>>GOOD GOOD MORNING EVERYBODY,
WE ARE GOING TO GET STARTED PER
DAY 2. MY NAME IS CHRISTINA--
NEW FACULTY FOR THE UNIVERSITY
OF MINNESOTA, INSTITUTE OF
AGING AND METABOLISM. WHAT CAN
TODAY TO FOR THE SESSION
INITIATED YESTERDAY ON ADVANCES
IN AGING, IMMUNITY AND CHRONIC
INFLAMMATORY DISEASES -- I
WANTED TO START BY GIVING A
SHORT FIVE MINUTE RECAP, OR A
10 MINUTE RECAP, AND THEN WE
WILL ROLL INTO THE FIRST
SPEAKER FOR THE DAY, KATRINA
ANDERSON.
ONE OF THE THINGS I WANTED TO
SORT OF HIGHLIGHT IS THAT THIS
WORKSHOP IS SUPPOSED TO BRING
TOGETHER IMMUNOLOGISTS,
NEUROSCIENTISTS,
GEROSCIENTISTS ALL OF THOSE
WITH EXPERTISE IN OUR
BACKGROUND, TO GET INSIGHT INTO
KEY FINDINGS AND RECENT WORK
AND GENERATE NEW
COLLABORATIONS. THAT ARE
ONGOING.
>>YESTERDAY HIGHLIGHTED AND
EVERYBODY AGREES THAT THE
IMMUNE SYSTEM IS CRITICAL TO
THE FIELD OF AGING. THIS IS
BOTH THE AGING WITHIN THE
IMMUNE CELL OR HOW THE IMMUNE
CELL IS RESPONDING TO CELLULAR
STRESS OR CATHOGENIC STRESSAS
TIME DEVELOPS. TO MAKE BETTER
UNDERSTAND HOW THE AGING WITHIN
THE IMMUNE CELL FOR THE
INTERACTION OF THAT IMMUNE
CELL, WORKS WITH THE PATHOCITES
WITH FIBROBLAST.
>>CHANGES IN EPIGENETIC, WE
HEARD ABOUT -- -- OF
INDETERMINATE POTENTIAL AND
THAT WILL CHANGE IN THE GENOME
OVER TIME OF THESE AGE CELLS
THAT LEAD TO CELLULAR
DYSFUNCTION AND THEN THUS
AFFECTING TISSUE DYSFUNCTION.
WE KNOW THERE CAN BE CHANGES IN
SIGNALING PATHWAYS AND WHETHER
THOSE SIGNALING
PATHWAYS ARE CHANGED FROM THE
INSIDE OUT OR FROM ANOTHER
PERSPECTIVE, WE HEARD CHANGES
IN TELOMERE LENGTH ALL OF THESE
THINGS PHENOMENONS THAT
CONTRIBUTE TO THE BIOLOGY OF
AGING, WITH AN INSULT TO
CONTRIBUTE TO THE ABILITY TO
APPROPRIATELY SENSE CELLULAR
STRANDS A RESPONSE.
>>
>>I WAS EXCITED BY IH TO
TRACK IMMUNOLOGICALLY, A
REQUIRED COMPONENT THE LEASE
GERIOSCIENCE AND IMMUNE FIELD.
AND IMPACTED BY THE NEED TO
BETTER SHARE INFORMATION AND
TISSUES, DEVELOP PIPELINES.
>>I AM DELIGHTED TO WELCOME
KATRIN ANDREDASSON, DEPARTMENT
OF NEUROLOGY AND NEUROLOGICAL
SCIENCES STANFORD UNIVERSITY
SCHOOL OF MEDICINE.
>>THANK YOU TO THE ORGANIZERS
WHO HAVE BEEN TERRIFIC, I AM
LEARNING A LOT.
>>
>>I'M GOING TO CONTINUE THE
NEUROSCIENCE THEME, THERE HAVE
BEEN ASSOCIATION STUDIES
LOOKING AT RISK FOR ALZHEIMER'S
DISEASE AND WHAT HAS TRANSPIRED
OVER THE LAST MAY BE DECADE OR
SO HAS BEEN REALLY GAME
CHANGING, AND POLYMORPHISMS
CROPPING UP PARTICULARLY
EXPRESSED IN THE MYELOID OF THE
IMMUNE SYSTEM.
OH BOY. I HOPE THIS WORKS.
AND NOW THE FIELD IS REALLY
FOCUSED ON MICRO GLIAL,
RESIDENT MACROPHAGES OF THE
BRAIN. HOWEVER A NUMBER OF
THESE PROTEINS THAT HAVE
POLYMORPHISMS ARE ALSO
EXPRESSED PERIPHERALLY IN THE
MACROPHAGES, IN THE MONOCYTES.
SO, I DRAW YOUR ATTENTION TO
TREM2, MENTIONED YESTERDAY, THE
BIG AREA OF INVESTIGATION BOTH
IN ACADEMIA AND PHARMA WITH
ANTIBODIES, TREM2 IS ALSO
EXPRESSED IN THE PERIPHERY. I
THINK WHAT WE NEED TO START
THINKING ABOUT IS THE FIELD,
THIS COULD BE SOMETHING WE CAN
DISCUSS IN THE AREA OF NEURAL
INFORMATION, NOT JUST BEING
MICRO GLIAL CENTRIC BUT ALSO
THINKING BIGGER, AND
INCORPORATING THE PERIPHERY. I
WILL GET TO THAT IN A BIT.
THE OTHER NICE SPREAD OF
RESEARCH HAS BEEN EPIDEMIOLOGY.
OBSERVATIONAL STUDIES HAVE
LOOKED AT NORMAL, AGING
POPULATIONS, COGNITIVELY NORMAL.
WHO SOMEHOW DID NOT DEVELOP
ALZHEIMER'S DISEASE. AND THEY
ACTUALLY WERE TAKING ANSET,
THERE AT LEAST FOUR
OBSERVATIONAL STUDIES,
INDICATING OUT OF THE VA,
COGNITIVELY NORMAL VETS THINGS
LIKE IBUPROFEN AND-- DID NOT
DEVELOP ALZHEIMER'S DISEASE,
BUT YOU HAVE TO TAKE IT FOR
ABOUT 4-5 YEARS CONSISTENT WITH
THESE DEGENERATIVE DISEASES.
SO, WE WERE VERY INTERESTED IN
AT THE BEGINNING, THIS IS WHAT
MY LAB IS CONSISTENTLY WORKING
ON SINCE THE BEGINNING.
IS THIS PATHWAY COX-2 TO PGE2?
COX-2 IS A MOTHER LOAD OF
INFLAMMATORY ENZYMES, GENERATES
DOWNSTREAM AS PGE2 AND PGE2
SIGNALS THROUGH A NUMBER OF--
SHOWING US WHICH WE SHOWING
THIS PREVENTIVE EFFECT AND HEAR
ENOUGH HOURS PATIENTS PGE2 WAS
VERY HIGH. WHAT WE WERE,
EVENTUALLY AFTER A LOT OF WORK
AND A LOT OF YEARS, A LOT OF
NIH FUNDING, WE WERE ABLE TO
IDENTIFY THE EP2 RECEPTOR A
MASTER SUPPRESSOR, A FAIRLY
NEFARIOUS RECEPTOR. IT IS
VITALLY EXPRESSED IN NEURONS
EMBRYONICALLY, POST NATALY. EP2
INHIBITS AND BLOCKS SEVERAL
(INDISCERNIBLE) INCLUDING
PHAGCYTOSIS AND IN THE BRAIN.
IN OUR EXPERIMENTS WAS
CONDITIONAL -- WE FOUND WE
COULD RESTORE AND A LOT OF THE
NORMAL HOMEOSTASIS FUNCTIONS
REDUCING THE LEVEL OF EP2 IN
THE BRAIN.
AGING IS CHARACTERIZED BY
INFLAMMATION AND I THINK IT IS
REALLY WONDERFUL THIS IDEA OF
(AUDIO CUTTING IN AND OUT) --
MALADAPTIVE. I DON'T KNOW WHAT
IS WRONG WITH THE SOUND. IT
KEEPS CUTTING IN AND OUT.
SO WE ALL ARE VERY FAMILIAR
WITH THE CONCEPT AND THE IDEA
THAT AGE ASSOCIATED
INFLAMMATION IS HITTING
EVERYTHING INCLUDING THE BRAIN
RIGHT HERE. AND SO ONE OF THE
MECHANISMS WE ARE INTERESTED
IN, IS WHAT IS DRIVING THIS AGE
ASSOCIATED INFLAMMATION,
ESPECIALLY FOCUSING ON THE
MYELOID; WE ARE NOT ADAPTIVE
IMMUNE PEOPLE.
ONE PROCESS WE HAVE BEEN VERY
INTERESTED IN IS ENERGY
METABOLISM, BY ENERGETICS OF
MYELOID SALES. AND DECLINING
GLYCOLS AND --.
ONE OF THE EARLIER STUDIES
THAT WE HAVE CARRIED OUT WAS
SIMPLY COMPARING YOUNG AND OLD
MACROPHAGES. WE LOOKED AT BOTH
MOUSE PRIMARY MACROPHAGES FROM
THE PERITONEUM, BUT ALSO
EVALUATED HUMAN MACROPHAGES.
WE ARE REGULAR CUSTOMERS. WE
BY BLOOD FROM YOUNG DONORS, 35
YEARS OR OR YOUNGER OR OLD
DONORS, 65 OR OVER. AND LOOK
AT METABOLOMICS. YOU CAN SEE
IN THE AGED HUMAN MACROPHAGES
THERE IS REALLY A MARKED
DEPLETION OF GLYCOLITIC
INTERMEDIATE AND PHOSPHATE
INTERMEDIATE AND THERE IS A
(INDISCERNIBLE).
AND THAT WHAT WE NOTED WAS
WHEN WE DID KEY HORSE
(PHONETIC), WHICH MEASURES BOTH
PHOSPHORYLATION-- IT WAS VERY
LOW AND AGED MACROPHAGES AND
THEN ALSO COUNTER TO WHAT WE
COME TO EXPECT WITH THE WARBIRD
PHENOMENA, GLYCOLYSIS WAS ALSO
LOWER AND WE GOT A BIT OF
PUSHBACK FROM THE REVIEWERS BUT
IT IS WHAT IT IS. AGING I
THINK IS METABOLICALLY QUITE
DIFFERENT FROM THE RUBRIC,
WHICH IS WHAT YOU GET WITH
CANCER.
WE WONDERED WHETHER THE EP2
RECEPTOR WHICH MEDIATES A LOT
OF NEUROTOXIC INFLAMMATORY
RESPONSES, MAYBE IT IS WORKING
BY SUPPRESSING BIOENERGETICS
BECAUSE WE KNOW THAT METABOLISM
REALLY DOES REGULATE A LOT OF
INFORMATION. AND I DON'T HAVE
TIME TO GO INTO ALL OF THAT,
BUT THERE ARE AMPLE EXAMPLES OF
TCA METABOLITES FOR EXAMPLE
REGULATING INFLAMMATORY
PROCESSES NOT TO MENTION LACK
OF ATP.
WHAT WE DID IS WE DID ADULT
RESPONSE OF PGE2 IN HUMAN
MACROPHAGES AND LOOKED AT
OXIDATIVE PHOSPHORYLATION IN
GLYCOLYSIS. WE ADDED THE PORE
(PHONETIC) -- WE ALSO TURNED TO
GENETICS AND I AM VERY MUCH A
MOUSE LAB. WE USE GENETICS
QUITE A BIT. CONDITIONAL AND
INDUCIBLE MODELS. IF WE NOW
LOOK AT MITOCHONDRIA IN
MACROPHAGES FROM YOUNG AND AGED
UNCONDITIONALLY KNOCKED OUT
YOUNG AND AGED MICE, YOU SEE
IMMEDIATELY THE DIFFERENCE
BETWEEN THE YOUNG AND AGED
MITOCHONDRIA, THEY LOOK
TERRIBLE. THEY ARE NOT VERY
ELECTRON DANCE, THEY ARE
BALLOON SHAPED.
BUT IF YOU NOW LOOK AT THE OLD
EP2 MICE, THE MITOCHONDRIA
LOOKS INDISTINGUISHABLE FROM
THE YOUNG SOMEHOW BUT PREVENTED
THE DEGRADATION OF MITOCHONDRIA
BY REDUCING EP2 JUST BY 50% AND
I THOUGHT THIS WAS WOW! COOL!
AND THEN WE TURNED THEN TO I
GUESS AGING. RIGHT. AGING IS
THE PRIMARY ASPECT OF
ALZHEIMER'S BUT HE WE CAN CRACK
THE AGING PROBLEM FIRST THAT
WOULD BE NICE. THAT IS FAR AND
ABOVE THE BIGGEST FACTOR FOR A
LOT OF THESE AGE ASSOCIATED
NEURODEGENERATIVE DISORDERS.
LOOKING AT THIS PATHWAY NOW, --
HOW DO I GO BACK?
IF WE LOOKED AT-- WE HAD A LOT
OF PGE2 THAT THE HUMAN
MACROPHAGES-- THIS IS SOMEHOW
SHOWING IN DIFFERENT-- I
APOLOGIZE -- ANYWAY, WHAT IT IS
SUPPOSED TO SHOW IS THAT EVERY
CULTURE HUMAN MACROPHAGES WE
LOOK AT PGE2 LEVEL AND WHEN YOU
LOOK AT YOUNG VERSUS OLD A
LEVEL OF PGE2 IN THE CELL AND
IN THE-- ARE SKYHIGH IN THE OLD
COMPARED TO THE YOUNG. HUMAN
MACROPHAGES ACTUALLY MAKE A LOT
MORE PGE2 WHEN WE ARE OLDER
THAN WHEN WE ARE YOUNGER AND
THEN WE TOOK THE SAME
MACROPHAGES AND LOOKED AT THE
EP2 RECEPTOR DISTRIBUTION FOUND
INCREASED EP2 RECEPTORS THERE.
IT IS VERY SPECIFIC.
THE NICE THING AGAIN, ALIGNING
HUMAN WITH MOUSE WHICH IS SUPER
IMPORTANT, IS THAT IF WE LOOK
AT THE MOUSE AGAIN WE SEE IN
THE OLD MILES TONS OF PGE2 IN
THE PLASMA. THESE MEASUREMENTS
WERE DONE BY OUR COLLABORATORS
AT KAO (PHONETIC), PGE2
RECEPTORS ARE SUPREMELY
DIFFICULT TO MEASURE. PGE2 WERE
UP IN THE PLASMA AS WELL AS IN
THE BRAIN BUT THE OTHER -- WERE
UNCHANGED WITH AGE. THIS WAS A
VERY SPECIFIC EFFECT AND IN THE
EP2 RECEPTORS WERE ALSO HIGH IN
MOUSE ROCK OF (CORRECTION)
MACROPHAGES.
WE AGE THIS MICE AND COMPARE
YOUNG TO OLD, BOTH GENOTYPES
AND FOUND THAT IN THE PLASMA AS
WELL AS IN THE HIPPOCAMPUS WE
HAD THIS BEAUTIFUL, BASICALLY
REJUVENATION OF THE PLASMA, IN
TERMS OF IMMUNE FACTORS. AND
PRETTY MUCH THE HIPPOCAMPUS AS
WELL.
HERE ON THE LEFT OR THE OLD
CONTROLLED MICE. YOU CAN SEE
YOUR FAVORITE INFLAMMAZOME IO1
BETA VERY HIGH AND BASICALLY
THE AGE CONDITIONAL KNOCKOUTS
ARE INDISTINGUISHABLE FROM THE
YOUNG. THAT WAS VERY
INTERESTING.
DR. -- TALK ABOUT YESTERDAY
VERY NICELY, WE CAN LOOK AT
HIPPOCAMPUS SPECIAL MEMORY
USING THE SPECIAL MEMORY TEST;
THE HIPPOCAMPUS IS EXQUISITELY
SENSITIVE TO INFLAMMATION. I
WANT TO DRAW YOUR ATTENTION TO
THIS DIAGRAM HERE, THIS IS A
DIAGRAM OF THE PATH TAKEN BY
THE MOUSE AFTER FOUR DAYS OF
TRAINING. THESE ARE BOTH OLD
MICE. THE OLD MILES REALLY
CANNOT REMEMBER AT ALL HOW TO
ESCAPE TO THE TARGET HOLE. BUT
THE OLD EP2 KNOCKOUT REALLY HAS
NO PROBLEM, GOES RIGHT TO IT.
SO WE SOMEHOW PREVENTED AGE-
ASSOCIATED COGNITIVE DECLINE.
SIMILARLY FOR THE
NEUROSCIENTISTS IN THE
AUDIENCE, WE LOOKED
ORTHOGONALLY, LOOKING A MEASURE
OF THE SYNAPTIC STRENGTH IN
HIPPOCAMPUS AND WHAT YOU CAN
APPRECIATE HERE IS HOW PALTRY
THE SIGNAL IS IN THE AGED
CONTROLS WHERE IN GREEN THE
AGED EP2 KNOCKOUTS ARE UP THERE
BASICALLY INDISTINGUISHABLE
SWITCHABLE FROM THE YOUNG. WE
ESSENTIALLY RESTORE NOT JUST
SPATIAL MEMORY FUNCTION BUT AT
A CELLULAR, MOLECULAR LEVEL WE
ACTUALLY RESCUED THE SYNAPTIC
STRENGTH IN THESE OLD MICE.
SO, TO CUT A LONG STORY SHORT,
THERE IS A TREMENDOUS AMOUNT OF
WORK THAT OUR STUDENTS DID
USING METABOLOMIC, MASS
LABELING, ORTHOGONAL APPROACHES
WE DON'T KNOW IF ANYTHING
HAPPENED IN THE T CELLS OR P
CELLS BUT AT LEAST IN THE PGE2
PATHWAY WE HAD NICE SIGNALING
THROUGH EP2 IMPROPER GLUCOSE --
FEEDING THE ATP TRANSFERRED AND
ENABLES NORMAL HOMEOSTATIC
IMMUNE FUNCTIONS.
HOWEVER IN THE AGED MYELOID
CELL, I SHOWED YOU THAT WE HAVE
A LOT MORE PGE2 FLOATING AROUND
AND WE HAVE AN UP REGULATION OF
EP2 RECEPTORS ON THE SURFACE OF
OUR MYELOID. AND WHAT I ALLUDED
TO BEFORE IS THAT THERE IS
ACTUALLY A SHUNT, EP2 DRIVES
THE SHUNTING OF GLYCOGEN. IT
IS SEQUESTERED IT IS NOT ABLE
TO FEED LIKE ALL INTO THE TCA,
AND WE HAVE THIS ENERGY
DEPLETED, LIMPING ALONG OLD
MYELOID CELL. THAT IS NOT
GOING TO BE ABLE TO SUPPORT
HOMEOSTATIC IMMUNE RESPONSES.
OKAY. SO I JUST WANTED TO
FINISH UP WITH SOME
INTERESTING, SORT OF
TRANSLATIONAL FINDINGS. SO
THAT NOW OF COURSE, WE WANT TO
TEST WHETHER WE CAN ELICIT A
SIMILAR THING
PHARMACOLOGICALLY. YES WE CAN.
THIS IS AN EP2-SELECTED
INHIBITOR THAT IS BRAIN
PENETRANT. SO WE BASICALLY
LOOKED AT THE SAME THREE
OUTCOMES, IMMUNE FACTORS IN THE
PLASMA AND THE HIPPOCAMPUS;
SPATIAL MEMORY, AND SYNAPTIC
PLASTICITY.
AND AGAIN WHAT WE FOUND IN THE
PLASMA, THE OLD VEHICLE CONTROL
MICE ARE SEGREGATING OVER HERE.
THE OLD EP2-INHIBITOR TREATED
ONES ARE INDISTINGUISHABLE FROM
THE YOUNG AND WE FIND A SIMILAR
PATTERN IN THE HIPPOCAMPUS.
WE ALSO CAN RESCUE HIPPOCAMPAL
MEMORY, SPECIAL MEMORY AND
PLASTICITY. BUT THE
INTERESTING THING-- THIS IS
GREAT-- BUT THE REALLY
INTERESTING THING IS THAT WE
COULD SEE THIS AFTER TWO WEEKS.
SO THIS HAS KIND OF SMACKED
THE METABOLISM IN OUR VIEW. AND
MAYBE ALL THE CIRCUITS ARE
RIGHT THERE; THEY MAY NOT BE
ALL THAT PERFECTLY TUNED BUT
THEY ARE THERE AND THE
STRUCTURE IS THERE. YOU JUST
KIND OF HAVE TO WAKE UP THE
NEURONS; IN ORDER TO WAKE UP
THE NEURONS YOU HAVE TO
BASICALLY IMPROVE THE LOCAL
MILIEU, ENVIRONMENTAL MILIEU.
IN THE BRAIN WE CAN DO TEM;
AND LOOK AT MITOCHONDRIA AND
MICHAEL -- (CORRECTION) MICRO
GLIAL CELLS. YOU CAN SEE IT
AGAIN IN THE OLD MICRO GLIAL
YOU HAVE THESE GLOBULAR PALE
MITOCHONDRIA BUT THIS IS ONLY
ABOUT 2-4 WEEKS, WE START TO
SEE ELONGATION OF THE
MITOCHONDRIA, SLIGHTLY MORE
ELECTRON DENSITY, AND THIS IS
CHRONIFIED OVER HERE.
THIS IS OUR FIRST MODEL. THIS
IS BROAD STROKES. BUT IT HELPS
US THINK ABOUT THINGS AND DRILL
DOWN IN THE RIGHT PLACES SO
THAT DECREASING MYELOID
BIOENERGETICS DRIVES
MALADAPTIVE INFORMATION AS WE
AGE.
ONE MECHANISM IS THROUGH THE
EP2 RECEPTOR, PGE2 SIGNALING
THROUGH THE EP2 RECEPTOR AND
THERE IS NOTHING LEFT FOR THE
PCA IN THE TRANSPORT AND I WANT
TO FINISH NOW WITH A VERY
TANTALIZING FINDING THAT WE CAN
ACTUALLY ACHIEVE THE SAME THING
WITH A NON-BRAIN PENETRANT EP2
INHIBITOR.
AND SO WHAT WE CAN DO IS
EXACTLY THE SAME THING. THIS
IS A NON-BRAIN PENETRANT EP2
DEVELOPED BY PFIZER, WENT INTO
PHASE 1 SAFETY FILES. THAT WAS
ABORTED. NOT SURE WHY.
PRESUMABLY THE REASON MOST
THINGS GET ABORTED IS BECAUSE
THERE IS TOXICITY.
IN MICE WE WENT AHEAD AND
TRIED IT IN YOUNG AND OLD MICE.
AGAIN AS WE EXPECTED WE SAW
THIS VERY NICE RESCUE OF IMMUNE
FACTORS IN THE PLASMA BUT WHAT
WE DID NOT EXPECT WAS TO ALSO
SEE RESCUE IN THE HIPPOCAMPUS.
THAT WAS VERY PUZZLING. THAT IS
NOT BRAIN PENETRANT.
WE ALSO SAW A RESCUE OF
SPECIAL MEMORY AND PLASTICITY.
THIS INDICATES THAT AT LEAST
FOR THIS PATHWAY, PERIPHERAL
INNOVATION OF THIS INFLAMMATORY
PGE2 PATHWAY IS SUFFICIENT TO
RESCUE AGING.
THIS IS OUR SECOND MODEL. WE
ARE WONDERING HOW THIS IS
HAPPENING. AND IF YOU THINK, IF
YOU CONSIDER MYELOID CELLS IN
THE BODY AND THIS IS AN PEOPLE
IN OUR BRAINS WE HAVE ABOUT 25
BILLION MICROGLIA. WE ALSO
HAVE-- BUT THAT'S REALLY
DWARFED BY THE NUMBER OF
MACROPHAGES AND MONOCYTES IN
THE PERIPHERY WHERE YOU HAVE 27
BILLION AND 200 BILLION
MACROPHAGES.
WHAT WE ARE THINKING IS THAT,
REALLY IT IS A PERIPHERY THAT
IS DRIVING A LOT. HOW? THAT IS
REALLY INTERESTING. WE ARE
LOOKING AT THAT, AND A NUMBER
OF FOLKS IN THE LAB ARE LOOKING
AT THAT.
SO IT IS POSSIBLE THAT WE MAY
BE ABLE TO KEEP THE BRAIN
HEALTHY BY TWEAKING THE
PERIPHERAL MYELOID SYSTEM. THAT
IS AN OVERSIMPLIFICATION. BUT
THAT IS ONGOING.
ANYWAY I WANTED TO ACKNOWLEDGE
MOST IMPORTANT SLIDE, ALL THE
FOLKS IN THE LAB ESPECIALLY --
-- AND A WONDERFUL
COLLABORATORS AND I WANT TO
HIGHLIGHT MAKATO AND YUKI,
REALLY GOOD BIOCHEMISTS. AND OF
COURSE BIG SHOUT OUT TO THE NIH
FOR SUPPORTING THIS THANK YOU
VERY MUCH.
>>THAT WAS TERRIFIC. LIZ OVER
HERE. I AM WONDERING IF THESE
TREATMENTS DECREASE OR SOMEHOW
ALTER THE NUMBER OF MICROGLIA
EITHER IN THE REGION WHERE
THERE IS A LESION OR ANYWHERE
ELSE.
>>WE LOOKED AT THAT. NO
DIFFERENCE IN THE MICRO GLIAL
NUMBER. WE HAVE NOT LOOKED AT
IT AT THE NON-BRAIN PENETRANT
YET BUT IN BRAIN PENETRANT NOT
MUCH DIFFERENCE.
>>BEHIND THE PILLAR AGAIN.
GREAT TALK. AFTER YOU TREAT
YOUR ANIMALS WITH EP2 INHIBITOR
DID YOU LOOK AT THE
MITOCHONDRIA? DID THEIR NUMBER
OR THE QUALITY DECREASE OR
CHANGE?
>>YES THAT WAS THE SLIDE WITH
THE BRAIN PENETRANT, EP2
INHIBITOR. WE ARE LOOKING NOW
AT THE NON-BRAIN PENETRANT EP2
INHIBITOR. I SUSPECT THEY ARE
COMPLETELY DIFFERENT MECHANISMS.
THE BRAIN PENETRANT, LOTS OF
EP2 ON MICROGLIA. WE ALSO DID
SOME MASS LABELING AND
BIOCHEMISTRY TO SHOW THAT THE
EP2 IS SIGNALING TO THE
MICROGLIA. BUT FOR THE
NON-BRAIN PENETRANT IT IS GOING
TO BE SOMETHING ELSE, WHICH IS
KIND OF INTRIGUING. THANK YOU.
>>THANK YOU VERY MUCH FOR THE
TALK. IT WAS REALLY EXCITING.
LET'S GET SLIDES UP FOR THE
NEXT SPEAKER.
AND I WOULD LIKE TO WELCOME
BERNARD KHOR FROM BENAROYA WHO
WILL SPEAK ON AGING AND
AUTOIMMUNITY DURING DOWN
SYNDROME.
>>I WOULD LIKE TO THANK THE
COMMITTEE FOR THE PRIVILEGE OF
SHARING A WORK ON IMMUNE
DYSREGULATION WITH PEOPLE WITH
DOWN SYNDROME, AGING AND OTHER
LARGE-- THESE ARE MY
DISCLOSURES AND NOTHING
RELEVANT IN TODAY'S TALK.
OWNER REMIND EVERYONE THAT
PEOPLE WITH DOWN SYNDROME
INCLUDING THESE LUMINARIES HERE
HAVE AN EXTRA COPY OF
CHROMOSOME 21, THE MOST COMMON
COMMENTS ON CONDITION THAT
AFFECTS ABOUT ONE IN 700, AND
THESE INDIVIDUALS ALL HAVE
PROFOUND IMMUNE DYSREGULATION.
MANY FEATURES OF THIS IMMUNE
DYSREGULATION LOOK LIKE THE
INFLAMMATORY FEATURES THAT
ACCOMPANY AGING, WHICH IS TO
SAY INFLAAGING.
