WELCOME TO THE CLINICAL CENTER GRAND ROUNDS,
A WEEKLY SERIES OF EDUCATIONAL LECTURES FOR PHYSICIANS AND
HEALTH CARE PROFESSIONALS BROADCAST FROM THE CLINICAL
CENTER AT THE NATIONAL INSTITUTES OF HEALTH IN
BETHESDA, MD.
THE NIH CLINICAL CENTER IS THE WORLD'S LARGEST HOSPITAL TOTALLY
DEDICATED TO INVESTIGATIONAL RESEARCH AND LEADS THE GLOBAL
EFFORT IN TRAINING TODAY'S INVESTIGATORS AND DISCOVERING
TOMORROW'S CURES.
LEARN MORE BY VISITING US ONLINE AT HTTP://CLINICALCENTER.NIH.GOV
GOOD AFTERNOON.
IT'S MY GREAT PLEASURE TO
WELCOME YOU TO THE GRAND ROUNDS.
THE CODE IS
PLEASE--WE KINDLY INVITE YOU TO
PROVIDE FEEDBACK BY SCANNING
THE QR CODE.
FOR THOSE APPLYING FOR CME, YOU
WILL RECEIVE A SURVEY LINK VIA
EMAIL.
THE SURVEY WILL BE USED TO
PROVIDE US WITH IMPORTANT
FEEDBACK ABOUT THIS
PRESENTATION AND ALLOWS YOU TO
MAKE ANY SUGGESTIONS FOR FUTURE
GRAND RUINSED TOPICS.
FOLLOWING THE PRESENTATION,
QUESTIONS WILL BE TAKEN FROM
THE MICROPHONE FROM THE AISLES.
IN ADDITION, YOU MAY SUBMIT
QUESTIONS BY PSYCHOLOGY DOWN
AND CLICKING THE LIVE FEEDBACK.
QUESTIONS WILL BE ANSWERED AS
TIME PERMITS AT THE CONCLUSION
OF THE PRESENTATION.
OUR SPEAKER TODAY IS DR. NATAN
BASISTY, AT NIA AND NIH
DISTINGUISHED SKOL LAR.
DR. BASISTY, COMPLETED HIS Ph.d
AT THE UNIVERSITY OF WASHINGTON
6789 FOLLOWING HIS GRAD YOU'D
WORK, HE JOINED THE BUCK
INSTITUTE OF AGING AS A POST
DOKE TORE AL LEVEL TO UNLDSING
AGING PROCESSES AND AGE RELATED
DISEASES.
IN 2021, HE JOINED NIA AS A
INVESTIGATOR.
HIS LABORATORY NIA, OR THE NIU,
IN THE LEVELS TO CLINICAL BIO
MARKERS AND THERAPY PICK FOR
PATHOLOGIST OF AGING.
DEVELOPS AND APPLIES ADVANCE
AND LARGE SCALE GEROPROTEOMIC
TO AGING SUCH AS TYPE 2
DIABETES AND MARKERS.
ULTER ITIONATIONS OF PROTEINS.
DR. BASISTY'S WORK HAS HAD OVER
20 PUBLICATION SXZ SHARED WORK
IN NATIONAL AND INTERNATIONAL
PRESENTATIONS ON AGING.
HIS RECOGNIZATIONS AND K99
PATHWAY TO INDEPENDENCE AWARD.
DR. BASISTY IS A PASSION AL
EDUCATOR AND AWARDED MENTOR
AWARD BACCALAUREATE.
RECOGNIZED TRACK INVESTIGATORS
WHO HAVE DEMONSTRATED DIVERSITY
AND INCLUSION.
TODAY, DR. BASISTY WILL BE
PRESENTING ON FORGING A PATH TO
TRANSLATIONAL GEROPROTEOMIC.
NOW JOIN ME IN WELCOMING OUR
SPEAKER NATAN BASISTY.
>> THANK YOU FOR THE
INTRODUCTION AND THANK YOU TO
BATITO FOR GETTING ME SAFELY.
I'M GOING TO BE PRESENTING ALL
UNPUBLISHED WORK FROM THE LAST
TWO YEARS SINCE I STARTED IN
NIA.
IF ANYTHING I HOPE YOU CAN WALK
AWAY FROM THIS TALK, A
PREACHING THAT THE BIOLOGY OF
AGING, TARGETING A BIOLOGY OF
AGING IS A WAY TO TARGET
DISEASES THAT IS WORTH SPENDING
OUR RESOURCES AND SECONDLY THAT
PROTEOMICS HAS TO OFFER.
OKAY, SO I HAVE NO DISCLOSURES
ACCEPT THAT MAYBE I'LL SAY THAT
I'M NOT A CLINICIAN I'M A BASIC
RESEARCH SCIENTIST AND SOMEBODY
THAT DOES MASS NNDS BECK.
BUT A LOT OF THE STUFF THAT I'M
SHOWING IS GOING TO BE
CLINICALLY ORIENTED SO I DO
INVITE FEEDBACK FROM THOSE WHO
DO FOR OF THIS WORK IN WHAT I
PRESENT TODAY.
SO LEARNING OBJECTIVES, TODAY I
HOPE THAT YOU CAN UNDERSTAND
THE POTENTIAL HEALTH IMPACT OF
UTILIZING THE GEROSCIENCE
APPROACH.
AND I THINK THIS APPLIES TO
USING BIOMARKERS FOR MY SORT OF
PATHOLOGY RIGHT AND THE
CHALLENGES TO THESE BIOMARKERS
SPECIFICALLY.
SO YOU KNOW, THE REASON THAT WE
FOCUS ON AGING, IS BECAUSE
AGING IS THE GREATEST RISK
FACTORS.
SO AS WE AGE, THE PREVALENCE
AND DEATH FROM MULTIPLE
DISEASES GOES UP AND ABOUT
MIDDLE AGE ON WARDS IT STARTS
TO GO EXPONENTIALLY ESPECIALLY
ALZHEIMER DISEASE.
NOT ONLY WILL WE DIE FROM ONE
OF THESE BUT WE'RE GOING TO DIE
OF MULTIPLE OF THESE.
SO IF YOU DIE OF HEART DISEASE,
YOU'LL HAVE PSYCHO PAOENIA,
LOSS OF MUSCLE AND THERE IS
ALSO A ISSUE OF MORE BIDITY.
AND WE DON'T THINK THIS IS A
COINCIDENCE.
SOMETHING ABOUT AGING ENABLES,
CREATES AN ENVIRONMENT THAT IS
PER MISSABLE TO THE DEVELOPMENT
AND PROGRESSION OF THESE
DISEASES.
AND THUS FAR WE'VE IDENTIFIED
WHAT WE CALL BASIC AGING
PROCESSES THAT ARE DRIVERS OF
MULTIPLE AGED RELATED DISEASES
AND THESE ARE TWO THAT MY
LABORATORY FOCUSES ON.
OUR NUMBER THAT WE NOW KNOW FOR
EXAMPLE, MIO CARDIO
DYSFUNCTION, DNA DAMAGE,
CHANGES THAT ARE THESE BASIC
UNDERLINED PROCESS THAT'S DRIVE
THE DEVELOPMENT OF DISEASES.
AND THIS IS ACTUALLY GOOD NEWS,
RIGHT, BECAUSE IF IT'S TRUE
WHICH I THINK WE HAVE STRONG
EVIDENCE THAT THIS IS TRUE THEN
WE CAN TARGET THESE AGING
PROCESSES AND MITIGATE MULTIPLE
RELATED DISEASES SIMULTANEOUSLY.
THIS WOULD BE A HUGE BENEFIT,
WE SPEND, CURRENTLY WE SPEND A
LOT OF HEALTHCARE AND RESEARCH
COST TO TRY TO CURE ALL OF
THESE INDIVIDUAL DISEASES, VERY
COMPLEX DISEASES ONE AT A TIME
AND WE SPEND A LOT OF
HEALTHCARE AT THE END OF LIFE,
RIGHT.
BUT, IF WE TAKE USE THE
GEROSCIENCE APPROACH, WE ARE
TARGET ONE PROCESS AND MITIGATE
MULTI AGE RELATED DISEASES.
