HELLO AND GOOD MORNING,
EVERYONE.
HWE WOULD LIKE TO WELCOME YOU TO
THE HEALTH AND AGING
TRAJECTORIES, SHARED AND
COMPETING RISKS AND RESILIENCES
FOR CHRONIC DISEASES ASSOCIATED
WITH AGING.
AGAIN WE WELCOME YOU.
SO GOOD MORNING, MY NAME IS
DEIRDRE O'NEILL, I AM THE NHLBI
WORKSHOP SUPPORT COORDINATOR.
THANKS AGAIN FOR JOINING US
VIRTUALLY.
AS WE WELCOME YOU TODAY, WE JUST
WANT TO SAY THAT WE'RE VERY
EXCITED FOR EVERYTHING THAT WE
HAVE PUT TOGETHER.
AND THEN WE'RE GOING TO HAVE
SOME WELCOME AND OPENING
HOUSEKEEPING SLIDES READ BY
GABRIELA.
>> GOOD MORNING, EVERYONE.
MY NAME IS GABRIELA RISCUTA, AND
I AM A PROGRAM OFFICER IN THE
DIVISION OF CANCER PREVENTION AT
THE NATIONAL CANCER INSTITUTE
AND I'M ONE OF THE CO-CHAIRS OF
THIS WORKSHOP SUPPORTED BY NCI,
NHLBI, ODS AND NIA.
IT IS MY PLEASURE TO WELCOME YOU
ALL TO THIS INFORMATIVE WORKSHOP
AND THANK YOU FOR TAKING TIME
FROM YOUR BUSY SCHEDULE TO
PARTICIPATE AND HELP US IDENTIFY
NEW GAPS IN KNOWLEDGE AND FUTURE
DIRECTIONS OF RESEARCHMENT AS
YOU ALL KNOW, LIFE EXPECTANCY IS
GOING UP, WHICH IS WONDERFUL
NEWS, BUT THE HEALTHY LIFE
EXPECTANCY IS NOT IMPROVING AT
THE SAME SPEED.
SO THE PURPOSE OF THIS WORKSHOP
IS TO INQUIRE IF THERE ARE
CERTAIN PATHWAYS OF AGING
LEADING TO ONE CHRONIC DISEASE
VERSUS ANOTHER, OR THERE ARE
COMPETING RISKS OR EVEN BETTER
IF WE CAN FIND THE PATHWAY
TOWARD RESILIENCE.
SO WE INVITED THE BEST EXPERTS
IN THE WORLD AND THEY ARE HERE
TODAY TO ENLIGHTEN US AND SHARE
WITH US THEIR TREMENDOUS WORK
AND HELP US TO FIND FUTURE
DIRECTION OF RESEARCH AND I ALSO
WANT TO THANK YOU NOT ONLY TO
THE SPEAKERS BUT ALSO TO THE
PLANNING COMMITTEE, WHICH WORK
VERY HARD TO PUT THIS WORKSHOP
TOGETHER, SO I'M GOING TO START
WITH MY CO-CHAIRS.
VERY SPECIAL THANK YOU, SHE DID
A LOT, A LOT OF WORK.
AND OUR WONDERFUL CONTRACTOR
TEAM LED BY DEIRDRE O'NEILL.
WE HOPE EVERYTHING IS GOING TO
GO WELL.
SO I HAVE JUST A VERY FEW
HOUSEKEEPING INFORMATION FOR
YOU.
SO THIS IS AN ENTIRELY VIRTUAL
WORKSHOP AND THIS WORKSHOP IS
BEING RECORDED AND WILL BE
AVAILABLE FOR FUTURE VIEWING AT
NIH VIDEOCAST WEB SIGH.
THE WORKSHOP COMPRISES OF FOUR
SESSIONS.
WE WILL HAVE TWO COFFEE BREAKS
AND A LUNCH BREAK AFTER EACH D
DAY.
KEYNOTE SPEAKERS WILL PRESENT
FOR 25 MINUTES FOLLOWED BY FIVE
MINUTES Q & A, AND ALL OTHER
SPEAKERS WILL PRESENT 15 MINUTES
FOLLOWED BY 5 MINUTES Q & A.
TO MAKE SURE WE WILL STAY ON
TIME, THERE WILL BE ONE TWO
MINUTES BEFORE THEIR TIME WILL
END.
AND WE HAVE 20 MINUTES MODERATED
PANEL DISCUSSION AFTER EACH
SESSIONS.
THE MODERATORS ALSO WILL KEEP
EVERYONE ON TIME.
WE HOPE THERE WILL BE NO ISSUES,
BUT IN CASE OF SYSTEM-WIDE
TECHNICAL DIFFICULTIES, PLEASE
WAIT A COUPLE OF SECONDS, DO NOT
TURN OFF YOUR ZOOM.
IF THE PROBLEM WILL TAKE TOO
LONG, THEN PLEASE CHECK YOUR
EMAIL AND YOU'LL FIND DIRECTION
OF HOW WE CAN MOVE FORWARD.
AND IF YOU WANT TO ASK, WE
ENCOURAGE YOU TO SEND YOUR
QUESTION THROUGH THE Q & A,
PLEASE MENTION THE SPEAKER NAME
SO WE KNOW TO WHICH SPEAKER YOU
ARE ADDRESSING YOUR QUESTION.
THANK YOU AGAIN AND NOW IT'S MY
PLEASURE TO INTRODUCE MY
CO-CHAIR, DR. ZORINA GALIS.
DO YOU WANT TO SAY A FEW WORDS?
>> SURE.
THANK YOU SO MUCH FOR THE
OPPORTUNITY TO SAY SOMETHING.
THANK YOU, YOU WERE VERY
COMPREHENSIVE IN YOUR REMARKS.
BUT I WOULD LIKE TO ALSO ADD A
VERY BRIEF WELCOME TO ALL OF YOU
AND ALSO SOME THINGS FROM THE
VIEW OF NHLBI.
WE ARE USING ALL THESE ACRONYMS.
I HOPE PEOPLE KNOW THIS IS THE
HEART, LUNG AND BLOOD INSTITUTE
SO I'M REPRESENTING THE HEART,
LUNG AND BLOOD INSTITUTE.
SO FIRST OF ALL, AS GABRIELA
POINTED OUT, THIS WAS THE DREAM
OF A GROUP OF DEDICATED NIH
EMPLOYEES FROM SEVERAL
INSTITUTES THAT INCLUDE AS YOU
HEARD CANCER, NCI, HEART, LUNG
AND BLOOD, NHLBI, NEUROLOGICAL
DISORDER AND STROKE, NINDS, AND
THE AGING INSTITUTE, NIA, AS
WELL AS THE OFFICE OF THE
DIRECTOR.
SO AS OUR NAMES INDICATE BY THE
WISDOM OF THE FOUNDERS, WE ARE
FOCUSING IN VARIOUS INSTITUTES
EITHER ON SPECIFIC BODY PARTS OR
THEIR FUNCTION, THEIR CYST
DYSFUNCTION OR POTENTIALLY ON
SPECIFIC CONDITIONS OR DIFFERENT
LIFE STAGES.
SO WE ARE AWARE OF THAT, AND THE
GROUP THAT YOU ALREADY HEARD
MENTIONED HAS FORMED A GROUP, A
WORKING GROUP THAT IS CALLED THE
SAME, HEALTH AND AGING
TRAJECTORIES, AND WHAT WE ARE
TRY DOGTRYING TO DO IS BASICALLE
OUT HOW WE CAN BRIDGE PERCEIVED
BARRIERS OUTSIDE THE KNOWLEDGE
DOMAIN TO BASICALLY BRING US
BACK TOGETHER INTO ONE BODY,
EXPERIENCING HEALTH OR
POTENTIALLY DISEASE, ESPECIALLY
AS IT MANIFESTS WITH AGING.
AND SO WE STARTED ASKING ALL
KINDS OF INTERESTING QUESTIONS,
COULD OUR INDIVIDUAL HEALTH AND
DISEASE TRAJECTORY BE DEFINED.
PERHAPS CAN THEY BE PREDICTED.
COULD WE ENHANCE RESILIENCE,
COULD YOU PREVENT OR INTERCEPT
THESE DISEASES, AND SPECIFICALLY
ARE THERE SIGNALS THAT WE SHOULD
OR MAYBE WE ARE ALREADY ABLE TO
MEASURE AND TRY TO REA SPOND TO
SOME OF THESE QUESTIONS.
THEN WE ALSO WOULD LIKE TO KNOW
WHETHER THERE ARE SHARED RISK
FACTORS OR RESILIENCE OR
POTENTIALLY TRADEOFFS SPECIFIC
FOR HEALTH AND AGING
TRAJECTORIES.
SO WITH GABRIELA, WE STARTED
FROM THE VERY SORT OF CLEAR FORK
THAT IS BECOMING CLEAR IN THE
PAST FEW YEARS BETWEEN
CARDIOVASCULAR DISEASE AND
CANCER, SO THAT'S KIND OF HOW WE
GOT STARTED.
SO FIRST I WANT TO THANK THIS
DEDICATED GROUP OF PEOPLE WHO
HAASK ALL THESE QUESTIONS BUT
PEOPLE IN VARIOUS DOMAINS TO
ANSWER THEM, AND OF COURSE I
WANT TO THANK OUR DISTINGUISHED
INVITED SPEAKERS, AND I WANT TO
THANK THEM IN ADVANCE FOR
HELPING US ANSWER SUCH QUESTI
QUESTIONS.
AS YOU PROBABLY ALREADY SAW FROM
THE AGENDA, THERE ARE FOUR
VIRTUAL SESSIONS, BUT EACH OF
THEM HAS BEEN DESIGNED
SPECIFICALLY TO ACTUALLY PRESENT
A VARIETY OF PERSPECTIVES, SO WE
ARE HOPING THAT YOU'LL BE GLUED
TO THE SESSIONS TO THE POINT OF
NOT LEAVING US, ESPECIALLY FOR
THOSE TALKS THAT MAY PRESENT
PERSPECTIVES THAT YOU MIGHT HAVE
NOT CONSIDERED PREVIOUSLY.
AS YOU HEARD, WE ARE ALSO VERY
INTERESTED IN ENGAGING THE
AUDIENCE AND I THANK YOU ALL,
THOSE WHO WERE ABLE TO JOIN US
THIS MORNING.
IF YOU JOINED US ON ZOOM, YOU
CAN PREFERABLY ASK QUESTIONS BY
Q & A, BUT YOU CAN ALSO ASK BY
CHAT.
WE ALSO HAVE PEOPLE WHO JOIN US
ON VIDEOCAST, ON NIH VIDEOCAST.
THOSE PEOPLE CAN SEND EMAILS AND
WE ARE GOING TO COLLATE ALL
THESE QUESTIONS AND PRESENT THEM
TO THE SPEAKERS AND THE
MODERATORS.
AS EXPECTED, WE ARE NOT PROBABLY
GOING TO HAVE TIME TO ASK ALL
THE QUESTIONS BUT I'M SURE THAT
THE SPEAKERS WILL MAKE EVERY
EFFORT TO ANSWER TO YOU IN Q & A
AND THE MODERATORS WILL COLLATE
SOME OF THESE QUESTIONS AND
POTENTIALLY ADDRESS THEM DURING
THE PANEL DISCUSSION.
SO WE WELCOME EVERY SINGLE ONE
OF YOU AND FINALLY, WHAT I HAVE
THE PLEASURE OF INTRODUCING
DR. DAVID GOFF, WHO WILL HELP US
KICK OFF THE WORKSHOP.
DR. DAVID GOFF IS DIRECTOR OF
THE DIVISION OF CARDIOVASCULAR
DISEASES AT THE NATIONAL HEART,
LUNG AND BLOOD INSTITUTE WHICH
IS THE HOST OF THIS SEMINAR.
SO I HOPE THAT DR. GOFF WAS ABLE
TO JOIN US MEANWHILE, I KNOW HE
HAD AN IMPORTANT STAFF MEETING
AND WE ARE LOOKING FORWARD TO
YOUR REMARKS, DR. GOFF, IF YOU
ARE ALREADY ONLINE.
THANK YOU.
CAN SOMEBODY LOOK WHETHER
DR. GOFF IS ONLINE?
IF NOT, MAYBE GABRIELA, YOU CAN
INTRODUCE DR. CASTLE.
>> IS DR. CASTLE ONLINE?
I KNOW HE WAS SUPPOSED TO BE 10
MINUTES LATER.
>> I DON'T SEE ANY OF THEM, I'VE
BEEN IN CONTACT WITH HIS
ASSISTANT AND SENT HIM AN EMAIL.
SHE SAID DR. GOFF SHOULD BE HERE
PROMPTLY.
APOLOGIES FOR THE INCONVENIENCE.
THERE HE IS.
>> DR. GOFF, WELCOME!
WE ARE LOOKING FORWARD TO YOUR
REMARKS KICKING OFF THE
WORKSHOP.
I HOPE YOU CAN CONNECT, IF YOU
HAVE SOME THOUGHTS FLOATING
AROUND.
YES, PLEASE GO ON.
DR. GOFF, PLEASE GO ON IF YOU
ARE ABLE.
CAN YOU DO A SOUND CHECK?
>> OH, HI, ZORINA.
GOOD TO SEE YOU.
JUST GOT HERE.
>> YES, THANK YOU SO MUCH!
I INTRODUCED YOU.
WE'RE WAITING FOR YOU TO KICK
OFF THE WORKSHOP.
THANK YOU SO MUCH.
>> WELL, THANK YOU.
SORRY THAT I'M RUNNING A LITTLE
LATE.
HAD A LEADERSHIP MEETING THIS
MORNING THAT USUALLY GOES UNTIL
10:00 BUT WE CLOSED IT EARLY SO
I COULD GET HERE TO WELCOME YOU,
BECAUSE THIS IS A REALLY
IMPORTANT WORKSHOP FOR US.
I'M DAVID GOFF, I LEAD THE
DIVISION OF CARDIOVASCULAR
SCIENCES AND IT MY PLEASURE TO
WELCOME YOU AND THANK YOU FOR
BEING HERE.
HERE TO REALLY HELP US
MOVE FORWARD IN THIS IMPORTANT
AREA OF HEALTH AND AGING AND HOW
WE CAN MAINTAIN AND ENHANCE
RESILIENCE AS WE ALL AGE.
WE KNOW THERE'S A LOT OF
DIFFERENT THINGS YOU CAN BE
DOING WITH YOUR TIME SO THE FACT
THAT YOU CHOSE TO SPEND SOME OF
IT WITH US TO GIVE US YOUR
THOUGHTS AND YOUR INPUT IS
SOMETHING FOR WHICH WE'RE VERY
GRATEFUL.
SO I WANT TO LET YOU KNOW WHAT
OUR EXPECTATIONS ARE FOR ACTING
ON THE INPUT THAT YOU GIVE US.
WE HAVE SEVERAL EXPECTATIONS OF
HOW WE'LL MOVE FORWARD WITH IT.
FIRST IS THAT WE ANTICIPATE
PUTTING A REPORT ON OUR WEBSITE
HOPEFULLY WITHIN ABOUT A MONTH
OF THIS WORKSHOP, SO WE
ENCOURAGE YOU TO GET THE
EXECUTIVE SUMMARY OF YOUR INPUT
TOGETHER IN A TIMELY MANNER SO
IT CAN BE SHARED WITH THE LARGER
BIOMEDICAL RESEARCH COMMUNITY
WHILE IT'S STILL FRESH AND
TIMELY.
SO THE GOAL IS TO GET THAT
EXECUTIVE SUMMARY ON OUR WEBSITE
WITHIN THE NEXT MONTH OR SO.
YOU MAY ALSO D DECIDE THAT YOU
WANT TO WRITE A PAPER FOR
SUBMISSION FOR CONSIDERATION AND
PUBLICATION IN A PEER REVIEWED
JOURNAL.
IF YOU DECIDE TO DO THAT, WE'LL
SUPPORT THAT EFFORT.
OUR TEAM WILL WORK WITH YOU.
AND AGAIN, WE WOULD ENCOURAGE
YOU TO DO THAT IN A TIMELY
MANNER, WITHIN A FEW MONTHS SO
THAT IT GETS OUT WHILE THE
INFORMATION IS STILL FRESH FROM
THE DISCUSSION FOR THE BENEFIT
OF THE LARGER BIOMEDICAL
RESEARCH COMMUNITY.
WE ALSO ANTICIPATE THAT AFTER
THE ROBUST EXCHANGE OF IDEAS
THAT OCCURS DURING THE WORKSHOP
THAT MANY OF YOU WILL GO HOME
AND WRITE COMPELLING
APPLICATIONS THAT WILL COMPETE
WELL IN THE INVESTIGATOR
INITIATED PEER REVIEWED POOL OF
APPLICATIONS.
THE VAST, VAST MAJORITY OF THE
RESOURCES THAT WE AWARD TO
RESEARCHERS EVERY YEAR GOES OUT
TO INVESTIGATOR INITIATED PEER
REVIEWED APPLICATIONS, AND SO WE
WOULD ENCOURAGE YOU TO GO HOME
AND WRITE GREAT APPLICATIONS.
I TELL PEOPLE IT'S SIMPLE,
WRITING A GOOD APPLICATION, GET
A GOOD SCORE, WE LOVE TO GIVE
MONEY AWAY.
I DIDN'T SAY IT WAS EASY, JUST
SIMPLE.
BUT WE MAY ALSO PUT OUT
INITIATIVES AS A RESULT OF THE
INPUT THAT YOU GIVE US.
NOW, WE DON'T DO THAT FOR EVERY
WORKSHOP BECAUSE WE HAVE MORE
WORKSHOPS EACH YEAR THAN WE CAN
PUT OUT, FUNDED INITIATIVES.
BUT WE MAY ALSO PUT OUT A NOTICE
OF SPECIAL INTEREST, WHICH
INDICATES TO THE COMMUNITY OUR
INTEREST IN AN AREA THAT MAY
ALSO INFLUENCE WHAT WE DO WITH
WHAT WE CALL OUR SELECT PAY
RESOURCES.
YOU PROBABLY KNOW THAT IN
ADDITION TO A PAYLINE FOR
R01s, WE ALSO HAVE A SMALL POT
OF RESOURCES THAT WE CAN USE FOR
WHAT WE CALL SELECT PAY
OPPORTUNITIES, AND THESE ARE
APPLICATIONS THAT ARE JUST ON
THE WRONG SIDE OF THE PAYLINE
BUT ARE STRATEGICALLY ALIGNED
WITH HIGH PRIORITIES, AND SO WE
SOMETIMES USE THE INPUT FROM
WORKSHOPS LIKE THIS TO GUIDE OUR
SELECT PAY OPPORTUNITIES AND KE
DECISIONS AS WELL.
SO I JUST WANTED TO GIVE YOU THE
FULL RANGE OF ACTIONS THAT WE
WOULD EXPECT TO TAKE BASED ON
THE ROBUST DISCUSSION AND INPUT
THAT WE ANTICIPATE GETTING FROM
THIS WORKSHOP SO THAT YOU KNOW
THIS IS REALLY IMPORTANT TO US
AND WE'LL TAKE IT QUITE
SERIOUSLY.
SO I WANT TO END WHERE I
STARTED, THANKING YOU FOR YOUR
CONTRIBUTION OF TIME AND ENERGY
TO THIS EFFORT.
I ESPECIALLY WANT TO THANK
ZORINA GALIS AND GABRIELA
RISCUTA FROM NIH WHO ARE LEADING
THIS, AS WELL AS THE CO-CHAIRS
FOR THE WORKSHOP.
SO WITH THAT, I'LL TURN THE
BATON BACK TO ZORINA OR MAYBE
IT'S GABRIELA WHO IS GOING TO DO
THE WELCOME.
GABRIELA, PLEASE.
>> GABRIELA IS ON.
>> THANK YOU, DR. GOFF.
SO IT IS MY PLEASURE AND HONOR
TO INTRODUCE DR. PHIL CASTLE,
THE DIRECTOR OF THE DIVISION OF
CANCER PREVENTION AT THE
NATIONAL CANCER INSTITUTE.
SO DR. CASTLE, WE ARE ON, SO
PLEASE HELP US START THIS
WORKSHOP.
>> WELL, THANK YOU FOR THE
OPPORTUNITY TO KICK THIS OFF.
IT'S A VERY EXCITING TOPIC,
OBVIOUSLY RELEVANT ACROSS THE
SPECTRUM OF HEALTH.
LET ME GO TO THE FIRST SLIDE,
PLEASE.
SO WE'LL JUST GO BACK ONE SLIDE,
PLEASE.
SO I'M, AS STATED.
THE DIRECTOR OF THE DIVISION OF
CANCER PREVENTION.
I'M ALSO AN INTRAMURAL
INVESTIGATOR, SENIOR
INVESTIGATOR IN THE DIVISION OF
CANCER EPIDEMIOLOGY AND GENET
GENETICS.
SO JUST SOME DISCLAIMERS.
THESE ARE MY OPINIONS ALONE, MY
COMMENTS ARE INFORMAL AND SHOULD
NOT BE TAKEN AS A SIGNAL, PER
SE, FOR FUNDING PRIORITIES AND
IF I MENTION SPECIFIC COMMENTS,
THEY SHOULD NOT BE TAKEN AS AN
ENDORSEMENT OF SAID PRODUCTS.
SO THE MISSION OF THE DIVISION
OF CANCER PREVENTION IN THE
NATIONAL CANCER INSTITUTE IS AS
FOLLOWS.
LEADS, SUPPORTS AND PROMOTES
RIGOROUS, INNOVATIVE RESEARCH
AND TRAINING TO REDUCE RISKS,
BURDENS AND CONSEQUENCES OF
CANCER TO IMPROVE THE HEALTH OF
ALL PEOPLE.
AS I'M SURE YOU CAN APPRECIATE
AGING INFLUENCES BOTH THE RISK
OF GETTING CANCER, WHAT HAPPENS
AFTER YOU GET CANCER, YOUR
ABILITY TO RESPOND TO CANCER
TREATMENT, AND THE QUALITY OF
LIFE WHILE YOU'RE A CANCER
SURVIVOR.
AND SO WE CAN'T REALLY ESCAPE
THE REALITIES OF AGING, BUT IF
WE COULD UNDERSTAND THEM BETTER,
PERHAPS WE COULD MITIGATE THEM
AND PERHAPS THEY COULD INFORM US
ON PRECISION MEDICINE APPROACHES
TO MITIGATING EACH OF THESE
STEPS IN THE CANCER CARE
CONTINUUM.
I JUST WANT TO HIGHLIGHT THAT
THIS IS THE DIVISION THAT I'M
GREATLY HONORED TO LEAD.
THEY DO ALL THE WORK.
SI JUI JUST GETTO STAND UP HEREW
INTRODUCTORY COMMENTS BUT THIS
IS AN AMAZING GROUP OF PEOPLE
AND I WANT TO ACKNOWLEDGE AND
THANK THEM FOR ALL THE HARD WORK
AND DEDICATION TO THE EXTRAMURAL
COMMUNITY.
ARE SO THISO THIS IS THE AGE CUF
YOU WILL, NORMALIZED INCIDENCE
FOR COLORECTAL, LEUKEMIA, LUNG,
PANCREAS, BREAST, PROSTATE, AND
ALL CANCERS SHOWN AGAINST THE
AXIS OF AGE GROUP.
YOU CAN SEE THAT CANCER BELOW
THE AGES OF ESSENTIALLY 50 ARE
VERY RARE, AND THEN THERE'S A
VERY SHARP INCREASE IN THAT.
THE AGE PEAKS ARE VERY SIMILAR
FOR THESE DIFFERENT CANCERS THAT
HAVE VERY DIFFERENT ETIOLOGIES.
IF WE HAD CERVICAL CANCER ON
HERE, IT WOULD BE A DECADE
EARLIER, BECAUSE THE KEY
EXPOSURE OCCURS AT A MUCH
EARLIER AGE.
IT'S THE SEXUAL TRANSMISSION OF
HUMAN PAPILLOMAVIRUS AND THE
DEVELOPMENT OF CHRONIC
INFECTION.
BUT IT ALL HAS AN AGE COMPONENT,
PARTLY BECAUSE OF THE EFFECTS OF
AGE AND PARTLY BECAUSE IT TAKES
TIME TO GO FROM INITIATION OF
CANCER TO OVERT FRANK INVASIVE
CANCER.
THESE ARE SOME OF THE HALL MARKS
OF CANCER, AND AS YOU'LL SEE IN
THIS SLIDE AND THE NEXT SLIDE ON
AGING MORE GENERALLY, THEY SHARE
A FAIR NUMBER OF CHARACTERI
CHARACTERISTICS, SUSTAINING
PROLIFERATIVE SIGNALS, INVADING
GROWTH SUPPRESSORS, ACTIVATING
AIMING METASTASIS, INVADING
REPLICATED IMMORTALITY, INDUCING
ANGIOGENESIS AND RESISTING CELL
DEATH.
SOME OF THE EMERGING HALL MARKS
AND CHARACTERISTICS INCLUDE
DEREGULATION OF CELLULAR
ENERGETICS, AVOIDING IMMUNE
DESTRUCTION, TUMOR PROMOTING
INFLAMMATION.
LET'S GO TO THE NEXT SLIDE,
PLEASE.
SO THIS IS MORE GENERAL BUT YOU
CAN SATISFY THINGS LIKE CELLULAR
SENESCENCE AND DYSFUNCTION AND
DYSREGULATION, GENOMIC
INSTABILITY, TE TE SOME OF THE L
HALL MARKS OF AGING APPLY VERY
DIRECTLY TO THE DEVELOPMENT OF
CANCER AND THE MORBIDITY AND
MORTALITY RELATED TO CANCER.
I WILL ALSO SAY THAT MY OWN
THINKING ABOUT THE WORLD IN
IMMUNE SENESCENCE IS EMERGING OR
MY THOUGHTS ABOUT THIS IS AN
IMPORTANT PART THAT WE ARE
CONSTANTLY BOMBARDED WITH
INITIATION EXPOSURES AND
MUTATION AND YET CANCER
RELATIVELY SPEAKING IS RARE, AND
I'M A FIRM BELIEVER THAT THE
IMMUNE SYSTEM PLAYS AN IMPORTANT
ROLE IN SWEEPING THE SYSTEM FOR
EARLY CHANGES AND ELIMINATING
THEM BEFORE THEY BECOME CANCER.
SO CANCE CANCER IS A RARE OUTCOA
LIFETIME OF EXPOSURES, BUT SINCE
EVERYBODY IS EXPOSED TO AGING
AND OTHER FACTORS, THE
CUMULATIVE INCIDENCE OF CANCER
IS PROBABLY ON THE ORDER OF 40%.
THAT IS 40% OF PEOPLE GET CANCER
SOMETIME IN THEIR LIFE.
THE OTHER THING THAT'S
INTERESTED ABOUT THIS AND CANCER
IN GENERAL IS THE ROLE OF
INFLAMMATION.
OBVIOUSLY INFLAMMATION PLAYS AN
IMPORTANT ROLE IN ESTABLISHING
AN EARLY EFFECTOR IMMUNE
RESPONSE, BUT CHRONIC
INFLAMMATION IS AN IMMUNE
SUPPRESSIVE STATE THAT DOES NOT
ALLOW THAT SURVEILLANCE SYSTEM
TO FIND THAT EARLY INITIATION,
AND ALMOST CERTAINLY AS WE
UNDERSTAND WHAT'S NORMAL, WE'LL
FIND OUT, WE'LL HAVE A BETTER
SENSE OF WHAT'S ABNORMAL IN
TERMS OF INFLAMMATION AND IMMUNE
SURVEILLANCE.
THIS AFFECTS ALL STAGES OF LIFE.
INCLUDING THOSE WITH
DISABILITIES.
SO CAN WE DO?
HOW DO WE IMPROVE THE QUALITY OF
LIFE AND THAT INCLUDES BOTH
PREVENTING CANCER, CONTROLLING
CANCER, TREATING CANCER, AND
IMPROVING THE QUALITY OF LIFE OF
CANCER SURVIVORS.
I WOULD SAY THAT FUNDAMENTALLY,
WE DON'T KNOW WHAT NORMAL IS.
WE DON'T KNOW WHAT NORMAL
PHYSIOLOGY IS AND WE CERTAINLY
DON'T KNOW WHAT A NORMAL HEALTHY
IMMUNE SYSTEM IS IN THE GENERAL
POPULATION.
WE LACK UNDERSTANDING OF MUCH OF
THE STEPS IN EARLY
CARCINOGENESIS IN THE NATURAL
HISTORY OF CANCER, AND SO WE
NEED TO UNDERSTAND THE BIOLOGY
OF AGING, THE BU BIOLOGY OF CANR
AND HOW IT INFLUENCES THE
LATTER.
HOW THE FORMER INFLUENCES THE
LATTER.
THAT WILL ALLOW US TO DO A
BETTER JOB OF RISK
STRATIFICATION, DEVELOP
BIOMARKERS OF CLINICAL
SIGNIFICANCE FOR SCREENING BUT
ALSO GUIDING PRECISION
INTERCEPTION AND FOR CANCER
PREVENTION AND INTERCEPTION.
AND WITH THAT, I THINK THAT WAS
THE LAST SLIDE.
YES, THANK YOU SO VERY MUCH.
I WISH YOU A VERY SUCCESSFUL
MEETING AND LOOK FORWARD TO THE
OUTCOMES OF THIS WORKSHOP.
THANK YOU.
>> THANK YOU SO MUCH,
DR. CASTLE.
, FOR YOUR WORDS.
SO IT IS MY HONOR NOW TO
INTRODUCE DR. LUIGI FERRUCCI.
DR. FERRUCCI HAS BEEN THE
SCIENTIFIC DIRECTOR AT THE
NATIONAL INSTITUTE ON AGING
SINCE MAY 2011.
BUT HE JOINED NIA IN SEPTEMBR
SEPTEMBER 2ND.
HE MADE A MAJOR CONTRIBUTION TO
THE LITERATURE ON AGING AND THE
FIELD OF AGING.
SO HE'S ONE OF THE MOST CITED
SCIENTISTS AND OF COURSE HE'S
EXTREMELY BUSY.
EVEN NOW, DR. FERRUCCI IS
TRAVELING, BUT HE KINDLY
ACCEPTED TO BE RECORDED SO WE'RE
GOING TO LISTEN TO HIS RECORD
RECORDING, AND DR. FERRUCCI IS
ASKING TO EMAIL HIM ONCE AFTER
THE HE IS GOING TO RESPOND TO
YOUR QUESTIONS VIA EMAIL.
THANK YOU.
>> GOOD MORNING OR GOOD
AFTERNOON.
WHENEVER YOU'RE LISTENING TO
THIS PRESENTATION.
THIS IS A VERY EXCITING
OPPORTUNITY TO OPEN THIS TRULY
FANTASTIC SERIES OF CONTRIBUTION
THAT TALKS ABOUT THE INTERFACE
BETWEEN AGING AND CANCER.
MY NAME IS LUIGI FERRUCCI.
I AM THE SCIENTIFIC DIRECTOR OF
THE NATIO NATIONAL INSTITUTE ON.
I AM ENTHUSIASTIC ABOUT THE
STUDY OF AGING, AND I THINK THAT
SO MANY INTERACTION AND
SIMILARITY BETWEEN THE BIOLOGY
OF AGING AND THE BIOLOGY OF
CANCER THAT, YOU KNOW, COMMON
STUDY CAN REALLY OFFER US MORE
AND MORE OPPORTUNITY TO
UNDERSTAND EACH OTHER TOPIC.
I WANT TO START BY TELLING YOU
THAT, YOU KNOW, WHY THIS IS SO
IMPORTANT.
AGING OF THE POPULATION IS
COMPLETELY CHANGING NOW IN THE
FACE OF THE WORLD.
YOU KNOW, AND BEFORE WE DO THAT
BY TAKING A VERY, VERY WIDE
PERSPECTIVE, YOU SEE THAT CHINA
IN 2017 WAS THE MOST POPULOUS
COUNTRY IN THE WORLD.
BELIEVE IT OR NOT, IT'S NOW IN
THIRD PLACE.
FIRST AND SECOND WILL BE INDIA
AND NIGERIA.
NIGERIA CURRENTLY IS NUMBER 7.
AND THAT IS ALSO -- ALL THIS
TRANSFORMATION ARE DIRECTLY OR
INDIRECTLY INDUCED BY THE AGING
OF THE POPULATION.
THIS AGING THAT IS OCCURRING AT
THE POPULATION LEVEL WAS
MEANINGFULLY SUMMARIZED BY JUNE
LAPEL, TO STUDY AGING IN THIS
PAPER THAT WAS PUBLISHED AROUND
THE YEAR 2000.
WHAT JEAN DID WAS TO TAKE THE
COUNTRY THAT WERE THE OLDEST
COUNTRIES IN THE WORLD, AND THEN
PUT THEM -- CREATED A SCATTER
PLOT OF THE TIME AND LIFE
EXPECTANCY.
BELIEVE IT OR NOT, THIS TREND
WAS ENCOURAGING HER.
WHEN WE DO STUDIES, THIS ADDS AN
R SCARE OF 0.99.
WE NEVER SEE THIS TYPE OF
CORRELATION WHEN WE DO OUR
STUDY.
STUDIES.
AND AT THIS POINT, AROUND TH 19,
PEOPLE STARTED LOOKING AT THESE
DATA AND SAID, WELL, OF COURSE
IT'S BEEN INCREASING BUT IT'S
GOING TO SLOW DOWN.
AND SO THEY MADE PROJECTIONS
THAT REALLY SHOW IN THESE D THID
LINE AND, IN FACT, DID NOT.
IN FACT, THE AGING OF THE
POPULATION IS INCREASING.
THEIR DATA ARE LIMITED TO 2018,
BUT I ASSURE YOU THAT THE OLDER
POPULATION IS STILL GROWING.
OF COURSE, THIS IS A MATTER FOR
CELEBRATION.
WE SHOULD BE HAPPY THAT THE
HUMAN BEINGS HAVE BEEN ABLE TO
DO THIS, AND THEN TO GIVE US
MORE OF A HISTORICAL PERSPEC
PERSPECTIVE, IF YOU LOOK AT THE
LIFE EXPECTANCY I IN 1800, YOU N
SEE MOST OF THE COUNTRIES IN THE
WORLD, THE LIFE EXPECTANCY WAS
BELOW 40 YEARS.
AND WE SWITCHED TO 1950, YOU
KNOW, THERE WAS A SUBSTANTIAL
INCREASE IN LIFE EXPECTANCY,
ALTHOUGH IN AFRICA, STILL, MOST
OF THE COUNTRY HAD THE LIFE
EXPECTANCY BELOW 40 BUT IF WE
LOOK AT 2015, WHICH IS THE MOST
UP TO DATE MAP THAT I COULD FIND
ON THE INTERNET, YOU CAN SEE
THAT THERE IS NO RED AREA,
THERE'S NO EVEN ORANGE AREA.
AND OLDER POPULATIONS HAVE A
LIFE EXPECTANCY THAT IS ABOUT 60
YEARS, WITH, YOU KNOW, MANY OF
THEM IN EUROPE AND NORTH AMERICA
AND IN OCEANA THAT IS ABOUT 80
YEARS OF AGE.
HOWEVER, WHAT IS IMPORTANT TO
CONSIDER IS THAT THIS PHENOMENON
IS RECENT.
LOOK, YOU KNOW, BETWEEN 1770 AND
1870, FOR 100 YEARS, THE LIFE
EXPECTANCY DID NOT CHANGE AT
ALL.
AND THIS LACK OF CHANGE AND THE
CHANGE OCCURRED AROUND 1870, AND
WHEN IT OCCURRED, IT OCCURRED IN
MANY DIFFERENT COUNTRIES A
LITTLE BIT LATER IN ASIA AND IN
AFRICA, WITH A LINEAR PACE.
SO IT'S ALMOST PARALLEL FOR
EVERY COUNTRY.
NOW, THIS IS AN IMPORTANT
CONSIDERATION BECAUSE, YOU KNOW,
A CHANGE IN LIFE EXPECTANCY
OCCURS SO SUDDENLY, AND WE DEEM
THIS RELATIVELY SHORT TIME FRAME
CANNOT BE DUE TO EVOLUTION OR
TO, YOU KNOW, GENETIC CHANGE.
BUT SIMPLY IT DUE TO CHANGE IN
THE ENVIRONMENTAL CONDITION.
YOU KNOW, PROBABLY THE MOST
IMPORTANT CAUSE OF INCREASE IN
LIFE EXPECTANCY WAS THE SUDDEN
AVAILABILITY OF WATER AND FOOD
OR A LARGE PART OF THE
POPULATION, AND THE -- LATER ON
CERTAINLY ALSO THE AVAILABILITY
OF HEALTHCARE AND THE MODERN,
YOU KNOW, PROGRESS OF MEDICINE
HAS CONTRIBUTED TO THIS INCREASE
IN LIFE EXPECTANCY.
OF COURSE THERE'S SOMETHING THAT
IS ALSO NEGATIVE IN THIS PROC
PROCESS.
AND THE MOST IMPORTANT THING IS
THAT THE INCREASE IN LIFE IS NOT
ALL ACCOUNTED FOR BY THE GOOD
LIFE.
YOU KNOW, LIFE, I BELIEVE,
WITHOUT DISEASE AND DISABILITY.
ALSO THE LIFE THAT IS
CHARACTERIZED BY ILLNESS AND
DISABILITY HAS ALSO EXPANDED.
SO IN A WAY, YOU KNOW, WE HAVE
GAINED GOOD LIFE BUT WE ALSO
GAIN DISEASE AND DISABILITY.
AND ONE VERY DISCONCERTING
PHENOMENON HAS BEEN THE INCREASE
IN UNHEALTHY LIFE EXPECTANCY IS
PROPORTIONAL TO THE HEALTHCARE
EXPENDITURE.
THIS GRAPH JUST SHOWS DIFFERENT
COUNTRIES AND THE RELATIONSHIP
WITH THE CURRENT HEALTH
EXPENDITURE PER CAPITA, AND HERE
WITH SOME DISABILITY.
CAN YOU SEE THE LINEAR
RELATIONSHIP, IT'S VERY, VERY
EVIDENT.
WITH THE UNITED STATES ON TOP OF
EVERY OTHER COUNTRY.
SO HOW COME THE MORE WE SPEND,
THE MORE OUR LIFE WITH
DISABILITY INCREASES?
AND THAT'S A VERY, VERY
IMPORTANT QUESTION THAT I WILL
TRY TO ADDRESS IN MY FOLLOWING
SLIDES.
SO FIRST OF ALL, HOW DO WE GET
TO A DECLINE IN MORTALITY?
AND INCREASE IN LIFE EXPECTANCY?
SO FIRST OF ALL, HEART DISEASE
WAS PROBABLY THE MOST IMPORTANT
CAUSE, THERE WAS A DECLINE IN
HEART DISEASE RELATED MORTALITY,
THERE WAS A DECLINE IN CANCER,
DECLINE IN STROKE, AND DECLINING
CANCER SEEMS TO BE MINIMAL
WHEN -- I'LL SHOW YOU WHEN WE
RELATE THIS TO THE CHANGE IN THE
AGE COMPOSITION OF THE
POPULATION.
IT'S VERY, VERY SIGNIFICANTLY
STRONG.
BUT ON THE OTHER HAND, OTHER
DISEASE THAT ARE TYPICAL OF
INDIVIDUALS WITH MULTIPLE
CHRONIC DISEASE AND DISABILITY
SUCH AS ALZHEIMER'S DISEASE, --
AND DIABETES NOT ONLY DID NOT
DECLINE BUT TEND TO INCREASE
OVER TIME.
AND AS WAS MENTIONED TO YOU,
WHEN WE LOOK AT THE CANCER
THERE, OF COURSE THERE IS AN
INCREASING CANCER THERE THAT,
YOU KNOW, IS DUE TO THE
INCREASED NUMBER OF PEOPLE IN
THE POPULATION, AND THE FACT
THAT THE OLDEST PEOPLE WITH THE
HIGHEST INCIDENCE OF CANCER ARE
ALSO THOSE THAT HAVE EXPANDED
MORE THAN ANY OTHER PART OF THE
POPULATION.
BUT WHEN WE LOOK AT THE AGE --
CANCER RATE FOR THE ENTIRE
WORLD, THERE'S A SUBSTANTIAL
DECLINE, ESPECIALLY IN EUROPE
AND IN THE UNITED STATES.
THERE'S SOME ACCUMULATION OF
CHRONIC DISEASE WITH AGING.
SO IT IS VERY CLEAR THAT AGING
AFFECT THE -- TO CHRONIC DISEASE
AND IN DIFFERENT ETHNICITY, YOU
SEE THAT THE NUMBER OF CHRONIC
DISEASE, ESTIMATED IN THIS CASE,
THE NUMBER, THE PERCENTAGE OF
INDIVIDUAL THAT HAVE AT THE SAME
TIME TWO OR MORE CHRONIC DISEASE
INCREASED DRAMATICALLY WITH
AGING, AND THIS IS TRUE EITHER
WHEN YOU TAKE ONE CHRONIC
CONDITION, TWO CHRONIC
CONDITIONS, THREE CHRONIC
CONDITIONS OR FOUR CHRONIC
CONDITIONS.
SO THERE'S A PROBLEM THAT WITH
AGING, THE DISEASE PRESENT
THEMSELVES IN CLUSTERS.
AND WE RECENTLY SUBMITTED FOR
PUBLICATION SHOWING THAT THE
MORE DISEASE YOU HAVE, THE
HIGHEST IS THE PROBABILITY THAT
YOU WILL DEVELOP AN ADDITIONAL
DISEASE, INDEPENDENT OF WHAT
KIND OF DISEASE I'M TALKING
ABOUT, WHICH MEANS THAT WHEN YOU
HAVE ONE DISEASE, THE
PROBABILITY OF DEVELOPING
ANOTHER IS HIGHER, AND SO THERE
IS A PRECIPITOUS ACCUMULATION OF
PATHOLOGY WHEN THE HEALTH
EXPECTANCY IS TERMINATED.
I CAN SHOW YOU THIS SAME
PHENOMENON IN ANOTHER WAY.
HERE, FOR AN EXAMPLE, I SHOW YOU
THE LIFE EXPECTANCY THAT IS
INTERRUPTED BY A CLINICAL
THRESHOLD, -- AFFECT THIS
HYPOTHETICAL INDIVIDUAL.
NOW, WE CAN THINK THAT SOMEBODY
ELSE MAY HAVE A LONGER
DISEASE-FREE LIFE EXPECTANCY,
BUT THE SAME CLUSTER OF DISEASE
OCCURS AFTER THIS PERIOD.
AND SOMEBODY HAS A DISEASE-FREE
LIFE EXPECTANCY THAT IS SHORTER,
AGAIN, AFTER THIS DATA, WE SEE
EPIDEMIOLOGICALLY A FIRST DIRECT
RELATION OF CHRONIC DISEASE
DEVELOP CLINICAL IN CLUSTER.
AND THE REAL PROBLEM IS THAT
WHAT WE DO IS THAT WE INTERVENE
ONLY AT THE TIME WHEN DISEASE
BECOMES CLINICALLY EVIDENT.
SO IT DOESN'T REALLY MATTER HOW
GOOD IS OUR MEDICAL CARE,
BECAUSE AT THIS POINT, THE ONLY
THING THAT WE CAN DO IS INCREASE
THE PERIOD -- DISABILITY AND
INTERVENING HERE WILL CERTAINLY
NOT AFFECT THE PART OF LIFE THAT
WE WANT TO EXTEND AND WHERE WE
CAN ENJOY ALL THE OPPORTUNITY
THAT LIFE CAN OFFER.
DO WE HAVE AN ALTERNATIVE HERE?
WELL, THE ALTERNATIVE IS TO
THINK WHY WE DON'T SEE DISEASE
EMERGING UNDERNEATH THE
ACCUMULATION OF PATHOLOGY.
AND IN DISEASE-FREE INDIVIDUAL,
THE ACCUMULATION OF PATHOLOGY
OCCURS AT A DIFFERENT RATE.
THIS INDIVIDUAL, FOR EXAMPLE, IS
FASTER AND SLOWER, IF I COULD
MEASURE THE RATE OF ACCUMULATION
OF PATHOLOGY IN THESE
INDIVIDUALS BEFORE THE EMERGENCE
OF CHRONIC DISEASE, CERTAINLY MY
INTERVENTION COULD BE A LOT MORE
EFFECTIVE.
WELL, IN THE FIELD OF AGING, WE
THINK THESE ACCUMULATIONS,
GREATER ACCUMULATION OF
PATHOLOGY IS REALLY DUE TO THE
PACE OF AGING.
THE GENERAL SCIENCE PARADIGM
POSES THAT THE BIOLOGY OF AGING
AT THE ROOT OF MOST CHRONIC
DISEASE AND DISABILITY OCCUR IN
LATE LIFE.
TO MAKE THIS IN A CONTEXT OF --
WHEN CHRONIC DISEASE OCCUR, WE
HAVE A FANTASTIC ARMAMENTARIUM
OF MEDICAL INTERVENTIONS THAT
CAN REDUCE THE SYMPTOMS AND
INCREASE THE LIFE EXPECTANCY OF
THE INDIVIDUAL THAT SEEK -- I
PUT SOME EXAMPLES HERE.
BUT AN ALTERNATIVE WILL BE TO
SAY CAN I SLOW DOWN THE PACE OF
AGING, AND BY SLOWING DOWN THE
PACE OF AGING, REDUCE THE
INCIDENT OF ALL CHRONIC DISEASE
AND EXPAND THE PERIOD OF HEALTHY
LIFE EXPECTANCY.
WELL, THERE ARE TWO THINGS THAT
I NEED TO DEMONSTRATE FIRST.
FIRST OF ALL, CAN I SLOW DOWN
THE PACE OF AGING?
AND EVEN MORE IMPORTANT, CAN I
MEASURE THE PACE OF AGING TO
DEMONSTRATE THAT SEVERAL
INTERVENTIONS CAN ACTUALLY SLOW
DOWN.
NOW, FIRST OF ALL, IS THAT
POSSIBLE?
AM I TALKING SOMETHING THAT IS A
DREAM?
I THINK THERE ARE MANY EXAMPLES
THAT SUGGEST THAT EXPANDING
HEALTH EXPECTANCY POSSIBLE.
ONE OF THE EXAMPLES IS A STUDY
ON CENTENARIANS.
THIS IS A STUDY FROM TOM PERTS
PUBLISHED AROUND THE YEAR 2000,
AND WHAT HE DID, HE TOOK
CENTENARIANS.
AVERAGE AGE 102 YEARS, AND THEN
HE DID A RETROSPECTIVE ANALYSIS
OF THEIR FUNCTIONAL STATUS IN
THE PREVIOUS YEAR.
YEARS, TWO YEARSBEFORE, THREE YE
YEARS BEFORE AND 10 YEARS
BEFORE.
YOU CAN SEE FOR EXAMPLE THAT
THREE YEARS BEFORE, ALMOST 55%
OF THEM, COMPLETE NORMAL
FUNCTIONAL STATUS.
YOU HAVE TO COMPARE THIS WITH
WHAT HAPPENED IN THE GENERAL
POPULATION, WHERE ONLY 40% OF
PEOPLE THAT ARE 80 AND OLDER
HAVE FULL, COMPLETE LACK OF
DISABILITY.
SO THAT SUGGESTS THE POTENTIAL
IN OUR GENOME FOR EXPANSION OF
HEALTH EXPECTANCY IS THERE.
IT TURNS OUT MEASURING THE PACE
OF AGING, THIS IS AN EXPANDING
LINE OF RESEARCH IN AGING.
AND THEN THIS IS PROBABLY THE
MOST IMPORTANT EXAMPLE, THE
GENETIC CLOCK THAT WAS DEVELOPED
BY STEVE HORVATH SHOWING THE
METHYLATION IN -- NUMBER OF
CBGs IN THE GENOME CAN BE
SUMMARIZED IN A SCORE, AND THE
SCORE IS STRONGLY RELATED TO
CHRONOLOGICAL AGE.
AND I TELL PEOPLE, IF YOU SEE A
DROP OF BLOOD IN THE CORRIDOR,
YOU CAN ANALYZE THAT DROP OF
BLOOD AND TELL WHAT AGE WAS THE
PERSON THAT LOST THAT DROP OF
BLOOD.
10 YEARS AGO, THIS IDEA WAS
COMPLETELY PREPOSTEROUS.
WE HAD ABSOLUTELY NO WAY TO
ESTIMATE THAT.
NOT ONLY THIS, WE KNOW THAT WHEN
WE FACTOR OUT CHRONOLOGICAL AGE,
BIOLOGICAL AGE CALCULATED WITH
EPIGENETIC CLOCK IS ASSOCIATED
WITH THE DIMENSION THAT WE KNOW
AFFECTING GOOD HEALTH AND BAD
HEALTH.
FOR EXAMPLE, SLOWER EPIGENETIC
AGING IS ASSOCIATED WITH FISH
CONSUMPTION, FRUITS AND
VEGETABLE CONSUMPTION, HIGH
SOCIOECONOMIC STATUS, AND FASTER
EPIGENETIC AGING IS ASSOCIATED
WITH OBESITY, HIGH TRIGLYCERIDES
AND INFLAMMATION.
IN THIS CASE, WE USE -- TO
CALCULATE THE CHRONOLOGICAL AGE.
THE PROBLEM WITH THIS METHOD IS
THE FACT THAT WE TUNE THIS
BIOMARKER AGE PREDICTOR BY USING
CROSS-SECTIONAL STUDIES.
AND CROSS-SECTIONAL STUDIES ARE
HIGHLY BIASED.
SO I WANT TO EXPLAIN TO YOU WHY,
AND FOR EXAMPLE, IF YOU WANT TO
COMPARE PEOPLE BETWEEN THE AGE
OF 20, 100 AND FIVE, YOU CAN
COMPARE THEM AND SAY THAT THEIR
DIFFERENCE IN SYSTOLIC BLOOD
PRESSURE ARE HIGHER THAN THOSE
AGE 105.
THE PROBLEM IS THIS INDIVIDUAL
AT THE AGE OF 20 IS AT THE AGE
OF 20 IN THE YEAR 2000, WHEN THE
UNEMPLOYMENT RATE IN THE UNITED
STATES WAS BELOW 4%, WHICH IS
NOT ALMOST -- IN THE UNITED
STATES.
WHY THIS PERSON THAT IS 90 WAS
AGE AT THE TIME OF THE GREAT
DEPRESSION, THERE WAS NO
PUBLICLY AVAILABLE WATER OR FOOD
FOR EVERYBODY.
SO NOT ONLY THESE INDIVIDUALS
ARE DIFFERENT BECAUSE OF THEIR
AGE, BUT THEY'RE DIFFERENT
BECAUSE OF THEIR VERY DIFFERENT
PAST EXPERIENCE.
SO THE ONLY WAY TO OVERCOME THIS
IS TO MEASURE INDIVIDUALS OVER
TIME, AND THAT IS WHAT THE NEW
SCIENCE IS DOING, REALLY
SCRATCHING THE SURFACE OF WHAT
WAS HAPPENING, THIS IS THE
ATTEMPT FROM DANIEL BELSKY TO
SUMMARIZE THE RATE OF AGING BY
LOOKING AT NUMBER OF PHENOTYPIC
PARAMETERS, AND THIS IS AN
EXAMPLE OF THE PARAMETERS THAT
ARE BEING STUDIED IN THE
BALTIMORE LONGITUDINAL STUDY OF
AGING.
AND ONE OF THE COMPLEXITIES THAT
WE FACE IN THIS WORK IS THAT,
YOU KNOW, WHY THERE IS SOME
PARAMETER THAT ARE DECLINING
LINEARLY.
FOR EXAMPLE, YOU KNOW, THERE IS
INTERLEUKIN 6, CHANGING
LINEARLY, OTHER PARAMETERS ARE
NOT.
YOU KNOW, FOR EXAMPLE, SOME OF
THE -- RATIOS ARE REALLY
CHANGING CURVILINEAR WITH AGING,
SO -- PERSPECTIVE IS QUITE
COMPLEX.
I WANT TO FINISH TO YOU BY, YOU
KNOW, LOOKING AT WHAT IS THE
UNDERNEATH MODEL FOR THE SCIENCE
OF AGING, WHY WE HAVE THIS
INCREASE IN CHRONIC DISEASE.
IMAGINE THAT AT BIRTH, YOU HAVE
COMPLETE HOMEOSTATIC EQUILIB
EQUILIBRIUM -- THE INTEGRITY OF
MACRO MOLECULES IN CELLS THAT
ARE EVOLUTIONARILY PRESERVED TO
EITHER AVOID, PREVENT OR TO
COUNTER ACT THIS ACCUMULATION OF
DAMAGE.
THE PROBLEM IS THAT THE
RESILIENCE IS ALSO A BIOLOGICAL
IPHENOMENON THAT TEND TO DECLINE
WITH AGING, -- THE DAMAGE
ACCUMULATION BECOMES FASTER AND
FASTER WITH AGE.
AND SO WE DEVELOP CHRONIC
DISEASE BECAUSE OF LACK OF
RESILIENCE.
AND SOME OF THE RESILIENCE
STRATEGIES, WE'RE STARTING TO BE
ABLE TO MEASURE, ALTHOUGH WE'RE
NOT AT THE LEVEL OF CLINICAL
APPLICATION AND TRANSLATIONAL
APPLICATION.
AND THEN IN VERY, VERY OLD AGE,
WE HAVE THE FRAILTY SITUATION,
WHERE THE INDIVIDUAL HAS SO
LITTLE RESILIENCY THAT EVEN THE
CHALLENGE OF LIVING A NORMAL
LIFE CAN BE REALLY PROBLEMATIC M
ONE LAST MESSAGE I WANT TO GIVE
YOU IS THAT IN THE YOUNGER AGE,
BEFORE DISEASE ARE ACCUMULATING,
THERE'S A LOT WE CAN DO TO BRING
FORTH OUR RESILIENCE.
WE KNOW, FOR EXAMPLE, STUDY THAT
GOOD SLEEP, BEHAVIOR MAINTAINING
HEALTHY WEIGHT AND PHYSICAL
ACTIVITY INCREASED OUR
RESILIENCY, THEREFORE,
COUNTERACT THE EFFECT OF AGING
ON THE -- FOR CHRONIC DISEASE.
ON THE OTHER HAND, THE OTHER
EVENTS OF EXPOSURE THAT
ACCELERATE AGING, SO INCREASE
THE -- TO CHRONIC DISEASE, THE
SCIENCE THAT IS MOVING FAST AND
MORE AND MORE WILL COME IN THE
FEWER TOUR.
FUTURE.
THANK YOU VERY MUCH FOR YOUR
ATTENTION, AND SINCE THIS IS
VIRTUAL, I WILL NOT BE ABLE TO
RESPOND DIRECTLY TO YOUR
QUESTION, BUT I INVITE YOU TO
EMAIL ME, AND I'LL BE HAPPY TO
ADDRESS ANY QUESTIONS YOU HAVE.
>> SO WE WANT TO THANK YOU,
DR. FERRUCCI.
I THINK YOU SEE HIS EMAIL IN THE
CHAT, SO IF THERE ARE QUESTIONS
FOR HIM, YOU WILL NOT BE ABLE
TO -- HE WILL NOT BE ABLE TO
ANSWER LIVE, BUT HE IS --
>> WE WANT TO THANK YOU,
DR. FERRUCCI.
I THINK --
>> I'M HEARING AN ECHO
UNFORTUNATELY IN MY ZOOM.
>> ZORINA, DO YOU HAVE A
INTERNET WINDOW OPEN?
>> NO, I ONLY HAVE THIS ONE.
>> YOU DON'T HAVE ANY OTHER
WINDOWS OPEN?
>> NO.
>> OKAY.
>> IF YOU DO, WHATEVER ELSE YOU
HAVE OPEN, YOU HAVE TO CLOSE IT.
>> OKAY.
IT WENT AWAY.
>> ALL RIGHT.
THANK YOU SO MUCH.
I HOPE THAT YOU DIDN'T HAVE
TROUBLE HEARING DR. FERRUCCI'S
TALK OR ME.
AND I APOLOGIZE FOR THAT.
I WOULD LIKE TO INTRODUCE THE
NEXT DISTINGUISHED KEYNOTE
SPEAKER WE HAVE TODAY.
DR. MICHAEL SNYDER, WHO IS TRULY
MASTERING THE ART OF
MULTI-OMICS.
HE IS CURRENTLY AND HAS BEEN
SINCE 2009, I BELIEVE, THE
DIRECTOR OF STANFORD DEPARTMENT
OF GENETICS AND PERSONALIZED
MEDICINE, AND OF NOTE, SINCE HIS
LEADERSHIP, STANFORD HAS BEEN
RANKED AS NUMBER ONE IN
PERSONALIZED MEDICINE AND
GENETICS FOR THE PAST DECADE.
DR. SNYDER IS NOT ONLY A VERY
TALENTED ACADEMIC RESEARCHER BUT
ALSO AN ENTREPRENEUR.
HE HAS SIGNIFICANT CONTRIBUTION
TO STARTING OR ADVISING A NUMBER
OF COMPANIES, SO HE CAN REALLY
GIVE US A VERY INTERESTING
COMPREHENSIVE VIEW FROM IDEA TO
POTENTIALLY IMPLEMENTATION OF
LONGITUDAL STUDIES.
WE ARE VERY MUCH LOOKING FORWARD
TO YOUR KEYNOTE AND THANK YOU
FOR LOGGING IN EARLY IN
CALIFORNIA.
THANK YOU.
>> OKAY, GREAT.
IT IS A PLEASURE TO BE HERE.
FLEUR SOMSOMEONE NEEDS TO STOP ,
ACTUALLY.
NOW IT'S WORKING.
GREAT.
HOPEFULLY YOU CAN SEE THIS.
SO IT IS A PLEASURE TO BE HERE,
AND I THINK MY TALK FEEDS NICELY
FROM WHAT LUIGI JUST PRESENTED.
SO I WILL TALK ABOUT USING NEW
DATA AND SOME OF THE NEW
TECHNOLOGIES WE'RE USING FOR
MONITORING HEALTH, AND I THINK
TRYING TO KEEP PEOPLE HEALTHY
AND EXTENDING THEIR HEALTHSPAN.
SO I LIKE TO START WITH THE FACT
THAT OUR HEALTHCARE SYSTEM IS
BROKEN, AS YOU MAY HAVE SEEN IN
THE CHAT.
WE REALLY DO TEND -- AS LUIGI
SAID, WE TEND TO EXECUTE SICK
CARE RATHER THAN HEALTHCARE, AND
EVEN WHEN WE DO TRY TO DO
HEALTHCARE, IT'S A VERY ARCHAIC
PROCESS IF YOU THINK ABOUT IT.
WE TYPICALLY GET IN A CAR, A BUS
OR SOMETHING AT A VERY
INCONVENIENT TIME TO TRAVEL TO A
PHYSICIAN.
WE ARRIVE AT A DOCTOR'S OFFICE
THAT PRETTY MUCH LOOKS THE SAME
AS IT'S LOOKED FOR THE LAST 40
YEARS.
WHEN YOU'RE THERE, THEY'LL STICK
IN A NEEDLE AND PULL OUT A LOT
OF BLOOD.
FROM THAT BLOOD AND THE TIME
YOU'RE THERE, THEY ACTUALLY
DON'T MAKE VERY MEASUREMENTS,
AND PERHAPS MOST IMPORTANTLY,
THEY'LL MAKE DECISIONS ABOUT
YOUR HEALTH BASED ON POPULATION
AVERAGES.
WE BELIEVE EVERY ONE OF THESE
STEPS CAN BE IMPROVED AND THAT'S
WHAT WE'VE BEEN WORKING ON AND
TRYING TO DO A LOT TO KEEP
PEOPLE HEALTHY.
WE DO A LOT IN NUTRITION AND
SUCH AS WELL WHICH I WON'T TALK
TODAY, AND LIFESTYLE, MAYBE
WE'LL TOUCH ON THAT.
BUT ANYWAY JUST TO ILLUSTRATE
THIS LAST POINT ABOUT POPULATION
AVERAGES BEING MAYBE NOT THE
BEST WAY TO THINK ABOUT PEOPLE,
IS SOMETHING YOU'VE BEEN TOLD
SINCE YOU'RE LITTLE IS THAT YOUR
TEMPERATURE WHEN YOU PUT A
THERMOMETER IN YOUR MOUTH IS
98.6.
IF YOU ACTUALLY LOOK AT THE DATA
THAT ARE OUT THERE, FIRST THAT
NUMBER IS WRONG, IT TENDS TO BE
MORE LIKE 97.5.
ONE BIG, BIG STUDY JUST GOT
PUBLISHED THAT SAYS IT'S 97.7.
BUT THE MORE IMPORTANT POINT IS
THERE'S THAT A SPREAD.
A SPREAD.
WHAT THIS MEANS IN TODAY'S
WORLD, IF YOUR NORMAL AVERAGE
HEALTHY BASELINE IS 94.6, YOU GO
TO A PHYSICIAN TODAY, THEY
MEASURE YOU AT 98.6, THEY'LL
TELL YOU, YOU KNOW, YOU'RE
NORMAL, YOU'RE HEALTHY,
EVERYTHING IS FINE BUT IF YOU'RE
4 DEGREES OVER YOUR BASELINE,
YOU'RE NOT FINE.
SO WE THINK THIS IS A BIG PART,
KNOWING WHAT YOUR HEALTHY
BASELINE IS SO IT CAN DETECT
SHIFTS FROM THAT AND DETECT
ILLNESS AT THE EARLIEST POSSIBLE
TIME.
SO YOUR HEALTH YOU PROBABLY KNOW
IS INFLUENCED BY MANY THINGS, BY
YOUR DNA, YOUR GENOME, BUT WHEN
IT COMES TO LONGEVITY, YOU MAY
KNOW THAT THE NUMBERS RANGE
QUITE A BIT, BUT IT'S ESTIMATED
ABOUT 16% OF LIFESPAN IS DUE TO
HERITABILITY, THE REST DUE TO
GENETICS.
THE REST IS PROBABLY
ENVIRONMENTAL FACTORS.
AND SO EXERCISE, FOOD, STRESS,
ENVIRONMENTAL EXPOSURES, WE ALL
KNOW THESE IMPACT YOUR HEALTH,
BUT WE'RE IN A WORLD NOW WHERE
WE CAN QUANTIFY SOME PRETTY WELL
BY ACTIVITY, OTHERS LIKE FOOD,
WE'RE WORKING A LOT HERE IN THIS
SPACE, I WON'T SPEND TIME
TALKING ABOUT THIS, MEASURING
ENVIRONMENT EXPOSURES.
SO WE SHOULD BE ABLE TO MEASURE
THESE THINGS AND ACTUALLY BETTER
UNDERSTAND HOW THEY IMPACT YOUR
HEALTH.
BUT EVEN IF WE DON'T MEASURE
THEM DIRECTLY, WE CAN MEASURE
THEIR EFFECTS BY ACTUALLY USING
DEEP DATA PROFILES ON PEOPLE.
AND THIS IS SOMETHING WE SET UP
A NUMBER OF YEARS AGO, WHAT WE
CALL PERSONAL OMICS PROFILING
WHERE WE'LL SEE PEOPLE'S GENOME
AND FROM THEIR BLOOD WE'LL
MEASURE THEIR METH LOAN,
TRANSCRIPTOME, PROTEOME OUT OF
THEIR IMMUNE CELLS, WE'LL ALSO
MEASURE PLASMA, THEIR PROTEOME
CYTOKINES, MICROBIOME, WE
ACTUALLY JUST FINISHED A STUDY
OF FOUR DIFFERENT MICROBIOMES,
QUITE INTERESTING.
THIS IS CLINICAL TESTS,
QUESTIONNAIRES, STRESS ECHOES,
GLUCOSE CONTROL, STRESS
MEASUREMENTS AND ABOUT 10 YEARS
AGO, FITNESS TRACKERS.
WE SAMPLE PEOPLE EVERY THREE
MONTHS WHILE THEY'RE HEALTHY,
AND IF AN ADVERSE EVENT COMES
ALONG LIKE VIRAL INFECTION,
WE'LL TAKE FIVE TO SEVEN
ADDITIONAL SAMPLINGS.
WE'VE BEEN RUNNING THIS ON A
COHORT, IT STARTED OUT AS A
PILOT GROUP BUT THE DATA GOT
RICHER AND RICHER, 109 PEOPLE.
WE'VE BEEN PROFILING THEM FOR
OVER 10 YEARS NOW, ONE OF THEM,
WE'VE BEEN DOING ME FOR ABOUT
13 1/2 YEARS, MOST ABOUT 10 1/2
YEARS.
SOME ARE DROPPING OFF OR ADDING
NEW.
YOU MIGHT SAY WHY ARE WE DOING
THIS?
WE'RE TRYING TO UNDERSTAND WHAT
IT MEANS TO BE HEALTHY, HOW DOES
THAT CHANGE OVER TIME, WHICH
RELATES NICELY TO AGING AND I'LL
TELL YOU ABOUT THAT A LITTLE
BIT.
YOU KNOW, HOW DOES IT VARY, HOW
DO PEOPLE'S PATTERNS VARY FROM
ONE PERSON TO THE NEXT.
WHAT HAPPENS AT THE TIME OF
ILLNESS LIKE A VIRAL INFECTION,
AND THEN RELEVANT FOR, I THINK,
THIS DISCUSSION, CAN WE USE
THESE ADVANCED TECHNOLOGIES LIKE
GENOME SEQUENCING, WEARABLES, ET
CETERA, TO BETTER MANAGE
PEOPLE'S HEALTH.
AND I CAN TELL YOU WHEN WE
STARTED THIS PROJECT, FUZZES IN
PARTICUPHYSICIANSIN PARTICULAR S
SEQUENCING PEOPLE'S GENOMES.
ACTUALLY NOW PEOPLE ARE WARMING
UP TO IT BETTER, WE'RE STILL NOT
THERE YET.
ANYWAY, CAN YOU USE THESE
ADVANCED TECHNOLOGIES FOR HEALTH
TRACKING?
THE ANSWER IS YES.
JUST FROM THE FIRST 3 1/2 YEARS,
WE HAD 49 PLAY J 49 MAJOR HEALTH
DISCOVERIES, AND IT SPANNED A
WIDE RANGE OF AREAS.
METABOLIC DISEASE,
CARDIOVASCULAR DISEASE,
INFECTIOUS, ET CETERA, ET
CETERA.
SO IT'S PRETTY BROAD AND SOME OF
THESE TURNED OUT TO BE A BIG
DEAL.
WE CAUGHT SOME LYMPHOMA, THAT
CAN CONVERT TO AGGRESSIVE
CANCERS.
I SHOULD POINT OUT THESE ARE ALL
FOUND PRESYMPTOMATICALLY.
SO NO SYMPTOMS.
TWO PEOPLE HAD SERIOUS HEART
ISSUES, ONE PICKED UP BY GENE
SEQUENCING, ANOTHER BY
VARIABLES.
NO ONE TECHNOLOGY FOUND THESE
THINGS.
SOMETIMES IT WAS GENOME
SEQUENCING THAT MADE A
PREDICTION THAT WE FOUND.
SOMETIMES WEARABLES.
LYMPHOMA WAS PICKED UP BY
IMAGING AND SOME BIOCHEMICAL
MARKERS THAT WERE OFF.
THESE ARE BIOCHEMICAL MARKERS.
SO THE WAY WE LIKE TO THINK
ABOUT THIS, WE'RE TAKING A
PRETTY COMPLETE PICTURE ON
PEOPLE, SO IF YOUR HEALTH IS A
THOUSAND PIECE JIGSAW PUZZLE,
WE'RE TRYING TO MEASURE 5- OR
600 PIECES TO TRY TO GET A
CLEARER PICTURE VERSUS FIVE OR
SIX WE MEASURE TODAY.
AGAIN BECAUSE OF THAT, YOU CAN
FIND THESE THINGS
PRESYMPTOMATICALLY.
ONE OF THE OTHER THINGS WE
LEARNED WAS THAT AS WE'RE
TRACKING PEOPLE OVER TIME, WE
CAN ACTUALLY SEE HOW THEY AGE.
AND IT TURNS OUT EVERYBODY AGES
DIFFERENTLY.
SO FOR EXAMPLE, FROM THIS
PERSON, JUST BY MEASURING PLASMA
COMPONENTS, AND MICROBIOME,
THEIR TOP PATHWAY FOR THIS
PERSON IS THEIR CARDIAC --
MEANING THEIR CARDIOAGE.
WE LATER LEARNED THEY'RE STAGE
II HYPERTENSIVE, WHICH SORT OF
MAKES SENSE.
THIS PERSON, TIP KEL AGER,
COAGULATION AND -- WE THINK WE
NEED AS FEW AS FIVE MEASUREMENTS
WITHIN TWO YEARS WE CAN TELL YOU
HOW YOU'RE AGING.
SO WE HAD 43 PEOPLE WITH ENOUGH
DATA TO ACTUALLY SEE HOW THEY
WERE AGING, AND AS THEY SAY,
EVERYBODY AGES DIFFERENTLY, WE
CLASSIFIED PEOPLE INTO AGER
TYPES.
SO THERE'S GOING TO BE MANY AGER
TYPES, WE ONLY STATISTICALLY
EMPOWER THE MAIN FOUR, KIDNEY,
LIVER, METABOLIC AND IMMUNE, SO
EACH COLUMN IS A DIFFERENT
PERSON, EACH ROW IS AN AGER TIME
AND THE PEOPLE HERE ARE AGING IN
ALL FOUR CATEGORIES.
THIS PERSON IS AGING IN THREE OF
THE FOUR, NOT MUCH OF A KIDNEY
AGER BUT AGING IN THE OTHERS,
I'M SOMEWHERE IN THE MIDDLE, I'M
NOT MUCH OF AN IMMUNE AGER BUT I
AGE IN THE OTHER CATEGORIES.
MAKES SENSE AS I'M TYPE~2
DIABETES IK.
KIDNEY, KIDNEY AND METABOLIC AND
SO ON, SO WE CAN SEE HOW THEY'RE
AGING.
AND THE OTHER THING I'LL TELL
YOU, AND I DON'T HAVE A SLIDE
TOGETHER THAT PICKS UP ON
LUIGI'S POINT, AGE SOMETHING NOT
LINEAR.
WE FIND THERE ARE TWO MAJOR
PERIODS, ONE IN THIS 40, 45
RANGE WHERE THERE'S BIG
BIOCHEMICAL SHIFTS.
AND THE OTHER, KNOWN FROM THE
DISEASE PLOTS, PEOPLE IN THEIR
MID 60s, YOU CAN SEE
BIOCHEMICALLY THEY SHIFT QUITE A
BIT AS WELL.
ONE OF THE OTHER THINGS WE FOUND
IS THAT WE THINK THAT THESE AGER
TYPES ARE CLINICALLY ACTIONABLE
BECAUSE THEY'RE ACTUALLY
MARKERS, CLINICAL MARKERS
ASSOCIATED WITH THEM.