IN THIS IS A DEFINED MODEL OF
INFLAMMATION CLINICAL FEATURES
INCLUDE INCREASED
PREDISPOSITION TO AUTOIMMUNITY
UP TO 100 FOLD. BECAUSE THE
LIFESPAN OF PEOPLE WITH DOWN
SYNDROME IS OVER 60 AND GROWING
IN AUTO IMMUNITY, THIS CHRONIC
MORBIDITY IS IMPACT LATIN
CLINICAL FEATURES INCLUDE
IMPAIRED RESPONSE INFECTION
PARTICULARLY RESPIRATORY
INFECTION. IMPAIRED RESPONSE TO
VACCINES INCLUDING THE VACCINES
TO PROTECT AGAINST INFECTION
AND IN ADDITION, THERE IS
INCREASING EVIDENCE BETWEEN THE
LINK OF IMMUNE DYSFUNCTION LIKE
WE HEARD BETWEEN IMMUNE
DYSFUNCTION IN DOWN SYNDROME
AND MANY NEUROLOGICAL FEATURES
THAT WE OBSERVE IN PEOPLE WITH
DOWN SYNDROME INCLUDING THE
HIGHLY INCREASED INCIDENCE OF
EARLY ONSET OF ALZHEIMER'S AS
WELL AS THIS REGRESSION
SYNDROME THAT WILL TALK MORE
AND REFERRED EARLIER YESTERDAY
ABOUT PERIO --.
TAKEN TOGETHER WE THINK OF ME
IN THIS RELATION IS A CLEAR AND
PRESENT AND GROWING THREAT OF
THE HEALTH OF PEOPLE WITH DOWN
SYNDROME AND AFTER THAT
CHROMOSOME 21 IS THE SMALLEST,
AND WE SEE UNIQUE OPPORTUNITY
AND NEED TO UNDERSTAND WHICH OF
THE 225 GENES IN CRUMBS AND 21
ARE DRIVING WHICH ASPECT OF
IMMUNE THIS REVELATION AND HOW
WE CAN LEVERAGE THAT ALTOGETHER
TO DEVELOP NEW PRECISION
THERAPIES TO HELP NOT ONLY
PEOPLE WITH DOWN SYNDROME IS
WITH PEOPLE WITHOUT.
WE NEEDED A MUCH HIGHER
DEFINITION OF UNDERSTANDING HOW
IMMUNE ARCHITECTURE IS ALTERED
IN PEOPLE WITH DOWN SYNDROME.
SO TO DO THAT WE PUT TOGETHER
A COHORT OF 28 INDIVIDUALS WITH
DOWN SYNDROME. THEY SPAN A
WIDE RANGE OF AGES BECAUSE WE
WANTED TO UNDERSTAND HOW THINGS
CHANGE WITH AGE.
WE SPECIFICALLY SELECTED THESE
INDIVIDUALS DO NOT HAVE
AUTOIMMUNITY. THAT IS
IMPORTANT AND UNUSUAL FOR A
TYPICAL DOWN SYNDROME STUDY,
BECAUSE WE UNDERSTAND THAT
AUTOIMMUNITY ITSELF CAN ALSO
ALTER THE IMMUNE ARCHITECTURE
AND WE HAVE CONTROL
INDIVIDUALS WHO DO HAVE TYPE I
DIABETES IS A REPRESENTATIVE
AUTOIMMUNE DISEASE NOT TREATED
WITH IMMUNE MODULATION. AND WII
IMMUNOPHENOTYPE THESE
INDIVIDUALS USING DIFFERENT
TECHNOLOGIES AND MOST OF THE
TALK IS ABOUT (INDISCERNIBLE)
-- ABOUT A MILLION CELLS PER
PERSON GENERATE A LOT OF DATA
AND GENERATE A BRAND-NEW
ALGORITHM TO ANALYZE THE DATA
CALLED IMPACD. LUNG STORIES IS
THAT THIS HELPS US BUILD THE
HIGH-RESOLUTION MAP OF THE
IMMUNE ARCHITECTURE OF PEOPLE
WITH DOWN SYNDROME TO DATE WE
CAN IDENTIFY THE FULL DISCOVERY
CORRECTION AND 621 SUBSETS OR
MARKER COMBINATIONS AND SPREAD
THROUGH ALL MAJOR PHENOTYPES,
YOU CAN SEE THIS IN RED, THEY
CLUSTER AWAY FROM PEOPLE WITH
DOWN SYNDROME AND THIS GRANULAR
DATA ALLOWS US TO DO A LOT OF
ANALYSES, I DO NOT HAVE TIME TO
TELL YOU ABOUT, BUT WE CAN DO
INTEGRATED ANALYSES WITH MANY
EXTERNAL DATA SETS INCLUDING
COMPANION OMICS, AND WHAT I'M
GOING TO TALK TO YOU TODAY IS
INTEGRATED ANALYSIS WITH
CLINICAL METADATA, SPECIFICALLY
WITH ONE METADATA WHICH IS AGE.
OKAY?
WHAT WE WANTED TO DO WAS TO
BUILD A SIMPLE LINEAR MODEL
THAT DESCRIBES HOW IMMUNE
ARCHITECTURE CHANGES WITH AGE.
THIS HAS HISTORICALLY BEEN A
VERY CHALLENGING EXERCISE. WE
REALIZED THAT WE CAN ACTUALLY
SUCCEED USING OUR IMPACD
PIPELINE IN FOR EXAMPLE IN A
FIRST CONTROL MODEL IS
IMMUNOLOGY COMING IN WITH HER
FAVORITE SUBSETS.
WHAT IT MEANS IS THAT WE CAN
IDENTIFY THE INFORMATION
SUBSETS TO CORRELATE WITH AGE
AND THERE'S A LONG WINDED WAY
OF SAYING LINEAR MODELS TO BEST
WITH LINEAR PARAMETERS. WHEN
YOU PUT IN THE NEW PARAMETERS
YOU CAN GET A LINEAR MODEL THAT
WORKS VERY WELL.
THIS IS AN R2=0.92. .5 IS
CONSIDERED REALLY GOOD.
BECAUSE OF THE SIMPLE LINEAR
MODEL, WHY DO WE DO THIS?
BECAUSE IN A SIMPLE LINEAR
MODEL WE CAN IMMEDIATELY SUBMIT
THE DATA FROM OUR PARTICIPANTS
WITH DOWN SYNDROME. WHEN WE DO
THAT WHAT WE FIND IS THAT
UNBALANCED IMMUNE ARCHITECTURE
OF A PERSON WITH DOWN SYNDROME
LIKE THIS INDIVIDUAL, RESEMBLES
THAT OF A CONTROLLED WHO IS 5.2
YEARS OLD WHEN WE SEE ADVANCED
IMMUNE AGING AND DOWN SYNDROME
OF +5.2 YEARS.
WE CAN PLAY WITH THIS APPROACH
IN DIFFERENT WAYS. SO INSPIRED
BY GENE ENRICHMENT ANALYSIS --
WHAT WE SAID IS, WHAT HAPPENS
IF WE START WITH 651 SUBSETS
DIFFERENT BETWEEN PEOPLE WITH
AND WITHOUT TOWN CENTER? THIS
IS WHAT WE CALL THE DOWN
SYNDROME LENS MODEL, IT BRINGS
IN A FLAVOR OF DANCE AND
BIOLOGY, IT STILL HAS CONTROL
DATA AND GENERATE A MODEL THAT
WORKS VERY WELL.
MORE IMPORTANT THAN THE
QUANTITATIVE DIFFERENT IS WHAT
WE THINK OF THIS MODEL SHOWING
A QUALITATIVE DIFFERENCES I'M
GOING TO GET IN THE NEXT SLIDE.
NOW I DON'T HAVE TIME TO SHOW
YOU DATA. WHEN WE LOOK AT
PARTICIPANTS WITH DOWN SYNDROME
AND OTHER IMMUNE DISEASE, WHAT
WE FIND IS THAT THE ADVANCED
IMMUNE AGING IS EXACERBATED AND
THOSE INDIVIDUALS. AGAIN
SUPPORTING THE IDEA THAT THIS
SIGNATURE CAN PICK UP THINGS
THAT ARE BIOLOGICALLY
IMPORTANT.
THIS LETTER IS TO ASK, WHAT
HAPPENS TO INDIVIDUAL WHO DON'T
HAVE DOWN SYNDROME WHO DO HAVE
AUTO IMMUNITY? NOW WE ARE
GETTING TO A TYPE I DIABETES
COHORT AND OUR FIRST CONTROL
LENS MODEL WE SEE NO DIFFERENCE
ON AVERAGE IN IMMUNE AGING IN
PEOPLE WITH TYPE I DIABETES.
BUT TO OUR SURPRISE WHAT WE
FOUND IS THAT THE DOWN SYNDROME
LENS MODEL REVEALS ADVANCED
IMMUNE AGING IN PEOPLE WITH
TYPE I DIABETES ACROSS 3.9
YEARS. THIS TELLS US THAT
THERE IS SOMETHING ABOUT HOW
THE IMMUNE ARCHITECTURE IS
ALTERED WITH PEOPLE WITH DOWN
SYNDROME, BUT SHARE SIMILAR
DYSREGULATION, SIMILAR FEATURES
IN PEOPLE WITH TYPE I DIABETES
WHICH IS TO SAY THAT DOWN
SYNDROME CAN BE USED AS A LENS
THROUGH WHICH TO UNDERSTAND
TYPE I DIABETES. WE ARE TRYING
TO BREAK DOWN THE MECHANISTIC
BASIS OF ALL OF THAT.
AND ANOTHER REASON WHY WE
THINK THESE METRICS ARE
IMPORTANT, IS WE FOUND ANOTHER
CORRELATION THAT WAS REALLY
INTRIGUING, WHICH IS TO SAY
THAT THE MORE ADVANCED THE
PERSON'S IMMUNE AGE THE HIGHER
THE ARE IN THIS GROUP. RIGHT?
THE YOUNG THAT THEY TEND TO BE
WHEN THEY DEVELOP TYPE I
DIABETES. THIS RELATIONSHIP
HOLDS AFTER WE CORRECT FOR
CONFOUNDERS INCLUDING THE
RELATIONSHIP OF THE AGE, AND SO
FORTH.
IT SUGGESTS THAT THE MORE
PRECOCIOUS IMMUNE SYSTEM MAY BE
ABLE TO MORE EFFECTIVELY
DESTROY ISLET BETA CELLS A
YOUNGER AGE.
WE CAN DO THIS EXERCISE WITH
OTHER DATA, ROOM WITH THE SAME
INDIVIDUALS AND WE CAN BUILD A
VERY NICE PERFORMING MODEL
ENTIRELY OF CONTROL DATE ON
THIS MODEL SHOWS ADVANCED
AGING IN DOWN SYNDROME OF +12.4
YEARS; WE SEE THIS PHENOTYPE
VERY ROBUSTLY BUT NOT BECAUSE
GENE FUNCTION IS MUCH BETTER
ANNOTATED THAN CELL PHENOTYPE
AND WE CAN TAKE THE GENES THAT
CORRELATE WITH AGING, AND OTHER
PATHWAYS THAT ARE ENRICHED IN
THEM. WE CAN DO THIS WITH GENE
ENRICHMENT ANALYSIS, THAT
TAPS INTO TEAM AT A BLOSSOM AND
TURNS OUT THIS IS VERY
REASSURING BECAUSE OF THE
ANALYSIS OF DATA ALSO
IDENTIFIED AS A PATHWAY MOST
TIGHTLY LINKED AGENT WAS A
STRONG ENRICHMENT OF IMMUNE
SIGNALING PATHWAYS, WHICH IS
VERY REASSURING FOR
IMMUNOLOGISTS WHO STUDY THIS
PROCESS.
WHAT THIS REALLY DOES I THINK
IS HIGHLIGHT AN APPROACH TO
CONTINUE TO DIG INTO MECHANISMS
WHICH WE ARE NOW APPLYING IN
MORE PRECISE WAYS TO MORE
TARGETED CELL TYPES. RIGHT?
NOW I WANT TO TURN FOR LITTLE
BIT TO AN OBSERVATION REMEMBER
THAT PEOPLE WITH DOWN SYNDROME
ARE HIGHLY PREDISPOSED TO
AUTOIMMUNITY. SO WE SCOURED THE
LITERATURE, PUT TOGETHER A LIST
OF ABOUT 33 SUBSETS THAT ARE
DYSREGULATED IN DIFFERENT
AUTOIMMUNE DISEASES LISTED HERE.
AND WHAT HAPPENS IN THE
SUBSETS WITH PEOPLE WITH DOWN
SYNDROME THE DON'T HAVE
IMMUNITY.
THIS IS A VOLCANO PART OF THE
RESULTS. EACH THOUGHT IS ONE OF
THOSE 33 SUBSETS AND THE Y AXIS
IS THE P VALUE. AND YOU SEE
THAT ALL 33 SUBSETS ARE
SIGNIFICANTLY ALTERED IN PEOPLE
WITH DOWN SYNDROME WHO DON'T
HAVE IMMUNITY. SOME SUBSETS GO
UP AND SOME SUBSETS GO DOWN.
ALL SUBSETS ARE ALTERED IN
EXACTLY THE SAME DIRECTION AS
YOU SEE IN PEOPLE WITH
AUTOIMMUNITY. OKAY?
THIS IS A MORE TRADITIONAL
VIEW OF THREE OF THOSE
REPRESENTATIVE SUBSETS. THE
NAMES ARE NOT TERRIBLY
IMPORTANT. BUT WHAT THIS IS
TELLING US IS THAT IN PEOPLE
WITH DOWN SYNDROME WE DON'T
HAVE OUR IMMUNITY IT'S ALSO
THAT THE TRISOME 21 IS
SUFFICIENT TO REMODEL THE
ARCHITECTURE FOR AUTOIMMUNITY.
WE ARE CERTAINLY INTERESTED IN
WHAT THE MECHANISM IS. THE
FIRST OBVIOUS THING TO LOOK FOR
WAS, IS THIS RELATED TO
ADVANCED IMMUNE AGING? WE KNOW
THAT INCIDENCE OF AUTOIMMUNITY
CAN INCREASE WITH AGE, SO FOR
EACH OF THE 33 SUBSETS WE TRY
TO DRAW A LINE AND WE ASK THE
COMPUTER TO TELL US WHAT IS THE
P VALUE OF THAT LINE ON THE
Y-AXIS AND WHAT IS THE SLOPE.
THIS IS AGAIN A VOLCANO PLOT
OF THAT EXERCISE, IF IT CHANGES
WITH AGE WE EXPECT THE DOCTOR
FROM THE RED BOXES. LONG STORY
SHORT ONLY ONE FALLS IN THE
RED BOX IN ONE WAY TO INTERPRET
THIS IS TO SUGGEST THAT THE
MECHANISMS THAT REGULATE THIS
AUTOIMMUNE SEEM TO BE QUITE
DISTINCT FROM THOSE REGULATE
IMMUNE AGING WHICH IS TO SAY
THAT WE THINK THE DOWN SYNDROME
IS AT -- HAS AT LEAST TWO VERY
IMPORTANT BIOLOGICAL ASPECT OF
IMMUNE REGULATION.
IF YOU LOOK AT PUBMED,
MECHANISMS OF IMMUNE THIS
RELATION IN DOWN SYNDROME 99%
ARE -- AND (INDISCERNIBLE) --
INTERFERENCE IS VERY IMPORTANT.
THE SIMPLE QUESTION WAS IS
INTERFERON DOING EVERYTHING?
THIS IS ONE PANEL FROM A WHOLE
SET OF -- TO SHOW ME THE
INFLAMMATORY -- -- DISABILITY
IS A LARGE BODY OF WORK BUT WE
ARE NOT THE FIRST TO OBSERVE
THAT.
BUT NOW WHAT WE CAN DO IS PAIR
THAT WITH WHAT WE ARE FINDING
IN OUR IMPACT ANALYSIS. AND
ONE OF THE THINGS IMPACTING FOR
US IN THE COMPETITION LOGARITHM
IS TO CLEARLY SHOW HOW EACH AND
EVERY SINGLE MARKER IS THIS
(CORRECTION) DYSREGULATED, IN
VARIOUS CELL SUBSETS OF
BIOLOGICAL INTEREST.
WHAT YOU WILL IMMEDIATELY SEE
IS THE NAïVE CD4S A
QUALITATIVELY REMODELING PEOPLE
WITH DOWN SYNDROME AND THE
STARS TELL YOU EXACTLY WHAT
MARKERS TO PAY ATTENTION TO.
NOW WE HAVE A GUIDE, A MAP, A
TREASURE MAP IF YOU WILL. WE
CAN DO A VERY SIMPLE
EXPERIMENT. WE CAN TREAT
HEALTHY CONTROLLED PBMCS, CAN
WE RECAPITULATE ANY OF THESE
DIFFERENCES? THE ANSWER TO OUR
SURPRISE WAS NO.
THE SAME TIME WE HAD DONE A
PARALLEL EXPERIMENT WHICH WAS
CAN ISLE 6 DRIVE ANY OF THESE
DIFFERENCES? ISLE 6 CAN DRIVE
THREE OF THESE DIFFERENCES. SO
SOME BUT NOT ALL. RIGHT?
SO THE LINE IN THE PAPER IS
THAT WE HAVE IDENTIFIED IL6 IS
A NOVEL DRIVER OF IMMUNE
DYSREGULATION IN PEOPLE WITH
DOWN SYNDROME. THIS WAS THE
WORK BY -- -- WELL DONE, BUT
WHAT I WANT TO POINT OUT IS
THAT THERE IS A LOT LEFT TO BE
UNDERSTOOD. IMMUNE
DYSREGULATION IN PEOPLE WITH
DOWN SYNDROME IS NOT ALL
INTERFERON; NOT ALL INTERFERON
AND IL6, WE HAD IDENTIFY THE
THIRD PLAGUE WHICH I DON'T HAVE
TIME TO SHOW.
WHAT AM SHOWING YOU IS THAT
DOWN SYNDROME CAN BE USED AS A
LENS THROUGH WHICH WE CAN
UNDERSTAND SPECIFIC PATHWAYS IN
AGING AND AUTOIMMUNITY. WE ARE
BUSY UNRAVELING THE MECHANISMS
OF THAT LENS AND I WANT TO WRAP
WITH SOME DISCUSSION OF WHAT WE
SEE IS FUTURE OPPORTUNITY.
WE ARE REALLY EXCITED ABOUT
THE IDEA OF USING DOWN SYNDROME
AS A LENS TO IDENTIFY AND
UNDERSTAND BROADLY RELEVANT
PATHWAYS OF PATHOBIOLOGY.
THERE ARE AT LEAST TWO THE
POP-UP ALREADY: AGING AND WHAT
WE THINK THE ANSWER WAS HELPING
US DO SOME STANDING AGING
BEYOND THE MONOLITHIC PROCESS.
AGING IS NOT JUST THE ONE
THING THAT HAPPENS. THERE ARE
SPECIFIC PROCESSES OF AGING
THAT SEEMED TO BE THIS RELATED
IN DOWN SYNDROME THAT
PREDISPOSES A SPECIFIC OUTCOME.
SO WE ARE GENERATING THE
ABILITY TO BUILD THESE IMMUNE
BLOCKS IN MANY DIFFERENT WAYS;
USE TRANSLATIONAL IMPLICATIONS
AND FOR EXAMPLE YOU THINK OF A
HIGH DOSE OF FLU VACCINE, THOSE
ARE SAFE AND EFFICACIOUS FOR
PEOPLE OVER 65 YEARS OLD. THAT
IS DRIVEN BUT WHAT I WOULD LIKE
TO CALL DRIVERS LICENSE AGE,
THE NUMBER OF A PIECE OF
PLASTIC AND WHAT YOU WANT IS A
BIOLOGICAL OUTCOME.
SO WE BUILT AN IMMUNE CLOCK TO
GIVE A BIOLOGICAL METRIC THAT
DOES BETTER. CAN WE USE THIS
TO PREDICT LIKELIHOOD OF OTHER
DISEASES BEGAN TYPE I DIABETES,
ALZHEIMER'S, UNHEALTHY AGING
OUTCOME? CAN WE BUILD OTHER
LENSES?
AND USING OTHER COHORTS TO GET
TO THIS IN A MUCH MORE
COORDINATED AND COMPREHENSIVE
FASHION AND WE THINK IT DOWN
SYNDROME TEACHES US A LOT MORE
ABOUT AUTOIMMUNITY. WITH
THINK IT IS A UNIQUE
OPPORTUNITY TO WATCH THE
PROGRESSION LONGITUDINALLY OF
AUTOIMMUNITY AND THIS IS
RELEVANT, NOT ONLY TRADITIONAL
THINGS IN THE NIAID PORTFOLIO
BUT PEOPLE WITH DOWN SYNDROME
ARE PREDISPOSED TO REGRESSION
SYNDROME WHICH HAS A LOT OF
THINGS REMINISCENT OF
AUTOIMMUNE DIMENSION AND WE ARE
CERTAINLY INTERESTED IN THE
MECHANISMS AND I WILL THANK THE
PEOPLE WHO DID THE WORK. I
CERTAINLY NEED TO THANK THE
PARTICIPANTS IN THE FAMILIES.
WONDERFUL CLINICAL
COLLABORATORS, UNIQUE CLINICAL
COLLABORATIONS THAT ALLOWS US
TO DO THIS WORK IN SEATTLE HARD
TO DO ELSEWHERE IN MY LONGTIME
COLLABORATOR JANE BUCKNER AND
GAUTAM GOEL, LONG-TERM
COLLABORATOR AND THIS IS OUR
FUNDING AND THANK YOU. I AM
HAPPY TO TAKE YOUR QUESTIONS.
>>(INDISCERNIBLE), PATIENTS
WITH DOWN SYNDROME,
AUTOIMMUNITY IS THERE
(INDISCERNIBLE).
>>THAT IS AN EXCELLENT
QUESTION. IT DEPENDS ON THE
OTHER IMMUNE DISEASE YOU ARE
TALKING ABOUT. FOR EXAMPLE IF
YOU LOOK AT CELIAC, THERE IS
STILL PREVALENCE OF RISK MAC
ALLELE ASSOCIATED, BUT THERE IS
INCREASED EVIDENCE THAT
SUGGESTED THAT ASSOCIATION IS
NOT AS TIGHT SO THERE SEEM TO
BE HLA RISKS, BUT THE TIGHTNESS
OF THAT ASSOCIATION MAY BE
ALTERED.
>>(INDISCERNIBLE) FROM
NATIONAL INSTIUTE ON AGING. I
SEE (INDISCERNIBLE) -- SO DOES
TI MEAN THAT T REX (PHONETIC)
NCREASE? OR DOES IT MEAN
(INDISCERNIBLE) INCREASES ON TD
4 CELLS.
>>WE THOUGHT THIS WOULD BE A T
REG PHENOTYPE. T REG NUMBERS
ARE NOT INCREASED IN PEOPLE
WITH DOWN SYNDROME AND
EXPRESSION I SHOWED WAS NOT IN
T REG, MOSTLY IT WAS AN
EXPRESSION IN DYSREGULATION,
WHAT WE CALL NAïVE TD 4
POSITIVE CELLS CLOSER TO WHAT
YOU ARE DESCRIBING. GREAT
QUESTION.
>>REALLY NICE. I AM CURIOUS.
NOW THAT WE HAVE A LITTLE
BETTER IDEA OF WHAT WE HEARD
YESTERDAY THE IMMUNOLOGICAL
(INDISCERNIBLE) GIVING US AN
IDEA OF CONNECTING IMMUNOLOGY
THROUGH DISEASE, DOWN SYNDROME
PATIENTS HAVE A LOSS OF --
(INDISCERNIBLE) CAN YOU PREDICT
THAT SOMEONE CAN MATCH WITHIN
NORMAL OLDER INDIVIDUAL.
>>I HAVE SOME ANSWERS BUT NOT
ALL THE ANSWERS TO THAT
QUESTION. CERTAINLY ONE OF THE
MOST PROMINENT FINDS YOU WILL
FIND IS A PROMINENT DECREASE IN
NAïVE CD4 AND NAïVE CD5S.
REPERTORY ANALYSES WE HAVE A
LITTLE BIT OF DATA, BUT
HONESTLY WE DON'T HAVE THE
MONEY. WE HAVE NOT HAD THE
MONEY TO ACT THAT RIGOROUSLY
YET. ALL OF THIS GETS INTO HOW
WE DEFINE AGING AND HOW WE
DEFINE AGING MATTERS. BECAUSE
TO ME THE GOLD STANDARD IS NOT
SIMPLY TO GET BACK TO WHAT MY
DRIVERS LICENSE TELLS ME. BUT
REALLY TOGETHER THIS IDEA OF,
HOW CAN WE LEVERAGE THIS TO
IDENTIFY WHO IS MOST AT RISK?
THAT IS A TYPE OF QUESTION WE
NEED TO ADDRESS. THANK YOU FOR
THAT.
>>HI. NICK-- UNIVERSITY OF
VIRGINIA. REALLY WONDERFUL TALK
LOOKS LIKE CELL SITE RELATION
WAS PART OF THE DOWN SYNDROME
TRANSCRIPTION NO PATHWAYS. YOU
HAVE AN IDEA OF WHAT THE ROLE
OF SELF-REGULATION IS? THE YOU
SEE MORE (INDISCERNIBLE), OR
SOME OTHER TYPE OF REGULATION?
>>WHAT WE ARE SEEING THERE IS
GENES AND RICH ANALYSIS FROM
FULL BLOOD RNC. WHERE IS THE
SIGNAL COMING FROM? I THINK IT
SUGGESTS THERE IS A PHENOTYPE
PROLIFERATION SOMEWHERE ACROSS
DIFFERENT SUBTYPES. IS IT IN
ONE TYPE OF CELL TYPE? THOSE OF
THE TYPES OF QUESTIONS WE NEED
TO ASK.
>>WONDERFUL TALK. I CANNOT
HELP BUT NOTE THAT YOUR
COMPLEMENT PATHWAY IS
HIGHLIGHTED; YOU DO NOT
HIGHLIGHTED, BUT IT IS LISTED
THERE. DOWN SYNDROME HAS NO
(INDISCERNIBLE) 21 THAT
INCLUDES ATP? THAT PREDISPOSES
THOSE INDIVIDUALS TO
ALZHEIMER'S DISEASE. IN THE
LAST REFERENCE SHOWED YESTERDAY
THIS PAPER THE PROFILE THOSE
COMPLEMENT PATHWAYS BETWEEN
AGING AND ALZHEIMER'S. I WAS
WONDERING IF YOU WOULD LOOKING
AT THIS COMPLEMENT PATHWAY IN
YOUR COHORT, AND WITH LATER
COHORTS AND WHETHER YOU CAN USE
SOME KIND OF--
>>THAT IS A GREAT QUESTION.
AFTER THAT TALK, I REALIZED I
NEEDED TO GO AND DO THAT MORE
CAREFULLY, THAT IS THE SHORT
ANSWER. (LAUGHTER) I HAD THE
DRAWBACK THAT I CAME TO, THE
MOUSE T CELL BIOLOGY. WHAT WE
ARE LEARNING HERE IS THAT THERE
IS A LOT OF INTERPLAY BETWEEN
ALL THE DIFFERENT CELL TYPES.
AND SO I THINK THAT WOULD BE
GREAT. IF THERE ARE
COLLABORATIVE OPPORTUNITIES IT
WOULD BE GREAT.
>>THANK YOU.
THANK YOU ALL VERY MUCH FOR THE
WONDERFUL TALKS AND SHARE YOUR
DATA YESTERDAY AND IF YOU COULD
MAYBE START BY TWO MINUTES, A
COUPLE OF SENTENCES MAJOR GAPS
IN THE FIELD.