AND TO ADD TO THIS, WE'VE SHOWN
THAT THIS IS THE CASE, AT LEAST
IN PRECLINICAL MODELS.
THE FIELD HAS IDENTIFIED A
NUMBER OF AGING AND SOME OF THE
MOST ROBUST ON THE BOTTOM RIGHT
OF THIS SLIDE.
FOR EXAMPLE, DIETARY
RESTRICTIONS, TREATMENT WITH
DRUGS THAT TARGET SENESIS CELLS
AND ALL OF THESE HAVE BEEN
SHOWN TO INCREASE LIFE SPAN.
THERE IS AT LEAST SOME EVIDENCE
THAT THIS IS TRUE IN PEOPLE,
BUT GOING FORWARD, IT WOULD BE
REALLY NICE TO APPLY THIS
APPROACH IN PEOPLE.
SO MY LAB IS CALLED THE
TRANSLATIONAL GEROPROTEOMIC, SO
WE'RE LOCATED IN THE NIA WHICH
IS BASED IN BALTIMORE.
FROM THE NAME, YOU CAN GUESS
WHAT WE DO.
WE DO GEROPROTEOMIC, SO WE
APPLY TO THE STUDY OF
GEROSCIENCE AND I THINK IT CAN
OFFER A LOT TO THIS FIELD.
WE CAN IDENTIFY THERAPEUTIC
TARGETS BUT ALSO BIO MARKERS
WHERE WE CAN MEASURE THE
ETHICACY OF INTERVENTIONS IN
THE CONTEXT OF AGING.
MY LAB HAS THREE PRIMARY
PROGRAMS, THE FIRST ONE AND THE
ONE THAT I'M GOING TO FOCUS
TODAY IS SINSES BIOMARKERS.
WE HAVE STUDIES BOTH IN HUMANS
AND IN MICE HERE.
BUT, WE ALSO EMPLOY OTHER
TECHNIQUES TO IDENTIFY THE
THERAPEUTIC TARGETS.
WHAT WE USE PROTEINS THAT ARE
BOUND TO DRUGSMENT SO WE CAN
IDENTIFY MECHANISMS AND NEW
THERAPEUTIC TARGETS AND BIO TO
IDENTIFY SELF TYPE OF INTEREST
SO IF YOU HAVE A CANCER SELL OR
A ZENNE SIS CELL THESE CAN BE
TARGETED.
THE NICE THING IS THAT WE DO A
LOT OF STUDIES TO IDENTIFY
CANDIDATE TARGETS.
IN THE NIA, WE HAVE THESE
FLAGSHIP STUDIES THAT WE CAN
ALSO USE TO THEN CONFIRM AND
VALIDATE THE THINGS THAT WE
FIND IN WITH PROTEOMICS.
WE ALSO LONGITUDINAL AND THE
STUDY OF LONGITUDINAL IN MICE.
WE'LL TALK ABOUT THAT LATER.
I'M NOT GOING TO TALK ABOUT
THIS UNTIL I HAVE TIME AT THE
END, THIS IS ALSO VERY
INTERESTING.
MOST PEOPLE MEASURE PROTEIN AND
HOW THEY CHANGE IN DIFFERENT
CONDITIONS.
AS IT TURNS OUT, PROTEIN
TURNOVER CHANGE A LOT DURING
CHANGING SO HOW WE REGULATE
CHANGES.
AND WE CAN UTILIZE MASSTOMTTRY
TO MEASURE TURNOVER RATES IN
HUMAN AND MOUSE STUDIES.
SXL AS IT TURNS OUT, THIS HAS A
REALLY STRONG, YOU KNOW,
CONNECTION WITH LONGEVITY.
SO IF THERE IS TIME, LATER I'LL
TALK ABOUT IT.
BUT OUR LAB MEASURES TURNOVER
RATES.
SO I THINK IN GENERAL MASS INTO
CLINICAL STUDIES.
AND WHAT I'M SHOWING NOW IS
ESSENTIALLY, THE PIPELINE AT MY
LAB IS USING TO IDENTIFY
SENOSES MARKERS.
WE CAN DEVELOP CANDIDATES,
CANDIDATES BIO MARKERS FROM
CELL CULTURE STUDIES.
WE CAN THEN VALIDATE THESE AND
WE CAN THEN TEST THESE IN REAL
HUMAN OR MOUSE TO VALIDATE IF
THEY'RE IMPORTANT.
FOR EXAMPLE, IF WE'RE LOOKING
AT SENESSES TO VALIDATE THAT
THESE ARE CHANGING.
IN ALL STAGES OF THESE
PIPELINE, IT CAN ACCELERATE THE
ABILITY TO DISCOVER THESE
BIOMARKERS.
AND HERE I WANT TO SHOW
DIFFERENT SAMPLES OF TECHNIQUES
THAT WE CAN USE IN TARGET
DISCOVERY.
ON THE BIOMARKER DISCOVERY, AND
THERE IS A LOT OF WORK FLOW.
I WANT TO GET THE POINT THAT
THAT IT'S A VERSIFY.
SO FOR BIOMARKER DISCOVERY WE
CAN COUPLE THESE PREPARATION
WHERE WE'RE SUPPOSE TO IMPROVE
THE COMPREHENSIVENESS AND THE
DEPTH OF OUR PROTEOMICSES.
MOST DON'T PAY ATTENTION TO THE
FORM OF THE PROTEIN BUT THERE
ARE SOME MASS METHODS, THAT
WILL LET US DO THAT AND THESE
CAN HELP US IDENTIFY MORE
SPECIFIC AND SENSITIVE
BIOMARKERS.
AND THEN WE HAVE A NUMBER OF
APPROACHES THAT WILL HELP US
IDENTIFY THE TARGETS OF DRUGS.
SO WE CAN USE THESE TO SCREEN
FOR POTENTIAL TARGETS AND ALL
OF THIS IS FURTHER BENEFITED BY
IMPROVEMENTS IN THE
TECHNOLOGIES THEMSELVES AND THE
ANALYTICAL APPROACHES.
SO WE REALLY HAVE, THERE IS A
LOT OF THAT PROTEOMIC CAN OFFER
TO THE BIOMARKERS AND TARGETS.
SO ONE OF THE, BASIC AGING
PROCESSES THAT WE'RE REALLY
FOCUS IS CALLED CELLULARSENIS.
IT'S A BASIC AGING PROCESS AND
IT'S A STRESS RESPONSE.
IF YOU IMAGINE HEALTHY CELL AND
IT ENCOUNTERED STRESS, THERE
ARE ONLY A FEW THINGS THAT CAN
DO, IF IT'S NOT STRONG ENOUGH
STRESS, IT WILL CONTINUE TO
DIVIDE, IF IT'S TOO STRONG IT
WILL DIE, BUT IF IT'S VERY
STRONG BUT NOT ENOUGH TO KILL
THE CELL, THE CELL CAN ENTER
THIS ALTERNATE STATE, CALLED
CELLULAR ZENSES.
SO THE WILL STOP STOP DIVIDING
AND THEN SECRETE ALL OF THESE
PROTEINS, OR SASS, JUST
REMEMBER SAS IS THE CREATE.
AND IT IT WILL CREATE IN ALL
THE ISSUE' AS WE AGE.
AND DURING AGING, THE CELLS CAN
GET A LOT OF STRESS.
THERE ARE THINGS FOR THE MOST
PART, GENO TOXIC STRESS THINGS
LIKE RADIATION, BUT ALSO
INDUCKTION AND CERTAIN
THERAPIES THAT PATIENTS ALREADY
TAKE.
SO THE CANCER CHEMOTHERAPY OR
EVEN H.I.V. MEDICINES CAN, SO
UNDERSTANDING THEIR BIOLOGY IS
IMPORTANT BUT CLINICALLY
RELEVANT FOR PATIENTS THAT ARE
ON THESE THERAPIES AND IT'S
SHOWING THAT SENESCENCE CAN BE.
IF YOU SELECTIVELY ELIMINATE
SENESENSE SELLS, YOU CAN
PROMODE LONGEVITY IN MICE.
