY.
IN FACT, WE SHOULD NOT BE
DISADVISED. IF YOU LOOK AT
EPIDEMIOLOGY OF MAJOR DISEASE, I
THINK MOST OF THE AGING OF THE
POPULATION ESPECIALLY IN THE
DEVELOPED COUNTRY IS DUE TO
DECLINE IN HEART DISEASE.
DECLINE IN HEART DISEASE IS DUE
TO REDUCTION OF THE MODIFICATION
OF RISK FACTORS SUCH AS
HYPERTENSION AND DISLIPIDEMIA.
ALSO CANCER MORTALITY TEND TO
DECLINE OVER TIME THOUGH LESS
STEEPER THAN HEART DISEASE,
THOUGH HERE THE DATA ARE MUCH
MORE PROMISING ESPECIALLY WITH
THE NEW TREATMENT DEVELOPED IN
PARTICULAR WITH NEW TREATMENT
FOR CANCER. STROKE IS DECLINING.
WHAT IS NOW DECLINING AT ALL,
THE DISEASE, THAT CHARACTERIZE
BY MULTI-MORBID COMPLEX
MULTI-MORE BUILDTY AND
DISABILITY. ALZHEIMER'S DISEASE
IS NOT E DECLINING IT IS
INCREASING. INFLUENZA, COPD,
DON'T SHOW ANY SIGN OF DECLINE
AND IN FACT WHAT IS INCREASING
IN TERMS OF CAUSE OF DEATH IS
THE MULTI-(INAUDIBLE) OF DEATH.
PEOPLE TEND TO HAVE -- DIE OF
MULTIPLE DISEASES, PHENOMENON OF
MULTI-MORBIDITY. LIFE THE AMOUNT
OF TIME WE HAVE GAIN IS
DETERMINED -- ESPECIALLY IN
PERCENTAGE, IN THE BAD PART OF
LIFE. THE LIFE CHARACTERIZED BY
DISEASE AND DISABILITY. AS A
PATIENT OF MINE TOLD ME ONCE,
THE ISSUE IS THAT WHEN LIFE IS
GOOD, IT GO REALLY FAS FAST. WHI
HAVE DISEASE AND DISABILITY THE
LIFE SEEM TO GO SLOWER AND
SLOWER AN SLOWER. SO THAT IS ONE
ISSUE WE SNEAD TO ADDRESS IN OUR
SOCIETY. SO THE WAY I THINK
ABOUT IT, IS THAT WE WANT THE
HEALTHY LIFE THAT WE HAVE LOST
OVER THE YEARS. THE ISSUES THAT
HOW DO WE DO THAT, HOW DO WE
ACCOMPLISH THAT? TO GO BACK TO
UNDERSTANDING WHY THIS IS
HAPPENING, IS THAT WE DISCOVERED
IN EPIDEMIOLOGICAL STUDY, THIS
HAS COME IN CLUSTERS. WHAT DO I
MEAN? WHEN YOU DEVELOP ONE
DISEASE THE PROBABILITY YOU
DEVELOP A SECOND ONE IS MUCH
HIGHER AT THE SAME AGE THAN IF
WE DIDN'T HAVE THAT FIRST
DISEASE. THIS IS TRUE
INDEPENDENT OF WHAT DISEASE YOU
ARE TALKING ABOUT. SO WHEN I
START EPIDEMIOLOGIST WE USED TO
SAY WELL, I THINK THAT WE WANT
TO KNOW WHAT HAPPEN IF WE
ELIMINATE CARDIOVASCULAR
DISEASE. THAT WAS REALLY THE
WRONG QUESTION BECAUSE
CARDIOVASCULAR DISEASE ONLY
MEANS ANOTHER DISEASE THAT IS
CLUSTER WITH THE FIRST ONE WILL
COME SHORTLY LATER. SO IF YOU
THINK ABOUT THE PERSON THAT IS
AN ARCH LIFE EXPECTANCY IS THE
PEAK BY THIS GRAPH. YOU CAN SEE
IN THE BLUE SHAPE PART OF THE
GRAPH YOU HAVE PERIOD WHERE
DISEASE EPIDEALOLOGY ACCUMULATE
BUT IS NOT EVIDENT BECAUSE IT IS
NOT EMERGE CLINICALLY AS SYMPTOM
OF FUNCTIONAL LIMITATIONS.
ANOTHER PERSON THAT HAS A LIFE
EXPECTANCY THAT IS LONGER YOU
WILL HAVE THIS BRIEF PATHOLOGY
WILL BE LONGER BUT YOU WILL
STILL SEE THE DISEASE THAT OCCUR
AS A CLUSTER. THEREFORE,
SOMEBODY WITH A SHORTER LIFE
EXPECTANCY YOU WILL SEE A
SHORTER PERIOD OF CLINICAL
PATHOLOGY BUT THEN THE SAME
CLUSTER OF DISEASE THAT OCCUR
RECENTLY THEREAFTER. REMEMBER
THIS SLIDE BECAUSE THIS IS THE
KEY TO UNDERSTAND WHAT I WILL BE
TALKING TODAY. THE REAL PROBLEM
IS WE HAVE A HEALTHCARE SYSTEM
THAT ONLY INTERVENE AT THE TIME
WHEN DISEASE BECOME CLINICALLY
RELEVANT. THAT IS THE TIME YOU
INTERVENE. BECAUSE YOU INTERVENE
AT THAT POINT, THE ONLY THING
THAT YOU CAN INFLUENCE IS WHAT
COME LATER. SO THE U.S. SPENT
LESS THAN 3% OF THE ENTIRE
BUDGET ON HEALTHCARE,
PREVENTION, SO ON THIS PERIOD IN
97% IN THIS PERIOD. THERE IS NO
DOUBT THAT ONLY THING WE CAN
ACCOMPLISH IS TO PROLONG THIS
LIFE EXPECTANCY ESPECIALLY THOSE
INCREASING LIFE EXPECTANCY
RELATED TO HEALTHCARE.
EXPERIENCE FOR ME, I GO TO THE
DOCTOR EVERY YEAR, I ASK THE
DOCTOR TO CHECK ME OUT, SEE WHAT
I HAVE PROBLEM AND DO A SCOPE OF
MY CHEST, PRETEND TO LOOK AT MY
HEART, THEN THEY TELL ME THAT
I'M GOOD. MY HEALTH IS GOOD, I
EXERCISE, I EAT PROPERLY, MY
WEIGHT IS NOT CHANGING, MY BLOOD
PRESSURE IS OKAY, MY CHOLESTEROL
IS OKAY. I GET FROM THERE UPSET
BECAUSE I KNOW THERE IS
PATHOLOGY, AQUME LATING IN MY
BODY. I KNOW -- I WANT TO KNOW
HOW MUCH AND I WANT TO KNOW WHY
AND WHAT I CAN DO ABOUT IT. SO
THE PROBLEM TO ME IS LIKE WE ARE
HAVING AN EGG AND THE EGG IS IN
THE MIDDLE OF THE AIR AND WE
KNOW THAT IS IN A (INAUDIBLE)
DOWN BECAUSE OF GRAVITY, WE
DON'T DO ANYTHING OR THE EGG
WILL BREAK. WHEN THE EGG BREAK,
PUTTING BACK THE BROKEN EGG
TOGETHER, IT IS GOING TO BE VERY
PROBLEMATIC. SO WHAT YOU REALLY
WANT TO DO IS TO CATCH THE EGG
AND DO SOMETHING WHEN THE EGG IS
STILL IN THE CHICKEN. WHEN IT IS
STILL IN THE CHICKEN YOU CAN
PREVENT THE EGG FROM BREAKING
DOWN AND DROPPING AND MAYBE
THERE'S SOMETHING THAT WE CAN DO
ABOUT IT. HOW DO WE DO THAT? I
THINK THAT WE HAVE TO GO BACK TO
MY INITIAL SLIDE AND SAY LIFE
EXPECTANCY DISEASE -- AS YOU CAN
SEE THE ACCUMULATION OF
PATHOLOGY THAT OCCUR PRETTY
CLINICALLY IN THIS THREE
INDIVIDUAL OCCUR ALSO AT
(INAUDIBLE) SO IF I TRY TO
AVERAGE THIS TRAJECTORY THAT ARE
CLINICAL, I CAN SEE THIS PROJECT
WILL HAVE DIFFERENT SLOPE IF I
ONLY LOOK AT THE SLOPE Z THIS
SLOPE TELL ME WHAT INCREASE
SUSCEPTIBILITY TO THE MULTIPLE
DISEASE. NEW SCIENCE IS
EMERGING CALLED GEE ROW SCIENCE
THEORIZE THE ONLY GENE OF
DISEASE, ROOT TO DISEASE IS THE
PACE OF AGING. GERO SCIENCE. THE
SAME THAT CAUSED THE PHENOTYPIC
MANIFESTATION OF AGING ARE THOSE
THAT CREATE THE OPPORTUNITY FOR
THE DEVELOPMENT OF CHRONIC
DISEASE. SO IF I MENTION PACE OF
AGING I CAN UNDERSTAND EARLY
BEFORE THE CLINICAL AROUND
REPRODUCIBILITY OF THE DISEASE
WHO ARE THE INDIVIDUAL SHOWING
RAPID AGING AN INTERVENE ON
THEM. THEN I THINK THAT THIS IS
OLD SLIDE BUT TO ME THE BEST
PRESENTATION OVER GERO SCIENCE
WANT TO DO. IF YOU SLOW DOWN
AGING INSTEAD OF IN PARALLEL TO
DO A SPECIFIC DISEASE
PREVENTION, WE WILL NOT ADDRESS
ONE SINGLE DISEASE BUT WILL
ADDRESS MULTIPLE CHRONIC DISEASE
OVER TIME AND INSTEAD OF
SPECIFIC TREATMENT WE WILL SLOW
DOWN AGING AND REDUCE THE
EMERGENCE AND INCIDENCE OF
MULTIPLE CHRONIC DISEASES. CAN
WE SLOW DOWN AGING? I SAY
SOMETHING LIKELY BUT IS THAT
POSSIBLE. I THINK MY CALLING
THAT WILL TALK AFTER ME WILL
TALK MORE ABOUT THE MODEL
ORGANISM SO I HAVE SOME SLIDES
BUT U I REMOVE THEM AND PROBABLY
MULTIPLE ORGANISM THERE IS SOME
EVIDENCE THAT WE CAN SLOW DOWN
AGING, I THINK THAT WHETHER WE
CAN DO IT IN HUMAN IS
QUESTIONABLE. BUT I HOPE WE CAN
AND THERE IS SOME INDICATION
THIS IS POSSIBLE. BUT THE SECOND
QUESTION THAT TO ME IS MORE
IMPORTANT, MORE URGENT IS TO SAY
HOW DO YOU KNOW THAT YOU CAN
SLOW OUR AGING IF YOU CANNOT
MANAGE AGING? HOW DO I KNOW AN
INTERVENTION WILL SLOW DOWN -- I
CAN -- CLINICAL TRIAL IN A
PERSON THAT IS BORN TODAY AND
SEE WHETHER THAT WILL SLOW DOWN
AGING REDUCE MORTALITY BUT
RESULT OF THAT TRIAL WILL BE
AVAILABLE IN (INAUDIBLE) SO IT
IS A LITTLE BIT NOT PRACTICAL. A
HUNDRED YEARS. SO NOT PRACTICAL.
WHAT PEOPLE ARE WORKING ON IS A
MODEL OF AGING THAT ALLOW US TO
MEASURE AGING. THIS IS HOW IT
PLAY OUT IN MY HEAD. THE WAY I
THINK ABOUT AGING IS THAT DURING
AFTER BIRTH WE ARE SUBJECT TO
ENTROPIC STRES STRES STRESS. ENN
PHYSICS CAN BE ELIMINATED. WE
HAVE A NUMBER OF EVOLUTIONARILY
SELECTED MECHANISMS THAT
CONTRAST ACCUMULATION OF DAMAGE.
AN EXAMPLE, YOU HAVE THE
STOCHASTIC DNA DAMAGE, YOU CAN'T
REPAIR THE DNA. YOU HAVE THE
DETERIORATION OF MITOCHONDRIA
AND YOU CAN ELIMINATE THEM BY
MYTO HAVE GIVE AND BIOGENESIS.
MY TO HA TO HAVE JUST. THEY ARE
SUBJECT TO STOCHASTIC DAMAGE AS
WELL SO OVER TIME RESILIENCE
DECLINE, ENTROPY ACCUMULATE AND
THEN YOU HAVE THAT IMBALANCE
BETWEEN THE ENTROPY DAMAGE
ACCUMULATION AND RESILIENCE.
THEN WHEN YOU SAY TO ME THIS
PART OF THE MANY DISCUSSION,
(INAUDIBLE) IS -- FRAILTY IS THE
CONDITION WHEN THE STRESS OF
NORMAL LIFE CANNOT BE AFFORD AND
LEAD TO FURTHER DAMAGE
ACCUMULATION. SOME OF THE
MECHANISM OF RESILIENCY HAS BEEN
IDENTIFY AND I WILL NOT TALK
ABOUT IT THOUGH I WILL PUT ONE
MOMENT ABOUT MITOCHONDRIAL
FUNCTION. THERE IS ALSO MANY
MECHANISM EPIDEMIOLOGIST HAVE
FOUND REALLY ACCELERATE AGING
PROCESS. THERE IS SOME ENTROPY
CAN KARMA STRESS, GENETICS ALL
CAN ACCELERATE AGING. SO HOW
DOES THIS HELP US? THINK ABOUT
MODEL OF RATIO DAMAGE
ACCUMULATION AND RESILIENCE
STRATEGY, I WILL SKIP THIS, YOU
CAN THINK ABOUT MEASURING
RESILIENCY, MEASURING THIS
MECHANISM OF RESILIENCY. IF I
MEASURE THE MECHANISM OF
RESILIENCY I WILL GO TO MY
DOCTOR AND THEY WILL TELL ME,
YOU ARE REALLY DOING WELL. WHEN
I MEASURE RESILIENCE MECHANISM,
YOUR RESILIENCE MECHANISM ARE
NOT DOING VERY WELL. I WILL SKIP
THIS SLIDE. SO THERE IS EVIDENCE
THAT WE CAN REALLY SLOW DOWN
AGING, IT IS REALLY INTRINSIC IN
THE MODEL OF IONS.LY SHOW YOU
ONE SLIDE ABOUT IT. SO THIS IS A
FAMOUS PAPER THAT WAS PUBLISHED
BY TOM PERTH IN THE LANSETT. WE
CALCULATED THE PERCENTAGE OF
CENTENARIANS THAT ARE
FUNCTIONING OVER THE COURSE OF
THE TEN PREVIOUS YEARS OF THEIR
LIFE. ON AVERAGE TWO YEAR BEFORE
THEY WERE STUDIES THERE WAS
THEIR LEVEL OF INDEPENDENCE,
90%, 75%, 60%. NOW, IF YOU LOOK
AT THE GENERAL POPULATION, AND
YOU LOOK AT THE PERCENTAGE OF
THOSE 80 YEARS AND OLDER,
INDEPENDENTLY FUNCTION IN
DEGENERATIVE COGNITION AND YOU
MAKE A COMPARISON, THIS PERSON
THAT IS 97 YEARS OLD WILL BECOME
A CENTENARIAN. AT THE AGE OF 97,
IN 75% OF THE CASES INDEPENDENT.
COMPARE TO ONLY 40% OF THOSE 80
PLUS IN THE GENERAL POPULATION.
SUGGESTING THAT THE PEOPLE THAT
REACH VERY LONG, LONGEVITY, THEY
ALSO HAVE A MUCH LONGER HEALTH
EXPECTANCY. SO THAT IS
INTRINSICALLY POSSIBLE IN OUR
GENOME AND WE NEED TO FIND WAY
TO ACCOMPLISH THIS POTENTIAL.
HOW DO WE MEASURE AGE SOMETHING
THIS IS A FRIEND OF MINE THAT I
THINK IS A GENIUS THAT
DISCOVERED THAT SPECIFIC
MODIFICATION -- CHEMICAL
MODIFICATION OF THE DNA CAN BE
SUMMARIZE IN A SCORE THAT IS
STRONGLY CORRELATED WITH AGING.
YOU CAN SEE THAT THIS IS
EPIGENETICS CLOCK. AND THIS IS
DISCOVERY, I WILL DISPLAY YOU IN
SIMPLE TERMS, IF YOU ARE IN THE
CORRIDOR IN A BUILDING YOU SEE A
DROP OF BLOOD ON THE GROUND,
SOMEBODY ANALYZE (INAUDIBLE) IN
THE DROP OF BLOOD THEY CAN TELL
YOU EXACTLY HOW OLD THAT PERSON
IS WITH TOLERANCE OF PLUS OR
MINUS 1.5 YEARS. THAT HAS NEVER
BEEN POSSIBLE BEFORE. WE ONLY
USE THE CLOCK AND THE BIRTHDAY
TO UNDERSTAND AGE OF PERSON AND
WE NOW KNOW BETWEEN THE
EPIGENETIC AGE AN CHRONOLOGICAL
AGE THERE IS STRONG DISCREPANCY
AND THIS DISCREPANCY PREDICT
OUTCOME. THE DISCREPANCY BETWEEN
CHRONOLOGICAL AGE AND EPIGENETIC
AGE FOR EXAMPLE SLOWER
EPIGENETIC AGE IS WITH FISH
CONSUMPTION, CRUISABLE
CONSUMPTION, EXERCISE AND FASTER
EPIGENETIC AGING THAT WE THINK
IS BIOLOGICAL AGING IS HIGH
SYSTOLIC BLOOD PRESSURE AND
INFLAMMATION. YOU CAN DO THIS
SAME THING INSTEAD OF USING
METHYLATION THAT IS A LITTLE
OBSCURE BY LOOKING AT THE
PROTEINS THAT WE MEASURE IN THE
BLOOD. I GRADUATED AS A
PHYSICIAN IN 1980. AT THAT TIME
WE WERE MEASURING 30 PROTEIN
ROUTINE FOR CLINICAL STUDIES.