>>HI. I THINK YOU SHOULD GET
INTO IT. SO THE KEY ASPECT OF
MY TALK YESTERDAY WAS
UNDERSTANDING THE ROLE OF --
INNOVATION AND (INDISCERNIBLE)
TO REJUVENATE TISSUE. HOW IS
THIS DONE? WE ARE WORKING ON IT
RIGHT NOW. -- I BELIEVE THAT
THERE ARE ACTIONS AND
ACTIVITIES THAT ARE IMPORTANT
IN HOMEOSTASIS, MAY BE ALTERED
IN VARIOUS DISEASES. THAT IS
ALL I HAVE TO SAY.
>>
>>I THINK THAT IS SOMETHING
VERY NICE THAT YOU JUST SAID.
BECAUSE EVERYTHING LINKS SO
MUCH, IT IS NOT TO THINK ABOUT
WAYS THAT WE CAN SET UP OUR
EXPERIMENT TO ENABLE OTHERS. I
AM NOT A PERIPHERAL NEUROLOGIST
BY ANY STRETCH OF THE
IMAGINATION BUT MEETINGS LIKE
THIS BRING CONNECTIONS ON HOW
WE CAN SET OF NUMBERS OF
MATERIALS.
>>THERE IS INCREASING INTEREST
IN HOW TO DO THE IMMUNE SYSTEM
FOR NEURODEGENERATIVE DISEASES,
PARTICULARLY ALZHEIMER'S
DISEASE. MY TALK YESTERDAY
SORT OF SUPPORTED THE PREMISE
THAT WE NEED TO REDUCE THE
IMMUNE SYSTEM BY TARGETING FOR
EXAMPLE THE COMPLEMENT PATHWAY.
THAT IS SUPPORTED BY OTHER
STUDIES.
ON THE OTHER HAND THE IMMUNE
SYSTEM NEEDS TO BE ACTIVATED.
A GOOD EXAMPLE IS
(INDISCERNIBLE). SO WHAT
HAPPENS IN THE (INDISCERNIBLE)
CASE, THE GENETIC POLYMORPHISM
INCREASES; THAT LEADS TO LOSS
OF FUNCTION. AND OF THOSE
MICROGLIA CANNOT BE ACTIVATED.
THE QUESTION IS, DO YOU REALLY
WANT TO ACTIVATE IT? DO YOU
WANT TO INACTIVATE IT? AT WHAT
POINT DO YOU WANT TO ACTIVATE
IT? AT WHAT POINT DO YOU WANT
TO INACTIVATE IT? WHAT IS THE
DURATION? ANOTHER IMPORTANT
POINT I WANT TO APPLY IS THE
PERIPHERAL EXPRESSION. IF YOU
JUST TARGET THE PERIPHERAL
EXPRESSION, YOU ALSO SEE THE
(INDISCERNIBLE), HOW DOES THIS
(INDISCERNIBLE)? THOSE ARE ALL
IMPORTANT QUESTIONS AND GAPS
AND OPPORTUNITIES IN THE FIELD.
>>YEAH, I ABSOLUTELY AGREE
WITH EVERYBODY. I THINK
THINKING OF OUR FIELD, IN A
MORE NARROW WAY, SO THE FIELD
OF TRYING TO TACKLE NEURO-
INFLAMMATORY,
NEURODEGENERATION, LIKE
ALZHEIMER'S OR PARKINSON'S
WHICH OF THESE REALLY LONG
PERIODS. PARKINSON'S FOR
EXAMPLE YOU HAVE GI SYSTEMS TWO
DECADES BEFORE PRESENTATION.
SO I THINK A HUGE CHALLENGE IS
PRETTY OBVIOUS. HOW DO YOU
ACTUALLY ANTICIPATE WHO'S GOING
TO GET THESE DISEASES? WE NEED
BETTER BIOMARKERS. PROBABLY
IMMUNE BIOMARKERS. PROBABLY. I
SUSPECT AT LEAST IN
ALZHEIMER'S, THE GENETICS IS
QUITE CLEAR. THE MYELOID SYSTEM
IS QUITE IMPORTANT. I WOULD
SAY IT PROBABLY IS NOT JUST
MICROGLIA BUT THE PERIPHERY.
THERE IS LITTLE BIT OF DOGMA IN
OUR AREA WHERE PEOPLE ARE NOT
THINKING OUTSIDE OF THE BRAIN.
BUT WHAT WE REALLY NEED, I
THINK THE BIGGEST PROBLEM IS WE
DO NOT HAVE BIOMARKERS. WE DO
NOT HAVE PROPER IMMUNE
BIOMARKERS TO ANTICIPATE OR TO
TRACK THESE FOLKS
LONGITUDINALLY. AND I KNOW IN
THE ALZHEIMER'S FIELD AND IN
PARKINSON'S, IT IS A BIG AREA
OF INVESTIGATION. IT IS GOING
TO BE TRICKY. YOU'RE TALKING
ABOUT LONGITUDINAL STUDIES WITH
20 YEAR TIMELINES.
>>I WILL OPEN IT UP TO THE
AUDIENCE IF THERE ARE OTHER
CONTRIBUTIONS OR GAPS IN THE
FIELD.
>>THAT WAS REALLY A NICE
PHRASE, THINK OUTSIDE THE
BRAIN. I'M GOING TO USE IT. I
THINK YOUR DATA WITH PERIPHERAL
EFFECTS IS REALLY GOOD. I WAS
WONDERING IF YOU HAVE ANY MORE
THOUGHTS ABOUT HOW THIS IS
AFFECTING THIS, OR IF THERE IS
-- THAT GOES BACK TO THE BRAIN.
A LOT OF CNS PEOPLE HAVE
FORGOTTEN ABOUT AFFERENCE AND
INFERENCE (PHONETIC).
DO YOU KNOW IF THERE ARE EP2
EFFECTS (INDISCERNIBLE), OR IS
THIS A HEMORAL EFFECT?
>>THAT IS A GREAT QUESTION WE
HAVE NOT THOUGHT ABOUT
EFERENCE. AGAIN, GETTING BACK
TO THE IDEA OF PERIPHERAL
NERVOUS SYSTEM, I THINK IT IS
REALLY IMPORTANT TO LOOK AT
IMMUNE EFFECTS ON THE
PERIPHERAL NERVOUS SYSTEM,
PARTICULARLY ON AGING AND MAYBE
IN THESE DISEASES. I WOULD
REALLY THINK ABOUT PARKINSON'S
HERE. BUT WE HAVE NOT LOOKED.
WE DON'T REALLY KNOW YET WHAT
IS DRIVING THIS, I SUSPECT THE
REDUCTIONIST APPROACH IS NOT
GOING TO BE VERY USEFUL.
PROBABLY MANY DIFFERENT THINGS,
ALL KIND OF SYNERGIZING TO
CHANGE PROBABLY THE
BLOOD-BRAIN BARRIER,
ENDOTHELIAL CELLS, WE ARE
SEEING CHANGES IN ASTROCYTES
WHEN WE DO TRANSCRIPTOMIC.
IT'S GOING TO BE A REALLY FUN
PROBLEM TO CRACK. YEAH.
>>MAYBE I WANT TO ADD. SO I
HAVEN'T HEARD ABOUT MENINGY.
THERE'S A LOT OF -- CELLS OVER
THERE (INDISCERNIBLE).
>>FOR ME IT IS A BALANCE OF
TRYING TO APPRECIATE THE
COMPLEXITY OF THE SYSTEM, I
HEARD A MENTION OF LOOKING AT
AN OVERLAP BETWEEN DIFFERENT
DISEASES, ALSO INCORPORATING
SYSTEM BIOLOGY AND ANALYSIS
THAT ALLOWS YOU TO APPRECIATE
THAT IMMUNE CELLS CAN INTEGRATE
MULTIPLE SIGNALS OVER A VERY
SHORT PERIOD OF TIME. AND
OFTEN TIMES THEY ARE QUITE
FLEXIBLE. RIGHT? HOW CAN WE
APPROPRIATELY TEASE OUT WHAT IS
HAPPENING IN THE PATHWAYS
MANNER? IT IS NOT ALWAYS
STRAIGHT.
THERE HAS BEEN A LOT OF
ADVANCES RECENTLY AS FAR AS
SINGLE CELL RNA SEQUENCING, AND
SYSTEM BIOLOGY WORK. I THINK
HOPEFULLY THAT WILL HELP
INTEGRATE MORE OF A
REDUCTIONIST APPROACH WITH A
BIGGER, BROADER APPROACH. I
DON'T KNOW IF-- I KNOW
PERIPHERAL NERVES ARE QUITE
DIFFICULT TO STUDY FROM SINGLE
CELLULAR APPROACH. PERHAPS
MOUSE MODELS OUT THERE WOULD BE
USEFUL.
>>SO WE DO NOT HAVE THE TOOLS
TO SPECIFICALLY LOOK AT
LOCATION. YOU CAN INTERRUPT
THE WHOLE SYSTEM, PERIPHERAL
NERVOUS SYSTEM, BUT HOW DO YOU
CONTROL THAT? SO WE CAN TREAT
WITH DIFFERENT DRUGS, YOU CAN
TREAT WITH DIFFERENT
(INDISCERNIBLE), BUT YOU WILL
ELIMINATE YOUR VEIN FROM
EVERYWHERE, (INDISCERNIBLE) IT
IS EVERYWHERE.
HOW CAN WE GET IT TO BE
SPECIFIC FOR LOCATION? THE
OTHER THINGS WE HAVE NO IDEA
HOW TO INTERACT WITH ALL THE
IMMUNE CELLS. THERE ARE A LOT
OF IMMUNE CELLS! WE ALL TALKED
ABOUT THE DIVERSITY OF THE
IMMUNE CELLS. HOW CAN WE PICK
OUT THE SYSTEM? THAT IS THE
COMPLEXITY HERE.
WE KNOW THAT THERE IS A LOT OF
INTERACTION WITH MACROPHAGES;
WITH THE PANCREAS,
PANCREATITIS. WHAT DO WE SEE?
A LOT OF MACROPHAGES ATTACHING
TO THOSE NERVES. SO IT IS
SOMETHING TO BE THINKING ABOUT.
THE IMMUNE CONNECTION. THE
NEURAL IMMUNE CONNECTION
OUTSIDE OF THE BRAIN AS WELL.
I DON'T STUDY THE BRAIN. THAT
IS BECAUSE I DON'T KNOW
ANYTHING ABOUT IT. SO, IT'S
VERY DIFFICULT. WE CAN DEVELOP
TOOLS TO BE ABLE TO INVESTIGATE
IT FURTHER. IT IS GOING TO BE
FURTHER STUDIED BY YOU GUYS. I
THINK THAT IS VERY IMPORTANT.
>>I THINK COMPLEXITY, WE HAVE
TO LOOK AT WHAT STAGE THE ONSET
OF DISEASES OCCURRING. AND WHY
IT IS ASSOCIATED WITH AGING.
WE KNOW THAT IN AGING,
MYELOPOESIS IS INCREASED AND
(INDISCERNIBLE) -- ACTIVATION
OF IMMUNE CELLS.
(INDISCERNIBLE) OR FROM BRAIN,
AND THEN ADAPTIVE IMMUNITY IS
DOING BAD THINGS. OR IS IT DUE
TO ACTIVATION IN ALZHEIMER'S
DISEASE? THESE ARE MYELOID T
CELLS (INDISCERNIBLE).
>>SO ALMOST EVERY TALK WE HAVE
HAD SINGLE CELL-- DATA. ONE
QUESTION WHICH WE HAVE IS
RELATED TO IMMUNE CELLS. DO YOU
DEFINE THEM BY SURFACE
PHENOTYPE? OR DO YOU DEFINE
THEM BY AUTOGENIC TRANSPORT?
MANY TIMES WRITING PAPERS
PEOPLE SAY CERTAIN THINGS, AND
YOU LOOK AT WHAT TRANSCRIPT
WERE USED AND I THINK THERE'S A
BIG GAP THAT LEADS INTO
COMPLICATED INTERPRETATIONS OF
THE DATA
THERE HAS TO BE SOME KIND OF
NOT CONSENSUS BUT SOME KIND OF
PLAN WE DECIDE HOW YOU DEFINE
THE IMMUNE CELLS OF TYPE. DO
YOU GO BY TRANSCRIPT? THE
ACTUALLY LOOK FOR PROTEIN
EXCRETION ON THE SURFACE?
>>I WOULD ADD, I TOTALLY
AGREE. WE HAVE BEEN BURNED BY
TRANSCRIPTOMIC SEVERAL TIMES
NOW. THERE IS A HUGE UP
REGULATION IN A PARTICULAR
PATHWAY, AND IT TURNS OUT THE
PROTEINS ARE DOWN. SO YOU
KNOW, IT HAS TO BE COUPLED;
WITH IMMUNE CELLS YOU CAN CHECK
SURFACE EXPRESSIONS BUT WITH
OTHER CELL TYPES TO BECOME
PROBLEMATIC.
>>CAN I ADD TO THAT? IT MIGHT
BE THAT CELL SURFACE MARKERS
CHANGE WITH AGING AND WE ASSUME
A CELL IS LOST IF YOU USE FLOW
CYTOMETRY OR ANY SURFACE
STAINING; THAT TERRIFIES ME.
>>OR CELLS UPREGULATE A MARKER
FOR DIFFERENT REASONS. I KNOW
THERE WAS A QUESTION IN THE
BACK.
>>SORRY. BEHIND THE COLUMN
AGAIN. I WANTED TO SAY THIS IS
A SIMILAR GAP THAT I BROUGHT UP
YESTERDAY. TO DEEPEN THE
DISCUSSION, IF WE THINK ABOUT
THE DEFINITION OF THE CELL
SUBPOPULATION, REALISTICALLY IF
YOU SHOW THAT IT IS
TRANSCRIPTIONALLY DIFFERENT,
DRIVEN BY A DIFFERENT SET OF
TRANSCRIPTION FACTORS AND THE
EPIGENETIC REVIEW, IS THE GOLD
STANDARD TO CALL THAT A CELL
TYPE. CAN YOU TRULY DEFINE IT
BY THE EXISTING SET OF
CYTOMETRY MARKERS? HOW WELL
DOES IT MATCH? THAT IS A BIG
CHALLENGE. DOES NOT MATCH
NECESSARILY RIGHT NOW.
EVEN MORE SO YOU CAN TALK
ABOUT THE SET OF MARKERS THAT
MATCH IT IN PARTICULAR
CONDITION SUCH AS HOMEOSTATIC
ONE; BUT ONCE YOU HAVE
INFLAMMATION AS YOU MENTIONED
SOME OF THE SURFACE MARKERS CAN
BEGIN TO LOSE EVEN BEFORE THE
(INDISCERNIBLE) CHANGES.
YESTERDAY IN THE TALK, THEY
START UP REGULATING SOME OF THE
MARKERS AND LOSING OTHERS
BEFORE THE GLOBALLY CHANGE OUR
FROM THE NAïVE CELLS. AND THE
FIRST STEP IN MATCHING THE
EXISTING SINGLE CELL RNA DATA,
IDEALLY I WOULD SAY SINGLE
CELLED RNA DATA SUCH AS IN --
PAPER WAS DONE. AND MATCHING
THE STATES TO DATING STRATEGIES
THAT WOULD BE IDEALLY
POPULATING. IT IS A HUGE
CHALLENGE AND I WANTED TO
UNDERSCORE THAT. THANK YOU.
>>I WOULD AGREE WITH THAT. I
DON'T THINK THAT THERE IS A
NEED TO SAY-- I AM NOT QUITE
SURE THAT WE ARE AT THAT POINT
THAT WE CAN DEFINE THAT THERE
IS ONE GOAL STANDARD WAY TO
GROUP THEM ALL. RATHER I THINK
THEY ALL PROVIDE IMPORTANT AND
COMPLEMENTARY DATA.
THE TRANSCRIPTION OF DATA IS
IMPORTANT. WE HAVE
(INDISCERNIBLE), AT THE END OF
THE DAY A LOT OF WHAT WE ARE
TALKING ABOUT IS PROTEIN
INTERACTION. AND DOES REQUIRE
PROTEINS. SO THEY ALL GIVE US
IMPORTANT IDEAS, AND IMPORTANT
LENSES, AND WE ALSO KNOW THESE
IMMUNE CELLS OR MORE OF THE
SPECTRUM. RIGHT?
>>I SUPPOSE MY COMMENT AT THIS
POINT WOULD BE RECOGNIZING THAT
MANUSCRIPT ARE PDF IN THE
COMPUTER AND OFTEN TIMES
SCIENTISTS THAT TRY TO
INCORPORATE WHAT THE LAB HAS
PUBLISHED CAN HAVE DIFFICULTIES
LOOKING AT THE HEAT MAP OR
EXPORTING EXCEL FILES. SO
PIPELINES THAT GET SINGLE CELL
RNA SEQUENCING TO THE PUBLIC ON
WEB-BASED PLATFORMS WOULD BE
HELPFUL; IN A WAY THAT YOU CAN
SEARCH FOR YOUR GENE OF
INTEREST OR YOUR PATHWAY OF
INTEREST. I KNOW THERE'S SOME
REALLY NICE ONES OUT THERE THAT
CAN BE USED TO SORT OF HAVE AS
A BACKDROP AND HOW TO SET THAT
UP. MAYBE. ANY FINAL COMMENTS
FROM OUR SPEAKERS?
WELL THANK YOU VERY MUCH FOR A
REALLY NICE SESSION. AND -- WE
WILL NOW TAKE A 15-MINUTE BREK
>>I WOULD LIKE
TO INTRODUCE DR. LAUREN -- FROM
THE UNIVERSITY OF MINNESOTA WHO
WILL BE TALKING TO US ABOUT THE
ROLE OF -- CELLS IN AGE-RELATED
DISEASES AND WE ARE VERY HAPPY
TO HAVE HER WITH US BECAUSE SHE
HAS BEEN FIGHTING A BUG AND SHE
HAS BEEN VERY KIND TO BE
PRESENT. THANK YOU LAURA.
>>THANK YOU VERY MUCH. IT IS
APPROVERS TO BE HEARD FROM AN
AGING PERSPECTIVE. I AM NOT AN
IMMUNOLOGIST BUT I LOOK FORWARD
TO COLLABORATING WITH YOU.
I WANT TO CONGRATULATE THE
MEETING'S ORGANIZER. THIS IS
BEEN AN EXCEPTIONAL COLLECTION
OF DIVERSE TOPICS COMING
TOGETHER THAT ARE REALLY GOING
TO BE IMPACTFUL. THANK YOU
VERY MUCH.
I DID ADD INFLAMMATION TO MY
TITLE. I AM SHOCKED THAT
SENESCENT CELLS HAVE NOT BEEN
FORMALLY INTRODUCED AT THIS
MEETING YET. I AM SURE MANY OF
YOU ARE FAMILIAR WITH SENESCENT
CELLS.
THERE IS A SET OF FACTORS BOTH
INTRINSIC AND ENDOGENOUS THAT
CAN TRIGGER SENESCENT CELLS. WE
NEED TO ARREST THIS IN ORDER TO
DUPLICATE CELLS THAT ARE
STRESSED OR DAMAGE.
SO HALLMARK FEATURES OF
SENESCENT CELLS ARE UP
REGULATION OF P53, P21, P16, SO
THAT WILL STABLY ARREST THE
CELLS ANOTHER HALLMARK GENOME
IS THERE IS ALWAYS EVIDENCE OF
GENE OF TOXIC STRESS. DOES NOT
HAVE TO BE AN INSTIGATOR BUT
YOU END UP WITH TELOMERE AND --
OTHER EVIDENCE OF GENOTOPIC
STRESS.
THERE IS MITOCHONDRIAL
CHANGES, TYPICALLY DNA IN THE
CELLS AND OF COURSE THE
SENESCENT ASSOCIATED PHENOTYPE,
THERE'S A NUMBER OF FACTORS
LISTED HERE MOSTLY
PRO-INFLAMMATORY BUT ALSO
INCLUDING A LOT OF PROTEASES,
AND THINGS THAT CAN MANIPULATE
THE EXTERNAL ENVIRONMENT OF
THESE CELLS. THESE ARE VERY
TISSUE DISRUPTING, AND
PRO-INFLAMMATORY CELLS.
THE IDEA IS THAT THIS --
ATTRACTS THE IMMUNE SYSTEM TO
TRY AND COME AND CLEAR THE
CELLS, BECAUSE THEY ARE
RESISTANT OR REALLY DON'T LIKE
TO UNDERGO APOPTOSIS AT ALL SO
WE COUNT ON THE IMMUNE SYSTEM
GETTING RID OF THE SENESCENT
CELLS.
ANOTHER POINT THAT I WANT TO
MAKE ABOUT THIS IS THAT THEY
ARE EXTREMELY HETEROGENEOUS.
THAT IS NOT A SINGLE THING ON
THE SLIDE THAT IS UNIQUE TO
SENESCENT CELLS SO YOU
OBLIGATED TO MEASURE THREE OR
FOUR ENDPOINTS TO DECLARE A
CELL SENESCENT.
THIS IS USUALLY A TRANSCRIPT
LIKE A CELL REGULATOR, EVIDENCE
OF DNA DAMAGE, AND LYSOSOMAL
ACTIVITY. SO BE VERY CAUTIOUS
WHEN YOU'RE LOOKING AT THE
LITERATURE AND YOU SEE OH, P16
POSITIVE CELLS, THESE ARE ALL
SENESCENT. THAT IS NOT
ADEQUATE SO PAY ATTENTION.
IT IS THOUGHT THAT THE
MICROENVIRONMENT AND CELL
LINEAGE WILL IMPACT THE
PHENOTYPE OF THE SENESCENT
CELL. SO THERE IS A HUGE
CONSORTIUM TO TRY TO
CHARACTERIZE THIS ACROSS 18
TISSUES THE FULL LIFE SPAN OF
HUMANS AND MICE AND WE HAVE OUR
WORK CUT OUT FOR US.
THE OTHER POINT THAT I WANTED
TO MAKE IS WHAT FASCINATES ME
ABOUT SENESCENT CELLS COMING
FROM THE PERSPECTIVE OF AGING,
IT REALLY GIVES AN OPPORTUNITY
TO THINK ABOUT OKAY THERE IS A
DAMAGE AND A STRESSED CELL. I
COME FROM A BAKKEN OF DNA
DAMAGE AND REPAIR ANYTHING
ABOUT THE CELL RESPONDING BY
CHOOSING A CELL PHATE. THAT IS
ONLY ONE OF THE CELL.
IT GIVES THE OPPORTUNITY FOR
THE PHENOTYPE TO CORRUPT THE
MICROENVIRONMENT EVEN
SYSTEMICALLY THROUGH THE
RELEASE OF THESE STRESS FACTORS
WE GIVES IT DAMAGED STRESSED
CELL TO SPREAD THAT.
THERE IS DEFINITIVE IMAGE THAT
THERE IS ONE HALLMARK OF AGING
THAT DOES CAUSE AGING, NOT
JUST HAPPENS BECAUSE OF AGING
AND THIS COMES FROM ELEGANT
WORK IN THE MAYO CLINIC. THEY
USE THE EPIGENETIC PRICK TO
PEAL OFF (INDISCERNIBLE) --
THEY ALSO ADDED A
(INDISCERNIBLE) DOMAIN. WHEN
YOU START ACCUMULATING
SENESCENT CELLS WITH AGING, IT
IS NOT UNTIL (INDISCERNIBLE).
BAKER AND COLLEAGUES
ORIGINALLY DID THIS IN THE
PROGENIC MODEL THERE ARE
DIFFERENT MODELS, THERE IS
DIFFERENCES WITH ANIMALS THAT
HAD SENESCENT CELLS VS. THOSE
THAT DID NOT.
THEN THEY WENT OUT IN THE WILD.
THE KEY FIGURE IN THE PAPER
FOR ME WAS THAT MEDIAN LIFESPAN
WAS EXTENDED BY CLEARANCE OF
THE SENESCENT CELLS WHAT THIS
SAYS TO ME IS THAT ALL CAUSE
MORTALITY WITH (INDISCERNIBLE).
SO YOU GET THESE DISEASES THAT
KILL MICE YOU DO NOT GET THE
LIFESPAN OF THE SPECIES IN THIS
CASE.
THIS IS REALLY IMPORTANT
BECAUSE IT TIES BACK TO THE
HYPOTHESIS THAT IF YOU DID
SOMETHING TO TREAT THE
FUNDAMENTAL BIOLOGY OF AGING,
YOU ACTUALLY COULD IMPACT
HEALTH SPAN AS OPPOSED TO JUST
EXTENDING LIFESPAN.
TWO KEY STUDIES IN THE FIELD
CAME FROM -- LAB. THIS IS FROM
KRISTIN BURDE, ON A PAPER
WORKING WITH HIM NOT A FACULTY
MEMBER AT OHIO STATE
UNIVERSITY. THAT BUILD THE
FIRST SENESCENT REPORT AND IT
TOOK THAT P16 REPORTER AND
MONITORED MICE AS THEY AGED OUT.
THIS IS TOTAL BODY
LUMINESCENCE AND AS YOU CAN SEE
THERE IS MORE BLUE TO THE RIGHT
OF THE SCREEN. THE SENESCENT
CELLS IS THE FIRST EVIDENCE
THAT THEY DO ACCUMULATE WITH
AGING. BUT YOU CAN ALSO SEE
INCREDIBLE HETEROGENEITY;
SOMETIMES THERE IS EVEN MICE WE
SEE THE SIGNAL AND THEN HE GOES
AWAY. THERE IS A LOT OF OTHER
REASONS TO HAVE P16.
WHEN YOU GRAPH THE DATA, WHAT
IS INTRIGUING IS THAT AT THE
YOUNG AGE YOU SEE ALL THE MICE
THAT HAD A LOW SIGNAL. BY THE
TIME YOU GET OUT TO THE MIDDLE
AGE HERE, YOU SEE THE
INCREDIBLE HETEROGENEITY IN THE
SIGNAL. THIS IS WHAT WE HAVE
TO DEAL WITH.
THERE ARE SENESCENT CELLS
ACCUMULATING WITH AGING BUT
VERY HETEROGENEOUS, HOW DO YOU
ACCOMMODATE WHEN YOU THINK
ABOUT ALL OF THE SENESCENT
CELLS IN IMMUNE REGULATION FOR
EXAMPLE?
THIS IS A GRAPH LOOKING AT
HUMAN AGE. WHAT IS THE LEVEL OF
P16? THIS IS NOW IN CD3+ CELLS.
BUT I WANT TO POINT OUT HERE
IS THAT SENESCENT CELLS ON
AVERAGE GO UP LOGARITHMICALLY
EVERY DECADE OF YOUR LIFE. BUT
AGAIN INCREDIBLE HETEROGENEITY.
AND SO WHAT I WANT TO SAY IS
WE HAVE TO ACCOMMODATE THE
METHOD IMMUNE CELLS ANOTHER
METHODS IN OUR STUDY WHICH GOES
UP IN OUR AGE.
ON TOP OF THAT THEY ARE
MODIFIABLE THE LEVEL OF P16 IN
THE PERIPHERY SO IF YOU'RE A
SMOKER THE CURVE GOES UP, IF
YOU EXERCISE THE CURVE GOES UP.
THIS IS AGAIN ADDING ANOTHER
LAYER OF HETEROGENEITY.
SO THIS IS THE MODEL SYSTEM
THAT WE USE, I WANT TO
INTRODUCE THIS BRIEFLY TO YOU.
THIS IS WANT TO START WHEN I
WAS A POSTDOCTORAL FELLOW. WE
FOUND A NOVEL HUMAN PROGEROID
SYNDROME THAT IS IS CAUSED BY A
DEFECT THAT LEADS TO THE
DISEASE WERE DEVELOPMENT IS
PERFECTLY NORMAL BUT WITHIN THE
SECOND DECADE OF LIFE, THESE
INDIVIDUALS ACCUMULATIVE
VIRTUALLY EVERY AGE-RELATED
DISEASE. I HAVE TO SAY
INCREDIBLY WE DON'T KNOW
ANYTHING ABOUT THE IMMUNE
SYSTEM IN THESE PATIENTS AT
THIS POINT.