SO THIS IS JUST SHOWING
EXAMPLES, THIS IS, FOR EXAMPLE,
TRACKING ONE OF THESE MARKERS,
HEMOGLOBIN A1C, A MARKER OF
DIABETES, AND WHAT YOU'LL NOTICE
IS A GROUP AS A WHOLE GOES UP
OVER TIME, THAT'S EXPECTED.
EACH BAR IS A DIFFERENT PERSON.
AND SO MANY DO GO UP.
DARK BAR MEANS IT'S
STATISTICALLY SIGNIFICANT BUT
SOME PEOPLE ACTUALLY REVERSE
THIS.
IN THIS CASE, IT'S PRETTY EASY,
IT'S OBVIOUS WHY.
TWO PEOPLE WENT ON A DIET, TWO
PEOPLE LOST WEIGHT, ONE PERSON
STARTED EXERCISING SO THEY WERE
ACTUALLY ABLE TO REVERSE THESE
MARKERS THAT WE THINK ALTER
THEIR AGER TYPE.
SO I THINK THIS INFORMATION IS
ACTIONABLE.
CREATININE IS ANOTHER
INTERESTING MARKER.
THE GROUP AS A WHOLE GOES UP BUT
MANY PEOPLE WENT DOWN, ACTUALLY
IMPROVED THEIR KR CREATININE
LEVELS.
ONE QUESTION I GET A LOT IS HOW
ARE YOU GOING TO SCALE THIS.
WHAT I SHOWED YOU IS A RESEARCH
STUDY, COST MILLIONS AND
MILLIONS OF DOLLARS.
BUT I'M IN SILICON VALLEY SO THE
WAY WE SCALE THESE THINGS AND
START UP COMPANIES, ACADEMICS
ARE PRETTY GOOD AT DISCOVERY AND
PROOF OF PRINCIPLE, WE'RE NOT
VERY GOOD AT SCALING.
SO MEDICAL VERSION, DOESN'T DO
RNA SEQ AND ALL THE DIFFERENT
THINGS THEY SHOW BUT DOES A LOT
OF THE ACTIONABLE INFORMATION.
AND ON TOP OF THAT, THEY ADDED
WHOLE BODY MRI.
ANY PHYSICIAN TODAY WILL TELL
YOU DON'T DO WHOLE BODY MRI, AND
THE REASON IS, YOU'LL HAVE
LESIONS.
MEN HAVE NODULES IN THEIR
PROSTATE, WOMEN IN THEIR OVARY.
100% OF THE TIME.
JUST DEPENDS HOW FINE YOU LOOK.
AND MY -- WILL TELL YOU YOU
ABSOLUTELY SHOULD DO WHOLE BODY
MRI.
THE ISSUE ISN'T DO YOU HAVE
LESIONS, THE ISSUE IS DO YOU
HAVE ANY GROWING LESIONS.
THE WAY YOU FIND OUT IS BY THESE
LONGITUDAL MEASUREMENTS, YOU CAN
SEE IF THINGS ARE SHIFTING.
SO IT TURNS OUT, SAME THING FROM
THE FIRST 100-PLUS PEOPLE.
THE MEDIAN AGE IS 50, OUR CASE,
53.4, ALSO IN THE 50s.
YOU CAN SEE THE Q BIO --
CARDIOVASCULAR DISEASE, EVEN
CAUGHT EARLY PANCREATIC CANCER
THROUGH THE EARLY PROFILING.
THESE ARE ALL FOUND
PRESYMPTOMATICALLY.
THESE DETAILED MEASUREMENTS DO
REVEAL THINGS EARLY, AND THEY
DON'T TURN PEOPLE INTO
HYPOCHONDRIACS SO WE THINK THIS
KIND OF CLOSE MONITORING IS
VERY, VERY IMPORTANT.
NOW, ONE THING THAT WE'VE ALSO
WORKED HARD ON THESE DAYS IS TO
TRY TO DO MORE FREQUENT AND
CONTINUOUS MONITORING, AND SO WE
ALSO LIKE THE IDEA THAT YOU
SHOULDN'T ALWAYS HAVE TO GO TO A
DOCTOR TO GET HEALTH
MEASUREMENTS.
SO WE'VE BEEN SO CALLED
AMAZONNIZEING HEALTHCARE.
THE REASON -- TWO APPROACHES,
ONE IS WEARABLES, ONE IS MICRO
SAMPLES, TAKE A DROP OF BLOOD
AND MAIL THEM IN.
OURS DOES WORK.
SO WEARABLES YOU MAY KNOW ARE
BECOMING VERY UBIQUITOUS.
20% OF THE U.S. WEARS THESE AND
THEY'RE POWERFUL BECAUSE THEY
MEASURE YOU 24/7.
WE GOT INVOLVED WHEN THESE FIRST
CAME OUT AS FITNESS TRACKERS SO
WE PUT THEM ON OUR COHORT.
I'M A BIG FAN.
IF YOU CAN SEE IF YOU LOOK UP,
I'VE GOT FOUR SMART WATCHES, A
GLUCOSE RING -- ALMOST RIGHT
AWAY WE DISCOVER YOU CAN TELL
PEOPLE ARE GETTING AN INFECTION,
IF YOU WILL, FROM A SIMPLE SMART
WATCH.
IN THIS CASE, SMART WATCH AND
PULSE OX.
SO IT ACTUALLY IS WHEN I
DISCOVERED MY LYME DISEASE OF
ALL THINGS, WHILE FLYING TO
NORWAY, BOTTOM LINE IS, MY BLOOD
OXYGEN DROPPED ABNORMALLY LOW ON
THIS AIRLINE, NEVER CAME BACK TO
NORMAL.
MY HEART RATE ON MY SMART WATCH
WENT UP, I LATER LEARNED MY SKN
TEMPERATURE WENT UP AS WELL.
THIS IS ALL PRESYMPTOMATICALLY.
SO THESE THINGS CHANGED, THEN I
GOT A FEVER OFF AND ON, IT WAS A
TRICKY.
I WENT TO A DOCTOR IN NORWAY.
HE RECOMMENDED PENICILLIN, I
SAID NO, I NEED DOXYCYCLINE
WHICH IS WHAT'S USED FOR LYME.
A LITTLE TENSE, HE GAVE IN, FAVE
TO ME, CLEARED IT RIGHT UP AND
THEN TWO WEEKS LATER, SURE
ENOUGH, I WAS LYME-POSITIVE.
I THOUGHT IT WAS PROBABLY LYME
BECAUSE IT WAS TWO WEEKS AFTER.
I HAD BEEN IN RURAL
MASSACHUSETTS WHERE 55% OF
TICKS -- ANYWAY BOTTOM LINE IS
WE CAN FIRST TELL WHEN I GOT
LYME FROM A SIMPLE SMART WATCH
AND PULSE OX, AND THEN WE WENT
ON TO WRITE ALGORITHM, I WON'T
SHOW YOU THIS, IT TURNS OUT FOR
EVERY TIME I HAD A RESPIRATORY
VIRAL INFECTION, EVEN ONE TIME I
WAS ASYMPTOMATICALLY -- MY CR
PSM WAS HIGH, EVERY SINGLE TIME,
WE CAN PICK IT UP WITH A SMART
WATCH BECAUSE OF THE RESTING
HEART RATE JUMPED UP.
AND WE WROTE ALGORITHMS THAT
WORKED FOR FINDING ALL THOSE FOR
ME AND THEN ACTUALLY OTHERS IN
THE COHORT.
ALL RETROSPECTIVE.
WE PUBLISHED THIS IN ABOUT 2017.
SO THEN ALONG COMES COVID, AND
OF COURSE IN 2020, WE'RE IN OUR
NEXT WAVE RIGHT NOW, YOU MAY
KNOW, SO WE WANTED TO SEE IF
SMART WATCHES COULD BE USED FOR
TRACKING THAT, DETECTING COVID.
SO WHEN THE INFECTION FIRST
BROKE OUT, WE QUICKLY PARTNERED
WITH FITBIT, GOT 5300 PEOPLE
ENROLLED.
HERE IS RESTING HEART RATE, THIS
IS OUR VERY, VERY FIRST CASE.
WE HAD 32 PEOPLE WHO HAD COVID
WHILE WEARING THEIR FITBIT, AND
THEY HAD A DIAGNOSIS DAY AND A
SYMPTOM DAY.
THIS WAS, AS I SAY, OUR FIRST
EXAMPLE.
THIS WAS RESTING HEART RATE, A
STANDARD DEVIATION PLOT.
THIS IS BASICALLY THEIR
DIAGNOSIS DAY IN PURPLE, THEIR
SYMPTOM DAY IN RED, AND YOU CAN
SEE THE RESTING HEART RATE
JUMPED UP 9 1/2 DAYS PRIOR TO
SYMPTOM ONSET.
VERY, VERY CLEAR SIGNAL.
WE WROTE SOME ALGORITHMS THAT
TRACK YOUR CIRCADIAN RHYTHM AND
LOOK FOR JUMP UP IN SIGNAL.
IT WORKED, 80% OF THE TIME WE
COULD TELL IF PEOPLE WERE
GETTING COVID AT OR BEFORE
SYMPTOMS AND THE MEDIAN IS
4 DAYS, TURNS OUT COVID HAS A
LONG PRESYMPTOMATIC PERIOD.
BY THE WAY, YOU CAN SIGN UP FOR
A STUDY RIGHT HERE.
WE'RE TRYING TO GET MORE DATA IN
SO WE CAN GET BETTER
PREDICTIONS.
SO THEN WE WENT ON TO BUILD A
REALTIME DETECTION SYSTEM, A
CLOUD-BASED SYSTEM THAT CAN
HANDLE MILLIONS OF PEOPLE.
NOW, WE HAVE ABOUT -- SOMETHING
LIKE 10 TO 20,000 PEOPLE
ENROLLED RIGHT NOW.
THE WAY THIS WORKS IS IT'S
TRACKING YOUR RESTING HEART
RATE, A FEW OTHER THINGS IN
REALTIME, AND IT HAS A WEIGHTED
SYSTEM.
AND IN A CIRCADIAN FASHION SO
THAT IF YOUR HEART RATE AND
THESE OTHER PARAMETERS ARE UP
HIGH ENOUGH FOR A LONG ENOUGH
PERIOD OF TIME, IT SETS OFF A
RED ALERT.
YOU HAVE TO CLICK ON IT, SOON
YOU WON'T HAVE TO DO THAT.
AND HERE IS BASICALLY ONE OF OUR
VERY FIRST CASES.
AGAIN, THIS IS WHEN THIS
PERSON'S SYMPTOMS FIRST
APPEARED, THEY'RE DIAGNOSED THE
NEXT DAY, BUT THEY WERE GETTING
RED ALERTS FOR THREE DAYS PRIOR
TO SYMPTOM ONSET.
SO THIS WORKS, SAME NUMBER, 80%
OF THE TIME IT WORKS ON APPLE,
FITBIT, SHOULD WORK ON ALL
DEVICES.
IT EVEN WORKS ON ASYMPTOMATIC
CASES.
HERE'S A DIAGNOSIS DAY, BUT YOU
CAN SEE THIS PERSON IS GETTING
RED ALERTS FOR ABOUT TWO WEEKS
PRIOR TO DIAGNOSIS.
NO SYMPTOMS IN THIS CASE.
IT ALSO TURNS OUT IT'S MOSTLY A
STRESS DETECTOR, MEANING IT'S
NOT SPECIFIC FOR COVID, AND IN
FACT, THE NUMBER ONE TRIGGER OF
RED ALERTS WITH PEOPLE WHO
HAVEN'T HAD COVID TURNS OUT TO
BE WORKPLACE STRESS SO IT'S ALSO
MONITORING YOUR MENTAL HEALTH
STRESS.
OTHER THINGS WILL TRIGGER THE
ALERT, INTENSE EXERCISE.
YOU MAY KNOW IF YOU RUN A
MARATHON, YOUR HEART RATE WILL
BE UP FOR A FEW DAYS, SETS OFF
ALERTS, INFECTIONS, EVEN
MYCOPLASMA, WE CAN PICK UP AS
WELL.
SO WE THINK THIS IS MORE
SENSITIVE THAN AN ANTIGEN TEST.
THIS IS DATA FROM MY DATA BUT
WE'VE SHOWN IT FOR OTHERS NOW
TOO, WHERE WHEN I FIRST HAD A
LITTLE BIT OF CONGESTION, WASN'T
SURE IF IT WAS ALLERGIES OR WHAT
WAS GOING ON, GOT AN ANTIGEN
TEST, I WAS NE NEGATIVE BUT MY
SMART WATCH SAID POSITIVE, SURE
ENOUGH THE NEXT DAY I CAME UP
POSITIVE.
I WAS IN NEW YORK CITY, I HAD TO
SPEND A WHOLE WEEK IN A HOTEL
ROOM, ALL BECAUSE I LISTENED TO
THIS, WHICH I SHOULDN'T HAVE
DONE, I SHOULD HAVE LISTENED TO
THIS.
SO IT CAN GIVE YOU EARLY ALERTS
AND MAYBE TELL YOU NOT TO GO OUT
AND PARTY AND THINGS LIKE THAT.
WE THINK THIS IS THE TIP OF THE
ICEBERG.
THESE SMART WATCHES CAN MEASURE
MANY, MANY THINGS ON YOU AS YOU
MAY KNOW.
SO WE'VE WRITTEN MACHINE
LEARNING ALGORITHMS TO BE ABLE
TO PICK UP THOSE RED BLOOD CELL
COUNT, HEMOGLOBIN, ET CETERA.
THESE AREN'T CLINICAL GRADE
MEASUREMENTS BUT THEY'RE GOOD
ENOUGH TO SEE IF THINGS SHIFT.
EVEN HEMOGLOBIN A1C AND FASTING
GLUCOSE CAN GET PICKED UP WITH A
SMART WATCH USING SOME OF THESE
ADVANCED ALGORITHMS.
THE OTHER AREA WE'RE PUSHING
VERY, VERY HARD WHICH I THINK IS
A BIG DEAL FOR EXTENDING
HEALTHSPAN IS GLUCOSE
MONITORING.
SO THESE ARE BEING USED AT THE
TIME FOR INSULIN-DEPENDENT TYPE
1 AND TYPE 2 DIABETICS.
WE STARTED PUTTING THEM ON
NORMAL AND PREDIABETICS.
AND WOULDN'T YOU KNOW THAT SOME
NORMAL PEOPLE ARE PRETTY NORMAL,
MEANING THEY DON'T SPIKE THEIR
GLUCOSE MUCH, BUT THEN A LOT OF
PEOPLE ARE MODERATE SPIKERS AND
EVEN A FEW PEOPLE ARE SEVERE
SPIKERS, WHEN TESTED NORMAL BY
HEMOGLOBIN A1C AND OTHER
MEASURES.
WE THINK THERE'S OTHER FORMS OF
GLUCODYSREGULATION THAT STANDARD
MEASURES MISS.
SO WE WROTE ALGORITHMS THAT
CLASSIFIED PEOPLE INTO
GLUCOTYPES.
LOW MEANS GOOD GLUCOSE CONTROL,
MODERATE, MODERATE SPIKING
LEVELS OF GLUCOSE, AND THEN
THERE'S SEVERE SPIKERS AS WELL.
AGAIN, NORMAL PEOPLE CAN BE
SEVERE SPIKERS, SO CALLED
NORMAL, PROBABLY NOT SO NORMAL
AFTER ALL.
SO ONE OF THE THINGS WE
DISCOVERED AS DID AARON SIEGEL,
SOME PEOPLE SPIKED AT BANANAS,
OTHERS TO PASTA, SOME TO POTATO,
SOME TO WHITE BREAD, SOME TO
BROWN BREAD.
SO THIS IS JUST SHOWING TWO
EXAMPLES FROM AARON'S WORK.
THIS IS AN INDIVIDUAL TWO SPIKES
ON BANANA BUT NOT A COOKIE.
PROBABLY THE ONLY PERSON ON A
PLANET THAT DOESN'T SPIKE TO A
COOKIE.
THIS PERSON, MORE TYPICAL,
SPIKES AT A COOKIE BUT NOT
NECESSARILY A BANANA.
SO AGAIN, AND IT'S THOUGHT FROM
AARON'S WORK THAT 21% OF THIS IS
DUE TO YOUR MICROBIOME.
MOST OF IT'S NOT EXPLAINED, AND
WE'RE WORKING HARD TO FIGURE
THIS OUT.
AND ALSO WHAT FOODS WILL
SUPPRESS SPIKES.
THE OTHER AREA WE'VE BEEN
PUSHING VERY, VERY HARD WHICH I
THINK IS GOING TO BE VERY
POWERFUL FOR HEALTH MONITORING,
THIS IS REMOTE SAMPLING.
SO WE SENT SPENT NOW ABOUT 6 12
YEARS WORKING ON THIS TRYING TO
FIND THE RIGHT MAY TRUCKS FOR
COLLECTING ANALYTES AND KEEPING
THEM STABLE AND GETTING VERY
REPRODUCIBLE RESULTS.
WHAT WE ULTIMATELY SETTLED ON
ARE THESE MITRAs, WHERE YOU
CAN SAMPLE -- YOU DO LITTLE
LANCET PRICKS, COLLECT 10 MICRO
LITERS OF BLOOD IN EACH OF THESE
PRICKS, FEDEX IT, IN THE END WEE
MEASURING ABOUT 2200 ANALYTES.
AND WE'VE GONE ON TO SHOW, I
DON'T HAVE TIME TO SHOW YOU
THIS, MOST PROTEINS ARE STABLE,
MOST METABOLITES ARE STABLE, BUT
A NUMBER OF THEM ARE OFF BUT WE
KNOW WHICH WILL GO OFF STABILITY
WISE, BUT WE KNOW WHICH ONES
THEY ARE AND CAN CORRECT FOR
THAT.
SO THEN WE DID SOME REALLY FUN
EXPERIMENTS, VERY RELEVANT TO
THIS MEETING.
WE HAD 32 PEOPLE DRINK THIS
ENSURE SHAKE THAT YOU CAN BUY AT
CVS.
BASICALLY WE SAMPLED THEM
BEFORE, 30 MINUTES, 60 MINUTES,
120, 240 MINUTES.
SO WE ACTUALLY WERE TRYING TO
SEAT EFFECT OF DRINKING A SHAKE
ON PEOPLE'S BIOCHEMISTRY.
WHAT WE DISCOVERED, THIS PART'S
NOT A SURPRISE, THEY DO THIS
AFTER FASTING, YOU KNOW,
HUNDREDS OF MOLECULES CHANGE,
BUT WHAT'S NICE IS WE CAN
QUANTIFY SOME VERY KEY MOLECULES
LIKE INSULIN, A C PEPTIDE,
THINGS INVOLVED IN GLUCOSE
CONTROL, INFLAMMATORY MARKERS
AND SO ON.
WHAT WE DISCOVERED MUCH TO OUR
SURPRISE IS THAT EVERYBODY
REACTED TO THE SHAKE VERY
DIFFERENTLY.
SO EACH BLOCK BOX IS A DIFFERENT
PERSON, AND WHAT YOU'LL SEE,
THESE ARE JUST SHOWING THREE
CARBS.
THIS PERSON'S CARBS RELATIVELY
SPEAKING PLUMMETED, THEY WENT
WAY DOWN, WHEREAS THIS PERSON'S
WENT WAY UP.
UP, UP, UP, KIND OF NEUTRAL,
DOWN, DOWN.
SO AGAIN, PEOPLE ARE REACTING
VERY DIFFERENTLY.
SO SOME PEOPLE, THEIR CARBS WILL
PLUMMET BUT AMINO ACIDS WILL GO
UP, FREE FATTY ACIDS MIGHT
CHANGE.
SO IT'S VERY, VERY DIFFERENT.
IN THE END, WE CAN GROUP PEOPLE
INTO FIVE GROUPS OF PEOPLE.
ONE OF THE COOL RESULTS IS
ILLUSTRATED HERE.
GREY IS THE AVERAGE OF THE
GROUP, OKAY, THE AVERAGE VALUE,
IF YOU WILL, ACROSS MULTIPLE
ANALYTES.
BROWN ARE THE INFLAMMATION
MARKERS.
SO THIS GROUP OF PEOPLE, THE
INFLAMMATION, INFLAMMATORY
MARKERS GO DOWN AFTER DRINKING
THAT SHAKE.
FOR THIS GROUP OF PEOPLE, THEY
ACTUALLY GO UP.
SAME WITH THIS ONE, UP.
SO FOR SOME PEOPLE, THE SHAKE IS
PRO INFLAMMATORY, AND FOR
OTHERS, IT'S ANTI-INFLAMMATORY.
SO WE'RE ALL REACTING
DIFFERENTLY TO THE FOOD.
WE DON'T KNOW THE BASIS OF THIS,
WE HAVE SOME HYPOTHESES AND
THAT'S SOMETHING WE'RE SEEING
NOW, BUT THE IDEA THAT PEOPLE
RESPOND DIFFERENTLY TO DIFFERENT
FOODS PROBABLY EXPLAINS WHY
QUITE A FEW PEOPLE HAVE IBS,
INFLAMMATORY BOWEL SYNDROME, ET
CETERA.
SO WE CAN MEASURE THIS, SO WE
THINK THIS IS THE WAY OF TEASING
ALL THIS OUT.
THE OTHER THING WE'VE DONE IS
WHAT I CALL THE ULTIMATE
EXPERIMENT.
WE HAD ONE PERSON TAKE SAMPLES
EVERY HOUR DURING WAKING HOURS
FOR SEVEN STRAIGHT DAYS.
THEY'RE WEARING A CGM,
CONTINUOUS GLUCOSE MONITOR, A
SMART WATCH AND DOING FOOD
LOGGING.
SO NOT SURPRISING, THOUSANDS OF
MOLECULES DID CHANGE, AND THEN
WE CAN ACTUALLY START
CORRELATING THESE BIOCHEMICAL
CHANGES WITH ACTIVITY AND
LIFESTYLE AND SO ON.
WHAT WE FIND IS THAT WE'VE
WRITTEN ALGORITHMS TO FIND TIME
LAG CORRELATIONS BECAUSE THE
IDEA IS CAUSATIVE EVENTS WILL BE
UPSTREAM OF DOWNSTREAM EVENTS SO
WE CAN SEE POTENTIAL CAUSE OF
EVENTS BY THIS KIND OF ANALYSIS.
SO WE FIND THOUSANDS OF
ASSOCIATIONS OF, SAY,
METABOLITES WITH STEPS, THESE
MAGENTA THINGS, PURPLE ONES ARE
ACTUALLY -- KNOWS THOSE ARE CY,
THE BLUE ONES ARE LIPIDS AND THE
METABOLITES ARE ACTUALLY GREEN.
WE'LL FIND THOUSANDS OF THESE
ASSOCIATIONS, THIS IS JUST
SHOWING SOME OF THE TOP ONES.
AND THEY'RE PRETTY COOL.
A LOT OF STUFF IS NEW, WE'LL SEE
NEW INFLAMMATORY MARKERS COME UP
AFTER GLUCOSE, FOR EXAMPLE.
THIS IS SHOWING C PEPTIDE COMES
UP AFTER GLUCOSE, THAT, WE WOULD
EXPECT.
WHAT'S NICE IS WE QUANTIFIED IN
THIS PERSON, WE KNOW EXACTLY
WHAT IT IS, 10-MINUTE LAG.
HERE'S A NEAT RESULT THAT WE
DIDN'T NECESSARILY EXPECT.
WE ACTUALLY PICKED UP ALPHA
SYNUCLEIN, WHICH ALSO SHOWS A
PRETTY INTERESTING PATTERN.
WE ACTUALLY THINK -- WE'RE STILL
ANALYZING THIS BUT WE THINK IT'S
ASSOCIATED WITH STRESS.
NOW, ALPHA SYNUCLEIN, YOU MAY
KNOW IT'S ASSOCIATED WITH
DEMENTIA, ALSO PARKINSON'S, SO
IMAGINE IF YOU'RE AT RISK FOR
THIS, I THINK WHAT YOU'D WANT TO
DO IS MITIGATE YOUR STRESS SO AS
TO AVOID SPIKING THIS AND
PERHAPS THAT WOULD HELP DELAY
THE ONSET OF DEMENTIA.
SO THE WAY WE'RE HANDLING THIS
IS THAT WE CAN PULL ON ALL THESE
DATA, THE WEARABLE DATA, THE
OMICS DATA, ALL THESE DIFFERENT
DATA TYPES AND DISPLAY IT ON A
DASHBOARD WE BUILT, PERSONAL
HEALTH DASHBOARD, SO WE THINK
THIS IS GOING TO EMPOWER
INDIVIDUALS TO BE ABLE TO BETTER
TRACK THEIR HEALTH.
SO WHERE IS ALL THIS GOING?
WELL, I THINK DEEP DATA IS GOING
TO BE VERY POWERFUL, JUST LIKE
IT'S BEEN DOING ALREADY, FOR
TRACKING PEOPLE'S HEALTH,
CATCHING DISEASE EARLY, AND
HAVING HEALTHY DISEASE
SIGNATURES.
BUT THERE'S MANY, MANY MORE
THINGS TO DO, IF YOU THINK ABOUT
IT.
THERE'S A LOT WE DON'T KNOW.
WE DON'T REALLY KNOW WHAT TO
MEASURE.
AS I SAY, YOU GO TO A DOCTOR
TODAY, THEY MEASURE 15 THINGS,
LIKE RESTING HEART RATE IN
DOCTOR'S OFFICE, IT'S ALL OVER
THE MAP, IT'S NOT NECESSARILY
TERRIBLY ACCURATE.
WE THINK THERE'S MANY MORE
THINGS THAT COULD BE MEASURED,
BUT WE DON'T KNOW THE BEST
MARKERS, I WOULD ARGUE.
WE ALSO DON'T REALLY KNOW HOW
FREQUENTLY YOU SHOULD BE
MEASURING PEOPLE, LIKE SHOULD
YOU BE MEASURING THEM EVERY WEEK
FOR CERTAIN THINGS, MONTHLY,
YEARLY, WHAT YOU HAVE.
ABANDONS WHY AND WHY DO WE ALWAE
AFTER FASTING?
MAYBE THERE'S OTHER TIMES WE
SHOULD BE MEASURING PEOPLE, SAY,
AFTER THEY RUN, THAT'S WHAT
STRESS ECHOCARDIOGRAMS ARE ALL
ABOUT, PUTTING PEOPLE THROUGH
CHALLENGES AND MEASURING THINGS.
I WOULD ARGUE MECHANISTICALLY,
WE DON'T KNOW HOW MOST OF THE
THINGS WE DO REALLY WORK.
WE DON'T KNOW HOW NUTRITION HAS
ITS EFFECTS ON PEOPLE AND
NUTRITION IS SO BROAD THAT WE'VE
NEVER BROKEN IT DOWN PROPERLY.
SAME WITH SLEEP, I WOULD ARGUE
WE DON'T KNOW HOW -- WE HAVE
ASSUMPTIONS ABOUT HOW IT WORKS
BUT I DON'T THINK IT'S REAL.
EXERCISE, BUT THERE IS A PROJECT
TO GO AFTER THAT.
AND CERTAINLY WE HAVE MENTAL
HEALTH, IT'S PRETTY CLEAR,
SOCIALIZATION IS VERY, VERY
IMPORTANT FOR THEIR LONGEVITY
AND HEALTHSPAN.
SO WE THINK IT WOULD BE NICE TO
UNDERSTAND HOW ALL THIS WORKS
MECHANISTICALLY.
THEN ULTIMATELY, WHAT WE REALLY
NEED TO DO IS KNOW HOW TO
OPTIMIZE PEOPLE'S PERSONAL
LIFESTYLE.
SO PEOPLE LIKE ME, LUIGI, I TAKE
MY ANTIOXIDANTS, AND I TRACK
THIS STUFF, SO MY CASE, I'VE
BEEN ABLE TO CATCH MY LYME, I
FIGURED OUT MY DIABETES FROM MY
GENOME SEQUENCE.
SO WE THINK THERE'S WAYS OF
ACTUALLY USING SOME OF THESE
ADVANCED TECHNOLOGIES TO MAKE
BETTER PREDICTIONS ABOUT
PEOPLE'S DISEASE RISK AND HEALTH
TRACKING.
SO THIS JUST HAPPENS TO BE MY
WEARABLES TEAM WHEN IT WAS AT
ITS PEAK AND THE MICRO SAMPLING
TEAM WAS LED BY SHAU SHAU RHINE.
I BELIEVE I'VE SAVED TIME FOR
SOME QUESTIONS.
SO IF YOU HAVE QUESTIONS, I'D BE
HAPPY TO TAKE THEM.
>> THANK YOU SO MUCH FOR A VERY
EXCITING TALK.
I WOULD LIKE TO START BY KIND OF
A FUN EXERCISE.
I MEAN, YOU ARE KNOWN TO BE PART
OF YOUR OWN STUDIES.
I THINK YOU PUBLISHED A PAPER IN
WHICH YOU REPORTED YOUR
EXPERIENCE WITH A VIRAL
INFECTION AND EFFECTS ON YOUR
METABOLISM AND SO FORTH, SO I'D
LIKE TO ASK YOU IF YOU WOULD
TELL US RIGHT NOW HOW MANY OF
THESE WEARABLE DEVICES ARE YOU
USING?
>> I NORMALLY USE ABOUT EIGHT
EVERY DAY, SO I HAVE MY FOUR
SMART WATCHES HERE, MY RING.
RIGHT NOW I DON'T HAVE MY
GLUCOSE MONITOR ON, JUST SIMPLY
BECAUSE I HAVEN'T GOT THE NEW
ONE HOOKED UP YET, SO THAT WOULD
BE SIX.
I NORMALLY CARRY AN EXPOSEOMETER
BECAUSE YOU DON'T KNOW WHAT
YOU'RE BREATHING RIGHT NOW BUT
WE CAN MEASURE THAT.
SOME OF THEM WE GET IN REALTIME
LIKE PM2.5, PM10, THAT'S WHAT'S
MEASURED HERE, BUT WE'RE
COLLECTING SAMPLES TO SEE WHAT
BIOLOGICALS AND CHEMICALS I'M
EXPOSED TO, SO THAT'S SEVEN.
AND THEN MY SMARTPHONE HAS
SEVERAL THINGS TOO, LIKE MOVES
APP, STUFF LIKE THAT THAT TRACKS
THINGS AS WELL.
SO YEAH, WE TRACK QUITE A FEW
THINGS.
OH, I FORGOT TO SAY, EVEN MY
HEARING AID IS -- IT IS FOR
HEARING, BY THE WAY, BUT IT ALSO
IS A TRACKER AS WELL.
MEASURES MY SOCIAL INTERACTIONS.
WHICH IS KIND OF INTERESTING.
AND SO WE THINK -- SO THAT WOULD
BE NINE IF YOU COUNT ALL THAT
STUFF.
>> SO THAT'S AN IMPORTANT
QUESTION, ESPECIALLY FOR US AS
WE ARE TRYING TO ENVISION HOW
WOULD YOU RUN A STUDY OF A
FAIRLY LARGE SCALE, I WOULD SAY,
WITH A LOT OF PEOPLE INVOLVED IN
IT?
HOW OFTEN, HOW MANY DEVICES, HOW
MUCH CAN BE SELF-REPORTED, HOW
MUCH NEEDS TO BE DONE THROUGH A
LAB AND SO FORTH, SO I KNOW YOU
ALREADY MENTIONED THAT WE DON'T
KNOW THAT YET, BUT IF YOU'RE
GOING TO LOOK INTO YOUR CRYSTAL
BALL, WHAT WILL YOU SAY?
>> WELL YOU NEED ONE TRACKER,
YOU DON'T NEED ALL FOUR.
WE DO FOUR BASICALLY BECAUSE I'M
EVALUATING THINGS.
SO WHEN I GOT COVID, I HAVEN'T
FINISHED EVALUATING WHI WHICH DE
WOULD HAVE BEEN BEST FOR PICKING
THAT UP AND WHY.
BECAUSE THEY'VE SAMPLED
RESOLUTIONS AND THEY MEASURE
DIFFERENT THINGS.
BUT I THINK FOR WRITING A STUDY
THE OBVIOUS THING TO DO IS JUST
GET ONE SMART WATCH ON PEOPLE.
I'M A BIG FAN OF TBLEU KOAS GLUE
MONITORS.
THEY'RE A LITTLE INCONVENIENT TO
PUT ON EVERY TWO WEEKS, THAT'S
HOW LONG THEY LAST, BUT WE
TYPICALLY RUN -- IT DEPENDS ON
WHAT THE STUDY DESIGN IS ALL
ABOUT, WE'LL TYPICALLY USE THEM
QUARTERLY, FOR EXAMPLE, OR MAYBE
YEARLY DEPENDING ON THE
PRINCIPLE OF THE STUDY, SO
THAT'S A GOOD ONE TO DO.
I THINK WE DON'T -- WE STILL DO
BIG BLOOD DRAWS WHEN WE LAUNCH A
STUDY BUT WE'RE SWITCHING
EVERYTHING OVER TO MICRO
SAMPLING, BECAUSE THEN YOU CAN
SAMPLE PEOPLE AT HOME, WHICH IS
MORE NATIVE, AND STILL MEASURE
THOUSANDS OF A ANALYTES.
SO I THINK THE FUTURE WILL BE TO
DO THESE MICRO SAMPLE
COLLECTIONS, SAVES A TON OF
MONEY, BY THE WAY, AND GETS, WE
THINK --
>> AND HOW OFTEN YOU WOULD SAY,
ONCE A MONTH WOULD BE --
>> THAT'S WHAT WE' TRY WHAT WE'O
DO.
WE HAVE A CHRONIC FATIGUE STUDY
RUNNING, THERE WE SAMPLE PEOPLE
EVERY TWO WEEKS, THEY GET
FREQUENT CRASHES, THEN WE SAMPLE
THEM DURING THE CRASH AND WHAT
THEY FEEL IS THEIR GOOD DAYS, SO
WE'LL SAMPLE THEM ON THEIR GOOD
DAYS AND BAD DAYS.
SO IT DEPENDS ON THE STUDY.
FOR THIS STUDY I TOLD YOU ABOUT,
THE IPOP ONE, WE ARBITRARILY
PICKED THREE MONTHS BECAUSE WE
DIDN'T REALLY KNOW WHAT TO DO.
QBIOWILL TELL PEOPLE TO SAMPLE
EVERY SIX MONTHS AS A WAY OF
FOLLOWING.
NOW, I PERSONALLY THINK THAT IN
THE LONG RUN, WHAT WE'RE GOING
TO BE DOING IS SAMPLING CERTAIN
THINGS LIKE METABOLITES QUITE
FREQUENTLY AT HOME, LIKE EVERY
MONTH, SO YOU CAN SEE THINGS
WHEN THEY GO OFF.
OTHER THINGS WILL DEPEND ON WHAT
YOU'RE AT RISK FOR.
I PERSONALLY THINK WHOLE BODY
MRIs, THEY TAKE A LONG TIME TO
RUN BUT THEY WON'T IN THE
FUTURE.
THEY'LL BE 15 MINUTES.
AND YOU'LL BE ABLE TO DO IT
WHILE YOU'RE AT THE DRUGSTORE,
AND MAYBE YOU DO THAT ONCE EVERY
SIX MONTHS.
I PERSONALLY THINK EVERY FEW
YEARS IS -- ESPECIALLY US A GET
OLDER, RIGHT, WHEN YOU HIT YOUR
50s IS WHEN THINGS HEAD OFF,
MAYBE EVEN 40s.
SO YOU'LL MEASURE WITH HIGHER
FREQUENCY LATER, BUT YOU STILL
NEED TO MEASURE EARLIER.
SO AGGRESSIVE CANCERS, THEY CAN
GO FROM ZERO TO PRETTY BAD
THINGS IN THREA MONTHS.
THAT'S PROBABLY A LOT TO DO, BUT
IT IS DOABLE IF WE CAN DO TEP 10
MINUTE SCANS ON PEOPLE AND ALSO
DO SENSITIVE BLOOD TESTS.
SO I THINK WE CAN INCREASE THE
FREQUENCIES, REDUCE THE COST AND
INCREASE OUR SENSITIVITY AND
SPECIFICITY.
SO THAT'S HOW I'D LIKE TO SEE
THINGS GO.
MY WORLD, THEY'D BE EVERY THREE
MONTHS ALL THE TIME.
I THINK RIGHT NOW THAT'S
PROBABLY NOT PRACTICAL.
BUT CERTAINLY MORE FREQUENT THAN
WE'RE DOING IT.
BUT NOBODY'S RUN THE PROPER
STUDY TO SAY HOW OFTEN SHOULD
YOU GET SCREENED FOR CANCER, AT
A CERTAIN AGE BASED ON CERTAIN
RISKS THAT YOUR GENOME SEQUENCE,
OR EVEN FOR RECURRENCE, QUITE
FRANKLY.
I DON'T THINK WE HAVE GOOD
GUIDELINES FOR RECURRENCE.
IT SHOULD DEPEND ON THE TYPE OF
CANCER YOU'VE GOT.
PROBABLY THE TYPE OF GENETIC
MUTATION YOU'VE GOT.
SOME ARE MORE AIF THAN OTHERS.
YOU'RE ASKING A GREAT QUESTION.
>> THANK YOU SO MUCH.
YOU ARE GIVING GREAT ANSWERS.
SO WE DO HAVE SEVERAL QUESTIONS,
I WANT TO REMIND PEOPLE EVEN IF
THEY ARE ON VIDEO CHAT, THERE IS
A BOX YOU CAN SEND A QUESTION,
THEY WILL COME BY EMAIL.
PEOPLE WHO ARE IN ZOOM, THEY CAN
PUT THE QUESTIONS IN Q & A.
WE ALREADY HAVE SEVERAL LINED
UP.
AND I THINK WE'RE ALSO GOING TO
OPEN THE CHAT IN CASE YOU COULD
NOT FIND THE Q & A BOX.
BUT HERE ARE SOME QUESTIONS THAT
CAME THROUGH Q & A.
AND IF WE RUN OUT OF TIME,
PLEASE SEE IF YOU CAN ANSWER
AFTER THE DISCUSSION.
HOW DO YOU DIFFERENTIATE TYPE
2 FROM AUTO ONSET TYPE 1 USING
THIS APPROACH, OR CAN YOU?
>> YEAH, I MEAN, WE DON'T FOR
OUR GROUP.
BUT WE DO SUBTYPE PEOPLE WHICH I
THINK IS A MORE RELEVANT THING.
ARE THEY HAVING INSULIN
RESISTANCE VERSUS, SAY, BETA
CELL EFFECTS.
SO WE ACTUALLY DEEPLY PHENOTYPE,
I DIDN'T GET INTO THAT, OUR
COHORT.
THESE DAYS WE THINK THAT'S
IMPORTANT.
I'M A CLASSIC CASE.
I'M ACTUALLY INSULIN-SENSITIVE.
I'M TYPE 2 DIABETIC PREDICTED
FROM MY GENOME.
I ACTUALLY MAKE INSULIN, I DON'T
RELEASE IT FROM THE PANCREAS.
I'M A METFORMIN NON-RESPONDER AS
WELL, BUT I RESPOND TO CERTAIN
DRUGS BUT NOT OTHERS, AGAIN,
PREDICTED BECAUSE I HAVE THE
RIGHT DATA.
SO WE THINK THAT'S MORE
IMPORTANT THAN CLASSIFYING TYPE
1, TYPE 2.
THAT IS IMPORTANT, YOU NEED TO
KNOW WHETHER YOU'RE MAKING
INSULIN OR NOT, BUT I THINK THE
MORE RELEVANT ISSUE IS WHAT'S
YOUR UNDERLYING DEFECT.
AND THAT ACCOUNTS FOR -- THAT'S
BY FAR THE MOST IMPORTANT THING
FOR CARRYING OUT PRECISION
DIABETES.
>> THANK YOU.
THE OTHER QUESTION IS, SINCE
THERE COULD BE CONCERN WITH DATA
PRIVACY, WOU WITH SOME OF THIS
WEARABLE, AND DO YOU HAVE ANY
SPECIFIC COMMENTS ABOUT THAT?
>> PEOPLE DO WORRY ABOUT THAT.
WE ARE AS SECURE AS POSSIBLE.
MY OWN PERSONAL VIEW IS THAT,
YOU KNOW, GET OVER IT, NOTHING
IS REALLY PRIVATE.
SO IF YOU THINK ABOUT WE ALL
HAVE CREDIT CARDS, WE ALL -- WE
DO THAT BECAUSE NOBODY WANTS TO
WALK AROUND WITH BAGS OF CASH.
CREDIT CARDS HAVE INCREDIBLY
PERSONAL INFORMATION.
I WOULD ARGUE MORE PERSONAL THAN
YOUR HEART RATE.
HEART RATE VARIABILITY THAT
PEOPLE CARE ABOUT.
SO BUT IN SPITE OF MY FLIP
ANSWER, WE DO TRY TO BE SECURE.
I DON'T THINK ANYBODY SHOULD BE
DISCRIMINATED AGAINST ON
PRE-EXISTING CONDITIONS SO I
THINK WE NEED A PROPER
HEALTHCARE SYSTEM THAT TAKES
CARE OF PEOPLE SO THAT YOU
AREN'T ABUSED BECAUSE SOME OF
YOUR DATA DOES GET OUT THERE IF
SOMEONE WERE TO EVER HACK IT.
>> OKAY.
THE OTHER QUESTION IS, IT SAYS
GREAT TALK WITH SO MUCH DATA,
DON'T YOU WORRY ABOUT
OVERFITTING?
>> WE HAVE TO CORRECT FOR THAT,
WE HAVE TO MAKE SURE WE'RE
STATISTICALLY VALID.
THAT'S A GOOD QUESTION.
AND MANY OF OUR STUDIES, AND
WE'LL ALSO HAVE AN INDEPENDENT
COHORT, THAT'S HARD TO DO FOR A
STUDY LIKE THIS WHERE VERY, VERY
DETAILED MEASUREMENTS ON PEOPLE,
BUT WE DO TRY TO ALSO FIND
ORTHOGONAL WAYS OF VALIDATING
YOUR RESULTS, BUT STATISTICALLY
SPEAKING, WE'RE VERY CAREFUL.
THE LONGITUDAL ANALYSES TEND TO
BE VERY SOPHISTICATED.
YOU GET A LOT OF POWER OUT OF
LONGITUDAL.
PEOPLE DON'T APPRECIATE THAT.
YOU GET WAY, WAY MORE POWER BY
TRACKING THE SAME PERSON AND
SEEING DISEASE SHIFTS THAT WAY
THAN YOU DO FROM CASE CONTROL
STUDIES.
BECAUSE IT'S VERY EASY -- THE
DIFFERENCES BETWEEN PEOPLE, I
DIDN'T PRESENT THIS, IS GREATER
THAN THE DIFFERENCE BETWEEN A
HEALTHY PERSON AND -- A PERSON
WHEN THEY'RE HEALTHY AND WHEN
THEY'RE ILL.
SO IT'S EASY TO TELL WHEN YOU'RE
GETTING ILL BY SEEING A SHIFT
FROM YOUR BASELINE, IT'S HARD TO
TELL BY COMPARING IT WITH 500
OTHER HEALTHY PEOPLE.
SO THIS IDEA OF SEEING SHIFTS,
THAT'S HUGE, PEOPLE DON'T REALLY
APPRECIATE THAT.
YOU CAN GET VERY ROBUST
STATISTICS ON A SINGLE PERSON.
>> SO ONE LAST QUESTION, TWO
MINUTES, THERE ARE SOME OTHER
FUN QUESTIONS INCLUDING ABOUT
BEER.
SO SOMEBODY ACTUALLY MADE A
CONNECTION BETWEEN YOUR TALK AND
DR. FERRUCCI AND THAT WAS THE
RESILIENCE.
SO WHAT DO YOU THINK WE COULD
MEASURE WITH WEARABLES THAT
COULD REPORT RESILIENCE?
>> GREAT QUESTION.
I THINK GLUCOSE IS NUMBER ONE
THAT WE SHOULD BE MEASURING.
THAT'S OBVIOUSLY A SPECIAL
WEARABLE.
THE SMART WATCH, HEART RATE,
HEART RATE VARIABILITY EXTREMELY
ACCURATE OFF A SMART WATCH
ACTUALLY.
BUT YOU CAN ALSO GET SOMETHING
CALLED GALVONIC STRESS RESPONSE
WHICH IS A BIG DEAL THAT'S
CONDUCTED ON YOUR SKIN.
SKIN TEMPERATURE, YOU CAN GET.
ALL THOSE ARE PRETTY IMPORTANT.
AND SO PEOPLE HAVE G GOTTEN THER
AFIB PICKED UP FROM A SMART
WATCH.
SO I THINK ALL THOSE THINGS ARE
PRETTY POWERFUL.
AS I MENTIONED FROM THE MACHINE
LEARNING, WE CAN TELL PEOPLE'S
RED BLOOD CELL COUNTS WHICH IS
RELEVANT FOR ANEMIA,
DEHYDRATION, THINGS LIKE THIS,
SO YOU CAN GET A TON OF STUFF
FROM A SMART WATCH.
IT'S A NO-BRAINER.
ALL STUDIES GOING FORWARD SHOULD
HAVE A SMART WATCH, OR SMART
RING, IN MY OPINION.
AND SLEEP, I THINK IS A BIGGIE.
SLEEP MEASUREMENTS ARE NOT
ACCURATE.
DURATION IS REASONABLE,
SOMETHING CALLED LATENCY WHEN
YOU FALL ASLEEP, AN ALSO --
WHAT'S THE OTHER ONE?
OH, RESTLESSNESS.
THOSE ARE ACCURATE.
REM, DEEP SLEEP, THEY'RE NOT
VERY ACCURATE FROM A SMART
WATCH.
BUT THEY'RE MEASURING SOMETHING,
IT'S JUST NOT CLEAR WHAT THEY
ARE.
BUT THE OTHER THINGS ARE PRETTY
GOOD, AND I THINK IMPORTANT
TO -- YEAH.
>> THANK YOU VERY MUCH.
YEAH, SLEEP IS ALSO VERY
IMPORTANT TO OUR INSTITUTE.
WE HOST THE NATIONAL CE NATIONAR
SLEEP DISORDERS.
SO I WOULD ASK YOU TO PLEASE
ANSWER THE OTHER QUESTIONS IF
YOU CAN DURING THE BREAK.
WE ALSO ASK EVERYONE TO STAY ON.
THERE IS A LITTLE BREAK THAT'S
COMING UP.
DR. SNYDER WAS ASKED TO MODERATE
THE FOLLOWING SESSION.
THAT WOULD BE A GREAT SESSION,
AND YOU ALREADY HAVE I THINK THE
AGENDA.
SO WE'LL SEE YOU ON THE OTHER
SIDE.
I THINK THE BREAK IS UNTIL
11:10.
SO PLEASE GO GET A CUP OF COFFEE
OR A BIO BREAK OR JUST A FEW
STEPS, DANCING MAYBE.
DR. SNYDER WILL TELL US TO MOVE.
THANK YOU SO MUCH.
COME BACK.
I'M A PROGRAM DIRECTOR IN THE
NATIONAL CANCER INSTITUTE IN THE
DIVISION OF CANCER BIOLOGY.
I'M CO-CHAIR FOR THE SESSION
TOGETHER WITH DR. BIRAGYN.
>> GOOD MORNING, I'M FROM THE
NATIONAL INSTITUTE ON AGING, AND
I'M CO-CHAIR.
>> IN SESSION 1, WE'LL DISCUSS
QUESTIONS LIKE HOW DO WE AGE, DO
WE AGE DIFFERENTLY AND HOW THE
AGING PROCESS CAN INCREASE THE
RISK FOR DISEASES SUCH AS
CANCER, CARDIOVASCULAR,
NEURODEGENERATIVE DISEASES CH
EACH SPEAKER WILL HAVE 15
MINUTES, THERE WILL BE 2-MINUTE
MARK, TRY TO STAY IN YOUR TIME.
AFTER EACH SPEAKER, WE'LL HAVE E
END OF THE SESSION, THERE WILL
BE PANEL DISCUSSION WITH ALL THE
SPEAKERS.
PLEASE IF YOU WANT TO ASK A
QUESTION, PLEASE USE THE Q &
A -- ZOOM Q & A CHAT.
WITH THAT, I'M GOING TO GO AHEAD
AND TURN IT OVER TO OUR
MODERATOR, OUR FANTASTIC KEYNOTE
SPEAKER, DR. MICHAEL SNYDER.
>> GREAT.
WE'RE GOING TO JUMP RIGHT IN.
OUR FIRST SPEAKER IS PEGGY
GOODELL WHO WILL TAKE IT AWAY.
PEGGY.
>> ALL RIGHT.
THANK YOU VERY MUCH.
I'M JUST TRYING TO MAKE SURE
EVERYTHING IS SET UP FOR ME
HERE.
OKAY.
SLIDES ARE GOOD AND EVERYTHING,
I HOPE.
>> YOU'RE GOOD.
>> GOOD, THANKS.
IT'S REALLY A PLEASURE TO BE
HERE AND TO TALK TO YOU ABOUT
SOME OF THE THINGS THAT WE'RE
THINKING ABOUT IN THE LAB,
PARTICULARLY THE RELATIONSHIP
BETWEEN HEMATOLOGY, AGING AND
CANCER.
SO WHAT I REALLY WANT TO FOCUS
ON TODAY IS CLONAL HEMATOPEE EE
CYST, REALLY DISCOVERED LESS
THAN 10 YEARS AGO, SOMETHING
THAT WE'RE REALLY BEGINNING TO
UNDERSTAND.
SO I JUST WANT TO GET EVERYBODY
ON THE SAME PAGE.
SO IN YOUR STEM CELLS IN YOUR
BONE MARROW ARE CONSTANTLY
REGENERATING ALL THE CELLS OF
THE BLOOD AND YOU'VE PROBABLY
GOT A COUPLE HUNDRED THOUSAND
STEM CELLS THAT ARE REALLY
RESPONSIBLE THROUGHOUT YOUR
WHOLE LIFETIME TO GENERATE ALL
OF THOSE DIFFERENTIATED BLOOD
CELLS.
EACH OF THOSE STEM CELLS GAINS
ABOUT 10 MUTATIONS PER STEM CELL
PER YEAR.
ORIGINALLY WE WOULD HAVE THOUGHT
THAT THE WHOLE HEMATOPOIETIC
STEM CELL POPULATION WAS FAIRLY
HOMOGENEOUS BUT WE REALIZED WITH
THIS MUTATION ACCUMULATION THAT
THAT ALLOWS REALLY A GENERATION
OF ENORMOUS DIVERSITY WITHIN
THAT STEM CELL POOL.
AND IT TURNS OUT THAT THROUGHOUT
TIME, NA THOSE STEM CELLS NOW
SLIGHTLY DIFFERENT BECAUSE
THEY'VE ACCUMULATED ALL THESE
MUTATIONS PER YEAR START TO
COMPETE WITH EACH OTHER SO THAT
TOWARDS THE END OF LIFE YOU HAVE
SOME WINNING AND SOME LOSING
STEM CELLS.
SO THAT STEM CELL FIELD, IF YOU
WILL, IS MUCH, MUCH MORE SIMPLE.
SO A 70-YEAR-OLD HAS ABOUT 7 TO
10 CODING MUTATIONS PER STEM
CELL AND THAT CREATES THAT
SUBSTRATE FOR STEM CELL AND
COMPETITION AND REALLY IT'S THAT
OUTCOME OF COLLAPSED DIVERSITY
OF YOUR STEM CELL POOL THAT WE
CALL CLONAL HIGH SCHOOL.
CLONAL HEMATOPOIESIS.
SO WHAT ARE THE CONSEQUENCES,
WHO REALLY CARES?
IT'S INEVITABLE IN EVERYBODY.
IF YOU SEQUENCE DEEPLY ENOUGH IN
YOUNG PEOPLE YOU WILL SEE IT.
BUT BY THE AGE OF 70 IT'S PRETTY
EASILY DETECTABLE IN EVERYBODY
AND BY THE TIME YOU'RE EVEN
OLDER, IF YOU LIVE LONG ENOUGH,
YOU WILL HAVE SIGNIFICANT
CLONES, ONE OR MORE CLONES THAT
YOU CAN SEE IN EVERYBODY.
SO THIS STATE OF CLONAL
HEMATOPOIESIS CONFERS ABOUT A
TENFOLD INCREASED RISK FOR
HEMATOLOGIC MALIGNANCY BUT ALSO
IT BEEN ASSOCIATED WITH ALL
CAUSE MORTALITY OF A WHOLE
VARIETY OF AGING ASSOCIATED
DISEASES, WHICH I'LL TOUCH ON IN
A MOMENT.
SO WHAT REALLY DRIVES CLONAL
HEMATOPOIESIS?
WELL, THOSE MUTATIONS THAT ARE
PICKED UP IN THE STEM CELLS,
SOME OF THEM CONFER A SELECTIVE
ADVANTAGE TO THE STEM CELL.
AND THERE'S 20 OR SO GENES THAT
WE'VE FOUND THAT ARE RECURRENTLY
MUTATED THAT REALLY PROMOTE THE
EXPANSION OF SOME OF THOSE STEM
CELL CLONES, AND SO THOSE 20 OR
SO MUTANT GENES ACCOUNT FOR MOST
CLONAL HEMATOPOIESIS, ALSO
SOMETIMES REFER TO IT AS C.H. IN
THE TALK.
AND YOU CAN GROUP THEM IN
VARIOUS GROUPS.
WE'RE NOT GOING TO GO INTO THIS
IN TOO MUCH DETAIL BUT THERE'S
EPIGENETIC REGULATORS, DNA
DAMAGE RESPONSE -- FACTORS AND
SOME OTHER CLASSES.
THESE ARE SOME OF THE AGING
ASSOCIATED DISEASES ASSOCIATED
WITH CLONAL HEMATOPOIESIS.
THESE ARE ALL PUBLISHED STUDIES
DONE BY A NUMBER OF GROUPS.
I HAVEN'T PUT THE CITATIONS ON
HERE AND HOPEFULLY YOU CAN SEE
THIS, I'M HAPPY TO SHARE THIS
SLIDE WITH PEOPLE LATER.
AND REALLY THERE'S JUST A WHOLE
SLEW OF THESE STUDIES THAT HAVE
TRIED TO SHOW THAT CLONAL
HEMATOPOIESIS CAN BE
STATISTICALLY LINKED TO THESE
AGING-ASSOCIATED DISEASES AND IN
THE MIDDLE, YOU'LL SEE SOME OF
THE MUTANT GENES THAT ARE
ASSOCIATED WITH THOSE STATES.
SO ONE OTHER THING I WANT TO
EMPHASIZE IS THAT ALTHOUGH I'M
MOSTLY FOCUSING ON THE BLOOD,
ALL TISSUES ARE KNOWN TO
ACCUMULATE THESE SOMATIC
MUTATIONS AND MOST EXPERIENCE
CLONAL EVOLUTION.
AND IT REALLY IS NOT UNDERSTOOD
AT THIS POINT, THE RELATIONSHIP,
THE CAUSE VERSUS THE CONSEQUENCE
OF AGING IS NOT CLEAR.
CERTAINLY THEY'RE A SUBSTRATE
FOR CANCER BUT THE DEGREE TO
WHICH THIS CONTRIBUTES TO AGING
ITSELF IS NOT YET CLEAR.
BUT REALLY EXCELLENT STUDIES
HAVE ALSO BEEN DONE IN THE SKIN,
ESOPHAGUS, COLON, UTERUS, LIVER
AND OTH OTHER TISSUES AS WELL.
THIS IS VERY, VERY NEW, BUT IS
SOMETHING THAT'S VERY IMPORTANT
THAT WE SHOULD THINK MORE ABOUT
IN THE FUTURE.
OKAY, SO BACK TO CLONAL
HEMATOPOIESIS.
SO WHAT ARE THE MECHANISMS
UNDERLYING CLONAL HEMATOPOIESIS?
I MENTIONED THESE MUTATIONS THAT
ACCUMULATE.
WE WERE INTERESTED IN
UNDERSTANDING HOW THESE
MUTATIONS AFFECT STEM CELL
FUNCTION.
WE WANTED INSIGHT INTO STEM CELL
BIOLOGY BUT ALSO UNDERSTANDING
HOW IT AFFECTS AGING AND CANCER.
SO WHEN YOU THENG ABOUT IT, THE
UNDERLYING PRINCIPLE OF CLONAL
HEMATOPOIESIS IS THIS
COMPETITION AMONG THE STEM
CELLS.
SO WHY DOES A PARTICULAR
MUTATION MAKE ONE VARIANT STEM
CELL BETTER THAN ALL THOSE OTHER
200,000 STEM CELLS IN THE
INITIAL POOL?
IT'S ALSO IMPORTANT TO CONSIDER
THAT ENVIRONMENTAL CONDITIONS
MATTER AND MUTATION IN ONE
INDIVIDUAL MAY NOT HAVE THE SAME
ADVANTAGE AS ANOTHER INDIVIDUAL,
AND WE REALLY THINK ABOUT THIS
IN A DARWINIAN SENSE THAT THE
MUTATIONS MAKE A BIRD SURVIVE
BETTER UNDER CERTAIN FOOD
CONDITIONS AND NOT SO MUCH UNDER
OTHER FOOD CONDITIONS SO THIS IS
SUSTAINED WITH THESE MUTATIONS
AND STEM CELLS.
THESE MUTATIONS, THESE 20 OR SO
MUTATIONS MIGHT HAVE COMMON
STRATEGIES FOR MAKING A STEM
CELL.
THEY COULD BE BASED ON SURVIVAL
PROLIFERATION, BUT THE IMPORTANT
THING IS THIS IS A MARATHON AND
NOT A SPRINT, SO A SMALL
ADVANTAGE PAYS OFF.
WE'RE TALKING ABOUT AGING OVER
THE LIFESPAN OF AN INDIVIDUAL
70, 80, NIEP TI YEARS, SO
ADVANTAGES OF STEM CELLS ARE NOT
SPRINTING ADVANTAGES, THEY ARE
REALLY LONG TERM ADVANTAGES THAT
ALLOW THAT STEM CELL TO WIN OVER
THAT LONG PERIOD OF TIME.
SO IN MY LAB, WE'VE STUDIED THE
WINNING STRATEGIES OF THREE
VARIANT GENES AND WE DON'T HAVE
MUCH TIME TODAY SO I'M GOING TO
JUST EXTREMELY BRIEFLY TOUCH ON
THREE OF THESE TO SHOW YOU HOW
THEY'RE SIMILAR AND DIFFERENT
FROM EACH OTHER AND HOW
DIFFERENT WINNING STRATEGIES CAN
PREVAIL.
SO ONE OF THE FIRST ONES THAT WE
STUDIED IS CALLED PPM1D.
IT WAS INTERESTING BECAUSE IT
REALLY HAD NEVER BEEN STUDIED IN
THE BLOOD SYSTEM BEFORE.
SO WE THOUGHT WHAT IS THIS
INTERESTING GENE DOING?
PPM1D IS COMMONLY SEEN IN CLONAL
HEMATOPOIESIS.
IT COMES UP IN ALL THESE
STUDIES.
IT TURNS OUT IT'S A NEGATIVE
REGULATOR OF P53.
P53, WE KNOW IS THE MASTER
REGULATOR OF MANY THINGS, OF
GENOME STABILITY, MANY ASPECTS
OF THAT.
SO PPM1D PARTLY WORKS THROUGH
P53.
IT TURNS OUT THAT MOST OF THE
MUTATIONS IN PPM1D IN CLONAL
HEMATOPOIESIS ARE THE THREE
PRIME INTO THE GENE, THEY
TRUNCATE THE GENE AND YOU END UP
WITH A TRUNCATED PROTEIN THAT'S
HIGHLY STABLE.
SO THAT STABLE PPM1D IS A
REGULATOR OF P53 SO IT'S
CONSTANTLY THERE, NOW AT A HIGH
LEVEL, ALWAYS SUPPRESSING THE
ACTIVITY OF P53.
SO IT SORT OF MIMICS A P53
KNOCKOUT OR KNOCKDOWN, IF YOU
WILL.
SO IF YOU STABILIZED PPM1D THIS
WAY, DO THOSE MUTANT STEM CELLS
HAVE AN ADVANTAGE IF YOU COMPETE
THEM HEAD TO HEAD IN A VEL
COMPETITION?
CELLCOMPETITION?
SO WE ESTABLISHED VARIOUS CELL
MODELS AND MOUSE MODELS TO TEST
THE COMPETITIVE ADVANTAGE OF
THESE MUTANT CELLS.
I'M JUST GOING TO FOCUS ON THE
IN VIVO DATA FROM THE MOUSE
MODEL, SO WE TOOK THESE MICE
THAT HAD OUR PPM1D MUTATION, WE
TOOK STEM CELLS OUT AND WE
COMPETED THEM HEAD TO HEAD WITH
WILD TYPE CELLS FROM ANOTHER
MOUSE, 20%, 80% RATIO,
TRANSPLANTED THEM INTO WILD TYPE
MICE AND WAITED OVER TIME, AND
WHETHER WE COMPETE WILD TYPE
VERSUS WILD TYPE OR MUTANT
VERSUS WILD TYPE, YOU CAN SEE
THE RED AND THE GREY BARS OVER
TIME.
THIS IS WEEKS POST TRANSPLANT.
THERE'S REALLY NO CHANGE.
SO UNDER NORMAL CONDITIONS, THE
PPM1D MUTANT CELLS ARE FINE, BUT
THEY HAVE NO COMPETITIVE
ADVANTAGE.
BUT AS SOON AS WE TREAT THE MICE
WITH A CHEMOTHERAPEUTIC AGENT,
IN THIS CASE CISPLATIN, THOSE
MUTANT CELLS TAKE OFF AND NOW
THEY HAVE A SPECIFIC SELECTIVE
ADVANTAGE.
LIKE THIS DARWINIAN CONTEXT.
AND WE CAN ALSO SEE THIS IN
HUMANS THAT HAVE BEEN EXPOSED TO
CHEMOTHERAPY, THEY TEND TO HAVE
MANY MORE OF THESE P PM1 DSMGHT
MU AT THAT PARTICULAR TIME
CLONES THAN INDIVIDUALS WHO ARE
NOT.
SO HOW DOES PPMD CONVEY THIS
ADVANTAGE IN WE TRY TO FIND A
PROLIFERATION DIFFERENCE,
VARIOUS DIFFERENT PARAMETERS.
THE MAJOR THING WE FOUND WAS A
TINY DIFFERENCE IN THEIR ABILITY
TO GO THROUGH CELL DEATH THROUGH
APOPTOSIS.
YOU CAN SEE IT WAS A 16%
DIFFERENCE, WHICH DOESN'T SEEM
LIKE MUCH BUT OVER YOUR LIFESPAN
WITH MULTIPLE INSULTS, YOU CAN
ACTUALLY HAVE A SMALL ADVANTAGE
AS I WAS REFERRING TO BEFORE AND
END UP WINNING AMONGST MANY OF
THE OTHER CELLS OVER TIME.
SO PPMD MUTANT CLONES THEY WIN
UNDER ADVERSE CONDITIONS.
HERE'S A LITTLE MARATHON BEING
TAKEN IN ANTARCTICA.
MOST OF THIS WORKS THROUGH P53.
ANOTHER GENE WE HAVE STUDIED
THAT WE THOUGHT MIGHT BE SIMILAR
IS SRCAPMECAP.
IT BRIDGES EPIGENETICS AND DNA
REPAIR SO IT WAS INTERESTING TO
US AS A CHROMATIN REMODELER.
ALSO HAD NOT BEEN STUDIED IN
HEMATOPOIETIC SYSTEM.
SO WE HAD SEEN SOME REPORTED
MUTATIONS IN THIS AND SO WE SORT
OF DID THE SAME THING THAT WE
HAD DONE WITH PPM1D.
WE MADE MUTANT CELL LINES AND
MUTANT MICE AND TRIED TO
UNDERSTAND WHAT THE PECK NISMS D
CONTEXTS WERE IN WHICH SRCAP
WOULD SHOW UP.
THERE'S SOME FLIPS IN THIS
SLIDE, BUT THE SHORT ANSWER IS
THAT SRCAP MUTATIONS SEEM TO
SHOW REDUCED DNA DAMAGE WITH
STRESS, ACTUALLY IT WAS OPPOSITE
FROM PPM1D WHICH SHOWED MORE DNA
DAMAGE AFTER STRESS.
AGAIN I'M NOT GOING TO GIVE YOU
THE WHOLE STORY THIS IS REALLY
JUST THE PUNCH LINE.
WE ACTUALLY HAVE A PAPER IN
PRESS ON THIS.
SRCAP LIKE PPM1D SHOWS THAT
THESE MUTATIONS ARE ADVANTAGEOUS
PARTICULARLY IN ADVERSITY, BUT
IN DIN DIFFERENT CONTEXTS SEEN H
P PM1D.
IT'S OTHER KINDS OF STRESSORS,
OTHERS AGENTS.
THE NORMAL FUNCTION OF SRCAP
SEEMS TO BE TO REPRESS THE DNA
DAMAGE RESPONSE AND THE STEM
CELL PROGRAM, AND SO WHEN IT'S
MUTATED, YOU GET BETTER STEM
CELLS, YOU GET BETTER DNA
REPAIR.
AND YOU GET EXPANSION OF STEM
CELLS AND YOU GET SOME MORE
LYMPHOID CELLS IN THE MICE AS
WELL.
SO ON TO MY FAVORITE GENE, D
DNMT3A.
WHAT WAS REMARKABLE TO US WHEN
CLONAL HEMATOPOIESIS WAS
DISCOVERED IS THAT DNMT3A WAS
THE MOST COMMON DRIVER OF CLONAL
HEMATOPOIESIS.
SO ABOUT 50% OF INDIVIDUALS IN
WHICH THERE'S AN IDENTIFIABLE
DRIVER HAVE CLEAR MUTATIONS IN
DNMT3A.
IT'S A DNA METHYL TRANS PHRASE,
IT CAN CHANGE THE METHYLATION
STATUS AT THE CPG DIE
NUCLEOTIDES SO WE'VE ALREADY
HEARD THAT THERE IS -- THAT DNA
METHYLATION CAN BE USED TO
MONITOR BIOLOGICAL AGE AND IT
COULD BE THAT SOME OF THESE
EPIGENETIC REGULATORS ARE PARTLY
UNDERLYING THAT.
SO HOW DO THESE MUTANT STEM
CELLS WIN?
THERE'S STILL A LOT OF WORK TO
BE DONE ON THAT BUT WE THINK
THAT THEY LARGELY WIN BECAUSE
THEY HAVE A BIAS TOWARDS MAKING
MORE STEM CELLS.
SO EVERY CELL DIVISION, SOME OF
THOSE DNMT3A MUTANT CELLS WILL
MAKE MORE STEM CELLS INSTEAD OF
GO ON TO DIFFERENTIATE, AND
AGAIN THAT SLIGHT BIAS, YOU'LL
END UP WITH MORE STEM CELLS IN
THE END AND YOU'LL END UP WITH
MORE DIFFERENTIATED CELLS IN THE
PERIPHERAL BLOOD.
WE'VE GONE ON TO STUDY IT IN A
LOT MORE DETAIL BECAUSE EVERYONE
ENDS UP WITH MUTANT CLONES, NOW
THERE'S LOTS AND LOTS OF DATA ON
THE MUTANT CLONES OUT THERE AND
THE SIZE OF THOSE CLONES IN
DIFFERENT INDIVIDUALS.
SO WE'VE STARTED TO DO
FUNCTIONAL GENOMICS ON SOME OF
THOSE MUTATIONS AND SHOWN THAT
SOME OF THOSE MUTATIONS ARE
ACTUALLY WORSE THAN OTHERS.
SO WE FOUND ABOUT A THIRD OF THE
MUTATIONS THAT MAKE THE PROTEIN
UNSTABLE, AND SO INDIVIDUALS
WITH AN UNSTABLE MUTANT
ESSENTIALLY HAVE SOMETHING LIKE
A HETEROZYGOUS LOSS OF FUNCTION,
THEY HAVE HALF THE AMOUNT OF
DNMT3A PROTEIN AS THEY WOULD
OTHERWISE.
THERE'S MANY OTHER MUTATIONS
THAT ARE STABLE THAT CAN CAUSE
DIFFERENT KINDS OF EFFECTS, BUT
YOU CAN CLASSIFY INDIVIDUALS
TOGETHER WHO HAVE 50% OF THIS
FUNCTIONAL PROTEIN.
THE BOTTOM LINE FOR ALL THAT IS
THAT INDIVIDUALS O.A.R.
INDIVIDUAL CELLS HAVE DIFFERENT
AMOUNTS OF DNMT3A ACTIVITY.
WE THINK THIS ACTIVITY REALLY
TRACKS VERY CLOSELY WITH THE
OUTPUT OF THE STEM CELLS AND
THAT AGAIN BACK TO THIS MARATHON
OR SPORTS ANALOGY, ANY REDUCTION
IN DNMT3A IS A PERFORMANCE
ENHANCER FOR THOSE STEM CELLS.
SO --
>> YOU HAVE 2 MINUTES REMAINING.
>> THANK YOU.
DNMT3A IS THE MARATHONER THAT
ALWAYS WINS, REALLY, IN ALL
CONTEXTS.
OKAY.
SO I'VE TOLD YOU VERY BRIEFLY
ABOUT THREE DIFFERENT GENES THAT
ARE INVOLVED IN CLONAL
HEMATOPOIESIS AND THEY ALL HAVE
SLIGHTLY DIFFERENT STRATEGIES
FOR WINNING OVER TIME AND
PROBABLY ALL HAVE DIFFERENT
IMPACTS.
IN THE LAST MINUTE HERE, I JUST
WANT TO TOUCH ON SOME OF THE
OTHER REMAINING QUESTIONS FROM
HERE AND HOW THIS RELATES TO
AGING MORE BROADLY.
WE NEED TO CATALOG THE WINNING
CLONES, WE NEED TO UNDERSTAND
HOW CLONAL HEMATOPOIESIS
CONTRIBUTES TO CANCER AND AGING
AND UNDERSTAND IF THEY'RE ALL
EQUALLY BAD.
SO I THINK HOW THESE CONTRIBUTE
TO AGING IS REALLY THE RESEARCH
FRONTIER.
THERE'S BEEN A LOT OF DISCUSSION
ABOUT IT'S AN INFLAMMATORY
PROCESS, THE CLONES THEMSELVES
BECOME MORE INFLAMMATORY BUT
THEY'RE ALSO MORE SENSITIVE TO
INFLAMMATION AND THAT MAY
FURTHER DRIVE THEIR EXPANSION
AND THE EXPANSION OF THEIR
DOWNSTREAM CELLS AND THIS MAY BE
DIFFERENT FOR DIFFERENT CH
CLONES.