AND WE ARE MEASURING THE SAME 30
PROTEIN, MANY, MANY YEARS LATER
IN FACT EXPERIMENTALLY, WE CAN
MEASURE 10,000 PROTEIN IN LESS
THAN 1 MILLILITER OF BLOOD. THAT
IS THE TECHNOLOGY WE WILL APPLY,
CERTAIN CAN BE APPLIED TO
MEASURE EPIGENETIC CLOCK, TO
MEASURE THE SCORE THAT CORRELATE
THE CHRONOLOGICAL AGE. THERE IS
AN INTRINSIC PROBLEM WITH THIS,
THE PROBLEM IS THAT THIS STUDY
HAVE BEEN CROSS SECTIONAL. SO AS
A PICTURE OF THE MOMENT IN TIME
IN CROSS SECTIONAL STUDIES ARE
PROBLEMATIC. WHY? I GIVE YOU
ONLY ONE EXAMPLE TODAY. THAT IS
VERY IMPORTANT. YOU THINK WHEN
YOU STUDY IN EFFECT AGING OVER
COMPARISON, 20, 50, 90 AND 105
YOU LOOK AT THE DIFFERENCEIOUS
THINK THEY ARE DIFFERENT BY AGE.
YOU WILL BE WRONG. BECAUSE THESE
105 YEARS OLD PERSON WAS AGE 20
DURING WORLD WAR 1. SO HE WENT
THROUGH WORLD WAR 1 AND AGE 90
WAS DURING THE GREAT DEPRESSION.
WHY THIS AGE OF 50 WAS AGE OF 20
DURING THE REVOLUTION, THE FIRST
TIME IN THEIR LIFE WHEN THERE IS
ENOUGH FOOD FOR EVERYBODY. THAT
REALLY MAKE THEM VERY, VERY
DIFFICULT BECAUSE OF DIFFERENT
EXPERIENCES. SO WE NEEDED TO
FIND A WAY TO MEASURING AGING
LONGITUDINALLY. THAT IS WHAT WE
DID. IN THE LONGITUDINAL STUDY,
IS REALLY UNBELIEVABLE STUDY,
THEY WERE DESIGNED IN 1958 BY
(INDISCERNIBLE) SO WE HAVE
PEOPLE IN OUR STUDY THAT HAVE
BEEN THERE FOR 50 OR 52 YEARS
AND STILL COMING TO BE STUDIED
IN OUR CLINIC. SO WHAT WE SAW IS
THAT SOME OF THE PHENOTYPE OF
AGING SUCH AS FAT MASS FOR
EXAMPLE DO NOT CHANGE WITH AGE.
FAT MASS TEND TO INCREASE WITH
AGE, AND THEN DECLINE WITH AGE.
IMAGINE THAT THOSE DASH LINE ARE
TRAJECTORY OF SPECIFIC SINGLE
INDIVIDUAL, WHY THOSE CONTINUOUS
LINE FOR THE POPULATION. THAT'S
TRUE, THIS GUY, THIS MAN, WILL
BE SHOWING ACCELERATED AGING
COMPARED TO THE GENERAL
POPULATION. BUT IF I COMPARE
THAT WITH SOMEBODY IN THIS AGE
GROUP, IT WILL BE NOTABLE. SO
THAT MEAN THAT IT CAN ONLY
EVALUATE AGE OF A PERSON WITHIN
A SPECIFIC AGE WINDOW WHEN YOU
DO THAT YOU COME UP WITH
SOMETHING EXTREMELY POWERFUL. SO
THIS IS JUST TO SHOW YOU
(INAUDIBLE) RESPIRATORY
FUNCTION, SOME OF THE TERMS --
SOME OF THE BIOMARKERS LEAN MASS
TIGHT AREA OR GRAY MATTER VOLUME
THEY DO NOT CHANGE LINEARLY,
THEY TEND TO HAVE CURVING
CHANGES SO WE NEED TO USE THIS
METHOD REALLY TO ADDRESS
ACCELERATED AGING. WHEN YOU
PULL THIS TOGETHER WHAT YOU CAN
DO IS SAY WELL, IN EACH
PHENOTYPE, I WILL LOOK AT THE
POPULATION LEVEL, AND THEN THIS
LINE OF EACH SPECIFIC
INDIVIDUAL. THEN ON THE RIGHT
SIDE, THIS IS A TRAJECTORY OF
CHANGE IN THAT PHENOTYPE WITH
AGING, THIS LINEAR ONE AND THIS
LITTLE DOT, DEVIATION NORMAL
(INAUDIBLE) SO I CAN DO THIS
WITH MANY OF THE PHENOTYPE SHOWN
BEFORE AND CREATE A SCORE. THIS
SCORE IS AMAZING PREDICTOR. AND
I WILL NOT GO HERE TO TELL --
BUT JUST TELL YOU THAT IF YOU
HAVE ONE STANDARD DEVIATION
HIGHER THIS LONGITUDINAL
PHENOTYPIC SCORE YOUR MEMORY FOR
EXAMPLE, VISUAL SPATIAL FUNCTION
IS 5 TO 10 YEARS EQUIVALENT TO A
PERSON THAT 10 TO 5 YEAR 15
YEARS OLDER. SUGGESTING REALLY
CHANGE OVER TIME IN THIS
PARAMETER AFFECT AXONAL CHANGES.
THE MOST IMPORTANT THING -- NOT
ALL I'M MISSING A SLIDE. WITHOUT
THIS SLIDE, THE NOT ONLY TRUE
THAT AGE OF 80 OR 70 TO 60, THIS
IS TRUE AT AGE 30. IF YOU
MEASURE AT 30 YEARS OLD AND
FOLLOW OVER TIME FOR FIVE YEARS,
YOU CAN PREDICT STRONGLY WHAT IS
HAPPENING WITH THEM VERY LATE IN
LIFLIFE. SUGGESTING THE SEEDS
ACCELERATED AGING ALREADY
PRESENT EARLY IN LIFE AND WE
COULD DETECT THEM AND USE THEM
TO UNDERSTAND WHAT THE
UNDERLYING MECHANISM AND ALSO TO
DO EARLY DIAGNOSIS OF VIGOMAROR
THAT NEED MORE ATTENTION. DO I
HAVE FEW MORE MINUTES? I TALK TO
YOU DIRECTLY BUT I WANT TO SHOW
HOW DIFFERENT TO OLDER PEOPLE
AND TO DO THAT I SELECT ONE OF
THE THING THAT I'M STUDYING IN
THE BIOLOGY OF NEURODEGENERATION
AND AGING WHICH IS
MITOCHONDRIAL. THE PASSION ABOUT
MITOCHONDRIA, IT IS RELATESSED
TO THE MODEL I PRESENT HERE
BEFORE. I TOLD YOU AGING IS
RATIO BETWEEN DAMAGE
ACCUMULATION AN RESILIENCE. THAT
IS IMPORTANT RESILIENCE TO WORK
REQUIRE ENERGY. ANY SINGLE
BIOLOGICAL INTERVENTION THAT
NATURE HAS CREATED WORKS ONLY IF
YOU CAN PROVIDE ENERGY AND MOST
DAMAGE IN OUR BODY COME FROM
THIS ORGANELLE, THE
MITOCHONDRIA. I WILL GIVE AN
EXAMPLE, IF YOU HAVE A MISFOLDED
RECORD DAMAGED PROTEIN, YOU CAN
REFOLD IT PROTEIN BY OTHER
PROTEIN (INAUDIBLE) THAT MOST OF
THE TIME WOULD REQUIRE ENERGY.
IF YOU HAVE A MITOCHONDRIA THAT
IS DAMAGE, THEIR MITOCHONDRIA
CAN BE REPAIR, RECYCLE OR
REPLACE BUT THESE REQUIRE
ENORMOUS AMOUNT, REMEMBER ANY
TIME WE SEE TO SYNTHESIZE
PROTEIN, PROTEIN SYNTHESIS IS
ONE OF THE MOST TELOMERE
BIOCHEMICAL PROCESS WE KNOW
AROUND SO YOU NEED ENERGY: WHAT
HAPPENED TO MITOCHONDRIA WITH
AGING? INTO SHOW YOU HOW WE
STUDY MITOCHONDRIA. THIS IS IN
MOVIE THAT WILL GO THROUGH THE
(INAUDIBLE) MITOCHONDRIA ARE
VERY IMPORTANT AND I WILL
INDICATE TO YOU THE STRUCTURE
THAT YOU SEE HERE. SO THIS IS A
NUCLEI AND THEN YOU SEE THIS
LITTLE STRUCTURE OF THE
MITOCHONDRIA, THAT CLUSTER THE
NUCLEI IS BLACK SPACE
INTRACELLULAR MATRIX AND THIS IS
THE FIBER OF COLLAGEN YOU SEE
HERE. THIS IS A -- AND WHAT YOU
CAN SEE WITHIN THE COPY OF RED
BLOOD CELLS IS HEPATOCYTES THEN
YOU SEE THE SARCO MERE, IT WILL
-- THE SACK WILL APPEAR. THE
SACK WILL APPEAR IN THE MUSCLE
AND BETWEEN THIS SARCO MERE VERY
CLOSE TO WHERE ENERGY IS
REQUIRED YOU CAN SEE A LITTLE
GLOBULE OF SHAPES THAT YOU HAVE,
OF THE INTERMITOCHONDRIAIA.
WHAT IS IMPORTANT IS THAT THIS
MITOCHONDRIA, WHEN YOU LOOK AT
THEM IN THREE DIMENSIONAL SPACE,
I WILL SHOW YOU, THEY ARE A
NETWORK THAT IS INVOLVED WITH
FIBER SO THE FIBER CAN RECEIVE
THE ENERGY THEY NEED TO
FUNCTION. THIS IS A THREE KY
MENTION PAL RECONSTRUCTION OF
THE MITOCHONDRIA, YOU CAN SEE
THERE IS -- AND YOU CAN SEE THAT
THERE IS A HOLE THERE. I DON'T
KNOW IF YOU CAN SEE THE HOLE
HERE, THIS IS WHERE THE
(INAUDIBLE) ARE. THIS IS A VERY
HEALTHY MUSCLE. YOU CAN SEE A
MUSCLE THAT IS A LITTLE BIT
HEALTHY. LESS HEALTHY, WITH THE
CONNECTION BUT STILL PRETTY
GOOD. THEN YOU GO TO THIS LAST
ONENA IS AN 80 YEARS OLD PERSON
AND YOU CAN SEE THAT THOSE
MITOCHONDRIA ARE NO LONGER
CONNECTED. THE FRAGMENTATION OF
THE NETWORK IS EXTREMELY
IMPORTANT BECAUSE THE
FUNCTIONING OF THE NETWORK OF
MITOCHONDRIA REQUIRE ELECTRICAL
TRANSMISSION, BETWEEN ONE
MITOCHONDRIA AND THE OTHER. WHEN
THIS ELECTRICAL TRANSMISSION,
DOES NOT OCCUR, THAT MEAN THAT
THE CENTER OF THE FIBER YOU
DON'T HAVE ENOUGH ENERGY. SO THE
CONTRACTION OF THE FIBER OCCUR
IN A SEQUENCE WAY. YOU CAN
MECHANICALLY DAMAGE, WE KNOW AT
LEAST IN ANIMAL MODEL WE CAN
KIND OF FIX THIS, WHETHER WE CAN
DO THIS IN HUMANS, IS STILL THE
QUESTION BUT I HOPE THAT THAT IS
WHAT THE FUTURE WILL BRING US AT
LEAST SOME ASPECTS OF THE HUMAN
AGING BIOLOGY WE WILL BE ABLE TO
ADDRESS. ONE OF THE FEW WE CAN
DO NOW JUST TO FINISH, IF YOU
EXERCISE, THOSE MITOCHONDRIA
RETURN CONNECTED AS THEY WERE
BEFORE THE AGING PROCESS. SO CAN
WE SLOW DOWN AGING? I REALLY
DON'T KNOW, CAN WE IMPROVE
MITOCHONDRIAL FUNCTION, ONE OF
THE HALLMARKS OF AGE SOMETHING
CERTAINLY WE CAN. THANK YOU
VERY MUCH. SO MY QUESTION IS,
CAN WE SLOW DOWN AGING? THERE IS
A LOT WE CAN DO, TO THIS PART OF
THE POPULATION BUT WE ALSO NEED
TO STUDY AGING IN THE LIFE
COURSE PERSPECTIVE. WE NEED TO
STUDY AGING IN THIS INDIVIDUAL.
BECAUSE IF THERE WHEN WE HAVE
THE CHANCE TO SLOW DOWN THE
PROCESS EVENTUALLY WILL CREATE
DISEASE AND DISABILITY. THANK
YOU FOR YOUR ATTENTION, LOOKING
FORWARD TO THE NEXT
PRESENTATION.
>>THANK YOU VERY MUCH, LUIGI.
THAT WAS REALLY EXCITING
PRESENTATION. NOW WE MOVE ON TO
SAUL VILLEDA. PLEASE GO AHEAD, SAUL.
>>THANK YOU TO DR.
ARIAS FOR THE INVITATION IN
GETTING A CHANCE TO SHARE OUR
WORK WITH EVERYONE. REALLY
QUICKLY, NO FINANCIAL
DISCLOSURES. . IN TERMS OF
LONG-TERM OBJECTIVE, I WOULD
LOVE TO EVALUATE SOME OF THE
MOLECULAR MECHANISMS THAT WE
HAVE IDENTIFIED IN ANIMAL
STUDIES WITH THE POTENTIAL WE
THINK TO RESCUE COGNITIVE
FUNCTION LATE IN LIFE. SO
BROADLY WHAT MY LAB IS
INTERESTED IN UNDERSTANDING AND
INVESTIGATING IS THIS IDEA OF
CAN THE EFFECT OF AGING ON THE
BRAIN BE REVERSED? WE JUST HEARD
ABOUT THE IDEA OF SLOWING DOWN
AGING AND FOR ME I'M FOCUS ON
INDIVIDUAL TISSUE WHICH WOULD BE
THE BRAIN. TACKLING ON ONE
TISSUE ONE FUNCTION AT A TIME
MAY ALLOW US TO IDENTIFY
MECHANISMS THAT MAYBE WE ARE
ABLE TO APPLY MORE BROADLY TO
OTHER TISSUES AS WELL. I LIKE
THIS IMAGE, WE ARE TRYING TO
START AT OLDER AGE AND TRYING TO
UNDERSTAND HOW MUCH FUNCTION CAN
YOU RESTORE? THINKING
REVERSIBILITY IS NOT ENGAGING
THE SAME MECHANISMS THERE WHEN
WE ARE YOUNG BUT ENGAGING
MECHANISMS THAT BRING BACK THE
FUNCTION THAT WAS THERE DURING
THE YOUTH. THAT IS WHAT WE THINK
OF AS TERMS LIKE REJUVENATION OR
DISABILITY. SO MY LAB WE ARE
INTERESTED IN FUNCTION. WHY DO I
THINK THAT THIS IS IMPORTANT? IN
THE BRAIN THERE IS INTIMATE
RELATIONSHIP BETWEEN AGING THE
OLDER YOU GET AND THIS DECLINE
YOU SEE IN BRAIN FUNCTION. THE
VULNERABILITY AN SUSCEPTIBILITY
TO NEURODEGENERATIVE DISEASES
THAT WE OFTEN THINK ABOUT AS
SOMETHING LIKE ALZHEIMER'S.
EVEN SOMEONE WITH GENETIC
PRE-DISPOSITION, IS NOT GOING TO
EXHIBIT OVERT PATHOLOGY
SOMETHING LIKE SAY 20 YEARS OLD.
IF YOU LOOK LATER IN LIFE YOU
WILL SEE THAT OVERT PATHOLOGY SO
THERE IS A CONNECTION BETWEEN
AGING AND DISEASE. WHAT WE WANT
TO KNOW, LIKE I MENTION, SOMEONE
IN THEIR 20s IS NOT GOING TO
NECESSARILY HAVE THAT OVERT
PATHOLOGY, SO NATURALLY DURING
YOUTH YOUR BODY STAVES OFF THIS
INSULT SO NATURALLY HAS
MECHANISMS THAT ARE PROTECT. HOW
DO WE UNDERSTAND WHAT THOSE
MECHANISMS ARE? WHAT HAPPENS IF
WE RESTORE THOSE MECHANISMS
LATER IN LIFE? CAN WE THEN
PREVENTS THIS ONSET OR INCREASE
IN NEURODEGENERATIVE DISEASE. WE
ARE NOT MANY MY LAB FOCUSING ON
LIFE SPAN OR EXPANDING LIFE
SPAN, WE ARE FOCUSING ON TACKLE
THIS FUNCTIONAL DECLINE THAT
COMES WITH AGE. I THINK ABOUT
THIS A LOT WITH THIS IS JUST A
GRAPHIC FROM THE UNITED NATIONS.
