>>WELCOME TO
THE SECOND DAY OF THIS
INCREDIBLY INTERESTING AND
CREATIVE MEETING. YOU KNOW,
MANY YEARS AGO, WHEN I WAS A
JERAT TRIGS ON THE FRONT LINE
CARING FOR OLDER PATIENT REALLY
IN THE BED AND OUTPATIENT
CLINIC, I THOUGHT I DIDN'T HAVE
THE WEAPONS I WANTED TO FIGHT
THE DEADLY FORTH MAKING MY
PATIENTS DISABLED AND ILL MY
PATIENTS. WE ARE MAKING
INCREDIBLE EFFORT TO GET GAIN IN
FUNCTION AND SEE COMING BACK
AFTER THE WEEK THAT HAVE LOST
EVERYTHING WE HAD GAINED AND MY
DREAM WAS THE SOME POINT THERE
WILL BE A SCIENCE THAT WILL HELP
JERAT TRIGS TO DO BETTER THAN
THAT AND THIS SUMMIT GAVE ME
INCREDIBLE HOPE THIS IS
HAPPENING IN OUR SCIENCE TO BE
TRANSLATED TO HEALTH OF OUR
PATIENT NOT IN 25 YEARS OR MAYBE
IN NEXT FIVE YEARS THAT IS A
MIRACLE AND FOR ME A TRULY DREAM
COME TRUE AND WE SAW YESTERDAY
THE DIVERSITY AND INEQUALITY IN
THE DISTRIBUTION OF HEALTH.
WE CAN UNDERSTAND BETTER
MECHANISM OF AGING PROCESS AND
LOOKING AT DIFFERENT POPULATION
AND SENTINARIAN AND PEOPLE
LIVING IN COUNTRIES WHERE HEALTH
CARE IS NOT AS DEVELOPED AND WE
LOOKED AT THE REALLY CLINICAL
RELEVANCE OF MULTIMORBIDITY AND
EXPLORE THROUGH ANIMAL MODEL HOW
TO DO TRANSLATION AND BAD
TRANSLATION AND HOW PEOPLE THAT
DO SCIENCE WITH PATIENTS AND
RESEARCH IN ANIMAL MODEL DO WITH
EACH OTHER AND REACH MORE
KNOWLEDGE AND TODAY WILL BE
TECHNICAL BUT NOT LESS
INTERESTING AND EXCITING AND
TALKING ABOUT MATHEMATICAL
MODELS AND BIOMARKERS TO ME THAT
IS THE MOST INTERESTING SESSION
FOR THIS MEETING.
SO, I WILL BE THERE WITH YOU
LISTENING AND HOPING THAT THIS
DISCUSSION AT LEAST A LITTLE BIT
WILL HAVE A FEW OF THE OLDER
PATIENTS OF THE FUTURE. THANK
YOU VERY MUCH FOR PARTICIPATION
FOR THOSE THAT ARE HERE AND TO
THOSE THAT ARE LISTENING FROM
THE VIRTUAL CONNECTION.
NOW, WE HAVE THE FIRST SPEAKER.
>>HELLO, EVERYONE. WELCOME.
IT IS MY PLEASURE TO INTRODUCE
SESSION 4 AND BE THE CHAIR FOR
SESSION ON METHODS FOR MEASURING
HEALTH. I'M LOLITA AN ASSISTANT
PROFESSOR AT JOHNS HOPKINS
UNIVERSITY AND WILL INTRODUCE
THE SPEAKERS AND FIRST THEY WILL
SPEAK AND THERE IS TIME AT THE
END FOR QUESTIONS. NEXT WE WILL
HAVE DR. EILEEN CRIMMONS AND
DIRECTOR AT UCLA CENTER FOR
BIODEMOGRAPHY AND POPULATION
HEALTH AT USC LEONARD SCHOOL OF
GERONTOLOGY SPEAKING ON
MULTILEVEL BIOMARKERS WITH HUMAN
AGING AND VICE PRESIDENT AND
PROFESSOR AT ACADEMIC AFFAIRS
FOR BUCK INSTITUTE FOR RESEARCH
AND AGING SPEAKING ABOUT THE
AGING INTERVENTION PIPELINE.
>>GOOD MORNING, EVERYONE.
THANK YOU TO THE ORGANIZERS FOR
LETTING ME COME TO TALK TO YOU
ABOUT WORK I HAVE DONE IN
COLLABORATION WITH OTHERS ON
DEFICIT ACCUMULATION ON AGING IN
ANIMAL MODELS AND WILL DO A
LITTLE BIT ON HUMANS AS WELL.
OKAY. SLIDE IS ADVANCING.
IT WAS WORKING BEFORE.
30 SECONDS ARE GONE. OKAY. I
LOST 30 SECONDS. IS IT BACK?
YOU MIGHT CONSIDER THIS CHEEKY
UK ROADSIDE, EXCUSE ME.
DEPICTING A SENSE OF OLDER
ADULTS AND YOU MIGHT THINK ABOUT
SOMEBODY LIKE EDWHIT LOCK, A
CANADIAN SETTING WORLD RECORD IN
THE MARATHON FOR 85 YEARS OF AGE
IN 2016 FOR SUB TIME AND PRETTY
IMPRESSIVE FETE AND IS CLEAR
THAT AGING IS HETEROGENOUS AND
CONCEPT OF FRAILTY WE HEARD
EXTENSIVELY AND COMES FROM OR IS
INITIALLY USED TO REFER TO
VARIABILITY IN THE RISK OF
HAVING ADVERSE HEALTH OUTCOME IN
INDIVIDUALS WHO ARE THE SAME AGE
THAT COMES FROM DEMOGRAPHER
LITERATURE ACTUIARYIES LOOKING
AT LIFE TABLES AND HOW LONG
SOMEONE IS EXPECTED TO SURVIVE
AND COME TO OPERATIONALIZE
FRAILTY IN SEVERAL WAYS
CLINICALLY AND 2001 TWO
APPROACHES DEVELOPED FOR
CLINICAL SAMPLES AND MANY
INSTRUMENTS I WOULD LIKE TO ADD
AND TWO HAVE BECOME WELL-KNOWN
AND ONE IS FRAILTY PHENOTYPE
LOOKING AT DEFICITS IN FIVE
PHYSICAL DOMAINS AND WON'T TALK
ABOUT THAT ONE. I WILL POINT OUT
IT IS OPERATIONALIZED FOR USE IN
ANIMAL MODELS AND FRAILTY INDEX
IN A LARGE NUMBER OF HEALTH
DOMAINS THAT IS A PRETTY SIMPLE
CONCEPT DEVELOPED BY KEN
ROBBINGWOOD AND [INDISCERNIBLE]
AT HOUSING UNIVERSITY WHERE I
WORK AND IDEA IS EXCUSE ME IF
YOU HAVE A NUMBER OF POTENTIAL
HEALTH DEFICITS YOU LOOK AT
DEFICITS IN INDIVIDUAL AND
DIVIDE BY TOTAL DEFICITS
MEASURED TO GET A NUMBER BETWEEN
0 AND 1 AND THIS DATA YOU IS
OBTAINED FROM OUR UNIVERSITY
FROM COMPREHENSIVE GERIATRIC
FORM. YOU CAN'T SEE BUT IF YOU
ZOOM IN YOU SEE ON FAR
RIGHT-HAND SIDE OF THE SLIDE
CURRENT STAGE OF THE INDIVIDUAL
THEY ARE INCONTINENT AND
INDEPENDENT IN ACTIVITIES OF
DAILY LIVING AND SEE WHAT THEY
LOOK LIKE TWO WEEKS AGO IF THEY
CAME IN TO SEE YOU AND SEE THEY
PREVIOUSLY WERE CONTINENT AND
INDEPENDENT AND ALL THESE THINGS
CAN BE CALLED DEFICITS AND FORM
LIKE THIS CAN GENERATE 70
POTENTIAL HEALTH DEFICITS AND
WHEN YOU LOOK AT FRAILTY INDEX
SCORES IN PEOPLE, WHAT YOU SEE
IS THIS IS PEOPLE FROM 15 TO
102. YOU CAN SEE FRAILTY STARTS
TO ACCELERATE IN THE LAST FEW
DECADES OF LIFE AND THESE ARE
MEAN DATA. YOU CAN SEE
EXPONENTIAL INCREASE IN FRAILTY
INDEX SCORES AND IN PEOPLE THAT
ARE 102 YEARS OLD YOU CAN SEE
AVERAGE IS .4 THAT SUGGESTS
SOMETHING INTERESTING ABOUT THE
IDEA OF FRAILTY THAT IS THAT
THERE IS A LIMIT. EXCUSE ME.
TO HOW FRAIL SOMEONE CAN BECOME.
THAT LIMIT SEEMS TO BE AT .67.
WHEN YOU ACCUMULATED 2/3 OF ALL
POSSIBLE DEFICITS IN A LIST YOU
CAN'T TOLERATE ONE MORE DEFICIT
EVEN IF FAIRLY SMALL AND 7
CYCLES OF NATIONAL POPULATION
HEALTH SURVEY REFLECTING LARGE
NUMBER OF PEOPLE SAMPLES OVER
AND OVER A GAIN. YOU CAN SEE IT
IS A CONSISTENT FUNCTION. SO,
WE HAVE BEEN IN MY LAB USING
OLDER MOOIS TO TRY TO BETTER
MODEL HUMAN DISEASES OF AGING
AND HAVE DONE CARDIOVASCULAR
RESEARCH FOR MANY YEARS LOOKING
AT IDEA WE SHOULD DO WORK IN
OLDER ANIMALS AND NOTICED THAT
WHILE SOME OF OUR OLD MICE
LOOKED REALLY QUITE GOOD LIKE
THIS YOUNG ADULT C57 BLACK
[INDISCERNIBLE] OTHERS START TO
DEVELOP DEFICITS. YOU SEE HERE
KYPHOSIS ON MOUSE ON LEFT AND
CURVATURE OF SPINE AND PATCHY
HAIR LOSS AND ALOPECIA AND
STIFFENING IN MICE AS THEY
DEVELOP IN AGE AND LOOKED LIKE
MICE LOOK LIKE THEY EXHIBIT
HETEROGENOUS AGING AND SOUGHT
OUT A WAY TO QUANTIFY THAT AND
DRAWING ON THE CLINICAL TOOL WE
DEVELOPED A MOST COMPREHENSIVE
GERIATRIC ASSESSMENT TOOL AND
PROJECT I DID WITH JOCELYN
WHITEHEAD IN LAB BACK IN 2014
AND A LITTLE EARLIER AND WE
LOOKED AT MANY DIFFERENT DOMAINS
MUSCULOSKELETAL DOMAIN AND WE
LOOKED AT WHETHER MOUSE THAT WE
WERE EXAMINING HAD A DEFICIT.
WE ARE SEEING FOR EXAMPLE A
SCORE OF 0 FOR TUMORS AND 0 FOR
EXTENDED ABDOMEN BUT 1 FOR
KYPHOSIS. IT IS SIMPLE AS THEY
DO FOR HUMAN INSTRUMENT WE ADD
DEFICITS IN INDIVIDUAL ANIMAL
AND DIVIDE BY TOTAL NUMBER TO
GET A FRAILTY INDEX SCORE.
IN WORK DONE WITH KIM
ROBBINGWOOD, WE COMPARED HUMAN
AND MOUSE CLINICAL FRAILTY DATA.
YOU SEE HERE MOUSE DATA AND 14
MICE AND 14 PEOPLE AND YOU SEE
THEY ARE SIMILAR NORMALIZING TO
MAXIMUM LIFESPAN OF SPECIES AND
FRAILTY INDEX SCORES AT EXTREMES
OF LIFE SHOW LIMITS OF .4 TO .5
AND DON'T SEE INCREASE IN
FRAILTY BEYOND THAT BECAUSE IT
IS LETHAL BEYOND .67. WE
PUBLISHED A NUMBER OF PAPERS ON
THIS AND ROBBINGWOOD 2017 PAPER
DOES HEAD TO HEAD COMPARISON
WITH MICE AND HUMANS AND REVIEW
IN NATURE FOR AGING FOR ANYONE
THAT IS INTERESTED. WHY IS THIS
IMPORTANT AND INTERESTING?
IF YOU LOOK AT FACTORS THAT
PREDISPOSE INDIVIDUALS TO BECOME
FIT OR FRAIL, YOU CAN SEE
BALANCE IS TIPPED IN FAVOR OF
FITNESS IF EATING A BALANCED
DIET AND EDUCATION IS HIGHLY
PROTECTIVE AND [INDISCERNIBLE]
COULD BE OF INTEREST AND
EXERCISE AND THINGS LIKE SOCIAL
ENGAGEMENTS LIVING IN SAFE
NEIGHBORHOOD ARE PREDISPOSED
TOWARDS FITNESS AND HIGH FAT
DIET AND RADIATION THERAPY AND
POOR MATERNAL HEALTH AND LOW
WEALTH AND PHARMACY, ET CETERA
AND LOOKED AT BALANCE AND
TALKING ABOUT THINGS WE HAVE
DONE TO LOOK AT FACTORS
PROMOTING FITNESS AND WORK DONE
WITH ALICE CANE POST DOCKED IN
LAB AND AUDIENCE AND YOU WILL
HEAR FROM LATER AND CAITLIN
KELLER A GRADUATE STUDENT TAKING
SAMPLE OF MAIL MALE AND FEMALE
MICE AND FOLLOWED THEM AND
MATCHED THEM FOR BASELINE
FRAILTY SCORES AND TREATED THEM
WITH ACE INHIBITOR CALLED
ANALOPRIL AND MEDICATION WITH
BENEFIT ROOZ HE DEUCE
INFLAMMATION IMPROVING MUSCLE
MASS AND STRENGTH AND HERE
LOOKING AT FRAILTY SCORES LEFT
SIDE ON MOOIS AND RIGHT SIDE ON
HUMANS.
THIS IS SEEN CLINICALLY. IN
ADDITION YOU SEE TREATMENT OF
ANALO INVENTED INCREASE WITH
FRAILTY IN OLDER LIFESPAN THAT
WAS HIGHLY SIGNIFICANT IN
FEMALES BY 20 MONTHS OF AGE.
WE LOOKED AT EXERCISE AS A
GERALD PROTECTIVE INTERVENTION
AND MICE THAT ARE SEDENTARY FOR
THEIR ENTIRE LIFE AT 22 MONTHS
SUDDENLY OPPORTUNITY TO USE
VOLUNTARY EXERCISE WHEEL AND
STARTED A 13 WEEK TRIAL OF
RUNNING VERSUS SEDENTARY.
THIS IS WORK DONE WITH SCOTT
GRANDY A COLLEAGUE OF MINE IN
KINESIOLOGY IN MY DEPARTMENT AND
ELISE WHO IS A GRADUATE STUDENT
IN MY LAB AND SAW SOMETHING
INTERESTING HERE. GIVING OLDER
MICE THE CHANCE TO EXERCISE, YOU
SEE FRAILTY INCREASED WITH TIME
IN FEMALES AND MALES AND WHEN
THEY EXERCISED, WE DIDN'T SEE
INCREASE IN FRAILTY AND IN FACT
MALES DIFFERENCE WAS SMALLER AND
FEMALES WE SAW SIGNIFICANT
DECREASE IN FRAILTY IN MICE WHO
EXERCISED.
WE HAVE ALSO DONE SOME OTHER
WORK WITH THIS MODEL.
SO, WE HAVE BEEN INTERESTED IN
THE IDEA THAT SOME OF THE
CHANGES THAT YOU SEE, YOU KNOW,
CAN BE DUE TO CHANGES IN THE
RELATIONSHIP BETWEEN DAMAGE AND
REPAIR.
SO, THIS IS WORK THAT IS DONE
DURING THE PANDEMIC WITH TWO
PHYSICISTS AT MY UNIVERSITY AND
PUBLISHED LAST YEAR IN ELIFE.
WE TRIED TO LOOK AT TRANSITIONS
THAT YOU CAN GELT LONGITUDINALLY
COLLECTING DATA FROM MICE
BETWEEN A DEFICIT BEING PRESENT
OR BEING ABSENT AND SEE WHILE
TRANSITION IS TO HIGHER STATE OF
FRAILTY SO ACCUMULATING MORE
DEFICITS YOU GET THINGS THAT
REPAIR AND WERE A DEFICIT EARLY
ON AND NO LONGER A DEFICIT
LATER.
WE MODELED THIS YOU SEE HERE AT
TOP THIS IS MOST DATA SET FROM
PAPER WE PUBLISHED FROM ALLISON
AND KAIN AND DAVID SINCLAIR'S
LAB MODELING DATA FROM MALE MICE
ON TOP AND DAMAGED RATES ON
BOTTOM AND AGE LOOKING AT AGE 26
TO TLOO HE 6 MONTHS AND YOU SEE
AGING PROCESS NEEDS TO BE
ASSOCIATED WITH DECREASE IN
REPAIR AND INCREASE IN DAMAGE.
SO, THAT IS SUMMARIZED HERE.
SO, WHAT WE THEN THOUGHT WAS,
WELL, WHAT ARE INTERVENTIONS
DOING TO THE RATES OF REPAIR AND
OF DAMAGE AND ARE WE DERIVING
ONE IN FAVOR OF THE OTHER?
WHAT WE SEE HERE IS THE DATA SET
FROM [INDISCERNIBLE] TREATED
ANIMALS YOU SEE REPAIR RATES ARE
HIGHER IN MALE AND FEMALE MICE
IN PRESENCE OF ANALOPRIL AND
DAMAGE RATES ARE LOWER AND DOING
THIS I'M LOOKING AT EXERCISE
GROUP. YOU SEE THROUGH REPAIR
RATES IN EXERCISE-TREATED MICE
ARE HIGHER ESPECIALLY IN FEMALES
AND DAMAGE RATES ARE LOWER.
TRYING TO LOOK AT THIS AND
COMPARING WHETHER ONE EFFECT WAS
STRONGER THAN THE OTHER, WE
FOUND THAT BOTH EXERCISE AND
ANALOPRIL APPEAR TO REDUCE DANL
RATE AND DON'T KNOW WHETHER WE
CAN SAY WHETHER ONE WAS MORE
POTENT THAN THE OTHER AND
REDEUCE REPAIR RATE AND TREATING
WITH EXERCISE AND ANALOPRIL YOU
GET DAMAGE AND REPAIR AND
FACTORS PREDISPOSE TO FRAILTY
AND STUDY WITH SARA AT
UNIVERSITY OF SIDNEY AND JOHN
MAC AND OTHERS AND HAVE POLICY
DIET THEY DEVELOPED FOR MANY
YEARS AND LOOK AT DRUGS WITH
HIGH BURDENED INDEX AND TAKEN BY
OLDER ADULTS IN AUSTRALIA AND
WHERE IN THE WORLD AND HAVE
SEDATIVE EFFECTS AND TREAT MICE
WITH FIVE DRUGS AND TAKING YOU
THROUGH SLIDES. THIS IS A
FRAILTY INDEX SCORE. YOU CAN
SEE CONTROL IS THE BLACK LINE AT
BOTTOM AND YOU CAN SEE CONTROL
FRAILTY SCORES ARE LOWER THAN
SCORES WITH MICE TAKING THIS
POLY PHARMACY DIET WITH ZERO
DRUG BURDEN INDEX AND LEAST
PROBLEMATIC DRUGS IF YOU WILL
AND LOW AND HIGH DBI AND YOU SEE
FRAILTY IS HIGHEST IN MICE
TAKING DRUGS WITH HIGH DRUG
BURDEN INDEX AND IS INTERESTING
THEN THAT THEY DEPRESCRIBED FOR
THREE MONTHS AT THE END AND YOU
SEE THAT IS THE DASHED LINE AND
FRAILTY ACTUALLY GOES DOWN WHEN
YOU DEPRESCRIBE.
THIS IS WORK DONE BY A GROUP IN
N
NEWCASTLE LED BY THOMAS ZALINKY.
MISPRONOUNCING HIS NAME AND THEY
DO SOMETHING INTERESTING LOOKING
AT FRAILTY INDEX AND DO A BRIEF
EXPOSURE OF YOUNGER ANIMALS TO
AN X RADIATION AND LOOK AT
FRAILTY SCORES AND RED LINE,
FRAILTY YOU SEE INCREASES
DRAMATICALLY AFTER EXPOSURE TO
RADIATION AND THEY TREATED A
GROUP OF MOOIS WITH MET FOR MIN
WITH IDEA IT COULD BE ASEINO
LYTIC RESTATIC INTERVENTION AND
DID IT FOR A PERIOD OF SEVERAL
MONTHS AND WITHDRAW THE MET FOR
MEN TREATMENT AND WHEN TREATED
WITH MET FOR MEN FRAILTY
PARALLELED THAT CONTROL OF
NONRADIATED MICE DIDN'T
DEVELOPED ACCELERATED PHENOTYPE
IN MICE THAT WERE EXPOSED TO
RADIATION I'D LIKE TO TOUCH ON
TRANSLATING MODELS TO USE IN
HUMANS AND WORK STARTED WITH
BRANDY PARKS A PHD STUDENT IN MY
LAB. WHAT WE DID IDEA STARTING
TO FIRST QUANTIFY FRAILTY IN
MICE I DIDN'T THINK OF CLINICAL
FRAILTY FIRST THIS IS OLDER
PAPER FIRST APPROACH LOOKING AT
WANTING TO GET MORE THAN 30
PARAMETERS TO MEASURE LOOKING AT
ACTIVITY LEVELS AND BODY
COMPOSITION STORE AND MEASURE
HEMODYNAMIC PARAMETERS WITH CALE
CUFF AND INTERESTING PARAMETERS
LIKE TAIL BLOOD VOLUME AND WE
HAD A POINT OF CARE EYE STAT
BLOOD ANALYZER TO DO ROUTINE
BLOOD WORK AND DEVELOPED A
FRAILTY INDEX FROM ALL MEASURES
BY LOOKING AT THINGS WITHIN OR
MANY STANDARD DEVIATIONS AWAY
FROM THE AVERAGE PERFORMANCE BY
YOUNG AND HEALTHY MICE.
WE THOUGHT, WITH THIS WORK AND
PEOPLE, COULD WE USE CLINICAL
DATA AND DEVELOP A -- WHAT WE
CALLED FI LAB FOR USE IN PEOPLE
AND WORK DONE WITH KEN AND
JOANNA AND OTHERS AND THIS IS
THE FI LAB AND WE USE THE SAME
SORT OF APPROACH AND DOG IN THIS
CASE FOR EXAMPLE SERUM POTASSIUM
AND VALUE IN INDIVIDUAL IS LOW
AND HIGH CUTOFFS RANGE OF 0 AND
HIGHER OR LOWER GET A 1 AND ADD
UP AND DIVIDE BY TOTAL NUMBER OF
VARIABLES TO GET A FRAILTY
SCORE.
THIS JUST SHOWS ONE PAPER WE
HAVE DONE THAT WE HAVE DONE A
FEW IN THE EUROPEAN MALE AGING
STUDY DATA BASE LOOKING AT 3,000
COMMUNITY DWELLING MEN WITH 7
YEAR FOLLOW UP AND SEE FI SCORE
ON LEFT PANEL D AND FI CLINICAL
SCORE IN MIDDLE AND FI COMBINED
SCORE. I THINK WHAT THIS SHOWS
IS THIS FRAILTY INDEX BASED ON
LABORATORY DATA YOU CAN SEE IT
IS SEPARATED BY NET FI SCORE AND
SEE THOSE WITH FRAILTY SCORES OF
.4 ON FI LAB ARE MORE LIKELY TO
LOW FRAILTY SKO R TO BE DEAD AT
7 YEAR FOLLOW UP AND COLLECTED
CLINICAL FRAILTY DATA WITH REAL
GOOD SEPARATION AND GAIN OF
DIFFERENT FRAILTY LEVELS AND
CHANCE OF BEING OR DYING WITHIN
7 YEARS AND BEST SEPARATION OF
THE GROUPS TURN WHEN YOU
ACTUALLY COMBINED FI LAB AND FI
CLINICAL READINGS TOGETHER.
THIS IS AN INTERESTING TOOL.
MANY LABS ARE NOW USING IT TO
ASSESS FRAILTY AND IS NICE
BECAUSE YOU CAN RETROSPECT IT
AND APPLY IT TO DATA YOU HAVE ON
HAND ALREADY ABOUT YOUR PATIENTS
OR IN SOME CASES IN ANIMALS AND
WOULD LIKE TO CONCLUDE BY SAYING
FRAILTY INDEX ALLOWS TO QUANTIFY
INDEX IN HEALTH AND PEOPLE AND
IN PRECLINICAL MODELS AND SHOULD
ADD WE HAD A REALLY INTERESTING
TALK YESTERDAY ABOUT FRAILTY IN
PRIMATES AND FRAILTY IN DOGS AND
SOME INSTRUMENTS ARE TRANSLATED
OR BEING TRANSLATED FOR USE IN
DIFFERENT ANIMAL MODELS AND
WORKS IN RATS AS WELL, I SHOULD
ADD AND FRAILTY SCORES RESPOND
AND THEY DO SO IN A DYNAMIC WAY
TO DELETERIOUS OR BENEFICIAL
CHANGES IN CIRCUMSTANCES SUCH AS
GEROPROTECTORS AND LIFESTYLE
EXERCISE AND DELETERIOUS BEING
ABBREVIATION AND POLYPHARMACY
AND LIKELY OTHER INTERVENTIONS
AS WELL AND WOULD LIKE TO POINT
OUT FRAILTY INDEX CREATED FROM
ENTIRELY LAB-BASED VALUES
DEVELOPED IN MICE CAN PREDICT
ADVERSE OUTCOMES IN PEOPLE AND
FINALLY, I THINK THESE -- REAL
POWER OF THIS TYPE OF INSTRUMENT
IN A MOUSE MODEL IS IT CAN BE
USED TO TEST GEROPROTECTIVE
INTERVENTIONS TO HEALTHY AGING
LIMITING LATE LIFE ILLNESSES
COMPRESSED AT LATE LIFE
MORBIDITY SO PEOPLE COULD QUOTE
ON QUOTE DIE HEALTHIER AND
MODELS PROVIDE OPPORTUNITY TO
TEST COMBINATIONS OF
INTERVENTIONS AND SEE WHETHER OR
NOT WE CAN ACTUALLY REALLY
OPTIMIZE PEOPLE'S HEALTH IN
LATER LIFE. I WOULD JUST LIKE
TO THANK THAT I MENTIONED MOST
PEOPLE THAT WORKED ON THIS AND
FUNDING AGENCIES AND CANADIAN
INSTITUTES FOR HEALTH AND
RESEARCH AND HEALTH AND STROKE
FOUNDATION AND PEOPLE IN MY LA B
THAT CONTRIBUTED TO THIS IN
BOLD. THANK YOU VERY MUCH.
>>[APPLAUSE].
>>>>GOOD MORNING. MY CHARGE
IS DISCUSSING GERIATRIC
ASSESSMENT. I WILL FOCUS MOST
OF MY COMMENTS ON MOBILITY.
ONE QUESTION: WHY IS THIS
IMPORTANT TO DO?
FIRST, IT IS CONSIDERED FINAL
COMMON PATHWAY REFLECTING IMPACT
OF DISEASE, COMORBIDITY AND
AGING AND SECOND IT IS OFRNL THE
PRIMARY OR IMPORTANT FOCUS OF
THERAPY AND POTENTIALLY
INCLUDING GEROTHERAPEUTICS AND
THIRD IS IMPORTANT FROM A
REGULATOR PERSPECTIVE. IT IS
INCLUDED AMONG THREE FDA KEY
OUTCOMES OF FEEL, FUNCTION,
SURVIVE.
LASTLY AND PERHAPS MORE OR MOST
IMPORTANTLY IT IS WHAT OLDER
PERSONS WANT IN LIFE,
PARTICULARLY LATER IN LIFE TO
MAINTAIN INDEPENDENCE AND THEIR
FUNCTION.
THIS IS A SLIDE, I BELIEVE, I
BORROWED FROM LOU EEJI YEARS AGO
THAT HAS A LIFESPAN PERSPECTIVE
TO MOBILITY EARLY IN LIFE
SHORTLY AFTER BIRTH TO LATER IN
LIFE AND ADVANCED OLD AGE AND
MOBILITY LIKE HIGHER LEVEL
FUNCTIONS TYPICALLY PEAK IN THE
LATE 20S AND EARLY 30S AND
DECLINE AGGRESSIVELY THEREAFTER.
MOBILITY IS CONSIDERED ONE OF
THE STRONGEST SINGLE PREDICTORS
OF MOST RELEVANT MORE DISTAL
OUTCOMES SUCH AS SURVIVAL AND
LONG-TERM DISABILITY THAT IS
OFTEN CONSIDERED ESSENTIAL TO
MAINTAINING HIGH QUALITY OF LIFE
IN ADVANCING AGE.
THIS IS A SLIDE BASED ON DATA
FROM IN KIANTI AND LUIGI LEADING
THE CHARGE. POINTS TO MAKE LEFT
SIDE OF THE SLIDE IS MALES AND
RIGHT SIDE IS FEMALES AND SHOWS
THREE TYPES OF MOBILITY TESTS
WITH USUAL DATE SPEED AT TOP AND
MIDDLE RAPID GAD SPEED AND
BOTTOM IS 400 METER WALK.
YOU WILL SEE WHEN PERSONS ARE
NOT CHALLENGED WITH USUAL GAD
SPEED AND LEAST STRENUOUS OF
THAT, THAT PERSONS TYPICALLY
DON'T FALL BELOW THERE ARE NOT
REDUCTIONS OBSERVED FOR FOLKS
BETWEEN 50 OR 60 OR 70 AND SLAT
OR HORIZONTAL LINE, ANYTHING
BELOW THAT REPRESENTS DECLINE.
MIDDLE PANEL YOU WILL SEE
STRENUOUS TEST AND THIS CASE
RAPID GATE AND AGE RELATED
CHANGES OCCUR EARLIER IN PERHAPS
THE 30S AND 40S AND STRENUOUS
TEST IN THIS CASE 400 METER WALK
THERE IS DECLINES OBSERVED IN
EARLY 20S RELATIVE TO EARLIER IN
LIFE. THIS IS SOMETHING TO
CONSIDER WHEN YOU ARE DEPENDING
ON THE POPULATION THAT YOU ARE
TARGET
TARGETING.
YOU MAY SELECT DIFFERENT
MOBILITY TESTS AND FIRST
IDENTIFYING POPULATIONS THAT ARE
VULNERABLE AND SERVING RELEVANT
OUTCOME MEASURES.
NEXT SEVERAL SLICES ASSESSMENT
OF SELF-REPORTED FUNCTION OR
PATIENT REPORTED OUTCOMES IT IS
REFERRED TO ALSO. AND THERE ARE
DOZENS OF DIFFERENT
SELF-REPORTED INSTRUMENTS OF
PHYSICAL FUNCTION. THIS IS ONE
OF THE MOST COMMONLY USED TESTS
PARTICULARLY IN HIGHER
FUNCTIONING PERSONS INCLUDING
OLDER ADULTS PF10 COMPONENT OF
MLS36 DEVELOPED MANY YEARS AGO
AND 10 ITEMS LISTED HERE AND
MAJORITY OF THEM ARE MOBILITY
RELATED SUCH AS CLIMBING STAIRS
AND WALKING DIFFERENT DISTANCES
THERE IS DIFFERENT CATEGORIES OF
LIMITATIONS FROM LIMITED A LOT
TO NOT AT ALL AND SCALED ON 0 TO
100 BASIS WITH 100 BEING A
PERFECT SCORE AND 0 BEING WORST
POSSIBLE SCORE AND PF10 HAS
SIGNIFICANT LIMITATIONS IN THOSE
LOWER FUNCTIONING FLORO FECHL
AND CAN'T DETECT CHANGES IN
PERSONS WITH LOWER LEVELS OF
FUNCTIONING. THERE HAVE BEEN
DIFFERENT STRATEGIES TO ADDRESS
THAT AND WHAT ARE CONSIDERED
TEMPORARY TECHNOLOGY AND THESE
ARE DESIGNED TO ADDRESS
COMPETING CONSIDERATIONS
ASSESSING FUNCTION IN TERMS OF
CONCEPTUAL BREADTH AND WHAT
ELEMENTS YOU THINK SHOULD BE
INCLUDED IN THAT ASSESSMENT
VERSUS DEPTH OF THE MEASUREMENT
AND YOU HAVE TO DEAL WITH ISSUES
RELATED TO FEASIBILITY AND
PRECISION AND TRADE OFFS THERE
WITH CONVENTIONAL SELF-REPORTED
MEASURES AND MESHED ALREADY
FLOOR EFFECTS AND COULD ALSO BE
CEILING EFFECTS DEPENDING ON THE
INSTRUMENT AND POPULATION
STUD
STUDIED.
ITEM RESPONSE THEORY ALLOWS YOU
TO CREATE HIERARCHICAL BANK OF
ITEMS YOU CAN DRAW UPON THAT
COULD BE IMPLEMENTED USING
COMPUTER ADAPTIVE TEST TG THAT
IS ALGORITHM THAT HAS ITEMS
DIRECTLY THAT ARE TAILORED TO
THE PERSON TO BE SHORTENED OR
LENGTHENED DEPENDING ON
PRECISION OF THE INSTRUMENTS
THAT YOU ARE HOPING TO GENERATE
OR PREDEFINED SHOPPING ROLES AND
NEXT SLIDE ILLUSTRATES HOW
PROCESS WORKS AND THERE IS ITEM
POOL NO. 1. ITEM IS SELECTED
FROM THAT POOL AND PATIENT
RESPONDS AND BASED ON RESPONSE,
INITIAL SCORE IS CALCULATED.
YOU HAVE PRE-SPECIFIED RULES AND
TERMS OF PRECISION OF ESTIMATES
AROUND THE SCORE YOU ARE LOOKING
FOR.
ESTIMATES NOT PRECISIONLY
PRECISE AND ANOTHER ITEM AND
CORE WILL BE RECALCULATED AND
CONTINUE GOING AROUND UNTIL YOU
REACH A PRE-SPECIFIED PRECISION
ESTIMATE OR IF YOU HAVE SET YOUR
MAX AT 6 OR 7 OR 8 QUESTIONS AND
THEN YOU WILL END UP AT A
FUNCTIONAL OUTCOME, TYPICALLY A
SCORE ON A SCALE THAT COULD BE 0
TO 100.
THIS IS THE BASIS OF PROMISE
ITEM BANK OF 162 AND
HIERARCHICALLY ORDERED
FUNCTIONAL ITEMS. YOU CAN SEE A
SELECTION OF FIVE DIFFERENT
ITEMS SCALED WOULT DIFFICULTY TO
UNABLE TO DO.
AND ITEMS FROM THIS ITEM BANK
ARE BEING USED FOR DIFFERENT
APPLICATIONS AND IN THIS CASE
FOR SARCOPENIA AND PHARMACOLOGIC
AND PHARMACEUTICAL COMPANIES ARE
INTERESTED IN DEMONSTRATING
BENEFITS OF AGENTS ON SARCOPENIA
AND FDA REQUIRES IMPROVEMENT IN
PATIENT-REPORTED OUTCOMES AND
FDA IS SUPPORTING A GRANT THAT
IS [INDISCERNIBLE] AT
NORTHWESTERN WHO IS A LEADING
FIGURE IN PROMISE TO IDENTIFY
AND TEST AND EVALUATE A SHORT
FORM FROM PROMISE 162 ITEM
PHYSICAL FUNCTION BANK FOR USE
IN SASHGOPENIA TRIALS AND FIRST
BASE IS COMPLETED AND REDUCED TO
30 ITEMS AND SECOND PHASE IS
ONGOING AND GOAL IS TO GET DOWN
TO LESS THAN 10 ITEMS FROM THAT
ORIGINAL BANK. THIS IS ANOTHER
WAY THAT SUCH ITEM BANKS COULD
BE USED YOU CAN PULL UPON THEM
AND HEAVY LIFTING IS ALREADY
DONE AND YOU WOULD PULL ITEMS
FROM THE BANK DEPENDING ON YOUR
STUDY POPULATION AND APPLICATION
IN THIS CASE SARCOPENIA.
I WILL TRANSITION TO PHYSICAL
PERFORMANCE MEASURES INVOLVING
ASSESSMENT IN WHICH AN
INDIVIDUAL IS ASKED TO PERFORM A
SPECIFIC TASK AND IS EVALUATED
IN OBJECTIVE AND STANDARDIZED
MANNER USING PREDETERMINED
CRITERIA INCLUDING COUNTING
REPETITIONS OR TIMING OF
ACTIVITY AS APPROPRIATE
RELATIVELY SHORT REPORTED
MEASURES NEITHER ARE BETTER
NECESSARILY THAN OTHER AND ARE
CONSIDERED COMPLEMENTARY
PERFORMANCE BASED MEASURES
ADVANTAGEOUS VALIDITY FOR TASKS
PERFORMED AND STAFF PROPERLY
TRAINED ARE TENDING TO BE HIGHLY
REPRODUCIBLE AND OFTEN
RESPONDING TO CHANGES THAT ARE
CLINICALLY MEANINGFUL AND BE
ADMINISTERED TO PERSONS
COGNITIVE DEFICITS UNLESS THEY
HAVE MOST ADVANCED DEMENTIA AND
COGNITIVE IMPAIRMENT OFTEN
IMPEDIMENT TO COMPLETION OF
SELF-REPORTED INSTRUMENTS AND
THENL CULTURE AND LANGUAGE IS
LESS PROBLEMATIC WITH
PERFORMANCE BASED SELF-REPORTED
MEASURES AND NONETHELESS,
DISADVANTAGES TO CONSIDER AND
TAKE MORE TIME TO COMPLETE AND
EXAMINERS HAVE TO BE TRAINED
HAVING STANDARDIZE THE VALID
MEASUREMENT AND THIS IN OUR
EXPERIENCE HAS BEEN AN UNCOMMON
PROBLEM AND SIMPLE TEST MAY NOT
REFLECT PERFORMANCE OF COMPLEX
TASKS AND DON'T CONSIDER
ENVIRONMENT AT ALL AND FUNCTION
INHERENTLY IS INTERPRETED IN
CONTEXT OF ONE'S ENVIRONMENT AND
ONE OF MOST COMMONLY USED TESTS
IS PERFORMANCE BATTERY HAVING
THREE COMPONENTS BALANCE
MANEUVER SIDE BY SIDE AND TANDEM
AND TWO TIMED TESTS FOUR METER
WALK AND SECOND IS A 5 TIME
STANCE.
THERE IS HUNDREDS OF ARTICLES
THAT HAVE BEEN PUBLISHED ABOUT
SBBB. IT IS A REALLY ROBUST
PREDICTOR OF MORTALITY AND OTHER
OUTCOMES AND LONG-TERM
DISABILITY AND NURSING HOME
ADMISSIONS AND EACH OF THE THREE
COMPONENTS IS A GRADED
RELATIONSHIP BETWEEN PERFORMANCE
AND IN THIS CASE MORTALITY AND
WITH WALK WITH MORTALITY BEING
1.9 WITH ROBUST GROUP WITH SCORE
OF 4 AND ALMOST 12 WITH FOLKS
THAT COULDN'T COMPLETE THE
WALKING TEST AND OTHER TWO
COMPONENTS OF SBB ARE NOT AS
GREAT AND GRADED R-
HELATIONSHIPS WITH BEST SCORE OF
4 HAVING LOWEST MORTALITY AND
WORST SCORE OF 0 WITH HIGHEST
MORTALITY AND WHAT YOU SEE WHEN
YOU TALLY THEM UP AND USUAL 12
POINT SCALE WITH 12 BEING A
PERFECT SCORE AND MORTALITY IN
YELLOW AND SEEING MORTALITY AT
SCORE OF 12 IS VERY LOW AND THIS
IS OVER A FOUR YEAR PERIOD THAT
YOU CAN SEE IT PROGRESSIVELY
INCREASES TO IN THIS CASE WORST
SCORE OF 4 IN WHICH MORTALITY IS
NEARLY 50% AND ABOVE THAT IS
ONSET OF MOBILITY DISABILITY AND
IN WHITE IS ONSET OF DISABILITY
AND ACTUALLY NO DISABILITY THAT
IS PROTECTED AND VERY UNLIKELY
TO BECOME DISABLED OVER COURSE
OF FOURIES WITH 12 ON SBBB.
AND JAX SPENT MANY YEARS
REFINING AND PERFECTING
MEASUREMENT TO POINT THAT IS NOT
A SMART PHONE APP THAT PROVIDES
INSTRUCTIONS TO ASSESSORS AND
SKIP PATTERNS ARE BUILT IN AND
BUTTON ON THE PHONE FOR STOPPING
AND STARTING AND STOPPING THE
TEST AND DATA ENTERED IN
AUTOMATICALLY AND THERE IS A
WIRELESS UPLOAD THAT REALLY
SIMPLIFIES WHAT USED TO BE DONE
IN PEN AND PAPER WITH A STOP
WATCH.
HE ALSO HAS DONE WORK LOOKING AT
EACH OF THE THREE COMPONENTS IN
TERMS OF PREDICTIVE VALUE
RELATIVE TO ENTIRE SBBB. IT IS
VERY CLEAR THAT MOST PREDICTIVE
VALUE OF SBBB IS FROM THE GATE
SPEED COMPONENT AND ARE ROC
CURVES THAT ON THE LEFT IS ADL
DISABILITY AT ONE YEAR.
ON RIGHT IS ANOTHER FOUR-YEAR
PERIOD AND BOTTOM IS MOBILITY
DISABILITY AND AGAIN OVER A 1 IN
FOUR YEAR PERIOD. YOU CAN SEE
CURVES, TOP CURVE BEING ENTIRE
SBBB AND ONE BELOW ON SOLID LINE
BEING GATE SPEED ALONE THAT
NEARLY IS AS STRONG AS ENTIRE
SBBB AND IS SHOWN IN SEVERAL
STUDIES AND BASED ON THOSE
RESULTS STEPHANIE SADIN SKI
LOOKED CAREFULLY THROUGHOUT
LITERATURE IN DIFFERENT COHORTS
FOCUSING ON GAIT SPEED ALONE
WITH DATA AND TALLYING STUDIES
DEMONSTRATING REDUCTIONS IN
MORTALITY PER .1 METER PER
SECOND INCREASED IN GATE SPEED
AND FINAL ESTIMATE IS AT BOTTOM
THAT IS ABOUT A 10% RELATIVE
REDUCTION IN MORTALITY FOR EACH
.1 INCREASE IN GAIT SPEED.
SHE HAS DONE WORK WITH A 4 METER
WALK AND WITH THESE CATEGORIES
AND WITH THE FOLKS WITH GAIT
SPEEDS ABOVE 1 THAT IS OFTEN
CONSIDERED THRESHOLD THAT FOLKS
ARE GENERALLY AT LOWER RISK WITH
OUTCOMES AND IN THIS CASE
DECLINING GLOBAL FUNCTION AND ON
LEFT IS A NEW DIFFICULTY AND
PERSONAL CARE ON THE RIGHT. YOU
SEE THOSE RATES ARE RELATIVELY
LOW OVER THE YEAR AT 6% AND
11.9% AND 8 SPEEDS BELOW .6 ARE
IDENTIFYING A HIGH-RISK GROUP
WITH OUTCOME RATES THAT ARE
NEARLY 36% FOR DECLINING GLOBAL
HEALTH AND 69% FOR NEW
DIFFICULTY AND PERSONAL CARE
WITH INTERMEDIATE GROUP OF .6 TO
1.
THOSE ARE SHORT DISTANCE WALK
RESULTS AND IS PROBABLY FAMILIAR
ALSO WITH LONGER DISTANCE WALK
RESULTS AND TWO BEING 6 MINUTE
WALK USED FOR MANY YEARS
INITIALLY IN PULMONARY
LITERATURE AND MORE IN THE LAST
DECADE OR SO IN GERIATRIC
LITERATURE AND KUDZIN IS 400
METER WALK AND 6 MINUTE WALK AND
MEASURE DISTANCE WALKED IN 6
MINUTES AND 400 METER WALK IS
ABOUT A QUARTER MILE THAT IS
DEVELOPED FOR THE LIFE TRIAL AS
A DICHOTOMOUS OUTCOME AND
ABILITY TO WALK 400 METERS
WITHIN 15 MINUTES.
AND YOU CAN SEE ON THIS VIDEO
THERE IS [INDISCERNIBLE] AT
PARTICIPATANT'S SIDE THAT IS
DEMONSTRATING, YOU KNOW, HOW TO
WALK A LAP. IT IS USUALLY A 20
METER COURSE WITH CONES AT ONE
END OR ANOTHER AND 6 MINUTE WALK
MEASURING DISTANCE AND WALKING 6
METERS AND YOU BEGIN TIMING WHEN
THEY START THEIR FIRST STEP.
FOR SAFETY REASONS AND TRAINER
OR OBSERVER IS AT THE SIDE AND
TEST FOR 400 METER WALK IS DONE
AND COMPLETED OR PASSED LINE FOR
10 COMPLETE LOOPS.
THERE IS CRITERIA FOR
RESPONSIVENESS CONSIDERING WHAT
MEANINGFUL CHANGES ARE FOR EACH
MESH YOOSHS AND SMALL CHANGES
ARE DETECTIBLE AND POTENTIALLY
CLINICALLY MEANINGFUL AND
SUBSTANTIAL CHANGES ARE
DETECTIBLE CONSIDERED CLINICALLY
MEANINGFUL FOUR YEAR WALK.
5 POINTS AND ONE POINT AND 12
POINT SCALE AND 6 MINUTE WALK IS
A SMALL CHANGE IS CONSIDERED 20
METERS AND SUBSTANTIAL CHANGE IS
50 METERS AND IN GAINING AND
INCREASING APPRECIATION ON
MEANINGFUL CHANGES DIFFER
PURPOSE BEING STUDIED AND
PURPOSE OF MEASURE ANALYSIS
COMPLETED FROM NIA SPONSORED
TESTOSTERONE TRIALS AND WERE MEN
AT BASELINE WITH GATE SPOOED OF
LESS THAN 1.2 AND BASED ON
ANCHORING METHODS AFTER TRIAL IS
DONE CLINICALLY IMPORTANT
DIFFERENCES FRAFRNG 6 TA ENTO 30
METERS THAT IS LOW IN STANDARD
IN PRIOR STUDIES AND SLIDE FROM
WORK JAMIE JUSTICE HAS DONE
ABOUT TRANSLATION AND MOBILITY
ACROSS SPECIES I WILL FOCUS ON
FUNCTIONAL LIMITATION COLUMN AND
SEEING AT TOP HUMANS TALKING
ABOUT LOCOMOTOR FUNCTION GAIT
SPEED AND SBB AND VARIATIONS ON
THAT SUCH AS TUG AND TIMED UP
AND GO WALKING ACROSS ROOM AND
RODENT AND MICE MODELS
LOCOMOTION WITH GAIT SPEED AND
NONPRIMATE HUMAN MODELS UNDER
LOCOMOTION GAIT SPEED. GAIT
SPEED IS SOMETHING THAT COULD BE
MEASURED HEARING EARLIER IN THE
MEETING ACROSS SPECIES PROVIDING
EVIDENCE IN USE OF HUMANS
INCREASING VALUE AND ANIMAL
MODELS AND ANOTHER SLIDE FROM
SAME PAPER BY JAMIE JUSTICE WITH
HUMAN PRIMATE MODELS AND RATS
AND RODENANT AND -- GOING TO RIT
79 FOR HUMANS EQUIVALENT AGES
FOR LOWER SPECIES AND LOWER
SURVIVAL AND WORK DONE IN BOTTOM
PANEL WITH THE SURVIVOR OR
MORTALITY RATE AT DIFFERENT AGES
AT DIFFERENT SPECIES THAT ARE
RELEVANT TO EACH OTHER AND IN
50S SURVIVED MORTALITY THAT ARE
ABOUT 10% AND THERE IS NO OTHER
SPECIES IN THOSE DATA AND TO THE
RIGHT IN 60S YOU CAN SEE THAT
MORTALITY IS COMPARABLE AND TO
FAR RIGHT WITH HUMANS IN 80S IN
COMPARABLE WHO ARE MICE AND
RODANT MODELS SEEING
RELATIONSHIP WITH SURVIVAL AND
THIS ALLOWS TO DO TRANSLATIONAL
RESEARCH ACROSS SPECIES.
IT HAS LED TO WORK DONE BY.
>>COUNTY ADMINISTRATOR VOSBURG:
IAL AND LOU EEJI WAS INVOLVED
PROBABLY IN THIS THIS IS A
TRANSFERABLE RATE AND SPECIES
DIFFERENCES AT TOP AND
NON-LINEAR DECLINE IN GAIT SPEED
AND IN HUMANS ON LEFT AND MICE
ON RIGHT AND LATER IN LIFE AND
ARE DRIVEN BY DIFFERENT FACETS
OF GAIT IN HUMANS THAT IT TENDS
TO BE WITH GAIT STEP LENGTH AND
THAT IS THE MIDDLE PANEL AND YOU
CAN SEE THERE IS A DIMMIN USHIA
OF STEP LENG NNL HUMANS NOT SEEN
IN MICE AND LOWER PANEL, HUMANS
MAINTAIN CADENCE IT THIS AIS
REDUCED DRIVING REDUCTIONS IN
GAIT SPEED IN MICE AND IS WORK
THAT HAS LED TO A NEW
PERSPECTIVE STUDY IN MICE THAT
IS EQUIVALENT TO THE BSLA AND
BALTIMORE LONGITUDINAL AGING
CALLED SLAM STUDY OF
LONGITUDINAL AGING IN MICE THAT
IS LED BY RAFAEL. IN SUMMARY,
MOBILITY IS ESSENTIAL ELEMENT OF
GERIATRIC ASSESSMENT MOBILITY IS
IMPORTANT FUNCTION OF TESTING IN
AGENTS AND ABILITY CAN BE
ASSESSED RELIABLY IN
SELF-REPORTED PERFORMANCE
MEASURES MEASURES OF DISABILITY
AND BEING REVERSE TRANSLATED TO
COMPARABLE MEASURES IN RODENTS
AND NONPRIMATES AND TRANSLATED
ACROSS SPECIES AND THANK YOU.
>>[APPLAUSE].
>>THANK YOU AND TO ORGANIZERS
FOR INVITING ME AND TURNING TO A
MORE HIGH-LEVEL COMPLEXITY TALK.
I THINK IT IS HIGHLY RELEVANT
FOR THE MATHEMATICAL MODELING
PIECE THAT WILL COME LATER TODAY
AND BIOMARKERS PIECE AND HEARING
ABOUT HOW TO MEASURE FRAILTY AND
RESILIENCE AND BIOLOGY THAT WE
THINK UNDERLIES IT WE NEED LOTS
OF DIFFERENT BIOMARKERS AND
MODELS TO COME UP WITH MORE
PRECISE MEASURES OF FRAILTY AND
MORE PRECISE WAYS TO ULTIMATELY
INTERVENE ON FRAILTY AND PROMOTE
RESILIENCE IN OLDER ADULTS AND
LIKE LUIGI SAID EARLIER IN FIELD
OF GERIATRICS AND SEEING END
STAGE OF MANY DIFFERENT
CONDITIONS IN LIFE, BUT,
EVERYBODY SORT OF WANTS THE SAME
THING AS THEY AGE AND WANT TO
MAINTAIN HIGH ENERGY LEVELS AND
ROBUST GOOD HEALTH DON'T WANT TO
BE IN HOSPITAL OR MEDICAL
SYSTEMS AND WANT TOIN DEPENDENT
IN CLEAR THINKING AND ENJOYING
SOCIAL CONTEXT IN MEANINGFUL
ACTIVITIES AND WHAT WE ARE DOING
HERE REMINDING OURSELVES DIVING
INTO PATHWAYS, BIG PURPOSE IS
OUT THERE TO TRY TO KEEP THESE
THINGS IN TACT AS PEOPLE AGE.
SO, I WILL TALK ABOUT
DEFINITIONS AND
CONCEPTUALIZATION AND FRAILTY
AND RESILIENCY AND BIOLOGIC
DISCOVERY AND I PROBABLY WON'T
HAVE TIME TO GET INTO THE
CLINICAL UTILITY PIECE TODAY.
WHY DO WE MEASURE IT?
IN CLINICAL PRACTICE, FRAILTY
HELPS US REALLY TO IDENTIFY HIGH
RISK INDIVIDUALS AS SUSAN
POINTED OUT EARLIER.
WHEN WE DO THAT, WE CAN OFTEN
HELP PREVENT CATASTROPHIC
CLINICAL OUTCOMES MODIFYING CARE
ACCORDINGLY AND RED FLAG PUT ON
THOSE PARTICULAR SUBSET OF
INDIVIDUALS THAT WE KNOW ARE
HIGH RISK AND WE SHOULDN'T BE
DOING ALL THINGS WE CAN DO TO
PATIENTS TRYING TO PROTECT THEM
A LITTLE BETTER.
WITH RESILIENCE, I THINK THAT
THE REASON THAT WE TRY TO
MEASURE RESILIENCE THAT IS A
WORK IN PROGRESS AS YOU WILL
HEAR REALLY IS TO ENABLE OPTIMAL
PERFORMANCE OF STRESS RESPONSE
PATHWAYS THAT EVERYBODY HAS
IMBEDDED IN THEM.
AND ULTIMATELY FOR PREVENTIVE
AND RECOVERY PURPOSES.
EXCUSE ME A SECOND.
I WILL GET INTO FRAILTY HERE
FIRST. SUSAN MENTIONED HUNDREDS
OF FRAILTY MODELS AND THERE IS
HUNDREDS TO MEASURE FRAILTY AND
OUR GROUP AT HOPKINS AND IN
CANADA 20 PLUS YEARS AGO REALLY
STARTED TO DESIGN THESE TOOLS
CALLED MEASUREMENT OF FRAILTY
THAT ARE CONCEPTUALLY DIFFERENT
AND CHEN LEE AND OTHERS HAVE
PUBLISHED PAPERS ON THAT AND ON
RIGHT SUSAN TALKED ABOUT DEFICIT
ACCUMULATION APPROACH TO FRAILTY
AND LOTS OF DEFICITS COMING INTO
THIS MAIN CONCEPT THAT COULD BE
CHRONIC ILLNESSES OR MOBILITY
DISABILITY AND COULD BE SOCIAL
SITUATIONS AND LOTS OF DIFFERENT
THINGS AND MORE DEFICITS AN
INDIVIDUAL HAS MORE LIKELY THEY
ARE TO BE FRAIL BY THIS MODEL
THAT WE CAME AT IT FROM A
DIFFERENT PERSPECTIVE THINKING
ABOUT THE FIRST DEEPER BUY OL
THAT IS HAPPENING AS PEOPLE AGE
AND DEEP AGING RELATED CHANGES
THAT THEN LEAD TO THESE SORT OF
CLINICAL CHARACTERISTICS WE SEE
IN A SUBSET OF VULNERABLE
PATIENTS WE CALL PHYSICAL
FRAILTY AND FRAILTY DEFICIT
ACCUMULATION INDEX AND MANY,
MANY DIFFERENT TOOLS HAVE SPUN
OFF FROM UNDERLYING CONCEPTS AND
WILL TALK TODAY ABOUT BIOLOGIC
UNDERPINNINGS WE THINK IS
RELATED TO PHYSICAL FRAILTY THAT
MAY WELL BE IN THE END AS WE
COME TO DISCOVER THE GEROSCIENCE
AGING RELATED BIOLOGY THAT IS
DRIVING BOTH CAUSES OF FRAILTY
AND REASON THAT OLDER PEOPLE
COLLECT ALL THESE COMORBIDITIES
AND CHANGES OVER TIME IS BECAUSE
OF THE SAME AGING RELATED
BIOLOGY.