IN ORDER TO LEVERAGE THIS IN
HUMANS, WE'RE GOING TO NEED
DRUGS, DRUGS THAT EITHER
ELIMINATE THE CELLS OR ALTER
THEIR, ONCE WE HAVE A
SENESCENCE, IT WILL HELP US
IDENTIFY THOSE AS WELL.
MY LAB, WELL ACTUALLY BEFORE I
NAME TO THE NIA ONE OF THE
THINGS THAT I FOCUSED ON IS
IDENTIFYING THE THESE
BIOMARKERS USING PROTEOMIC.
SO THIS WAS IN 2020 AND WE USED
THE PROTEOMICS TO SEE THE CELLS.
IN MULTIPLE CONDITIONS AND WE
ASKED WHETHER THESE WERE
ASSOCIATED WITH AGING HUMANS.
SO WHAT WE SHOWED IS THERE IS A
COURSE THAT ARE IN CIRCULATION
AND THEY'RE STRONGLY ASSOCIATED
WITH AGING.
AND WHILE, IN THE DEVELOPMENT
OF THIS STUDY, WE ALSO PUT
TOGETHER A DATABASE WHICH WE
CALL SASP AND WE HOPE THIS WILL
HELP ENABLE RESEARCHERS IF YOU
HAVE A PROTEIN THAT YOU'RE
INTERESTED, YOU CAN QUAER' THIS
TO SEE IF CELLS ARE SECRETING
THE THING THAT YOU'RE STUDIES.
HOPEFULLY THIS IS A RESOURCE
THAT THE COMMUNITY CAN UTILIZE.
BUT WE ALSO WANT TO KNOW,
PRODICT AGE RELATED OUTCOME
BECAUSE THAT'S WHAT WE'RE
INTERESTED IN.
ALSO PREDICTORS IN MORTALITY
AND MORBIDITY AND THIS STUDY
WAS DONE IN THE STUDY BASED IN
ITALY.
BUT, SINCE COMING TO NIA, A LOT
OF THESE STUDIES WERE REALLY
IMPORTANT AND WHAT WE NEED TO
DO IS FURTHER VALIDATE THESE
SPECIFIC PATHOLOGISTS AND
DIFFERENT COHORTS.
BUT SINCE COMING TO THE NIA, A
LOT OF THESE SIGNATURES WERE
BUILT IN FIBERGLASS AND
EPTHLIAL CELLS, BUT IN RESENT
YEARS IT'S BEEN SHOWN THAT I
NAOUN SENSE IS A IMPORTANT FORM
OF SENESCENCE, THERE IS BEEN
STUDIES IN MICE THAT SCENE
SENSE CAN ACT AS ANY SENESCENCE
CELL THEY SECRETE THE SASP AND
DRIVE IN INFLAMMATION.
BUT IT CAN--SO IT'S SORT OF UP
STREAM DRIVER OF SENESCENCE
SYSTEMATICALLY.
SO SINCE COMING HERE, YOU KNOW,
ONE OF THE THINGS THAT I WAS
REALLY INTERESTED IN DOING IS
IDENTIFYING BIOMARKERS FORESEEN
SENSE IN IMMUNE SYSTEM AND THE
REASON FOR THIS IS BECAUSE
THEY'RE UP STREAM, BECAUSE
BECAUSE MONOSENCE ARE IMPORTANT
TO THE BLOOD.
THEY'LL BE EASILY SORTED IF WE
WANT TO LOOK AT THE SCENE SENSE
CELLS IN ISOLATION.
SXL THERE IS SOME EVIDENCE THAT
SENESCENCE IS IN MONOSITE.
WE HAD TO DEVELOP A MODEL OF
SENESCENCE USING--YOU'RE ABLE
TO PRODUCE SENESCENCE USING,
AND INDUCTION AND CONFIRM THESE
IN KNOWN MARKERS.
WE THEN APPLIED PROTEOMICS TO
ASSOCIATE PROTEINS COMING FROM
MONO CYTES.
AND THIS BEEN DONE, BY
RESEARCHERS.
WHAT THEY WERE ABLE TO SHOW
THAT THESE WHITES IN THE MONO
CYTES AND ABOUT 160 OF THESE
PROTEINS ARE INCREASED WITH
SENESCENCE.
AND ONE THING I WANT TO POINT
OUT, IT'S PRETTY CLEAR JUST
LOOKING, THAT INTERFERON
RESPONSES IS ONE OF THE MAINL
OR RESPONSES.
SO ONE OF THE BIGGEST AND MOST
SIGNIFICANT IS INTERFERON AND
THIS IS IMPORTANT FOR THE
BIOLOGY OF THE CELLS AND IT
COULD BE A BIO MARKER.
UNFORTUNATELY AT THE NIA, WE
ALSO HAVE CLINICAL, WE HAVE
CLINICAL COHORTS THAT WE CAN
KIND OF LOOK FOR THESE
SENESCENCE.
SO ONE OF THE FLAGSHIP THAT'S
BALTIMORE STUDY ON AGING AND
HERE, WE HAPPEN TO HAVE A
PROTEOMICS STUDY THAT HAS BEEN
PERFORMED IN OVER 1100 USING
THE SOMO SKIN PLATFORM.
WE HAVE ANOTHER THAT IS NOT AS
BIG BUT THIS IS ONE OF THOSE
STUDIES WHERE THEY DO IN DEPTH
ANALYSIS WHERE THEY DO A LOT OF
OMICS.
AND WE'RE FORTUNATE THAT ONE OF
THE TISSUES.
SO WE CAN TRY TO EXTRACT IT
FROM THE CIRCULATING AND ALSO
THE MONO CYTES AND CIRCULATION
AND ASK WHETHER THE SIGNATURES
ARE PRODICT I HAVE OF DIFFERENT
AGING RELATED OUTCOMES, RIGHT
AND CAN WE DEVELOP SIGNATURES
THAT ARE PREDICTING THESE
THINGS?
SO I'M GOING TO START BY
SHOWING YOU THE DATA THAT WE A
RIDER USING THE BLSA STUDIES.
AGAIN BLSA IS A FLAGSHIP STUDY,
THE LONGEST LONGITUDE STUDY TO
THIS DAY AND THEY MEASURE A LOT
OF AGING OUTCOMES.
FOR THIS, WE HAVE INDIVIDUALS
FROM 92 TO 96 AND HALF OF THEM
ARE FEMALE.
I WANT TO ACKNOWLEDGE, KIENAN
WALKER WHO IS THE RESEARCHER,
HE'S REALLY TALENTED.
HE WOULD BE A REALLY GREAT
PERSON TO INVITE.
HE SPEAR HEADED THE PROTEOMIC
ANALYSIS IN THE BLSA, AND THE
CODIRECTORS OF THE BLSA.
WHAT WE WERE TO DO, WE WERE
ABLE TO FIND THAT THERE WERE 64
MONO CYTES THAT ARE AGE
ASSOCIATED.
AND JUST TO POINT SOME OF THEM,
I'M HIGHLIGHTING THEM IN THIS
VOLCANO PLOT.
SOME TARGETS, WE CAN SEE
INCLUDING OUR INTER FERON
SIGNATURE.
THIS IS ONE OF THE, IN ONE OF
OUR OTHER STUDIES, WE
IDENTIFIED THIS AS A CELL
SURFACE PROTEIN, WE THOUGHT
THIS WAS INTERESTING, WE CAN
SEE THIS EVEN IN CIRCULATION
AND ALSO CD68 IS A WELL-KNOWN
MONOCYTE MARKER.
THAT EVEN IN CIRCULATION, WE
CAN IDENTIFY THESE INTER
CELLULAR MARKERS NOT JUST THE
SECRETED STUFF.
SO WE WANTED TO ASK, OKAY, WITH
THIS 64-PROTEIN SIGNATURE CAN
WE BEGIN TO PREDICT CLINICAL
OUTCOMES?
SO TO DO THIS I HAVE A TALENTED
GRAD STUDENT WHO SPHERE HEADED.
THIS IS ANALYSIS APPROACH THAT
DOES FEATURE SELECTION AND DOES
NOT OVER FIT LIKE IF YOU DID
LINEAR MODELING AND IT
IDENTIFIES A SIGNATURE PROTEINS
THAT ARE BEST PREDICTORS OF
DIFFERENT OUTCOMES.