WHEN MY PARENTS WERE BORN, THEY
WERE BORN IN 1951. WHEN THEY
WERE BORN, ABOUT 8% OF THE
POPULATION AT LEAST IN THE U.S.
WAS OVER THE AGE OF 65 65. SO WT
WE THINK OF AS RETIREMENT AGE.
BY THE TIME I RETIRE AROUND
2050ISH, DURING THE PANDEMIC I
TURNED 40. SO WHEN I THINK ABOUT
IT BY THE TIME I RETIRE IT WILL
BE OVER 21%, CLOSE TO 22% OF THE
POPULATION WILL BE OLDER THAN
RETIREMENT AGE. AND I JUST SAID,
THERE IS THIS INTIMATE
RELATIONSHIP BETWEEN AGING AND
SUSCEPTIBILITY VULNERABILITY AND
ONSET OF THINGS LIKE
NEURODEGENERATIVE DISEASE. SO
THEN THIS GRAPH TAKES ON NEW
URGENCY IN THAT NOT ONLY DO WE
KNOW THAT THIS IS COMING IN
TERMS OF THE ONSET OF THESE
DISEASES, NOW WE KNOW IT WILL
HAPPEN IN A MUCH LARGER
POPULATION. SO WHAT CAN WE DO
ABOUT IT? JUST TO GIVE AN IDEA,
A LITTLE BIT WHAT WE THINK OF IN
MY LAB AS AGE RELATED COGNITIVE
DECLINE WHICH IS WHAT WE WILL
FOCUS ON, WE ARE GOING TO FOCUS
ON PRIOR TO OVERT SIGNS OF THAT
DISEASE. I WILL GIVE AN EXAMPLE
OF AGE RELATED COGNITIVE
DECLINE. I'M IN SAN FRANCISCO,
UNIVERSITY OF CALIFORNIA SAN
FRANCISCO. SO THERE ARE A
RIDICULOUS NUMBER OF TESLAS IN
THE ROAD. SO PRETEND I'M GOING
TO DRIVE MY TESLA, I DON'T OWN
ONE BUT HOPEFULLY ONE DAY,
PRETEND I AM DRIVING IT INTO THE
PARKING LOT AND THERE'S A BUNCH
OF OTHER TESLA'S THERE. I'M
GOING TO NEED TO BE ABLE TO FIND
MY ELECTRIC CAR AT THE END OF
THE DAY. SO MY BRAIN IS
NATURALLY GOING TO LOOK AT
QUEUES THAT ARE AROUND WHERE I
PARKED THE CAR. ON A NICE SUNNY
DATE, I MIGHT HAVE IT ON A HILL,
DURING THE SUM ME RAINBOW FLAG
DURING PRIDE OR MAYBE A FOOD
TRUCK NEARBY. I GO TO WORK COME
BACK AND MY BRAIN NATURALLY SEES
THAT AND SAYS YOU PARKED CLOSER
TO THE VIEW OF THE GOLDEN GATE
BRIDGE AND FURTHER FROM THE FOOD
TRUCK. WHEN YOU ARE YOUNG YOU
HAVE NO ISSUES WITH THIS. BUT
PERHAPS YOU HAVE BEEN IN A
PARKING LOT WHERE YOU START
SEEING MAYBE AN ELDERLY PERSON
USING THEIR CAR ALARM, THAT IS
SORT OF ONE SIGN OF THIS AGE
RELATED COGNITIVE DECLINE, FULL
DISCLOSURE BECAUSE KNOW THERE
ARE STUDENTS OUT THERE THAT
ALWAYS FREAK OUT A LITTLE BIT,
IT MAY BE HAPPENING AS WELL
CHRONIC STRESS IS ANOTHER REASON
YOU WOULD SEE THIS TYPE OF
COGNITIVE DECLINE SO AGING AS
WELL AS CHRONIC STRESS.
UNIVERSITY STUDENTS NEAR FINALS
THAT ARE WORRIED. SO THIS IS
TYPES OF FUNCTION WE ARE LOOKING
AT WHEN WE ARE THINKING ABOUT
AGE RELATED COGNITIVE DECLINE.
HOWEVER WE STUDY THINGS IN THE
HUMAN CONTEXT TO FIND
APPLICATIONS AND OF COURSE
TRYING TO TRANSLATE WHAT WE DO
BUT WE DO USE ANIMAL MODELS AND
WHAT IS INTERESTING IS THIS SAME
TYPE OF COGNITIVE DECLINE IS
CONSERVED ACROSS SPECIES
INCLUDING ANIMAL MODEL. SO OUR
MODEL OF CHOICE IS THE MOUSE.
AND THE REASON WE USE THIS IS
REALLY THERE IS A LOT OF POWER
WITH RESPECT TO MOLECULAR
BIOLOGY AND GENETICS AND JUST
DIFFERENT INTERVENTIONS AND
MANIPULATIONS WE CAN DO IN
THESE. HERE I'M SHOWING YOU A
YOUNG MOUSE AND OLDER MOUSE UX
SEE A LOT OF PHENOTYPES ARE
STILL THERE. THERE IS CHANGE IN
WEIGHT, YOU CAN SEE GRAIN AT THE
FUR SO THERE IS REAL
DIFFERENCES. IF YOU WERE TO ZOOM
IN THEIR ICE START DEVELOPING AT
SOME POINTS CATARACTS SO YOU CAN
START SEEING AGING APPROACH JUST
TO ORIENT EVERYONE A LITTLE BIT,
THIS IS FROM THE JACKSON
LABORATORIES WHICH IS A HUGE
ENTITY THAT PROHAVE SLIDES PLUS
MODELS TO THE SCIENTIFIC
COMMUNITY. IF YOU WERE TO
EXTRAPOLATE LOOSELY THE MOUSE
AGES TO HUMAN AGE, WE HAVE THESE
MORE MATURE ANIMALS, 3 TO 6
MONTHS, FROM 21 TO 30, MORE
MIDDLE AGE MOUSE ABOUT A YEAR.
THERE'S MORE MY AGE AND WE ALSO
HAVE THE OLDER ANIMAL MODELS
AROUND HERE, THEY WOULD BE
CLOSER GOING UP TO THE LATE
'60s OR SO, THOSE ARE THE AGE
CHANGES WE USE. SIMILAR TO WHAT
I MENTION ABOUT FINDING MY
ELECTRIC CAR IN THE MIDDLE OF A
PARKING LOT, WE CAN TRAIN
ANIMALS TO FIND A HIDDEN
PLATFORM IN A POOL OF WATER.
MICE ARE GREAT SWIMMERS BUT THEY
HATE COLD WATER SO THEY WILL DO
WHAT THEY CAN TO GET OUT OF THAT
POOL OF WATER FAST. SO THEY
REALLY GOOD FINDING THIS HIDDEN
WATER WITH RELATION TO QUEUES
AROUND THE ROOM SIMILAR TO THE
GOLDEN GATE BRIDGE, MAYBE A TRY
YANGING SIMILAR TO RAINBOW FLAG,
MAYBE STRIPES AND GO MY PLATFORM
IS CLOSER TO TRIANGLE THAN TO
THE STRIPES OR THE RECTANGLE.
WITH AGE THIS IS SIMILAR TO WHAT
WE SEE, WE SEE IMPAIRMENT. SO
NATURALLY OVER TIME AND TRAINING
A YOUNG ANIMAL CAN GET GOOD,
DOESN'T MAKE MISTAKES MANY. BUT
OTHER ANIMAL MIGHT GO A
DIFFERENT DIRECTION, IN THE END
THEY WILL FIND THE PLATFORM THEY
JUST HAVE MISTAKES ON THEIR WAY
THERE. SO WE CAN ASK A FEW
QUESTIONS WITH REALLY BASIC
BEHAVIORAL ASSAYS. NUMBER ONE,
WHAT IS DRIVING THIS IMPAIRMENT?
ARE THERE MECHANISMS WE CAN FIND
THAT INCREASE OR EMERGE WITH AGE
THAT CAN MIMIC THIS IMPAIRMENT.
ALTERNATIVELY, CAN WE RESTORE
IDENTIFY AND RESTORE POTENTIALLY
BENEFICIAL MECHANISMS TO BRING
OLDER MECHANISM TO MORE YOUTHFUL
FUNCTIONAL STATE. CAN WE IMPROVE
THESE TYPES OF LEARNING AND
MEMORY. WE FOCUS ON PARTS OF
THE BRAIN THAT REGULATES ASPECT
OF LEARNING AND MEMORY KNOWN AS
HIPPOCAMPUS. HERE IS IN SALMON
COLOR AND THIS IS BEFORE DISEASE
ONSET. SAY LIKE ALZHEIMER WE
DON'T HAVE GROSS
NEURODEGENERATION SO NOT A LOT
OF CELL DEATH BUT WE HAVE SERIES
OF CELLULAR CHANGES THAT ARE
HAPPENING. WE FOCUS ON
HIPPOCAMPUS ONE BECAUSE IT IS A
MOUSE REGULATOR OF LEARN AND
MEMORY AND TWO, IT IS VULNERABLE
REGION TO EFFECT AND AGING ONE
OF THE FIRST POINTS OF CONTACT
BETWEEN BRAIN AND AGING. SO
WHAT IS AGING LOOK LIKE IN IF WE
LOOK AT THE NEURONS WHAT CHANGES
IS NOT REALLY NECESSARILY THEY
ARE DYING BUT RATHER CONNECTION
BETWEEN NEURONS BECOME FAULTY SO
NO LONGER STABLE. NORMALLY YOU
HAVE THESE STABLE CONNECTIONS,
IT KIND OF LOOKS LIKE A ROSE
STEM AND YOU CAN SEE LITTLE
THORNS, JUST CALLED SYNAPTIC
SPINES. THAT IS THE PHYSICAL
CONTACT WHERE THE SYNAPSES
OCCUR. HOW THE NEURONS
COMMUNICATE WITH ONE ANOTHER.
NOSE BECOME UNSTABLE FAULTY, WE
LOSE SOME OF THEM. ADDITION
A.M.LY WE ALSO HAVE CHANGES IN
REGENERATIVE CAPACITY SO NEURAL
STEM CELLS THAT GIVE RISE TO
NEURONS, WE HAVE OTHER
PROGENITORS THAT MYELINATE AND
GIVE RISE TO MYELINATI MYELINATE
HAVE DYSFUNCTION. THIS IS
CONTROVERSIAL IN HUMANS SOME
REPORTS SAY THIS DISAPPEARS BY
PUBERTY, OTHER REPORTS SHOWING
NO, YOU HAVE THESE STEMS UNTIL
LATE IN LIFE AND THEY ARE
DECLINE ACTUALLY CORRELATES WITH
COGNITIVE IMPAIRMENT. RIGHT NOW
THERE IS LARGER NUMBER OF PAPERS
THAT ARE.
COMING IN SUPPORT OF THAT SORT
OF POOL BEGIN INTO OLD AGE BUT
THAT IS ONGOING RESEARCH. IN OUR
ANIMAL MODEL IT IS QUITE CLEAR
THIS PERSISTENT. WE HAVE
INFLAMMATION BECOMING MORE
RELEVANT IN CONTEXT OF AGE. WE
KNOW IT HAS A HUGE ROLE IN
PROMOTING THESE AGING PHENOTYPES
BOTH IN THE PERIPHERY AS WELL AS
IN THE BRAIN. LASTLY, THE
COMMUNICATION BETWEEN WHAT IS IN
THE BRAIN AND OUT OF THE BRAIN,
GETS FALLY AS WE GO OVER TO
BLOOD -- FAULTY AS WE GO OVER
BLOOD BRAIN BARRIER AND
VASCULATURE IS EMERGING AS
ANOTHER HALLMARK OF AGING AND IT
IS NOT THAT THE BARRIER BREAKS
AND EVERYTHING GETS INTO THE
BRAIN BUT SELECTIVITY OF WHAT
GETS IN AND DOESN'T GET IN IS
CHANGING WITH AGE SO SIGNALS
THAT ARE GETTING TO YOUR BRAIN
ARE SHIFTING BETWEEN WHEN YOU
ARE YOUNG AND WHEN YOU ARE OLD.
WORK FIRST AS GRADUATE STUDENT
AT STANFORD WORKING WITH DR. TOM
(INAUDIBLE) WAS USING THIS VERY
OLD MODEL FIRST DESCRIBED IN THE
LATE 1700S WHERE YOU PHYSICALLY
CONNECT A YOUNG AND OLD -- ADD
THEM TOGETHER IN THIS PARTICULAR
CASE MICE, TWO HEARTS PUMP ONE
BLOODSTREAM SO TWO QUESTIONS.
NUMBER ONE, WHAT IS IMPACT OF
OLD BLOOD AND OLD BLOOD SIGNALS
ON TO THE YOUNG ANIMAL? AND WHAT
ARE THE IMPACT OF THOSE YOUNG
FACTORS OR YOUNG BLOOD TO OLD
ANIMAL? AND WORK BY DR. TOM
RANDO AND AMY WAGER IS STARTED
SHOWING THAT THERE ARE SIGNALS,
THAT ARE -- THAT HAVE
INFORMATION THAT CAN REALLY
REJUVENATE OR RESTORE FUNCTION
IN THAT OLDER ANIMAL
PARTICULARLY IN THE CONTEXT OF
STEM CELL BIOLOGY. TOGETHER WITH
TONY AND NUMBER OF DIFFERENT
LIVES AROUND THE WORLD, WE
DEMONSTRATED THAT THESE AGE
FACTORS CAN PROMOTE AGENING THE
BRAIN A LOT A AGING IN NATURE. T
FACTORS IMPROVE FUNCTION IN THE
BRAIN INCLUDING LEARNING AND
MEMORY. WHAT IS INTERESTING AT
THE BEGINNING WHEN I STARTED
RESEARCH I THOUGHT THERE WAS
SOMETHING UNIQUE ABOUT YOUNG
BLOOD. THERE MUST BE SOMETHING
THAT IS UNIQUE TO THIS ONE
CONDITION. IT TURNS OUT IF YOU
LOOK AT A LONG, LONG HISTORY,
LONG HISTORY OF RESEARCH, IT IS
NOT JUST ABOUT A MODEL OF
PARABAYOUSIS I CONSIDER A
SYSTEMIC INTERVENTION BUT THERE
IS A NUMBER OF LIFESTYLE
INTERVENTIONS THAT CAN ALSO
IMPACT AND RESTORE FUNCTION OR
REJUVENATE TISSUE. FOR EXAMPLE
EXERCISE, WE JUST HER EXERCISE
IMPACT MITOCHONDRIA WHICH IS A
HALLMARK OF AGING, EXERCISE ALSO
IMPROVE LEARN AND MEMORY. WE
KNOW THERE SHAH CORE
RESTRICTION. THROUGH PRIMATE, IT
SEEMED TO IMPROVE HEALTH IN
ANIMAL MODELS, IMPROVE LIFE SPAN
IN CERTAIN CASES AS WELL ALSO
LESS STUDIED ALSO HAS IMPACT ON
COGNITIVE FUNCTION DURING OLD
AGE. SO WE KNEW THERE WAS ALL
THESE DIFFERENT TYPES OF
INTERVENTIONS. WHEN WE STARTED
DOING THE WORK IN PARABIOSIS WE
WERE ASKED ABOUT THE
TRANSLATABILITY OF THIS
APPROACH. YOU CAN'T SEW
INDIVIDUALS TOGETHER. WE DID IS
WE CAME UP WITH AN ALTERNATIVE
WHERE WE FOUND THE VOLUME OF
PLASMA IN THIS CASE, MOSTLY
FACTORS IN BLOOD AND WE INJECTED
THEM INTO THESE OLDER ANIMALS
AND WE JUST ASKED CAN WE MIMIC
OR TRANSFER SOME OF THE BENEFITS
OF THIS SURGERY THROUGH
ADMINISTRATION OF YOUNG BLOOD
FACTORS. THIS IS WHERE I STARTED
MY LAB AND STARTED DOING WORK
HERE AT UCSF AND I WILL SHOW YOU
ONE PIECE OF DATA, AGAIN, I WILL
UTILIZE THAT WATER MAZE I TALKED
TO YOU ABOUT TO TRY TO FIND THAT
PLATFORM WITH RESPECT TO QUEUES.
WHAT WE ARE GOING TO DO IS COUNT
HOW MANY ERRORS WE DIVIDE THIS
POOL TO SERIES OF ARMS, THEY
HAVE TO GET HERE, SO IN THIS
PARTICULAR CASE THEY MADE THREE
ERRORS AND WE CAN QUANTIFY
ERRORS, THIS IS GREAT BECAUSE IT
GETS AROUND A YOUNG OR OLDER
ANIMAL SWIMMING AT DIFFERENT
SPEEDS, THIS WILL FORCE THEM TO
JUST MAKE A SERIES OF DECISIONS
WE INJECT 5% VOLUME OF BLOOD IN
OLDER ANIMAL WITH YOUNG PLASMA.