IN PHYSICAL FRAILTY WORLD, WE
USE FIVE MEASURES PUTTING
TOGETHER OPERATIONALIZING IT IN
AN EXAM AND IF PEOPLE HAVE THREE
OR 4 OR FIVE OF THESE CRITERIA,
THEY WERE PUT IN A FRAIL
CATEGORY AND 0 WITH ROBUST AND 1
OR 2 IN NEBULOUS PREFRAIL
CATEGORY AND WHEN PEOPLE ARE
PREFRAIL THEY ARE HEADED TOWARDS
FRAILTY IN A FEW YEARS AND THIS
CHARACTERIZATION OF HUMAN
SUBJECTS MADE US TO BE ABLE TO
DIFFERENTIATE AND STUDY BIOLOGY
AND ROBUST AND FRAIL GROUPS TO
SEE WHAT HAPPENS TO THEM OVER
TIME. IT THIS IS JUST A
PREVALENCE STUDY THAT KAREN AND
OTHERS DID SEVERAL YEARS AGO IN
US POPULATION AND SHOWS THAT
ABOUT 15% OF OLDER ADULTS LIVING
IN COMMUNITY FELL INTO THE
FRAILTY CATEGORY AND 40% IN
ROBUST AND LOTS OF OTHER PEOPLE
WERE IN-BETWEEN. AS PEOPLE GET
OLDER, THEY ARE CERTAINLY MORE
LIKELY TO FALL INTO FRAIL
CATEGORIES.
WE OFTEN -- WE -- AGAIN, WE
THOUGHT OF THIS AS A BIOLOGIC
CONSTRUCT AND THINKING VERY
EARLY ON ABOUT WHAT IS IT ABOUT
AGING THAT MAKES OLDER PEOPLE
MORE VULNERABLE?
AGE RELATED CHANGES IN MANY
MOLECULAR AND PHYSIOLOGICAL
SYSTEMS PROVIDE A PLATFORM FOR
VULNERABILITY AND ALTERATIONS WE
THOUGHT PROBABLY PERSISTED FOR
YEARS BEFORE THEY END UP
BECOMING CLINICALLY MANIFESTED
IN SIGNS AND SYMPTOMS AND SAME
THING. WE -- THINKING WAS
ALWAYS THAT THE SAME AGE ALT
ALTERALTERED
BIOLOGIC CHANGE -- HIGH RISK OF
FALLING AND MANY CHRONIC DISEASE
STATES TRAVEL TOGETHER WITH
FRAILTY. HEART FAILURE AND
HYPERTENSION AND DEPRESSION AND
ANXIETY AND DIFFERENT CONDITIONS
TEND TO AGGRIFATE LATER IN LIFE
AND WE PUT TOGETHER A BIOLOGIC
CYCLE OF FRAILTY THAT, AGAIN, I
TELL MY JUNIOR FOLKS WORKING
WITH ME THAT WE GENERALLY
RECOMMEND AGAINST WRITING A
CHAPTER THAT NEVER SEEMS TO HELP
YOUR CAREER. THIS REALLY HELPED
MINE. WE PUT THIS MODEL
TOGETHER VERY EARLY ON WITH A
CYCLE OF DECLINE AND WITH
FRAILTY AND SARCOPENIA THAT IS
PUT TOGETHER AND YOU CAN SEE
LOTS OF DIFFERENT PIECES THERE
WITH SOME MOLECULAR MEASURES AND
SOME PHYSIOLOGIC MEASURES AND
SOME MOBILITY MEASURES AND GIVES
YOU A SENSE OF THE SORT OF MESSY
MEASUREMENT ISSUES RELATED TO
FRAILTY AND I THINK THAT I HAVE
SPENT MOST OF MY CAREER NOW
TRYING TO UNRAVEL SOME PIECES
AND BECOMING MORE PRECISE IN THE
MEASUREMENT.
FAST FORWARD 20 YEARS, LOTS AND
LOTS OF EPIDEMIOLOGIC STUDIES,
HUNDREDS IF NOT THOUSANDS OF
EPIDEMIOLOGIC STUDIES LOOKING AT
RELATIONSHIP BETWEEN VARIOUS
BIOLOGIC INDICATORS OR MEASURES
AND OUTCOMES AND ON RIGHT YOU
SEE OUTCOMES THAT ARE RELATED TO
PHYSICAL FRAILTY AND HIGH RISK
OF BECOMING DEPENDENT AND HIGH
RISK OF BECOMING DISABLED AND
LOTS OF CHRONIC DISEASE BURDEN
AND EARLY MORTALITY AND MEASURES
OUT THERE IN OUTCOMES AND
SYMPTOMS AND SIGNS AND SYMPTOMS
OF PHYSICAL FRAILTY MENTIONING
EARLIER DETERMINING WHO IS FRAIL
AND NOT FRAIL IN THE YELLOW BOX
AND BIG SUMMARY OF EPIRELATED
STUDIES SHOWING DETAIL ON THIS
IN PAIL MRU BOX ALTERED STRESS
RESPONSE SYSTEMS THAT ARE VERY
CHARACTERISTIC OF SOMEBODY THAT
IS FRAIL AND I WILL TALK ABOUT
THEM AND ENERGY METABOLISM AND
CHANGES IN WAY THAT PEOPLE
PROCESS ENERGY MITOCHONDRIAL
ENERGY AND PCA CYCLE AND GLUCOSE
TOLERANCE AND THERE IS TWO ARMS
THERE AND FINALLY OUT ON FAR
LEFT, DARK BLUE BOXES BIOLOGIC
AGING HEART OF GEROSCIENCE WE
HAVE THOUGHT ABOUT MANY YEARS
WHAT MOLECULAR CHANGESES
TRIGGERING THIS PHYSIOLOGY IS
AND ULTIMATELY SYNDROMES WE SEE
LATER IN LIFE AND BAD OUTCOMES
AND CERTAINLY GENES AND HEARING
YESTERDAY SOCIOECONOMIC
CONDITIONS AND DIET AND ACTIVITY
PLAY CERTAINLY BIG ROLES IN THAT
AND CHRONIC DISEASES ALSO CAN
DRIVE THAT SAME PHYSIOLOGY IN
LIGHT BLUE BOX AND ALSO
ALTERNATIVELY PROBABLY
PHYSIOLOGY IS MAKING MANY
DISEASE CONDITIONS WORSEN.
SO, THIS IS A KIND OF BIG
PICTURE HOW WE TRIED TO
CONSTRUCT THINKING ABOUT THAT.
AND PERFORMING MEASURES ALONG
PATHWAYS TRYING TO RELATE THEM
OUT TO EITHER THE SIGNS AND
SYMPTOMS OF FRAILTY OR
ULTIMATELY TO OUTCOMES THAT HAS
BEEN SORT OF THE WAY THAT WE
TRIED TO EXPLORE THE BIOLOGY.
THIS IS ANOTHER WAY OF LOOKING
AT IT A LITTLE BIT MORE DETAILED
ON LEFT THERE AND POINTING TO
MOLECULAR AGES AND MEASURES OF
MITOCHONDRIAL DESIGNS
DEMETHYLATION AND SIN ESSENCE
CELL MEASUREMENTS AND THOSE ARE
DEEPLY MOLECULAR MEASURES HARD
TO DO IN HUMAN SUBJECTS YOU CAN
DO THEM SUPER EXPENSIVE TISSUES
SOMETIMES AND SPECIAL ASSAYS NOT
READY FOR CLINICAL PRIME TIME
AND THINGS WE WOULD LOVE TO GET
TO IN NEXT FEW YEARS IN PATHWAYS
THAT COULD BE DONE ON SERUM
SAMPLES AND THINGS THAT WOULD BE
RELATIVELY EASY TO MEASURE IN
HUMAN SUBJECTS AND PATIENTS
OTHER BOXES I WON'T TALK ABOUT
TODAY AND [INDISCERNIBLE] IS
RIPE FOR EXPLORATIONINATE IMMUNE
SYSTEM CHRONIC INFLAMMATION
ASSOCIATED WITH THAT IS CLEARLY
NOT ONLY HIGHLY RELATED TO
ADVERSE OUTCOMES SEEING IN OLDER
ADULTS AND FRAILTY AND
PHENOTYPES IN OLDER ADULTS AND
KNOW NOW IS DRIVING MANY OTHER
PROCESSES THAT ULTIMATELY SEEM
TO MAKE OLDER ADULTS VULNERABLE
TO LOTS OF CONDITIONS NOT JUST
EPIPHENOMENON COMMONLY SAID TO
20 YEARS AGO THERE IS BUY LOGIC
STUDIES CONNECTING CHRONIC
INFLAMMATION AND MEDIATORS TO
CHANGES IN MUSCLE AND IN IMMUNE
SYSTEM AND CHANGES IN BRAIN
TISSUE FOR EXAMPLE IN THE END
DRIVE SOME PHENOTYPES WE SEE AND
THERE IS A STRESS RESPONSE
SYSTEM HPA ACCESS SYMPATHETIC
NERVOUS SYSTEM THAT IS IN FRAIL
PEOPLE TENDING TO GET TURNED ON
NOT OFF AND ENERGY PRODUCTION
ANANABOLIC HORMONES AS WELL AND
OTHER MARKERS TO PICK UP ON
CHANGES IN FIZZ LOGIC SYSTEMS NO
THE SORT OF NECESSARILY READY
FOR CLINICAL PRIMETIME AND
ASSOCIATED IN EPISTUDIES AND IS
ANOTHER WAY THAT WE TRY TO THINK
ABOUT IT IN CLINICAL PRACTICE
AND ABOVE OLDER PERSON THAT IS
FRAIL AND WE KNOW WHAT THEY CAN
LOOK LIKE AND CHARACTERIZE THEM
BY FRAILTY AND TOP OF RIM OVER
THERE WEAKNESS LOW ACTIVITY AND
SLOW WALKING SPEED FOR EXAMPLE.
THERE IS LAB TESTS WE PICK UP
AND IN PEOPLE WE SEE LOW
ALBUMINCHOLESTEROL LEVELS AND
ANEMIA AND INCREASING CLOTTING
FACTORS AND THINGS DO YOU
ROUTINELY IN CLINICAL PRACTICE
YOU MIGHT SEE THAT AND THEY
ASSOCIATE WITH FRAILTY AND
UNDERNEATH THAT LINE AND OVALS
ARE THINGS GETTING RAMPED UP IN
FRAIL OLDER PEOPLE.
WE DON'T REALLY KNOW HOW TO
CAPTURE THEM CLINICALLY IN
CLINICALLY MEANINGFUL WAYS AND
ARE DOZENS IF NOT HUNDREDS OF
IMBEDDED BIOMARKERS DOWN THERE
AND WE WILL HOPEFULLY HEAR MORE
ABOUT THAT TODAY AND ULTIMATELY
THINKING ABOUT MEASURES AROUND
CIRCLES AT BOTTOM MOLECULAR
MEASURES AND SIN ESSENCE AND BIG
GROUPS ACTIVELY WORKING IN THESE
AREAS THINKING ABOUT HOW TO GET
TRANSLATED INTO CLINICALLY
MEANINGFUL MEASUREMENTS ARE
SUPER IMPORTANT AND ONE THING
THAT COULD COME OUT OF THIS
MEETING THAT WILL NEED A LOT OF
BIOLOGISTS WORKING ON THIS AND
STATISTICIANS THINKING ABOUT
MATHEMATICAL MODELING THINKING
ABOUT HOW TO PUT THESE TOGETHER
THINKING OF WHICH IS MOST
PREDICTIVE PATHWAY TO INTEGRATE
AND RESILIENCE I WILL SPEND REST
OF TIME TALKING ABOUT THAT, THAT
IS SOMETIMES THOUGHT OF AS
FLIPSIDE OF FRAILTY AND PEOPLE
THAT ARE RESILIENT OLDER PEOPLE
ARE GENERALLY NOT FRAIL AND
BEING RESILIENT IS NOT
NECESSARILY MEASURED IN SAME
WAY.
THESE ARE THEORIES PUT OUT OVER
LAST 20 OR 30 YEARS NOW
MAINTENANCE OF COMPLEXITY LOU IS
SITTING THERE GIVING SHOUTOUT TO
20-SOME YEARS AGO AND THOUGHT OF
HOMEO STATIC REGULATION AND DEEP
INTERNAL BUY LOGIC RESPONSES AND
IN STRESS SYSTEMS AND OTHER
AREAS THAT HOLD FUNCTION AND
SYSTEMIC FUNCTION TOGETHER AND
AS THOSE THINGS BECOME
UNRAVELLED THEY TEND TO BE LESS
COMPLEX AND SYSTEMS BECOME LESS
COMPLEX AND REGULATIONS WANE AND
COLLABORATORS FROM DUKE AND
INFORMATIVE THINKING ABOUT MODEL
OF RESILIENCY AND THINK OF IT AS
SORT OF COMMON UNDERPINNINGS
WITH FRAILTY AND NOT QUITE THE
FLIPSIDE AND ABILITY WE DEFINE
IT AS OBLT TO RECOVER FROM
POTENTIALLY DANLING STRESSORS
RETURNING TO HOMEO STATIC
FUNCTIONAL BASELINE AND
UNDERLYING HYPOTHESIS HAS BEEN
AGING RELATED LOSS OF PHYSICAL
REDISTILL YENLS HAPPENS WHEN
PHYSIOLOGIC SYSTEMS ARE UNABLE
TO MAINTAIN EQUILIBRIUM AND FACE
OF STRESSORS PEOPLE HAMMERED
WITH PSYCH LOGIC OR PHYSICAL
STRESS OR ILLNESS AND BODY CAN
GENERALLY BOUNCE BACK.
PHYSIOLOGICAL SYSTEMS ARE IN
TACT AND PEOPLE BECOMING LESS
AND LESS REDISTILLENT GET TO
TRANSITION TOWARDS FRAILTY THAT
IS A FIGURE THAT CHEN LEE AND
OTHERS HAVE USED OVER YEARS AND
YOU SEE STRESSORS HAPPENING IN
PEOPLE'S LIVE AND YOUNGER
NONFRAIL PEOPLE CAN GENERALLY
BOUNCE BACK YOU SEE IN CLINICAL
PRACTICE ALL THE TIME AND SOME
PEOPLE DON'T BOUNCE BACK AND
GENERALLY PEOPLE ARE BELOW FRAIL
THRESHOLD IN THE MIDDLE THERE
THEY ARE NOT AGE TO WITHSTAND
STRESSORS DOING POORLY
CLINICALLY AND FIGURE OUT HOW TO
MEASURE RESILIENCE THAT LED TO
US WORKING ON A GRANT THAT WAS
FUNDED 5 YEARS AGO NOW END
STAGES FOR COLLECTING DATA AND
ARM OF OLDER PEOPLE GETTING BONE
MARROW TRANSPLANTS AND GETTING
DIALYSIS AND GETTING KNEE
REPLACEMENTS BIG CLINICAL
STRESSORS HAPPENING IN HOSPITAL
GENERALLY AND WE HAVE AN
OPPORTUNITY TO MEASURE LOTS OF
BIOMARKERS AND FUNCTION AND
COGNITION BEFOREHAND AROUND TIME
OF THE STRESSOR AND WE FOLLOW
THEM OUT FOR A YEAR AND PICKED
UP LOTS OF BIOLOGIC AND CLINICAL
MARKERS DURING THAT PERIOD AND
HOPEFULLY SOON WE WILL BE ABLE
TO START ANALYSIS THAT IS A
GREAT RESOURCE FOR YEARS TO COME
FOR PEOPLE THAT WANT TO
COLLABORATE WITH US.
THIS IS THE BIG MODEL WE PUT
TOGETHER AND CENTER IS
EDISTILLIENCE CAPACITY OF AN
ORGANISM TO WITHSTAND STRESS AND
THINGS WHAT YOU ARE TRYING TO
MEASURE THERE AND BOXES WE CAN
MEASURE AND VARIOUS CLINICAL OR
BIOLOGIC OR OTHER KINDS OF
MACCERS AND AT LEFT YOU SEE
STRESSORS THAT WE SEE NOW THAT
ARE BONE MARROW TRANSPLANT BIG
HAMMER AND KNEE REPLACEMENT THAT
IS MODERATE HAMMER AND DIALYSIS
THAT IN SOME PEOPLE ARE REALLY
BAD HAMMERS AS WELL.
WE CAN CHARACTERIZE THEM AND
MEASURE THEM AND BEFOREHAND
PEOPLE'S AGE AND PHYSIOLOGIC AND
PSYCHOSOCIAL HEALTH PROFILES,
BEHAVIORS AHEAD OF TIME AND
DISEASE BURDEN.
FUNCTIONAL AND COGNITIVE MARKERS
AND JERO SCIENCE MARKERS RELATED
TO SIN ESSENCE AND GROUP AT MAYO
AND EPIGENETICS AND BIOPHYSICAL
PROPERTIES OF SELVES AND AGE
RELATED UNIQUE MARKERS HERE
THOSE ARE DUMPED INTO THAT
CENTER AND WE KNOW THOSE THINGS
WILL CONTRIBUTE TO SOMEBODY'S
RESILIENCE.
WE THINK IT IS PHYSIOLOGIC
SYSTEMS THAT DRIVE THAT AND WAY
TO STUDY SYSTEMS IS TWEAKING
THEM A BIT TO DO STRESS AND
YELLOW BOX AT LEFT AND DYNAMIC
STIMULATION OF VARIOUS
COMPONENTS OF STRESS RESPONSE
SYSTEMS WE HAVE IMBEDDED THAT I
WILL TALK ABOUT A BIT ABOUT THAT
STATIC MEASURES OF RESILIENCE
AND THINGS LIKE FRAILTY AND
FATIGUE FOR EXAMPLE COLLECTING
DATA IN LIGHT BLUE BOX AND WHAT
PEOPLE ARE LOOKING LIKE OVER 1,
3, 6, ONE YEAR OUT AND SEE WHAT
HAPPENS TO THEM IN END
TRAJECTORIES OF THOSE WITH BONE
MARROW TRANSPLANT AND DIE IN
THREE MONTHS AND DO OKAY
FUNCTIONALLY AND COGNITIVELY
PROBABLY DIMINISHED BUT ARE
STILL ALIVE AND HAVEN'T DIED AND
OTHER PEOPLE ARE COMPLETELY
CURED AND CHARACTERIZING SYSTEMS
THAT ARE DRIVING OUTCOMES AND SO
I WHETHER QUICKLY MOVE THROUGH
DYNAMIC SYSTEMS STUDIES AND STEM
TESTS HPA AXIS WITH -- WE HAVE
HOLTER MONITORING GIVING
AUTONOMIC NERVOUS SYSTEM
ACTIVITY VARIABILITY AND
CONTRASTING VARIABILITY BETWEEN
HIGH FREQUENCY VARIATION AND
TOTAL HEART RATE VARIABILITY
MEASURED ON HOLTER MODELS
OBSERVED FATIGUABLE ON HOLTER
SITES AND LYMPHOCYTES IMAGINING
IN HAMMER AND TEST TUBE AND WHAT
EXPLODES OUT OF THEM AND
ORTHOSTATIC BLOOD PRESSURE
MEASUREMENTS MODERATE TWEAKS IN
SYSTEMS AND HYPOTHESIZE THOSE
THAT ARE EDISTILLIENT WILL DO
LOW ON TEST AND THOSE THAT ARE
NOT WILL GIVE INSIGHTS INTO
WHICH STRESS RESPONSE SYSTEM
MAIZE BE IMPACTED IN RESILIENCE
OR LACK OF RESILIENCE.
AGAIN, WE MENTION MANY
GEROSCIENCE MEASUREMENT DOMAINS
WE PUT IN THERE AND LOOKING
FORWARD TO TALKS LATER TODAY.
I THINK THAT ONE THING THAT WE
THOUGHT THROUGH THIS IS AN AIR
WHY THAT REALLY NEEDS TO BE
MOVED FORWARD IS TAKING THESE
SORT OF VERY DEEP MOLECULAR
MEASURES PEOPLE ARE WORKING ON
IN MITOCHONDRIA FOR EXAMPLE OR
ETOPAGY AND SYNESSENCE AND
THINGS RELATE TODAY THAT PROET
TEOMICS AND METABOLOMICS ARE
MOVING MORE INTO THE MAINSTREAM
BUT HAVEN'T SEEN LOTS OF
PRODUCTS GETTING PUSHED INTO THE
SORT OF CLINICAL SIDE AND
HOPEFULLY AS WE MOVE FORWARD IN
RESEARCH FIELDS IN COMING YEARS
WE WILL BE ABLE TO CHERRY PICK
HOPEFULLY IMPORTANT MARKERS FROM
THESE INSTEAD OF SPENDING
THOUSANDS AND THOUSANDS OF
DOLLARS ON TESTS WITH ASSAY THAT
IS $50 LIKE HEMOGLOBIN OR
SOMETHING.
I WILL SKIP THAT. SUMMARY AND
PHYSICAL FRAILTY AND PHYSICAL
RESILIENCE ARE NOT SAME BUT
LIKELY HAVE COMMON BIOLOGIC
UNDERPINNINGS AND DEFICIT
ACCUMULATION AS WELL PROBABLY.
THAT TYPE OF FRAILTY AND
IDENTIFICATION OF FRAILTY
ENABLES DEVELOPMENT OF
PROTECTIVE CARE PLAN WE USE IN
CLINICAL PRACTICE LIKE THAT TO
FIND PEOPLE THAT ARE VULNERABLE
PUTTING A SHIELD AROUND THEM AND
IDENTIFICATION AND
CHARACTERIZATION OF RESILIENCE
FROM BUY LOGIC PERSPECTIVES YOU
SEE IS A WORK IN PROGRESS
BETWEEN OUR GROUP AND OTHERS
AROUND THE COUNTRY WE WILL HAVE
LOTS OF INFORMATION COMING OUT
OF THAT IN THE NEXT COUPLE YEARS
AND I WILL ACKNOWLEDGE
RESILIENCE AND FRAILTY GROUP WE
HAVE AT HOPKINS AND WE HAVE
TUESDAY MORNING CALLS AND
WEDNESDAY MORNING EVERY OTHER
WEEK AND WELCOME PEOPLE TO JOIN
CALLS AND HAVE PEOPLE FROM ALL
OVER THE COUNTRY THAT JUMPED IN
AND HAVE REALLY HELPED TO INFORM
THE FIELD THROUGH THEIR INPUT
AND NIA I HAVE TO ACKNOWLEDGE
HAS BEEN INCREDIBLY SUPPORTIVE
OF FRAILTY FOR MORE THAN 20
YEARS IN OUR CENTER AND THROUGH
PHYSICAL RESILIENCY AWARDS THAT
WILL ENABLE LOTS OF DATA TO COME
OUT. I WILL STOP. THANK YOU.
GOOD MORNING. HAPPY TO BE HERE.
THIS SESSION IS HANGING TOGETHER
PRETTY WELL THAT IS SOMEWHAT A
SURPRISE GIVEN THREE WEEKS AGO
OR SOMETHING WHEN WE HAD A CALL
AND NONE OF US HAD A CLUE WHAT
THIS WAS ALL ABOUT. I WANT TO
NOTE THAT I -- WHAT -- I WASN'T
SUPPOSED TO SAY THAT?
YOU HAD A CLUE. IT CAME
TOGETHER SO NOTE THAT I WILL
TALK ABOUT MATERIAL THAT I HAVE
PRODUCED WITH MY POST DOC ERIC
AND GIVEN MY ABILITIES, ERIC
PROBABLY DID MOST OF IT. I WANT
TO JUST MAKE THAT CLEAR FROM THE
BEGINNING. WE WERE TOLD THIS
WAS A SESSION ON MEASUREMENT AND
SYSTEMS AND IT SEEMED TO FIT IN
PRETTY WELL WITH WHAT WE WERE
DOING AT THE TIME.
FOR A LONG TIME, I HAVE WORKED
ON TRYING TO GET AT MEASURES OF
BIOLOGICAL AGING AND ALLOSTATIC
LOAD. I MEAN, WE GO BACK
DECADES HERE.
THINGS GET SOME HANDLE ON WHAT
IT IS IN THIS MULTISYSTEM
PROCESS THAT ACTUALLY UNDERLIES
THIS AGING EXPERIENCE AND CAN BE
USED TO PREDICT AGING OUTCOMES
AND SO WE HAD THIS IDEA THAT
MANY SYSTEMS WERE INVOLVED IN
AGING FOR QUITE A WHILE. AND
THEN GEROSCIENCE KIND OF CAME
ALONG AND SAID, WELL, THERE IS
ACTUALLY ANOTHER LEVEL. IT IS
NOT JUST SYSTEMS AND THERE IS A
MORE BASIC MOLECULAR AND
CELLULAR LEVEL OF AGING. IT IS
-- IT WORKS ACROSS SYSTEMS AND
BOTH SYSTEMS AND LEVELS SHOULD
BE CONSIDERED HERE.
SO, I'M RETURNING TO THIS SAME
QUESTION THAT I PROBABLE WILL I
ADDRESSED A FEW TIMES ALREADY.
BUT, WHAT HAPPENS IS THAT EVERY
TIME WE GET A LOT MORE MARKERS
AND A LOT MORE MEASURES.
NOW WITH THE WEALTH OF
BIOMARKERS WE NOW HAVE AND
MULTISYSTEM APPROACH CAN WE
BETTER UNDERSTAND AGING HEALTH
OUTCOMES?
WE ALSO HAVE NEW ANALYTIC
TECHNIQUES TO APPROACH THIS.
AS NUMBER OF MARKERS GROWS
ABILITY TO USE OLD TECHNIQUES IS
REDUCED GETTING TO NEW WAYS OF
ACTUALLY ANALYZING THINGS.
I WILL USE A MACHINE LEARNING
APPROACH TODAY.
I'M ALWAYS DOING THIS FROM THE
PERSPECTIVE OF SOCIAL SCIENTISTS
THAT I AM. WHAT I'M REALLY
INTERESTED IN IS WHAT UNDERLIES
THE DIFFERENCES IN SOCIETY IN
TERMS OF PACE OF AGING AND
HEALTH OUTCOMES AND SOCIAL
VARIABLES CONNECTED TO IT AND
CAN I USE BIOLOGY TO BETTER
UNDERSTAND SOCIAL DIFFERENCES?
THAT IS WHERE I WILL END UP.
THIS IS THE MODEL OF HEALTH WE
ARE FITTING ALL THE TIME NOW
MOST SOCIAL SCIENTISTS WITH --
OH, SUPPOSED TO DEMOGRAPHIC
DOCTORS AND SOCIOECONOMIC STATUS
BEING MOTIVATING FACTORS TO
UNDERSTAND HOW THEY ARE LINKED
TO HEALTH OUTCOMES ON THE
RIGHT-HAND SIDE.
WHAT ARE PHYSIOLOGICAL MEASURES
AND WHAT ARE THE MOLECULAR AND
CELLULAR MEASURES THAT ACTUALLY
INTERVENE TO MEDIATE THAT
PROCESS AND ACTUALLY HELP US TO
UNDERSTAND THAT PROCESS?
THAT -- THIS IS KIND OF THE
MODEL I'M FITTING AND I WILL
TALK ABOUT THESE TWO LEVELS
MOLECULAR AND CELLULAR HALLMARKS
THAT WE CAN MEASURE NOW ABOUT
HALF -- OF WHICH WE CAN GET AN
INDICATOR OF ABOUT HALF. THEN I
WILL LOOK AT INDICATORS THAT ARE
IN 12 DIFFERENT PHYSIOLOGICAL
SYSTEMS THAT ARE SYSTEMS AND --
I WILL TREAT GENERAL AGING AS A
SEPARATE LEVEL. I WILL TREAT
THESE SYSTEMS THAT ARE LISTED
HERE, 12 DIFFERENT SYSTEMS.
I WILL INCLUDE IN THEM 75
DIFFERENT BIOMARKERS AND I WILL
USE AN APPROACH TO BUILDING
SYSTEM-BASED RISK INDICATORS
THAT WAIT THE DIFFERENT
BIOMARKERS WITHIN SYSTEMS AND
TODAY I WILL TALK ABOUT
PREDICTION OF MORTALITY AND THE
SYSTEMS ONLY HAVE ONE MEASURE
AND ENDOCRINE HAS DHES IN
RESPIRATORY AS A PEAK FLOW
OTHERS HAVE MULTIPLE MEASURES I
WILL USE EXTREME GRADIENT
APPROACHING TO MACHINE LEARNING
THAT IS A FLEXIBLE APPROACH IN
TERMS OF ASSESSING RELATIONSHIPS
OF VARIABLES THAT DOESN'T
REQUIRE LINEARITY OR THINGS LIKE
THAT.
I WILL TAKE A SAMPLE AND DIVIDE
IT IN HALF INTO A TESTING OR
TRAINING SAMPLE AND TESTING
SAMPLE AND I WILL FIRST TAKE THE
MARKERS THAT ARE WITHIN EACH
SYSTEM AND I WILL USE MACHINE
LEARNING APPROACH TO DEFINING
WHICH MARKERS WITHIN THAT SYSTEM
THAT ELATE MOST STRONGLY TO
MORTALITY AND DEVELOP AN INDEX
THAT IS BASED ON THE VALUES OF
THOSE MARKERS AND WEIGHTS THAT
THEY SHOULD HAVE IN THE
MORTALITY INDEX AND I WILL DO
THAT FOR ALL OF THE SYSTEMS
INDIVIDUALLY AND I WILL TAKE
THOSE INDICATORS THAT I HAVE
BUILT BY SYSTEM AND USE THEM IN
THE TESTING SAMPLE TO THEN
ESTIMATE MORTALITY.
AND TO SEE WHICH SYSTEMS ARE
STRONGEST IN ESTIMATING
MORTALITY AND TO ASSESS WHETHER
THESE SYSTEMS ACTUALLY DO
EXPLAIN SOCIAL DIFFERENCES WE
START WITH IN MORTALITY AND
BEGINNING WITH, I WILL SHOW YOU
HOW THE VARIOUS INDIVIDUAL
BIOMARKERS ARE RELATED TO
MORTALITY CHOSEN BY MACHINE
LEARNING APPROACH IN TERMS OF
STRENGTH AND RELATIONSHIP AND
HEALTH AND RETIREMENT STUDY MANY
PEOPLE KNOW ABOUT ACTUALLY THAT
IS A NATIONALLY REPRESENTATIVE
SAMPLE OF AMERICANS OVER AGE OF
50 AND IS 30 YEARS OF DATA.
ONLY EXTENSIVE BIOMARKER DATA
FROM 2006 TAENTHAT CAME FROM A
SAMPLE HERE OF ABOUT 4 THOUSAND
PEOPLE THAT IS GROUP ON WHICH WE
HAVE ALL THESE BIOMARKERS AND
TESTING AND TRAINING SAMPLES ARE
APPROXIMATELY 2000 PEOPLE A
PIE
PIECE.
I WILL BEGIN WITH GENERAL AGING
AND I WILL INDICATE RELATIVE
IMPORTANCE OF 7 FACTORS IN
GENERAL AGING INDICATOR THAT ARE
NUMBER OF EPIGENETIC CLOCKS THAT
WE INCLUDED ALL OF THEM. THEY
ARE NOT THAT HIGHLY RELATED TO
EACH OTHER AND TELOMERE LENGTH
MITOCHONDRIAL NUMBER IN THIS.
YOU SEE THAT IN ALL CASES WHAT
WE ARE -- THE RANGE OF EFFECT
HERE IS FROM 0 TO 1 AND SIZE OF
THE EFFECT REPRESENTS
EXPLANATORY POWER OF INDIVIDUAL
BIOMARKER THAT IS USED TO
CONSTRUCT INDEX AND EPIGENETIC
CLOCKS PHENOAND GRIM AGE IS
STRONG HERE AND ARE ONES THAT
ARE MOST IMPORTANT IN THIS
GENERAL AGING MEASURE.
IF I LOOK AT CARDIOVASCULAR
SYSTEM BY FAR PRO-BNP MEASURE IS
VERY STRONG. IT OUTWEIGHS EVERY
OTHER INDICATOR.
AND IF I LOOK AT MY INNATE
IMMUNE AND INFLAMMATORY SYSTEM
IT IS THE CYTOKINES THAT ARE
WAITING MOST HEAVILY UP NEAR TOP
AND THINGS THAT DON'T RELATE
THAT ARE SOMEWHAT INTERESTING
AND FOR INSTANCE CRP NEVER SEEMS
TO DO ANYTHING ANYMORE WHEN WE
GET ALL CYTOKINES MEASURED AND
LOOKING AT ADAPTIVE IMMUNE,
LYMPHOOCYTES ARE STRONGEST IN
TERMS OF RELATIONSHIP WITH
MORTALITY AND IF I LOOK AT
METABOLIC MARKERS BMI AND HB1C
AND GLUCOSE THAT ARE
APPROXIMATELY EQUAL IN SHARING
EXPLANATORY POWER AND HAVE
EXPLANATORY POWER IN TERMS OF
MORTALITY AND I INCLUDED
NEURODEGENERATIVE OR
NEUROLOGICAL MEASURES BASICALLY
BECAUSE THEY ARE SORT OF SENT
AND BRAIN AGING IS CENTRAL TO
AGING IN GENERAL AND WHILE ONE
MIGHT NOT EXPECT IT TO BE
RELATED TO MORTALITY IN WAYS
THAT OTHER MEASURES ARE IT IS
INTERESTING TO TEST THAT. AMONG
BRAIN INDICATORS NORA FILAMENT
LIGHT IS STRONGEST HERE IN THIS
SAMPLE IN TERMS OF RELATIONSHIP
WITH MORTALITY. RENAL MEASURES
SIFT ATTIN C IS STRONGEST AND
QUITE STRONG AND NUTRITION IS A
SET OF MARKERS THAT ALL PROBABLY
RELATE FAIRLY SIMILAR LY.
LIPIDS, CHOLESTEROLS AND
TRIGLYCERIDES RELATE FAIRLY
SIMILARLY AND CIRCULATORY LIVER.
NOW, I LOOKED AT THE SCORES
ACROSS ALL OF THE 12 SYSTEMS AND
GENERAL AGING MARKERS TO SAY
THAT ARE THEY TOO RELATED TO
EACH OTHER?
ARE THEY EXPLAINING SAME THING?
SENSES IS CORRELATION AS CROSS
ALL SYSTEMS ARE NOT THAT STRONG
AND STRONGEST WITH GENERAL AGING
MEASURE THAT IS PROBABLY GOOD,
SENSIBLE, FOR THE WAY THAT WE
LOOK AT THE WORLD.
NONE OF THEM REALLY REACH WHAT
WE WOULD SAY IS LEVEL OF
MULTI-COLLINIARITY THAT WOULD
PREVENT EVERYONE FROM LOOKING AT
MEASURES AT SAME TIME AND ONES
WITH HIGHEST LEVEL OF
CORRELATION OR RENAL MARKERS
RELATED TO SOME SYSTEMS WITH A
.6 CORRELATION COEFFICIENT AND
MOST OTHERS ARE RELATIVELY LOW
AND COULD END OF A LEVEL TO BE
ENTERED INTO A MODEL
SIMULTANEOUSLY.
THAT IS WHAT WE DO NEXT.
WE NOW GO TO THE TESTING SAMPLE.
WE TAKE INDICATORS FOR EACH
SYSTEM THAT WERE DEVELOPED USING
WEIGHTS ON BIOMARKERS SHOWN TO
MAKE INDIVIDUAL SYSTEM MEASURES
TO ELATE THEM TO MORTALITY DOING
THAT, WE REDUCED OUR 70 MEASURES
HERE TO 12 MEASURES DIDN'T
INCLUDE GENERAL AGING MEASURE IN
FIRST REGRESSION AND SYSTEM ON
MORTALITY 5 SYSTEMS ARE RELEVANT
AND CARDIOVASCULAR AND
RESPIRATORY AND NEXT STEP IS TO
THEN INTRODUCE GENERAL AGING
MEASURE AND IN THEORY THAT
PRECEDES THE DOWNSTREAM SYSTEM
MEASURES AND QUESTION IS WHETHER
GENERAL AGING MEASURE ACTUALLY
ELIMINATES THE SIGNIFICANCE OF
SOME DOWNSTREAM MEASURES AND HOW
IT EXPLAINS IN AND OF ITSELF AND
ANSWER IS STRONGEST MEASURE HERE
IN TERMS OF MORTALITY PREDICTION
IS GENERAL AGING MEASURE AND
THAT IS TOP LINE THAT IS BY FAR
STRONGEST AND WHAT IS MAINTAINED
AMONG OTHER SYSTEMS ARE
CARDIOVASCULAR MEASURE AND
RESPIRATORY MEASURE AND OTHER
SYSTEMS THAT WERE SIGNIFICANT
BECOMES INSIGNIFICANT AND STRONG
LENGTH OF GENERAL AGING MATTER
AND MORTALITY OUTCOME AND IF I
LOOK AT DIFFERENCES OBSERVED IN
MORTALITY IN AGE AND SEX AND
RACE AND EDUCATION MOST HAVE
BEEN EXPLAINED BY THESE SYSTEM
MEASURES IN GENERAL AGING SO
ALMOST NONE ARE SIGNIFICANT
ANYM
ANYMORE.
IT IS WHAT I WOULD EXPECT AS IF
THEORETICALLY POZITIED THAT
THOSE ARE METHODS BY WHICH
SOCIAL STATUS GETS UNDER THE
SKIN AND IS FOR US TO EXPLAIN
DIFFERENCES AND SUMMARY I WOULD
SAY CARDIOVASCULAR RESPIRATORY
GENERAL SYSTEMS ARE SIGNIFICANT
EXPLAINING MORTALITY AND GENERAL
AGING MECHANISM ELIMINATES THREE
SYSTEMS EXPLAINING VARIANCE
ADAPTIVE IMMUNE CIRCULATORY AND
NEUROLOGICAL AND THINK
IMPORTANCE OF GENERAL AGING
MEASURE AND GRIM AGE IN PHENOAGE
RE-ENFORCE VALUE OF EPIGENETIC
DNAM AS AN UNDERLYING MECHANISM
OF THIS AGING PROCESS.
SOME OF THE MARKERS APPEARING TO
BE IMPORTANT FOR MORTALITY
PREDICTION ARE PERHAPS SOMEWHAT
SURPRISING IF GOING TO LOOK FOR
A HALF DOZEN MARKERS THEY MIGHT
NOT BE THESE.
MACHINE LEARNING DOES SORT OF
INDICATE THAT PRO-BNP IS AN
IMPORTANT MARKER MOMMING TO --
AND GENERAL AGING IN SYSTEMS WE
INVESTIGATED EXPLAIN MOST SOCIAL
DIFFERENCE WRANDZ DO WE GO FROM
HERE? GENERAL AGING IS
STRONGEST PREDICTOR OF MORTALITY
AND OTHER PREDICTORS SEEM TO
INDICATE FAILURE OF SYSTEMS AND
PRO-BNP BEING STRONG IN
CARDIOVASCULAR SYSTEM IS
INDICATOR OF FAILING HARD AND
YOU HAVE A SET OF INDICATORS OF
SYSTEM FAILURE FOR PHYSIOLOGICAL
SYSTEMS ON TOP OF GENERAL AGING
MEASURE THAT IS WHAT EXPLAINS
THIS MORTALITY. NOW, I'M ONLY
ABLE -- I WAS ABLE TO
INVESTIGATE IN THIS ANALYSIS
MORTALITY WITHIN 4 YEARS AND
DATA THAT IS COLLECTED IN 2016
AND MORTALITY IS UP THROUGH 2020
AND IF INTERESTED IN AGING
PROCESS YOU DON'T WANT TO
PREDICT SHORT TERM MORTALITY YOU
WANT LONGER TERM MORTALITY MY
GUESS LOOKING AT LONGER TERM
MORTALITY, YOU WOULD GET A
DIFFERENT SET OF INDICATORS THAT
WOULD COME OUT STRONG.
THAT BUILDS ON EARLIER WORK AND
OTHER WORK WE HAVE DONE WHEN WE
LOOK AT WHAT ARE PREDICTORS OF
DIFFERENT OUTCOMES CLEARLY AGE
RELATED IMPORTANT HEALTH OURT
COMES INCLUDING COGNITIVE
FUNCTIONING AND LOSS OF PHYSICAL
FUNCTIONING AND MULTIMORBIDITY
WE END UP WITH DIFFERENT MARKERS
AND HOW THINGS WILL GO. MORE
MARKERS WE GET, MORE DIFFERENCES
WE WILL GET ACROSS INDIVIDUAL
BIOMARKERS PREDICTING OUTCOMES.
WE HAVE DONE THIS ALREADY FOR
COGNITION. WE KNOW THAT
NEUROLOGICAL MARK ERRS COME OUT
STRONGEST FOR COGNITION AND
GENERAL AGING MEASURE AND FEEL
LIKE WHILE WE HAVE BEEN DOING
THIS A LONG TIME, PREDICTORS
THAT AS WE GET MORE AND MORE
PREDICTORS TO ADD INTO MODELS,
WE GET DIFFERENT PREDICTORS
COMING OUT OF THE MODELS AND WE
ARE NOT DONE YET.
WE HAVE CERTAINLY MORE TO DO IN
TERMS OF INTEGRATING BASIC
HALLMARKS OF AGING OR
GEROSCIENCE MEASURES THAT ARE
INTO A GENERAL AGING MEASURE.
I THINK THAT THIS OFFERS A
POTENTIAL WAY TO GO IN THE
FUTURE TO DEVELOP BETTER
PREDICTOR MODELS AND
LONGITUDINAL MEASUREMENT HEALTH
AND RETIREMENT STUDY COMING OUT
OF FIELD FOR SECOND TIME
MEASUREMENT THAT WAS DELAYED BY
THE PAN DEM THAK WE WILL HAVE
MEASURES OF CHANGE THAT ARE
BEGINNING IN THE NEXT YEAR.
SO, THANK YOU.
>>[APPLAUSE].
>>GOOD MORNING, EVERYONE. I
APOLOGIZE FOR NOT BEING THERE IN
PERSON TODAY.
HOW DOES THAT LOOK?
>>IT IS GOOD. GO AHEAD.
THANKS.
>>EXCELLENT. THANK YOU. FIRST
OF ALL, I'M SUPER EXCITED AND A
LITTLE HUMBLED TO HEAR
PRESENTATIONS YESTERDAY AND THIS
MORNING AND JUST THE IDEA THAT
SOME CONCEPTS FROM BASIC BIOLOGY
FROM AGING HAVE MADE IT INTO A
NEW WORLD OF HUMAN AGING IS
FANTASTICALLY EXCITING AND
THANKS TO ROHAN AND
[INDISCERNIBLE] BEFORE HIM TO
MAKE THAT HAPPEN.
THE TOPIC HERE IS A LITTLE BIT
OF AN OUTLIAR. REASON WE ARE
TALKING ABOUT IT, WE HAD A
PRESESSION CHAT. AND ONE
QUESTION THAT AROSE THAT I HAVE
BEEN THINKING ABOUT FOR A WHILE
ACTUALLY IS THE NOTION THAT WE
ARE TALKING ABOUT GEROPRETEKTORS
AND MEASURES OF AGING BUT IS NOT
REALLY CLEAR TO ME WE HAVE A
PATHWAY TOWARDS THE NEXT
GENERATION OR GENERATION AFTER
THAT OF INTERVENTIONS IN AGING.
SO, THE QUESTION IS REALLY, IS
THERE AN AGING INTERVENTION
PIPELINE?
I WOULD LIKE TO CONTRACT WHAT WE
HAVE BEEN CURRENTLY DOING IN
ACADEMIC RESEARCH TO WHAT YOU
WOULD SEE IN THE PHARMACEUTICAL
INDUSTRY WHERE PIPELINE IS QUITE
CLEAR STARTING WITH MILLIONS OF
DIFFERENT CHEMICAL STRUCTURES
AND GO AFTER A SINGLE PROTEIN
TARGET AND SINGLE ACTIVITY AND
NARROW DOWN QUICKLY TO SERIES OF
HITS AND LEAD COMPOUNDS THAT GO
INTO PRECLINICAL STUDIES.
THERE HAS BEEN SOME ACTIVITY
LIKE THAT IN AGING ITSELF.
BUT, IT IS NOT CLEAR THAT THIS
IS THE SAME KIND OF PROCESS THAT
PARTLY IS IN AGING OUTCOME IS
AGING PATHOLOGY OR LIFESPAN
ITSELF AND TEND TO BE LIMITED TO
FUNCTIONAL COMPOUNDS IN SCREENS
LAERNL THAN DIRECT SCREENS WE
THINK ABOUT IN PHARMACEUTICAL
COMPANY DO WE NEED A PIPELINE?
WHAT DOES IT LK LIKE NOW?
THERE IS OBVIOUSLY CHALLENGES
THINKING OF PROCESSES OF
DISCOVERY THAT ARE HUMAN
RELEVANT CLEARLY AND COSTS OF
TRANSLATION INTO THE PRECLINICAL
WORLD ARE LARGE THAT IS A MAJOR
BARRIER AND HUMAN TRIALS IS ON
AGING ITSELF THAT I WILL KEEP
SAYING THAT. IT IS REALLY A
SMALL NUMBER OF INTERVENTIONS
WITH ACTUALLY RELATIVELY SMALL
EFFECTS ON AGING AND ANIMAL
MODELS AND WE NEED TO REALLY
THINK ABOUT GENDER SPECIFIC
EFFECTS THAT IS CLEAR FROM MOST
EXPERIMENTS INCLUDING
INTERVENTIONAL TESTING PROGRAM
EXPERIMENTS GENDER SPECIFIC
EFFECTS ARE COMMON.
WE REALLY HAVE NOT GOTTEN INTO
GENETIC BACKGROUND OR
PERSONALIZED EFFECTS AT ALL.
HERE IS GOOD NEWS.
GOOD NEWS IS THAT WE HAVE
REASONABLE CANDIDATES THAT ARE
BEING TESTED IN -- IN CLINICAL
TRIALS.
RAPAMYCIN FORMIN AND METABOLITES
AND SO ON AND LOOKING AT NUMBER
OF PUBLICATIONS HERE CITING
COMPOUNDS AND DRUGS AND LIFESPAN
THERE IS [INDISCERNIBLE] AND
WHERE THIS STARTED FUNDAMENTAL
BIOLOGY THAT ILLUSTRATED THAT
COMPOUNDS WERE INTERACTING WITH
AGING ITSELF CAME FROM MODEL
SYSTEMS LIKE [INDISCERNIBLE] AND
YEAST AND GENETIC ANALYSIS AND
COMPOUND TREATMENTS.
HOW DO WE TARGET AGING?
GEROSCIENCE CONCEPT -- HOW DO
YOU TARGET AGING AND NEXT SLIDE
HOPEFULLY WON'T ANNOY TOO MANY
PEOPLE AND SOMETHING TO SAY TO
STUDENTS THAT I THINK IS WORTH
THINKING ABOUT THAT DOESN'T AMRI
TO VAST SWANLS OF AGING RESEARCH
IF NOT DOCTOR YOU MIGHT NOT BE
TARGETING AGING THAT IS OLD IDEA
GOING TO TOM JOHNSON IN EARLY
1990S WHO WAS YOU KNOW A PIONEER
IN DOG GENETIC RESEARCH IN
LIFESPAN AND ELEGANCE AND MADE A
SIMPLE POINT IT IS VERY EASY TO
MAKE ANIMALS SICK WITH GENETIC
MUTATIONS IT IS HARDER TO FIND
GENETIC MUTATIONS THAN HAVE
ANIMALS LIVE LONGER WHEN YOU
FIND MUTATIONS IT IS LIKELY YOU
ARE WORKING ON AGING PROCESS AND
WHAT HAS GIVEN US 20 YEARS OF
ENRICHED GENETIC ANALYSIS OF
LIFESPAN AND ESSENTIALLY MOST
HALLMARKS OF AGING COME FROM
CENTRAL PRINCIPLE AND THINKING
ABOUT INTERVENTIONS WHETHER
NUTRITIONAL OR CHEMICAL OR DRUG
DEVELOPMENT IS WORTH COMING BACK
TO CONCEPT AND ASSUMING TO MAKE
ANIMALS LIVE LONGER AND THING
THAT GETS YOU EXCITED A COUPLE
MORE SURVIVAL [INDISCERNIBLE]
FROM LAB AT [INDISCERNIBLE] AND
BLACK CURVE THAT IS HIDDEN BY
ORANGE CURVE IS CONTROL ANIMALS
TWOOND GENETIC INTERVENTIONS
HERE ONE IN SIGNALING PATHWAY
AND ONE IN MTORE PATHWAY AND
DRAMATIC CHANGES ON ANIMAL
INCREASING LIFESPAN HERE TO FIVE
FOLD AND REMARKABLE THINGS ARE
POSSIBLE AND SOME ACTIVITY IS IN
TRYING TO REPRODUCE THIS TO
GENERATION OF INTERVENTIONS AND
-- METABOLITES AND NUTRIENTS AND
NOT BY OUR LAB BUT MANY OTHER
LABS AND INCLUDING
[INDISCERNIBLE] WHO HAS DONE.
BLACK CURVE IS THE CONTROL WORMS
AND WE HAVE SERIES OF
CONCENTRATIONS OF COMPOUND HERE
THAT HAPPENS TO BIND AMILLOID
THAT I WILL COME BACK TO LATER
AND YOU SEE HERE OPTIMAL
CONCENTRATION IN THE BLUE IS
SHIFTING SURVIVAL CURVE
DRAMATICALLY TO RIGHT 70%
INCREASE IN LIFESPAN THAT IS
POSSIBLE TO FIND CHEMICAL
INTERVENTIONS THAT HAVE DRAMATIC
EFFECTS ON LIFESPAN IN THIS
SIMPLE CELEGANS AND COMPLEX
SLIDE TO ACKNOWLEDGE ROLE OF
THIS INTERVENTION TESTING
PROGRAM FUNDED BY NIA AND WHAT
WE HAVE HERE ARE TWO GRAPHS WITH
TWO DIFFERENT COMPOUNDS AND
THYOFLAVIN T COMPOUND ON RIGHT
AND TC CYCLE ON LEFT AND EACH
POINT ON GRAPHS IS THE
INDIVIDUAL LIFESPAN EXPERIMENT
WITH SOMETHING LIKE 100
INDIVIDUAL C ELE GANS WORMS AND
SHOWING ANYTHING ABOVE DOTTED
LINE IS LIFESPAN INTERVENTION
AND DESPITE VARIABILITY YOU SEE
HERE EKG METABOLITE AND COMPOUND
ARE DOG WELL AT EXTENDING WORM
LIFESPAN AND PATRICK AND MONICA
THERE IS COLOR CODING HERE IN
DIFFERENT LABS THREE LABS YOU
SEE LIFESPAN EXTENSION GIVING
CONFIDENCE AND SECOND POINT HERE
USING MULTIPLE STRAINS AND X
AXIS YOU SEE A LAB STRAIN AND
USUAL STRAIN EVERYBODY USES AND
TWO WILD STRAINS AND REMIT OF
THIS CITP IS LOOKING AT STRAINS
WITH GREAT GENETIC DIVERSITY AND
MAP HERE IS ILLUSTRATION OF
WHERE THESE COME FROM ALL OVER
THE WORLD YOU FIND SPECIES AND
STRAINS TESTING GENETIC
DIVERSITY RESPONSES TO DRUG
TREATMENT AND IN THESE TWO CASES
HERE YOU SEE THESE COMPOUNDS ARE
VERY ROBUSTLY EXTENDING LIFESPAN
ACROSS GENETIC DIVERSITY THAT
COULD BE IMPORTANT LATER IN
ASSESSING HOW TO TAKE COMPOUNDS
FORWARD AND IN A TRANSLATIONABLE
WAY. JUST ASIDE FOR NOW THAT IS
GRA GREAT AND PREMISE HERE
EXTENDING LIFESPAN YOU ARE
PROBABLY WORKING ON AGING AND
GEROSCIENCE CONCEPT COMPOUNDS
THEREFORE SHOULD HAVE EFFICACY
IN DISEASE ILLUSTRATING WITH
WORM EXAMPLE THEN A COUPLE MOUSE
EXAMP
EXAMPLES.
WHAT WE HAVE HERE IS A
COLLABORATION WITHBERG OT
SCHILLING AND WE ARE LOOKING AT
ACCUMULATION WITH INSOLUBLE
PROTEIN WITH AGE THAT IS RELATED
IN WAYS TO DISEASES TO ALT
SDIEMERS AND PAR KINSON AND
INSOLUBLE AGGREGATES AND FAIRLY
SIMPLE SYSTEM HERE THAT WE
EXPRESSED A HUMAN MUNO TOXIC
PROTEIN BETA ASSOCIATED WITH
ALZHEIMER'S DISEASE IN WORMS
COMPARING THOSE WORMS TO CONTROL
WORMS GOING FROM LEFT DOWN HERE
TO PROTOCOL DOING A DETERNLIENT
EXTRACTION AND DETERJIENT
INSOLUBLE PRAKS IS BEING
ANALYZED BY MASS SPECTROMETRY IN
BER GOTS LAB.
THE OTHER THING THAT HAPPENS IS
ACCUMULATING INSOLUBLE PROTEINS
AT RAPID RATE THAT IS QUANTITY
TITTATION ON RIGHT HERE AND
SEEING THESE PROTEINS IN FOLDING
THESE WORMS ARE DAY 1 OF
ADULTHOOD AND WE ARE TAKING
NEUROTOXIC PROTEIN ASSOCIATED
WITH INSOLUBLE PROTEIN AND
ACTIVE EXPRESSING DISEASE
RELATED PROTEIN IN WORMS IS
TAKING THIS MOLECULAR PHENOTYPE
ACCELERATING AGING.
THIS IS WHAT IT LOOKS LIKE THESE
WORMS ON THE LEFT HERE. LITTLE
WHITE ARROWS ARE POINTING TO
INSOLUBLE AGGREGATES OF A BETA
PROTEIN AND DRUG I MENTIONED SO
FAR COMPOUND THIGHO FLAFIN T
PRESENCE HERE WHERE INSOLUBLE
AGGREGATES FOR MUCH, MUCH LATER.
SO, HERE IS A EXAMPLE OF A
COMPOUND THAT EXTENDS LIFESPAN
IN THE WORM AND IS HAVING AN
EFFECT ON AGE-RELATED DISEASE
PANELOLOGY AND A BETA
AGGREGATION.
SO, COMPLEX GRAPH BUT IS SIMPLE
IN THE INTERPRETATION, I THINK.