A LITTLE BIT MORE ABOUT THIS
ENDONUCLEASE. BOTH GENES
CREATE A PROTEIN THAT MUST
HETERODYMERIZE (PHONETIC) IN
VIVO. AND THEY REPAIR THE
NUCLEASE. IT TURNS OUT THAT IF
YOU KNOCKOUT EITHER GENE YOU
LOSE ALL ENZYME AND SO IN THE
MICE WE ARE ABOUT TO SHOW YOU
WE ASCRIBE THIS TO A LOSS OF
THE ENZYME AND DNA REPAIR
CAPACITY.
IT TURNS OUT THIS IS A
PROMISCUOUS ENZYME. IT IS
INVOLVED IN MULTIPLE DIFFERENT
REPAIR PATHWAYS. AND THE OTHER
POINT I WOULD LIKE TO MAKE
ABOUT THE ENZYME IS WE ONLY
FIND IT IN THE NUCLEI. SO ALL
OF THE PHENOTYPES THAT YOU SEE
AGAIN WE ASCRIBED TO FAILURE TO
PROTECT THE NUCLEAR GENOME FROM
ENDOGENOUS DNA DAMAGE. WE
NEVER REALLY TREAT OUR MICE
WITH ANYTHING. IT IS JUST
ENDOGENOUS DNA DAMAGE THEY ARE
GRAPPLING WITH.
THIS IS A MOUSE MODEL WE MADE
CREATED BY (INDISCERNIBLE)-- A
HYPOMORPHIC ALEAL. IN MICE THE
ANIMALS ACTUALLY AS ADULTS HAVE
BEEN QUITE HEALTHY AND IN THE
FALL APART VERY QUICKLY. AND
SPONTANEOUSLY DEVELOP VIRTUALLY
EVERY AGE-RELATED DISEASE YOU
CAN IMAGINE. LIKE CANCER IN
THEIR SIX OR SEVEN MONTH
LIFESPAN. AND THEY ALSO
DEVELOP THERAPIES THAT TARGET
SENESCENT CELLS.
IF YOU IMPORTANT POINT ABOUT
ANIMALS. THEY DO ACTUALLY
ACCUMULATING EXCESSIVE OXIDATE
ENDOGENOUS DNA DAMAGE AND YOU
SEE THESE VERY ELEGANT BASED
ASSAYS TO MEASURE LOW ABUNDANCE
OXIDATIVE SOLUTION. THESE
REQUIRE (INDISCERNIBLE) FOR
REPAIR. AND IT IS MEASURED IN
TISSUES THAT ARE MICE.
THIS HISTOGRAM SHOWS THE
CUMULATIVE TOTAL OF THE LESION
AND RENAL TISSUE.
IMMUNE ANIMALS ARE IN RED. WE
FOUND THAT IN EARLY 80S WHEN
THE MICE DO NOT HAVE GENOTYPE
THE LEVELS OF THESE OXIDATIVE
DNA LESIONS ARE NOT ELEVATED
BUT BY THE TIME THEY ARE OLD
THEY ARE SIGNIFICANTLY
ELEVATED.
THIS IS THE MOST IMPORTANT BAR
IN THIS GRAPH. THIS IS WILD
TYPE MICE A TWO AND HALF YEARS.
EVEN IF YOUR ARE FULLY DNA
REPAIR COMPETENT YOUR
COMMUNITIES ACTIVATED DNA
LESIONS WITH AGING AND THEY CAN
BE DETECTED IN HUMAN SAMPLES AS
WELL.
WHAT WE THINK IS WHAT IS
HAPPENING IN OUR MICE IS A
COMPRESSION OF WHAT IS
HAPPENING WITH NORMAL AGING.
IT IS VERY SIMILAR AT THE LEVEL
OF SENESCENT. THIS IS A
HISTOGRAM, P16 MRNA LEVELS IN
TISSUES AND ALL WHILE TYPES
COMPARED TO YOUNG COUNTERPARTS
AND THEN OUR MUTANT ANIMALS AT
4 TO 5 MONTHS OF AGE.
WHAT WAS SURPRISING TO US IS
SORT OF THE RANK ORDER OF HIGH
TO LOW OF P16 LEVELS, VIRTUALLY
IDENTICAL FOR MUTANT ANIMALS
COMPARED TO AGING AND ARE MICE
NEVER EXCEED THE LEVELS OF
SENESCENTS THAT OCCUR WITH
NORMAL AGING. WE DID THIS WITH
A NUMBER OF DIFFERENT MARKERS
FOR SENESCENT CELLS; OUR MICE
AGAIN ARE EXPERIENCING
SENESCENT AT 4-5 MONTHS AS
OPPOSED TO TWO AND HALF YEARS.
THESE AGAIN HAVE BEEN VALUABLE
FOR TESTING DRUGS TO TARGET
SENESCENT CELLS. WHAT WE HAVE
BEEN UP TO SINCE THEN HAS
REALLY BEEN TO ASK WHICH TYPE
OF SENESCENT CELLS ARE THE MOST
DELETERIOUS? THE REASON I'M
HERE TODAY IS BECAUSE OF THE
IMMUNE CELL. THE WAY WE HAVE
BEEN TACKLING THIS IS WE HAVE
BEEN DELETING ERRC1 IN ONE
TISSUE OR ANOTHER TO UNDERSTAND
THIS. IN EVERY SINGLE CASE WE
END UP WITH AN AGE-RELATED
DISEASE OF THE TARGETED TISSUE.
SUPPORTS THE NOTION THAT
ENDOGENOUS DNA DAMAGE IS AN
IMPORTANT DRIVER OF AGING. AND
NOW WE ARE LOOKING AT SPECIFIC
CELL TYPES.
I WANT TO HIDE IN THREE IT IS
VERY QUICKLY. MYOCITES, B-CELLS
AND (INDISCERNIBLE). ONE OF
THE FIRST MODELS WE MADE WAS WE
DELETED ERCC1 IN DIFFERENT
MYOCITES WE SAW THAT THE MICE
DIED VERY PREMATURELY. IT
TURNED OUT THAT IT WAS FROM
DILATED CARDIOMYOPATHY. WHAT IS
IMPORTANT TO KNOW IS HERE'S A
MUTANT ANIMAL. THE PARCEL
PERFECTLY FINE AT A YOUNG AGE.
BUT BY 4-5 MONTHS OF AGE TO
HAVE DILATED VENTRICLES. WE
ARGUED THAT THIS IS A
DEGENERATIVE DISEASE PROCESS.
AND THEY HAVE THE HEART FAILURE
MARKERS AND WHAT IS INTERESTING
IN THIS MODEL THOUGH, IS WE
NEVER FOUND THE SENESCENT
CELLS. AND LIKE EVERYBODY ELSE
IF YOU GRIND UP IN ALL HEART
YOU CAN FIND THE SENESCENT
MARKER BUT I DON'T BELIEVE THAT
THE DIFFERENT --
(INDISCERNIBLE) ANOTHER EXAMPLE
IS WE DELETED THE ERCC1 IN
B-CELLS. WE STARTED TO SEE
IMPAIRED GLUCOSE HOMEOSTASIS;
IN THE MUTANT ANIMALS ARE IN
SOLID RED BARS. FASTING GLUCOSE
ALSO WAS ALTERED. WE FOUND
THAT WE CHALLENGE THE ANIMAL
WITH AN ORAL GLUCOSE BULLET,
THEY HAVE IMPAIRED TOLERANCE
AND THEY CANNOT BRING SERUM
GLUCOSE LEVELS BACK DOWN TO
NORMAL AND THIS IS DUE IN PART.
THIS IS 15 MINUTES AFTER THE
ORAL GLUCOSE BULLETIN YOU CAN
SEE THE AMOUNT OF -- IN MICE.
CREATES A MODEL OF TYPE II
DIABETES.
WHAT IS INTERESTING IS WHEN WE
LOOK AT THE PERIPHERAL ORGANS
OF THESE MICE WE SEE A LOT OF
DAMAGE AS WELL. THE MICE DUES
CONTINUALLY DEVELOP STEATOSIS,
AND HAVE LOTS OF MARKERS OF
SENESCENT, INFLAMMATION AND
INSULIN RESISTANCE IN THE LIVER
AS WELL AS IN THE FAT BUT NOT
THE SKELETAL MUSCLE.
HERE WE ARE SEEING PERIPHERAL
SENESCENT, NOT IN THE TARGETED
CELLS BUT PERIPHERALLY, WHAT
YOU WOULD EXPECT IN DIABETES.
WE ARE TRYING TO SEE IF THIS IS
BECAUSE OF INSULIN RESISTANCE
OR HIGH GLUCOSE ALL THE TIME.
WE NEED MORE DATA PAST OUR
VIEWERS AND ENDOCRINOLOGISTS.
THIS IS THE ONE YOU ARE
PROBABLY INTERESTED IN WHEN WE
HAVE ERCC1 IN HEMATOPOIETIC
CELLS. THE INDUCED ANIMALS ARE
IN RED AND THE HAVE A
PROGRESSIVE LEUKEMIA. WE LOOK
FOR SENESCENT IN YOUNG ANIMALS
AND WE DO NOT SEE IT IN THE
IMMUNE COMPARTMENT. BUT OLDER
ANIMALS SAY OUT TO ABOUT A YEAR
THEY SAID TO HAVE ELEVATED
LEVELS OF P16, P21 AND SOFT
FACTORS, VERY ANALOGOUS TO WHAT
HAPPENS IN NORMAL AGING. I
SHOULD POINT OUT THAT ALL OF
THESE MICE ARE IN >>F 1
BACKGROUND.
WE ARE ACTUALLY LOOKING AT
PROTEIN LEVELS.
WHAT WAS SURPRISING IS WE SEE
SENESCENTS EVERYWHERE IN THE
SLIDE LOOKING AT SOLID ORGANS
LOOKING AT ELEVATED LEVELS OF
P16 IN OTHER MARKETS AND WE USE
FISH TO SHOW THAT P16 IS
UPREGULATED IN RENAL EPITHELIAL
CELLS -- -- NOT JUST IMMUNE
CELLS IN THESE ORGANS.
SURPRISINGLY, THIS IS ENOUGH
TO CAUSE DAMAGE TO MANY OF
THESE ORGANS. WE SEE ELEVATED
SERUM-- EXPRESSED IN THERE IS
LIVER DAMAGE. THERE IS ALSO
PROTEINURIA IN MY SO THERE IS
LIVER, RENAL AS WELL AS
PANCREATIC DAMAGE. THERE ARE
CHANGES IN GLYCOSAMINOGLYCANS.
AND ACTUALLY THESE MICE ARE
SHORT-LIVED, WHEN THEY HAVE A
REDUCED MAXIMUM LIFESPAN AND
MEDIAN LIFESPAN.
THERE IS A LOT OF DAMAGE GOING
ON IN THESE MICE JUST BECAUSE
WE GROW THE DNA DAMAGE AND THE
SENESCENT OF THE IMMUNE
COMPARTMENT. SOME OF THE CELLS
DIE.
WE ARE ACCUSING THE SENESCENT
CELLS OF WREAKING HAVOC; THE
WAY TO TEST THIS IS TO ADOPT
THE TRANSFER AND WE TOOK --
FROM MICE AND PUT THEM IN AS
P16 AND WE SEE ELEVATED SIGNALS
UP IN THE RECIPIENT MICE. THIS
GOES UP WITHIN A WEEK AND LASTS
FOR ABOUT FIVE WEEKS. AND THEN
(INDISCERNIBLE), AND EVEN
ELEVATED -- FACTORS AND
INFORMATION IN THE RECIPIENT
MICE.
THE OPPOSITE IS ALSO TRUE
THOUGH. IT TURNS OUT IF YOU
TAKE YOUNG PHENOCYTE AND PUT
IT INTO THE PROGENERATIVE
ANIMAL -- WHAT IS GOING ON IS
TWO THINGS. AGAIN A FUNCTION
WHICH THE FACT WITH THE
SENESCENT CELLS, AS WELL IS
LOSS OF FUNCTION WITH
FUNCTIONAL RED CELLS TO CLEAR
(INDISCERNIBLE).
-- -- SO FAR IT LOOKS LIKE
MACROPHAGES ARE GOING TO HAVE
THE GREATEST IMPACT. I WOULD
PREDICT T CELLS ARE GOING TO BE
IMPORTANT BUT WE ARE BEHIND IN
STUDYING THESE ANIMALS. CX
WITH THE 3CR1 PROMOTER, I THINK
THE MICRO GLIAL ARE GOING TO
WIN AT THE DOMINANT PHENOTYPE.
THESE MICE ARE IN HIGH INPUT
WITH ME IN IF ANYBODY WANTS
MICE TISSUE TALK TO ME THERE'S
A LOT OF WORK TO DO.
IN AN AGED SENESCENT IMMUNE
SYSTEM CAN DRIVE SENESCENT IN
TRANS, THE GAIN OR LOSS OF
FUNCTION MECHANISMS. THIS CELL
NON-AUTONOMOUS SENESCENT IS
SIGNIFICANT ENOUGH TO DAMAGE,
AND IT IS IMPORTANT FOR AGING.
I WANT TO TELL YOU A COVID
STORY, WITH A LOT OF GREAT
COLLABORATION FROM CHRISTINA
KAMELL (PHONETIC) WHO LED THE
STUDY BUT IT WAS EARLY IN THE
PANDEMIC. ONE OF THE THINGS IN
COMMON OF THOSE AT RISK WITH
SEVERE OUTCOMES FROM COVID-19
IS THAT A LOT HAD SENESCENT
CELLS. WE TAKE YOUR SPF MICE
AND EXPOSE THEM TO PET STORE
MICE THIS IS GOING TO, PARADIGM
EXPOSURE TO NORMAL MICROBIAL
EXPERIENCE. WHAT WE LEARNED
VERY QUICKLY TO OUR HORROR,
YOUNG MICE ARE FINE UPON THIS
EXPOSURE. BUT OLD MICE ARE
100% DEAD WITHIN TWO WEEKS.
IT TURNS OUT THAT BY
SERENDIPITY THE KILLER IS A
BETA CORONAVIRUS. WHAT WE FOUND
IS BEFORE THEY WERE ALL DEAD
THE ONLY EVIDENCE OF ALL THE
BUGS SUBMITTED BY THESE PET
STORE MICE WERE ANTIBODIES
AGAINST MAC. IT LOOKS LIKE THIS
BETA CORONAVIRUS WAS HARMFUL TO
THE NAïVE, OLD, WILD-TYPE MICE.
YOU CAN SEE THIS IN THE LIVER
OF THE OLD MICE BUT NOT THE
YOUNG AND A CRUCIAL EXPERIMENT
RUN BY THE CENTER OF IMMUNOLOGY
WAS TO INOCULATE YOUNG AND OLD
MICE WITH MHC PRIOR TO EXPOSURE
TO THE PET STORE MICE FOR
NORMAL MICROBIAL EXPERIENCE AND
SURE ENOUGH THAT RESCUE, THE
BLUE LINE, RESCUED ALL OF THE
ANIMALS WHICH IS THE BETA
CORONAVIRUS KILLING THE OLD
MICE AND WE WANTED TO ASK IF
GETTING RID OF THE SENOLYTIC
FISINT PROTECTS THE ANIMALS. WE
STARTED TREATING THE ANIMALS
AND IN TRANSLATIONAL APPROACH
AND IN THIS CASE 50% OF THE
MICE DIED UPON EXPOSURE OF THE
ENVIRONMENTAL PATHOGEN.
FISETIN IS A LOPPY DRUGR,
SENESCENT CELLS SETTING UP
THESE MICE WERE FAILURE. WE
DID A COUPLE MORE EXPERIMENTS
WHERE WE USED THE MAYO CLINIC
ABLATION OF THE SENESCENT
CELLS, IT WAS PRETTY GOOD AT
RESCUING THE MICE, NOT AS GOOD
BECAUSE IT IS ONLY TARGETING
P16-POSITIVE CELLS AND THEN WE
USE OUR FAVORITE COCKTAIL,
RESCUED THE SAME EXTENT.
WE THINK THE REASONS FOR
SENESCENT CELLS MAKING ANIMALS
VULNERABLE IS THAT THE CAUSE
AND TO OVERREACT TO INFECTION.
AND SO THIS IS AN EXAMPLE IN
VITRO WHERE WE WERE COMPARING
NON-SENESCENT CELLS CHALLENGED
WITH LPS, THE SENESCENT CELLS
HYPER REACT. IL6 GO TO THE ROOF
IF YOU ARE OLD BUT NOT YOUNG.
HE WE DID THIS IN AN NME, IL6
IS NOT ELEVATED IN YOUNG
ANIMALS BUT TO THE ROOF AND OLD.
AND IF WE TREAT ANIMALS WITH
FISETIN, WE CAN BRING THESE
LEVELS DOWN.
WE THINK THAT THE OVERREACTION
IS WHAT SETS THESE ANIMALS UP
FOR CYTOKINE STORM AND
MULTIORGAN FAILURE AND
ULTIMATELY IN FACT THIS COULD
IMPROVE RESPONSE TO THE VIRUS
IF WE LOWER THE AMOUNT OF
TRANSCRIPT FROM THE VIRUS,
PROTECTED IN THE
FISETIN-TREATED ANIMALS AND
HAVE AN APPROPRIATE ANTIBODY
RESPONSE EQUIVALENT TO YOUNG
MICE COMPARED TO THE UNTREATED
ANIMAL.
SO QUICK THOUGHTS. HERE
STUDYING AGING, IMMUNITY AND
CHRONIC INFLAMMATORY DISEASES
IN SPF MICE MAY NOT MAKE A LOT
OF SENSE. WE HAVE TO THINK
ABOUT THE REALITY IN THE WORLD.
SENOLYTICS REDUCE ADVERSE
OUTCOMES IN ORGANISMS ABOUT
INFECTION WITH A NOVEL
PATHOGEN. I THINK THIS WAS ONE
OF THE STRONGEST EVIDENCE FOR
GEROSCIENCE. I UNDERSTAND THAT
IF YOU BUILD UP SENESCENT CELLS
WITH AGING AND CHRONIC DISEASE
WHICH IS DISTINCT IN AN OLDER
PERSON, THEIR PRIME TO BE
VULNERABLE TO INFECTION AS WELL
AND SENESCENT CELLS, THE WAY WE
ARE THINKING ABOUT THIS IS, SET
OF CLIENTS FROM (CORRECTION)
CYTOKLINE FROM THE CELL
CONFUSES THE PATHOGEN.
THE OTHER PAGE I WANT TO MAKE
IS, I THINK THERE IS A LOT TO
LEARN FROM CANCER, AND CANCER
IMMUNOLOGY. IT WILL BE
EXCITING TO SEE NCI JOIN YOU
GUYS AT SOME POINT OF THIS
COMES MAINLY FROM TWO RECENT
PUBLICATIONS IN CANCER
DISCOVERY, 2023. EMMANEUL --
AND SCOTT LOWE (PHONETIC) THIS
IS AN INTERESTING PARADIGM, YOU
ARE OLD AND YOU HAVE CANCER YOU
HAVE SENESCENT CELLS, YOU HAVE
CHEMOTHERAPY AND THEN YOU HAVE
MORE SENESCENT CELLS AND
IMMUNOSUPPRESSION, THAT LEADS
TO MORE SENESCENT CELLS.
INCREDIBLY COMPLICATED CASCADE.
WE KNOW THAT RECRUITMENT
ANTIGEN PRESENTATION AND
INTERFERON ARE DISRUPTED BY
SENESCENT CELLS.
BONE TRANSPLANT IS ALSO
COMPLICATED. THERE IS A LOT OF
EVIDENCE OF ACCELERATED AGING.
IT IS TIED TO COGNITION AND IT
IS A FULL ALLOGENEIC TRANSPLANT
THE DRIVES COMMISSION DEFICIT.
THE AMOUNT OF DNA DAMAGE AND
SENESCENT CELLS IS THAT FROM A
FULL OR PARTIAL ALLOGENEIC
TRANSPLANT.
THE SECOND LIKE THE WILD WEST.
THERE'S A LOT YOU CAN LEARN
FROM THEM IN THE START WITH
CANCER, THEY GET CHEMOTHERAPY,
THEY FAIL AND THAT DRIVES
SENESCENT CELLS. THEY GET
ABLATION AND YOU GET MORE
SENESCENT CELLS AND THEN MORE
THERAPY. AND IF THAT DOES NOT
WORK YOU GET IMMUNOSUPPRESSION,
POSSIBLY ABLATION AND A LOT OF
SENESCENT CELLS. SO THERE'S A
TON OF CLINICAL DATA ON THESE
PATIENTS AND I WOULD URGE YOU
TO THINK ABOUT THIS. YOU ARE
SMARTER THAN ME.
MY SUGGESTION IS MORE
INTERDISCIPLINARY WORKSHOPS,
REVIEWS OF DISCIPLINES REPAIRED
AND WE WILL NEED AI TO FIND THE
PHENOTYPES AND KEEP TRACK OF IT
WITH COVID. IT IS WELL BEYOND
THE HUMAN.
A LOT OF CARDIOMIC. TRANSFER
IS ONE THING THAT WE NEED TO
THINK ABOUT THE BIOLOGY. ALSO
MAKING A PLUG FOR SPATIAL
(INDISCERNIBLE). SINGLE CELLS
DO NOT CAPTURE SENESCENT CELLS.
THINK ABOUT YOUR METHODS VERY
CAREFULLY BEFORE YOU SAY
SENESCENT CELLS ARE NOT
IMPORTANT.
ULTIMATELY WHERE WE ARE HEADED
TOWARDS THIS CHANGES IN
CLINICAL PRACTICE. YOU GET NEW
DIAGNOSES.
QUICK THINGS TO PAUL ROBBINS,
CHRISTINA CARNELL, OUR
COLLEAGUES AT THE MAYO CLINIC.
MATT YOUSEFZADEH FACULTY MEMBER
AT COLUMBIA -- MY LABORATORY
POST DOC, INCREDIBLE CREW OF
GRADUATES AND UNDERGRADUATES.
AND GRATEFUL FOR OUR FUNDING
SOURCE. THANK YOU VERY MUCH.
>>THANK YOU LAURA. TIME FOR
QUESTIONS. >>THAT WAS SO
INTERESTING. I HAVE STARTED
DEVELOPING AND REGENERATION OF
SENESCENT CELLS BY THEIR ROLE
IN THE NICHE. I WAS WONDERING
IF YOU GET (INDISCERNIBLE),
THINKING ABOUT CANCER AS WELL,
I THINK IT WOULD BE AN
IMPORTANT ASPECT OF
FUNDAMENTALLY UNDERSTAND NICHE
POPULATIONS OF SENESCENT CELLS.
WHAT DO YOU THINK?
>>THAT IS A BRILLIANT IDEA.
CHICKEN AND EGG. REALLY HARD.
I SHOULD HAVE POINTED OUT THAT
SENESCENT CELLS ARE NOT ALL BAD
WE NEED THEM FOR
(INDISCERNIBLE) -- WHEN WE CAN
CLEAR THAT YOU'RE IN GOOD
SHAPE. IT IS A COMBINATION OF
THE NICHE CHANGING AND YOUR
IMMUNE SYSTEM NOT RESPONDING.
>>ALSO (INDISCERNIBLE) WITH
THE CELLS RIGHT NEXT TO THEM.
UNDERSTANDING THAT THE NICHE
AND THE CELLS THAT WILL BE
COMMUNICATING WITH --
(INDISCERNIBLE).
>>REALLY COOL, THE -- MOUSE
EXPOSURE WAS REALLY INTERESTING.
I WANTED TO ASK YOU IF YOU
THOUGHT THAT THE PET SHOP MICE
BECAUSE THEY HAD THE
CORONAVIRUS WOULD NOT MAKE IT
FOR TWO YEARS OR THE REASON
THAT THE MICE DIED WAS THE
FIRST EXPOSURE.
>>I THINK THE OLD MICE ARE
NAïVE. I DON'T KNOW ABOUT THE
PET STORE MICE AND HOW LONG
THEY LIVE. OBVIOUSLY THEY ARE
MEANT FOR PREDATION OR
SOMETHING BUT MICE LIVE FOR A
LONG TIME AS PETS. IF YOU
PROTECT THEM, THEY ARE FINE AND
THE YOUNG MICE SURVIVE WHEN
THEY'RE EXPOSED TO THE PET
STORE MICE. I DON'T THINK THAT
IS A LIFESPAN CHANGER, BUT A
CHRONIC DISEASE.
>>HI. MARI -- SPAIN.
CONGRATULATIONS FOR YOUR
BRILLIANT WORK. I WAS WONDERING
IF YOUR MUTANT MICE JUST IN THE
IMMUNE SYSTEM, IS THE PREMATURE
SENESCENTS PHENOTYPES COULD BE
RELATED TO DYSREGULATION IN THE
MICE (INDISCERNIBLE).
>>YES. I AM CONFIDENT THAT
THAT PLAYS A ROLE IN THAT; WE
HAVE NOT STUDIED IT THOROUGHLY.
ACTUALLY THOSE MICE ARE NOW IN
THE MME EXPOSURE PARADIGM NOW.
WE ARE LOOKING FOR HELP THROUGH
ANALYZING THE MICROBIO. I
DON'T THINK WE KNOW A LOT OF
HOW THE ENEMY CHANGES THAT.
THERE IS A CAVEAT, MME MICE DO
NOT COME IN ONE FLAVOR BUT THAT
IS A WEAKNESS THE MICROBIOME
WILL BE CRITICAL.
>>THANK YOU FOR A WONDERFUL
TALK. THERE IS A LOT OF WORK
IN THE IMMUNOLOGY FIELD RELATES
TO T CELL EXHAUSTION. I AM
WONDERING HOW YOUR SENESCENT
T-CELLS LOOK OR THEY ARE
SIMILAR TO THE EXHAUSTED T
CELLS. IN YOUR COMMENTS ABOUT
SENESCENT CELLS BEING LARGER
AND MORE FRAGILE. AND I KNOW
THAT IT LOOKED AT IT A LOT IN
VITRO AND I WAS WONDERING IF
THERE WAS EVIDENCE IN VIVO, AND
THE PEOPLE WERE DOING
AUGMENTING IMAGING. THERE IS
SOME QUESTION ABOUT THAT.
>>THESE ARE GREAT QUESTIONS.
WE HAVE PRELIMINARY AND
SUPERFICIAL EVIDENCE THAT
REVEAL THERE ARE
(INDISCERNIBLE)-- WE HAVE A LOT
OF WORK TO DO AND HOPEFULLY
CHRISTINA CAN HELP WITH THAT.
>>YOU ARE ABSOLUTELY CORRECT.
MOST OF THE DATA ABOUT FRAGILE
STATE SENESCENT CELLS COMES
FROM IN VITRO. WE ARE SEEING
EVIDENCE OF THAT IN VIVO AS
WELL; MOSTLY THEY ARE POLYPRO
NUCLEI (PHONETIC) -- AND HOW TO
DECIPHER THAT. WE NEED A LOT
MORE SPECIAL WORK. BUT
PRELIMINARY EVIDENCE SHOWS THAT
HAS BEEN CARRIED THROUGH TO IN
VIVO. YEAH?
>>DID I UNDERSTAND CORRECTLY
THAT WHAT YOU CALL SENESCENT
CELLS IS CAPABLE OF
PROLIFERATION?
>>NO. I HAVE NOT COMMENTED ON
THAT.
>>WHEN YOU DO THE TRANSFER
EXPERIMENT THERE IS A SMALL
NUMBER OF CELLS. THE ONLY WAY
IT WORKS IS IF THERE IS
PROLIFERATION IN THE TRANSIT
CELL. LET ME ASK YOU THIS,
HAVE YOU DONE DRDU?
>>WE HAVE NOT AND THAT IS A
GOOD POINT. WE HAVE TO MAP THE
CELLS AND WE DO NOT SEE A LOT;
THEY DID NOT APPEAR TO BE A LOT
OF PROLIFERATION.