SO HE TOOK AND TRAINED THIS
MODEL AND TESTED OUT OF SAMPLE
PREDICT I HAVE POWER ON THE
REMAINING 20 PERCENT OF THE BLS
A PARTICIPANTS.
AND WHAT WE FOUND,
SURPRISINGLY, IT PREDICTS A
PRETTY WIDE VARIETY OF THINGS.
AND ONCE OF THE THINGS THAT WE
INCLUDED IN THE ANALYSIS WAS
INFLAMMATION.
THIS IS SOMETHING THAT WE
EXPECTED TO SEE.
WE'RE KIND OF A POSITIVE
CONTROL BUT THESE WERE NOT EVEN
THE STRONGEST THINGS THAT WE
CAN PREDICT CAN SENESCENCE.
SO WE SEE A LOT OF MOBILITY
METRICS.
SO YOU THINK ABOUT WALK PACE,
CHAIR STANDS, THINGS LIKE THAT.
AND THESE ARE GOOD, YOU KNOW,
MARKERS OF OVERALL HEALTH, THEY
ENGAGE A LOT OF SYSTEMS IN THE
BODY AND THESE ARE KNOWN TO BE
GOOD MARKERS OF AGING.
SO I THINK IT'S INTERESTING
KNOWING, WHAT, IF THERE IS MORE
SENESCENCE PROTEINS IN
CIRCULATION, WE CAN PREDICT
THESE METRICS OF OVERALL HEALTH.
WE ALSO SEE, METABOLIC
PARAMETERS, ADL, GLUCOSE, GLIE
GLIS RIDE.
AND WE CAN ALSO SEE THAT THESE
ASSOCIATIONS WERE GOING IN THE
DIRECTION THAT WE EXPECT THEM
TO SEE.
THIS IS A SUB SET, WE KIND OF
PLOTTED, WE TOOK THE SCORES AND
PLOTTED SO WE CAN LOOK AT THE
DIRECTION OF THE ASSOCIATION.
AND YOU CAN SEE THAT ALL OF
THESE ARE AS EXPECTED.
SO NEGATIVES, MORE
INFLAMMATION, BIGGER WAIST SIZE
IS CONNECTED TO SENESCENCE.
AND POSITIVE HEALTH METRICS,
PHYSICAL HEALTH STRENGTH, THOSE
ARE NEGATIVELY ASSOCIATED WITH
HIGHER SENESCENCE.
BUT ONE OF THE THING THAT STUCK
OUT AT THE BEGINNING BECAUSE
ONE OF OUR INITIAL ANALYSIS, IT
WAS THE THING THAT WE CAN MOST
STRONGLY PREDICT IN THE STUDY
WAS WAIST SIZE.
AND THIS REALLY STUCK OUT TO
US, BOWS THERE IS A CLEAR
LINEAR ASSOCIATION BETWEEN THE
LEVEL OF PROTEINS AND WAIST
SIZE.
WE WERE KIND OF CURIOUS WHAT
THIS MIGHT BE AND WHETHER WE
CAN DISSECT IT FURTHER.
BUT THE THING WE WANT TO DO,
ONE OF THE FACTORS IS AGING
ITSELF, AGE ITSELF.
SO AGE ITSELF IS ENOUGH TO
PREDICT MANY TRAITS.
SO WE WANTED TO SEE HOW MUCH
THE SIGNATURE HELPS US TO
PREDICT WAIST SIZE OR OBESITY.
WHAT BRAD DID, HE TOOK THE
PATIENTS AND PUT THEM INTO BMI
OVER 30 OBESE, OVER 30 NON
OBESE AND ASKED HOW WELL WE CAN
PREDICT IF SOMEBODY IS OBESE OR
NOT, BASED ON OUR AGENT SACKS
RIGHT HERE IN THE LINE.
SO AGE DOES NOT HAVE STRONG
PREDICT I HAVE POWER.
BUT, NOW IF WE INCLUDE THE
SENESCENCE, WE SEE SIGNIFICANT
IMPROVEMENT IN OUR ABILITY
WHETHER SOMEBODY IS OBESE.
IT HAS INDEPENDENT OF AGING,
SENESCENCE HAS SOME IMPORTANT
LINKS TO OBESITY.
SO NOW I WANT TO PIVOT FOR JUST
A FEW SLIDES TO THIS GASTAL
STUDIES.
I SHOWED YOU THE ASSOCIATES IN
CIRCULATING PLASMA AND NOW
ASSOCIATION AT THE MONOCYTES
THEMSELVES.
HERE I WANT TO ACKNOWLEDGE
THERE ARE A NUMBER OF
COLLABORATOR WHO WORKED ON THE
GAS TAL WITHOUT WHO THIS WOULD
NOT BE POSSIBLE.
WE ASKED THE SAME QUESTION, CAN
WE IDENTIFY SIGNATURES IN
GASTALTS.
SO THIS COHORT IS MUCH SMALLER.
WE HAD A SIMILAR AGE RANGE, 22
TO 9 4 YEARS, ABOUT 44% FEMALE.
WE WERE ABLE TO SEE IN THE
SMALLER SET, WE WERE ABLE TO
FIND ABOUT 11 PROTEIN THAT'S
WERE ASSOCIATED WITH MONOCYTE
CHANGING WITH AGE.
BUT INTERESTINGLY DESPITING
HAVING A SMALLER DATA SET AND
SMALLER NUMBER OF INDIVIDUALS,
WHEN BRAD TOOK THIS DATA SET
AND DID THE TRAINING AND AUTO
SAMPLE PREDICTION, OUR ABILITY
TO PREDICT WAIST SIZE WAS JUST
AS STRONG.
SO THIS REALLY STUCK OUT, THIS
IS SUCH A SMALLER COHORT, SO
WE'RE NOW INTERESTED IN FINDING
WHAT IS BEHIND THIS ASSOCIATION.
AND WE CAN ALSO PREDICT A FEW
OF THE OTHER ASSOCIATIONS THAT
WE WERE ABLE TO FIND IN THE
BLSA, SO FOR EXAMPLE, WE HAVE A
GRIP STRENGTH AND BMI HERE AS
WELL.
SO ONE THING THAT WE THOUGHT,
OKAY WE'RE GOING BACK TO THE
BLS A NOW, WHERE WE HAVE
INFORMATION ABOUT PEOPLE'S BODY
FAT.
SO WE WANTED TO ASK IS THIS
WAIST SIZE CORRELATION, EXPLAIN
OR BM PI BY FAT?
IS IT BODY SIZE OR FAT?
WE WENT BACK AND ASKED, CAN YOU
CORRELATE FAT WITH PROTEINS.
AND WE APPLIED THE SAME
APPROACH AND WHAT WE FOUND,
HERE I'M PLOTTING A LOT OF FAT
DEPOTS.
NONE OF THEM REALLY STUCK OUT
TO BE THAT MUCH STRONGER THAN
THE OTHER.
THIGH IS A LITTLE BIT HIGHER
BUT ALL ABOUT 4.5 OR HIGHER.
SEEMS THAT THE BODY FAT SEEMS
TO EXPLAIN MOST OF IT.
BUT, WHAT WAS INTERESTING IS IF
WE CORRECT TO BODY SIZE,
BASICALLY IF WE NOW TAKE THESE
VALUES AND TAKE FAT PERCENT
RATHER THAN JUST THE FAT LEVEL.
THIS CORRELATION BECOMES
STRONGER.
SO IT SEEMS TO SUGGEST THAT
INDEPENDENT OF BODY SIZE THAT
EXPLAINS MOST OF THE
CORRELATION THAT WE SEE WITH,
WITH WAIST SIZE.
SO OUR HYPOTHESES IS THAT THERE
IS OBESITY ASSOCIATED IN
SENESCENCE, THIS IS WELL-KNOWN
IN LITERATURE.
WE THINK THAT WE'RE PICKING UP
AN ABBIESITY SIGNATURE.
WE ALSO WANTED TO SEE IF THESE
CORRELATION WZ FAT WERE
INDEPENDENT OF AGE WITH BODY
FAT PERCENTAGE.