WHAT WE HAVE GOT HERE IS A RANGE
OF COMPOUNDS NOW GOING BEYOND
THIGHO FLAFIN T AND RANGE THAT
EXTEND LIFESPAN IN THE WORM AND
ANALYSIS TAKEN BY UNIVERSITY OF
OREGON PART OF CIPT PROJECT
LOOKING AT RELATIVE RISK OF
PARALYSIS AND AMAZING TO EXPRESS
HUMAN PROTEIN IN WORMS
ASSOCIATED WITH ALZHEIMER'S THAT
MAKES THEM SICK AND IS EASY TO
SEE THAT WE BECOME PARALYZED AND
STOP MOVING ON AR PLATES YOU SEE
HERE A RANGE OF EFFECTS THAT IS
A REALLY EFFECTIVE THING THAT
FOCUSES ON COMPOUNDS TO RIGHT OF
THE GRAPH AND THESE COMPOUNDS
EXTEND LIFESPAN AND ARE
SUPPRESSING THE PARALYSIS
PHENOTYPE AND IN OTHER WORDS
THEY ARE -- THEY ARE PREVENTING
THE A BETA TOXICITY.
AND LOOK AT THE NUMBER OF
COMPOUNDS THAT ARE DOING THAT.
THIS IS AN INCREDIBLY HIGH HIT
RATE BASED ON ANY SCREEN YOU
WOULD WANT TO THINK ABOUT IN
TERMS OF, YOU KNOW, PREVENTING A
BETA TOXICITY IN ANY SYSTEM AND
ANY NORMAL SCREEN UNDERTAKEN BY
PHARMAINDUSTRY AND BY PERHAPS
MANY OF YOU WITH HIT RATES
AROUND ABOUT .1% AND HERE WE ARE
SEEING SOMETHING LIKE 40% OF
COMPOUNDS BECAUSE OF THE
PRESELECTION OF EXTENDING
LIFESPAN IN THE WORM, 40% IN
COMPOUNDS HAVE AN EFFECT ON THIS
PATHOL
PATHOLOGY. LOOKING AT MICE AND
PIO FLAFIN AND HBTX AND LARGE
STUDY WE DID A LATE LIFE
INTERVENTION WITH HBX.
AND WE MADE REGULAR ASSESSMENTS
OF FUNCTIONAL METRICS INCLUDING
BONE DENSITY AND HEART FUNCTION
AND SO ON AND OUTSTANDING RESULT
WAS THAT SIMON IDENTIFIED THE
FACT THAT MICE [INDISCERNIBLE]
AS HUMANS DO. THIS IS A
RELATIVELY GOOD SARCOPENIA
MODEL. OSTEOPOROSIS MODEL AND
COMPOUND THIGHO FLAFIN T REDUCES
BONE LOSS BY 30% THAT IS AS GOOD
AS MOST THINGS ON THE MARKET AND
HERE WE HAVE A COMPOUND THAT IS
DISCOVER THE IN WORM TO EXTEND
LIFESPAN TARGETING AGING
MECHANISM PREVENTING BETA
TOXICITY IN THE WORM AND MOVING
TO MICE HAS EFFECT ON BONE
HEALTH AND REMINDER THAT WORMS
DON'T HAVE BONES AND IS A
METABOLITE I MENTIONED EARLIER
EKG. IN THIS CASE WE DID A
SIMILAR STUDY DESIGN ORIGINALLY
AND DIDN'T DO FANCY SCANS AND
WHAT WE DID DO IS TO WITH
SUSAN'S HELP IS ADOPTING FANCY
REALTY INDEX THAT IS VERY
INTERESTING.
JUST LOOKING AT THE TOP LEFT
GRAPH HERE. THIS IS FOR A COAT
COLLAR. WHAT YOU SEE HERE IN
THE BLUE ARE THE CONTROL
ANIMALS.
YOU CAN SEE FRAILTY INDEX IS
RISING OVER PERT OF 18 TO 31
MONTHS AND RED IS WORMS ON A
DIET THAT IS CONTAINING ELEVATED
LEVELS OF EKG THAT GOES DOWN
WITH AGE AND IN OURSELVES AND IN
MICE. SO, WHAT WE ARE DOING IS
RESTORING EKG LEVELS TO
RELATIVELY NORMAL YOU SEE HERE
IS SUPPRESSING PARTICULAR
MEASURE OF FRAILTY AND GREAT
POWER OF FRAILTY INDEX IS
COMBINING SCORES TOGETHER.
JUST AS A QUICK VISUAL, MICE ON
THE RIGHT ARE CONTROLS AND IF
THIS IS A VIDEO THAW WOULD SEE
THEY WERE HAVING DIFFICULTY WITH
MOVEMENT AND THERE IS HIVOSIS
GOING ON AND YOU CAN SEE COAT
COLLAR AND LOSS OF FUR AND MICE
ON LEFT HAVE ATG-FED MICE THAT
ARE DOING QUITE A BIT BETTER IN
THIS CASE AND I GUESS THAT MAJOR
TAKE-HOME MESSAGE FROM EKG STORY
AND SOMETHING I HOPE CAN
EXTRAPOLATE TO OTHER THINGS THAT
IS BY USING FRAILTY INDEX WE ARE
ABLE TO ASK QUESTIONS ABOUT
PERIOD OF MORBIDITY THAT IS
CLEARLY AN INTERPRETATION OF THE
DATA. BUT, LET'S SEE WHAT YOU
THINK. ON LEFT HERE IS TWO LIFE
COURSES THAT IN ANY POPULATION
YOU HAVE ANIMALS LIVING SHORTER
AND LONGER TIME AND ON LEFT OF
CONTROL ANIMALS YOU SEE
DIFFERENT LIFESPANS HERE ANIMALS
LIVING 24 TO 32 MONTHS AND BASED
ON FRAILTY SCORE ASSIGNING
PERIOD OF MORBIDITY ANIMALS ON
RIGHT ALPHA KETOGLISERRATE 16%
GENDER SPECIFIC EFFECT WE SAW
ESSENTIALLY INCREASE IN HEALTH
SPAN BASED ON PERIOD OF TIME
BEFORE FRAILTY SCORES BEGIN TO
ARISE ON PREVIOUS SLIDE ANALYSIS
OF PERIOD THAT AT SCALE FRAILTY
SCORE TO LIFESPAN ITSELF TO
INDIVIDUAL ANIMALS YOU CAN COME
UP WITH A SCORE FOR PERIOD OF
MORBIDITY I'M SURPRISED BY THAT
AND DON'T KNOW WHY IT IS
HAPPENING AND MECHANISTIC WHY IT
IS HAPPENING GOOD NEWS WITH
INTERVENTION GO TO CLINICAL
STUDIES AND INTERVENTIONS FOR
HUMANS AND CLINICAL TRIALS AND
PERSONAL EXPERIENCE DOESN'T DO
LITERATURE IN FIELD AT ALL GOING
INTO THAT IN QUESTION SESSION
AND 40% OF COMPOUNDS EXTENDING
LIFESPAN AND WORKS SUPPRESS
AGING PATHOLOGY IN THE MOUSE
THAT IS PERSONAL EXPERIENCE
BASED IN PUBLISHED AND
UNPUBLISHED DATA THAT IS
EXTRAORDINARY AND HIT RATE THAT
IS UNSURPRISING TO ME AND 6
MILLION YEARS CONSERVE AGING
MECHANISMS AND WHAT DO CLINL CAL
SCIENTIST AND HUMAN RELATED
SCIENTISTS NEED FOR BASIC
BIOLOGY TO TAKE THINGS GOING
FORWARD IS THIS DATA IMPORTANT
TO YOU? WITH THAT COLLABORATION
WITH JULIE ANDERSON'S LAB HERE
AND WORMS AND NAMES WITH PEOPLE
INVOLVED ON SLIDES I WENT
THROUGH AND ARE FUNDING
PARTNERS. THANK YOU.
>>AGAIN SHGS THANK YOU TO
SPEAKERS FOR GREAT TALKS AN WOD
LIKE TO INVITE YOU TO COME UP TO
THE STAGE FOR THE DISCUSSION
SESSION. WE WILL OPEN IT TO THE
AUDIENCE FOR QUESTIONS AND AS
THEY COME UP I THINK TO
HIGHLIGHT A FEW COMMON THREADS
WOVEN THROUGH SERIES OF TALKS
THIS MORNING BUILDING OFF THESE
TALKS THAT ARE LOOKING AT
BENEFITS AND CONSIDERATIONS WITH
USING ANIMAL MODELS THAT IS
REALLY CRITICAL TO CONTINUE
DEVELOPING MEASURES FOR
COMPRESSION OF MORBIDITY DIBEING
CLINICAL MODEL FOR OLDER ADULTS
IN CLINIC WORKING WITH RESEARCH
AND IS A THREAD THAT IS SHOWING
ITERATIVE PROCESS OF TRANSLATION
AND REVERSE TRANSLATION AND
REALLY NOT ONLY BRINGING BENCH
RESEARCH TO BEDSIDE AND GOING
BACK TO THE BENCH TO REALLY
IDENTIFY FURTHER PATHWAYS FOR
INTERVENTION AND DEVELOPMENT AND
GOING FORWARD.
PLEASE THOSE WITH QUESTIONS COME
UP.
HELLO CAN YOU HEAR ME? MAYO
CLINIC AND QUESTION HOW SOME
BLOOD AND BIOMARKERS COMPARE TO
CLINICAL GOAL STANDARDS LIKE
GATE SPEED?
>>IS THIS -- OKAY. GREAT
QUESTION THAT I OFTEN WONDERED
THAT THERE HAVE NOT BEEN A LOT
OF GREAT HEAD TO HEAD
COMPARISONS OF THESE EMERGING
WITH POPULATION STUDIES TO SEE
IF ONE PERFORMS BETTER THAN
OTHER AND PUTTING AGGREGATE
MEASURES TOGETHER AND DON'T KNOW
IF ANYONE HAS KNOWLEDGE OF THOSE
COMPARI
COMPARISONS.
>>FASCINATING TALK, THOMAS FROM
KATELLA INSTITUTE AND WONDERING
HOW MUCH WORK IS DONE TO TEASE
OUT FRAILTY AND MENTAL DOUGH
KLEIN AND ARE THEY SILOED
DOMAINS?
I KNOW GATE SPEED AND GROUP
STRENGTH AND THOSE SORTS OF
THINGS AND EQUIVALENCE OF THEM
ARE BARELY STARTING OUT IN
COMPUTERIZED TESTING FOR MENTAL
ABILITY AND IF YOU CAN COMMENT
ON FRAILTY THAT IS MOST VISIBLE
SIGN OF AGING AND QUALITY OF
LIFE PEOPLE ARE VERY INTERESTED
IN MENTAL DECLINE AS WELL.
>>OKAY. SURE. I CAN COMMENT
SOMEWHAT AND THINK THAT
LIMITATION OF THE WORK WITH THE
MICE SO FAR IS THAT WE HAVE NOT
REALLY INCLUDED COGNITIVE
ASSESSMENT TEST AND COGNITIVE
ASSESSMENT WOULD BE INCLUDED IN
FRAILTY INDEX ASSESSMENTS FOR
PEOPLE AND SO THAT COULD BE PART
OF IT. IF DOING A LAB RATTORY
BASED FRAILTY INDEX BASED ON
MORE OR LESS BIOMARKERS IN THE
BLOOD YOU PROBABLY WOULDN'T HAVE
THAT UNLESS YOU ADDED IT AS A
SEPARATE CATEGORY TO -- FOLDED
INTO DATA IF YOU HAD THAT
AVAILABLE. I HOPE THAT ANSWERS
YOUR QUESTION. SOMEONE MIGHT
WANT TO COMMENT.
SORRY THERE WE GO. IN PHYSICAL
FRAILTY RESEARCH PROGRAM THAT WE
DO THERE, DEFINITELY PEOPLE
WORKING ON WHAT IS OFTEN A TERM
CLINICALLY MILD COGNITIVE
IMPAIRMENT AND TEND TO TRAVEL
TOGETHER CLOSELY AND PEOPLE AS
THEY AGE AND ESPECIALLY FRAIL
SUBSET. A LOT OF THE BIOMARKERS
THAT WE HAVE LOOKED AT AND TFN
ALPHA ECREPTOR ONE IS BEST
PREDICTOR OF FUTURE COGNITIVE
DECLINE IN COHORT POPULATIONS WE
LOOKED AT AND BIOOLG IS SIMILAR
AND SEPARATING THEM AND HONING
IN ON GEROSCIENCE SIGNAL AND
GETTING MORE AND MORE
INFORMATION TOGETHER WE ARE
PROBABLY IN PROCESS OF MERGING
THEM AND VERY INTERESTING THE
NEUROLOGIC PIECE THAT EILEEN
BROUGHT UP IS CERTAINLY AN
IMPORTANT PART OF FRAILTY
WHETHER PERIPHERAL, LOSS OF
PERIPHERAL NERVES AND SIGNALING
HAPPENING WITH SKELETAL MUSCLE
AND SARCOPENIA AND MILD
COGNITIVE THINGS HAPPENING THAT
IS IMPORTANT EMERGING AREA.
EILEEN, DO YOU WANT TO --
>>YEAH.
>>ONE ISSUE ABOUT COGNITIVE
VERSUS NONCOGNITIVE PREDICTION
IS A LOT OF THE PREDICTION OF
COGNITIVE LOSS COMES FROM THE
FACT THAT PEOPLE HAVE EARLY LIFE
EXPERIENCES EFFECTING THEIR
COGNITIVE ABILITY AND SUBSEQUENT
DECLINE AND RATE OF DECLINE INTO
DEMENTIA AND DIFFERENT WAITING
OF FACTORS THAT ARE PREDICTING
COGNITIVE AND NONCOGNITIVE LOSS
BECAUSE OF DIFFERENT LIFECYCLE
PATTERNS THAT ARE DETERMINANTS
OF LONG-TERM OUTCOMES.
>>I WILL COMMENT ON INCREASING
EVIDENCE IN EPIDEMIOLOGIC
LITERATURE ABOUT COGNITIVE
FRAILTY AND IS DISTINCT FROM
PHYSICAL FRAILTY AND THAT IT IS
AN INTERACTION FRAIL IN BOTH
SPHERES DISPROPORTIONATE RISK
FOR ADVERSE OUTCOMES REFLECTING
CLINICAL EXPERIENCE WORKING ON
SERVICE AND SOMEONE THAT IS
PHYSICALLY FRAIL AND ABLE TO
MANAGE COGNITIVELY FRAIL AND
ABLE TO MANAGE AND GOD FORBID
THEY ARE FRAIL IN SPHERES AND
THEY WILL DO VERY POORLY IN THE
HOSPITAL AFTER THEY LEAVE THE
HOSPITAL AND INCREASING
EPIDEMIOLOGIC EVIDENCE TO
SUPPORT THAT.
>>SO, I WANTED TO CONGRATULATE
EVERYBODY FOR THE REALLY
INTERESTING SESSION THAT KIND OF
MELDED TOGETHER SO MANY
DIFFERENT EXPERTISE THAT SHOW
HOW THEY ARE COMPLEMENTARY TO
EACH OTHER AND MY QUESTION
REALLY COMES FROM THE LAST
QUESTION THAT GORDON ASKED. YOU
KNOW, I WANT TO ASK THESE TO
GORDON THAT IT IS TO ALL OF YOU
AS WELL.
I FEEL LIKE ALTHOUGH WE ALL TALK
ABOUT TRANSLATION FROM ANIMAL
MODEL TO HUMANS, THEY ARE STILL
NOT THERE MANY AND MOST OF THE
WORK DONE IN ANIMAL IS NOT
TRANSLATED MOST MODEL IN
BIOMARKET DEVELOPED IN HUMANS
ARE NOT PUT BACK INTO ANIMAL
MODEL WHAT IS GOING ON AND WILL
MAKE AN EXAMPLE.
WE DON'T KNOW WHY IS PREDICTOR
OF DEMENTIA AND SECOND IS GDF15
COMES OUT IN EVERYTHING WE DO
AND WHAT IS MISSING IN
TRANSLATION IN YOUR OPINION, OF
COURSE?
>>GORDON, GO AHEAD.
>>PHENOMENAL QUESTION THAT
WORRIES ME A LOT AND WE HAVE
AMAZING THINGS WE SEE IN ANIMAL
MODELS THAT WE THINK ARE
IMPORTANT AND WE DON'T HAVE
ORGANIZED PIPELINE FORWARD AND
HOW YOU GET FROM AGING ITSELF
LIFESPAN AND GETTING ALL THE WAY
TO SOMETHING HUMAN RELEVANT AND
DON'T HAVE ANSWER TO THAT AT ALL
OTHER THAN DOG MORE OF WHAT WE
ARE DOING TODAY.
IN OUR WORK WE ARE THINKING
ABOUT WAYS TO TRANSLATE
ESPECIALLY ANIMAL FINDINGS
TOWARDS HUMANS AND BIG BARRIERS
I SEE ARE COLLECTING HUMAN
SUBJECT SAMPLES AND TIMES WE
NEED MUSCLE AND BRAIN TISSUE AND
THINGS YOU CAN'T COLLECT FROM
HUMAN SUBJECTS AND THAT HAS BEEN
A HUGE STOPPING POINT AND DURING
MY TALK TALKING ABOUT NEEDING
ACCESSIBLE MEASURABLE BIOMARKERS
COMING OUT OF STUDIES SO
SYNESSENCE OR ETTO FANLY AND
GETTING TISSUE BIOPSIES AND
DISDAINS AND THINGS TO TRANSLATE
MEASUREMENTS MAKING THEM
CLINICALLY RELEVANT WE HAVE TO
MOVE INTO AREAS WHERE WE CAN GET
A BLOOD SAMPLE AND MEASURE
SOMETHING. THEN JUST HUMAN
SUBJECTS PROTECTIONS ARE
CERTAINLY SUPER IMPORTANT WE
JUST -- THAT IS A BIG BARRIER
THAT PREVENTS US FROM MOVING
FORWARD AND IS NECESSARY AND NO
THE ARGUING AGAINST THAT.
>>I WILL MAYBE COMMENT TOO.
THIS COULD BE POTENTIALLY TRIED.
>>COMMENTING ON THAT.
>>I TOTALLY AGREE. REPURPOSING
IS AN IMPORTANT WAY FORWARD.
EFFECTS ON AGING ITSELF IS
FAIRLY SMALL FOR SOME THINGS IN
ANIMAL SYSTEMS AND GUESS WHAT
I'M TRYING TO SAY IS WE HAVE NOT
EXPLORED CHEMICAL SPACE AND
HAVEN'T LOOKED AT WHAT IS OUT
THERE IN TERMS OF AGING
INTERVENTIONS IN ANY GRAND WAY
AND IN DOING SO MIGHT FIND
THINGS MUCH MORE POTENT THAN MET
FOR MEN AND APPOMYCIN.
>>RESPONDING TO GORDON A LITTLE
BIT. I FEEL SOME OF YOUR SLIDES
ARE REALLY SHOW IING STRONG
EFFECTS AT YOUNG ER AGES OF
ANIMALS AND MIGHT BE USEFUL FOR
YOUR GROUP TO SORT OF
DIFFERENTIATE ACROSS THE LIFE
CYCLE A LITTLE MORE IN TERMS
WHERE YOU ARE GETTING EFFECTS OF
CERTAIN THINGS THAT AID INTO
MOVING IDEAS TO HUMANS.
>>ECHOING WHAT IS SAID THERE IS
STUDIES LOOKING AT MIDLIFE
CHRONIC INFLAMMATION FOR EXAMPLE
AND HOW THAT IS ASSOCIATED WITH
ADVERSE COGNITION AND PHYSICAL
OUTCOMES AND REALLY GETTING OR
HONING IN ON WHAT IDEAL TIME TO
INITIATE AN INTERVENTION WOULD
BE ALSO IS ANOTHER CONSIDERATION
FOR THESE INTERVENTIONS.
>>HI, THANK YOU. QUESTIONS FOR
EILEEN AND HER TALK AND OTHERS
AND FEEL FREE TO CHIME IN AND IN
LIGHT OF SESSION ON HEALTH
DISPARITIES AND WORK ON SOCIAL
HALLMARKS OF AGING AND CURIOUS
YOU PUT EXPLAINS IN QUOTES WHEN
EDUCATION AND ETHNICITY AND SES
MEASURES AND GETS WASHED OUT IN
THE ANALYSIS.
BUT, CLEARLY, THERE IS STORIES
THERE. I WILL JUST BE KIND OF
CURIOUS IN LIGHT OF GEROSCIENCE
IDEA ABOUT AGING ABOVE AND
BEYOND SPECIFIC DISEASES AND
HEALTH DISPARITIES THAT ARE LIFE
LONG EXPERIENCES AND PROCESSES
IN DIFFERENT GROUPS AND STATES
OF DISADVANTAGE AND WHAT NOT.
ARE ALL OF THE EFFECTS
MODERATION EFFECTS INSTEAD OF
MEDIATION?
WHAT CAN YOU SAY FROM ANALYSIS
THAT STILL, YOU KNOW, INVOKES
THAT THESE SOCIAL EXPERIENCES
THROUGH DIFFERENTIAL EDUCATION
AND THROUGH SES ARE STILL HAVING
CASCADING EFFECTS OVER THE LIFE
COURSE. IF YOU HAVE BIOLOGICAL
MEASURES, SURE. THAT STUFF
WASHES OUT AND LEADS SOMEONE TO
THINK MAYBE THOSE THINGS DON'T
REALLY MATTER. I'M WONDERING
CAN I COMMENT A LITTLE BROADLY
TRYING TO UNITE PERSPECTIVES
ABOUT IMPORTANCE OF HEALTH
DISPARITIES AND DIFFERENTIAL
EXPERIENCES AND SOCIAL HALLMARKS
OF AGING AT SAME TIME
GEROSCIENCE IDEA AND IN WAY IF
YOU HAVE ALL BIOLOGICAL MEASURES
YOU DON'T NEED ANYTHING ELSE.
>>I DON'T THINK THAT MEANS YOU
DON'T NEED ANYTHING ELSE.
>>YEAH.
>>I GUESS WHAT IS DIFFERENT IS
WHAT I DID TODAY WIPED OUT
DIFFERENCES THAT HAVEN'T BEEN
WIPED OUT BEFORE WHEN WE HAVE
INCLUDED A VARIETY OF THINGS AND
BASICALLY SEEING THEM AS
MEDIATORS OF AN EXPERIENCE AND
MAYBE MODERATORS ALSO BUT
MEDIATORS BASICALLY.
I DON'T THINK THAT I ADDED MUCH
TO THE UNDERSTANDING OF SOCIAL
DIFFERENCES TODAY THAT ARE
EXTRAORDINARILY STRONG.
I DO THINK THAT UNDERSTANDING
THE SPECIFICS OF SOCIAL
DIFFERENCES AND SES AND
SPECIFICS OF BIOLOGICAL
MECHANISMS CAN LEAD US SOMEWHERE
BUT THIS INITIAL SAYING THAT
STATISTICALLY THEY ARE WIEBED
OUT AND I PUT QUOTES AROUND
EXPLANATION AND DON'T REALLY
THINK IT SAY FULL EXPLANATION
AND AGREE WITH YOU IN YOUR
ASSESSMENT OF THIS.
>>I WOULDN'T PROPOSE
MATHEMATICAL EXPERTISE
WHATSOEVER BUT CENTRAL BIOLOGY
THAT IS DRIVING THIS. AS WE PUT
MODELS TOGETHER AND ESPECIALLY
WITH STRESS RESPONSE SYSTEMS, I
MEAN, WE NEED TO HAVE SIDE
CONVERSATIONS ABOUT THIS. I
THINK THERE IS A LOT OF
COMMONALITIES IN THAT CENTER,
YOU KNOW, PHYSIOLOGY THAT IS
HAPPENING WHETHER IT IS A -- YOU
KNOW, SOCIAL STRESSOR OR SOME
CLINICAL STRESSOR OR SOME
GENETIC, YOU KNOW,
PREDISPOSITION TO ACTIVATING
STRESS RESPONSE SYSTEMS THAT I
THINK THAT THE CENTER WILL BE
VERY COMMON AMONGST ALL THESE
DIFFERENT THINGS AND FOR ME IS
THINKING ABOUT PREVENTION AND
PEOPLE WILL END UP IN CENTER BOX
WITH LOTS OF ADVERSE OUTCOMES
THAT ARE DRIVING ON OTHER SIDE
OF THAT AND WE HAVE TO CAREFULLY
DISSECT WHAT IS PUSHING THOSE IN
BOXES AND TRY TO PREVENT FROM
THERE AND IS PUBLIC HEALTH
THINKING.
>>THANK YOU.
>>EXPRESSING OBSERVATION AND
CONCERN ABOUT BIOMARKERS IF YOU
KNOW ONE OLDER PATIENT YOU KNOW
ONE OLDER PATIENT AND WE HAVE
SEEN 80 YEAR OLDS WITH A HOST OF
DISEASES IN PROBLEM LIST THAT IS
FUNCTIONAL AND SAME LIST TALKING
ABOUT NOW VARIETY OF THINGS
SEEMING CONTRADICTORY HOW WE
APPROACH BIOMARKERS TALKING
ABOUT TALKING ABOUT INTEGRATION
OF SYSTEMS AND DYNAMICS REFERRED
TO AND STRESS RESPONSES AND
APPROACHES BUNDLE OF MEASURES
ADDING THEM UP IN A LINEAR WAY
AND PREDICTORS WHAT A PERSON
MIGHT LOOK LIKE AND OUTCOME
MIGHT BE AND TROUBLED WITH THAT
BECAUSE OF FACT THAT IS
RECOGNIZED THAT ALL FACTORS THAT
WE TALK ABOUT ARE NON-LINEAR AND
ARE INTERACTING WITH EACH OTHER
AND OPERATING ON DIFFERENT
SCALES FROM MOLECULES TO
BIOCHEMICAL BIOMARKERS THROUGH
CELLS AND THROUGH ORGANS AND
ORGANISMS AND THROUGH SOCIAL
SYSTEMS AND NETWORKS AND
ENVIRONMENT AND CAN'T THINK
ABOUT LUMPING THEM TOGETHER
WITHOUT THINKING ABOUT HOW THEY
INTERACT WITHIN A GIVEN
INDIVIDUAL AND THINK WHAT WE
HAVE TO DO TO MOVE OUR SCIENCE
FORWARD IS DEVELOP MATHEMATICAL
MODELS CAPABLE OF NOT JUST SORT
OF LINEARLY ADDING THEM UP OR
WITH WEIGHTS AND STUFF BUT
FOCUSED ON EILEEN SPECIFICALLY
BUT HOW WE ACTUALLY INTEGRATE
THEM THINKING ABOUT ACTIVITY ON
DIFFERENT SCALES OVER TIME AND
INDIVIDUALS AND THINKING ABOUT
INDIVIDUAL AS A COMPLEX SYSTEM
AND HOW IT MIGHT BREAK DOWN WITH
AGING AND GOOD NEWS IS SOME
COMPLEXITY COULD BE RESTORED AND
SAW REALLY GOOD EXAMPLES WITH
THAT WITH NH INHIBITOR OR
EXERCISE AND OTHER INTERVENTIONS
AND WE NEED BIOMARKERS THAT
INTEGRATE SYSTEMS ACROSS
DIFFERENT SCALES AND WHAT
COMPLECHLTY SCIENCE IS ALL ABOUT
AND THANK YOU TO JEREMY ABOUT
THE CALLOUT TO COMPLEXITY.
>>CAN I COMMENT ON THAT?
I WOULD LIKE TO SUGGEST THAT
POWER OF TRAILTY INDEX AS AN
APPROACH IS WE ARE SAMPLING A
LARGE NUMBER OF ITEMS AND WORK
DONE WITH CLINICAL FRAILTY INDEX
DATA HAS SHOWN WHEN YOU GET TO
LARGER NUMBER OF ITEMS YOU CAN
SWAP ITEMS IN FRAILTY INDEX AND
IT WON'T CHANGE THE SCORE AND
FACT IT IS NOT WEIGHTED ON ONE
PARTICULAR THING AND FRAILTY
INDEX ON BLOOD MARKERS AGAIN YOU
ARE LOOKING AT ALMOST A FRAILTY
INDEX COMPOSED OF BIOMARKERS AND
ALLOWS PEOPLE TO BE FRAIL IN
MANY DIFFERENT WAYS SO THEY
TOENT HAVE TO TAKE SAME PATH IF
THAT IS WHAT YOU ARE SUGGESTING
THAT MIGHT BE A UTILITY OF THE
FRAILTY INDEX APPROACH.
I WAS GOING TO SAY MODELING AND
RESULTS COMING OUT OF THAT CAN
PROVIDE REALLY POTENT CLUZ FOR
THINGS WE SHOULD BE TARGETING
AND GOING BACK TO RECEPTOR 1
FINDING AND PB [INDISCERNIBLE]
AND FOR CLINICAL PRACTICE WE CAN
ULTIMATELY FIGURE OUT IN THIS
EVERY R- INVESTIGATIVE PHASE
FIGURE OUT WHERE IT IS COMING
FROM AND TARGET SYSTEMS
INDIVIDUALLY AND IN SOME PEOPLE
WILL BE MEANINGLESS AND NOT HAVE
INNOVATIONS OR CIRCULATORY OR
HEART FAILURES AND IN OTHERS
SHOULD BE ABLE TO SAY THIS IS
SOMETHING TO THINK ABOUT AND
FIGURE OUT IF THERE IS
DISREGULATION GOING ON IN
PARTICULAR AREAS AND SHOULD
TARGET IN THOSE PEOPLE AND GOES
BACK TO PRECISION MEDICINE AREAS
WE TALK ABOUT THAT ULTIMATELY
WILL GET US CLOSER TO BEING ABLE
TO IDENTIFY PEOPLE EARLY PUTTING
THEM ON DIFFERENT TRAJECTORY
AWAY FROM FRAILTY AND RESILIENT
SYSTEM AND.
>>I THINK YOUR SUGGESTIONS ARE
VERY GOOD. I THIS I THAT WHAT
WE ARE ON IS A PANEL OF
DISCOVERY.
AND THERE IS SORT OF A PATH TO
DETERMINING WHAT IS IMPORTANT
AND PERHAPS DETERMINING
INTERACTIONS OF THOSE THINGS AND
COMPLEXITY THAT IS REQUIRED TO
THINK ABOUT IT AND HOW TO DO IT
AND REALLY ASSESS IN INDIVIDUALS
IN PRECISION MEDICINE KIND OF
WAY IS TECHNICALLY DIFFICULT.
I THINK IT IS AN IMPORTANT AIM
THAT WE SHOULD TRY TO GET THERE
EVENTU
EVENTUALLY.
>>I'M HEATHER FROM DUKE AND
WANTED TO GET THE PANEL SORT OF
COMMENTS GOING BACK TO GORDON'S
STATEMENTS ABOUT BIOLOGICAL
AGING AND LONGEVITY AND THINK
THAT THE STATEMENT BEING THAT IN
ANIMAL MODELS IF YOU ARE
STUDYING BIOLOGICAL AGING YOU
SHOULD INCREASE LONGEVITY AND IF
YOU ARE NOT INCREASING LONGEVITY
YOU ARE PROBABLY NOT STUDYING
BIOLOGICAL AGING AND THINK
CERTAINLY IN HUMAN HEALTH THOSE
TWO THINGS WE CAN GET IN TROUBLE
CONFLATING THOSE THINGS AND CAN
ALSO REALLY APPRECIATE THAT IN
CONTROLLED ENVIRONMENT OF A LAB
ANIMAL THAT IT IS PROBABLY TRUE
THAT BIOLOGICAL AGING WE SHOULD
SEE INCREASED LONGEVITY AND
WONDER IF YOU THINK THERE IS
SOME VALUE IN LOOKING AT THOSE
THINGS SEPARATELY WE SAW AN
EXAMPLE OF INTERVENTION THAT
BOTH SAW INCREASED LONGEVITY AND
COMPRESSED MOSH ITDTY AND
IMAGINE AN INTERVENTION THOSE
ARE UNCOUPLED AND THINGS DIDN'T
SEE TOGETHER AND DO WE
POTENTIALLY SEE A MECHANISM
DOING ONE MORE THAN THE OTHER OR
SOME MECHANISMS WHERE WE MAY BE
SLOWING BIOLOGICAL AGING BUT NOT
EFFECTING LONGEVITY OR VICE
VERSA AND THINKING ABOUT
EILEEN'S HUMAN DATA THAT
CONFIRMED FIRST THING I SAID
THAT BIOLOGICAL AGING IS
IMPORTANT TO PREDICTING HUMAN
MORTALITY BUT THERE ARE -- CAN
YOU HAVE THINGS CAUSING CERTAIN
VERY IMPORTANT SYSTEMS TO GO
DOWN THAT WILL ALSO DRIVE
LONGEVITY.
>>MAYBE I CAN COMMENT IF YOU
CAN HEAR ME.
NO. ABSOLUTELY. WHAT I SAID
WAS A VERY SIMPLISTIC GUIDELINE
FOR HOW WE TRY TO FIND
INTERVENTIONS THAT TARGET AGING
AND WE KNOW ALREADY THAT THERE
ARE INTERVENTIONS AND GENETIC
INTERVENTIONS BY HEIDI AND WORM
FOR EXAMPLE SHOWING MUTATIONS
THAT EXTEND LIFESPAN DON'T
NECESSARILY IMPROVE HEALTH THAT
MUCH AND WORMS CAN SPEND A
LONGER TIME IN GENERAL PHASE
WHERE THEY ARE UNHEALTHY.
IT IS A STARTING POINT IS ALL I
WAS REALLY TRYING TO INDICATE.
YOU ARE ABSOLUTELY RIGHT.
RELATIONSHIP BETWEEN HEALTHSPAN
AND LIFESPAN IS COMPLEX AND NOT
WAY WE WANT IT TO BE AND
FANTASTIC AND SEEING EKG IN MICE
WE ACTUALLY SEE BOTH IMPROVING
IN SAME TIME AND IS JUST A
SOURCE OF HOPE.
>>SO, I THINK THAT WE HAVE TO
MONITOR LIFESPAN AND HEALTH SPAN
CONSTANTLY. HEALTH SPAN CAN BE
ASSESSED IN A NUMBER OF
DIFFERENT WAYS.
BUT, I THINK THAT SO FAR, IF WE
HAVE MADE IMPROVEMENTS AND IN
LENGTHENING LIFE, WE HAVE ALL --
WE HAVE ALSO SORT OF PUSHED UP A
LITTLE BIT.
THE -- MORBIDITY. DISABILITY
AND FRAILTY MIGHT BE A DIFFERENT
ORDER OF MAGNITUDE. IT DOESN'T
APPEAR THAT WE HAVE ACTUALLY
CHANGED ALL THAT MUCH IN RECENT
DECADES AMONG AMERICANS, LET'S
SAY.
I THINK, YOU KNOW, IT IS A
COMPLEX SYSTEM THAT IS FITTING
TOGETHER HEALTH AND LENGTH OF
LIFE.
THAT -- WE ARE AIMING FOR LENGTH
OF HEALTHY LIFE AND THAT IS WHAT
WE HAVE TO MONITOR.
>>HI. MINA CRED RICK FROM CITY
OF HOPE AND APPRECIATE THIS
PRESENTATION AND WHAT LUIGI SAID
WHAT ARE THINGS WE CAN DO TO
MOVE PIPELINE FORWARD FOR THESE
AGING INTERVENTIONS?
AS A MEDICAL ONKOLGS AND
CLINICAL TRIALIST ONE THING THAT
ONCOLOGY HAS DONE REALLY WELL IS
DEVELOPED THESE -- THIS PIPELINE
TO TAKE DRUGS FROM THE LAB INTO
THE CLINIC AND THROUGH THE FDA.
ONE OF THE THINGS THAT THEY HAVE
DONE THAT I SEE THAT WE ARE
STILL STRUGGLING WITH IS THEY
HAVE VERY CLEAR DEFINITION ON
WHAT PURPOSE OF WHAT THEY ARE
DOING IS. IT IS OVERALL
SURVIVAL OR PROGRESSION-FREE
SURVIVAL OR OVERALL RESPONSE
RATE THAT IS VERY WELL DEFINED
AND MEASURED THE SAME WAY
THROUGHOUT ALL OF THE STUDIES
FROM PRECLINICAL TO CLINICAL
LEVEL.
IN AGING WE HAVE SEEN AND HEARD
IN THIS LAST PRESENTATION
MULTIPLE DIFFERENT STUDIES USING
DIFFERENT MEASURES OF AGING.
WHEN DEVELOPING THE TRIALS AND
TAKING DRUGS THAT GORDON HAS
STUDIED AND OTHERS IN MODEL IN
THE LAB AND WE WILL NOW DEVELOP
THEM INTO THE CLINIC, WHAT IS
THE MEASURE WE WILL BE CHANGING?
HAVE WE COME UP WITH A CONSENSUS
ON THIS IS WHAT WE ARE REALLY
TRYING TO HONE?
IS IT GOING TO BE SURVIVAL OR
GOING TO BE ANOTHER CLINICAL
MEASURE?
HOW DO WE RECONCILE THIS?
I THINK THERE ARE MANY BARRIERS
TO MOVING FORWARD.
I SEE IT AS A KEY IMPORTANT
BARRIER THAT WE AS, YOU KNOW,
NIA AND AS A SOCIETY NEED TO
IDENTIFY.
>>OKAY. ANY TAKERS?
>>I WILL LET YOU TAKE IT A
LITTLE LATER.
NO. REALLY IMPORTANT POINT. I
DO -- I THINK THAT IT HAS BEEN
HARD IN GERIATRICS AND TO FIND
THESE SORT OF OUTCOMES; RIGHT?
IN CANCER YOU HAVE A DISEASE;
RIGHT? A VERY CLEAR DISEASE AND
BIOPSIES YOU KNOW WHAT YOU HAVE
AND BIOLOGIC PATHWAYS THAT ARE,
YOU KNOW, COMPLEX. THEY AT
LEAST KNOW WHAT AND HOW THE
CANCER HAS BEEN DRIVEN AND WHY
IT IS GETTING MET ASS TA CRIED
AND IN AGING PHENOTYPES IT HAS
BEEN MORE DIFFICULT AND WE DON'T
HAVE GREAT DEFINITIONS YOU SEE
TWO MAJOR DEFINITIONS OF
FRAILTY; RIGHT?
YOU MIGHT BE ABLE TO IMPACT
BIOLOGY AND IN ANOTHER ONE IF
DIFFERENT VARIABLES IN ONE GROUP
OF PEOPLE THAT LEAD TO AN INDEX.
YOU KNOW, YOU DON'T KNOW WHICH
OF THE VARIABLES TO TARGET;
RIGHT?
THERE IS A COMPLEXITY IN THE
PHENOTYPIC MEASUREMENT THAT HAS
MADE IT A LITTLE MORE DIFFICULT
AND THERE HAS BEEN PROGRESS IN
SARCOPENIA FOR EXAMPLE AND
OSTEOPOROSIS AND THESE KIND OF
OVERALL PHENOTYPES THAT EMERGE
AS PEOPLE AGE AND SO I THINK
THAT THE BEST HOPE IS TO KIND OF
GO AFTER THESE SUBPHENOTYPES FOR
NOW AND NOT AFTER, YOU KNOW,
LONGEVITY. SOME HEALTH SPAN
RESEARCH I THINK WILL HELP US
FIGURE OUT WHAT SHOULD BE IN
THERE. I MEAN, IT MIGHT BE
WALKING SPEED THAT IS SOMETHING
THAT ENDS UP BEING A TARGET AND
WE TRIED THAT PATH YEARS AGO AND
FDA DIDN'T THINK IT WAS A GREAT
WAY TO GO. THINGS ARE EVOLVING
AND WE WILL HOPEFULLY GET TO
RIGHT PHENOTYPES EVENTUALLY.
>>HUH?
OKAY. SORRY YEAH. I GUESS
THERE IS ALSO THE IDEA IF YOU
INTERVENE WITH SOME SYNO LYTIC
OR SYNO STATIC INTERVENTION YOU
CAN LOOK AT REDUCTION IN CHRONIC
DISEASES OF AGING ONE COULD GET
THAT COULD BE A USEFUL OUTCOME
THAT IS BEING WORKED ON.
SO --
>>I THINK WE WILL NEED TO AGREE
ON THE DEFINITION OF AGING
PROCESS THAT IS ONE THAT COULD
BE APPLIED EARLY IN LIFE AND
THINK WAY THAT PEOPLE ARE
STUDYING DEMENTIA AND
ALZHEIMER'S DISEASE NOW ARE
LOOKING FOR MARKERS TO INTERVENE
ON PEOPLE WHO ARE DECADES BEFORE
ACTUALLY HAVING THE DISEASE
OCCUR CLINICALLY. I THINK THAT
IS WHAT AGING IS GOING TO
REQUIRE. I THINK THAT WE ARE
GOING TO NEED A DEFINITION OF
WHO IS AGING RAPIDLY. THAT
ALLOWS US TO DEFINE PEOPLE INTO
THAT CATEGORY IF 30 OR 40 YEARS
OLD, ACTUALLY, IF WE HAVE AN
IMPACT WHEN WE INTERVENE.
>>ONE RELATED POINT IN MUCH OF
THE WORK THAT WE HAVE HEARD
DURING THE MEETING FOR ANIMAL
MODELS FOCUSING ON SURVIVAL OR
MORTALITY AS THE OUTCOME. I
THINK THAT THE ANIMAL MODEL WILL
NEED TO INCORPORATE NONMORTALITY
OUTCOMES THAT GET AT THE HEALTH
SPAN PART OF THE EQUATION AND
WHETHER IT IS GAIT SPEED OR
SOMETHING COMPARABLE SO WHEN
INVESTIGATING BIOMARKERS FOR
CHANGES IN MORE APPROXIMATE
INDICATORS OF SURVIVAL THAT
TRIALS WILL BE MORE FEASIBLE ONE
COMMENT ABOUT DISCUSSION BEFORE
ABOUT BIOMARKER COMPARED TO
CLINICAL FINDINGS.
YOU KNOW, ONE COMMENT I HAVE
THAT IN OUR STUDIES AND OUR
LONGITUDINAL STUDIES THAT WE
COLLECT A WEALTH OF INFORMATION
WE DO MRI AND MEASURE WALKING
SPEED AND BLOOD TEST AND KEEP
PARTICIPANT THREE DAYS IN UNIT
AND MEASURE BIOMARKER. WE CAN'T
REALLY COMPARE WHAT WE GET
CLINICALLY WITH BIOMARKER.
CLINICALLY THEY ARE MORE
POWERFUL AS PREDICTOR AND
PROVIDE MORE INFORMATION THAT IS
ABOUT HEALTH STATUS IN GENERAL
AND IN PARTICULAR AND HOWEVER WE
THINK ABOUT TRANSLATION THAT
PHENOTYPING WILL NEVER BE DONE
IN PATIENTS. TOO EXPENSIVE AND
REQUIRE SO MUCH MORE TIME.
CAPTURING THOSE INFORMATION
THROUGH LENS OF BIOMARKER REALLY
MAY FACILITATE TRANSLATION OF
THIS INFORMATION TO THE BED OF
THE PATIENT.
THINK ABOUT EPIGENETIC CLOCK I
CAN MEASURE IN A DROP OF A BLOOD
AND WE KNEE $1,000 NOW OR $250
NOW NO REASON IT SHOULDN'T COST
FIVE CENTS. IT SHOULD. IF YOU
SCALE IT UP, IT WILL COST 5
CENTS AND WORK ON BIOMARKER GOES
TOWARDS TRANSLATION AND
MEASURING BIOMARKER IS FAST AND
THEORETICAL WILL I COULD BE VERY
CHEAP AND ECONOMIC.
>>JUST TO COMMENT ON EXCELLENT
POINTS AND, AGAIN, BEING A
CLINICIAN AS WE INTEGRATE
TECHNOLOGIES FOR BIOMARKER
DEVELOPMENTS ARE REALLY KEEPING
IN MIND THAT CLINICAL RELEVANCE
AS WELL FOR PATIENT AND WHETHER
IN TERMS OF PRODUCING
COMORBIDITY BURDEN OR, AGAIN,
COMPRESSING THAT MORBID PHASE
THAT IS GOING TO BE CRITICAL FOR
CHOOSING WHICH BIOMARKERS WE END
UP USING TO COME UP WITH THIS
MORE -- A MORE WELL-DEFINED
DEFINITION FOR FUTURE STUDIES WE
ARE THINKING ABOUT. YEAH.
>>IF I CAN MAKE A QUICK
COMMENT. I THINK MAYBE WHAT I
HEARD IS THAT SOME FRAILTY
ASSESSMENTS ARE COMPLEX AND I --
I KNOW IN THE UNITED KINGDOM,
FOR EXAMPLE, THEY ARE PRODUCING
ELECTRONIC FRAILTY INDEX OR EFI.
THEY HAVE THAT ON -- I DON'T
KNOW. ONE PAPER PUBLISHED
FAIRLY RECENTLY WAS HALF A
MILLION OR 600,000 PEOPLE AND
NOW IS NOR AND FOUND WAY TO AUTO
MA ET IT WITH ELECTRONIC DATA
CAPTURE AND DO IT INDEPENDENTLY
AND TECHNOLOGIES MIGHT BE ABLE
TO ALLOW YOU TO COLLECT DATA
THAT WOULD BE INTERESTING IF
LOOKING AT SPECIFIC BIOMARKERS.
>>HOW SHARP OF A DISTINCTION
SHOULD I DRAW BETWEEN DELAYING,
AGING, AND REJUVENATION?
IT IS ALL ONE STORY.
BUT --
>>>>HEATHER CAN YOU HELP ME
OUT? IN MY TALK I TALK ABOUT
DIFFERENCE OF REDILIGENCE AND TO
ME IS BIT OF END STAGE GERIATRIC
CONDITION THAT IS HARD TO PULL
PEOPLE BACK FROM AND CLINICAL
PRACTICE SOMEBODY WITH 3 ORE 4
OR 5 OF PHYSICAL FRAILTY ISSUES
IS REALLY HARD TO MOVE THEM BACK
INTO PREVENTIVE CARE.
>>MED TECH FOR THEM OPPOSED TO
FARM COLONL CAL.
>>WE DO MORE PALLIATIVE CARE
THINGS ACTIVITIES AND DIETARY
CHANGE AND CAN YOU HELP TO KEEP
PEOPLE OUT OF THE HOSPITAL AND
PREVENT THEM FROM HAVING
CATASTROPHIC OUTCOMES AND USE IT
AS A BIT OF A RISK ASSESSMENT IN
CLINICAL PRACTICE AND PROBABLY
FOR THE INDEX.
RESILIENCY AND RESILIENCE
RESEARCH IS FOCUSED ON
PREVENTION AND THINKING ABOUT
PATHWAYS BECOMELE UNRAVELLED
PUTTING PEOPLE AT HIGHER RISK
DOWN THE ROAD AND WANT TO FIND
THEM EARLY AND TRY TO THINK OF
THEM AS SEPARATE IN REJUVENATION
WORD THAT YOU MEAN SETTING IN
MIDDLE THAT I DON'T KNOW IS HARD
TO MOVE PEOPLE BACKWARDS
PROBABLY OR BACK TOWARDS FULL
RESILIENCE AND MAY BE WAYS TO
DELAY TRAJECTORIES THAT IS HOW I
THINK ABOUT IT AND WILL LET
HAENLER TALK ABOUT IT TOMORROW.
>>THANK YOU FOR YOUR
PRESENTATIONS WHEN UNDERSTANDING
CREATURE AND UNDERSTANDING OF
HUMAN BEING THERE IS SUBJECTIVE
EXPERIENCES AND HUMAN MIND THAT
CAN REALLY INFLUENCE BIOLOGY AND
BIOMARKERS WE ARE LOOKING INTO
AND THINKING OF MOBILITY YOU CAN
TURN AROUND A 6 MINUTE WALK TO
AVERAGE ONE PRIMING THEM WITH
IMPLICIT BIAS AND AGEISM.
YOU CAN CHANGE ALSO PSYCHOSOCIAL
INFLUENCES AND SOCIAL
DETERMINANTS OF AGING GOING
THROUGH SUBJECTIVE EXPERIENCES
AND JEREMY I WAS STRUCK BY LIST
OF BEAUTIFUL ASSESSMENTS YOU ARE
RUNNING AND LOTS ARE KNOWN TO BE
DOWNSTREAM OF PSYCHOLOGICAL
STATES AND HP ACCESS AND
GLYCEMIC CONTROL AND THESE CAN
BE INFLUENCED IN RANGE OF
MINUTES, SECONDS TO MINUTES
BLOOD PRESSURE AUTONOMIC NERVOUS
SYSTEM WITH BILOGICAL FACTORS
AND HOW WE ARE THINKING ABOUT
THIS AND HUMAN MIND AS A
CONTRIBUTOR AND SOMETHING TO
BIOMARK IN WAY THAT IS NOT JUST
LOOKING AT CIRCULATING MOLECULES
AND IS THIS A REAL CONTRIBUTOR
TO HUMAN AGING AND SHOULD IT BE
PART OF GEROSCIENCE AGENDA?
WOULD LOVE TO HEAR YOUR THOUGHTS
ON THIS.
>>I GUESS THAT CERTAINLY PEOPLE
THINK OF THE STATE OF THE HUMAN
MIND AS AN INCREDIBLE INPUT INTO
THE AGING. AND THE CHANGES IN
BIOMARKERS AND IN HEALTH THAT
MIGHT OCCUR AND ISSUE IS SHOULD
IT BE INCORPORATED AS INDICATOR
OF AGING OR IS IT A CAUSE OF
FASTER OR SLOWER AGING?
I FEEL THE WAY IT IS BEING USED
NO YOU IS KIND OF APPROPRIATE.
>>UH-HUH.
>>WE TRY TO CAPTURE SOME OF THE
PSYCHOSOCIAL VARIABLES THAT I
THINK DO DRIVE KIND OF THE BRAIN
FUNCTION IN WAYS THAT IMPACT
PHYSIOLOGY.
YOU KNOW, HOW TO PUT IT ALL INTO
ONE BIG MODEL IS HOPEFULLY
FRIENDS FROM THIS AFTERNOON THAT
WILL TELL US HOW TO DO THAT.
IT IS COMPLEX AND TRYING TO
DISSECT OUT THINKING ABOUT
INDIVIDUAL PATIENTS AND I COME
BACK TO PRECISION APPROACH AND
PEOPLE WILL HAVE A BIG DRIVING
FACTOR BASED ON RECENT SPOUSAL
DEATH OR MAJOR OR CHILDHOOD
TRAUMA THAT KEEPS COMING UP AND
PATIENT ONCE IN WORLD WAR II
THAT WAS YEARS AGO AND AT END OF
THE WORLD NEXT TO FELLOW BRITISH
SOLDIER SHOT IN THE HEAD WALKING
DOWN STREET AND SURVIVED AND HAD
NIGHT TERRORS LASTING UNTIL HE
WAS IN 80S AND HAD HUGE IMPACT
THROUGH SYSTEMS THROUGHOUT HIS
WHOLE LIFE AND WHEN HE WAS OLDER
AND THERE ARE SORTS OF THINGS,
AGAIN, GOING BACK TO WHAT LIU
SAID AND THINKING ABOUT TAKING
INFORMATION THAT WE HAVE TO COME
UP WITH MUCH MORE SORT OF
PRECISE METHODS AND LIKE, YOU
KNOW, THIS PARTICULAR PIECE OF
THE PIE IS REALLY RELEVANT FOR
THIS PATIENT AND FOR SOMEBODY
ELSE IS TOTALLY IRRELEVANT AND
WE HAVE TO GET TO THAT POINT. I
DON'T KNOW IF IT GETS AT WHAT
YOU ARE ASKING?
>>YES. THANK YOU.
>>UNIVERSITY OF MONTREAL,
CANADA AND COMING BACK TO
OUTCOMES AND THINKING OF
CONSIDERATION FOR WHAT HEALTH
SYSTEM WANT AND MENTIONING
LONGER YEARS WITHOUT COMORBIDITY
AND LONGER YEARS WITHOUT
DISABILITY AND IN THAT SENSE ARE
WE DEFINING CLEARLY TARGET
ORGANS INSTEAD OF BEING
OVERAMBITIOUS IN STOP OF AGING
AND PROLONGING LIFE SURVIVAL ARE
WE TARGETING MOST IMPORTANT
DETERMINANTS OF DISABILITY AND
YEARS FREE OF THAT DISABILITY?
JEREMY MENTIONED OSTEOPOROSIS
AND SAR CO PINA FIELDS IN THAT
SENSE AND DETERMINING AND
TARGETING MECHANISMS THAT COULD
BE MORE VALUABLE AND EFFECTIVE
IMPROVING YEARS WITHOUT
DISABILITY?
>>I CAN TRY.
I KNOW WHAT YOU ARE SAYING.
PEOPLE GET FRAIL IN SO MANY
DIFFERENT WAYS IT MIGHT BE HARD
TO ACTUALLY SAY THESE ARE ONLY
THINGS I WILL TARGET, IF YOU
KNOW WHAT I MEAN.
SO, I THINK THAT DEVELOPING
THERAPIES THAT TEND TO ATTENUATE
FUNDAMENTAL PROCESSES THAT ARE
GOING AWRY IN AGING AND DRIVING
FRAILTY IN AGING IS A PROMISING
APPROACH AND RATHER THAN JUST
DECIDING ON ONE SPECIFIC
OUTCOME. LIKE YOU KNOW, I'M NOT
A CLINICIAN AND FEELING OUT OF
MY DEPTH ANSWERING SOME CLINICAL
QUESTIONS.
>>YEAH. I MEAN THAT WORK THAT
HAS BEEN PUBLISHED CONSISTENTLY
IS SHOWING WHAT OLDER PERSONS
VALUE ABOVE ANYTHING ELSE IS
THEIR INDEPENDENCE DEFINING AS
ABSENCE OF VARIABILITY AND NOT
RELYING ON SOMEONE ELSE TO CARRY
OUT ACTIVITIES OF DAILY LIVING,
THAT AND MOST SURVEYS WILL BE
TOP PRIORITY.
IT IS ALMOST ALWAYS TOP 3
PRIORITIES AND WHY WE HAVE TO BE
CONSIDERING COMPLEMENTARY HEALTH
SPAN INDICATORS AS OUTCOMES AND
FRAILTY INDEX HAS ATTRACTIVE
FACTORS BUT DIMINISHING THAT
SCORE MAY NOT BE MEANINGFUL TO
THE INDIVIDUAL PATIENT BECAUSE
THINGS THAT ARE CORRECTED ARE
NOT RELEVANT TO THEIR LIFE.
SO, I -- I WOULD ENCOURAGE, YOU
KNOW, AS THE FIELD MOVES FORWARD
TO REFLECT CAREFULLY WHAT
PATIENTS ARE TELLING US, YOU
KNOW, CONSISTENTLY WHEN THEY
COME INTO THE CLINIC AND OTHER
HEA
HEALTHCARE SETTINGS.
>>BEAUTIFUL SESSION THIS
MORNING AND FANTASTIC PANEL AND
WANT TO BRING YOU BACK TO SOME
THINGS THAT SUSAN WAS MENTIONING
WITH THE FRAILTY INDEX AND ALSO
TO BIOMARKERS FIELD.