AND WE JUST DO THESE EXPERIMENTS
ABOUT A MONTH LATER. I WANT TO
POINT OUT THESE ARE NATURALLY
NORMALLY AGED ANIMALS. THEY ARE
NOT GENETIC MODELS THEE ARE JUST
NORMAL ANIMALS, WHENEVER
POSSIBLE, EVEN LITTER MATES A
LOT BORN TOGETHER. WHAT WE KNOW
IS THAT AT THIS AGE THERE ARE
ABOUT A LITTLE UNDER TWO YEARS
OLD. SO EQUIVALENT TO 60s IN A
HUMAN. WE SEE WHEN YOU GIVE THIS
NORMAL OLD BLOOD IN GRAY YOU
CONTINUE TO MAKE ERRORS THEY
START ABOUT FOUR AND THEY GO
DOWN TO TWO, BUT OLD ANIMALS IN
RED THAT RECEIVED THAT YOUNG
PLASMA WENT DOWN CLOSE TO ONE
ERROR SO YOU CAN RESTORE
FUNCTION. THIS IS EXCITING FOR A
FEW REASONS. NUMBER ONE, YOUR
BRAIN IS CAPABLE OF BEING
RESTORED. THERE IS ENOUGH
PLASTICITY LEFT IN THOSE THAT
YOU CAN BRING BACK FUNCTION.
THAT MEANS WE JUST NEED TO CRACK
THE CODE. WHAT ARE THE CHANGES,
WHICH CELL TYPES ARE THE MOST
IMPORTANT TO HAVE THIS
RESTORATION. WHAT ARE THE
MOLECULES POTENTIALLY THAT
HAPPEN, BUT IT DID GIVE US AN
IDEA THAT THERE IS THE ABILITY
TO RESTORE FUNCTION. IN MANY MY
LAB WE HAVE ONGOING WORK GOING
ON FOCUSING ON HALLMARK OF
CHANGING, DO YOU HAVE TO RESTORE
EVERY FUNCTION TO GET THAT
COGNITIVE RESTORATION OR
REJUVENATION OR MAYBE IT IS A
COMBINATION, MAYBE IF WE
DECREASE INFLAMMATION GNAT BRAIN
THAT ENOUGH AND ALLOWING NEURONS
THERE TO COMMUNICATE. IF YOU
TALK ABOUT SAY REGENERATION AND
NEURONAL COMMUNICATION MAYBE
THAT IS ENOUGH TO REJUVENATE. SO
WE ARE FOCUSING ON THE
CONTRIBUTION OF DIFFERENT
HALLMARKS AS WELL AS WHAT YOU
HAVE TO TARGET. THE OTHER THING,
WE ARE STARTING TO LOOK AT THE
DIFFERENT INTERVENTIONS. NOT
JUST YOUNG BLOOD BUT WHAT ABOUT
EXERCISE OR CAN CALORIC
RESTRICTION. ONE PROBLEM WE HAVE
ESPECIALLY IN THE ELDERLY
POPULATION OR THOSE WITH
ALZHEIMERS OFTEN TIMES COMPANY
WITH FRAILTY, THEY ARE NOT ABLE
TO ADHERE OR PHYSICALLY DO THE
ACTIVITY ITSELF, THEY CAN'T
ACTUALLY EXERCISE THOUGH WE KNOW
BENEFICIAL IN THE HUMAN
CONDITION. SO THEN WHAT MY LAB,
ESPECIALLY A POST DOC GRADUATE
STUDENT IN MY LAB GOT EXCITED,
THEY WERE LIKE WELL, WE KNOW
EXERCISE IS ACCOMPANIED WITH
IMPROVED HEALTH SPAN AND
BENEFITS AND I LOVE THIS IMAGE
I'M SHOWING YOU THE THIS
PICTURE, THIS GENTLEMAN,
MR. SING PREPARING FOR THE
MARATHON. HE IS A HUNDRED YEARS
OLD AND JUST HEALTH SPAN IS
INCREDIBLE. HE'S BOTH A
CENTENARIAN BUT ALSO A HISTORY
OF EXERCISE SO REALLY
UNDERSCORES THIS BENEFIT THAT
CAN HAPPEN. WHEN MY STUDENTS
SAID WHEN THEY WERE THINKING
EXERCISE THEY WERE LIKE EXERCISE
HAS A LOT OF THE SAME BENEFITS
WE SEE IN PARABIOSIS.
REGENERATION, NEURONAL
COMMUNICATION, INFLAMMATION,
IMPROVED COGNITION. SO THEY WERE
REALLY INTERESTED IN ASKING IF
YOU CAN TRANSFER THE EFFECT OF
PARABIOSIS THROUGH BLOOD
ADMINISTRATION CAN YOU DO THE
SAME WITH EXERCISE? CAN WE
IDENTIFY FACTORS? SO THAT IS
WHAT THEY DID. THEY ASKED THAT
QUESTION, CAN THE BENEFITS OF
EXERCISE JUST BE TRANSFERRED
THROUGH BLOOD AND THIS IS
SHELLEY, TALENTED. THEY WENT OFF
AND SET UP AN EXERCISE PARADIGM,
WELL REPORTED MANY LABS FOR A
LONG TIME HAVE SEEN THE BENEFITS
YOU GIVE A LITTLE VOLUNTARY
WHEEL RUNNING, WE DID IT FOR
ABOUT SIX WEEKS THEN WE DID
BEHAVIORAL ANALYSIS. WE DID
CELLULAR PREDOMINANTLY ON
BEHAVIOR. SO USING THAT SAME
MODEL, YOU STARTED AROUND 4 AND
YOU END UP MAKING HERE ABOUT TWO
AND A HALF ERRORS IN THE
NORMALLY OLD ANALYSIS BUT PUT IN
RUNNING WHEEL IT GETS DOWN TO
ONE. ONE OF THE STRONGEST
INTERVENTIONS THAT WE HAVE SEEN
TO RESTORE FUNCTION. SO
EXERCISE, REALLY IS GOOD EVEN AT
OLD AGE IN THIS MOUSE MODEL.
NEXT THEY RAN OLD MICE AND USED
IT TO TEASE APART THE BENEFIT OF
YOUNG BLOOD FROM BENEFIT OF
EXERCISE FACTORS. SO EXERCISE
OLD MICE THAT COULD EXERCISE,
THEY TOOK PLASMA, INJECTED INTO
OLD MICE AND THEN AGAIN LOOKED
AT BEHAVIOR AGAIN WE SAW A
FRACTION OF THAT BENEFIT THAT WE
SEE WITH EXERCISE CAN ACTUALLY
BE TRANSFERRED THROUGH JUST
ADMINISTRATION OF THOSE BLOOD
FACTORS SO THAT WAS REALLY
EXCITING TO US. SO OF COURSE WE
WANTS TO KNOW WHAT ARE THE
MOLECULAR MECHANISM?
I WILL USE THIS OPPORTUNITY JUST
TO SAY THE IDEA OF
ADMINISTRATING BLOOD CAPTURED
THE ATTENTION OF THE PUBLIC BUT
I WILL SAY AND THE FDA SAID, YOU
CANNOT JUST INJECT BLOOD WHETHER
YOUNG BLOOD OR EXERCISE BLOOD
INTO HUMANS THAT IS NOT A TENIAL
SOLUTION OR THERAPEUTIC.
LIMITATIONS IN TERMS OF AMOUNT
OF BLOOD, THERE IS NOT ENOUGH TO
TREAT THE ALZHEIMER'S PATIENTS
TODAY LET ALONE ONES COMING AND
NUMBER TWO, REAL DANGERS TO IT
IN TERMS OF PRESSURE IN YOUR
LUNG AND OTHER POTENTIALS SORT
OF CONTAMINATION FROM THE BLOOD.
SO THE ALTERNATIVE WHAT WE ARE
TRYING TO ACHIEVE IS TRYING TO
UNDERSTAND WHAT ARE THE
MOLECULAR MECHANISMS, WHAT IS IT
IN THE BLOOD THAT CAN CONFER
THIS BENEFIT, WHAT ARE THE CELL
TARGETS WHETHER THEY BE OUTSIDE
OF THE BRAIN OR IN THE BRAIN.
WHAT IS IT ELICITING INSIDE THE
CELLS? IS IT GENE, IS IT
EPIGENETICS, PROTEINS? SO WE ARE
TRYING TO TACKLE ALL THAT. AS WE
IDENTIFY THESE FACTORS THAT CAN
NOW BE PRODUCED, THEY CAN THEN
BE DOSED AND WE CAN GO THROUGH
TRADITIONAL CLINICAL TRIALS IN A
CONTROLLED SETTING TOWARDS
SOMETHING THAT CAN BE APPLIED SO
I WANT TO STRESS THAT IS THE
REASON THE FIELD IS REALLY AFTER
THE MOLECULAR MECHANISMS, WHAT
IS IT THAT IS DOING. WHAT WE
ENDED UP TRYING IS WE DID WHAT
IS CALLED PROTEOMICS. WE TOOK
THE BLOOD OF THOSE EXERCISE OR
NON-EXERCISE ANIMALS AND WE JUST
SAID WHAT ARE THE DIFFERENCES?
ARE THERE ANY PROTEINS THAT ARE
DIFFERENT IN ONE CONDITION
VERSUS OTHER? WE CAME UP WITH A
HANDFUL OF FACTORS THAT DID
CHANGE BETWEEN THE TWO
CONDITIONS. WE LOOK AT WHERE
THEY GENERALLY COMING FROM, AND
EXPRESSED AND WE WERE SURPRISED
BECAUSE WE EXPECTED TO SEE
MOSTLY MUSCLE FACTORS BUT WE SAW
TWO-THIRDS BEGIN LIVER FACTOR,
DIDN'T MATTER OLD MICE OR
SLIGHTLY YOUNGER MICE. IT WAS
PREDOMINANTLY LIVER FACTORS. SO
THEN WE LOOK AT ALL FACTORS AND
SAID ARE THEY INVOLVED IN
PARTICULAR PROCESSES IN THE
BRAIN? AND IF SO, DO ANY FACTORS
LIKE JUMP OUT AT US? WHAT WE DID
IS WE JUST TOOK THOSE FACTORS
AND JUST BIOINFORMATICS ASKED
ARE YOU INVOLVED IN ANY
PARTICULAR PROCESSES? AND IT WAS
A LOT OF METABOLIC PROCESSES
THAT CAME OUT. THAT MAKES SENSE
BECAUSE IT IS LIVER PROTEINS.
BUT ONE FACTOR, ACTUALLY TWO,
CAME UP A LOT. ONE OF THEM I
WILL TALK ABOUT TODAY, IT IS AN
ENZYME CALLED GPLT 1, ONE IS
RIVER FACTOR CALLED POL 1 THAT
DID NOTHING WHEN WE TESTED SO
NEGATIVE DAS, IT ISN'T A
SUPPLEMENT OF THE PAPER, IT IS
LIKE FIGURE 17. BUT WE DID TEST
BOTH AND THERE WAS ONE THAT
SHOWED PROMISING EFFECTS AND
THAT IS WHAT I WILL FOCUS ON
TODAY WHICH IS GPLD 1. IT ACTS
AS A SCISSOR SO ON A CELL
SURFACE WE HAVE PROTEINS STUCK
THE SURFACE, THEY ARE ANCHORED
BY THE LITTLE TAGS AND ALL THIS
ENZYME DOES IT COMES AN CLEAVES
AND THE PROTEIN CAN GO AND IT
CAN ACTIVATE PATHWAYS, INHIBIT
PATHWAYS OR THE PROTEINS JUST
GET DEGRADED SO IT CAN HAVE A
NUMBER OF DIFFERENT FUNCTIONS.
WE LIKE THAT BECAUSE THAT MEANS
IT WILL HAVE BROAD EFFECTS. SO
FOCUS ON THIS ONE LIVER DERIVED
FACTOR, YOU EXERCISE, IT GOES
UP, IT'S COMING FROM THE LIVER
AND WE WANTED TO KNOW IS IT
ASSOCIATED WITH THAT BENEFIT.
HERE I'M SHOWING YOU IN ANOTHER
GROUP OF OLD MICE WE EXERCISE,
IT IS HIGHER, THIS IS JUST
MEASUREMENT WESTERN BLOT IT IS
HIGHER IN ANIMALS THAT RUN. WE
CORRELATED IT SO THAT HIGHER
LEVELS IN THE BLOOD OF THIS
FACTOR CORRELATE WITH LESS ROARS
IN THAT WATER SO NICE
ASSOCIATION. WE HAD ACCESS TO
BLOOD FROM ELDERLY INDIVIDUALS,
OTHER AGE 70 THAT HAD FIT BITS
FOR A MONTH AND LOOKED AT THEIR
ACTIVITY. WE ALSO SAW THAT THE
MORE ACTIVE INDIVIDUALS, WE USE
SPORTS MEDICINE CUT OFFS FOR
THIS, THE MORE ACTIVE THE
ELDERLY INDIVIDUAL, THE HIGHER
THE LEVEL OF GPLD 1. IN MY LAB
WE USED HUMAN DATA AS SORT OF
LIKE FILTERS FOR WHICH FACTORS
WE PURSUE. ONLY PURSUING ONES WE
IDENTIFY FROM ANIMAL MODELS THAT
WE ALSO SEE CORRESPONDING
CHANGES IN THE HUMANS AS WELL.
WE GOT EXCITED. THERE'S NICE
ASSOCIATIONS BETWEEN LIVER
FACTOR AND SORT OF FUNCTION AND
SEEMS RELEVANT IN HUMANSS. SO
WHAT ABOUT IT? CAN WE INCREASE
IT THEN? CAN YOU CONFER SOME
BENEFIT THROUGH INDIVIDUAL
FACTORS THAT ARE INDUCED BY
EXERCISE? THE FIRST THING WE
WANTED TO KNOW IS WHERE IS THIS
FACTOR COMING FROM, AND IS IT
GOING UP IN ANY PARTICULAR
TISSUE? WE KNEW IT WAS
PREDOMINANTLY LIVER DRIVE, WE
LOOKED ACROSS HE CAN
PRESENTATION LUNG FAT SPLEEN
BRAIN HEART AND SAW HIGHEST
EXPRESSION IN LIVER. WHEN WE
LOOK AT AFTER EXERCISE, ONLY
WENT UP IN THE LIVER. SO IT
REALLY IS COMING FROM THE LIVER.
SO REMEMBER I SAID THAT WE USE
THESE MOUSE MODELS BECAUSE WE
ARE ABLE TO MANIPULATE AND USE
GENE EDITING AND MOLECULAR
BIOLOGY TO DO THEM. SO WE USED A
TRICK THAT IMMUNOLOGISTS USE.
WHAT WE DID IS MAKE A LITTLE
JUST CIRCULAR DNA THAT ENCODES
YOUR SOMEWHERE GENE OF INTEREST
IN THIS PARTICULAR CASE OR
ENZYME, GPLD 1. WHAT YOU CAN DO
WITH A LARGE VOLUME, JUST INJECT
THIS INTO THE BLOODSTREAM OF A
MOUSE AND BECAUSE IT IS A LARGE
VOLUME IT GETS TAKEN UP INTO THE
LIVER. AND THEN THE LIVER STARTS
MAKING THE PROTEIN FOR YOU. AND
IT STARTS SPITTING OUT INTO THE
BLOOD SO WE ARE ABLE TO MIMIC
THAT EXERCISE EFFECT BY USING IN
A WAY THIS GENE EDITING APPROACH
OR OVEREXPRESSION APPROACH. O SO
THREE THINGS, CONTROL, SEPARATE
PROTEIN NORMALLY NOT IN A MOUSE,
COMES FROM A JELLY FISH. WE THEN
PUT PROTEIN OF INTEREST GPLD 1.
I TOLD YOU IT ACTS AS A SCISSOR
SO WHAT WE ENDED UP DOING IS
COMPLETELY TOOK AWAY ITS ABILITY
TO CUT. WE MADE A MUTATIONS
FORM ONE LITTLE POINT MUTATION
AND IT CAN NO LONGER CUT THOSE
PROTEINS ANY MORE. THEN WE SAID
WHAT ABOUT BEHAVIOR? SO HERE I'M
SHOWING YOU THAT CONTROL, AND
THESE OLDER ANIMALS WERE SMARTER
TO BEGIN WITH, BUT THEN WHEN WE
JUST LOOKED AT THESE INDIVIDUAL
OLDER ANIMALS COMPARED TO GPLD
1, THE GPLD 1 WAS BETTER. SO IT
IMPROVED BEHAVIOR A LOT. WHEN
WE LOOK AT THE ONE THAT CAN NO
LONGER CUT THE EFFECT WENT AWAY.