SO AGAIN, WE DID THE ROCK PLOTS
AND SHOWED THAT BEYOND THE SEX
A LOENL, IN THE PINK LINE HERE,
I'M SORRY IN THE RED LINE, IF
WE NOW ADD OUR MONO CYTE
PROTEINS THEN WE HAVE A BETTER
PREDICTION OF BODY FAT.
THIS IS DISTINGUISHING PEOPLE
ON THE TOP QUARTILE VERSE THE
BOTTOM QUARTITLE.
WE WONDERED WHAT ARE THE
SENESCENCE CAN PREDICT.
IN THE GRAY LINE IS THE
PREDICTION WHICH IS AGE AND
CORE VARIETIES.
AND ON THE BLUE BARS, SO SOME
OF THESE THINGS THAT WE HAD
SHOWN YOU BEFORE ARE REALLY
EXPLAINED BY INCLUDING AGE IN
THE MODEL OR SEX, GRIP STRENGTH
THAT'S REALLY ASSOCIATED WITH
SEX.
BUT OTHER THINGS WE CAN PREDICT
WITH SENESCENCE, SO THESE
METABOLIC.
SO ANOTHER QUESTION THAT WE CAN
ASK IN THE STUDY IS IS THERE
SEXUAL DIE MORPHISM.
AND THERE IS EVIDENCE IN MICE
TO SUGGEST SO.
SO WE WANTED DOES SENESCENCE GO
UP IN FEMALE VERSUS MALE.
YOU CAN SEE THAT HALF ARE MALE
AND FEMALE.
WE DO HAVE A HIGHER DENSITY
BETWEEN 50 AND 60.
AND IF WE ASK WHICH SENESCENCE
PROTEINS ARE ASSOCIATED WITH
FEMALE?
THERE ARE SOME WITH MORE WITH
FEMALE AND SOME HAVE BEING MALE.
THE ONES THAT I SHARED BETWEEN
THE TWO, IS THERE A DIFFERENCE
IN THE DYNAMIC OF WHEN THESE
BUILDUP.
SO WE WANT TO SEE THE
SENESCENCE GO UP IN ONE VERSUS
THE OTHER.
SO WE DID THIS DIFFERENTIAL
EXPRESSION AND WHAT THIS DOES,
IT PUTS ALL OF THE AGES INTO
BINS AND THEN IT KIND OF SLIDES
ACROSS THE AGE RANGE AND ASKED
DURING THE ANALYSIS DOES THIS
HAVE HIGHER EXPRESSION OF
SENESCENCE THEN THE PREVIOUS
AND BIN AND SUBSEQUENT BIN.
AND WE USE THIS TO IDENTIFY AT
WHAT AGES DO WE SEE INCREASES
OF SENESCENCE BURDEN?
AND WHAT WE FOUND IN BOTH
SEXES, WE SEE A PEEK IN THE 70s.
BUT INTERESTINGLY IN MALES, WE
SEE IT GOING UP IN EARLY AGE.
THIS IS THE GREEN LINE AND
FEMALES WE HAVE THE PURPLE LINE.
SO IT SEEMS TO GO UP ABOUT A
DECADE EARLIER IN MALES THAN
FEMALES.
SO AND WE PART OF THIS
ASSOCIATION IS EXPLAINED BY THE
FACT THAT WE HAD BETTER
STATISTICS HERE BECAUSE THIS IS
WHERE WE HAD THE MOST
INDIVIDUALS BUT WE CONTROL FOR
THIS.
WE SHUFFLED ALL THE AGES AND WE
WOULD ALL OF THIS AFFECT WOULD
GO AWAY.
AND INTERESTINGLY, IF WE JUST
TAKE AND PLOT THE SENESCENCE
PROTEIN, OVER AGE, YOU CAN SEE
THIS PHENOMENA IN MALES AT
ABOUT 60 YEARS OLD, YOU CAN SEE
IT BEGINS TO BE HIGHER IN MALES.
AND IT TAKES FEMALES ABOUT A
DECADE TO CATCH UP TO THAT
LEVEL.
SO IT SEEMS LIKE IT GOES UP
HIGHER IN MALES IF WE COMPARE
INDIVIDUALS OVER 60 TO
INDIVIDUALS UNDER 60, RIGHT.
SO UNDER 60, WE SEE A
DIFFERENCE IN THE SENESCENCE
BUT ONCE GE GET BEYOND 60, IT
NORMALIZED OUT.
SO IN CONCLUSION, THIS
CONCLUDES THE KIND OF HUMAN
PART OF THE TALK.
WHAT I SHOWED YOU, IS WE'RE
ABLE TO SEE THAT SENESCENCE
THAT THESE PROTEIN CHANGES WE
CAN USE THEM AS POTENTIAL
BIOMARKERS IN PEOPLE AND
THEY'RE CORRELATED OF DIFFERENT
AGING RELATED CLINICAL OUTCOMES.
AND PARTICULARLY FAT AND
OBESITY.
IT'S INTERESTING THAT
SENESCENCE INDEPENDENT OF AGE
CAN PREDICT OBESITY IN PEOPLE.
THIS IS INDICATIVE OF OBESITY
AND UNDERLINES THAT, YOU KNOW,
WHEN WE DO STUDIES OF
SENESCENCE OF PEOPLE, TO DO NOT
ONLY FOLKS OF AGED INDIVIDUALS
BUT ALSO OBESE INDIVIDUALS THEY
MAY BENEFIT MORE FROM THESE
INTERVENTIONS.
AND I SHOWED YOU THAT MALE HAVE
HIGHER SENESCENCE.
SO I WANT TO BACK UP A LITTLE
BIT IN THIS TALK.
ONE QUESTION THAT I'M REALLY
INTERESTED IN MY LAB IS HOW
GOOD CAN A CIRCULATING
BIOMARKER OF AGING EVEN BE?
RIGHT.
SO LOOKING AT PROTEINS AND
CIRCULATION, I MEAN, CAN THAT
BE, EVEN A COULD THAT BE EVEN A
USEFUL SURROGATE MARKER?
AND SO, THIS IS REALLY
INTERESTING QUESTION TO US.
BUT THE ANSWER TO THIS
QUESTION, WE'RE GOING TO NEED A
FEW THINGS.
FIRST OF ALL, WE WOULD NEED A
REALLY RIGOROUS LONGITUDINAL
STUDY THAT MEASURES, AGING AND
ALSO COLLECTS THE SPECIMEN
COUPLED TO THAT.
THEN WE CAN WRIGLEY ASKED THE
QUESTION, HOW WELL DO THESE
CIRCULATING BIOMARKERS PREDICT
ALL THE STUFF THAT WE CARE
ABOUT MEASURING.
AND IT TURNS OUT IT'S VERY
TECHNICALLY CHALLENGING AND
I'LL EXPLAIN THAT A LITTLE BIT
LATER.
WE CANNOT REALLY EASILY DO THIS
IN HUMANS BUT WE CAN ADDRESS
THIS IN MICE.
WE CAN CONDUCT THE WHOLE
LIFETIME STUDY AS WELL AS
COLLECTING THE SERUM, SO WE CAN
PREDICT USING SERUM PROTEINS.
IN MICE, WE CAN AT LEAST BEGIN
TO ANSWER THIS QUESTION AND
FORMULATE STRATEGIES, YOU KNOW,
WHAT IS THE BEST WAY TO MAKE A
PREDICTION, WHAT KIND OF THINGS
CAN WE PREDICT WHICH WE CAN
THEN APPLY INTO HUMAN STUDIES.
AND SO, WE'RE ABLE TO ADDRESS
THIS QUESTION LUCKILY, THANKS
TO ONE OF THE OTHER FLAGSHIP
STUDIES AT NIA, WHICH IS THE
STUDY LONGITUDINAL STUDY ON
MICE.
IT STARTED BACK IN 2015 AND
NEARING 4,000 MICE NOW.
BUT WHAT IS REALLY COOL IS THAT
IT'S EXTREMELY COMPREHENSIVE
AND LONGITUDINAL.