SO, IN MOUSE BIOLOGY FIELD WE
HAVE DONE INTERVENTIONS AND
COLLECTING IN SOME CASES
MEASUREMENTS OF HEALTH SPAN AND
ALSO WHEN DOING INTERVENTIONS
DEPENDING WHEN WE START WITH
INTERVENTIONS WE SEE REVERSAL OF
TRENDS IN BIOMARKERS AND FIELD
IS NEEDING BIOMARKERS
RESPONSIBLE TO INTERVENTIONS AND
DESCRIBING PHARMACY MODEL WHEN
YOU ELIMINATE POLYPHARMACY HOW
QUICKLY MILES RETURN TO NORMAL
STATE OF TRANL JEKTTRY FOR
FRAILTY AND CAN WE DEFINE
BIOMARKERS ALTERED IN SHORT
PERIOD OF TIME THAT IS FOR LONG
TERM OR SHORT TERM INTERVENTIONS
AND HOW THAT CAN ACCELERATE
TRANSLATION INTO THE FIELD.
WHEN WE STARTED THIS PROJECT WAS
MENTIONED THANKS, TOM, FOR
MENTIONING IT TO PREDICT
TRAJECTORIES OF AGING IN MICE
AND TRYING INTERVENTION
MEASUREMENTS TO BE IS IN SHORT
TERM DECLINE IN SPEES AND
INTERVENTION WITH EXERCISE WILL
MOUSE RECOVER IN GAIT SPEED IN
THREE MONTHS LOST IN PRECEDING
THAT INTERVENTION AND WE HAVE TO
START THINKING AND US INCLUDING
CONCEPT EACH MOUSE WHEN
GENETICALLY IDENTICAL THEY HAVE
A DIFFERENT RESPONSE TO THAT
GIVEN INTERVENTION.
I WILL GIVE YOU WELL-KNOWN
ESTABLISHED THING ABOUT
[INDISCERNIBLE].
YOU PUT IT ON HIGH FAT DIET AND
20% OF THAT POPULATION WOULD NOT
GAIN WEIGHT. WE DON'T EVEN
UNDERSTAND THAT AND WHY AND WE
KNOW THAT THERE IS A RESPONSE TO
INTERVENTIONS EVEN IN VERY WELL
CHARACTERIZED AND WELL
CONTROLLED STUDIES THAT I THINK
THAT CONCEPT OF PERSONALIZED
RESPONSES TO A TREATMENT IS ALSO
SOMETHING WE HAVE TO START TO
CONSIDER IN THE BROAD SPECTRUM
ON BASIC BIOLOGY OF AGING.
>>I THINK THAT IS REALLY
INTERESTING AND I MEAN THAT EVEN
IN MOST THINGS WE HAVE TRIED TO
DO TO ALTER TRAJECTORY OF
FRAILTY WE HAVE SEEN ARRESTING
THE DEVELOPMENT OF FRAILTY AND
NOT REVERSING IT. ONE EXCEPTION
I POINTED OUT WAS IMPACT OF AGE
AND INTERVENTION IMPACTFUL IN
FEMALE ANIMALS AND IN STUDIES
AND NOT ONLY PERSON THAT HAS
SEEN THAT AND THERE IS
DEFINITELY THAT MALE AND FEMALE
DIFFERENCE SHOWING UP AND SPEAKS
TO IDEA THAT THERE IS
HETEROGENEITY WITHIN THE
POPULATION AND WE HAVE TO REALLY
THINK ABOUT THAT.
>>BRIAN CHEN, FOXO TECHNOLOGIES
AND WANT TO GET EVERYONE'S
COMMENTS ON AGE IN WHICH THE
BIOMARKER OR CLINICAL MEASURES
ARE MEASURED AT AND WHETHER
UTILITY CHANGES DEPENDING ON AGE
AND SEEMS LIKE AN EASY WIN FOR
US TO STRATIFY BY AGE AND YOU
GET INTO SITUATIONS.
TWO EXAMPLES, ONE IS BMI THAT WE
KNOW IS BAD FOR YOU WHEN AGE 40
AND WHEN AGE 100 IT IS ACTUALLY
POSSIBLY BENEFICIAL AND THERE
ARE BIOMARKERS THAT COULD HAVE A
FLIPPED ASSOCIATION AND OTHER
QUESTION KIND OF MOST
HIGHLIGHTED IN DR. WALSTON'S
TALK WITH RESILIENCE IN
PHENOTYPES OR PHENOTYPES OF
AGING THAT IS PROBABLY GOOD FOR
OLDER INDIVIDUALS AND AS YOU GO
YOUNGER THEY MIGHT NOT HAVE ALL
PHENOTYPES SHOWING UP YET AND
WHAT YOU ARE LEFT WITH IS THE
CONTRIBUTORS THAT I THINK IS
WHAT YOU CALLED IT. IT COULD BE
PREDICTIVE THEMSELVES AND SO I
AM JUST THINKING THAT ACROSS THE
LIFE COURSE ARE WE LOOKING IN
THE FUTURE TO HAVE DIFFERENT
MODELS THAT USE DIFFERENT
COMPONENTS FOR DIFFERENT AGES?
SO, I WOULD LOVE TO GET ALL YOUR
THOUGHTS ON VARIOUS MARKERS YOU
HAVE.
>>THANK YOU.
>>I WILL TAKE THE LAST ONE
FIRST BEFORE WE FORGET IT. SO,
I THINK THAT WE -- WE NEED TO --
I MEAN, I GUESS IN CLINICAL
PRACTICE THAT REALITY IS THAT
NOBODY IN EARLY WORKING LIFE
WITH KIDS RUNNING AROUND AND
NOBODY IS THINKING ABOUT THIS
STUFF. THAT IS JUST A -- I
PROBABLY -- AND PEOPLE TEND TO
BE LIKE IN THEIR 50S AND 60S AND
HAVE MONEY AND SUDDENLY THINK
THAT WE NEED TO GET THESE
GEROSCIENCE INITIATIVES GOING
AND I THINK THAT CHANGES
PROBABLY DO START TO HAPPEN.
YOU KNOW, I CAN'T REMEMBER WHO
MENTIONED LUIGI AND SORT OF YOU
PEAK IN 30S WITH PHYSICAL
FUNCTION AND I DON'T KNOW WHEN
COGNITION PEAKS.
THERE IS A PERIOD THAT PROBABLY
I WOULD GUESS IN THE TO URTIES
WHERE IT STARTS TO BE DECLINES
THAT PROBABLY IS AN AREA WE
SHOULD TARGET AND THAT IS WHEN
THE -- CLINICALLY, THAT IS WHEN
TRAJECTORIES START TO
DIFFERENTIATE. YOU KNOW, I
DON'T THINK WE CAN -- WE KNOW
THAT WORKING WITH, YOU KNOW,
EARLY STRESS RESPONSE PATHWAYS
AND PSYCHOSOCIAL DYNAMICS EARLY
IN LIFE WILL PROBABLY MAKE A BIG
DIFFERENCE THAT IS KIND OF A
DIFFERENT AREA OF CLINICAL
PRACTICE AND BACK TO YOUR
QUESTION. I THINK IN THE MID
40S THAT WE START TO SEE A
DIFFERENTIATION IN SOME SYSTEMS
IN GETTING BIOMARKERS IN
POPULATIONS WILL HELP US TO BE
PRECISE ABOUT SETTING UP
CLINICAL TREATMENT PLANS.
>>YEAH. I THINK THAT YOU ARE
-- YOUR ASSESSMENT IS RIGHT ON
AND THINK WHAT WE NEED TO DO IS
LOOK AT THESE ACROSS DIFFERENT
AGES AND DON'T KNOW IF DAN IS
STILL HERE BUT THINK WORK DONE
OUT OF DON HAS BEEN REALLY
IMPORTANT IN TERMS OF INDICATING
DIVERGENCE EARLY IN LIFE ON A
VARIETY OF THESE MARKERS AND
WILL SAY THAT WHAT I SHOWED
TODAY I WAS SURPRISED THAT DON
PACE DIDN'T DO WELL IN PICKING
UP MORTALITY WITHIN FOUR YEARS
AMONG THIS OLDER POPULATION AND
USUALLY IN TERMS OF HEALTH
OUTCOMES THAT DOES AS WELL AS
GRIM AGE AND THINK IT IS AN
INDICATION THAT DIFFERENT
MEASURES MAY PREDICT DIFFERENT
OR BETTER AT DIFFERENT AGES AND
ALSO DIFFERENT OUTCOMES AND I
THINK THAT IT IS THE BEGINNING
OF UNDERSTANDING A COMPLEX WORLD
AND THINK WE HAVE TO ADD TO
UNDERSTANDING AT A MUCH YOUNGER
AGE.
>>THANK YOU.
>>THANK YOU, DAN FOREMAN,
PITTSBURGH AND JEREMY I WANTED
TO RESPOND TO YOU PARTICULARLY
AND WHEN ONE IDENTIFIES THE
DEGREE OF RISK FROM FRAILTY AND
OTHER MEASURES ASSOCIATED WITH A
WONDERFUL TALK THIS MORNING AND
ARE OPPORTUNITIES TO INTERVENE I
DON'T THIS IS APPRECIATED AND
WORK IN CARDIAC REHABILITATION
AND DRAWS FOR CARDIAC CLINICIANS
AND OPPORTUNITY FOR TAKING
PEOPLE WITH CARDIAC DISEASE
PREDOMINANTLY IN OLD AGE WITH
BIOMARKERS AND WHO HAVE DISEASE
AND IN MANY CASES ARE BENEFITING
AT LEAST INITIALLY FROM THE
INTERVENTION THAT RESTORES BLOOD
FLOW AND RESTORES VAL VUL AR
FLOW THROUGH CRITICAL STENOSIS.
THAT IS AN OPPORTUNITY TO THINK
ABOUT SARCOPENIA AND OPPORTUNITY
TO THINK ABOUT MUSCLE MASS AND
IS AN OPPORTUNITY TO PERHAPS
INTEGRATE MET FOR MIN AND
INTERVENTIONS WITH JERO SCIENCE
BENEFIT AND THINK THERE ARE
TOOLS WE HAVE THAT ARE GENERALLY
NOT EMBRACED BY WAY THAT WE
MANAGE PATIENTS IN 2023 AND FOR
LAST DECADES AND AS POPULATION
AGES I THINK THAT THE NOTION OF
REJUVENATION IS REALLY CRITICAL.
IT IS ASSOCIATED WITH HIGH COST
AND HIGH MORBIDITY AND HIGH
DISABILITY AND HIGH LOSSIN
DEPENDENT AND ARE OPPORTUNITIES
TO INTERVENE AND RIGHT NOW
CARDIAC REHAB PROGRAMS ACROSS
COUNTRY ARE MASSIVELY
UNDERUTILIZED BY OLDER ADULTS
AND DOESN'T MAKE SENSE AND THERE
IS A VERY STRIKING PARADOX
BETWEEN USE OF PROGRAMS AND
NATURE OF PATIENTS THAT MIGHT
BENEFIT.
I TOTALLY AGREE DIDN'T MEAN TO
SAY WORD NO INTERVENTIONS NOT
COMING OUT OF MOUTH AND DON'T
KNOW WHAT TO SAY AND THANKS FOR
POINTING IT OUT AND AGAIN
EXERCISE AND DIET I HIGHLIGHTED
THEY ARE TWO THINGS THAT HAVE
BEEN SHOWN OVER AND OVER AND
OVER AGAIN TO IMPACT POSITIVELY
IMPACT EVEN MOST FRAIL
INDIVIDUALS AND WHAT I WAS
MEANING TO SAY IS HITTING 3 OR 4
OR 5 CRITERIAS YOU CAN'T REVERSE
THOSE THINGS BUT MAKE PEOPLE
FEEL BETTER IMPROVING QUALITY OF
LIFE AND KEEPING PEOPLE OUT OF
THE HOSPITAL AND IMPORTANT
MARKERS AND NOT EXPERT GETTING
PEOPLE TO EXERCISE THAT HAS
NEVER WORKED IN CLINICAL
PRACTICE AND MAYBE TOM HAS HAD
BETTER LUCK.
>>THERE ARE EXAMPLES SUCH AS
DELAYING KITSMAN AND SOME ARE
DISEASE SPECIFIC IN HIS CASE
HEART FAILURE AND I GENERALLY
AGREE WITH JEREMY IT IS A TOUGH
NUT TO CRACK WHEN YOU HAVE
SOMEONE WHO HAS MORE ADVANCED
PHASES OF FRAILTY PHENOTYPE THAT
IS HARD TO TURN BACK HANDS OF
TIME AND THINK THAT SOME
INTERVENTIONS BEING PLANNED ARE
ON THE MORE PREVENTIVE PHASE OF
THE SPECTRUM.
>>JUST TO ECHO WHAT HAS BEEN
SAID AND LOOKING AT SURGICAL
COMANAGEMENT SERVICES IN THE
HOSPITAL AND LIKE FOR EXAMPLE,
OUR HOSPITAL HAS A SERVICE WHERE
INDIVIDUALS COMING IN HAVE BEEN
IDENTIFIED AS FRAIL USING
ELECTRONIC MEDICAL RECORDS AND
VARIABLES TO HAVE CLOSE
GERIATRIC [INDISCERNIBLE] FROM
EVEN PRIOR TO ELECTIVE SURGERY
AND THERE ARE WAYS TO HELP FOLKS
ONCE THEY ARE IN THE HOSPITALS
AS WELL DESPITE BEING FRAIL TO
HELP SHEPHERD THEM THROUGH THAT
HOSPITALIZATION AND LAST TWO
QUESTIONS.
>>A FEW PANELISTS HAVE
MENTIONED ALREADY THINKING ABOUT
THE PATIENT AND IN CLINICAL
PRACTICE AND LUIGI ENCOURAGED US
TO THINK ABOUT PEOPLE THAT WE
ARE TRYING TO THINK ABOUT SEEMS
BUILDING ON RAPHAEL'S POINT
GENETICALLY MICE RESPONDING TO
DIET AND EXERCISE AND TO DRUGS
AND COULD THERE BE STRATEGIES TO
AGING AND PERHAPS FACTORS
MATTERING FOR PEOPLE AND NOT SO
MUCH FOR OTHER PEOPLE?
WONDERING STATISTICAL METHODS
USING AND GROUPS AND REGRESSION
METHODS SEEMING TO GET US AT
UNDERSTANDING MOST LIKELY OR
MOST COMMON PATH OR COMMON
ASSOCIATIONS GENERALLY TRUE
ACROSS PEOPLE THAT FOR SOME
PEOPLE THAT KNOW MIGHT NOT BE
ACCURATE OR MISSING OTHER THINGS
DO WE HAVE APPROACHES WE NEED TO
IDENTIFY INDIVIDUAL SPECIFIC
TRAJECTORIES OR PHYSIOLOGICAL
STRATEGIES TOWARDS RESILIENCE OR
TOWARDS AGING?
MAKE ANY SENSE?
>>THAT IS A REALLY IMPORTANT
POINT THAT HASN'T BEEN DONE YET
AND LOTS OF INFORMATION THAT WE
ARE LEARNING ABOUT TODAY AND
VARIABLES POPPING OUT OF
DIFFERENT ANALYSIS WILL HELP
INFORM DEVELOPMENT OF THAT AND
IT IS REALLY IMPORTANT TO HAVE
CLINICIANS AND BASIC SCIENCE
INVESTIGATORS AND PEOPLE IN
MIDDLE AND TRANSLATIONAL KIND OF
UNDERSTANDING BIOLOGY AND IS
IMPORTANT THAT PEOPLE ARE IN THE
ROOM TO HELP DESIGN THOSE THINGS
THAT MIGHT BE AN OUTCOME OF THE
MEETING TO REALLY THINK ABOUT
WAYS TO START TO PUT SOME OF
THIS INTO PRACTICE OR A ROAD MAP
FOR FUTURE PRACTICE PATTERN
DEVELOPMENT.
>>IT IS SETTING ASPIRATIONS IN
RIGHT PLACE THAT IS COMPLEX AND
THINK THAT LIFETIME OF
LONGITUDINAL DATA GOES A LONG
WAY TO DOING EXACTLY WHAT YOU
ARE PROPOSING AND WHAT WE SHOULD
AIM FOR.
>>I THINK IN THE WORLD WE ARE
LOOKING FORWARD TO SLAM STUDY
THAT RAFA IS DOING AND LONG TIME
PEOPLE THOUGHT OF ANIMALS AS
BEING SIMILAR AND C57 BLACK 6S
IS A FAIRLY NEW RECOGNITION THAT
I THINK I DON'T KNOW IF WE KNOW
ENOUGH TO COHORT THEM IN ANY WAY
AND IDENTIFYING ONE ASPECT
RESPONSE TO HIGH FAT FEEDING AND
FEMALE DIFFERENCES AND THERE IS
SOMETHING THERE AND INTERESTING
TO LEARN MORE.
>>THANK YOU.
>>NEXT QUESTION.
>>[INDISCERNIBLE] FROM JAIL AND
POINTING OUT EARLIER THAT MENTAL
HEALTH IS EXCLUDED FROM AGING
STUDIES AND DIFFERENT SYSTEM
EXCLUDED FROM STUDIES IS
REPRODUCTIVE AGEING THAT WILL BE
A SIGNIFICANT OUTCOME TO
CONSIDER IF THERE IS SYMPTOMS
RELATED TO REPRODUCTIVE SYSTEMS
IMPACTING QUALITY OF LIFE FOR
OLDER ADULTS AND SPECTRUM AS 35
YEAR OLD SPENDING TIME IN CAREER
PEERS ARE MOST CONCERNED ABOUT
REPRODUCTIVE AGING AND FERTILITY
AND QUESTION TO YOU IS HOW TO
INTEGRATE REPRODUCTIVE SYSTEM
MEASURES INTO CONSIDERING IT AS
AN OUTCOME?
>>DO YOU KNOW THE ANSWER?
>>I DO NOT.
>>CERTAINLY PEOPLE HAVE STARTED
TO INCORPORATE MEASURES OF
TIMING OF MENOPAUSE AND VARIETY
OF HORMONAL THINGS.
I THINK IT IS ANOTHER SYSTEM TO
BE ADDED TO THE MIX AND.
>>BRIEFLY CHIMING IN
CONSIDERATION EXPERIENCE WITH
MOUSE WORK AND FEMALE MICE WE
TYPICALLY USE ARE NOT BREEDERS
FOR STUDIES AND FACTORS WE ARE
NOT INCLUDING WITH MANY AGING
RELATED STUDIES WE ARE DOING
WITH MOUSE COHORTS GENERALLY.
>>I HAVE A QUESTION FOR EILEEN
PRETENDING I'M IN AUDIENCE IF
YOU HAVE OPPORTUNITY OR THOUGHT
LOOKING AT DISEASE SPECIFIC
MORTALITY AND FINDINGS IN
WHETHER BIOMARKERS YOU
IDENTIFIED MIGHT DIFFER
DEPENDING ON CAUSE OF DEATH?
>>ABSOLUTELY NOT TO DATE SHORT
TERM OF MORTALITY HARD TO
DIFFERENTIATE BUT THEY
ABSOLUTELY WOULD AND THINK THAT
THIS WILL OBVIOUSLY BE RELATE
TODAY HEARTDISEASE AND CANCER
COULD BE QUITE DIFFERENT.
>>JUST COMMENTING ON
REPRODUCTIVE BIOLOGY AND IN
GERIATRIC MEDICAL PRACTICE NOT A
BAD ISSUE AND SOME CONVERSATIONS
ABOUT SEX DIFFERENCES AND HOW
PEOPLE AGE THERE IS A HUGE
DIFFERENCE. THIS IS A BROAD
OVERGENERALIZATION PROBABLY
HOPEFULLY BACKED UP BY EPIDATA
AND WOMEN TEND TO DRIFT ON FOR
MANY, MANY YEARS BECOMING
DISABLED AND HAVING A LOT OF
THINGS WE ARE TALKING ABOUT
FRAILTY AND FRAILTY STUDIES THEY
DROP OUT FOR SOME REASON THERE
IS A SEX DIFFERENCE THERE
PULLING THEM APART AND STUDIES
WILL GET THERE AND NOT SURE IF
IT HAS TO DO WITH REPRODUCTIVE
SYSTEM OR NOT BUT IS AN
IMPORTANT THING TO THINK ABOUT.
>>ALBERT IT IS DOABLE AND
TAKING OVER MANAGEMENT OF ADD
HEALTH ADOLESCENT STUDY IT
STARTED OFF AS AND NOW THEY ARE
MIDDLE AGED AND THEY HAVE
RESPONDED TO LOTS OF INFORMATION
ON FERTILITY AND REPRODUCTION IN
REAL-TIME IN KONL TRAFT TO OLDER
PEOPLE WITH REPRODUCTIVE
HISTORIES IN THE PAST THAT GAVE
THIS PROJECT AND COHORT MERGING
WITH OLDER COHORTS AND THESE ARE
SAME AS BEING PICKED UP IN
HEALTH AND RETIREMENT STUDIES
AND THINK YOU CAN DO MORE
INFORMED WORK ON THAT TOPIC THAN
PERHAPS HAS BEEN AVAILABLE IN
THE PAST.
>>I WILL COMMENT ON IT TOO. MY
UNDERSTANDING RUTH HUB BARRED IN
UNIVERSITY OF QUEENSLAND IN
AUSTRALIA LOOKED AT PARITY AND
FRAILTY AND FOUND A NO CHILDREN
-- U-SHAPED RELATIONSHIP WITH NO
AND MANY CHILDREN AND SWEET SPOT
IN AND BETWEEN AND AROUND 2 AND
WHAT I HAVE DONE AND HAVEN'T
DONE WORK IN MICE.
>>THANK YOU AGAIN TO SPEAKERS
FOR A REALLY GREAT SESSION.
>> NEXT SESSION IS
MATHEMATICAL MODELING FOR BASIC
AND TRANSLATIONAL RESEARCH AND I
WILL CHAIR THIS SECTION. THIS
SECTION AIMS TO EXPLORE THE
STATE OF BIOLOGICAL AGING MAJORS
AND HIGHLIGHTING IMPORTANCE FOR
MODELING AND BASIC AND
TRANSLATIONAL RESEARCH AND THERE
WILL BE FOUR PRESENTATIONS
TODAY. AFTER THE PRESENTATIONS
OTHER TWO PANELISTS WILL JOIN
ME. WE WILL GIVE AN OVERVIEW
INCLUDING COMMENTS ON
PRESENTATIONS.
FIRST SPEAKER IS TREY IDEKER WHO
IS FROM THE UNIVERSITY F KALOF
CALIFORNIA, SAN DIEGO. LET'S
WELCOME HIM.
>>HOW IS THAT. CAN PEOPLE HEAR
MY SCREEN -- HEAR ME AND SEE MY
SCREEN?
>>WE CANNOT SEE YOUR SCREEN.
>>YOU CANNOT?
>>WE CANNOT HEAR YOU CLEARLY.
>>HELLO. CAN YOU HEAR ME?
>>YES.
>>YOU CAN HEAR ME NOW. OKAY.
LET ME TRY. YOU CANNOT SEE MY
SCREEN?
>>NOT YET.
>>OKAY. LET ME TRY ONCE MORE.
>>WHAT ABOUT NOW?
>>IT IS GOOD.
>>THANK YOU FOR THAT
INTRODUCTION AND OTHER
CONFERENCE ORGANIZERS FOR THE
INVITATION TO PARTICIPATE.
SORRY I COULDN'T BE THERE IN
PERSON. I WAS VERY HAPPY TO
ZOOM IN A TALK. I WAS JUST AT
NIH LAST WEEK FOR A MEETING AND
NOW I HAVE TEACH IING BACK HERE
THIS WEEK. I WAS ASKED TO TALK
ABOUT MULTIPLE WAYS OF MODELING
AGING AND AS YOU WILL SEE HERE
SHORTLY, ALMOST ALL OF MY LABS
RESEARCH HAS INVOLVED THIS
SO-CALLED EPIGENETIC MEASUREMENT
OF AGE. I WILL TALK ABOUT
HISTORICAL RESEARCH. I WILL TRY
TO GET THROUGH THE NARRATIVE
PRETTY QUICKLY TO WHAT WE ARE
WORKING ON CURRENTLY THAT IS
DISSECTING THIS EPIGENETIC AGE
AND MEASURE AS BEST AS WE CAN
AND IN TERMS WHAT MY LAB WORKS
ON MORE BROADLY, IT IS REALLY
FOUR POINTS HERE.
STARTING WITH A SORT OF GENOTYPE
AND PHENOTYPE EQUATION HOW WE
TAKE GENETIC VARIANCE AND
MUTATIONS AND UNDERSTAND
PATHWAYS BY WHICH THEY INFLUENCE
OUTCOMES AND DISEASE AND AGE AND
OF COURSE WHEN YOU START TO
STUDY IMPACTS OF MUTATIONS THAT
RAPIDLY GETS YOU INTO THE
EPIGENOME AS WELL. THERE IS
ESSENTIALLY THREE PHASES OF
RESEARCH IN MY LAB ON THE AGING
ANGLE AND TEAM OVER THREE PHASES
STARTING IN 2010 AND TALKING
ABOUT WORK BY GREG HANN EM AND
JUSTIN GRAY WITH [INDISCERNIBLE]
LAB AND TINA WONG I SHOULD SAY
ALL THESE ARE PHD STUDENTS AT
UCSD WHO IS A GRAD STUDENT IN
BIOENGINEERING AND TINA WONG
BIOMEDICAL SCIENCES HERE AT UCSD
AND DROVE SECOND WAVE INTO
MAMMALS AND DOGS YOU WILL SEE
AND RECENT IS COLLABORATION WITH
STEVE COMINGS AT CSF AND TALKING
ABOUT WORK LED BY SDAIN HOCK.
IN MY LAB, THIS STARTED IN A
COLLABORATION WITH CONJONG WHO
HE AND I BACK IN 2011 HAD JUST
WORKED WITH ILLUMINA DOWN HERE
IN THE STREET IN SAN DIEGO TO
GENERATE WHAT WERE SOME FIRST
METHO LOAMWIDE PROFILES OF
HUMANS THAT WERE STARTING THEN.
WE HAD 656 OR SO HUMANS WHERE WE
EXTRACTED WHOLE BLOOD AND
MEASURED CPG METHYLATION SITES
AND AT NEARLY 500,000 SITES
GENOMEWIDE.
ORIGINAL GOAL WAS TRYING TO
UNDERSTAND MARKERS FOR CANCER IN
THE BLOOD.
THOSE EFFORTS SINCE HAVE BEEN
MORE SUCCESSFUL FOR OTHER
PEOPLE'S HAND AND IN OUR CASE WE
KEPT GETTING, YOU KNOW, WASHED
OUT. ANY CANCER SIGNAL WAS
ENTIRELY WASHED OUT BY THE
OVERWHELMING CO-VARIATE THAT
GREG HANN EM FOUND TO BE AGED
AND WE RAPIDLY REALIZED WE HAD
TO PICK AND THAT WAS VERY
INTERESTING AND WE RAPIDLY
REALIZED WE HAD TO PIVOT AND
STUDY AGE FOR THIS WORK RATHER
THAN FOCUS ON CANCER THAT GIVES
YOU ONE EXAMPLE OF A CYTOSINE
MARK THAT IS IN DNA WHERE THE
FRACTION OF REEDS WITH THAT --
WHERE THAT CYTOSINE IS MENL
ILLATED AND SO-CALLED MENL ILL
CPG INCREASES RELIABLY OVER YOUR
POPULATION WITH AGE.
EVERY POINT THERE IS A HUMAN AND
INDIVIDUAL AND THEIR AGE
CHRONOLOGICALLY ON X AXIS AND
FRACTION OF CPGS MEASURED AT
THAT SITE INDIVIDUAL AND IS
SHOWN AT Y AXIS THAT IS NOW AN
OLD HAT.
IT IS STILL GOOD TO LOOK AT EACH
INDIVIDUAL SIDE AND SEE HOW WELL
SITES TRACK AGE AND WE WENT ON
TO USE A LINEAR REGRESSION MODEL
BASED ON ELASTIC NET AND COMMON
REGULARIZATION TECHNIQUE FOR
LINEAR REGRESSION PREDICTING
CHRONOLOGICAL AGE USING A SMALL
NUMBER OF METHYLATION SITES IN
INDIVIDUALS AND COULD COME UP
WITH A QUITE GOOD PREDICTOR THAT
IS NOW CALLED EPIGENETIC CLOCK
AND NOW THESE POINTS ARE PEOPLE.
THEY ARE WHOSE AGES ARE
PREDICTED OR ARE ON THE Y AXIS
AND -- AND THE X AXIS IS THEY
ARE AN ACTUAL CHRONOLOGICAL AGE
AND OF COURSE PEOPLE WE AND
OTHERS HAVE SINCE BECOME VERY
INTERESTED IN OFF-AXIS
PREDICTION AND PEOPLE ABOVE
DIAGONAL ARE AGING QUICKLY BELOW
POPULATION AND DIAGONAL IS AGING
MORE SLOWLY THAN THE POPULATION
AND OF COURSE WE AND -- AND MANY
OTHERS NOW HAVE HAD -- HAVE
SHOWN THAT THERE IS A RELATION
FOR WHAT LOOKS LIKE ERROR HERE
IN THESE LINEAR REGRESSION PLOTS
THAT DO ACTUALLY ASSOCIATE WITH
DISEASE STATES OVERALL.
MARIONI BACK IN THE STUDY BACK
IN 2015 SHOWED THAT THIS TYPE OF
CLOCK ASSOCIATES WITH ALL CAUSE
MORTALITY.
AND, OF COURSE, YOU KNOW,
RAPIDLY FOLLOWING OUR STUDY WAS
FAMOUS STUDY WHERE HE USED OUR
DATA AND SOME MORE METHYLATION
PROFILES FOR HIS PAPER. HE
CHOSE A DIFFERENT SET OF SITES.
AGAIN, THERE IS A HUGE NUMBER OF
CPG SITES IN METHYL OHM THAT
APPEAR WITH TRACKING AGE AND
SIMPLY IN TWO MODELS YOU WANT TO
HAVE A GOOD SELECTION THAT IS
PREDICTIVE AND LOTS OF OTHERS
FOLLOWING THAT PAPER HAVE
REVISED SO-CALLED EPIGENETIC
CLOCKS IN DIFFERENT WAYS AND AS
WELL AS USE THEM IN SOME NEW
COMPANIES THAT WE ARE SEEING IN
THE WELLNESS SPACE.
WHAT DID MY LAB DO? DO ANYTHING
USEFUL FOR HUMANS AFTER THAT?
HECK NO. WE -- I SHOULD NOW SAY
TINA WONG ENTERED THE PICTURE
FRESH INTO GRAD SCHOOL AND CAME
INTO MY OFFICE AND SAID, YOU
KNOW, ALL THAT EPIGENETIC WORK
FOR HUMANS IS INTERESTING FOR A
PRETTY YOUNG AGE. YOU KNOW,
TREY, YOU KNOW PEOPLES AGE.
WHAT ABOUT PREDICTING SOMEBODY'S
AGE THAT YOU WANT TO KNOW BUT
YOU DON'T. DOGS WERE HER PRIME
EXAMPLE.
90% OF DOGS AND MIGHT BE MORE
THAN THAT IN AMERICA ARE
ADOPTED.
AND IN WHICH CASE THE OWNERS
TYPICALLY DO NOT KNOW THEIR AGE
OTHER THAN THIS IS A YOUNG DOG
OR THIS IS AN OLD DOG AND SHE
SPENT TWO YEARS AT THE BEFRNL
DESIGNING AN EQUIVALENT SOLID
PHASE TECHNOLOGY WENT LIQUID
PHASE CREATING EQUIVALENT DOG
METHYLATION ARRAY ENRICHED FOR
SEINETENIC CPG SITES AND REGIONS
THAT WERE ALREADY DESIGNED ON
THAT ALUM IN A CHIP.
THAT IS WHAT SHE DID. DID SHE
BUILD AN EPIGENETIC CLOCK? NO.
SHE DID NOT. SHE SIMPLY ALIGNED
EVERY DOG METHO LOAM 100 LAB RAD
DOR RETRIEVER MENLO LOAMS THAT
MOSTLY CAME FROM [INDISCERNIBLE]
AT UC DAVIS IN COLLABORATION
WITH NIH AND PETER WHO IS IN
TOUNL AT BURN HAM AND ALIGNED
EACH OF THE DOG METHO LOAMS
AGAINST POPULATION IN PUBLIC
DOMAIN BY THAT TIME HUMAN METHO
LOAMS LOOKING AT WHAT NEAREST
NEIGHBORS IN ALIGNMENT WERE AND
SIMILAR SPECIES YOUNG DOGS ARE
SIMILAR TO HUMAN METHO LOAMS AND
VICE VERSA AND YOU CAN IN FACT
QUANTITATIVELY DRAW A CURVE THAT
LOOKS LIKE THIS. WHAT YOU SEE
IS IN FACT NOT A LINEAR
RELATIONSHIP OR IS NOT THE SORT
OF 7 NUMON YEARS TO ONE DOG
ADAGE THAT MAY IN FACT BE TRUE
BY THE END OF LIFE. WAY YOU GET
THERE IS HIGHLY NON-LINEAR AND
ESSENTIALLY IS A ONE YEAR OLD
DOG OR NINE-MONTH OLD DOG LIKE
AN EARLY ADULT 20 TO 30 YEAR OLD
IN HUMAN SPACE IN RETROSPECT IS
NOT SURPRISING DOGS CAN'T
PUPPIES FAR WELL IN ADVANCE OF
ONE AGE. 7X MAP SIMPLY DOESN'T
WORK PHYSIOLOGICALLY EITHER.
WHAT WAS EXCITING ABOUT METHO
LOAM IS GETTING A QUANTITATIVE
CURVE AND WHAT WAS EVEN MORE
EXCITING IS YOU CAN NOW LOOK AT
THE GENOME OR EPIGENOME TO
FIGURE OUT WHAT REGIONS OF
GENOME ARE WITH SIMILARITY THAT
IS MAXIMAL OR SIMPLY DISTRIBUTED
WIDELY AND TURNS OUT SIMILARITY
DOES CLUSTER AND NAL THAT IS NOT
PERFECT AND FOUND TWO CLUSTERS
THROUGH ANALYSIS AND PROTEIN
INTERACTION NETWORKS ANATOMICAL
DEVELOPMENT 1 AND 2 AND HERE
SHOWN ABOVE EACH OF THESE
CLUSTERS SHOWN TO CONSERVE
METHYLATION COURSE OF GENOME
REALM THAT IS OVER LIFE COURSES
OF DOGS AND HUMANS AND WE ARE
ALIGNING MICE. YOU HAVE THREE
SPECIES THAT AGE WITH DIFFERENT
CHRONOLOGICAL LIFESPANS AND
ALIGNING THEM THROUGH FRACTION
OF LIFESPAN THEY ARE AND LOOK IN
ALL THREE SPECIES LOOKING AT
CONSENSUS METHYLATION PATTERNS
LOOKING MOSTLY AT GENES TOP AND
YOUNG AND BOTTOM INCREASING
METHYLATION AS WE AGE AND YOU
ASK OVER HERE DECREASING
METHYLATION AS WE AGE AND GENES
RESPONSIBLE FOR GROWING OF ARMS
AND LEGS AND TAILS.
SHE WENT ON IN A CONSERVATION
MODE TO LOOK WITH PETER ADAMS
AND HOLY BROWN MORGUE WITH MICE
RESTRICTION AND DOFSHISM AND
RAPPAMYCIN TREATMENT AND IS
SHOWING AMAZING WORK BY TINA
WONG WHEN SHE WAS HERE THAT WILD
TYPE MICE IN GRAY MOSTLY FALL ON
DIAGONAL THAT YOU WOULD EXPECT
AND DO BETTER ALREADY SORT OF
EPIGENETIC AGES YOUNGER YOU
EXPECT BY CHRONOLOGICAL AGE AND
LOOK WHAT HAPPENS WHEN YOU TREAT
WITH RAPPAMYCIN AND RETARD E
EPIGENETIC AGE AND REGRESSION OF
MENLO LOAM SHOWING THAT THESE
EPIGENETIC CLOCKS ARE GOOD
MEASURE OF WHATEVER LIFESPAN
EXTENDING TREATMENT YOU ARE
TRYING IS WORKING AND POINTING
OUT TWO PAPERS COMING OUT AROUND
THE SAME TIME WITH SIMILAR
RESULTS IN CASE OF AGING SELF
HAS MORE DATA THAN WE HAD AND
PLEASE TAKE A LOOK AT THOSE AS
WELL IN LAST MINUTE OR TWO I
RESERVE TIME TO TALK ABOUT WHAT
WE ARE DOING NOW THAT IS
UNPUBLISHED STUFF ALREADY AND SO
VERY PRELIMINARY BUT I THINK IS
INTERESTING AND WE ARE
INTERESTED IN WHAT DRIVES
EPIGENETIC AGING SIGNALS GOOD AS
DIAGNOSTIC BUT ARE CAUSAL FOR
SOMETHING OR REACTION FOR
SOMETHING AND BOTH AND WHAT
WOULD BE THOSE THINGS AND THAT
IS A NONEXHAUSTIVE LIST OF
EXPLANATIONS POSED BY MANY
PEOPLE OVER MANY DECADES NOW.
ONE, EPIGENETIC CHANGES ARE
CONSEQUENCES OF DAMAGE THAT IS
ACCRUING OVER TIME AND THIS IS A
CLASSIC, YOU KNOW, AGING THEORY
AND THESE DAYS IT IS POSITIED
FOLLOWED BY DAVID SINCLAIR AND
ALEX ANDROF IN CANCER COMMUNITY
AND OTHERS. SORRY LOTS OF
PEOPLE HERE. WANTED TO SAY A
FEW NAMES AND 5 TO OTHERS AND
THAT IS ONE THEORY AND OTHER
THEORY WITH DOG CONSERVATION
PAPER WITH OWN WORK ARE MAYBE
CHANGES HAPPENING DURING
DEVELOPMENT IN A CONSERVED WAY
AND AGING IS SIMPLY AN EXTENSION
OF THAT DEVELOPMENTAL PROGRAM
AND HERE ARE OTHERS WHO ARE
CERTAINLY PROPONENTS OF THIS
THEORY AND, YOU KNOW, THERE HAS
BEEN A BIT OF BUZZ LATELY ABOUT
RECENT ARTICLE AGING SOFTWARE
DESIGN FLAW THAT CAME OUT THAT
REALLY FALLS INTO THIS
PARTICULAR THEORY CLASS AND
PETER AND SEVERAL OTHERS HAVE
SAID YOU KNOW THIS IS ALL NOT AS
IMPORTANT AS LOOKING AT CHANGES
IN CELL TYPE COMPOSITION AS WE
AGE AND NOT HAPPENING WITH
INDIVIDUAL CELLS BY ANY MEANS
AND THINK THAT WE STARTED A FEW
LATE BUT WANT TO SAVE TIME FOR
QUESTIONS AND WHAT I WILL DO IS
SKIP TO THE END TAKING QUESTIONS
AND WE CERTAINLY THINK THERE ARE
INTERESTING ANALYSIS THAT COULD
BE DONE TO LOOK AT RELATIONSHIP
BETWEEN EPIGENETIC CHANGE AND
SOMATIC MUTATIONS IN EXISTING
DATA SETS OUT THERE IN THE
PUBLIC DOMAIN AND I'M HAPPY TO
ANSWER QUESTIONS ABOUT THAT
LATER. JUST AS A SUMMARY, YOU
KNOW, AGING, I THINK, IT IS
WELL-KNOWN NOW TO BE TRACKED
WELL BY METHYLATION CHANGES AND
CYTOSINE AND KWAUN EVEN SITES
OVER MANY DIFFERENT SITES AND
SIGNATURE SO-CALLED CLOCK IS
EFFECTED BY DISEASE STATES AND
SLOWED BY CLASSIC LIFESPAN
ENHANCING TREATMENTS.
IT IS CONSERVED IN MAMMALS AND
WHICH CAN PINPOINT -- PINPOINTS
DEVELOPMENTAL GENES AND THEORIES
OF AGING AND IN WORK THAT I RAN
OUT OF TIME TO SHOW ONE CAN ALSO
TURNS THROUGHOUT IS A GLIMMER
THERE IS A RELATIONSHIP BETWEEN
DNA MUTATIONS AND CHANGES IN
HYPOAND HYPERMETHYLATION
GENOMEWIDE SUPPORTING ANOTHER
THEORY OF AGING AND MUTATION
THEORY AND THANK YOU VERY MUCH.
>>THIS TALK IS ON HOW TO
MEASURE AGING AND LOTS OF WORK
IN PAST FEW DECADES FROM STUDIES
WE KNOW HUNDREDS IF NOT
THOUSANDS OF GENES EXTENDING
LIFESPAN ACROSS A RANGE OF
DIFFERENT MODEL ORGANISMS AND IN
FACT INSIGHTS DERIVED FROM
STUDIES ARE AT VERY HOERT AND
FOUNDATIONAL CONCEPTS TO BIOLOGY
OF AGING AND ONE REPRESENTATION
OF THAT HALLMARKS OF AGING HERE
NOT GOING INTO TOO MANY DETAILS
AND STRESSING FACT THAT IDEAS
ARE BASED ACTUALLY ON LIFESPAN
DATA THAT IS IN A WAY A BIT
PROBLEMATIC STRUDYING LIFESPAN
AND AGING IS NOT SAME THING AND
LIMITED DISEASES AND WE HEARD
TODAY AND YESTERDAY THAT RATHER
THAN GENERAL PHYSIOLOGICAL
DECLINE THAT IF YOU CONSIDER THE
CONTEXT IN MICE FOR EXAMPLE IS
PRETTY WELL KNOWN THAT CANCER IS
A MAJOR KILLER IN OLD AGE AND
ARE STUDIES SHOWING 70 TO 90% OF
MOUSE STRAINS CAN DIE TO CANCER
IN OLD AGE AND TRYING TO DO A
SCREEN FOR EXAMPLE GENETIC
LIFESPAN IN MICE YOU WOULD
LIKELY PICK UP MODIFIERS OF
PLASTIC DISEASE BASED ON
CONSIDERATIONS AND YOU WOULDN'T
NECESSARILY KNOW IF MODIFIERS OF
LIFESPAN REGULATE AGING AND IS
KIND OF SHOWN IN THIS CARTOON
HERE AND IF WE VIEW AGING AS
LARGE COLLECTION OF AGE
SENSITIVE PHENOTYPES AND USING
LIFE SPAN AS READ OUT WE WILL
LEARN ABOUT REGULATORS OF ORE
MECHANISMS THAT ARE LIFE
LIMITING CAUSES OF DEATH FOR
EXAMPLE AND WOULDN'T LEARN ABOUT
MODULATORS OF AGE SENSITIVE
PHENOTYPES THAT ARE NOT LIFE
LIMITING AND MIGHT BE MANY OF
THESE -- ORGANISMS WHETHER THEY
ARE MORE BROADLY HAVING EFFECTS
ON AGING AND AGE RELATED
MORTALITY AND APPROACH THAT WE
HAVE TAKEN IS TO PERFORM
PHENOTYPING ACROSS RANGE OF
TISSUES AND ORGAN SYSTEMS AND
BIOLOGICAL COMPLEXITY COMPARING
ORGAN MODELS AND LIKE GOING FROM
HOSPITAL TO HOSPITAL AND
SPECIALIST TO SPECIALIST GETTING
HEALTH CHECKS PUTTING DATA
TOGETHER TO BUILD
MULTIDIMENSIONAL REPRESENTATION
OF BIOLOGICAL AGE AND CAN USE TO
TEST POSSIBLE ANTIAGING
INTERVENTIONS AGAINST.
FRAMEWORK WHILE APPLYING CERTAIN
INTERVENTIONS TO MICE WE CAN TRY
TO UNDERSTAND WHICH POTENTIAL
PROCESS IS LINKED TO WHICH AGE
SPECIFIC PHENOTYPE THAT IS NOT
SUFFICIENT TO LOOK AT AGE
SENSITIVE PHENOTYPE IN OLD
ANIMALS BECAUSE A TREATMENT
COULD INFLUENCE A PHENOTYPE IN
MANY WAYS WHICH ALL ARE NOT
INFLUENCING AGE DEPENDENT
PHENOTIPIG CHANGE AND COST
EFFECTIVE TREATMENTS HERE AND
SHOWING TWO EXAMPLES TO
ILLUSTRATE THAT POINT. SO, FROM
SYMPTOMATIC TREATMENTS WE CAN'T
ACTUALLY INFER AGING MECHANISMS
WITH AGING MECHANISMS I MEAN
MECHANISMS THAT HAVE PHENOTYPIC
CHANGE TO GIVE YOU ONE EXAMPLE
AND AGING PHENOTYPE EFFECTING
HAIR AND LET'S ASSUME THAT
BIOLOGICAL MECHANISMS WITH AGE
SENSITIVE PHENOTYPE IS
DISFUNCTION OF [INDISCERNIBLE]
STEM CELLS AND ANY TREATMENT
THAT TARGETS ROOT CAUSES
PHENOTYPE ADDRESSING BUY LOGIC
CHAFKS AND IS POSSIBLE WE CAUSE
CHANGE SENSITIVE PHENOTYPE IN
SENSITIVE WAY WITHOUT ALTERING
-- WE COULD COLOR HAIR AND
POTENTIALLY CONVERT WHITE TO
BLACK HAIR FOR EXAMPLE AND
WOULDN'T BE ABLE TO LEARN
ANYTHING ABOUT AGING MECHANISMS
FROM THIS EFFECT GIVING A SECOND
EXAMPLE AGE RELATED COGNITIVE
DECLINE THAT IN A FICTITIOUS
PERFORMANCE ON COGNITIVE TEST
THAT IS STABLE FOR SOME TIME AND
IS DECLINE BASED ON WHEN DECLINE
OCCURS DISTINGUISH BETWEEN
ASYMPTOMATIC TO SYMPTOMATIC
PHASE AND TARGETS MECHANISMS
UNDERLYING AGE RELATED DECLINE
AND TREATMENT HERE AND IT SLOWS
DECLINE ONCE IT STARTED TO
EMERGE AND FICTITIOUS EXAMPLE IN
GENERATION AND CONTEXT OF
ALZHEIMER'S DISEASE AND IF WE
SEE TREATMENT EFFECTS IN YOUNG
AND HEALTHY INDIVIDUALS THAT
DON'T HAVE SDEESED AND TREATMENT
EFFECT IS TARGETING MECHANISMS
OF DISEASED AND TREATMENT EFFECT
IN PEOPLE GOING ON TO DEVELOP
COGNITIVE DECLINE AND
ALZHEIMER'S DISEASE AND SEE
EFFECT PRIOR TO BEGINNING OF
MANIFESTATION OF DISEASES THAT
WOULDN'T BE EVIDENCE THAT WE ARE
TARGETING MECHANISMS OF DISEASE.
EXAMPLE MIGHT BE WE COULD USE
PSYCHOSTIMULANTS FOR
[INDISCERNIBLE] FOR EXAMPLE TO
ENHANCE COGNITIVE NAUFRNGS WOULD
NOT BE EVIDENCE WE ARE TARGETING
MECHANISMS OF AGE RELATED
COGNITIVE DECLINE AND WITH THESE
CONSIDERATIONS WE CAN DESIGN
EXPERIMENTS WHERE WE TEST AND
WOULD INCLUDE YOUNGER ANIMALS TO
TEST BEFORE ONSET OF PHENOTYPIC
CHANGE TO DISSECT WHETHER
TREATMENT ACTS IN AGING
INDEPENDENT WAY OR IN FACT SLOWS
AGE DEPENDENT PHENOTYPIC CHANGE
AND IF YOU SEE TREATMENT EFFECTS
THAT ONLY EMERGE ONCE AGE
DEPENDENCE CHANGE STARTS TO
EMERGE AND NOT BEFORE IS
CONSISTENT WITH NOTION WHAT YOU
ARE DOING IS TARGETING AGE
DEPENDENT PHENOTYPIC CHANGE AND
IF YOU SEE TREATMENT EFFECTS
PRIOR TO EMERGENCE OF AGE
DEPENDENT PHENOTYPE THAT IS NOT
EVIDENCE YOU ARE ACTUALLY
TARGETING MECHANISMS THAT
UNDERLIE THIS AGE DEPENDENT
CHANGE IN PHENOTYPE.
TO BE ABLE TO USE THIS WE HAVE
TO KNOW WHAT TRAJECTORIES OF
PHENOTYPES ARE WE ARE USING IN
ANALYSIS AND WANTED TO APPROACH
IT BY ASKING FOR PHENOTYPES WE
ARE INCLUDING IN ANALYSIS WHAT
IS PHENOTYPIC TRAJECTORY OF
LIFESPAN OF ANIMAL AND DOG THIS
STARTING WITH CROSS-SECTIONAL
ANALYSIS IN CONTEXT COMPARING
3581420 END 6 MONTH OLD ANIMALS
AND ESTABLISHED PHENOTYPE
TRAJECTORIES AND PERFORMED
NUMBER OF MOLECULAR ANALYSIS AND
TRANSCRIPTOMICS AND WILL FOCUS
ON RESULTS HERE AND ALLOWS TO
HAVE EACH PHENOTYPE TO ESTIMATE
TRAJECTORIES AND HYPOTHESIZE
THERE IS LIKELY IN YOUNG
ADULTHOOD STAPLED PHASE THERE IS
NOT MUCH PHENOTYPIC CHANGE AND
IF TRUE WE CAN USE THIS TO TEST
WHETHER TREATMENTS HAS AGING
INDEPENDENT EFFECTS SUMMARY OF
PHENOTYPIC RESULTS I WOULD LIKE
TO HIGHLIGHT THEY ARE NOT BEING
SELECTIVE AND SELECT WHAT CAN BE
DONE WITH STATE OF THE ART
PHENOTYPING ACROSS RANGE OF
TISSUES AND ORGAN SYSTEMS
FINDING COMPARING ACROSS AGE
GROUPS THAT ROUGHLY OVER HALF OF
THEM TURN OUT TO BE AGE
SENSITIVE SHOWING FORMS OF
DIFFERENCE BETWEEN AGE GROUPS
AND WE CAN SEE AGE SENSITIVE
PHENOTIECHS ACROSS ALL DOMAINS
THAT IS NOT A SURPRISE AND WE
WANTED TO THEN KNOW IF WE
COMPARE ALL AGE GROUPS BACK TO
THE THREE MONTH YOUNG ADULT
REFERENCE GROUP WHEN WE WOULD
FIRST BE ABLE TO SEE DEPARTURES
FROM YOUNG ADULT BASELINE.
WE FOUND EXAMPLES OF PHENOTYPES
ALREADY SHOWING CHANGES EARLY ON
AND EXAMPLE HERE IS STARTLE
AMMRITTUDE AND MOTOR RESPONSE
FOR STIMULATION THAT DECLINES
EARLY ALREADY AND MAKES SENSE
GIVEN THAT MOUSE STRAIN WE USE
FOR STUDIES BECOME DEAF
RELATIVELY EARLY ON AND THINK
PHENOTYPE IS CONSISTENT WITH
THIS NOTION AND THERE ARE SOME
PHENOTYPES ALTHOUGH NOT MANY
THAT SHOWED FIRST DEPARTURES
FROM YOUNG ADULT BASELINE BY 8
MONTHS AND EXAMPLE SHOWN HERE IS
PROPORTION OF CD14 T-CELL AND
NUMBER OF PHENOTYPES SHOWING
SIGNIFICANT DIFFERENCES FROM
YOUNG ADULT BASELINE AND MIDLIFE
WITH 14 MONTHS AND EXAMPLE SHOWN
HERE IS ELECTROCARDIO GRAPHIC
PHENOTYPE AND LOOKING AT
DURATION OF S COMPLEX REFLECTING
DEPOLARIZATION OF THESE KNOWN TO
INCREASE IN MICE AND MEN WITH
AGING AND THERE WERE ALSO A
NUMBER OF PHENOTYPES SHOWING
FIRST DEPARTURES FROM YOUNG
ADULT BASELINE AT 20 MONTH THAT
IS SHOWN HERE AS EXPLORATORY
LOCOMOTOR NOVELTY IN LOCAL
ENVIRONMENT AND THERE IS A FEW
PHENOTYPES SHOWING FIRST
DEPARTURES FROM YOUNG ADULT
BASELINE IN OLDEST GROUP AND
EXAMPLE I SHOWED HERE IS
PLATELET MORPH LOGICAL PHENOTYPE
AND THERE WERE FINALLY ALSO
CASES WHERE WE DIDN'T HAVE THIS
MONOTONIC TYPE OF CHANGE I
DESCRIBED IN EXAMPLES BEFORE AND
EXAMPLE FOR THIS MIGHT BE
[INDISCERNIBLE] THAT PEAKS
MIDLIFE AND DECLINES AGAIN AND
GROUPING AGE SENSITIVE
PHENOTYPES INCLUDING IN ANALYSIS
INTO DIFFERENT CATEGORIES, WE
SEE VERY FEW SHOW CHANGES EARLY
ON AT 5 OR 8 MONTH AND MOST SHOW
SIGNIFICANT DEPARTURES FROM
BASELINE ONLY IN OLDER GROUPS
AND IF WE PERFORM PRINCIPLE
COMPONENT ANALYSIS ON PHENOTYPIC
VARIABLES INCLUDED A THOUGHT
HERE BASICALLY AN ANIMAL WE SEE
3 AND 5 MONTH ANIMALS ARE PRETTY
MUCH CLOSE ON TOP OF EACH OTHER
AND THERE IS A PROGRESSIVE SHIFT
TO THE RIGHT WITH ADVANCING AGE.
AND THAT WOULD SUGGEST THAT IN
FACT 3 AND 5 MONTH OLD ANIMALS
ARE PRETTY SIMILAR
PHENOTYPICALLY AT LEAST WITH
REGARDS TO PHENOTYPES REGARDED
IN ANALYSIS THAT IS IMPORTANT
BECAUSE IT ALLOWS US TO TEST
WHETHER TREATMENT EFFECTS IN
THAT PERIOD HAPPENED AND IF THEY
DO AT THEIR LIKELY INDEPENDENT
OR AGE DEPENDENT PHENOTYPIC
CHANGE AND WANTED TO USE
APPROACH IF LONG LIVED MICE AGE
MORE SLOWSLY AND INCLUDED IN
THIS STUDY THREE DIFFERENT
INTERVENTIONS AND ONE IS GENETIC
LOSS OF FUNCTION MODEL M TORE
AND HOMOZYGOUS MICE FOR ALLELE
THAT IS CREATED AT NATIONAL
CANCER INSTITUTE AND MICE SHOWN
TO BE LONG-LIVED AND INCLUDED
MOUSE MODEL WITH LOSS OF
FUNCTIONING GROWTH HORMONE
SIGNALING HAVING POINT MUTATION
GROWTH RELEASING HORMONE
RECEPTOR AND MICE ARE DWARFS AND
KNOWN TO BE LONG-LIVED AND
FINALLY WE HAD A DIETARY
RESTRICTION REGIME THAT WE
INCLUDED AND ONE THAT FOCUSED ON
INTERMITTENT FASTING AND MORE
SPECIFICALLY THIS INTERMITTENT
FASTING REGIME INCLUDED EVERY
OTHER DAY FEEDING REGIME
ALTERNATING PERIODS OF
STARVATION WITH PERIODS OF FREE
ACCESS TO FOOD AND EACH BEING 24
HOURS AND WE START AT 8 WEEKS OF
AGE AND CONTINUE THROUGHOUT
ENTIRE COURSE OF THE STUDY FOOD
INTAKE OVER ENTIRE STUDY PERIOD
WE SEE INITIALLY SIGNIFICANT
REDUCTION IN FOOD INTAKE IN
FASTED ANIMALS AND APPEARS THAT
THEY LEARN TO WATCH AND EAT MORE
WHEN FOOD IS AVAILABLE ON
FEEDING DAY THAT COMPENSATES
OVERALL FOR LACK OF FOOD ON
OTHER DAY LOOKING AT ENTIRE
STUDY PERIOD THERE IS MODEST
REDUCTION FOOD INTAKE OF 10% OR
SO AND NEVERTHELESS MICE STAY
SUBSTANTIALLY UNDERWEIGHT TO
LIMIT CONTROLS AND TWO CURVES
HERE CORRESPOND TO MEASUREMENTS
AND BOTH ARE CLEARLY UNDER
CONTROL VALUES.