>>YOU SPOKE A LOT ABOUT
MULTIPLE -- (INDISCERNIBLE) IN
SENESCENT, AND IF I UNDERSTOOD
IN THE FOLLOWING SLIDE YOU SHOW
THE ONLY DEFINITIVE PROOF OF
THE CAUSALITY OF THE P16
KNOCKOUT OR CONDITIONAL
KNOCKOUT. AND TAKING THE
IMMUNOLOGY SIDE OF THINGS, P16
IS ALSO HIGHLY EXPRESSED IN
TUMORS SO REMOVING P16 POSITIVE
DOES NOT MEAN YOU REMOVE ONLY
THE SENESCENT CELLS. SO THE
LOAN EXPERIMENT, IS APPROVED
FOR THE CAUSALITY OF THE
SENESCENT CELLS? OR THE P16
POSITIVE CELLS?
>>EXCELLENT POINTS. SO THERE
ARE NOW NEW TOOLS, P21
OPERATORS THAT I WOULD
ENCOURAGE YOU GUYS WHO ARE
IMMUNOLOGIST TO CONSIDER THESE
MODELS FROM THE MAYO CLINIC.
ON THE FLIPSIDE WE HAVE NOT
SEEN AN ADVERSE EFFECT FROM A A
-- ABLATING P16 CELLS. WE ARE
DOING OUR BEST BUT IT IS A
LITTLE BIT OF A CAVEAT INDEED
SO THANK YOU FOR POINTING IT
OUT. >>HOW TO DIFFERENTIATE
INFLAMMATION AND
(INDISCERNIBLE)?
>>IMPOSSIBLE.
>>WHAT YOU THINK ABOUT
TOLERANCE OR LACK OF IN MME IN
ADULT MICE?
>>WAY BEYOND MY EXPERTISE. I
AM SORRY.
>>HOW DO YOU EXPLAIN THE
INCREASE OF P16 IN CANCER BUT
ENDS UP HAVING A FASTER
RELATION BETWEEN AGING AND
CANCER AND P16 ACTIVATION?
>>WHAT IS REALLY-- THE BIG
QUESTION IS IF YOU START
ABLATING P16 CELLS YOU'RE GOING
TO SET YOURSELF UP FOR CANCER
AND THAT IS NEVER THE CASE AT
ALL. WHEN YOU HAVE A DAMAGED
STRESS CELL, REGARDLESS OF WHAT
IS GOING ON, IF YOU CAN PUT OUT
A TECH POINT THAT'S GOOD.
>>I HAVE A QUESTION YOU MAY
NOT KNOW THE ANSWER FOR, BUT
THERE WAS SOMEBODY WHO ALLUDED
TO THE WORK OF LONGO AND THE --
DIET AND CALORIC RESTRICTION
AND THAT WHOLE FIELD. I AM
SURE SOMEBODY HAS TRIED TO LOOK
AT TO SEE IF ONE OF THE
MECHANISMS IS ENHANCED
(INDISCERNIBLE) AND CLEARANCE
OF SUBOPTIMAL CELLS. DOES
ANYBODY LOOK TO SEE IF
SENESCENT CELLS ARE CLEARED IN
THE MODEL?
>>YES, FLOW RESTRICTION AND
EXERCISE TO CLEAR SENESCENT
CELLS. I WOULD ALSO SAY IN OUR
MODEL (INDISCERNIBLE) IT IS
AMAZING. THAT DEFINITELY
WORKED. THE OTHER THING I
WOULD POINT OUT IS WE
SYSTEMATICALLY LOOKED AT ALL
THE HALLMARKS OF AGING IN OUR
MUTANT ANIMALS. WE KNOW WE
STARTED WITH THE PRIMARY
PROBLEM OF GENOTYPE EXPRESSED;
EVERY SINGLE HALLMARK IS
ALTERED. AND SO I THINK THESE
ARE ALL VERY INTEGRATED.
>>I HAD A QUESTION. MAY BE
TOO SIMPLISTIC. THINKING ABOUT
SENELITICS FOR HUMANS MAY BE IN
THE T CELL COMPARTMENT, THE
MAJORITY OF THE T CELLS ARE
SENESCENT AND YOU ELIMINATE
THEM WITH VISITS SENELITIC,
THERE IS NO NEW PIECE OF
(INDISCERNIBLE) TO SPEAK OF.
>>HARD FOR ME TO ANSWER BUT I
WILL SAY THAT THERE HAS BEEN A
LOT OF THOUGHT ON THIS BECAUSE
THE OTHER QUESTION IS THERE IS
EVIDENCE THAT SENESCENT CELLS
PLAY A BIG ROLE IN ALZHEIMER'S
DISEASE. SOME PEOPLE SAY IT IS
A NEURON SENESCENT, I AM NOT
SURE I AGREE BUT IF YOU CLEAR
THE NEURONS, IS THAT BETTER
THAN HAVING-- I DON'T KNOW-- NO
NEURONS BETTER THAN HAVING
THICK NEURONS?BIG QUESTION. I
DON'T KNOW. THERE'S 40 OR SO
CLINICAL TRIALS GOING ON NOW.
I THINK IT IS SCREAMING FOR
HELP.
>>WANT TO MAKE A COMMENT.
MANY MUCOSAL EPITHELIAL CELLS
AS THE AGE ARE SENESCENT. IN
MANY IN OUR BODY ARE SENESCENT,
GIVEN ANY KIND OF PRESSURE OR
INSULT THEY WILL FALL OFF A
RETREAT WITH SENELITICS WE
COULD HAVE DETRIMENTAL EFFECTS
ON BARRIER FUNCTIONS.
>>GREAT POINT. ONE COMMENT I
WOULD MAKE ABOUT THAT IS THE
THOUGHT ABOUT SENELITICS IS YOU
GIVE THEM QUARTERLY AND CLEAR
OUT AND RECOVER. WHEN YOU HAVE
SOMETIMES IT CAN RECOVER, THAT
MAY BE BENEFICIAL BUT WE DON'T
KNOW. THANK YOU.
>>THANK YOU LAURA FOR A GREAT
TALK. MY QUESTION GOES TO DNA
DAMAGE. YOU VERY NICELY SHOWED
THE ACUMEN LEADING DNA DAMAGE
IS SUFFICIENT TO DRIVE THE
SENESCENT PHENOTYPES. IS THERE
ANY DATA LOOKING AT THE
CAUSALITY? AND THE BOOST TO THE
PROTECTIVE MECHANISMS AGAINST
DNA DAMAGE IF THEY HAVE AN
EFFECT ON THE COMMISSION OF
SENESCENT CELLS WITH AGING? THE
OTHER SIDE OF THE COIN.
>>THAT IS A GREAT QUESTION.
WE HAVE BEEN THINKING ABOUT
THIS FOREVER. I HEARD A LOT OF
TALK ABOUT DNA REPAIR IS
IMPORTANT. ARE THERE MMETICS
THE CAN IMPROVE IT (PHONETIC)?
IT WORRIES ME. (INDISCERNIBLE)
IS A GOOD METHOD TO DO THAT BUT
I DO THINK THAT IT'S THE
CHRONIC STIMULATION FROM DNA
DAMAGE, HARD TO GET RID OF DNA
DAMAGE THAN SIGNALING
DOWNSTREAM. THANK YOU.
>>THANK YOU FOR A FANTASTIC
DISCUSSION.
>>I CAN NOW OPEN SESSION 4,
IMMUNO METABOLIC CHECKPOINTS OF
INFLAMMAGING.
THE FIRST SPEAKER IS VISHAW
DEEP DIXIT FROM YALE. HE WILL
TALK ABOUT THE MODULATION OF
DIET AND THE IMPACT ON IMMUNE
FUNCTION. YOU WILL HAVE 15
MINUTES FOR YOUR PRESENTATION.
AFTER 13 MINUTES SHE WILL START
MAKING SOME SIGN THAT YOU HAVE
TO START WRAPPING UP. PLEASE
DEEP.
>>THANK YOU DANIELA. THANK
YOU TO PREEDE AND MECY AND --
GREAT TO BE HERE. THIS NEXT
LECTURE, LEAVE $10 WHEN YOU'RE
DONE WITH THE COFFEE.
(CHUCKLING).
WE HEARD YESTERDAY FROM
GEORGE. AND FROM EMMANUEL.
IL-1 BETA REGULATED STEM CELLS
AND AGING IN YOUR FROM
KATHERINE ANDERSON ABOUT IL-18
IS ONE OF THE COMPONENTS THAT
SHOWS UP ON THE AGING PLASMA
AND MORE DATA FROM LAURA BUT
THE CYTOKINES REGULATING
INFLAMMATION.
THIS WORK WAS DONE BY MY
COLLEAGUE YUN YOUM, SHE IS IN
THE BACK OVER THERE. WHAT WE
FOUND WAS THAT IN AGING, THERE
IS THIS MULTI-PROTEIN COMPLEX
CALLED THE NLRP3 INFLAMMASOME
EXPRESSED IN THE -- AND IT IS
PROMISCUOUS IN ITS ABILITY TO
SENSE DAMAGE, WHICH IS WHY YOU
THINK IT IS IMPORTANT FOR
AGENT BECAUSE IT CAN SEND
STRUCTURALLY DIVERSE DAMAGE
ASSOCIATED WITH MOLECULAR
PATTERNS LISTED HERE.
ALL OF THEM GO UP IN AGE AND
THE KEY PART WITHIN THAT IS
ONCE IT SENSES THE DAMAGE IT
ASSEMBLES, CLEAVES AND -- THE
TWO PRIMARY RECEPTORS ARE IL-1B
AND IL-18. WHAT STRUCK US WHEN
WE LOOKED AT THESE ANIMALS 2, 2
1/2 YEARS OLD THEY WERE IN FACT
PROTECTED FROM MULTIPLE
FEATURES LISTED HERE, RANGING
FROM BONE LOSS TO MAINTENANCE
OF SENSITIVITY INCLUDING LESS
TIME IN EVOLUTION BECAUSE OF
RESIDENT MACROPHAGES AND LESS
CNS INFLAMMATION AND
IMPROVEMENT OF COGNITIVE
FUNCTION, WHICH REALLY APPROVED
WHAT PEOPLE HAVE BEEN PREDICTED
100 YEARS AGO.
RESIDENT MACROPHAGE
INFLAMMATION IS KEY. THIS WORK
BASICALLY SETS THE TONE FOR US,
AND I THINK SEVERAL OTHERS IN
THE FIELD, THAT THE MECHANISM
THAT REALLY CONTROLS
INFLAMMAGING CONTROLS-- --.
WHAT WE HAVE BEEN VERY
INTERESTED IN IS THE ORIGIN OF
INFLAMMATION WITH AGE. THIS IS
A SLIDE FROM A COLLEAGUE DARCY
JOHANSSON AT NIH. YOU CAN SEE
THE INDIVIDUALS WITH THE SAME
BODY MASS INDEX IN THE SAME
BMI, AND THE PRESENCE OF
ECTOPIC FAT IS EVIDENT
INCLUDING ECTOPIC FAT IN THE
LIVER. THERE'S A LOT OF
INTEREST IN TERMS OF WHAT THIS
ECTOPIC MAP MEANS IMPORTANT IN
THE REGULATION OF SEVERAL
CLINICAL DISORDERS.
ONE THING I WOULD LIKE TO
EMPHASIZE IS THAT IN FACT --
THE TISSUE IS AN ACTIVE
IMMUNOLOGICAL ORGAN AND WE ARE
LOOKING AT MILARD CELLS
INDELIBLY MARKED. BY THE WAY
THESE ARE HEALTHY AS ADIPOSE
TISSUE.
ESSENTIALLY THIS IS IMPORTANT
IN (INDISCERNIBLE), AN ACID
EXPANDS WITH H WE HAVE BEEN
INTERESTED IN THIS ORGAN AND
EMILY TOUCHED UPON THIS
YESTERDAY. ONE OF THE THINGS
THAT WE FOUND EARLY ON IN
ADDITION TO LOSS OF INNATE
CELLS LIKE ILCS, WAS A
REDUCTION OF HOMEOSTATIC
MACROPHAGES THROUGH AGE. BY
THE WAY THIS IS OPPOSITE TO
WHAT YOU MIGHT EXPECT WITH
OBESITY; OBESITY IS NOT ALWAYS
ACCELERATION OF AGING. WITH
OBESITY YOU GET EXPANSION OF
MACROPHAGES.
WE ARE INTERESTED IN THE
RESIDENT MACROPHAGES AND WHAT
THEY HAVE BEEN DOING THE
ORIGINAL DISCOVERY WAS MADE BY
CHRISTINA, A COLLEAGUE OF MEAN
WHAT SHE WAS STILL IN MY LAB.
AND THE MAIN THING WE FIND
QUITE SERENDIPITOUSLY WAS THAT
THE MACROPHAGES ARE INFLAMED.
ONE THING WE ARE DOING IS
BASICALLY BREAKING DOWN THE
NEUROTRANSMITTERS LIKE
CATECHOLAMINES MADE BY THE
NERVOUS SYSTEM AND THE UP
REGULATION OF THE ENZYME. THE
KEY FINDING WAS THAT CHRISTINA
WAS ABLE TO SHOW THE REDUCTION
OF LIPOLYSIS THAT HAPPENS WITH
AGES DUE TO THE BREAKDOWN OF
THIS INFLAMED MACROPHAGES THAT
BREAKS DOWN THE
(INDISCERNIBLE).
THAT LED US INTO THIS AREA
WHICH WE COVERED AND LED TO THE
DISCOVERY OF WHAT WE THINK OF
THE CELLS IS NOW NERVE
ASSOCIATED MACROPHAGES.
THIS IS A PHOTON IMAGE DONE BY
CHRISTINA ON MG ANIMALS. YOU
CAN IDENTIFY THE SYMPATHETIC
NATURE, AND YOU NOTICE THE
CELLS, BECAUSE THERE ARE CELLS
THAT ARE RESIDENTS ON THE
NERVES. YOU CAN SEE THAT THEY
ARE BASICALLY HAVING DENDRITES
AND SOME ARE STRETCHED OUT.
THEY ARE OBVIOUSLY QUITE
DISTINCT.
BECAUSE WE WERE REALLY
INTRIGUED, CHRISTINA AND I, IF
THEY HAVE THESE MONOAMINE
OXIDASE, WHERE ARE THE -- FROM?
AND THEY LET US TO FIND
NERVES-- NERVES ARE REALLY
IMPORTANT-- THERE ARE NERVES
THAT RESIDE ON THE CELLS. AT
THE TIME WE THOUGHT IT WAS
DEGRADATION OF CATECHOLAMINES.
WE KNOW NOW THAT THERE IS MUCH
MORE HAPPENING IN THE AGE TO
VISCERAL FAT, NOT ONLY
DEGRADATION BUT ALSO
(INDISCERNIBLE).
HERE YOU ARE LOOKING AT
CLARIFIED IMAGES OF VISCERAL
ADIPOSE TISSUE. IT IS PRETTY
OBVIOUS. THIS WAS DONE IN
COLLABORATION WITH -- --. YOU
CAN SEE CLEARLY THAT WITH AGING
NOT ONLY DO YOU HAVE MACHINERY
THAT DEGRADES CATECHOLAMINE,
BUT YOU HAVE LESS SYMPATHETIC
NERVES. WHAT IS GOING ON?
SO THIS IS A PROJECT THAT HAS
BEEN GOING ON FOR A WHILE IN
THE LAB AND IT HAS BEEN
CHALLENGING AND IT IS GREAT TO
HAVE FANTASTIC SCIENTISTS IN
THE LAB -- -- A POST DOC AND A
STUDENT IN THE LAB LEADING THIS
PROJECT AND BASICALLY LC IS
TRYING TO UNDERSTAND WHAT ARE
THE CELLS AND WHAT ARE THEY
DOING? LC EMPLOYED SCANNED
ELECTRON MICROSCOPY. YOU CAN
FIND THE NERVE ASSOCIATED
MACROPHAGES RIGHT NEXT TO A
MYELINATED AXON.
AND YOU WILL FIND THE COMPLETE
WITH ADULT ANIMALS THE OLD
MACROPHAGES ARE LOADED WITH
MYELIN; IT MAY HAVE SOMETHING
TO DO WITH POTENTIALLY
IMPAIRMENT OF NERVE FUNCTION.
SO THE APPROACH WE TOOK WAS TO
SEE-- MY COLLABORATORS GET OLD
COLLABORATING WITH ME, TOO MUCH
STRESS, TOO MUCH STRESS! BUT
YOU KNOW, BECAUSE THE APPROACH
WE TOOK WAS AN REACH CELLS THAT
ARE TRULY RESIDENTS. EMILY HAD
ESTABLISHED THIS PROCEDURE SHE
TOLD ABOUT-- SELF SEQUENCING
AND CHRISTINA FOUND THAT
MONOAMINE OXIDASE IS ONE OF THE
GENES THAT IS EXPRESSED IN
NERVE ASSOCIATED MACROPHAGES.
WHAT WE DID IN COLLABORATION
WITH MY FRIEND AND COLLEAGUE --
-- THE ANALYZE WHAT DATA WAS
OUT THERE TO SEE IF WE COULD
IDENTIFY NERVE ASSOCIATED
MACROPHAGE SIGNATURES
TRANSCRIPTIONALLY. THERE'S A
COUPLE OF CLUSTERS THAT ENRICH
FOR IT. MONOAMINE OXIDASE IS
ONE OF THE THINGS THAT
REGULATES IT. THE OFFICE
QUESTIONS IS WHAT HAPPENED WITH
AGE?
HE A RESIDENT MACROPHAGES IN
THE ADULT MOUSE, AND ON THE
RIGHT ARE THE OLD ANIMALS. AND
SO WHAT YOU WILL SEE IS THAT
THERE ARE CERTAIN CLUSTERS THAT
ARE DISAPPEARING. YOU CAN SEE
THIS HERE. AND THINGS
COMPLETELY EMERGE, WHICH ARE
NOT PRESENT IN YOUNG ANIMALS.
WHAT STRUCK US WAS THAT THESE
TWO CLUSTERS OF THE CLUSTERS
THAT WE THINK ARE RICH FOR
NERVE ASSOCIATED MACROPHAGES.
AND ALSO WITH H1 OF THE THINGS
THAT IS HAPPENING IN THE CELLS
IS ACTIVATION OF THE COMPLEMENT
WHICH I THINK WE HAVE HEARD
OVER AND OVER AGAIN THROUGHOUT
THIS MEETING SO IT IS REALLY
IMPORTANT MOLECULE.
I'M NOT GOING TO GO INTO
DETAILS THERE IS A POSTER
OUTSIDE AND YOU CAN TALK TO OUT
ELSE ABOUT IT.
HERE'S ANOTHER INTRIGUING FIND
THAT LC MADE. THESE MACROPHAGES
ARE NOT ONLY VERY NEURAL BUT
ALSO INTRA-NEURAL. IN THE
GREEN AT THE NERVE ASSOCIATED
MACROPHAGES. AND WE HAVE NOT A
WAY TO ISOLATE THEM AND
CHARACTERIZE THEM. I DO HAVE
TIME TO GO OVER IT OTHERWISE --
WILL KICK ME OUT. HERE ARE A
FEW TAKE-HOME POINTS. NUMBER
ONE IS NAMS ARE PRESENT IN
NICHES IN ADIPOSE TISSUE. AND
ARE TRANSCRIPTIONALLY
HETEROGENOUS.
MAOA ENRICHES FOR A SUBSET OF
NAMS.
LOSS OF ADIPOSE INNOVATION IS
ASSOCIATED WITH NAM ACTIVATION
IN AGING.
DOES TARGETING NAMS CONTROLLER
FUNCTION ORGANISMAL AGING? WE
HAVE TENTATIVE EVIDENCE THAT
SUGGEST THE INFLUENCE ON THE
INTEGRITY OF THE NERVES. I HAVE
TWO MINUTES? THREE MINUTES.
THAT IS A LOT.
I WOULD END BY SHOWING YOU
SOME DATA THAT WE HAVE RECENTLY
PUBLISHED, WITH THE IDEA THAT,
YOU KNOW, WHEN THE HOST HAS AN
NEGATIVE BALANCE HOW DOES IT
INTEGRATE WITH THE IMMUNE
SYSTEM AND INFLAMMATION?WE HAVE
KNOWN FOR AGES. AT THIS POINT
IT HAS TO INTEGRATE MULTIPLE
RESPONSES, MULTIPLE NEURAL
RESPONSES.
ONE PROBLEM WITH THIS THOUGH,
WE DO GET LONGEVITY IN RODENTS
AND IN MODEL ORGANISMS BUT IT
COMES WITH THE TRADE-OFF.
SOMETHING THAT WE HAVE KNOWN
FOREVER, BUT WE DON'T WANT TO
SAY IT TOO LONG.
ONE IS THAT THE ANIMALS HAVE
PROBLEMS REGULATING CORE BODY
TEMPERATURE. THEY HAVE
REPRODUCTIVE STATUS, THEY DO
NOT REPRODUCE WELL AND THEY DIE
OF INFECTIONS BECAUSE OF IMMUNE
RESPONSE PROBLEMS. YOU WONDER
WHETHER IT IS PHYSIOLOGICALLY
RELEVANT. WHAT SHOULD WE BOTHER
TO STUDY IT? AND THAT IS WHAT
THE NIH WANTED TO DO. THERE
ARE ACTUALLY STUDIES THAT SHOW
THAT IN ANIMALS OF CERTAIN
STRAINS NOT ONLY DID NOT LIVE
LONGER BUT IN FACT LIVE SHORTER.
I'M NOT GOING TO BELABOR THE
POINT THAT MARK DAVIS SAID
ENOUGH ABOUT IT.
THE KEY POINT IS THAT I THINK
RANDOMIZED CONTROLLED TRIALS
REALLY CRITICAL, ESPECIALLY FOR
THE DIET IN HUMANS. AND
WORKING WITH A GROUP OF
PSYCHOLOGISTS AND PSYCHIATRISTS
I REALIZED ONE OF THE KEY
THINGS WE DO NOT PAY ATTENTION
TO IS THAT OUR MICE AND FLIES
DO NOT SIGN CONSENT FORMS TO
LIMIT THE CALORIES AND HUMANS
DO. THERE IS A BIG VARIABLE
BECAUSE PEOPLE ARE MOTIVATED;
THEY KNOW THEY ARE NOT GOING TO
STARVE. THE DOES NOT INDUCE THE
STRESS RESPONSE.
THE IDEA WAS THAT WE STUDIED
THIS WITH RELEVANCE TO THE
HUMAN PHYSIOLOGY, AND IF WE
COULD IDENTIFY CAUSALITY WE
COULD DISCOVER SOMETHING NEW.
THAT IS A TRIAL AND I'M NOT
GOING TO SHOW YOU BECAUSE IT
WAS PUBLISHED, DONE BY CALERIE.
THE IDEA IS TO RESTRICT
CALORIES FOR TWO YEARS IN
HEALTHY PEOPLE, AND STUDY THEM.
PEOPLE CAN RESTRICT ONLY 15%
AND END TO MAKE AN IMPORTANT
POINT. WE ARE GOING TO LOOK AT
BIOMARKERS. WHAT WILL IT TELL
YOU? DID YOU ALTER THE COURSE
OF ANYTHING? LUCKILY THIS IS
WHY PEOPLE SHOULD STUDY
IMMUNOLOGY. BECAUSE AGING OF
CERTAIN ORGANS RECEIPT AGING OF
OTHER ORGANS.
AND YOU LOOK AT THE CHEMICAL
SHIFT OF THE MRI OF THE THYMUS
IN A HEALTHY PERSON ON THE
LEFT. EVERYTHING IS ALMOST
COMPLETELY INTO FAT. WE
FOCUSED ON THE CORNER AND WAS
STRUCK US WAS AMAZING. WHEN THE
DATA WAS UNBLINDED, WE FOUND
WAS IN FACT THIS IS A
REPRESENTATIVE INDIVIDUAL THAT
CAME AS A BASELINE AFTER TWO
YEARS OF CR. , YOU ARE LOOKING
AT FAT SATURATION SIGNAL IN
THIS CASE YOU ARE LOOKING AT A
SIGNAL FROM THE WATER. LYMPHOID
TISSUE.
SO THIS INTERVENTION WAS WHAT
ENABLED THE REVERSE. YOU
MOBILIZE THE LIPID. I DON'T
HAVE TIME BUT YESTERDAY WE
HEARD THERE ARE MARKERS WE CAN
STUDY. I'M GOING TO END BY
SHOWING YOU WORK FROM OLGA
SPADARO. WE ALSO SEQUENCED THE
ADIPOSE, IN THOSE DAYS THERE
WAS NO SINGLE CELL SEQUENCING.
I STARTED MY LAB IN 2007. MAX
YOU ARE NOT THE ONLY ONE
GETTING OLDER.
I WILL AND BY SHOWING YOU THE
SUMMARY THAT WE WERE ABLE TO
FIND REALLY REMARKABLE
DIFFERENCES WITH CALORIE
RESTRICTION IN THE HUMAN
TRANSCRIPTOME. THIS TRIAL HAS
ENDED THE DEBATE WHETHER CR IS
RELEVANT TO HUMAN PHYSIOLOGY OR
NOT. ABSOLUTELY IT IS RELEVANT.
IT AFFECTS LONGEVITY. THE 15%
REDUCTION DOES NOT SEEM TO
MATTER WHAT TIME OF THE DAY YOU
EAT YOUR FOOD OR WHAT YOU EAT
AS LONG AS YOU REDUCE YOUR
CALORIES.
VERY CRITICAL POINT. I THINK
THE HOLY GRAIL OF IMMUNOLOGY.
THYMIC AGING IS REVERSIBLE IN
HUMANS. IF YOU CAN TARGET IT IN
THE RIGHT WAY. I DO NOT SHOW
YOU THE DATE OF THIS WAS JUST
PUBLISHED LAST YEAR THAT WE
WERE ABLE TO HARNESS AT LEAST
TWO MOLECULES PLA2G7 AND SPARC.
ONLY THE FUTURE WILL TELL US
WHETHER WE CAN ACTUALLY DEPLOY
THESE INTERVENTIONS.
LAST THIS THING WOULD NEVER BE
POSSIBLE UNLESS THERE WAS A
TEAM SCIENCE APPROACH LED BY A
GROUP OF INVESTIGATORS THAT
WERE PART OF THE CALORIE. SORRY
I WENT A LITTLE BIT OVER.
>>THANK YOU. ALWAYS GREAT
TALK FROM YOU. YES PLEASE
SARAH?
>>I CANNOT HELP BUT ASK. THE
FIRST IS ABOUT THE LEVEL OF
INNOVATION. (CORRECTION)
INTERVENTION. DO YOU THINK THAT
HYPER INTERVENTION RESULTS
(INDISCERNIBLE)? I AM WONDERING
IF THE MACROPHAGE POPULATION
COULD BE EXPANDED? HOW CAN IT
BE ATTRACTED SYNTHETICALLY?
>>I DID NOT SHOW YOU THE DATA,
THE LINEAGE TRACKING OF THE
CELLS AND WHERE THEY COME FROM.
THEY ARE NOT AS CLEAN-CUT AS
THE MICROGLIA. THEY ARE ONLY
PARTIAL FROM THE YOLK SAC AND
PARTIAL FROM THE FETAL LIVER.
A CRITICAL POINT YOU RAISE IF
WE CAN JUST EXPAND THE
HOMEOSTATIC MACROPHAGES I THINK
IT WILL BE VERY BENEFICIAL IN
CLEANING UP STUFF. HOW TO DO
THAT? WE ARE NOT AT THAT POINT.
THESE MACROPHAGES OR MAMS ARE
DEDICATED TO THE NERVES. THEY
ARE VERY UNIQUE AND TIME WILL
TELL WHAT THEY REALLY MEAN FOR
THIS. RIGHT NOW THERE IS NO
WAY TO TARGET THEM. WE ARE IN
THE PROCESS OF DISCOVERING
THOSE PATHWAYS.
>>ANOTHER QUESTION?
>>I SAW A LECTURE RECENTLY
FROM-- ACETYLCHOLINE
(INDISCERNIBLE)-- INTERESTED
ABOUT EXERCISE AND CALORIC
RESTRICTION. I AM WONDERING IF
THERE IS AN EXERCISE
EQUIVALENCY ALSO WITH YOUR 15%
REDUCTION?