SO ALL WE KNOW IS IT HAS TO BE
SOME OF THOSE PROTEINS THAT ARE
COMING. THAT'S ONE PARTS THAT MY
LAB IS DOING, WE ARE TRYING TO
FIGURE OUT WHAT THE TARGET CELLS
ARE, WHAT ARE THE FACTORS THAT
THEY ARE TARGETING, DO WE WANT
TO HAVE AS MANY POTENTIAL
MOLECULAR TARGETS AS POSSIBLE TO
SEE WHICH MAY BE APPLICABLE AND
TRANSLATABLE TO HUMAN. I WILL
END QUICKLY WITH JUST ONE LAST
THING. ONE THING I GET ASKED A
LOT IS WE FOCUS ALMOST EXCLUE
SUVLY ON BIOLOGY OF AGING AND
THE AGING CONTEXT. WE DON'T GO
MUCH INTO THE DISEASE. I'M
ALWAYS ASKED, WELL YOU ARE
FINDING THESE MOLECULES, DO WE
HAVE TO TREAT ONLY THE ELDERLY
OR IS IT POSSIBLE THEY MIGHT
HAVE SOME BENEFIT EVEN IN THE
CONTEXT OF DISEASE? SO I HEAR
THAT A LOT AND A FOURTH QUARTER
WAS INTERESTED IN ADDRESSING
THIS. WE USED THIS EXERCISE
EXAMPLE, THIS MOLECULE, TO ASK,
WELL, COULD THEN THESE AGING
FUNDINGS APPLY TO DISEASE
CONTEXT? WHAT HE DID IS USED AN
ANIMAL MODEL OF ALZHEIMERS
DISEASE PATHOLOGY. NOW, THIS
PATHOLOGY IS VERY AGGRESSIVE AND
IT HAPPENS WHEN MUCH YOUNGER. IT
HAPPENS BY THE TIME THEY ARE
MATURE MAX MIDDLE AGE BEFORE
THEY EVER HAVE IMPAIRMENTS FOR
BEING OLD. HE EXERCISED THEM IN
BEHAVIOR, IN THIS PARTICULAR
CASE WE USE A DIFFERENT BEHAVIOR
BUT STILL HIPPOCAMPUS. THESE
ANIMALS ARE SUPER CURIOUS SO IF
YOU PUT TWO IDENTICAL OBJECTS
THEY WILL EXPLORE BOTH. IF YOU
COME BACK THE NEXT DAY, AND YOU
JUST PUT A DIFFERENT OBJECT, IF
THEY REMEMBER THIS ONE THEY WILL
EXPLORE THE NOVEL ONE MORE SO
CALL IT A NOVEL OBJECT
RECOGNITION. THE MORE TIME WITH
A NOVEL OBJECT THE MORE YOU
REMEMBER THE OLD OBJECT SO
METRIC OF MEMORY. WE JUST LOOKED
AFTER EXERCISE, THESE
ALZHEIMER'S DISEASE PATHOLOGY
MODEL THEY SPEND MORE TIME WITH
THE OBJECT SO BETTER AT MEMORY
OLD. WE LOOK AT GPLD 1
EXPRESSION IT WENT UP AND IT
CORRELATED IN THIS MODEL OF
DISEASE SO WE ARE LIKE OKAY THE
SAME MECHANISMS BY EXERCISE ARE
BEING ENGAGED WHICH IS GOOD. WE
THEN USED AGAIN OUR MOLECULAR
CHECK WE OVEREXPRESS FACTOR ONLY
IN LIVER IN YOUNGER BUT
ALZHEIMER'S DISEASE PATHOLOGY
MODELS. WE LOOK AT PATHOLOGIES
SO THESE ARE PLAQUES WE
TRADITIONALLY THINK OF IN
ALZHEIMERS SO WE SEE LESS OF
THESE AND YOU SEE THEY ARE
SMALLER SO WE HAVE LESS OF THAT
A BETA WITHIN THEIR BRAIN. WE
DID BEHAVIOR, THE FIRST THING IS
THESE -- THIS ANIMAL MODEL GETS
SICK SO WE CAN USE THESE WELL
BEING METRICS AND NORMAL MOUSE
LIKES TO MAKE THESE CUTE LITTLE
NESTLETS. BUT ALWAYS MYERS
MODELS ARE NOT GOOD, ALZHEIMERS
ARE NOT GOOD ATE. THE ONES
EXPRESSED IN BLOOD WERE BETTER
AT MAKING THE LITTLE NESTS.
WHEN WE LOOK AT NOVEL OBJECT
LIKE BEFORE THEY ARE IMPAIRED
THIS MODEL IS IMPAIRED YOU CAN
MAKE THEM A BIT BETTER, BY JUST
EXPRESSING THIS LIVER FACTOR. SO
JUST TO WRAP THIS UP, WE THINK
THAT WE CAN TRANSFER SOME OF THE
BENEFIT OF EXERCISE, THIS IS
REALLY EXCITING FOR THOSE THAT
CAN'T ACTUALLY EXERCISE. WE
THINK THE LIVER IS SECRETING
CERTAIN PROTEINS THAT GO IN. AND
WE ARE ALSO FINDING THE
MECHANISMS IN THE BRAIN. WE
DON'T THINK IT GOES INTO THE
BRAIN, WE THINK IT MIGHT BE
WORKING THROUGH THE IMMUNE
SYSTEM AND VASCULATURE BUT PLACE
IT IS LIVER IN AN INTERESTING
POT.POSITION. CAN AFFECTS OF AGG
BE REVERSEDD? IN ANIMAL MODELS
ITS CAN. THERE'S CERTAIN
MANIPULATIONS THAT INVOLVE THE
BLOOD CAN HAVE A BENEFIT EVEN ON
-- IN INDIVIDUALS WITH
ALZHEIMER'S. THERE IS A GROUP
IN SOUTH KOREA AS WELL AS
BARCELONA AND SPAIN THAT HAVE
NICE EVIDENCE. SO WE FIND THIS
REALLY PROMISING. THAT IS WHERE
MY LAB IS GOING. WITH THAT, I
WANT TO THANK NUMBER OF MY LAB,
THESE ARE THE HAPPY PEOPLE THAT
ARE THERE. WITH THAT, I THINK WE
ARE GOING TO TAKE QUESTIONS.
>>THANK YOU VERY MUCH. THIS IS
REALLY VERY EXCITING. LET ME
LOOK THROUGH THE QUESTIONS HERE
AND PUT THEM IN SOME GROUP SO WE
CAN GET IT TOGETHER. SO WE HAVE
A QUESTION ABOUT -- THERE WE
ARE. SO IS THERE A ROLE FOR THES
ARE VEER TROLL AND SERTUIN
DEACETYLATION PATHWAY? THAT IN
YEAST SEEMS TO HAVE ROSE VEER
TROLL SEEMS TO HAVE SUBSTANTIAL
FUNCTION IN TERMS OF AGING. WHAT
IS THE CURRENT VIEW ABOUT THAT
WITH REGARD TO THE AN MALL
STUDIES OR HUMAN AGE -- ANIMAL
STUDIES ANDOR OR HUMAN AGE
SOMETHING
>>I CAN TRY AND THEN SAUL CAN.
I THINK THAT BEING THE
ENTHUSIAST ABOUT THE METHYLATION
OF (INAUDIBLE) RESVERTROL AS YOU
KNOW IT WAS CONSIDERED THE
REASON WHY THE FRENCH PEOPLE CAN
EAT, DRINK SO MUCH WINE AND NOT
GETTING CARDIOVASCULAR DISEASE.
THE STUDY IN MICE SHOW THAT
STRONG STRONG EFFECT IN -- WHEN
THE MICE WERE FED WITH FAT, FAT
RICH DIET, THERE WAS INCREMENTAL
LIFE EXPECTANCY ALSO IN
PATHOLOGY THAT WITH BASICALLY NO
EFFECT. THEY WERE FED A NORMAL
DIET. THEY WERE NOT -- VERY
LITTLE EFFECT. I HAVE TO TELL
YOU WE RECENTRY STUDIED THE
MUSCLE OF THE CALORIE STUDY, THE
CALORIE STUDY IS THE ONLY STUDY
IN HUMANS THAT LOOK AT THE FAT
OF CALORIE RESTRICTION. IN THE
MUSCLE OF PEOPLE THAT WERE
CALORIE RESTRICTION, WE SEE
IMPROVEMENT IN MUSCLE QUALITY
THAT IS PARALLEL BY
OVEREXPRESSION OF (INAUDIBLE)
PATHWAY. SO I THINK THAT WHILE
RESVERTROL I DON'T THINK IS
GOING TO WORK I THINK THE SIP 1
STUDY IS NOT CONCLUDED YET.
>>JUST TO FOLLOW-UP A LITTLE
BIT, AS THE LAB IS ENGAGING IN
MORE INTERVENTION WE WAS THE
YOUNG BLOOD, OLD BLOOD,
EXERCISE, CALORIC RESTRICTION,
THEY ALL ENGAGE DIFFERENT
MECHANISMS AT LEAST WHEN WE LOOK
INTO THE TISSUE. SO WHEN WE LOOK
AT THIS BROAD SEQUENCING OF
EXERCISE, SAY IN THE BRAIN, WE
SEE MITOCHONDRIA, WE SEE MPTOR
SIGNATURES. WHEN WE LOOK AT
YOUNG BLOOD WE SAW KREB AND KREB
ACTIVATION, DIFFERENT
TRANSCRIPTION FACTORS IN THAT
CONTEXT. SO HEARING WHAT LUIGI
SAID IN TERMS OF CALORIC
RESTRICTION AND ENGAGING THE
PATHWAYS, THAT P GOES WITH WHAT
WE ARE SEEING WHICH IS DIFFERENT
INTERVENTIONS AT LEAST AT THE
POINT OF TISSUE ENGAGE DIFFERENT
PATHWAYS.
>>HERE IS A QUESTION, YOU THINK
THERE IS A LINK IN SOME WAY
BETWEEN THE PROPOSE SIRTUIN
MECHANISM AND SEE ONE ALPHA
LEADING THE MITOCHONDRIAL
BIOGENESIS, IS THERE A LINK
BETWEEN THAT AND WHAT YOU ARE
OBSERVING WITH THE
>>ABSOLUTELY. WELL, I DON'T
KNOW ABOUT EXPERIMENTAL, SAUL
WILL ADDRESS THAT BUT ABSOLUTELY
WE SEE A IN THE STUDY THAT WAS
MENTION BEFORE, WHAT WE SEE IS
AN INCREMENT IN MITOCHONDRIAL
BIOGENESIS THAT IS DRIVEN BY PDC
1 ALPHA IN INCREMENTING IN
TRANSCRIPTION FACTOR THAT ACT AT
LEVEL OF MITOCHONDRIAL DNA. SO
WE THINK THAT MITOCHONDRIA
REALLY PLAY IMPORTANT ROLE IN
THE POSSIBLE BENEFICIAL EFFECT
OF SERTU ISHN ACTIVATORS.
>>I GUESS BROADRY IN THE
INTERVENTION WE ARE SEEING,
ABSOLUTELY MITOCHONDRIA
SIGNATURES COME UP AUTOPHAGY
SIGNATURES COME UP, ONCE YOU GET
TO LEVEL OF CELLULAR MECHANISMS
YOU ARE ABSOLUTELY ENGAGING
THEM. WHAT WE SEE FOR EXAMPLE,
IN SOMETHING LIKE EXERCISE LOT
OF PEOPLE ALSO SEEN MUSCLE
DERIVED FACTORS, LIVE DERIVED
FACTORS IN THOSE CONTEXT
ABSOLUTELY. TRYING TO IDENTIFY
MASTER REGULATORS WHAT REGULATES
THE FACT YOU ARE SPINNING OUT SO
MANY LIVER FACTORS AND A LOT OF
THINGS LIKE P BGC ALPHA A LOT OF
REGULATORS ARE COMING UP AS
WELL.
>>HERE IS ANOTHER SEEMS AS IF
THE GENERAL VIEW ABOUT AGING, IT
IS PROBABLY A GOOD THING, TO EAT
LESS, EXERCISE MORE, PROBABLY
EAT LESS RED MEAT THAN FISH AND
VEGETABLES AND DON'T TAKE DRUGS
DON'T SMOKE. DON'T DRINK TOO
MUCH AND BE EXPOSED TO THE COLD
A LITTLE BIT BIT. MORE THAN ONE
MIGHT NORMALLY DO. IF THOSE HAVE
THOSE ASPECTS BEEN EXPLORED IN
EITHER OF YOUR WORKS? LUIGI,
FROM THE STANDPOINT OF
EPIDEMIOLOGY?
>>WE WILL STUDY ALL OF THE
ABOVE. OF COURSE. I THINK THAT
STARTING WITH DIET, DIET IS
PROBABLY THE MOST IMPORTANT
INTERVENTION WE CAN DO. IF YOU
CAN IDENTIFY WHAT ARE THE FACTOR
ACESORBIATED WITH THE BENEFICIAL
EFFECT OF GOOD DIET, THE PROBLEM
IS THAT WE DON'T KNOW VERY WELL
HOW TO MEASURE DIET IN HUMANS.
CHANGING THE DIET OF PEOPLE IS
CHALLENGCHALLENGING. THE CALORIY
REDUCE THE CALORIC INTAKE WE ARE
CALLING PEOPLE TWICE A WEEK. SO
THAT WAS PRETTY INTENSE AND THEY
WERE NOT ABLE TO REACH THE LEVEL
OF WHAT THEY WANTED. I THINK WE
SEE CERTAINLY BENEFICIAL EFFECT
OF THE (INAUDIBLE) DIET
ASSOCIATED WITH REDUCE RISK OF
CARDIOVASCULAR DISEASE, SUCH AS
BASIC MORTALITY, RECENTLY A
PAPER SHOWING ALSO THAT THERE IS
AN EFFECT ON PREVENTION OF
CANCER. WE KNOW THAT PHYSICAL
ACTIVITY NOT ONLY INCREASE
LONGEVITY BUT INCREASE ACTIVE
LIFE EXPECTANCY. IT IS REALLY
EXPAND THE PORTION OF LIFE THAT
IS WITHOUT DISEASE AND
DISABILITY. SO EXERCISE I ALWAYS
SAY IS A JEWEL, I LIKE TO GIVE
TO EVERYBODY BECAUSE IT IS GOING
TO GIVE SO MUCH BENCH THERE IS
OTHER RESPECT COMPARED TO WHAT
THE ONE YOU WERE TALKING ABOUT,
PEOPLE DON'T THINK ABOUT, ONE IS
SLEEP. THE IMPORTANCE OF SLEEP
IS COMING OUT INCREDIBLY STRONG.
BOTH IN THE TERMS OF OUR
INTERNAL CLOCK, THE CLOCK THAT
IS IN OUR ORGANISM BUT ALSO IN
TERMS OF THE RECOVERY, THE
ORGANISM GO THROUGH. WE DO KNOW
FOR EXAMPLE THAT PEOPLE THAT
SLEEP CONTINUOUSLY LESS THAN 7
HOURS A DAY, TEND TO HAVE
ACCELERATED ACCUMULATION OF BETA
AMYLOID AND PERHAPS EVEN TAU AND
THE REASON ACCELERATED COGNITIVE
DECLINE. I SAY THERE ARE PEOPLE
PEOPLE CAN DO TO SLOW DOWN THEIR
AGING NOW. ONE IMPORTANT THING,
I TALKED EXERCISE BEFORE, IT IS
NOT THAT YOU NEED TO GO OUT AND
JOG FOR THREE HOURS. THE REAL
DIFFERENCE IS BETWEEN SEDENTARY
STATE AND WALKING TEN MINUTE.
THAT DIFFERENCE IS HUGE. IF YOU
EXERCISE MORE IT IS BETTER BUT I
THINK THE PUBLIC MESSAGE IS
DON'T STAY IN FRONT OF THE
TELEVISION OR THE -- GET OUT
ROUND THE BLOCK AND THAT WILL
IMPROVE INCREDIBLE BENEFIT TRUE
IN ANIMAL MODEL AS WELL AS
HUMANS.
>>FOLLOWING UP ON THE ANIMAL
MODEL, MY STUDENTS AND POST-DOCS
GOT TO ME BECAUSE WHEN WE THINK
ABOUT THE ELDERLY POPULATION,
OFTENTIMES THEY CAN'T EXERCISE
AND YOU ARE NOT GOING TO PUT
THEM ON CALORIC RESTRICTION. SO
HOW DO WE START CONFERRING THAT?
THAT IS ONE OF THE ASPECTS WE
HAVE BEEN DOING AND I SHARE THE
EXERCISE STORY. IF WE TAKE BLOOD
FROM SHORT TERM CALORIC
RESTRICTION OLD IN LIFE AND
INJECT IT, YES, THERE'S
BENEFITS. AND IT IS JUST
ENGAGING SOMETHING DIFFERENT.
THE FACTORS ARE COMING FROM
DIFFERENT PLACES. I THINK ABOUT
OTHER THINGS, I HAVE BEEN
THINKING A LOT ABOUT THE HUMAN
CONDITION LATE IN LIFE. IT IS
NOT JUST ABOUT EXERCISE CALORIC
RESTRICTION, THERE'S SLEEP AN
WHAT ABOUT LIKE SOCIAL
ISOLATION, VERSUS SOCIAL
INTERACTION. WE KNOW THAT THAT
IS ALSO ASSOCIATED AND
CORRELATED WITH HEALTH SPAN AND
AGE. SO ANYTHING THAT IMPACTS AN
ORGANISM, I THINK WILL HAVE SOME
MECHANISMS THAT I THINK WE CAN
LEVERAGE.