WE CONFIRM THAT THESE LEAD TO
SIGNIFICANT SIZE OF EXTENSION IN
MICE AND WANTED TO KNOW WHAT
LIKELY CAUSE OF DEATH IN MICE IS
AND CARCASS ANIMALS
SPONTANEOUSLY DIED FOR AUTOPSY
ANALYSIS AND SHOWS CONTROLS 86%
OF MICE LIKELY DUE TO CANCER IN
FORMS THAT ARE COMMON AND NO
SURPRISE AND SHOW THAT MICE
COMMONLY DIE TO CANCER AND 72%
OF CASES PROPORTION BEING
SLIGHTLY REDUCED LOOKING AT
PROPORTION OF MICE WITH MULTIPLE
INDEPENDENT TUMORS THAT WE THEN
SEE IN CONTROLS THIS IS 1/3
REDUCED TO 10% IN FACET MICE AND
THESE DATA ARE CONSISTENT WITH
FASTING MIGHT LEAD TO EXTENSION
BY SUPPRESSING CANCER
DEVELOPMENT AND EVENTUALLY MOST
OF MICE STILL DEVELOP CANCER BUT
DO SO AT AN OLDER AGE BASICALLY
SUBJECT WILLING THREE
EXPERIMENTAL APPROACHES TO
ANALYSIS PIPELINE AND PERFORMED
ANALYSIS WHERE WE HAVE
INTERVENTION THAT WE TREATED
CONTROL GROUP IN YOUNG ADULTHOOD
AND OLDER AGE AND 20 MONTH AND
SUBJECTED THEM SIDE BY SIDE TO
LARGE SCALE PHENOTYPE APPROACH
AND SUMMARIZING FINDINGS AND
SHOWN HERE IS PROPORTION OF AGE
SENSITIVE PHENOTYPES AND EITHER
INTERVENTION THAT ARE NOT
EFFECTED BY TREATMENT IN GRADE
THAT WERE COUNTERED BY
TREATMENTS AND WOULD BE
ANTIAGING EFFECTS IN GREEN ALSO
SOME CASES PHENOTYPES ACKRENATED
AND ARE IN RED AND MIXTURE OF
CASES WE WANTED PRIMARILY KNOW
WHETHER AGE SENSITIVE PHENOTYPES
AND EFFECTS COUNTERED BY
TREATMENT AND WHETHER MORE
RELATED TO AGE INDEPENDENT
EFFECTS OR TO EFFECTS CONSISTENT
WITH SLOWING AGING LOOKING AT
THAT COMPARING EFFECT SIZES IN
ANIMALS AND EMERGENCE OF
PHENOTYPIC CHANGE TO EFFECT SIZE
IN AGE ANIMALS UNDER CHRONIC
TREATMENT AND EACH DOT
CORRESPONDS TO PHENOTYPE FOR
EACH INTERVENTIONS IN GREEN ARE
PHENOTYPES WHERE THERE WAS NOT A
SIGNIFICANT DIFFERENCE BETWEEN
YOUNG AND OLD AND PHENOTYPES AND
AGING EFFECTS THAT COUNT ERRED
VIA INDEPENDENT EFFECTS THAT IS
SOMETHING REALLY IMPORTANT THAT
WE HAVE TO KEEP IN MIND FOR
FUTURE STUDIES FROM THIS STUDY
CONCLUDING THREE LONGEVITY
INTERVENTIONS WE EXAMINED HERE
FREQUENTLY HAVE PHENOTYPIC
EFFECTS COUNTERING AGE EFFECTS
SEEN IN YOUNG ANIMALS BEFORE AGE
DEPENDENT PHENOTYPIC CHANGE AND
ARGUING WITH TREATMENTS WITH
RESPECT TO PHENOTYPES ARE OFTEN
NOT TARGETING CAUSES OF AGE
DEPENDENT PHENOTYPIC CHANGE THAT
I THINK OF AS AGING AND WE
HAVING SYMPTOMATIC TREATMENT
EFFECTS THAT I THINK IS
IMPORTANT AND SHOULD TELL US TO
CLOSELY RE-EVALUATE SOME
MECHANISMS OF AGING THAT WE ARE
PRIMARILY INFORMED BY LIFESPAN
STUDIES TO SEE WHAT EXTENT
ACTUALLY PROCESSES ARE INVOLVED
IN SHAPING ORGANIZE MAL
PHENOTYPIC CHANGE OR NOT AND
WITH THIS WOULD LIKE TO CLOSE
AND THANK PEOPLE INVOLVED IN
THIS WORK AND MY LAB
HIGHLIGHTING CONTRIBUTION AND
BIG THANKS TO COLLABORATORS AT
[INDISCERN
[INDISCERNIBLE].
THANK YOU FOR YOUR ATTENTION.
>>HI, EVERYBODY. I'M ALEX AND
FOUNDER AND CEO OF A COMPANY
INSILICO MEDICINE AND WISH I
COULD BE THERE IN PERSON WE ARE
WORKING ON A MEGA EXPERIMENT AND
HAVE TO MAKE SURE MY LAB IS
PROPERLY OPERATIONAL AND HAVE TO
SLEEP AND LIVE HERE FOR THE NEXT
WEEK. WITHOUT FURTHER ADO I
WILL SHARE MY SLIDES PRESENTING
TO YOU SOME NEW CONCEPTS FOR
AGING RESEARCH AND HOPE THEY CAN
SEE MY SCREEN AND TITLE OF TALK
TODAY IS USING AGING CLOCKS FOR
DRUG DISCOVERY AND EXTRACTING
TARGETS FROM RESEARCH AND TOPICS
PUBLISHED ABUNDANTLY IN 2015 AND
16 USING ARTIFICIAL INTELLIGENCE
TO TRAIN PREDICTORS FROM ANY
DATA TYPE AND REALIZED OVER THE
YEARS MANY AGING CLOCKS HAVE
LIMITED PRACTICAL UTILITY.
EASY TO PREDICT AGE AND HOWEVER
IS DIFFICULT TO TURN AGE
PREDICTORS INTO PRACTICAL
THERAPEUTIC APPLICATIONS UNLESS
YOU KNOW HOW TO DISCOVER PROTEIN
TARGETS TO FIT AGING CLOCK INTO
CLASSICAL TRADITIONAL
PHARMACEUTICAL DISCOVERY
BUSINESS MODEL FOR THIS PURPOSE
WE STARTED IN SILICON MEDICINE
TO ENSURE DISEASE AND AGING OAF
TIME AND TELLING YOU ABOUT
COMPANIES AND PLATFORM CONSISTS
OF THREE ELEMENTS AND THOSE
TOOLS ALLOW YOU TO IDENTIFY
TARGETS AND GENERATE CHEMISTRY
AND PREDICT OUTCOMES OF CLINICAL
TRIALS AND HOWEVER WE USE THIS
PLATFORM NOT ONLY TO PROVIDE
SOFTWARE AND AI SOLUTIONS FOR
OTHERS AND CURRENTLY
PHARMACEUTICAL COMPANIES USING
IT IN ONE OR ANOTHER WE USE TO
DEVELOP PIPELINE OF INTERNALLY
DERIVED THERAPEUTIC PROGRAMS
SOME FOCUSING ON AGE ASSOCIATED
DISEASES AND SOME FOCUSED ON
CANCER IMMUNOLOGY AND INFECTIOUS
DISEASES AND GLOBAL WE SPAN ALL
TIME ZONES AND HAVE TWO REGIONAL
HEADQUARTERS IN HONG KONG AND
NEW YORK AND LAB I'M IN RIGHT
NOW IS IN CHINA AND IT IS A FULL
ROBOTICS LAB AND WE HAVE DRUG
DISCOVERY SITES IN SHANGHAI AND
TYPEPAY AND AI RESEARCH IS DONE
IN MONTREAL AND UAE. MANY KNOW
THAT ARDD CONFERENCES AND WOULD
REALLY LIKE TO INVITE YOU TO
AGING RESEARCH AND DRUG
DISCOVERY MEETING 29TH OF AUGUST
AND 2ND OF SEPTEMBER THIS YEAR
AND WONDERFUL CONFERENCE AND
DISCUSS HOW AGING RESEARCH COULD
HAVE PHARMA-AND VICE VERSA AGING
PHARMA-ARG AND A BIT ABOUT THE
COMPANY WE ARE ONE OF LARGEST IN
OUR FIELD SINCE 2013 AND
EMPLOYEES AND DEEPLY COMMIT
TODAY AGING RESEARCH AND PUBLISH
PROBABLY 1 TO 2 RESEARCH PAPERS
A MONTH RAISED OVER $400 MILLION
AND HAVE OVER 30 THERAPEUTIC
PROGRAMS AND AS YOU KNOW DRUG
DISCOVERIES ARE COMPLEX AND
TEDIOUS INEFFICIENT PROCESS AND
LONGEVITY MIGHT BE LONGER TO
REPURPOSE ENSURING DRUG PREVENTS
DISEASES AND SLOWS DOWN
HOPEFULLY AGING AND WE HAVEN'T
SEEN LONGEVITY THERAPEUTICS ON
THE MARKET YET AND PROCESS
WITHIN TRADITIONAL
PHARMACEUTICAL APPROACH STARTS
WITH TARGET DISCOVERY AND
TARGETS DONE WITHIN ACADEMIC
INSTITUTIONS AND USUALLY IS
GOVERNMENT FUNDED AND NIH SPANS
ANNUALLY RESEARCH AND TARGETED
DISCOVERY COMES FROM SCIENTIFIC
SERENDIPITY FROM BASIC RESEARCH
AND INTELLIGENTLY SEARCHING FOR
TARGETS AND WE SEE PROBABILITY
OF SUCCESS AT EVERY STAGE BOTTOM
LINE IS NUMBERS OF MILLIONS OF
DOLLARS IT TAKES FOR AVERAGE
FROM BIG PHARMACEUTICAL COMPANY
AND COMPANY MANAGED TO GO FROM 0
TO PHASE 1 COMPLETE IN UNDER 4
YEARS AND FOR A DRUG THAT IS
TARGETING INTERASSOCIATED
DISEASE AND AGING AS WELL. AS I
MENTIONED, WE HAVE THREE
PLATFORM AND CHEMISTRY 2 AND
CLINICAL AND PAN DAYOMICS IS
USED FOR EUROPEAN LEADERS AND
FOCUSING ON THAT TODAY AND
DESIRED MOLECULES AND DESIRED
PROPERTIES AND EXPLORING
CHEMICAL SPACE THAT IS NOT
REPRESENTATIVE OF CHEMICAL
LIBRARIES AND YOU DESIGN SMALL
MOLECULES DESIGNING PROPERTIES
FROM SCRATCH THINKING OF DEEP
FAKES FROM CHEMISTRY AND
THINKING OF SINCE 2016 AND
CLINICAL PREDICTING OUTCOMES
PHASE 2 AND 3 TRANSITIONS
LOOKING AT PREDOMINANT SUCCESS
AND EFFICACY AND IMPLICATED
TARGET IS DISEASE AND
HETEROGENOUS POPULATION
FOUNDATION IS AND UTILIZES
PREDOMINANTLY METHYLATION AND
WHOLE GENOME SEQUENCING DATA
WHERE NOVELTY COMES FROM
CURRENTLY INTEGRATE PROBABLY 5
TO 10 MILLION SAMPLES DEPENDING
ON HOW IT COUNTS AND QUITE A BIT
OF ANIMAL DATA AND WE HAVE A LOT
OF TEXT THAT ALSO PROVIDES YOU
WITH CONFIDENCE. IF THEY TARGET
THAT HAVE BEEN ANNOTATED AND
LITERATURED SUBSTANTIALLY AND
ARE PRESENT IN MULTIPLE CLINICAL
STUDIES AND YOU HAVE MUCH HIGHER
LEVELS OF CONFIDENCE IN A
TARGET. YOU ALSO HAVE SAFETY
INFORMATION AND MANY OTHER DATA
POINTS THAT ARE VERY USEFUL. WE
INTEGRATE APPROXIMATELY 2
TRILLION DOLLARS WORTH OF DATA
IN THE SYSTEM AND FOLLOW BIOMED
GRANTS OVER PAST 50 YEARS AND
PATENTS AND CLINICAL TRIALS AND
PARTS FROM BIOMEDICAL COMPANIES
INTEGRATED IN THE SYSTEM THAT
ALLOWS YOU TO RAPIDLY IDENTIFY
LIST OF TARGETS WITH DESIRED
CONFIDENCE NOVELTY THAT GOES
HAND IN HAND AND LOADING MORE
NOVELTY YOU NEED TO VALIDATE
LONGER AND RISKIER AND
CONFIDENCE AND COMMERCIAL
[INDISCERNIBLE] IS LOWER BECAUSE
SOMEBODY ELSE IS TRYING ALREADY
AND SYSTEM ALLOWS YOU TO
PRIORITIZE TARGETS EFFICIENTLY
AND VALIDATED USING PUBLICATIONS
PUBLISHING AROUND 70 PAPERS ON
USING DIFFERENT APPROACHES
PATHWAY ANALYSIS TO DEEP
LEARNING AND TO TRANSFORMER ERA
TALKING ABOUT PAPERS HERE WHAT
WE ARE LOOKING FOR TALKING ABOUT
AGING IS LOOKING FOR TO IDENTIFY
DUAL PURPOSE THERAPEUTICS
IMPLICATED ON AGING AND DISEASE
AT SAME TIME FOCUSING ON AGING
IS DIFFICULT TO DEVELOP
COMMERCIALLY TRACTABLE PROGRAMS
INVESTORS WANT YOU TO FOCUS ON
DISEASES AND IN LICIENCE
MOLECULES DRUG DISCOVERY IS
EXPENSIVE TEDIOUS PROCESS AND
PRESENT VIABLE BUSINESS MODEL
WITH REASONABLE NOVELTY AND
CONFIDENCE TO INVESTOR COMMUNITY
IT IS DIFFICULT TO FUNDRAISE FOR
AGING AND SEE A LOT OF EFFORTS
AROUND THE WORLD WHERE
NON-PROFIT INSTITUTIONS AND
GOVERNMENTS ARE PROVIDING
SUBSTANTIAL RESEARCH DOLLARS TO
GO AND DISCOVER TARGETS PURELY
FOCUSED ON AGING AND REPURPOSE
TO DISEASE IT WILL NOT BE ENOUGH
AND YOU HAVE TO DEVELOP
SUSTAINABLE BUSINESS MODEL TO
RESEARCH AGING AT SCALE IN MY
OPINION AND FOCUSED ON DUAL
THERAPIUTE IBLGS AND PUBLISHED
PAPER DEMONSTRATING HOW TO
IDENTIFY TARGETS USING PANDOMICS
TARGETED DISCOVERY ENGINE AND WE
UTILIZE MANY DIFFERENT
PHILOSOPHIES FOR TARGET
DISCOVERY PHARMACEUTICAL
COMPANIES USE TO PRIORITIZE
TARGETS IMPLICATED IN AGE
ASSOCIATED DISEASES AND IN
NORMAL AGING AND CLASSIFY THEM
INTO HALLMARKS OF AGING AND IN
THIS PARTICULAR STUDY WE USED
MULTIPLE DATA SETS COMING FROM
AGE ASSOCIATED DISEASES TO
SEPARATE THEM AND SEPARATE
TARGETS THAT ARE PRESENT IN
NONASSOCIATED DISEASES AND
LOOKING AT THOSE THAT ARE
FOCUSED ON AGE ASSOCIATED
DISEASES INTEGRATING NORMAL
AGING AND PROCESSED DATA THROUGH
PAN DOMIC AND WENT THROUGH
MULTIPLE FILTERS AND DEVELOPMENT
LEVEL ASSESSMENT AND COMMERCIAL
TRIPT ABILITY AND STRUCTURED
POSSIBLE TARGETS IN THIS CASE A
LIST INTO DIFFERENT HALLMARKS OF
AGING USINGOMICS AND TEXT-BASED
SCORES AND CREATED THIS AND CAN
USE AS A DARTS BOARD IF YOU LIKE
AND PLAY DARTS WITH IT.
WE STRUCTURED TARGETS INTO HIGH
CONFIDENCE AND MEDIUM
NOVELTIABILITY AND
[INDISCERNIBLE] BY HALLMARKS AND
SOME OF THOSE TARGETS ARE VERY
WELL KNOWN AND ESTABLISHED
ALREADY IN AGING ASSOCIATIVE
DISEASES AND SOME ARE NORMAL
REQUIRING RESEARCH AND
SCIENTIFIC BASIS AND ANALYSIS
BEHIND TARGETS ALLOWING FOR
FURTHER VALIDATION AND APPLIED
SAME METHODOLOGY TO AGE
ASSOCIATED DISEASE ALS AND FIND
STUDY AT WWWALSPAI AND PROVIDE
SCREEN CAST OF PAN DOMICS AND
TOOLS IN STUDY AND STUDY UTILIZE
DATA FROM ALS CONSORTIUM AND
PROBABLY LARGEST CONSORTIUM ON
ALS DATA SETS IN WORLD AND RUN
BY [INDISCERNIBLE] WHO DEVELOPED
A FLY MODEL OF ALS AND WE HAVE
HUMAN LS PATIENT CELLS AND WE
PROGRAMMED BACK INTO NEURONS AND
HAVE GENETIC BACKGROUND IN THERE
LOST EPIGENETICS AND HAVE A BIT
OF SAMPLES THAT ARE COMING FROM
ALS PATIENT SAMPLES AND UTILIZE
PUBLIC ALS DATA INCLUDING TEXT
AND WE RUN DATA SETS THROUGH
PANDOMICS QUICKLY IN A MATTER OF
DAY AND IDENTIFIED LIST OF
TARGETS AND DRUGS TO REPURPOSE
AND UTILIZE VERY ESTABLISHED ALS
MODEL OUT OF MAYO CLINIC FLY
MODEL ALS NO GOOD MODEL ASIDE
FROM PATIENTS AND LOTS THAT IS
VERY IDIOPATHIC TO IDENTIFY WHAT
WILL WORK OR NOT.
WE VALIDATED HYPOTHESIS IN A FLY
MODEL AND UTILIZING RNRI AND
REAL COMPOUNDS ALSO. WE TESTED
1 IN 6 PROPOSED TARGETS OUT OF
PAN DOMICS AND MOST WORK AND 21
WORK MILDLY.
WE VERIFIED ALSO 8 PREVIOUSLY
UNREPORTED GENOMES AND
PERTURBATIONS RESCUE
NEURODEGENERATION AND FIND
DETAILS STUDY OF ALS.AI AND
PUBLISH AGING NEUROSCIENCE QUICK
PUBLICATION BECAUSE THERE IS
ADDITIONAL COOL AND INTERESTING
DATA POINT I WILL TELL YOU
ABOUT. HERE ARE SOME TARGETS
THAT GOT VALIDATED USING RNAI
AND SEE IN FIGURE B HERE NUMBER
OF GENES PREDICTED TO WORK THAT
SHOWED A STRONG M- RESCUE
INTERMEDIATE RESCUE AND GENES
DIDN'T DEMONSTRATE FACTS OR MILD
OR MODERATE ENHANCEMENT OF THIS
ALS PHENOTYPE AND
NEURODEGENERATIVE PHENOTYPE AND
SHOWS YOU THE SYSTEM IS PRETTY
GOOD AT PICKING UP PROMISING
TARGETS AND PROFESSOR AT
UNIVERSITY ONE OF LEADING
NEUROSCIENTISTS IN ASIA AND
GLOBALLY AND HE IS A CO-FOUNDER
OF TECHNOLOGIES AND THEY MANAGE
TO ENROLL PATIENTS IN A CLINICAL
STUDY IN A VERY SHORT PERIOD OF
TIME AND THEY ACTUALLY PICKED
SOME TARGETS FROM DECLARATION
AND NOW ARE DOING REPURPOSING
STUDIES AND FINGERS CROSSED AND
SHOWS YOU CAN GO FROM DISCOVERY
TO PATIENTS IN UNDER ONE YEAR
AND CONDUCT ADDITIONAL BIOMARKER
STUDIES TO DEMONSTRATE HOW
POSSIBLE REPURPOSING CANDIDATES
WORK AND MENTION I GOT FREE
SYSTEMS CHEMISTRY 2 AND
PRECLINICAL THAT ALLOW US TO GO
AFTER OUR OWN PIPELINE AND IN
2019 WHERE WE HAVE IDENTIFIED
SOME PROMISING TARGETS IN
FIBROSIS AND DECIDED TO GO AFTER
FIBROSIS AS BIOLOGICAL PROCESS
DRIVING MULTIPLE AGE ASSOCIATED
DISEASES IDENTIFYING 20 NOVEL
TARGETS BECAUSE OF FINANCIAL
CONSTRAINTS GENERATING NOVEL
CHEMISTRY DON'T EXIST IN
LIBRARIES USING CHEMISTRY 2 AND
CONDUCTED 20 CLINICAL
EXPERIMENTS AND MANY DIFFERENT
MICE EXPERIMENTS AND MODELS AND
PHASE 0 HUMAN STUDIES HEALTHY
VOLUNTEERS IN AUSTRALIA AND
PROPER PHASE 1 STUDY MORE THAN
80 PATIENTS IN NEW ZEALAND AND
BRANCH OF 43 PATIENTS IN CHINA
AND HEALTHY VOLUNTEERS
ESTABLISHING SAFETY AND
PREPARING FOR PHASE 2. IT IS
PRETTY COOL. THIS IS THE
PIPELINE OF THERAPEUTIC ASSETS
THAT WE CURRENTLY HAVE THAT WE
COULDN'T TALK ABOUT AND WE HAVE
ASSETS WE COULD NOT TALK ABOUT
NOT PROGRESSING BEYOND LEAD
STAGE AND TARGETS BEYOND THIS
AND ACCESS ON CLOSE AND PURPOSE
FOR KINNE FIBROSIS AND WE
DECIDED TO GO AFTER NO MOLECULE
FOR PRETTY ESTABLISHED TARGET
AND IS GOING AFTER THAT AND
WORKING TOWARDS GUT RESTRICTED
MOLECULE AND INTERESTING TARGET
GOLGI COMPLEX IDENTIFYING USING
AGING RESEARCH AND PURPOSING
TOWARDS ONCOLAND PARTNERING WITH
CO-DEVELOPMENT 50/50 AND
PROMISING TARGETS SHOWING THIS
APPROACH COULD BE USED TO
DEVELOP A PIPELINE OF VALUABLE
THERAPEUTICS AND NOW WANT TO
CONCLUDE BRIEFLY I'M ALMOST AT
TIME AND NOW WE ARE ALSO
DEVELOPING A FULLY AUTOMATED LAB
RATTORY TO ACCELERATE AGING
BIOMARKER STUDIES SHOWING
TYPICAL WORKFLOW OF THE LAB.
I'M IN THE LAB RIGHT NOW.
AND HERE IS THE REAL WORKFLOW OF
THE SLAB AND TAKING TISSUES OR
CELLS AND THROWING IT INTO THE
SAMPLE PROCESSING MODULE.
THE CELLS OR TISSUES ARE BEING
PICKED UP AND QUALITY CONTROL
AND USING AUTONOMOUS GUIDED
VEHICLES THAT ARE BEING PLACED
IN THE INCUBATOR AND SOME GET
INTO IMAGING MACHINES AND YOU
GET SALIGGOS AND TS7 IMAGING AND
YOU ALSO GET OTHER IMAGING DATA
TYPES.
PART OF THE SAMPLE GETS INTO THE
NGS WORKLOAD AND THERE WE
PREPARE THREE LIBRARIES AND
WHOLE GENOME SEQUENCING RNA SEEK
LIBRARY AND METHYLATION AND
TRANSCRIPTOMICS ARE POPULAR AND
GIVING TO ALUMINUM SEQUENCER
THAT SEQUENCES RNA SEEK
METHYLATION AND WHOLE GENOME
SEQUENCING GIVING TO PAN DOMICS
CLINICAL AND THIS WORKFLOW
COMPOUNDS ARE PICKED FROM
LIBRARIES UNCAPPED PLACED ON
LIQUID HANDLER FOR TRANSFER ON
TO CELLS THAT ARE USED IN THE
INCUBATOR.
AND THEN WE INCUBATE CELLS FROM
INCUBATOR FROM COMPOUND
PREDICTED TO WORK AND FROM
DIFFERENT CONCENTRATIONS PLACING
INTO INCUBATOR HERE 26 OR 48 OR
72 HOURS AND BROAD CONNECTIVITY
MAP AND LINKS AND OTHER DATA
SOURCES AND WE SEE IF THE
EXPERIMENTAL RESULTS THAT
CONFIRMED WHAT WE PREDICTED AND
AI LEARNS AND WE FIND VALUABLE
TARGETS VALIDATING THEM
EXPERIMENTALLY.
SO, THAT IS OUR CURRENT WORKFLOW
THAT IS ACTUALLY MY LAB.
THIS IS THE SAMPLE INTAKE ROOM.
THIS IS THE ACTUAL COMPOUND
MANAGEMENT SYSTEM. WE ARE
PREPARING FOR A BIG RUN RIGHT
NOW.
IT IS GOING TO TAKE US TWO WEEKS
AND THIS IS THE CULTURE MEDIUM
CHANGE THAT WE CAN WORK WITH
MULTIPLE DIFFERENT CELL AND
TISSUE TYPES AND IMAGING
STATIONS AND HERE WE HAVE
SEVERAL IMAGING MACHINES AND
HERE IS THE LIBRARY
[INDISCERNIBLE] TO PREPARE
DIFFERENT LIBRARIES AND SEE
THERE IS AGV THERE AND NGS ROOM
AND A FEW OTHER FACILITIES
ALLOWING YOU TO COLLECT OTHER
DATA TYPES AND VERY
COLLABORATIVE AND WOULD LOVE TO
WORK WITH YOU ON MULTIPLE
PROJECTS. IN THIS PARTICULAR
LAB WE CAN ACTUALLY PROCESS MANY
DIFFERENT DATA TYPES AND
CURRENTLY FOCUSED ON MOUSE AND
MONKEY DATA TYPES TO ESTABLISH
TRANSLATIONAL MODELS AND OF
COURSE WE ARE ALSO READY TO GO
HUMAN.
WE ARE -- MY DREAM IS TO MODIFY
THIS LAB OR MINIATURIZE IT TO
MAKE SURE IT IS SMALL ENOUGH TO
BE PLACED IN A HOSPITAL TO DO
HOSPITAL SIZE DISCOVERY AND
THANK YOU SO MUCH. LET'S
COLLABORATE. BYE, BYE.
>>THANKS SO
MUCH FOR ACCOMMODATING ME BY
ZOOM TITLE OF MY TALK WAS GIVEN
TO ME BY RON IT IS REJUVENATION
TO MODEL AGING. I LOVE IT.
THANK YOU, RON. USING AI MODEL
AND MACHINE LEARNING TO
FACILITATE DEVELOPMENT OF
HYPOTHESIS AND WONDERFUL TALKS
TODAY ON AI AND MACHINE LEARN
ING MODELS SAVING TIME BY
INTRODUCTION AND EFFICIENCY OF
REPAIR THAT IS FAIR RIT
COMPARISON OF [INDISCERNIBLE].
THEN THE QUESTION IS IF
IMPROVING REPAIR IN INDIVIDUALS
UNDERSTAND TISSUES AND CELLS ND
ORGANELLES IS DEFICIENT AND --
STEM CELLS AND DIFFERENTIATED
SOMATIC CELLS AND MANY THINGS OF
DAMAGE THAT ACCUMULATED IN THERE
AND INTERESTINGLY, DAMAGE WILL
BE RAPIDLY REDUCED AND TISSUES
YOUNGER IN OLD ANIMAL AND OLDER
IN YOUNG ANIMAL THROUGH WHAT WE
CALL BLOOD KRONISTY AND SEVERAL
EXPERIMENTAL MODELS THAT OLDEST
ONE IS HYDRO CHRONIC PARABIOSIS
AND ERIC WHO IS THE DIRECTOR
WITH SOME SLIDE AND THERE IS
HYDRO CHRONIC FORESIS AND THERE
IS DESIGNER FLUID EXCHANGE AND
THIS IS REALLY NOT JUST BLOOD
EXCHANGE BECAUSE ORGANS ARE
SHARED AND ENVIRONMENTS SHARED
AND ANIMALS BECOME PERHAPS
BETTER FROM EXERCISE AND BETTER
NUTRITION AND BETTER GI TRACT
AND BLOOD OXYGENATION AND HYDRO
CHRONIC FORESIS OLD CONTROL AND
NEWER DEVICE ALLOWS TO FOCUS ON
WHAT HAPPENS WITH EXCHANGED
BLOOD OR FLUIDS AND QUESTION IS
THIS, YOU KNOW, GLASS HALF EMPTY
AND HALF FULL IS YOUNG OR OLD
BLOOD THAT IS [INDISCERNIBLE]
AND REJUVENATION AND OLD
EXPERIMENTS THAT DID AND IT IS
IN EARLY 2000S AND SEEMS TO US
OLD BLOOD DOMINATES YOUNG AND
NEED TO REMOVE AGE ELEVATED
PROTEINS RATHER THAN ADD
PROTEINS ON TOP OF OLD BLOOD AND
FASCINATION AND THIS ROMANTIC
IDEA THAT YOUNG BLOOD COULD BE
HELPFUL ILLUSTRATED BY CARTOON
IN ECONOMIST OF ONE OF OUR
PAPERS AND AT SAME TIME THESE --
THERE IS ALSO ACCUMULATING
EVIDENCE THAT [INDISCERNIBLE] OR
BLOOD EXCHANGE DON'T REJUVENATE
YOUNG ANIMALS BECAUSE OF OLD
BLOOD BUT THEY AGE YOUNG ANIMALS
BECAUSE OF OLD BLOOD AND THIS
GROUP THAT WAS PUBLISHED IN
REJUVENATION RESEARCH SHOWS IF
YOU HAVE -- SHARED IN BLOOD AND
ORGANS WITH YOUNG ANIMALS DON'T
LIVE LONGER YOUNG ANIMALS LIVE
SHORTER COMPARED TO ISOCHRONIC
YOUNG TO YOUNG PAIRS THAT IS ONE
PIECE OF EVIDENCE THAT IS
RECENTLY PUBLISHED IN
REJUVENATION RESEARCH AND EDITOR
REJUVENATION RESEARCH PLEASE,
PLEASE WITH SUGAR ON TOP SEND
GOOD PAPERS. ANOTHER PIECE OF
EVIDENCE THAT OLD BLOOD IS
DOMINATING OVER YOUNG AGING
REJUVENATION IS NOT BY OLD BUT
RATHER EXCESSIVE FACTORS COMES
FROM ALSO SOMEWHAT RECENT PAPER
PUBLISHED WITH GROUP THAT
[INDISCERNIBLE] WHO IS
[INDISCERNIBLE] POST DOC NOW WHO
HAS BEEN RUNNING OWN LABORATORY
AND CAREER. THIS PAPER SHOWS IF
YOU START WITH YOUNG ANIMALS
WITH ALL YOUNG ORGANS AND
TISSUES AND SHORTENED TELOMERES
AND EXCELLENT DNA AND EXCHANGE
WITH 50% OLD BLOOD THEY BECOME
OLD SEINE ES EXTNESCENT.
SOLELY FROM EXCHANGE OF OLD
BLOOD AND PAPER IS PUBLISHED YOU
CAN OBSERVE PHENOMENA OR
PARATIME BY CULTURING CELLS WITH
YOUNG VERSUS OLD SERUM THAT
COULD BE HUMAN OR
[INDISCERNIBLE] AND ADAP TAF
TRANSFER TO SENESCENCE TO CELLS
WHICH IS VERY RAPID IF YOU
COMPARE YOUNG SERUM YOU SEE OLD
SERUM IS INDUCING SENESCENCE IN
CELLS AND IF YOU LOOK AT CELL
PROTURATION AND ASSAY AND IF
LEUK AT HUMAN CELLS OR MOUSE
CELLS MOUSE CELLS AND HUMAN
CELLS WHEN MIXED KIND OF
PROVIDES A THOUGHT FOR CAN YOU
MAKE OLD PERSON HELP THERE AND
YOUNGER BY AGING YOUNG FACTORS
ON TOP OF OLD FACTORS AND AS I
MENTIONED MY CELL YOU SAW IN OLD
EXPERIMENTS LIKE 20 YEARS AGO
AND HERE WE HAVE OKG REPEATED
THEM IN NEW LABORATORY AND
RESULT IS THE SAME.
AGAIN, LOOKING AT 16 TO 21 AND
I'LL 6 AMONG P3 AND COMPARED TO
SERUM OLD SERUM AND YOUNG PLUS
OLD THAT IS KIND OF LIKE OLD AND
YOUNG PLUS OLD IS EXACTLY LIKE
OLD AND EXACTLY LIKE OLD AND
EXACTLY LIKE OLD AND KIND OF
LIKE OLD. IT MEANS REJUVENATED
FOR OLD BLOOD MANNED REASONS
THAT PROTEINS ARE PERHAPS
FILTERED OUT REMOVED BY YOUNG
PARTNER AND ALL STATUS THERE IS
NOTICEABLE PREMATURE AGING OF
YOUNG ANIMAL.
SAME WAS SHOWN NOW ANOTHER POINT
OF TRA FROM NATURE METABOLISM
PAPER USING THIS AND ANALYZING
MUSCLE REPAIRS AFTER SENESCENCE
CELLS ARE ELIMINATED SEE CONTROL
STATUS ON TOP IS DIMINIMOUS AS
ONE WOULD EXPECT AND LEVEL OF
CYTOKINES AND PROTEINS ARE
DIMINISHED IN BLOOD OF MICE AND
GENERATION IS NOT IMPROVED AND
FORMATION OF NEW MUSCLE FIBERS
AND INDEX AND MINIMAL ROBUSTNESS
OF NEW FIBERS AND MEANS THAT
REMOVAL OF SENESCENCE CELLS
ALONE DOESN'T SUFFICE AND THEN I
MENTIONED THAT WE DON'T HAVE TO
JUST EXCHANGE YOUNG WITH OLD
BLOOD ANYMORE WE CAN EXCHANGE
YOUNG BLOOD WITH SOLUTION AND
FIRST CONTROL EXPERIMENT IS
SIMPLY TO USE SALINE WITH
ALBUMIN AS SOLUTION AND SEE WHAT
EFFECTS ARE PLASMA PROTEINS ARE
PHYSICALLY DILUTING PLASMA
PROTEINS BY 50% WHAT HAPPENS?
DISCOVERING MANY GOOD THINGS
HAPPEN THAT IS REALLY AT
MAGNITUDE OF THOSE SHOWN IN
HYDRO CHRONIC PARABIOSIS AND
THREE LAYERS BECOMING
REJUVENATED AND COGNITION
IMPROVES INFLAMMATION IS
ACONTINUATED AND THESE SIMPLE
PROCEDURES THAT IS PERFORMED
ONCE MAKES TISSUES THE SAME AS
YOUNG AND NEVER SEEN APPROACHES
TO COLLEAGUES AND OUR OWN
RESEARCH BEFORE.
THEN, YOU KNOW, PAPERS HAVE BEEN
PUBLISHED ALMOST THREE YEARS AGO
AND GOING TO REPEAT A LOT OF
THAT. JUST SOME SUMMARY HERE
AND WHAT I WOULD LIKE TO MENTION
IS THAT SOME PEOPLE ARE STILL
KIND OF CLINGING TO THIS IDEA
THAT IT IS ALBUMIN DOING TRICK
AND REGENERATING SOMETHING AND
NO NET ADDITIONAL ALBUMIN THAT
POWDER THAT IS SHAPED AND STORED
AT ROOM TEMPERATURE THAT IS 99%
PURE ALBUMIN PROTEIN AND WITH
PROTEINS THERE ARE OTHER
PROTEINS MIGHT INADVERTIENTLY
CONTAMINATED AND SOME BEING
DENATURED ARE PRESENT AND ABOUT
WHAT YOU CALCULATED 10,000 TO
200 TIMES LESS CONCENTRATION
THAT THEY NEED TO ACT. IF
SOMEBODY WOULD LIKE TO TRY
ISOLATE SOMETHING REJUVENATING
FROM ALBUMIN POWDER INJECTED
INTO OLD ANIMAL ONCE AND
OBSERVED STATISTICALLY
SIGNIFICANT REJUVENATION OF GERM
LAYERS IS GREAT DISCOVERY AND IS
NOT REALISTIC.
SO, NOW HOW DOES PLASMA DILUTION
WORK COMING FROM OLDER STUDY IN
MICE AND PEOPLE AND BEFORE AND
AFTER EXCHANGES AND IN THIS HEAT
MAP YOU SEE THAT MANY PROTEINS
BECOME INTERESTINGLY UPREGULATED
AT SOME TIME AND ONE WEEK IN
MYOSIN AND 1 MONTH IN HUMANS
AFTER BLOOD DILATION AND WHAT IS
JUST ILLUSTRATION AND WHAT YOU
BELIEVE IS IF INHIBITIVE PROTEIN
THAT IS ELEVATED AND ONE THAT IS
DILUTION AND LEVEL DROPS DOWN IT
GOES DOWN MORE BECAUSE IT IS
INDUCING ITSELF AND NOW WE HAVE
POSTED FEEDBACK AND DOES NOT
REPRESS POSITIVE PROTEIN HOOER
AND THERE IS SOME OTHER INTERNAL
LINKS IN THE PATHWAY OF THE
MODEL HERE THAT IS VERY, VERY
SIMPLE SIMPLISTICALLY AND WHAT
HAPPENS IS YOU HAVE SLIGHTLY
LOWER OVERALL LEVEL OF THE
INHIBITORY PROTEIN THAT IS
CLOSER TO YOUNG LEVELS AND
SLIGHTLY HIGHER LEVELS OF USEFUL
PROTEIN THAT IS NOW NOT
REPRESSED AND CLOSER TO YOUNG
LEVELS AND ILLUSTRATION AND WHAT
YOU PLAN AND HOPE TO DO AND
ILLUSTRATION WITH ACTUAL DATA
FOUR DIMENSIONAL DATA AND
PROGRESSION AFTER PLASMA FORESIS
NEUTRAL BLOOD EXCHANGE AND
SYNONYMS AND WHAT HAPPENS WHICH
ARE KEY DETERMINANT PROTEINS
INHIBITORS DROPPED DOWN AT WHAT
TIME AND WHAT ARE PROTEINS THAT
ARE USEFUL NOW ARE REPRESSED AND
ELEVATED AND HOW WHOLE
TRANSDUCTION NETWORKS REGULATED
SYSTEMICALLY IS NOW
[INDISCERNIBLE] THAT IS A BIG
ENDEAVOR AND IS AN IMPORTANT PO
INT THAT TELLS THAT PLASMA
FORESIS OR NEUTRAL BLOOD
EXCHANGE OR PLASMA DILUTION
SHOULD SUFFICE BY THEMSELVES AND
WE DON'T NEED TO IN THEORY ADD
USEFUL FACTORS THEY DID NOT
DISAPPEAR FROM OUR GENOME AND
THEY ARE SIMPLY REPRESSED AND
COME BACK AND GIVING A QUICK
OVERVIEW OF DATA THAT I
MENTIONED AND HAVING WHAT IS
NEUTRAL BLOOD EXCHANGE COMPARED
TO ISOCHRONIC YOUNG YOUNG OLD
OLD EXCHANGES SEEING IMPROVED
COGNITION OR NEW OBJECT
RECOGNITION TESTS WHERE
TYPICALLY YOUNG MICE ARE MUCH
MORE INQUISITIVE AND KNOW WHICH
ONE AND WHICH ONE IS NEW AND OLD
AND OLD MICE ARE OLD AND ARE IN
CORNER OF [INDISCERNIBLE] AND
AFTER BLOOD OF MICE COGNITIVELY
BECOMES STATISTICALLY THE SAME
AS YOUNG. THOSE SHOW REDUCTION
OF BRAIN SENESCENCE OF NEUTRAL
BLOOD EXCHANGE THAT IS SIMILAR
TO THAT.
WE SHOW REDUCTION OF
NEUROINFLAMMATION THAT IS
ISOCHRONIC EXCHANGE NEUTRAL
BLOOD EXCHANGE MAKING ALL THESE
STATISTICALLY SAME AS YOUNG AND
WHAT IS INTERESTING IS THAT
COMPARED TO NEUTRAL BLOOD
EXCHANGE THAT IS ANALYTIC IS NOT
CAPABLE OF OTHER HIPPOCAMLE POE
NEUROGENESIS AND INFLAMMATION
SEEN HERE AND PUBLISHED IT AND
CURRENTLY MENTIONING TO ME THAT
THESE DO NOT CROSS BLOOD BRAIN
BARRIER AND INTERESTINGLY, EVEN
THOUGH IT DOESN'T IT REDUCES
NUMBER OF BRAIN SENESCENCE CELLS
CONNECTION BETWEEN CELLS IN
PERIPHERY AND IMPROVING THINGS
IN THE BRAIN AND NEUTRAL BLOOD
EXCHANGE AND DILUTION OF PLASMA
DOESN'T CROSS BLOOD BRAIN
BARRIER EITHER ELIMINATE
SENESCENCE IN BRAIN
[INDISCERNIBLE] AND ALSO
INDUCTION AND INFLAMMATION AND
HOW DOES IT HAPPEN? WE DON'T
KNOW YET PUBLISHED BRAIN ORGAN
CHIPS THAT IS WE CAN START
INTERACTION BETWEEN BRAIN AND
BLOOD AND OPENS MANY
OPPORTUNITIES FOR RESEARCH AND
LAST COUPLE SLIDES RELEVANCE FOR
HUMANS AND WORK DONE BY POST
DOCTORAL FELLOW SENIOR SCIENTIST
IN LAB HE RUNS HIS OWN CLINIC
AND IS DIRECTOR OF BRAIN AGING
CORRECTOR AT UCSF AND WHAT WE
DID THERE IS START
LONGITUDINALLY RESPONSES OF
PEOPLE THAT ARE MIDDLE AGE AND
PLASMA FORESIS AND 8 PEOPLE
STUDYING MANY PARAMETERS AND
PROETEE OHMO PROTEINS STARTING
TRANSCRIPTOMICS AND FIND IN
THESE SAMPLE DATA SETS USING DIG
DATA AND EXPERIMENTAL APPROACH
FOEKUSING ON ROBUST CHANGES I
THINK DISCOVERIES ARE POSSIBLE
PURCHASED IN COHORT A AND B AND
LONGITUDINALLY AND IN PEOPLE
BECOMING GRADUALLY YOUNGER IN
PROCEDURE AND LOOKING AT PBMC WE
SEE DECLINES AND EACH LINE HERE
IS INDIVIDUAL AND EEP IS ROUND
OF PLASMA FORESIS THAT IS 0 IS
WHEN STARTED AND SENESCENCE OF
CLIENTS AS WELL AND PLASMA
FORESIS AND IS DIFFERENT IN
PERSON TO PERSON AND OVERALL
TREND IS AMBIGUOUS AND
STATISTICALLY SIGNIFICANT AND
ONE PROFOUND EFFECT OF AGING IN
PBMC IS [INDISCERNIBLE] AND
INFLAMMATORY CELLS AND SHIFT IS
YOURS USING SEVERAL MARKERS AND
RECEPTORS CD4CDA CORECEPTORS AND
KILLER CELL MARKERS AND METRICS
AGAIN AVAILABILITY BETWEEN
SUBJECTS FOR CLEAR TREND AND
MOST SUBJECTS AT SOME POINT FOR
FORESIS THIS IS STATISTICALLY
SIGNIFICANT AND CAN OBSERVE SAME
TREND LOOKING AT RATIOS AND SO
FORTH. SEEMS THAT VERY QUICKLY
THAT PROFILE OF PBMCS IS
RESTORED AND COMPARTMENT OF
BLOOD IS RESTORED TO THAT OF THE
YOUNG PERSON.
ALSO, I WAS VERY WORRIED THAT
WHILE IT WAS RESTORED WE ARE
REDUCING ONCO GENESIS AND EITHER
WE DID NOT SEE EXCHANGE OR IN
FACT TUMOR SUPPRESSORS ARE
INCREASED IN SUBJECTS THAT IS A
GOOD SIGN AND IF YOU LIKE TO
LOOK AT INDIVIDUAL MARKERS AND
INFLAMMATORY CELLS MACROPHAGES
ARE DECLINED IN OR NOT IN ALL OF
THE SUBJECTS AND SHIFTING GEARS
TO PARTS OF SYSTEMIC MILIEU
ANALYZE 160 PROTEINS AND
THOUSANDS AND THOUSANDS OF DATA
POINTS AND THE -- EVENTUALLY
DISCOVERED 73 BIOMARKERS THAT
SHOW PRETTY MUCH IN COLOR CODED
SCHEMATIC OF THIS HEAT MAPPING
HOW AGING AND MORE
[INDISCERNIBLE] IS DILUTING THE
BLUE. THIS IS OLD SAMPLES AND
YOUNG SAMPLES AND PEOPLE
UNDERGOING ROUND OF PLASMA
FORESIS AND MEETINGS CALLING IT
THESE. HE DISCOVERED THOSE AND
VERY INTERESTINGLY SAME PATHWAY
ANALYSIS SHOWS SINGLE PROTEIN
THAT IS CROSSROADS OF
TRANSDUCTION PATHWAYS AND
INCREASED WITH AGING AND BECOMES
NOISY WITH AGING AND ANOTHER WAY
USING DAY 173 IS MAPPING THESE
INDIVIDUALS AND MAPPING BLOOD
PROETEE OHM OF VARIOUS PEOPLE
AND DISTINCTION BETWEEN PEOPLE
WITH NEUROCOGNITIVE DISEASE
VERSUS PEOPLE WHO ARE YOUNG
VERSUS OLD AND TWO DIFFERENT OLD
POPULATIONS FROM INDEPENDENT
STATUS OR PEOPLE UNDERWENT
PLASMA FORESIS ROUNDS OR THOSE
THAT ARE MIDDLE AGED AND DAY 173
ALLOWS TO VISUALIZE WITHOUT
PREDICTIONS AND LEARNING MODELS
BY USING THEM AND CLUSTERING AND
DIFFERENT GROUPS OF PEOPLE WHO
ARE YOUNG OR OLD OR HAVE OR
DON'T HAVE DISEASE.
LAST PART WILL BE ON KIND OF
COMPARISON BETWEEN PREDICTION
AND MEASUREMENT AND LAST SLIDE
AND THIS IS THAT WE CAN PREDICT
PEOPLES WEIGHT AND GUESS THEIR
WEIGHT AND POPULATION STATISTICS
METHOD SHOULD BE SUCCESSFUL
BASING IT ON SIZE AND COLONIALS
THAT PEOPLE ARE WEARING OR FOOD
THEY ARE EATING AND ALL THESE
SITUATIONS IT WILL BE RELATIVELY
ACCURATE PREDICTION AND MORE
PEOPLE THAT WE USE, BETTER
PREDICTION WILL BECOME. OF
COURSE, IT IS NOT ABSOLUTE.
SOMETIMES PEOPLE ARE WEARING
BAGGILY CLOTHES OR EAT FOOD AND
HAVE GREAT METABOLISM SO IT
DOESN'T REALLY HIT AND ON OTHER
HAND IF YOU SIMPLY HAVE A SCALE
AND KNOW WHAT TO MEASURE AND
MEASURING PARAMETER WE CAN DO IN
BLINDED FASHION AND IN RESILIENT
WAY REPRODUCIBLY AND DO NOT JUST
FOR PEOPLE BUT INANIMATE OBJECT
AND ELVANTS AND SO ON AND WHAT
YOU DO IN LAB COULD BE IN
MEASUREMENT AND BE USED OUR
BLOOD PROTEOMIC STUDY TO
IDENTIFY PROTEINS BECOMING
DYSREGULATED AND NOISY WITH AGE
AND HYPOTHESIZE PROTEINS WOULD
BE TOO MUCH FOR WEIGHING PEOPLE
AND WILL TELL US WHAT HAPPENS
WITH GOING THROUGH DISEASE OR
CHRONOLOGICAL AGE AND THIS IS
EXAMPLE OF PROTEIN -- NOISE
DECREASES AND THIS IS HERE IS
MIDDLE AGE AND APPLYING
PARAMETER TO LARGE DATA
IDENTIFIES DETECTORS OF
BIOLOGICAL AGE FROM BLOOD
PROETEE OHM AND COMPARING YOUNG
AND OLD AND OLD MIDDLE AGED OLD
AND OLD WITH DISEASE AND OLD
REJUVENATED BY ROUNDS OF TP AND
TAKING LEVELS OF YOUNG
ARBITRARILY TO 1 SEE AGE RELATED
INCREASE TO PROTEINS THAT IS
STATISTICALLY SIGNIFICANT AND IT
IS FASHIONABLE TO CALL
BIOLOGICAL OR WE CAN TRANSFORM
IT TO RELATIVE YEARS OR
BIOLOGICAL AGE AND SEE THAT WHEN
PEOPLE ARE YOUNG THEY ARE VERY
CLOSE TO THESE LINES OF WHEN
PEOPLE ARE MIDDLE AGE THERE IS
EFFECT THAT IS MORE AND IS
PERFECT PEOPLE MIDDLE AGE OR
ORDER DEVELOP VARIOUS CONDITIONS
AND DISEASES AND IF YOU DON'T
KNOW WHAT THOSE ARE YET YOU SEE
BIOLOGICAL AGE NOW IS NOT NEATLY
ALIGNED TO THIS ONE LINEAR MODEL
THAT IN MY OPINION IS HOW IT
REFLECTS REALITY AND PATIENTS
WITH BIOCOGNITIVE IMPAIRMENT
MOST ARE OLDER THAN BIOLOGICAL
AGE AND PEOPLE THAT HAVE BEFORE
VERSUS AFTER TP ASSESSMENT OF
BIOLOGICAL AGE IS MIRROR IMAGE
SUCH AS THIS ABOVE AND THIS
BELOW AND SO FORTH AND EXCHANGE
REDUCES BIOLOGICAL AGE BASED ON
WHAT YOU CALL DAY 1 OR 10
BIOMARKERS AND PROTEINS AND
EMPHASIZE YOU DON'T NEED PROTEIN
LEVELS HIGH OR LOW OR SAME CARE
ABOUT PROTEIN LEVELS BECOME
DYSREGULATED 20 PEOPLE IN SAME
AGE STANDARD DEVIATION INCREASE
WHEN GROWING OLDER OR HAVING
DISEASES AND AGAIN EMPHASIZING
LOOKING AT ROBUST PHENOMENA ALL
OF THE PEOPLE ARE 50S AND 60S
AND 70S AND PLASMA FORESIS YOU
HAVE 8 PEOPLE AND SEE REDUCTION
OF BIOLOGICAL NOISE OR AGE RIGHT
AWAY THIS IS KIND OF PROMISING
PHENOMENA IDENTIFYING THOSE YOU
DON'T HAVE TO USE PREDICTIONS
ABOUT YOU COULD FOCUS ON
MEASUREMENTS AND NOT THROWING
SHADE AND THINK THIS IS AWESOME
AND SO MANY WONDERFUL GROUPS DO
THIS RESEARCH AND IN OUR GROUP
WE ARE USING ACTUALLY ALL DATA
SETS AND MODELS TO GIVE OUR OWN
HUMAN INTELLIGENT BRAIN IDEAS
WHAT WE CAN MEASURE AND ONE MORE
LAST POINT HERE IF YOU LOOK AT
PEOPLE IN THEIR 40S AND 50S
BEFORE AND AFTER PLASMA FORESIS
DROP DOWN IN NOISE IS NOT MUCH
LOOKING AT OLDER PEOPLE THEY ARE
SIGNIFICANTLY REJUVENATED AND
DID BEFORE AND AGING IS YOU ARE
ON PRESS POWS OF SUCCESS AND ALL
ADAPTATIONS NOT VISIBLE BOOST
ADDITIONALLY HEALTH AND CONTRIB
AUTO AUTO UT TO REJUVENATION AND
MENTIONING AGE HERE IS 250 YEARS
AND DOES NO THE MEAN THAT THIS
PERSON WITH MIOCOGNITIVE
IMPAIRMENT THAT IS 70 OR 75 IS
250 ACTUALLY. WHAT IT MEANS IS
IF YOU DO MUCH AND REMAIN
ACCURATELY YES IN BIOLOGICAL
PEERS IS EQUIVALENT TO BLOOD PRO
TEE OHM TO SOMEBODY THAT COULD
BE 150 AND ANOTHER POINT I WANT
TO BRING UP HERE IS WHEN YOU
MEASURE BIOLOGICAL AGE IT STBT
HAVE TO BE ANALOGOUS OR PARALLEL
TO CHRONOLOGICAL AGE IT IS BLOOD
PROET EE
PROETEE OHM IT IS AGGREGATE OF
DIFFERENCES THAT FORM BIOLOGICAL
AGE AND IS THIS WEIGHT HEALTHY
IS NEXT ONE HERE CONCLUSIONS
[INDISCERNIBLE] PROTEINS AND
THEY ARE VITAL AT YOUNG LEVELS
CAN'T TURN OFF NEED TO CALIBRATE
THEM AND BLOOD DILUTION DOESN'T
ACT SIMPLY BY [INDISCERNIBLE]
AND SIN ALYTICS AND
[INDISCERNIBLE] IS DIFFERENT
FROM EACH OTHER AND IT IS NOT
SYNONYMOUS AND DEPENDENT ON TIME
AND YOUNG MICE AND BLOOD CELLS
THAT ARE YOUNG AND BLOOD THAT IS
YOUNG AND BASICALLY EVERYTHING
IS YOUNG. WE EXCHANGE 50% OF
ADULT BLOOD BEGS QUESTION HOW
BLOOD FACTORS HELP ENTIRELY OLD
ORGANISM.
I'M NOT DOUBTING IT CAN. IT
WOULD BE VERY INTERESTING
MECHANISM.
NOT PREDICTING BIOLOGICAL AGE IS
BASED ON DETECTORS OF BIOLOGICAL
NOISE CALLING DAY 10 AND PUT IN
PAPER AND THAT IS LABORATORY
THANKS TO PEOPLE AND BEFORE
PANDEMIC THAT IS BEFORE PANDEMIC
DURING AND AFTER PANDEMIC AND
MANY THINGS TO DEFINING SOURCES.