RECENTLY THERE WAS ONE PAPER
THAT SHOWED LOSS OF FUNCTION
MUTATION OF CH WITH DNMT3A
AND -- 2 ACCELERATED HEART
DISEASE, AND CONCORDANT WITH
MACROPHAGE PHENOTYPES, AND THE
OPPOSITE WAS SHOWN BY THE SAME
GROUP BUT DIFFERENT COMBINATION
OF PEOPLE THAT CLONAL
HEMATOPOIESIS MIGHT PROTECT FOR
ALZHEIMER'S IN SOME CASES.
OBVIOUSLY WE NEED ADDITIONAL
STUDIES AND I WILL JUST SAY THAT
THERE'S ONE FROM A COLLEAGUE AT
BAYLOR WHERE THEY'VE BEEN USING
A MOUSE MODEL TO ALSO LOOK AT
BOTH TE T2 AND DNMT3A IN AN
ALZHEIMER'S MODEL, AND THEY
FOUND OPPOSITE RESULTS FOR THESE
TWO.
SO DNMT3A HAD ONE OUTPUT AND TE
T2 HAD A DIFFERENT OUTPUT IN
TERMS OF EXACERBATING FEATURES.
SO CLEARLY THERE'S REALLY A LOT
MORE TO DO.
I THINK BECAUSE WE'RE OUT OF
TIME I REALLY WON'T TOUCH ON
THESE.
I CAN LEAVE THIS SLIDE UP AND WE
CAN TALK ABOUT WHAT THE KEY
RESEARCH GAPS ARE AND
OPPORTUNITIES, AND THANK YOU ALL
AGAIN FOR HAVING ME.
THANK YOU.
>> THANKS, PEGGY.
LET'S SEE WHAT QUESTIONS WE HAVE
HERE.
OKAY, LET'S START WITH THE ONE
IN THE Q & A.
NEGATIVE REGULATION -- AMPLY
FAKES FIXES DETECTED IN CH?
>> THAT'S GREAT QUESTION.
NOT SO FAR THAT I HAVE SEEN,
THEY HAVE NOT SHOWN UP YET.
SO YOU WOULD NEED, THOUGH, AN
ACTIVATION OF THAT, RIGHT?
THAT'S ESSENTIALLY WHAT THESE
PPM1D MUTATIONS DO, THEY
STABILIZE THE PROTEIN, YOU GET A
LOT MORE.
SO IF THERE'S A WAY TO MAKE IT
HYPERACTIVE, THOSE ARE THE
MUTATIONS YOU WOULD WANT TO LOOK
FOR.
>> GOT IT.
HOW ABOUT P53 ITSELF, WHILE
WE'RE ON THAT TOPIC?
>> THEY ARE QUITE COMMON
ACTUALLY IN CLONAL HEMATOPOI
HEMATOPOIESIS.
YES.
AND THEY SHOW UP SORT OF SIDE BY
SIDE WITH PPM1D AND THEY'RE
POSITIVELY SELECTED FOR SO
PROBABLY ALMOST COMPETING WITH
EACH OTHER IN SOME CASES AS
WELL.
>> GOT IT.
MAYBE ONE MORE QUESTION.
GO AHEAD, ZORINA.
>> I WAS GOING TO ASK, WE WERE
VERY EXCITED IN THE
CARDIOVASCULAR FIELD WHEN A FEW
YEARS BACK, THE DICHOTOMY
BETWEEN CANCER AND
CARDIOVASCULAR WAS ACTUALLY
PINNED ON THIS CLONAL
HEMATOPOIESIS, SO I WAS
WONDERING IF YOU HAD SOME
COMMENTS ABOUT THAT.
>> WELL, I THINK IT'S A GREAT
QUESTION.
IT'S REALLY ONE OF THE BIG
FRONTIERS, I THINK, THAT WE NEED
TO LOOK AT SOME MORE.
NOW THERE'S BEEN ENOUGH STUDIES
THAT REALLY VALIDATED THIS
STATISTICAL LINK IN HUMANS
BETWEEN CLONAL HEMATOPOIESIS AND
CARDIOVASCULAR DISEASE.
BUT WE REALLY DO NOT UNDERSTAND
THE MECHANISMS.
WE DO NOT UNDERSTAND IF ALL
CLONAL HEMATOPOIESIS CLONES ARE
EQUALLY BAD IN PROMOTING
CARDIOVASCULAR DISEASE.
I THIF THINK STUDIES NEED TO BE.
SOME OF THE NEEDS OVER THE NEXT
FIVE YEARS WOULD BE LARGE SCALE
STUDIES OF THE MUTATIONS ACROSS
INDIVIDUALS AND ACCESSIBLE
TISSUES EVEN TO LOOK AT SOMATIC
MOSAICISM.
SOME OF THIS MIGHT BE ABLE TO BE
DONE IN EXISTING AGING COHORTS
TO REALLY LOOK AT THOSE LINKS.
LINKS.ANOTHER THING I WOULD LIKE
TO MENTION, IT'S SORT OF TOUCHED
ON BY HAVING THIS CONFERENCE IN
THE FIRST PLACE, IS THE CANCER
AND NON-CANCER RELEVANCE.
NIH AS WAS MENTIONED IN THE
BEGINNING LIKES TO BUCKET ALL OF
THESE DIFFERENT AGING-ASSOCIATED
DISEASES BUT THEY'RE CLEARLY
INTERTWINED AND I THINK THIS
REALLY OFFERS AN OPPORTUNITY TO
STUDY THEM TOGETHER.
AND CLONAL HEMATOPOIESIS IS
IMPLEMENTED IN BOTH.
>> THANK YOU.
>> PEGGY, I HAVE A QUESTION.
SO YOU SHOWED THIS IMPRESSIVE
TABLE OF GENES IN CLONAL
HEMATOPOIESIS LINKED TO
DIFFERENT DISEASES.
DO YOU THINK THERE'S GOING TO BE
LIKE SPECIFIC MUTATION
SIGNATURES ASSOCIATED WITH
DISEASE?
>> WELL, I THINK IT'S EARLY.
YOU KNOW, A LOT OF THESE STUDIES
HAVE NOT BEEN VERY LARGE, AND SO
IT'S BEEN DIFFICULT TO REALLY
PINPOINT IT.
SO FOR EXAMPLE, FOR THE HUMAN
ALZHEIMER'S STUDY THAT WAS DONE
THE A STANFORD LED BY SYD
JASWALL, FANTASTIC STUDY,
REALLY, REALLY GREAT, BUT THE
POWER WAS NOT ENOUGH TO REALLY
SAY WELL, IT WAS LINKED WITH
DNMT3A AND TET 2 OR A LOT OF
OTHER DETAILED ASPECTS OF THAT.
AND HOW THIS RELATES TO THE
METHYLATION CLOCK THAT HAS BEEN
DISCUSSED A LOT, YOU KNOW, IS
CLONAL HEMATOPOIESIS GOING TO BE
A BETTER OR WORSE MARKER OF
BIOLOGICAL AGING.
I THINK IT'S PROBABLY GOING TO
TRACK VERY CLOSELY WITH IT.
TALKING ABOUT MONITORING WITH
DR. SNYDER'S TALK.
I PERSONALLY THINK WE ALL SHOULD
BE MONITORED FOR CLONAL
HEMATOPOIESIS TOO AS WE GET
ABOVE A CERTAIN AGE BECAUSE WE
PROBABLY EVENTUALLY WILL
UNDERSTAND HOW IT TRACKS WITH
THESE RISKS, ALTHOUGH WE DON'T
REALLY UNDERSTAND IT RIGHT NOW,
BUT AS DR. SNYDER SAID, THE
LONGITUDAL MONITORING HAS
ENORMOUS VALUE.
>> PHIL, IF YOU DON'T MIND
WAITING FOR THE PANEL.
>> SURE, TO TALK ABOUT ALL THOSE
THINGS.
>> OR POP IT IN THE Q & A,
EITHER WAY.
WE BETTER KEEP MOVING.
SO THANK YOU FOR THE AWESOME
TALK THERE, PEGGY.
AND OUR NEXT SPEAKER IS ASHANI
WEERARATNA.
SORRY, I KNEW I'D STUMBLE OVER
THAT ONE.
APOLOGIES THERE.
AGE AGAINST THE MACHINE: HOW
THE AGING MICRO ENENVIRONMENT
DRIVES TUMOR PROGRESSION.
TAKE IT AWAY, ASHANI.
>> HI, EVERYONE.
I HOPE YOU CAN HEAR ME OKAY.
>> YOU'RE GOOD.
>> I WILL TRY TO GET THROUGH
THIS VERY QUICKLY.
AND PEGGY SET ME UP VERY NICELY
SAYING THAT THERE'S A LOT OF
INTERSECTIONS BETWEEN AGING AND
CANCER, SO HERE'S A SLIDE I WAS
ASKED TO PRESENT TO YOU, SO
HOPEFULLY YOU'LL ALL BE ON THE
SAME PAGE BY THE END OF THIS
PRESENTATION, AND UNDERSTAND
THAT THERE ARE BOTH COMMON ALES
BETWEEN AGING AND CANCER CELLS
AND THAT AGE CAN DRIVE TUMOR
PROGRESSION.
AS I'VE ALWAYS SAID, CANCER IS A
DISEASE OF AIMING AND WHEN I
WORKED AT THE NIA ALMOST A
DECADE AGO, THAT WAS FROWNED
UPON.
HOWEVER, FOR EVERY HUNDRED
PEOPLE DIAGNOSED WITH CANCER,
OVER 90% OF THEM ARE OVER THE
AGE OF 50, AND THIS IS ALSO TRUE
FOR THOSE WHO DIE OF CANCER FOR
ALL CANCERS COMBINED GLOBALLY.
THERE ARE MANY, MANY MOLECULAR
AND CELLULAR SIMILARITIES
BETWEEN CELLS THAT ARE AGING AND
CELLS THAT ARE CANCER CELLS.
WE HAVE THIS MAP OF THE
HALLMARKS OF CANCER THAT TALKS
ABOUT ALL OF THE DIFFERENT
FEATURES OF CANCER CELLS THAT
MAKE THEM CANCER CELLS.
WE SEE THE SAME THING WITH AGING
CELLS.
AND WE SEE THAT BETWEEN BOTH
AGING CELLS AND CANCER CELLS,
THERE ARE VERY -- THERE ARE LOTS
OF SIMILARITIES LIKE
METHYLATION, GENOMIC
INSTABILITY, CHANGES IN
METABOLISM, CHANGES IN
TELOMERES, ALTHOUGH IN THIS CASE
IN OPPOSITE DIRECTIONS, AS WELL
AS THE ONSET OF SENESCENCE IN
BOTH CONDITIONS.
THERE HAS BEEN SOME BEAUTIFUL
WORK DONE BY PEOPLE LIKE JOAO
PEDRO DE IS THE MAGALHAES AT THE
UNIVERSITY OF LIVERPOOL.
WHAT HE HAS DONE IS LOOK AT
MUTATIONS IN CANCER CELLS IN
MULTIPLE CANCER TYPES OVER THE
SPECTRUM OF AG AGING AND HE FINS
AN INCREASE IN GENOMIC STABILITY
AND THERE'S ALSO CRITICAL
CHANGES IN THESE SOMATIC COPY
NUMBER ALTERATIONS, AND THEY
OCCUR IN CANCER DRIVER GENES.
AGAIN, THEY INCREASE WITH AGE
AND THEY OCCUR OVER THE SPECTRUM
OF AGING AS WELL.
WE ALL KNEW IT'S NOT JUST AGING
BUT ALSO -- NOT JUST GENETICS
BUT ALSO EPIGENETICS.
PEOPLE LIKE JEAN-PIERRE AND
SHELLEY BERGER HAVE DONE A BUTTE
TESTIMONY JOB LOOKING AT
EPIGENETIC DRIFT WITH AGING AND
NOT HOW ONLY AGING BUT OTHER
FACTORS SUCH AS OBESITY AND
SMOKING CAN COMBINE TO DRIVING
EPIGENETIC DRIFT THAT LEADS TO
CHANGES IN CANCER CELLS.
HARI EASWARAN AT JOHNS HOPKINS
HAS ALSO MADE ORGANOIDS OUT OF
COLON CELLS, AND THESE ARE WILD
TYPE, THEY'RE NOT CANCER, AND HE
SHOWS THAT IF HE AGES THEM OVER
A YEAR TO A YEAR AND A HALF, HE
FINDS EPIGENETIC CHANGES THAT
OCCUR IN WNT GENES AND THAT
THESE EPIGENETIC CHANGES DRIVE
FURTHER MUTATIONS OR FURTHER
CHANGES, I SHOULD SAY, THAT LEAD
THESE NORMAL COLON CELLS TO
BECOME MORE AND MORE PRIMED TO
BECOME TUMOR CELLS.
MY GOOD FRIEND JAMES DEGREGORI
AT THE UNIVERSITY OF COLORADO
WHO YOU'LL HEAR FROM LATER IN
THIS SERIES HAS SUMMARIZED ALL
OF THIS QUITE BEAUTIFULLY INTO
THIS SPECTRUM OF CHANGES WITH
AGE, WHERE HE SHOWS THAT THERE
ARE CHANGES THAT OCCUR WHEN WE
ARE YOUNG THAT HAVE A
STABILIZING SELECTION SO, FOR
EXAMPLE, IF THERE'S GENETIC
DAMAGE AND MUTATIONS, THOSE STEM
CELLS ARE QUICKLY PURGED FROM
THE POOL.
BUT AS WE AGE, THERE BECOME AS
CHANGE THAT GOES FROM A
STABILIZING SELECTION TO A
POSITIVE SELECTION, POSITIVELY
EXCELLENTING CSELECTING THAT HAR
DRIVER MUTATIONS.
MY LAB HAS FOCUSED ON SOMETHING
ENTIRELY DIFFERENT.
WE'VE BEEN LOOKING AT THE TUMOR
MICROENVIRONMENT AND THE
QUESTION WE HAVE ASKED OURSELVES
IS, WHAT IS HAPPENING TO ALL
THOSE CELLS THAT ARE NOT CANCER
CELLS?
AS WE AGE.
AND SO, YOU KNOW, I LIKE TO SAW
NO TUMOR IS AN ISLAND, IT EXISTS
IN THIS MILIEU OF FIBROBLASTS
AND ENDOTHELIAL CELLS AND FAT
CELLS AS WELL AS THE BIOPHYSICAL
MATRICES THAT SOME OF THESE
CELLS CREATE.
WE HAVE FOCUSED LARGELY ON THE
FIBROBLAST POPULATION IN
MELANOMA, BECAUSE IT'S A CANCER
OF THE SKIN AND THE MELANOMA
CELL SPENDS MUCH OF ITS LIFE
RIGHT HERE AT THE EPIDERMIS AND
THE DERMIS BECOMING MALIGNANT
AND THE DERMIS IS LARGELY
INSTRUCTED BY THESE FIBROBLASTS
WHICH WE CALL THE CONSTRUCTION
WORKERS OF THE SKIN BECAUSE THEY
LAY DOWN ALL THE BIOPHYSICAL
SCAFFOLDS AND WE HAVE FOUND THAT
OVER TIME, THESE CHANGE AND
THOSE SCAFFOLDS CAN THEN FURTHER
CONTRIBUTE TO THE WAY TUMOR
CELLS MOVE THROUGH THIS DERMIS
TO BECOME METASTATIC.
THE QUESTION I'M OFTEN ASKED IS,
WELL, DON'T THESE FIBROBLASTS
TURN OVER, AND BEAUTIFUL WORK
FROM VAL TINA GRECO SHOWS
THERE'S A LOT OF FIBROBLAST
HOMEOSTASIS IN THE SKIN WHICH --
SO INSTEAD OF WHEN CELLS DIE OR
DURING AGING THAT ARE LOST,
INSTEAD OF THE OTHER CELLS
RAPIDLY PROLIFERATING TO FILL IN
THOSE GAPS, INSTEAD WHAT WE SEE
ARE THE EXISTING CELLS KIND OF
STRETCHING THEIR WAY IN TO THOSE
GAPS TO MAINTAIN THE POSITIONAL
STABILITY OF THESE FIBROBLASTS.
IN ADDITION, I'M OFTEN ASKED
ABOUT SENESCENCE, AND I HAVE, I
GUESS, A SOMEWHAT CONTROVERSIAL
VIEW ON SENESCENCE.
AGING AND SENESCENCE ARE OFTEN
CONFLATED.
THEY ARE NOT THE SAME THING.
WE SEE A LOT OF DIFFERENCE
BETWEEN OUR AGING FIBROBLASTS
AND SENESCENT FIBROBLASTS, AND
REMEMBER THAT SENESCENCE OCCURS
ACROSS THE LIFESPAN, EVEN IN
EMRYOGENESIS.
SO THERE ARE BEAUTIFUL REVIEWS
ON SENESCENCE, BUT I WOULD ADD
OF COURSE JUDY CAMPISI IS
ACTUALLY THE PERSON WHO INSPIRED
ME TO GO INTO ANY OF THE THIS
AGING FIBROBLAST WORK AS HER
WORK SHOWED SO BEAUTIFULLY THAT
THESE SENESCENT CELLS CAN DRIVE
TUMORIGENESIS.
BUT PLEASE REMEMBER NOT ALL
SENESCENCE IS CREATED EQUAL.
NOT ALL SENESCENCE IS TERMINAL.
AND AGING AND SENESCENCE ARE NOT
INTERCHANGEABLE.
SO HAVING SAID THAT, I KNOW MY
FRIEND SHE THAT STEWART IS ON
THIS CALL AND SHE ALWAYS ASKED
ME WHAT KIND OF FIBROBLASTS ARE
OUR AGING -- ARE AGING
FIBROBLASTS.
THE SIMPLE ANSWER IS THAT THEY
EXPRESS MANY OF THE FEATURES OF
THE DIFFERENT SUBTYPES OF
FIBROBLASTS, SO THIS IS FROM A
REVIEW WRITTEN BY A VERY
BRILLIANT FACULTY IN MY LAB.
SHEILA HAD TELL YOU ABOUT
ICAFs, ANTIGEN PRESENTING, BUT
WHAT WE SEE IS THAT EACH
FIBROBLAST ACTUALLY EXPRESSES
DIFFERENT FEATURES OF EACH OF
THESE FIBROBLASTS AND WE THINK
REALLY WITH AGING, IT PRIMES THE
FIBROBLASTS SUCH THAT THEY JUST
NEED A LITTLE NUDGE TO BE PUSHED
OVER INTO A CANCER ASSOCIATED
FIBROBLAST FE PHENOTYPE, AND THT
ENDS UP OCCURRING WHEN THERE ARE
INITIATED TUMOR CELLS IN THE
MICROENVIRONMENT.
OVER THE YEARS WE'VE FOUND AGING
FIBROBLASTS DRIVE MULTIPLE
CHANGES THAT LEAD TO TUMOR
PROGRESSION FROM CHANGES IN THE
MATRIX DRIVING METASTASIS TO
THERAPY RESISTANCE,
ANGIOGENESIS, METABOLISM, THE
IMMUNE MICROENVIRONMENT, I'LL
TALK A LITTLE BIT ABOUT OUR NEW
WORK IN SEXUAL DIMORPHISM AND
AGING AND SOME RECENT DORMANCY
WORK AS WELL.
SO LIKE I SAID, WE ARE
INTERESTED IN MELANOMA AND WE
COLLABORATED WITH FORMER
COLLEAGUES AT THE NATIONAL
INSTITUTE ON AGING INITIALLY,
AND THEN STARTED USING THESE
FIBROBLASTS FROM THE CORIEL
DATABASE THAT COME FROM THE
BALTIMORE LONGITUDAL STUDY OF
AGE, AND WE TOOK FIBROBLASTS
FROM HEALTHY DONOR, EITHER IN
THAIRD MID 20s TO MID 30s OR
MID 50s TO MID 60s WHICH IS
WHERE THE INCIDENCE OF MELANOMA
TAKES OFF AND WE USE THEM TO
MAKE ARTIFICIAL SKIN.
IF WE PLACE MELANOMA CELLS IN
THOSE ARTIFICIAL SKIN THEY WILL
INVADE RAPIDLY INTO THIS DERMIS,
AS THEY WERE IN THE DERMIS OF
THE ACTUAL SKIN AND WE SEE THAT
PREDOMINANTLY WITH THE AGED
FIBROBLAST.
SO MITCH FANE IN MY LAB WANTED
TO KNOW WHETHER THEY METASTASIZE
MORE QUICKLY IN YOUNG OR AGED,
AND WHAT HE SAW IS THAT IN
YOUNG -- THE TUMOR CELLS WOULD
GET TO THE LUNG AND THEY WOULD
GROW OUT FAR MORE RAPIDLY IN THE
AGED LUNGS THAN THE YOUNG LUNGS.
THIS HAS ALREADY BEEN PUBLISHED
SO I'M JUST SKIPPING VERY
QUICKLY THROUGH THIS, BUT WHAT
MITCH ALSO SAW, HE LACKED FOR
WHAT COULD BE DRIVING THAT AND
HE LOOKED AT LUNG FIBROBLASTS.
HE IDENTIFIED SECRETED FACTORS
IN THE AGED LUNG FIBROBLASTS
THAT COULD CONTRIBUTE TO THE
OUTGROWTH, THIS RAPID OUTGROWTH
WE WERE SEEING OF MELANOMA
CELLS.
AND WHEN HE QUERIES WHETHER OR
NOT MANIPULATING THOSE FACTORS
CAN IMPACT TUMOR CELLS, HE FINDS
THAT INDEED THEY CAN.
SO IF HE TAKES OUR AGED MICE, HE
GIVES THEM THESE MELANOMA CELLS,
ALLOWS THREE WEEKS FOR THE
INITIAL DISSEMINATION, LETS THEM
GET TO THE LUNG, THEN HE TREATS
WITH AN ANTIBODY AGAINST THIS
PARTICULAR PROTEIN, SFRP1.
HE FINDS HE CAN KEEP THESE CELLS
IN THEIR SINGLE CELL STATE IN
THE AGED LUNGS, WHEN HE CAN
REALLY REDUCE THE OUTGROWTH OF
THESE METASTATIC COLONIES.
WE'VE ALSO BEEN VERY INTERESTED
ON HOW AGE IMPACTS CANCER
THERAPY.
AGAIN, IF WE LOOK AT THE HALL
MARKS OF CANCER, WE HAVE
MULTIPLE GREAT INHIBITORS, BUT
MOST OF THE CLINICAL TRIALS
DON'T REALLY TAKE AGE INTO
ACCOUNT EXCEPT TO EXCLUDE
PATIENTS WHO ARE OLDER AND LESS
HEALTHY, SO THAT DOESN'T REALLY
HELP.
WE FOUND THAT IN TUMORS GROWING
IN AGED ANIMALS, THERE WAS FAR
MORE ANGIOGENESIS.
HOWEVER, THAT ANGIOGENESIS WAS
NOT DRIVEN BY VEGF, AND IN FACT,
IF WE LOOK AT VEGF AND ITS
RECEPTORS ACROSS AGING, THE
EXPRESSION OF THOSE WERE
ACTUALLY REDUCED, AND SO WE
ASKED THE QUESTION, WHETHER THAT
MEANT THESE PATIENTS WOULD BE
LESS RESPONSIVE TO EFASTIN.
THERE WAS THIS HUGE STUDY
CONDUCTED IN THE UK WHERE A
THOUSAND MELANOMA PATIENTS WERE
GIVEN AVASTIN AND THE CONCLUSION
OF THE STUDY WAS THERE'S NO REAL
CHANGE IN OUTCOME SO WE ASKED
THE INVESTIGATORS TO GO BACK,
REANALYZE THE DATA AND THEN BY
AGE WHICH THEY VERY KINDLY DID.
SORRY, MY TIMER IS ON FOR SOME
REASON.
AND WHAT WE SEE IS THAT ACTUALLY
PATIENTS UNDER THE AGE OF 45 DO
RESPOND TO AVASTIN, WHEREAS
THOSE 65 AND OLDER DO NOT
RESPOND TO AVASTIN.
SO WE WANTED TO KNOW WHAT WERE
THE MECHANISMS BEHIND THIS.
WHAT WE FOUND WAS THAT THIS
OTHER MOLECULE, SO A SISTER
MOLECULE TO THE ONE I JUST
TALKED ABOUT CALLED
SFRP2 SECRETED FRIZZ EL RELATED
PROTEIN 2 IS A DRIVER OF ANG
GENESIS SPECIFICALLY IN TUMORS
IN AGED MICE AND AGED HUMANS
WHEREAS THOSE SAME TUMORS HAVE
FAR LESS EXPRESSION OF VEGF.
AND SO THE CONCLUSION FROM THIS
STUDY WAS THAT DURING AGING
SFRP2 INCREASES AND VEGF
INCREASES, AND IT'S SFR PSM
2 THAT DRIVES ANGIOGENESIS SO
THERE'S NO POINT IN TREATING
WITH AVASTIN BECAUSE IT'S NOT
THE DRIVER OF ANGIOGENESIS IN
THIS CASE.
SO I'M TRYING TO SHOW YOU
SNAPSHOTS OF THESE STUDIES TO
SAY HOW IMPORTANT IT IS TO
CONSIDER WHAT'S HAPPENING IN THE
AGING MICROENVIRONMENT SO THAT
WE CAN PROPERLY TREAT OUR CANCER
PATIENTS.
HERE'S ANOTHER EXAMPLE.
WE FOUND THAT AGED FIBROBLASTS
SECRETE LIPIDS.
WHEN THEY SECRETE THOSE LIPIDS,
MELANOMA CELLS EXPOSED TO AGED
FIBROBLASTS BUT NOT YOUNG
FIBROBLASTS UPREGULATE THIS
RECEPTOR TON THEIR -- FATTY ACID
PROTEIN TRANSPORTER 2 AND WHEN
THEY DO THAT, THEY'RE ABLE TO
ACCUMULATE THE LIPIDS.
WE FOUND FATP2 IS EXPRESSED IN
MELANOMA PATIENT OVER THE AGE OF
50 SO WE ASKED THE QUESTION WHAT
HAPPENS WHEN WE TARGET FATP2 IN
TUMORS.
SO WE TOOK OUR MOUSE TUMORS AND
WHAT WE SEE -- AND WE TREATED
THEM WITH -- SORRY, I SHOULD
BACK UP.
SO WHAT WE FOUND WITH THE
ACCUMULATION OF THESE FATTY
ACIDS CREATED A FATTY ACID
OXIDATION IN THESE MELANOMA
CELLS THAT WE SUSPECTED WOULD
MAKE THEM RESISTANT TO TARGETED
THERAPY IN MELANOMA.
THE THERAPY THAT WE USED TO
TARGET MELANOMA IS TARGETED
AGAINST A MUTANT BRAF ONCOGENE,
AND SO WHAT WE DID WAS TO TREAT
TUMORS IN YOUNG AND AGED MICE
WITH BRAF MEK INHIBITORS IN THE
ABSENCE OR PRESENCE OF FATP2.
WHAT WE SEE IS THAT HAVING THE
FATP2 THERE DOESN'T REALLY
AFFECT THE GROWTH AT ALL OF THE
TUMORS, AND IN YOUNG MICE, WHEN
WE TARGET THE TUMORS WITH THE
BRAF INHIBITORS THEY RESPOND AND
THEY EVENTUALLY COME BACK.
THIS IS SOMETHING WE SEE
ROUTINELY.
IF WE FIRST KNOCK DOWN FATP2,
THEY DO EXACTLY THE SAME THING.
THERE'S NO IMPACT IN THE YOUNG
MICE.
IN THE AGED MICE, HOWEVER, IT'S
A VERY DIFFERENT STORY.
WHAT WE SEE IN THE AGED MICE,
THOSE TUMORS TREATED WITH BRAF
ME CMEK INHIBITORS, STOM STOP A
SECOND, THINK ABOUT IT AND KEEP
ON GOING.
>> SPEAKER, YOU HAVE 2 MINUTES
REMAINING.
>> GREAT.
THANK YOU.
IF WE DEPLETE FATP2, THESE
TUMORS DISSOLVE AND GO AWAY.
SO I'LL FINISH WITH JUST A
COUPLE OF SLIDES FROM THIS VERY
TALENTED FACULTY IN MY LAB.
YASH CHHABRA, WHO HAS BEEN
LOOKING AT THE INTERSECTIONALITY
OF AGE AND MELANOMA.
WHILE YOU CAN SEE THAT WHILE
MORTALITY AND INCIDENCE
INCREASES IN BOTH SEXES BY AGE,
IT'S WORSE IN THE MALES, AND
YASH HAS DONE THIS HUGE AMOUNT
OF WORK THAT SHOWING AGED MALE
FIBROBLASTS AND AGED FEMALE
FIBROBLASTS UNDERGO VERY
DIFFERENT CHANGES.
I'M SHOWING YOU THIS VERY
QUICKLY IN THE INTEREST OF TIME.
THE AGED MALE FIBROBLASTS UNDER
UNDERGO AGE-RELATED SENESCENCE.
THERE IS AN INCREASE IN THE
INVASION OF MELANOMA CELLS, BUT
I WANT TO GET TO THE IB THE INO
DATA.
YASH DID THIS BIG EXPERIMENT
WHERE HE TOOK MALE AND FEMALE
MELANOMA CELLS AND PUT THEM IN
EITHER MALE OR FEMALE YOUNG AND
AGED MICE.
HE DID THIS BIG CRISSCROSS
EXPERIMENT AND HE FOUND NO
MATTER WHAT THE SEX OF THE
MELANOMA CELL WAS, IT GREW
SLOWER IN THE AGED MALE MICE BUT
METASTASIZED -- I'M SORRY.
METASTASIZED MORE EFFECTIVELY IN
THE AGED MALE MICE.
SO THE AGED MALE
MICROENVIRONMENT WAS DRIVING
CHANGES IN METASTASIS, CHANGES
IN DNA DAMAGE.
AGAIN, NO MATTER THE SEX OF THE
TUMOR CELLS, THE AGED MALE MOUSE
DN KENTUCKY SHOWED M
SHOWED MORE INCREASES IN -- BMPD
SPECIFICALLY IN THE AGED MALE
MICROENVIRONMENT, AND EXPRESSED
IN TUMORS THAT GROW IN THE AGED
MALE MICROENVIRONMENT.
THIS PROTEIN WHEN WE GIVE TO THE
AGED MALE MICE, IT INCREASES
THEIR METASTASIS.
IT ALSO MAKES THEM MORE
RESISTANT TO THERAPY.
AND SO I HOPE THAT I'VE SHOWN
YOU ALL THAT UNDERSTANDING, IT'S
REALLY CRITICAL FOR US TO
UNDERSTAND ALL OF THESE
ENVIRONMENTAL FACTORS, IT'S
CRITICAL FOR SUCCESSFUL THERAPY
IN CANCER, CANCER REALLY IS A
DISEASE OF AGING, AND OUR GOAL
OF THIS IS TO TRY TO FIGURE OUT
HOW TO TARGET THE INTERSECTION
OF ALL OF THESE DIFFERENT
PARAMETERS IN MELANOMA, AND
FIGURE OUT HOW TO HARNESS ONE TO
DISRUPT THE IMPACT OF THE
OTHERS.
THESE WERE SOME OF THE THINGS
YOU ASKED ME TO LIST.
I GUESS I WENT A LITTLE BIT
ROGUE HERE.
THERE'S A TON OF STUFF.
WE NEED MORE MECHANISTIC
UNDERSTANDING, WE NEED
BIOMARKERS THAT ALLOW US TO COME
IN AND MAYBE IMPACT CANCER RISK
WITH AGE.
WE NEED TO BETTER UNDERSTAND HOW
ENVIRONMENTAL FACTORS INTERSECT
WITH LIFESTYLE, AND AGING.
WE NEED MORE LONGITUDAL STUDIES
OF CANCER AND AGING, AND
UNDERSTANDING THE HETEROGENEITY
OF BOTH OF THESE DISEASES AND
HOW WE CAN TARGET THOSE
INTERSECTIONS IS GOING TO BE
CRITICAL.
OBVIOUSLY UNDERSTANDING CHANGES
IN THE IMMUNE SYSTEM WITH AGE IS
CRITICAL, GIVEN IMMUNOTHERAPY
AND CANCER AND WE HAVE A LOT OF
ONGOING PROJECTS HERE AS WELL.
AND OVER THE NEXT FIVE YEARS,
WE'RE GOING TO NEED MORE
RELIABLE ANIMAL MODELS, BETTER
ACCESS TO AGING MICE, CLEARER
MANDATE ON THE DESIGN OF BOTH
PRE-CLINICAL AND CLINICAL TRIALS
TO INCLUDE AGE AS A FACTOR IN
CANCER TRIALS.
AS WELL AS DEVELOPING ORGANOID
MODELS, AND BUILDING ACCESSIBLE
DATABASES FOR TUMORS THAT
INCLUDE AGING AND OUTCOME, AS
WELL AS NORMAL TISSUE ACROSS THE
SPECTRUM OF AGING.
SO I'LL STOP THERE.
I WANT TO THANK -- OH, MY SLIDE
FELL OFF.
I HAD AN ACKNOWLEDGMENT SLIDE
FOR EVERYONE IN THE LAB WHO HAVE
JUST BEEN AMAZING.
>> THANKS, ASHANI, GREAT.
AWESOME STUFF.
I THINK WE HAVE TIME FOR ONE
QUESTION.
I DON'T SEE ANY IN THE Q & A.
SO DO YOU THINK THIS IS ALL
GROWTH FACTORS FROM THE
FIBROBLASTS OR IS IT ALSO THE
ECM, LIKE THE COLLAGEN AND --
>> YEAH.
>> HOW DO YOU THINK THIS WORKS?
>> YEAH, IT'S DEFINITELY A
MIXTURE OF BOTH.
SO WE'VE SHOWN THAT FIBROBLASTS
THAT ARE AGED LAY DOWN A VERY
DIFFERENT ECM THAN FIBROBLASTS
THAT ARE YOUNG, AND THAT ECM IS
PERMISSIVE TO TUMOR INVASION,
BUT RESTRICTIVE TO IMMUNE CELL
INFILTRATION.
AND SO THAT'S DEFINITELY ONE
ASPECT.
THE OTHER ASPECT IS THE GROWTH
FACTORS, AND THEN WE ARE FINDING
CHANGES IN AGE-RELATED OWE DIP
SITES, AGE-RELATED ENDOTHELIAL
CELLS, BREAKDOWN IN VASCULARITY
AND PERMEABILITY.
SO HOST OF FACTORS.
>> YEAH, PROBABLY LOTS THERE.
ALL RIGHT.
I THINK WE CAN SAVE OTHER
QUESTIONS FOR THE PANEL.
WE'LL TRY TO STAY ON TIME SINCE
THE PANEL IS A LITTLE BIT SHORT
SO THANKS, ASHANI.
COMING UP, ZORINA IS PROMPTING
ME SO THIS IS GREAT.
I REMEMBER ANYWAYS, MIRANDA ORR.
HERE IT IS ON THE SLIDE.
PLN TALKING ABOUT SENESCENT CEL.
LET'S SEE IF SHE CAN COME BACK
AND RESCUE THEM.
ALL RIGHT, MIRANDA.
>> THANKS SO MUCH FOR THE
INTRODUCTION, AND I'M SO HAPPY
TO BE HERE.
MY NAME IS MIRANDA ORR.
I'M AN ASSOCIATE PROFESSOR AT
WAKE FOREST UNIVERSITY SCHOOL OF
MEDICINE.
AND A RESEARCH HEALTH SCIENTIST
AT THE SALISBURY VA IN NORTH
CAROLINA.
MY LAB, WE ARE A TRANSLATIONAL
NEUROBIOLOGY LAB AND WHAT WE'RE
INTERESTED IN IS UNDERSTANDING
WHAT IS THIS BLACK BOX OF AGING,
AND HOW IS IT THAT A VERY YOUNG,
HEALTHY, VIBRANT MIND, MY
EXAMPLE HERE IS MY MATERNAL
GRANDMOTHER, SHE GRADUATED HER
CLASS VALEDICTORIAN, THROUGH THE
COURSE OF A LIFESPAN CAN TURN
THIS ONCE VIBRANT ORGAN INTO
SOMETHING VERY DYSFUNCTIONAL
THAT'S NOT ONLY FRUSTRATING FOR
THE PERSON EXPERIENCING IT, BUT
DEVASTATING TO THE FAMILY.
SO TO ANSWER THIS QUESTION, OUR
LAB REALLY FOCUSES ON LESSONS
FROM THE BIOLOGY OF AGING FIELD
THAT HAVE IDENTIFIED FUNDAMENTAL
CELLULAR AND MOLECULAR PROCESSES
THAT NOT ONLY CO-OCCUR WITH
AGING BUT IF THEY'RE PERTURBED,
THEY CAN INCREASE THE -- OR
DECREASE THE AGE IN WHICH
AGE-ASSOCIATED DISEASES HAPPEN,
BUT IF THEY'RE INTERVENED UPON
APPROPRIATELY, YOU CAN DELAY THE
ONSET OF THESE DISEASES.
SO ONCE WE IDENTIFIED SOMETHING
WE THOUGHT MIGHT BE RELEVANT TO
ALZHEIMER'S DISEASE, THE NEXT
STEP IS TO LOOK FOR EVIDENCE IN
PEOPLE.
SO WE SPENT A LOT OF TIME
LOOKING AT POSTMORTEM HUMAN
BRAINS AND DATASETS GENERATED BY
OTHERS IN THE FIELD AND ONCE WE
DO FIND EVIDENCE THAT THESE ARE
ABERRANTLY PERTURBED IN
ALZHEIMER'S, THEN WE CAN TAKE
THIS BACK TO THE LAB, IDENTIFY
MICE TO TEST MECHANISTIC
STUDIES, DO INTERVENTIONS
FOCUSING ON CLINICALLY RELEVANT
OUTCOMES LAKE BEHAVIOR, BRAIN
IMAGING, NEUROPATHOLOGY AND IF
TRIALS WORK IN MICE, WE MOVE TO
EARLY PHASE CLINICAL TRIALS.
SO THAT IS THE PERSPECTIVE IN
WHICH YOU WILL HEAR MY
PRESENTATION, AND BRIEFLY WHAT
I'M GOING TO TRY TO ACCOMPLISH
IN THE NEXT 12 MINUTES OR SO IS
TALK ABOUT SHARED AND UNIQUE
CO-MORBID CONDITIONS OF POOR
BRAIN AGING WITH RELATED FOCUS
ON DEMENTIA, TALK ABOUT
BIOLOGICAL AGING DRIVERS OF
BRAIN HEALTH DECLINE WITH FOCUS
ON CELLULAR SENESCENCE, THAT IS
MY LAB'S EXPERTISE, AND TALKING
ABOUT SENESCENCE AS A SHARED
RISK AND TALK ABOUT PRESSING
NEEDS MOVING FORWARD AT LEAST
FROM MY PERSPECTIVE.
SO RECENTLY, DEMENTIA HAS BECOME
THE NUMBER ONE MOST FEARED
HEALTH CONDITION OF GROWING
OLDER ACROSS THE GLOBE, SO
PEOPLE FEAR THIS MORE THAN
DEVELOPING CANCER OR STROKE.
AND BY FAR THE GREATEST RISK
FACTOR FOR DEVELOPING DEMENTIA
IS ADVANCED AGE.
THROUGHOUT THE WORKSHOP, YOU
WILL HEAR LOTS OF ADVICE ON
HEALTHY LIFESTYLE CHOICES TO
REDUCE YOUR RISK OF DISEASES AND
MANY OF THEM ARE SHARED WITH
DEMENTIA, SO CONTROLLING HIGH
BLOOD PRESSURE, GETTING ENOUGH
SLEEP, HEALTHY DIET, PHYSICALLY
ACTIVE, REALLY THE MANTRA OF
HEALTHY AGING, AS WELL AS
STAYING CONNECTED WITH FAMILY
AND FRIENDS.
BUT EVEN INDIVIDUALS THAT MANAGE
TO DO ALL OF THESE THINGS TO THE
BEST OF THEIR ABILITY, THERE IS
AN INCREASED CHANCE OF
DEVELOPING DEMENTIA IN LATER
LIFE.
SO TRYING TO THINK ABOUT RISK
FACTORS THAT MIGHT BE DRIVING
DEMENTIA, SOME CLUES HAVE BEEN
TAKEN FROM COMMON CO-MORBID
CONDITIONS THAT PEOPLE WITH
ALZHEIMER'S AND DEMENTIA
EXPERIENCE.
SO SOME OF THEM ARE LISTED HERE.
SO GOING FROM ASSOCIATION STU
STUDIES IN HUMAN POPULATIONS TO
UNDERSTANDING THE MECHANISM
DRIVING THIS, WE REALLY -- MY
LAB REALLY FOCUSES ON THE
BIOLOGY OF AGING WITH A
PARTICULAR EMPHASIS ON CELLULAR
SENESCENCE.
NOT ONLY BECAUSE WE WERE VERY
CURIOUS, WI BUT BECAUSE THERE WS
EMERGING DATA IN THE LITERATURE
THAT SENESCENT CELLS WERE
ACCUMULATING IN ALL OF THESE
DIFFERENT CONDITIONS.
WE'VE HEARD DID SENESCENCE
ALREADY BUT I DID PUT TOGETHER A
FEW SLIDES AND ANIMATION OF WHAT
CELLULAR SENESCENCE IS TO GET
EVERYBODY ON THE SAME PAGE, SO
IF YOU THINK OF THESE CELLS,
THESE OVALS AS HEALTHY CELLS AND
YOU CAN THINK OF THIS AS NATISH
EU, AND YOUR CELL UNDERGOES
DAMAGE AND IF WE THINK OF THIS
AS SKIN, SAY YOU'RE OUTSIDE ON A
HOT SUMMER DAY AND YOU GET UV
DAMAGE, THE CELL HAS CELL FATE
OPTIONS.
ONE IS THAT IT CAN CONTINUE TO
DIVIDE WITH DAMAGE AND THIS IS
BAD, IT CAN BECOME CANCER.
ANOTHER IS THAT IT MAY UND UNDEO
APOPTOSIS.
IF THIS IS A REGENERATIVE
TISSUE, THAT CELL CAN BE
REPLACED.
THE THIRD, HOWEVER, IS NEITHER
PROLIFERATION NOR APOPTOSIS BUT
IT CHANGES CELL FATE.
THESE CELLS CHANGE THEIR
MORPHOLOGY, THEIR TRANSCRIPTOME,
THEIR PROTEOME.
THEY REALLY CANNOT DIE, THEY
REALLY RELY ON THE IMMUNE SYSTEM
TO CLEAR THEM AND THEY RELEASE A
BUNCH OF FACTORS, EXTRACELLULAR
MATRIX REMODELING PROTEINS, SO
IF AN IMMUNE SYSTEM DOESN'T
CLEAR THEM, THEY ACCUMULATE WITH
TIME, THEY CAUSE HEALTHY CELLS
TO UNDERGO APOPTOSIS OR
TRANSFORM THEM INTO SENESCENT
CELLS.
SO OUR QUESTION REALLY WAS, DO
SENESCENT CELLS ACCUMULATE IN
THE BRAIN?
WHEN WE FIRST STARTED TESTING
THIS, OR INVESTIGATING THIS, WE
HAD A HYPOTHESIS-DRIVEN
QUESTION, AND THAT WAS TO LOOK
AT BRAIN CELLS IN ALZHEIMER'S
THAT ARGUABLY HAD THE HIGHEST
LEVEL OF DAMAGE.
AND THAT ARE NEURONS WITH
NEUROFIB LEFIBRILLARY TANGLES.
YOU CAN SEE THIS CELL SO REALLY
ENCASED IN THIS PURPLE DYE.
THEY ARE PREDICTED TO SURVIVE
MANY DECADES IN THE HUMAN BRAIN
BUT THEY CLOSELY CORRELATE WITH
DEMENTIA.
WE DID FIND A SENESCENT
SIGNATURE IN NEURONS WITH
TANGLES.
THE NEXT STEP WAS TO USE AN
UNBIASED APPROACH TO REALLY GET
A BETTER SURVEY OF SENESCENT
CELLS IN THE BRAIN.
SO WE LOOKED AT ABOUT 140,000
CELLS DERIVED FROM 76 POSTMORTEM
HUMAN BRAINS WITH DIFFERENT
LEVELS OF ALZHEIMER'S DISEASE,
NEUROPATHOLOGY AND USED FOUR
EMBRYONIC BRAINS AS CONTROL.
WHAT WE FOUND WAS ABOUT 2% OF
THE BRAIN CELLS WERE SENESCENT,
AND LARGELY OVERLAPPED WITH
NEURONS WITH TANGLES.
SO NOW THAT WE KNEW THAT WE
COULD FIND SENESCENT CELLS IN
THE BRAIN, THE QUESTION IS, DO
THEY MATTER?
TO ANSWER THIS, WE TREATED TAU
TRANSGENIC MICE WITH ADVANCED
NEUROPATHOLOGY SO HIGH LEVELS OF
THESE TANGLES WITH DRUGS THAT
SELECTIVELY CLEAR THESE
SENESCENT CELLS.
YOU WILL HEAR A LOT MORE ABOUT
THIS THERAPY IN THE LATER
SESSION, BUT IN OUR EXPERIMENT,
WHEN WE TREATED THESE MICE, WE
SAW THAT CLEARING SENESCENT
CELLS IMPROVED BRAIN STRUCTURE
AND FUNCTION, REALLY PROVIDING
EVIDENCE THAT THESE SENESCENT
CELLS WERE DETRIMENTAL.
SO MOVING THAT FORWARD, WE
RECENTLY COMPLETED A PHASE ONE
CLINICAL TRIAL WHERE WE WERE
INTERESTED IN DETERMINING BLOOD
BRAIN BARRIER PENETRANCE OF THE
16 LYTICS, SAFETY AS WELL AS --
RELEVANT TO SENESCENCE AND
ALZHEIMER'S DISEASE.
THIS WAS DONE IN COLLABORATION
WITH A FANTASTIC TEAM AT UT
HEALTH IN SAN ANTONIO.
THIS IS -- YOU CAN SEE IT
ONLINE, I'M GOING TO BRIEFLY
DISCUSS OUR PRIMARY OUTCOMES.
SO IN THIS TRIAL WE RECRUITED
OLDER ADULTS WITH MILD
ALZHEIMER'S DISEASE AND WE HAD
FIVE PEOPLE THAT COMPLETED THE
STUDY AND WE WERE LOOKING AT
ONE, BLOOD BRAIN BARRIER
PENETRANCE AND PHARMACOLOGY.
SO SHOWN HERE ARE THE BLOOD
LEVELS, THESE WERE GIVEN ORALLY,
INTERMITTENTLY FOR THREE MONTHS
AND COMPARED TO PRE-TREATMENT
VERSUS POST TREATMENT, YOU CAN
SEE THAT WE DID FIND ELEVATED
AMOUNTS OF THESE DRUGS IN THE
PLASMA.
WHEN WE LOOKED IN THE C IS SF,
WE FOUND DASATINIB IN FOUR OF
THE FIVE.
WE DID NOT FIND -- I'M HAPPY TO
TALK TO YOU ABOUT THAT IN THE Q
& A.
OVERALL THE TREATMENT WAS WELL
TOLERATED, WE DIDN'T HAVE ANY
EARLY DISCONTINUATIONS.
WE SAW SEVERAL FACTORS THAT
MODESTLY DECREASED AND OVERALL
WE INTERPRETED THE ORAL -- WAS
WELL TOLERATED, DEEP PENETRATED
THE CENTRAL NERVOUS SYSTEM AND
THERE WERE SUBTLE HINTS FOR CSF
BIOMARKERS.
WITH THAT WE HAVE NOW MOVED TO
PHASE 2.
THIS IS FUNDED BY THE
ALZHEIMER'S DRUG DISCOVERY
FOUNDATION.
IT IS A MULTISITE TRIAL AND IT
RUN HERE AT WAKE FOREST AND SITE
PIs IN SAN ANTONIO, AND IN
THIS TRIAL WE ARE INCLUDING A
PLACEBO ARM ADDING MORE
PARTICIPANTS.
OUR TARGET ENROLLMENT IS 48.
WE ALSO HAVE INCLUDED AN
EXTENDED FOLLOW-UP.
AFTER THE INDIVIDUALS OR STUDY
PARTICIPANTS COMPLETE TREATMENT,
THEY REMAIN ENROLLED AND WE
COLLECT DATA FROM THEM EVERY
THREE MONTHS OR NINE MONTHS TO
DETERMINE IF AND WHEN SENESCENT
CELLS RE-APPEAR AND WE ALSO
ADDED AGING OUTCOMES THANKS TO
THE PEPPER CENTER.
BECAUSE SENESCENT CELLS ARE
ACCUMULATING IN ALL OF OUR
TISSUES AS WE GROW OLDER, WE
THINK THAT REMOVING THEM, THERE
IS A CHANCE TO IMPACT OVERALL
HEALTH, AND THIS FIGURE IS FROM
A REVIEW THAT WAS PUBLISHED IN
2019.
AT THAT TIME THE STATUS OF THE
FIELD, SENESCENT CELLS HAD BEEN
IDENTIFIED AND WHAT DISEASES
THEY CONTRIBUTED TO.
SO IN ADDITION TO OUR TRIAL
OUTCOMES OF TRADITIONAL
ALZHEIMER'S MEASURES, COGNITION,
BRAIN IMAGING AND ALZHEIMER'S
DISEASE MARKERS AND BIOFLUIDS,
WE HAVE ADDED A LOT OF OUTCOMES
REALLY RELEVANT TO BIOLOGICAL
AGING.
SO OF COURSE SENESCENCE AND --
WE'RE NOT COLLECTING DATA ON
STEM CELL EXHAUSTION OR TELOMERE
ATTRITION BUT REALLY TRYING TO
COVER ALL OF THE OTHER HALL
MARKS.
WE'VE ALSO INCLUDED
PHYSIOLOGICAL MEASURES OF AGING,
AS WELL AS GRIP STRENGTH.
SO WE ARE HOPING TO BE FULLY
ENROLLED NEXT SPRING WITH DATA
IN 2025.
NEUROSCIENCE FIELD WAS A BIT
LATE TO STUDY SENESCENCE IN OUR
FAVORITE TISSUES IN THE BRAIN
AND CENTRAL NERVOUS SYSTEM IN
GENERAL, BUT WHAT I'VE PUT HERE,
I'M GOING TO TOGGLE BACK AND
FORTH BETWEEN THESE TWO SLIDES
REALLY TO HIGHLIGHT WHAT
ACTIVITY IS IN THE NEUROSCIENCE
FIELD EVALUATING SENESCENCE.
THESE ARE FROM 2018 AND BEYOND,
SO REALLY A LOT OF ACTIVE
RESEARCH SHOWING HOW IMPORTANT
SENESCENT CELLS MIGHT BE IN MANY
NEURODEGENERATIVE DISEASES.
SO THEN THINKING ABOUT WHAT
FACTORS COULD IMPACT THE ONSET
OF SENESCENT CELLS IN THE BRAIN
AND LEAD TO DEMENTIA, A LOT OF
THOSE CLUES HAVE COME FROM
COLLEAGUES IN THE NEUROSCIENCE
SPACE.
SO THERE HAVE BEEN RESEARCH
GROUPS THAT HAVE SHOWN
PERIPHERAL INSULIN RESISTANCE
CAN DRIVE SENESCENCE IN THE
BRAIN, OBESITY, DEPRESSION AND
AKITE, VIRAL INFECTION AND
TRAUMATIC BRAIN INJURY.
SO ALL OF THESE ARE DRIVING
SENESCENCE IN THE BRAIN, AND
DRIVING THE INCREASED ONSET OF
NEURODEGENERATIVE DISEASES.
SO WE THINK THAT THERE MAY BE A
PUSH TOWARDS A DEGENERATIVE
TRAJECTORY WITH SENESCENCE.
AND WE HEARD THE BEAUTIFUL TALK
EARLIER ABOUT CLONAL
HEMATOPOIESIS, AND THAT PAPER
WAS REALLY INTERESTING TO ME
BECAUSE IT HAD AN INVERSE
CORRELATION WITH ALZHEIMER'S
DISEASE, SO PERHAPS IN THIS WAY
SENESCENCE, IF A CELL HAS A CELL
FATE OPTION TO MAKE, IT IS
BLOCKING THE PROLIFERATIVE
TRAJECTORY.
BUT OF COURSE THIS IS ALL VERY
COMPLICATECOMPLICATED AND THERES
ENVIRONMENT, AGE, GENETICS AND
WHAT TYPE OF STRESSORS NEED TO
BE CONSIDERED AND WHEN WE'RE
INTEGRATING ALL OF THESE DATA,
WE THINK IT'S ALSO REALLY
IMPORTANT TO GET BEYOND JUST
BULK TRANSCRIPTOMICS OR EVEN
SINGLE CELL TRANSCRIPTOMICS AND
REALLY LOOK AT HIGH RESOLUTION,
HIGH-PLEX MULTI-OMICS DATA
WITHIN A CELL AND SUBCELLULAR
RESOLUTION TO SEE WHAT'S
HAPPENING IN THAT CELL IN ITS
NEIGHBORING ENVIRONMENT AND
BEYOND.
SO IN THE LAST FEW MINUTES THAT
I HAVE, I'M GOING TO TOUCH ON
SOME KEY RESEARCH GAPS AND
OPPORTUNITIES FROM MY
PERSPECTIVE AND I'VE BROKEN
THESE INTO BOTH CLINICAL AND
DISCOVERY SCIENCE.
ON THE CLINICAL SIDE, I THINK
THERE IS A BIG NEED TO
UNDERSTAND BRAIN HEALTH AND RATE
OF AGING ACROSS DIVERSE
POPULATIONS AND ACROSS THE
LIFESPAN.
SO WE REALLY DON'T KNOW MUCH
ABOUT BRAIN HEALTH AND AGING IN
RACIAL AND ETHNIC MINORITIES,
SEXUAL AND GENDER MINORITIES,
INDIVIDUALS FROM RURAL AND
UNDERSERRED AREAS, ACROSS THE
ECONOMIC STRATA AND MILITARY
VETERANS AND UNDERSTANDING HOW
THESE BRAINS ARE CHANGING WILL
REALLY HELP US BETTER ANSWER
THIS QUESTION, WHAT ARE COMMON
AND SHARED RISK FACTORS.
WE ALSO REALLY DON'T HAVE A GOOD
IDEA OF HOW PEOPLE WITH DEMENTIA
AGE.
THEY ARE TYPICALLY EXCLUDED FROM
AGING STUDIES.
WE'VE HEARD THAT IN THE LAST
TALK.
THERE'S DIFFERENT EXCLUSION
CRITERIA FOR AGE BASED ON WHAT
DISEASE OF AGING YOU'RE
STUDYING, SO I'D LIKE TO SEE
PEOPLE WITH DEMENTIA INCLUDED IN
THESE STUDIES IF AND WHEN
POSSIBLE.
ANOTHER POINT IS THAT MANY
METRICS OF BRAIN HEALTH AND
PERFORMANCE PEAK IN THE 30s
BUT AGING STUDIES BEGIN MUCH
LATER.
I THINK WE NEED TO START
YOUNGER.
THAT WAS ANOTHER POINT THAT WAS
BROUGHT UP EARLIER AS WELL.
I THINK WE NEED A BETTER
DEFINITION OF AGING FOR RESEARCH
PURPOSES.
IT'S REALLY CHALLENGING TO
IDENTIFY INTERVENTIONS AND
DESIGN TRIALS WITHOUT A CLEAR
DIFFICULT NIGDEFINITION OF OUTC.
I THINK WE NEED A MORE
AGGRESSIVE TRANSLATION OF
PROMISING PRE-CLINICAL
THERAPIES.
ON THE DISCOVERY SIDE, THERE'S A
LOT OF NEED TO BETTER UNDERSTAND
MIMECHANISMS MEDIATING WITHIN
TISSUES.
WE KNOW THAT NOT ALL OF OUR
ORGANS ARE AGING AT THE SAME
RATE.
IT'S LIKELY THAT OUR CELLS
AREN'T AGING AT THE SAME RATE
EITHER, AND I PROVIDE SENESCENCE
AS ONE EXAMPLE BUT THERE ARE A
LOT OF OTHER BIOLOGICAL AGING
HALLMARKS THAT ARE IMPORTANT TO
INCORPORATE.
I MENTIONED INCORPORATING
SPATIAL OMICS DATA --
>> SPEAKER, YOU HAVE 2 MINUTES
REMAINING.
>> THANK YOU SO MUCHMENT I ALSO
THINK THAT WE MIGHT BE AT A
PLACE OR GETTING CLOSE TO A
PLACE FOR PRECISION MEDICINE
APPROACHES FOR AGING, SO REALLY
TESTING COMBINATION THERAPIES
THAT TARGET MULTIPLE AGING HALL
MARKS, DOING THIS IN MODEL
ORGANISMS AND IDENTIFYING THE
APPROPRIATE AGES FOR EACH
THERAPY.
SO THEN JUST CLOSING WITH THE
NEEDS OVER THE NEXT FIVE YEARS,
THIS IS SOMETHING THAT A LOT OF
US SAY THAT STUDY AGING, THERE'S
A NEED FOR GREATER AND LONGER
BUDGET PERIODS FOR IN VIVO
MAMMALIAN AG AGING STUDIES.
THESE ARE LONG AND EXTENSIVE.
I MENTIONED THIS IN MY PRIOR
SLIDE BUT I THINK IT WOULD BE
REALLY IMPORTANT TO HAVE -- FOR
OBSERVATIONAL AND INTERVENTIONAL
RESEARCH SIMILAR AS FOR
ALZHEIMER'S DISEASE.
SO FOCUSING ON A BIOLOGICAL
FRAMEWORK WHICH THE AGING FIELD
ALREADY HAS AND NOT BIOLOGICAL
CONSEQUENCES.
REALLY CATAPULT THESE CLINICAL
STUDIES.
IF WE'RE NOT HERE, I THINK WE
NEED A PLAN TO GET HERE QUICKLY.
I THINK IT'S ALSO IMPORTANT TO
HARMONIZE A CONSISTENT LIST OF
AGING OUTCOMES FOR CLINICAL
TRIALS THAT INCLUDE BRAIN AND
COGNITIVE HEALTH.
I DON'T KNOW IF THIS WOULD
REQUIRE A CONSENSUS GROUP, BUT
THERE ARE A LOT OF METRICS TO
CONSIDER.
HOW ARE WE ASSESSING BRAIN AGING
THROUGH THE LIFESPAN.
IS IT BIOMARKERS IN FLUIDS,
THERE'S A LOT OF ACTIVE AND
FANTASTIC RESEARCH IN DIGITAL
BIOMARKERS.
AND THEN INCORPORATE METRICS OF
BRAIN HEALTH IN AGING STUDIES,
WHICH I THINK INTERDISCIPLINARY
COLLABORATIONS WILL BEST TACKLE
THAT.
I WOULD LIKE TO END WITH A QUOTE
FROM MY FATHER-IN-LAW THAT HE
GAVE ME OVER DINNER ONE NIGHT,
AND THAT WAS, "IF I FOLLOWED ALL
OF THE HEALTHY LIFESTYLE ADVICE,
I WOULDN'T HAVE TIME FOR
ANYTHING ELSE."
I THINK THAT KIND OF SUMS UP OUR
FIELD.
THERE'S SO MUCH INFORMATION
THAT'S COMING UP, COMING OUT,
TRYING TO COH COHESIVELY UNDERSD
IT IS CHALLENGING BUT WE ARE
GETTING THERE.
WE DO NEED TO TAKE TIME TO FOCUS
ON OUR HEALTHY LIFE.
AND SO WITH THAT, I WOULD JUST
LIKE TO ACKNOWLEDGE MY AMAZING
LAB, MY COLLABORATORS HERE AT
WAKE FOREST AND AT OTHER
INSTITUTIONS AND MY FUNDING
SUPPORT ALLOWS ME TO CONTINUE
DOING THIS EXCITING RESEARCH.
SO THANK YOU SO MUCH FOR YOUR
TIME AND I THINK I HAVE LEFT
TIME FOR SOME QUESTIONS.
>> YOU HAVE.
GREAT TALK.
YOU ONLY HAVE TO FOLLOW THE GOOD
ADVICE, YOU CAN IGNORE ALL THE
BAD.
ANYWAY, LET'S START WITH ONE
FROM DR. YAZ IN THE Q & A.
DR. ORR, YOU PREVIOUSLY
PRESENTED AN ABSTRACT ON
SUPPLEMENTING NAD WITH --
RIBOSIDE TO ADDRESS MILD
COGNITIVE IMPAIRMENT.
HOW DOES THIS IMPACT SENESCENCE
IN THIS STUDY?
>> THAT IS A GREAT QUESTION.
SO THAT PAPER IS CURRENTLY UNDER
REVIEW.
WE DID NOT LOOK AT CELLULAR
SENESCENCE IN THAT CLINICAL
STUDY.
WE ABSOLUTELY SHOULD HAVE.
WE DIDN'T.
BUT I DO KNOW THAT THERE IS A
LOT OF ACTIVE RESEARCH IN THAT
BY OTHER LABS IN THE FIELD
LOOKING AT HOW NICK TIN MIGHT OR
ANY NAD BOOSTERS MAY ALTER
CELLULAR SENESCENCE.
THAT'S A REALLY GOOD QUESTION.
>> LIKE SENESCENT CELLS, DO
SENESCENT NEURONS SECRETE SAS
FACTORS WHICH AFFECT OTHER
NEIGHBORING YOUNG NEURONS?
>> I CAN TELL YOU WHAT WE ARE
SEEING PRELIMINARILY.
PLEAS DON'T TAKE THIS TO THE
BANK BECAUSE IT NEEDS TO BE
REPEATED.
SO ONE THING THAT WE ARE TRYING
TO IDENTIFY IS WHAT MAY BE
NEURONAL SPECIFIC SAS.
NEURONS ARE REALLY INTERESTING
BRAIN CELLS IN THAT THEY
COMMUNICATE TO EACH OTHER IN A
VERY DIFFERENT WAY THAN OTHER
CELLS SO WE'RE TRYING TO FIGURE
OUT WHEN NEURONS BECOME
SENESCENT IF THEY CHANGE THAT
MESSAGE, AND IF THEY'RE
IMPACTING THEIR LOCAL
ENVIRONMENT AS WELL AS THEIR
SYNAPTICALLY CONNECTED
ENVIRONMENT.
WE HAVE EVIDENCE THEY ARE
IMPACTING BOTH.
I AM DEFINITELY NOT BRAVE ENOUGH
TO GIVE YOU ANY CONCRETE ANSWERS
BEYOND THAT BUT WE'RE ACTIVELY
LOOKING INTO THAT.
>> BY DEFINITION, THEY SHOULD BE
EXPRESSING, THAT'S HOW WE FIND
SENESCENT CELLS, SO THEY MUST BE
EXPRESSING THEM SOMEHOW.
COOL.
THERE'S SOME OTHER COMMENTS HE
HERE.
OH, SAME QUESTION UP HERE.
I HAVE A QUESTION WHICH IS ABOUT
THE -- SO REALLY SHARP PEOPLE,
DO THEY HAVE MORE OR LESS
SENESCENT CELLS IN THEIR BRAIN?
I COULD ARGUE IT EITHER WAY.
>> SO I CAN ALSO TELL YOU SOME
PRELIMINARY DATA.
WE HAVE AN R01, THE GOAL IS TO
DETERMINE WHEN IN THE ADULT
LIFESPAN DO SENESCENT CELLS
FIRST APPEAR.
SO WE'RE LOOKING AT POSTMORTEM
VIEW OF BRAINS ACROSS THE ENTIRE
ADULT LIFESPAN, AGE 20 TO
100-PLUS, AND THEN ONCE WE HIT
THE AGE OF 60, WE'RE LOOKING AT
THOSE WITH DEMENTIA VERSUS THOSE
THAT DON'T.
I DON'T KNOW THE TRUE COGNITIVE
STATUS ON OUR DEMENTIA-NEGATIVE
PEOPLE TO KNOW IF THEY'RE SUPER
SHARP, BUT I CAN TELL YOU THAT
WE'RE FINDING SENESCENT CELLS
FAR YOUNGER IN THE LIFESPAN THAN
I EVER HOPED.
WE'RE DEFINITELY FINDING THEM AS
EARLY AS THE 40s.
I DON'T KNOW IF WE WILL FIND
THEM EARLIER.
BUT THEY'RE HAPPENING.
I'M SURE I HAVE SOME IN MY
BRAIN.
>> WELL, WE ALL DO, JUST LIKE WE
ALL HAVE C.H. CELLS APPARENTLY.
ALL RIGHT.
>> ANOTHER QUESTION, MIKE.
SO ALZHEIMER'S DISEASE IS ALMOST
TWICE AS COMMON IN WOMEN
COMPARED TO MEN SO DO THE WOMEN
ACCUMULATE MORE SENESCENT CELLS,
DO YOU KNOW?
>> SO RIGHT NOW WE HAVE NOT SEEN
A SEX DIFFERENCE, BUT THAT IS
JUST ON TOTAL SENESCENT CELL
BURDEN.
BUT WE'RE TRYING TO GET BETTER
WITH OUR REFINEMENT AND LOOKING
AT DIFFERENT TYPES OF SENESCENT
CELLS.
NOT ALL SENESCENT CELLS ARE BAD.
SO STAY TUNED.
WE DON'T KNOW THAT ANSWER YET.
>> VERY NICE TALK.
HOW MUCH SYSTEMIC INFLAMMATION
PLAYS A ROLE, AND IS SENESCENCE
SORT OF DISGUISED BY SYSTEMIC
INFLAMMATION OR VICE VERSA?
>> THAT IS A QUESTION THAT I GET
ALL THE TIME AND I DON'T HAVE A
FANTASTIC ANSWER BECAUSE IT'S SO
CHALLENGING.
HOW DO YOU DETERMINE
INFLAMMATION COMING FROM
SENESCENT CELLS VERSUS
INFLAMMATION COMING FROM OTHER
SOURCES.
I THINK THE BEST WAY TO LOOK AT
THAT IS IN ANIMAL MODELS, BUT
THE.WITH OUR CLINICAL TRIAL, A T
OF OUR FACTORS WE'RE MEASURING
ARE GOING TO BE DIFFICULT TO
ATTRIBUTE ONLY TO SENESCENT
CELLS.
IF WE COULD FIND SENESCENT CELL
SPECIFIC BIOMARKERS OF
INFLAMMATION, THAT WOULD BE FABE
FANTASTIC.
I DON'T KNOW IF WE EVER WILL.
>> WELL THANKS VERY MUCH.
WE BETTER MOVE TO THE NEXT
SPEAKER WHICH I THINK SEGUES
REALLY NICELY.
FILIP SWIRSKI IS GOING TO TELL
BUS LIFE STYLE EFFECTS ON BRA
BRAIN-BODY COMMUNICATION.
>> THANK YOU VERY MUCH.
THIS IS A FANTASTIC WORKSHOP,
VERY HAPPY TO BE HERE.
WHAT I WANT TO DO FOR THE NEXT
15 MINUTES IS TO SHARE WITH YOU
THE WORK THAT WE DO, AND HERE WE
VERY MUCH STUDY LIFE STYLE
FACTORS ON BRAIN-BODY
COMMUNICATION AND WE APPROACH
THIS FROM THE PERSPECTIVE THAT
WE'RE NOT HERE -- OUR STUDIES
ARE NOT DESIGNED TO DETERMINE
WHETHER A PARTICULAR LIFESTYLE
IS GOOD OR BAD FOR YOU.
WE CERTAINLY KNOW THE BENEFITS
OF SLEEP, THE DIET, AVOIDING OR
MANAGING STRESS.
RATHER, WE ARE MOTIVATED BY THE
QUESTION, YOU KNOW, HOW DOES
THIS HAPPEN, AT A TISSUE PLE LAR
AND CELLULAR SCALE.
SO BEFORE I LAUNCH INTO WHERE
OUR SPECIFIC STUDIES HAVE TAKEN
US, I WANT TO INTRODUCE OR AT
LEAST TOUCH ON SOME CONCEPTS
THAT HAVE ALREADY BEEN ACTUALLY
INTRODUCED TODAY VERY
BEAUTIFULLY BY PREVIOUS SPEAKERS
THAT I THINK SERVE TO REALLY
ANIMATE AND CONTEXTUALIZE SOME
OF THE STUDIES.
SO THE FIRST IS THIS IDEA THAT
HOMEOSTASIS AND DEVIATION FROM
HOMEOSTASIS THAT CAN ULTIMATELY
LEAD TO DISEASE REALLY ENGAGES
MULTIPLE SYSTEMS.
IT'S ALREADY A TRANS SYSTEM
PHENOMENON, AND IN ORDER TO
UNDERSTAND HOW DISEASES ACCRUE
AND WHAT EFFECTS DO THEY HAVE,
WE REALLY NEED TO DO STUDIES
THAT GO BEYOND STUDYING A SINGLE
SYSTEM.
SO IF WE ENGAGE AND BETTER
UNDERSTAND HOW THE NERVOUS
SYSTEM, HOW THE IMMUNE SYSTEM,
HOW THE METABOLIC SYSTEM AND
CIRCULATORY SYSTEMS ENGAGE
TOGETHER, THAT I THINK ALLOWS US
TO BETTER UNDERSTAND HOW WE
ACCRUE DISEASES DURING AGING.
SO WHILE A PARTICULAR DISEASE
MAY HAVE ONE CAUSE, ONE MUTATED
GENE, THE EFFECTS OF THAT REALLY
DOES ENGAGE MULTIPLE PATHWAYS.
THE SECOND IS A CONCEPT THAT
WE'VE ALREADY HEARD A NUMBER OF
TIMES HERE, SO THIS IDEA OF
CHRONOLOGICAL AND BIOLOGICAL
AGE, SO I WON'T DWELL ON THIS,
EXCEPT TO SAY THAT IN ASKING HOW
DOES CHRONOLOGICAL AGE DEVIATE
FROM BIOLOGICAL AGE, WE HAVE
THIS VERY HANDY CONCEPT OF THE
EXPOSOME, WHICH AGAIN WAS ALSO
INTRODUCED.
AND HERE WE CAN LOOK AT SO
CALLED PERSONAL EXPOSOME, MUCH
OF WHICH MAY BE RELATED TO
LIFESTYLE FACTORS SUCH AS
EXERCISE, DIET, SLEEP AND
STRESS, AND MORE OF A GENERAL
EXPOSOME OVER WHICH WE PERHAPS
HAVE LESS CONTROL, SUCH AS OUR
ENVIRONMENT, CLIMATE CHANGE
ENVIRONMENT, EVEN THINGS LIKE
INFECTION.
SO WITH THAT IN MIND, KEEPING
THESE IDEAS, WHAT I WANT TO DO
IS GIVE YOU VERY SPECIFIC
EXAMPLES OF HOW WITH THESE
CONCEPTS WE STUDY HOW LIFESTYLE
FACTORS AFFECT BIOLOGY AND
LIFESTYLE FACTORS, EITHER
PROTECT AGAINST DISEASE OR
ELEVATE RISK FOR DISEASE.