>>IT WAS-- WHO FIRST SHOWED
THAT (INDISCERNIBLE) -- I THINK
IT COULD BE REALLY IMPORTANT.
WE HAVE NOT LOOKED INTO IT AND
IT COULD BE IMPORTANT BECAUSE
-- DOES NOT HAVE
PARASYMPATHETIC INTERRELATION.
I DON'T HAVE DATA TO SAY THE
SECOND QUESTION WAS EXERCISE
AND CR?
>>LOOKING AT ATHLETES, EATING
IS A BIG PART OF IT. AND I
WONDER OF EXERCISES EQUIVALENT
OF THE -- PART OF
(INDISCERNIBLE).
>>I MUST TELL YOU THIS. I WAS
RECENTLY GIVING A TALK
SOMEPLACE AND SOMEONE GET
REALLY ANNOYED WITH ME. THEY
THINK THAT I'M SOME SORT OF CR
PROPONENT AGAINST EXERCISE. I'M
NOT. BUT THERE ARE LOTS OF
STUDIES DONE BY PEOPLE THAT
HAVE SHOWN CLEARLY THAT
EXERCISE DOES NOT CAUSE WEIGHT
LOSS. THIS IS VERY
CONTROVERSIAL POINT. PEOPLE
HATE IT WHEN I SAY THAT.
BUT UNDER THEORY OF NEGATIVE
ENERGY BALANCE, UNLESS YOU ARE
IN NEGATIVE ENERGY BALANCE THE
EFFECTS OF CR AND EXERCISE ARE
NOT ANALOGOUS AND THAT IS THE
KEY POINT. IN CR YOU ARE IN
NEGATIVE ENERGY BALANCE AND
OTHER EFFECTS WHICH ARE NOT
ENERGY NEUTRAL ARE OBVIOUSLY
MEDIATED. CALORIE SHOWED THAT
IN PHASE 1, DONE WITH EXERCISE
AND DIET AND THERE WAS NO THE
EFFECT OF EXERCISE. SORRY.
>>BUT IT COULD BE STRESS
REDUCTION.
>>ABSOLUTELY.
>>THANK YOU DEEP. THANK YOU
FOR THE QUESTIONS.
I'M GOING TO INTRODUCE THE
NEXT SPEAKER MARIA MITTELBRUNN,
UNIVERSITY OF MADRID, SPAIN.
SHE WILL TALK ABOUT THE
MITOCHONDRIA DYSFUNCTION.
>>HELLO AND THANK YOU VERY
MUCH. THANK YOU TO THE
ORGANIZERS FOR THIS AMAZING
MEETING.
WHAT DO THEY HAVE IN COMMON?
THE HUMAN PATHOLOGIES,
CARDIOVASCULAR DISEASE,
METABOLIC DISORDERS, BONE AND
MUSCULAR DISEASES, AUTOIMMUNE
DISEASE? THEY HAVE THREE
FEATURES IN COMMON. THEY
DISRUPT THE (INDISCERNIBLE)
SPACES, THEY INVOLVE
INFLAMMATION -- AND THE THIRD
IS THEY INCREASE IN A SO THEY
ARE CONSIDERED AGE ASSOCIATED.
IN FACT WE KNOW THAT AGING IS
ASSOCIATED WITH CHRONIC
INFLAMMATION. WE LEARNED
YESTERDAY THAT WE CAN PREDICT
HOW WE AGE BY MEASURING
INFLAMMATORY -- IN OUR BLOOD.
WHAT IS THE CONTRIBUTION OF THE
DIFFERENT (INDISCERNIBLE)? ONE
OF THE QUESTIONS THAT WE HAVE
IN THE LAB.
WE ARE ESPECIALLY INTERESTED
IN T CELLS. IT WAS JUST
MENTIONED THAT THYMUS
INVOLUTION IS THE FIRST
MANIFESTATION OF AGING. THERE
IS A DRAMATIC CHANGE IN T CELL
REPERTOIRE. IF YOU HAVE HIGH
NUMBERS OF NAïVE CELLS, WE
START TO ACTUALLY T CELLS WITH
MEMORY, EFFECTOR AND SENESCENT
FEATURES.
SO IN THE T CELL COMPARTMENT
THIS MAKES US MORE VULNERABLE
TO INFECTIONS, CANCER, LOW
VACCINATION RESPONSE,
AUTOIMMUNITY AND COULD ALSO
CHRONIC INFLAMMATION.
SO A SUCCESSFUL INFLAMMATORY
RESPONSE AS YOU KNOW IS
(INDISCERNIBLE) THERE IS A PEAK
AND AFTER RESOLVING THE
CHANNELS YOU NEED TO STOP DOWN
THE INFORMATION FOR THE
INFLAMMATORY RESPONSE. IT IS
ESSENTIAL TO CONTROL CHRONIC
INFLAMMATION. WHILE THE IMMUNE
CELLS ADAPTER METABOLISM TO
THIS RESPONSE. AND WHEN THERE
IS (INDISCERNIBLE) THE DIESELS
DEPEND ON MITOCHONDRIA
(INDISCERNIBLE).
ONCE THE CHALLENGE IS FINAL
THEY HAVE INCREASED
(INDISCERNIBLE).
THEY COME BACK TO MORE
QUIESCENT METABOLISM.
THIS IS WHAT HAPPENS IN A
SUCCESSFUL INFLAMMATORY
RESPONSE WHEN WE ARE YOUNG.
WHEN WE ARE OLD, THE HYPOTHESIS
IS THAT IN MANY OF THE CELLS IN
THE BODY, IMMUNE CELLS ALSO
HAVE MITOCHONDRIA DECLINED. AND
AS A CONSEQUENCE HE ARE NOT
ABLE TO WRAP AROUND THE
METABOLISM TO FULFILL THE
(INDISCERNIBLE) RESPONSE AND
STOP INFORMATION. THIS IS THE
HYPOTHESIS WE HAVE BEEN
STUDYING IN THE LAB FOR THE
LAST YEARS.
FIRST TO CONFIRM THIS
HYPOTHESIS, WHAT WE DID IS WE
CONFIRMED IF T CELLS-- IF THERE
IS A MITOCHONDRIAL DECLINE
DURING AGING. IT IS WELL-KNOWN
THAT MITOCHONDRIA DNA IS
ESPECIALLY SENSITIVE TO DAMAGE.
IN CONTRAST TO NUCLEAR DNA,
MITOCHONDRIAL DNA IS NAKED,
UNPROTECTED FROM STRESS. THERE
ARE VERY FEW REPAIR MECHANISMS,
MITOCHONDRIAL DNA IS LOCATED IN
THE MITOCHONDRIA WHERE THERE
ARE A LOT OF EXPRESSED
OXIDATIVE STRESSORS.
T CELLS ACCUMULATE
MITOCHONDRIAL DAMAGE DURING
AGING. WE ISOLATED THEM FROM A
DIFFERENT AGES. AS YOU CAN SEE
HERE IN THIS PLOT, WE OBSERVED
THAT YOUNG T-CELLS FROM YOUNG
MICE HAVE MITOCHONDRIA WITH
HIGH MITOCHONDRIAL POTENTIAL.
WE FOUND THAT THERE IS
MITOCHONDRIA WITH LOW MEMBRANE
POTENTIAL. THE ACCUMULATION OF
THIS DAMAGE MITOCHONDRIA
PERFECTLY CORRELATES WITH THE
AGE OF THE MICE.
WE CONFIRMED THIS
MITOCHONDRIAL DECLINE IN
T-CELLS BY T-FORCE ANALYSIS AND
WE OBSERVED THAT
(INDISCERNIBLE) IS PRODUCED IN
OLD T-CELLS COMPARED TO YOUNG
T-CELLS.
ALSO T-CELLS DECLINING
MITOCHONDRIAL FUNCTION WITH
AGING. THE NEXT STEP WAS TO
MIMIC THIS AGE ASSOCIATED
MITOCHONDRIAL DYSFUNCTION IN
YOUNG MICE. TO DO THIS, WHAT
WE DID IS WE TAKE ADVANTAGE OF
MITOCHONDRIAL TRANSCRIPTION
FACTOR A. THIS IS A
TRANSACTION FACTOR ENCODED BY
THE NUCLEAR GENOME THE CONTROL
THE TRANSCRIPTION REPLICATION
AND STABILITY OF MITOCHONDRIAL
BEGINNING SO YOU DO YOU DEPLETE
TFAM, AND YOU PRODUCE
MITOCHONDRIAL DNA AND INDUCE
DRAMATIC MITOCHONDRIAL
DYSFUNCTION.
WE TAKE ADVANTAGE OF TFAM MICE
GENERATED IN THE LAB AND CROSS
THEM WITH CD4 MICE. BY
FOLLOWING THIS STRATEGY WE DID
TFAM IN ALL CELLS INCLUDING TB4
AND TB 8.
USING THE STRATEGY, WE OBSERVE
THAT OUR MUTANT MICE, T CELLS
FROM THE MUTANT MICE WHEN THEY
ARE YOUNG THEY HAVE
(INDISCERNIBLE) MITOCHONDRIAL
RESPIRATION. THESE MICE ARE IN
RED AND WE COMPARED THEM WITH
OLD CONTROLS THAT ARE IN BLUE.
SO WE HAVE MIMICKED THE SAME
AGE-ASSOCIATED MITOCHONDRIAL
DECLINE THAT OCCURS NATURALLY
IN T-CELLS FROM THE MUTANT
MICE.
BY DOING THIS, BY MIMICKING
THESE DEFECTS ASSOCIATED WITH
MITOCHONDRIAL DECLINE, WE
REPLICATE THE MAIN FORMAT OF
T-CELL AGING. WE OBSERVED IN
THE YOUNG MICE REDUCTION IN THE
NAïVE POOL OF T-CELLS AND
REGULATION OF MEMORY T-CELLS
THAT ACQUIRE SENESCENT AND
INFLAMMATORY MARKERS INCLUDING
THE INFORMATION FOR T-CELLS
THAT START TO PRODUCE
INTERFERON, GAMMA AND TNF, AND
OTHER SENESCENT FEATURES.
BESIDES THIS MOLECULAR
HALLMARK OF T-CELL AGING ARE
MUTANT T CELLS ARE ALSO
IMMUNOCOMPROMISED WHERE WE
PERFORM INFECTION EXPERIMENTS
AND WHAT WE OBSERVE IS A YOUNG
MUTANT MICE DIE IN THE FIRST 10
DAYS FROM ECTOMELIA (PHONETIC)
INFECTION THAT ALSO
(INDISCERNIBLE).
WE MEASURE THE CYTOKINES IN A
YOUNG MUTANT MICE AND OBSERVED
SIMILAR LEVELS OF HIGH TNF AND
-- JUST BY MIMICKING IT
ASSOCIATED MITOCHONDRIAL
DECLINE IN T-CELLS WE
PRECIPITATE IMMUNOGENESIS AND
INFLAMMATION.
WHAT WE OBSERVED IS THAT THESE
MICE LOOK TO BE IN A BAD SHAPE.
THEY START LOSING WEIGHT. THEY
HAVE A REDUCTION IN THE
LIFESPAN ABOUT 50%. ,
WHERE THE DYING? WE FIRST
LOOKED AT THE CARDIOVASCULAR
ARTERATIONS. WE FOUND DRAMATIC
ARTERATIONS (PHONETIC),
SIASTOLIC DYSFUNCTION, AORTIC
DILATION, LUNG CONGESTION.
WE ALSO OBSERVED BESIDES THE
CARDIOVASCULAR ALTERATIONS THE
YOUNG MUTANT MICE HAD ANEMIA,
COGNITIVE DECLINE, PHYSICAL
DISABILITY AND PREMATURE DEATH.
WE PROPOSE THAT DEATH BY
ACCELERATING AGING IN T-CELLS
CAN INDUCE AGE ASSOCIATED MULTI
MORBIDITY IN THE REST OF THE
TISSUE.
WE PUBLISH THE DATA AND LAURA
I THINK PROVIDES USING A
DIFFERENT STRATEGY AND
DIFFERENT MODELS, SIMILAR
RESULTS.
SO WE WONDER, WHAT IS THE
MOLECULAR MECHANISM? HOW CAN
AGE-RELATED CHANGES IN T-CELLS
RELATED TO DETERIORATION IN
OTHER TISSUES?
WE FOUND THIS PAPER VERY
INSPIRING. THE AUTHOR PROPOSE
THAT TH-1 INDUCED SENESCENT CAN
BE DONE IN TUMOR CELLS AND AS
THE AGE ASSOCIATED MITOCHONDRIA
T-CELLS SHOWED THEM
INFLAMMATORY PHENOTYPE WHEN
PRODUCED IN -- AND GAMMA AND
ALPHA (INDISCERNIBLE).
WE DETECTED CHANGES IN THE
LIVER, AND PANCREAS AND HEART
AND ADIPOSE TISSUE. GOING
FARTHER IN THE MOLECULAR
MECHANISM, WE TOOK THE SERUM
FROM THE MUTANT MICE AND
INCUBATED HEALTHY CELLS FOR
SEVEN DAYS AND THIS IS ENOUGH
TO INDUCE P21 CELL EXPRESSION.
AND WHEN WE PRODUCE THIS IN
VIVO WE PERFORMED MARROW
TRANSPORTATION. WE WAITED FOR A
MONTH. THIS IS HOW THEY LOOK,
TWO LITTER MATES. THIS ONE HAS
BEEN TRANSPLANTED WITH BONE
MARROW PRECURSOR FROM CONTROLS.
THIS IS BEEN TRANSPORTED WITH
BONE MARROW FROM THE MUTANT
MOUSE. IT LOOKS IN A VERY BAD
STATE AND THEY PRESENT
SENESCENT CHARACTERISTICS.
TO CONFIRM THE MOLECULAR
MECHANISM, WE HAVE THE DNA
ALPHA, IN THE QUESTION TO DELAY
AGE ASSOCIATED MULTI MORBIDITY.
HOW OLD T CELLS ACT AS AGING
ACCELERATORS? OUR DATA SUGGEST
THAT OLD T-CELLS ACQUIRE
PRO-INFLAMMATORY-- THIS
INFLAMMATION COULD INDUCE
SENESCENCE AND THE REST OF THE
TISSUE BUT ALSO --
(INDISCERNIBLE) -- RECEPTORS
THAT CAUSE TISSUE DAMAGE IN THE
PTR-INDEPENDENT MANNER. AN
SPOILER ALERT. WE ALSO OBSERVED
THAT OUR OLD T-CELLS ARE WAKING
UP IN IMMUNITY. THERE IS A
CONTRIBUTION, PRETTY RESILIENT
BY INNATE IMMUNE CELLS.
BESIDES THESE PATHOGENIC
FUNCTIONS, ALL T-CELLS COULD
ALSO ACT AS AGENT ACCELERATED
BY LOSING THE PROTECTIVE
FUNCTIONS, SO THEY LOSE THEIR
ABILITY TO RECOGNIZE SENESCENT
CELLS TO DELETE THEM.
SOMETHING THAT IS QUITE
INTERESTING-- IS THAT OUR
IMMUNITY AND OUR IMMUNE SYSTEM
CONTROLS OUR GUT MICROBIOME.
ALL OF THE IMMUNE SYSTEM THE
DOES THIS, THIS COULD
CONTRIBUTE TO AGE ASSOCIATED
MULTI MORBIDITY.
I THINK I HAVE NO TIME TO GO
FARTHER. I WILL GO INTO THE
FUTURE PERSPECTIVE OF THE LAB.
WE INDUCED (INDISCERNIBLE) OF
T-CELLS AND ACCELERATE BOTH THE
AGING AND WE WANT IN THE NEXT
YEARS TRY TO REVERSE THE
PHENOTYPE. THE GENERAL IDEA OF
THE NEXT YEARS IS TO SEE IF WE
CAN BOOST RESILIENCE TO
INFLAMMATORY AND SENESCENCE BY
TARGETING IMMUNE CELLS AND FOR
THIS I FOUND SOME GAPS IN THE
FIELD.
FIRST I THINK WE HAVE TO BE
ABLE TO DECODE THE DRIVERS OF
T-CELLS AGING THAT INCLUDES
INTRINSIC AND EXTRINSIC FACTORS.
IF WE ARE ABLE TO FIND THESE
DRIVERS WE WILL FIND
VULNERABILITIES THAT MAKE US
TARGET T-CELLS.
IS ALSO IMPORTANT TO
UNDERSTAND THE MOLECULAR
MECHANISM BY WHICH ALL T CELLS
OR IMMUNE CELLS INDUCE OR
PRECIPITATE AGING. THIS COULD
BE IF THEY ARE QUITE
PATHOGENIC, OR BECAUSE THE
LOOSE PROTECTIVE FUNCTION THIS
IS ESSENTIALLY WANT TO FIND
STRATEGIES TO REVERSE,
DEPENDING ON IF THERE ARE
PATHOGENIC FUNCTIONS WE FIND
DIFFERENT STRATEGIES TO DEPLETE
OLD T-CELLS OR BLOCK THE
CYTOKINES OR REJUVENATE THE
METABOLISM OF OLD IMMUNE CELLS.
IF YOU LOOSEN THE PRODUCTION
FUNCTION WE WILL THINK ABOUT
STRATEGIES OF THYMUS
REJUVENATION, THYMUS
RESISTANCE. CAN ALSO IMPROVE
THE T-CELL RESILIENCE OR
IMPROVE THE CONTROL OF
COMMUNITY TO THE MICROBIOME.
WE THINK THAT WITH THE
STRATEGIES MAYBE WILL BE ABLE
TO DELAY INFLAMMATION IN AGE
ASSOCIATED MULTI MORBIDITY.
THANKS TO THE PEOPLE INVOLVED
IN THE WORK. AND ALL THE
FUNDING AND COLLABORATORS.
THANK YOU VERY MUCH.
>>THANK YOU MARIA. VERY
INTERESTING UNFORTUNATELY WE
HAVE TO STOP TALKING. DEEP,
FIRST QUESTION.
>>MARIA, THANK YOU. I THINK
THE TFAM AS YOUR WORK IS SHOWN
IS CRITICAL FOR T-CELL FUNCTION
IN GETTING RID OF THE TFAM
ALLELE IS DOING SOMETHING. I
CAN TELL YOU THAT WE DID THIS
EXPERIMENT ALMOST 7 YEARS AGO
WITH THE TFAM GLOBAL -- THERE
WAS NO PHENOTYPE IN THOSE
ANIMALS WITH LOTS OF JUST
LOWERING THE HETEROZYGOUS TFAM.
I'M WONDERING WHETHER THESE
MOLECULES THAT WE THINK ARE
REALLY DRIVING AGING ARE HAVING
AN EFFECT REALLY BECAUSE THEY
ARE CLEARLY IMPORTANT IN
BIOLOGY, BUT THEY MAY NOT BE
RELEVANT FOR ACTUAL BIOLOGICAL
AGING. BECAUSE IN AGING THERE
IS NO CHANGE IN TFAM, RIGHT?
>>WE OBSERVED A REDUCTION IN
TFAM IN T-CELLS ALSO. BUT IT
IS TRUE. THIS IS A DRAMATIC
SYSTEM. THE IMPORTANT POINT
IS, IT HIGHLIGHTS THE ROLE OF A
SUCCESSFUL IMMUNE SYSTEM DURING
AGING. I THINK THIS IS NOT THE
ONLY MODEL JUST BY
MANIPULATING--
>>CLEARLY IMPORTANT BUT WHAT
I'M SAYING IS THE HETEROZYGOUS
DEFICIENCY KILL THE ANIMAL AT
THE AGE OF (INDISCERNIBLE).
>>YES, IT HAD NORMAL
MITOCHONDRIAL LEVELS.
>>I WANTED TO FOLLOW UP. IF
WE HAVE TFAM IN -- GLANDS, THIS
WAS CONDITIONAL LOCKOUT. WE
DID NOT GET ANY PHENOTYPE AT
ALL. WE GOT A VERY STRONG
PHENOTYPE DISEASE. YOUR
KNOCKOUT, IS NOT INDUCED?
>>NOT INDUCED.
>>IT IS AFFECTING -- SELECTION
IN YOUR MODEL?
>>20 WE HAVE TO BE AWARE WITH
TFAM KNOCKOUT -- IS THAT YOU
HAVE MITOCHONDRIAL DNA IN EACH
SET. WE STILL HAVE
MITOCHONDRIAL DNA. THE CELL
NEEDS TO DIVIDE TO GET RID OF
THE MITOCHONDRIAL DNA. IF YOU
CAN DEPLETE TFAM IN MANY CELLS
BUT THE CONCEPT DEPENDS ON THE
PROLIFERATION RATE OF T-CELLS.
IF THERE IS NO PROLIFERATION
RATE, THEY ARE STILL HAVING
MITOCHONDRIAL DNA. AND
EVERYTHING GOES WELL.
>>QUESTION IN THE BACK. THE
LAST QUESTION FROM THE AUDIENCE.
AND THEN WE HAVE ONLINE
QUESTIONS.
>>THANK YOU MARIA REALLY
BEAUTIFUL WORK. I WAS
WONDERING IF YOU COULD TELL US
MORE ABOUT WHAT YOU THINK THE
RELATIVE CONTRIBUTION OF THE
T-REG VERSUS THE T CONVENTIONAL
IS IN YOUR MICE?
>>THIS IS VERY IMPORTANT IF
YOU KNOCKOUT TFAM IN T REG YOU
HAVE A -- PHENOTYPE. THE MICE
DIED IN THE FIRST THREE WEEKS,
AN AUTOIMMUNE SYNDROME. THIS
REFLECTS THE BALANCE BETWEEN
THE DIFFERENCE SUBSTANCES IF
YOU DON'T HAVE FUNCTIONAL T REG
VERSUS UNCONVENTIONAL T REG YOU
HAVE (INDISCERNIBLE) IMMUTABLE
YOU HAVE CONVENTIONAL T-CELLS
NOT SO GOOD, T REG NOT SO GOOD,
YOU HAVE THIS CHRONIC
INFLAMMATION. WE HAVE NO TIME
FOR ANTIBODY PRODUCTION. I
THINK IT IS AN IMPORTANT
BALANCE BETWEEN THE DIFFERENT
T-CELLS.
>>THESE LOOK LIKE GLIAL CELL
MICE (INDISCERNIBLE) --
>>THERE IS A DRAMATIC WEIGHT
LOSS IN OUR MICE. THEY LOOK
SICK BECAUSE OF THE CHRONIC
INFORMATION. WHAT WE DID WAS WE
FED THEM WITH A -- DIET, IS IN
A SLIDE THAT I HAVE NO TIME TO
PRESENT BUT THIS THERE IS THE
LIFESPAN OF THE MICE
SIGNIFICANTLY.
>>OTHERS HAVE OBSERVED THAT
THE OVARIES AGE BEFORE OTHER
ORGANS IN THE BODY.
>>WHAT I CAN SAY REGARDING
GENDER DIMENSION, IS IT IN OUR
MOUSE MODEL FEMALES ARE MORE
VULNERABLE TO THIS CHRONIC
INFLAMMATION ON HOW TO LOOK.
THE PHENOTYPE APPEARS. BUT IT
IS LATE.
>>ANOTHER QUESTION.
>>THANK YOU FOR YOUR GREAT
TALK. I WAS CURIOUS ABOUT YOUR
PERSPECTIVE ON THE STUDY CAME
OUT A LITTLE WHILE AGO ON MOUSE
T-CELLS THAT WERE KEPT IN
CULTURE FOR 10 YEARS AND WERE
STILL RATHER HEALTHY,
SUGGESTING THAT THESE CELLS DID
PRETTY WELL OVER A LONG TIME,
EVEN BEYOND THE LIFESPAN OF THE
ANIMAL.
AND THEN I WAS CURIOUS ABOUT
THE COMPENSATORY, BROADER
IMMUNE CHANGES WHEN YOU DO HAVE
YOUR DISRUPTION. ONE THING I
HAVE NOT MENTIONED MUCH AT THE
MEETING YET PARTICULARLY THE
GAMMA DELTA T-CELL WHICH
INCREASES WITH AGING,
PARTICULARLY WITH BARRIER AND
OTHER ANTIGROWTH
(INDISCERNIBLE).
>>THE FIRST QUESTION IS VERY
CHALLENGING. I THINK T-CELLS
COULD-- THERE IS A POOL OF
T-CELLS THAT CAN PROLIFERATE
FOREVER. THIS EXPERIMENT IS
PERFORMED IN YOUR MICE. I
WOULD LIKE TO SEE WHAT HAPPENS
IF YOU PERFORM THIS EXPERIMENT.
AND ALSO WE KNOW THE
ENVIRONMENT IS VERY IMPORTANT
FOR THE AGING OF T-CELLS. ALSO
I AGREE WITH YOU THAT THAT IS
IN THE FIELD THAT WE HAVE TO
LOOK AT.
>>THANK YOU SO MUCH.
>>THANK YOU TO THE AUDIENCE
FOR THE PARTICIPATION. SO WE
COME BACK AT 1:00 PLEASE,
SHARP, SO WE CAN START ON TIME,
AND WE CAN DO THE SECOND PART
OF THE SESSION.
>>WE MOVE ON QUICKLY TO THE
NEXT PRESENTATION FROM -- FROM
THE NIA, HE IS GOING TO TALK
ABOUT IMMUNE DYSREGULATION IN
AGING AND ITS ROLE IN CANCER.
>>GOOD AFTERNOON. FIRST OF
ALL THANK YOU SO MUCH FOR
ORGANIZING THIS FANTASTIC
MEETING. I LEARNED AN
INCREDIBLE AMOUNT OF THINGS.
ALMOST LIKE I AM ILLITERATE
NOW.
I'LL TALK ABOUT CANCER. IT
SEEMS HARDLY ANYONE TALKED
ABOUT CANCER. SO OF COURSE
NOW, EVERYONE TALKS ABOUT
MACROBIOTICS, MARIA ALLUDED A
LITTLE BIT ABOUT MACROBIOTICS.
NOT SURE IF IT IS THE CHICKEN
OR THE EGG. BUT IT SEEMS IT
CONTROLS EVERYTHING WHAT
HAPPENS IN AGING AND SO ON.
OF COURSE I WILL TALK ABOUT
LITTLE HUMANS. IN THIS LITTLE
HUMAN WE FIND THAT ACTUALLY IN
AGING, EVEN IN HEALTHY AGING,
IT IS JUST NORMAL HEALTHY AGING
MICROBIOTA CHANGE.
BECAUSE OF THIS CHANGE WE FIND
SOME PATHOGENIC INCREASE IN
GOOD COMMENSAL INCREASE, EVEN
ONE BACTERIA CALLED
(INDISCERNIBLE).
THE FIELD IS VERY INTERESTING.
ACTUALLY IT DOES A LOT OF
THINGS. IT RESTORES THE MUCUS
LAYER, AND SUPPORTS OTHER GOOD
THINGS. BECAUSE OF THE
DECREASE OF THIS -- WE SEE THE
MUCUS LAYER DECREASED IN THE
AGING AND TOGETHER SYSTEMICALLY
YOU CAN SEE THE ENDOCRINE
CIRCULATION IS DECREASED.
HOWEVER IF YOU TAKE
AKKERMANSIA MUCINIPHILA IN
HUMANS YOU CAN SEE THE MUCUS
LAYER IS RESTORED AND THE --
DECREASES.
WHEN THE GUT IS LEAKING,
TOGETHER -- IS DECREASED. BUT
ALSO IN PERITONEAL CAVITY,
BUTYRATE IS DECREASED. YOU
KNOW SO MANY THINGS ABOUT
BUTYRATE, IT IS THIS INHIBITOR
FOR THE (INDISCERNIBLE). AND IN
LPS THE RATIO IS CHANGED. AND
THE ENDOTOXINE (PHONETIC)
ACTIVATES MONOCYTES. YOU SEE
THAT -- MONOTICES ARE RECRUITED
AND THEY PRODUCE MANY THINGS.