>>I MISSED THE POINT. WHAT
ABOUT THE QUESTION OF COLD AND
BROWN FAT, HAVE YOU INVESTIGATED
THAT
>>IT WAS A BEAUTIFUL QUESTION
BUT WE HAVE NOT INVESTIGATED
THAT. I THINK SLIGHT UNCOUPLING
SHOULD BE REALLY GOOD BECAUSE
THE OXYGEN RADICALS BUT WE HAVE
NOT DONE THAT. I THINK THAT WHAT
I CAN TELL YOU IS PEOPLE THAT
LIVE LONGER TEND TO BE A LITTLE
BIT COLDER. I THINK YOU LOOK AT
INTERNAL INNER TEMPERATURE IN
THE BLSA PARTICIPANT, THOSE THAT
HAVE LOWER INNER TEMPERATURE
HAVE LOWER MORTALITY AND TEND TO
HAVE BETTER PHYSICAL FUNCTION.
IT COULD BE SOMETHING THERE, BUT
I'M NOT SURE THERE THIS HAHN
STUDY. REGENERATION AND STEM
CELL FUNCTION IN TERMS OF ACUTE
COLD, TIMING HAS TO DO WITH IT
SO IT CAN'T BE CHRONIC, THAT
BECOMES DETRIMENTAL, THE AMOUNT
OF COLD YOU GIVE THESE
ANIMALLINGS HAS A HUGE EFFEC EF
NOT SURE IF IT TRANSLATES TO ALL
TISSUE OR NOT, THERE'S SOME
EVIDENCE WHERE IN SORT OF HUMAN
CONDITIONS, IF THEY DO IT IN THE
WRONG WAY CAN BE DETRIMENTAL FOR
COGNITIVE FUNCTION AT LEAST IN
THE SHORT TERM. SO I THINK THIS
ONE WILL BE A LITTLE MORE
NUANCED BUT THERE ARE GROUPS IN
THE ANIMAL DOING ANIMAL
EXPERIMENTS IN THE CONTEXT OF
REGENERATION. THERE'S PROMISING
STUFF THERE.
>>HERE ARE SOME QUESTIONS ABOUT
GPD 1.
>>THE ENZYME.
[LAUGHTER]
>>IS THE LIVER THE ONLY SOURCE
OF IT?
>>SO NO, IT IS -- THE
PREDOMINANT SOURCE OF IT BUT IT
IS EXPRESSED IN P OTHER TISSUES
AND KRILLS. IT IS JUST THAT
WHEN WE LOOKED AT EXERCISE IT
WAS THE ONLY TISSUE THAT
ACTUALLY GOT INDUCED. THE
HIGHEST EXPRESSION PREDOMINANTLY
IN THE LIVER AND AFTER EXERCISE
IT WAS THE ONLY ONE ELEVATED AND
THAT ONE IS SECRETED TO THE
BLOOD.
>>SO DO YOU THINK PEOPLE WHO
HAVE CHRONIC LIVER DISEASE WHO
DON'T EXERCISE TOO MUCH, COULD
GPD 1 BE A FACTOR CONTRIBUTING
TO THEIR COGNITIVE DECLINE?
>>YES. I SHOULD MENTION, THIS
FACTOR ACTUALLY DOESN'T CHANGE
WITH AGE. SO WE ARE NOT LOSING
IT AS WE ARE GETTING OLDER. SO
WE DON'T REALLY THINK IT IS
ENGAGING NECESSARILY LIKE
PROJERONIC MECHANISMS. THIS IS
JUST INDUCED BY EXERCISE. AND IT
IS REALLY ACROSS AGES, WHY IT
CAN WORK IN SOME OF THESE
DISEASE MODELS. SO I'M NOT SURE
WHETHER IT WOULD -- I DON'T HAVE
IF IT IS CONTRIBUTING TO THAT
DECLINE BECAUSE ITS LEVELS ARE
STEADY STATE THROUGH AGING, IT
IS REALLY A BOOST WE ARE SEEING.
THAT IS A LITTLE BIT DIFFERENT
OF THE MECHANISM THAN LIKE YOUNG
BLOOD.
>>LEVEL OF THE STUDY STATE --
>>SO LIKE WHETHER YOU ARE YOUNG
OR OLD YOUR LEVEL IS NOT
CHANGING, JUST WHEN YOU ENGAGE
IN EXERCISE IT GOES UP AND THAT
INCREASE IS WHAT IS CAUSING SOME
OF THESE BENEFITS WE SEE.
>>AND IT IS UNAFFECTED BY
CHRONIC LIVER DISEASE.
>>THAT I DON'T KNOW, THAT IS A
GREAT QUESTION. I DO KNOW IT IS
IMPACTED BY THINGS LIKE DIABETES
AND ANYTHING THAT HAS TO DO SORT
OF WITH THAT INSULIN PATHWAY, WE
HAVE TO FIGURE OUT LIKE HOW DOES
IT WORK IN THAT CONTEXT. BECAUSE
THAT IS VERY DIFFERENT.
ABSOLUTELY. THAT IS A VERY GOOD
POINT. SOUNDS LIKE MUCH OF THE
WORK BOTH OF YOU PRESENTED BUT
PERHAPS MORE SO HAVE ENORMOUS
OPPORTUNITIES FOR HEPATOLOGISTS,
CLINICAL INVESTIGATORS, ARE THEY
INTERESTED AND AWARE OF YOUR
WORK?
>>SO I WAS INVITED TO GIVE A
TALK I THINK LATER THIS YEAR TO
A GROUP ACTUALLY, PHYSICIANS
INTERESTED IN LIVER BIOLOGY. I
ALWAYS COME WITH A BIG
DISCLAIMER WHICH IS I'M
TECHNICALLY A NEUROSCIENTIST, I
APPARENTLY DON'T STUDY THE
BRAINNA MUCH ANY MORE. I FOLLOW
THE BIOLOGY, SO ANY TISSUE OR
THINGS WE SEE THE BIOLOGY
TAKING, IT MEANS I WILL LEARN A
LOT ABOUT IT. IT IS AN
INTERESTING ROLE FOR IF THE
LIVER, BUT I DIDN'T THINK I
WOULD END UP WITH HERE.
>>SO IN HUMANS, THE STUDY THAT
HAVE BEEN DONE ON GENE
EXPRESSION METABOLOMICS SHOWED
MOST OF THE TIME SIGNAL
(INAUDIBLE) SO THERE IS RELATED
TO PATHOLOGY. AND ONE PAPER THAT
WAS PUBLISHED LONG AGO BY GEORGE
(INAUDIBLE) A CITY IN ITALY
WHERE EVERYBODY GETS AN AUTOPSY,
THIS OBSERVATION WAS THAT ALL
THE SENNARYIANS HAVE GOOD LIVER
-- CENTENARIANS HAVE GOOD LIVER,
THAT WHAT DISTINGUISH FROM MY
AUTOPSY, WHETHER THIS IS TRUE, I
THINK YOUR PRESENTATION REALLY
PROMPTED MY CURIOSITY. AND I'M
GOING TO LOOK INTO THAT.
>>PLEASE DO. KEEP ME POSTED.
>>SO ONE OF MY HATS IS I'M A
LIVER DOCTOR AND I CAN TELL YOU
THAT A LOT OF VERY GOOD ONES AT
UCSF, I WOULD THINK THEY WOULD
WANT TO COLLABORATE WITH.
>>CHATTING WITH THE WHOLE LIVER
CENTER. YES.
>>SO HAVE YOU OR ANYONE ELSE
BEEN SUCCESSFUL IN KNOCKING OUT
GPD 1?
>>GOOD QUESTION. WHAT WE HAVE
BEEN DOING IS WE MADE ANTISENSE
OLIGONUCLEOTIDES TARGETING GPLD
1 SPECIFICALLY IN LIVER AND THEN
EXERCISING MICE AND WANT TO SEE
WHAT IS THE RELATIVE
CONTRIBUTION OF THIS INCREASE.
AGAIN, IT GETS AT NECESSITY
VERSUS SUFFICIENCY, SO SOMETHING
CAN BE REALLY GOOD BUT DOESN'T
HAVE TO BE THE ONLY THING
INVOLVED IN BENEFIT. THE IDEA
THAT THERE IS ONLY ONE FACTOR,
WE KNOW THERE IS ADDITIVE
MECHANISMS AND IT IS IMPORTANT
THAT THERE IS MORE THAN ONE. WE
ARE ALL AGEING A LITTLE BIT
DIFFERENTLY.
>>WHAT MIGHT PHENOTYPE BE IN A
SPECIES LIKE THIS PROTEIN?
>>I THINK WE GET -- IT WOULD BE
-- I THINK LIKE THE SERT
CONDITION WHERE IF THEY ARE FAT
AND OBESE YOU SIGH IT, IF THEY
ARE NOT MAYBE NOT NECESSARILY.
SO BECAUSE IT DOESN'T CHANGE
WITH AGE WE HAVE TO PERTURB THE
SYSTEM SOMEHOW. WE ALSO THINK IT
IS INVOLVED WITH THE IMMUNE
SYSTEM SO IN THE CONTEXT OF
INFLAMMATION IT WOULD HAVE
SOMETHING. WHAT WE ARE SEEING
OVEREXPRESS IS IT IS GOOD AT
(INAUDIBLE) FUNCTION, IF YOU
GIVE INFLAMMATION TO A YOUNG
ANIMAL, IT HAS A CHANGE IN THE
BRAIN YOU CAN BLOCK THAT WITH
THIS FACTOR. BUT WHEN EVERYTHING
IS NORMAL, IT DOESN'T SEEM TO DO
ANYTHING. SO IT DOESN'T SEEM TO
BE A BOOSTER, IT REALLY JUST
SEEMS TO BE SUPPRESSING
IMPAIRMENT.
>>SO WE HAVE SOME MORE
QUESTIONS ABOUT THIS PROTEIN:
HEPATOCYTE, THE CELL OF ORIGIN,
AND WHAT IS KNOWN AT THE MOMENT
ABOUT THE CELL BIOLOGY OF IT?
HOW DOES IT GET OUT OF THE CELL?
YOU HAVE NEWS ABOUT WHAT IT IS
DOING ONCE IT GETS OUT, HOW DOES
IT INTERACT?
>>WE HAVE A WHOLE -- WE HAVE
TWO POST DOCS THAT ARE CURRENTLY
LOOKING INTO NUMBER ONE IN THE
BRAIN, YES, IT IS EXPRESS BY
HEPATOCYTES RIGHT NOW WHAT WE
ARE TRYING TO DO IS IDENTIFY THE
TRANSCRIPTION FACTORS THAT ARE
INDUCED BY EXERCISE THAT ALLOW
IT TO COME OUT. UNDER NORMAL
CONDITIONS IT IS JUST SECRETED
BY HEMATOCYTES THEN IT GOES INTO
CIRCULATION. THE WAY IT WORKS
IS BY CLEAVING THOSE PROTEINS ON
THE CELL SURFACE AND THEN IT
IMPACTS PROCESSES LIKE
COMPLIMENT IN THE IMMUNE SYSTEM.
MOST OF THE CELLS THAT HAVE
THOSE ANCHOR PROTEINS ARE IMMUNE
CELLS OR VASCULATURE. THOSE ARE
ENRICHED FOR MOST OF THESE
PROTEINS WE CLEAVE SO IT
SUGGESTS THEN AN INVOLVEMENT IN
THE IMMUNE SYSTEM, PROBABLY SOME
SORT OF INFLAMMATION. WE ARE
ALSO LOOKING AT VASCULATURE,
THINGS LIKE BLOOD BRAIN BARRIER.
THAT IS AS FAR AS WE HAVE GONE.
>>ANOTHER QUESTION FOR YOU TO
SOLVE. SO SOME STUDIES HAVE BEEN
DONE LIKE WITH THE PARABIOTIC,
TALKING ABOUT CELLS. AND STUDIES
WITH STEM CELLS AND OTHER KINDS
OF CELLS IN THE PROCESS. THEN
YOU HAVE STUDIES WITH PLASMA.
PRESUMABLY COMPLETELY CELL FREE.
SO DOES THAT SUGGEST THAT THERE
ARE MULTIPLE FACTORS RESIDING IN
DIFFERENT SOURCES, IN SOME SENSE
RELATED TO THE CELLS, STEM CELL
OR OTHER? AND OTHERS RELATING TO
CIRCULATING COMPONENTS; IS THAT
WHAT THE THINKING IS AT THE
MOMENT?
>>YES. I THINK THAT THE FIELD,
IF YOU TALK TO SOME OF THE
FACULTY THAT ARE IN THIS FIELD,
I THINK THE IDEA IS IN AD ACTIVE
MECHANISMS I THINK -- -- EVEN IF
YOU THINK ABOUT ONE FACTOR LIKE
A CYTOKINE TO A RECEPTOR, IF IT
HAS TWO OR THREE RECEPTORS YOU
SIGNAL TO MORE THINGS. SO IDEA
IS YES, EVEN IN YOUNG BLOOD
THERE COULD BE YOUNG FACTORS YOU
CANNOT FORGET YOU CAN TARGET OR
BLOCK AGING FACTORS OR PRO
GERONIC FACTORS. T THAT HAS
BENEFIT. PEOPLE EXCHANGED AND
DILUTED THE OLD FACTORS THAT CAN
CAUSE A BENEFIT. SO I THIS I IT
REALLY SUGGESTS TO THIS HUGE
INNER PLAY BETWEEN ORGANS AND
BLOOD AND AGING. ANYTHING THAT
CHANGES THAT COMPOSITION HAS
POTENTIAL TO HAVE IT BUT
ABSOLUTELY THERE ARE ADDITIVE
MECHANISMS DEPENDING ON THE
CELLULAR SOURCE AND THE
INTERVENTION.
>>LUIGI, YOU HAVE THIS
WONDERFUL STATEMENT WE WANT THE
HEALTHY LIFE WE HAVE LOST. WHEN
DID WE EVER HAVE A HEALTHY LIFE?
AND IN ORDER TO ACHIEVE IT,
DOESN'T IT REQUIRE HUGE CHANGES
IN OUR SOCIOECONOMIC AND
POLITICAL WAY OF LIFE?
>>YEAH. THAT IS ABSOLUTELY. WE
NEED TO CHANGE THE WAY WE USE
OUR HEALTHCARE. I THINK WE USE
GRADUAL AM OF MONEY TO CURE
PEOPLE WHEN THEY HAVE DEVELOPED
DISEASE, WHILE IDENTIFYING THE
EARLY, WOULD BE MUCH MORE
EFFECTIVE. MUCH LESS EXPENSIVE
AND WILL ALLOW US TO EXPAND THE
GOOD PART OF LIFE. WHEN I WAS
SAYING THE LIFE WE HAVE LOST, I
THINK THAT IS REALLY THE IDEA
THAT WITH INCREASE LIFE
EXPECTANCY, WHICH AS I SAY
SOMETHING PEOPLE (INAUDIBLE)
MOST OF WHAT WE GAIN IS DISEASE
AND DISABILITY LIFE EXPECTANCY
OF THE LIFE WHERE YOU ARE SICK.
SO IT IS NOT A GOOD LIFE. WHAT I
WANT TO KNOW IS WHETHER WE CAN
COMPRESS THE PERIOD OF DISEASE
AND DISABILITY LATER IN LIFE. I
THINK THAT THERE IS EVIDENCE
THAT CAN BE DONE. ANIMAL MODEL
FOR EXAMPLE STUDIES ON REMOVAL
OF SENESCENCE CELLS HAVE SHOWN
YOU HAVE A VERY LITTLE EFFECT ON
LIFE EXPECTANCY THAT YOU HAVE
DELAY SOME OF THE MAJOR
CONDITION THAT CHARACTERIZE
AGING, FOR EXAMPLE HEARING LOSS.
YOU HAVE A DECLINE IN THE
DEVELOPMENT OF (INAUDIBLE) A
DECLINE A A REDUCTION OF
SARCOPENIA, DELAYED SARCOPENIA.
SO THIS CAN BE DONE BUT WE HAVE
A MODEL OF MEDICINE THAT IS ONLY
CENTERED ON DAMAGE. WE WANT TO
SEE THE SYMPTOM, WE WANT THE SEE
PATHOLOGY, WHAT IS GOING ON, WE
NEVER MEASURE WHAT IS DEFENDING
US FROM OUR ORGANISM BEFORE
FALLING APART. WE DON'T HAVE
THAT SIDE OF THE STUDY.
DEVELOPING THAT SIDE OF THE
STUDY IS IMPORTANT, IF WE HAVE A
FACTOR THAT PROMOTE HEALTHY
AGING WE WANT TO KNOW HOW THAT
FACTOR WORKS. BECAUSE THAT CAN
BE APPLY NOT WHEN SOMEBODY SHAH
ALREADY DEVELOPED DEMENTIA BUT
FOR SOMEBODY THAT WE SAW ALREADY
THAT HAS A PATHWAY GOING THAT
DIRECTION, MAYBE WE CAN
INTERVENE EARLY AND AVOID THAT
PERSON TO DEVELOP ACCELERATED
COGNITIVE DECLINE. I THINK THE
RATIONALE IS THERE. WE HAVE NOT
LOST HEALTH. WE HAVE (INAUDIBLE)
TO BE THE HEALTH WE THOUGHT WE
WERE GETTING. AND -- FAILED TO
GET THE HEALTH WE THOUGHT
THOUGHT WE WERE GETTING. I WANT
THAT BACK. THERE IS STRATEGY
THAT CAN BE ACCOMPLISHED. SOME
OF THAT IS NOW, YOU KNOW WHAT IS
SECRET OF HEALTHY LIFE. I CAN
TELL YOU, YOU SAID THAT. DO NOT
SMOKE, EXERCISE, TRY TO MAINTAIN
YOUR WEIGHT, SLEEP, DO
SCREENING. PEOPLE HAVE SHOWN
THAT YOU CAN GAIN GOOD DEAL OF
LIFE BY JUST DOING THAT. BUT THE
PROBLEM IS PEOPLE DON'T DO IT
BUT YOU COULD. SO ONCE I DO NEW
DISCOVERY, ONE SIDE WILL NEED TO
IMPLEMENT THE COOPERATION, THE
DISCOVERY THAT WE ALREADY HAVE
MADE. THE KNOWLEDGE WE ALREADY
HAVE. THOSE ARE TWO
COMPLIMENTARY BY BUT REALLY
IMPORTANT GOALS.