THE FOUR HERE THAT I HAVE ARE
STRESS, DIET, EXERCISE AND
SLEEP, JUST BECAUSE THAT'S WHAT
WE'VE BEEN WORKING ON FOR THE
LAST SEVEN OR EIGHT YEARS.
THERE'S OF COURSE OTHERS, AND I
THINK I'M JUST GOING TO TOUCH ON
THREE OF THEM JUST IN THE
INTEREST OF TIME.
SO LET'S START WITH SLEEP.
SO ONE OF THE WAYS THAT WE
STUDIED THIS IS, AGAIN, TO
REALLY ENGAGE WITH MULTIPLE
SYSTEMS USING TOOLS OF
NEUROSCIENCE, OF IMMUNOLOGY, OF
VASCULAR BIOLOGY, OF HEMATOLOGY.
SO FOR EXAMPLE, IN UNDERSTANDING
HOW SLEEP MAY PROTECT US AGAINST
DISEASE OR CONVERSELY HOW SLEEP
DEPRIVATION MAY ELEVATE RISK FOR
CARDIOVASCULAR DISEASE OR OTHER
TYPES OF DISEASES, WHAT WE WANT
TO UNDERSTAND IS, FIRST, HOW
DOES THE NERVOUS SYSTEM, HOW
DOES THE CENTRAL NERVOUS SYSTEM,
THE BRAIN SORT OF UNDERSTAND
SLEEP AND PERTURBATIONS OF
SLEEP, AND THEN CONNECT THAT
WITH PLACES WHERE THE IMMUNE
SYSTEM IS VERY RELEVANT.
SO THE BONE MARROW, WHICH IS
WHERE IMMUNE CELLS ARE BORN OR
LYMPHOID ORGANS WHERE THERE IS
GENERATION OF MEMORY, AND THEN
CONNECT THAT TO IF WE'RE
STUDYING, FOR EXAMPLE,
CARDIOVASCULAR DISEASE TO
VESSELS, TO THE VESSEL WALLS AND
THE PROCESSES THAT OCCUR DURING
ATHEROSCLEROSIS AND ITS
COMPLICATIONS.
SO JUST AS AN EXAMPLE OF, YOU
KNOW, WHERE DOES WORK LIKE
THIS -- WHERE IT CAN LEAD US, SO
JUST A CARTOON OF SUMMARIZING
SOME OF THE STUDIES THAT WE'VE
DONE OVER THE LAST FEW YEARS.
SO FOR EXAMPLE, AND I HOPE YOU
CAN SEE MY MOUSE HERE, FOR
EXAMPLE, ONE INSIGHT THAT WE CAN
GAIN FROM ST STUDYING SLEEP
DISRUPTION ON THIS BRAIN-BODY
COMMUNICATION IS THAT IN THE
HYPOTHALAMUS, THERE IS A
NEUROPEPTIDE THAT REALLY CONT
CONTROLS HEMATOPOIESIS.
WE KNOW THIS BY LOOKING AT
HEMATOPOIESIS IN THE BONE MARROW
AND FINDING THAT THERE ARE IN
BONE MARROW NICHES SPECIFIC
CELLS THAT RESPOND TO
HYPERCRETIN AND REGULATE THE
PRODUCTION OF IMMUNE CELLS.
WE ALSO KNOW FROM STUDIES THAT
WE HAVE DONE IN THE MOUSE AS
WELL AS IN THE HUMANS THAT SLEEP
DISRUPTION REALLY ACCELERATES
HEMATOPOIESIS, AND WE HEARD
ABOUT CLONAL HEMATOPOIESIS.
THIS IS AN EXAMPLE OF SO-CALLED
REVERSE CAUSATION WHERE A
LIFESTYLE FACTOR, IN THE ABSENCE
OF ANY DRIVER OF MUTATIONS, CAN
ACTUALLY INCREASE PROLIFERATION
AND, THUS, BY INCREASING
PROLIFERATION, VIA A SO CALLED
NEUTRAL DRIFT CAN INCREASE THE
HETEROGENEITY OF MYELOID CELLS
THUS INCREASE CL CLONALITY.
STRESS IS VERY COMPLICATED,
THERE IS THIS CONCEPT OF USE
STRESS OR BENEFICIAL STRESS
VERSUS DISTRESS.
THERE'S, OF COURSE, THIS IDEA OF
THE DIFFERENCE BETWEEN ACUTE
STRESS AND CHRONIC STRESS AND IT
REALLY HAS ALL SORTS OF
DIFFERENT EFFECTS ON OUR
PHYSIOLOGY, BUT REALLY A LOT OF
WHAT WE CALL STRESS STARTS IN
THE BRAIN, AND THE QUESTION IS,
HOW DOES THE BRAIN UNDERSTAND
WHAT WE WOULD THEN CALL STRESS.
SO HERE IS ONE EXAMPLE OF
STUDIES WE HAVE DONE RECENTLY
LOOKING AT ONE EXAMPLE OF WHAT
ACUTE STRESS CAN DO AND AGAIN
I'M JUST GOING TO FOLLOW THIS,
SO ONE OF THE THINGS THAT WE
FOUND IS THAT UNDER CONDITIONS
OF ACUTE STRESS, CERTAIN REGIONS
IN THE BRAIN, FOR EXAMPLE, THE
HORMONES IN THE PERIVENTRICULAR
HYPOTHALAMUS LEAD TO THE
PRODUCTION OF CORTICOSTERONE
WHICH INDUCES CXCR4, A CHEMOKINE
RECEPTOR ON MONOCYTES THAT
ESSENTIALLY GUIDES MONOCYTE
RECRUITMENT AND PROVOKES THEIR
ENTRY INTO THE BONE MARROW.
ALTERNATIVELY OTHER AREAS OF THE
BRAIN, NOTABLY HERE THE MOTOR
CORTEX, VIA COMMUNICATION WITH
SKELETAL MUSCLE, INCREASES
ANOTHER CHEMOKINE THAT HAS SORT
OF AN OPPOSING EFFECT ON
NEUTROPHILS WHICH ARE RAPIDLY
MOBILIZED OUT OF THE BONE
MARROW.
SO THIS IS REALLY AN EXAMPLE
WHERE ON THE ONE HAND, ACUTE
STRESS ENGAGES DIFFERENT REGIONS
IN THE BRAIN THAT HAVE A
PROFOUND EFFECT ON THE
REORGANIZATION OF THE MAJOR
LEUKOCYTE CLASSES THROUGHOUT THE
BODY.
OF COURSE THERE'S OTHER AREAS OF
STRESS AND PARTS OF THAT STRESS
RESPONSE SUCH AS THE SYMPATHETIC
NERVOUS SYSTEM WHICH WE KNOW HAS
AN EFFECT ON ADHESION, AND THIS
IS AN EXAMPLE OF ACUTE STRESS
THAT WE KNOW UNDER CHRONIC
STRESS CONDITIONS, WE SEE AN
UNCREASE IN PROLIFERATION, AND
AN INCREASE IN THE PRODUCTION OF
IMMUNE CELLS IN THE BONE MARROW
AND THIS IS MEDIATED BY THE
SYMPATHETIC NERVOUS SYSTEM.
SO JUST LASTLY, JUST VERY
BRIEFLY I WOULD LIKE TO TOUCH ON
DIET.
AGAIN, THERE'S MANY, MANY
DIFFERENT WAYS THAT WE CAN STUDY
DIETMENT WEDIET.
WE CAN STUDY DIET IN TERMS OF
WHAT WE EETD, COMPONENTS OF
FOOD, FAT, PROTEIN, SUGAR, ET
CETERA.
WE CAN STUDY WHEN WE EAT, AND
THAT REALLY ENGAGES MULTIPLE
DIFFERENT SYSTEMS.
AND SO AGAIN I'LL JUST GIVE YOU
A VERY BRIEF SUMMARY OF SOME OF
THE WORK THAT WE HAVE DONE IN
THINKING ABOUT DIET.
THIS IS WORK LOOKING
SPECIFICALLY AT FASTING, AND SO
AGAIN HERE, WE FIND THAT FASTING
ENGAGES SPECIFIC REGIONS IN THE
BRAIN, SO I'M JUST GOING TO
START ON THE RIGHT SIDE HERE,
RECENTLY GENERATED WHERE WE FIND
THAT SPECIFIC NEURONS IN THE
LATERAL HYPOTHALAMUS, INDUCE
EXPRESSION OF CHEMOKINE
RECEPTORS, WE HAVE A PROFOUND
EFFECT ON THE REORGANIZATION OF
IMMUNE CELLS THROUGHOUT THE
BODY.
AND OF COURSE MIGRATION IS ONE
KEY FEATURE OF LEUKOCYTES.
THIS IS ONE OF THEIR DEFINING
FACTOR, THIS IS WHAT ALLOWS THEM
TO ACCESS VARIOUS ORGANS, ACCESS
THE CIRCULATORY SYSTEM.
THEIR MOTILITY IS CENTRAL TO
THEIR FUNCTION.
BUT THIS IS NOT THE ONLY WAY BY
WHICH, FOR EXAMPLE, FASTING
REALLY ENGAGES BRAIN-BODY
COMMUNICATION.
WE KNOW FROM OTHER WORK THAT
UNDER CONDITIONS OF FASTING,
THERE IS COMMUNICATION BETWEEN
THE BRAIN AND THE LIVER AND THE
BONE MARROW, WHICH RESULTS IN
THE PRODUCTION OF SPECIFIC
CHEMOKINES THAT TRAP THE
MONOCYTES IN THE BONE MARROW,
PREVENTING THEIR RE-ENTRY, AND
THIS HAS IMPLICATIONS ON AGING
OF THE HEMATOPOIETIC SYSTEM
BECAUSE WHAT WE FIND IS THAT
WHEN MONOCYTES MIGRATE BACK OR
RE-ENTER THE BONE MARROW, THEY
HIBERNATE IN THE BONE MARROW,
THEIR LIFESPAN IS PROLONGED AND
THAT CHANGES THEIR CAPACITY TO
RESPOND TO INFLAMMATORY CUES.
AND SO JUST TO FINISH HERE, THE
QUESTION IS WHAT ARE THE KEY
RESEARCH GAPS AND OPPORTUNITIES.
CERTAINLY WE'RE VERY MUCH
INTERESTED IN THIS IDEA OF
BRAIN-BODY COMMUNICATION AND HOW
DOES THIS ALTER BIOLOGICAL AGE.
WE WANT TO BETTER UNDERSTAND
WHAT COMMUNICATION NODES ARE
RELEVANT TO DISEASE RESILIENCE,
WE'VE ALREADY HEARD ABOUT
RESILIENCE IN EARLIER TALKS AND
SUSCEPTIBILITY, AND WHAT ARE THE
LIMITATIONS OF RESILIENCE AND
SUSCEPTIBILITY AS WE THINK ABOUT
SPATIAL AND OTHER COMPONENTS.
NEEDS OVER THE NEXT FIVE YEARS,
WE CERTAINLY NEED TO KEEP
DEVELOPING NEW TECHNOLOGIES.
IT IS TECHNOLOGY SUCH AS CHEMO
AND OPTIGENETICS -- TO ALLOW US
TO BETTER UNDERSTAND BRAIN-BODY
COMMUNICATION AND BRING THAT IN
THE CONTEXT OF CARDIOVASCULAR
DISEASE.
AND CERTAINLY WE NEED TO DEVELOP
FUNDING MECHANISMS.
AS THIS IS A WORKSHOP, I THINK
THIS IS AN IMPORTANTIS ISSUE TO
RAISE, TO SUPPORT -- NOT JUST
THAT FOCUS ON THE IMMUNE SYSTEM
OR METABOLISM, NERVOUS SYSTEM,
ET, THIS IS ABOUT REALLY MOVING
BEYOND AND REALLY WORKING IN THE
IN BETWEEN, THAT SPAN THESE
VARIOUS SYSTEMS, BECAUSE IT'S
SOMETIMES DIFFICULT TO FIND
SPECIFIC PLACES WHERE SUCH WORK
CAN BE FUNDED.
AND THEN ALLOW US TO CONNECT
THESE MECHANISTIC STUDIES THAT
WE OBTAIN IN ANIMAL MODELS WHICH
I SHOWED YOU, WITH OBSERVATIONAL
STUDIES IN HUMANS.
AND AGAIN TOUCHING ON SOMETHING
THAT WAS ALREADY BEAUTIFULLY
DISCUSSED EARLIER TODAY, THRFERS
A NETOBETTER DEFINE HEALTH AND H
TO DISEASE TRANSITIONS.
SO HOW CAN WE APPLY THIS
INFORMATION?
WE'LL NEED TO DEFINE MODES OF
COMMUNICATION.
THIS IS WHAT DRIVES A LOT OF OUR
WORK.
IT'S NOT THAT WE WANT TO
UNDERSTAND WHETHER LIFESTYLES
ARE GOOD OR BAD FOR YOU, IT'S
THAT WE WANT TO UNDERSTAND HOW
IT IS THAT THEY CONFER RISK OR
PROTECT US AGAINST RISK.
>> SPEAK E YOU HAVE 2 MINUTES
REMAINING.
>> AND I WILL BE DONE IN
30 SECONDS.
SO THIS GETS US TO THIS WHOLE
IDEA THAT LIFESTYLES ALSO CHANGE
AS WE AGE.
THIS IS AN IMPORTANT CONCEPT.
OUR SLEEP NEEDS BECOME DIFFERENT
AS WE AGE, CAPACITY TO EXERCISE
BECOMES DIFFERENT, OF COURSE.
THIS IS WHERE WE CAN DISCUSS
ISSUES OF FRAILTY, AND JUST
GENERAL AGING IN TERMS OF HOW
HIGH OUR HEARTBEAT CAN GET TO AS
WE AGE.
THIS IS SOMETHING THAT EVERY
RUNNER UNDERSTANDS AS WE
EXERCISE THROUGHOUT LIFE AND OUR
CHANGING METABOLISM, AND THIS,
OF COURSE, WE CAN PUT IN THE
CONTEXT OF BRAIN-BODY
COMMUNICATION.
SO I WILL STOP HERE.
THIS IS MY LAB AND SOME OF THE
PEOPLE WHO HAVE DONE SOME OF THE
WORK AND A LIST OF
COLLABORATORS, SO THANK YOU VERY
MUCHMENT
>> GREAT, THANKS.
LOTS TO UNPACK THERE.
SO MAYBE I'LL START WHILE THE
QUESTIONS COME IN.
SO I THOUGHT FASTING ACTUALLY
INDUCED, YOU KNOW, APOPTOSIS OF
YOUR BAD AND WIMPY CELLS, MAYBE
YOUR SENESCENT CELLS.
IS THAT BEING MEDIATED THROUGH
SOME OF THESE CYTOKINES OR WHAT
DO YOU THINK IS GOING ON THERE?
>> I THINK, YOU KNOW, FASTING IS
NOT A -- AN ALL-ENCOMPASSING
TERM WHICH IS TO SAY THAT WE
HAVE TO BE VERY CAREFUL, AND OF
COURSE I WENT IN THE INTEREST OF
TIME VERY CAREFULLY, VERY
BROADLY HERE.
IT REALLY DEPENDS ON WHEN THE
FAST OCCURS AND FOR HOW LONG.
SO THAT'S -- YOU KNOW, THE
ULTIMATE CONSEQUENCE OF FASTING
IS DEATH.
IF YOU DON'T BREAK THE FAST, YOU
WILL DIE.
RIGHT?
AND SO I THINK THERE WAS A
LEGITIMATE DISCUSSION TO HAVE
ABOUT WHEN -- THE BENEFITS OF
FASTING VERSUS WHEN DOES FASTING
BECOME A PROBLEM.
AND A LOT HAS TO DO WITH TIMING
AND DURATION.
IN THE CONTEXT OF THE SPECIFIC
STUDY TO WHICH I ALLUDED, THIS
WAS A FASTING THAT WAS
RELATIVELY LONG WHERE WE DO NOT
ACTUALLY SEE DEATH OF THOSE
PARTICULAR CELLS.
THE IMMUNE CELLS, MONOCYTES
WHICH ARE TYPICALLY FAIRLY SHORT
LIVED, ACTUALLY LIVE MUCH LONGER
UNDER CONDITIONS OF FASTING, AND
THERE'S, I THINK, A VERY
INTERESTING CONCEPT THAT WE CAN
EXPLORE HERE, BECAUSE FASTING
DECREASES HEMATOPOIESIS, AND
HEMATOPOIESIS IS AN
ENERGETICALLY COSTLY PROCESS
THAT GIVES RISE TO ALL OF THESE
IMMUNE CELLS, SOME OF WHICH ARE
LONG LIVED, SOME OF WHICH ARE
SHORT LIVED DEPENDING ON WHETHER
WE'RE TALKING ABOUT LYMPHOCYTES
AND NEUTROPHILS, SO AS TO
PRESERVE ENERGY, ONE COULD SORT
OF THINK ABOUT THE DECREASE OF
HEMATOPOIESIS NECESSITATING AN
INCREASE IN THE LIFESPAN OF
THESE OTHERWISE SHORT LIVED
CELLS.
SO I THINK THERE'S A LOT TO
UNPACK HERE, AND SOMETHING THAT
I DON'T THINK WE'RE GOING TO BE
ABLE TO GET TO JUST WITH THE
TIME WE HAVE.
>> GREAT, THANKS.
OKAY.
WE HAVE A QUESTION IN THE Q & A
FROM FRANK.
DOOL POOR HABITS LIKE DIET, LACK
OF EXERCISE, ET CETERA, GENERATE
AN EARLY AGE PHENOTYPE IN YOUNG
PEOPLE TOO?
>> THAT'S THE CONCEPT I THINK
THAT IS SOMETHING THAT WOULD HE
NEED TO DISCUSS, AND MIRANDA
WOULD HELP US AS WELL IN TERMS
OF SENESCENCE.
CLEARLY FROM THE STUDIES THAT
WE'VE DONE AND FROM THE WORK
THAT IS BEING DONE ACROSS, THE
ANSWER WOULD BE YES, THAT THERE
IS THIS ACCELERATED AGING IN THE
ABSENCE OF SOME OF THESE
LIFESTYLE FACTORS.
SO THIS IS REALLY A QUESTION
THAT GOES DEEP INTO THIS IDEA OF
THAT SORT OF CHRONOLOGICAL AGE,
WHICH IS THE PASS PASSAGE OF TE
WHICH WE CELEBRATE EVERY TIME WE
HAVE A BIRTHDAY IN THE
BIOLOGICAL AGE, AND HOW THE
EXPOSOME AND LIFESTYLE FACTORS
AND ENVIRONMENTAL FACTORS
MODULATE THIS, AND CERTAINLY
BAD, QUOTE-UNQUOTE BAD LIFESTYLE
HABITS SHIFT US TOWARD OLDER
BIOLOGICAL AGE, AND THERE'S
DIFFERENT WAYS WE CAN, OF
COURSE, LOOK AT THIS EPIGENETIC
MODIFIER, THE HETEROGENEITY OF
T --SENESCENCE AND SO ON.
>> OR AT LEAST HOW IT'S THOUGHT.
I WOULD ARGUE MAY NOT BE GOOD
DEFINITIVE STUDIES OUT THERE
LIKE WE'D LIKE TO SEE, PERHAPS.
YOU HAVE ANOTHER QUESTION HERE
FROM BETHANY EVERETT.
LET'S SEE.
DISCLAIMER, SHE'S A SOCIOLOGIST,
YOU DON'T HAVE TO WORRY ABOUT
THAT, BETHANY.
WOULD APPRECIATE IF YOU COULD
SPEAK ABOUT CARDIOVASCULAR
DISEASE RISK AND
CARDIOVASCULAR -- I SLEEP DURING
THE NEWBORN PERIOD WHICH
THEORETICALLY RETURNS NORMAL
WITH LONG TERM ISSUES OVER THE
LIFE COURSE.
SO HOW ABOUT TEMPORARY
PERTURBATIONS --
>> VERY GOOD QUESTION, A VERY
RICH QUESTION THAT AGAIN WE
COULD SPEND A LONG TIME
DISCUSSING.
I WILL JUST MENTION VERY BRIEFLY
THAT THE AMERICAN HEART
ASSOCIATION, LAST YEAR, INCLUDED
SLEEP AS ONE OF LIFE'S
ESSENTIAL -- ONE OF LIFE'S
SIMPLE SEVEN, SLEEP WAS ADDED
AND NOW IT'S ESSENTIAL EIGHT.
SO I HOPE ONE DAY STRESS WILL BE
ADDED AND THEN WE WILL HAVE ONE
OF THE NECESSARY NINE, LIFE'S
NECESSARY NINE.
SO SLEEP IS RECOGNIZED AS THE
MAJOR CONTRIBUTOR TO
CARDIOVASCULAR HEALTH.
THERE HAS BEEN MANY STUDIES
OBSERVATIONAL HUMAN, SOME LARGE,
SOME SMALL, THAT HAVE SHOWN HOW
DISRUPTION IN SLEEP, EITHER
SLEEP FRAGMENTATION, OR JUST
SLEEP REDUCTION ACCELERATES RISK
FOR VARIOUS CARDIOMETABOLIC
PHENOMENA.
A LOT OF THIS WORK HAS BEEN DONE
IN THE CONTEXT OF SLEEP APNEA.
OF COURSE SLEEP APNEA ALSO
INCORPORATES HYPOXIA, BUT THERE
HAS BEEN A NUMBER OF STUDIES
THAT HAVE LOOKED AT SLEEP, PER
SE.
AND SO -- AND OF COURSE SORT OF
THE SECOND PART OF QUESTION IS
ABOUT SORT OF THE ACCRUAL, LIKE
IF YOU DON'T SLEEP FOR A WHILE,
LET'S SAY BECAUSE YOU HAVE A N
NEWBORN, WHAT IS THE LASTING
IMPACT OF THIS?
I THINK THAT'S ANOTHER
CONVERSATION WHERE SOME OF THE
STUDIES THAT ARE EMERGING
SUGGEST THAT CERTAINLY WE HAVE A
FANTASTIC CAPACITY TO
REGENERATE, SO IT'S NOT LIKE
ABANDON ALL HOPE YE WHO ENTER
HERE THAT WE HAVE IN THE GATES
OF -- AT THE ENTRANCE TO THE
INFERNO, BUT THERE ARE CERTAIN
ECHOES, EPIGENETIC ECHOES AT THE
HEMATOPOIETIC SYSTEM THAT REMAIN
FOR LONGER THAN WE HOPED THEY
WOULD REMAIN FOR.
THOSE ARE SOME OF THE WORK THAT
ARE COMING OUT IN MICE AND ALSO
IN HUMANS.
SO AGAIN, A LOT TO UNPACK HERE,
BUT THAT'S SORT OF THE OVERALL
WAY THAT I THINK A LOT OF PEOPLE
ARE THINKING ABOUT IT.
>> GREAT, THANKS.
SO LET'S NOW MOVE TO -- THANKS
AND LET'S MOVE TO OUR LAST
SPEAKER BEFORE THE BREAK.
I'LL REMIND PEOPLE -- OR I
SHOULD SAY PANEL.
WE HAVE A 20-MINUTE PANEL, SO
SAVE UP SOME QUESTIONS FOR THE
PANEL.
AND YEAH, ESPECIALLY PROFOUND
ONES.
ALL QUESTIONS WELCOME.
STO OSO OUR LAST SPEAKER IS GOIO
BE TUDOR OPREA, TALKING ABOUT
MAPPING DISEASE TRAJECTORIES IN
DRUG DISCOVERY.
TAKE IT AWAY, TUDOR.
>> CAN YOU GUYS SEE ME AND HEAR
ME AND SEE MY SCREEN?
>> YOU'RE GOOD, YEP.
>> OKAY.
BECAUSE I CAN'T SEE MY SLIDES,
BUT HOPEFULLY --
>> THEY'RE FINE, WE CAN TELL
YOU.
I GUESS THAT'S BEEN HAPPENING.
>> I WANT TO THANK THE ORGANI
ORGANIZERS, DR. RISCUTA AND
GALIS FOR ORGANIZING THIS
MEETING AND REALLY EXCELLENT
TALKS BY DRS. FERRUCCI AND
SNYDER AND, OF COURSE, THE
ESTEEMED MEMBERS OF THE PANEL.
SO I AM PROBABLY THE ODD PERSON
IN THIS SESSION SINCE MY
INTEREST IS ARTIFICIAL
INTELLIGENCE AND MACHINE
LEARNING.
AND I'LL JUST BRIEFLY MENTION IN
THE INTEREST OF DISCLOSURE THAT
I CURRENTLY AM NOT NIH-FUNDED.
I ACTUALLY WORK AT A STARTUP
CALLED EXPERT SYSTEMS IN
SAN DIEGO, AND HAVE PREVIOUSLY
CONSULTED WITH THE INDUSTRY AND
HAVE BEEN WORKING WITH A NUMBER
OF INDUSTRIAL COMPANIES
PREVIOUSLY.
SO WHEN I WAS APPROACHED TO TRY
TO PUT SOME THOUGHTS ON THIS
TOPIC, I WAS GIVEN THE TASK OF
LOOKING AT RESILIENCE AND
LONGEVITY AND OF COURSE I
STARTED BY SEARCHING THINGS ON
THE INTERNET, AND IF YOU GO TO
GOOGLE, THIS IS PERHAPS A FEW
MONTHS BEFORE BART SO MAYBE
THINGS HAVE CHANGED A LITTLE BIT
BUT IT CAME UP IN THESE WISE
CHOICES LIKE GET MOVING, DON'T
SMOKE, KEEP YOUR BRAIN ACTIVE,
BE GOOD TO YOURSELF.
AND OF COURSE I ADDED STAY
HYDRATED BECAUSE NHLBI HAD
RECENTLY POINTED OUT THE
IMPORTANCE OF HYDRATION.
SO I THOUGHT, YEAH, THAT'S A
GOOD START.
AND ALSO THANKS TO THE EARLIER
SPEAKER, WE GOT THE INTRODUCTION
TO THE EXPOSOME SO I'M GLAD HE
MENTIONED THAT BECAUSE IT MEANS
I DON'T HAVE TO EXPLAIN IT.
EVERYONE SEEMS TO BE INTERESTED
IN THE INTERSECTION BETWEEN
GENES, PHENOTYPES AND THE
ENVIRONMENT, AND WE'RE TRYING TO
SOLVE THE HUMAN HEALTH EQUATION
BASED ON TERMS THAT FEED INTO
THIS AREA.
AND OF COURSE WE'RE INTERESTED
IN BIOCHEMICAL ASPECTS OF
PHARMACOLOGY, ET CETERA, ET
CETERA, AND HOW ALL THESE THINGS
AT THE MOLECULAR LEVEL ARE
INFLUENCED.
SO IT SEEMS LIKE A GOOD WAY
FORWARD.
BEFORE I CONTINUE WITH MY
THOUGHT ON THIS, I'D LIKE TO
JUST PUT A PLUG ON SOME OF THE
RESEARCH I'VE BEEN DOING BECAUSE
I THINK WE CAN EXTEND TO THE
TYPES OF QUESTIONS THAT ARE
BEING ASKED AND I WILL CLOSE
THAT LOOP AT THE END OF MY TALK.
JUST VERY BRIEFLY WE SEE A DRUG
DISCOVERY AS HAVING THREE
PILLARS THAT RELY ON DISEASES,
TARGETS AND DRUGS AND EACH OF
THESE AREAS, I'VE OPINION BEEN D
WITH MACHINE LEARNING AND
MODEL-TYPE DEVELOPMENT AND
THERE'S A RECENT REVIEW IN
ANNALS OF PHARMACOLOGY
TOXICOLOGY THAT COVERS THIS.
PART OF THE TOOLS I'VE BEEN
CO-DEVELOPING FOR THIS INCLUDES
A DATABASE THAT WAS STARTED AT
THE UNIVERSITY IN DENMARK WHICH
IS CALLED DISEASES.
AND ESSENTIALLY WITH DISEASE,
YOU CAN RAPIDLY PRETTY MUCH READ
USING A COMPUTER ALL OF PUBMED.
THIS DATABASE IS UPDATED ON A
WEEKLY BASIS AND IT USES NAMED
ENTITY RECOGNITION AND
ESSENTIALLY TRIES TO IDENTIFY
LINKS BETWEEN DISEASES AND GENES
SO I THINK IT'S A VERY POWERFUL
SORT OF PRECURSOR TO WHAT WE
CURRENTLY EXPERIENCE WITH
GPT4 AND BART AND CLOT.
BUT JUST ESSENTIALLY IF YOU CAN
THINK OF INTERACTION AT THE
PAPER BETWEEN A PROTEIN AND THE
DISEASE, IF YOU HAVE 100 PAPERS
DISCUSSING, SAY, TYPE OF
DIABETES AND 100 PAPERS
DISCUSSING INSULIN, THEN THE
INTERSECTION OF THAT GIVES YOU
INFERENCE OF THAT STRENGTH.
OF COURSE WE HAVE TO ADJUST BY
THE NUMBER OF OTHER DISEASES AND
GENES OR PROTEINS THAT ARE
MENTIONED IN THAT PAPER SO
THERE'S A FEW ADJUSTMENTS THAT
ARE MADE, IT'S CALLED A FRACTION
FRACTIONAL PAPER COUNT.
WE USE IT ALL THE TIME.
WORK FROM JEREMY IN MY GROUP
ADDED AN EXPERIMENTAL CHANNEL TO
THE DISEASES DATABASE WHICH
PRETTY MUCH POST PROCESSES DATA
FROM THE GWAS CATALOG.
SO WITH THAT IN MIND, WE USED
THIS COMBINED RESOURCE TO
DEVELOP A KNOWLEDGE GRAPH WHICH
FEEDS A DISEASE CHANNEL AND A
MOLECULE CHANNEL AND I DON'T GO
INTO DETAILS HOW WE BUILD THOSE,
BUT VERY BRIEFLY THIS IS PRETTY
MUCH BASED ON THAT DATABASE, AND
IT'S SISTERS LIKE CLINVAR,
CLINGEN AND A NUMBER OF
RESOURCES.
AND ON THE MOLECULES WE PRETTY
MUCH LOOK AT PATHWAYS,
EXPRESSION DATA, SMALL
MOLECULES, PROTEINS, GENES, ET
CETERA.
SO ALL THAT IS FED INTO A
KNOWLEDGE GRAPH WHICH IS SORT OF
DEPICTED HERE WITH FUZZY LITTLE
COLORED CIRCLES, AND ON TOP OF
THAT, WE USE A TECHNOLOGY CALLED
META PATH, WHICH ALLOWS US TO
FOLLOW THE PATH BY WHICH TWO
NODES ARE CONNECTED, SO IT'S
LITERALLY LOOKING AT THE EDGES
THAT CONNECT THE NODES.
AND OF COURSE THE NODES CAN BE
DISEASES OR PHENOTYPES OR
CHEMICALS, ET CETERA, ET CETERA,
AND THEN THE EDGES ARE THINGS
LIKE EXPRESSION DATA, INCUBATION
OR ANTAGONISM, THAT SORT OF
THING.
ONCE WE GENERATE FEATURES, WE
SEPARATE THE DATA INTO TESTS AND
TRAINING SET, TRAINING SET WE
BUILD TO USE MAN LEARNING MODELS
AND THEN OF COURSE THE TEST THAT
IS USED TO PROTECT.
AND PART OF THE STORY AND WHAT
WE DID, WE JUST PUBLISHED THIS
LAST YEAR IN COMMUNICATIONS
BIOLOGY SO WE WROTE A SUPPLEMENT
FOR THE ALZHEIMER'S DISEASE AS
PART OF AN NIH FUNDED GENOME
PROJECT, AND IN THAT MACHINE
LEARNING MODEL, WE ESSENTIALLY
USED SOMETHING SIMILAR TO WHAT I
JUST DESCRIBED AND WE LOOKED AT
THE TOP 20 GENES AND WROTE A
PROPOSAL, IT GOT FUNDED AND IT
ACTUALLY ALLOWED US TO RUN THE
EXPERIMENTS.
SO OUT OF THE TOP 20 GENES, THE
VALIDATION WHICH IS SHOWN IN THE
FIRST PANEL HERE ON THE LEFT
SIDE, WE TOOK --
[PLEASE STAND BY]
AND WE PUBLISHED A PAPER SIX
MONTHS AFTER WE PUBLISHED
SCIENCE HAD THIS INVESTIGATION
WHERE THEY PRETTY MUCH SHOWED --
I REALLY LOVE THE WORK OF
ELIZABETH BIK, SHE PRETTY MUCH
SAID THAT THE EXPERIMENTAL
RESULTS MIGHT NOT HAVE BEEN THE
DESIRED RESULTS AND DATA MIGHT
HAVE BEEN CHANGED TO BETTER FIT
THE HYPOTHESIS.
IN OTHER WORDS, WE PROBABLY
WOULD HAVE BEEN GIVEN MORE
ATTENTION WITH OUR THEORY OF
INFECTION IF THIS HAD BEEN
PUBLISHED EARLIER.
THE OTHER PROBLEM OF COURSE IS
WHEN YOU BUILD MACHINE LEARNING
MODELS, YOU HAVE TO BE AWARE TO
FEED THE TRUE DATA IN THE
MACHINE LEARNING MODEL SO YOU
KIND OF HAVE TO BE AWARE WHAT
TYPE OF PUBLICATIONS YOU INCLUDE
IN YOUR TRAININGS OR WHAT TYPE
OF DATA EMERGES FROM THOSE
PUBLICATIONS.
AND OF COURSE THE OTHER
PHILOSOPHICAL THING THAT COMES
FROM THIS IS THAT MACHINE
LEARNING BIAS IS INTRODUCED BY
HUMANS, EITHER AT INCEPTION
WHICH IS WHEN YOU SELECT THE
DATA, OR WHEN YOU GET THE
RESULTS.
BUT AS LONG AS YOU KEEP IT
UNBIASED, YOU'RE FINE.
ANOTHER MODEL THAT WE PUBLISHED,
THIS WAS A SLIGHTLY DIFFERENT
EXPERIMENT, I PUBLISHED THIS IN
2019 ON A -- ARCHI BIORXIV.
I LEFT ACADEMIA, SO A STUDENT
PICKED IT UP 3 1/2 YEARS LATER
AND WE LOOKED AT WHAT WE HAD
PREDICTED IN 2019 AND 3 1/2
YEARS LATER, SEVEN OF THE TOP 40
PREDICTED GENES HAD CONFIRMED
AND SOME OF THE BOTTOM ONES HAD
CONFIRMED TOO, SO THAT SORT OF
LED ME TO ANOTHER QUESTION, CAN
WE REALLY LEARN FROM THE BOTTOM
RANKED GENES IN A BINARY MODEL.
AND THE ANSWER IN MY OPINION IS
DEFINITELY YES, SO CERTAINLY
WHEN YOU RUN KNOWLEDGE GAP
PREDICTIONS AND YOU FEED THE
LIST OF POSITIVE GENES THAT ARE
ASSOCIATED WITH THE PHENOTYPE
YOU'RE INTERESTED IN AND A SET
OF NEGATIVE GENES, THEN THE
MODEL HAS TO DECIDE BETWEEN
1 AND 0.
SO THE TRUTH IS IF IT DECIDES
1 OR 0, IT DOESN'T NECESSARILY
MEAN THAT THE BOTTOM ONES ARE
REALLY NEGATIVE.
THE ONES THAT ARE REALLY
UNDECIDED AND WHAT THE MODELS
CONSIDERS TO BE NOT INTERESTING
AT ALL ARE THE ONES WITH THE
SCORE CLOSE TO 0.5.
SO AS A COMMON PRACTICE FOR MAN
LEARNERS, WE CURRENTLY RECOMMEND
THAT EVERYONE LOOKS AT THE
BOTTOM PREDICTIONS, NO T NOT JUE
TOP PREDICTIONS.
SO WITH THAT, I THOUGHT I WOULD
GIVE YOU A PITCH ON WORK DONE BY
THE GROUP AT THE UNIVERSITY OF
COPENHAGEN, CENTER FOR PROTEIN
RESEARCH, WHICH IS DISEASE
TRAJECTORIES.
I THOUGHT DISEASE TRAJECTORIES
ARE RELEVANT TO EVERYONE ON THE
PANEL AND EVERYONE INTERESTED IN
UNDERSTANDING SENESCENCE BECAUSE
IT PRETTY MUCH GIVES YOU THE
POSSIBILITY TO STUDY PATIENT
STRATIFICATION AND HOW DIFFERENT
DISEASES MAY PROGRESS FROM ONE
TO ANOTHER, AND IT ALSO BRINGS
IN A MORE CLEAR DATASET FOR
STUDYING THE IMPACT OF THE
EXPOSOME.
AND I WON'T GO INTO THE
TECHNICAL DETAILS, JUST SUFFICE
TO SAY THIS HAS PROCESSED THE
ENTIRE POPULATION REGISTRY OF
DEB MARK MORE THAN 20 YEARS OF
DATA, 7 MILLION PATIENTS, ET
CETERA, ET CETERA, THEY USE --
CORRECTIOBONFERONNI SIGNALS, YON
INTERACT WITH THE BROWSER
YOURSELF SO IF YOU ASK THE
QUESTION ABOUT IBS IN WOMEN, YOU
GET THIS TAPE OF TRAJECTORY, AND
I SORT OF LIST IT HERE BY HAND,
I EXTRACTED THE DATA BECAUSE YOU
CAN JUST SEE THE PATIENT NUMBERS
HERE, BUT IT'S INTERESTING TO
LACK LOOK AT PERCENTAGES AS WEL.
IT LOOKS AS YOU PROGRESS FROM
DIABETES 1 ALL THE WAY TO
DIVERTICULITIS, THERE'S A
DECREASED PERCENTAGE IN THE
FEMALE POPULATION, AND THAT
TRAJECTORY SEEMS TO CONFIRM IF
YOU START FROM A DIFFERENT
DISEASE AS WELL.
SO IT'S NOT LIKE IT'S A SINGLE
TRAJECTORY.
IN MEN IT'S A DIFFERENT
TRAJECTORY.
IT STARTS MOSTLY WITH F10, WHICH
IS PRETTY MUCH MENTAL PROBLEMS
RELATED TO THE USE OF ALCOHOL.
AND LEADS TO GI INFLAMMATION,
AND OF COURSE YOU CAN SEE THAT
WITH THE MALES, IT'S THE
PREDOMINANT FACTOR IN THAT
TRAJECTORY.
I ALSO THOUGHT I'D BE INTERESTED
IN LOOKING AT A NEUROLOGICAL
PROBLEM, SO STATUS EPILEPTICUS
AND THE EVOLUTION STARTED FROM
TYPE 2 DIABETES, ANGINA AND THE
F10 ALCOHOL-INDUCED BEHAVIORAL
PROBLEMS, AND AGAIN, IF YOU
FOLLOW THE TRAJECTORY ALL THE
WAY TO EPILEPSY AND IS THAT TUS
EPILEPTICUS, YOU CAN PRETTY MUCH
SEE HOW IT MIGRATES INITIALLY AT
LEAST WITH F10, THERE'S ONLY 25%
WOMEN, BUT BY THE TIME YOU GET
TO CEREBRAL INFARCTION OR STROKE
AND GO TO EPILEPSY, THE NUMBERS
SORT OF EQUILIBRATE.
CONVERSELY YOU SEE THE OPPOSITE
WITH A LARGER PERCENTAGE OF MEN
WHEN YOU START FROM THE F10 NODE
OR THAT FIRST DIAGNOSIS ALL THE
WAY TO STATUS EPILEPTICUS.
WHAT I'M BASICALLY SAYING, AND
THIS IS ONE OF THE MOST PRESSING
NEEDS IN MY OPINION, WE REALLY
NEED TO ESTABLISH A U.S.
EQUIVALENT OF THIS.
THIS IS NOT EPIDEMIOLOGY AS WE
KNOW IT, IT DOESN'T LOOK JUST AS
COMORBIDITIES AS A COOCCURRENCE.
IT TRIES TO IDENTIFY
COMORBIDITIES IN A TEMPORAL
FASHION, SO WHEN YOU LOOK AT
TEMPORAL DISEASE TRAJECTORIES,
YOU PRETTY MUCH CAN TRY TO
UNDERSTAND THIS RELATIONSHIP,
AND OF COURSE THE PRINCIPLE
WOULD START TO LOOK AT THE GENES
THAT ARE RELATED TO DISEASE ONE
AND THEN HOW THEY EVOLVE INTO
DISEASE TWO, THREE, 4 FOUR, FIVE
AND SIX.
THE DATABASE ALLOWS YOU TO
PURSUE UP TO SIX DISEASES.
THE PROBLEM, THE LIMITATION WITH
THE STUDY IN DENMARK IS
7 MILLION PATIENTS BUT ONCE YOU
BREAK DOWN THE DISEASE
TRAJECTORY FOR FIVE, SIX
DISEASE, THE NUMBERS BECOME VERY
SMALL, SO IT'S REALLY IMPORTANT
TO HAVE MORE DATA.
>> SPEAKER, YOU HAVE 2 MINUTE
REMAINING.
>> I WAS THINKING WHAT'S
MISSING, AND I CAME UP WITH
THIS, THE POWER OF THOUGHT.
SO THIS IS SOMETHING THAT HAS
BEEN POORLY DESCRIBED AND I
THINK THIS IS A GAP IN FUNDING
IN HEALTHCARE AND PARTICULARLY
I'D LIKE TO INTRODUCE A NEW
TERM, WHICH IS THE PSYCHOME.
THIS IS PARTLY INSPIRED BY THE
WISE CHARGES THAT GOOGLE
SUGGESTED.
THE INDIVIDUAL'S PSYCHOLOGICAL
TRAITS AND COGNITIVE PROCESS
SHOULD BE TAKEN INTO ACCOUNT
WITH RESILIENCE AND AGING.
THE TERM WAS FIRST INTRODUCED BY
ANDREW LIPPMAN FROM MIT.
HE WAS COMING FROM THE
PERSPECTIVE OF GOOGLE AND THE
ABILITY OF MARKING TRACKING
DEVICES TO KNOW MORE ABOUT YOU.
SOMEBODY MENTIONED CREDIT CARD,
SO IF YOU STUDY YOUR CREDIT CARD
HISTORY, YOU'LL KNOW MORE ABOUT
THE PSYCHOLOGY OF THE PERSON.
BUT THE PROBLEM IS HOW DO WE PUT
THAT INTO THE DISEASE CONTEXT?
AND I THINK THIS IS A GREAT
OPPORTUNITY FOR NIH OR PERHAPS
ARPA-H TO TRY TO STUDY THE
IMPACT OF THE MIND ON DISEASE
AND HOW WE CAN FIGURE OUT THE
MENTAL BIOMARKERS AND THE MENTAL
HEALTH BIOMARKERS TO STUDY THAT.
TO UNDERSTAND THE RESILIENCE.
SO HOW DO RELATIONSHIPS IN EARLY
DEVELOPMENT IN CHILDHOOD
INFLUENCE A PERSON DURING HER
LIFETIME OF SELF-REFLECTION,
UNDERSTANDING, ET CETERA.
THESE ARE THINGS THAT OF COURSE
PSYCHOLOGISTS HAVE BEEN
INTERESTED IN FOR QUITE SOME
TIME BUT NOBODY HAS REALLY PUT
TOGETHER THE IMPACT OF
GENOMICS -- AND EXPOSOMES INTO
THE FUTURE.
SO TRYING TO LOOK INTO THAT I
THINK IS A TREMENDOUS
OPPORTUNITY THAT NIH MIGHT BE
INTERESTED IN.
SO HOW DO WE APPROACH THIS IN
THE NEXT FIVE YEARS?
AND THIS IS WHERE STRATEGIES
MIGHT COME IN.
WE CLEARLY NEED AN ASSOCIATION
WITH GWAS STUDIES TO TRY TO
UNDERSTAND VARIANTS WHICH MAY OR
MAY NOT LEAD TO SPECIFIC
PSYCHOLOGICAL TRAITS.
WE SORT OF DISCUSS MENTAL
DISABILITIES OR INTELLIGENCE AS
BEING GENETICALLY PREDISPOSED SO
I THINK THERE ARE DIFFERENT
FACTORS THAT CAN BE APPLIED.
OF COURSE LONGITUDAL STUDIES, WE
HEARD FROM DR. SNYDER AND
FERRUCCI ABOUT THE IMPORTANCE OF
THIS, SO WE REALLY SHOULD START
TO INCLUDE MENTAL HEALTH, NOT
NNECESSARILY MENTAL ILLNESS BUT
MENTAL ILLNESS BIOMARKERS INTO
THE TOPIC.
EQUALLY IMPORTANT IT'S TIME TO
ADD THE FMRI AND PETs AND
UNDERSTAND WHAT PARTS OF THE
BRAIN MIGHT BE LIGHTING UP
DURING THE IMPACT OF -- I KNOW
PEOPLE HAVE STUDIED METADATA, SO
HIGHLY SKILLED BUDDHISTS, WHEN
THEY MEDITATE, I THINK THAT'S
TIME TO DO THAT WITH THE MORE
GENERAL POPULATION, NOT
NECESSARILY MEDITATING, AND
EQUALLY IMPORTANT UNDERSTANDING
CAUSALITY.
I THINK THE INFLUENCE OF
POSITIVE THINKING HAS BEEN SORT
OF UNDERSTOOD WHEN WE LOOK AT
THINGS LIKE SAY THE PLACEBO
EFFECT.
SO WE LOOK AT PLACEBO AND SAY
OH, YEAH, PEOPLE THINK THEY'RE
BEING VISITED BY A DOCTOR
BECAUSE THEY'RE WEARING A WHITE
COAT AND SUDDENLY THEY FEEL
BETTER.
WHY IS THAT?
DO WE EVEN UNDERSTAND WHAT'S
GOING ON WITH THE PATIENT?
AND THEN THAT'S WHERE I COME IN,
BIG DATA, AND I WOULD REALLY
LIKE TO HAVE A CHANCE TO DEPLOY
SOME MACHINE LEARNING,
ARTIFICIAL INTELLIGENCE, GPT IF
YOU WANT, MAYBE GEMINI IF IT'S
IN FIVE YEARS FROM NOW, TO TRY
TO MAKE THIS WORK BETTER.
SO MY TAKE-HOME MESSAGE FOR
EVERYONE I IN THIS WORKSHOP IS
IT'S TIME TO STUDY THE CYCLE.
THIS IS AN INVITATION, IF YOU
ARE PARTICIPATING IN THIS
WORKSHOP AND YOU HAVE SOME
REALLY GOOD THOUGHTS ABOUT THIS,
WE WOULD LIKE TO PUT A POSITION
PAPER OUT THERE.
SO FAR WE HAVE CONTRIBUTORS THAT
ARE LISTED HERE.
PETER ROBINSON, NOMI HARRIS,
MELVIN MCINNIS, MARCIA MORIARTA,
WE WOULD LIKE TO HEAR FROM YOU,
SO PLEASE CONTACT ME.
MY EMAIL IS IN THIS SLIDE SO
TOPREA@EXPERTSYSTEMS.INC.
WITH THAT I'D LIKE TO ANSWER
QUESTIONS.
>> I THINK WE'RE KIND OF AT THE
END OF YOUR TIME ALIQUOT SO I
THINK WE'LL MOVE RIGHT INTO THE
PANEL TO GIVE US MORE TIME AND
PEOPLE CAN ASK YOU QUESTIONS
DURING THAT PERIOD.
SO DO PUT YOUR QUESTIONS IN THE
CHAT.
THERE'S SOME SPECIFIC QUESTIONS
FOR YOU, THOUGH, THAT YOU MIGHT
PICK UP ON IN THE CHAT, I'M NOT
SURE HOW TO MOVE THEM INTO THE Q
& A THERE, TUDOR, SO AGAIN,
THANKS.
SO HERE'S A -- IF ALL THE
PANELISTS CAN PUT THEIR VIDEOS
ON SO WE CAN SEE THEM.
NOW YOU'RE ALL TINY, BUT MAYBE
IT'S BET INVENTORY TER TO HAVE T
PICTURE WITH THEIR NAMES
UNDERNEATH THAN THIS BIG DIAGRAM
HERE.
WE COVERED A LOT OF SPACE, WE
COVERED CLONAL HEMATOPOIESIS,
TUMOR MICRO ENVIRONMENTS AND
THESE TRAJECTORIES, SO REALLY
QUITE A BIT DR., THERE.
ONE COMMON THEME THAT'S COME UP,
ESPECIALLY ONE YOU BROUGHT UP AT
THE END, TUDOR, SO WAY TO DRAW
YOU RIGHT IN, IS THIS
LONGITUDINAL PROFILE.
YOU THINK EVERYBODY MADE A
LITTLE BIT OF AN ARGUMENT THAT
WE NEED LONGITUDINAL PROFILES
FOR STUDIES.
THERE REALLY IS A DERTH OF SUCH
STUDIES IN THE AGING FIELD,
WHICH IS KIND OF SURPRI SURPRISG
BECAUSE AGING IS THE MOST
OBVIOUS ONE.
MAYBE YOU COULD EACH SUMMARIZE
WHAT YOUR IDEAL THING,
LONGITUDAL PROFILE WOULD LOOK
LIKE, WHAT KINDS OF COMMON
THINGS, AND MAYBE WE SHOULDN'T
HAVE 10 DIFFERENT COHORTS
RUNNING ACROSS, MAYBE YOU SHOULD
HAVE ONE COHORT THAT'S STUDYING
ALL THE DIFFERENT PARAMETERS.
I JUST HEARD ABOUT IN THIS
MORNING'S SESSION OR MORNING FOR
ME, SORRY, PROBABLY AFTERNOON
FOR YOU.
SO WHY DON'T WE START, I GUESS
WE'LL GO IN THE ORDER OF
SPEAKERS, IF YOU WANT TO START,
PEGGY, SOME OF YOUR THOUGHTS ON
LONGITUDAL PROFILING, HOW IT CAN
IMPACT THIS WHOLE FIELD.
>> SURE, THANK YOU.
WELL, AS WE TALKED ABOUT, CLONAL
HEMATOPOIESIS IS REALLY
INTERESTING, AND MOSTLY IT'S
BEEN MEASURED AT ONE POINT IN
TIME AND THEN KIND OF POPULATION
LEVEL ASSOCIATED WITH VARIOUS
DISEASE STATES.
AND WE REALLY DON'T UNDERSTAND
HOW IT VARIES OVER TIME.
THERE'S A SMALL NUMBER OF
STUDIES THAT HAVE LOOKED AT AND
INTERVIEWED PEOPLE BUT WE NEED
TO UNDERSTAND HOW IT VARIES OVER
TIME AND HOW IT RELATES TO
PATHOLOGIES OR EFFECTS IN
INDIVIDUALS.
AND ACTUALLY CLONAL
HEMATOPOIESIS IS NOT THAT
EXPENSIVE TO LOOK AT ESPECIALLY
IF YOU USE A PANEL OF GENES, I
THINK IT'S QUITE ACCESSIBLE.
WE ALREADY HAVE SOME COHORTS
ACROSS THE NIH THAT THIS KIND OF
THING CAN BE APPLIED TO.
IN FACT, THERE ARE BLOOD SAMPLES
FROM SOME OF THESE COHORTS THAT
ARE -- THAT HAVE BEEN TAKEN OVER
TIME THAT ARE BEING MINED FOR
SOME OF THESE QUESTIONS RIGHT
NOW.
>> MAYBE I'LL THROW IN A
COMMENT, I DON'T THINK THE CHAT
IS AVAILABLE TO ALL OUR
PARTICIPANTS.
SHE SALES -- FUNDS A LOT OF
THESE INCLUDING LARGE
POPULATION.
I DON'T KNOW ABOUT THE DETAILED
PROFILES THAT COME OUT.
ASHANI, IF YOU WANT TO ADD
ANYTHING TO THIS, YOUR THOUGHTS
ON THE LONGITUDAL?
>> I MEAN, I THINK THESE ARE
GOING TO BE ABSOLUTELY CRITICAL
FOR US IN THE CANCER FIELD.
BECAUSE AS I SAID A LOT OF THE
CLINICAL TRIALS ARE NOT TAKING
AGE AS A FACTOR INTO ACCOUNT.
AND TRYING TO UNDERSTAND CANCER
HEALTH DISPARITIES AS WELL.
IT'S GOING TO BE IMPORTANT TO GO
BACK THROUGH ALL OF THESE
STUDIES BUT ALSO TO HAVE
INTENTIONAL STUDIES THAT INCLUDE
RACE, AGE, ET CETERA, OVER A
PERIOD OF TIME OVER THE NEXT 10
TO 20 YEARS.
BECAUSE WE'RE NOT REALLY GOING
TO UNDERSTAND HOW TO TREAT THIS
DISEASE UNTIL WE HAD THOSE.
>> MIRANDA, I'M SURE YOU HAVE
PLENTY TO SAY WHEN IT COMES TO
DEMENTIA AND ALZHEIMER'S.
>> I THINK IT'S REALLY IMPORTANT
THAT EVERYBODY BECOMES THEIR OWN
BASELINE AND THE ONLY WAY WE CAN
DO THAT IS LONGITUDAL, BUT THOSE
STUDIES, THEY HAVEN'T REALLY
BEEN DONE WELL OR AT ALL.
I THINK GETTING BACK TO WHAT
METRICS OF BRAIN AGING ARE WE
LOOKING AT, AN ARGUMENT AGAINST
ENROLLING PEOPLE AT A YOUNGER
AGE IS BECAUSE THERE'S A CEILING
EFFECT.
ALL OF OUR COGNITIVE TESTS, MOST
OF US WOULD HAVE A CEILING
EFFECT ACROSS THE LIFESPAN UNTIL
SOMETHING MAJOR IS HAPPENING, SO
I THINK WE NEED TO RE-EVALUATE
THAT TO MAYBE HAVE SOME MORE
SENSITIVE TESTS OR JUST THINK
ABOUT SOME DIFFERENT METRICS.
AND THEN IN TERMS OF SENESCENCE,
THERE'S A LOT OF WORK, LARGE
EFFORTS BY THE NIH, THE COMMON
FUND, WITH THE -- TRYING TO
IDENTIFY TISSUE-SPECIFIC MARKERS
OF SENESCENT CELLS WHICH WILL BE
REALLY IMPORTANT TO KNOW WHICH
TISSUES ARE CONTRIBUTING AND AT
WHAT AGE.
BUT YEAH, I AGREE WITH
EVERYBODY, THE LONGITUDAL
STUDIES ARE REALLY CRITICAL.
>> I WOULD THINK ADDING, FIL,
PUTTING WHAT YOU DO WITH THE
LIFESTYLE MEASUREMENTS ON TOP OF
EVERYTHING WE JUST HEARD IN
TERMS OF CH AND DEMENTIA AND
SUCH JUST SEEM SO CRITICAL.
WE'RE FOLLOWING PEOPLE'S SLEEP,
WE CAN SEE ALL THESE ADVERSE
EFFECTS, INCLUDING TUMOR
MICROENVIRONMENTS, HOW ALL THAT
SHIFTS.
SO M SO OF YOUR THOUGHTS THERE?
>> EXACTLY.
SO JUST TO PUT THIS IN THE
PERSPECTIVE OF CARDIOVASCULAR
DISEASE, BY THE WAY,
NEURODEGENERATIVE DISEASES AND
CARDIOVASCULAR DISEASES HAVE SO
MANY SHARED PATHWAYS.
WHEN WE THINK ABOUT
CARDIOVASCULAR DISEASE, OFTEN
WHAT THAT MEANS FOR A LOT OF
PEOPLE IS THAT ACUTE EVENT,
STROKE, M.I., THAT YOU HAVE
HEART FAILURE, BUT IT'S
RECOGNIZING THAT THESE -- THAT
MOST OF THE DISEASES ARE
ACTUALLY SUBCLINICAL.
YOU WERE MENTIONING, MICHAEL,
ABOUT WE GO TO THE DOCTOR, WE
GET OUR CHOLESTEROL, WE GET OUR
BLOOD PRESSURE, AND THIS ONE
LITTLE POINT, NOT REALLY
MONITORING OVER TIME, AND WHAT
LONGITUDAL STUDY ALSO ALLOW US
TO BETTER UNDERSTAND IS HOW DOES
THE DISEASE PROGRESS OVER TIME.
BECAUSE THE GUIDELINES TELL US,
DON'T GIVE A PERSON STATIN UNTIL
THEY'RE 50.
THAT MIGHT BE WAY, WAY TOO LATE.
WHAT HAPPENS IF YOU HAVE
INFLUENZA INFECTION AT 20 AND
THAT DAMAGES YOUR HEART?
YOU DON'T EVEN KNOW THAT BECAUSE
YOU'RE NOT GOING TO DO A CALCIUM
TEST, YOU'RE NOT NECESSARILY
GOING TO DO A VERY THOROUGH
UNDERSTANDING OF YOUR HEART
FUNCTION, BUT IT MAY HAVE AN
IMPACT.
I THINK STUDIES THAT CAN REALLY
TRACK HEALTHY INDIVIDUALS OVER
TIME INCORPORATING THE EXPOSOME
AND INCORPORATING VARIOUS
EXPOSURES, NOT JUST LIFESTYLE
BUT ALSO COMORBIDITIES THAT
OCCUR, BECAUSE OF COURSE ACCRUAL
OF COMORBIDITIES IS SUCH A
HALLMARK OF AGING, IS GOING TO
REALLY HELP US UNDERSTAND, YOU
KNOW, THE ETIOLOGY OF THESE
DISEASES AND HOW WE CAN PREVENT
THEM BEFORE IT'S TOO LATE,
BEFORE THEY MANIFEST THEMSELVES.
>> I'M GOING TO GET TO SOME
COMMENTS LIZ HAS IN THE CHAT,
BUT I THINK THE TOOLS YOU'RE
BRINGING UP, TUDOR, AND ALSO THE
IDEA ABOUT BRINGING IN THE --
YOU CALL IT THE PSYCHOME KIND OF
MEASUREMENTS, I THINK WE ALL
AGREE WITH THAT.
I'M SURE YOU'RE GOING TO GET A
LOT OF PEOPLE REACHING OUT TO
YOU AFTER YOUR LAST COMMENT.
BUT I WOULD THINK THE TOOLS
YOU'RE BUILDING WOULD BE VERY,
VERY VALUABLE FOR PEOPLE, DRA
DRAWING --
>> SO I CAN SEE IN THE CHAT THAT
PEOPLE ARE TALKING ABOUT ONGOING
LONGITUDAL STUDIES THAT THE NIA
IS SPONSORING AND I THINK THAT'S
COOL.
PART OF THE QUESTION IS HOW MUCH
DETAIL DO WE CAPTURE IN THOSE
LONGITUDINAL STUDIES, DO WE LOOK
AT COGNITIVE FUNCTION LIKE
MEMORY TESTS AND REACTION TIMES.
DO WE LOOK AT THE PSYCHOLOGICAL
WELL-BEING, LIKE THE WHOLE PART
OF THE PSYCHOME, RESILIENCE,
DEPRESSION, DO WE CATCH THOSE.
I READ THAT THE JAPANESE, FOR
INSTANCE, USE SMART WATCHES TO
KIND OF PREDICT SUICIDAL
TENDENCIES, AND HOW DO WE EVEN
TRACK THAT, RIGHT?
SENSORY MOTOR FUNCTIONS?
DO WE CAPTURE ALL THAT?
OF COURSE COMORBIDITIES HAVE
BEEN MENTIONED AND THE EXPOSOME
THAT FIL IS CLEARLY STUDYING.
HOW ABOUT MITOCHONDRIA?
DO WE LOOK AT MITOCHONDRIAL
FUNCTION?
HOW MANY MEDICATIONS?
POLYPHARMACY.
A LOT OF AMERICANS TAKE, YOU
KNOW, FIVE, 10 DRUGS ON A DAILY
BASIS, THEY HAVE A WHOLE MEAL,
THEY COUNT CALORIES WITH THEIR
MEDICATION.
ALL THESE THINGS ARE NOT REALLY
WELL UNDERSTOOD OR STUDIED FOR
THAT MATTER.
SO WE NEED TO START PUTTING A
LOT MORE PRESSURE INTO THE KIND
OF DATA WE NEED FROM LONGITUDAL
STUDIES.
>> 100% AGREE.
SO WHAT TUDOR WAS REFERRING TO
IN THE CHAT, LIZ NIELSEN PUT A
COMMENT, THERE ARE ALREADY MANY
LONGITUDAL AND LIFE COURSE
STUDIES OF AGING SUPPORTED BY
NIA, MANY OF THEM ARE POPULATION
REPRESENTATIVE AND DIVERSE,
WHICH I APPLAUD THEM FOR.
EXACTLY WHAT ARE THEY SAMPLING,
WHAT ARE THEY MEASURING, AND
WHAT'S THE FREQUENCY?
BECAUSE I'VE BEEN ARGUING WE
STILL DON'T KNOW THE
FREQUENCIES, MEASURES ONCE EVERY
SEVEN YEARS, THAT'S NOT ENOUGH
TO BUILD RESILIENCE MODELS, IN
MY OPINION.
I'M NOT EVEN SURE ONCE A YEAR IS
ENOUGH TO BUILD GOOD RESILIENCE
MODELS IF YOU WANT MY OPINION.
WE CERTAINLY GET A LOT OF
INFORMATION BY SAMPLING EVERY
THREE MONTHS.
>> A VIRTUAL HUMAN WHERE YOU
HAVE THE TRANSCRIPTOME AT 20 AND
SEE HOW IT EVOLVES ALL THE WAY
FROM 20 TO 80 AND SEE ALL THE
CHANGES THAT HAPPEN.
I WOULD LIKE TO SEE THE
TRANSITION WITH ALL THE NETWORKS
AND ALL THE EPIGENETICS, ALL THE
METHYLATIONS, THE POST
TRANSLATION, THAT WOULD BE
REALLY FASCINATING.
AND I THINK WE ARE ALMOST THERE,
WE CERTAINLY HAVE THE DATA, WE
JUST NEED TO TAG IT PROPERLY AND
BUILD THE MACHINE LEARNING --
>> WELL, I'M NOT SO SURE, I
DON'T KNOW IF WE HAVE FREQUENT
SAMPLING ENOUGH.
>> OKAY, WE CAN DO IT ON THE
SNYDER LAB DATA.
>> I THINK THAT'S A HEALTHY
ARGUMENT.
OUR DATA IS ALL, BY THE WAY,
PUBLIC.
I DIDN'T BRING THAT UP, BUT 85%
IS PUBLIC, INCLUDING GENOME
SEQUENCING.
I PERSONALLY WOULD START BEFORE
CONCEPTION, BY THE WAY, TAKE IT
ALL THE WAY UNTIL POST DEATH.
>> I SAID 20 FOR -- YEAH.
>> OKAY.
FEEL FREE TO KEEP JUMPING IN.
SO ANYWAY, IF SOME OF THE FOLKS
WANT TO UNMUTE, WE'RE GETTING A
LOT OF CHAT STUFF UP HERE --
>> I HAVE A QUESTION TO -- SO
PEGGY, ABOUT THE CLONAL
HEMATOPOIESIS, AND OF COURSE IN
AGING, HEMATOPOIESIS INCREASES
AND SO ON.
DATA THAT THE MONOCYTES DURING
CALORIC RESTRICTION GO BACK TO
BONE MARROW AND NO IDEA WHAT
HAPPENS WITH THOSE MONOCYTES,
WHETHER THEY DIFFERENTIATE INTO
OTHER MYELOID SUBSETS OR NOT, SO
QUESTION IS, IN THE AGING
SETTING, AND IN SETTING OF
VARIOUS CALORIC RESTRICTION AND
SO ON, WHAT HAPPENS WITH CLONAL
HEMATOPOIESIS?
>> I DON'T REALLY KNOW THAT THAT
HAS BEEN EXAMINED.
AGAIN, YOU WOULD NEED A COHORT
OF INDIVIDUAL, FIL MAY HAVE
OTHER DATA ON THAT, BUT YOU'D
NEED A COHORT OF INDIVIDUALS
THAT YOU WOULD REALLY FOLLOW.
I MEAN, I THINK FOR THE MOST
PART, CLONAL HEMATOPOIESIS IS
NOT SOMETHING THAT CHANGES
QUICKLY, RIGHT?
SO IF YOU HAD A COHORT THAT WAS
FASTING OR HAD A CERTAIN
LIFESTYLE OVER A PERIOD OF TIME,
THAT MIGHT BE OF MORE INTEREST
THAN THE SHORT TERM
PERTURBATIONS.
SHORT TERM PERTURBATIONS, I
THINK YOU WOULD SEE THINGS
CHANGING IN THE BLOOD AND FIL
AND OTHER PEOPLE HAVE SHOWN BUT
YOU'RE NOT GOING TO SEE MAJOR
CLONAL CHANGES IN THEIR OUTPUT
IN THE BONE MARROW.
>> BUT WOULD IT EVEN DURING
SHORT TERM, GIVE PRESSURE FOR
SURVIVAL -- CLONES CHANGE THAT
SURVIVAL.
>> WELL, I THINK THAT IS A GREAT
QUESTION, AND I WOULD SAY AGAIN
ONE OF THE FRONTIERS OF THE
FIELD IS UNDERSTANDING HOW LET'S
SAY A SMALL CLONE, 5% OF THE
BLOOD OF THE BONE MARROW LIKE A
TET2 CLONE WHICH WE THINK IS
VERY HYPERINFLAMMATORY, HOW DOES
THAT HAVE AN OUTSIDE EFFECT ON
CARDIOVASCULAR DISEASE?
PROBABLY THOSE CELLS ARE
INTERACTING IN A MALIGNANT
FASHION WITH WILD TYPE CELLS OR
OTHER CELLS IN -- ACROSS THE
BODY, AND SO REALLY THAT'S
SOMETHING THAT WE DON'T
UNDERSTAND.
IT'S ACTUALLY TECHNICALLY
DIFFICULT TO STUDY, THESE CELLS
ARE ALL INTERACTING, SO THAT'S
REALLY KIND OF THE NEXT FRONTIER
IN MY VIEW.
MAYBE PHIL HAS ADDITIONAL
COMMENTS.
>> MAYBE JUST ADDITIONAL -- A
FEW THINGS.
SO IT IS ABSOLUTELY NOT MUTUALLY
EXCLUSIVE THAT THERE IS SORT OF
THIS BIDIRECTIONAL RELATIONSHIP
BETWEEN WHERE DOES CLONAL
HEMATOPOIESIS SIT WITHIN SORT OF
THE FABRIC OF WHAT WE CALL, YOU
KNOW, HOMEOSTASIS AND DEVIATION
FROM IT.
SO ONE CAN THINK OF IT AS OVER
TIME THERE IS THIS ACCRUAL OF
MUTATIONS WHICH ENDOW CLONES
WITH THE SURVIVAL ADVANTAGE,
PROLIFERATIVE ADVANTAGE, MAYBE
THERE IS A CONNECTION BETWEEN
TET2 AS A DRIVER MUTATION AND
IL-1 BETA PRODUCTION.
ON THE OTHER HAND, AGAIN I WANT
TO STRESS THIS, THESE ARE NOT
MUTUALLY EXCLUSIVE IDEAS,
ALTHOUGH SOME PEOPLE THINK THE
REFLECTIVE KIND OF DEFENSE
MECHANISM IS THES ARE MUTUALLY
EXCLUSIVE, THAT THERE'S A
REVERSE CAUSALITY, WHICH IS TO
SAY -- AND VERY TALENTED PEOPLE
WHO APPLY MATHEMATICAL MODELS TO
THIS WOULD SAY THAT SOME OF
THOSE PRESSURES, EXPOSOMEAL
PRESSURES IF YOU WILL,
COMORBIDITIES, SO ON AND SO
FORTH, JUST BY THE SHEER IMPACT
ON THE HEMATOPOIETIC SYSTEM AND
SPECIFICALLY ON INCREASING
PROLIFERATION, THOSE
PERTURBATIONS BY THE NATURE OF
PURE SORT OF MATHEMATICS,
DECREASE DIVERSITY OF THE
HYDROXYCHLOROQUINE CYST AND SORT
OF INCREASE CLONAL
HEMATOPOIESIS, IN FACT, 50% OF
CLONAL HEMATOPOIESIS DOESN'T
HAVE A KNOWN DRIVER MUTATION.
I THINK WE ARE NOW APPROACHING A
POINT WHERE WE'RE GETTING A MUCH
MORE SOPHISTICATED -- WELL OF
COURSE BECAUSE A LOT OF PEOPLE
ARE WORKING ON THIS, MORE
NUANCED AND SOPHISTICATED
UNDERSTANDING OF WHERE CLONAL
HEMATOPOIESIS RESIDES WITHIN
THIS FABRIC THAT WE WOULD
GENERALLY SORT OF CALL
HOMEOSTASIS AND A DEVIATION.
ONE LAST POINT HERE BECAUSE YOU
ASKED ABOUT AGING.
THERE IS THIS VERY INTERESTING
PHENOMENON CERTAINLY VERY WELL
DOCUMENTED IN THE MOUSE ABOUT
SORT OF A MYELOID BOY AS AS WE
AGE, THIS IDEA THAT WHEN YOU
LOOK AT THE HYDROXYCHLOROQUINE
TREE, THERE IS A PREPONDERANCE
OF PRODUCING MYELOID CELLS,
NEUTROPHILS, MONOCYTES IN
RESPONSE TO VARIOUS STIM LAY AT
THE EXPENSE OF LYMPHOID CELLS, I
THINK THERE'S A LOT OF THINGS
THAT WITH THIS CONCEPT WE CAN
ALSO EXPLORE AGING ABOUT THIS
IDEA OF INFLAMMATORY TONE OR
INFLAMMATORY FITNESS, BECAUSE I
THINK INFLAMMATION IS SUCH A KEY
ELEMENT OF AGING AND -- MAY
BE PART OF THAT, THAT ALSO
DOVETAILS WITH CLONAL
HEMATOPOIESIS.
>> GREAT.
WE'VE GOT A FEW MORE QUESTIONS
SO I WANT TO KEEP IT MOVING.
WE'LL PROBABLY SHOOT FOR SHORT
ANSWERS IF YOU CAN.
>> SORRY.
>> NO, NO WORRIES, THAT WAS
GREAT.
THAT WASN'T MEANT TO CHASTISE
YOU.
THAT WAS JUST TO TRY -- WE HAVE
FOUR MINUTES LEFT SO I WANT TO
PACK AS MUCH INFO IN AS
POSSIBLE.
SO THIS ONE IS FOR MIRANDA, I
THINK, IN THE Q & A.
WE KNOW THE SENESCENT CELLS OF
NORMAL BENEFICIAL PSYCHOLOGICAL
FUNCTION, BUT EXCESS SENESCENCE
IS DETRIMENTAL AND CONTRIBUTES
TO AGE-RELATED DISEASE AND
CONDITIONS.
YEAH.
SO BASICALLY GETTING AT THIS
ISSUE OF TITERING IN SENESCENT
CELLS.
MAYBE, ASHANI, YOU'D LIKE TO
WEIGH IN ON THIS ONE TOO.