THIS IS OCCURRING IN THE
OMENTOM (PHONETIC), AND THEN
THROUGH THE PATHWAY INDICATED,
IT CONVERTS ADVANCES IN AGING,
IMMUNITY AND CHRONIC
INFLAMMATORY DISEASES (DAY
(CORRECTION) T 1 CELLS, THE
UPREGULATED -- AND IT EXPRESS
CLASS 1. AND THIS T 1 CELL
INDUCES (INDISCERNIBLE) IN
SQUIRRLES, MACAQUES AND ALSO
HUMANS. THE SAME PATHWAY
EXISTS.
I DON'T WANT TO TALK ABOUT
MECHANISMS BECAUSE IT IS
PUBLISHED. IF YOU BLOCK THIS
PATHWAY, EVERYTHING CHANGES.
YOU CAN WATCH THE MUCINIPHILA
AND THIS STOPS THE
(INDISCERNIBLE), AND IT ALSO
DECREASES AND IN MAXINE'S TALK
YOU HEARD ABOUT HOW THIS
INCREASES. BUT IN HUMANS AND
ELDERLY HUMANS, THE CD 8 CELLS
INCREASE.
HOWEVER B1A CELLS PEOPLE
ASSOCIATE WITH THE SUPRATING
(PHONETIC) NATURE. IN ELDERLY
PEOPLE INSULIN RESISTANCE IS
DECREASED AND THE SAME IN MICE.
THE QUESTION IS WHAT HAPPENS
WHEN THIS SALE BECOMES A
(INDISCERNIBLE) CELL? THEY
EXPRESS MUCH MORE IL-10. DO
YOU EXPECT IT WILL BLOCK
INSULIN RESISTANCE? WHAT IS IT
THAT IN EARLY HUMANS AND MICE
INSULIN RESISTANCE INCREASES?
YOU CAN SEE THAT INSULIN
RESISTANCE IS INCREASED IN ALL.
YOU CAN SEE THAT INSULIN
RESISTANCE GOES DOWN AND INTO
THE RECEPTOR SIGNALING GOES UP
AGAIN. BUT IF YOU TRANSFER 4BL
CELLS, INSULIN RESISTANCE WHICH
WAS RESTORED WILL BE BACK AGAIN
IN S&H. IF YOU TRANSFER -- ALL
THE B1A CELLS, INSULIN
RESISTANCE IS STILL HIGH WHICH
INDICATES THESE CELLS ARE
RESPONSIBLE FOR INSULIN
RESISTANCE AND AGING AT LEAST
THROUGH PPL.
SO OKAY, I WILL SHIFT GEARS TO
THE MAIN TOPIC, TODAY'S TOPIC.
B1A CELL SUPPRESSION. WE WOULD
EXPECT TUMOR INCREASES IN
AGING. HOWEVER I TOLD YOU THAT
FOR BL CELLS, WE ASKED THE
QUESTION, THERE IS A BEAUTIFUL
PAPER FROM-- USED TO BE AT THE
-- IS IT TOO LONG AGO AND
PUBLISHED IN THE EARLY 80S A
PAPER SHOWING THAT IN AGING
MELANOMA THE -- REDUCE GROWTH.
WHETHER THIS PATHWAY IS
RESPONSIBLE FOR THE REDUCTION
OF BL 16.
YOU CAN SEE HERE THAT THE
TUMOR GROWS VERY POORLY. AND
THEN YOU CAN ISSUE A TRANSFER,
YOUNG CD5 POSITIVE B CELLS, FOR
SUPPORT TUMOR GROWTH BUT IF YOU
INJECT ALL THE B1 CELLS WHICH
WILL BE ALL THE B1 CELLS, THE
TUMOR GROWTH BECAUSE OF THIS
EXPRESSION OF THE MELANOMA.
AND IN THIS PATHWAY YOU CAN
ALSO REVERT WITH
(INDISCERNIBLE) OR ENROFLOXIN
TREATMENT. YOU CAN SEE THAT
AFTER THE TREATMENT WITH
ENROFLOXICIN, THE TUMOR IS
INCREASED. IT CORRELATES WITH
INVERSELY EXPRESSION OF OPL
CELLS AND (INDISCERNIBLE).
YOU ASK, OKAY WE KNOW THAT IN
AGING ALL OF THESE CANCERS GO
UP. WHAT ARE YOU TALKING ABOUT?
SO THERE ARE OTHER MOTIVES.
YOU CAN SEE THAT AT3 TUMOR
GROWTH, IN AGING IT HAS
BEAUTIFULLY GROWN. IF YOU
DEPLETE THE ACD20 CELLS IT
GROWS. MORE ANTITUMOR
(INDISCERNIBLE). IS THAT WHY IT
INCREASED? NO, IF YOU TAKE
(INDISCERNIBLE), ESSENTIALLY
THE TUMOR DOES NOT GROW. IT
HAS NO EFFECT. THIS INDICATES
SOMEHOW -- INVOLVED IN THIS
PROCESS BUT NOT THROUGH 4BL
CELL. AND TO UNDERSTAND HOW IT
IS IN THE WALL, WE DECIDED TO
FIRST CHECK WHAT IS HAPPENING
IN JUST TUMOR-FREE NAïVE AND
AGING AND YOUNG MICE?
WE DID SOME SCREENING, SIMPLE
SCREENING. ONE THING CAME OUT.
YOU CAN SEE THAT AGED ITSELF
COMPARED TO AGED CD4 OR EVEN
AGED CD CELLS COMPARED TO YOUNG
ONES, YOU CAN SEE A LOT OF
EXERTION. ONE INTERESTING
THING IS THAT THEY ARE RELATED
TWO ENZYMES, CD 58, CD39 AND
(INDISCERNIBLE).
YOU CAN SEE THAT IN THE YOUNG
CD CELLS, IN ALL CELLS THE CD
39, 73 AND EXERTION MARKER
CONTAINING UP REGULATORS, ALL
UPREGULATIONS DECREASED. IT
LOOKS LIKE WITH THIS EXERTION
OF CD CELLS, I CALL THAT
EXPLOSION (INDISCERNIBLE) IT
SHOWS PD1 IS INCREASED.
SORRY THERE IS A MISTAKE. NO,
NO, THERE IS SOMETHING WRONG.
IT IS SUPPOSED TO BE PD1
INCREASED IN AGING AND
(INDISCERNIBLE) DECREASES.
SORRY MY LABELS ARE TYPOS.
ANYWAY, ALL THIS EXERTION.
THEN TO UNDERSTAND, WHAT IS
THIS? INCREASED IN CIRCULATION
AND HOW IT AFFECTS CANCER
OUTCOME? WE DID THIS
SIDE-BY-SIDE, B16 MELANOMA, AT3
IN MICE ALL YOUNG, THIN
CONDITIONS EXCEPT THROUGH CD
57. THE BACKGROUND IS THE SAME
AGAIN YOU CAN SEE THAT WHILE IN
B16 MELANOMA IT DECREASES, YOU
CAN SEE THAT IN ALL TUMOR
INFILTRATING LYMPHOCYTES YOU
CAN SEE THE CELLS DO NOT HAVE
DOUBLE POSITIVITY FOR ENZYMES.
YOU CAN SEE IN AGED AT3 TUMOR
GROWTH IS INCREASED.
YOU CAN SEE IT IS AN EFFECTIVE
PIPE FOR CELLS,
(INDISCERNIBLE)-- OPPOSITE
EVERYTHING.
AND THEN, WE SEE THAT BECAUSE
AT TUMOR ALREADY HAD
PRE-EXISTING (INDISCERNIBLE)
COMPARED TO MELANOMA EXISTING
CONDITIONS.
YOU CAN COMPARE AGAIN THE
TUMOR INFILTRATED DH CELLS AND
YOU CAN APPRECIATE THE
INFILTRATED CELLS IN AT 3
TUMOR, INCREASING THE ENZYMES
AND THE EXERTION MARKERS. AND
THIS EXOENZYME EXPRESSES ITSELF
AND IT IS MORE IN CLUSTER 22.
ALTHOUGH IT IS PRESENT IN
ALMOST CDH CELL OF AT3.
YOU CAN PROVE THAT THESE CDH
CELLS ARE DOING SOMETHING YOU
CAN SEE WITH RAG KO WITH AT3
AND WITH YOUNG ADOPTIVE
TRANSFER IT ALL HAD A
SIGNIFICANT DEFECT. ANOTHER WAY
IS IT THAT THE AT3 TUMOR
(INDISCERNIBLE), AND THE
CREATION OF THE CD REDUCES THE
TUMOR GROWTH, INDICATING THE CD
ITSELF RECRUITMENT INTO TUMOR
DOING (INDISCERNIBLE).
IN SUMMARY, I SHOWED YOU THAT
THE B CELLS IN AGING ARE
CHANGING AND THERE ARE MANY
DIFFERENT TYPES OF B CELLS, AND
THE OUTCOME CHANGES. THROUGH
(INDISCERNIBLE) CHANGE, IT CAN
EITHER INCREASE TUMOR GROWTH IN
ALL OR DECREASE. IT INCREASES
TUMOR GROWTH AND ALL OF THOSE
CD8 CELLS RECRUITED INTO THE
TUMOR. THANK YOU.
>>THANK YOU ARIA. THANK YOU
VERY MUCH AND WE HAVE TIME FOR
A FEW QUESTIONS. MICROPHONE
PLEASE.
>>WITH AT CELLS, IT IS VERY
INTERESTING. DO YOU OBSERVE
THE RECEPTORS BECOMING MUCH
MORE CONAL WITH AGING?
>>THIS IS A MUTUAL QUESTION.
WE DID NOT CHECK ANY B CELL
RECEPTORS. VERY GOOD QUESTION.
>>IN OLDER TUMORS, IS THERE A
DIFFERENCE IN IMMUNE CELL
INFILTRATES? MELANOMAS
(INDISCERNIBLE), I WAS
WONDERING IF YOU SEE A SHIFT IN
TERMS OF THE INFILTRATE?
>>ANOTHER GOOD QUESTION. THAT
IS EXACTLY OUR GOAL, TO FIND
THE IMPORTANT DATA
COLLABORATING WITH
(INDISCERNIBLE). WE DO NOT
HAVE ACCESS TO TUMORS FROM ALL
(INDISCERNIBLE), BUT CERTAINLY
CD8 CELLS ARE THERE. WE ARE
TALKING -- TUMORS.
>>I CAN MAYBE ADD THE COMMENT
FROM THE B CELL SIDE. THERE IS
A LOT OF INFILTRATION OF
INFLAMMATORY B CELLS IN BREAT
CANCER IN WOMEN THAT ARE OLDER,
OVER THE AGE OF 60. REALLY,
REALLY A LOT AND ALMOST ALL THE
CELLS THAT INFILTRATE HAVE THE
PRO-INFLAMMATORY PHENOTYPE OF
THE DOUBLE NEGATIVE. THEY TAKE
THE LEAD AMONG THE
(INDISCERNIBLE) INSIDE BREAST
CANCER.
ARE THERE OTHER QUESTIONS FOR
ARIA? WELL IF NOT THANK YOU SO
MUCH.
AND NOW, IT IS TIME FOR MY
PRESENTATION. I WILL TALK TO
YOU TODAY ABOUT A RESEARCH
TOPIC THAT IS BECOMING VERY
INTERESTING TO ME IN THE RECENT
YEARS. IT IS THE METABOLIC
RELATION OF HUMORAL RESPONSES
IN B CELL FUNCTION IN MICE AND
INDIVIDUALS WITH INFLAMMATORY
CONDITIONS. MY MAIN INTEREST IS
IN OBESITY AND TYPE II DIABETES
ESPECIALLY IN THE -- TISSUE AND
ALSO AGING AND TODAY I'M GOING
TO SHOW YOU THAT AGING CHANGES
THE METABOLIC PHENOTYPE OF B
CELLS. I'M GOING TO SHOW YOU
THAT AGING ALSO INDUCES OTHER
PRO-INFLAMMATORY IMMUNE CELLS,
AND I WILL TALK TO YOU
SPECIFICALLY ABOUT CD4. WE
ALSO HAVE DATA ON MONOCYTES.
I WILL SHOW YOU THE EFFECT OF
LACTATE, WHICH IS ONE OF THEM
METABOLIZES THEIR MASSIVELY
SECRETED BY AGED B CELLS AND
ALSO OTHER IMMUNO CELLS. AND
FOR THE FIRST POINT. I DON'T
NEED TO INTRODUCE YOU TO THE
SEAHORSE TECHNOLOGY. WE USE
THE MITRAL STRESS TEST TO
MEASURE IN REAL-TIME
(INDISCERNIBLE) AND THE
ACIDIFICATION RATES WHICH ARE
MEASURES OF OXPHOS AND
ANAEROBIC GLYCOLYSIS AND
LACTATE SECRETION IN THIS IS
DONE IN REAL-TIME. WE DID IT
IN UNSTIMULATED CELLS BECAUSE
THE (INDISCERNIBLE).
WHILE THESE ARE THE RESULTS
FROM THE ELDERLY INDIVIDUALS AT
A HIGHER END IN BOTH MEASURES
ESPECIALLY IN ANAEROBIC
GLYCOLYSIS. WE WANTED TO
CONFIRM THE SEAHORSE RESULTS BY
MEASURING RNA TRANSFERS FOR
ENZYME SYMBOL IN THIS METABOLIC
PATHWAY, PARTICULARLY
REMEASURED PDHX, A COMPONENT OF
THE PYRUVATE DNA COMPLEX
RESPONSIBLE FOR CONVERSION OF
PYRUVATE INTO (INDISCERNIBLE) A
LINK BETWEEN GLYCOLYSIS AND
(INDISCERNIBLE).
WE MEASURED LDAH, LACTATE --
THE ENZYME RESPONSIBLE FOR THE
SECRETION OF LACTATE.
EVERYTHING STARTS WITH AN
UPTAKE OF NUTRIENT, THE UPTAKE
OF GLUCOSE. THE FIRST MEASURE
WE DID WAS STEALING AND --
UNSTIMULATED B CELLS, IN OLDER
ADULTS COMPARED TO YOUNGER ONES
AND CONCOMITANTLY WE HAD MUCH
MORE GLUCOSE UPTAKE USING THIS
GLUCOSE CODE TO
(INDISCERNIBLE).
AND THE PATHWAYS OF OXI
PHOSPHORYLATION WERE CONFIRMED
BY AN EXPRESSION OF THE PDHX
MARKER, AS WELL AS THE ROS
SECRETION AND THIS IS THE CITO
(INDISCERNIBLE)-- FROM THE
MITOCHONDRIA.
THE MAJOR DIFFERENCE BETWEEN
THE YOUNG AND OLD WAS SEEN AT
THE LEVEL OF ANAEROBIC
GLYCOLYSIS AND LACTATE
SECRETION SO THIS IS IN FACT
THE RESULTS FROM THESE
INDIVIDUALS. THAT HAVE A LOT OF
LDHA TRANSCRIPTS AND THESE ARE
ASSOCIATED WITH INCREASED
SECRETION OF LACTATING CULTURE
AFTER STIMULATION FOR EIGHT
HOURS WITH A MITOGEN. THE SAME
CULTURE WAS ABLE TO SECRETE BIG
AMOUNTS OF LACTATE AND WE WERE
ALSO ABLE TO SECRETE ANTIBODIES
THE TWO MAJORS WERE CORRELATED,
AND NOW WE HAVE MORE
INDIVIDUALS IN THIS PANEL.
AND SO TO SUMMARIZE THIS FIRST
RESULT, WE DEMONSTRATED THAT
THE B CELLS FROM OLDER
INDIVIDUALS ARE -- AND
UPREGULATED ANAEROBIC
GLYCOLYSIS, ONE OF THE FIRST
EVIDENCE OF SECRETION OF
LACTATE OF HUMAN B CELLS.
AND THEN WE WANTED TO SEE THEY
ARE SO HYPER METABOLIC AND ARE
ABLE TO TURN ON INFLAMMATORY
RESPONSE. WE DID THIS IN
CULTURES AND WE PUT AT THE TOP
OF THE TRANSWELL CD4 T-CELLS
ISOLATED FROM YOUNG INDIVIDUALS
AT THE BOTTOM B CELLS FROM
OTHER YOUNG OR ELDERLY
INDIVIDUALS. AND THEN WE WERE
ABLE TO SEE IN ONLY 24 HOURS,
VERY QUICKLY IN THE ABSENCE OF
ANY EXOGENOUS STIMULATION THE
T-CELLS WERE ABLE TO TURN ON
GLUTON AND LDHA, AND THEY
BECOME GLYCOLYTIC, AND THEY
BECOME MARKERS OF ANAEROBIC
GLYCOLYSIS, AND THEY WERE ABLE
TO TURN ON WITH THE SAME
MECHANISMS THAT HAPPEN IN B
CELLS.
IN THIS CULTURE, WE HAVE
SECRETION OF LACTATE, NOT SO
MUCH AS THE ONE THAT I SHOWED
YOU BEFORE AFTER MITOGEN
STIMULATION. THESE LIKE THAT
COME FROM THE -- ONLY BECAUSE
THE CD4 HAD TO BE HEAVILY
STIMULATED IN ORDER TO PRODUCE
LACTATE AND WE HAVE SECRETION
OF PRO-INFLAMMATORY CYTOKINES,
AND THIS IS SHOWN AS INCREASE
INTEGRATION COMPARED TO THE CD4
ALONE IN CULTURE AND BECAUSE OF
THE PRESENCE OF LACTATE, WE
WANTED TO SEE IF THERE IS
POSSIBLE TO BLOCK THIS PATHWAY
OF ACTIVATION OF
PRO-INFLAMMATORY CD4 BY USING
SPECIFIC LACTATING INHIBITORS,
WE CREATED THE CELLS FROM ALL
INDIVIDUALS WITH TWO DIFFERENT
LACTATE, ONE IS THE SMALL
MOLECULE, FX11, AND WE HAVE
INCREASE SECRETION OF
(INDISCERNIBLE) AND USING AN
ANTIBODY THE BLOCK SELECTED
TRANSPORTER SLC BLAH BLAH BLAH,
A LONG NAME. THIS IS VERY
EFFECTIVE IN BLOCKING SECRETION
OF THE CYTOKINES.
THIS MEANS THAT B CELLS USE
THE PATHWAYS THAT ARE LIKELY
DRIVEN IN ORDER TO TURN ON
INFLAMMATORY CD4, AND I CAN
TELL YOU (INDISCERNIBLE).
WHAT IS THE LIKELY DOING TO
THE T CELLS, THE B CELLS
THEMSELVES? WE USED TO GET IN
THE SEAHORSE TECHNOLOGY AND
USING GLYCOLYTIC TEST DONE IN
THE PRESENCE OF THREE DIFFERENT
INJECTIONS OF GLUCOSE,
OLIGOMYCIN ANDN -- AND IT COMES
FROM INDIVIDUALS AFTER
OVERNIGHT STIMULATE IN THE
ABSENCE OR PRESENCE OF LACTATE
IN THE PRESENCE OF LACTATE
THERE IS A HIGHER GLYCOLYTIC
PHENOTYPE AND IS CONFIRMED BY
THE EXPRESSION OF THE
UPREGULATED EXPRESSION OF
MARKERS LIKE GLUT 1 AND LDHA,
NOT SO MUCH PDHX.
WE PUT THE OLDER INDIVIDUALS
IN THIS PICTURE, AND IT LOOKS
EXACTLY LIKE THE YOUNG TREATED
WITH LACTATE. SO LACTATE
INDUCES IMMUNO SENESCENCE AND
WHEN WE LOOK AT THIS TRANSCRIPT
THEY WERE ABSOLUTELY
OVERLAPPING. THE TWO GROUPS,
THE YOUNG WITH LACTATE AND
ELDERLY ARE SIMILAR. THE CELLS
ARE ABLE TO SECRETE MULTIPLE
TRANSCRIPT FOR INFLAMMATORY
MARKERS, SOME OF WHICH ARE
MEMBERS OF THIS SAS,
PRO-INFLAMMATORY MICRO RNA,
MANY MARKERS OF IMMUNE
ACTIVATION AND CANONICAL
SENESCENT MARKERS BUT NOT ONLY
THIS BUT THEY'RE ABLE TO
SECRETE IN VITRO AUTOIMMUNE
ANTIBODIES AFTER THE EXPOSURE
TO LACTATE IS SIMILAR TO WHAT
HAPPENS AGAIN TO B CELLS FROM
ELDERLY INDIVIDUALS; THEY WERE
ALSO ABLE TO SECRETE THE
PRO-INFLAMMATORY CYTOKINES IN
IL6 AND (INDISCERNIBLE).
WHY DID WE DO THIS? THIS IS
CONSTITUVILEY EXPRESSED. USING
THE ANTIBODY SHORTENED BEFORE
IS POSSIBLE TO DOWN REGULATE
THE EXPRESSION OF THE LACTATE,
AND AT THE SAME TIME DOWN
DIRECTLY COMPLETED THE
SECRETION OF ANTIBODIES AND
PRO-INFLAMMATORY CYTOKINES.
AND WITH THE PRESENCE OF
LACTATE (INDISCERNIBLE).
WHEN WE TALK ABOUT B CELLS AND
AGING, THERE IS A DISTRIBUTION
OF B CELLS. THERE IS NOTHING
SIMILAR TO WHAT WE SEE IN YOUNG
PEOPLE. IN THIS AND MANY OTHER
GROUPS WE WERE PARTICULARLY
INTERESTED IN THE EXPANSION OF
THIS DOUBLE NEGATIVE; WHEN WE
STAIN WITH CD27 AND IDG, THE
MOST AND PRO-INFLAMMATORY THE
GROSS UP IN ALL INFLAMMATORY
CONDITIONS, AGING, OBESITY,
TYPE II DIABETES, CHRONIC
INFECTIONS WITH BUYERS AND
PARASITES AND ALSO IN ACUTE
COVID AS HAS BEEN SHOWN
RECENTLY THAT THIS HAS TAKEN
THE LEAD IN THE BLOOD OF PEOPLE
WITH COVID.
SO WHY ARE WE INTERESTED IN
THIS? BECAUSE WE SHOWED MANY
YEARS AGO THAT THESE DOUBLE
NEGATIVES, FIRST OF ALL MEMORY,
BUT NOT NAïVE, IN BOTH THE
ELDERLY AND IN THE YOUNG ARE
ABLE TO SECRETE
PRO-INFLAMMATORY MEDIATORS AND
EXPRESS TRANSCRIPTS LIKE IN
THIS PARTICULAR CASE BUT THESE
MEDIATORS.
WE TESTED MANY OF THESE
INCLUDING SASP MARKERS AND WHEN
YOU DO AN ANALYSIS YOU SEE THAT
THE DOUBLE NEGATIVE TAKES THE
LEAD IN THE MEMORY OF B CELLS.
BECAUSE THEY ARE THE HIGHEST IN
TERMS OF SECRETION, AND ALSO IN
TERMS OF METABOLIC SUPPORT. WHY
ARE THEY SO METABOLICALLY
SUPPORTIVE? BECAUSE THIS MAKES
PRO-INFLAMMATORY CYTOKINES AND
ANTIBODIES AND THEY HAVE LEVELS
OF INFLAMMATION THEY HAVE TO
PERFORM A METABOLIC INVITATION
TO THESE INFLAMMATORY
CONDITIONS TO PERFORM THEIR
JOB, WITH THE SECRETION OF
IMMUNE ANTIBODIES AND
CYTOKINES.
YOU SEE THAT THESE CYTOKINE
NEGATIVES AGAIN ARE NOT ONLY
VERY HIGH, AND THEY ARE
INFLAMMATORY MARKERS IN GENERAL
BUT THEY ARE ABLE IN THE
EXPRESSION OF ALL THESE MARKERS
AND WE WILL LOOK CAREFULLY TO
THE DIFFERENT PATHWAYS IN THE
ANAEROBIC GLYCOLYSIS, THERE ARE
MANY MARKERS.
THIS IS MY LAST SLIDE OF
RESULTS. I DON'T THINK I HAVE
TIME TO MAKE A SUMMARY. I WANT
TO INTRODUCE EFFECTIVE IN THE
LAB WE ARE ALSO WORKING WITH
OTHER METABOLIC INHIBITORS LIKE
METFORMIN AND (INDISCERNIBLE)
-- BECAUSE THEY ARE ALREADY IN
THE CLINICAL TRIALS, AND THEY
HAVE BEEN APPROVED.
THIS IS MY THANK YOU SLIDE.
THIS WORK WAS DONE SPECIFICALLY
BY MRIA, DENISSE AND KEVIN AND
KATE IN THE LAB. I WANT TO
ACKNOWLEDGE THE BE
COLLABORATION WITH THE CFAR
PEOPLE IN OUR DEPARTMENTS,
SURESH AND SAVITA PAHWA. THE
DOCTORS WHO HELPED WITH THE
STUDY AND THE FUNDING. IT IS
VERY IMPORTANT TO HAVE A GOOD
METABOLOMIC ANALYSIS AND A
SIGNATURE FOR EACH INDIVIDUAL.
THIS IS GOOD FOR HEALTHY AGING,
GOOD FOR EVERYTHING THAT IS NOW
ASSOCIATED WITH ANTIAGING. AND
IT HAS TO BE A REALLY THOROUGH
METABOLIC ANALYSIS. WE NEED TO
UNDERSTAND HOW THE METABOLIC
PHENOTYPE AND THE INFLAMMAGING
PHENOTYPE TALK TO EACH OTHER
AND HOW THESE TWO IN
COLLABORATION REGULATING THE
COMMUNICATION BETWEEN HEALTH
AND TISSUES, HEALTH AND ORGANS
NOT ONLY IN INFLAMMATORY
DISEASE BUT IN MANY OTHER
CONDITIONS. IT CAN BE RELEVANT
FOR CANCER, AUTOIMMUNE
DISEASES, AND SO ON. AND OF
COURSE THIS WILL ALLOW THE
IDENTIFICATION WITH OTHER
TARGETS, METABOLIC TARGETS,
THAT CAN BE USEFUL FOR TREATING
THESE CONDITIONS AND IMPROVE IN
YOUNG RESPONSE.
LAST BUT NOT LEAST, A BIG
THANK YOU TO -- --THIS IS BEEN
A FANTASTIC LOCATION FANTASTIC
MEETING AND I LEARNED A LOT. A
LOT OF NEW INTERACTION AND A
LOT OF OLD FACES, NOT BECAUSE
WE ARE IN AN AGING MEETING BUT
FACES THAT I HAVE KNOWN FOR A
LONG TIME. THANK YOU SO MUCH.
INCLUDING ONE IN THE BACK.
WELCOME REBECCA. GOOD TO SEE
YOU.
>>[APPLAUSE]
>>OKAY QUESTIONS? WE HAVE A
COUPLE OF MINUTES FOR
QUESTIONS. MY FRIEND CONNIE.
>>SO THIS IS ACTUALLY A VERY
EXCITING CONCEPT YOU'RE
PRESENTING HERE. YOU ARE
SAYING THAT AUTO ANTIBODY
PRODUCTION WILL DEPEND ON THE
TISSUE ENVIRONMENT. AND YOU
WOULD SAY THAT AUTOANTIBODY
PRODUCTION WOULD BE FAVORED IN
A LACTATE RICH ENVIRONMENT.
THAT I THINK IS A VERY
IMPORTANT THING FOR US TO ROLL
INTO OUR UNDERSTANDING OF HOW
WE LOOK AT AUTOIMMUNE DISEASE,
BECAUSE WE LOOK AT IT I THINK
IT HAS TO DO WITH THE
AVAILABILITY OF AUTO ANTIGEN.
THIS BRINGS A MODIFIER OF
AUTOIMMUNITY, VERY INTERESTING.
THANK YOU VERY MUCH.
>>I WANT TO TELL YOU SOMETHING
WE DID NOT HAVE TIME TO TALK
ABOUT. ANOTHER VERY, VERY
IMPORTANT WAY TO BLOCK THESE
POLARIZING EFFECT IS TO USE
ICOSLIGAN BLOCKAGE (PHONETIC),
YOU KNOW VERY WELL THIS IS
EXTREMELY RELEVANT FOR THE
GENERATION OF PATHOGENIC B AND
T-CELLS AND INFLAMED TISSUE OF
PATIENTS WITH RHEUMATOID
ARTHRITIS.