SO WHAT THEY DO IS THEY TAKE
MANY DIFFERENT MICE AND THEY
INCLUDE HERE HERE TWO DIFFERENT
STRINGS, WE HAVE MALE AND
FEMALE, THEY HAVE PLANNED
COLLECTIONS OF MANY DIFFERENT
SPECIMENS AND ONE OF THOSE
FORTUNATELY FOR US IS SERUM
THROUGHOUT THE LIFE SPAN, MANY
A LOT OF THESE AGING RELATED
OUTCOMES THAT WE CARE ABOUT ARE
MEASURED.
WE BEGIN TO ANSWER THESE
QUESTIONS ABOUT WHAT WE CAN
PREDICT ABOUT THE SERUM
BIOMARKER.
SO WHAT I'M GOING TO SHOW YOU
NOW IS TWO PARTS THIS IS AN ON
GOING STUDY.
AND FIRST I WANT TO SHOW YOU
HOW WE'RE ABLE TO ESTABLISH TO
THIS WORK AND THEN, SHOW YOU
HOW WE APPLY THIS METHOD IN THE
SCIENCE STUDY.
SO, ONE OF THE MAJOR CHALLENGES
OF DOING THIS IS THAT THERE ARE
TECHNICAL TO DOING PROTEOMICS
AND SERUM.
ALL OF THESE THOUSANDS OF
POTENTIAL MARKERS ARE WITHIN
THAT 1 PERCENT OF FRACTION.
YOU CAN IMAGINE IF YOU TRY TO
DO PROTEOMICS, ALL IS MEASURED.
AND BY THE WAY, ALBUMIN IS
ABOUT THE 60% OF THE TOTAL MASS.
AND ALL OF THOSE TO TENSION
BIOMARKERS MAY BE AT THE END,
SO WE SEE THINGS THINGS LIKE
AISLE 6 AND BETA AND THESE ARE
TOWARDS THE BOTTOM OF THE RANGE.
SO THE IF WE HAVE TO DO A
COMPREHENSIVE, WE HAVE TO
FIGURE OUT.
AND THE OTHER CHALLENGE THAT WE
HAD IS VERY LOW VOLUME OF
SAMPLE.
SO IN HUMANS YOU CAN COLLECT
MILL BUT IN MICE, ONLY MICRO,
YOU CANNOT TAKE TOO MUCH BLOOD
WITHOUT AFFECTING THE HEALTH OF
THE ANIMALS AND ON TOP THAT, A
STUDY LIKE SLAM, YOU CAN
IMAGINE THE SAMPLES ARE
PRECIOUS AND THEY CANNOT ONLY
GIVE THEM TO PROTEOMICS AND
WHATEVER IS REMAINING GOES TO
PROTEOMICS.
SO WE HAD TO DEAL WITH THE
RANGE AND LOW VOLUME.
UNFORTUNATELY WE HAPPEN TO
COLLABORATE AND PARTNER WITH A
COMPANY WHO HAS THE METHOD TO
ADDRESS THE DYNAMIC RANGE
PROBLEM IN SERUM.
THEY'RE CALLED SEAR AND I DON'T
HAVE TIME TO GO INTO DETAIL
ABOUT THIS BUT I'M HAPPY TO
ANSWER QUESTIONS LATER,
ESPECIALLY WHEN THEY USE THESE
NONO PARTICLES.
SO THEY INCUBATE THE SERUM,
THERE IS A SET OF PROTEINS
OUTSIDE, THEY CALL THIS, THIS
IS CALLED THE PROTEIN CORONA
AND PROTEIN CORONA HAS A MORE
DYNAMIC RANGE COMPARED TO THE
ORIGINAL SAMPLE AND CONTAINS.
SO WE TAKE THE PROTEIN CORONA
AND ANALYZE THAT AND WE AN MIEZ
BY MASS RESPECT.
AND THIS ANALYSIS WAS SPHERE
HEADED BY A, HE'S LIKE THE MASS
MASTER AND DOES THIS ANALYSIS.
SO THE FIRST THING WE WANTED TO
KNOW, WHAT IS THE LOWEST VOLUME
THAT WE CAN USE AND STILL GET
COMPREHENSIVE PROTEOMIC
APPROXIMATES.
SO WE TOOK DIFFERENT VOLUMES
AND COMPARED THAT WITH SERUM.
AND WE WERE REALLY HAPPY TO SEE
IS THAT WE CAN GO AS LOW AS TEN
MICRO LITTERS AND STILL GET
VERY COMPREHENSIVE PROTEOMICS.
AND AT THE LOWEST, EVEN AT THE
LOWEST VOLUME, WE HAD A HUGE
IMPROVEMENT SO IT'S AT LEAST
5-FOLD BETTER THAN WHAT WE CAN
DO WITHOUT DOING THESE SPECIAL
SAMPLE PREPARATIONS.
WE ALSO EVALUATED THE TECHNICAL
VARIANCE IN THIS APPROACH.
SO WE LOOKED AT THE CVs AND SAW
THERE WAS ABOUT 6% SO THIS WAS
A PRETTY REPRODUCABLE METHOD.
WE ALSO LOOKED AT THE PROTEINS
THAT WE IDENTIFIED, RIGHT SO WE
WANT TO SEE ARE THESE
BIOLOGICALLY RELEVANT AND WE'RE
ABLE TO SEE THAT A NUMBER OF
THESE PROTEINS, AND WHAT WE
LABELED ARE KNOWN TO PROTEINS,
RIGHT.
SO WE'RE GLAD THAT IN OUR AGING
STUDY, HE'LL BE ABLE TO SEE
THESE PROTEINS WHICH WILL BE
ONE SET OF THE PROTEINS THAT WE
REALLY CARE ABOUT.
SO WE, GIVEN THIS APPROACH, WE
WORKED NICELY FOR LOW VOLUME,
WE NEXT WANTED TO ASK, CAN WE
APPLY THIS TO LIKE AWE MINI
STUDY OF AGING?
IN A SMALL SUB SET OF THAT
STUDY?
SO WHAT WE DID, WE DECIDED TO
GO WITH 20 MICRO LITRE.
AND WE APPLIED THIS INTO A SUB
SET OF 30 MICE THAT WERE EITHER
YOUNG, 12-MONTH-OLD,
24-MONTH-OLD WHICH IS OLD FOR A
MOUSE AND 30-MONTH-OLD WHICH WE
CALL GERRIATRIC.
SO ONE OF THE THINGS THAT WE
DID IS, SO HERE'S JUST A LITTLE
REVIEW OF THE STUDY.
SO WE WERE HAPPY TO SEE IN THIS
PILOT STUDY, WE SAW SIMILAR
PERFORMANCE TO BEFORE, SO ABOUT
2300 PROTEINS ON AVERAGE FOR
SAMPLE AND WE WERE ABLE TO
IDENTIFY LIKE ABOUT 4500
PROTEINS.
WE LOOKED FOR LINEAR SO THINGS
THAT CHANGE ACROSS THE AGE
GROUPS.
AND HERE, WE WERE ABLE TO
IDENTIFY A NUMBER OF PROTEINS
THAT DECREASE AND INCREASE WITH
AGE.
AND YOU CAN SEE HERE ON THE
RIGHT EXAMPLES OF SOME OF THE
TOP INCREASING PROTEINS, WHICH
THE, THE WE THOUGHT THE SCENE
LOR MODELS WERE REALLY NICE.
INCREASING SOMETHING THAT IS
AGING STUDIES THAT YOU SEE, NO
MATTER WHAT YOU'RE MEASURING,
THERE IS ALWAYS INCREASE
HETERNE INCREASE.
WE ALSO WANTED TO KNOW IF WE
CAN IDENTIFY SEX ASSOCIATED
PROTEINS.
OH GETTING AHEAD OF MYSELF.
WE CAN LOOK AT WHAT ARE THE
FUNCTIONAL PATHWAYS THAT THESE
FALL INTO AND ARE THEY WHAT WE
EXPECT.
SO WE WERE HAPPY TO SEE THE
PATHWAYS OR LIPID TRANSPORT AND
METABOLISM PROTEINS WHICH ARE
THINGS THAT WE WOULD EXPECT TO
CHANGE IN THE GERRY.