START WITH MIRANDA.
>> SO THE Z WE'RE NOT GIVING TRT
EVERY DAY, IT IS CYCLICAL.
IN OUR STUDY PEOPLE GET THIS FOR
TWO DAYS, THEN THEY HAVE TWO
WEEKS OFF, SO THE GOAL IS NOT TO
PREVENT SENESCENCE FROM ARE
HAPPENING FOR THE REASONS
MENTIONED BY THE -- WHOEVER
SUBMITTED THE QUESTION, BUT TO
CLEAR THEM WHEN THEY START TO
ACCUMULATE.
AND PART OF THE PHASE TWO TRIAL
IS TO DETERMINE HOW LONG IT
TAKES FOR THIS RE-EMERGENCE OF
SENESCENT CELLS AND THINKING
ABOUT HOW FREQUENTLY YOU MIGHT
NEED TO CLEAR SENESCENT CELLS.
>> GOT IT.
>> I WOULD JUST ADD ALSO THAT I
THINK WE DON'T FULLY UNDERSTAND
SENESCENCE YET.
IT DESCRIBED AS SO MANY THINGS.
IT'S DESCRIBED AS TERMINAL BUT
IT'S NOT TERMINAL.
YOU CAN THROW BACK SOME ROY BOW
NUCLEOTIDES AND REACTIVATE
SENESCENCE.
WE HAVE SEEN SENESCENT CELLS
THAT PHYSICALLY MOVE FROM THE
SKIN TO THE LUNG AND THEN GROW
OUT WHILE EXPRESSING BETA -- AND
KI67 AT THE SAME TIME.
SO UNTIL WE HAVE A BETTER
UNDERSTANDING OF SENESCENCE AND
WHAT IT DOES, SOMETHING THAT I
KIND OF VERY QUICKLY SKIMMED
OVER IN MYRA PID FIRE TALK WAS
THE FACT THAT WE SEE SENESCENCE
IN YOUNG FEMALE FIBROBLASTS THAT
ACTS TO REPAIR DNA DAMAGE, AND
SO THOSE FIBROBLASTS BECOME LESS
SUSCEPTIBLE TO THE GENOMIC
INSTABILITY DRIVEN BY AGE,
WHEREAS AGING MALE FIBROBLASTS
HAVE A DIFFERENT KIND OF
SENESCENCE THAT SECRETE A
SENESCENCE ASSOCIATED SECRETORY
PHENOTYPE AND THEREFORE ARE MORE
CONDUCIVE TO PROMOTING TUMOR
PROGRESSION.
SO UNTIL WE FULLY UNDERSTAND
THIS PHENOMENON OF SENESCENCE,
WE HAVE A LONG WAY TO GO, I
THINK.
>> OKAY, GREAT.
ZORINA REMINDED US THERE'S MORE
SENESCENCE TALKS COMING UP SO IF
YOU'RE INTO THAT, MAKE SURE YOU
ATTEND THOSE.
OKAY, THERE'S A TON OF COMMENTS
IN THE CHAT ABOUT RESOURCES AND
STUDYISTUDIES RUNNING.
AGAIN, I DON'T KNOW IF ALL THE
PARTICIPANTS CAN SEE THAT.
SOMETIMES IT'S JUST RESTRICTED
TO THE PANELISTS, I DON'T KNOW
HOW THIS IS STRUCTURED, BUT
MAYBE THERE'S A WAY TO SEND
THESE OUT TO THE WHOLE --
>> WE JUST ACTIVATED THE OPTION
FOR ALL PANELISTS TO BE ABLE
TO -- WITH EVERYONE.
>> IT WOULD BE HARD TO
SUMMARIZE, THERE'S SO MANY
COMMENTS HERE.
SO PLEASE TAKE A LOOK AT THESE.
I DON'T KNOW ALL THE DETAILS OF
THEM, LIKE I SAY, I DON'T KNOW
EXACTLY WHAT THEY'RE MEASURING,
THEIR FREQUENCY AND ALL THAT.
IT WOULD BE FUN TO GET THAT ALL
COLLECTED AND SEE DO WE HAVE THE
ULTIMATE LONGITUDAL STUDY THERE.
>> THERE WAS ONE QUESTION I
WANTED TO HIGHLIGHT ABOUT AGING
AND WHEN DO WE -- DO WE AGE FROM
MOMENT ZERO ON, AND SO WHEN DO
WE CONSIDER AGING AND IS AGING
EQUAL FOAL.
GLL THE COMMENT IS AGING ISN'T
ASSOCIATED WITH BEING OLD BUT
AGING, I WOULD ARGUE, WOULD GO
THROUGHOUT THE ENTIRE LIFESPAN.
>> I CAN CLARIFY THE QUESTION.
I WASN'T SAYING THAT AGING
EQUALS OLD.
I SAID THE WAY WE STUDIED AGING
IS THAT IT SEEMED LIKE WE SAY
AGING EQUALS OLD, AND SO IF WE
VIEW IT THAT WAY, YOU SEE
LONGITUDAL STUDIES OF AGING
STARTING AT THE AGE OF 45.
WELL, THAT'S NOT AGING.
THAT IS A STUDY FOR PEOPLE 45
YEARS AND OLDER.
BECAUSE AGING IN MY MIND IS A
PROCESS THAT STARTS FROM THE DAY
YOU GO FROM ONE CELL TO TWO
CELLS, BECAUSE IT'S A CELL
DIVISION PROCESS.
THAT'S WHAT MAKES AGING START
AND THAT'S A PROCESS THAT
CONTINUES.
AND SO MAYBE THE WAY WE LOOKED
AT AGING, EVEN THOUGH SOMETIMES
IS THE WAY FUNDING AGENCY MAKE
US LOOK AT AGING, IS BY STARTING
AT AN OLDER AGE.
SO SHOULDN'T WE BE THINKING,
ESPECIALLY IN THIS WORKSHOP, AT
LOOKING AT THE WHOLE AGING
PHENOMENON AS SOMETHING THAT
STARTS THE DAY YOU GO FROM ONE
TO TWO CELLS AND AS SUCH, MAYBE
THAT DIFFERENTIATES A LOT OF
THESE THAT WILL HELP US REDEFINE
THE WAY WE LOOK AT AGING STUDIES
OR DESIGNING AGING STUDIES IN
PARTICULAR, BECAUSE WHAT WE'VE
DONE IS TRY TO WORK BACKWARDS BY
STUDYING ALL THE PEOPLE AND SAY
OKAY, WHAT HAPPENED IN THE
1920s?
WELL, FOR CHRIST SAKE, WE DON'T
KNOW WHAT HAPPENED IN 1920s.
WE CAN ONLY INFER, BUT IF WE
HAVE STARTED IN THE 1920s, WE
WILL KNOW EXACTLY WHAT WAS
HAPPENING IN THE 1920s, RATHER
THAN STUDYING AN 80-YEAR-OLD AND
WONDERING WHAT HAPPENED TO THE
80-YEAR-OLD FROM 1920 FROM
RECOLLECTION AND HISTORICAL
RECORDS AND THINGS LIKE THAT.
>> I WOULD SAY THAT -- YOU KNOW,
ENGLISH IS NOT MY FIRST
LANGUAGE.
WHEN WAYS LEARNING ENGLISH, I
WAS PERPLEXED BY WHEN YOU'RE
ASKING SOMEBODY ABOUT, YOU KNOW,
HOW MANY YEARS THEY'VE BEEN
ALIVE ON THE PLANET, YOU ASK
THEM HOW OLD ARE YOU.
NOT HOW YOUNG ARE YOU.
SO THAT'S A GOOD POINT.
>> I THINK MAYBE BECAUSE WE'RE
AT THE END OF THE HOUR, I THINK
WE'D ALL HAVE -- I THINK WE'D
ALL AGREE THAT WE SHOULD BE
REALLY STUDYING PEOPLE AS WE
SAID AS EARLY AS POSSIBLE.
AND IT'S AMAZING HOW FEW
CHILDHOOD STUDIES ARE THERE FOR
LONGITUDAL STUDIES.
IT'S INCREDIBLE.
ALTHOUGH WE'LL PROBABLY GET A
LOT OF THINGS IN CHAT, MAYBE
THEY'RE OUT THERE AND I DON'T
KNOW ABOUT IT.
BECAUSE WE'RE AT THE END OF THE
HOUR, I'LL LET US ALL PONDER ON
THAT' WITH MOVE INTO THE NEXT
SESSIONS COMING UP.
SO I WANT TO THANK ALL THE
PANELISTS.
I THINK FOR ME, IT WAS A LOT OF
FUN.
I LEARNED A TON, WHICH TO ME IS
A SIGN OF A GOOD PANEL, AND I DO
WANT TO THANK ALL THE SPEAKERS
AND ALL THE GREAT COMMENTS WE'VE
HAD, AND SO I THINK WE RECONVENE
AT WHAT TIME?
DOES SOMEONE WANT TO JUMP IN AND
SAY WHEN DO WE RECONVENE?
>> 1:50.
THANK YOU.
ALL RIGHT.
WHICH IS 10:50 MY TIME.
ALL RIGHT.
SO HAVE A QUICK LUNCH OR A SNACK
AT BREAKFAST, WHEREVER YOU ARE,
AND WE'LL SEE YOU GUYS IN A HALF
AN HOUR.
THANKS, ALL.
>> WONDERFUL.
SO I WOULD LIKE TO WELCOME, MY
NAME IS ANIL WALI, PROGRAM
DIRECTOR AT THE CENTER TO REDUCE
CANCER HEALTH DISPARITIES AT
NATIONAL CANCER INSTITUTE.
AND WE WILL BE MANAGING SESSION
2 WITH MY TWO ESTEEMED
COLLEAGUES, DR. LOUISE
MCCOLLOUGH AND DR. KOTLIARO VA.
>> HI, EVERYONE.
I'M LOUISE MCCOLLOUGH, A STROKE
YEUROLOGIST AND CHAIR OF
NEUROLOGY HERE AT U.T. HEALTH
HOUSTON.
WE'RE REALLY LOOKING FORWARD TO
THIS SECOND SESSION THAT'S
REALLY GOING TO TALK ABOUT
MOLECULAR MECHANISMS OF CHRONIC
AGE-RELATED DISEASES AND WE'LL
BE HITTING IT OFF WITH
DR. KIRKLAND
>> DR. KIRKLAND, IT'S ALL YOURS,
THE FLOOR IS YOURS.
GO AHEAD.
>> THANKS VERY MUCH.
CAN EVERYONE SEE MY SLIDES ALL
RIGHT?
>> YES.
>> PERFECT.
OKAY.
SO I'M KIRKLAND, CURRENTLY AT
MAYO.
I HAPPEN TO BE FOR NOW PRESIDENT
OF OUR CONFEDERATION FOR AGING
RESEARCH.
TOM RANDALL WILL TAKE OVER,
THANK GOD, IN JANUARY, AND IT'S
A GREAT ROLE, BUT IT'S VERY BUSY
AND I'M ALSO PRINCIPAL
INVESTIGATOR OF THE
TRANSLATIONAL NEUROSCIENCE
NETWORK, WHICH I'LL EXPLAIN A
BIT ABOUT.
SO MUCH OF THE SESSION I THINK
PAUL ROBINS AND OTHERS FOLLOWING
ME WILL BE TALKING ABOUT SOLAR
SENESCENCE, A SULFATE LIKE
REPLICATION -- IT OCCURS ACROSS
THE VERTEBRATES AND MANY
INVERTEBRATE IT IS CAN OCCUR AT
ANY POINT DURING LIFE.
FOR EXAMPLE, DOWN SYNDROME
APPEARS TO BE -- WHICH IS
RELATED TO AGING OF THE OOCYTE
APPEARS TO BE A SOLAR SENESCENCE
DRIVEN SYNDROME SUSCEPTIBLE TO
SOME OF THE -- SO SENESCENCE IS
A RESPONSE TO DAMAGE, SO CELLS
CAN ENTER THE SENESCENT CELL
FATE.
IT TAKES A LONG TIME FOR A CELL
TO BECOME FULLY SENESCENT, AT
LEAST A WEEK, UP TO SIX WEEKS,
INCLUDING IN VIVO.
SO IT VERY SLOW TO DEVELOP.
THERE'S A RANGE OF INSULTS THAT
CAN TEND TO PUSH A CELL INTO THE
SENESCENT CELL FATE.
THES CAN BE REPLY KAYTIVE STRESS
AND THAT INCLUDES THE EFFECTS OF
ONCOGENES, IGF1 AND SO FORTH
THAT CAN DRIVE REPLICATION AND
SENESCENCE IS GENERALLY A
DEFENSE AGAINST CANCER.
SO SENESCENCE ENTAILS
ESSENTIALLY -- ALTHOUGH
SENESCENT CELLS CAN CONTINUE TO
MUTATE, IT IS GENERALLY A
DEFENSE AGAINST CANCER SO IF YOU
INTERFERE WITH THE ABILITY OF A
CELL TO BECOME SENESCENT, YOU
CAN DRIVE TUMORIGENESIS.
THERE ARE ALSO MECHANICAL AND
SHEER STRESS CAN DRIVE A CELL TO
BECOME SENESCENT, BUY FUR CA BI,
AND PATHOGENS CAN DRIVE CELLS
TOWARDS SENESCENCE.
MOST DEVELOP SASP.
THE SASP IS HIGHLY VARIABLE.
IT DEPENDS ON THE KIND OF CELL
THAT BECAME SENESCENT, WHAT
INDUCED SENESCENCE AND THE
MICROENVIRONMENT.
AND THE SASP CAN ENTAIL
PRODUCTION OF A RANGE OF
PROTEINS, PEPTIDES, BIOACTIVE
MOLECULES INCLUDING BIOACTIVE
LIPIDS LIKE FOS SPHENOIDS AND A
RANGE OF NOT COATING NUCLEOTIDES
INCLUDING VARIOUS MICRORNAs
AND THINGS LIKE MITOCHONDRIAL
DNA.
SOME OF THESE COMPONENTS CAN BE
EXOSOME RELATED, BUT SENESCENT
CELLS ALSO PRODUCE -- THEY CAN
PRODUCE CELL-FREE NUCLEOTIDES
THAT APPEAR TO BE RESPONSIBLE
FOR MUCH OF THE EFFECT THAT
SENESCENT CELLS HAVE, IN
ADDITION TO THE CYTOKINES,
EXTRACELLULAR PROTEASES AND SO
FORTH THAT THEY CAN PRODUCE.
SENESCENT CELLS ARE RESISTANT TO
DYING AND THIS IS BECAUSE OF THE
ACTION -- THERE ARE AT LEAST 10
PATHWAYS.
SO IF YOU TAKE THE SUBSET OF
SENESCENT CELLS THAT ARE TISSUE
DAMAGING AND TRANSPLANT THEM
INTO ANIMALS AND IN THIS CASE
WE'RE TAKING FIBROBLASTS THAT
HAVE BECOME SENESCENT BY
RADIATION.
IT TAKES 1 IN 10,000 CELLS IN
THE TRANSPLANTED ANIMAL TO
DEVELOP A FRAILTY-LIKE STATE
AFTER A FEW MONTHS AND TO DIE
EARLY AND THEY DIE EARLY OF ALL
DISEASES THAT MICE NATURALLY DIE
FROM.
EVEN THOUGH THERE'S A VERY SMALL
NUMBER OF SENESCENT CELLS AND
EVEN THOUGH THEY REMAIN WITHIN
THE PERITONEUM.
THERE'S A THRESHOLD EFFECT.
SO 1 IN 10,000 CELLS MEANS THAT
YOU'VE TRANSPLANTED INTO
1 MILLION SENESCENT CELLS.
IF INSTEAD YOU TRANSPLANT
500,000 CELLS NOTHING HAPPENS.
IF YOU TRANSPLANT THEM INTO AN
OLD MOUSE THEN THEY DEVELOP THIS
SYNDROME.
SENESCENCE SPREADS BOTH LOCALLY
AND SYSTEMICALLY SO IF YOU
TRANSPLANT AND LABEL THEM SO YOU
KNOW WHICH ARE THE TRANSPLANTED
CELLS YOU FIND SENESCENT CELLS
START APPEARING IN THE ARMS,
LEGS AND BRAIN AND ELSEWHERE.
FROM THE RECIPIENTS' OWN CELLS.
SO SENESCENCE SPREADS.
THIS IS PARTLY RELATED TO
PROTEINS AND PEPTIDES THAT ARE
PART OF THE SASP, PARTLY RELATED
TO REACTIVE SMALL MOLECULES BUT
MAINLY RESPONSE TO EXTRACELLULAR
KNEW CNUCLEOTIDES.
SO NED SHARPLESS HAD A VERY
IMPORTANT PAPERBACK IN 2004 IN
JOURNAL OF CLINICAL
INVESTIGATION WHEN HE SHOWED
THAT INTERVENTIONS THAT ENHANCE
HEALTHSPAN IN EXPERIMENTAL
ANIMALS, CALORIC RESTRICTION OR
RELATIVE IGF1 DEFICIENCY ARE
LINKED TO DECREASE?
SENESCENT CELL BURDEN.
THAT LED US TO BEGIN TO ASK BACK
IN 2004, IS THIS AN ASSOCIATION
OR IS IT -- SO WE BEGAN TO TRY
TO DEVELOP SENOLYTICS.
WE WORKED WITH OTHERS FOR A LONG
TIME TRYING TO DEVELOP FUSION
PROTEINS THAT WOULD BIND ON ONE
END TO THE SENESCENT CELL AND
CARRY IT -- GOT NOWHERE, TRIED
HIGH-THROUGHPUT SCREENS WITH
SANFORD BARNUM IN SAN DIEGO, GOT
NOWHERE THEN IT EVENTUALLY HIT
US, THE 30 TO 70% OF SENESCENT
CELLS ARE TISSUE DAMAGING,
THEY'RE KILLING CELLS AROUND
THEM DESPITE THE FACT THEY
THEMSELVES SURVIVE.
WE ASK IF THEY USED SURVIVAL
NETWORK TO DEFEND THEMSELVES
AGAINST THE THINGS THEY'RE USING
TO KILL CELLS AROUND THEM AND
AVOID COMMITTING SUICIDE.
WE FOUND THESE PATHWAYS.
THERE ARE 10 OF THEM.
THAT HE TOGETHER IN A NETWORK
AND DIFFERENT SENESCENT CELLS OF
UPREGULATION -- AND THIS
DIFFERED BETWEEN DIFFERENT KINDS
OF HUMAN SENESCENT CELLS WHICH
NODES WE HAD TO HIT.
SO WITH HUMAN NSCs, WE HAD TO
HIT -- KINASE-RELATED PATHWAYS.
WHEREAS WITH ENDOTHELIAL CELLS,
WE MAINLY TARGETED PATHWAYS
RELATED TO BCL2 AND CERTAIN
OTHER THINGS, ABL AND -- PAUL
ROBINS MAY TALK MORE ABOUT THAT
LATER.
SO WE LOOKED FOR DRUGS THAT WERE
REPURPOSED OR ALREADY IN HUMAN
USE OR NATURAL PRODUCTS THAT
WOULD TARGET THESE NODES THAT
ARE AVAILABLE OR THAT COULD BE
ADMINISTERED ORALLY AND THAT
EXTRAORDINARILY LIMITED HALF
LIVES.
WE FOUND A TYROSINE KINASE
INHIBITOR BUT UNLIKE OTHERS, IT
TARGETS THE AFRIN DEPENDENT --
KINASE.
WE FOUND THAT CONCENTRATIONS
THAT WOULD KILL 30 TO 70% OF
SENESCENT SITES THAT ARE TISSUE
DAMAGING AND PRO APOPTOTIC.
IT DID NOT TOUCH HUMANS.
CONVERSELY -- SELECTIVELY KILLED
SENESCENT HUMAN EPITHELIAL CELLS
BUT NOT PREADIPOCYTES.
THERE'S NO COMBINATION THAT I'M
AWARE OF THAT WILL KILL EVERY
KIND OF SENESCENT CELL.
SO SINCE THEN, MANY OTHER
SENOLYTICS HAVE BEEN DISCOVERED
USING THAT ORIGINAL MECHANISM
BASED HYPOTHESIS DRIVEN APPROACH
AND HIGH-THROUGHPUT SCREENS NOW
HAVE BEEN SET UP AND WHERE
PEOPLE HAVE LOOKED AT DRUGS THAT
HAVE A HISTORY OF TARGETING
MULTI-MORBIDITY LIKE THOSE
TREATING FOR OSTEOPOROSIS BUT IS
NOTED TO DECREASE INCIDENCE OF
CANCERS AND DIABETES AND OTHER
THINGS, IT TURNS OUT TO BE
PARTLY SENOLYTIC.
CAR-T APPROACHES AND VACCINES
HAVE BEEN DEVELOPED INCLUDING A
VACCINE DEVELOPED BY A PERSON
WHO'S NOW IN MY LAB, HE
ORIGINALLY DEVELOPED ONE WHEN HE
WAS IN JAPAN AGAINST A GPNMB.
IF YOU TREAT ANIMALS WITH
ORAL -- THAT HAVE BEEN
TRANSPLANTED WITH SENESCENT
CELLS, YOU KILL 30 TO 70% AND
YOU TEND TO LEAVE NORMAL CELLS
ALONE.
IF YOU TAKE HUMAN TISSUE
EX-PLANTS FROM DIABETIC YOUNGER
WOMEN WITH RENAL FAILURE WHO
HAVE A LOT OF SENESCENT CELLS IN
THEIR ABDOMINAL FAT TISSUE, YOU
FIND THAT IT TAKES A 30 MINUTE
TO THREE-HOUR EXPOSURE FOR AN
IRREVERSIBLE PROCESS OF
APOPTOSIS TO OCCUR WHICH TAKES
18 HOURS AFTER SENOLYTICS HAVE
BEEN APPLIED.
SO YOU CAN APPLY SENOLYTICS FOR
30 MINUTES TO THREE HOURS,
REMOVE THEM AND IRREVERSIBLE
APOPTOSIS IS INITIATED WITHIN
SENESCENT CELLS BY THAT.
SO IN OTHER WORDS A VERY SHORT
EXPOSURE TO SENOLYTICS IS
SUFFICIENT TO DRIVE SENESCENT
CELLS DEATH THROUGH APOPTOSIS.
AS I MENTIONED BEFORE,
SENESCENCE TAKES 1 TO 6 WEEKS TO
DEVELOP, SO THESE DRUGS CAN BE
GIVEN INTERMITTENTLY BECAUSE
THEY TEND NOT TO DIVIDE, SO THIS
MEANS IN VARIOUS DISEASE STATES,
WE FIND WE CAN ADMINISTER THESE
DRUGS ONCE EVERY TWO WEEKS OR
ONCE A MONTH, AND WE PERSONALLY
SELECT THE DRUGS -- SO THAT THEY
WOULD BE GONE AND WE COULD DEAL
THEN AND TRY TO REMOVE OFF
TARGET AND SIDE EFFECTS.
SO IF YOU BLAST ONE LEG OF THE
MOUSE WITH SUFFICIENT RADIATION
TO MAKE THE -- LEG GO GREY AND
IT HAS TROUBLE WALKING A
TREADMILL, IF YOU GIVE A SINGLE
DOSE OF SENOLYTICS, THAT CAN
PARTIALLY RESTORE THE ABILITY --
ITS ABILITY TO RUN ON A
TREADMILL FOR THE REMAINDER OF
ITS LIFE BECAUSE UNLIKE CANCER
CELLS, SENESCENT CELLS GENERALLY
DON'T DIVIDE.
WITH THOSE TRANSPLANTED ANIMALS,
WE RESTORE -- ALLEVIATE FRAILTY
PARAMETERS, SO NOW THERE ARE
AROUND 70 CONDITIONS IN
EXPERIMENTAL ANIMAL MODELS, MI
MICE, AND OTHER SPECIES WHERE IT
LOOKS LIKE SENOLYTICS HAVE AN
EFFECT.
RAPALOGS, METFORMIN WHICH DOES
AS WELL OR NAD PRECURSORS.
SO SOMETHING THAT'S BEEN SET UP,
I DON'T HAVE MUCH TIME LEFT SO
I'LL JUST GO THROUGH IT BRIEFLY,
IS THE TRANSLATIONAL GEROSCIENCE
NETWORK FUND FUNDED BY THE NATIL
INSTITUTES OF HEALTH, TRYING TO
CONDUCT CLINICAL TRIALS IN
PARALLEL OF NOT JUST SENOLYTICS
BUT OTHER AGENTS THAT TARGET
FUNDAMENTAL AGING PROCESSES.
CURRENTLY THERE ARE 82 CLINICAL
TRIALS UNDERWAY THAT ARE
ASSISTED BY THE NETWORK, 30 OF
WHICH ARE WITH SENOLYTICS, AND
THEY RANGE -- THESE ARE TRIALS
FOR PEOPLE WITH VERY SERIOUS
CONDITIONS FOR WHICH THERE ARE
NO GOOD INTERVENTIONS BECAUSE
WE'RE WORRIED ABOUT THE
RISK-BENEFIT RICCIOS AND WE'RE
WORRIED ABOUT SIDE EFFECTS.
AND THEY RANGE FROM TRIALS FOR
ADULTS -- SURVIVORS OF CHILDHOOD
CANCER WHO CAN DEVELOP AN
ACCELERATED AGING STATE DUE TO
THINGS LIKE COVID, SPACE TRAVEL,
ALZHEIMER'S DISEASE AND MIRANDA
ORR WILL SPEAK ABOUT THAT OR HAS
SPOKEN ABOUT THAT, FOR LT AND A
WHOLE RANGE OF OTHER DISORDERS
AND DISEASES.
EARLY TRIALS WERE PUBLISHED
LOOKING AT IDIOPATHIC PULMONARY
FIBROSIS OPEN LABEL TRIAL WITH
ALL THEIR BIASES BUT IT DID LOOK
LIKE THAT MIGHT HAVE BEEN SOME
IMPROVEMENT IN FRAILTY
PARAMETERS IN THESE PEOPLE.
IT'S A CENSUS DRIVEN DISORDER
AND THEIR MAIN PROBLEM IS
FRAILTY.
ANOTHER EARLY TRIAL THAT WAS
PUBLISHED THAT THERE'S TARGET
ENGAGEMENT, SO IN OBESE DIABETIC
WOMEN WITH INCIPIENT RENAL FAIL
EU WE FIND WE CAN GET REDUCTION
IN MARKERS OF SENESCENCE WITH
THREE DAYS OF ORAL -- AND WHEN
WE DO THE SECOND BIOPSY 11 DAYS
AFTER LAST DOSE WHEN THESE DRUGS
ARE LONG GONE BECAUSE THEY HAVE
SHORTY LIMB NATION HALF LIVES.
WE FIND THESE PROCESSES ARE
INTERLINKED SO IN 20 OUT OF 20
PEOPLE WHEN WE LOOKED AT
ALPHA -- A JAIR YOE PROTECTIVE
PROTEIN IN URINE, WE FOUND THAT
IT WAS INCREASED IN ALL 20
SUBJECTS.
WE'RE LOOKING AT DEVELOPING
ACROSS THE NETWORK GERODIKE NOS
TICS ANGERODIAGNOSTICS, THESE WE
THINGS ACCEPTABLE TO THE FDA AS
POTENTIALLY MAYBE ONE DAY SER
GAT END POINT.
SER
SURROGATE END POINTS.
THE IDEA IS TO GO AFTER THINGS
THAT RESPOND TO INTERVENTIONS.
BIOLOGICAL CLOCKS ARE NOT GOOD
ENOUGH.
IN OUR VIEW THEY HAVE TO RESPOND
TO INTERVENTIONS, PICK WHICH
INTERVENTION TO USE AND
PREDICTIVE AFTER THE
INTERVENTION IS GIVEN IF THERE'S
A CHANGE OF PHENOTYPIC
IMPROVEMENT.
SO THE FIRST GERODIAGNOSTIC
SCORE BASED ON SENESCENCE WE DID
REALLY DRIVEN BY DAVID ALISON --
>> DOCTOR, YOU HAVE TWO MINUTES
REMAINING.
>> OKAY, WAS WITH A SMALL NUMBER
OF SUBJECTS AND IT LOOKED LIKE
IT SORT OF WORKED.
SO IN THE NETWORK, WE'RE
MEASURING LITERALLY HUNDREDS OF
PARAMETERS ACROSS ALL THE
TRIALS.
THE SAME THINGS WERE BEING
MEASURED BY THE FACILITY FOR
GEROSCIENCE WHICH IS FUNDED BY
THE NIH.
OTHER THINGS ARE BEING MEASURED
IN BLOOD INCLUDING NON-COATING
NUCLEOTIDES.
THERE ARE 35 PARAMETERS BEING
MEASURED IN URINE.
WHEN WE CAN GET IT, THERE ARE 50
PARAMETERS IN CSF.
THERE ARE PARAMETERS THAT ARE
BEING MEASURED IN SALIVA, TEARS,
AND THEN WE'RE KEEPING SAMPLES,
BUCCAL SWABS AND THINGS LIKE
THAT FOR METHYLATION ANALYSIS AS
WELL AS HAIR CLIPPINGS, NAIL
CLIPPINGS, MICROBIOME, ET
CETERA.
I DON'T HAVE TIME TO GO THROUGH
IT, BUT ONE OF THE THINGS THAT
WE'RE WORKING ON IN
COLLABORATION WITH THE GROUP AT
HARVARD IS TRYING TO REHA BILL
TATE ORGANS FROM YOUNGER DONORS
SO THEY CAN BE USED IN
RECIPIENTS, SO THERE ARE TRIALS
UNDERWAY NOW LOOKING AT THIS
WITH RENAL TRANSPLANTS AT THE
BRIGHAM AND HEPATIC TRANSPLANTS
WITH THE GROUP IN HOLLAND WHERE
I AM RIGHT NOW.
PAUL ROBINSON AND -- MAY SPEAK
ABOUT THIS MORE BUT THERE'S A
LINK BETWEEN SENESCENCE AND
CORONAVIRUS.
CORONAVIRUS DRIVE SENESCENCE,
SENESCENT CELLS TAKE OUT MORE
CORONAVIRUS TH -- SOIN A STUDY,N
FROM A -- REMOVING HE?
TICK CELLS GENETICALLY.
IT LOOKS LIKE QUERCETIN GIVEN IN
DAILY DOSES REDUCED
HOSPITALIZATION PERCENT NEEDING
ICU ADMISSION.
WE RECENTLY FOUND, WORKING WITH
VEIL THAT THERE'S SOME EVIDENCE
THAT CLEAR SENESCENT CELLS IN
HUMANS, IT'S CLOSELY RELATED TO
QUERCITIN SO THERE ARE TRIALS
UNDERWAY.
IN CONCLUSION, PERSISTENT
SENESCENT CELLS CAN CAUSE
DYSFUNCTION, SPREAD OF
SENESCENCE AN BE RELATED TO
MULTIPLE DISORDERS IN
EXPERIMENTAL ANIMALS.
THE TARGET OF SENOLYTICS IS --
THE BRANCH OF THE FDA WE'RE
DEALING WITH IS THAT DE BRANCH T
DEALS WITH ANTIBIOTICS WHERE
THEY DON'T CARE SO MUCH ABOUT
ABOUT -- -- TREATMENT INDUCED
SENESCENT CELLS IN CONTEXT OF
CANCER.
HIT-AND-RUN APPROACH APPEARS TO
BE AS OR MORE EFFECTIVE THAN
CONTINUOUS DOSING.
30 TRIALS WERE UNDERWAY AND
THESE AGENTS MAY BE, JUST MAYBE
MIGHT LEAD TO INTERVENTIONS IN
HUMANS IF THE TRIALS WORK.
I VIEW THERE'S REALLY NO PLACE
FOR GIVING THESE AGENTS OUTSIDE
CONTEXT OF CAREFULLY CONTROLLED
FDA OR EMA MONITORED CLINICAL
TRIALS UNTIL WE KNOW IF THEY'RE
SAFE AND EFFECTIVE.
SO I'LL JUST CONCLUDE BY
THANKING A LOT OF PEOPLE
INCLUDING SHEILA, PAUL ROBINSON
WHO'S FOLLOWING ME AND ALSO
LAURA NIEDERNHOFER AND TAMARA
WHO WORK WITH ME ON DEVELOPING
SENOLYTICS.
THANKS.
>> THANK YOU, DR. KIRKLAND.
WE HAVE ONE QUESTION AND HARDLY
A COUPLE OF MINUTES LEFT.
SO WE HAVE A QUESTION ON IF YOU
COULD TALK ABOUT DIFFERENT
SUSCEPTIBILITY TOXICITY OR
EFFECTS OF SENOLYTICS ON
DIFFERENT TYPES OF ENDOTHELIAL
CELLS.
>> WELL, DIFFERENT SENOLYTICS
WORK ON DIFFERENT CELL TYPES.
SO THERE'S A HUGE NUMBER OF
SENOLYTICS.
NOW THERE ARE SEVERAL HUNDRED,
THERE ARE DOZENS OF COMPANIES
WORKING ON THEM.
BUT IN VIVO, THAT MAY BE -- CELL
SPECIFICITY MAY BE A LITTLE BIT
LESS OF AN ISSUE THAN IN VITRO.
THE THRESHOLD PHENOMENON RESULTS
FROM SPREAD OF SENESCENCE AND
THE FACT THAT SENESCENT CELLS
ARE CLEARED BY THE IMMUNE
SYSTEM, ESPECIALLY NATURAL
KILLER CELLS, BUT ALSO CERTAIN T
LYMPHOCYTE SUBSETS.
SO OUR VIEW IS IF YOU GET BELOW
THE THRESHOLD IN THE BODY, AND
WE'VE GOT SOME EVIDENCE FOR TH
THIS, YOUR OWN IMMUNE SYSTEM
STARTS TAKING OUT REMAINING
SENESCENT CELLS THAT MAY BE
RESISTANT TO SENOLYTICS.
AND WE'VE ACTUALLY GOT DATA
SHOWING THAT WITH RESPECT TO THE
BRAIN.
SO IF WE CLEAR SENESCENT CELLS
ONLY IN ADIPOSE TISSUE IN THE
CONTEXT OF OBESITY, WE START
SEEING CLEARANCE OF SENESCENT
CELLS IN THE BRAIN BY ASTROCYTES
AND MICROGLIA, SO THE BODY'S OWN
IMMUNE SYSTEM IS ABLE TO TAKE
OVER.
FURTHERMORE, ONCE YOU GET ABOVE
A THRESHOLD OF SENESCENT CELLS,
THEY START POISONING THE IMMUNE
SYSTEM.
SO THEY RESULT IN IL-23
PRODUCTION, THEY PRODUCE
IL-6 WITH INTERFERES WITH
MACROPHAGE, THESE MITOCHONDRIAL
DNAs AFFECT DENDRITIC CELLS,
SO ONCE YOU'RE BEYOND A
THRESHOLD, YOU ENABLE THE IMMUNE
SYSTEM TO START KILLING CELLS,
SO YOU MAY NOT NEED THE KIND
OF -- YOU MAY NOT NEED CELL TYPE
SPECIFICITY IF YOU'RE ACTUALLY
DOING A CLINICAL TRIAL.
>> THANK YOU, THANK YOU SO VERY
MUCH.
IN THE INTEREST OF TIME, I WOULD
LIKE TO ASK DR. ROBINS TO GO
AHEAD WITH HIS PRESENTATION.
>> FANTASTIC.
>> GREAT.
CAN YOU SEE MY SLIDES?
>> YES.
>> GREAT.
AND JIM, THANK YOU VERY MUCH FOR
A WONDERFUL OVERVIEW OF
SENESCENCE AND SENOLYTICS.
WHAT I'D LIKE TO DO IS ACTUALLY
FOCUS ON A FEW DIFFERENT
SENOTHERAPEUTICS, HOW WE CAN USE
THEM TO TREAT DIFFERENT
DISEASES.
SO TO CHARACTERIZE WHAT MY LAB
HAS DONE OVER THE LAST 10 YEARS,
WE'VE DONE NUMEROUS TYPES OF
ASSAYS TO IDENTIFY SENOLYTICS.
SO FOR EXAMPLE, WE SCREEN
LIBRARIES OF NATURAL COMPOUNDS
AND IDENTIFY THING SUCH AS HSB
INHIBITORS AND FISETIN, IDENTIY
VARIANTS IN CENTENARIANS AND TRY
TO IDENTIFY DRUGS WHICH MIMIC
THE EFFECTS OF THOSE VARIANTS.
IT TURNS OUT SOME OF THESE DRUGS
ACTUALLY AFFECT HE?
CENTS, WE SCREEN CLINICALLY USED
COMPOUNDS, ZOLEDRONIC ACID,
THOSE THAT HAVE 16 THERAPEUTIC C
ACTIVITY.
SEE IF WE CAN IMPROVE THEIR
ACTIVITY AND IMPROVE THEIR
SAFETY PROFILE.
WE'VE DONE BIOINFORMATIC
ANALYSIS, ALSO OTHER CLASSES OF
COMPOUNDS THAT HAVE BEEN
IDENTIFIED WITH USE OF THESE
METHODS.
AND THEN WE'VE ALSO SHOWN THAT
YOUNG FUNCTIONAL ADULT STEM
CELLS RELEASE VESICLES THAT CAN
SUPPRESS SENESCENCE.
AND WE HAVE IDENTIFIED
MICRORNAs IN OLDER MICE AS
WELL AS OTHER MICRORNAs THAT
MODULATE SENESCENCE, SO THEIR
BIOLOGICS, DO THIS NATURALLY
WITH AGING.
BUT I'D LIKE TO JUST HIGHLIGHT
TWO OF THESE.
I LIKE TO REFER TO WORK WE'VE
DONE OVER THE LAST 10 YEARS
LOOKING AT N OF KB -- AND THEN
CLOSE WITH A FEW EXAMPLES OF HOW
WE CAN USE FISETIN, THAT HAS
SENOLYTIC ACTIVITY.
SO NF KB IS SOMETHING I THINK
MOST PEOPLE HAVE SOME KNOWLEDGE.
IT CAN BE INDUCED BY A VARIETY
OF INFLAMMATORY FACTORS,
INFECTION AND STRESS, BUT NF KB
ALSO CAN BE INDUCED BY DNA
DAMAGE.
SO FOR EXAMPLE, IT CAN ACTIVATE
ATM, WHICH LEADS TO SUMMALATION,
NEMO CAN TRAP IT BACK TO THE
CYTOPLASM WHERE NOW IT CAN WORK
THROUGH THE CANONICAL ACTIVATION
PATHWAY LOADING TO
PHOSPHORYLATION OF I KB,
UBIQUINATION OF THIS REGULATORY
SUBUNIT, DEGRADATION, AND THEN
AN ACTIVE TRANSCRIPTION FACTOR
TRANSPORTED TO THE NUCLEUS,
WHERE IT CAN TURN ON A VARIETY
OF THINGS WHICH ARE IMPORTANT
FOR NORMAL SURVIVAL.
BUT IF IT'S ABERRANTLY REGULATED
IT WILL LEAD TO A VARIETY OF
DIFFERENT DISEASES, AGING AND
STEM CELL DYSFUNCTION.
SO JUST TO HIGHLIGHT THE REASON
WHY WE FOCUSED ON NF KB, IT'S
BEEN SHOWN THAT IT'S
DOWNREGULATED BY LONGEVITY
FACTORS SUCH AS SIRTUINS, B53,
BUT UPREGULATED BY INSULIN, IGFO
ALTHOUGH NF KB HAS A LOT OF
NORMAL FUNCTIONS, IF IT'S
MISREGULATED, IT CAN DRIVE A
VARIETY OF ADVERSE OUTCOMES.
AND WORKING WITH -- WE PUBLISHED
RECENTLY IN CENTENARIANS, THERE
ARE NOP CODING VARIANTS IN
DIFFERENT SUBUNITS OF NF KB,
ALTHOUGH IT DAMPENS ACTIVITY.
SO REDUCING NF KB LATER IN LIFE
CAN EXTEND HEALTHSPAN AND
POTENTIALLY LIFESPAN.
SO SOME YEARS AGO WE LOOKED TO
SEE WHERE NF CAP PA B WAS
ACTIVATED WITH AGING.
WE SHOWED THAT IN THE MOUSE
MODEL, THIS IS DRIVEN BY
REDUCTION IN THE DM REPAIR
COMPLEX, THAT MICE THAT LIVE SIX
MONTHS, THE MINUS DELTA MICE
SHOW EVIDENCE OF UPREGULATION OF
NF KB IN KIDNEY WHICH WE SEE IN
THE MOUSE MODEL WAS ONE MONTH
WHICH IS THE MINUS MINUS CCOC
MICE BUT ALSO IN NATURAL AGING,
WE SEE UPREGULATION OF NF KB IN
A SCAS T SEW CASS SOC, A SASTI.
SO WE THEN SET OUT TO SEE IF WE
COULD INHIBIT NF KB AND THE WAY
WE FIRST DID THIS IN THE CONTEXT
OF AGED MICE WAS UTE A PEPTIDE
LINK TODAY A PROTEIN
TRANSDUCTION DOMAIN THAT
DISRUPTS INTERACTION BETWEEN
NEMO, THE REGULATORY SUBUNIT AND
THE CATALYTIC KINASES.
SO WITH THIS PEPTIDE, WE SHOWED
THAT IF YOU TREATED THIS
ACCELERATED AGING MODEL THAT
LAURA DEVELOPED IN THE DELTA
MOUSE THAT WE COULD ACTUALLY SEE
AT LEAST APPEARANCE-WISE THAT
MICE LOOK MUCH HEALTHIER AFTER
TREATMENT AND THIS TREATMENT WAS
THREE DAYS A WEEK, STARTING AT
FOUR WEEKS OF AGE.
AND THIS LED TO A DELAY OF ONSET
OF MULTIPLE SYMPTOMS.
THERE WASN'T A DRAMATIC DELAY IN
ONSET BUT THIS COMBINATION OF
DELAY OF MULTIPLE MEASUREMENTS
OF HEALTHSPAN LED TO A VISIBLE
CHANGE IN THE APPEARANCE OF THE
MICE.
WE SAW EFFECTS ON -- AND LIVER,
THE KIDNEY, EFFECTS ON GLIOSIS
IN THE BRAIN AND EFFECTS
ACTUALLY ON OSTEOPOROSIS,
LOOKING AT THE VERTEBRAE OF
THESE MICE.
THE PROBLEM WITH THE PEPTIDE IS
IT'S NOT ORALLY ACTIVE, IT'S
EXPENSIVE, SO WE SET OUT SOME
YEARS AGO TO DEVELOP A SMALL
MOLECULE WHICH MIMICS THIS
PEPTIDE.
AND SO USING THE CRYSTAL
STRUCTURE OF THIS INTERACTION
BETWEEN THE NEMO REGULATORY
DOMAIN AND THE CATALYTIC KINASE,
WE IDENTIFIED THROUGH A
PHARMACO -- MODELING SYSTEM
FOLLOWED BY SEVERAL ROUNDS OF
SAR, A SMALL MOLECULE CALLED
SR12343 ACTUALLY INSERTS ITSELF
INTO THE HYDROPHOBIC POCKET OF
NEMO, SO THIS WILL NOW BLOCK THE
INTERACTION BETWEEN THESE TWO
SUBUNITS OF THE KINASE THAT
ACTIVATES NF CA KB.
SO THIS MOLECULE WHICH WE'VE
SHOWN DISRUPTS THIS COMPLEX IN
CELL CULTURE WILL INHIBIT NF KB
ACTIVITY IN A LUCIFERASE ASSAY
IN CELL CULTURE, BUT IF YOU
TREAT DIFFERENT ANIMAL MODELS OF
DISEASE, IN PARTICULAR, WE
TREATED THE DUCHENNE'S MUSCULAR
DYSTROPHY MOUSE MODEL, TREATING
IT THREE TIMES A WEEK FOR FOUR
WEEKS, WE SEE A DRAMATIC
IMPROVEMENT IN THE MUSCLE
PATHOLOGY AND REDUCTION IN
INFLAMMATION, IF WE TREAT
LAURA'S MOUSE MODEL -- MINUS
DELTA, STARTING AT 6 TO 7 WEEKS
OF AGE, WE HAVE A DELAY IN ONSET
OF SYMPTOMS AND NOT SHOWN HERE,
REDUCTION IN SEVERITY OF
SYMPTOMS.
WE'VE ALSO TREATED A MOUSE MODEL
OF HUTCHINSON GILFORD PROGERIA
SYNDROME, REDUCING FIBROSIS.
INTERESTINGLY, WE CAN ALSO PUT
THIS ON THE SKIN AND SHOW ON THE
MOUSE MODEL IMPROVEMENTS IN THE
SKIN APPEARANCE AS WELL AS
REDUCTION IN MARKERS OF
SENESCENCE SUCH AS P16.
WE'VE GONE ON TO
TREAT ---YEAR-OLD MICE, WE
TREATED THEM THREE TIMES A WEEK
FOR 17 WEEKS.
AND WE SHOWED IN LIVER THIS
REDUCES PHOSPHORYLATION OF THE
P65 SUBUNIT OF NF KB BUT ALSO
P21 IN THE LIVER.
YOU SEE A REDUCTION IN
SENESCENCE MARKERS AND SASP
MARKERS IN THE LIVER.
WE ALSO SEE THIS IN DIFFERENT
MUSCLES.
THIS IS THE QUADRICEPS BUT ALSO
IN GASTROC WE SEE A REDUCTION IN
SENESCENCE MARKERS.
AND JUST THE APPEARANCE OF THE
MUSCLE IS DIFFERENT.
SO DRAMATIC EFFECTS WITH 17
WEEKS OF TREATMENT OF OLD MICE.
RECENTLY WE TRIED TO APPLY THIS
TO OTHER MODELS.
WE EXAMINED THE EFFECT OF THIS
COMPOUND IN BLOCKING THE ADVERSE
EFFECTS OF A CHEMOTHERAPY
COCKTAIL THAT'S USED TO TREAT
MANY TYPES OF CANCERS AND SHOWED
THE CO-DELIVERY OF THIS DRUG
WITH THIS CHEMOTHERAPEUTIC
COCKTAIL, SO THE DRUG IS IN RED,
TREATING WITH SR12343 IS IN
GREEN, WE CAN PREVENT REDUCTION
OF BODY WEIGHT -- MASS AND THE
LOSS OF FAT MASS BY BLOCKING IKK
NF KB, AND SIMILARLY IF YOU LOOK
AT LIVER AS WELL AS OTHER
TISSUES, TREATMENT WITH
CHEMOTHERAPY DRIVES MARKERS OF
SENESCENCE IN SASP BUT THIS DRUG
PREVENT THIS INCREASE.
SUGGESTING IT COULD BE USED FOR
BLOCKING ADVERSE EFFECTS OF
CHEMOTHERAPY BUT ALSO CANCER
CACHEXIA.
WHAT ACTIVATES NF KB WITH AGING?
THE HYPOTHESIS WAS THIS WAS
PREDOMINANTLY THROUGH DNA DAMAGE
AND NOT FACTORS SUCH AT -- OR
IL-1 BETA.
WE USED A MOUSE MODEL WHERE
MUTATIONS WERE INSERTED IN NEMO
TO BLOCK ITS SIMULATION AFTER
DNA DAMAGE.
THIS IS MADE BY SHIGEKI MIYAMOT
OSM.
IF YOU RADIATE SPLENOCYTES, IF
YOU MAKE THIS TWO AMINO ACID
CHANGE IN NEMO THAT'S NOT
SIMULATED, THIS ACTIVATION GOES
DOWN, BUT THE ACTIVATION BY LPS
IS NOT IMPAIRED BECAUSE THAT'S
THROUGH A DIFFERENT SIGNALING
PATHWAY.
SO THIS HAS REDUCED NF K KB
SIGNALING WITH DNA DAMAGE.
INTERESTING IF YOU CROSS THIS
MOUSE MODEL INTO THE PROGERIA
MOUSE MODEL, WE SEE A REDUCTION
OF MARKERS OF SENESCENCE IN
EVERY TISSUE THAT WE'VE ANALYZED
THAT'S SHOWN HERE FOR LIVER,
REDUCTION IN P16 AND PSM 21 AND
SASP FACTORS.
IF YOU ISOLATE STEM CELLS FROM
THE MUSCLE, THEY NOW
DIFFERENTIATE THE MYOFIBERS MUCH
MORE EFFECTIVELY, SHOWING THIS
INHIBITION OF NF KAPPA BY
ACTIVATION WITH DNA DAMAGE
ALLOWS STEM CELLS TO
DIFFERENTIATE MORE EFFECTIVELY,
AND THE MUSCLE FIBERS LOOK MUCH
MORE LIKE A YOUNGER MUSCLE FIBER
WITH A YOUNGER SIZE, SUGGESTING
THAT DNA DAMAGE DRIVES NF KB
ACTIVATION WITH AGING WHICH
DRIVES SENESCENCE AND SASP.
SO I'D LIKE TO CLOSE BY SHOWING
A FEW EXAMPLE FS A DIFFERENT
COMPOUND.
THIS IS A FLAVONOID FISETIN, WE
SHOWED AT LOW DOSES OF THESE
DIFFERENT FLAVONOIDS THAT FI
FISETIN WAS MORE EFFECTIVE.
IN OTHER CELL TYPES IT
FUNCTIONED AS -- MORPHIC.
WE SHOWED A FEW YEARS AGO WITH
JIM THAT IF YOU TREATED OLD --
MICE THAT ALLOWS US TO ASSESS BY
EXPRESSION THE P16 PROMOTER THAT
FIVE DAYS OF ACUTE TREATMENT
WITH FICETIN REDUCED SA BETA --
BUT ALSO REDUCED THE PERCENT OF
DIFFERENT TYPES OF CELLS OR
DIFFERENT TYPES OF SENESCENT
CELLS INCLUDING CD4s, CD8s
AND NK CELLS WITH THIS ACUTE
TREATMENT.
WE SHOWED ALSO IF YOU PUT FIC
FICETIN IN THE -- IF THEY TAKE
IT TAILY -- SUGGESTING
IMPROVEMENT IN PANCREATIC
FUNCTION, LIVER FUNCTION, AND
WHAT HISTOPATHOLOGY WITH THE
GEROPATHOLOGY GRADING PLATFORM
WE SEE AN IMPROVEMENT IN
PATHOLOGY IN BRAIN, KIDNEY, THE
LUNG AND THE PAW, SO DRAMATIC
EFFECTS OF EXPOSURE OF THESE
MICE TO FICETIN.
THE LAST EXAMPLE I WANT TO GIVE
OF HOW WE CAN USE S
SENOTHERAPEUTICS, WE'VE USED THE
MODEL EXTENSIVELY WHERE YOU
ACTUALLY EXPOSE AN SPF MOUSE TO
A PET STORE MOUSE.
WE CALL THIS THE NORMAL
MICROBIAL EXPERIENCE AN, DEVELOD
AT THE UNIVERSITY OF MINNESOTA,
BUT EXPOSING THE SPF MOUTH TO
PATHOGENS HAD AN INTERESTING
RESULT.
SHOWN IN GREY ARE YOUNG MICE
EXPOSED TO A PET STORE MOUSE,
AND THEY SURVIVE ALMOST 100%.
BUT A 2-YEAR-OLD -- MOUSE DIED
WITHIN 14 DAYS.
SO WE VIEW THIS AS A LOSS OF
RESILIENCE DUE TO A UNEDUCATED
IMMUNE SYSTEM.
WHAT WAS INTERESTING WAS LOOKING
AT THE ANTIBODIES TO THE
PATHOGENS THAT COULD BE
TRANSFERRED, THE FIRST PATHOGEN
WHERE AN ANTIBODY WAS DEVELOPED
AGAINST THESE OLD MICE WAS MHV,
THE MURINE CORONAVIRUS MOUSE
HEPATITIS VIRUS.
SO WHAT WE SHOWED WAS THAT IF
YOU INFECT OR EXPOSE OLD MICE TO
PATHOGENS AS SHOWN HERE IN BLACK
WITH THE OLD MOUSE, THAT THESE
PATHOGENS DRAMATICALLY INCREASE
SENESCENCE AS COMPARED TO THE
OLD SPF MOUSE SHOWN IN MAGENTA.
SO DRAMATIC EFFECTS IN
INCREASING SENESCENCE, BUT ALSO
IMFLAM TRI MARKERS SUCH AS IL-6,
MCP1 AND TNF ALPHA.
SO -- DRIVE INCREASE IN
SENESCENCE AND INCREASE IN SASP.
AND THEN WE'VE ACTUALLY EXPOSED
THESE MICE OR TREATED THEM WITH
INTERMITTENTLY WITH FI SE TIN.
BY PUTTING IT INTO THE CHOW.
AND WE SHOWED THAT WE CAN
PROTECT 50% OF THESE MICE FROM
DEATH.
WHY IT'S ALWAYS 50% IS STILL IN
QUESTION BUT FISETIN AND OTHER
SENOLYTICS ALWAYS SEEM TO HAVE
AN EFFECT OF RESCUING 50% --
>> YOU HAVE 2 MINUTES LEFT.
>> THERE ARE NOW 16 CLINICAL
TRIALS, YOU CAN SEE THEY'RE
AGAINST A VARIETY OF DIFFERENT
CONDITIONS INCLUDING CARPAL
TUNNEL SYNDROME, COVID,
OSTEOARTHRITIS, KIDNEY DISEASE,
FRAILTY, SKELETAL HEALTH, CANCER
SURVIVORS, OBESITY AND
DEPRESSION.
SO CLEARLY A WIDE RANGE IN
DISEASE TARGETS.
SO WITH THAT, I'D JUST LIKE TO
CLOSE BY TALKING ABOUT KIND OF
WHAT THIS DATA AND HOW IT MAY
ALTER OUR THOUGHTS ABOUT WHAT
CAN DRIVE RESILIENCE AND
INTERCEPT DISEASES.
I THINK WE'VE SHOWN DNA DAMAGE
PLAYS A KEY ROLE IN DRIVING
ACTIVATION OF NF KB AND THE
SUBSEQUENT EFFECTS INCLUDING
SENESCENCE, INFLAMMATION, STEM
CELL DYSFUNCTION.
SENOTHERAPEUTICS CAN -- BECAUSE
OF THE FACT THEY'VE NOT
EXPERIENCED ANY EXPOSURE OF THE
PATHOGENS SO WE SHOULD BE
CONSIDERING THAT IN THE FUTURE.
AND WE CAN APPLY
SENOTHERAPEUTICS TO A WIDE
SPECTRUM OF DISEASES AND
DISORDERS.
I DIDN'T TALK ABOUT THIS BUT WE
PUBLISHED A FEW YEARS AGO THAT
IMMUNE CELLS LIKELY ARE A KEY
TARGET FOR SENOTHERAPEUTICS,
BECAUSE OF THE FACT THAT THEY
CAN INFILTRATE INTO A VARIETY OF
TISSUES.
AND I THINK IN THE NEXT THREE OR
FOUR YEARS, THESE ONGOING
CLINICAL TRIALS ARE REALLY
DOCUMENTING THE HEALTH BENEFITS
OF REDUCING THE SENESCENT CELL
BURDEN.
SO WHAT ARE THE KEY GAPS?
QUESTION IS, WHAT CELLS DO YOU
SEE SENESCENCE OCCURRING IN AND
NF KAPPA BY ACTIVATION, AND THEN
WHAT ARE THE SUBSET OF THESE
CELLS WHICH ACTUALLY CONTRIBUTE
TO AGING AND AGE-RELATED
DISEASES?
AND THEN THE QUESTION IS WHAT
ACTUALLY DRIVES THIS ACTIVATION,
WHAT TYPE OF STRESS?
THIS COULD BE PSYCHOSOCIAL
STRESS, INFLAMMATORY STRESS,
MECHANICAL STRESS, COULD BE
OXIDATIVE STRESS, PATHOGEN
EXPOSURE, SO WHAT ACTUALLY
DRIVES THESE AGENTS WITH AGE, AT
LEAST IF YOU EXPOSE A MOUSE TO A
NORMAL MICROBIAL EXPERIENCE.
SO I THINK WHAT WE NEED OVER THE
NEXT FEW YEARS IS WE REALLY HAVE
TO IDENTIFY THE KEY CELL TYPES
WHERE SENESCENCE AND NF KB OR
INFLAMMATION ARE BEING ACTIVATED
AND THERE ARE DIFFERENT
APPROACHES WE CAN TAKE USING
TRANSGENIC MOUSE MODELS AS WELL
AS ADOPT A TRANSFER OF DIFFERENT
TYPES OF SENESCENT CELLS.
AND I THINK WE REALLY NEED TO
OPTIMIZE SENOMORPHIC AND
SENOLYTIC DRUGS -- TARGETING THE
KEY CELL TYPES RESPONSE IIBLE
RIBLE FOR DRRESPONSIBLE FORDRIV.
WITH THAT, I'LL STOP AND ANSWER
ANY QUESTIONS.
THANK YOU.
>> THANK YOU SO MUCH.
THAT WAS VERY, VERY INTERESTING
AND THOROUGH.
I THINK OUR FIRST QUESTION IS
ACTUALLY COMING FROM SVETLANA
ABOUT ADJUNCTIVE OR ADDITIVE
THERAPIES.
>> YES, SO MY COUPLE OF
QUESTIONS ARE HOW WE CAN
OPTIMIZE THE TIMING AND DURATION
OF SENOLYTIC AGENTS FOR MAXIMUM
BENEFIT IN AGE-RELATED DES AND
WHEDISEASESAND WHETHER WE CAN C-
SECOND PART OF THE QUESTION --
WHETHER WE CAN COMBINE
SENOLYTICS WITH OTHER POTENTIALS
LIKE EXERCISE -- CHANGES.
>> GREAT QUESTIONS.
I THINK -- I DON'T KNOW IF JIM
IS STILL ON, HE MIGHT BE ABLE TO
ANSWER THE ONE ABOUT TIMING.
I DON'T KNOW IF WE KNOW THE
RIGHT TIMING WHERE IF YOU DON'T
HAVE ACTIVATION OF NF KB OR
INCREASE IN CELL BURDEN, IT
MIGHT HAVE MINIMAL EFFECT SO WE
HAVE TO HAVE WAYS OF MEASURING
THESE CHANGES, A BIOMARKER THAT
CAN INCREASE ABSENCE OF
SENESCENCE WILL BE ABSOLUTELY
ESSENTIAL.
YOU DON'T WANT TO TREAT SOMEBODY
THAT HAS NO BURDEN WITH A
SENOLYTIC.
AND I THINK A COCKTAIL IS WHAT
WE END UP WITH.
IT'S NOT GOING TO BE ONE
SENOLYTIC OR SENOMORPHIC THAT
GOING TO I THINK CROSS THE
SPECTRUM OF ALL THE DIFFERENT
SENESCENT CELLS AS WELL AS
PENETRATE THE BRAIN AND OTHER
TISSUES.
SO I THINK WE'RE GOING TO HAVE
TO HAVE A COCKTAIL.
AND WHEN TO START THOSE
TREATMENTS WITH THOSE DIFFERENT
COMPONENTS OF THE COCKTAIL WILL
STILL HAVE TO BE DETERMINED
THROUGH FDA-APPROVED CLINICAL
TRIALS.
>> AND DO YOU THINK THERE WILL
BE ADDITIVE THINGS TO SENOLYTICS
LIKE LIFESTYLE FACTORS OR --
>> OH, YES.
ABSOLUTELY.
IN FACT, LIFESTYLE FACTORS ARE
PROBABLY AS GOOD AS A LOT OF THE
SENOLYTICS WE HAVE.
IT'S BEEN SHOWN THEY REDUCE
SENESCENCE.
THE PROBLEM IS I WOULD ARGUE
100% OF AMERICANS ARE NOT GOING
TO BE EXERCISING, EATING WELL,
SLEEPING WELL AND DOING ALL THE
THINGS WE'RE SUPPOSED TO BE
DOING.
SO IT'S FOR THE 80% WHO CAN'T OR
DON'T THAT WE'RE TRYING TO
DEVELOP THESE DRUGS FOR.
>> FANTASTIC.
AND WE'RE GOING TO HEAR MORE
FROM LAURA AS WELL.
I HAD A QUESTION ALSO, IF
DR. KIRKLAND IS STILL ON.
ONE OF THE THINGS ABOUT THESE
SENESCENT CELLS IS THEY MAY BE
VERY IMPORTANT IN HOMEOSTASIS.
HAVE THERE BEEN LONG TERM
CHRONIC STUDIES, BECAUSE THERE'S
ALWAYS THE CONCERN THAT THIS
COULD LEAD TO DYSFUNCTION OF THE
IMMUNE SYSTEM AND IT'S ALWAYS
THE SECOND SIDE OF THE COIN WITH
THINGS LIKE CANCER.
SO HAS THAT BEEN KIND OF
EVALUATED YET?
IS THAT ONE OF THE AREAS OF
CONCERN THAT YOU HAVE WITH THESE
AGENTS?
>> ACTUALLY I'LL JUMP IN FIRST.
I THINK THE DATA REALLY SUGGESTS
THAT CLEARING SENESCENT CELLS
DELAYS ONSET OF CANCER, BECAUSE
SENESCENT CELLS AND ANTICANCER
MECHANISM -- BREAK THROUGH
SENESCENCE LEAD TO CANCER, SO
THAT HASN'T BEEN A CONCERN.
YOU KNOW, LIFELONG TREATMENT, AT
LEAST IN MOUSE MODELS WITH THE
INITIAL D PLUS Q IF F -- WE HAT
OBSERVED ANY AT LEAST WITH THE
END POINTS THAT HAVE BEEN
MEASURED.
>> I BELIEVE THERE WAS ANOTHER
QUESTION ABOUT THE CLINICAL
TRIALS FROM DR. GEHLS, WONDERING
IF THERE WAS ANY RANDOMIZED OR
CLINICAL TRIALS FOR
CARDIOVASCULAR DISEASE.
AS SHE DIDN'T SEE IT ON THE
LIST, WHICH IS A MAJOR
AGE-RELATED DISEASE.
>> IF JIM IS STILL ON, I'LL LET
HIM ANSWER THAT ONE.
I KNOW THERE'S DISCUSSION OF A
TRIAL STARTING AT THE MAYO
CLINIC.
JIM, CAN YOU --
>> HE MAY NOT BE ABLE TO GET ON
BECAUSE HE'S IN HOLLAND.
>> ONE HASN'T STARTED BUT IT'S
PLANNED AT THE MAYO CLINIC.
>> THIS ONE IS FROM ME.
BASICALLY IT WAS VERY
INTERESTING WITH KIND OF WILD
TYPE VERSUS DIRTY PET STORE, AND
THIS COMES BACK TO THE COVID
STUDY.
DO YOU THINK THIS HAS ANYTHING
TO DO WITH COVID SPECIFICALLY?
OR WILL ANY VIRAL INFECTION OR
ANY TYPE OF OVERWHELMING SEPSIS,
IT'S JUST THAT WE SAW SUCH A
LARGE NUMBER DURING THE
PANDEMIC, IS THIS ANY DIFFERENCE
THAN ARDS OR BEING ON ECMO OR
BEING INTUBATED FROM THE FLU,
FOR EXAMPLE, DO YOU THINK
THERE'S SOMETHING SPECIFIC THAT
IS PRO SENESCENT ABOUT COVID OR
DO YOU THINK THAT IT'S JUST WE
HAVE THIS HUGE POPULATION THAT
WE'RE NOW STUDYING?
>> THERE'S BEEN REPORTS THAT
COVID ACTUALLY CAUSES DNA DAMAGE
AND THAT MIGHT CONTRIBUTE TO
DRIVING SENESCENCE.
OUR DATA SUGGESTS THAT MAYBE AN
INFLAMMATORY RESPONSE DRIVES THE
SECONDARY SENESCENCE.
BUT HAVING SAID THAT, WE HAVE A
COLLEAGUE, SCOTT BUDDING EV R AT
NORTHWESTERN WHO'S LOOKING AT
THE EFFECT OF FLU INDUCING THESE
SAME FACTORS AND HE THINKS THAT
ALL VIRUSES OR MOST PATHOGENS
WILL HAVE A SIMILAR EFFECT.
THAT MAYBE THE MAGNITUDE IS
DIFFERENT, BUT I THINK THEY'LL
ALL CONTRIBUTE TO DRIVING NOT
ONLY IMMUNE EXHAUSTION BUT ALSO
SENESCENCE.
>> FANTASTIC.
A LOT OF THE COVID TRIALS DON'T
HAVE NON-COVID INFECTED DISEASE
MATCHED CONTROLS, AND THAT IS --
>> RIGHT.
>> -- THE LIMITATIONS OF SOME
OF THOSE STUDIES.
I DON'T SEE ANY OTHER QUESTIONS
IN THE CHAT.
GO AHEAD, PAUL.
>> IF I COULD JUST THROW IN, I
THINK THAT THERE'S DATA AND JIM
COULD COMMENT ON IF HE WAS STILL
ON THAT LONG COVID PATIENTS HAVE
AN INCREASE IN SENESCENCE.
AND SO THE QUESTION IS, IS
WHETHER LONG COVID COULD BE
TREATED PARTIALLY USING
SENOLYTICS.
SO THAT'S ANOTHER AREA OF
INVESTIGATION.
>> FANTASTIC.
AND I THINK WE ARE OUT OF TIME,
SO WE ARE GOING TO NOW MOVE ON
TO LAURA.
LAURA, I BELIEVE YOU ARE UP
NEXT.
SHE'S GOING TO BE TALKING ABOUT
EXOGENOUS MEDIATORS OF CELLULAR
SENESCENCE.
HIT IT!
LAURA, YOU'RE MUTED.
WE HAVE TO SAY THAT AT LEAST
ONCE IN EVERY BIG ZOOM MEETING.
LAURA, I THINK YOU ARE STILL
MUTED.
I THINK WE WILL BE TALKING A
LITTLE BIT ABOUT PATHOGENS AND
OTHER THINGS AS WELL IN THE
DISCUSSION, SO HOPEFULLY YOU'LL
ALL STAY ON AFTER THIS SESSION
TO BE PART OF THE PANEL.
LAURA, I BELIEVE YOU'RE NOW OFF
MUTE.
HIT IT.
>> GREAT.
THANK YOU.
I APOLOGIZE FOR THAT.
DIDN'T MEAN TO THROW A MONKEY
WRENCH IN YOUR TIMING HERE, BUT
I ONLY HAVE ONE ARM.
SO IF I FALL OFF MY CHAIR, OR
ANYTHING STRANGE HAPPENS, PLEASE
CARRY ON WITHOUT ME.
SO YEAH, I'M GOING TO EXPAND ON
A COUPLE OF TOPICS THAT BOTH
PAUL AND DR. KIRKLAND HIT ON AND
JUST TO TRY AND MAKE OTHER
POINTS AND IDEALLY PROVOKE SOME
MORE CONVERSATION DURING THE
PANEL DISCUSSION AT THE END OF
THE DAY.
SO I'M GOING TO START WITH MY
RATIONALE FOR FOCUSING ON
CELLULAR SENESCENCE, AS BOTH JIM
AND PAUL VERY WELL JUSTIFIED,
BUT I'VE ALWAYS SPENT MY CAREER
VERY INTERESTED IN THE HEALTH
IMPACT OF ENDOGENOUS DNA DAMAGE.
SO DNA DAMAGE, WE CAUSE THROUGH
NORMAL METABOLISM AND NORMAL
HUMAN EXPOSURES.
SO WE START FROM A VANTAGE POINT
OF THERE.
THIS.
WE KNOW THIS IS A POTENT DRIVER
OF CELLULAR SENESCENCE, AND THEN
WE'VE LED TO ATTACKING CELLULAR
SENESCENCE WITH DRUGS.
SO PART OF MY INTEREST IN THIS
COMES FROM THINKING ABOUT
GEROTHERAPEUTIC -- I WANT TO
GIVE A SHOUT OUT TO THOSE
CHAMPIONING THIS APPROACH OF
TARGETING FUNDAMENTAL BIOLOGY OF
AGING AND NOT INDIVIDUAL HALL
MARKS NECESSARILY BUT
FUNDAMENTAL AGING BIOLOGY
BECAUSE I THINK THAT'S GOING TO
BE MORE PRODUCTIVE THAN
TARGETING ANY PARTICULAR
AGE-RELATED DISEASE TRAJECTORY.
SO THE REASON WE FOCUSED ON
SENESCENCE IS WHEN WE LOOK
ACROSS TISSUES OF AGED WILD TYPE
MICE, WHICH IS SHOWN HERE IN A
HEAT MAP FOR P16 MESSENGER RNA,
WE SEE EVIDENCE OF SENESCENCE IN
MANY, MANY TISSUES.
AND WHAT'S INTRIGUING TO US IS
THESE DNA REPAIR-DEFICIENT MICE
THAT PAUL IS USING IN HIS
STUDIES, THEY ACTUALLY HAVE A
VERY SIMILAR HEAT MAP TO NATURAL
AGING.
SO I WOULD LIKE TO THINK OF THIS
AS EVIDENCE THAT ENDOGENOUS DNA
DAMAGE IS ONE OF THE POTENT
DRIVERS OF CELLULAR SENESCENCE
IN VIVO UNDER NORMAL PHYSIOLOGIC
CONDITIONS.
THIS IS WORK OF MATT
YOUSEFZADEH, FACULTY MEMBER AND
COLUMBIA.
HE REALLY TORE THE MICE APART
AND LOOKED AT DIFFERENT MEASURES
OF SENESCENCE.
THEY ALWAYS MATCHED NORMAL,
AGING AND WILD TYPE MICE.
SO ANOTHER KEY STUDY FROM NED
SHARPLESS THAT REALLY GOT MY
ATTENTION AS WELL IS, HE SHOWED
WELL OVER A DECADE AGO THAT P16
GOES UP IN HUMANS AS THEY AGE.
SO THIS IS SHOWING JUST HIS
ASSAY OF MEASURING P16 MESSENGER
RNA IN PERIPHERAL BLOOD
CD3 POSITIVE CELLS, AND YOU SEE
IT GO UP EXPONENTIALLY WITH
EVERY DECADE OF LIFE.
BUT IMPORTANTLY, NED SHOWED IN
THE SAME EXACT PAPER THAT
THEY'RE ALSO MODIFIABLE.
SO THIS IS SHOWING SAME MEASURE
OF P16 MESSENGER RNA, BUT YOU
SEE THAT SMOKERS IN THE ORANGE
CURVE ACTUALLY HAVE A GREATER
SLOPE WHEREAS EXERCISES CAN
REDUCE THAT SLOPE.
SO THIS GIVES US A GER
GEROTHERAPEUTIC TARGET THAT WE
CAN BE THOUGHTFUL.
I WANTED TO COVER FOUR TOPICS
BEING AND THIS IS LARGELY THE
WORK OF OTHER FOLKS SO CANCER
THERAPY, INFECTIOUS DISEASE,
PSYCHOSOCIAL STRESS, AND ORGAN
TRANSPLANTATION.