THANK YOU FOR YOUR ATTENTION.
>>WE ARE RUNNING OUT OF TIME
AND LET'S QUICKLY WRAP UP THE
SECTION AT THE END THREE
PANELISTS INCLUDING ME WOULD
LIKE TO GIVE OVERVIEW TO SHARE
OUR VIEWS ABOUT BIOLOGICAL AGING
MAJORS AND AS YOU CAN TELL
DIFFERENT PRESENTATIONS ARE
DIFFERENT AND HOPE YOU FIND WAY
TO RELATE TO EACH OTHER BRAVE
OKAY. GOING FIRST AND BRIAN
FROM FOXO TECHNOLOGIES AND
[INDISCERNIBLE] FROM COLUMBIA
UNIVERSITY WILL FOLLOW ME.
PEOPLE HAVE DIFFERENT MOLECULAR
DATA FROM SYSTEMS TO ESTIMATE
BIOLOGICAL AGE.
OR TO PREDICT TRAJECTORY OF
BIOLOGICAL AGING THAT YOU SEE IN
DATA FROM SINGLE TIME POINT OR
FROM TIME FORCE.
BUT, LET'S THINK ABOUT THIS. WE
CANNOT EXACTLY YOU KNOW MAJOR
BIOLOGICAL AGING AND NEED TO DO
IT THROUGH CERTIFIGATE. PEOPLE
SURE THEY USE CHRONOLOGICAL AGE.
BUT IS THAT ENOUGH? PERHAPS WE
NEED OUTCOME TOWARDS SCIENCE
INDICATION THAT IS SUCH LIKE A
DISEASE FREE OUTCOMES AND
COMPOSITE OUTCOMES THAT ARE
INCLUDING SEVERAL AGE SENSITIVE
PHENOTYPES.
VALIDATION OF CLOCK, LET ME PUT
IT CLOCK.
IT IS ESTABLISHED BY COMPARING
TO CHRONOLOGICAL AGE THAT IS FOR
STRONGER ASSOCIATIONS WITH A
NUMBER OF AGE RELATED OUTCOMES
THAT MAJOR CHRONIC DISEASE
OUTCOMES THAT YOU CAN THINK OF.
AND PERHAPS TYPICAL AGING
OUTCOMES THAT ARE SUCH AS
FRAILTY THAT GET SPEED AND
STRENGTH.
THERE IS A THEORY. ALSO,
EVIDENCE THAT SHOWS THAT
DIFFERENT BIOLOGICAL AGE
PREDICPRED
PREDICTORS CAPTURE DIFFERENT
ASPECTS OF BIOLOGICAL AGING AND
RESEARCH SHOWS THAT DIFFERENT
BIOLOGICAL AGE PREDICTORS ARE
NOT SO CORRELATED AND HAVE
DIFFERENT ASSOCIATIONS WITH
DIFFERENT AGING RELATED
OUTCOMES.
SO, TO GAIN BIOLOGICAL INSIGHTS,
WE COULD USE [INDISCERNIBLE]
DATA TO ASSOCIATE WITH DIFFERENT
BIOLOGICAL AGE PREDICTORS TO GET
TO KNOW UNDERLYING PATHWAYS, FOR
EXAMPLE.
IN FIRST TALK, TREY ALSO
SUGGESTS THREE DOMAINS TO LOOK
AT FOR EXAMPLE DNA DAMAGE
MUTATION OR DUE TO CHANGE IN
CELL TYPE COMPOSITION.
OVERALL PICTURE IS TAKING INPUT
AND DATA TO APPLY MSH LEARNING
METHOD AND PEOPLE USE PENALIZED
REGRESSION MODEL WITHOUT
PRESELECTING FEATURES.
SO, IN THE END WHAT INCLUDED IN
A PREDICTOR ARE NO LONGER THE
MEANINGFUL.
SO, TO UNDERSTAND DIFFERENT
BIOLOGICAL AGE PREDICTORS YOU
HAVE TO TREAT AS WHOLE TO
ASSOCIATE WITH DIFFERENT AGE
SENSITIVE PHENOTYPES OR MAYBE
DIFFERENTOMIC DATA TO HAVE
BETTER UNDERSTANDING AND OF
COURSE TO HAVE GOOD BIOLOGICAL
AGE PREDICTOR TO BE STRONGLY
ASSOCIATED WITH AGE RELATED
OUTCOMES IN GENERAL.
IN THE END, WE WILL HAVE A
CLOCK, BIOLOGICAL AGE PREDICTOR
THAT IS TO MONITOR THE
BIOLOGICAL AGING PROCESS FOR
INDIVIDUALS WITH AND WITHOUT
INTERVENTION THAT COULD BE VERY
USEFUL TOOL IN RANDOMIZED
CONTROL TRIALS TO MONITOR
TREATMENT EFFECTS FOR EXAMPLE.
NOW, I WILL PASS IT TO BRIAN.
>>BEFORE I GET INTO MY NEXT
SLIDE, I WANT TO PREFACE A
DECLARATION AND WARNING THAT WE
KNOW ARTIFICIAL INTELLIGENCE IS
MATURING VERY RAPID WILL I TO
THE POINT WHERE I THINK IT WILL
BE ACCESSIBLE TO A LOT MORE
PEOPLE AND THAT PART OF THE
BUILDING CLOCKS OR MATHEMATICAL
MODELING WON'T BE THE CHALLENGE
ANYMORE AND IT WILL BE DATA
QUALITY AND QUANTITY AND WHAT I
WOULD CALL HUMAN INTELLIGENCE
THAT IS WHAT MY NEXT SLIDE IS
DESCRIBING BASED OFF EXAMPLES
WHERE HUMAN INTELLIGENCE IS
NEEDED IN ARTIFICIAL
INTELLIGENCE CAN'T SOLVE FOR AND
ARE BASICALLY THE STUDY DESIGNS.
WHAT IS THE QUESTION THAT YOU
ARE ASKING?
WHAT IS INPUT DATA YOU ARE
PUTTING IN THERE?
THINKING THROUGH WHAT USE CASE
CLINICAL PREDICTOR FRAMING HAM
RISK SCORE WHAT IT IS MEANT TO
DO AND WAY I WOULD DESIGN THAT
STUDY IF TRYING TO GET
BIOLOGICAL MECHANISMS I WOULD
DESIGN STUDY DIFFERENTLY AND
ANOTHER EXAMPLE IS ON MACHINE
LEARNING PART AND I SPEND MY
TIME THINKING WHAT IS TARGET
VARIABLE IS IT MECHANISM AND IS
IT A PHENOTYPE IF A PHENOTYPE AT
WHAT AGE WHAT ARE OTHER
COMPETING OUTCOMES AND
PHENOTYPES I'M LOOKING AT AND
YOU DON'T HAVE TO LOOK AT TARGET
BUT ON PERIPHERAL AND BIGGER
PICTURE AND HOW PRECISE TO BE ON
TARGET VARIABLE AND USE A LOOSE
TERM AND BIOLOGICAL AREA WE TALK
ABOUT FRAILTY AND THERE IS
MULTIPLE DEFINITIONS OF FRAILTY
AND TO ME IS MULTIPLE
DEFINITIONS THAT IS NOT PRECISE
ENOUGH OFTEN TIMES CAN WE GO
MORE PRECISE WHAT ARE SOME
ASPECTS OF FRAILTY YOU ARE
TRYING TO LOOK AT?
I THINK THAT GENERALLY SHOULD
YOU EXPECT A SUMMARY SCORE TO BE
ABLE TO CAPTURE EVERYTHING THAT
IS ABOUT BIOLOGY.
BUT, THERE IS A UTILITY FOR
SINGLE SCORES OFTEN TIMES AND WE
CAN TALK ABOUT THAT LATER. ALSO
IN THE VALUATION, THERE NEEDS TO
BE HUMAN INTELLIGENCE IN
SELECTING HOW YOU WILL VALIDATE.
THERE IS A LOT OF WAYS TO FOOL
YOURSELF INTO THINKING YOU
VALIDATED A MODEL AND IT IS
ACTUALLY AN ARTIFACT HOW YOU
DESIGN VALIDATION AND OFTEN TIME
TIMES I THINK NONREPLICATION
BIOLOGICAL CLOCK IN ONE
POPULATION AND TRY ANOTHER IT
DOESN'T WORK IN ONE OF THOSE AND
TRY TO DISSECT WHAT ASPECTS OF
ONE OF THE COHORTS AND STUDIES
ARE AND TRY TO UNDERSTAND WHY
ARE THERE DIFFERENCES THAT MIGHT
INFORM ME TO GO BACK TO REDEFINE
WHAT TARGET VARIABLE IS AND IT
IS AN ITERATIVE PROCESS.
SO, TO GIVE YOU ONE EXAMPLE, I
SEE DATA SETS WHERE YOU MIGHT
HAVE MULTIPLE OMICS THAT ARE
MEASURED SLIGHTLY DIFFERENT
TIMES THAT COULD BE DIFFERENT BY
A YEAR OR BY AN HOUR AND WHEN
YOU ARE TALKING ABOUT SOME OF
THE OMICS RNA GENE EXPRESSION
AND PROTEOMICS COULD FOOL YOU.
IF THEY ARE AN HOUR DIFFERENCE
OR SOMETHING IS THAT TRULY A
VALIDATION IS THE QUESTION.
THE OTHER QUESTION THAT I ELUDED
TO ARE SUMMARY SCORES VERSUS
COMPONENTS AND THERE ARE SCORES
WE USE IN GERIATRICS AND AGING
AND ARE USEFUL AND WE ARE
COMFORTABLE WITH THOSE AND WE
KNOW HOW THEY ARE BUILT AND THEY
ARE MEANT TO BE AVERAGE AND
SUMMARY SCORE AND TALKING ABOUT
EPIGENETIC CLOGS AND AGE
MEASURES WITH MATHEMATICAL
MODELS WE ARE NOT BUILDING IT
FROM GROUND UP WE ARE STARTING
FROM TOP DOWN. IT IS A BLACK
BOX. WE DON'T KNOW WHAT ITS
MEANING OR WHAT IT IS MEASURING
AND KNOW THAT MAKES US
UNCOMFORTABLE AS SCIENTISTS AND
THINK WITH MACHINE LEARNING
OFTEN TIMES IT IS A BLACK BOX
THAT IS HARD TO TRY TO UNPACKING
MECHANISMS BEHIND THAT AND AS
LONG AS WE VIEW THESE AS
PREDICTION AND CLASSIFICATION
PURPOSES, WE MIGHT SLEEP BETTER
AT NIGHT. I THINK THAT EARLIER
WE SAW THIS EXAMPLE WHERE YOU Z
A SYMPTOMATIC EFFECT OR
CAUSALITY THAT IS IMPORTANT TO
TEASE OUT TALKING ABOUT
PREDICTION CLASSIFICATION IT
DOESN'T MATTER GRAY HAIR IS A
SIGN OF AGING AS IMPERFECT AS IT
IS AND THIS IS A EXAMPLE WHERE
USE CASE MIGHT MATTER AND MY
LAST SLIDE HERE I WILL LET ALLAN
TAKE OVER. THEY ARE ALL TOOLS
AND NOT ALL TOOLS ARE PERFECT
AND YOU WOULDN'T USE A WRENCH TO
DRIVE A NAIL THROUGH A 2 x 4 OR
HAMMER TO SCREW A LUG NUT. WE
HAVE TO THINK THROUGH REALLY
TOOLS YOU ARE USING.
>>HI. THANK YOU TO THE FOUR
SPEAKERS FOR FOUR GREAT
PRESENTATIONS AND I PREPARED
SLIDES AND I WILL GO BACK AND
NOT USE SLIDES I HAD -- IF WE
THINK ABOUT OUR SELVES THAT WAY,
CHANGES QUESTIONS WE ASK AND HOW
WE THINK ABOUT THINGS AND IN
PARTICULAR I WOULD LIKE TO GIVE
YOU THE IDEA THAT MAYBE WE ARE A
TYPE OF COMPUTER OR INFORMATION
SYSTEM AND TO KEEP OURSELVES
GOING WE NEED INTERNAL
[INDISCERNIBLE] SIMULTANEOUSLY
TO KEEP PHYSIOLOGY AND BIOLOGY
IN RIGHT STATE.
MOST BIOLOGICAL MOLECULES ARE AT
SAME TIME DOING SOMETHING AND
GIVING INFORMATION ABOUT SYSTEM
ATP IS ENERGY AND TELLING YOU
ENERGY YOU HAVE. IN THAT
CONTEXT WITH THAT AS A
BACKGROUND I WOULD LIKE TO MAKE
A FEW COMMENTS ON THE
PRESENTATIONS AND ONE THING THAT
I THINK CUTS ACROSS ALL FOUR OF
THEM IS REALLY A CHALLENGE AND
IS A NOTION THAT YOUNGER STATES
ARE BETTER STATES AND I THINK
THAT THERE IS A LOT OF CASES
WHERE CHANGES THAT ARE
AGE-RELATED ARE PATHOLOGICAL AND
DON'T THINK ANYBODY WOULD DOUBT
THAT AND CHAFKS WITH AGE ARE
ADAPTIVE AND FOR EXAMPLE
ADOPTIVE IMMUNE SYSTEM HAS
DECREASED FUNCTION WITH AGE
WHICH IS A GOOD THING PROBABLY
IN CONTEXT OF ANCESTRAL
CONDITION EXPOSED TO PASSAGES
THAT WE WILL SEE EARLY IN LIFE
AND SO DOES THAT MEAN THAT ALL
ASPECTS OF CHANGE HAVE ACTIVE
IMMUNE SYSTEM ARE ADAPTIVE?
NOT NECESSARILY AND CHALLENGE IS
WE DON'T HAVE GOOD WAY TO FIGURE
OUT WHAT AGE RELATED CHANGES WE
ARE SEEING THAT ARE PATHOLOGICAL
ADAPTIVE NEUTRAL CORRELATED IS
IT ADAPTIVE IN SENSE THAT IT IS
ALL INDIVIDUALS WILL DO THAT AND
IT IS RELATIVELY ADAPTIVE OR ONE
INDIVIDUAL ADAPTING TO HIS OR
HER PARTICULAR CIRCUMSTANCES AND
THESE ARE VERY DIFFICULT THINGS
TO TEASE OUT.
SO, I FEEL THERE IS OFTEN AN
UNDERLYING ASSUMPTION THAT YOUNG
IS GOOD. I THINK THAT DOES
REFLECT A CULTURAL BIAS WHERE WE
HAVE LOTS OF INHERENT AGEISM
THAT IS NOT TRUE IN ALL CULTURES
ALL THE TIME AND WE HAVE TO BE
AWARE OF MOST CULTURAL BIAS IN
THINKING THE YOUNGER STATE IS
BETTER STATE AND TRYING TO TEASE
THAT OUT AND A FEW COMMENTS TO
MORE SPECIFICALLY IN TALKS THAT
I CAN'T WORK WITH. GENETIC
AGING AND CURVE WE HAVE THERE
AND ONE THOUGHT FOR FUTURE WORK
IN THAT DIRECTION IS DOING THAT
FOR MORE SPECIES WE MIGHT BE
ABLE TO PARAMETERIZE THAT SHAPE
IN DIFFERENT SPECIES IN HOW IT
VARIES ACROSS SPECIES AND
LOOKING FOR GENES THAT ARE
CONTROLLING EVOLUTION OF SHAPE
OF THAT CURVE THAT MIGHT REFLECT
DEVELOPMENT.
THAT IS AN INTERESTING DIRECTION
TO GO.
IN TERMS OF DAN'S TALK, R I
THINK IT IS VERY INTERESTING
THAT YOU ARE FINDING WITH CANON
CAL AGING PATHWAYS THAT YOU ARE
GETTING A MIX OF EFFECTS THAT
ARE QUOTE ON QUOTE PROAGING AND
ANTIAGING FROM THE SAME
INTERVENTION; RIGHT?
THIS REFLECTS IN MY OPINION THAT
WE OVERSIMPLIFY THINGS THINKING
THERE IS A SINGLE AGING
PHENOMENON. REALLY EACH OF THE
PATHWAYS IS REGULATING SOME
THINGS THAT ARE PROAGING OR
ANTIAGING THINGS WE CAN SAY
THOSE THAT WILL BE VERY MIXED
AND EXPECT THAT AND PATHWAYS ARE
DOING INTEGRATING ABOUT ORGANIZE
SITUATION AND USING THAT TO
GENERATE DOWNSTREAM BEST
CONDITIONS FOR ORGANISM AND
GIVEN ALL THAT AND DIDN'T HAVE
ANYTHING SPECIFIC TO ALEX'S TALK
AND FOR IRINA'S TALK I THOUGHT
IT WAS INTERESTING OLD FACTORS
DOMINATE AND THINKING WHAT IT
MEANS IN ADAPTIVE VERSUS PANEL
LOGICAL ASPECTS OF AGING AND
WHAT WE ARE THINKING ABOUT AND I
REALLY LIKE THE IDEA OF USING
INCREASING HETEROGENEITY AS
MEASURE OF BIOLOGICAL AGING AND
THERE IS A LOT TO BE DONE WITH
THAT AND IT IS EXCITING TO SEE
THAT WORK AND STOPPING THERE IF
WE HAVE TIME FOR QUESTIONS.
>>[APPLAUSE].
>>SO, ANY QUESTIONS FOR US?
>>HI. I'M FROM UNIVERSITY OF
CONNECTICUT. I HAVE QUESTIONS
FOR DR. EHNINGER AND WHAT YOU
SHOWED, I LOVE THAT YOU DID 3 TO
5 MONTH THAT WE DO THAT TO LOOK
AT MATURATION VERSUS AGING AND I
STUDIED BLADDERS WHEN I COMPARE
A MOUSE THAT IS 2 TO 4 MONTHS TO
A MOUSE THAT IS 8 TO 10 MONTHS I
CONSIDER WHATEVER HAPPENS THERE
TO BE MATURATION CHANGE AND WHEN
I COMPARE 8 TO 10 MONTH OLD
MONTH US TO MY 22 AND HIGHER I
CONSIDER IT TO BE AN AGIING
CHANGE AND WHEN YOU DID STUDIES
DID YOU PICK WHAT WAS CHANGING
FROM MIDDLE AGE/MATURE AGING TO
INCLUDE IN FUTURE STUDIES OR
CONTINUE TO USE ALL ASPS FOR
THOSE FINAL GENETIC AND DIETARY
INTERVENTION STUDIES?
>>CAN YOU HEAR ME?
>>WE DESIGNED STUDIES SUCH THAT
ARE YOUNG GROUP THAT IS YOUNG
ADULT AND COUPLE GROUPS THAT ARE
CLOSE BY TO SEE WHETHER OR NOT
MOST PHENOTYPES ARE STABLE
DURING PERIOD OF YOUNG ADULTHOOD
AND COVERED UP TO AGE OF 20
MONTHS THAT IS BEFORE SURVIVAL
CURVE GOES DOWN AND LOST
POPULATION AND THERE IS
SURVIVORSHIP BIAS IN OLDEST
GROUP AND FUTURE STUDIES WE ARE
NOT -- THIS IS PART OF
PHENOTYPING PIPELINE APPROACH
WHERE YOU OFTEN GET A NUMBER OF
PHENOTYPES FROM SAME KIND OF
MEASUREMENT OR FROM THE SAME
KIND OF EXPERIMENTAL APPROACH
NOT MEANINGFUL TO RESTRICT TO
SUBSETS OF PHENOTYPES THAT THERE
MIGHT BE WITHIN ONE EXPERIMENTAL
DOMAIN MIGHT BE AGE SENSITIVE
PHENOTYPES AND OTHERS THAT ARE
NOT AGE SENSITIVE AND CONTINUE
TO MEASURE THEM ALL BASICALLY
AND WE DIDN'T REALLY THEY ARE
ALL AND ONES THAT CHANGE EARLY
ON AS I SHOWED AN EXAMPLE AT
HEARING LOSS; RIGHT?
THIS IS SOMETHING THAT IS VERY
SPECIFIC TO THAT PARTICULAR
MOUSE STRAIN; RIGHT? THERE ARE
OTHER ONES THAT YOU DO SEE EARLY
CHANGE CONTINUING TO PROGRESS
EARLY AGE TO REFLECT SOMETHING
YOU CONSIDER AGING AND REDUCTION
OF CD4 T-CELLS AND PHENOTYPES IN
PATHOLOGIES IN PARTICULAR YOU
SEE THOSE EMERGING IN OLDER AGE
GROUPS THAT MIGHT BE WHAT WE
CLASSICALLY THINK OF AS AGING
PHENOTYPES.
>>THANK YOU.
ANOTHER QUESTION FOR YOU. FOR
JEANETTE KALILY TWO MODELS YOU
SHOWED WITH GENETIC TREATMENTS
WERE THEY UNUSABLE OR WERE THEY
I MISSED THAT PART WERE THEY
MUTATED?
>>[INDISCERNIBLE] -- IT IS NOT
KNOWN SPECIFIC STRAINS
GENETICALLY MODIFIED ONES WE
DON'T KNOW HOW THEY AGED
DIFFERENTLY TO CONTROL IF USED
OUT OF MIDDLE AGE I GUESS YOU
WOULD BE ABLE TO TELL IF I
WONDER ABOUT HAVING COMPARED
THEM WILD TYPE C57 CAN YOU
COMMENT ON THAT?
>>GROUPS WE HAVE FOR GENETIC
LINES AND YOUNG ADULTHOOD AND
COMPARISON OF 20 MONTHS OF AGE
AND WE HAVE TWO SNAPSHOTS THAT
ARE CROSS-SECTION ALLEY ACROSS
LIFESPAN OF THESE WHERE WE CAN
ESTIMATE INTERVENTION EFFECTS IN
THAT PARTICULAR CASE GENOTYPE
EFFECTS AND COMPARE THEM TO
GENOTYPE EFFECTS YOU SEE IN AGE
ALMOST RIGHT.
>>FOR SAME STREAM.
>>FOR SAME STREAM?
>>THAT IS ALL SAME STREAM.
THIS IS ALL EXCHANGE.
>>THANK YOU.
>>WELCOME.
>>GENERAL QUESTION ABOUT
PHENOTYPE WE SEE IN MULTIPLE
AGING SYSTEMS THAT IS UP
REGULATION OF PROCESSES AND
PROTEINS AND GENES AT MOLECULAR
LEVEL THAT IS WHAT SEEMED LIKE
GAIN OF FUNCTION IN TERMS OF
SIGNALING OR SENESCENCE PROFILE
AND GENES INDUCED WITH EACH AND
PHENOTYPIC LEVEL WE SEE LOSS OF
FUNCTION AND DECLINE IN SENSORY
CAPABILITIES AND LOCOMOTION AND
THINGS AND SEEMS LIKE
INTERESTING PARADOX AND WONDER
NOT SURE IF IRINA IS STILL THERE
AND HER EXPERIMENTS DILUTING
BLOOD OF OLD ANIMALS AND
RESCUING THIS GAIN OF FUNCTION
AND MORE SIGNALING PROTEINS AND
CIRCULATION AND SOMEHOW THIS
ENDS UP IMPROVING AGING RELATED
PHENOTYPES AND ONE POSSIBILITY
THERE COULD BE THAT HAVING A LOT
OF SIGNALING FACTORS AND
CIRCULATION COSTS A LOT TO
ORGANISM AND IF WE THINK THERE
IS A FINITE AMOUNT OF ENERGY
THAT AGING ORGANISM HAS ACCESS
TO AND ENERGY IS MONOPOLIZED BY
PRODUCING FACTORS AND HAVING TO
FOR TARGET ORGANS TO EXPERIENCE
SIGNALING EFFECTS OF THIS AND
ALL THESE DIFFERENT STEPS OF
THESE COST ENERGY RELIEVING
THAT, THAT MAYBE FREES UP ENERGY
BUDGET THAT ALLOWS HIGHER LEVEL
FUNCTIONS AND NEEDING TO OPERATE
MORE EFFECTIVELY.
IF SOMEONE CAN COMMENT ON THIS.
>>I WILL TURN TO DR. FARUCHI TO
COMMENT ON THEORY OF ADAPTATION
AND HOW THAT IS BEHIND SCENES
HOUSEKEEPING THAT IS HAPPENING.
>>MY QUESTION IS RELATED VERY
MUCH AND PUTTING IN PERSPECTIVE
AND THINK THAT FOR THE MOMENT
THAT WE BELIEVE THAT AGING IS
RATIO BETWEEN SKOE CASTIC DAMAGE
OF AACCUMULATE LAITION AND
STRATEGIES PREVENTING AND
REPAIRING THAT DAMAGE AND MY
IDEA IS THAT HAS TO BE DIFFERENT
RATE OF AGING AND COST DIFFERENT
TISSUES BECAUSE DEMAND OF ENERGY
IN DIFFERENT TISSUE IS
DIFFERENT.
YOU KNOW, MUSCLE AND BRAIN AND
HEART WILL HAVE ENORMOUS AMOUNT
OF DEMAND. THERE WILL BE ENERGY
MUCH SOONER AND SISTER WILL BE
CRITICALLY IMPACTED FASTER THAN
ANOTHER TISSUE THAT IS
ACQUIESCIENT OR CALLED INTO
ACTION AND YOU KNOW MUCH, MUCH
LESS.
SO, I THINK THAT, YOU KNOW, WHEN
WE SAY WE NEED TO BE CAREFUL
ABOUT FINDING -- IT IS USEFUL
FOR CLINICALLY TO FIND A
BIOMARKER OF AGING THAT IS
UNIQUE AND THERE IS AVERAGE AGE
ON [INDISCERNIBLE] AND I HAVE
ANOTHER QUESTION. CAN I ASK
ANOTHER QUESTION THAT I THINK IS
RELATED. OTHER RELATED QUESTION
IS THAT IN ALL THESE
DISCUSSIONS, I HAVE NOT HEARD
SOMETHING THAT TO ME IS
EXTREMELY IMPORTANT THAT IS
EPIGENETIC THAT IS REALLY THE
WAY THAT THE SYSTEM CHANGES AND
TRANSCRIPTIONAL PROGRAM WITHIN
ONE LIFE IS NOT -- YOU KNOW,
INDEPENDENT BY EVOLUTION IN A
WAY. IF YOU CAN CHANGE THAT
WITHIN ONE LIFE COURSE.
SO, TO ME, EPIGENETICS IS
ADAPTIVE AND WHY WE ARE LOOKING
AT EPIGENETIC AS A CAUSE OF
DISEASE AND WE ARE NOT LOOKING
AT EPIGENETIC AS, YOU KNOW,
ADAPTIVE STRATEGY THAT WE FOUND
THAT IS RELATED TO AGING BECAUSE
WITH AGING AND ACCUMULATION OF
DAMAGE, YOU HAVE TO READJUST
YOUR GENETIC AND GENOMIC PROGRAM
TO ADAPT TO THESE LOSS OF
FUNCTION AND YOU NEED COMPLEXITY
AND BECAUSE PROBABLY NATURAL
FUNCTION IS SIMPLE AND DIRECT.
YOU NEED TO FIND ALTERNATIVE
STRATEGIES AND THOSE NEED MUCH
MORE COMPLEXITY OF ACTION FROM
THE GENOME.
>>SOMEWHAT RELATED.
>>I WILL SAY THAT I COMPLETELY
AGREE WITH THAT AND THAT IS AN
EXCELLENT EXAMPLE OF WHERE
ADAPTATION MIGHT BE COMING IN
AND WE HAVE WORK IT DO TO TRY TO
FIGURE OUT HOW TO DISTINGUISH
ASPECTS THAT ARE PANEL LOGICAL
OR ADAPTIVE THERE.
>>I WILL STICK UP FOR
EPIGENETICS AND I THINK THERE IS
SOMETHING THAT IS UNIQUE WITH
AGING AND IN PARTICULAR WITH
EPIGENETICS HEARING OF ORIGIN
STORIES OF EPIGENETIC CLOCKS
THEY ARE ALWAYS LOOKING FOR
SOMETHING ELSE AND SIGNAL FROM
AGING IS ABSURDLY LOUD AND THEY
COULDN'T DROWN IT OUT AND
SHIFTED TO LOOKING AT THAT.
THERE IS SOMETHING UNIQUE THERE.
WE ARE ASKING TOO MUCH OUT OF
EPIGENETICS TO TRY TO EXPLAIN
ALL OF BIOLOGY FOR US AND AGREE
WE HAVE TO LOOK DEEPER.
>>DO YOU THINK WE NEED MORE
CLOCKS, MORE SPECIFIC CLOCKS AND
TISSUE SPECIFIC CLOCKS FOR MAYBE
DIFFERENT POPULATIONS?
WE HAVE ALREADY MANY, MANY.
>>YEAH. I THINK.
>>THIS IS AN OPEN QUESTION TO
MYSELF AND PROBABLY TO YOU TOO.
>>SUCH AN IMPORTANT QUESTION
AND THINK THAT WE HAVE TO DREAM
BIG.
WHEN WE DREAM BIG WE NEED TO
HAVE AN EPIGENETIC CLOCK THAT
APPLIES TO A PATIENT AND COMES
TO YOU BECAUSE THEY HAVE
[INDISCERNIBLE] IN LEFT
SHOULDER. YOU CAN DO EPIGENETIC
CLOCK AND SAY THIS PERSON HAS
THAT AND IS BRINGING THIS PERSON
OBSERVATION AND HAS IMPENDING
PROBLEM THAT IS RTERY AND
IMPENDING CARCINOMA INSITU THAT
IS SOMEWHERE ELSE AND IS TYPES
OF DETAIL WE DREAM TO HAVE.
THAT MEANS THAT WHY IT IS USEFUL
TO START WITH SOMETHING THAT IS
AVERAGE.
WE NEED TO BE ABLE TO GRAB A LOT
MORE INFORMATION. THERE IS
EVIDENCE THAT IS DOABLE,
ACTUALLY. I THINK THAT SOME
WORK THAT IS INDELIVERABLE SHOWS
THAT THERE IS SOME SPECIFICITY
OF DIFFERENCE OF APGS FOR
PREDICTION OF SPECIFIC DISEASE.
>>IF I CAN RIFF ON THAT, I
THINK THERE IS INFORMATION
COMING OUT THAT WE CAN
DECONVOLUTE CELL TYPES WITH
EPIGENETICS AND MENL ILL OHM AND
BEING PRECISE IN WHAT WE PREDICT
AND TRAIN AND GETTING CLOCKS NOT
JUST CLOCKS BUT PREDICTORS OF
MANY DIFFERENT THINGS AND DOG
HOMEWORK UPSTREAM TO BE PRECISE
ABOUT WHAT WE WANT TO PREDICT.
>>HI. I THINK IT HAS BEEN SAID
AT THIS POINT I HAVE BEEN
LISTENING IN. [INDISCERNIBLE]
QUESTION ABOUT WHY WE ARE
FOCUSING ON EPIGENETICS AND
COMPLETELY AGREE WITH THE
QUESTION AND BRIAN'S ANSWER AND
IT IS CERTAINLY QUITE
DIAGNOSTIC.
YOU KNOW, THERE HAS BEEN A LOT
OF WORK TO LOOK AT HOW MUCH
INFORMATION IS IN METHYLOME
VERSUS TRANSCRIPTOME AND
TELOMERES AND THINGS LIKE THAT
AND IS CERTAINLY VERY
QUANTITATIVE AND COMPLETELY
AGREE WITH EXTENSION TO WORK
TOWARDS CAUSAL -- YOU KNOW
INTERESTING QUESTION THAT IS NOT
ONLY QUESTION.
>>ROUND OF APPLAUSE FOR
SPEAKERS AND PANEL IFTS AND
RECONVENING AT 3:20.
>>IT IS 3:24.
WE SHOULD PROBABLY GET STARTED
AND LAST SESSION OF THE DAY.
ONLY THING THAT STANDS BETWEEN
YOU AND AFTER DINNER DRINKS OR
DINNER ITSELF IS US. THANKS
VERY MUCH. WE WILL TALK ABOUT
BIOMARKERS FOR GEROSCIENCE AND
HAVE A NICE LINEUP OF SPEAKERS
TO COVER THIS TOPIC. I'M REALLY
HAPPY FOR THOSE AND IT
DOVE-TAILS NICELY WITH SOME
OTHER TALKS THAT PRECEDED THIS.
WE WILL FIRST HEAR FROM STEVE
KRICH EF SKI AND ALICE KANE
FOLLOWED BY A PANEL DISCUSSION
WRAP-UP AND BRINGING STEVE UP
FOR THE FIRST TALK. HE IS MY
MENTOR AT WAKE FOREST SCHOOL OF
MEDICINE AND PROFESSOR OF
GEROSCIENCE AND INTERNAL
MEDICINE AT WAKE FOR EEST STEVE
RESEARCH FOCUSES ON NUTRITIONAL
INFLUENCES IN OLDER ADULTS AND
ESTABLISHING FRAMEWORKS FOR
CLINICAL SCIENCE AND EXTENSIVE
WORK IN BIOMARKERS.
>>I HAVE ENJOYED THIS
CONFERENCE SO FAR AND GUESSING I
DON'T HAVE TO PUSH ANYTHING.
THERE WE GO.
SO, I WANT TO REALLY LEVEL SET
IN THIS TALK. BIOMARKERS IS A
FRAUGHT AREA AND LOTS OF TIMES
ALL PEOPLE USING WORD THAT IS
SOMETHING DIFFERENT AND TALKING
ABOUT HOW TO MAKE SENSE OUT OF
ALL OF THE WAYS THAT PEOPLE USE
WORD BIOMARKERS AND TALKING
ABOUT THEIR VALIDATION AND IN
PARTICULAR WITH REFERENCE TO
BIOMARKERS OF AGE AND TALKING
ABOUT A HOLY GRAIL FOR THE FIELD
THAT IS DEVELOPMENT OF VALIDATED
SURROGATE BIOMARKERS SO WE HAVE
THINGS WE CAN TRACK SO THAT IF
WE INTERVENE ON SOMEBODY AND
THAT BIOMARKER CHANGES, WE ARE
CONFIDENT WE HAVE HAD SOME
IMPORTANT BENEFIT FOR THEIR
LIFESPAN OR HEALTH SPAN.
THIS IS TOWER OF BABEL AND OFTEN
I FEEL THIS WAY IN THIS FIELD.
PEOPLE ARE ALL USING THE WORD
BIOMARKER IN DIFFERENT WAYS AND
FDNC ACT -- MOST PEOPLE IN THIS
ROOM PROBABLY MEAN SOMETHING
THAT YOU MEASURE IN A TISSUE AND
IN BLOOD AND DON'T HAVE TO BE
AND COULD BE ANYTHING AND
BIOMARKER COULD BE AN INDIVIDUAL
MEASURE OR PANEL AND DOESN'T
HAVE TO BE A SINGLE ENTITY.
FDA IN THE GUIDEBOOK IN THE
FOOTNOTE THERE DISTINGUISHES 7
APPLICATIONS OF BIOMARKERS AND
PEOPLE USE THE WORD AND MEAN
SOME WORD OR SET OF THESE AND
OTHERS VARIOUSLY AND IS UP TO
YOU USUALLY TO FIGURE OUT WHICH
ONE RUNNING THROUGH THEM IS
SUSCEPTIBILITY OF RISK MARKER
FOR DEVELOPING DISEASE OR
CONDITION AND DIAGNOSTIC
BIOMARKER THAT TELLS YOU A
PERSON HAS A DISEASE OR
CONDITION AND PROGNOSTIC
BIOMARKER THAT IDENTIFIED A
LIKELIHOOD OF CLINICAL EVENT
DISEASE REOCCURRENCE OR
PROGRESSION AND A PREDICTIVE
BIOMARKER IF A PERSON IS LIKELY
TO HAVE A RESPONSE THAT IS BASED
ON AN INTERVENTION AND OF
MONITORING BIOMARKER THAT IS
SOMETHING THAT WOULD MEASURE
REPEATEDLY TO LOOK FOR EVIDENCE
OF EXPOSURE OR EFFECT OF AN
AGENT. SAFETY BIOMARKERS
INDICATING LIKELIHOOD OF
PRESENCE OF TOXICITY AND
RESPONSE TO BIOMARKER AND ARE
HERE TWO FLAVORS FARMICO DYNAMIC
THAT INDICATES BILOGIC ACTIVITY
OF AGENT THAT YOU ARE GIVING
SOMEBODY AND A SUR ENDPOINT THAT
I WILL TALK ABOUT LATER THAT IS
A SUBSTITUTE FOR A DIRECT
MEASURE OF HOW A PATIENT FEELS
THAT FUNCTIONS SURVIVE AND A
BIOMARKER COULD SERVE MANY ROLES
AND BLOOD PRESSURE IS A GOOD
EXAMPLE IF IN CONTINUOUS FORM
AND IS A RISK BIOMARKER AND IN
DICHOTOMOUS FORM THERE IS A
DISEASE DIAGNOSTIC BIOMARKER AND
PROGNOSTIC BIOMARKER AND
MONITORING BIOMARKER. SORRY IT
IS ALSO A RESPONSE BIOMARKER AND
IN FACT IS INDEED A SURROGATE
ENDPOINT AND CALLING YOUR
ATTENTION THIS IS AN FDA
APPROACH.
FDA APPROACH IS PREDICATED ON
THEIR BEING A SPECIFIC DISEASE
OR HEALTH CONDITION OF INTEREST.
TALKING ABOUT AGING BROADLY
DEFINED.
IT IS A LITTLE TRICKY TO APPLY
THIS EXACTLY TO THAT AND CALLING
AN AGING AND DISEASE WILL NOT
HELP THIS PROBLEM.
IF WE WANT TO DEVELOP AN
INTERVENTION THAT COULD BE
MARKETED UNDER FDA RULES NEEDS
TO BE CLEAR CUT RULES TO SAY WHO
HAS CONDITIONS AND WE ARE NOT
THERE YET.
FUNDAMENTAL EVALUATION
CONSIDERATIONS WITH A CANDIDATE
BIOMARKER NEEDS TO KNOW WHY --
WHAT MAKES IT VARY FROM -- AT
ALL?
WHAT ARE SOURCES OF VARIANTS AND
THERE ARE SOURCES IN THE ASSAYS
THEMSELVES AND HOW THEIR PROCESS
AND LABORATORY PROBLEMS OR
PROBLEMS OF SOURCES AND VARIANCE
IN POST PROCESSING IN THE
INFORMATION THAT COMES OFF
CERTAINLY WITH PLATE READERS AND
THAT SORT OF THING AND WITHIN
PERSON ARE SOURCES OF
VARIABILITY AND DIURNAL AND
DAY-TO-DAY AND SEASONAL
VARIATION AND MOST PEOPLE DON'T
REALIZE THAT SERUM CHOLESTEROL
COULD EAT 15 POINTS PLUS OR
MINUS DEPENDING WHAT SEASON OF
THE YEAR IS MEASURED AND
BIOMARKERS WE WANT IT TO SAY
SOMETHING ABOUT THE TRUE FEATURE
OF THE THING IN WHOM WE MEASURED
IT. IF THERE IS A LOT OF
VARIABILITY WE ARE NEVER QUITE
SURE THAT THE MEASUREMENT WE
HAVE REFLECTS THE THING WE WANT
TO SAY ABOUT THAT PERSON.
THEN THE EPIDEMIOLOGISTS IN ME
THINKS ABOUT SCALABILITY AND HOW
MUCH DOES IT COST AND IS IT
TRICKY TO COLLECT THE SAMPLE.
SO, THINGS THAT COULD BE DRAWN
INTO EDTA PLASMA TUBE AND LEFT
OUT, GREAT. OTHER THINGS WE
FINISHED THE STUDY WITH 850
MUSCLE BIOPSIES IN ORDER TO LOOK
AT MITOCHONDRIAL ENERGETICS AND
IN MUSCLE BUNDLES AND THAT TOOK
EACH ONE TAKES ABOUT FOUR HOURS
BETWEEN COLLECTION AND
PROCESSING IN THESE AND ABOUT
THREE OR FOUR PEOPLE IN IT.
THAT IS NOT SCALEABLE.
CAN THE -- HOW -- IS THERE
SOMETHING THAT IS FANCY ABOUT
THE STORAGE?
WHAT DO WE TELL PARTICIPANTS IN
WHOM WE ARE DRAWING THIS MEASURE
AND DO THEY HAVE TO BE FASTED
AND SHOULD THEY EXERCISE AND CAN
THEY EXERCISE AND ARE THERE
MEDICATIONS TO WORRY ABOUT AND
DOES DIETS HAVE TO BE
STANDARDIZE THE?
DO YOU FINALLY NEED OTHER
MEASURES TO FULLY INTERPRET. IN
SOME CASES IT IS IMPORTANT TO
KNOW BODY SIZE OR BINDING
PROTEIN CONCENTRATIONS THAT
WOULD TELL YOU THE FREE AMOUNT
AVAILABLE TO INTERACT AND A LOT
OF THE MEASURES OF BIOMARKERS OF
NEURODEGENERATION THAT ARE
HIGHLY DEPENDENT ON KIDNEY
FUNCTION AND IS IMPORTANT TO
KNOW WHAT KIDNEY FUNCTION
INTERPRETS CIRCULATING LEVELS.
THIS IS A EXAMPLE OF A
VALIDATION OF MEASURE.
IT IS OF A KIND OF VALIDATION.
THAT IS ANOTHER WORD THAT HAS A
TOWER OF BABEL AROUND IT AND
PEOPLE USING VALIDATION THEY
MEAN A LOT OF DIFFERENT THINGS
AND USE IT IN LOTS OF DIFFERENT
WAYS AND THIS IS AN EXERCISE
THAT WE UNDERTOOK THAT JUST GOT
PUBLISHED RECENTLY AND WORKING
WITH A MACHINE LEARNING
STATISTICIAN DR. RAMON KAS ANOVA
THAT HAD USED MACHINE LEARNING
TO COME UP WITH AN ALZHEIMER'S
DISEASE AND PATTERN SIMILARITY
SCORE BY APPLYING MRI DATA AND I
MEAN THESE ALGORITHMS TO MRI
DATA FROM ADMI COHORT AND OTHER
COHORTS LOOKING AT DATA SHOWING
IT TO OUR GROUP. IT OCCURRED TO
US THAT THERE WAS NOTHING REALLY
IN THE IMAGES THAT IT WAS
ACTUALLY SPECIFIC TO ALZHEIMER'S
DISEASE THERE IS NO
[INDISCERNIBLE] THAT IS JUST
ANATOMICAL FEATURES AND AGE IS A
STRONG RISK FACTOR FOR
ALZHEIMER'S DISEASE RISK MAY BE
THIS IS ACTUALLY COULD BE
CONSIDERED A MEASURE OF BIOLOGIC
BRAIN AGE.
SO HOW DO YOU VALIDATE THAT
THOUGHT AND TAKE THAT AND
VALIDATE IT?
YOU ASK YOURSELF IF THIS WERE A
MEASURE OF BRAIN AGE, WHAT WE
WOULD EXPECT TO SEE, WE WOULD
EXPECT IT TO CORRELATE WITH
OTHER AGE RELATED MEASURES THAT
ARE NOT BRAIN RELATED. THIS IS
SOMETIMES ON THIS CONVERGENT
VALIDITY THAT CONVERGES ON
THINGS ALL MEANT TO MEASURE THE
SAME THING THAT SHOULD HANG
TOGETHER.
IT SHOULD PREDICT AGING OUTCOMES
AND OTHER THAN ONES THAT ARE
RELATED TO BRAIN HEALTH IF IT IS
A MEASURE OF OVERALL AGING THAT
IS PREDICTIVE VALIDITY AND
ASSOCIATIONS SHOULD BE
INDEPENDENT OF CONLOGIC AGE THAT
IS DISCRIMINATIVE OF VALIDITY
AND ALL KINDS TLOOEND WE PICK TO
PURSUE AND WE LOOKED AT THIS IN
ATHLOW SCLEROSIS COMMUNITIES
COHORT AND HAD MRI IMAGES AT
VISIT 5 FROM THAT SAME VISIT WE
WERE ABLE TO CALCULATE A FRAILTY
INDEX FROM 38 MEASUREMENTS
AVAILABLE IN THE DATA SET AT
THAT TIME.
WE ALSO HAD AVAILABLESOMO LOGIC
APTIMER-BASED SCAN OF THOUSANDS
OF APTIMERS SOME ARE AGE RELATED
AND PREDICTIVE VALIDITY COULD
THIS PREDICT ALL CAUSE NON-CNS
RELATED MORTALITY? FRAILTY
INDEX THIS IS WHAT IT LOOKS
LIKE. IT IS A DEFINITION OR
DEFICIT ACCUMULATION INDEX.
IT IS INDEX THAT LOOKS -- THIS
LOOKS LIKE A FRAILISH
POPULATION. IT IS. THIS IS
PRETTY -- THIS COHORT WAS PRETTY
AGED AT THIS POINT.
THERE WAS A -- A SIGNIFICANT
ASSOCIATION BETWEEN THIS EDPS
SCORE AND FRAILTY INDEX AND WAS
TRUE EVEN AFTER ADMITTING
COGNITIVELY IMPAIRED FROM THE
ASSOCIATION.
FOR THE AGE-RELATED APTO MERS WE
REFERRED TO PAPERS BY JOHNSON
AND COLLEAGUES AND LOOKED AT ALL
ONES THAT THEY IDENTIFIED AS
BEING CONSISTENTLY RELATED WITH
KRON LOGIC AGE ACROSS A NUMBER
OF POPULATIONS AND AFTER
ADJUSTING FOR MULTIPLE
COMPARISONS, TWO THAT REMAINED
WERE PLEOTROPHEN THAT ARE
ASSOCIATED WITH MEASURE OF
ANATOMICAL BRAIN AGING AND
FINALLY FOR MORTALITY RISKS,
FIRST -- THE FIRST SET OF
NUMBERS SHOWS THAT THE LOWEST
QUARTILE ARE PEOPLE THAT ARE
BEST BRAINS WHEN WE OBSERVE
THEM.
AND WE HAD HALF OF THE RISK OF
ALL CAUSE MORTALITY. THAT WAS
STILL TRUE AFTER WE OMITTED
PEOPLE WITH COGNITIVE IMPAIRMENT
AT BASELINE THAT IS STILL TRUE
LOOKING AT COGNITIVELY NORMAL
REMOVING CNS-RELATED CAUSES OF
DEATH FROM OUTCOME TREATING IT
AS COMPETING CAUSE OF DEATH.
ABOUT 40% REDISCUSSUCTION IN
PREDICTION OF MORTALITY IN THIS
WAY SOMETHING LOOKING AT BRAIN
IS CONNECTING TO SOMETHING WITH
OVERALL AGING AND WHAT IT MIGHT
BE IS A GREAT QUESTION. WE
WOULD LIKE TO KNOW MORE ABOUT
THAT.
A LOT OF PEOPLE VALIDATE
MEASURES BY AGING WITH
CORRELATIONS WITH KRON LOGIC AGE
THAT IS DONE IN SINGLE VISIT IN
A STUDY WITH POPULATION AND MANY
PEOPLE IN IT AND AGES TO SPAN
AND WARNING EVERYONE IF YOU
HADN'T THOUGHT OF THIS AND
BIOMARKERS ARE VALIDATED BASED
ONLY ON ASSOCIATION WITH NORTH
CHRONOLOGIC AGE SAMPLE SINGLE
POINT OFTEN BIASED AND OFTEN
SEVERELY BIASES AND MANY REASONS
FOR THIS AND THREE TO KEEP IN
MIND IS COHORT HE EFFECTS AND 30
YEAR OLD IN 2020 HAS DIFFERENT
LIFE HISTORY THAN 30 YEAR OLD IN
1980. YOU HAVE A 70 YEAR OLD IN
SAME POPULATION AND YOU ARE
CLAIMING ANY BIOMARKER
DIFFERENCE YOU SEE IS BECAUSE OF
40 YEARS AGE LAPSE MAY OR MAY
NOT BE TRUE AND KNOW FOR EXAMPLE
THAT PEOPLE THAT ARE 30 IN 2020
THAT WHOLE BIRTH COHORT IS
HEAVIER AND MORE OBESE THAN
BIRTH COHORT FROM THE PERSON WHO
IS NOW 70 WHEN THEY WERE BORN IN
1950.
ANOTHER IMPORTANT CAVEAT IS
SELECTIVE SURVIVAL.
IF YOU HAVE A VERY BENEFICIAL
CHARACTERISTIC, SAY IT MAKES YOU
IMMORTAL.
THAT CHARACTERISTIC WILL BECOME
MORE COMMON AT OLDER AGES AND
ALL PEOPLE WITHOUT IT CAN DIE
AND PEOPLE WITH IT CAN'T.
NOW, THAT IS THE MOST EXTREME
VIEW AND WORKS BOTH WAYS IF YOU
HAVE A DELETERIOUS EFFECT IT
WILL LOOK TO GO DOWN WITH AGE.
PEOPLE WITH IT ARE REMOVED.
AND THEN ALSO REALIZING THAT
WHATEVER YOU MEASURE AND
WHATEVER CORRELATION, IT CAN
INDEX THE CUMULATIVE AGING
EFFECTS AND DOESN'T NECESSARILY
REFLECT CURRENT STATE.
SO, IF YOU HAVE A
CROSS-SECTIONAL ASSOCIATION AND
RELATE THIS TO ANY OTHER MEASURE
AND WE WILL, I THINK WE WILL
HEAR ABOUT EPIGENETICS A LITTLE
BIT LATER. YOU MIGHT SAY THAT
PEOPLE ARE OLDER BECAUSE OF
THEIR EPIGENETICS AND THAT AGING
IF IT IS AGING, IT COULD HAVE
OCCURRED ANY TIME DURING THEIR
LIFE COURSE AND DOESN'T TELL YOU
THEY ARE AGING FASTER RIGHT THEN
BUT AT SOME POINT IN LIFE
HISTORY UP TO THAT POINT THEY
MAY HAVE AGED OR QUICK LY THIS S
DATA FROM LONGITUDINAL AGING AND
TRACKING LONGITUDINALLY 20
DIFFERENT AGE RELATED PHENOTYPES
AND MEASUREMENTS TO REPRESENT
FOUR PHENOTYPIC DOMAINS BODY
COMPOSITION ENERGY HOMEOSTASIS
AND NEURODEGENERATION AND EACH
OF THE LINES REPRESENTS A PERSON
IN BLSA AND LOOKS AT TRAJECTORY
OF MEASURE OVER TIME AND ENERGY
USE WITH SLOW WALKING AND ENERGY
USE OF SLOW WALKING RATIO OF
PEAK ENERGY CONSUMPTION THAT YOU
SEE GOES UP WITH AGE AT ALL TIME
POINTS FITTING AS A
CROSS-SECTIONAL STUDY AND TAKING
MIDPOINTS OF BLUE LINES
CONNECTING THEM YOU WOULD HAVE
SEEN IT IN A CROSS-SECTIONAL
STUDY AND LOOKED LIKE NO CHANGE
IN MEASUREMENT BETWEEN AGES OF
25 AND 50 AND THEN WOULD RISE
THEREAFTER. THIS IS A EXAMPLE
OF BIAS THAT YOU WOULD ATTRIBUTE
OR BIAS YOU WOULD MAKE LOOKING
AT CROSS-SECTIONAL DATA RATHER
THAN HAVING ACTUAL LONGITUDINAL
MEASU
MEASURES.
LET'S TALK P MORE ABOUT
SURROGATE ENDPOINTS THAT ARE
THINGS PEOPLE WOULD REALLY WISH
THEY HAD AND SO A SURROGATE
ENDPOINT IS AN ENDPOINT IN A
CLINICAL TRIAL AND SUBSTITUTE
FOR DIRECT MEASURE OF PERSON AND
HOW THEY FEEL FUNCTIONS AND
SURVIVES THAT COULD BE
REASONABLY LIKELY AND VALIDATED
AND SO DR. JUSTICE WITH PEOPLE
WORKING WITH TAME WENT THROUGH
EXERCISE TO IDENTIFY POTENTIAL
THINGS THAT WE ALREADY KNEW THAT
COULD BE CONSIDERED AS
REASONABLE ONES AND REASONABLY
LIKELY ONES AND CAME UP WITH A
LIST OF THE FOUR OR FIVE
BIOMARKERS THAT ARE INCLUDING
TNF ALPHA SOIL RECEPTORS AND
STATUS C AND PROBIANP AND NT
PROBIAN NP BRINGING UP FEATURING
IN DR. KRIMON'S TALK EARLIER AND
TO FULLY VALIDATE MARKER, YOU
HAVE TO HAVE DATA SHOWING
CLINICAL BENEFIT OF THE
INTERVENTION THAT YOU ARE
CONSIDERING.
WE HAVE A GOOD REFLECTION OF
THIS. IT IS IN BONE MINERAL
DENSITY WHERE IT TOOK 12 OR 13
TRIALS OF 7 TO 20,000 PEOPLE FOR
THREE OR MORE YEARS TO GENERATE
DATA TO SHOW THAT EXTENT OF
REDUCTION IN BONE DENSITY IS
RELATED TO EXTENT OF REDUCTION
IN RISK OF FRACTURE THAT ALLOWED
VALIDATION OF BONE DENSITY IN
THIS REGARD.
THESE ARE SUCCESSFUL SURROGATES
AND FAILED ONES AND WON'T
BELABOR THIS. YOU CANNOT
VALIDATE SURROGATE WITHOUT TRIAL
SHOWING EFFICACY AND I WILL
LEAVE YOU WITH THIS THOUGHT. IF
WE HAVE A VALID SURROGATE
BIOMARKER, WHAT IS ENDPOINT THAT
WE WANT THE SURROGATE FOR? THAT
IS A GEROSCIENCE CHALLENGE
COMING UP WITH DEFINITIONS OF
PHENOTYPIC AGING THAT WE CAN
APPLY IN A TRIAL.
WE CAN FIND BIOMARKERS RELATING
TO IT. WE DON'T HAVE IT YET.
WE DON'T OR HAVEN'T HAD A TRIAL
LARGE ENOUGH WITH INTERVENTIONS
TO SHOW EFFICACY ON THIS NOW
HYPOTHETICAL ENDPOINT WE HAVE TO
DEVELOP. THANK YOU.
>>THANK YOU, STEVE. NEXT IS
DAN AND I WILL GIVE A TALK HE IS
A PROFESSOR AT EPIDEMIOLOGY
COLUMBIA SCHOOL OF MAILMAN
HEALTH. DAN'S WORK IS AT
INTERSECTION OF SOCIAL SCIENCE
AND GENOMICS AND PUBLIC HEALTH
AND RECENT WORK EVALUATED
METHODS QUANTIFY IING --
APPLICATION OF THESE LIFE
HISTORY AND SOCIAL FACTORS AND
AGING PROCESS AND HOW TO BE
MODIFIED WITH INTERVENTION AND
ORIGINATING METHOD -- DAN TAKE
IT AWAY.
>>OKAY. THANK YOU VERY MUCH.