WE HAVE MORE QUESTIONS PRIMARILY
FOR YOU. I'M GOING TO BUNCH THEM
TOGETHER. SAUL. WHAT HAPPENS TO
A MOUSE THAT OVEREXPRESSES GPLD
1 FROM BIRTH AND HOW LONG DOES
IT LIVE, DO YOU KNOW?
>>WE HAVE NOT DONE THAT. ONE
THING TO KEEP IN MIND IS
EXERCISE IS OPPOSED TO CALORIC
RESTRICTION IN TERMS OF LIFE
SPAN STUDIES IN MICE, IT IS NOT
AS CLEAR CUT, CALORIC
RESTRICTION IT IS VERY YES AND
NO SO I WOULDN'T EXPECT FACTORS
THAT ARE MORE EXERCISE
ASSOCIATED TO IMPACT -- AND I'M
REALLY INTERESTED IN EXACTLY
WHAT LUIGI SAID WHICH IS
SHORTENING THE TIME OF THAT
DECLINE NOT NECESSARILY JUST
EXTENDING LIFE SPAN. THE WORST
THING I CAN THINK OF IS LIVING
150 YEARS AND LITERALLY 75 BEING
WITH DEMENTIA BECAUSE I -- THAT
TO ME IS NOT WHAT WE ARE TRYING.
SO WE DON'T FOCUS OR THAT IS NOT
ONE OF OUR CONSIDERATIONS WOULD
BE KIND OF LIFE SPAN EXTENSION.
BUT BECAUSE THIS IS AN EXERCISE
FACTOR, I WOULD IN MY HYPOTHESIS
NOT BE ABLE TO EXTEND LIFE SPAN
>>ANOTHER QUESTION, DO YOU KNOW
ANYTHING ABOUT THE REGULATION OF
THE EXPRESSION OF GPLD 1?
>>THAT IS WHAT I MENTION. WE
HAVE BEEN DOING SOME RNA
SEQUENCING WE HAVE DONE
PROTEOMICS, NOT SURE WHETHER WE
DID AWE TACK SEQ OR NOT, WE
TRYING WHAT ARE THE
TRANSCRIPTION FACTOR UPSTREAM OR
PROPROMOTER REGIONS, INCREASE
GENE WITH EXERCISE. EXERCISE IS
ALL SORT OF CHROMATIN HYDROXY
METHYLATION. SO WE ARE
INTERESTED IN UNDERSTANDING WHAT
IS IT ABOUT EXERCISE THAT ENAGES
THAT TO BE EXPRESSED. IT IS
USUALLY THESE AN OFF SWITCHES OR
USUALLY THINGS THAT TITRATE
ACCESSIBILITY. WE KNOW THAT IS
VERY LINKED TO AGING. SO IT IS
KIND OF THE ROUTES WE ARE GOING
>>LUIGI, ARE BENEFITS O
EXERCISE ACHIEVED WITH EPISODIC
WHETHER THAN CHRONIC EXERCISE?
>>THERE IS MANUSCRIPT RECENTLY
PUBLISHED SHOWING THAT PEOPLE
THAT EXERCISE ONLY ONCE A WEEK
ON SUNDAY ALREADY HAVE BENEFIT
IN TERMS OF HEALTH EXPECTANCY
AND LIFE EXPECTANCY. I THINK
THAT EXERCISE, IS A VERY STRANGE
INTERVENTION BECAUSE IF YOU HAVE
NEVER BEEN EXERCISING AND YOU
EXERCISE THE FIRST TIME, YOU THE
EFFECT YOUR SEE BIOCHEMICALLY
BIOLOGICALLY, YOU SEE
INCREMENTING OX DATING STRESS,
YOU SEE INFLAMMATION THROUGHOUT
THE BODY, PEOPLE FEEL THAT HAVE
PAIN AND ACHE EVERYWHERE. BUT
THE ISSUE THAT HAS (INAUDIBLE)
SO IS RESPONDED, VERY ROBUST
RESILIENCE OF RESPONSE, WITH
STRONG -- ANTI-INFLAMMATORY
PATHWAY, SO THAT OVER TIME, AS
YOU BUILD ON THAT, THE EFFECT
BECOME BETTER AND BETTER. I
THINK THAT WE SEE THIS IN OUR
STUDIES, WE HAVE DONE FOR
EXAMPLE, VERY RECENTLY A STUDY
ON CHANGE IN ACUTE METABOLOMICS
AND YOUR PRESENTATION MADE ME
THINK WE SHOULD TAKE THOSE
SERUM. BEFORE WE PUT YOU ON THE
TREADMILL AND WE DO SERIAL ZERO,
10, 15, 20, 30, ONE HOUR, 2
HOUR, 12 HOURS TO SEE WHAT THE
METABOLOMIC CHANGES AND WHAT WAY
THEY -- THOSE CHANGES ARE
ACUTELY EFFECT METABOLISM AND
HOW THEY CHANGE CHRONICALLY
BECAUSE WE LOOK AT THE WAY THEY
ARE. WE STUDY MITOCHONDRIAL
FUNCTION WITH MRI. THE NEGATIVE
OR POSITIVE RESPONSE WITHIN
METABOLOMICS THE RELATED TO THE
BASIC MITOCHONDRIAL FUNCTI FUNCF
YOU HAVE GOOD MITOCHONDRIAL
FUNCTION THE BENEFIT OF EXERCISE
ARE BETTER. THAT IS ACUTE
EXERCISE. SO IN A WAY, TRAIN
MITOCHONDRIA AND ALLOW THE
EXERCISE TO EXERT MUCH BETTER
BENEFIT THAN IF YOU ARE NOT
TRAINING. SO I THINK THAT
EXERCISE IS GOOD IN ANY FORM,
CONTINUOUS EXERCISE IS PROBABLY
BETTER. BUT AS I SAY, AND I HAVE
ALWAYS SAID THAT, BECAUSE IT IS
IMPORTANT, DON'T STAY ON THE
COUCH. TEN MINUTES AROUND YOUR
HOUSE, SO MUCH BETTER THAN DOING
NOTHING. SO MUCH BETTER.
>>THERE IS A QUESTION I GUESS,
IS THERE ANY INFORMATION, AN
UPDATE ON THE PLASMA FACTOR TEMP
2 DEMONSTRATED BY ANOTHER GROUP
EARLIER I THINK THIS YEAR?
>>YES. THE ORIGINAL FINDING
WHERE I DID MY Ph.D., IT WAS
DONE BY DR. JOSEPH
(INDISCERNIBLE) HE NOW HAS A
GROUP AT THE ICAN MEDICAL SCHOOL
NEW YORK AND ME HAS AN ENTIRE
RESEARCH PROGRAM, ON IT, I
BELIEVE HE'S LOOKING AT HIS
ROLES IN ALZHEIMER'S AND MODELS
AND POTENTIAL INTERACTIONS WITH
SOME GENETIC RISK FACTORS SO
HE'S DEFINITELY CHAMPIONING THAT
AND HE'S GOING IN THE ROUTE OF
SOME DISEASES AS WELL.
>>LUIGI, THERE IS INQUIRY ABO
ABOUT, HAS COVID, THE PANDEMIC
ILLUMINATED ANYTHING ABOUT THE
AGING PROCESS? DO WE HAVE ANY
THOUGHTS ABOUT THAT?
>>THE SHORT ANSWER IS YES, WE
DO KNOW THAT OLD AGE HAS BEEN
ASSOCIATED WITH ACTIVITY TO BE
AFFECTED, ESPECIALLY TO HAVE
DISASTROUS EFFECT FROM THE
DISEASE, THE SO CALLED CYTOKINE
STORM, THAT LEAD TO RAPID
RESPIRATORY FAILURE AN
ASSOCIATES WITH HIGH MORTALITY.
MANY STUDIES SHOWING THE
INTERACTION BETWEEN AGE AND
FATALITY. FATALITY NUMBER OF
PEOPLE THAT GET INFECTION AND
THEY DIE BECAUSE OF INFECTION
COMPARED TO ALL THOSE THAT ARE
INFECTED. SO ACTIVITY TO AGING
AND THERE IS ALSO AREAS THAT IS
JUST NOT CHRONOLOGICAL AGE,
PEOPLE THAT HAVE ACCELERATED
EPIGENETIC AGE THEY TEND TO HAVE
HIGHER FATALITY RATE COMPARED TO
THOSE THAT HAVE -- NORMAL
EPIGENETIC AGE. SO WHEN I SAY
RESILIENT, HOW MUCH RESILIENCE
DO YOU HAVE, THAT IS GOING TO
AFFECT ALSO WHAT WOULD BE THE
FACTOR OF INFECTION. CAN YOU
OVERCOME THE INFECTION OR NOT.
WE DON'T KNOW HOW TO MEASURE
THAT. THERE IS PRELIMINARY
EVIDENCE THAT ALSO THE LUNG
COVID IS A LITTLE MORE FREQUENT
IN OLDER PEOPLE. ONE OF MY
SCIENTISTS, HAVE LOOKED AT THE
WHETHER THERE IS VIRUS IN THE
MICROVESICLE IN THE BLOOD. THEY
FOUND (INDISCERNIBLE) IS THE
NAME, WHO I DON'T KNOW WHETHER
IT IS LISTED OR NOT AND THEY
HAVE ENVIRONMENT PARTICLE IS
TRANSPORTED IN MICROVESICLE IN
(INAUDIBLE) PEOPLE BUT NOT ONLY
IN THOSE THAT DEVELOP LUNG COVID
AND IN THOSE THAT DON'T DEVELOP
LUNG COVID. SO LONG STORY IS WE
DON'T KNOW WHAT THE EFFECT OF
LONG COVID LONG TERM. I THINK WE
ARE LIVING THE SITUATION AND WE
WILL SEE, I WI WILL WILL BE AN R
IN THE NEXT YEAR NEXT TEN YEARS
THE EPIDEMIOLOGICAL DATA THE
MIGHTY STUDIED NIH IS DOING,
ESPECIALLY NIAID, WILL PUBLISH
THE RESULTS.
>>HERE IS A QUESTION THAT DEALS
ON THE ISSUE OF WHETHER THE
PARABIOTIC EXPERIMENTS OR PLASMA
EXPERIMENTS, YOU STUDY OR SAW
THE EFFECT ON THE HIPPOCAMPUS
AND THE BRAIN AND SO FORTH. SO
THE QUESTION REALLY IS, HOW
UNION VERSAL ARE THESE EFFECTS
ON DIFFERENT -- UNIVERSAL ON
DIFFERENT TISSUE SYSTEMS? AND
THIS UNDOUBTEDLY HAS SOME DEGREE
ON THE QUESTION WE RECEIVED ON
WHETHER THE INFUSIONS EFFECT
FERTILITY IN MALE OR FEMALE MICE
OR MEN OR WOMEN.
>>YES. T SO I THINK THE
EVIDENCE NOW IS THAT NO, THE --
WHETHER IT BE PARABIOSIS, DO NOT
IMPACT ALL TISSUES, SOME OF THEM
DO SEEM TO BE THERE'S SOME
EVIDENCE THAT SOME DO SEEM TO BE
REFRACTORY TO SOME OF THESE
INTERVENTIONS. ALSO THE
MAGNITUDE IS DIFFERENT, THERE
WERE A FEW SEQUENCING PAPERS
THAT CAME OUT, STEM CELL AND
NATURE, THEY DID SINGLE CELL TO
SEE THE MAGNITUDE AND IT IS NOT
THE SAME. I THINK WE ARE STILL
WAITING ON SOME BROADER
EPIGENETIC SORT OF
CHARACTERIZATION AS WEL WELL. NT
ALL TISSUES RESPOND THE SAME
WAY. SOME HIGHER MAGNITUDE, SOME
LOWER, I THINK IT DEPENDS ALSO
ON THE LEVEL OF GENERATIVE
CAPACITY OF EACH INDIVIDUAL
TISSUE. IN TERMS OF
REPRODUCTION, I BELIEVE THERE
WAS ONE PARABIOSIS, PARABIOSIS
STUDY THAT CAME OUT, IT WAS NOT
NECESSARILY THOUGH LIKE THE
YOUNG AND THE OLD, I FORGOT WHAT
IT WAS THEY PUT TOGETHER BUT
THERE WERE HUMAN MORAL
COMPONENTS THAT HAD AN EFFECT.
THERE'S BEEN PAPERS THAT FOCUS
MORE ON THINGS LIKE NAD PLUS
NADH, THAT HAD IMPACT ON THE
FOCUNDITY AS WELL AS EQUALITY,
BUT NOT TOO MUCH, IT'S TOTALLY
UNDERSTUDIED.
>>HERE IS AN INTERESTING
QUESTION, THAT CAME IN. HAVE YOU
OR ANYONE REPEATED SOME OF YOUR
STUDIES IN TRANSGENIC MICE WHICH
HAVE A HUMANIZED LIVER?
>>NO. I DO KNOW THAT THERE ARE
STUDY BEING DONE WITH CHIMERIC
ANIMALS WHERE THEY HAVE BEEN
MIXING LIKE RAT AND MOUSE OR
OTHER SPECIES LONGER LIVED WITH
NOT. THAT MIGHT GET INTO THAT
TYPE OF QUESTION. I DON'T KNOW
IF THEY ARE DOING IT IN A TISSUE
SPECIFIC MANNER OR NOT. BUT
YEAH, I HAVE HEARD OF THOSE
TYPES OF EXPERIMENTS IN TERMS OF
INNER SPECIES.
>>HUMANIZED LIVER, I DIDN'T
KNOW THAT.
(OVERLAPPING SPEAKERS)
>>YOU DO IT NSG SO THE HUMAN
UMBILICAL CORD BLOOD WAS NSG AND
YOU CAN DO IT IN IMMUNE
COMPROMISED MICE. THEY SHOW
SOME ACCELERATED AGING
PHENOTYPES BUT THEN YOU ARE
TAKING AWAY THE IMMUNE
COMPONENT. SO YOU TAKE THE MODEL
BUT THERE ARE RESTRICTIONS.
>>SO WE HAVE -- HERE IS A
PROVOCATIVE QUESTION. IS AGING
OR -- IS AGING AND
NEURODEGENERATION, ARE THEY
CAUSALLY OR ARE THEY CAUSE OR
EFFECT? IS AGING THE CAUSE OF
NEURODEGENERATION OR IS
NEURODEGENERATION ACTUALLY CAUSE
OF AGING?
>>I THINK AGING IS FINALLY,
AGING IS MACRO MOLECULAR
ORGANELLE AND CELLULAR DAMAGE
AND THAT HAS AN EFFECT IN
MULTIPLE LEVEL. AND IN THE BRAIN
MORE THAN ANYWHERE ELSE BECAUSE
OF THE INTRINSIC COMPLEXITY OF
THIS STRUCTURE IS MORE SUSES
ACCEPTABLE TO DAMAGE
ACCUMULATION. ONCE THE BRAIN --
SUSCEPTIBLE TO DAMAGE
ACCUMULATION. ONCE THE BRAIN IS
AFFECTED, THERE'S A MULTIPLE --
OF THE EFFECT ON THE PHENOTYPE
BECAUSE THE BRAIN REALLY
CONTROLS SO MANY THINGS. THE
BRAIN IS AFFECTING THE INNER
CLOCK, IT IS AFFECTING HORMONE
PRODUCTION. WE KNOW THAT THE
BRAIN IS AFFECTING IMMUNOLOGY,
SYMPATHETIC AND PARASYMPATHETIC
SYSTEM. SO (INAUDIBLE) NOT
WORKING MOST REGULATORY
MECHANISM THAT MAINTAIN STABLE
HOMEOSTASIS IN THE BODY START
COLLAPSING. SO I THINK ONCE THE
BRAIN IS INVOLVED THERE IS
ACCELERATION OF THE PROCESS. WE
SEE PEOPLE, WE SEE CLEARLY
CLINICALLY THAT BRAIN PATHOLOGY
IS ACCELERATOR. THE OTHER THING
IS THAT WE CLEARLY SEE THAT
GENERAL HEALTH IS A STRONG
PREDICTOR OF COGNITIVE DECLINE
AND DEMENTIA. GENERAL HEALTH,
PEOPLE THAT MANY, MANY
MULTI-MORBIDITIES TEND TO HAVE
ACCELERATED COGNITIVE DECLINE.
SO TWO THINGS VERY CORRELATED.
>>VERY GOOD. DO YOU WANT TO
COMMENT ABOUT THAT, SAUL?
>>I GUESS I THINK ABOUT IT IN
TERMS OF TEMPORAL COMPONENT.