SO I'M GOING TO START WITH
CANCER THERAPY, AND THIS IS THE
WORK OF BESHAY ZORDOKY, WHO'S AT
THE UNIVERSITY OF MINNESOTA.
AND HE -- BEFORE I JUMP INTO HIS
WORK, LET ME MAKE ONE OTHER
COMMENT.
TO THIS GROUP, BECAUSE I THINK
THIS IS FOOD FOR THOUGHT TOO.
I THINK WE HAVE TO BE THINKING
ABOUT HEALTH TRAJECTORIES OF
DISEASE SURVIVORS, AND NOT JUST
CANCER SURVIVORS.
AND THE REASON I BRING THIS UP
IS I'M GETTING ASKED TO RUN
CLINICAL TRIALS BY PEDIATRICIANS
IN EVERY DISCIPLINE YOU CAN
IMAGINE.
IN RESPONSE TO YOUR QUESTION,
LOUISE, WE'RE PLANNING ONE IN
SEPSIS USING A SENOLYTIC, SO IT
WILL BE ALLCOMERS OF INFECTIOUS
DISEASE BASICALLY.
BUT WHAT WE'VE NOTICED IS
PATIENTS WITH RARE GENOME
INSTABILITY DISORDERS KIND OF
LIKE OUR MICE, THEY ARE LIVING
UNPRECEDENTED LIFESPANS, AND
THEY'RE AGING VERY QUICKLY.
THERE'S CLEARLY METABOLIC
DISORDERS THAT DRIVE MORE RAPID
AGING, AND AS JIM HIT ON,
TRANSPLANTATION HAS NEGATIVE
EFFECTS ON YOUR HEALTH
TRAJECTORY.
AS DOES TREATMENT IN CHILDHOOD
WITH CANCER KEEM THERAPEUTICS.
SO THE POINT OF ALL OF THIS IS
JUST THAT I THINK WE'RE ACTUALLY
UNDERESTIMATING THE CHALLENGES
WE ARE FACING WITH AGING
BIOLOGY.
IT'S NOT JUST OLD PEOPLE, BUT A
LOT OF DISEASE SURVIVORS.
AND I THINK THIS ALSO PROVIDES A
WINDOW OF OPPORTUNITY FOR
SPECIALIZED CLINICAL TRIALS AS
JIM ELEGANTLY POINTED OUT.
SO THIS IS THE WORK OF BESHAY
AND HE WAS USING HUMAN
ENDOTHELIAL CELLS, TREATING THEM
WITH A CANCER CHEMOTHERAPEUTIC
AGENT DOCKS REUB SON AND
MEASURING SENESCENCE IN A
VARIETY OF DIFFERENT WAYS.
THIS IS JUST AN EXAMPLE OF
MEASURING BETA GLAK TA CYDASE
ACTIVITY WHICH GOES UP
SIGNIFICANTLY AND AT THE PROTEIN
LEVEL, STABLE EXHAUSTION OF P53,
P21, CYCLIN D1.
HE SHOWS THAT ALSO THIS CANCER
CAME IN -- OTHER EVIDENCE OF
CELLULAR SENESCENCE LIKE THESE
SCAPs.
SO OBVIOUSLY THERE'S AN
ABUNDANCE OF EVIDENCE THAT
CHEMOTHERAPEUTICS DRIVE
ACCELERATED AGING, THEY WORSEN
YOUR HEALTH TRAJECTORY, BUT I
WOULD ARGUE THAT HAS ANYTHING TO
DO WITH YOUR EXPOSOME THAT
HAS -- THAT TOUCHES ON GINO GENC
STRESS.
SO THERE'S LOTS OF OTHER THINGS
WE SHOULD BE THINKING ABOUT IN
OUR ENVIRONMENT, INCLUDING EVEN
SOME DIETARY SUPPLEMENTS AS WELL
AS ADDITIVES.
SO JUMPING BACK ON THE
INFECTIOUS DISEASE STORY, I WANT
TO FIRST ACKNOWLEDGE THOSE WHO
CONTRIBUTED TO THIS COVID-19
STORY.
JIM, PAUL, CHRISTINA AND MATT.
SO AS WAS INTRODUCED, WE ARE
COMBINING THESE PRISTINE NIA
AGED WILD TYPE MICE WITH PET
STORE MICE TO GIVE THEM A MORE
HUMANIZED IMMUNE SYSTEM OR
NORMAL MICROBIAL EXPERIENCE.
THESE STUDIES ARE VERY TRICKY
BECAUSE ALL THE OLD MICE DIED
VERY RAPIDLY.
AS PAUL SHOWED YOU THAT MHV IS
THE AGENT THAT SEEMS TO BE
KILLING THE OLD WILD TYPE MICE
BECAUSE JUST BEFORE THEIR DEATH
AT TWO WEEKS, THAT'S THE ONLY
ANTIBODY WE FIND IN THEIR SERUM
DESPITE THE PET STORE MICE
CARRYING A WHOLE BUNCH OF
DIFFERENT MICROBES.
THE ANIMALS GET PATHOGNOMIC
IMAGE STAINING LESIONS,
POSITIVELY FOR HEPATITIS VIRUS,
AS WELL AS SHOWING THESE LARGE
SIN SI SHA IN THE LIVER.
SO THE POINT I WANT TO MAKE IS
THIS IS A FECAL-ORAL
TRANSMISSION.
SO THIS IS CLEARLY SOMETHING
WHERE THE MICROBIOME OF YOUR GUT
IS TIED IN, AND THERE'S ALL SORT
OF EXPOSURES THAT WE NOW KNOW
CAN REALLY ACCELERATE YOUR
AGING.
SO THE IMMUNOLOGISTS IN OUR
GROUP VACCINATED OUR ANIMALS
AGAINST MHV, AND THIS WAS
ADEQUATE TO RESCUE 100% OF THE
OLD WILD TYPE MICE AS SHOWN IN
BLUE.
SO IT REALLY SHOWS THAT MHV WAS
THE DEADLY KILLER, AND THEN THIS
IS THE EXPOSURES THROUGH THE GUT
BASICALLY.
PLAWSH SO AS PAUL SHOWED YOU, WE
ARE ABLE TO RESCUE THESE
ANIMALS, THE OLD WILD TYPE MICE
THAT ARE EXPOSED TO NME EITHER
WITH THE MAYO CLINIC GENETIC
OPPORTUNITY TO CLEAR SENESCENT
CELLS, OR WITH EITHER -- PLUS
THE FLAVONOID FESETIN.
THIS IS AGAIN GOING BACK TO
BESHAY'S WORK WHERE HE
CHALLENGED HIS CELLS IN VITRO
WITH LPS, SO BACTERIAL PAMP, AND
DOES SO EITHER IN SENESCENT
CELLS EXPOSED TO DOCKS REUB SON,
VEHICLE-TREATED CELLS OR CELLS
THAT GOT BOTH DOCKS REUB SON AND
METFORMIN.
WHAT'S INTERESTING TO SEE IS
THIS PRO INFLAMMATORY CHEMO
TRACK TIN FOAS THROUGH THE ROOF
PARTICULARLY IN SENESCENT CELLS
AS DOES P21 AND THIS ACTIVATED
NF KB.
SO THAT'S JUST QUANTITATED IN
THE THREE GRAPHS HERE WHERE YOU
SEE A SIGNIFICANT INCREASE IN
THE RED HATCHED BARS IN THE
DOXORUBICIN -- CHALLENGED WITH
LPS.
IF YOU USE A GEROTHERAPEUTIC,
IT'S NOT NECESSARILY TACKING ATG
SENESCENT CELLS, IT'S MORE A
SENOMORPHIC WHICH IS ALTERING
THE INFLAMMATORY RESPONSE.
SO BACK TO THIS FIGURE THAT JIM
SHOWED, WHAT WE THINK IS GOING
ON IS, IN A VIRAL INFECTION,
BACTERIAL INFECTION, IF YOU HAVE
SENESCENT CELLS BECAUSE YOU'RE
OLDER, THEN THIS LEADS TO DIRECT
IMPABLGHT ON HOW YOUR BODY
RESPONDS TO THAT VIRUS.
SO THERE'S UPREGULATION OF VIRAL
ENTRY PROTEINS, LOSS OF
ANTIVIRAL ACTIVITY.
THIS ALSO AFFECTS ADAPTIVE
IMMUNITY, AND NOW THERE IS
ABUNDANT EVIDENCE THAT VIRAL
INFECTION DIRECTLY INDUCES
ADDITIONAL DNA DAMAGE.
THIS IS WORK OF FABRIZIO DABDA,
VIRUS INFECTION WILL DRIVE
ADDITIONAL SENESCENCE, AND I
THINK WE HAVE MORE WORK TO
FIGURE OUT IF THERE'S FOREVER OR
A TRANSIENT PHASE.
SO THAT'S A GAP IN KNOWLEDGE FOR
SURE.
I THINK THIS IS REALLY
INTERESTING AND HAS NOT BEEN
BROUGHT UP YET AT THIS MEETING.
THIS IS THE WORK OF ALESSANDRO
BARTOLOMUCCI, ALSO AT THE
UNIVERSITY OF MINNESOTA, AND HE
GOT A DIRECTOR'S GRANT AT ONE
POINT TO STUDY THE EFFECT OF
PSYCHOSOCIAL STRESS ON AGING
PHENOTYPES.
SO WHAT HE DOES IS HE ACTUALLY
TAKES A REALLY AGGRESSIVE STRAIN
OF MICE, LETS IT -- PHYSICALLY
WITH KIND OF A WIMPY MOUSE
THAT'S SUBORDINATE, SO THESE
ANIMALS FIGHT IT OUT FOR A
PERIOD OF TIME, AND THEN THEY
ACTUALLY GET SEPARATED BUT SO
THAT THEY CAN SEE EACH OTHER
THROUGH PLEXIGLASS FOR THE REST
OF THEIR LIFE.
ALESSANDRO HAS BEEN ABLE TO GO
ON AND SHOW THAT THIS IS ENOUGH
TO SHORTEN THE SUBORDINATE
ANIMAL'S LIFESPAN.
IT MAKES THEM MORE PRONE TO
ALZHEIMER'S PATHOLOGY, AFFECTS
HEALTHSPAN, THE EPIGENETIC
CLOCK.
IT'S REALLY UNUSUAL BECAUSE SOME
OF THESE SUBORDINATE MICE WILL
ACTUALLY DIE OF CARDIOVASCULAR
DISEASE BUT IN THE ABSENCE OF A
HIGH FAT DIET OR ANY SORT OF
PECULIAR MANIPULATION.
SO REALLY A POTENT STRESSOR OF
ATTENUATING YOUR HEALTH
TRAJECTORY FOR SURE.
SO WHEN WE LOOK AT CELL
SENESCENCE IN THESE ANIMALS,
THIS IS USING THE NED SHARPLESS
ASSAY IN P BMCs, HE SEES P16
MESSENGER RNA GO UP AND IN A
REALLY SHORT PERIOD OF TIME
ACTUALLY, AND IF YOU QUANTIFY
THIS, YOU SEE THAT IT'S ALSO
PROGRESSIVE.
THIS IS LOOKING AT A HEAT MAP OF
P16 AND P21 IN A VARIETY OF
DIFFERENT TISSUES, AND I'D LIKE
TO POINT YOUR ATTENTION TO WHITE
ADIPOSE TISSUE, SO THIS IS
REALLY A STRONG RESPONDER TO
PSYCHOSOCIAL STRESS, AND SO THAT
ALSO, I THINK, ILLUMINATES THE
POSSIBILITY THAT THE STRESS PLUS
OBESITY OR METABOLIC SYNDROME
COULD BE PARTICULARLY HAZARDOUS.
SO I WANTED TO TOUCH BACK ON
TRANSPLANTATION.
AGAIN, THE WORK OF STEFFAN
TULLIUS AT HARVARD.
HE WAS ABLE TO SHOW THAT
DENDRITIC CELLS WHICH MODIFY THE
RESPONSE TO A TRANSPLANTED ORGAN
ACTUALLY HAVE AN EFFECT ON
OUTCOME, AND THIS IS IN A MODEL
OF CARDIAC TRANSPLANT.
SO WHAT HE DID WAS HE
TRANSPLANTED EITHER OLD OR YOUNG
DENDRITIC CELLS INTO RECIPIENT
MICE, THEN THEY DID THE
TRANSPLANT.
SO YOU SEE THE OLD MICE GETTING
OLD CELLS IN ORANGE.
BUT LOOK HOW THAT HAS SHIFTED IF
YOU GIVE THEM YOUNG DENDRITIC
CELLS.
SO YOU GET A MUCH HEALTHIER
RESPONSE TO THIS CH CHALLENGE OF
ORGAN TRANSPLANT.
SO STEFAN THINKS A LOT OF THIS
HAS TO DO WITH CELLULAR
SENESCENCE THAT'S PARTICULARLY
DRIVEN BY THIS MY TOE PLASMIC
DNA, AND IN FACT -- THINKS THAT
MITOCHONDRIAL DNA IS A KEY
DRIVER OF CELLULAR SENESCENCE,
YOU REALLY DON'T SEE MUCH
SENESCENCE OR SASP AT ALL.
SO IN THIS DATA, STEFAN SEES A
LOT OF MY T MITOCHONDRIAL DNA IN
OLDER DONORS IN THEIR PLASMA, SO
THIS IS USING TWO DIFFERENT
MARKERS.
SO THIS MIGHT HAVE SOMETHING TO
DO --
>> DOCTOR, YOU HAVE TWO MINUTE
REMAINING.
>> THANK YOU VERY MUCH.
SO THIS MAY HAVE A LOT TO DO
WITH THE AGE CAP, BUT AS JIM
QUICKLY ALSO POINTED OUT, OTHER
PLACES WHERE THEY'RE ACTUALLY
PERFUSING ORGANS, THERE'S AN
OPPORTUNITY, I THINK, TO REALLY
TUNE UP THESE AGED ORGANS SO
THAT WE CAN HAVE HEALTHIER
OUTCOMES.
SO VERY QUICKLY AGAIN BACK TO
THE NED SHARPLESS ASSAY, WE ARE
FULL OF SENESCENT IMMUNE CELLS
AS WE GET TO CERTAIN AGES, AND
AS PAUL ALLUDED TO, WE SHOWED A
COUPLE YEARS AGO THAT IMMUNE
CELLS FROM AGED DONORS ARE VERY
DELETERIOUS.
SO THIS IS SORT OF CLIP CHAR
EXPERIMENT WHERE WE'RE DOING
ADOPTIVE TRANSFER OF SPLENOCYTES
FROM MUTANT ANIMALS WHERE WEE
DRIVEN SENESCENCE ONLY IN THE
HEMATOPOIETIC SYSTEM, DOCTOR WE
PUT T -- WE PUTTHEM IN A P16 RE,
MONITORED OUTCOMES AND WE FOUND
THAT THESE TRANSPLANTED
SPLENOCYTES COULD DRIVE
SENESCENCE THAT LASTED AT LEAST
FIVE WEEKS TO THE RECIPIENT
ANIMALS.
WE PROBABLY SHOULD GO BACK AND
DO LONGER TIME POINTS.
SO P21 IS ALSO ELEVATED -- I
WANTED TO POINT TO THE BRAIN TO
HIGHLIGHT MIRANDA'S WORK AS
WELL.
WE ARE SEEING A TON OF
SENESCENCE IN THE BRAIN OF
ANIMALS.
SO THIS IS JUST P16 MESSENGER
RNA IN WILD TYPE 2-YEAR-OLD AND
3-YEAR-OLD ANIMALS.
SO YOU CAN SEE THE LEVELS ARE
JUST THROUGH THE ROOF.
SASP IS ALSO HIGH, SO IN CASE WE
DIDN'T COVER IT, I JUST WANTED
TO SAY THERE'S NO DOUBT IN MY
MIND THAT CENTRAL NERVOUS SYSTEM
CELLULAR SENESCENCE IS A HUGE
DRIVER OF NEURODEGENERATION.
SO I THINK ALL OF THESE ARE
MODULATORS OF HEALTH
TRAJECTORIES, CANCER THERAPY,
ANY EXPOSURE FROM YOUR
ENVIRONMENT THAT GIVES YOU DNA
DAMAGE, ENVIRONMENTAL MICROBES,
PSYCHOSOCIAL STRESS, ORGAN
TRANSPLANT, BUT IT IS BETTER TO
BE ALIVE THAN DEAD, SO WE WANT
TO GIVE -- YOU KNOW, WE HAVE TO
TREAT PEOPLE BUT WE HAVE TO BE
THINKING ABOUT THEIR HEALTH
TRAJECTORIES FOR BEYOND WHAT'S
GOING ON WITH IMMEDIATE
EMERGENCY.
SO WE DID A VERY QUICK STUDY
WHERE WE WERE LOOKING AT
TRANSPLANT PATIENTS.
THIS IS THE WORK OF KIRCHNER AND
MILLER.
WHAT'S INTERESTING IS THE NED
SHARPLESS ASSAY ACTUALLY SHOWS A
SIGNIFICANT CORRELATION WITH
FRAILTY AND LENGTH OF STAY IN
THE HOSPITAL, BUT ACTUALLY HAD
NOTHING TO DO WITH THE
SERIOUSNESS OF THE LIVER DISEASE
OR THE CHRONOLOGIC AGE OF
INDIVIDUALS.
SO I THINK THERE'S A LOT TO BE
DONE IN THIS ASSAY.
INTERESTINGLY, A LOT OF THE
ONGOING CLINICAL TRIALS ARE
TARGETING THESE HALL MARKS OF
AGING AND NOT THE PRIMARY ONES,
AND I WOULD ARGUE THAT IT'S
BECAUSE THOSE ARE REALLY
DIFFICULT TO MEASURE, THEY'RE
TIGHTLY REGULATED, THEY'RE
EVOLUTION AIRILY HIGHLY
OPTIMIZED, I THINK IF YOU
OVERSHOOT CORRECTION IT WILL
HAVE VERY NEGATIVE CONSEQUENCES.
SO WE NEED MEASURABLE RISK
FACTORS AS MANY PEOPLE HAVE
TALKED ABOUT.
JUST A QUICK PLUG FOR A PAPER
FR,THERE'S A LOT OF FDA-APPROVED
DRUGS OUT THERE THAT REALLY
AFFECT HEALTHSPAN, LIFESPAN,
MULTIPLE ORGAN SYSTEMS.
WE'VE GOT A TON OF DATA IN
PRE-CLINICAL MODELS, EVEN IN
HUMANS.
SO I WOULD ARGUE WHAT WE NEED IS
MORE CLINICAL TRIALS, AND I WAS
GOING TO GIVE A SHOUT OUT TO PLN
MIRANDA, BECAUSE YOU JUST HAVE
TO BE BOLD.
THIS IS NOT A HUGE TRIAL, IT'S
GETTING INTO A GREAT JOURNAL AND
IT'S MOVING THE NEEDLE, SO I
WOULD ARGUE FOR MORE OF THIS.
THANK YOU VERY MUCHMENT
>> THANK YOU, LAURA, THANK YOU
SO VERY MUCH FOR SUCH A
FASCINATING TALK.
SO IN ORDER FOR US TO REMAIN ON
TIME, I WOULD ASK DR. STEWART TO
TURN ON HER CAMERA AND GET
STARTED.
IN THE INTEREST OF TIME.
THANK YOU.
>> AND WE WILL HAVE TIME FOR
QUESTION AND ANSWERS AND
DISCUSSION IN THE PANEL.
>> ABSOLUTELY.
YOU'RE UNMUTED.
YOU ARE MUTED.
STILL MUTED.
>> THERE.
OKAY.
>> GOOD, GOOD, GOOD.
>> YOU WOULD THINK AFTER THIS
LONG IN DOING THIS, WE'D ALL
REMEMBER.
BUT LAURA, YOU AND I GET THE
PRIZE FOR THIS, RIGHT?
OKAY.
SO I WANT TO THANK EVERYONE FOR
THE INVITATION, EVERYONE FOR
STAYING ON.
HOPEFULLY YOU CAN ALL SEE THIS.
ARE WE GOOD?
YOU COMPLETELY SET ME UP AND I
DON'T HAVE TO DO A LOT OF
BACKGROUND.
I'M ACTUALLY GOING TO FOCUS ON
REALLY OUR THOUGHTS ABOUT THIS
IN RELATION TO CANCER.
USING SOMETHING JAMES WILL
PROBABLY SHOW LATER WHEN HE
TALKS, I DON'T HAVE TO REALLY
CONVINCE EVERYBODY, I THINK AGE
REMAINS THE LARGEST RISK FACTOR
FOR THE DEVELOPMENT OF CANCER.
AND WHEN ONE SEES THIS TYPE OF A
GRAPH, YOU HAVE TO TAKE THAT
STEP BACK AND ASK YOURSELF, WHAT
IS IT ABOUT AGING THAT DRIVES
NOT A SUBTLE BUT AN INCREDIBLY
RAPID INCREASE IN THE FIFTH TO
SIXTH DECADE OF LIFE.
AND YOU KNOW, IT'S OBVIOUSLY
GOING TO BE A COMPLICATED
ANSWER.
CANCER IS A DISEASE OR DISEASES
OF MULTIPLE MUTATIONS, AND IN
THE FACE OF ROBUST DNA REPAIR
MECHANISMS THAT HAVE ALREADY
BEEN DISCUSSED TODAY, IT'S GOING
TO TAKE TIME NOT JUST TO GET
MUTATIONS BUT THAT RIGHT
COCKTAIL OF MUTATIONS THAT
DRIVES A NORMAL CELL TO THAT
FULLY TRANSFORMED STATE.
BUT WE REALLY BECAME INTERESTED
IN THIS QUESTION WHEN WE STARTED
THINKING ABOUT A REALLY
INTERESTING PAPER THAT WAS
PUBLISHED NOW NEARLY TWO DECADES
AGO BY JUDY CAMPESE IN WHICH SHE
NOTED THAT SENESCENT CELLS WHICH
WE NOWAK LATE IN TISSUES ACROSS
AGE, YOU'VE HEARD QUITE A FEW
TALKS ABOUT THAT ALREADY TODAY,
BUT THAT THESE CELLS WHEN WE
THINK ABOUT THE STROMAL
COMPARTMENT, THE NON-TUMOR
CELLS, IF YOU WILL, SENESCENT
CELLS WERE ABLE TO RECAPITULATE
EVERY PHENOTYPE THAT HAD BEEN
ASCRIBED TO A CANCER ASSOCIATED
FIBROBLAST IN THEIR ABILITY TO
DRIVE TUMOR CELL PROLIFERATION,
MIGRATION INVASION, ALTER
ANGIOGENESIS AND ALSO TO REALLY
SET UP IMMUNOSUPPRESSIVE AREAS,
IF YOU WILL, AROUND TUMOR CELLS.
AND SO THIS DATA HAD BEEN OUT
THERE AND TRANSPLANT TYPES AND
JE NEIGHBORING STUDIES BUT I
THINK SOME OF THE BEST DATA TO
REALLY ARGUE THAT THESE CELLS
ARE IMPORTANT AND ALSO IN ANSWER
TO LUIS'S QUESTION EARLIER ON
WAS A PAPER THAT CAME OUT FROM
DARREN BAKER BACK IN 2016, WHERE
USING THE INK ATTAC MOUSE,
YOU'RE ABLE TO INDUCE BLI KILL
SENESCENT CELLS WIDELY ACROSS
THE ANIMAL, IT DIDN'T MATTER IF
UR WERE MALE, DIDN'T MATTER IF
YOU WERE FEMALE, IT DIDN'T
MATTER IF UR WERE ON A PURE
BACKGROUND OR A MORE DOCILE
MIXED BACKGROUND AS LAURA JUST
INFORMED ME, SIMPLY BY
ILLUMINATING HE?
SEPTEMBER CELLS YOU WERE ABLE TO
SIGNIFICANTLY DELAY THE ONSET OF
TUMORIGENESIS.
IT DOES INDICATE THAT THESE
CELLS ARE IMPORTANT.
HOWEVER, I WILL REMIND YOU THESE
ARE NOT YOUR PET STORE MICE,
HAVING MORE HETEROGENEITY AND
DIFFERENT MICROBIOMES MIGHT
AFFECT THIS, WE JUST DON'T KNOW.
SO THE QUESTION IS, HOW DO THESE
CANCER ASSOCIATED FIBROBLASTS,
HOW DO THEY DO SO MANY DIFFERENT
THINGS IN THE CONTEXT OF
TUMORIGENESIS?
THE SASP OR THE SENESCENCE
ASSOCIATED SECRETORY PHENOTYPE
HAS ALSO ALREADY BEEN
INTRODUCED.
IN SHORT FROM THE CANCER
UNIVERSE, THEY MAKE EVERYTHING
YUMMY YOU CAN IMAGINE IF YOU
WANT TO BE A TUMOR CELL, THEY
CAN DRIVE PROLIFERATION THROUGH
THE EXPRESSION OF M MITOGENS,
SECRETE NUMEROUS FACTORS -- CAN
GREATLY CHANGE TRANSFORMATION
PROCESSES, AND THEY MAKE A LARGE
CADRE OF INFLAMMATORY CYTOKINES,
OF COURSE THE SECOND LARGEST
RISK FAR T FACTOR AFTER GETTINGS
CHRONIC INFLAMMATION.
AND SO WE GOT INTERESTED QUITE
SOME YEARS AGO IN TRYING TO
MODULATE SPECIFICALLY THE
STROMAL COMPARTMENT AND ASK HOW
DO THESE CELLS INFLUENCE
DIFFERENT COMPONENTS, DIFFERENT
STEPS IN THE TRANSFORMATION
PROCESS?
I'M GOING TO TRY TO GIVE YOU A
FLAVOR OF HOW WE THINK ABOUT
THESE CELLS.
SO SEVERAL YEARS AGO, WE MADE A
MOUSE THAT WE CALLED FASST MOU
MOUSE, THEY GET TUMORS FASTER.
THE DETAILS AREN'T REALLY
IMPORTANT BUT SUFFICE TO SAY
THAT WE WERE ABLE TO INDUCE
SENESCENCE SPECIFICALLY WITHIN
FIBROBLASTS USING THIS MOUSE.
WHAT WAS INTERESTING, I'M JUST
GOING TO SUMMARIZE THIS IN
GRAPHICAL FORMAT, WE FOUND THIS
MOUSE IN TWO DIFFERENT STUDIES.
ON THE ONE HAND, WE COULD SHOW
THAT WHEN WE INDUCE SENESCENCE
SPECIFICALLY IN THIS COMPONENT
IN OSTEOBLASTS, THESE ARE THE
CELLS THAT NORMALLY MAKE YOUR
BONE, MINERALIZE YOUR BONE, IF
YOU WILL, THESE CELLS UNDERWENT
SENESCENCE, THEY SECRETED THEIR
OWN UNIQUE SAASP, AND IN DOING
SO, THEY WERE ABLE TO DRIVE
LOCALIZED OSTEOCLASS TOE GENESIS
THAT RESORBED THE BONE BUT MORE
IMPORTANTLY, ALLOWED TUMOR CELLS
TO SEED AND/OR PREFERENTIALLY
SURVIVE IN THESE AREAS, LEADING
TO HIGHER RATES OF METASTASIS IN
THESE ANIMALS.
HOWEVER WHEN WE LOOKED INTO THE
SKIN OF THESE ANIMALS WHERE WE
KNEW WE WERE ACTIVATING AGAINST
SENESCENCE IN THIS CONTEXT IN
FIBROBLASTS, WE WERE ACTUALLY
ABLE TO SHOW THAT THROUGH
SECRETION SPECIFICALLY OF
IL-6 FROM THE SENESCENT
FIBROBLASTS, WE WERE RECRUITING
IN IMMATURE MYELOID CELLS OR
MDSCs WHICH WERE CAPABLE OF
SPECIFICALLY INHIBITING CD-8
T-CELL RESPONSES ALMOST CREATED
IN A BUBBLE OF TUMOR
SUPPRESSION, IF YOU WILL, AROUND
THESE INCIPIENT TUMOR CELLS,
LEADING TO INCREASED
TUMORIGENESIS.
INTERESTINGLY WHEN WE LOOKED IN
HUMAN AGING SKIN, WE COULD ALSO
SEE THESE REGIONAL CHANGES
AROUND -- CERTAINLY THERE WAS A
PAPER THAT WAS JUST PUBLISHED BY
DARREN BAKER'S GROUP SHOWING
SENESCENT MACROPHAGES ACTUALLY
ARE ABLE TO INHIBIT T-CELL
RESPONSES IN THE CONTEXT OF LUNG
ADENOCARCINOMAS, LEADING TO
INCREASED TUMORIGENESIS.
SO TISSUES REALLY MATTER, AND
OUR FOCUS IN THE LAB FOR SOME
TIME HAS REALLY BEEN ON BREAST
CANCER.
SO JENNIFER YI, VERY TALENTED
GRAD STUDENT IN THE LAB, DECIDED
TO START LOOKING INTO PRIMARY
BREAST CANCER SAYING DO WE SEE
SENESCENT STROMAL CELLS AND IF
WE DO, ARE THEY IMPORTANT IN ANY
DEMONSTRABLE WAY.
SHE ACTUALLY FOUND THIS STUDY
THAT WAS BACK FROM 2011, WHERE
IT WAS REPORTED THAT PATIENTS
WITH DCIS WHO REPORTED -- OR
SORRY -- SHOWED POSITIVE P16
STAINING WITHIN THEIR STROMAL
COMPARTMENT EX-EXCLUSIVELY,
THOSE PATIENTS SUFFERED
RECURRENCES.
THEY DIDN'T DO AS WELL AS
PATIENTS THAT HAD P16 NEGATIVE
STROMA.
JENNIFER WAS ACTUALLY ABLE TO
OBTAIN THE EXACT SAME CASES THAT
WAS REPORTED IN THE STUDY, AND
DOING A LARGE MULTIPLEX STUDY, I
CAN'T REALLY TELL FROM THIS IF
YOU CAN ACTUALLY SEE THE
STAINING, BUT IMPORTANTLY WAS
ABLE TO SHOW THAT THOSE P16
POSITIVE STROMAL CELLS ARE, IN
FACT, FIBROBLASTS.
SHE WAS ABLE TO GO ON AND SHOW
THAT WHEN SHE COMPARED THIS TO
BREAST CANCER, LOOKING AT ALL
SUBTYPES, WHETHER WE'RE LOOKING
AT TRIPLE NEGATIVE, HR2 NEW OR
POSITIVE, SHE COULD AGAIN FIND A
LOT OF DIFFERENT STROMAL CELLS
BUT IMPORTANTLY, AND I'M NOT
SHOWING YOU ALL THE DATA IN THE
INTEREST OF TIME, SHE COULD FIND
P16 POSITIVE CELLS, AND SHE
COULD RECAPITULATE THIS WHEN SHE
LOOKED AT AN M M.T.V. MODEL OF
BREAST CANCER, AGAIN ABLE TO
DISTINCTLY FIND SENESCENT
FIBROBLASTS THAT WERE UNIQUELY
DEFINED BY THEIR EXPRESSION
PATTERNS FROM OTHER PATH
POPULATIONS OR CANCER ASSOCIATED
FIBROBLAST POPULATIONS,
SUGGESTING THAT SENESCENT CELLS
ARE NOT SOCASTICLY ARRIVING --
BUT THEY MAY IN FACT BE AN END
POINT FOR SPECIFIC CAF SUBTYPES.
I'M SKIPPING ALL THE DATA THAT
GOT ME TO THIS PARTICULAR GRAPH
HERE AGAIN IN THE INTEREST OF
TIME, BUT WHAT JENNIFER WAS ABLE
TO SHOW IN THE BREAST, WHICH IS
QUITE DISTINCT FROM WHAT DARREN
SAW IN THE LUNG AND WE SAW IN
THE SKIN, IS THAT THESE
SENESCENT FIBROBLASTS WERE
SPECIFICALLY MODIFYING NATURAL
KILLER CELLS AND THEIR ABILITY
TO CLEAR TUMOR CELLS.
SO I THINK IT'S IMPORTANT, WHEN
WE START THINKING ABOUT
CHALLENGES AND THINGS WE NEED TO
THINK ABOUT, IS TUMOR -- EXCUSE
ME -- SENESCENT CELLS CAN BE
POTENTLY ANTITEUM ROWGENIC.
THIS HAS BEEN BROUGHT UP ALREADY
PARTICULARLY WHEN IT OCCURS
WITHIN INCIPIENT TUMOR CELLS,
NATURAL KILLER CELLS,
MACROPHAGES CAN DIRECTLY CLEAR
THESE CELLS GIVEN THE RIGHT
SIGNALS, BUT THEY CAN BE
POTENTLY TUMOR-PROMOTING
PARTICULARLY WHEN THEY OCCUR IN
THE STROMAL COMPARTMENT.
SO I THINK AN IMPORTANT
CHALLENGE IS REALLY THE
SENESCENT CELL ITSELF.
I THINK IT'S INCREDIBLY
IMPORTANT THAT WE IDENTIFY WHAT
THE CELLS ARE THAT ARE
SENESCING, THE EXACT STROMAL
CELLS, AND WE HAVE TO THENG THIK
ABOUT THIS IN THE COU CONTEXT OE
TISSUE IN WHICH THEY ARISE.
THEY'RE NOT ALL THE SAME,
THEY'RE NOT MODULATING THINGS IN
THE SAME WAY.
I WANT TO TAKE A STEP BACK AND
BRING THIS PICTURE I ALREADY
SHOWED YOU SPECIFICALLY LOOKING
AT THE SECRETORY PHENOTYPE.
I THINK IT'S IMPORTANT TO START
THINKING ABOUT THE MOLECULAR
MECHANISMS THAT ACTUALLY DRIVE
EXPRESSION O.
QUITE SOME YEARS AGO, ALSPACH
WAS ABLE TO SHOW THAT P38
ACTATION THROUGH MK2 WAS ABLE TO
LEAD TO STABLE SAYS OF MANY OF
THESE SASP FACTORS AND THE
EXPRESSION OFTEN CORRELATED WITH
BETTER OUTCOMES IN BREAST CANCER
PATIENTS.
WE GOT REALLY INTERESTED IN THIS
IN THE CONTEXT OF METASTASIS,
WHICH OF COURSE WHEN WE'RE
THINKING ABOUT BREAST CANCER IS
WHAT KILLS MOST OF OUR PATIENTS,
AND WHEN MURULI WAS A GRADUATE
STUDENT IN THE LAB WAS ABLE TO
GO ON TO SHOW THAT EXPRESSION OF
MANY OF THESE SASP FACTORS,
THINGS WE THINK ABOUT ASSOCIATES
WITH SENESCENCE, CAN BE FOUND IN
THE STROMAL COMPARTMENT OF
METASTATIC LESIONS.
I'M SHOWING YOU A PICTURE -- THE
ORGAN THAT YOU SEE MOST
METASTASIS IN BREAST CANCER
PATIENTS.
SO SHE WANTED TO KNOW COULD SHE
ACTUALLY TARGET THIS.
SO WHAT SHE DID, AND I'M GOING
TO SHOW YOU DATA FROM ONE CELL
LINE, SHE'S DONE THIS IN MANY,
MANY CELL LINES, IS TO TAKE
ANIMALS AND TREAT THEM -- OR I
SHOULD SAY INDUCE TUMOR CELLS
AND THEN TREAT THEM WITH EITHER
P38 AS A SINGLE AGENT OR PT --
WHICH IS STILL USED IN THE
SETTING OF BREAST CANCER
PATIENTS.
AND IMPORTANTLY WHETHER SHE
LOOKED AT BONE METASTASIS ON THE
RIGHT OR VISCERAL METASTASIS AT
LARGE IN THE LEFT, P38 IS A
SINGLE AGENT, AS EFFECTIVE AS
PACK TACK SILL, BUT THIS BRINGS
UP ANOTHER CHALLENGE WE HAVE TO
THINK ABOUT, MOST OF US IN THE
CANCER UNIVERSE FOR PRACTICALITY
AND FINANCIAL REASONS, WE DO OUR
EXPERIMENTS IN YOUNG ANIMALS.
THE QUESTION IS, DOES THIS
ALWAYS REPEAT WHEN WE THINK
ABOUT OLD ANIMALS?
IN THE CONTEXT OF THE P38
INHIBITOR, IT DOES, WHEN WE DO
THE EXACT TYPE OF AN EXPERIMENT
USING 18-YEAR-OLD MICE, AGAIN
USING P38 AS A SINGLE AGENT, WE
DO, IN FACT, SEE THAT IT'S
EFFECTIVE AT LIMITING VISCERAL
METASTASIS AND BONE M METASTASIS
WHICH I'M NOT SHOWING YOU, BUT I
SHOULD POINT OUT THIS IS NOT
ALWAYS THE CASE.
THERE ARE PLENTY OF THERAPYS
THAT HAVE BEEN SHOWN TO NOT BE
AS EFFECTIVE IN OLDER
INDIVIDUALS.
AND I THINK THAT BRINGS UP
ANOTHER CHALLENGE WHICH IS HOW
DO WE START TO LOOK AT THESE
DIFFERENCES?
SOMETIMES IT MATTERS, SOMETIMES
IT DOESN'T, BUT MOST OF THE
TIME, EXPERIMENTS ARE NOT BEING
DONE IN OLDER ANIMALS AND THE
OTHER QUESTION IS ARE OLDER
ANIMALS ACTUALLY GOOD ENOUGH.
PAUL BROUGHT UP THIS IDEA OF THE
PET STORE MOUSE.
WE'RE LOOKING AT A VERY
HOMOGENEOUS, OLD POPULATION.
IS THAT GOOD ENOUGH?
THE ANSWER IS I THINK WE DON'T
KNOW, WE HAVEN'T DONE ENOUGH IN
THAT AR RENA.
IT'S ALSO BEEN BROUGHT UP THAT
MOST OF OUR CLINICAL TRIALS ARE
NOT DONE IN OLDER INDIVIDUALS,
SO ARE THE CLINICAL TRIALS THAT
WE'RE DOING REALLY REFLECTING
MOST OF WHAT'S GOING TO HAPPEN
IN OUR PATIENT POPULATION?
FINALLY, OUR CO-MOR COMORBIDITIT
ARE INDUCED WE BRING TO BEAR TO
SAVE PEOPLE'S LIVES CAN HAVE
DRASTICALLY DIFFERENT EFFECTS
WHEN WE LOOK AT AGED VERSUS
YOUNGER PATIENTS.
THIS IS ONE EXAMPLE LOOKING AT
PERIPHERAL NEUROPATHY, STINGING
PAIN, AFTER CHEMO, 70% OF ALL
PATIENTS TREATED WITH PACLITAXEL
WILL EXPERIENCE SOME LEVEL OF
NEUROPATHY BUT IF YOU'RE OVER
THE AGE OF 65 WHEN TREATED
YOU'RE MUCH LESS LIKELY TO RE
SOLVE THAT.
LUCKILY OUR MICE SEEM TO
RESEMBLE THAT.
THIS IS A MEASURE OF CIPN.
I'M NOT GOING TO GO INTO THE
DETAILS OF THE ASSAY, BUT YOU'LL
NOTICE WHEN YOU START OUT AS AN
18 MONTH OLD MOUSE, YOU'RE
ACTUALLY ALREADY IN MORE TROUBLE
THAN A YOUNGER MOUSE, AND YOUR
NEUROPATHY GETS WORSE.
I'M NOT SHOWING THE FUNCTIONAL
READOUT, BUT IT'S MUCH WORSE.
SO HOW DO WE MODEL?
COULD WE BE USING THE PROGERIA
MICE THAT WERE MENTIONED BY PAUL
AND LAURA?
ARE THEY GOOD ENOUGH?
DO WE NEED TO THINK OF DIFFERENT
MODELS?
FINALLY IN THE LAST THREE
MINUTES I WANT TO GO BACK TO
THIS PARTICULAR SLIDE.
SO I MENTIONED ALREADY THAT IN
THE CONTEXT OF YOUNG AND OLD
MICE, THANKFULLY, P38 IS A
SINGLE AGENT IS AS EFFECTIVE AS
PACK LA TAX ILL AS TREATING MICE
BUT OUR GOAL IS NOT TO BE AS
GOOD AS CURRENT THERAPY.
OUR GOAL IS TO PUSH THE CURVE TO
THE RIGHT.
SO THERE THERE WAYS TO ACTUALLY
MAKE THESE TREATMENTS BETTER?
ARE WE TREATING SENESCENT CELLS
IN THE CONTEXT OF THESE YOUNG
ANIMALS OR ARE WE FOE CAN
CUSSING MORE ON
CANCER-ASSOCIATED FIBROBLASTS?
I DON'T KNOW THE ANSWER TO THAT
TODAY BUT WHAT I CAN TELL YOU IS
THROUGH A SERIES OF EXPERIMENTS
THAT WERE RECENTLY PUBLISHED,
WHAT WE FOUND IS THAT P38 IS
ACTUALLY FUNCTIONING BOTH
THROUGH MACROPHAGES AS WELL AS
CD4 T-CELLS TO LIMIT TUMOR
GROWTH.
BUT NONE OF THIS AS I SAID
PUSHED THAT CURVE TO THE RIGHT.
>> DOCTOR, YOU HAVE TWO MINUTES
REMAINING.
>> WHEN WE STARTED LOOKING AT
THE ACTUAL METASTATIC LESIONS,
WHAT WE FOUND IS WHAT WAS
MISSING IN OUR ANIMALS WAS THE
ACTIVATION OF OX40 WHICH IS LIKE
GAS ON YOUR T-CELLS.
AND THIS WAS TRUE IN HUMAN
DATASETS AS WELL.
AND SO WHAT WE FOUND IS WHEN WE
COUPLED THE P38 INHIBITOR WITH
AN OX40 AGONIST, WE WERE ABLE TO
SIGNIFICANTLY REDUCE METASTATIC
TUMORS.
WHAT I DIDN'T TELL YOU IS THAT
CD8 T-CELLS ARE NOT INVOLVED IN
THIS.
EVEN THOUGH WE COULD PUSH THE
CURVE OUT.
SO WHAT WE DID WAS TO PUT IN A
SLEDGEHAMMER OV A WHICH
ACTIVATES CD4 AND CD8 SCH
T-CELLS AND IN DOING SO WE WERE
ABLE TO CURE 100% OF OUR ANIMALS
AND CREATE DURABLE MEMORY.
AGAIN BY COUPLING BOTH THE
STROMAL INHIBITOR OF P38,
ACTIVATING OUR T-CELLS AND
FORCING OUR CD8 T-CELLS TO BE
ENGAGED.
SO FINALLY, WHAT ARE THE NEXT
STEPS?
THERE'S A LOT OF THEM.
I DON'T HAVE ENOUGH TIME TO GO
THROUGH ALL OF THESE.
MOST OF THESE HAVE ALREADY BEEN
MENTIONED BY MY COLLEAGUES
BEFORE ME BUT I THINK WE NEED TO
BE THINKING OF WHAT IS THE
TARGET.
WE NEED TO BE THINKING ABOUT
WHAT IS THE ADVANTAGE OF
SENOLYTICS OVER SENOMORPHICS.
WE'VE ALREADY HEARD NOT ALL HIT
THE SAME EXACT CELLS.
NOT ALL SENESCENCE IS BAD.
WE NEED TO THINK ABOUT HOW WE'RE
IMPACTING THOSE GOOD CELLS.
IS JUST PERIODIC TREATMENT GOOD
ENOUGH?
WE NEED TO KNOW WHAT THE CELLS
ARE.
WITH THAT, I'LL END WITH THE
MOST IMPORTANT SLIDE WHICH IS
THE PEOPLE THAT DO ALL THE WORK,
AND I'D BE HAPPY TO TAKE ANY
QUESTIONS IF I'VE LEFT ANY TIME.
THANK YOU.
>> THANK YOU SO MUCH.
I THINK DR. DEGREGORI HAS A
QUESTION.
>> THANKS.
SHEILA, REALLY GREAT STUFF.
I HAVE A QUESTION THAT KIND OF
RELATES BACK TO WHAT YOU WERE
TALKING ABOUT EARLIER AND THAT
SOME OF THE OTHER SPEAKERS HAVE
TOUCHED UPON WHICH IS THIS
HETEROGENEITY OF SENESCENCE, IN
TERMS OF BOTH DIFFERENT CELL
TYPES AND EVEN DIFFERENT FLAVORS
WITHIN CELL TYPES.
I'M WONDERING, HAS ANYONE REALLY
DONE THIS COMPREHENSIVELY,
REALLY THE SAME GROUP BUT THE
SAME METHODS, LOOKING AT CHEMO,
OLD AGE, OTHER CONTEXTS, AND
ASKING -- DO WE GET SORT OF
DIFFER FLAVORS AND TYPES FOR
DIFFERENT INSULTS?
WHEN YOU COMPARE BETWEEN GROUPS,
IT'S ALWAYS HARD TO KNOW.
>> THE ANSWER IS WE HAVEN'T DONE
IT WELL ENOUGH AS A FIELD.
PART OF THE CHALLENGE HAS BEEN
WE DON'T HAVE GREAT MARKERS.
I CAN HONESTLY TELL YOU IN THE
QUICK STUDY I SHOWED, IT TOOK US
THREE YEARS TO FIND THOSE CELLS
AND CHASE THEM DOWN SO THIS
ISN'T A TRIVIAL PROBLEM.
BUT I THINK MARCOUX DEMAROIO
PROBABLY HAS THE BEST DATA ON
THIS.
ANY OTHER DATA HE COULD FIND
PUBLICLY AVAILABLE, I CAN TELL
YOU, CELLS KNOW WHERE THEY CAME
FROM AND THEY KNOW HOW THEY GOT
HURT.
THAT'S TO SAY YOU TAKE THE SAME
FIBROBLAST AND YOU HIT IT WITH
DIFFERENT INSULTS, THE SASP HAS
THE SAME GO TERMS BUT THE
DETAILS ARE COMPLEECTLY
DIFFERENT.
YOU CAN TAKE FIBROBLASTS FROM
TWO DIFFERENT SOURCES, HIT THEM
WITH THE SAME DAMAGE, IT'S THE
SAME STORY.
SO IT'S INCREDIBLY HETEROGENEOUS
AND I THINK THIS IS, IN FACT,
THE CHALLENGE.
IF WE DON'T IDENTIFY THE CELL
TYPE AND WHAT IT DOING, WE'RE
NEVER GOING TO KNOW WHERE THE
POSITIVE AND NEGATIVES ARE HERE.
IT'S A GREAT QUESTION AND IT'S
AN IMPORTANT PROBLEM.
>> THANKS.
>> FANTASTIC.
REALLY INTERESTING TALK,
DR. STEWART.
I THINK WE ARE ACTUALLY ON TIME
FOR OUR 10-MINUTE BREAK.
WHICH WILL BE FROM NOW UNTIL
3:10 IF YOU'RE ON THE EASTERN
TIME, SO 10-MINUTE BREAK.
THERE IS ANOTHER QUESTION.
COULD DDR TARGETING IN
SENOLYTICS SYNERGIZE?
I DO THINK THAT'S SOMETHING WE
WILL TALK ABOUT IN THE PANEL
DISCUSSION, SO WE HAVE SAVED A
HALF AN HOUR FOR THAT.
WE WILL COME BACK AT 3:20, AND
WE WILL BE HEARING ABOUT HEALTHY
HEARTBEAT TRAJECTORIES, BY
DR. LAKATTA AT 3:20, SO WE HAVE
A 9-MINUTE BREAK.
SO FOR THE SAKE OF TIME, WE WILL
CONTINUE.
AND THANK YOU FOR JOINING US
THIS AFTERNOON.
FOR THOSE WHO JUST JOINED OUR
ZOOM MEETING AND VIDEOCAST, WE
PROCEED WITH SESSION 2,
MOLECULAR MECHANISMS OF CHRONIC
AGE-RELATED DISEASES.
AND I'M THE PROGRAM DIRECTOR,
TOGETHER WITH ANIL, WE'RE
CHAIRING THIS SESSION.
AND BEFORE THE BREAK, WE LEARNED
ABOUT EXCITING RESEARCH IN
CELLULAR SENESCENCE AND STROMAL
CHANGES.
IN THE SECOND PART OF THIS
SESSION PROMISES TO BE JUST AS
EXCITED WITH TOPICS INCLUDING
THOSE THAT YOU CAN SEE IN THE
PROGRAM, HEARTBEAT TRAJECTORIES,
CELLULAR DYSFUNCTION,
ENVIRONMENTAL DETERMINANTS,
VASCULAR SENESCENCE AND ROLE OF
MICROBIOME.
SO PREPARE TO BE EXCITED, AND
DR. MCCOLLOUGH WILL CONTINUE TO
MODERATE THE SESSION AND THE
FOLLOWING PANEL DISCUSSION.
SO OUR FIRST SPEAKER FOR THIS
PART IS DR. EDWARD LAKATTA, FROM
NATIONAL INSTITUTE OF AGING AT
NIH AND THE TITLE OF THE TALK IS
HEALTHY HEARTBEAT TRAJECTORIES
WANE AS HEARTBEAT DEMENTIA
TRAJECTORIES EMERGES IN ADVANCED
AGE IN THE CONTEXT OF THE WHOLE
BODY FRAILTY.
THANK YOU.
TAKE IT AWAY.
>> GOOD AFTERNOON, LADIES AND
GENTLEMEN.
I'M THE LAB CHIE LABORATORY OF
CARDIOVASCULAR SCIENCE IN THE
INTRAMURAL PROGRAM IN THE
NATIONAL INSTITUTE ON AGING, AND
WE'RE GOING TO TALK ABOUT
HEARTBEAT FRAILTY TODAY.
SICK SINUS SYNDROME IS A
CONDITION IN WHICH YOUR HEART'S
PACEMAKER FAILS TO INITIATE
HEART BEATS, AND IT REQUIRES
ELECTRONIC PACEMAKER INSERTION.
THIS IS THE ANNUAL INCIDENCE OF
SICK SINUS SYNDROME, AND YOU CAN
SEE THAT THE TRAJECTORY IS
MOVING UPWARD SEVERELY DUE TO
THE DEMOGRAPHIC IMPERATIVE.
HANG ON A MINUTE.
OKAY.
SORRY ABOUT THAT, FOLKS.
I WANT TO START BY GOING THIS
WAY.
SO WE HAVE BEEN INTERESTED IN
HEARTBEAT REGULATION IN THE
BALTIMORE LONGITUDAL STUDY ON
AGING.
WE HEARD A LOT ABOUT LONGITUDAL
STUDIES.
THIS STUDY IS 65 YEARS OLD AND
I'VE BEEN WITH IT FOR ABOUT 50
YEARS.
THIS IS THE HEART RATE RESERVE
IN BALTIMORE LONGITUDAL STUDY
PARTICIPANTS WHO ENTER AT
DIFFERENT AGES AND ARE FOLLOWED
FOR DIFFERENT PERIODS OF TIME.
AND THIS IS THE ONLY
CARDIOVASCULAR BIOMARKER THAT IS
NOT CHANGED BY ANY KNOWN
INTERVENTION.
AND THIS SHOWS THE RATE OF
CHANGE OF DECLINE IN THIS
LONGITUDAL ANALYSIS.
IT'S ABOUT ONE BEAT PER YEAR.
SO TO GET MORE MECHANISTIC
INSIGHT, I CREATED THE BALTIMORE
LONGITUDAL STUDY OF AGING IN
MICE, AND THESE 58 MICE ARE
STUDIED WITH THE
ELECTROCARDIOGRAM, PLUS OR MINUS
BRAIN INPUT, AND ECHOCARDIOGRAM
FOR LEFT VENTRICULAR STRUCTURE
AND FUNCTION, AND THOSE ARE
MEASURED EVERY THREE MONTHS,
FROM 6 MONTHS OF AGE UNTIL THE
END OF LIFE.
SO THE AVERAGE MORTALITY CURVE
OF THE WHOLE COHORT IS IN THE
PINK, THE MEDIAN LIFESPAN IS 24
MONTHS OF AGE.
THOSE THAT DON'T MAKE IT, WE
REFER TO AS SHORT-LIVED, BUT
THOSE THAT ACHIEVE THE MEDIAN OR
BEYOND LIFESPAN, THOSE ARE
CALLED LONG-LIVED AND THEY'RE ON
THE GREEN LINE AND THEIR
HEALTHSPAN IS EXTENDED, AND
WE'RE GOING TO SEE WHAT HAPPENS
TO THOSE MICE WITH RESPECT TO
THEIR HEART RATE AND RHYTHM.
WE ACTUALLY DON'T TREAT THEM TO
MAKE THEM BACK LIKE THAT YET.
SO THIS IS HOW FRAILTY EMERGES.
THIS IS A FRAILTY INDEX IN THOSE
MICE.
NOT ONLY DOES IT INCREASE AT
THESE LATER AGES, THIS IS WHOLE
BODY FRAILTY.
BUT THE RATE AT WHICH IT
INCREASES ACCELERATES WITH
AGING.
THIS IS AN AUTONOMIC NEURAL
SURVEILLANCE CARTOON.
WE HEARD ABOUT HEART-BRAIN
SIGNALING EARLIER IN SOME OF THE
PRESENTATIONS.
I WANTED TO POINT -- ALTHOUGH
WE'RE GOING TO TALK ABOUT THAT
AS WELL HERE, IT'S WELL-KNOWN
NOW THAT THE HEART TALKS TO THE
BRAIN THROUGH THESE AFFERENT
SIGNALING PATHWAYS THAT ARE
SHOWN HERE.
WE BLOCKED THE AUTO NO MIBG
INPUT WITH DOUBLE AUTONOMIC
BLOCKADE WITH ADRENERGIC AND
CHOLINERGIC REACC RECEPTORS ON E
SIGH KNOW ATRIAL NODE.
THERE'S NOT MUCH HAPPENING UNTIL
ABOUT 21 MONTHS OF AGE AND THEN
WE SEE THIS MODEST INCREASE IN
THE RR INTERVAL, THAT MEANS THE
EKG RR INTERVAL, THE TIME
BETWEEN THEIR HEART BEATS.
WHEN THE AUTONOMIC INPUT IS
BLOCKED, WE SEE A SEVERE MARKED
INCREASE.
SO THE DIFFERENCE BETWEEN THE
TWO IS THE AUTONOMIC INPUT
EFFECT, THE SIGNATURE OF THE
AUTONOMIC SURVEILLANCE.
AND THAT'S NET SYMPATHETIC,
BECAUSE IT'S REDUCING THE TIME
BETWEEN THE MEAN HEARTBEAT
INTERVAL, BUT NOT FULLY
RESTORING TO THIS YOUTHFUL
LEVEL.
THIS IS AN ELECTROCARDIOGRAM,
AND AS A CARDIOLOGIST, I WOULD
SAY THAT'S NORMAL SINUS RHYTHM.
BUT AS A PHYSICIAN RESEARCHER,
WHEN WE LOOK MORE CLOSELY AT
THIS, THE SINOATRIAL NODE IS NOT
A METRO NOME AND ITS RHYTHM IS
NEVER IN A TRUE STEADY STATE,
AND THIS HEART INTERVAL
VARIABILITY IS SOMETIMES CALLED
THE HEART RATE INTERHEART RATE
VARIABILITY.
SO WE WANT TO KNOW WHAT -- NOT
WHAT'S THE MEAN HEART RATE WITH
AGING BUT WHEN WILL THE NEXT
HEARTBEAT OCCUR?
AND THIS IS IN THE PRESENCE OF
DOUBLE AUTONOMIC BLOCKADE, SO
THE SINOATRIAL NODE IS ON ITS
OWN AND AT 6 MONTHS OF AGE, THE
RR INTERVAL OCCURRENCE IS
BETWEEN 120 AND 130
MILLISECONDS.
THAT'S HOW LONG WE HAVE TO WAIT
FOR THE NEXT ONE.
DURING AUTONOMIC BLOCKADE IN THE
OLD, WE SEE NO INTERVALS OCCUR
BEFORE 225 MILLISECONDS, AND THE
DISTRIBUTION IS VERY DIFFERENT.
THIS IS IN THE RANGE IF YOU
CHANGE THE RR INTERVAL TO HERTZ,
IT'S BETWEEN 4 AND 8 HERTZ.
NOW IF WE LOOK IN THE PRESENCE
AND AK SENSE OF DOUBLE AUTONOMIC
MIBG BLOCKADE, THIS IS WHAT YOU
JUST SAW IN THE YOUNG.
THIS IS THE SAME MOUSE, BY THE
WAY, SAME MOUSE IN THE YOUNG AND
THE OLD.
NOW THE SAME MOUSE WITH THE
AUTONOMICS INTACT, YOU SEE THE
EFFECT AT SIX MONTHS, AND
ALTHOUGH THERE'S A MARKED
INCREASE IN THE HEART RATE OR
REDUCTION IN THE RR INTERVAL,
YOU SEE THESE OLD MICE HEARTS
CANNOT GET TO THESE FAST
INTERVALS OR EVEN PAST THIS
INTERVAL IF YOU LOOK AT THE
SHARP DISTRIBUTION HERE IN THIS
MOUSE.
SO THIS IS THE SAME MOUSE AND
HAD IS WHAT THE RR INTERVAL
ELECTROCARDIOGRAM WOULD LOOK
LIKE.
AT THE YOUNG AGE AND THE
AUTONOMIC INPUT INTACT YOU SEE
THESE RECURRENT CORRELATIONS IN
RR INTERVALS.
AND YOU SEE THE SAME MOUSE AT 30
MONTHS OF AGE, VERY LONG TIME,
SHORT STEPS TO GET UP AND DOWN,
SO YOU SEE TWO CORRELATIONS HERE
INSTEAD OF NINE.
THERE.
AND WHAT WE WANTED TO DO WAS TO
THINK ABOUT WHETHER THOSE NOTES,
THOSE INTERVALS, MIGHT SOUND
LIKE MUSICAL NOTES AND WE TEAMED
UP WITH ELAINE CHEW IN LONDON,
AND THIS IS THE SAME MOUSE WITH
BRAIN INPUT.
SHE IMPROVISED AND PLAYED
DIFFERENT TYPES OF MUSIC THAT
SHE KNEW ABOUT.
LET'S TRY TO GO ALL THE WAY OVER
HERE NOW TO SAVE TIME.
THAT WAS A VIOLIN AT SIX MONTHS
AND THE SAME MOUSE AT 30 MONTHS,
THIS IS A BASE.
BASS.
THERE GOES MY ANIMATION.
SORRY ABOUT THAT.
WE JUST HAVE TO WAIT IT OUT.
[MUSIC PLAYING]
NOW MAYBE WE CAN MOVE FORWARD.
SO THIS IS WHAT YOU JUST HEARD
AGAIN AT 30 MONTHS OF AGE
WITHOUT BRAIN INPUT.
THIS IS NEAR THE END OF THE
MOUSE'S LIFE.
OKAY, SO WE WANTED TO KNOW WHAT
HAPPENED, WHAT'S HAPPENING.
SO WE TAKE THE SINOATRIAL CELLS,
WE CAN STUDY THOSE IN SINGLE
CELLS, AND WE'VE DISCOVERED SOME
TIME BACK THE EXISTENCE OF A
COUPLED OSCILLATOR SYSTEM
THAT -- CALCIUM OSCILLATOR THAT
WE CALL THE CALCIUM CLOCK AND WE
RENAMED THE SURFACE MEMBRANE
ELECTROGENIC MOLECULES THE
MEMBRANE CLOCK.
AND LOCAL CALCIUM RELEASES
ACTIVATE THE MEMBRANE CLOCK TO
INITIATE ACTION POTENTIALS.
AND IF WE MEASURE CALCIUM
SIGNALS, I'LL SHOW YOU IN THESE
SINGLE SINOATRIAL NODAL CELLS,
THESE ARE SIMULTANEOUSLY
MEASURED MEMBRANE POTENTIAL IN
CALCIUM.
YOU SEE THIS FLICKERING.
THESE ARE SCAS TICK LOCAL
CALCIUM RELEASES THAT
SELF-ORGANIZE.
IT'S A STATE OF CONTINUOUS PHASE
TRANSITIONS THAT SELF-ORGANIZES,
WE CALL THAT A CRITICALITY
MECHANISM AND WHEN IT REACHES
CRITICALITY, WE SEE THE RAPID
UPSTROKE OF THE ACTION
POTENTIAL, AND THEN THE ACTION
POTENTIAL LEADS THE KALS SEUM.
WHEN WE TAKE THE SINOATRIAL NODE
TISSUE OUT AND MEASURE THE LOCAL
CALCIUM RELEASES WE SEE THIS
TYPE OF BEHAVIOR, LOCAL CALCIUM
RELEASES LIKE FIBRILLATION OCCUR
HETEROGENEOUSLY WITHIN WITHIN
AND AMONG PACEMAKER CELLS.
SO IF I SHOWED YOU IF I SHOWED
YOU CALCIUM SIGNALS IN A MOUSE'S
HEAD BRAIN AND THE HEART BRAIN,
YOU MIGHT HAVE TROUBLE IF YOU
HADN'T SEEN THE PREVIOUS SLIDE
AT KNOWING WHICH IS THE HEAD
BRAIN AND WHICH IS THE HEART
BRAIN.
OF COURSE THIS IS THE SINOATRIAL
NODE BRAIN SO WE'RE REFERRING TO
A BRAIN NOW.
IT HAS THE CYTOARCHITECTURE AND
FUNCTION VERY SIMILAR TO THE
HEAD BRAIN.
SO NOW I'M GOING TO SHOW YOU WHY
THE AGING HEART'S BRAIN OPERATES
AT THE EDGE OF DISEASE.
THESE ARE THE PACEMAKER CELLS
IMMUNOLABELED IN RED, THIS IS
THE CENTRAL SINOATRIAL NODE.
YOU CAN SEE THE MARKED CHANGE IN
STRUCTURE IN THIS EXAMPLE
BETWEEN FOUR MONTHS AND 29
MONTHS.
THESE ARE NOT THE SAME MOUSE, OF
COURSE.
AND YOU CAN SEE THAT THE
BEATING, RATE AND RHYTHM IS VERY
DIFFERENT.
SO AGAIN, WHAT HAPPENED?
THIS IS THE COUPLED CLOCK SYSTEM
THAT I TOLLED YOU ABOUT BEFORE
AND WITH AGING, SOME OF THE
CRUCIAL MOLECULES THAT PUMP
CALCIUM INTO THE STORAGE SITE
THAT'S THE CALCIUM CLOCK, THE
RELEASE CHANNELS, AND THE
SURFACE MEMBRANE PROTEIN THAT
THE CALCIUM TALKS TO ONCE IT'S
RELEASED CHANGE WITH AGING, AND
THAT'S SHOWN HERE.
THIS IS THE PERCENT REDUCTION
FROM THE YOUNG MOUSE, CIRCA 2,
THAT'S THE SODIUM CALCIUM
EXCHANGER ON THE RECEPTOR.
WE CAN STUDY THE CALCIUM CLOCK
DIRECTLY WITHOUT ANY
INTERFERENCE FROM THE MEMBRANE
CLOCK, WE SEE THESE LOCAL
CALCIUM RELEASES IN THE YOUNG
EXAMPLE HERE, THEY'RE VERY
DIFFERENT IN THE OLD, AND
PERFORMING A FAST FOUR YR
TRANSFORM ON THAT DATA WE CAN
SEE QUITE CAREERLY THAT THE
PREFERRED RESONANCE FREQUENCY IS
REDUCED IN OLDER AGE COMPARED TO
THE YOUNGER ADULT.
AND IF WE LOOK HERE, THIS IS
PROBABLY THE MOST CRITICAL SLIDE
THAT I'VE SHOWN YOU SO FAR, WITH
RESPECT TO MECHANISM, CALCIUM IS
THE ACYL TRI SUBSTRATE, OF
COURSE, AND THE FREQUENCY THAT
THIS CALCIUM CLOCK -- INCREASES
WITH CALCIUM -- I THANK YOU VERY
MUCH -- BUT YOU SEE THE CURVE
HAS SHIFTED DOWNWARD TO THE
RIGHT IN THE OLD, AND THIS
ORGANELLE, THE MEMORY OF THIS
ORGANELLE OF THE
CALCIUM CLOCK IS HOW MUCH
CALCIUM IS THERE, AND THE
CALCIUM THAT CAN LOAD INTO IT IS
REDUCED IN OLDER AGE.
SO IN SUMMARY, THEN, THE SAN
BRAIN WE CAN CONSIDER --
SINOATRIAL NODE BRAIN IS A
COMPUTER NETWORK IN WHICH
INDIVIDUAL COMPUTERS ARE HARD
WIRED WITH THIS COUPLED
OSCILLATOR SYSTEM.
DIFFERENT APPS ARE APPLIED TO
ENCODE VARIATIONS IN THE MEMORY
WITHIN THE INDIVIDUAL COMPUTERS
THAT DETERMINE ITS MEAN
PREFERRED RESONANCE FREQUENCY
AND VARIABILITY AROUND THAT
FREQUENCY.
I PREFER RESIDENCE FREQUENCIES
REQUIRE VERY SYNCHRONIZED
KINETICS OF THESE FUNCTIONAL
TRANSITIONS THAT I TOLD YOU
ABOUT, KINETIC TRANSITIONS, SO
THAT WITH AGING, WE HAVE A
SITUATION OF PROGRESSIVE
MOLECULAR DISORDER, AND I LIKE
TO ENVISION IT AS AGING EXTRACTS
CHAOS FROM ORDER, THERE'S
REDUCED MOLECULAR DENSITY, POST
TRANSLATIONAL MODIFICAT
MODIFICATIONS, DISORDERED AND
DESYNCHRONIZED MOLECULAR
INTERACTIONS, SEVERE DISTORTION
OF PROTEOSTASIS, INFLAMMATION,
FIBROSIS AND INCREASED ENTROPY
WITHIN CELLS, TISSUES, ORGANS
AND ORGANISMS.
AND THE OLD SAN CAN'T REMEMBER
HOW TO HIT THE HIGH NOTES, THAT
IS TO GENERATE THE SHORT
INTERVALS, BECAUSE BOTH THE
HARDWARE THAT IT HAS AND THE APP
THAT ENCODESSITY MEMORY FOR
THOSE HIGH FREQUENCY GENERATION,
THAT SYMPATHETIC, AUTONOMIC,
BOTH DETERIORATE IN ADVANCED
AGE.
IN OTHER TERMS, THE FRAIL SAN
BRAIN BECOMES DEMENTED IN
ADVANCED AGE AND THUS THE
HEART-BRAIN MEMORY FAILURE
UNDERPINS THE FLAT HEARTBEAT
MUSIC THAT RESULTS IN AN
INABILITY TO BEAT AT FASTER
RATES, AND WE REFER TO THAT AS
THE HEARTBEAT FRAILTY IN OLDER
AGE.
FINALLY, WE MIGHT CONSIDER THAT
THE ROAD TO HEARTBEAT FRAILTY IS
THE SYNCHRONIZED MOLECULAR
INTERACTIONS BECOME
DESYNCHRONIZED WITH AGING.
THIS LEADS TO HEART DISEASES AND
TO HEARTBEAT FRAILTY AS I JUST
DESCRIBED, AND AMONG THOSE IS
THE SICK SINUS SYNDROME WHERE WE
STARTED, OTHER ARRHYTHMIAS,
CONTRACTILE DYSFUNCTIONS AND
CHRONIC HEART FIT.
SO THANKS FOR YOUR ATTENTION.
>> THANK YOU VERY MUCH,
DR. LAKATTA.
>> THANK YOU.
I THINK WE HAD ONE QUESTION.
I DON'T KNOW IF YOU WANT TO
UNMUTE, DR.?
>> HI, DR. LAKATA.
VERY INTERESTING TALK AND VERY
ENTERTAINING.
I'M GOING TO ASK SORT OF A
PHILOSOPHICAL QUESTION THAT MAY
BE IMPORTANT TO ALL OF US.
IT LOOKS LIKE THE HEART CLOCK OR
THE BRAIN AND HEART CLOCK ARE
MEANT TO SLOW DOWN TOWARDS A
HALT, AND I WAS WONDERING
WHETHER THERE IS A WAY TO
PREDICT WHEN THEY WILL STOP.
SOME PEOPLE HAVE HIGHER HEART
BEATS AND EVEN SOME OF THE
GREATEST ATHLETES ARE SUPPOSED
TO HAVE VERY SLOW HEARTBEAT.
SO IS THIS A TYPE OF LONGITUDAL
MEASUREMENT THAT YOU MIGHT
ENVISION WE MIGHT NEED OR HOW
WOULD YOU GO ABOUT
INVESTIGATING?
>> ABSOLUTELY.
THE ATHLETES HAVE A SLOW HEART
RATE AT REST BECAUSE OF THE
VAGAL INPUT, BUT THE HEART RATE
RESERVE THAT I TALKED ABOUT IS
IMMUTABLE, SO IT'S THE SAME, THE
HEART RATE RESERVE FROM -- THE
MAXIMUM HEART RATE IN ATHLETES
AS WELL AS SEDENTARY OLDER
PERSONS, AND WE DO NEED
LONGITUDINAL STUDIES.
WE HAD A LOT OF DISCUSSION ON
THAT THIS MORNING BECAUSE
THERE'S VARIABILITY AT OLDER
AGES WHEN WE GET INTO THE HEART
RATE IN THE MOUSE, FOR EXAMPLE,
PAST 21 MONTHS OF AGE, THIS IS
WHERE ALL THE ACTION HAPPENS AND
WE GET AN EXPONENTIAL
ACCELERATION OF THE
DESYNCHRONIZATION WITHIN THE
SINOATRIAL NODE.
SO KNOWING WHEN THE AUTONOMIC
INPUT HAS TO BE APPLIED TO TRY
IT MAINTAIN THE YOUTHFUL
HEARTBEAT, THAT'S THE BEGINNING,
SO THAT CAN BE FOUND
LONGITUDALLY BY APPLYING DOUBLE
AUTONOMIC BLOCKADE, YOU GET THE
AUTONOMIC SIGNATURE.
THAT'S WHEN THE HEART IS TALKING
TO THE BRAIN TO SAY, GIVE ME
SOME MORE JUICE, THE BODY NEEDS
MORE BLOOD.
>> FANTASTIC.
THANK YOU.
AND I THINK YET AGAIN, WE ARE
RUNNING SHORT ON TIME AND WE
WILL HAVE THE PANEL DISCUSSION.
I THINK WE ARE NEXT SCHEDULED
FROM 4:00 TO 4:20, WITH DR. LISA
LESNIEWSKI FROM THE UNIVERSITY
OF UTAH WHO'S GOING TO BE
TALKING ABOUT TARGETING SULFUR
AMINO ACID METABOLISM FOR
LONGEVITY AND TUMOR SUPPRESSION.
OH, NO, APOLOGIES.
LISA, YOU'RE NOT TALKING ABOUT
SULFIDE, YOU'RE TALKING ABOUT
MECHANISMS AND CON QENSES OF
AGE-RELATED ENDOTHELIAL
DYSFUNCTION AND CAN WE
INTERVENE.
SO GO AHEAD AND HIT IT.