AND WE WANTED TO SEE THE SEX
ASSOCIATED PROTEINS, THAT WERE
HIGHER IN MALE AND FEMALES AND
THINGS THAT ARE KNOWN TO BE
HIGHER IN MALES.
WE WERE ABLE TO SEE IN THE MICE.
SO IN HUMAN IT'S KNOWN THAT THE
PROTEINS ARE HIGHER IN THE
MALES.
AND WE WERE ABLE TO SEE THAT
WITH COMPLIMENT, WITH THIS
STUDY.
SO WE'RE HAPPY TORO PRODUCE
KNOWN CHANGES AND WE'RE
INTERESTED IN NOT ONLY WHAT IS
ASSOCIATED BUT IS THE AGE
RELATED CHANGE THE SAME?
IS THE TRAJECTORY WITH THE AGE
OF THE PROTEINS THE SAME WITH
MALES AND FEMALES?
SO FOR EXAMPLE, THIS PROTEIN IS
ON AVERAGE HIGHER ON MALE BUT
THIS DIFFERENCE GOES DOWN WITH
AGE.
AND FINALLY, ONE THING THAT WE
WERE ALSO REALLY INTERESTED IN
THE SLAM SITE, WAS TO LOOK AT
PROTEINS ASSOCIATED WITH
GLUCOSE LEVELS.
SO WHAT IS INTERESTING ABOUT
MICE, IS GLUCOSE LEVELS HAVE A
DIFFERENT RELATIONSHIP THAN
WHAT YOU SEE WITH HUMANS AND
THIS IS ALL PUBLISHED WORK,
HAVING HIGHER BLOOD GLUCOSE IS
BAD AND PREDICTS A SHORTER LIFE
SPAN.
IN MICE, IF YOU HAVE A HIGHER
GLUCOSE, IT PROVIDES A LONGER
LIFE SPAN.
THESE ARE KEY DIFFERENCES, BUT
WE WERE INTERESTED IN THE
PROTEINS ASSOCIATED IN GLUCOSE
ON MICE BECAUSE THAT MAY ALSO
PROTICKET DICT LONGER LIFE
SPANS.
AND INTERESTINGLY WE WERE ABLE
TO FIND ABOUT 100 PROTEINS THAT
WERE ASSOCIATED WITH GLUCOSE
LEVELS.
AND RJ10 WHICH IS A NICE LINEAR
ASSOCIATION.
SO THIS IS SOMETHING THAT WE
CONTINUE TO FOCUS IN PREDICTIVE
WITH AGE.
WE'RE ABLE TO NOW APPLY,
SUCCESSFULLY APPLY THIS
PROTEOMICS.
SO THE METHOD WORKS AND WE WERE
ABLE TO IDENTIFY SOME CHANGES
THAT WE EXPECTED TO SEE.
SO NOW THE QUESTION, SINCE
WE'RE REALLY ENCOURAGED BY
THESE RESULTS SO WE DECIDED NOW
THAT WE WANTED TO APPLY THIS
METHOD AT SCALE.
AND WE WANT TO GET TO THIS
QUESTION WHAT CAN WE ACTUALLY
PREDICT?
SO TO ANSWER THIS QUESTION, WE
HAVE TO USE A LOT MORE SAMPLES.
THIS DATA HAS BEEN RECENTLY
COLLECTED BUT I'LL JUST SHOW
YOU A LITTLE BIT OF WHAT WE'VE
SEEN.
SO NOW WE HAVE, UP TO 6
LONGITUDINAL SAMPLES HER MOUSE.
WE HAVE INTRODUCED BOTH STRAINS
SO WE HAVE SIX, THREE MALE AND
FEMALE.
AND HIGH IN GLUCOSE.
AND WE HAVE AGE RELATED OUTCOME
SO WE CAN ASK THE QUESTION WHAT
CAN THE PROTEINS PREDICT.
SO I WOULDN'T SHOW YOU MUCH
HERE, BECAUSE THIS IS PRESH
DATA.
BUT ONE OF THE THINGS THAT WE
ADDED THAT WE HAD NOT SEEN IN
THE PILOT WAS THE STRAIN
COMPONENT.
WE WANTED TO SEE HOW STRONG IS
IT?
BEFORE I GET TO THAT, JUST TO
GIVE YOU A LITTLE OVERVIEW OF
THE DATA SET.
SO HERE WE HAVE THE SCALE OF
THE DATA SET, THIS IS NOW 7
TERABYTES OF DATA.
SO I DON'T KNOW IF THERE IS
ANYBODY THAT DOES MASS SPECT
BUT THIS IS A LOT OF DATA.
I'VE NEVER HAD DONE SOMETHING
ON SUCH A LARGE SCALE.
THE PERFORMANCE WAS AS
EXPECTED, CUMULATIVE ABOUT
4,000 PROTEINS.
BUT NOW WE CAN ADDRESS THIS
QUESTION OF, YOU KNOW, HOW
IMPORTANT IS STRAIN OR GENETIC
BACKGROUND FOR THE
CIRCULATING--AND THE ANSWER IS
IMPORTANT.
VERY IMPORTANT.
THE SERUM PERTIUM REALLY
DEPENDS ON THE MOUSE.
I'M SHOWING YOU PROTEINS THAT
ARE HIGHER IN THREE.
AND IN THE 115 PROTEINS THAT I
PLOTTED, 370 ARE HIGHER, SO A
HUGE FRACTION OF THE SERUM IS
DEPENDENT ON THE GENETIC
BACKGROUND OF THE MOUSE.
SO THIS, THIS WILL COMPLICATE
THINGS.
SO CONSIDERING GENETIC
BACKGROUND IS IMPORTANT WHEN
LOOKING AT SERUM MARKERS.
THESE AFFECT SIZES ARE EVEN
LARGER THAN WHAT HI SHOWN YOU
WITH AGE, RIGHT.
SO THE AFFECT SIZE IS BOTH THE
SIGNIFICANCE AND MAGNITUDE OF
THE AFFECTS.
SO THESE A SAMPLE OF A PROTEIN
THAT IS DIFFERENT.
SO EVEN THOUGH YOU CAN SEE
THERE IS A DIFFERENCE BETWEEN
THE BLOCK 6 AND MICE.
IS THERE SOMETHING THAT THEY
ENRICH TOO?
AND INTERESTINGLY, THEY HAD
VERY STRONG, VERY
CHARACTERISTICS PATHWAYS THAT
THEY'RE ASSOCIATED WITH.
SO IN THE C56 BLOCK MICE, THESE
CHANGES ARE ENRICHING FOR
IMMUNITY AND PATHWAY.
INFLAMMATION SEEMS TO BE MUCH
HIGHER IN THE BLOCK 6 MICE, WE
SEE CELLULAR BUT IBQUUTENT.
AND YOU KNOW, IT'S NOT ONLY
IMPORTANT TO SEE WHAT IS
DEPENDENT ON THE STRAIN BUT HOW
THE CHANGE, IS AGING DIFFERENT
BETWEEN ONE STRAIN AND THE
OTHER?
WE LOOKED AT WHAT ARE
TRAJECTORIES?
AND THE ANSWER HERE IS ALSO
THAT IT'S QUITE IMPORTANT.
SO WE SEE A LOT OF THINGS THAT
ARE DIFFERENT IN THE AGE
GENOTYPE INTERACTION.
I SHOWS A NOT VERY GOOD SAMPLE
BUT I WANT TO ILLUSTRATE THAT
WE CAN DEMONSTRATE HIGHER
STRAIN.
IN ONE STRAIN THEY WOULD BE
GOING UP AND ONE THEY MAY BE
GOING DOWN.
THESE ARE THE KIND OF THINGS
THAT ARE GOING TO BE IMPORTANT
FOR US IN THE BIOMARKER STUDY.
ALL RIGHT, SO IN SUMMARY, WHAT
I'VE SHOWN YOU IS THAT WE WERE
ABLE TO USE THIS NANO PARTICLE
TO DO IN A LOW VOLUME MOUSE
SERUM AND AT SCALE.
AND YOU KNOW, FROM OUR INITIAL
DATA SET, WE'RE ALREADY ABLE TO
SEE THE GENETIC BACKGROUND HAS
A HUGE AFFECT AND ABOUT A THIRD
ABOUT SERUM IS ASSOCIATED WITH
STRAIN AND THAT THESE CHANGES
ARE CHARACTERISTIC OF CERTAIN
PATHWAYS.