THERE IS A TEMPORAL COMPONENT,
TO NEURO-- AGE RELATED DEMENTIA
RELATED NEURODEGENERATION. YOU
CAN'T UNCOUPLE THE TIMING AND
PROGRESSION OF TIME WITH ONSET
AND SORT OF ACCUMULATION AND
EXACERBATION OF THAT DISEASE. I
DON'T KNOW ABOUT CAUSE
CONSEQUENCE BUT I DO KNOW ABOUT
ASSOCIATION. YOU CAN'T UNLINK
THE ONE FROM THE OTHER. SO I
THINK ABOUT THEM TOGETHER IN
THAT WAY. I DO THE SAME THING
WHEN TRYING TO PLAN EXPERIMENTS
AND DESIGN EXPERIMENTS. TEMPORAL
COMPONENT IS ALWAYS THERE.
>>INTERESTED, SEVERAL MONTHS
AGO I WAS READING ABOUT AGING IN
SPECIES OF DIFFERENT LIFE SPAN.
AND I WAS FASCINATED BY THE IDEA
THAT BIG ANIMALS, ELEPHANTS AND
ALL, WHEN THEY FINALLY DIE, AND
THEY ARE AUTOPSIED, THEY DON'T
FIND VERY MUCH, THEY DON'T DIE
OF DEGENERATIVE DISEASES LIKE WE
HAVE. THEY JUST SORT OF LIKE OLD
SOLDIERS THEY JUST FADE AWAY. IS
THAT THE AGING PROCESS? AS
COMPARED TO WHAT HAPPENS IN
ANIMALS HAVING A SHORT HALF
LIFE, OR IN HUMANS WHERE WE DO
ALL KINDS OF THINGS THAT AREN'T
GOOD FOR US. BUT IN A SHORT HALF
LIFE YOU CAN DO THINGS TO AFFECT
THE PROCESS THAT IS OPERATING
OVER A MUCH SHORTER TIME FRAME.
WHAT DO YOU THINK ABOUT THAT?
ANY TAKERS?
>>I HAVE NO IDEA. I THINK THAT
I HAVEN'T HAD THAT PARTICULAR --
THAT SOUNDS QUITE INTERESTING.
WE DO KNOW VERY DIFFERENT BIC
DIFFERENCE BETWEEN SMALL ANIMAL
AND LARGE ANIMAL, THE THEORY
THAT I DON'T KNOW HOW MUCH IS
FOLLOW NOW THAT THERE IS THE IN
RELATIONSHIP BETWEEN THE SIZE
AND LONGEVITY. THE THEORY OF
ALLO STATIC LOAD, IT SEEM TO BE
THERE IS A CORRELATION, OF O
COURSE, THERE'S BEEN ARGUED THAT
THIS CORRELATION HAS EXCEPTIONS
THAT BREAK THE RULES. FOR
EXAMPLE BIG DOGS LIVE LESS THAN
SMALL DOGS AND PEOPLE HAVE BEEN
ARGUING THAT THIS IS BECAUSE
DOGS ARE NOT SELECTED BY NATURE
BUT BREED. SO THEY ARE NOT
SUBJECT TO SAME NATURAL
SELECTION. ALSO THERE IS
BIRDINGS SEEM TO VIE -- BIRDS
VIOLATE THIS RULE. BUT PEOPLE
SAY THAT IS BECAUSE THEIR
MITOCHONDRIA ARE SEALED BECAUSE
THEY HAVE SO MUCH NEED TORR
ENERGY DURING FLYING. SO
EVOLUTION SEALED THEM SO THEY
CANNOT PRODUCE AT ALL THAT GO
BEYOND BOUNDS OF MITOCHONDRIA.
IT IS ALL INTERESTING
SPECULATION, I'M ALWAYS
FASCINATED. THE LAST ONE I READ
IS REALLY BEAUTIFUL
DEMONSTRATION OF THE RATE OF
SOMATIC MUTATION. THE LEAST
SOMATIC MUTATION YOU HAVE THE
HIGHEST LONGEVITY SUGGESTING
THAT THE ONLY THING THAT
EVOLUTION HAS DONE IS IMPROVE
THE SURVEILLANCE AND REPAIR OF
SOMATIC MUTATION. WHETHER THIS
IS TRUE OR NOT, I DON'T REALLY
HAVE AUTHORITY TO SAY.
>>SO SAUL WE HAVE ANOTHER
QUESTION FOR YOU. DO FACTORS
LIKE ALCOHOL OR TOXINS OR SOME
STUFF THAT IS BAD FOR THE LIVER,
IS THERE ANY EVIDENCE THAT THAT
AFFECTS THE LEVEL OF THE
PROTEINS YOU'RE STUDYING OR THE
EFFECT OF PLASMA FROM SUCH
ANIMALS IN YOUR EXPERIMENTS? HAS
THAT BEEN INVESTIGATED? ANY WAY?
>>THERE VERY LITTLE KNOWN ABOUT
THE ENZYME WHICH MAKES IT EXCITE
BUG DIFFICULT BECAUSE YOU KIND
OF JUST EXPLORING SOMETHING.
WHAT I WILL SAY IS EVEN IN THE
ANIMAL MODEL FOR EXAMPLE IF YOU
WERE TO INCREASE INFLAMMATION IN
THE CONTEXT OF EXERCISE IT CAN
BLOUNT SOME OF THE EFFECTS, THE
SAME FOR YOUNG BLOOD IF YOU WERE
TO INCREASE INFLAMMATION SO
THERE IS AN IMMUNE COMPONENT. SO
JUST THE REACTION OF A TOXIN
THAT WOULD ELICIT THAT RESPONSE
IN THE IMMUNE SYSTEM, I WOULD
THINK IT WOULD HAVE SOME
DETRIMENTAL EFFECT THAT CAN
BLUNTED THAT FROM HAPPENING. WE
SEE THAT AS WELL THINGS LIKE
SAYS FROM SENESCENCE THERE IS SO
MUCH OVERLAP BETWEEN SAS AND PRO
JERONIC FACTORS A LOT IMMUNE IN
NATURE. SO THERE ARE THINGS THAT
PROMPT AGING MECHANISMS AS WELL,
THAT CAN'T JUST -- WE HAVE TO
REMEMBER IT GOES BOTH WAYS, IT
IS BIDIRECTIONAL.
>>SO WHAT THE TWO OF YOU
PRESENTED US WITH IS AN
INCREDIBLE POTPOURRI LIST OF
EXCITING DEVELOPMENTS IN ONE OF
THE MOST CHALLENGING AREAS OF
PUBLIC HEALTH MEDICINE AND BASIC
BIOLOGY. SO MAYBE EACH ONE OF
YOU WOULD LIKE TO TAKE A COUPLE
OF LAST MINUTES THAT WE HAVE AND
IF YOU FEEL LIKE IT, LOOK IN
YOUR CRYSTAL BALL AND TELL US
WHAT YOU WOULD LIKE DO SEE
HAPPEN OR WHAT YOU THINK IS
LIKELY TO HAPPEN AND BEHIND ALL
THIS OF COURSE IS THE ENORMOUS
OPPORTUNITY FOR YOUNG PEOPLE
INTERESTED IN SCIENCE TO BE
INTERESTED IN THIS PROBLEM AS
BOTH OF YOU HAVE REFLECTED BOTH
FROM THE STANDPOINT OF CLINICAL
INVESTIGATION AND FROM
STANDPOINT OF BASIC MECHANISMS.
YOU WANT TO BE --
>>I WILL GO FOR IT. I REALLY
WANT TO HEAR WHAT LUIGI HAS TO
SAY. WE TALKED ABOUT THIS BEFORE
THE EVENT STARTED WITH YOU AS
WELL AS WITH LUIGI, FOR ME, THE
FACT WE ARE NOW SEEING DIFFERENT
INTERVENTIONS HAVE DIFFERENT
EFFECTS THERE'S MULTIPLE FACTORS
THAT'S ADDITIVE, COUPLE THAT
WITH THE FACT WE ARE ALL AGING
SLIGHTLY DIFFERENTLY OR
DIFFERENT SYSTEMS MIGHT BE GOING
FIRST OR SECOND OR THIRD. I LOVE
THIS IDEA OF A PERSONALIZED
APPROACH. I WOULD LOVE TO BE
ABLE TO GO TO THE PHYSICIAN,
GETTING A CHECK UP AND THEY TAKE
MY BLOOD, MEASURE MY PROGERONIC
FACTORS OR SAS FACTORS, TAKE MY
BLOOD AND THEN DO A EPIGENETIC
CLOCK AND THEY CAN GIVE ME AN
IDEA OF KIND OF WHAT IS
HAPPENING RIGHT NOW AT THIS
STAGE. EXERCISE EFFECTS THE
VASCULATURE BUT MAYBE THE
ANTI-GERONIC EFFECTS THE STEM
CELLS AND WE SEE YOUR
REGENERATION MARKERS ARE LOW. I
WOULD LOVE THAT. WHICH IS IN A
PERSONALIZED WAY, USING
BIOMARKERS AND USING SOME OF
THESE MECHANISMS ANALYTICS,
BLOOD, ALL THAT WE ARE
IDENTIFYING BE PERSONALIZE AND
TAILORED TO EACH INDIVIDUAL
PERSOPERSON. THAT'S WHAT I WANTI
WILL PUT LUIGI ON THE SPOT,
BECAUSE I ASKED EARLIER DO YOU
THINK WE ARE CLOSE AND DO YOU
THINK WE ARE FAR? I THINK I HAVE
MORE EXCITED TWO HOURS IN THAN I
WAS TWO HOURS AGO BECAUSE LUIGI,
HE'S LIKE YES, I THINK WE ARE
CLOSE. I'M AT THE BASIC WHYOLOGY
PERSPECTIVE AND IT IS NICE TO BE
-- BIOLOGY PERSPECTIVE, NICE TO
HAVE THOSE CONVERSATIONS WITH
CLINICIANS AND PEOPLE AT LEVEL
OF THE PATIENTS AND THE HUMAN
CONDITICONDITION. BECAUSE SOMETR
BASIC SCIENTISTS WE FORGET HOW
IS IT THAT WE ARE -- WHAT WE ARE
DOING CAN IMPACT IN THE NEXT
YEAR OR TWO, BUT WE HAVE SEEP IT
IN MY FELTED BETTER OR WORSE, I
SAW PEOPLE TRYING TO DO THINGS
THEY SHOULDN'T WITH YOUNG BLOOD
SO I KNOW BASIC CAN HAVE A HUGE
IMPACT ON THE HUMAN CONDITION.
NOW I HOPE THAT WE CAN COURSE
CORRECT AND DO IT IN THE
APPROPRIATE WAY.
>>RIGHT ON.
>>I THINK THAT WHAT I HAVE --
FIRST OF ALL, I AM A DOCTOR. I'M
STILL A DOCTOR. I FEEL LIKE FOR
ME, EVERYTHING I DO HAS TO BE A
REFLECT IN HEALTH. SO I THINK IN
THIS TERM OF WHAT WOULD BE THE
IDEAL DREAM WHAT WE CAN
ACCOMPLISH. THIS IS SIMILAR TO
WHAT SAUL WAS SAYING. BUT LET ME
TRY TO ARTICULATE A DREAM. THE
DREAM WILL BE SOMEBODY GOES TO
THE DOCTOR, BECAUSE THEY HAVE
HAVING SOME PAIN IN THE LEFT
SHOULDER AND THE DOCTOR LOOK AT
THEM, LOOK AT THE LEFT SHOULDER
AND THEN THEY ALSO TAKE 1 MILL F
BLOOD. THEY DO PROTEOMIC
METABOLOMICS METH LOAMICS AND
THESE TODAY IN RESEARCH WILL
COST $5,000 BUT THERE IS NO
REASON WHY SHOULDN'T COST 30
CENTS. THOSE 30 CENTS WILL
PRODUCE ENORMOUS AMOUNT OF
INFORMATION AND THERE IS ALREADY
STRONG EVIDENCE THAT PROFILE
THIS BIOMARKER PREDICT DISEASE,
INCLUDING ALZHEIMER'S DISEASE.
THOSE ARE ALGORITHM MAY NOT BE
PERFECT BUT IF WE CAN APPLY THE
BIOMARKERS TO MILLIONS OF PEOPLE
THAT GO TO A DOCTOR AND
INTRODUCE THOSE INFORMATION INTO
A MEDICAL RECORD, ELECTRONIC
MEDICAL RECORD THAT ALLOW
ARTIFICIAL INTELLIGENCE FAR
LOWER ON THOSE TAP INTO THESE
PEOPLE BASED ON INTERVENTION.
THOSE ARE MORE AUTOMATICALLY
IMPROVE ALGORITHM AND BE MORE
INFORMED SO WE WILL HAVE A
HEALTHCARE SYSTEM WHERE WHATEVER
WE DO, WE LEARN MORE, WE CAN
RELATE THAT EXPERIENCE AND THAT
WILL TELL US EARLY LIFE WHAT WE
NEED TO DO. WE DON'T HAVE THE
ENTIRE ARMAMENTARIUM TO ANSWER
THOSE QUESTIONS BUT WE ARE
DEVELOPING THEM AS WE DEVELOP
THEM AND INTRODUCE THEM INTO THE
SYSTEM, OUR KNOWLEDGE WILL
EXPAND PROGRESSIVELY. SO I AM
OPTIMISTIC. I THINK THIS IS
GOING TO HAPPEN. AND NEEDS TO
MAP BECAUSE IF IT DOESN'T HAPPEN
THE DEMOGRAPHIC IMPERATIVE WILL
COLLAPSE ANY HEALTHCARE SYSTEM
IN THE WORLD. IT DOESN'T MATTER
HOW MUCH MONEY THE COUNTRY HAS.
WE CAN'T AFFORD NOT TO
ACCOMPLISH THIS.
>>ONE STATEMENT ABOUT THE
STUDENTS YOU SAID ABOUT WHY THEY
SHOULD DO AGING VERGE. SO I WANT
TO POINT OUT THAT AGING IS ONE
OF THE FEW THINGS THAT'S
IMPACTING ABSOLUTELY EVERYONE
AND IT IS ABSOLUTELY BLIND TO
BACKGROUND. IT DOESN'T MATTER
WHETHER YOU GREW UP AFFLUENT OR
GREW UP POOR. AND I THINK WHAT
IS GREAT IS MYSELF, I'M A FIRST
GENERATION TO COLLEGE, MY
PARENTS CAME ILLEGALLY INTO THE
UNITED STATES, GREW UP POOR YET
THIS FIELD BECAUSE IT IS SO
BLIND, IT DOES IMPACT EVERYONE
INCLUSIVE SO NOT JUST THE
SCIENTIFIC CURIOSITY PERSPECTIVE
BUT ALSO BROADER FROM THE SOCIAL
PERSPECTIVE SOCIOECONOMIC, THIS
IS A WONDERFUL FEEL TO BE FROM
THE ACCEPTANCE PERSPECTIVE AND
THE IMPACT YOU CAN HAVE JUST
ACROSS SOCIETY. SO IN THINKING
ABOUT THOSE YOUNG STUDENTS THAT
ARE OUT THERE, I WOULD ENCOURAGE
THEM TO LOOK INTO THE SPACE OF
AGING.
>>WELL, ON BEHALF OF THE
HUNDREDS IF NOT THOUSANDS WHO
HAVE BEEN WATCHING THIS PROGRAM,
I'M SURE THEY SHARE THE
MR. SIMON: THAT I HAVE IN
LEASAME, YOUGAVE ELOQUENT TALKSA
PICTURE OF WHAT THE CHALLENGES
ARE AND WHAT THE EXCITING
DEVELOPMENTS ARE, AND
FURTHERMORE I THINK IT WAS NEAL
SPORE WHO SAID PREDICTION IS
VERY DIFFICULT PARTICULARLY
ABOUT THE FUTURE. BUT I THINK
THE PICTURE BOTH OF YOU
PRESENTED CAN BE SUMMED UP INTO
ONE BIG WORD. WHICH IS
EXCITEMENT. CERTAINLY A LOT IS
GOING TO HAPPEN THOUGH AT THE
MOMENT NOBODY QUITE KNOWS WHAT
THAT IS GOING TO BE. AND THAT IS
THE WAY SCIENCE MOVIN MOVES. SON
BEHALF OF EVERYONE, THANK YOU
VERY MUCH. THIS HAS BEEN AN
EXCITING AFTERNOON. AND I HOPE
YOU ENJOY BEING PART OF IT.
LASTLY, I WOULD JUST MENTION --
WHAT HAPPENED? FOR THE CME
CREDIT, 45385. (443)541-5052. I
WANT TO MENTION THAT NEXT WEEK
MARCH 21ST, WE HAVE AN UNUSUAL
PROGRAM. WE WILL HAVE ONE
SPEAKER ANDREW KNOLL, THE
CHAIRMAN OF THE DEPARTMENT OF
GEOLOGY AT HARVARD UNIVERSITY.
AND EXTRAORDINARY BIOLOGIST. HE
IS GOING TO TALK ABOUT SUBJECT
OF IT'S A BACTERIAL WORLD AND
I'M SURE THIS WILL BE AN
EXCITING REWARDING PRESENTATION
AND WE HOPE YOU WILL ALL JOIN US
THEN. THANK YOU ONCE AGAIN.
IT'S BEEN A PLEASURE TO MEET
YOU.
>>THANK YOU, EVERYBODY.
>>THANK YOU, EVERYONE, TAKE CARE