>> YEAH, I CAN'T SEEM TO SEE THE
WHOLE SCREEN FOR LIKE THE ZOOM
SCREEN FOR SOME REASON.
>> I THINK YOU JUST NEED TO HIT
THE PRESENTATION MODE OR THE
LITTLE SLIDE ICON DOWN IN THE
BOTTOM AND IT SHOULD COME UP.
>> ALL I CAN SEE IS LIKE PEOPLE,
LIKE YOU AND MY FACE.
>> THAT'S UNFORTUNATE.
>> I'M NOT SURE HOW TO MAKE THIS
WORK.
CAN YOU SEE THE --
>> TRY TO RESHARE, SOMETIMES
THAT WORKS.
>> OH, WAIT.
DOES THAT WORK NOW?
>> THERE, PER FORECAST.
YEP.
>> LET ME SHRINK THIS BACK DOWN
AGAIN.
SO I WOULD LIKE TO THANK THE
ORGANIZERS FOR INVITING ME TO
PRESENT, AND TODAY I'M GOING TO
SHARE SOME RECENT WORK FROM OUR
LABORATORY THAT'S BEEN EXPLORING
THE POTENTIAL ROLE FOR THE ENT
THELIUM IN MODULATING NOT ONLY
VASCULAR BUT METABOLIC FUNCTION
IN AGING.
SO BOTH METABOLIC AND VASCULAR
DISEASES ARE COMMON IN OLDER
ADULTS.
AND THIS GRAPH IS THE PREVALENCE
OF DIABETES AMONG U.S. ADULTS
AND WHAT CAN BE APPRECIATED IS
THAT THERE'S AN ALMOST LINEAR
INCREASE IN DIABETES WITH
ADVANCING AGE.
THIS AGE-ASSOCIATED INCREASE IN
METABOLIC DISEASE IS
CHARACTERIZED BY IMPAIRED
GLUCOSE TOLERANCE AND INSULIN
RESISTANCE, ADIPOSE TISSUE
DYSFUNCTION, ECTOPIC LIPID
ACCUMULATION AND LIPOTOXICITY,
CHRONIC STERILE INFLAMMATION AS
WELL AS TISSUE SENESCENCE.
LIKEWISE, AGING IS ALSO
ASSOCIATED WITH A LINEAR
INCREASE IN THE PREVALENCE OF
CARDIOVASCULAR DISEASES.
AND THIS INCREASE IS ASSOCIATED
WITH BOTH AGE-RELATED LARGE
ARTERY STIFFENING AND
ENDOTHELIAL DYSFUNCTION.
AND TODAY, ALTHOUGH WE HAVE DATA
ON THE LARGE ARTERY STIFFENING
PART OF THIS, WE'RE REALLY GOING
TO FOCUS ON ENDOTHELIAL
DYSFUNCTION.
IN MY LAB, WE'RE PARTICULARLY
INTERESTED IN THE MECHANISMS AND
CONSEQUENCES OF ENDOTHELIAL
DYSFUNCTION.
SO I JUST WANT TO TAKE A STEP
BACK AND LET EVERYTHING KNOW
ABOUT THE ENDOTHELIUM WHO MIGHT
NOT.
IT'S A SINGLE LAYER OF CELLS
THAT LINES THE INSIDE OF OUR
BLOOD VESSELS.
WHILE IT WAS ONCE THOUGHT TO BE
AN INNER BARRIER, THE
ENDOTHELIUM IS NOW APPRECIATED
TO BE A DYNAMIC ORGAN THAT PLAYS
A CRITICAL ROLE NOT ONLY IN THE
VASCULAR BARRIER FUNCTION BUT
ALSO CONTROLS VASCULAR TONE AND
AS A RESULT BOTH PERIPHERAL
RESISTANCE AND BLOOD FLOW
DISTRIBUTION.
AN THE THELIUM IS OF PARTICULAR
INTEREST TO US BECAUSE IT REALLY
INTERACTS WITH ALL TISSUES OF
THE BODY AS CAN BE APPRECIATED
BY LOOKING AT THIS VASCULAR
CASTING OF A HUMAN.
SO THE ENDO THELIUM PRODUCES A
NUMBER OF VASOACTIVE SUBSTANCES
BUT ONE IN PARTICULAR IS VERY
IMPORTANT, AND THAT'S NITRIC
OXIDE, SO THAT'S SHOWN HERE AS
NO.
NO IS PRODUCED BY THE ENZYME
ENDOTHELIAL NITRIC OXIDE
SYNTHASE IN RESPONSE TO EITHER
AGONISTS SUCH AS ACETYLCHOLINE
OR INSULIN OR SHEER STRESS.
AND THIS NITRIC OXIDE ACTS TO
RELAX THE SMOOTH MUSCLE AND
PRODUCE VASODILATION IN THE
VESSELS.
BUT NITRIC OXIDE ALSO HAS
IMPORTANT ANTI-INFLAMMATORY
EFFECTS BIM -- AS WELL AS
THROMBOTIC EFFECTS THROUGH
PLATELET INHIBITION.
AND IN ADDITION, NITRIC OXIDE
CAN ALSO INHIBIT PROLIFERATION
IN THE SMOOTH MUSCLE.
AND WHAT IS COMMONLY KNOWN WITH
AGING IS THAT WE HAVE A LOSS OF
ENDOTHELIAL FUNCTION THAT'S
CHARACTERIZED BY A REDUCTION IN
ENDOTHELIUM DEPENDENT DILATION
AND A REDUCTION IN NITRIC OXIDE.
SO WHILE IT'S EASY TO APPRECIATE
THAT THERE'S A ROLE FOR THE
ENDOTHELIUM IN CONTROLLING
VASCULAR FUNCTION, THERE'S
EVIDENCE IN THE LITERATURE THAT
THE ENDOTHELIUM MAY ALSO PLAY A
ROLE IN MODULATING METABOLISM.
SO WE SOUGHT TO DETERMINE IF
EXPERIMENTALLY IMPAIRING
ENDOTHELIAL FUNCTION WOULD HAVE
A DIRECT EFFECT ON SYSTEMIC
GLUCOSE AND INSULIN METABOLISM.
SO DO SO, WE UTILIZED A MODEL OF
ENDOTHELIAL R6 KNOCKOUT THAT WE
OBTAINED FROM A COLLEAGUE AT THE
UNIVERSITY OF UTAH.
SO R6 IS A SMALL GTP ACE IN THE
RAS FAMILY THAT IS SHOWN TO BE
INVOSMED IN SOME FUNCTIONS OF
THE ENDOTHELIUM INCLUDING THE
CONTROL OF PERMEABILITY AND
SENSING OF SHEER STRESS AS WELL
AS AN NF KAPPA BY -- R6 KNOCKOUT
MODEL THAT WAS CREATED USING A
CDH5 -- IN WHICH A ROLE FOR --
THIS ANIMAL HAD BEEN USED
PREVIOUSLY TO SHOW A ROLE FOR RN
IN THE SETTING OF DIABETIC
RETINOPATHY BUT WHAT HAD NOT
BEEN LOOKED AT IS IF THERE'S A
ROLE FOR R6 IN THE VASODIAL TRI
ACTIONS OF THE ENDOTHELIUM.
SO USING THIS MODEL, WE WERE
ABLE TO INDUCE A SIGNIFICANT
REDUCTION IN R6 PROTEIN
EXPRESSION AND ISOLATED LONG
PRIMARY ENDOTHELIAL CELLS AFTER
TAMOXIFEN TREAT M.
AND YOU CAN SEE THAT HERE.
SO USING THIS, WE THEN SOUGHT TO
EXPLORE THE ROLE OF R6 IN
ENDOTHELIUM DEPENDENT DILATION
AS WELL AS THE POTENTIAL IMPACT
OF THIS DYSFUNCTION ON GLUCOSE
AND INSULIN METABOLISM.
SO WE FIRST ASSESSED
VASODILATION IN FEED ARTERIES
EXCISED FROM THE GASTROCNEMIUS
JUST MUSCLE.
THESE ARTERIES ARE CANNULATED
INTO THE STAGE OF A MYOGRAPH AND
THEN VISUALIZED USING AN
INVERTED MICROSCOPE AND WE'RE
ABLE TO MEASURE THE LUMINAL
DIAMETER.
AND DEVELOPED CURVES IN RESPONSE
TO DIFFERENT AGONISTS.
AND IN THIS CASE, WE APPLIED
INCREASING CONCENTRATIONS OF
INSULIN TO THE BATH, AND WERE
ABLE TO ASSESS VASODILATION HERE
TO THE WILD TYPE ANIMALS IN
BLACK AND WE COULD SEE A ROBUST
STYDILATION IN THE FEED ARTERY N
RESPONSE TO INSULIN FROM THE
WILD TYPE ANIMALS.
BUT WHEN WE DID THIS IN THE
ENDOTHELIAL R6 KNOCKOUT ANIMALS
WE SAW ALMOST ABOLISHED DILATION
TO INSULIN.
WE COULD THEN PUT A NITRIC OXIDE
SYNTHASE INHIBITOR IN THE BATH
AND BLOCK NITRIC OXIDE COMPONENT
OF VIE SEW DILATION TO GET OUR
MEASURE OF NITRIC OXIDE
BIOAVAILABILITY.
WHEN WE DO THAT, THAT'S GRAPHED
HERE AND WE CAN SEE THIS
REDUCTION IN DILATION WAS
ASSOCIATED WITH AN ALMOST
COMPLETE LOSS OF NITRIC OXIDE
BIOAVAILABILITY.
I JUST WANT TO NOTE THESE ARE
DIFFERENCES TO WHAT WE'VE SEEN
PREVIOUSLY IN AGED MODELS.
SO TO DETERMINE IF THIS
ENDOTHELIAL FUNCTION OR
DYSFUNCTION IMPACTED GLUCOSE AND
INSULIN METABOLISM, WE FIRST
PERFORMED GLUCOSE TOLERANCE
TESTS SO TO DO THIS, MICE ARE
FASTED FOR SIX HOURS IN THE
MORNING AND A BLOOD GLUCOSE
MEASUREMENT IS MADE AND SHOWN
HERE AT TIME ZERO FOR OUR FASTED
MEASURE.
MICE ARE THEN INJECTED WITH
GLUCOSE AND WE THEN ASSESS
GLUCOSE OVER THE COURSE OF TWO
HOURS.
WE ALSO COLLECTED BASELINE BLOOD
AND BLOOD AT 15 MINUTES AFTER
GLUCOSE INJECTION IN ORDER TO
MEASURE THE INSULIN RESPONSE TO
THE INCREASE IN BLOOD GLUCOSE.
ALTHOUGH YOU CAN SEE HERE THERE
WAS NO DIFFERENCE IN GLUCOSE
TOLERANCE BETWEEN THE WILD TYPE
AND KNOCKOUT ANIMALS, THERE WAS
A DIFFERENCE IN INSULIN, AND SO
WE COULD SEE BOTH IN THE FASTED
STATE AND AFTER GLUCOSE
STIMULATION THE ENDOTHELIAL
R6 KNOCKOUT ANIMALS RESPONDED
WITH A GREATER INSULIN RELEASE.
THIS IS SUGGESTIVE OF IMPAIRED
INSULIN SENSITIVITY.
SO WE WANTED TO FOLLOW THAT UP
WITH MORE ADVANCED METABOLIC
TESTING.
SO TO DO THIS, WE PERFORMED
CLAMP STUDIES WITH THE HELP OF A
COLLEAGUE IN UTAH.
AND WHEN WE DO THESE STUDIES,
THE GLUCOSE INFUSION RATE
PROVIDES A MEASURE OF INSULIN
SENSITIVITY.
WITH A LOWER RATE OF GLUCOSE
INFUSION INDICATING INSULIN
RESISTANCE.
WHAT WE FOUND WAS THERE WAS
IMPAIRED INSULIN SENSITIVITY
HERE, AND THIS WAS ASSOCIATED
WITH A REDUCTION IN GLUCOSE UP
TAKE INTO THE SKELETAL MUSCLE,
WHICH WE ASSESSED BY INFUSING A
RADIO LABELED GLUCOSE DURING THE
CLAMP.
SO LASTLY TO SEE IF THE
ENDOTHELIAL DYSFUNCTION THAT WE
PREVIOUSLY SAW COULD UNDERLIE
THIS INSULIN RESISTANCE IN THE
MUSCLE, WE USED FLUORESCENTLY
LABELED MICROSPHERES TO ASSESS
BLOOD FLOW INTO THE SKELETAL
MUSCLE IN RESPONSE TO
EXOGENOUSLY ADMINISTERED
INSULIN.
WE DID FIND THERE WAS A SMALL
REDUCTION IN FASTED SKELETAL
MUSCLE GLUCOSE IN THE
ENDOTHELIAL R6 KNOCKOUT ANIMALS.
IN RESPONSE TO INSULIN ALTHOUGH
THERE WAS A ROBUST INCREASE IN
BLOOD FLOW TO THE MUSCLE IN WILD
TYPE ANIMALS, THIS WAS ABOLISHED
IN THE ENDOTHELIAL R6 KNOCKOUT
MICE.
SO THESE STUDIES PROVIDED
EVIDENCE THAT ENDOTHELIAL
DYSFUNCTION COULD INDEED IMPERIL
METABOLIC HOMEOSTASIS.
SO WE WANTED TO SEE IF THE
OPPOSITE MIGHT BE TRUE, IF AN
IMPROVEMENT IN ENDOTHELIAL
FUNCTION IN AGED MICE COULD
RESTORE METABOLIC FUNCTION AS
WELL.
SO WORK FROM OUR LAB AND OTHERS
HAS INDICATED THE HALLMARKS OF
AGING IN BOTH VASCULAR AND
METABOLIC AGING AND THESE
INCLUDED ALTERED CELLULAR
COMMUNICATIONS SUCH AS THE
INTERACTION OF IMMUNE CELLS WITH
TISSUES AND INFLAMMATION AS WELL
AS CELLULAR SENESCENCE AND
DEREGULATED NUTRIENT SENSING.
AMONG THESE, INCREASE MTOR
SIGNALING HAS BEEN DESCRIBED AS
A CULPRIT IN AGING AND
AGE-RELATED DYSFUNCTION.
SO MTOR IS A KINASE THAT
REGULATES SELF PROLIFERATION,
AUTOPHAGY AND APOPTOSIS.
WORK BY RICHARD MILLER'S GROUP
HAS DEMONSTRATED THAT INHIBITION
OF MTOR SIGNALING WITH RAPAMYCIN
CAN EXTEND LIFESPAN IN BOTH MALE
AND FEMALE MICE.
WE WERE INTERESTED IN SEEING IF
MTOR MIGHT ALSO BE PLAYING A
ROLE IN ENDOTHELIAL DYSFUNCTION.
SO TO EXPLORE THIS, WE BEGAN BY
TREATING YOUNG AND OLD MICE WITH
RAPAMYCIN.
SO FIRST WE EXAMINED
PHOSPHORYLAPHOSPHORYLATED S6K.
IF HE FOUND THERE WAS INDEED AN
INCREASE IN MTOR ACTIVATION WITH
AGING IN MTOR TISSUE AND
FOLLOWING RAPAMYCIN OR MTOR
INHIBITION, THERE WAS A
REDUCTION IN THIS PHOSPHORYLATED
S6K.
WE THEN EXAMINED ENDOTHELIAL
FUNCTION AND EXCISED ARTERIES
FROM THESE MICE AND FOUND THE
EXPECTED REDUCTION IN
ENDOTHELIUM-DEPENDENT DILATION
AS WELL AS REDUCTION IN NITRIC
OXIDE BIOAVAILABILITY IN AGING.
AND THAT BOTH OF THESE WERE
IMPROVED AFTER RAPAMYCIN
TREATMENT.
INTERESTINGLY AS PART OF THIS
STUDY, WE ALSO PERFORMED
METABOLIC TESTING ON THESE MICE.
AND HERE YOU CAN SEE THE AREA
UNDER THE CURVE DURING A GLUCOSE
TOLERANCE TEST AND THAT WITH
AGING, THERE WAS A SIGNIFICANT
INCREASE IN THE AREA UNDER THE
CURVE, INDICATIVE OF IMPAIRED
GLUCOSE TOLERANCE, AND THAT
RAPAMYCIN TREATMENT IN THE OLD
ANIMALS LED TO AN IMPROVEMENT IN
GLUCOSE TOLERANCE.
BUT RAPAMYCIN IS A SYSTEMIC
TREATMENT AND AS SUCH, THE
METABOLIC EFFECTS MAY HAVE BEEN
DUED TO ALTERED MTOR SIGNALING
IN ANY NUMBER OF TISSUES.
WE'RE STILL INTERESTED IN THE
IMPACT OF AGING ON MTOR IN THE
ENDOTHELIUM SPECIFICALLY, SO WE
WANTED TO SEE IF REDUCING
ENDOTHELIAL MTOR WAS SUFFICIENT
TO IMPROVE NOT ONLY VASCULAR
FUNCTION BUT METABOLIC FUNCTION
IN AGING AS WELL.
SO WE FIRST WANTED TO CONFIRM
THAT THERE WAS ACTUALLY AN
INCREASE IN ENDOTHELIAL MTOR
SIGNALING WITH AGING.
SINCE OUR PREVIOUS DATA WAS IN
WHOLE AORTIC LYSATES, IT'S
DIFFICULT TO DETERMINE WHICH
TISSUE WAS CONTRIBUTING TO THAT
INCREASE IN ACTIVATION.
SO HERE WE USE CONFOCAL
MICROSCOPY ON END PHASE
PREPARATIONS OF ARTERIES FROM
YOUNG AND OLD ANIMALS AND
EXPLORED THE EXPRESSION OF
PHOSPHORYLATED S6K.
YOU CAN SEE IN THE ENDOTHELIAL
CELLS SHOWN IN RED THERE WAS A
SIGNIFICANT INCREASE IN
PHOSPHORYLATED S6K.
AND ALTHOUGH THERE WAS ALSO AN
INCREASE IN THE SMOOTH MUSCLE,
IT REALLY WAS MUCH LESS THAN
WHAT WE SAW IN THE ENDOTHELIAL
CELL.
SO NEXT WE AGAIN UTILIZE DOLLARS
THE CDH5 CRE ANIMAL T TO GENERAE
AN INDUCIBLE ENDOTHELIAL
SPECIFIC KNOCKOUT MOUSE FOR
MTOR.
AFTER TAMOXIFEN TREATMENT WE SAW
APPROXIMATELY 75% REA DUCKS IN
MTOR EXPRESSION USING THIS
MODEL.
SO SIMILAR TO WHAT WE FOUND IN
THE RAPAMYCIN STUDIES, WE FOUND
THAT AGING IMPAIRED MAXIMUM
VASODILATION IN OUR OLD ANIMALS
AND ENDOTHELIAL DELETION OF MTOR
LED TO AN INCREASE IN BOTH
VASODILATION AND N.O.
BIOAVAILABILITY.
AND IN THESE AGED MICE, WE FOUND
THAT ENDOTHELIAL-SPECIFIC MTOR
KNOCKOUT WAS SUFFICIENT TO
IMPROVE GLUCOSE TOLERANCE.
AND THIS IS EVIDENCED BY A
REDUCTION ACROSS THE ENTIRE
CURVE OF THE GLUCOSE TOLERANCE
TEST.
SO LAST WE WERE INTERESTED IN
EXPLORING SOME OF THE POTENTIAL
MECHANISMS FOR THE METABOLIC
IMPROVEMENTS THAT WE SAW AND
CHOSE TO EXAMINE OTHER HALL
MARKS OF AGING SUCH AS IMMUNE
CELL ACCUMULATION, INFLAMMATION
AND SENESCENCE.
AND WE FOUND THAT BOTH CD3 AND
FOX P3, WHICH ARE MARKERS OF
T-CELL INFILTRATION, WERE BOTH
REDUCED IN THE ADIPOSE TISSUE OF
THE AGED END THEE ENDOTHELIAL KT
MICE.
>> DOCTOR, YOU HAVE TWO MINUTES
REMAINING.
>> OKAY.
LIKEWISE, MEASURES OF
INFLAMMATORY FACTORS SUCH AS
MCP1, TNF ALPHA, CLCX2, IL-1
BETA AND IL-6 WERE ALSO REDUCED
IN THE ADIPOSE.
AS THESE INFLAMMATORY MEDIATORS
ARE OFTEN DESCRIBED AS SASP
FACTORS, AGING IS ASSOCIATED
WITH ADIPOSE TISSUE SENESCENCE,
WE NEXT ASSESSED MARKERS OF
SENESCENCE P16 AND P21 AND FOUND
THAT BOTH WERE ALSO REDUCED IN
THE ADIPOSE TISSUE OF THE AGED
MSM AGEMTOR KNOCKOUT MICE.
SO TAKEN TOGETHER, WE SEE THAT
AMELIORATING THE AGE H-RELATED
INCREASE IN MTOR SIGNALING CAN
IMPROVE BOTH VASCULAR AND
METABOLIC DYSFUNCTION.
THAT TARGETING THIS REDUCTION IN
MTOR TO THE END OF FAILURE MAY
BE SUFFICIENT TO PRODUCE THE
BENEFICIAL EFFECTS WE SAW.
AND LASTLY, THAT THE ENDOTHELIAL
REDUCTION IN MTOR MAY BE CAPABLE
OF REDUCING OTHER HALL MARKS OF
AGING, SUCH AS INFLAMMATION AND
SENESCENCE, EVEN IN TISSUES
OUTSIDE OF THE ENDOTHELIUM.
AND I DON'T THINK THE EFFECTS
THAT WE'RE SEEING HERE WOULD BE
LIMITED TO MTOR SIGNALING, BUT
RATHER IF WE COULD TARGET
INTERVENTIONS TO IMPROVE
ENDOTHELIAL FUNCTION THROUGH A
VARIETY OF MECHANISMS, I THINK
WE CAN HAVE THE SYSTEMIC
BENEFITS.
SO IN THE TITLE OF MY TALK, I
ASKED THE QUESTION, CAN WE
INTERVENE.
AND I THINK THAT THE ACCUMULATED
EVIDENCE IN A LOT OF THE TALKS
HERE WOULD SAY THAT
INTERVENTIONS TO IMPROVE
HEALTHSPAN WILL NEED TO IMPACT
ON MULTIPLE SYSTEMS, MULTIPLE
TISSUES, AS WELL AS MULTIPLE
MECHANISMS OF AGING TO BE
EFFECTIVE.
INTO AND OUR AND OUR DATA SUGGT
THE ENDOTHELIUM MAY BE A VIABLE
TARGET TO HELP ACCOMPLISH THIS
GOAL.
SO WITH THAT, I JUST WANT TO
THANK MEMBERS OF MY LAB WHO
WORKED ON THESE PROJECTS BUT IN
PARTICULAR TORIKUL ISLAM, AND
COLLABORATORS AT THE UNIVERSITY
OF UTAH, WILL HOLLAND WHO
PERFORMED THE GLYCEMIC CLAMP
STUDIES AND WENDY WHO GAVE US
THE R6 KNOCKOUT ANIMALS AND THEN
MY FUNDING SOURCES.
SO WITH THAT, I CAN TAKE
QUESTIONS.
>> FANTASTIC.
AND I THINK WE HAVE TWO MINUTES
FOR QUESTIONS.
DID YOU DO BOTH MALES AND
FEMALES IN THOSE STUDIES, OR
MALE AND FEMALE ARTERIES?
>> YEAH, THEY WERE -- ALL OF
THESE WITH THE GENETIC MODELS
WERE BOTH SEXES.
>> AND NO DIFFERENCES?
>> NO, WE HAVEN'T REALLY FOUND
ANY DIFFERENCES TO SPEAK.
EVERY ONCE IN A WHILE THERE WILL
BE LIKE A SMALLER CHANGE IN ONE
GROUP OR THE OTHER BUT NOT
SOMETHING THAT WAS LIKE, YOU
KNOW, DIFFERENTIALLY CHANGED
BETWEEN THE SEXES.
>> GOT IT.
AND THEN WE HAVE A QUESTION FROM
MICHAEL SNYDER.
SO DOES NITRIC OXIDE -- DO
NITRIC OXIDE GENERATORS INCREASE
HEALTHSPAN?
FOR EXAMPLE, SOMETHING LIKE BEET
EXTRACT?
>> YOU KNOW, I THINK THAT
THERE'S PLENTY OF PEOPLE WHO
TAKE THOSE KINDS OF SUPPLEMENTS
AND I DON'T THINK WE HAVE THE
DATA YET TO KNOW IF THE
NUTRACEUTICALS ARE IMPROVING
HEALTHSPAN NECESSARILY.
I THINK THERE'S EVIDENCE FROM
PRE-CLINICAL MODELS THAT YOU CAN
GET IMPROVEMENTS IN METABOLIC
AND CARDIOVASCULAR OUTCOMES.
I DON'T KNOW -- I DON'T KNOW
THAT WE HAVE THE DATA OR THE
CLINICAL TRIALS HAVE BEEN DONE
TO PROVE THAT THEY'RE ACTUALLY,
LIKE, IMPROVING HEALTHSPAN OR
LIFESPAN AT THIS POINT.
>> I THINK THERE IS A TRIAL FOR
BEET EXTRACT USING THIS
MECHANISM FOR PR PERIPHERAL
VASCULAR DISEASE PATIENTS
BECAUSE IT'S A PRETTY LOW RISK
INTERVENTION, SO MAYBE WE'LL GET
SOME DATAMENT THEN I HAVE
ANOTHER QUESTION FROM DR. GALIS.
CAN YOU PLEASE COMMENT ON THE
POTENTIAL ROLE OF MTOR SIGNALING
AS AN ANTITUMOR APPROACH?
>> WHOA.
I DON'T KNOW THAT MUCH ABOUT
TUMOR STUFF SO I WOULD LEAVE
THAT TO SOMEBODY WHO ACTUALLY
WORKS WITH TUMORS.
SORRY.
>> I THINK THEY HAVE SOME LINK
TO METFORMIN, WHICH MIGHT REDUCE
CANCER, BUT I DON'T KNOW EITHER,
SO -- BUT IT TURNS OUT YOU'RE
SAVED BY THE BELL, BECAUSE IT IS
4:00 EASTERN STANDARD, SO WE
WILL GET BACK TO YOU IN THE
PANEL DISCUSSION.
NEXT WE'RE GOING TO HEAR ABOUT
TARGETING SULFUR AMINO ACID
METABOLISM FOR LONGEVITY AND
TUMOR SUPPRESSION BY CHRISTOPHER
HINE AT THE CLEVELAND CLINIC.
CHRISTOPHER.
>> THANK YOU VERY MUCH.
YOU CAN HEAR ME LOUD AND CLEAR?
>> YES, THAT'S QUITE GOOD.
>> OKAY.
GREAT.
YOU CAN SEE THE SLIDES?
>> YES.
>> PERFECT.
THANKS A LOT.
>> YOU MAY WANT TO MUTE.
THERE'S A FEW PEOPLE THAT AREN'T
MUTED.
>> THANKS A LOT FOR THE KIND
INVITATION TO SPEAK AT THE
WORKSHOP.
IT'S BEEN FANTASTIC SO FAR.
MY NAME IS CHRIS HINE WITH THE
CLEVELAND CLINIC.
A MAJORITY OF THIS TALK IS GOING
TO BE FOCUSING ON TARGETING
SULFUR AMINO ACID, AGING AND
TUMOR SUPPRESSION.
SO A VERY BRIEF PRESENTATION
OVERVIEW.
POPULATION SHIFTS, MORBIDITIES
AND GEROSCIENCE APPROACHES TO
ADDRESS AGING AS A WHOLE.
NEXT WE'LL GO INTO INTRODUCTION
ON AN ENZYME, CGL.
OTHERS WILL ALSO CALL IT CSC OR
KRFLT TH, AND HYDROGEN SULFIDE
AS COMMON HALLMARKS IN
GEROSCIENCE APPROACHES.
DATA FOR ONGOING MOUSE LONGEVITY
PROJECTS TESTING THE REQUIREMENT
OF CGL AND HYDROGEN SULFIDE FOR
LIFESPAN AND HEALTHSPAN
EXTENSION RELATED TO DIET
RESTRICTION.
LAST BUT NOT LEAST WE'LL GO INTO
A MORE TRANSLATIONAL APPROACH
LOOKING AT PFAU TOUR CLINICAL
DIRECTIONS FOR HARNESSING
HYDROGEN SULFIDE AS A TUMOR
SUPPRESSOR IN GLIOBLASTOMA.
SO IF ANY OF YOU HAD NOTICED,
BACK IN NOVEMBER OF THIS PAST
YEAR, THE WORLD POPULATION HIT
8 BILLION.
NOW THAT RAPID INCREASE IN THE
WORLD POPULATION ISN'T EQUAL
AMONGST ALL AGE GROUPS.
AS WE CAN SEE HERE, DATA, THE
GLOBAL POPULATION AS A FUNCTION
OF AGE RANGE, FROM 1990 TO TO
2000, YOU CAN SEE THE YELLOW
GETS BIGGER AND BIGGER AS WE GO
DECADE BY DECADE AND BY THE YEAR
2050 IT'S ESTIMATED THE
POPULATION IS GOING TO BE 65 OR
OLDER.
-- TRAVEL, DO GREAT THINGS WITH
FRIENDS.
WITH AGE COMES AGING-RELATED
MORBIDITIES.
WHAT THESE ARE, BRAIN AND
COGNITIVE DECLINE,
CARDIOVASCULAR DISEASE, DECLINES
IN IMMUNITY AND INFLAMMATION AND
MOST IMPORTANTLY, AN INCREASE IN
ONCOLOGICAL -- SUCH AS CANCERS.
SO CURRENTLY IN TERMS OF WESTERN
MEDICINE, THE WAY WE DEAL WITH
THESE AGE-RELATED MORBIDITIES
AND THESE DISEASE, WE TREAT THEM
INDIVIDUALLY.
A DRUG FOR CANCER, A DRUG FOR
HIGH BLOOD PRESSURE, FOR THE
MOST PART WHAT'S GOING TO
HAPPEN, YOU TREAT THE CANCER,
END OF -- ALL OF A SUDDEN YOU
TREAT THE CARDIOMYOPATHY, YOU'LL
GET NEURODEGENERATIVE DISORDER.
SO TREATING THEM INDIVIDUALLY
ISN'T THE WAY TO GO, AND IF WE
KEEP ON THAT TRAJECTORY, AND WE
DEVELOP FANTASTIC CHEMO
THERAPEUTICS, FANTASTIC
CARDIOMYOPATHY DRUGS, IN THE END
WE END UP EXTENDING LIFESPAN BUT
NOT NECESSARILY EXTENDING
HEALTHSPAN.
SO APPROACHES WHERE WE CAN APPLY
AN INTERVENTION WHEN HUMANS
START TO AGE, SAY IN SOMEONE'S
MID 30s WHEN DEVELOPMENT IS
OVER AND AGING BEGINS, THAT
SLOWS THE PROGRESSION OR THE
ONSET OF THESE AGING-RELATED
MORBIDITIES.
SO WE'RE NOT NECESSARILY
EXTENDING LIFESPAN TO ALMOST A
SCIENCE FICTION LEVEL, MAYBE
SOMEONE'S MID 90s TO 100s,
BUT WE'RE REALLY FOCUSING ON
EXTENDING THE HEALTHSPAN OF THE
INDIVIDUAL AND THE POPULATION AS
A WHOLE.
SO WHAT ARE THE OVERARCHES
QUESTIONS RELATED TO
GEROSCIENCE?
WHAT ARE THESE EXPERIMENTAL
GEROSCIENCE APPROACHES, WHAT ARE
THE MECHANISMS OF A BEINGTION,
CAN THEY BE LEVERAGED FOR
PREVENTION OR TREATMENT OF AGING
RELATED MORBIDITIES?
SO THERE'S REALLY THREE WE'RE
GOING TO ADDRESS HERE.
ONE IS DATING BACK TO THE LATE
1900s, DIETARY RESTRICTION.
REALLY AN UMBRELLA TERM, OVERALL
REDUCTION OF CALORIES WITHOUT
IMPINGING UPON THE RATIOS OF THE
PROTEIN AND CARBOHYDRATE.
INTERMITTENT FASTING OR
TIME-RESTRICTED FEEDING.
ALSO LOOKING AT PROTEIN
RESTRICTION.
LAST BUT NOT LEAST BUT VERY
POTENT IS METHIONINE
RESTRICTION, WHERE JUST THE
REDUCTION OF THE INTAKE OF
SULFUR METHIONINE CYSTINE HAS
BEEN SHOWN TO EXTEND LONGEVITY
IN MA MAMMALS.
ANOTHER APPROACH WITH
GEROSCIENCE IS ENDOCRINE
MANIPULATION.
HORMONE LEVELS ARE DECREASED --
LONGEST LIVED MICE -- STUDIED
THOSE, AND ALL THESE FOR THE
MOST PART HAVE REDUCTION OF
GROWTH HORMONE, IGF-1 SIGNALING.
LAST BUT NOT LEAST THERE'S
PHARMACOLOGICAL INTERVENTIONS
THAT CAN BE USED TO EXTEND
HEALTHSPAN AND LIFESPAN, THREE
MAIN DRUGS RAPAMYCIN, MET FOR
MAN AND ACARBOSE, I'D ALSO LIKE
TO POINT OUT, THERE'S A TALK
LATER ON IN THE SESSION, THAT
MANY OF THESE DRUGS, AT LEAST
TWO OF THESE THREE ARE ALSO --
THAT TERM -- METABOLITES, HOW
DOES THE MICROBIOME PRODUCE SOME
OF THESE METABOLITES THAT COULD,
IN FACT, IMPINGE UPON OR
STIMULATE HEALTHY PATHWAYS IN
THE BODY IS REALLY AN AREA
THAT'S WIDE OPEN FOR RESEARCH IN
THE FUTURE.
SO ARE THERE COMMON PATHWAYS
IMPACTED BY ALL THREE OF THESE
INTERVENTIONS, AND CAN WE FOCUS
ON THAT PATHWAY.
THEY LIKED AT DIETARY
INTERVENTION, ENDOCRINE
MODELS -- IN MICE, ALSO
PHARMACOLOGICAL INTERVENTIONS.
WHAT THEY SAW AT LEAST LOOKING
NE LIVER OF THESE MICE WAS
INCREASED EXPRESSION OF AN
ENZYME CALLED GAMMA LYASE.
INCREASED BY MOST --
INTERVENTIONS THAT CAN BE USED
AS A SIMPLE MOLECULAR BIOMARKER
ASSOCIATED WITH LONGEVITY.
I REALLY WANT TO PUT SOME STRESS
ON THE ASSOCIATED BECAUSE AT
THIS POINT AT LEAST IN THE
MAMMAL, IT'S CORRELATIVE.
IT DOESN'T MEAN INCREASING CGL
IS GOING TO EXTEND LIFE SPAN BUT
AT LEAST WITH ALL THESE
DIFFERENT TYPES OF INTERVENT
INTERVENTIONS, THEY DO EXTEND
LIFESPAN AND HEALTHSPAN, THERE
IS AN INCREASE IN CGL AT LEAST
IN THE LIVER.
SO WHAT DOES CGL DO?
WHAT I'M FOCUSING ON HERE IS
METABOLISM OF AMEA KNOW ACIDS.
SO WE START WITH METHIONINE,
ESSENTIAL AMINO ACID,
METABOLISM, YOU REACH
HOMOCYSTEINE.
THE HOMOCYSTEINE CONTINUES ON
THE TRANS OPERATION PATHWAY,
CBS, WHICH IS A PLP-DEPENDENT
ENZYME.
TO FORM CYSTINE.
HOWEVER, IT SHOULD BE NOTED THAT
CGL IS ACTUALLY QUITE PROMIS
QUEUE US IN THE SUBSTRATE OF
PRODUCTS THAT IT MAKES.
CGL CAN BRING IN CYSTINE ITSELF
AND HOMOCYSTEINE IN A VARIETY OF
PRODUCTS AND ALSO ONE BYPRODUCT
IN THIS PROCESS IS THE
TRANSMITTER HYDROGEN SULFIDE
GAS.
WHY ARE WE TALKING I ABOUT IT N
AN AGING-RELATED STUDY?
FOR THE MOST PART IT'S AN
OCCUPATIONAL HAZARD ESPECIALLY
IN THE -- DON'T GO HOME AND
START SNIFFING IT BECAUSE IT IS
TOXIC AT HIGH LEVELS.
HOWEVER, LOOKING AT IT FROM A
MEDICAL STANDPOINT, ESPECIALLY
BACK IN THE LATE 1800s, EARLY
1900s, INDIVIDUALS WOULD
TRAVEL WIDE AND FAR AND SPEND
QUITE A BIT OF MONEY TO GO TO
THESE SULFIDE POOLS SUCH AS
THESE INDIVIDUALS HERE AND BATHE
IN THESE SULFIDE POOLS THINKING
IT WOULD BE CURATIVE OF WHAT
AILS THEM.
IT WASN'T A FOUNTAIN OF YOUTH.
HOWEVER, IN THE EARLY 2000s,
THERE WAS A RENAISSANCE IN
HYDROGEN SULFIDE BIOLOGY
RESEARCH.
ESPECIALLY WHEN IT CAME TO AGING
AND LI LIFESPAN EXTENSION.
THEY SAW BOTH IN WORMS AND FLIES
THAT INCREASING EXPOSURE TO
HYDROGEN SULFIDE GAS OR BOOSTING
ENDOGENOUS PRODUCTION OF THE GAS
BY THE ENZYME CGRCBS COULD
EXTEND LIFESPAN IN THESE MODEL
ORGANISMS.
BUT WHAT ABOUT IN THE MAMMAL?
SO WHAT I'VE SHOWN WHEN I WAS IT
THE HARVARD SCHOOL OF PUBLIC
HEALTH IN MY OWN LABORATORY OVER
THE LAST SIX YEARS IS THAT UNDER
DIETARY RESTRICTION,
INTERMITTENT FASTING AND
METHIONINE RESTRICTION --
THERE'S AN INCREASE IN CGL
EXPRESSION AND LEAST IN THE
LIVER AND INCREASED PRODUCTION
CAPACITY IN THE HYDROGEN SULFIDE
GAS.
THIS INCREASE WAS NECESSARY AND
SUFFICIENT TO GIVE STRESS
RESISTANCE, CARDIOVASCULAR
FITNESS AND MUSCLE ANGIOGENESIS
IN LATE LIFE.
ALSO ENDOCRINE AND METABOLIC
RESPONSES TO FASTING.
HOWEVER THE BIG QUESTION IS WHAT
ABOUT LONGEVITY AND LIFESPAN?
I MENTIONED BEFORE IT WAS SHOWN
TO BE NECESSARY TO DRIVE
EXTENSION IN THE FLIES AND WOR
WORMS.
ONE OF THE VERY FIRST THINGS I
DID IN MY LABORATORY IS WE TOOK
MALE AND FEMALE WILD TYPE AND
KNOCKOUT MICE, -- AND SO ALL THE
ANIMALS WERE KEPT UNDER --
CONDITIONS FOR THE FIRST FIVE
MONTHS OF LIFE, AND THEN AROUND
MONTH SIX, THE CALORIC
RESTRICTION ARM WAS PUT ON DAILY
RESTRICTION OF CALLYS, OVERALL
REDUCTION BY 35%.
AT 10 MONTHS OF LIFE WE UPPED
THAT TO 45% CALORIC RESTRICTION
AND THEY WERE MAINTAINED ON THAT
45% CALORIC RESTRICTION TO FOR E
REMAINDER OF THEIR LIFE.
ALSO HEALTHSPAN TESTS, BOTH
QUALITY AND QUANTITY OF LIFE.
-- COGNITIVE IMPROVEMENTS.
26 TO 46 MICE PER GENOTYPE/DIET
GROUP.
5:00 P.M. DAILY, SEVEN DAYS A
WEEK FOR OVER 3 1/2 YEARS, SO
REALLY I HAVE TO GIVE PROPS TO
ALL THE PEOPLE IN MY LABORATORY,
ESPECIALLY DURING COVID, THEY
NEVER MISSED ONE DAY OVER THE
WHOLE 3 1/2, ALMOST FOUR YEARS
THAT SOME OF THESE MICE HAVE
LIVED.
THE CALORIE COMPOSITION OF THE
BASE DIET WAS 20% PROTEIN, 20%
FAT, 60% CARBOHYDRATES.
THE ANIMALS WERE ALL TRACKED
UNTIL FOUND DECEASED OR
EUTHANIZED AT SIGNS OF BEING
MORIBUND.
SO TO START IT OFF, WHAT WE
ACTUALLY SEE IS THERE'S ACTUALLY
NO DIFFERENCE IN LIFESPAN
BETWEEN CGL WILD TYPE AND
KNOCKOUT MICE WHICH IS ACTUALLY
GOOD.
MOCKING UP CGL -- PRO --
PHENOTYPE, SO NEXT LOOKING AT AT
THE CALORIC RESTRICTION AT THE
CLEVELAND CLINIC TO EXTEND MICE
LIFESPAN, AND WE SAW THAT IT DID
SO THE MICE ON CALORIC
RESTRICTION HAD 24% INCREASE IN
MEDIAN LIFESPAN SO THIS IS
BASICALLY HUMAN EQUIVALENT GOING
FROM 7 TO 8 YEARS FOR EXPECTED
LIFE SMAN TO -- AND THE MAXIMUM
WAS EXTENDED BY 11% IN THESE
MICE.
SO THE BIG QUESTION WAS IS
KNOCKING OUT CGL IMPINGE UPON
LIFESPAN EXTENSION UNDER CALORIC
RESTRICTION.
WE SAW IN FACT IT DID, WE SAW AN
8% DECLINE IN MEDIAN LIFESPAN
AND 8.5% DECLINE IN THE CGL
KNOCKOUTS COMPARED TO THE CGL
WILD TYPE MICE UNDER CALORIC
RESTRICTION.
ONE GRAPH HERE BEING LOOKING AT
CGL WILD TYPE -- KNOCKOUT, CORE
RESTRICTION BUT AGAIN THE CGL
WILD TYPE UNDER CALORIC
RESTRICTION MEDIAN SURVIVAL
AND -- SURVIVAL.
I'D LIKE TO REALLY POINT OUT
THERE'S NO NOTICEABLE DIFFERENCE
AT THE MAXIMUM BETWEEN CGL
KNOCKOUTS AND CGL KNOCKOUTS --
SO SLIGHT INCREASE, NOT
COMPLETELY ABLATED AT THE MEDIAN
BUT AT THE MAXIMUM IT'S
COMPLETELY ABLATED.
AND THEN JUST REALLY QUICK
LOOKING AT -- I MENTIONED THE --
HEALTHSPAN, WE SAW IMPROVEMENTS
IN BOTH THE WILD TYPES AND
KNOCKOUTS,
PHYSIOLOGICAL/MUSCULOSKELETAL
TESTS, METABOLIC AND COGNITIVE.
HOWEVER IN TERMS OF THE
METABOLIC AND COGNITIVE
IMPROVEMENTS THOSE WERE MAIN LOW
ONLY SEEN IN THE WILD TYPE SO
THAT IS -- FOR THE MOST PART IN
THE CGL KNOCKOUT MICE.
>> DOCTOR, YOU HAVE TWO MINUTES
REMAINING.
>> THANKS A LOT.
AND SO JUST SUMMARIZING AT THIS
POINT, SO CALORIC
RESTRICTION/TIME RESTRICTED
FEEDING WE SAW A BOOST IN CGL,
BEAST IN H2S, AND MAXIMIZED
LIFESPAN BUT BY WHAT MECHANISM?
PERSULFIDATION AND LIKEWISE
MITOCHONDRIAL BIOENERGETICS, TO
MAKE ATP THROUGH SULFITE -- SQR,
OR UNDER TOXIC CONDITIONS,
COMPLEX 4 BASICALLY KILLS OFF
MITOCHONDRIA.
FOR THE FOCUS OF THIS TALK WE'LL
FOCUS ON PERSUL FI. DATION.
THE LIVER, KIDNEYS, MUSCLE AND
BRAIN, WE SAW REALLY NICE
ENRICHMENT IN PROTEIN, SO THIS
CAN MODIFY THE PROTEIN
STRUCTURE, ITS FUNCTION, IT CAN
ALSO PROTECT AGAINST
IRREVERSIBLE OXIDATIVE STRESS ON
THE CYSTINES THAT ARE MODIFIED.
QUITE A BIT OF CHANGES TO THE
PROTEOME.
THEN WE LOOKED AT THE DEPENDENCE
OF CGL FOR THAT SHIFT IN PER
SUFFICIENTLY DAITION, SO ALL THE
TISSUES COMBINE INTO ONE, IT'S
REALLY NICE ENRICHMENT UNDER
CALORIC RESTRICTION LOST ON CGF
KNOCKOUTS.
WE PLUG THEM INTO PATHWAY
ANALYSIS WE SEE THERE'S A
VARIETY OF AGING-RELATED
PATHWAYS THAT ARE IMPACTED OR AT
LEAST ENRICHED FOR THESE PER
SULFIDATED PROTEINS.
AT THE VERY LEAST ALL THESE
PATHWAYS HAVE ENRICHMENT FOR
PROTEIN PERSULFIDATION UNDER
CALORIC RESTRICTION.
SO AGAIN SUMMARY HERE, DIETARY
RESTRICTION IS GOING TO GIVE
MAXIMIZED LIFESPAN, MAXIMIZED
HEALTHSPAN.
WE FELT THIS PATHWAY BY
STIMULATING H2S PLAYS A PART IN
IT BUT IT'S PROBABLY NOT THE
ENTIRE PICTURE, THESE DOTTED
LINES OVER HERE, AND HOW DO WE
APPLY THIS MECHANISTIC KNOWLEDGE
FOR CLINICAL TRANSLATION.
REAL QUICK I'M LOOKING AT
HUMANS, I PUBLISHED THIS LAST
YEAR, IN IS A REDUCTION IN
CIRCULATING -- AS A RESULT OF
AGE.
LOOKING AT VERY DANGEROUS
AGE-RELATED DISEASE IN HUMANS IS
GLIOBLASTOMA, HOW DOES -- WE SAW
THERE WAS A MASSIVE LOSS IN
PROTEIN PERSULFIDATION IN HUMAN
BIOPSIES OF GLIOBLASTOMA TUMORS
COMPARED TO THE NON-TUMOR BRAIN
TISSUE.
SO THERE WAS A LOSS OF THE
SIGNALING THAT OCCURS.
AND ALSO WE SAW THAT IF WE
INHIBIT CGL THROUGH A BACTERIAL
METABOLITE, WE CAN ACTUALLY
ENHANCE GLIOBLASTOMA -- IN
CULTURE IN ADDITION TO
INHIBITING ITS H2S PRODUCTION.
LAST BUT NOT LEAST BY DELIVERING
H2S INTO THE TUMORS IN IN VIVO
MODEL, WE CAN DECREASE TUMOR
VOLUME AND ALSO DECREASE THE
TUMOR -- PHENOTYPE -- EXPRESSION
IN THE TUMORS OF THOSE MICE.
AGAIN, REAL, REAL QUICK, SO
ACTUALLY APPLYING THIS IN A
CLINICAL TRIAL, WE'RE ACTUALLY
LOOKING AT BOOSTING H2S
PRODUCTION NOT THROUGH DIET BUT
ACTUALLY THROUGH LOWERING
HORMONE ACTIVITY.
WE CAN ACTUALLY SEE IS BY
TREATING AT LEAST IN THIS CASE
MICE WITH PROPYL THIOURACIL, WE
CAN ENHANCE PRODUCTION CAPACITY
WENCAPACITY. -- EXPENDED PATIENL
THREE FOLD.
SO WE'RE GOING TO BE REVISITING
THIS AS A CLINICAL TRIAL USING A
SAFER DRUG METHIMAZOLE TO
ENHANCE H2S ACTIVITY -- CAN
BOOST THEIR H2S PRODUCTION AT
LEAST IN THEIR LIVERS.
THIS IS IN CLINICAL TRIAL RIGHT
NOW, WHERE PATIENTS WITH
RECURRENT GLIOBLASTOMA WILL BE
TREATED WITH -- THIS WILL BE
USED WITH STANDARD OF CARE
CHEMOTHERAPIES.
SO I'LL SKIP THIS FOR THE SAKE
OF TIME BUT -- COLLABORATORS,
FUNDING THAT MADE ALL THIS
POSSIBLE.
THANK YOU VERY MUCH.
>> THANK YOU VERY MUCH.
UNFORTUNATELY I THINK WE HAVE TO
MOVE ON BECAUSE WE ARE OUT OF
TIME.
COULD YOU INJECT THIS IN
PATIENTS WITH GLEE OWE BLASTOMA?
IS THAT A REE A FEASIBLE APPROA?
>> -- WITH THE GAS IS
DANGEROUS.
-- IT'S GOING TO BE THE SAFEST
AND MOST EFFECTIVE WAY.
>> ALL RIGHT.
FANTASTIC.
HOPEFULLY MORE IN THE PANEL
DISCUSSION.
OKAY, SO OUR NEXT TALK, OUR NEXT
SPEAKER WILL BE DR. PATTI LEE
FROM THE ICAHN SCHOOL OF
MEDICINE AT MOUNT SINAI.
SEAL BE SPEAKING ABOUT
ENVIRONMENTAL DETERMINANTS AND
MODELS OF LUNG VASCULAR
SENESCENCE.
DR. LEE?
IS DR. LEON?
>> I ACTUALLY DON'T SEE HER.
GLRL ALL RIGHT.
LET'S GIVE HER A MINUTE OR TWO.
MAYBE ONE OF YOU CAN TEXT OR
EMAIL HER.
WE CAN RUN A MINUTE OR TWO LATE.
THIS IS A QUESTION FOR DR. HINE
IF YOU'RE STILL ON.
DISULFIDE BONDS ARE VERY
IMPORTANT IN THE FUNCTION OF
MANY MOLECULES.
DOES HYDROGEN SULFIDE REACT WITH
DISULFIDE BONDS?
>> THAT'S A GREAT QUESTION.
>> GR GALIS, NOT ME.
>> THAT'S A GREAT QUESTION.
SO THE PERSULFIDATION I SHOWED
YOU, THAT'S ACTUALLY NOT
FAVORABLE JUST TO ADD A SULFIDE
ON TO A -- MOST HAVE TO BE
PRIMED AND ONE WAY TO PRIME THEM
IS -- THROUGH DISULFIDES, AND IT
SHOWS YOU IN TERMS OF EACH
FEEDING ELECTRONS INTO ELECTRON
TRANSPORT CHAIN THROUGH THE --
SQR, IT ACTUALLY DOES THAT BY
MODIFYING THE DISULFIDE BONDS IN
THAT SQR.
SO IF THE DISULFIDE BONDS ARE ON
THE EXTERNAL SIDE OF THAT
PROTEIN, IT IS POSSIBLE THEY CAN
BE MODIFIED THROUGH
PERSULFIDATION PROCESS.
>> OKAY, FANTASTIC.
AND I'M NOT SURE IF OUR NEXT
SPEAKER IS ON, SO WE CAN GO
SLIGHTLY OUT OF ORDER AND I CAN
GO NEXT.
IS SHE ON?
>> NO.
>> OKAY.
ALL RIGHT.
SOMEBODY COULD EMAIL HER SO
MAYBE SHE CAN COME ON FOR THE
FINAL ONE, OTHERWISE WE'LL HAVE
A SLIGHTLY LONGER BREAK, OR I'LL
JUST RAM DELL BELL ON FOREVER.
NO, I WON'T, I PROMISE.
OR WE CAN HAVE A LONGER
DISCUSSION SECTION.
SO I'LL JUST INTRODUCE MYSELF.
MY NAME IS LOUISE MCCOLLOUGH,
I'M THE CHAIR OF NEUROLOGY SO
IT'S ALL ABOUT STROKE.
WE ARE GOING TO TALK ABOUT
AGE-RELATED CHANGES IN THE
MICROBIOME IN HEALTH AND
DISEASE.
SO FIRST OF ALL, WHAT IS THE
MICROBIOME?
IT'S REALLY THE COMMUNITY OF
MICROORGANISMS.
WE'VE HEARD A BIT ABOUT
PATHOGENS BUT IT INCLUDES FUNGI,
BACTERIA AND VIRUSES.
A LOT OF THE MICROBIOME WORK IS
REALLY FOCUSED ON BACTERIA, BUT
IT CAN EXIST IN MULTIPLE
DIFFERENT ENVIRONMENTS.
THE ONE I'M GOING TO SPEAK ABOUT
TODAY IS PRIMARILY FOCUSED ON
THE GUT MICROBIOME.
IT'S ACTUALLY INITIALLY
COLONIZED AT BIRTH.
SOME PEOPLE HAVE SUGGESTED THERE
MIGHT BE A PLACENTAL BIOME, BUT
THAT'S A LITTLE BIT DEBATABLE.
IT'S REALLY VERTICALLY
TRANSMITTED FROM THE MOTHER.
THAT WILL BECOME IMPORTANT AT
THE VERY END OF MY TALK.
THESE MICROORGANISMS ARE VERY
DYNAMIC.
THEY CAN CHANGE IN RESPONSE TO
DIET, MEDICATION, STRESSORS,
ENVIRONMENTAL EXPOSURES, ALL THE
THINGS WE'VE HEARD ABOUT THIS
MORNING AND THIS AFTERNOON.
THESE ORGANISMS MAKE A VARIETY
OF METABOLITES, SOME OF WHICH WE
CAN'T MAKE, SUCH AS INGULS
REALLY REQUIRE THE PRESENCE OF
A -- ESPECIALLY WITH THEIR
METABOLIC PRODUCTION OR HARMFUL
OR PATHOGENIC AS WE SEE
ESPECIALLY IN STROKE WITH
POST-STROKE INFECTIONS BEING A
LEADING CAUSE OF DEATH.
WE DO KNOW THE BIOME CHANGES
WITH AGE WITH THE INCREASING
DYSBIOSIS.
MANY DON'T LIKE THAT WORD BUT
IT'S A PATHOLOGICAL SHIFT IN THE
MICROBIOME.
WHAT I'M GOING TO TALK ABOUT
TODAY IS, IS THE BIOME A
POSSIBLE SOURCE OR TRIGGER FOR
THAT SENESCENCE WE SEE WITH
AGING.
SO WE'RE GOING TO TALK ABOUT
STROKE.
AS YOU HEARD FROM THE OTHER
SPEAKERS, MANY OF THE DISEASES
WE'VE HEARD ABOUT LIKE CANCER
ARE AGE-RELATED DISEASES.
STROKE IS NO EXCEPTION.
THE VAST MAJORITY OF STROKE
PATIENTS ARE OVER 65, AND IF
YOU'LL RECALL THIS MORNING,
THERE WAS A SLIDE SHOWING COMMON
CAUSES OF DEATH, AND STROKE IS
ON THERE.
IT IS THE NUMBER -- ONE OF THE
LEADING CAUSES OF DEATH BUT I
THINK EVEN MORE IMPORTANTLY
ESPECIALLY AS A CLINICIAN, IT IS
THE MOST COMMON CAUSE OF LONG
TERM DISABILITY.
BOTH GLOBALLY AND IN THE U.S.
SO HOW DO WE MODEL STROKE?
WE USE A MOUSE MODEL, WE CAN USE
RATS, WE CAN USE PRIMATES, BUT
WE TEND TO USE THE MOUSE MODEL.
WE USE A MIDDLE CEREBRAL ARTERY
OCCLUSION, WHICH IS WHERE WE PUT
A FILAMENT, AND I'M NOT SURE IF
YOU CAN SEE MY LITTLE MOUSE
HERE, BUT WE PUT A FILAMENT UP
HERE INTO THE INTERNAL CAROTID
OF THE MOUSE, AND THAT BLOCKS
THE MIDDLE CEREBRAL ARTERY.
IT'S THE MOST COMMON STROKE THAT
WE SEE IN PATIENTS, AND THIS IS
VERY RELEVANT BECAUSE WE PULL
OUT THE SUTURE AND ALLOW FOR
REPERFUSION, WHICH IS ACTUALLY
WHAT WE DO CLINICALLY.
IT'S CALLED THROM BECKETT ME, TF
THE MOST POTENT TREATMENTS WE
HAVE IN MEDICINE WITH A NUMBER
NEEDED TO TREAT FOR BENEFIT OF
TWO.
THIS LEADS TO AN INFARCT, AND
YOU CAN SEE HERE THIS WHITE AREA
IS THE AREA OF INFARCT.
SO STROKE DAMAGE PROGRESSES OVER
TIME, BUT THE STROKE IS USUALLY
HISTOLOGICALLY COMPLETE IN THIS
MODEL BY 24 HOURS.
THIS WILL BECOME IMPORTANT
AFTER.
THESE ARE CORONAL SEC SHOULD
BEESSHOSECTIONS OF AMOUSE BRAIN.
THIS IS A THING CALLED A TTC
DYE.
IT'S PICKED UP BY MIGHT TOE CON.
YOU CAN SEE BETWEEN 24 HOURS,
3 DAYS, 7 DAYS, THERE ISN'T MUCH
CHANGE IN THE SIZE OF THE
STROKE, BUT THERE'S A LOT OF
STUFF GOING ON IN HERE AS FAR AS
INFLAMMATION.
AND AGAIN AS I MENTIONED, THIS
IS A CAT SCAN OF A STROKE
PATIENT WITH A RIGHT MIDDLE
CEREBRAL ARTERY STROKE.
SO YOU CAN SEE IT KIND OF
RECAPITULATES WHAT WE SEE.
NOW, TO GET TO THE BIOME, I
DIDN'T HAVE ANY SORT OF STRATEGY
FOR THIS.
I KIND OF STUMBLED UPON IT ABOUT
10 YEARS AGO, MAYBE EVEN LONGER
BECAUSE I STARTED ASKING
OURSELVES WHY ARE WE MODELING
STROKE, DISEASE THAT PRIMARILY
AFFECTS AGING IN 8 WEEK OLD C57
BLACK MICE.
SO WE STARTED TO SAY OKAY, THE
IMMUNE RESPONSE IS DIFFERENT IN
AGING, THE VASCULATURE IS
DIFFERENT, WE NEED TO USE AGED
MICE.
AND SURPRISINGLY, IN A YOUNG
MALE, YOU SEE THIS RELATIVELY
LARGE INFARCT, THESE MICE WITHIN
A WEEK ARE LIKE SCAMPERING
AROUND THEIR CAGE.
THIS IS AN AGED MALE AND YOU SEE
THE STROKE IS ACTUALLY SMALLER
AND IT'S NOT DUE TO A REDUCTION
IN BLOOD FLOW, WE CHECKED IT
EVERY WAY.
THEY JUST HAVE THESE SMALLER
STROKES.
THEY ALSO HAVE A VERY DIFFERENT
IMMUNE RESPONSE TO STROKE WITH A
PRIMARILY NEUTROPHIL IK
INFLAMMATION WHICH IS PROBABLY
WHY AGING ANIMALS AND THA HUMANS
HAVE HIGHER RATES OF BLEEDING
AFTER STROKE.
BUT INTERESTINGLY THESE AGED
STROKE ANIMALS DESPITE HAVING A
MUCH SMALLER STROKE ARE MUCH
WORSE NEUROLOGICAL DEFICITS AND
NEVER RECOVERED.
THEY ALSO HAD MUCH HIGHER
MORTALITY THAN THEIR YOUNG
COUNTERPARTS.
WHEN WE FIRST STARTED MODELING
STROKE IN AGED, WE DIDN'T KNOW
IF WE'D BE ABLE TO DO IT BECAUSE
70% OF OUR MICE WERE DYING.
WHEN WE STARTED TO UNDERSTAND A
LITTLE BIT MORE, WE HAVE A LOT
OF WAYS TO KEEP THESE MICE
ALIVE, IF ANY OF YOU ARE
INTERESTED I'M HAPPY TO SEND YOU
PROTOCOLS THAT HAVE TAKEN US
MANY YEARS TO ENHANCE SURVIVAL.
BULL YOU BUT YOU CAN SEE WHEN WD
AT WHY THEY WERE DYING, THEY
HAVE A VERY ROBUST INFLAMMATORY
RESPONSE TO STROKE.
IT'S NOT DIFFERENT THAN THE
YOUNG MICE, BUT IT'S MUCH MORE
CHRONIC.
AND YOU CAN SEE ELEVATIONS AND
THINGS LIKE IL-6, EVEN WEEKS TO
MONTHS AFTER STROKE, AND WE ALSO
SAW FEATURES OF IMMUNE
SUPPRESSION IN THE AGED MICE
BASED ON THEIR -- RATIOS.
SO MICE ARE DYING, THEY HAVE ALL
THIS INFLAMMATION, THEY LOOK
LIKE THEY'RE IMMUNE-SUPPRESSED,
WHAT'S KILLING THEM?
SO WE STARTED LOOKING AT ALL THE
ORGANS IN THE BODY, GRINDING
THEM OUT AND PLATING THEM.
YOU CAN DO ANAEROBIC FOR THE
MICROBIOME, AND YOU SEE ALL
THESE LITTLE WHITE DOTS HERE?
THESE ARE COLONY-FORMING UNITS
OF BACTERIA, AND YOU CAN SEE THE
AGED STROKE MICE HAS MUCH MORE
PERIPHERAL EFFECTS FROM THE
STROKE.
AND YOU CAN SEE THAT'S
QUANTIFIED HERE.
THEN WE TOOK THESE LITTLE
COLONIES AND SENT THEM FOR
SEQUENCING.
AND WHAT WE FOUND IS NOT ONLY
WERE THERE A LOT MORE -- THERE
WAS A LOT MORE LOSS OF BACTERIAL
CONTAINMENT, IF HAPPENS TO BE
THE MESENTERIC LYMPH NODES, THEY
ALSO WERE COMPLETELY DIFFERENT
BACTERIA.
SO THAT LED US TO SAY OKAY,
WELL, THESE BACTERIA FROM THE
MESENTERIC LYMPH NODES WHICH
DRAIN THE GUT, WHY ARE THEY
DIFFERENT?
NOT ONLY ARE THEY MORE, THEY'RE
DIFFERENT.
SO ARE THERE AGE-RELATED CHANGES
IN THE MICROBIOME ITSELF?
AND THE ANSWER IS YES, ALMOST
COMPLETELY NON-OVERLAPPING IN A
YOUNG BIOME AND AN AGED BIOME.
THIS IS FROM FECAL SAMPLES.
AND A QUICK WAY TO LOOK AT THIS
IS JUST A BACK TIER ROY
DECEMBER -- RATIO WHICH IS VERY
SHIFTED AND DYSBIOTIC WITH VERY
MORE -- IN THE AGED ANIMALS.
ALSO THE GUT ITSELF CHANGES WITH
AGE.
THIS IS A HISTOLOGICAL SECTION
OF THE GUT.
THIS IS THE LAMINA APPROPRIATE
REA.
THIS IS THE EPITHELIUM WHICH IS
US, THE HOST.
THIS HAS A LOT OF IMMUNE AND
INFLAMMATORY CELLS IN HERE BUT
WHAT I'M SHOWING YOU HERE IS
THIS RED, THIS IS A FISH STAIN,
WHICH STAINS THE BACTERIA, AND
YOU SEE THIS DISTANCE BETWEEN US
AND THE BACTERIA.
THE HOST AND THE POTENTIAL
PATHOGEN.
AND YOU SEE WITH AGING, YOU LOSE
THIS MUCOUS BARRIER BECAUSE OF A
REDUCTION IN GOBLET CELLS AND
THINGS THAT HAPPEN IN THE IMMUNE
COMPARTMENT WHICH I DON'T HAVE
TIME TO TALK ABOUT TODAY.
BUT AGING ITSELF CHANGES THE GUT
AND THE MUCOUS BARRIER, LOOK AT
WHAT HAPPENS WITH STROKE.
WE FOUND WITH STROKE IN AGED
ANIMALS, THEY HAD A LOT OF FITC,
WE COULD SEE IT IN THEIR BLOOD
AND IT WAS CORRELATED WITH
THEIR DEGREE OF NEUROLOGICAL
DISABILITY, AND CAN YOU SEE WHAT
HAPPENS WITH STROKE.
HERE IS A MOUSE AND HERE IS THE
BACTERIA, HERE'S THE EPITHELIUM,
NICE MUCOUS BARRIER.
IT'S COMPLETELY DESTROYED AFTER
STROKE.
AND YOU CAN SEE THESE BACTERIA
STARTING TO CLIMB INTO THE HOST.
SO WE WANTED TO SAY OKAY, NOW WE
SEE THAT THE BACTERIAL
COMPOSITION OF THE AGED BIOME IS
DIFFERENT, IS IT MALLEABLE, CAN
WE CHANGE IT?
SO AGAIN, USING THAT KIND OF
DIPSTICK OF DYSBIOSIS, THE F TO
B RATIO, WE FOUND, YES, WE CAN
CHANGE IT.
THIS IS A YOUNG MOUSE GIVEN
EITHER A YOUNG FECAL TRANSPLANT
OR AN AGED DONOR TRANSPLANT.
YOU CAN SEE IN THE YOUNG
RECIPIENT, WE RECAPITULATE
AGE-RELATED DYSBIOSIS.
SO IT DOES TAKE HOLD IN THE
HOST.
MORE IMPORTANTLY IN THE AGED
RECIPIENT THAT HAVE DYSBIOSIS AT
BASELINE HERE, YOU CAN SEE
GIVING THEM A YOUNG BIOME IS
REJUVENATING.
YOU HAVE TO DEPLETE THE NICHE TO
ENSURE A SUCCESSFUL FECAL
TRANSPLANT, WHICH MEANS YOU HAVE
TO USE ANTIBIOTICS.
YOU HAVE TO GIVE THE BACTERIA AN
AREA TO KIND OF COLONIZE.
SO THAT IS ONE OF THE
LIMITATIONS OF SOME OF THE
STUDIES WE'VE DONE.
WHEN WE TOOK AGED FECAL
TRANSPLANT AND PUT IT INTO YOUNG
HEALTHY ANIMALS AND GAVE THEM A
STROKE, YOU CAN SEE ALMOST NONE
OF OUR YOUNG MICE THAT GOT A
YOUNG BIOME, NONE OF THEM DIE.
OUR YOUNG MICE ARE VERY HARDY
EVEN AFTER A BIG STROKE.
BUT YOU CAN SEE WHAT TED, BY
GIVING AN AGED BIOME, IN IS
STILL A YOUNG HOST, THE
MORTALITY WAS 40%.
SO IT'S STILL A YOUNG MOUSE,
YOUNG BRAIN, YOUNG VASCULATURE.
THE ONLY THING THAT'S AGED IS
THE BIOME AND IT REDUCED
SURVIVAL BY 40%.
SO WE FIRST SEVERAL YEARS AGO,
PROBABLY EIGHT YEARS AGO NOW,
DID A BIOME TRANSPLANT ABOUT A
MONTH BEFORE STROKE AND WE FOUND
WE COULD RECAPITULATE THE
YOUTHFUL BIOME AND THAT THE AGED
MICE THAT GOT A YOUNG BIOME DID
MUCH BETTER AFTER STROKE.
HOWEVER, STROKE IS AN
UNPREDICTABLE EVENT.
I MAY NOT BE ABLE TO CHANGE YOUR
BIOME AFTER YOU COME IN WITH
YOUR STROKE, SO WHAT WE WANTED
TO DO IS SEE HOW MALLEABLE IT
WAS DAYS AFTER THE STROKE.
SO IN THIS EXPERIMENT, WE TOOK
AGED STROKE MICE, SO ALL OF THE
RECIPIENTS ARE AGED, AND WE GAVE
THEM EITHER AGED DONOR OR YOUNG
DONOR BIOME BY FECAL TRANSPLANT
GA VAJ.
WE GAVE THEM A STROKE FIRST, WE
GAVE THEM ANTIBIOTICS, WE HAD
THE APPROPRIATE ANTIBIOTIC
CONTROLS, AND THEN WE DID A
FECAL TRANSPLANT GAVAGE AND SACK
SACRIFICED THEM.
AS YOU CAN SEE HERE, THEY HAD
MUCH BETTER REGAIN OF WEIGHT,
THEY HAD BETTER MOTOR ACTIVITY
IN THE OPEN FIELD.
THEY HAD BETTER COGNITION IN THE
NOVEL OBJECT RECOGNITION, AND
THEY HAD A DOO CRE DECREASE IN
DEPRESSIVE-TYPE BEHAVIOR.
NOW, DO WE NEED TO USE A FECAL
TRANSPLANT.
WHAT IS THE BIOME DRIVING THIS
BENEFICIAL EFFECT?
SO WE REALLY FOCUSED INITIALLY
ON SHORT CHAIN FATTY ACIDS.
THEIR END PRODUCTS OF
FERMENTATION OF DIETARY FIBERS
BY THE MICROBIOTA.
WE KNOW THAT THEY MAINTAIN AND
ENHANCE GUT HEALTH, THEY ENHANCE
GUT BARRIER MUCOUS BARRIER
FUNCTION, IT REDUCES
INFLAMMATION, IT HAS POTENT
ANTI-INFLAMMATORY EFFECTS BOTH
ON THE PERIPHERAL IMMUNE
COMPARTMENT AND THE CNS IMMUNE
COMPARTMENT IN THE MICROGLIA,
AND WE THINK THEY'RE LIKELY,
EVEN MORE IMPORTANT THAN THE
BACTERIA, IT'S NOT THE BACTERIA,
IT'S WHAT THEY'RE PRODUCING.
SO WE LOOKED AT SHORT CHAIN AND
FATTY ACID LEVELS BY
METABOLOMICS AND YOU CAN SEE
HERE THE YOUNG BIOME IS VERY,
VERY ENRICHED IN THESE SHORT
CHAIN FATTY ACIDS AND THIS BOTH
IN -- CONTENT AND FECAL SAMPLES
AND THE AGED BIOME, YOU LOSE
THOSE SHORT CHAIN FATTY ACIDS.
SO WHAT WE WANTED TO DO THEN IS,
WELL, IF THE SHORT CHAIN FATTY
ACIDS OR THE METABOLITES ARE
MEDIATING THE EFFECT, CAN WE
REFINE OUR THERAPY?
ONE OF THE ISSUES WITH GIVING A
FECAL TRANSPLANT IS YOU
TRANSPLANT NOT ONLY BACTERIA BUT
POTENTIALLY VIRUS, FUNGUS AND
OTHER DETRIMENTAL THINGS.
SO WE DECIDED TO GIVE AGED
STROKE MICE, THIS IS THE SAME
DESIGN AS BEFORE WHERE THEY GOT
TREATMENT AFTER STROKE, WELL
AFTER THE STROKE WAS
HISTOLOGICALLY COMPLETE, WE GAVE
THEM A STROKE, GAVE THEM
ANTIBIOTICS AND THEN WE GAVAGED
THEM WITH A COCKTAIL OF SHORT
CHAIN FATTY ACID PRODUCING
BACTERIA.
VERY IMPORTANTLY, WE GOT VERY
LUCKY, A VERY CLEVER POSTDOC IN
THE LAB SAID SHOULDN'T WE GIVE
THEM SOMETHING TO EAT?