SO, WE ARE NEARLY OUT OF TIME
NOW.
SO I'M GOING TO MAYBE SKIP THIS
BUT I THINK, THERE IS VERY
STRONG EVIDENCE IN THE
LITERATURE THAT YOU KNOW, ONE
OF THE THINGS THAT WE CARE
TURNOVER BUT THERE IS A STRONG
EVIDENCE THAT TURNOVER RATES
ARE ALSO ASSOCIATED WITH
LONGEVITY, SO THIS IS SOMETHING
WORTH STUDIES IN THE FUTURE.
AND I'LL GET TO THE FUTURE
SLIDE HERE, IS THAT I HOPE I
SHOWED YOU THAT PROTEOMICS CAN
BE USED TO HELP WITH
TRANSLATIONAL GEROSCIENCE.
THAT THEY GET US GET BETTER
COVERAGE AND FLUIDS,
IMPORTANTLY INCLUDING THESE, IF
WE CAN COLLECT THESE SAMPLES IN
OUR AGE RELATED STUDIES,
CLINICIANS ARE OUT THERE AND
BANK THEM AND HOPEFULLY LATER
WE CAN BEGIN TO DO THESE
STUDIES.
THESE WELL DESIGNED
LONGITUDINAL ARE ALSO VERY
HELPFUL IN ADDRESS THE AGING.
AND YOU KNOW, I THINK THAT,
PROTEOMICS CAN HELP A LOT.
THIS IS NOT SOMETHING THAT I
COVERED TODAY BUT WE CAN USE
NEWER METHODS TO GET MORE
SENSITIVE.
SO ALL OF THESE DISCOVERY
METHODS ARE VERY AGNOSTIC TO
THE VARIANT THAT YOU'RE
MEASURING.
SO A LOT OF NOISE COULD BE THAT
WE'RE NOT MEASURING THE
SPECIFICALLY VARIANT BUT IT
COULD HAVE A PTM, BUT WE'RE
AGGREGATING THESE MEASUREMENTS
WITH DISCOVERY.
SO YOU KNOW, USING DEVELOPING
METHODS THAT ALLOW US TO DO
MORE SPECIFIC SCALE WILL BE
IMPORTANT FOR THE FUTURE.
AND WITH THAT, WOULD I LIKE TO
THANK A LOT OF PEOPLE WHO WERE
INVOLVED IN THIS WORK FROM MY
LAB, PARTICULARLY AMID AREMA
AND BRAD WHO ARE COLLABORATORS.
WE HAVE KIENAN WALKER, WHO DID
THE PROTEOMICS BUT THIS ENTIRE
BLSA TEAM, ASIR, THE
TRANSLATION BRANCH
PARTICULARLY, LEE RAFA AND ALL
THE INVESTIGATORS WHO DID THE
SLAM STUDY.
AND OF COURSE I WANT TO THANK
ALL THE PARTICIPANT OF THE
STUDIES AND OF COURSE THE MICE
WHO SACRIFICE TO BE ABLE TO
GIVE US THIS DATA.
I'M HAPPY TO ANSWER YOUR
QUESTIONS.
THANK YOU.
[APPLAUSE]
>> THANK YOU, BASISTY.
>> SO THIS CAME FROM THE
VIRTUAL AUDIENCE AND I THINK
YOU ADDRESSED IT PARTIALLY.
ARE ANY OF THESE TESTS BEING
MADE AVAILABLE OR IS THIS JUST
A RESEARCH.
>> THAT'S A GREAT QUESTION.
RIGHT NOW, WHAT I SHOWED YOU IS
IN THE RESEARCH STAGE BUT THERE
ARE EXISTING METHODS THAT WOULD
BE NOT TOO HARD TO INCLUDE IN
THE CLINICAL STUDY.
FOR EXAMPLE, ACTUALLY I HAVE A
SLIDE FOR THIS. THIS IS THE
METHODS THAT ARE OUT THERE
EXISTING.
ALSO THESE OTHER PROTEOMICS
STUDIES THAT CAN ALSO OFFER
REALLY BIG COVERAGE.
AND THEY'RE PRETTY
COMPREHENSIVE.
WHAT I'M SHOWING IS VERY MUCH
RESEARCH BUT HOPEFULLY WE CAN
INTEGRATE IT SOON.
I WOULD ENCOURAGE ANYONE TO
JUST COLLECT THE BLOOD BEFORE
AND AFTER THE TREATMENT AND
SAVE IT AND HOPEFULLY YOU'LL
RUN INTO A MASS EXPERT IF YOU
HAVE MONEY, YOU CAN JUST PAY TO
HAVE THINGS LIKE SOMA LOGICS TO
THEN FOLLOW-UP WITH MORE
TARGETED METHODS.
>> AND THEN JUST AS A QUESTION
THAT I HAVE, I'M A PEDIATRIC
ONCOLOGIST INTERESTED IN
SURVIVALSHIP, THE QUESTION I
HAVE IS YOU SAID THERE WAS A
CORRELATION BETWEEN THE
TREATMENT AND SIDE AFFECTS.
HAS THAT BEEN LOOKED AT AND IS
THAT A REVERSABLE THING WHERE
YOU PROTEINS LATER THEY CAN
DWINDLE DOWN OR IS IT RELATED
TO THE THERAPEUTIC CHALLENGE?
>> THAT'S A VERY GOOD QUESTION.
WE DON'T HAVE, THERE IS VERY
LIMITED DATA IN HUMANS, JUST
NOW PEOPLE ARE LOOKING AT THE
HUMAN.
BUT THE BOTTLE AND THE MICE,
HAVE SHOWN THAT IT IS RELEVANT.
SO FOR EXAMPLE, IN MICE, THAT
ARE GIVEN, YOU KNOW, DOXRUBESON
IT'S A CHEMOTHERAPY, ONE OF THE
SIDE AFFECTS IS KAOEM BRAIN, SO
IN MICE, COGNITIVE DEFICITS,
GIVEN THE MICE A SANA LETIC
RELIEVED.
THERE IS SOME SUGGESTION THAT
IT CAN HELP IN THE SIDE AFFECTS
OF THIS THERAPY.
>> ALL RIGHT, WELL THANK YOU.
OKAY.
>> THANK YOU FOR THAT GREAT
TALK.
SO I HAVE A QUESTION, AND IN
OUR LAB, WE STUDY AUTO
INFLAMMATORY DISEASE AND WE
STUDY A SPECIFIC DISEASE WHERE
WE SEE SOME RETINAL
DEGENERATIVE IN PATIENTS AS
EARLY AS IN THEIR TEENS, ADULTS
AGE.
DO YOU THINK LIKE, SENESCENCE
IMMUNE CELLS HAVE SUCH A ROLE
IN THESE TYPES OF DISEASES AND
CAUSING A RAPID DEGENERATION
EARLY ON?
>> YEAH, THAT'S A GOOD QUESTION.
SO THERE IS I'M NOT SURE ABOUT
THE SPECIFIC DISEASE, BUT THEY
CAN BE INVOLVED IN EYE DISEASE.
THERE IS A COMPANY UNITY
BIOTECHNOLOGY WHO DEVELOPING
THESE.
ONE OF THE FIRST SUCCESSFUL
TRIALS I'VE SEEN ON DRUGS IS
TARGETING AMD.
AGE RELATED, SO THERE IS SOME
DATA THAT SUGGEST THAT YOU
KNOW, SENESCENCE IS DRIVING AGE
RELATED PATHOLOGIST.
BUT IN YOUR STUDY, IF YOU HAVE
PROTEINS THAT YOU SEE IN YOUR
MODEL TO SEE IF THOSE ARE
ASSOCIATED WITH SENESCENCE.
YEAH, ALL RIGHT, THANK YOU.
DR. BASISTY, THANK YOU FOR
YOUR SHARING YOUR WORK.
WE WILL NOT HAVE A GRAND ROUND
NEXT WEEK BUT WE WILL SEE
EVERYBODY IN ABOUT TWO WEEKS.