SEEING IF I CAN DO THIS STANDING
STILL AND NOT PREFERRED MODE OF
OPERATION AND DISCLOSURE KEEP IN
MIND IN TALK AND REMIND US WHERE
WE CAME FROM. WE HAVE NOT SEEN
THIS KIND OF CARTOON I FEEL LIKE
SO FAR IN LAST COUPLE OF DAYS OR
I HAVEN'T AND WITH AGING
ACCUMULATING CELLULAR LEVEL
CHANGES FEEDING FORWARD TO
UNDERMINE CAPACITY AND ORGANS --
ULTIMATELY DISABLE AND KILL US.
BY INTERVENTION ON THESE
MOLECULAR CHANGES WE CAN DELAY
OR SLOW PROCESS FOR CHANGE AND
PRESERVING HEALTHY LIFESPAN AND
FRAMING FOCUSING ON MEASUREMENTS
TO MAKE WITH INTEGRITY CHANGE
AND PACE AND PROJECTS ULTIMATELY
SOURCE OF CHANGE AND CARTOON IS
WHERE PROGRAM OF RESEARCH THAT I
HAVE BEEN AFTER SINCE ABOUT 2014
BEGAN WITH TERRY AND
IDENTIFICATION OF THE MIDLIFE
AND HEALTHY PERIOD OF LIFE WITH
OPTIMAL POINT FOR THERAPEUTICS
AND DIVERGENT TRAJECTORIES OF
AGING WHEN POSSIBLE TO INTERVENE
AND PRESERVE SYSTEM INTEGRITY
AND DECLINE AND CHALLENGES
MANLING ONE OF STEVE'S TRIAL AND
LATENCY TO ONSET OF DISABLING
CONDITIONS AIMING TO PREVENT IS
STREAMLY LONG NOBODY HAS TIME OR
MONEY TO RUN A CLINICAL TRIAL
AND SUROGATES WE HAVE IN MIND
ARE CALLED PACE OF AGING AND
MEASUREMENTS TAKEN OUT OVER
YEARS OR MONTHS AND READING OUT
SLOWING DOWN ACCUMULATION OF
BIOLOGICAL CHANGE IN TREATMENT
RATHER THAN CONTROL GROUP AND
WENT ABOUT DOING THAT IN FIRST
CASE THAT IS FAIRLY OLD WORK
FROM 2015 COMPILING RECORDS
FUNDED IN NIA AND -- ACROSS A
HALF CENTURY.
WITH ALMOST PERFECT RETENTION
AND 95% AS RECENT FOLLOW UP AND
FROM AGE OF 26, PARTICIPANTS
WERE BROUGHT INTO CLINIC
UNIVERSITY AND RECEIVED A
COMPREHENSIVE CLINICAL EXAM AND
RECEIVED MEASUREMENTS TAKEN IN
PARALLEL WITH TIME POINTS
PARTICIPANTS WERE 26 AND 32 AND
38 YEARS OF AGE ON FIGURE ON
YOUR LEFT AND READ OUT ON
VARIOUS ORGAN SYSTEMS THROUGHOUT
BODIES OF INDIVIDUALS HEART AND
LUNGS AND KIDNEYS AND LIVERS AND
ALIGNING THAT DATA AND TRACKING
INDIVIDUALS CHANGE ACROSS 20
YEARS OF FOLLOW UP AND SAW WITH
YOUNG PEOPLE BODIES EVIDENCED
DECLINE IN INTEGRITY OVER THE
COURSE OF A LIFETIME AND WITH 18
BIOMARKERS COMPOSITING
INDIVIDUAL DIFFERENCES TO FORM A
SINGLE INDEX WE SEE VARIATION
AND HOW FAST PEOPLE'S BODIES ARE
CHANGING AND METRIC MEAN AVERAGE
BIOLOGICAL CHANGE PER YEAR IN
INDIVIDUAL IN LONGITUDINAL STUDY
POPULATION REPRESENTATIVE BIRTH
COHORT AND ONE ADMITTEDLY
ENTIRELY WHITE AND SOURCED FROM
SINGLE CITY AT BOTTOM OF THE
WORLD AND SOME PEOPLE'S BODIES
ARE NOT CHANGING AT ALL AND
OTHERS THAT BODIES ARE CHANGING
NEARLY TWICE AS FAST AND 30-A AT
TIME WE CONDUCT STUDY THERE IS
NO FOLLOW UP FOR DISEASE OR
MORTALITY AND OBSERVE THAT
INDIVIDUALS BODIES CHANGING MORE
SLOWLY SHOW SUPERIOR PHYSICAL
FUNCTIONING AND COGNITIVE
FUNCTIONING REDUCING COGNITIVE
DECLINE LOOKING YOUNGER SHOWING
PICTURES OF GRADUATE FACES AND
SUBSEQUENT WORK MAX ELLIOT
SHOWED THEY HAVE YOUNGER LOOKING
BRAINS AND IN ADDITION LOOKING
BACKWARDS IN LIVES WE SEE THOSE
AGING FASTER HAVE LIFE HISTORIES
CHARACTERISTIC OF PEOPLE TENDING
TO HAVE SICKER SHORTER LIVED
LIVES AND GROWING UP IN POVERTY
AND GREAT EAR ACCUMULATIONS OF
ADVERSE CHILDHOOD EXPERIENCES
AND YOUNG PEOPLE SHOW SIGNS OF
RISK FOR LATER AGE-RELATED
DISEASE AND IS NOT A MEASURE
PUTTING INTO CLINICAL TRIAL
REQUIRING 12 YEARS FOLLOW UP AND
GREAT DEAL OF COMPLEX
EXAMINATION AND GOAL FROM HERE
IS TO TRY TO BOTTLE THIS PACE OF
AGING INTO A BLOOD TEST THAT
COULD BE DELIVERED OVER COURSE
OF REPEATED MEASUREMENTS IN
CONTEXT OF RCT AND TO DO THAT WE
TURNED TO THIS MOLECULE THAT WE
HEARD SOMETHING ABOUT AND
EPIGENETIC CLOCKS THAT PAVE THE
WAY AND DNA METHYLATION AND MENL
ILL GROUPS BONDED TO CG DIO
NUCLEOTIDES AND TURNING GENES ON
AND OFF AND NOT HOW WE ARE
STUDYING THEM HERE AND TINY
BLACK BOXES RECORDING
INFORMATION INDIVIDUALS BIOLOGY
AND POTENTIALLY ENVIRONMENT TO
DATA MINE AND TRY TO UNDERSTAND
DERIVING MEASUREMENT OF
PHENOTYPE IN THIS CASE THAT IS
THE AGE OF PACING AGING AND CAME
TO WORK CONDUCTED BY LAB AND
[INDISCERNIBLE] AND COLLEAGUES
AND FIRST CASE SHOWED METHO LOAM
WAS EXTRAORDINARY TIME KEEPER
GOOD AT RECORDING HOW OLD PEOPLE
WERE AND THEORY DERIVING
PREDICTIONS PREDICTING THOSE
FROM METHYL OHM AND EPIGENOMIC
AGE AND FAST OR RANGING SLOW AND
DIDN'T TURN OUT TO BE TRUE
CONSISTENTLY AND FIRST
GENERATION OF EPIGENETIC CLOCKS
UNRELIABLE PREDICTORS LIKE PACE
OF AGING IN PART BECAUSE OF
LIMITATIONS THAT STEVE NOTED
SURVIVAL BIAS COHORTS MOST OF
ALL AND COULD BE SIGNS OF
RESILIENCE AND OF SURVIVABLE OR
TRIVIAL BILOGICAL CHANGE NOT
SUBSTANTIVE BILOGICAL DAMAGE WE
ARE AIMING TO PREVENT AND
BECAUSE OR MOTIVATED BY OVENGSS
SECOND GENERATION OF EPIGENETIC
CLOCKS WAS DEVELOPED BY MORGAN
LEVINE DESIGNED TO PREDICT
BACKWARD TO TIME OF BIRTH --
CAUSES OF DEATH IN OLDER PEOPLE
AND CHANGES ACCUMULATIVE AND
GREAT DEAL OF LIFE COURSE NOT
NECESSARILY CHANGE THAT IS
HAPPENING RIGHT NOW AND
CRITICALLY IMPORTANT DELIVERING
CLINICAL TRIAL THINKING OF
SLOWING DOWN PACE OF AGING TODAY
AND NOT REVERSING LIFETIME WORTH
OF BIOLOGICAL DAMAGE AND IN
RESPONSE TO LIMITATIONS WE
SOUGHT TO DEVELOP ALTERNATIVE
EPIGENETIC CLOCK AND THIS ONE
DESIGNED TO PREDICT PACE OF
AGING AND WE HAVE DONE
SUBSTITUTING COMPOSITE PACE OF
AGING MARKER FOR CHRONOLOGICAL
AGE OF MORTALITY IN MACHINE
LEARNING PARADIGM ATTEMPTING TO
DERIVE EPIGENETIC PREDICTION OF
PACE OF AGING AND WHAT COMES OUT
IS UNLIKE PREVIOUS CLOCK. YOU
CAN THINK OF ORIGINAL EPIGENETIC
CLOCK OR ODOMETER MEASURES
TELLING BUT MILES TRAVELED AND
WE ARE DOING A SPEED OM TER OR
RADAR GUN AND BLOOD TEST TELLING
YOU HOW FAST YOU ARE GOING NOW
-- FORMING PHENOTYPE IN MACHINE
LEARNING THAT DELIVERS THE FINAL
EPIGENETIC CLOCK ALGORITHM IN
PACE AND TIME POINTS BIOLOGICAL
MEASUREMENT FOUND TO BE
IMPORTANT REFINING GREAT DEAL OF
SIGNAL THAN 3 TIME POINT SLOPE
MEASUREMENT IS ABLE TO AND
POINTING OUT BECAUSE WE ARE
INITIATING FOLLOW UP IN YOUNG
ADULTHOOD IS A CLOCK DEVELOPED
FREE OF CONTAMINATION OF
SURVIVAL BIAS THAT IS DEVELOPED
IN A SINGLE YEAR BIRTH COHORT
AND WE KNOW THERE IS NO COHORT
EFFECTS CONTAMINATING THE SIGNAL
AND BECAUSE WE ARE CONDUCTING
REPEATED MEASUREMENTS TO
PHENOTYPE LONGITUDINAL CHANGE
CRITERIA MEASURE IS DATA MINING
PHENOTYPE AND KNOW WHEN IT IS
OCCURRING WITHIN HUMAN LIVES
ADDITIONALLY COULD SUGGEST DONE
A NUMBER OF TIMES BECAUSE PEOPLE
ARE IN MID LIFE MEASURING THEM
THAT MIGHT BE A TO BE DETERMINED
THING AND FEW WORDS WHAT IT IS
FIRST IS A TECHNICAL PROPERTY
AND STEVE HELPED PUT KAREN'S
PAPER UP EARLIER AND WILL
MENTION AGAIN OBSERVED IN 2020
PAPER SITES ON ALUM IN AN EPIC
RELAY HAVE LO HE RELIABILITY
IMPLEMENTED IN BLOOD RUNNING
SAME DNA TWO DIFFERENT ARRAYS
COMPARING CPG SITE BETWEEN THEM
YOU HAVE DIFFERENT ANSWERS
STUDYING CHANGE RESPONSE TO
TRIAL AND DEVELOPED EVEN PACE
TRAINING ALGORITHM ON SUBSET OF
PROBES OF ARRAY SHOWING BEST
TEST AND RETEST RELIABILITY YOU
SEE CONSEQUENCES OF EFFORT IN
BLOT AND Y AXIS COEFFICIENTS
REPEATABILITY OF MEASURE SAME
DNA TWO ARRAYS HOW SIMILAR ARE
MEASUREMENTS PACE AND GOLD AND
GENERATION IN ORANGE AND
EPIGENETIC CLOCKS IN BLUES AND
PURPLES AND SEE THAT IT PAYS IN
FACT REPRODUCIBLE AND FINAL
FARNLEST RIGHT GRAPH IS SHOWING
COMPARISON OF TWO DIFFERENT
FLAVORS ALUM IN AN ARRAY AND
THESE ARE GOING DOWN AND IS
WORTH NOTING ALBERT SPEAKING
NEXT SOLVING IN A PROBLEM IN A
GENERAL WAY OFFERING ELEGANTLY
FOR OTHER CLOCKS AND SPEAKING
BRIEFLY ABOUT THAT CHECKING OUT
HIGGINS JEN PAPER AND WE HAVE
THIS THING AND WHAT DOES IT DO
AND ONE THING IT DOES THAT IS
INTERESTING TO US IS SHOWING
HIGHER VALUES FASTER PACE OF
AGING IN OLDER PEOPLE AND THIS
IS A CLOCK THAT IS TRAINED IN
1,000 PEOPLE THAT ARE ALL SAME
CHRONOLOGICAL AGE AND BORN IN
SAME YEARS AND NO CHRONOLOGICAL
AGE VARIATION IN SOURCE MATERIAL
AND THERE IS WITH CHRONOLOGICAL
AGE IN MIXED POPULATIONS AND
1200 ADULTS IN UK AND RANGING IN
AGE 30 TO 90 -- MORTALITY RISK
WITH ADVANCING AGE AND WHAT WE
KNOW ABOUT DECLINING
PHYSIOLOGICAL INTEGRITY IN
PEOPLE'S BODIES GROWING OLDER
FOR EXAMPLE WITH LONGITUDINAL
STUDY OKAY IT DOES THE THING
THAT IT IS MAINLY SUPPOSED TO DO
PREDICTING WHEN TO GET SICK AND
HOW LONG TO LIVE NOT PERFECTLY
OF -- CARDIOVASCULAR DISEASE AND
STROKE AND DEMENTIA AND HEART
STUDY AND RIGHT SIGH DATA
SURVIVAL HEALTH ADMINISTRATION
AND FRAMING HAM HEART STUDY
OFFSPRING COHORT AND EFFECT
SIZES ARE COMPARABLE AND
REFERRING TO EARLIER WITH EFFECT
SIZES WE SEE FOR WHAT WE THINK
IS AS BEST IN CLASS BIOMARKER
PREDICTION IN MORTALITY -- WE
ALSO CARE ABOUT AGING AND THAT
IS SOMETHING I BROUGHT UP ON THE
FIRST DAY IN FIRST HALF AS WELL
CRITICALLY IMPORTANT SOMETHING
LOOKING TO INVALIDATING
BIOMARKERS AND DATA ON SCREEN
FROM ERISK LONGITUDINAL STUDY
CHILDREN BORN IN BRITAIN 1994
AND 1995 BLOOD SAMPLES TAKEN
WHEN 18 YEARS OLD AND SEEING
DIFFERENCE IN PACE BY CHILDHOOD
FAMILY SOCIAL CLASS MEASUREMENT
TAKEN IN AGE 5 AND HISTORY OF
VICTIMIZATION ACCUMULATED THESE
BETWEEN HAVING HARD CHILDHOOD
EVIDENCING FAST AGING ON DAWN OF
ADULTHOOD AND BOTTOM OF THE
SCREEN HIGHLIGHTING ON PREVIOUS
SLIDE AS WELL AND HANDFUL OF
COHORTS MIXED ANCESTRY AND RACE
ETHNICITY AND DIFFERENT
COUNTRIES REPLICATING BROAD
PATTERNS DRAWING ATTENTION TO
PAPER THAT WAS IN PARTICULARLY
IN GERONTOLOGY SHOWING
PATTERNING OF PACE BY
EDUCATIONAL ATTAINMENT AND TA
PAPER BY LAUREN SMITH AND FASTER
PACE OF AGING IN LATE LIFE AND
RETIREMENT STUDY AND AT END OF
THE DAY WE WANT TO KNOW HOW DOES
THIS MEASURE PERFORM IN CONTEXT
OF RTC AND HAD A CHANCE TO TEST
HYPOTHESIS AND CALORIE TRIAL
RANDOMIZED TRIAL OF LONG TERM
CALORIC RESTRICTION IN ADULTS
AND CONTROL FOR TWO YEARS
FAMOUSLY INTERVENTION ACHIEVED
HALF PRESCRIBED DOSE ON AVERAGE
PRODUCED SUBSTANTIAL WEIGHT LOSS
KILOGRAMS AND PUBLISHED BY KRAUS
AND COLLEAGUES AND ALSO IN OUR
HANDS SHOWS A SLOWING OF
INCREASE IN BLOOD CHEMISTRY
MEASURES OF BIOLOGICAL AGEING
THAT ARE ALSO COOL MOLECULAR
SCIENCE ANALYSIS PAPER FROM LAB
A COUPLE YEARS AGO SHOWING IT
MAY HAVE SLOWED IMMUNE AGING AND
YOU CAN SEE HERE EPIGENETIC
CLOCKS SECOND GENERATION DON'T
RESPOND TO INTERVENTION RATE OF
INCREASE IN ALBERT'S HIGH
TECHNICAL RELIABILITY OF
VERSIONS OF THESE ARE IDENTICAL
BETWEEN AD-LIB AND CONTROL AND
CONTRACT AND PAYS SHOWING
REDUCTION IN PACE OF AGING
RESPONSE INTERVENTION OVER FIRST
12 MONTHS OF FOLLOW UP AND
MAINTENANCE OF SLOWED RATE OF
AGING IN SECOND MONTHS OF FOLLOW
UP AND RUNNING OUT OF TIME WON'T
TELL YOU WHY THAT HAPPENED AND
SAVING FOR Q & A, PERHAPS. I
WILL LEAVE YOU WITH BROAD
CONCLUSION THAT WE THINK PACE OF
AGING IN GENERAL AND PACE IN
PARTICULAR MAY BE USEFUL
BIOMARKERS FOR SCIENCE AND MAY
IN PARTICULAR OFFER BENEFIT OF
INCREASED SENSITIVITY TO SHORT
TERM INTERVENTIONS AND FORGET
WHO BROUGHT THIS UP YESTERDAY.
MORAL IMPERATIVE EXPANDING
RESEARCH TO OTHER POPULATIONS IS
A CLEARLY CRITICAL FRONTIER
ACKNOWLEDGING NIA FUNDED DATA
GENERATION IN COHORTS NO THE
WELL WHITE EDUCATED -- AND
SEEING VALIDATION OF METRICS IN
COHORTS THAT IS TREMENDOUSLY
IMPORTANT AND CODE THAW WANT
PACE IS AVAILABLE WRITTEN BY
DAVID AND MAINTAINED BY KALIN
AND THANKS TO FUNDERS AND
COLLABORATORS AND TEAM AT
COLUMBIA. SO --
>>>>ALL RIGHT. THANKS TO DAN,
NEXT SPEAKER IS ALBERT HIGGINS
CHEN WHO IS ASSISTANT PROFESSOR
IN DEPARTMENT OF PSYCHIATRY AND
DEPARTMENT OF PANELOLOGY AT YALE
UNIVERSITY DURING TRAINING AT
UNIVERSITY OF MICHIGAN WORKED
WITH -- AGING AND LONGEVITY AND
DURING CLINICAL PSYCHIATRY
RESIDENCE AT YALE UNIVERSITY
WORKED WITH DR. MORGAN LEFIN AND
STUDIED HOW BIOMARKERS ALTERED
IN HUMAN HEALTH AND TREATMENT
AND CONSTRUCTING AGING
BIOMARKERS FOR SPECIFICALLY
LONGITUDINAL INTERVENTION
STUDIES AND THOSE COMPLEMENTING
CLINICAL KNOWLEDGE AND DATA.
ALBERT, THANK YOU.
>>THANK YOU, JAICHLEE.
SO, ONE BIOLOGICAL AGE VERSUS
MANY BIOLOGICAL AGES AND LOTS OF
DISCUSSION AT SUMMIT ABOUT THE
QUEST
QUESTION.
MY TALK WILL BUILD OFF TALKS
BEFORE. IN PARTICULAR, THERE IS
SERENDIPITOUS COMPLEMENTIARITY
WITH EILEEN'S TALK AND AGING IN
HRS AND SHE WENT DEEP INTO ONE
STUDY AND I WANT TO GO BROAD AND
ASK BIGGER PICTURE QUESTIONS AND
COMPARISONS AND WHY AND WHAT IS
MOTIVATION FOR SYSTEMS
SPECIFICITY AND THIS IS A VERY
NEW TREND IN LITERATURE THOUGHT
IT WOULD BE USEFUL TO GO THROUGH
COMPARISON OF RECENT APPROACHES
AND ONE OF WHICH I'M PART OF
THAT WILL BE SPECIFIC
[INDISCERNIBLE] AND WILL END
WITH OUTSTANDING QUESTIONS ABOUT
THIS APPROACH AND AGING UNFOLDS
OVER TIME.
AGING WILL INVOLVE ACCUMULATION
OF BIOLOGICAL CHANGES OVER TIME
LEADING TO INCREASING RISK OF
DISFUNCTION AND DEATH AND
BIOMARKERS WE HAVE ARE ANCHORED
TO SINGLE TIMELINE AND WE HAVE
THOSE THAT PREDICT CHRONOLOGICAL
AGE TIME VERSUS BIRTH AND
PREDICTING MORTALITY AND DEATH
AND PREDICTIVE PACE OF AGING AND
AS SPEAKERS BEFORE ME DISCUSSED
LOTS OF CAVEATS TO MEASURES AND
ONE I WANT TO POINT OUT IN
PARTICULAR IS A MAJOR CONCEPTUAL
ONE THAT IS ASSUMING THAT AGING
IS A SINGLE STRAIGHT TIMELINE.
EACH OF THEM REPORTS OUT A
SINGLE NUMBER AND WHEN YOU USE
THEM TOGETHER, YOU ARE TREATING
AGING AS SINGLE UNIT DIMENSIONAL
PROCESS AND SINGLE BILOGICAL
AGE. COULD AGING BE LOTS MOR
LIKE THIS WHERE THERE COULD BE
MANY DIFFERENT TRAJECTORIES OF
AGING? CAPTURING SOMETHING LIKE
THIS, YOU NEED OR CAN'T JUST
HAVE A SINGLE NUMBER AND HAVE A
LOT MORE RICH DATA.
ONE TREND HAS BEEN TO LOOK AT
BIOLOGICAL AGES FOR DIFFERENT
ORGAN SYSTEMS THAT IS A PRETTY
NATURAL LEVEL AT WHICH TO DEFINE
MANY BIOLOGICAL AGES AND EACH
ORGAN SYSTEM IS DEFINED BY
COMMON FUNCTIONS AND RESPIRATORY
SYSTEM IS GETTING OXYGEN AND C02
OUT AND PROTECTING FROM
EXPOSURES AND IT IS ILLUMINATING
URINE AND THERE IS A SET NUMBER
OF SYSTEMS ABOUT A DOZEN
DEPENDING HOW YOU ARE FINDING
THEM AND GET A NUMBER OF
BIOLOGICAL AGES THAN SAY
DIFFERENT NUMBER FOR EVERY CELL
OF THE BODY AND DISEASES LINKED
TO ORGAN SYSTEMS AND MANY
DISEASES INVOLVE MULTIPLE
SYSTEMS YOU CAN STILL POINT TO
ONE OR TWO THAT ARE TYPICALLY
INVOLVED IN PANELOLOGY AND
OTHERS ARE SECONDARILY EFFECTED
AND RECENT TRENDS HAVE BEEN TO
MODIFY THE EXISTING PIPELINE FOR
DEVELOPING AGING BIOMARKERS TO
MAKE THEM MORE ORGAN SPECIFIC
AND RIGHT NOW YOU CAN USE A WIDE
VARIETY OF DATA AND FOR EXAMPLE
CLINICAL MARKERS AND CLINICAL
LABS AND VITAL SIGNS AND MEDICAL
TESTS AND MEDICAL HISTORY AND
SELF-REPORT, ET CETERA, ET
CETERA. THESE ARE COLLECTED BY
CLINICIANS AND RESEARCH STUDIES
AND CLINICIANS KNOW ALREADY HOW
TO ACT UPON THIS INFORMATION TO
MAKE AN AGING BOMBER YOU HAVE TO
AFRNGSOR ONE OF THREE OUTCOMES
CHRONOLOGICAL MORTALITY AGE OF
[INDISCERNIBLE] AND DATA YOU
HAVE CLINICAL LABS MORTALITY
BUILDING MORTALITY PROJECTOR
FROM THIS AND YOU HAVOMICS DATA
MENLO LOAM AND TRANSCRIPTOME, ET
CETERA AND ADVANTAGE IS
DISCOVERING NEW MARKERS NOT
CURREN
CURRENTLY USED CLINICALLY AND
DISADVANTAGED YOU DON'T
NECESSARILY KNOW WHAT CLINICAL
REFERENCE IS. THEREFORE, IT IS
COMMON FOR EXAMPLE WITH PACE
MEASURE OR PHENOAGE MEASURE TO
PREDICT CLINICAL THOUGHT
FROMOMICS DATA.
SO, THE -- THERE HAVE BEEN A
SLEW OF PAPERS OVER THE LAST
COUPLE YEARS TRYING TO MODIFY
THIS MOST COMMON STRATEGY IS
ORGANIZING MARKERS FIRST BY
SYSTEM THAT IS A PAPER THAT CAME
OUT LAST EARLIER THIS MONTH. IT
IS IN NATURE MEDICINE AND THEY
LOOKED AT SO MANY DIFFERENT BODY
PHENOTYPES AND 29 COGNITIVE
MEASURE AND MRI DERIVED BRAIN
MEASURES AND SIMPLY ORGANIZED
ALL THESE BIOMARKERS INTO
SYSTEMS BY MANUAL ANNOTATION AND
EXPERTS WOULD SAY THAT THESE
MARKERS OR WHAT SYSTEM EXPERTS
WOULD SAY THESE BELONG TO.
SO, THEY GENERATED TOOK
PHENOTYPES IN PULMONARY CLOCK
TRAINING PREDICTOR IN
CHRONOLOGICAL AGE AND PREDICTOR
OF CHRONOLOGICAL AGE, ET CETERA,
ET CETERA TO AVOID HAVING LOTS
OF ERRORS ON MY SLIDESLY DENOTE
THIS WITH A SINGLE BRACKET AND
KNOW THAT, THAT MEANS THAT EACH
OF THE CLOCKS WERE TRAINED
SEPARAT
SEPARATELY ADVANTAGE HERE IS
USING THIS IN SYSTEM AND WHAT TO
DO WITH THEM AND ADVANTAGE IS
DATA TO COLLECT ON LARGE NUMBER
OF PEOPLE IN A STANDARDIZED
FASHION AND ANOTHER PAPER THAT
IS FROM 2022 USED NOT JUST
CLINICAL DATA AND ALSO INCLU
INCLUDEDOMICS DATA AND
METABOLOMICS AND MYCOBIOME THAT
IS NOT IN THE CLINIC AND
DISCOVERING NEW BIOLOGY BY DOG
THIS THEY -- ISSUES THEY ARE
STILL ASSIGNING BIOMARKER
SYSTEMS BY MANUAL ORIENTATION
AND JUST LOOKING AT WHAT IS
KNOWN AND SEEING WHICH SYSTEM
THEY THINK THEY BELONG TO.
THEY PREDICTED CHRONOLOGICAL
AGE.
THIS IS A PAPER FROM -- THERE IS
AT TERNTIVE METHODS AND PAPER
FROM 2020 THAT TOOK BLOOD,
STOOL, AND NASAL SAMPLES
PERFORMNESS OMICS ANALYSIS AND
CLINICAL BLOOD TEST THANDZ IS
INTERESTING DIDN'T DO MANUAL
ORIENTATION AND WERE STILL
PREASSIGNING DOING ITERATIVE
PATHWAY ANALYSIS AND THEY HAVE
FOUR PATHWAYS TO DELIVER
METABOLISM AND INFORMATION AND
RICH LONGITUDINAL DATA SET FOR
INDIVIDUALS AND WERE ABLE TO
HAVE PACE OF AGING MEASURE ONE
ADVANTAGE HERE MAKING
ASSUMPTIONS WHAT BIOMARKERS
BELONG TO AND WHAT IS
SIGNIFICANT SEEING FROM VENN
DIAGRAM SIGNIFICANT OVERLAP
BETWEEN PATHWAYS ANOTHER WAY
QUITE INTERESTING FROM PAPER
INTERESTING EXPLAINABLE AI WORK
AND TRAINING WORK IS THEY DIDN'T
PREASSIGN BIOMARKERS TO ANY
SYSTEM AT ALL AND THEY TOOK 250
FEATURES FROM DATA TYPES AND
DEFINITION OF SPECIFICITY COMES
AT OUTCOME LEVEL AND THEY USE
DIFFERENT FEATURES FIRST TRAIN
OF THOUGHT FOR MORTALITY DUE TO
CANCER HEART DISEASE AND
DIGESTIVE DISEASE AND OTHER
CAUSES THAT IS A VERY
INTERESTING WAY. YOU ARE NOT
MAKING ANY PREASSUMPTIONS ABOUT
WHAT BELONGS TO WHAT. YOU CAN
DISCOVER NEW RELATIONSHIPS
ALTHOUGH ARGUABLY THIS WILL LEAD
TO A LOT MORE RELATIONSHIPS DOO
YOU TO CORRELATION NOT
CAUSATION.
ALL THESE GROUPS DID AN
INCREDIBLE AMOUNT OF WORK AND I
CAN'T DO JUSTICE TO ALL OF THEM.
I WANT TO POINT OUT THAT THE
GENERAL CONSENSUS IS THAT
RESULTS FROM MULTIPLE STUDIES
SUGGEST THAT SPECIFICITY IS
USEFUL AND ORGANIZATIONS VARY IN
WHICH SYSTEMS AGE AND MOST
SYSTEMS CONTRIBUTE TO PREDICTION
OF MORTALITY AND MUTUALLY
SUBJECTIVE MODELS YOU ARE
GETTING MORE INFORMATION BY
USING MULTIPLE BILOGICAL AGES
AND IN ONE SYSTEM COULD EFFECT
AGING RACE IN OTHER SYSTEMS THAT
LARGELY SHOW ASSOCIATIONS MAKING
SENSE.
SO, THIS IS GETTING THE IDEA OF
SYSTEM SPECIFICITY.
SO, I WANT TO TALK A LITTLE
ABOUT SOMETHING WE DID WE WERE
ASKING HOW FAR WE CAN ACTUALLY
TAKE THIS CONCEPT.
SO, THIS IS WORK DONE BY RAGO
SEGAL FIRST AUTHOR IN AUDIENCE
AND PROJECT LED BY MORGAN LEVINE
AND BROUGHT ON AFTER RAJ JOINED
MY LAB AT YALE AND HELPING TO
CONSIDER CLINICAL IMPLICATIONS
OF THE MEASURE.
BUT, ESSENTIALLY, ALSO IN THE
HEALTH AND RETIREMENT STUDY AND
EILEEN'S STUDY LOOKING AT AGING
BIOMARKERS 11 SYSTEMS IN
BIOMANUAL [INDISCERNIBLE] AND
WHEN WE THOUGHT ABOUT THIS FACT
THAT THERE IS A LOT OF
BIOMARKERS TO COLLECT.
THERE IS A LOT OF FUNCTIONAL
MEASURES YOU NEED TO HAVE
TRAINED RATERS AND TRAINED
CLINICIANS AND WHAT NOT AND WE
ASKED WHETHER OR NOT YOU COULD
ACTUALLY JUST COMPRESS
INFORMATION INTO BLOOD DNA
METHYLATION AND BLOOD BECAUSE IT
IS A HIGHLY ACCESSIBLE TISSUE
AND WE
USED PAIRED -- CLINICAL MARKER
TO TRAIN A CLOCK AND PREDICTORS
OF VARIOUS ASPECTS OF KIDNEY
AGING AND HERE SINCE I MENTIONED
IT WE ARE USING THE HIGH
RELIABILITY CLOCK APPROACH AND
METHYLATION AND ALSO FOR KIDNEY
BIOMARKERS AND METHYLATION DATA
IS IN OTHER COHORTS YOU CAN
EASILY RECALCULATION METHYLATION
MARKERS IN ONE DATA SET AND
IMPORT TO ANOTHER AND
METHYLATION MORTALITY DATA FROM
FRAMING HART STUDY TO TRAIN
MORTALITY PREDICTOR AND GET A
LONGER FOLLOW UP TIME FOR
MORTALITY AND SAME THING FOR
HEART AND DOING THE SAME FOR
OTHER 11 SYSTEMS THAT PROVIDES
11 DIFFERENT [INDISCERNIBLE] AND
WHAT IS INTERESTING IS THAT YOU
DON'T NEED INITIAL 130 DIFFERENT
BIOMARKERS THAN CALCULATING
DIFFERENT 11 EPIGENETIC CLOCKS
AND GETTING FROM SINGLE DNA
METHYLATION ASSAY AND RAGA WAS
ABLE TO CALCULATE THIS AND THESE
IN WOMEN'S HEALTH INITIATIVE AND
HAS 20 YEARS OF FOLLOWUP AND SO
HE FORMED METAANALYSIS SYSTEMS
OUTCOMES AND SO FOR BREVITY WE
SUMMARIZED AND TOOK Z SCORE
PLOTTED ON BODY PLOT AND TEXT
SIDE IS PROPORTIONAL TO Z SCORE
AND THERE IS -- MUSCULOSKELETAL
INFORMATION AND HEART AND
COMORBIDITIES BASELINE
MUSCULOSKELETAL WITH DIABETES
AND DISEASES HORMONE AND HEART
AND SKELETAL INFORMATION AND
CATARACT MULTIPLE SYSTEMS AND
TIED TO DISEASE EVENTS AND
PEOPLE WITHOUT DISEASE AND
DEVELOP DISEASE AND LUNG CANCERS
PREDICTED BY LUNG AND HEART AND
-- CORONARY HEART DISEASE AND
INFLAMMATION GETTING TO SYSTEM
MORTALITIES AND IT IS NOT
RANDOMLY ASSOCIATED WITH LOTS OF
DIFFERENT OUTCOMES AND WE ALSO
COMBINE THEM IN SINGLE SYSTEMS
AGE SCORE AND DUE TO TIME I
WON'T GO -- I WILL PREEFLY SAY
WE COMPARE THESE OTHER CLOCKS
FOR VARIETY OF CONDITIONS AND
SYSTEMS AGE FIRST PREDICTS EACH
SYSTEM INDIVIDUALLY AND WON'T BE
BIASED AND ALL SYSTEMS ALLOWED
TO CONTRIBUTE TO FULL MEASURE
NOT BIASED TOWARDS ANY
PARTICULAR OUTCOME AND TRAINED
PREDICTOR OF MORTALITY STRAIGHT
OFF GETTING THINGS LIKE HEART
DISEASE OR CANCER.
SAME QUESTIONS, SO, SHALL
SYSTEM SPECIFIC IS BASED ON
PRE-EXISTING NOTIONS WHAT
BIOMARKERS AND OUTCOMES BELONGS
TO EACH SYSTEM RAISING A
PHILOSOPHICAL QUESTION AND
ULTIMATELY FROM PRACTICAL
STANDPOINT WE ARE SIMPLY
LEVERAGING CLINICAL WIS COME
THAT WE ALREADY ACCUMULATED IN
TRYING TO MAKE THESE JUDGMENTS.
SOME SUBJECTIVE IS ACTUALLY OKAY
ONE IMPORTANT THING WE HAVE
CLINICAL JUDGMENTS TAKING INTO
ACCOUNT WIDE VARIETY OF
INFORMATION FAMILY HISTORY AND
SOCIAL DETERMINANTS OF HEALTH,
ET CETERA AND ARE BIOMARKERS
ADDING PREDICTIVE INFORMATION?
I WILL SAY IT IS IMPORTANT GIVEN
RELATIVE INTERPRETABILITY OF
MEASURES YOU KNOW WHAT
BIOMARKERS GOES INTO SYSTEMS AND
IS BEST TO ASK CLIN IKSS ABOUT
ANY GIVEN RESULT AND PEOPLE KNOW
ABOUT THESE BIOMARKERS WHEN WE
HAVE THESE SPECIFIC BIOMARKERS
ENOUGH TO PARTITION THEM INTO
DIFFERENT SYSTEMS AND IF YOU
WILL BE HAVING HUNDREDS OF
MEASUREMENTS OF DIFFERENT TYPES
IT WILL BE CHALLENGING TO
OPTIMIZE THEM AND CONSIDERING
PREDICTIVE INFORMATION AND
MISSING VALUES AND BETWEEN
CLINICIANS AND LABS, ET CETERA.
MOVING TOWARDS COMPRESSING
RELEVANT INFORMATION AND FEWER
TESTS COULD BE PROMISING
STRATEGY.
FINALLY, QUESTIONS THAT OTHERS
HAVE MENTIONED THAT APPLY TO
GENERAL BIOMARKERS APPLY HERE
AND WE NEED TO THINK MORE ABOUT
EXPLAINABILITY AND UNDERLYING
MECHANISMS AND WHETHER OR NOT IN
COULD BE USED AS SURROGATE
BIOMAR
BIOMARKERS.
SINGLE NUMBER IF ANY THIS IS
SOMETHING WE SHOULD BE
CONSIDERING AND HERE ARE ALL OF
THE REFERENCES.
>>[APPLAUSE].
>>NEXT SPEAKER IS MARTIN AND HE
HAD SP [INDISCERNIBLE] AND
COMPLETED POST DOCTORAL
FELLOWSHIP WITH DOUG WALLACE AT
UNIVERSITY OF PENNSYLVANIA
ASSOCIATE PROFESSOR OF
BEHAVIORAL MEDICINE IN
PSYCHIATRY AND NEUR OL AND
DIRECTS MITOCHONDRIAL
PSYCHOBIOLOGY GROUP.
RESEARCH PROGRAM FOCUSES ON
IDENTIFYING ORGANELLE TO
ORGANISM PROCESSES AND SMALL
INTRACELLULAR ORGANELLES
SUSTAINING LIFE AND RESILIENCE
AND ARE LOOKING FORWARD TO
HEARING ABOUT COLLABORATIVE WORK
FROM CLINICAL AND CELLULAR
COMPUTATIONAL APPROACHES FROM
PROCESSES IN BRAIN BODY UNITS.
>>THANK YOU. HAPPY TO BE HERE.
I AM HAPPY TO BE HERE TO TALK TO
YOU. BEFORE I DIVE INTO
MITOCHONDRIA SHOWING SOMETHING
WE CAME ACROSS MICROSCOPY OF
HUMAGE HAIR AND TRAVELING ALONG
TIP OF HAIR AND TRAVELING DOWN
AND SEEING YOUNG DARK HAIR
TURNING WHITE AND NOW WE ARE IN
OLD PART OF THE HAIR LOST
PIGMENTATION UNDENIABLE HALLMARK
OF HAIR AGING HAIR GRAIN AND
OBSERVING IN SINGLE HAIR YOU SEE
PIGMENT COMING BACK AND BROWN IS
SOMEHOW RETURNING AND ALL OF A
SUDDEN HAIR IS DARK AGAIN
REVERSAL OF HAIR GRAIN IN HUMAN
HAIR DEVELOPING APPROACH TO MAP
THIS AND TAKING SINGLE HAIR AND
PUTTING ON HIGH RES SCANNER AND
PROFILE IS ORIGINALLY ON GRAPH
AND LOSING PIGMENTATION AND
RECOVERS PIGMENTATION AND FOUND
IN PARTICULAR PARTICIPANT AND
OTHER PEOPLE CORRELATED ARE
LEVELS OF REPORTED LIFE STRESS
AND THAT PARTICULAR PERSON
EXPERIENCED SAYING IN WORDS MOST
STRESSFUL TWO MONTHS OF HER LIFE
AND MATCHED STRESS GRAPH HERE.
FINISHED PHD AND SHE WAS GOING
THROUGH DIFFICULT LIFE STRESS
WITH RELATIONSHIP ISSUES AND
BROKE UP WITH PARTNER AND MOVED
ACROSS COUNTRY AND LIFE WAS GOOD
AGAIN AND HAIR RECOVERED COLOR
AND ILLUSTRATES PLASTICITY AND
HUMAN IMAGING IN QUANTITATIVE
WAY AND PSYCHOLOGICAL STATES AND
STRESS IN HUMANS.
WE DID SINGLE HAIR PROTEOMICS
HELL OF A CHALLENGE BUT
INTERESTING WHAT CHANGES IN HAIR
WHEN GOES OLD AND LOSES COLOR
AND RECOVERS COLOR AND TURNS OUT
YOU SEE VOLCANO PLOT HERE
PROTEINS DOWNREGULATED ON LEFT
OR UPREGULATED ON RIGHT AND
MAJORITY OF PRO E- TEENS ARE UP
REGULATED WHY CARE ABOUT ENERGY
AND MITOCHONDRIA PAINTING A
BRIEF PICTURE LOU EVENI DID GOOD
WITH THIS YESTERDAY AND GIVING A
BRIEF SUMMARY FROM MY
PERSPECTIVE WE CARE ABOUT THESE
AND PRESERVING PERSON AND
BIOLOGY AND FIZZ YOL AND
COGNITION AND HUMAN
CONSCIOUSNESS RELIES ON HUMAN
FIZZ YOL AND DEVELOPMENT AND
AGING PROCESSES AND THAT ENERGY
COMES FROM MITOCHONDRIA AND
WON'T GO INTO DETAILS THERE BUT
MITOCHONDRIA'S JOB IS TAKING
ENERGY IN FORM OF CHEMICAL FORM
TRANSFORMING INTO ELECTRICAL
FORM AND ELECTRICITY USING
BATTERIES TO POWER CELLS TO CARS
ORGANISM USES MITOCHONDRIAL
BATTERIES TO POWER EVERYTHING
ELSE AND COMES FROM WHERE? FOOD
WE EAT AND OXYGEN WE BREENL AND
MITOCHONDRIA TRANSFORMING
CHEMICAL TO ELECTRICAL ENERGY
PRODUCES C02 AND WATER CLOSING
LIFE CYCLE IN INTERESTING WAY
AND THAT COMES ULTIMATELY FROM
SUN POWERED BY NUCLEAR REACTOR
IN SPACE AND MITOCHONDRIA PORTAL
FORM OF ENERGY COMING THROUGH
IMMATERIAL RADIATION THAT IS
TURNED INTO LIFE INTERESTING TO
CONSIDER LIFE STARTED WITH
METABOLISM BEFORE GENES AND
CELLS EXIST TD WAS METABOLISM
AND TRANSFORMATION OF SOME
ENERGY TO ANOTHER FORM AND
METABOLISM FOUND WAY TO BECOME
ENGRAINED AND SUSTAIN ITSELF
THROUGH GENES. WE ARE
UNINTERRUPTED CLAIM OF ENERGY
BEFORE IMPACT OF GENES.
THIS IS LIVING CELL IF FORTUNATE
TO WORK IN A LAB AND SEE
MITOCHONDRIA FLUORESCENT THESE
ARE WHAT YOU SEE AND MIDDLE HERE
ARE BELOVED GENES AND EPIGENOME
AND TELOMERES APD SO ON AND
OUTSIDE ARE ENVIRONMENTAL THINGS
CARING ABOUT UNDERSTANDING HOW
THOSE ACTUALLY IMPACT WHAT
HAPPEN INSIDE AND EPIGENETIC
CLOCKS THAT REFLECT THAT AND X
FACTOR CONNECTING THESE AND
SEVERAL ARGUMENTS ILLUSTRATING
TYPICALLY MITOCHONDRIA
INTERPHASE THAT LIE BETWEEN
OUTSIDE AND INSIDE WORLD AND
CELL OF EPIGENOME MAKING
POTENTIAL IN PROCESS AND
INTERACTION EMERGES PROCESS AND
HEALTH AND AGING AND HOW WE
STUDY THIS QUESTION THAT WE CARE
ABOUT WE WANT TO APPROACH THIS
IN WAY TO ALLOW US TO TEST ROLE
OF MITOCHONDRIA IN REGULATING
HALLMARKS OF AGING AND HUMAN
AGING THAT IS CHALLENGING TO DO
FOR MANY REASONS AND TRACKING
PEOPLE OVER LONG PERIODS OF TIME
AND COLLECTING SAMPLES IS
DIFFICULT AND WORK THAT HAD BEEN
DONE BEFORE CAN SHOW YOU CAN AGE
CELLS IN A DISH AND WE TRIED TO
DO THIS IN A SIMPLE WAY AND
WHERE YOU PASS PRIMARY
NONTRANSFORMTIVE HUMAN CELLS IN
ADDITION AND ALLOWS YOU TO STUDY
MITONUCLEAR SYSTEM AND YOU SEE
NUCLEUS IS IN BLUE AND CYTOPLASM
AND PAIL GREEN IS OUTSIDE WORLD
AND MITOCHONDRION IS A RIBBON
AND STRUCTURES IN BETWEEN AND
PICTURE ON RIGHT ARE -- IT IS A
ZOOMED IN VERSION OF MITONUKE
LEEACE THAT IS THERE FEW HUNDRED
NANOMETERS AWAY FROM CHROMATIN
AND GENES THERE BEING REGULATED
AND YOU CAN DEPLOY SAME TOOLS WE
HEARD ABOUT THAT ARE EPIC
DEMETHYLATION ARRAY AND DID THIS
WITH 500 PERSON/TIMEPOINTS
TRACKING SAME THINGS AND -- AND
ALSO HAVING THE ABILITY IN VITRO
AND EVERYTHING IS CONTROLLED
EXCEPT ONE THING EXPERIMENTALLY
MANIPULATING EXPOSURE AND ASKING
CAUSAL QUESTIONS AND EXAMPLE
WHAT WE FOUND EARLIER ON THAT
CONVINCED ME THAT THERE WAS
SOMETHING TO THIS THAT IS L2 AND
LOCI THAT COMES -- OUT IN SWEDEN
I BELIEVE AND THEN YOU CAN SEE
THAT YOUNGER INDIVIDUALS ARE
OLDER INDIVIDUALS ARE BLUE AND
PURPLE AND SEE AT THIS SITE HERE
THAT IS I HAVE A POINTER AND
SITE WHERE THERE IS A SPIKE
THERE WITH CPG HIGHLIGHTED IN
COLOR AND LOCI THAT COMES UP IN
ASSOCIATION STUDIES AND YOU CAN
SEE IN VITRO SYSTEM WE HAVE
CELLS THAT ARE ADVANCING IN AGE
AS WE CULTURE THEM AND IN THE
LAB AND YOU CAN SEE SAME KIND OF
PATTERN AND ON THE RIGHT IS
ACTUALLY THE CHANGE OVER TIME IN
THE METHYLATION LEVEL IN BETA
VALUE FOR CBG AND CONCORDANCE
BETWEEN IN VITRO DATA AND
DEPLOYING FIRST CONVENIENTATION
CLOCKS AND SKIN AND BLOOD CLOCK
AND CLOCKS WORK IN A DISH TAKING
CELLS FROM SOMEONE'S SKIN AND
PUT IN A DISH PASSAGE OVER TIME
AND AGE CELLS AND YOU SEE SAME
PATTERNS THAT IS INTERESTING AND
REMARKABLE IS COMPARE TODAY RATE
OF AGING IN HUMAN BODY CLOCKS
ARE RETURNED TO ON ONE YEAR
PREDICT AGE ONE YEAR
CHRONOLOGICAL TIME AND RATES 50
TO 100 TIMES FASTER AND
EVERYTHING SEEMS TO HAPPEN
FASTER AND THINK WE KNOW WHY
THAT HAPPENS AND MIGHT RELATE TO
ENERGETICS AND DATA SET THAT
THOSE THAT MIGHT BE INTERESTED
IS GABRIEL A WONDERFUL STUDENT
IN LAB CREATED THIS APP TO GO ON
TO THERE AND TRACK DEMETHYLATION
AND RNA SEQUENCING DATA SEEK
CRETETIVE FACTORS AND GENETICS
AND OTHER THINGS. THAT IS THE
APPLICATION.
SO, LET'S SEE WHAT THIS LOOKS
LIKE AND HOW TO MANIPULATE
MITOCHONDRIA AND BASIC DESIGN TO
COLLECT UP TO 42 TIME POINTS AND
EVERY REGULAR INTERVALS
COLLECTING INFORMATION ABOUT
WHAT CELLS LOOK LIKE AND HOW BIG
THEY ARE AND HOW MANY THERE ARE
AND YOU CAN COLLECT CELLULAR
ENERGETICS AND METABOLIC RATE
AND ENERGY CONSUMPTION PROXY
GLYCOLYSIS COLLECTING DNA AND
TELOMERE LENGTH AND
MITOCHONDRIAL DELETIONS AND
GENOME STABILITY COLLECTING TO
DO RNA SEQUENCING AND MEDIA
COLLECTING FOR PROXY TO BLOOD
LOOKING AT SECRETIVE FACTORS AND
CELL DNA FOR EXAMPLE DOING IN
THREE HEALTHY DONORS AND THREE
PATIENT DERIVED FIBRO BLASTS
WITH KNOWN MITOCONDREEAL TOOE
FEKTS THAT IS WAY TO HAVE
MITOCHONDRIA AND ORTHOGONAL
METHOD WE HAVE THIS FOR ENERGY
TRANSFORMATION WITHOUT KILLING
CELLS AND ASKING WHAT
CONVERGENCE IS AND CONVERGING
FINDINGS BETWEEN GENETIC AND
FARM COLONL CAL MODEL THAT MIGHT
HAVE OWN DRAWBACK AND WHAT WAS
ASTONISHING DOING THIS GENETIC
AND FARM COLONL CAL MODEL
MITOCHONDRIA CELLS ARE NOT HAPPY
SLOWING DOWN DIVISION
CONSIDERABLY AND MOVING SLOWLY
AND MEASURING ENERGETICS AND
THIS IS COMBINED AMOUNT OF
ENERGY THAT CELLS ARE CONSUMING
EVERY HOUR AND DAY TO STAY ALIVE
AND SEE IN THREE DONORS WITH
THIS ONE THIS IS GENETIC
MITOCONDREEAL PERTUBATION AND
DOUBLING ENERGY INCREASE ENERGY
CONSUMED PER TIME AND UNIT PER
CELL VOLUME AND THIS IS FARM
COLONL CAL MODEL AND COSTS CELLS
TWICE AS MUCH ENERGY TO STAY
ALIVE AND CELLS WITH HEALTHY
MITOCHONDRIA AND LOOKING BACK AT
THIS PROXIMITY AND MITOCHONDRIA
PERTURBED MITOCHONDRIA CHANGING
CELL RATE AS WHICH THEY ARE
DIVIDING AND CAN ASK WHAT IS
HAPPENING THERE THIS WAS
PUBLISHED RECENTLY AND SUMMARY
WHAT WE FOUND ON TOP HERE IS
CONTRASTING CELLS WITH HEALTHY
MITOCON DREE AYOU ON LEFT AND --
ON RIGHT AND FIND CELLS SLOW
DOWN DIVISION RATE AND HAVE
MITOCONDREEAL DNA AND PROTEINS
RELEASING DNA INTO THE MEDIA AND
THEY ILLUSTRATE HYPERSECRETARY
PHENOTYPE RECAPITULATING WHAT WE
SEE IN HUMAN AGING AND PLASMA
PRO TEUMS ASSOCIATED WITH
INTEGRATED STRESS RESPONSE
ACTIVATION WITH GENE EXPRESSION
AND INCREASE IN AMOUNT OF
TRANSCRIPTION AND TRANSLATION
ACTIVITY AND CELLS DOING MORE
UPREGULATING PATHWAYS AND CELL
SIGNALING AS WAY TO COMPENSATE
OR TRY TO COOPERATE IN WAY THAT
ORGANS AND CELLS IN HUMAN BODY
DO AND ATTRIBUTE PATHWAYS FOR
DEVELOPMENT AND DIFFERENTIATION
AND ALL THESE ARE ENERGY
EXPENSIVE AND WE SEE AT
ENERGETIC LEVEL THERE IS
HYPERMETABOLIC SIGNATURE
ASSOCIATED WITH TELOMERE
SHORTENING AND END OF
CHROMOSOMES AND IF YOU PERTURB
MITOCHONDRIA CELLS LOSE MORE
TELOMERES FOR EACH CELL DIVISION
AND UNCOUPLING OF THEM AND IN
CONTEXT OF MITOCHONDRIAL
PERTUBATION AND WHAT SETS PACE
OF AGING PERTURBING MITOCHONDRIA
ACCELERATE BIOMARKERS OF
ACCELERATED AGING AND TWO
BEAUTIFUL PAPERS COMING OUT IN
NATURE AND SCIENCE IN LAST FEW
MONTHS AND THEY CONVERGE ON THE
SAME FINDING WHERE MITOCHONDRIA
AND ACTIVITY OF ENL ERNL JI
TRANSFORMATION AND ELECTRON
TRANSPORT CHAIN ETC REGULATES
CHEMICALS AND REGULATES RATE OF
PROTEIN SYNTHESIS AND BY
MANIPULATING MITOCHONDRIA SHOW
REGULATION OF TIME PERCEPTION AT
CELLULAR LEVEL AND RATE OF
CELLULAR ENERGETICS AND I WILL
SUMMARIZE IT IN THIS WAY AND
THINKING ABOUT ENERGY FLOW.
IT CREATES ENTROPY AND MORE THAT
THERE IS FASTER THINGS DECAY AND
THERE IS FINITE LIFESPAN AND
MOST EPHEMERAL THINGS IN WORLD
RELATE TO FIRE COMBUSTION AND
FLAME LAST AS I SECOND AND IS
GONE AND THINGS WHERE ENERGY
FLOWS SLOWLY AND 1,000 YEAR OLD
LIVING TREE AND THEN THERE IS
LIVING CREATURES THAT LIE
IN-BETWEEN TWO EXTREMES AND
WONDERFUL ORGANISMS ENERGY FLOWS
AT REGULATED AND CONTROLLED PACE
UNLIKE A FLAME AND FLOW MORE
ENERGY THAN A ROCK OR TREE AND
HYPERMETABOLISM IS A NOTION THAT
RATE OF ENERGY EXPENDITURE CAN
ACTUALLY SPEED UP AND ARE
PREDICTIONS THAT COULD BE MADE
AROUND THIS AND WE HAVE TESTED
SOME OF THAT AND I WON'T TALK
ABOUT IT TODAY. WE CAN
ACCELERATE RATE OF ENERGY FLOW
AND RATE OF ENERGY FLOW AND
REGULATE PACE OF AGING AT
CELLULAR LEVEL AND A FEW WORDS
ABOUT MITOCHONDRIA AND HOW WE
SHOULD THINK ABOUT IT TALKING
ABOUT BIOMARKERS AND USE THAT
IMAGE TO ILLUSTRATE WHAT WE HAVE
DONE WITH AGING AND
MITOCHONDRIAL BIOLOGY AND BLIND
MEN AND SCIENTISTS THAT ARE
LOOKING AT AN OBJECT AND ARE
MAKING VALID OBSERVATIONS ABOUT
PARTS OF THE WHOLE THAT ARE
BLINDED AND CAN'T SEE THE HOLE.