SO WE GAVE THEM A PREBIOTIC
KNOWN AS INNULIN, THAT WAS
IMPORTANT.
WHAT WE FIRST DID IS WE WANTED
TO SHOW THAT WE COULD INCREASE
SHORT CHAIN FATTY ACIDS, AND YOU
CAN SEE IN THE BLUE IS A VEHICLE
TREATED MOUSE OR MOUSE TREATED
WITHOUT THE ACTIVE METABOLITE,
AND BY GIVING THIS METABOLIC
COCKTAIL, WE WERE -- THIS
COCKTAIL OF BACTERIA THAT
PRODUCED THESE METABOLITES, WE
WERE ABLE TO REALLY INCREASE THE
SHORT CHAIN FATTY ACIDS.
SO IT WAS A COCKTAIL OF FOUR OR
FIVE SHORT CHAIN FATTY ACID
PRODUCING BACTERIA.
WE COULD INCREASE IT NOT JUST IN
THE GUT, BUT ALSO IN THE BRAIN.
>> DOCTOR, YOU HAVE TWO MINUTES
REMAINING.
>> MM-HMM.
AND THAT WAS ENOUGH TO IMPROVE
OUTCOMES, SUGGESTING YOU DON'T
NEED THE WHOLE FECAL TRANSPLANT.
TRANSLATIONALLY THIS WAS
IMPORTANT BECAUSE WE DID MA
TABLEAU MIX IN OUR STROKE
PATIENTS.
YOU CAN SEE THEY COMPLETELY
DROPPED 24 HOURS AFTER STROKE
SUGGESTING THERE MAY BE A WINDOW
OF INTERVENTION WHERE WE CAN
GIVE THESE BENEFICIAL METABO
METABOLITES.
I'M GOING TO GO THROUGH THIS
SECTION REALLY QUICKLY.
TRYPTOPHAN IS ANOTHER METABOLITE
WE'RE LOOKING AT.
INTERESTINGLY IT CAN BE MICRO
BIOTA OR HOST DERIVED.
THEY PRODUCED INDOLES WHICH WE
THINK ARE BENEFICIAL.
SO WHICH METABOLITES ARE -- WE
FOUND SOME OF THESE INDOLES, WE
DON'T MAKE THEM.
IN A GERM FREE MOUSE WITHOUT A
BIOME, NO INDOLES.
WE THEN GAVE SUPPLEMENTAL
INDOLES AFTER WE SAW THAT INDOLE
PRODUCING BACTERIA WERE
DECREASED WITH AGING, WE THEN
DID THE SAME THING AS WE DID IN
SHORT CHAIN FATTY ACIDS AND WE
FOUND THAT GIVING EXOGENOUS
INDOLES IMPROVED STROKE IN BOTH
WILD TYPE AND GERM-FREE MICE.
AND THIS IS NOT JUST STROKE.
IF YOU LOOK AT GERM-FREE MICE
AND YOU RECOLONIZE THEM WITH
EITHER YOUNG OR AGED MICROBIOME,
ANIMALS, THE GERM-FREE ANIMALS
THAT GET AN OLD BIOME DEVELOP
MEMORY IMPAIRMENT AND DEPRESSIVE
PHENOTYPES.
THE LAST TWO SLIDES ARE BECAUSE
OF S SOMETHING THAT I FOUND VERY
INTRIGUING TODAY, WHEN DOES
AGING BEGIN?
AGING BEGINS I GUESS AT
CONCEPTION OR PRECONCEPTION IF
YOU HAVE EPIGENETIC CHANGES IN
THE SPERM OR THE EGG, BUT
BECAUSE THE BIOME IS MATERNALLY
DERIVED AND ADVANCED MATERNAL
AGE IS BECOMING VERY, VERY
PREVALENT AND IT'S A MAJOR RISK
FACTOR FOR STROKE, WE
RECOLONIZED YOUNG FEMALE MICE
WITH EITHER YOUNG OR AGED BIOME,
AND WE FOUND A TREMENDOUS LOSS
IN FERTILITY AND PECUNDITY AND
WE FOUND A LARGE NUMBER OF
UNBORN PUPS, SO THESE ARE YOUNG
FEMALE MICE, GIVEN AGED BIOME
AND THEY LOSE PUPS.
WHAT'S INTERESTING IS WE LET
THESE ANIMALS AGE AND THESE
CHANGES IN THE BIOME THAT WERE
INDUCED BY GIVING AN AGED BIOME
CONTINUED INTO MIDDLE ADULTHOOD,
THEY CONTINUED TO HAVE
DYSBIOSIS, AND THIS WAS WORSE IN
MALE MICE, AND IT CAUSED A
METABOLIC PHENOTYPE.
THE ANIMALS THAT WERE BORN OF
DYSBIOTIC MOMS HAD A HIGHER
WEIGHTS, HAD METABOLIC FEATURES
AND GLUCOSE SENSITIVITY.
YOU CAN SEE THEY ALSO HAD
CHANGES IN BEHAVIOR, AND THIS
WAS MUCH MORE PRONOUNCED IN
MALES.
AND THOSE WERE THE ONES WHERE WE
REALLY FOUND THE MOST CHANGES IN
THEIR BIOME.
SO JUST TO SUMMARIZE AGING AND
STROKE LEAD TO SIGNIFICANT
DYSBIOSIS.
THIS LEADS TO A LOSS OF
BOTTOMS-UP SIGNALING FROM THE
GUT TO THE BRAIN.
WE THINK IT MIGHT BE MEDIATED BY
VAGAL NERVE FUNCTION.
ALTERING THE MICROBIOME CAN
REDUCE MICROGLIAL ACTIVATION AND
IMPROVE OUTCOME.
YOU CAN ENHANCE THE COMPOSITION
OF THE MICROBIOME TO GIVE
BENEFICIAL BACTERIA WHICH THEN
PRODUCE BENEFICIAL METABOLITES,
AND THE BIOME IS MALLEABLE.
JUST WANTED TO GIVE A SHOUT OUT
TO EVERYONE IN MY LAB WHO'S BEEN
VERY INVOLVED IN THESE STUDIES
OVER THE PAST DECADE, AND I HAVE
A COUPLE POINTS BUT I WILL SAVE
THEM FOR THE DISCUSSION ABOUT
KEY GAPS AND STRATEGIES THAT WE
WILL NEED FOR THE NEXT FIVE
YEARS.
SO THANK YOU VERY MUCH FOR
LISTENING, AND SORRY TO GO OUT
OF ORDER.
>> THANK YOU VERY MUCH FOR THAT
EXCELLENT TALK.
WE HAVE ONE QUESTION FOR YOU.
SO WHAT KIND OF DIET CHOW WERE
THESE MICE ON, AND WERE THEY
[INAUDIBLE]
>> THAT'S A GREAT QUESTION.
THEY'RE ON STANDARD LAB CHOW BUT
ALSO WHEN WE DO OUR INDOLE
STUDIES, WE'LL DO A RADIATED
CHOW LIKE WE USE FOR GERM-FREE
MICE.
THEY WERE XPF MICE BUT WE ALSO
HAVE SOME STUDIES THAT WE'VE
ALSO DONE IN GERM-FREE MICE.
AND AGAIN, HEARING THE EARLIER
TALKS ABOUT WILD CAUGHT VERSUS
WILD TYPE, AND THE HEPATIC VIRUS
CAN BE REALLY DEVASTATING FOR A
COLONY, THESE ARE PROBABLY NOT
COMPLETELY NORMAL MICE AND
INDEED THE MICE THAT WE GET FROM
THE NIA INTERESTINGLY WHICH HAVE
A SLIGHTLY DIFFERENT DIET HAVE A
BETTER AGING PHENOTYPE.
THEY ARE LESS FAT AND FASTER
THAN SOME OF THE MICE THAT WE
BREED IN-HOUSE, SO NOW WE DO
EVERYTHING IN-HOUSE.
TO CONTROL FOR THE DIETARY
FACTORS.
>> THANK YOU.
AND WE ARE ON TIME, AND WE HAVE
PATTI LEE JOINED US SO THAT'S
GREAT.
SO SHE'S PREPARING FOR HER TALK.
OKAY, WE CAN SEE THE SLIDES.
THE TOUTLE OF THE TALK IS
ENVIRONMENTAL DETERMINANTS AND
MODELS OF LUNG-VASCULAR
SENESCENCE.
GO AHEAD.
I THINK YOU'RE MUTED.
>> IT LOOKS LIKE YOU'RE UNMUTED
ON YOUR MONITOR BUT WE CAN'T
HEAR YOU.
IS YOUR VOLUME UP?
I KIND OF HEAR A SOFT BEEP.
NOW YOU'RE ECHOING.
>> THIS IS MY BACKUP.
>> GOOD JOB!
THAT ONE SOUNDS GOOD.
HOW'S THAT?
>> YEP.
>> THIS IS GOOD?
>> YES, WE CAN HEAR YOU.
GO AHEAD.
>> I'LL HAVE TO SPEAK EXTRA
FAST.
HOW IS THE SLIDES?
>> WE CAN'T SEE YOUR
PRESENTATION.
I THINK YOUR SETTING WINDOW IS
UP.
>> IT LOOKS LIKE YOU HAVE TWO
COMPUTERS SO I'M HOPING THAT
THERE WILL BE NO ECHO.
>> HOW IS THIS?
>> PRESENTER MODE, AND THAT
SHOULD BE GOOD TO GO.
>> IF YOU SELECT THE TAB WHERE
IT SAYS "SLIDE," ON YOUR
POWERPOINT, IT SHOULD PUT YOU IN
WHERE YOU CAN SELECT PRESENTER
MODE.
WHERE IT SAYS SLIDE, YES.
SLIDESHOW.
WHERE IT SAYS SLIDESHOW.
>> THANK YOU FOR YOUR PATIENCE.
I THOUGHT I WOULD START WITH
TRYING TO COVER SOME OF THE KEY
GAPS.
THE FIRST IS CLINICALLY RELEVANT
SENESCENCE IN AGING MODELS WHICH
IS WHAT MY LAB PARTICULARLY
WORKS ON.
IDENTIFYING AND MEASURING TISSUE
SENESCENCE AT SINGLE KREND AND
SINGLE ORGAN LEVELS, AND THAT IS
WHAT -- I'M PART OF THE
CONSORTIUM TISSUE MAPPING CENTER
TO ACHIEVE NUMBER TWO.
THIRDLY ALSO RELEVANT TO WHAT MY
LAB SPECIFICALLY WORKS ON IS --
IN MORE OF A LUNG AND VAST CLA
TRI TARGETED MANNER.
I WON'T HAVE TIME TO GO INTO
PRIMARY DATA.
I HAVE TWO DATA SUMMARY SLIDES.
JUST TO GIVE A TASTE.
BUT THESE ARE THE THREE AREAS I
THOUGHT I WOULD ADDRESSED TO.
SO MY RESEARCH GROUP FOCUSES ON
AGE AND CIGARETTE SMOKING
RELATED EMPHYSEMA, WHICH IS
PROBABLY THE MOST LETHAL FORM OF
A DISEASE SYNDROME CALLED
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE OR COPD.
AND I INTENTIONALLY PUT MOST
LITERATURE, ESPECIALLY IN THE
PAST, KIND OF WHAT OUR MEDICAL
STUDENTS LEARNED, FOCUSES ON C
OMENT PD IN MEN, BUT I
INTENTIONALLY PUT WOMEN THERE
BECAUSE WOMEN ALSO DEVELOPED
SIGNIFICANT COPD, PROBABLY AT
AGES EARLIER THAN MOST OF OUR
MALE POPULATION, BUT IT LOOKS
DIFFERENT.
THE PHENOTYPICALLY CELLULARLY
MOLECULARLY IT TENDS TO BE
DIFFERENT.
I ALSO THINK THE
PHARMACOGENOMICS WILL SHOW THAT
WOMEN WILL RESPOND DIFFERENTLY
TO ANTI-COPD TREATMENTS OR
PREVENTIVES THAN MEN DO.
THAT'S PROBABLY A TOPIC FOR
ANOTHER SEPARATE TALK, BUT JUST
TO GIVE YOU SOME CONTEXT OF WHAT
WE'RE WORKING ON.
SO WHAT IS LONG AGING?
I THINK OF LONG AGING IN TERMS
OF CHRONOLOGY BUT ALSO THE
PHYSIOLOGY.
ON THE LEFT, STEVE HAD DEVELOPED
KIND OF WHAT I THINK IS STILL
QUITE ACCURATE OVER THE DECADES
OF WHAT HAPPENS TO LUNG FUNCTION
WITH AGE.
LIKE MOST ORGAN OR PHYSIOLOGIC
FUNCTIONS, LUNGS DO BECOME MORE
AND MORE TOWARDS THE DISABILITY
LINE WITH AGE, EVEN IF YOU'RE
NOT A SMOKER, AND THE PURPOSE OF
WHAT I SEE BEING THE MOST
POWERFUL IN LUNG
SENOTHERAPEUTICS WOULD BE TO TRY
TO SHIFT THE CURVES TO EITHER
SLOW DOWN THE DECLINE OR SHIFT
THE CURVE UP SO THAT LIMITATION
IS LESS WITH LUNG FUNCTION.
THEN A VERY GOOD COLLEAGUE OF
MINE WHO HAPPENED TO BE DOUBLE
TRAINED IN BOTH GERIATRICS AND
PULMONOLOGY HAS PUBLISHED REALLY
WHAT I THINK WERE SOME OF THE
SEMINAL CLINICAL PAPERS SHOWING
THAT LUNG FUNCTION INDEPENDENT
OF SMOKING OR OTHER
ENVIRONMENTAL RISK FACTORS SUCH
AS FLY ASH OR INDOOR COOKING
EXPOSURE, THAT HAPPENS MOSTLY
GLOBALLY, THAT LUNG FUNCTION --
A DECLINE IN LUNG FUNCTION IN
AND OF ITSELF CAN BE PREDICTIVE
OF SIGNIFICANT MORBIDITY AND
MORTALITY AND THAT'S PROBABLY
BECAUSE LUNG FUNCTION IS A
FAIRLY GOOD READOUT FOR
INTEGRATED OR MULTISYSTEM AREAS
THAT I'VE LISTED HERE.
I DEVELOPED THIS PICTORIAL BASED
ON A FEW OTHER PUBLICATIONS AND
IN THE LUNGS AT LEAST WHERE
THERE'S OVER 55 INDIVIDUAL CELL
TYPES.
I MEAN, QUITE PHENOTYPICALLY
MORPHOLOGICALLY DIFFERENT CELL
TYPES IN THE LUNG.
LOCATION IS KEY.
IT IS ALL ABOUT LOCATION IN
TERMS OF DYSFUNCTIONAL AGING, IN
TERMS OF ENVIRONMENTAL RESPONSES
TO INHALED TOXINS AS WELL AS
CIRCULATING TOXINS, LUNG IS
PROBABLY THE SECOND MOST
VASCULAR ORGAN IN THE HUMAN
BODY, SO IT HAS TO REALLY
INTEGRATE THE SIGNALS COMING
FROM THE ENVIRONMENT, THE AREA
AND FROM ITS CIRCULATION.
BUT ITS CONDUCTING ZONE, THE
RESPIRATORY ZONE AND THE AREA
THAT I WORK ON MOST WHICH IS
THESE ALVEOLAR SACS IS KIND OF
BUSINESS END, STROMAL CELLS,
FIBROBLASTS, MACROPHAGE,
RESIDENT MACROPHAGES AS WELL AS
THE MICRO CIRCULATION TO DO ITS
MAIN BUSINESS, AND ITS MAIN
BUSINESS IS GAS EXCHANGE.
GAS EXCHANGE AS WELL AS IMMUNE
FUNCTION.
THIS IS ANOTHER BLOWN UP
PICTORIAL OF WHAT HAPPENS WHEN
WE AGE YOU DON'T HAVE TO SMOKE
TO GO FROM A NORMAL ALVEOLUS
WHEN YOU'RE YOUTHFUL.
YOUR LUNG FUNCTION PROBABLY
PEAKS WHEN YOU'RE ABOUT 21,
BETWEEN 21 TO 25.
FROM THERE IT'S ALL ABOUT A LOSS
OF A 1 10 EE -- EQUIVALENT OF 10
CCs PER YEAR.
AS WE AGE WE ACTUALLY START
GETTING AN OBSTRUCTIVE PICTURE
BECAUSE OF A LOSS OF NORMAL ALAS
TIN.
THESE AIR SACS JUST BALLOON OUT,
THEY LOSE THEIR ABILITY TO HAVE
NORMAL GAS EXCHANGE AND THEIR
BLOOD DEVELOPS START BECOMING
EITHER -- THEY START GETTING
PRUNED AND/OR THE LARGER VESSELS
START GETTING REMODELED, ALMOST
A FIBROTIC PICTURE.
THIS, I ADAPTED FROM THE SUMMARY
PUBLICATION WHERE THERE'S BOTH
GENETIC AND VARIABILITY TALL
LUNG DETERMINANTS OF LUNG AGING.
AND AS EARLIER TALKS HAVE REALLY
KIND OF HIGHLIGHTED QUITE WELL,
PROBABLY THERE IS A
PREDISPOSITION AT THE GERMLINE
LEVEL, SO THERE'S PROBABLY
GENETIC COMPONENT TO HOW THE
LUNGS WILL REACT TO A VARIETY OF
ENVIRONMENTAL TOXINS, WHETHER
IT'S SMOKING, MICROBES, AIR
POLLUTION, OZONE, THAT WILL
MODIFY OR KIND OF COLOR, GIVE
DIFFERENT COLORS TO HOW THE
LUNGS ACTUALLY RESPOND TO THESE
ENVIRONMENTAL CHALLENGES AND
THAT'S WHERE EPIGENETICS COMES
IN.
THE EPIGENETICS, I ACTUALLY
BELIEVE THAT THERE'S PROBABLY A
PERMANENCE TO SOME OF THE
EPIGENETICS, BUT I ACTUALLY
BELIEVE THERE'S ALSO A
REVERSIBLE COMPONENT, AND THAT'S
SOMEWHAT SPECULATION BASED ON A
LITTLE BIT OF DATA, BUT THIS
EPIGENETICS WILL COLOR OUR
GENETIC PROGRAMMING TO DETERMINE
HOW THE LUNGS WILL REACT TO A
VARIETY OF ENVIRONMENTAL
CHALLENGES, WHETHER THAT IS THIS
OOBSTRUCTIVE PULMONARY LUNG
DISEASE I STUDY, WHETHER IT'S
ABNORMAL PROLIFERATION,
EFFICIENTLY TUMOR OR CANCER, OR
WHETHER IT'S THIS KIND OF
NON-MALIGNANT FIBROTIC
PHENOTYPE.
AGAIN JUST TO CLARIFY, I'M SURE
THIS GROUP KNOWS VERY WELL,
AGING IS NOT EQUIVALENT TO
SENESCENCE.
WHEN I REFER TO SENESCENCE, I
SEE IT MORE AS AN ASSOCIATED
CELL FATE DECISION OR CELL FATE
PROCESS IN AGING TISSUES.
AND SENESCENCE IS TYPICALLY
REALLY CLASSIFIED AS THE SECOND
DEPENDENT KINASE, JUST IN A
VERY, VERY RUDIMENTARY -- AT A
VERY RUDIMENTARY LEVEL.
WE OF COURSE KNOW IT'S MUCH MORE
COMPLEX THAN THIS.
AND AS A MATTER OF FACT, WE
PROBABLY DON'T HAVE A RELIABLE
OR WELL AGREED UPON SENESCENCE
BIOMARKERS, ESPECIALLY IN THE
LUNG.
THESE ARE ALL THE DIFFERENT
AREAS OF KIND OF TRIGGERS OF
SENESCENCE.
WE HEARD ABOUT DNA DAMAGE,
CERTAINLY MITOCHONDRIAL
DYSFUNCTION, EPIGENETICS AND OF
COURSE THE CLA C CLASSIC TELOMEE
EROSION.
BUT THESE ARE THE OUTPUTS, OTHER
THAN THE P16/19/21/53, USUALLY
AT THE LEVEL OF TRANSCRIPT, STEM
CELL EXHAUSTION, AND OF COURSE
INFLAMMATION OF AGING.
THIS IS JUST TO GIVE YOU A BRIEF
OVERVIEW OF WHAT SOME OF MY LAB
HAS BEEN WORKING ON FOR NOW
ABOUT A DECADE.
SO JIN, WHO'S GOING TO BE
JOINING ME IN SINAI SHORTLY, HAS
WORKED OUT REALLY WHAT LOOKS TO
BE A SYNERGISTIC KIND OF SIGNAL
TRANSDUCTION THAT HAPPENS WHEN
YOU STRESS LUNGS, ESPECIALLY THE
LUNG VASCULATURE, WITH EXPOSURE
TO CIGARETTE SMOKE OR WHAT I PUT
AS INTERNAL STRESSOR JUST FOR
CONVENIENCE BUT REALLY JUST KIND
OF THE CHRONOLOGY OF JUST AGING
OUR MICE OR LOOKING AT AGED
HUMAN LUNG TISSUES.
SHE'S BEEN ABLE TO MAP OUT A
REALLY IMPORTANT ROLE FOR THE
INNATE IMMUNE RECEPTOR PATHWAY
TLR4, AND THAT IN ITS USUAL
CANONICAL CLASSICAL
TLR4 SIGNALING, PLAYS A
HOMEOSTATIC ROLE IN PREVENTING
LUNG SENESCENCE, AND THESE ARE
JUST SOME OF THE EPIGENETIC AS
WELL AS SOME OF THE CELL TYPES
AFFECTED.
THE FINAL PHENOTYPE WE SEE WHEN
YOU HAVE AGE PLUS CIGARETTE
SMOKE, ESPECIALLY IN MURINE
MODELS, WE'VE USED GENETIC
MURINE MODELS AS WELL AS JUST
WILD TYPE AGING.
WHEN YOU HAVE THE SYNERGISTIC
EFFECT, YOU GET ACTUALLY A LOSS
OF NORMAL INNATE IMMUNE
SIGNALING VIA TLR4 THAT LEADS TO
EXTRUSION OF SENESCENCE,
SECRETED PROTEIN, MITOCHONDRIAL
DYSFUNCTION, WE GET A VERY
SPECIFIC CELL DEATH, IT'S NOT
APOPTOSIS, IT TENDS TO BE MORE
OF A NECROTIC CELL DEATH, AND
THEN EVENTUALLY WE GET A
PHENOTYPE OF EMPHYSEMA OR COPD
IN OUR MICE.
THIS IS ANOTHER PART OF MY LAB
WITH CLOSE COLLABORATIONS WITH
RICK BUCALA AND MAOR SAULER.
WE WERE ABLE TO IDENTIFY WHAT WE
BELIEVE TO BE A LUNG VASCULAR
RESILIENCY PATHWAY THAT IS
SLOWLY DEGRADED WITH EITHER AGE,
EXPOSURE TO TOBACCO SMOKE,
PNEUMOCOCCAL PNEUMONIA.
THIS PATHWAY IS A MIF
CD74 PATHWAY.
WE HAVE HUMANIZED MICE THAT CAN
ACTUALLY MIMIC THE MIF GENETICS
THAT WE FIND IN PEOPLE, AND WE
FIND THAT THIS MIF C
CD74 SIGNALING PATHWAY IS
CRUCIAL FOR THE ABILITY OF THE
LUNGS TO WITHSTAND CIGARETTE
SMOKE OR PNEUMONIA AND EVEN AGE.
THIS IS SOME OF THE EXPERIMENTAL
MODELING THAT WE DO.
WE USE A VARIETY OF DNA TOXIC
DNAED INTERP LAY TORES OR
DAMAGERS.
WE'VE USED RADIATION CIGARETTE
SMOKE CLEARLY, JUST NORMAL
BILATERAL -- AND WE STARTED
TESTING SOME THERAPEUTICS TO SEE
IF WE CAN BRING ON SENESCENCE IN
LUNG CELLS, AND THEN WE TAKE IT
IN VIVO.
AND THEN WE GET HUMAN LUNG
EX-PLANTS OR HUMAN LUNG DONOR
SAMPLES TO CREATE ORGANOIDs.
AS WELL AS WHAT WE'RE WORKING ON
NOW, AN ALVEOLAR SPHERE WITH A
VESSEL TO TEST SOME OF OUR SINO
TRIGGERS.
THIS IS JUST A BLOWUP OF
ALVEOLUS WITH THE MICRO
CIRCULATION HERE AND A THEN
LISTING WHAT'S BEEN PUBLISHED
AND WHAT WE TRIED TO ASSAY IN
THE VARIOUS CELL COMPARTMENTS OF
THIS ALVEOLUS FOR SENESCENCE.
AGAIN THIS IS JUST ANOTHER WAY
TO LOOK AT SOME OF THE -- I
GUESS THE ARCHITECTURE OF WHAT
WE'RE LOOKING AT WHEN WE CREATE
THESE 3D ALVEOLUSPHERES.
THE ALVEOLAR STEM CELLS AS WELL
AS THE ENDOTHELIAL CELLS ARE
KEY, BUT THERE'S A COMPLEX 3D
STRUCTURE THAT WE HAVE NOT
REALLY QUITE RECAPITULATED VERY
WELL IN A 3D ORGANOID, BUT THAT
IS A PLAN FOR THE FUTURE.
AND THESE ARE SOME OF THE
SENESCENCE MARKERS.
MARKERS THAT WE
ASSESS.
SO I TOLD YOU VERY BRIEFLY ABOUT
IT. LR4, MIF, THESE IMMUNE MADE
LAY TORES SENESCENCE.
I THINK THERE ARE POTENTIAL
OPPORTUNITIES FOR SENO
THERAPEUTIC, BUT OF COURSE THERE
ARE A VARIETY OF OTHER
CATEGORIES OF SENOTHERAPEUTICS
THAT HAVE BEEN PUBLISHED BY
PEOPLE WITHIN THIS GROUP AS WELL
AS THE JUDY CAMPISI GROUP.
AND WHAT WE'RE DOING IS PART OF
TAS PART OFMY SINAI INITIATIVE E
HELP OF OUR CONSORTIUM WHERE WE
ARE SAMPLING A VARIETY OF HUMAN
LUNG AS WELL AS HUMAN COLON
SAMPLES ACROSS THE AGE, COLON IS
18 TO OVER 65, LUNG, WE CAN
ACCESS FROM FETAL, FROM
UNFORTUNATE FETAL DEMICE BUT
OSTENSIBLY OTHERWISE NORMAL IN
THE LUNG TO OTHER 90.
>> DOCTOR, YOU HAVE TWO MINUTES
REMAINING.
>> THIS IS THE TRAJECTORY OF
WHAT I SEE HAPPENING ONCE WE
HAVE OUR DATASETS FOR HUMAN
TISSUE ACQUISITION FOR
SENESCENCE DETECTION.
IT'S REALLY GOING FROM OUR
PATIENTS IN PARTNERSHIP WITH OUR
CLINICIANS, OUR RESEARCHERS,
TRANSLATIONALLISTS AND OF COURSE
OUR EXPERIMENTALISTS.
AND BE ABLE TO INTEGRATE
CLINICAL AS WELL AS
TRANSLATIONAL AND BASIC SCIENCE
DATA TO MAKE SOME INRHODES AS TO
ROADS AS TOWHAT ARE THE SENESCET
BIOMARKERS IN LUNG TISSUE AND
COLON, AND WHAT ARE SOME OF THE
INTERVENTIONS OR THERAPEUTICS
THAT CAN BE DEVELOPED BASED ON
THE DATA.
THIS IS MADE POSSIBLE BY THE
FACT THAT I WAS FORTUNATE ENOUGH
TO BE ABLE TO GET A TISSUE
MAPPING CENTER FUNDED WHILE I
WAS AT DUKE.
IT HAS NOW EXTENDED TO MOUNT
SINAI AND THEN THESE ARE ALL THE
OTHER CENTERS INVOLVED.
THE GREEN ARE THE TISSUE MAPPING
CENTERS.
THERE ARE EIGHT OF THEM.
THERE ARE ALSO EIGHT IN KIND OF
THE BROWN TECHNOLOGY DEVELOPMENT
AWARDS, AND THEN OF COURSE THERE
ARE DATA COORDINATING CENTERS,
THE KODAK IN THE PURPLE, AND
INTERNATIONAL COLLABORATORS AS
WELL AS THE NATIONALLY BASED
COLLABORATORS.
I'D LIKE TO THANK THE NIH, THE
NCI, FOR THIS OPPORTUNITY TO
SHOW YOU SOME OF THE THINGS
WE'RE DOING.
>> THANK YOU SO MUCH.
>> GO AHEAD.
I THINK WE MOVE RIGHT INTO THE
PANEL DISCUSSION.
>> YES, THAT'S THE TIME, YEAH.
WE ARE.
EXACTLY ON TIME FOR THAT AND WE
CAN TAKE ALL THE QUESTIONS
INCLUDING QUESTIONS FOR OUR LAST
SPEAKER, DR. LEE, DURING THE
PANEL DISCUSSION.
>> OKAY.
SO IF ALL THE SPEAKERS FROM THIS
LAST MAMMOTH MARATHON SESSION
CAN HOP ON AND HOPEFULLY PEOPLE
CAN JUST UNMUTE, THEY CAN SEND
TO EVERYONE IN THE ZOOM QUESTION
AND ANSWER FUNCTION, AND WE WILL
ADDRESS THEM IN TURN.
THERE WERE SOME QUESTIONS
EARLIER FOR BOTH DR. ROBBINS AND
DR. KIRKLAND, WHO'S HANGING IN
THERE DESPITE BEING IN HOLLAND.
SO THANK YOU AGAIN FOR REJOINING
US, DR. KIRKLAND.
IF PEOPLE HAVE QUESTIONS, THEY
CAN EITHER SEND THEM TO THE CHAT
FUNCTION OR JUST SIMPLY UNMUTE
AND ASK AND I WILL BE QUIET AND
SEE IF PEOPLE WANT TO ASK SOME
QUESTIONS.
>> WELL, I COULD GET STARTED ON
THAT.
ON THE LAST TALK, DR. LEE
BROUGHT ME BACK TO MY PREVIOUS
LIFE, WHERE I STARTED MY
RESEARCH CAREER ON FETAL --
MATURITY AND LUNG SURFACTANTS,
AND THEN MOVING ON TO LUNG
CANCER AND MESOTHELIOMA.
SO IT ALL STARTED WITH TYPE
2 CELLS AND FETAL LUNG MATURITY.
SO I WAS JUST WONDERING,
SURFACTANT PROTEINS, DO THEY
TAKE ANY PART IN THE
CARCINOGENESIS EFFECT IN TERMS
OF WHAT WE USED TO CALL --
MALIGNANCIES?
BECAUSE ALL THE EXPOSOMES AFFECT
LUNG AS WELL AS OUR DIGESTIVE
SYSTEM.
HAVING SOME -- AS YOU STARTED
WITH YOUR WOMEN CASES, SO IT'S A
MYSTERY AS TO WHY NON-SMOKER
FEMALES TEND TO GET LUNG CANCER.
>> THAT'S RIGHT, YEAH.
I THINK THAT'S A REALLY KEY -- I
THINK THOSE ARE REALLY
IMPORTANT, ESPECIALLY BECAUSE WE
DON'T HAVE A GREAT
UNDERSTANDING, ALTHOUGH I THINK
IT'S KEY, JUST AS THE RECURRING
THEME IS, WHICH IS THE
TRAJECTORY FROM DEVELOPMENT, I
THINK WE HAVE TO GO ON TO
DEVELOPMENT ALL THE WAY INTO
OLDER AGE, AND SURFACTANT
PROTEINS, WE DON'T HAVE A LOT OF
DATA AS TO SURFACTANT PROTEIN
AND ITS ROLE IN SENESCENCE OR
LUNG AGING, PER SE.
BUT MY CO P.I. ON THIS
SENESCENCE WORK IS ACTUALLY A
SURFACTANT PERSON.
SHE STUDIES SPECIFICALLY
SURFACTANT PROTEIN A, AND SHE --
FOR ANTI-INFLAMMATORY EFFECTS,
SO THERE MAY BE, WE'LL PROBABLY
BE ABLE TO GENERATE THAT DATA
AND FIND OUT WHAT ITS ROLE IS IN
LUNG AGING AND SPECIFICALLY IN
SENESCENCE.
AND THIS ARROW DIGESTIVE, I
THINK IT'S KEY.
OTHER THAN THE MICROBIOTA WHICH
IS CRITICAL, THERE'S SIGNIFICANT
AMOUNTS OF AERO DIGESTIVE KIND
OF BIOCHEMICAL CHANGES HAPPENING
BECAUSE WE'RE CONSTANTLY
ASPIRATING, WE CONSTANTLY BRING
OUR MOUTH, NASAL AND G.I.
CONTENTS INTO OUR AIRWAYS.
THAT'S PART OF NORMAL BIOLOGY.
IT'S JUST AS WE GET OLDER, IT
HAPPENS MORE FREQUENTLY AT
LARGER VOLUMES, SO IT'S ACTUALLY
CHANGING THE MICROENVIRONMENT OF
OUR AIRWAYS.
>> I THINK AS A FOLLOW-UP ON
THAT, BECAUSE THERE'S A LONG
LATENCY PERIOD OF DEVELOPING
MESOTHELIOMA AND LUNG CANCER.
IT TAKES 40 YEARS FOR CHILDREN
WHO MIGHT HAVE GOTTEN EXPOSED TO
ASBESTOS AND LONG LATENCY PERIOD
OF 40 YEARS, WE SEE THE
DEVELOPMENT OF MESOTHELIOMA.
AND DEPENDING UPON THE EXPOSURE
OF ASBESTOS, WHETHER IT WAS
INHALED INTO LUNG, VERSUS
DIGESTIVE SYSTEM, YOU GET
PERITONEAL OR PERIPHERAL
MESOTHELIOMA.
>> I THINK LAURA, YOU HAD A
QUESTION?
>> THANK YOU.
SHEILA, THIS IS A QUESTION FOR
YOU.
I WAS SURPRISED TO HEAR FROM OUR
COLLEAGUES IN THE CENTER FOR
IMMUNOLOGY THAT IMMUNE CELLS
DON'T ALWAYS HAVE RECEPTORS FOR
ALL OF THESE THINGS SPEWED OUT
FROM THEIR PARTNERS IN THE
IMMUNE SYSTEM, BUT ALSO FOR
SENESCENT CELLS.
HAVE YOU THOUGHT ABOUT LIKE
SURFACE RECEPTORS AND WHICH
CELLS TYCELLTYPES ARE GOING TO O
CERTAIN SIGNALS.
I FEEL LIKE WE CAN MAKE EDUCATED
GUESSES ABOUT THE BIOLOGY.
HAVE YOU THOUGHT WITH THAT OR
HAD THAT OPPORTUNITY?
>> ARE YOU REFERRING TO WHY IN
DIFFERENT TISSUES DIFFERENT
IMMUNE CELLS ARE RESPONDING?
IS THAT WHAT YOU'RE TRYING TO
GET AT?
>> YEAH, I MEAN, -- I MEAN, THES
PROBABLY.
WHAT I CAN TELL YOU, WHAT WE'VE
DONE TENDS TO BE MORE CYTOKINES,
AS FAR AS WHAT WE'VE
SPECIFICALLY LOOKED AT.
BUT CLEARLY YOU GET DOWN
REGULATION, UPREGULATION OF -- I
THINK IT'S LIKELY TO BE A
COMBINATION OF BOTH SECRETED
FACTORS AS WELL AS ALL SURFACE
MARKERS.
>> OKAY, THANK YOU.
I WOULD JUST ADD TOO, I THINK WE
SHOULD MENT MENTION -- SENESCENT
CELLS CAN ALTER THEIR SURFASOME
AS WELL SO IT REALLY TRICKY.
>> I BELIEVE DR. ROBBINS HAD A
QUESTION?
>> ACTUALLY A QUESTION FOR YOU.
MICROBIOME AND STROKE, SO
ACTUALLY TWO QUESTIONS.
SO WE PUBLISH IN COLLABORATION
WITH -- MASTERMACK AND JIM
KIRKLAND AND LAURA A WHILE BACK
SHOWING -- CHANGED THE GUT
MICROBIOME.
I'VE BEEN ALWAYS ASKED DOES THE
GUT MICROBIOME INFLUENCE
SENESCENCE.
I WAS WONDERING IF YOU'VE LOOKED
AT THAT, AND THEN ALSO IF YOU
LOOKED AT SENESCENCE IN YOUR
AGED STROKE OR MICE -- OLDER
MICE WITH STROKE.
>> YES AND THERE'S ACTUALLY
SOMEBODY IN THE LAB DOING BOTH A
CHRONIC STROKE AND A TBI WITH
SENOLYTICS AS WELL, BUT IT'S
VERY INTERESTING BECAUSE IF YOU
GIVE THIS AGED BIOME AND YOU CAN
SHOW EVEN WHEN WE DID IT EVEN
WITHOUT STROKE, YOU FOLLOW THE
AB MALLS FOR A MONTH, THE
ANIMALS THAT HAVE THE AGE
DYSBIOTIC BIOME NOT ONLY HAVE
CONTINUED CHANGES BASED BOTH ON
SHOTGUN SEQUENCING AND CHANGES
IN THEIR METABOLIC PROFILE.
THE GUT ITSELF LOOKS VERY
DIFFERENT AND LOOKS AGED.
THERE'S A LOT OF INFLAMMATION IN
THE LAMINA PROPRIA, THERE'S A
TREMENDOUS AMOUNT OF IMMUNE
CELLS IN THE GUT, AND WE FOUND
THAT THOSE IMMUNE CELLS CAN
ACTUALLY TRAFFIC TO THE BRAIN AS
OTHERS HAVE SHOWN, SO WE SEE
THESE GAMMA-DELTA T-CELLS WHICH
ARE KIND OF A BRIDGE BETWEEN
ADAPTIVE AND INNATE IMMUNITY,
THEY CHANGE WITH THESE GUT
MANIPULATIONS, AND THEN THOSE
CAN TRAP TO THE BRAIN AND I
DIDN'T SHOW ANY OF THIS DATA
BECAUSE IT WAS A SHORT TALK, BUT
WE FOUND CHANGES IN MOSTLY
T-CELL POPULATIONS, T REGS AND
GAMMA-DELTA T-CELLS, AND ONE OF
THE OTHER THINGS WE'VE SEEN IN
THE BRAIN WITH AGING, THIS IS
NOT WITH STROKE, BUT IN ANIMAL
MODELS OF ALZHEIMER'S AND EVEN
IN OUR HUMAN, WE HAVE A LARGE
HUMAN BRAIN BANK SO WE DO A LOT
OF MICROGLIA ASSESSMENT IN THESE
AGED HUMAN BRAINS AS WELL.
AND WE'VE FOWNDZ THERE'S THESE
REALLY PRONOUNCED PRO
INFLAMMATORY CHANGES OVER THE
LIFE THAT SEEM TO GET
ACCELERATED WITH ANY TYPE OF
INJURY, WHETHER IT'S A TBI, A
STROKE, IT REALLY SEEMS TO
ACCELERATE THE SENESCENCE THAT
YOU SEE THAT'S KIND OF THAT
BASAL INFLAMMAGING, YOU GIVE IT
AN INSULT AND KIND OF THE GATES
OPEN.
AND WITH AGING IN THE BRAIN, YOU
SEE A LOT MORE T AND B CELLS.
WE THINK THE B CELLS ARE VERY
IMPORTANT FOR COGNITION, WE ALSO
SAW -- COVID THAT HAVE COGNITIVE
IMPAIRTS SO WE THINK THOSE B
CELLS MAY BE DOING SOMETHING.
SO RIGHT NOW WE'RE DEPLETING THE
B CELLS USING A FEW DIFFERENT
MODELS.
B CELL DEPLETION THERAPIES ARE
AVAILABLE BECAUSE OF MULTIPLE
SCLEROSIS AND OTHER AUTOIMMUNE
DISEASES.
SO IT'S REALLY INTERESTING.
HAVEN'T PUT ALL THE DOTS
TOGETHER AND IT'S HARD TO KNOW
BECAUSE WITH THE BIOME, THAT'S
THE BOTTOMS-UP SIGNALING, THE
GUT TO THE BRAIN, BUT THE BRAIN
ALSO COMPLETELY CONTROLS THE
GUT.
YOU GIVE A STERILE STROKE INJURY
AND WITHIN SIX HOURS, THE GUT IS
DEVASTATED.
IT'S LEAKY, THE BACTERIA START
TO TRAFFIC IN, SO THAT'S GOT TO
BE -- IT COULD BE A HUMERAL
SIGNAL BUT WE THINK A LOT OF IT
IS MEDIATED BY THE VAGAL NERVE.
THE PROBLEM IS DOING VAGOTOMIES,
YOU HAVE TO DO SUBDIE A FRAG
MATIC, BUT WE'VE SHOWN A STROKE
ALSO REALLY SLOWS DOWN GUT
TRANSIT TIME.
AND THAT MAY ALLOW MORE OF THOSE
HARMFUL BACTERIA TO CROSS THIS
IMPAIRED BARRIER WITH AGING OR
WITH STROKE, AND THAT'S A BIG
COMPLAINT IN PATIENTS AS WELL.
ONE OF THE BIGGEST SYMPTOMS IS
CONS TA PAITION.
SO THEN THEY CAN GET THIS
BACTERIAL OVERGROWTH SYNDROME SO
WE THINK THE BRAIN CONTROLS THE
GUT MOTILITY AS WELL AND THEN
THE GUT FEEDS BACK TO THE BRAIN.
THERE'S ALSO A LIVER AND AN
ADIPOSE CONNECTION TOO.
SO IT'S ALL MORE COMPLICATED
THAN JUST ME KILLING OLD MICE.
LIKE, I KIND OF WENT DOWN THE
RABBIT HOLE, BUT IT'S VERY
INTERESTING AND PROBABLY ALSO
RELEVANT FOR ALZHEIMER'S
DISEASE, BECAUSE A LOT OF THESE
BACTERIA CAN PRODUCE THINGS
CALLED CURLIE WHICH ARE LIKE
SEEDS.
IN PARKINSON'S YOU SEE
CONSTIPATION, THE ALPHA
SYNUCLEIN PROAT NOP THEE CAN
START IN THE GUT, BUT THEN
TRAVELED BY THE VAGAL NERVE OR
SOMEHOW GET ADDRESSING THE
QUESTION TO?
>> I'M FROM NATIONAL INSTITUTE
ON AGING.
HI, EVERYONE.
FANTASTIC TALKS.
SO QUESTION TO LOUISE.
SO WE PREVIOUSLY REPORTED THAT
WHEN IN AGING, OF COURSE
DYSBIOSIS AND SO OH, WE F ON, WD
ONE INTERESTING MICROBE --
DECREASES IN AGING, BUT THE AG
WHAT -- PRIMARILY THROUGH
MONOCYTES, THEY WERE ACTIVATING
B CELLS.
AND SPEAKING ABOUT -- ACTUALLY
WE PUBLISHED LAST YEAR OR TWO
YEARS AGO NOW THAT B CELLS
ACTUALLY PLAY SIGNIFICANT ROLE
IN ALZHEIMER'S DISEASE IF YOU
REMOVE B CELLS, THEN ALZHEIMER'S
DISEASE STARTS PROGRESSING, SO
QUESTION FOR YOU IS THAT HAVE
YOU LOOKED TO -- BECAUSE --
ACTUALLY PROMOTES THE SURVIVAL
OF SHORT CHAIN PRODUCER
MICROBES.
>> IT'S A HUGE TARGET OF HOURS.
WOF OURS.WE'RE DOING A SUPPLEMEN
STUDY IN SOCIALLY ISOLATED
ANIMALS.
YOU GUYS HEARD THIS IS ANOTHER
AREA WE DO IN THE LAB, IS
LOOKING AT THE DETRIMENTAL
EFFECTS OF SOCIAL ISOLATION
WHICH ARE VERY BIOLOGICAL.
IT'S NOT EVEN LIKE COMPLIANCE.
IF YOU SEPARATE TWO C57 BLACK
MICE FOR TWO WEEKS, THEIR
STROKES ARE TWICE AS LARGE.
EVEN IF YOU SEPARATE THEM AFTER
STROKE, THEIR MORTALITY
INCREASES AND WE FOUND THAT WAS
LINKED TO METABOLIC DYSFUNCTION
AND A LOSS OF -- IT'S ALSO MUCUS
DEGRADER.
SO WE SMARTLY WE'RE LIKE OH,
LET'S GIVE SOMETHING, THERE'S
THIS THING CALLED KAMU KAMU
WHICH THEY USE IN SOUTH AMERICA,
IT'S LIKE A PRO LONGEVITY THING,
SO WE SAID LET'S GIVE TO OUR
AGED MICE AND SEE WHAT HAPPENS.
IT TURNS OUT IT CAUSED THIS
DRAMATIC BLOOM AND WE WERE DOING
16S SEQUENTIALLY, AND THE BLOOM
PRECEDED DEATH IN THE MICE.
SO YOU HAVE TO BE VERY CAUTIOUS
IS WE GOT IT BLOOM, IT ATE ALL
THE MUCOUS, AND THEN THE ANIMALS
ALL GOT SEPTIC AND DIED.
SO I THINK WHENEVER YOU
MANIPULATE THE BIOME, YOU HAVE
TO BE VERY CAUTIOUS BECAUSE
THERE'S SO MANY DOWNSTREAM
EFFECTS THAT WE'RE NOT REALLY
YOU AWARE.
BUT ACT MAN'S YA IS A REALLY
IMPORTANT TARGET FOR METABOLIC
PHENOTYPES AS WELL SO WE'LL SEE
HOW THAT NEW STUDY GOES, THEN
ALSO MAKING SURE YOU CAN DELIVER
EITHER THE BACTERIA OR THE
METABOLITES THAT THEY PRODUCE TO
THE RIGHT AREA OF THE GUT IS
GOING TO BE ANOTHER CHALLENGE.
BUT I ACTUALLY AM SENDING TO THE
NIA A WHOLE COHORT OF TWO TO
FOUR MONTH, 12 MONTH, 18 MONTH
AND 24 MONTH WILD TYPE AND
GERM-FREE MOUSE BRAINS TO DO
SOME SEQUENCING, SO MAYBE WE'LL
GET SOME IDEAS FROM THAT DATA.
PATTY, SORRY, GO AHEAD.
>> SORRY.
LOUISE, I THINK THAT REALLY GOES
TO THE ENTIRE CONCEPT OF IS
AGING OR AT LEAST DYSFUNCTIONAL
AGING OR THE CHRONIC DISEASES
ASSOCIATED WITH AGING, REALLY
KIND OF THEMATICALLY LINKED BY
ENTROPY.
IT IS THIS INCREASING CHAOS OR
RANDOMNESS OR DISORDER AT LEAST
IN PHYSICS, BUT BIOLOGICALLY,
WHAT REALLY MAKES SENSE IS THAT
ENTRY INCREASES WITH TIME AND IN
ISOLATED SYSTEM.
SO IF YOU HAVE A MOUSE OR A
PERSON WHO IS ISOLATED AND WE
ALREADY KNOW FROM THE HARVARD
STUDY THAT SOCIAL ISOLATION IS
KIND OF ONE OF THE BIGGEST
PREDICTORS OF ACCELERATED
NEUROCOGNITIVE DECLINE AND
DEATH, THAT PERHAPS THAT'S WHERE
THERE'S SOME MECHANISM AS TO WHY
IS IT THAT SOCIAL ISOLATION FOR
A SINGLE -- BECAUSE WE ARE
SOCIAL BEINGS, WHY IS THIS
ISOLATION -- ALL THESE
DOWNSTREAM EFFECTS OF
NEUROCOGNITION, METABOLISM,
IMMUNE DEFICIENCIES, RIGHT?
>> I MEAN, IT'S FASCINATING.
SOCIAL ISOLATION AND THE
SUBJECTIVE FEELING OF LONELINESS
WHICH OF COURSE YOU CAN'T GET IN
ANIMAL MODELS BUT YOU CAN IN
HUMANS COMPLETELY CHANGES THE
BIOME.
WHEN WE GET FECAL SAMPLES FROM
OUR PATIENTS AS WELL AS --
SOCIAL NETWORK SCORES AND UCLA
SCORES AND THERE'S DEFINITELY A
PATHOGENIC SHIFT IF PEOPLE FEEL
OR REPORT LONELINESS.
I THINK IT'S KIND OF AN
OVERARCHING THING, BUT THE WHOLE
ISSUE IS WHAT DO THESE THINGS
MEAN.
ARE THE REASON WE HAVE SENESCENT
CELLS, DO WE HAVE TO HAVE
SENESCENT CELLS TO SURVIVE IN
PROBABLY NOT, LOOKING AT
DR. KIRKLAND'S AND DR. ROBBINS'
WORK, BUT IT'S INTERESTING
BECAUSE THE SYSTEM ALWAYS TRIES
TO MAINTAIN HOMEOSTASIS.
SO I'M JUST NOT SURE, BUT SOCIAL
ISOLATION DEFINITELY DISTURBING
HOMEOSTASIS, BOTH MICROGLIA GET
ACTIVATED, ALL THESE IMMUNE
CHANGES, HOW IT'S MEDIATED, I'M
NOT SURE, BUT IT DEFINITELY
CHANGES THE BIOME AS WELL.
>> -- JUST SAID YOU COULD
EXPERIMENTALLY REPRODUCE
ISOLATION.
>> AND THEY HAVE TO FEEL
SOCIALLY ISOLATED BECAUSE
PATIENTS, IF THEY DON'T FEEL
SOCIALLY ISOLATED, ARE NOT GOING
TO HAVE THAT DETRIMENTAL
PHENOTYPE.
THEY HAVE TO FEEL SUBJECTIVELY
LONELY OR DISCONNECTED.
LOTS OF PEOPLE LIVE ALONE AND
THEY'RE HAPPY TO LIVE ALONE.
SO THAT'S WHY YOU HAVE TO BE
PRETTY CAUTIOUS ABOUT USING LIKE
MARITAL STATUS OR -- BUT IT'S
SUPER BIOLOGICAL BECAUSE YOU CAN
RECAPITULATE IT IN ANIMALS THAT
ARE OF THE SAME GENETIC
BACKGROUND, FED THE SAME THING,
AND THEN THE OTHER THING IS,
WHEN YOU JUST ROOK LOOK AT MIC,
THERE'S BEEN QUESTIONS ABOUT THE
ACTUAL DIET AND THE SPF.
WHAT'S INTERESTING IS IF YOU
LOOK AT THE BIOME IN A TWO
MONTH, SIX MONTH, 18 MONTH, THE
BIOME CHANGES, NOTHING ELSE
CHANGES IN THESE ANIMALS,
THEY'RE STILL HOUSED THE SAME,
THEY'RE STILL FED THE SAME CHOW,
SO THERE'S GOT TO BE A HOST
FACTOR THAT ALLOWS THAT MORE
PATHOGENIC DYSBIOTIC BIOME TO
TAKE HOLD AND KIND OF CONTINUE.
SO IT CAN'T ALL BE JUST BIOME
DRIVEN.
THERE'S OBVIOUSLY HOST FACTORS
THAT ARE GOING TO ENRICH FOR
MORE PATHOGENIC BACTERIA.
OKAY.
SORRY I'M JUGGLING.
>> IT WAS A NICE SEGUE BECAUSE
COMING FROM THE CENTER TO REDUCE
CANCER AND HEALTH DISPARITIES,
SO WE HAVE TO LOOK INTO THE
RACIAL/ETHNIC DIVERSITY
PROPORTION AND THIS QUESTION IS
ESSENTIALLY FOR ALL THE
PANELISTS.
OF SO HAVE WE LOOKED INTO
VARIOUS ASPECTS OF BIOLOGICAL
VERSUS CHRONOLOGICAL AGING AMONG
VARIOUS RACIAL/ETHNIC GREUNS,
ANDGROUPS ANDDOES IT CORRELATE E
AGGRESSIVE EARLY ONSET DISEASES.
CANCER, WE SEE VERY AGGRESSIVE
PROSTATE CANCER AMONG AFRICAN
AMERICANS, THE INTENSITY, THE
PROGRESSION AND METASTASES
VARIES WITH THE VARIOUS RACIAL
AND ETHNIC POPULATION GROUPS.
IS IT TIED UP WITH SOCIAL
DETERMINANTS OF HEALTH?
DOES THE DIET, EXERCISE AND ALL
THOSE FACTORS AFFECT THE
CLINICAL MANIFESTATION OF
DISEASE AND CLINICAL OUTCOMES?
LONG WINDED QUESTION BUT PLEASE
PITCH IN, EVERYONE.
>> WELL, I WOULD JUMP IN AND SAY
THAT DEPENDING ON YOUR ZIP CODE,
YOU CAN BE MUCH BIOLOGICALLY
OLDER THAN OTHER GROUPS.
SO I HAVE HEARD FROM CLINICIANS
THAT YOUR ZIP CODE IS THE BEST
PREDICTOR OF HOW YOU'RE GOING TO
LIVE, BETTER THAN YOUR
HEMOGLOBIN A1C OR ANYTHING ELSE,
WHICH IS SHOCKING AND APPALLING
ACTUALLY.
>> ACTUALLY, LAURA, THERE'S DATA
TO SUPPORT THAT.
SO I RECENTLY -- I'M A
"NEW YORKER" FROM A LONG TIME
AGO BUT I WAS AWAY.
HAVING MOVED BACK TO NEW YORK,
THERE ARE THESE STUDIES, THESE
EPIDEMIOLOGIC STUDIES, PUBLIC
HEALTH AND EPIDEMIOLOGIC STUDIES
GOING ON LOOKING AT WHO THE
LONGEST LIVED ARE, IN WOMEN,
WITHIN WOMEN, AND IT WAS BY ZIP
CODE.
IT WAS BY ZIP CODE IN A VERY
SPECIFIC AREA IN NEW JERSEY OF
ALL PLACES.
IT WASN'T THE HAMPTONS, IT
WASN'T WESTCHESTER.
IT WAS NEW JERSEY.
SO THERE'S ACTUALLY DATA TO
SUPPORT THAT.
ANIL, I THINK YES TO ALL YOUR
QUESTIONS, ALL THOSE SOCIAL
DETERMINANTS OF HEALTH,
LIFESTYLE, I THINK THEY
ABSOLUTELY OVERRIDE SOME OF WHAT
WE UNDERSTAND AS BEING IMPORTANT
BIOLOGY.
IT'S JUST A MATTER OF HOW THEY
INTERACT AND HOW DO YOU START
TEASING APART WHAT THE RELATIVE
CONTRIBUTIONS ARE THAT IT GETS
VERY, VERY COMPLICATED.
BUT AGING AND HUMAN BIOLOGY IS
VERY COMPLICATED.
I THINK A BIG LIMITATION OF
THESE CLINICAL TRIALS WHICH ARE
REALLY IMPORTANT TO ANSWER SOME
OF THESE QUESTIONS IS A PROBLEM,
BECAUSE LESS THAN 5% OF AFRICAN
AMERICANS JOINED CLIN
SO WE HAVE TO IMPROVE
REPRESENTATION IN OUR CLINICAL
TRIALS.
ALZHEIMER'S, FOR EXAMPLE, IS A
MUCH MORE SIGNIFICANT DISEASE IN
WOMEN AND PEOPLE USED TO THINK
IT WAS JUST THEIR LONGEVITY.
BUT IT'S NOT.
AND STROKE IS ANOTHER EXAMPLE.
MOSTLY DRIVEN BY THE OLDER AGE
THAT WOMEN HAVE THEIR FIRST
STROKE, BUT I THINK IT'S VERY
IMPORTANT.
AND THE SOCIAL DETERMINANTS OF
HEALTH ARE VERY DIFFICULT TO
KIND OF UNRAVEL, AND THEY'RE
OBVIOUSLY HARDER TO MODEL IN
PRE-CLINICAL STUDIES.
I JUST WANTED TO ANSWER ONE
QUESTION BECAUSE THEY TEXTED ME
TO SAY, HAVE I INVESTIGATED
SHORT CHAIN FATTY ACIDS IN OTHER
SPECIES?
YES, INCLUDING HUMANS.
SO WE KNOW THAT SHORT CHAIN
FATTY ACIDS CHANGE IN HUMANS
AFTER STROKE.
WE'VE BEEN LOOKING AT INDOLES,
THOSE CHANGE, AND SOME OF THESE
CHANGE WITH OTHER
NEURODEGENERATIVE DISEASES, SO
YES, IT'S PROBABLY NOT JUST A
MOUSE THING.
SOME RUMINANTS LIKE WE WERE
USING A RABBIT MOTTLE, THAT'S
DIFFICMMODEL, THAT'SDIFFICULT W.
BUT THEY'RE PRI PRE TI SIMILAR
PATTERNS.
>> THERE IS ALSO A COMMENT FROM
DR. FERRUCCI, I CAN'T REMEMBER
WHAT TIME IT IS IN VENICE BUT
APPARENTLY HE'S ON.
>> AND ALSO MICHAEL SNYDER A --
HAD SOME GOOD COMMENTS.
>> I'M TRYING TO KEEP UP WITH
THE QUESTIONS.
>> I KNOW, IT'S HARD.
>> MICHAEL SNYDER SAID ONLY 16%
OF LONGEVITY IS EXPLAINED BY
GENETICS.
DO YOU WANT TO EXPOUND ON THAT,
DR. SNYDER?
>> SURE.
THERE'S A LOT OF TWIN STUDIES
OUT THERE THAT HAVE LOOKED AT --
I DON'T THINK THAT'S HEALTHSPAN,
I THINK THAT'S HOW LONG PEOPLE
LIVE.
BUT THAT'S BASICALLY WHERE THAT
NUMBER COMES FROM.
SO CLEARLY NON-GENETIC FACTORS
HAVE A BIGGER EFFECT THAN
GENETICS.
I'M CHAIR OF GENETICS TOO, SO I
CAN --
>> THAT'S SAYING SOMETHING.
YES, I MEAN, THOSE ENVIRONMENTAL
FACTORS AND OTHER -- YOU KNOW,
THE MULTIPLE HITS, AND THEN
DR. FERRUCCI SAID IN THE
AUDIENCE, ONE IMPORTANT DETAIL
SAID IN AGING, THE NORMAL
CONDITION IS ALLOSTASIS, NOT
HOMEOSTASIS, TOTALLY CORRECT,
WHICH IS THE FLUCTUATION WITHIN
SPECIFIC BOUNDARIES OF
VARIABILITY.
THERE'S EVIDENCE THAT
PSYCHOLOGICAL STRESS COMPRESSES
EMOTION AND IS ASSOCIATED WITH
REDUCED CAPACITY TO RESPOND TO
STRESS.
AND THAT IS TRUE, I DON'T KNOW
IF YOU GUYS ALL SAW THE SURGEON
GENERAL'S REPORT SAYING SOCIAL
ISOLATION WAS BECOMING A PUBLIC
HEALTH CRISIS, AND CAN AFFECT SO
MANY DIFFERENT ASPECTS OF OUR
HEALTH AND WE'RE BECOMING MORE
AND MORE SOCIALLY DISCONNECTED.
DR. FERRUCCI, I DON'T KNOW IF
YOU WANTED TO ADD ANYTHING ELSE?
SORRY, I'M TRYING TO KEEP UP.
>> I THINK HE TO DROP OFF.
>> OKAY.
>> SO DR. KIRKLAND HAS HIS HANDS
UP.
AND THEN WE CAN GO TO LAURA.
>> I JUST WANTED TO MAKE A
POLITICALLY INCORRECT STATEMENT,
BEYOND ZIP CODE, VOTING
PREFERENCES HAVE A MUCH STRONGER
INFLUENCE, ANYWHERE FROM 18.8 TO
19.2% YEARS' DIFFERENCE IN NEAR
MAXIMUM LIFE EXPECTANCY.
SO WHAT I'D ASK THE NIA IS
WHETHER THERE ARE GOING TO BE
COLONIES OF REPUBLICAN AND
DEMOCRATIC MICE.
[LAUGHTER]
>> IT DEPENDS ON THE SHUTDOWN
PROBABLY.
>> WE'RE NOT DOING THAT.
>> THERE WAS A COMMENT ABOUT
ZNA, ZIP CODE AND YOUR DNA.
SO KIND OF MULTI-PARAMETRIC
INDICES.
>> I THINK IT'S SUPER
INTERESTING BECAUSE THE
EPIGENETICS EFFECTS OF STRESS,
AND THAT'S THE ONLY REASON I PUT
IN THAT SMALL AMOUNT ABOUT HOW
THE MATERNAL BIOME MATTERS,
BECAUSE THESE ANIMALS THAT ARE
BORN OF THESE DYSBIOTIC MOMS
HAVE LONG LASTING CHANGES,
MIDDLE AGE, AND WE'RE NOW DOING
STROKES IN THEM AND THEY HAVE
INCREASED STROKE SENSITIVITY,
AND SO HOW IS THAT PUT FORWARD
AND IS THAT A PUBLIC HEALTH
ISSUE.
WE'RE SEEING INCREASE OF
DIABETES, OBESITY, HYPERTENSION,
ADVANCED MATERNAL AGE, IS THAT
AFFECTING THE NEXT YEAR -- WHEN
THEY GIVE BIRTH TO LOW BIRTH
WEIGHT CHILDREN BUT THOSE
CHILDREN WHEN THEY GROW TO
ADULTHOOD HAVE MUCH HIGHER RATES
OF CARDIOVASCULAR DISEASE,
DIABETES, OBESITY, SO THAT'S WHY
I WAS SHOUTING OUT, THAT
SOMETIMES AGING MAY BEGIN IN THE
WOMB OR AT CONCEPTION OR
PRECONCEPTION, SO IT'S JUST A
WAY OF THINKING ABOUT IT.
>> IT MAY 50 FOR GENERATIONS.
>> THEY'RE HERITABLE.
>> SO WE KNOW THAT FROM WARTIME
FAMINE, THAT IT'S LIKE -- IT
GOES -- THEY HAVE THESE MARKS,
THESE EPIGENETIC MARKS FROM THE
FAMINE THAT LASTS MULTIPLE
GENERATIONS.
>> AND THEY'RE INHERITED AND
THIS IS THE SAME WITH
PREECLAMPSIA OR HYPERTENSIVE
DISORDER OF PREGNANCY, THE MOM
HAS A FOUR FOLD INCREASED RISK
OF HYPERTENSION WHEN SHE'S IN
HER 50s AND A TWOFOLD INCREASE
RISK OF STROKE.
SO DOES THE CHILD, HAS A TWOFOLD
INCREASE RISK OF STROKE AND A
FOUR FOLD INCREASED RISK OF
HYPERTENSION AND IT'S NOT ALL
GENETIC BECAUSE A SIBLING BORN
TO THE SAME MOTHER WHEN SHE WAS
NOT PREEE CL PREECLAMPSIA IK DOT
HAVE THAT RISK AND THERE ARE
GENETIC MARKERS OF ADVANCED
SENESCENCE IN AGING.
CHRISTOPHER, YOU HAD A QUESTION?
>> I'D JUST LIKE TO MENTION THAT
PATTY HAD MENTIONED BEFORE IN
TERMS OF THE ZIP CODE IN
NEW YORK AND NEW JERSEY AND
THESE DIFFERENTIALS.
THE SAME THING ALSO EXISTS IN
THE CLEVELAND AREA.
CLINIC WE'RE LOCATED, IT'S
CALLED THE FAIRFAX NEIGHBORHOOD,
AND AVERAGE LIFE EXPECTANCY IN
THE NEIGHBORHOOD IS ONLY 65, AND
YOU GO 3 MILES EAST AND ANOTHER
SUBURB, LIFE EXPECTANCY IS 85.
SO EVEN WITHIN A 3-MILE RANGE,
YOU HAVE A 20-YEAR DIFFERENTIAL,
WHICH IS QUITE EXTREME.
WHAT'S ALSO REALLY INTERESTING
IS THAT I NEIGHBORHOOD WHERE ITS
85, IT'S NOT THE RICHEST
NEIGHBORHOOD.
IF YOU ACTUALLY GO TO THE
RICHEST NEIGHBORHOOD, IT
ACTUALLY DROPS BY ANOTHER FIVE
YEARS.
I THINK IT'S WHERE YOU GET TO
THAT SOCIAL ICIZATION, BIG
HOUSES, BIG YARDS, MAYBE YOU
HAVE THE STRESS OF A HUGE
MORTGAGE, YOU KNOW, THAT BRINGS
DOWN LIFE EXPECTANCY.
BUT I THINK DEFINITELY LIFESTYLE
IN THE ZIP CODE, YOU KNOW,
RELATED TO THE ZIP CODE
DEFINITELY IMPACTS LIFE
EXPECTANCY.
>> MAYBE THEIR SOCIAL
CONNECTEDNESS.
>> LAURA, PLEASE GO AHEAD.
YOU HAVE BEEN WAITING.
>> JUST A COUPLE OF QUICK
COMMENTS TO FOLLOW UP, PLEASE.
ONE IS I WOULDN'T DISMISS THE
GENETICS ENTIRELY.
THE WORK IN CENTENARIANS IS I
THINK REVEALING SOMETHING REALLY
UNEXPECTED SO IF HE WERE HERE,
HE WOULD SAY THAT CENTENARIANS
ACTUALLY HAVE SEQUENCE VARIANTS
THAT CONFER PROTECTION AGAINST
SOME OF THESE HEALTH TRAJECTORY
FEATURES.
SO FOR INSTANCE, CERTAIN
MUTATIONS OR SNPs CAN OVERCOME
AN APOE MUTATION, WHICH IS
INCREDIBLE.
SO I THINK THAT'S POWERFUL.
I JUST WANTED TO REITERATE THE
COMMENT ABOUT THE PSYCHOSOCIAL
STRESS, SO THAT MODEL THAT
ALESSANDRO IS WORKING IN, HE HAS
A GRANT THAT PROVIDES FUNDING IF
ANYBODY WANTS TO SORT OF ADD
WHAT THEY'RE DOING, THE
MICROBIOME WITH STRESS, BUT THIS
JUST -- IT'S THE EQUIVALENT OF
FEELING LIKE AN ETHNIC OR RACIAL
GROUP THAT'S PICKED ON.
SO IT'S A HUGE HEALTH DETERMINE
NAN.
THE LAST POINT I WANTED TO MAKE
JUST BEFORE WE GOT ON THE ZOOM
THIS MORNING, PAUL FOUND A LINK
THAT SAID THAT MORE THAN SEVEN
HOURS OF ZOOM A WEEK WILL ALSO
DESTROY YOUR MEL.
SO THE -- YOUR MENTALHEALTH.
SO THERE'S AN ACTION ITEM FOR --
>> THAT WAS PER WEEK, NOT PER
DAY.
>> EXACTLY.
WE'RE GOING TO DIE TOMORROW.
SO A COUPLE COMMENTS.
EPIGENETICS IS AFFECTED BY
NUTRITION AND EXERCISE, FROM
MICHAEL SNYDER.
YES, ABSOLUTELY.
AND STRESS INCLUDING SOCIAL
STRESS, AND IMPLICIT BUY A
SYSTEMIC RACISM ARE OBVIOUSLY
GOING TO HAVE A LARGE EFFECT AS
WELL.
THERE WAS ANOTHER QUESTION,
DR. KIRKLAND, DID YOU HAVE
ANOTHER QUESTION?
I SEE YOUR HAND IS UP.
>> IT MIGHT BE A PREVIOUS
QUESTION.
I THINK HE DIDN'T LOWER DOWN HIS
HAND.
DR. KIRKLAND?
>> I ALSO SEE A QUESTION FOR DR.
[MULTIPLE SPEAKERS]
>> I THINK WE COVERED THAT ONE.
>> YEAH, I CHATTED TO LAVERNE.
BUT ESSENTIALLY, KIND OF
CLASSICAL THINKING THAT
EPIGENETICS IS PERMANENT IS KIND
OF COMING UNDER QUESTION.
SO WE HAVE DATA THAT THERE ARE
THESE NEW CLASSES OF EPIGENETIC
PROTEINS, IF YOU WILL, TETs
AND DNMTs THAT MAY CONFER
SOME DEGREE OF REVERSIBILITY.
BUT IN WHAT TISSUES AND TO
WHAT DEGREE THEY'RE REVERSIBLE,
THOSE ARE STILL PENDING, PENDING
ANSWERS.
>> I SEE ALSO A QUESTION FOR
LOUISE IN THE Q & A.
HAVE YOU INVESTIGATED THE --
SCFAs IN OTHER TISSUES?
>> YEP, I THINK I ANSWERED THAT.
YES, WE HAVE.
IN HUMANS ESPECIALLY.
METABOLOMICS IS A HUGE AREA BUT
WE'RE PRETTY CRUDE WITH IT RIGHT
NOW, BUT YEAH, WE HAVE SHOWN
THAT IT'S NOT SPECIES-DEPENDENT.
AND I THINK SOMEBODY ASKED --
DAN Z ASKED IF ANYBODY COULD
SHARE THE REFERENCE PAPER ABOUT
THE ZIP CODE STUDY AND AGING.
SO IF SOMEBODY COULD SHARE THAT?
>> I'M RESPONDING TO HIM.
>> FANTASTIC.
AND I THINK WE ARE OUT OF TIME,
SO UNLESS THERE'S OTHER BURNING
QUESTIONS, DR. KIRKLAND, GO TAKE
A NAP.
[LAUGHTER]
>> YOU'RE A TROOPER.
>> IT'S GETTING CLOSE TO
MIDNIGHT.
>> IT IS.
IT IS CLOSE.
AND REMEMBER, SLEEP IS SUPER
IMPORTANT, SO -- AND CIRCADIAN
RHYTHMS, WHICH WE DIDN'T REALLY
TALK MUCH, BUT A GREAT FIRST
DAY, SO THANK YOU VERY MUCH.
I'LL LET ANIL AND -- TAKE IT
FROM HERE.
>> THANK YOU, THANK YOU SO VERY
MUCH.
IT WAS THE WHOLE DAY EDUCATIONAL
AND INFORMATION OVERLOAD FOR ALL
OF US.
I WAS GLUED TO MY COMPUTER.
WHICH RARELY HAPPENS.
THANK YOU, THANK YOU SO VERY
MUCH FROM THE BOTT BOTTOM OF OUR
HEART.
IT'S NOT EASY TO GET ALL OF YOU
DISTINGUISHED SPEAKERS IN ONE
PLACE AT THE SAME TIME.
THANK YOU, THANK YOU.
>> SO ONE OF THE SECRETS OF
HAVING ZOOM MEETINGS IS BECAUSE
YOU CAN ALL BE HERE WITHOUT
TRAVELING.
>> GOOD FOR THE BUDGET TOO.
>> OF COURSE.
SWE
>> HOPE YOU CAN PARTICIPATE
TOMORROW AS MUCH AS YOU CAN,
PLEASE.
OF COURSE.
SO THANK YOU VERY MUCH. I'M GOING TO SIGN OFF.
THANK YOU ALL. BYE-BYE.