MEASURING DIFFERENT PIECES
MAKING VALID OBSERVATIONS
DRAWING SPECIFIC CONCLUSIONS AND
MISSING THE WHOLE POINT AND WHAT
WE HAVE DONE WITH MITOCHONDRIAL
BIOLOGY AND POWERHOUSE MAKING
ATP THAT IS 1957 FROM AN ARTICLE
IN AMERICAN SCIENTISTS AND IF
YOU LOOK AT MITOCHONDRIA FROM
DIFFERENT ANGLES CONCLUSIONS
THEY DO THIS KILL CELL AND
TRIGGER DIFFERENTIATION AND
REGULATE EPIGENOME AND
PERSPECTIVE WE HAVE TO ADOPT AND
PIECE COMING OUT TOMORROW WE ARE
VERY EXCITED ABOUT LAYING OUT
IDEA MITOCHONDRIA COMPLEX AND
DYNAMIC AND MODEL THAT IS
EMERGING IS ONE THAT INVOLVES
MITOCHONDRIAL SIGNAL
TRANSDUCTION AND DO MORE THAN
TRANSFORMING ENERGY AND
COMMUNICATE INFORMATION AND
RECEIVE INFORMATION AND
TRANSFORM INFORMATION PROOND AND
PRODUCE -- THESE ARE THINGS
ALONG WHEEL I WON'T GO INTO THAT
MITOCHONDRIA ARE SENSITIVE TO
RECEPTORS ON SURFACE AND
TRANSPORTER AS LOUING TO SEND
FACTORS AND PRODUCE AS SIGNALS
AND EXAMPLE MITOCHONDRIA ARE
SOURCE OF STEROID HORMONES THAT
ALLOW NEW LIFE AND THESE ARE
MADE INSIDE OF THE MITOCHONDRIA
FOR EVOLUTIONARY REASONS THAT
ARE QUITE INTERESTING AND I WILL
FINISH WITH THIS MITOCHONDRIA
PRODUCE SIGNALS AND INFORMATION
PROCESSING SYSTEM PROVIDING
STRUCKTIVE INFORMATION FOR
NUMBER OF SYSTEMS RELEVANT TO
AGING AND WE NEED TO BRING MIND
INTO THE PICTURE. ALL OF THE
ASPECTS OF METABOLISM AND ENERGY
METABOLISM MITOCHONDRIA FOR
DESCENDING INPUTS REGULATING
METABOLISM IN MITOCHONDRIA THAT
REGULATES PROCESSES IN THE BRAIN
AND IN SUMMARY I TOLD YOU WHERE
ENERGY COMES FROM AND WHY IT IS
CRITICAL SUGGESTING THAT
MITOCHONDRIA MIGHT BE DYNAMIC
ENERGETIC INTERFACE BETWEEN
OUTSIDE AND INSIDE WORLD AND
STUDYING THINGS IN VITRO
STUDYING RATE OF AGING AND
THINKING OF MITOCHONDRIA AGING
BIOLOGY IN INTEGRATED WAY AND
MITOCHONDRIAL SIGNAL TRANSLATION
AND THIS WORK AND IN TOP RIGHT
AND DOING CELLULAR LIFESPAN WORK
IN COLLABORATION WITH MANY
OTHERS AND [INDISCERNIBLE] DID
WORK ON HAIR I MENTIONED IN
BEGINNING AND POST DOCS IN
LABORATORY DEVELOPING THIS AND
AMAZING COLLABORATE YRS AND
FUNDING WORK THAT MADE THIS
POSSIBLE. THANK YOU.
>>[APPLAUSE].
>>>>WE ARE HERE FOR THE LAST
TALK OF THE DAY. THIS IS ALICE
KANE STARTED AT INSTITUTE FOR
SYSTEMS BIOLOGY AND ASSISTANT
PROFESSOR IN THE FALL OF LAST
YEAR 2022 AND -- IN BOTH SEXES
USING INTEGRATIVE APPROACH. SHE
IS FOCUSED ON ASSOCIATION
BETWEEN FRAILTY AND EPIGENETIC
USES OF AGE AND BIOMARKERS OF
FRAILTY. ALICE.
>>THANK YOU TO ORGANIZERS FOR
OPPORTUNITY TO TELL YOU A LITTLE
BIT ABOUT SOME WORK TODAY AND
TALKING ABOUT BIOMARKERS FOR
SCIENCE AND COMING BACK TO MOUSE
PERSPECTIVE NOW AND LITTLE BIT
OF AN OVERVIEW I WILL TALK A
LITTLE ABOUT FIRST GENERATION
VERSUS SECOND GENERATION
EPIGENETIC [INDISCERNIBLE] THAT
WAS INTRODUCED NICELY IN THE
BEGINNING AND VANLS OF STUDYING
BIOMARKERS AND [INDISCERNIBLE]
IN MICE AND DEVELOPMENT OF
SECOND GENERATION CLOGS IN MICE
THAT WE CURRENTLY DON'T HAVE AND
A FEW OPEN QUESTIONS AND DAN
ALREADY COUGHED THIS NICELY.
THIS IS A EXAMPLE OF EPIGENETIC
CLOCK THAT I DID DEVELOPED WITH
A GRADUATE STUDENT IN DAVID
SINCLAIR'S LAB AND NEW TECHNIQUE
THAT IS SLIGHTLY DECREASING COST
OF GETTING THESE EPI GENETIC
CLOCKS AND EXAMPLE FROM MOUSE
CLOCK FROM BLOOD PREDICTIVE AGE
OF DEMETHYLATION ON X AXIS AND
AGE ON Y AXIS AND SEEN MANY
TIMES TODAY LOOKING AT
METHYLATION OF SPECIFIC CPGS
MODELING AGAINST AGE WE CAN
ACCURATELY PREDICT HOW OLD A
MOUSE OR HUMAN IS AND GET A NICE
CURVE AND ASSUMPTION DAN ELUDED
TO IS DIFFERENCE FROM ACTUAL
PREDICTED AGE TELLS SOMETHING
INTERESTING ABOUT YOUR BIOLOGY
OR YOUR HEALTH AND MOUSE HERE
THAT IS 25 MONTHS OF AGE IS
PREDICT TODAY BE 20 MONTHS OF
AGE AND POTENTIAL BIOLOGICAL AGE
THAT IS FIVE MONTHS YOUNGER THAN
ACTUAL AGE AND WOULD BE PRESUMED
TO BE HEALTHIER AND OPPOSITE OF
MICE ON OTHER SIDE OF THE CURVE
WE ASSUME TO BE BIOLOGICALLY
OLDER THAT IS ASSUMPTION THOUGH
AND NOT ALWAYS THE CASE AS THAT
WE HAVE HEARD. THERE IS
ASSOCIATION BETWEEN RESIDUALS
AND NUMBER OF HEALTH OUTCOMES IN
SPECIFIC DISEASES IN HUMANS AND
IN MICE WE NEVER LOOKED AT
WHETHER RESIDUALS AND
DIFFERENCES ARE CORRELATED ARE
HEALTH OUTCOMES AND THIS IS A
FIGURE FROM THE SAME PAPER I WAS
DISCUSSING WHERE WE HAVE A
DIFFERENCE OF PREDICTED VERSUS
ACTUAL AGE BASE ON EPIGENOME ON
Y AXIS AND LOOKING AT DIFFERENCE
FROM NORMALIZED FRAILTY ON X
AXIS AND EXPECTED MICE THAT ARE
MORE FRAIL TO HAVE HIGHER
BIOLOGICAL AGE AND VICE VERSA
AND WE SAW ABSOLUTELY NO
RELATIONSHIPS AND THESE ARE TWO
CLOCKS TELLING US DIFFERENT
THINGS PERHAPS GETTING AT
DIFFERENT MECHANISMS AND WE ARE
NOT SEEING SAME ASSOCIATION WE
MIGHT HAVE EXPECTED HERE.
SO, ALL THIS COMES TO SECOND
GENERATION CLOCKS AND FIRST
CLOCKS THAT ARE MODELED TO
PREDICT CHRONOLOGICAL AGE AND
ARE DEVELOPED ENTIRE WILL I TO
TELL US HOW OLD A SAMPLE IS.
SECOND GENERATION CLOCKS PREDICT
NOT CHRONOLOGICAL AGE BUT
SOMETHING USEFUL HEALTH OR
MORTALITY AND TRUE MEASURE OF
BIOLOGICAL AGE THAT INCLUDE GRIM
AGE AND PHENOAGE THAT WE HEARD
ABOUT THAT BASICALLY PREDICT AGE
FROM MORTALITY RISKS AND OTHER
CLINICALLY RELEVANT OUTCOMES
THAT WE HAERRED ABOUT AGING
CLOCK THAT LOOKS AT CHANGE RS IN
CLINICAL OUTCOMES AND THERE IS A
RECENT CLOCK DEVELOPED TO
SPECIFICALLY PREDICT FRAILTY
FROM EPIGENETIC MEASURES THAT
ARE ALL HUMAN CLOCKS PROVIDING
CLINICALLY RELEVANT OUTCOMES WE
ARE MORE INTERESTED IN AND
MODELING SPECIFIC DNA
METHYLATION TO PREDICT CLINICAL
OUTCOMES RATHER THAN ASSUMING
THAT FROM PREDICTION OF AGE AND
WE DON'T HAVE YET ANY SECOND
GENERATION CLOCKS OR CLOCKS TO
PREDICT COMPOSITION MEASURES IN
MICE STUDIES AND WANT TO TELL
YOU A LITTLE WHY I THINK GREAT
MODELS TO STUDY BIOMARKERS FOR
GEROSCIENCE AND HEARD ABOUT
LIMITATIONS OF HUMAN STUDIES OF
ACR AND -- FOLLOWED FOR ENTIRE
LIFESPAN LONGITUDINALLY AND
DEEPLY PHENOTYPED AND THERE IS A
LOT OF DISCUSSION OVER LAST FEW
DAYS ABOUT WHETHER WE WANT TO
MEASURE LIFESPAN AND HEALTH SPAN
AND HOW THEY ARE DIFFERENT AND
MICE PROVIDED OPPORTUNITY TO
MESH YOUR BOTH AND WE CAN DO
LIVE SCALE LIFESPAN STUDIES
HISTORICAL FOCUS OF RESEARCH AND
RANGE OF HEALTH SPAN WE CAN DO
IN THESE MICE AND PARTICULARLY
FRAILTY INDEX THAT SUSAN
BEAUTIFULLY INTRODUCED THIS
MORNING AND WE CAN QUICKLY AND I
PUT IN QUOTATIONS BECAUSE MOUSE
STUDIES TAKE SEVERAL YEARS AND
IF YOU HAVE DONE AGING STUDIES
AS POST DOC YOU KNOW THIS.
COMPARED TO HUMAN INTERVENTION
STUDIES WE CAN FAIRLY QUICKLY
ASSESS EFFECT OF INTERVENTIONS
ON AGING HOWEVER WE CHOOSE TO
DEFINE THAT.
AND THIS THEN PROVIDES
PRECLINICAL EVIDENCE IN WELL
CONTROLLED POPULATION TO DECIDE
WHAT TO TRANSLATE TO CLINICAL
POPULATIONS.
WHAT I AM PERHAPS MOST
INTERESTED IN AND WHY I THINK
THESE MOST INTERESTING MODELS TO
USE INVESTIGATE BIOMARKERS IN
MOST INVASIVE WAY WE CAN IN
CLINICAL STUDIES AND I USED SOME
STUDIES THAT ARE MICE AND
LONGITUDINAL ASSESSMENTS IN MICE
TO DEVELOP THESE IN STUDIES
DOING THIS HAVING MALE AND
FEMALE MICE AND STARTED WITH
LIFESPAN 13 MONTHS OF AGE ABOUT
MIDDLE AGE FOR HUMAN AND EVERY
COUPLE MONTHS WE DID FRAILTY
ASSESSMENT AND WE TOOK A BLOOD
SAMPLE FOLLOWING MICE THROUGH
LIFESPAN THROUGH NATURAL
MORTALITY BLOOD SAMPLES
COLLECTED THESE AND ISOLATED DNA
WE DID DNA METHYLATION TIPS ON
WITH BRIAN AT FOXO WHO WE HEARD
FROM EARLIER AND LOOK AD THE
WIGGLE METABOLOMICS IN PLASMA
WITH METABOLOME AND DID BLOOD
COUNTS USING DATA AND NUMBER OF
THINGS TO DO WITH THIS
LONGITUDINAL DATA SET AND WHAT
PARTICULARLY INTERESTED IN IS
USING DATA TO MAKE CLOCKS FOR
MICE PREDICTING NOT
CHRONOLOGICAL AGE BUT FRAILTY
INDEX AND -- MEASURE CLINICAL
MEASURE FROM MORGAN LEVINE AND
MADE CLOCKS TO PREDICT THAT AS
WELL AND QUICKLY I WILL
HIGHLIGHT MOUSE CLINICAL FRAILTY
INDEX MAIN OUTCOME PREDICTING
SUSAN TALKED ABOUT BRIEFLY
REVERSE FROM DEFICIT APPROACHING
HUMANS 31 HEALTH DEFICITS FAST
NOT INVASIVE TO MEASURE AND HAVE
A VIDEO THAT IS ALWAYS RISKY AND
ITEM TAIL STIFFENING AND MICE
THERE AND BEAUTIFUL CURVATURE
AROUND TAIL AND THIS MOUSE GETS
LOW SCORE AND OLD MOUSE NO
RESPONSE TO [INDISCERNIBLE] AND
MOUSE WOULD RECEIVE A HIGH SCORE
THIS IS A EXAMPLE OF ITEMS WE
ASSESS AND WE HAVE FRAILTY INDEX
DATA AND DNA METHYLATION DATA
USING ELASTIC APPROACH TO
DEVELOP A CLOCK TO PREDICT
FRAILTY AND YOU SEE HERE
PREDICTIVE FRAILTY INDEX ON Y
AND -- WE SEE A NICE CORRELATION
HERE THAT WE ARE PRETTY HAPPY
WITH TO PRETTY ACCURATELY
PREDICT THIS FROM MARKERS AND
METABOLOMICS DATA AND
INCORPORATING EPIGENETIC AND
METABOLOMICS DATA TO ACCURATELY
PREDICT FRAILTY INDEX AND
INPROVED IT SPLIETH WILL YOU BUT
NOT ENOUGH TO JUSTIFY COSTS OF
EXPENSIVE EXPERIMENTS AND
METABOLOMICS CLOCK ALONE WAS AS
PREDICTIVE AS EPIGENERAL EMIC
ALONE AND TO BE GAINED FROM
EVALUATION OF DATA SETS, YEAH.
WE THEN DEVELOPED PHENOAGE
CLOCKS THAT IS PREDICTING
FRAILTY INDEX AND WONDER WHETHER
A MORE COMPOSITE MEASURE OF
BIOLOGICAL AGE AND HOWEVER WE
WANT TO TERM THIS AGING PROCESS
MAY ENABLE US TO PREDICT BETTER
AND DEVELOPED MOUSE PHENOAGE
MODEL BASEDONTIRELY ON APPROACH
OF LIVING AND CLINICAL GROUP OF
PHENOAGE AND MEASURES IN
CLINICAL MARKERS NO THE IN MICE
AND WE HAD 31 FRAILTY MEASURES
AND WHOLE BLOOD COUNTS AND
INCORPORATED THEM INTO
REGRESSION TO BASICALLY MAKE A
MODEL OF MORTALITY RISK WITHIN
NEXT FOUR MONTHS AND SOLVED THIS
FOR A SIMILAR REGRESSION FOR AGE
THAT GIVES PHENOAGE MEASURE FOR
A MOUSE THAT IS BASICALLY A
CHRONOLOGICAL AGE AND ADJUSTED
FOR BOTH FRAILTY AND MORTALITY
AND BLOOD COUNTS THAT YOU CAN
SEE PHENO-ATR ON Y AXIS AND
ACTUAL AGE ON X AXIS AND NICE
CORRELATION THAT WE WOULD EX
EXPECT.
WE APPLIED SAME MODELING TO SEE
IF WE COULD PREDICT MODEL
PERHAPS BEST MEASURE OF
BIOLOGICAL AGING IN MOUSE MODELS
AND DID THE SAME PROCESS AND
ELASTIC APPROACH PREDICTIVE
PHENOAGE AXIS AND WE SEE A NICE
CORRELATION HERE AND
PREDICTABILITY OF EPIGENETIC
DATA TO PREDICT PHENOAGE
INCORPORATING MULTI OMIC DATA
AND NOT HUGE IMPROVEMENT WITH
COMBINED DATA SETS AND
METABOLOMICS WAS AS GOOD AS DNA
METHYLATION DATA BY ITSELF AND
PROVIDES TOOLS FOR ONGOING MOUSE
STUDIES TO MEASURE AND PREDICT
BIOLOGICAL AGE THAT IS A LOADED
TERM THAT I ASSUME IN THE PANEL
AFTER THIS WILL BE DISCUSS ABOUT
WHAT THAT MEANS AND PROVIDES
SOME COMPOSITE MEASURES THAT WE
CAN USE IN MOUSE STUDIES THAT WE
CAN PREDICT WITH OUR MULTI OMIC
DATA YOU THAT IS OFTEN COLLECTED
IN STUDIES AS WELL.
WHAT I'M INTERESTED IN AS I SAID
IS USING MODEL AND MEASURESES TO
UNDERSTAND MECHANISMS UNDERLYING
FRAILTY AND HETEROGENEITY IN
AGING LOOKING AT BASIC INITIAL
PRELIMINARY ANALYSIS CORRELATION
OF METHYLATION OF EACH OF THE
CPGS WITH FRAILTY INDEX AND HUGE
AMOUNT OF CPGS IT CORRELATED
WITH FRAILTY AND COUPLING THESE
WHICH WE KNOW IS A PROET TERROID
MOUSE MODEL AND [INDISCERNIBLE]
THAT WE HEARD ABOUT EARLIER
COMMONLY ASSOCIATED CPGS WITH
COMING UP WITH AGING IN HUMAN
STUDIES AND THERE IS
CROSS-CORRELATION HERE LOOKING
AT FRAILTY AND BREAKING DOWN
NUMBER OF CPGS OF VARIOUS
PHENOTYPES INTERESTED IN NUMBER
OF CPGS CORRELATED ACROSS FOUR
PHENOTYPES AND CPGS CORRELATING
WITH FRAILTY AND LONGEVITY AND
COMBINATION OF THESE AND
INTERESTING TO LOOK INTO SUBSETS
OF CPGS ASSOCIATED GENES
ASSOCIATED WITH FRAILTY AND
INDEPENDENT AGE AND THAT WORK IS
ONGOING AND ANALYSIS FOR
METABOLITES AND METABOLOMICS
DATA AND WE CAN MEASURE AND SEE
NUMBER OF SIGNIFICANT
CORRELATIONS HERE AND WHAT WE
ARE INVESTIGATING FURTHER AND
TAKEAWAYS USING -- TO PREDICT
COMPOSITE HEALTH OUTCOMES
CALLING PERHAPS BIOLOGIC AGES IN
HUMANS THAT WE HEARD A LOT ABOUT
AND NOW IN MOUSE MODELS AVEND
PROVIDE POTENTIAL BIOMARKERS FOR
PRECLINICAL INTERVENTION STUDIES
AND ANOTHER PLUG FOR MICE THERE
ARE VALUABLE MODELS TO STUDY
BIOMARKERS AND OPPORTUNITY TO
GIVE CLUES ABOUT MECHANISMS
UNDERLYING AGING AND HETDERRO
JENAETY AND CONSIDERATIONS THAT
I THINK THAT WE CAN DISCUSS MORE
IN THE PANEL OR MORE IDEAS OF
OTHER THINGS TO CONSIDER WE
HAVEN'T HEARD ALL THAT MUCH
ABOUT SEX DIFFERENCES TODAY THAT
IS REALLY IMPORTANT AND WE
GROUPED MALE AND MICE FULLY
ANALYSIS DIDN'T SEPARATE OUT AND
QUICK MAP THIS IS DNA
METHYLATION DATA AND DATA
ENTIRELY ALMOST SPLITS AND MALE
AND FEMALE CALLING IT
DIFFERENTLY HERE AND IS SEX
SPECIFIC CHANGES HAPPENING HERE
REQUIRING LOTS MORE
INVESTIGATION AND THERE IS ALSO
OTHER DATA THAT COULD BE
INCORPORATED IN MOUSE STUDIES
ESPECIALLY LOOKING AT MICROBIOME
AND PROTEOMICS AND LOTS IS
ONGOING AND IN THE SLAM STUDY
THAT RAFA IS UNDERTAKING AND
FINALLY I THINK AS I SAID MICE
PROVIDE EXCITING OPPORTUNITY TO
DELVE INTO MECHANISMS AND
DETERMINANTS OF FRAILTY AND
AVAILABILITY OF BIOLOGICAL AGE
AND FIGURING OUT STILL HOW BEST
TO DO THIS AND COMING BACK TO
CIRCULAR ARGUMENTS WHAT MEASURES
OF AGE ARE THAT WE ARE TRYING TO
UNDERSTAND.
WOULD LIKE TO THANK EVERYONE
INVOLVED IN THIS WORK AND DATA
COLLECTED IN DAVID SINCLAIR LAB
AND GRADUATE STUDENT PATRICK
GRIFFIN WAS A HUGE PART OF THIS
AND MY COLLABORATORS AND MY
FUNDING. THANK YOU.
>>[APPLAUSE].
>>INTRODUCING DISCUSSANTS
BEFORE CALLING PANEL BACK UP.
FIRST IS NATE TENURE TRACK
INVESTIGATOR AT NIH AND HEAD OF
TRANSLATIONAL GEROPROTEOMICS
UNIT AT NIAAA. THINK I GOT THAT
RECEIVED PHD AT UNIVERSITY OF
WASHINGTON -- AND JUDY
[INDISCERNIBLE].
>>THANK YOU, JAMIE. SO, YES.
I WOULD LIKE TO SPEND A SLIDE
REFLECTING ON THINGS WE HEARD IN
TALKS TODAY AND WOULD LIKE TO
GIVE PERSPECTIVE AS SOMEBODY
COMING IN AS A MORE BASIC
BIOLOGIST AND PROTEOMICS PERSON.
SO, YOU KNOW, I THINK THAT
TAKING A STEP BACK THINKING WHAT
WE WANT FROM A BIOMARKER THERE
IS A FEW YOU KNOW I THINK IT
BOILS DOWN ESSENTIALLY TO MAINLY
WE WANT TO MEASURE A CHANGE IN
RATE OF BIOLOGICAL AGING OR
AGING PHENOTYPE WITHIN A SHORT
PERIOD OF TIME AND TO MEASURE
SPAN WITHIN A CLINICAL TRIAL TO
TRANSLATE INTERVENTIONS INTO
PEOPLE; RIGHT?
SECONDLY AND PREFERABLY WE WOULD
LIKE TO MEASURE AGING CHANGES
AND AGING PHENOTYPES BEFORE
CLINICAL ONSET. WE WANT TO
MINIMIZE AMOUNT OF TIME THAT WE
SPENT WITH THAT AGING PHENOTYPE.
SO, AS WE HEARD FROM SPEAKERS
TODAY THERE IS A NUMBER OF WAYS
TO APPROACH THIS PROBLEM AND
THAT WE CAN BEGIN TO MEASURE
BIOLOGICAL AGING TO LOOK AT
CURRENT BIOLOGICAL AGE AND PAST
EXPOSURES LOOKING AT FUTURE
HEALTH AND MORTALITY AND LOOK AT
PACE OF AGING AND TRAJECTORIES
OF AGING AND VALUE ORGANIZING
THEM AT OR BEGANIS MAL LEVEL AND
OR BEGAN SPECIFIC LEVEL THINKING
OF TAILORING INTERVENTIONS TO
SPECIFIC DISEASES AND MYRIAD OF
HALLMARK APPROACH AND TWO TYPES
OF BIOMARKERS THAT WERE
DISCUSSED AND INTRODUCED NICELY
BY STEVE. FIRST IS
STRATIFICATION BIOMARKERS AND
THINK THEY WILL BE EXTREMELY
IMPORTANT IF WE WILL CARRY OUT A
SUCCESSFUL CLINICAL TRIAL AND
WANT TO IDENTIFY POPULATION OF
PEOPLE THAT GET MOST BENEFIT
FROM A POTENTIAL AGING
INTERVENTION AND FOR EXAMPLE IF
I WANT TO DO A SEINO WILLITYIC
TRIAL SENESCENCE BURDEN; RIGHT?
IDENTIFYING POPULATION WITH HIGH
SENESCENCE BURDEN TREATING WITH
SENOLYTIC REMOVAL TO MAXIMIZE
CHANCES OF HAVING A POSITIVE
RESULT IN THE CLINICAL TRIAL AND
NOT ONLY THAT BIOMARKER COULD BE
A BIOMARKER INDICATING THAT
INTERVENTION WHERE TRYING WAS
EFFECTIVE AND WAY THAT WE WERE
HOPING FOR THAT COULD INDICATE
THAT WE SUCCESSFULLY REMOVED
SENESCENCE CELLS.
MIGHT NOT NECESSARILY TELL US
THAT WE SUCCESSFULLY SLOWED
AGING THAT IS NEXT TYPE OF
BIOMARKER TO HIGHLIGHT AND IS AN
IMPORTANT ONE THAT WILL PROBABLY
BE TRICKIEST ONE FOR US TO
IMPLEMENT AND STEVE DID A GOOD
JOB INTRODUCING US LEAVING
QUESTION OPEN IN LAST SLIDE AND
WE NEED TO THINK REALLY CAREFUL
AND MAYBE DISCUSS WHAT WE EXPECT
AND IN AN INTERVENTION
RESPONSIVE BIOMARKER TO LOOK
LIKE AND MIGHT BE MORE STRAIGHT
FORWARD WITH CLINICAL AND
FUNCTIONAL MEASUREMENTS AND WHEN
TALKING ABOUT OTHER MOLECULAR
MEASUREMENTS WE NEED TO ASK WHAT
EXACTLY DO WE EXPECT IT OWE TO
LOOK LIKE CONSIDERING DIFFERENT
SCENARIOS AND PAST SESSION WE
SAW SOMETHING TALKING ABOUT
NONAGING SPECIFIC INTERVENTIONS
THAT HAVE NONAGING SPECIFIC
EFFECTS THAT MIGHT ACTUALLY
EXTEND LIFESPAN AND WOULD
INTERVENTION LIKE THAT, THAT WE
ARE STILL INTERESTED IN WOULD
THAT NECESSARILY REVERSE AN
AGING BIOLOGICAL AGING CLOCK WAY
WE EXPECT IT TO OR HAVE AGING
INDEPENDENT MECHANISM AND WITH
INTERVENTION RESPONSIVE
BIOMARKERS PARTICULARLY WITH
MOLECULAR ONES WE NEED TO
DISCUSS WHAT DATA WE NEED TO SEE
TO CONVINCE OURSELVES THAT THIS
IS A RELIABLE SURROGATE FOR
SOMETHING COMPLEX AS BIOLOGICAL
AGING AND CAN WE GET TO THAT
POINT?
SECONDLY, I WANT TO REITERATE
WHAT ALICE PRESENTED THAT IS
IMPORTANCE OF MODEL ORGANISMS
AND MICE WILL BE EXTREMELY
IMPORTANT FOR DEVELOPING AGING
BIOMARKERS AND FOR ALL REASONS
THAT ALICE SAID, WE CAN DEVELOP
PRECLINICAL BIOMARKER CANDIDATES
IN MICE AND GO INTO HUMANS TO
TEST WHETHER THEY ARE
TRANSLATABLE.
AND IT WILL BE REALLY IMPORTANT
TO DETERMINE WHICH ARE AND
ONGOING EFFORTS TO DO THIS AND
FOR EXAMPLE HEARING ABOUT BLSA
AND SLAM STUDIESALITY NIAAA THAT
ARE COLLECTING SIMILAR PHENOTYPE
DATA FROM BOTH MODELS GETTING AT
QUESTIONS WHAT ARE TRANSLATABLE
BETWEEN MICE AND HUMANS AND I
THINK THAT ANOTHER GREAT
OPPORTUNITY IS [INDISCERNIBLE]
AND CONSORTIUM OF RESEARCHERS
MAPPING SENESCENCE CELLS IN
TISSUES IN MICE AND HUMANS AND
GREAT OPPORTUNITY TO TELL US
WHAT SENESCENCE SPECIFIC MARKERS
THAT ARE TRANSLATABLE BETWEEN
INTERVENTIONS THAT I'M NOT EVEN
-- I DON'T NECESSARILY KNOW HOW
MANY SPECIFIC BIOMARKERS WILL
TRANSLATE BETWEEN MICE AND
HUMANS AND IF THERE ARE NO
BIOMARKERS TRANSLATING, I THINK
THAT, YOU KNOW, MICE ARE
INCREDIBLY USEFUL TOOLS FOR US
TO TEST BIOMARKER THEORY; RIGHT?
IN MICE AS ALICE POINTED OUT WE
CAN FOLLOW THEM INDIVIDUALLY AND
LONGITUDINALLY UNTIL END OF
LIFESPAN TESTING INTERVENTIONS
LOOKING AT INTERVENTIONS AND
RESPONSES AND SHOWING WE CAN
BUILD SAME CLOCKS WE DID FOR
HUMANS AND WITH MICE WE ASK
QUESTIONS WHICH CLOCKS HAVE MOST
UTILITY FOR PREDICTING OUTCOMES
THAT WE ARE INTERESTED IN AND
VERY LEAST MICE CAN GIVE US AND
LET US OR HELP US TO STRATEGIZE
HOW TO APPROACH BIO-MMARKERS -
BIOMARKERS. AND TECHNOLOGICALLY
THERE IS ROOM FOR DEVELOPMENT OF
SENSITIVE AND SPECIFIC
BIO-MACERS AND LEAVING THIS
EXAMPLE HERE THAT IS A PROTEOMIC
EXAMPLE AND APPLIES TO
TRANSCRIPTOMICS THAT IS MOST
LARGE SCALE DISCOVERY PROTEOMIC
PLATFORMS IS AGNOSTIC TO PROTEIN
VARIANCE OR PROET TEE OE FORMS
AND THINKING FOR APTO MER OR
ANTIBODY BINDING SPECIFIC REGION
OF PROTEIN THAT WILL HAVE PROET
TEE OE FORMS AND ASSAY IS DOG
AND AGGREGATING DIFFERENT FORMS
OF PROTEIN THAT IS INTO A SINGLE
READ OUT; RIGHT?
IF YOU -- SAY GLYCOSCILLATED
FORM OF PROTEIN IS BIOMARKER OF
AGING YOU ARE LOOKING FOR
AGGREGATING DATA INTO A SINGLE
MEASUREMENT YOU ARE DILUTING OUT
SENSITIVITY OF BIOMARKER THAT
INTERVENTIONS ARE GOING AND
TECHNOLOGIES ARE GOING FORWARD
THAT CAN PAY MORE ATTENTION TO
PROET TEE OE FORM AND GENE
VARIANCE WHEN WE MAKE
MEASUREMENTS.
THAT IS ALL FOR ME. I THINK
THAT I WOULD LIKE TO PASS IT ON
TO LAURA.
>>AS LAUREN IS COMING UP SHE IS
AN ASSISTANT PROFESSOR OF --
POPULATION RESEARCH CENTER AND
FACULTY AFFILIATE IN CORRECTOR
OF AGING AND POPULATION SCIENCES
AT UNIVERSITY OF TEXAS AUSTIN.
>>THANK YOU. THANK YOU TO THE
ORGANIZERS FOR REALLY EXCITING
SESSION AND FOR INVITING ME TO
COMMENT.
I WAS ASKED TO PROVIDE
REFLECTIONS IN FIVE MINUTES
ENCOURAGE TODAY BE BOLD AND
CONTROVERSIAL MAKING PREDICTIONS
FOR THE FUTURE AND TALL ORDER I
CAN'T PROMISE FOR FIRST TWO. I
WILL STICK TO FIVE MINUTES AND
CONCENTRATING COMMENTS ON
RELEELATED POINTS REGARDING
DEVELOPMENT AND USE OF
BIOMARKERS FORMED BY MY POSITION
AS A DEMOGRAPHER AND DRAWN TO
POPULATION PERSPECTIVE AGING AS
LIFE COURSE PROMISE PROMISES AND
PITFALLS OF LONGITUDINAL DATA
AND THESE COMMENTS ARE MOTIVATED
BY WHAT ARE BIGGEST CHALLENGE RS
IN COLLECTION AND DEVELOPMENT
AND USE IN BIO-MACERS AND
SCIENCE REGARDING DATA AND
APPROACH AND HOPE TO CONSIDER
LOOKING TOWARDS FUTURE OF
GEROSCIENCE AND FIRST
GEROSCIENCE FRAMEWORK FOR
CONCEPTUAL AGING EXTENDS WELL TO
UNDERSTANDING OF AGING AS LIFE
COURSE PROCESS LATE LIFE AND
HEALTH DISEASE OUTCOMES WE
TYPICALLY OBSERVE IN OLD AGE ARE
ROOTED IN EXPOSURES AND
EXPERIENCES ACROSS ALL AGES AND
MEANS TO ADDRESS AGING OUTCOMES
WE HAVE TO ADDRESS ANTECEDENTS
OF ANTIAGING ACROSS THE LIFE
COURSE AND COULD BE DIFFICULT
STUDYING AGING AND DISEASE AND
YOUNG POPULATIONS ON SURFACE
APPEAL HEALTHY AND BIOMARKERS
COULD BE PARTICULARLY POWERFUL
AND WHERE WE FACE CHALLENGES
GIVEN WORK ON BIOMARKER
DEVELOPMENT AND VALIDATION IS
THAT OLDER INDIVIDUALS IS STILL
AN OPEN QUESTION EXTENT TO WHICH
MARKERS INDICATE RISK AT EARLIER
AGES AND WHAT DO BIOMARKERS OF
AGING MEAN IN YOUNG PEOPLE AND
IN PARTICULAR EARLY LIFE COURSE
STAGES HOW DO WE KNOW WHAT IS
ACCELERATED AGING VERSUS WHAT IS
ACCELERATED HEALTHY OR NORMAL
DEVELOPMENT AND ARE THESE
DISTINCTION OR REFLECTIVE OF
SHARED LIFE COURSE PROCESS OF
BIOLOGICAL ACCELERATION AND
BRINGING TO SECOND POINT
PROMISES AND PITFALLS OF
LONGITUDINAL DATA TALKING ABOUT
PERILS OF CROSS-SECTIONAL
STUDIES AND CONSIDERING
OPPORTUNITIES AND CHALLENGES OF
LONGITUDINAL STUDIES RELATED TO
LIFE COURSE PROCESS AND INSTEAD
OF THINKING ABOUT INDIVIDUALS AT
VARIED LIFE STAGES WE CONSIDER
SAME PERSON FOLLOWED OVER TIME
AND LONGITUDINAL DATA IS
VALUABLE AND CAN HELP TO PROVIDE
LEVERAGE ON SOME MOST PRESSING
QUESTIONS ABOUT CHANGE AND AGING
AND IT IS OFTEN CHALLENGING TO
KNOW WHAT IS TRUE CHANGE AND
MEASURED ERROR? DAN TALKED
ABOUT NICELY SELECTION OF PROBES
FOR PACE STUDY AND HOW MUCH
CHANGE SHOULD WE EXPECT OVER A
PARTICULAR PERIOD OF TIME?
DOES IT DEPEND ON WHEN IN THE
LIFE COURSE THAT WE ARE LOOKING?
THEN FINALLY, IMPROVEMENTS
CONSISTENT WITH
CONCEPTUALIZATION OF AGING THAT
FOCUSES ON DECLINE.
SO, FINALLY, IMPORTANCE OF
REPRESENTATIVENESS AND
REPRESENTATION AND MUCH DATA WE
USE IN BIOMARKER RESEARCH AND
GEROSCIENCE RELIES ON CLINICAL
SAMPLE VOLUNTEER SAMPLE
CONVENIENT SAMPLES OR PARTICULAR
GEOGRAPHIC POPULATIONS AND OWE
VEN TIMES SAMPLES ARE
PREDOMINANT WILL I FROM
INDIVIDUALS RACIALIZED AS WHITE
AND RELIANCE ON DATA SOURSS HAVE
EFFECT OF SUSTAINING REPRODUCING
HEALTH DISPARITIES AND BOOKENDS
US WITH WHERE WE STARTED
YESTERDAY AND LACK OF DIVERSITY
AND POPULATION REPRESENTATION IN
BIOMARKER RESEARCH THAT BOTH I
THINK IN PARTICIPANTS AND IN
SCIENTISTS THAT PRESENTS MAJOR
CHALLENGE TO PROGRESS AND
GEROSCIENCE AND WHAT I WANT TO
ENCOURAGE US TO THINK ABOUT IS
IMPROVING SCIENCE THROUGH
POPULATION REPRESENTATION AND WE
MUST BE SURE WE DON'T MOTIVATE
OR USE BIOMARKERS IN WAYS THAT
BIOLOGY JIEZ GROUP DIFFERENCES
AND PART OF ANSWER INCLUDES
RECOGNIZING AND RECKONING WITH
HARMS AND MALTREATMENT OF
MARGINALIZED GROUPS AND IN DOING
THIS WORK, INVITE US TO THINK
ABOUT HOW WE ENSURE USE AND
EMPHASIS ON BIOMARKERS DOESN'T
DESTRUCT FROM SOCIAL
DETERMINANTS OF HEALTHY AGING
USING BIOMARKERS -- AND
DISMANTLING SYSTEMS OF
OPPRESSION AND THANK YOU AND
LOOK FORWARD TO OUR DISCUSSION.
>>[APPLAUSE].
>>OKAY. SO, LET'S SEE. I'M
JAMIE. I HAVE A COUPLE SLIDES
AND I'M RUNNING LATE AND IF
SLIDES DON'T POP UP, WELL,
EITHER WAY HOW ABOUT I CALL
EVERYBODY UP HERE. IF YOU SPOKE
THERE IS A NAME CARD FOR YOU.
WE WILL SEE IF SLIDES COME UP
AND MAYBE THEY WILL OR MAYBE
THEY WON'T AND IF NOT I WON'T
CRY ABOUT IT OKAY. I GUESS WE
ARE NOT HAVING SLIDES WE WILL GO
AHEAD AND JUMP INTO THE Q & A
AND I DID HAVE A COUPLE THINGS.
WE HAVE PEOPLE LINING UP AND I
WILL GO AHEAD AND ROLL IT OVER
TO THE AUDIENCE.
>>PLOTS.
>>SO, FOR THOSE SO WE ARE
SHOWING Z SCORES THAT IS RELATED
TO STATISTICAL SIGNIFICANCE AND
IS SOMETHING THAT IS GOING TO BE
GREATER THAN 2 IS GREATER OR
WILL BE STATISTICALLY
SIGNIFI.
>>COULD YOU HIT THE BUTTON ON
YOUR MIC? I CAN'T HEAR YOU.
>>YEAH. SO, I WAS SHOWING Z
SCORES THERE THAT IS, YOU KNOW,
WHICH YOU WILL DERIVE BEFORE
CALCULATING A P VALUE AND SO,
YOU KNOW, LOOKING AT P VALUE AND
LESS THAN .05 LOOKING FOR Z
SCORES DEPENDING ON 1 OR 2 TAIL
TESTS APPROXIMATELY GREATER THAN
2 THAT ARE ALL SIGNIFICANT.
SO, ONE THAT I SHOWED FOR
MUSCULOSKELETAL AND PHYSICAL
FUNCTION FIRST THAT IS 9 AND
ENDS UP BEING VERY SIGNIFICANT.
>>SO SH, PERHAPS TALKING TO SE
THE SLIDE?
>>YEAH.
>>WHEN YOU LOOK AT COMMENTS.
>>YEAH.
>>[INDISCERNIBLE].
>>OKAY. JORNL CONNECTICUT AND
FOLLOW UP COMMENT FROM
[INDISCERNIBLE] AND SHOUTOUT FOR
WONDERFUL INVESTMENT TO DEFINE
SENESCENCE CELLS AND LINK TO
MICE AND SEVERAL WERE THERE
THURSDAY AND FRIDAY AND YOU AND
RAFI AND OTHERS AND THINK THERE
IS ANOTHER OPPORTUNITY THERE
THAT WE NEED TO TALK ABOUT THAT
IS WHAT WE HEAR ABOUT HERE IS
EXTENT TO WHAT ONE HAS TO DO
WORKING WITH HUMANS TO TRY TO
UNDERSTAND WHAT CHANGES IN
TISSUES CAN GET ACCESS TO LIKE
BLOOD MEAN IN SPECIFIC OCCURRING
IN SPECIFIC OR BEGANS SENDING
AMAZING OPPORTUNITY AND 18
TISSUES CHARACTERIZED AND
COLLECTED AND HUGE INVESTMENT
TERM TERMS LOOKING FOR HEALTHY
INDIVIDUALS IN ALL AGES
DESCRIBING WHOLE EFFORT AT
CONFERENCE TALKING ABOUT
DISCUSSION ACTUALLY OF DOING
EPIGENETIC CLOKZ IN INDIVIDUAL
TISSUES AS WAY OF GETTING SENSE
OF BIOLOGICAL AGE OF INDIVIDUAL
THAT IS COMING FROM AND
OPPORTUNITY TO LOOK AT
BIOLOGICAL PROCESSES IN BLOOD
AND 18 DIFFERENT TISSUES
INCREDIBLE OPPORTUNITY FOR
COMMUNITY AT LARGE TO LEVERAGE.
>>JOVRJ THANK YOU FOR THE
COMMENT.
AGREE AND IN FACT WITH THESE IN
PARTICULAR WE HAVE A GREAT
OPPORTUNITY TO NOW LOOK AT
CHANGES AND TISSUE SPECIFIC
CHANGES LONGITUDINALLY THAT IS
SOMETHING WE ARE DOING WITH RAFA
AND [INDISCERNIBLE] AND
BEGINNING TO QUANTIFY THINGS EPI
GENETIC CLOCKS OR SENESCENCE
CELL BURDEN BUT CAN GO BACK INTO
BIO FLUIDS AND BACK INTO THE
BLOOD AND TRACK LONGITUDINALLY
HOW MARKERS CHANGE R AS
SENESCENCE CELL BURDEN CHANGES
AND EVENTUALLY WOULD BE GREAT TO
UTILIZE MODELS TO KIND OF YOU
KNOW DO SOMETHING LIKE REMOVE
SENESCENCE CELLS OR ACCELERATE
THEM TO SHOW THESE ARE FOLLOWING
DOSE DEPENDENT EFFECTS WE EXPECT
THAT MAY HELP US GET INTO
IMPROVED PLASMA BIOMARKERS AND
THERE IS COOL STUFF WE CAN DO ON
THAT STUDY.
THANK YOU.
>>HI.
SO, ALICE, YOU KIND OF PREEMPTED
MY QUESTION BY SHOWING THAT
PROFOUND MALE/FEMALE DIFFERENCE
IN MARKERS AT VERY END OF THE
TALK. I WAS INTERESTED IN SEX
DIFFERENCE AND PERHAPS I WILL
ASK -- FIRST, I WILL ASK DAN.
HE SHOWED ONE SLIDE THAT WAS THE
PACE DATA AT PLOTTED IS A
FUNCTION OF AGE AND IS WHERE IT
WAS CROSS-SECTIONAL DATA IF NOT
MISTAKEN GOING TO 60 OR 70 YEARS
OLD AND TWO DIFFERENT CURVES
THROUGH OR LINES THROUGH MALE
AND FEMALE AND SHOWED ACTUALLY A
SLOWER RATE OF AGING IF NOT
MISTAKEN IN FEMALES COMMENTING
ON THAT AND IF YOU HAVE OLDER
DATA TO DRAW ON.
>>YES. THAT IS RIGHT.
CROSS-SECTIONAL DATA AND OLDEST
FOLKS IN SAMPLE WR A LITTLE
ABOVE 90 AND SLOPE IS STEEPER
FOR MEN THAN WOMEN AND WE SEE
THAT IN OTHER DATA SETS AND IT
IS POSSIBLE THAT, THAT
CORRESPONDS TO WHAT HAS BEEN
OBSERVED AS AN IN EARLIER
MORTALITY IN MEN AND THINK THAT
THERE IS A LOT WE DON'T KNOW
ABOUT WHY WE MIGHT SEE THAT
INCLUDING WHAT ARE LIFESTYLE
DIFFERENCES PARTICULARLY IN
COHORTS OF INDIVIDUALS IN 70S
AND 80S AND 90S IN DATA SETS WE
ARE LOOKING AT HIGHER RATES OF
SMOKING IN LIVES OF MEN IN THE
PAST AND WE HESITATE TO MAKE
ATTRIBUTION TO BIOLOGICAL SEX AT
THIS POINT AND IS SOMETHING TO
EXPLORE.
>>SURE. I MEAN, IF YOU THINK
ABOUT FRAILTY FOR EXAMPLE YOU
FIND FEMALES ARE FRAILER BUT
LIVE LONGER AND LOOKING AT RATE
OF AGING AND THOUGHT IT WAS AN
INTERESTING PIECE AND WANTED
COMMENT ON IT. ANYONE HAVE A
COMMENT ON MALE/FEMALE? NO?
OKAY MALE OR FEMALE ANY DATA YOU
MIGHT HAVE DONE.
>>SOMETHING I MIGHT OFFER ABOUT
SEX DIFFERENCES IN HOW WE
DEVELOP MEASURES OF BIOLOGICAL
AGING AND CASE OF PACE OF AGING
IT IS BUILT ON IS NORMALIZED
WITH INSECTS AND VALUE OF ONE
CORRESPONDS TO AVERAGE RATE FOR
A MAN AND IF MAN AVERAGE RATE
FOR A WOMAN AND IF WOMAN.
>>RIGHT.
>>AND IN THE DENEDON COHORT AND
SEE DIFFERENCES IN BIOLOGICAL
CHANGES ACROSS LIFESPAN IN MEN
AND WOMEN AND NOT YET A DECISION
IN FIELD ABOUT MODELING
SEPARATELY OR LUMPING TOGETHER
OR SEEKING TO ACCOMMODATE A
BROADER SPECTRUM OF BIOLOGICAL
SEX OR GENDER IDENTITIES AS WE
INCORPORATE DATA FROM NEWER
COHORTS.
>>RIGHT.
>>BUT THAT IS DIFFERENT FROM
THE WAY THAT FOR EXAMPLE
MORTALITY IS MODELS IN OTHER
SECOND GENERATION CLOCKS IN CASE
OF PHENOAGE IS SEX NAÏVE AND
GRIM AGE PARTICIPATE REPORTED
SEX IS ON RIGHT-HAND SIDE OF
EQUATION INDEPENDENT PREDICTOR
IN MODEL DEMETHYLATION PART OF
THE GRIM AGE IS SEX DEPENDENT
CONSTRUCT IN THAT WAY.
>>ENERGY METABOLISM TERMS THERE
IS KNOWN ESTABLISH THE
DIFFERENCES BETWEEN WOMEN AND
MEN AND THINK WE ARE AWAKENING
TO IDEA ALSO GENDER NOT
BIOLOGICAL SEX BUT GENDER MIGHT
PLAY ROLE IN SHAPING BEHAVIORS
AND THINGS ENDING UP SHAPING
MITOCHONDRIAL BIOLOGY AND
DOMAINS OF METABOLISM AND
IMPORTANT QUESTIONS THAT HAVE
NOT BEEN TACKLED DIRECTLY BUT
NEED TO.
>>RIGHT. OKAY.
>>I'M FROM UNIVERSITY OF
CONNECTICUT HEALTH AND FIRST
QUESTION IS TO DAN.
CAN WE NOT TRACK FIRST OR SECOND
GENERATION CLOCKS OVER TIME SO
CAPTURE CHANGE ACROSS TIME THAT
ARE ADVANTAGES OF USING CLOCKS
IN THE TEST OF AGING?
>>SO, THE QUESTION IS COULD WE
USE LONGITUDINAL DNA METHYLATION
DAT
DATA.
>>NO TRACKING FIRST OR SECOND
GENERATIONAL CLOCKS OVER TIME TO
CAPTURE CHANGE.
>>OKAY.
>>OVER TIME AND WHY DO WE NEED
CLOCKS IN THE PAST OF AGING?
>>GOOD QUESTION. WHY CAN'T WE
USE REPEATED MEASURES
DEMETHYLATION DATA TO PHENOTYPE
PACE OF AGING AND THERE I THINK
THAT THERE IS A FEW ANSWERS AND
ONE IS THAT THERE MAY BE
INTRINSIC VALUE IN SPEEDOMETER
MEASURES VERSUS ODOMETER
MEASURES AND TRUE BY CHA
TRACKING CHANGE OVER TIME IN
EPIGENETIC CLOCK YOU CAN DERIVE
PACE OF AGING AND MIGHT BE VALUE
IN SINGLE POINT TIME ASSESSMENT
HOW AGING IS OCCURRING AND RICH
MILLER HAS COMMENTARY ON THIS IN
AGING CELL THAT CAME OUT EARLIER
THIS YEAR OR END OF LAST YEAR HE
IS WORKING ON SPEEDOMETERS IN
MICE AND SO THE SECOND REASON IS
THAT DNA -- LONGITUDINAL DNA
METHYLATION DATA UP TO NOW HAS
BEEN RELATIVELY RARE AND
OPPORTUNITIES FOR PHENOTYPING
PACING AGING IN THAT FASHION ARE
LIMITED AND THIRD REASON, AS WE
HAVE LOOKED AT IT, CHANGES OVER
TIME IN FIRST GENERATION CLOCKS
ARE NOT SYSTEMATIC WITH OTHER
CHANGES THAT WOULD BE
COMMENSURATE WITH AN AGING
PROCESS AND IN OTHER WORDS AGE
ACCELERATION RESIDUAL INCREASING
OVER TIME DOES NOT CORRESPOND TO
OTHER SIGNS OF WHAT WE MIGHT
THINK OF AS ACCELERATED AGING
PROCESS IN DATA THAT WE HAVE
LOOKED AT AND AS YOU COULD SEE
IN THE CALORIE DATA AND SECOND
GENERATION CLOCKS MEASURED
REPEATEDLY OVER TIME DID NOT
DETECT THE BIOLOGICAL CHANGES
OCCURRING IN THE INDIVIDUALS
UNDER THE CALORIC RESTRICTION
REGIME THAT ARE OBSERVED IN
BLOOD CHEMISTRY ANALYSIS OF
INDIVIDUALS OR IN PACE OF AGING
MEASURE AND I GUESS TO CONCLUDE
IN PRINCIPLE, YES. AND IT WOULD
BE GOOD TO SEE MORE OF THAT KIND
OF WORK AS MORE LONGITUDINAL
DATA IS AVAILABLE.
>>THANK YOU. CAN I QUICKLY ASK
A QUESTION TO ALBERT?
HAVE YOU TRIED TO LOOK AT
CORRELATIONS THAT ARE BETWEEN
ORGAN SPECIFIC CLOCKS IF LAID
OUT LIKE HIGHLY CORRELATED AND
WE PROBABLY DON'T NEED SO MANY
ORGAN SPECIFIC CLOCKS. IT WOULD
BE INTERESTED TO LOOK AT
[INDISCERNIBLE] ACROSS ORGAN
SPECIFIC CLOCKS?
>>SO, THE QUESTION ABOUT
CORRELATION BETWEEN DIFFERENT
SYSTEMS SCORES.
SO, FOR THE RAW VALUES HIGHLY
CORRELATED BECAUSE THEY ARE ALL
ASSOCIATED WITH CHRONOLOGICAL
AGE AND IF YOU CAN RESIDUALIZE
OUT AGE LOOKING AT CORRELATIONS
MANY ARE SHOWING CORRELATIONS .5
AND .6 AND SOME ARE WEAKER AND
LESS CORRELATED WITH OTHERS AND
THINK THAT ACTUALLY I DIDN'T GET
A CHANCE TO SHOW THIS AND IN
MANY CASES SIMILAR TO WHAT WAS
SHOWN FOR CORRELATIONS BETWEEN
SYSTEMS.
>>I SEE. SECOND QUESTION WOULD
IT BE -- SORRY TO LOOK AT
PATIENTS ACROSS CLOCKS.
>>LOOKING AT WHAT?
>>PATIENTS ACROSS ORGAN
SPECIFIC CLOCKS.
>>ARE YOU TALKING ABOUT
POTENTIALLY CLUSTERING.
>>MAYBE CLUSTERING STUFF.
>>CLUSTERING INDIVIDUALS?
YEAH. RAGAF HAS DONE THAT IN
WOMEN HEALTH INITIATIVE COHORTS
HE WAS ABLE TO DERIVE 9
DIFFERENT CLUSTERS DIDN'T QUITE
SHOW IT THERE ARE IF YOU TAKE
THREE PEOPLE EXACT SAME AGE AND
SEX AND YOU KNOW EPIGENETIC AGE
YOU SEE SOME ARE HIGHLY
ACCELERATED IN SOME SYSTEMS
TOTALLY DIFFERENT PERSON MIGHT
ACCELERATE IN OTHER SYSTEMS
USING THAT TO CLUSTER
INDIVIDUALS AND WE ARE WORKING
NOW TO CLUSTER IN LONGITUDINAL
DATA.
>>THANK YOU.
>>FINAL QUESTION.
>>SCOTT FROM UCSF. I WANTED TO
ASK THE PANEL ABOUT STEVE YOUR
COMMENT ABOUT BIOMARKERS THAT
ARE -- BIOMARKERS USED AS
SURROGATE AND UNDERSTANDING IS
THEY HAVE TO BE ON CAUSAL
PATHWAY FROM INTERVENTION TO
OUTCOME AND WANT TO CONFIRM
THAT. IF SO, I WAS CURIOUS HOW
CONFIDENT ARE WE THAT THESE
CLOCKS ARE ON CAUSAL PATHWAY?
I KNOW THERE IS A FEW LIKE
CALORIE STUDY LOOKING AT
INTERVENTION AND WHAT WORK IS
BEING DONE TO PROVE CAUSALITY ON
PATHWAY? IF NOT, CAN THEY EVER
BECOME SURROGATE OUTCOMES?
THANKS.
>>THAT IS TO YOU.
>>WELL, I THINK THAT YOU CAN
MAKE AN EASY CASE FOR SURROGATE
OUTCOME WHEN YOU KNOW BIOMARKER
IS ON CAUSAL PATHWAY YOU CAN
IMAGINE THINGS HIGHLY CORRELATED
WITH THINGS ON CAUSAL PATHWAY
THAT MIGHT ALSO SERVE.
LOOKING BLOOD PRESSURE IS
SURROGATE OUTCOME FOR LOTS OF
THINGS AND SOME THAT ARE
CONSIDERED TO BE AGNOSTIC SORT
OF. FDA WILL ALLOW IT TO BE
USED ADS SURROGATE ON OWN NOW
BECAUSE IT IS RELATED TO SO MANY
DIFFERENT THINGS AND WE WILL
NEED TO HAVE STUDIES WHERE WE
ACTUALLY HAVE AN INTERVENTION
AND HAS AN EFFECT AND WORK IT
OUT I THINK AND LARGELY IS AN
EMPIRICAL QUESTION I THINK TO ME
ANYWAY.
>>THANK YOU TO EVERYBODY FOR
STAYING LATE. WE HAD A REALLY
DEEP BENCH HERE FOR THE LAST
SESSION OF THE DAY AND THANK YOU
TO EVERYONE FOR HANGING IN IF
YOU HAVE FURTHER QUESTIONS I
KNOW I DO FEEL FREE TO GRAB
FOLKS WHILE THEY ARE HERE FOR
THE MEETING.
>>[APPLAUSE] A