ACTUALLY THE BEST WAY TO
COMPLETELY AGGREGATE ANTIBODY
SECRETION, ALL ANTIBODY
SECRETION AND LACTATE SECRETION
IS BLOCKING THE B CELLS WITH AN
ANTI-LYCOS LIGAND ANTIBODY,
EXTREMELY POWERFUL AND THIS IS
ALSO POWERFUL WHEN WE ROLL INTO
THE TISSUE EVEN MORE BECAUSE OF
THE LEVEL OF INFORMATION.
>>SO THIS IS GOING TO -- THE
ABCS GO INTO THE
(INDISCERNIBLE) STRUCTURE?
>>YES WE SHOW THAT WITH THE
ABC IN MINE AND THE HUMAN
(INDISCERNIBLE).
>>ARE B CELLS PRESENTING
ANTIGEN?
>>THEY DO IT NORMALLY. I HAVE
NOT TESTED THE CAPACITY IN THIS
CONTEXT BUT YES. THEY DO AND I
AM EXPECTING -- THIS IS VERY
PRELIMINARY, WE STILL HAVE A
LOT OF PIECES TO ADD TO THE
PUZZLE, BUT I THINK IT IS
RELEVANT FOR B CELL BIOLOGY.
THANK YOU FOR THE QUESTION. YES?
>>I AM WONDERING IF YOU HAVE
HAD THE OPPORTUNITY TO EXPLORE
THE RELATIONSHIP OF THE
CHANGING B CELL REPERTOIRE WITH
IH WITH THE METABOLIC CHANGES?
>>THAT WOULD BE FANTASTIC.
MAYBE WE CAN TALK TO SCOTT AND
DO SOMETHING TOGETHER. I HAVE
NOT DONE ANYTHING LIKE THAT.
WE DO NOT HAVE THE POSSIBILITY
TO DO IT. WE HAVE TO GO WITH
THE BEST IN THE FIELD,
HOPEFULLY SOON.
>>ONLINE QUESTION. GREAT
TALK. YOU LOOK AT THE PPF CYCLE
OF (INDISCERNIBLE) OF AGE AND
DOUBLE NEGATIVE IN THE BALANCE
OF OCR IS CHANGING OR IS
EVERYTHING RAMPING UP EQUALLY?
>>WE HAVE DONE THIS IN THE
DOUBLE NEGATIVE AS COMPARED TO
THE OTHER MEMORY TOGETHER.
AND YES THEY ARE HIGHER, BUT
NOT TOO MANY CHANGES IN THE BCA
CYCLE.
>>A LOT OF YOUR GENES LOOK
LIKE TARGETING. HOW LONG DOES
THIS LAG ONCE YOU TAKE THE
LACTATE?
>>I DON'T KNOW THIS. THIS IS
SOMETHING THAT WE HAVE TO
CHECK. I CAN TELL YOU THAT
ONCE YOU HAVE THE LACTATE IN
CULTURE, THE -- SET CAN BE SEEN
FOR THREE DAYS. BUT I THINK IT
IS METABOLIZED. BUT I DON'T
KNOW VERY WELL IF IT REALLY IS
IN THIS CONDITION. IN VIVO IT
IS. IT IS DOWN REGULATED VERY
QUICKLY BECAUSE IT IS EXTREMELY
HIGH INFLAMMATORY. IN FACT IT
IS IMPOSSIBLE TO MEASURE IN
SERUM. IF YOU MEASURE THE
ENZYME YOU CAN MEASURE THE
PRODUCT; YOU MEASURE THE
LACTATE METABOLIZING, BUT
NOTHING ELSE. THAT IS
SOMETHING WE NEED TO CHECK
ESPECIALLY IN TISSUES. GOOD
FIND. ANOTHER QUESTION?
>>DO YOU HAVE ANY INFORMATION
ABOUT LACTATE TO THE GPR
(INDISCERNIBLE)? IT DOES?
>>ONE OF THE TRANSPORTERS
BELONGS TO THE FAMILY, YES.
THIS IS THE MAJOR ONE IN THE B
CELLS. YES THAT IS THE FAMILY
OF LACTATE TRANSPORTERS.
>>DOES INCREASE GLYCOLYSIS
INCREASE OXIDATIVE STRESS?
>>WELL ANAEROBIC GLYCOLYSIS
AND OXIDATIVE STRESS ARE BOTH
COMING FROM PYRATE (PHONETIC).
I THINK IN INFLAMMATORY
CONDITIONS YOU HAVE ONE
PREVAILING ON THE OTHER. IT IS
NOT 0 OR 100 OR VICE VERSA.
THERE IS A PROGRESS FROM ONE TO
THE OTHER DEPENDING ON THE
MICROENVIRONMENT.
IN THIS CONDITION AND AGAIN
AGING IS NOT THE MOST
INFLAMMATORY STATUS THAT WE
HAVE MEASURES. SO WHEN WE GO
TO THE TISSUE, THE HUMAN
ADIPOSE TISSUE THERE IS AN
ANAEROBIC GLYCOLYSIS THAT IS
ELEVATED.
YES SCOTT?
>>
>>WAS A DEFINING THE DOUBLE
NEGATIVE CELLS ARE MORE
ANAEROBIC GLYCOLYSIS- ORIENTED?
AND ON A PER CELL BASIS, IS
THAT MORE SO IN ELDERLY OR IS
IT THAT JUST ELDERLY PEOPLE
HAVE MORE DOUBLE NEGATIVE?
>>I CONTINUE TO HAVE MORE
DOUBLE NEGATIVES. THIS IS WHY
THE POOL OF B CELLS REFLECTING
THIS. BUT WHEN YOU LOOK AT THE
DOUBLE NEGATIVE FROM YOUNG AND
OLD AND YOU PULL THEM TOGETHER,
THERE IS A LOT OF THESE
PATHWAYS UPREGULATED. I THINK
IT IS BOTH. WHEN YOU LOOK AT
THE TOTAL DIFFERENCE POOL, THIS
HAPPENS BECAUSE OF THE
EXPANSION OF THE DOUBLE
NEGATIVE. IF YOU SORT THE
DOUBLE NEGATIVE-- -- IT GOES TO
THE LEVEL OF THE PHENOTYPE.
>>I WAS ALSO CURIOUS RELATED
TO THE -- QUESTION, IS THERE IN
ABOUT WHAT UPSTREAM FACTORS
MIGHT PREVENT THE CHANGE IN THE
METABOLIC PATTERN?
>>I CAN TELL YOU THAT I HAVE
NOT CHECKED IN THE PERIPHERAL
BLOCK, I HAVE IT IN THE ADIPOSE
TISSUE. LACTATE (INDISCERNIBLE)
-- ONLY IN ALPHA. IT IS VERY
STABILIZED BY OTHER SIGNALS
THAT HAPPEN IN THE ADIPOSE
TISSUE. THAT IS HOW IT HAS TO
WORK. YES ARIA?
>>VERY QUICK QUESTION. YOU
KNOW THAT IN INFANT CONDITION
CELLS, B CELL PROGENITORS CAN
EMIGRATE INTO CIRCULATION.
COULD IT BE SOME OF YOUR DOUBLE
NEGATIVES ACTUALLY BELONGING TO
THE IMMIGRANTS FROM BONE MARROW
TISSUE?
>>THIS IS NOT OUR WORK WITH
THE ANSWER IS THEY CANNOT BE. I
AM NOT SHARING MYSELF, JUST
RESPONDED TO THE QUESTION WHICH
IS A VERY (INDISCERNIBLE), I
CAN KEEP GOING BUT I THINK WE
HAVE TO STOP. IF YOU DON'T
WANT TO STOP I CAN KEEP GOING.
THANK YOU SO MUCH.
>>
>>(INDISCERNIBLE). >>MAYBE
WE CAN START OFF. WHO WANTS TO
GO FIRST ON YOUR GAP? WHICHEVER
WAY YOU WANT TO START. WHAT DO
YOU THINK ARE THE BIGGEST GAPS?
>>I WOULD LIKE TO START BY
SAYING THAT WE ALL AGREE THAT
INFLAMMATION IS AN IMPORTANT
SUBJECT, WITH ASSOCIATED
DISEASE. THE IMMUNE CELLS
COULD PLAY AN IMPORTANT ROLE
CONTROLLING THIS INFLAMMATION.
NOW IS THE MOMENT TO FIND THE
BEST WAY TO TRY TO RESOLVE
THESE AGE ASSOCIATED
INFLAMMATION BY TARGETING
IMMUNE CELLS. THERE ARE
DIFFERENT STRATEGIES. I THINK
THE GAP IS TO FIND WHAT IS THE
BEST STRATEGY TO FIND THIS.
AND ALSO, I WANT TO MENTION
THAT IN THE LAST 10 YEARS WE
OBSERVED HOW IMMUNOTHERAPY HAS
CHANGED AGING CELLS. I HOPE
THAT THE NEXT 10 YEARS WILL BE
THE TIME OF IMMUNOTHERAPY TO
CHANGE AGE ASSOCIATED DISEASES.
>>OKAY.YOU ALREADY HEARD HOW
IMPORTANT IT IS TO HAVE
METABOLIC INFORMATION FOR EACH
INDIVIDUAL BECAUSE IT IS
DICTATING WHAT IS THE METABOLIC
STATUS OF DIFFERENT IMMUNE
CELLS AND (INDISCERNIBLE).
THIS IS EXTREMELY IMPORTANT TO
KNOW BECAUSE YOU JUST BROUGHT
UP THE IMMUNOTHERAPY. THERE
ARE SOME CHECKPOINTS AND
INHIBITORS THAT WORK ONLY IF
THE TARGETS ARE METABOLICALLY
OKAY. FOR EXAMPLE OXIDATIVE
PHOSPHORYLATION IS EXTREMELY
IMPORTANT IN PD1 THERAPY, THAT
HAS GOOD OXIDATIVE STATUS.
YESTERDAY SOMEBODY BROUGHT UP
THE IMPORTANCE TO LOOK AT
METABOLIC STATUS, WHICH
REFLECTS THE ENVIRONMENT, THE
DIET, THE CONDITION OF EACH
INDIVIDUAL. SO IT IS SOMETHING
THAT NEEDS TO BE AVAILABLE.
THIS MEANS THAT WE WILL HAVE,
WE WILL NEED REPOSITORIES FOR
DATA FOR HUMAN AND ANIMALS IN
ORDER TO ACCESS AND KNOW
EXACTLY WHERE TO GO AND WHAT TO
LOOK FOR, AND HOW TO DO THE
BEST WAY POSSIBLE THESE KINDS
OF STUDIES.
>>
>>YEAH, ALWAYS A CHALLENGING
QUESTION. WHAT IS NEXT? I
REALLY DON'T KNOW. A LOT OF
THINGS THAT WE ARE DOING WE
HAVE NO IDEA WE WERE DOING IT
FIVE YEARS AGO. WE HAVE NO
IDEA WHERE THE NEXT DISCOVERIES
GOING TO COME FROM.
FIRST THING TO ORGANIZE WHAT
WE HAVE, I THINK THERE IS
ENOUGH CONSENSUS IN RELATION TO
INFLAMMATION FROM AGING THAT --
DATA AND -- ARE KEY TO DRIVING
MULTIPLE ASPECTS OF
INFLAMMATION.
ACTUALLY WE NOW HAVE
THERAPEUTICS AGAINST THEM. BUT
ALWAYS THE PROBLEM IS THAT
THOSE THERAPEUTICS ARE GIVEN TO
PEOPLE THAT ARE HAVING
AUTOIMMUNE DISEASES AND IF YOU
GO DOWNSTREAM AND BLOCK OUT --
-- OBVIOUSLY YOU HAVE PROBLEMS
WITH INFECTIONS.
ONE OF THE GAPS I WOULD THINK
THAT SHE MOVES IN THE DIRECTION
OF TRANSLATION, WE HAVE DATA
WHICH COMPLEMENTS
(INDISCERNIBLE), ALWAYS SHOWING
UP IN INTERFERON RESPONSE. BUT
WHAT PEOPLE THINKING ABOUT IN
TERMS OF TRANSLATIONS, AND
EPIDEMIOLOGIST HAVE A MUCH
BETTER HANDLE ON THIS IS TO
ACTUALLY GO UPSTREAM. SO IN
THIS CASE FOR EXAMPLE YOU GO
UPSTREAM WHERE YOU BLOCK THE
PATHWAYS THAT CONTROL IL1 BETA,
WHICH IS CONTROLLED BY MULTIPLE
INFLAMMASOMES, CAN YOU BLOCK
THE INFLAMMASOME OR LOWER IT
THAT IS CRITICAL FOR AGING.
SO WE ALREADY HAVE A FEW
CHECKPOINTS IN MY VIEW.
COMPLEMENTARY INHIBITORS ARE
FDA APPROVED. IT IS ALWAYS UP
IN MULTIPLE PLACES. SEVERAL OF
US ARE NOT INTERESTED IN
LIFESPAN, BUT WE ARE REALLY
INTERESTED IN TARGETING
INFORMATION TO SEE BETTER
OUTCOMES WHICH I THINK CAN BE
DONE.
THE LAST PART IS THAT, YOU
KNOW, BIG KUDOS, BIG SHOUT OUT
TO THE TEAM THAT DID THE
CALORIE STUDY BY THE NIA. IT
HAD A LOT OF ISSUES WITH
CALORIE RESTRICTION AND DATA
GOING BOTH WAYS. BUT NOW WITH
THE STUDY HAS BEEN ABLE TO DO
IS PROVIDE REALLY GOOD
MECHANISTIC EVIDENCE THAT IF IN
HUMAN PHYSIOLOGY, IF YOU HAVE A
NEGATIVE ENERGY BALANCE, THERE
ARE LOTS AND LOTS OF PATHWAYS
THAT WERE PREVIOUSLY SHOWN TO
BE IMPORTANT, AND NOW SHOWING
UP IN PEOPLE. AND THE WORK FROM
THIS CONSORTIA WHICH IS NOW
COMING OUT OFFERS I THINK ALL
OF YOU APPROACH IS WHERE YOU
CAN LOOK FOR POTENTIAL, NEWER
TARGETS THAT ARE IMPACTED BY
INTERVENTION, BUT IT IS NOT TO
EXTEND LIFESPAN BUT IN THIS
CASE WITHOUT TRADE-OFFS AND
PEOPLE. SO I THINK THERE IS A
LOT THAT CAN BE DONE, IN A WILL
BE DONE.
AND LASTLY I THINK I WOULD SAY
THE SAME THING THAT SARAH
MENTIONED. THE PERIPHERAL
NERVOUS SYSTEM AND OTHER
PERIPHERAL NERVOUS SYSTEMS ARE
IMPORTANT NOT ONLY FOR THE
INTER-ORGAN PHYSIOLOGY BUT HOW
THE RESIDENT IMMUNE CELLS ON
THOSE NERVES ARE IMPORTANT.
THERE IS SO MUCH TO DO IN THAT
CASE. I THINK WE HAVE A LOT TO
LEARN.
F >>VERY GOOD COMMENTS TO ADD
TO THIS, I THINK ONE KEY THING,
WHAT WE ALL ASK, BUT VERY
LITTLE IS DEDICATED TO THIS
RESEARCH, WHY IS IT THAT MOST
CLINICAL TRIALS FAIL? IS IT
BECAUSE ALL OF OUR CASES ARE
MOSTLY DONE IN YOUNG MODELING
SYSTEMS? BECAUSE OF MONEY AND
SO ON? AND SOME WOULD SAY OKAY,
MICE ARE NOT REALLY HUMANS.
YOU CANNOT EXTRAPOLATE.
IN FACT WHAT WE SEE IS MANY OF
OUR INTERVENTIONS IN CANCER OR
EVEN INSULIN RESISTANCE, FOR
EXAMPLE ONLY WORK IN CERTAIN
WAYS, CONTEXT DEPENDENT WAYS IN
AGED ANIMALS. BUT IN THE YOUNG
IT CAN BE THE OPPOSITE. AND
THEREFORE THE APPROPRIATE
MODELING SYSTEM LOOKS LIKE IT
IS LACKING (INDISCERNIBLE).
LAST THING IS THAT WE SHOULD
NOT ALSO DISREGARD THE
IMPORTANCE OF METHODS THAT ARE
(INDISCERNIBLE), AND OF COURSE
EVERYONE AND ALL OF THE
POSTDOCS AND STUDENTS USE PLOT
DATA, BUT IT IS VERY
SUBJECTIVE. AND DEPENDING ON
WHAT KIND OF TISSUE IS USED,
IT MIGHT AS WELL DISAPPEAR.
THE EXAMPLE IS 138, DEPENDING
ON WHAT THE ASSOCIATION MARKER
YOU USE IT WON'T BE THERE. IN
THE CONCLUSION IS THAT THE
CELLS ARE NOT THERE.
THEREFORE WE NEED TO DEDICATE
TIME ALSO AND ENERGY ON PROPER
METHODS AND MODEL EXAMPLES.
>>ANYBODY FEEL FREE TO CHIME
IN OR VETO ANYTHING YOU HEARD.
I HAD A QUESTION. I KNOW MARIA
YOU BROUGHT UP THE CONCEPT OF
RESOLUTION IN YOUR GRAPHIC, THE
SECOND ONE ON THE AGED ONE. DO
WE KNOW ENOUGH ON REPRODUCTIVE
IMMUNITY? WE DO SEE WHAT IS
GOING AWRY, BUT IN TERMS OF
METABOLIC, IS THERE ANY LONG
HANGING FRUIT THAT WE CAN
(INDISCERNIBLE)?
>>I THINK IT IS A GAP, HOW TO
EMPLOY THIS RESOLUTION. IN
ACUTE INFLAMMATION IT IS WELL
KNOWN. BUT IN CHRONIC CARE,
CHRONIC INFLAMMATION, I THINK
IT IS COMPLETELY UNKNOWN.
METABOLICALLY. LIPID
METABOLITES CAN ALSO ISSUE.
>>I HEAR THAT. WE
(INDISCERNIBLE). AND OTHERS
THAT HAVE SOME EFFECT KNOWN. I
DON'T KNOW IF ANYBODY KNOWS,
THE AGING ASPECT OF IT.
>>REALLY INTERESTING
MOLECULES. OBVIOUSLY, RECENTLY
THEY HAVE ALSO BEEN
METHODOLOGICAL ISSUES THAT SOME
PEOPLE ARE CHALLENGING WHETHER
THEY ARE REAL OR NOT. YOU HAVE
TO BE CAUTIOUS.
>>I THINK IT IS ALSO A
METHODOLOGY OF LIPID
QUANTIFICATION. MY
UNDERSTANDING (INDISCERNIBLE)
AND YOU USE THAT BUT THEN THE
GROWING BIOLOGICAL APPLICATIONS
FROM IT. THERE IS CHEMISTRY AND
BIOLOGY FUNCTIONALITY. THAT IS
WHAT I WAS ASKING. THIS IS THE
ANGLE THAT IS MISSING, AND THE
PROGRESS THAT IS MADE.
(INDISCERNIBLE).
ANYBODY ELSE? ANY QUESTIONS
ONLINE? ANYBODY? OKAY. ARIA,
NORMAL B1A I HIGHLY CHOLGENIC.
DO YOU KNOW ANYTHING ABOUT THE
CHOLINERGIC STATUS OF THESE
ABNORMAL B1A CELLS?
>>NO WE WERE MOSTLY INTERESTED
IN CONVERTED T 1 CELLS, WHAT
THEY DO TO THE T-CELL, WHETHER
THEY CONVERT T-CELLS INTO
PATHOGENIC T-CELLS. WE DID NOT
CHECK THAT.
>> (INDISCERNIBLE) (READING
FROM CHAT) DO WE NEED TOOLS?
>>OF COURSE, WE SHOULD WORRY
ABOUT SECONDARY METABOLIC. WHAT
IS IT AN AGING THE MICROBE
DISAPPEARS? IS IT AN IMMUNE
PROCESS. IT QUESTIONS THE
POSSIBILITY OF REPLENISHING THE
MICROBES WHICH WOULD REDUCE THE
THAT, MAKING EVEN MORE.
BECAUSE IT IS IMMUNE DRIVEN, WE
WOULD INDUCE MORE RESPONSES.
ONE STUDY THAT WE DID NOT
PUBLISH, VERY LONG-TERM
PROJECT, WE ALL KNOW WHAT
(INDISCERNIBLE) REDUCES INSULIN
RESISTANCE. BUT NO ONE TESTED
LONG-TERM PROBLEM. WE ACTUALLY
ASKED THAT QUESTION. AND
ACTUALLY WE DO SEE LONG-TERM --
(INDISCERNIBLE), A DIFFERENT
QUESTION IS ALL OF OUR
INTERVENTIONS, WHAT HAPPENS IF
WE DO IT LONG-TERM? WOULD WE
CAUSE HARM? IF WE HANDED A MORE
IMMUNOLOGIC PROCESS?
>>GOOD POINT.
>>I HAVE A QUESTION ONLINE.
WOULD FINDING A WAY TO SWITCH
FROM WARBURG TO OXPHOS HELP
INFLAMMAGING?
>>THESE THINGS ARE NOT VERY
BINARY IN VIVO. SO TO THE
EXTENT YOU COULD DO THAT--
>>THE QUESTION IS SHOULD WE
NOT SWITCH BLANCE?
>>SOME OF THE HUMAN WORK THAT
CAME OUT PUTTING WORK FROM
CALORIE AND THE WORK FROM OTHER
INTERVENTIONS, IT IS CLEARLY
MITOCHONDRIAL OXIDATION, IT
APPEARS TO BE ONE OF THE KEY
COMPONENTS THAT IS LIGHTING UP
THESE PATHWAYS, LIGHTING UP NOT
ONLY PREVIOUS STUDIES FOR MODEL
ORGANISMS BUT ALSO HUMANS. I
THINK THAT'S WHICH IS VERY
IMPORTANT.
OBVIOUSLY WE KNOW THAT WORK IN
OUR GROUP AND OTHERS; FOR
EXAMPLE IF YOU SWITCH THE
METABOLISM AWAY FROM GLUCOSE IN
THE -- STATE, AND YOU START TO
CONSUME KETONES OR PRODUCE
KETONE BODIES --
(INDISCERNIBLE) -- CLEARLY
THERE IS A METABOLIC COMPONENT
TO IT IN THE CONTEXT BUT THE
HOST HAS TO BE IN -- STATE.
WHETHER THE CELLS ARE TRUE
GLYCOLYSIS WORSENS THE OXO
STATE IS LESS BINARY IS WHAT WE
FIND IN VIVO, ALSO IN VITRO.
>>(OFF MIC) ANYBODY ELSE?
>>DO WE NEED A FIVE SECOND
STRETCH BREAK? THAT IS THE GAP
HERE. LET'S DO THAT! THANK YOU
>>THANK YOU EVERYONE. THANK
YOU FOR STAYING SO FAR. THIS
IS THE FINAL SESSION BEFORE WE
CLOSE THE FRONT OF THE
WORKSHOP.
THE FIRST SPEAKER IS PROFESSOR
ALBERT SHAW. PROFESSOR OF
MEDICINE AND INFECTIOUS DISEASE
AT YALE UNIVERSITY SCHOOL OF
MEDICINE. AND THE TITLE OF HIS
TALK IS THE EFFECTIVE AGE AND
INFLUENZA VACCINATION ON HUMAN
PLATELET FUNCTION.
>>FOR THIS SESSION WILL SHOW
YOU TWO FINGERS WHEN YOU HAVE
TWO MINUTES LEFT.
F I WILL DO MY >>I WILL DO MY
BEST. THANK YOU VERY MUCH FOR
THE ORGANIZERS FOR INVITING ME
TO SPEAK. IT HAS BEEN A
TERRIFIC, AMAZING WORKSHOP.
WHAT I'M GOING TO DO IS TALK
ABOUT SOME NEW AREAS THAT WE
HAVE BEEN WORKING ON IN TERMS
OF SOURCES FOR INFORMATION
INVOLVING HUMAN PLATELETS. IT
IS IN SESSION ON VACCINE
RESPONSE. THE DISCLOSURE I
HAVE A RESEARCH GRANT FROM
BOEHRINGER- UNIVERSITY.
WE HAVE BEEN INTERESTED IN
USING INFLUENZA VACCINATION IS
A TOOL TO PERTURB THE HUMAN
IMMUNE SYSTEM FOR YEARS. THE
BURDEN OF INFLUENZA IN OLDER
ADULT REMAINS QUITE
SUBSTANTIAL. THIS IS A TALE OF
TWO DISEASES. A FEW YEARS AGO
THERE WAS A LARGE NUMBER OF
HOSPITALIZATION WITH DEATHS
OCCURRING IN THE AGE 65, AND
THIS YEAR WE HAD A TRIPLE
ENDEMIC, THE DATA IS NOT ALL
AND FROM THE SEASON, ALL CDC
DATA. BUT YOU CAN SEE ILLNESSES
LIKE ILLNESSES IN OLDER ADULT
APPEAR FOR OUTSTRIPPED THAN ANY
OTHER GROUP.
AND THE VACCINATIONS HAVE
COMPLICATED THE STUDY OF THE
VACCINE. WE REGRET IT BECAUSE
IT IS MEMORY RESPONSE, QUITE
COMPLICATED AS PEOPLE HAVE
DISCUSSED.
REDUCING THE CHRONIC
INFLAMMATION HAS SOMETHING TO
DO WITH THIS DIMINISHED
RESPONSE, THE AGE ASSOCIATIVE
INFLAMMATORY STATE. MANY YEARS
AGO WE HAD SOME EVIDENCE OF
THIS, OLD DATA AND PRIMARY
DENDRITIC CELLS FROM HUMANS
WHERE YOU SEE A SUBSTANTIAL
ELEVATION IN CYTOKINE CREATION.
IN ALPHA, P40, IF YOU LOOK AT
THE CLEAR SYMBOLS LOOKING YOUNG
INDIVIDUALS.
IN ADDITION TO THIS WE ALSO
SAW SOME EVIDENCE FOR UP
REGULATION NOT ONLY OF
INFLAMMATORY CYTOKINES,
SPECIFICALLY MONO CYTOKINES IN
OLDER ADULTS THAT WE TRACED TO
ALTERED FUNCTION OF PHOSPHATASE
DUST 1 (PHONETIC).
THERE IS EVIDENCE FOR THE FACT
THAT INFLAMMATORY PATHWAYS SUCH
AS MONOCYTES PRIOR TO
INFLAMMATION ARE PREDICTABLE IN
ANTIBODY RESPONSE.
WE HAVE BEEN INTERESTED IN THIS
QUESTION AS WELL. THIS IS VERY
OLD DATA ON BLOOD TRANSCRIPTION
MODEL ACTIVITY IN YOUNG AND
OLDER ADULTS. THEY WERE VACCINE
RESPONDERS AND NONRESPONDERS.
WE ALSO HAD PERIPHERAL HOLDERS
AND WILL SPEAK ABOUT THAT A
LITTLE BIT LATER BUT WHAT WE
FOUND WERE SEVERAL SIGNATURES
OF TREATED ACTIVATION THAT
SEEMED TO BE PRESENT. THEY WERE
MODULATED FOLLOWING
VACCINATION. THIS IS AN
ANALYSIS OF PBMC, THEORETICALLY
THEY ARE NOT SUPPOSED TO BE
THERE, WE PRESUME THEY ARE
TAGGING ALONG FOR THE LINE IN
ADHERENCE TO LEUKOCYTE AND THIS
PROVOKES US TO START THINKING
MORE ABOUT IT, AND WHETHER WE
SHOULD START CONSIDERING THEM
IN KIND OF CONTRIBUTING TO
CHRONIC INFLAMMATORY STATE.
AND WHEN WE THOUGHT ABOUT IT
MORE, THEY ARE IN A UNIQUE
POSITION TO CONTRIBUTE TO
CHRONIC INFORMATION AND MOST OF
US KNOW THAT THIS IS BEEN
INVOLVED IN BLOOD CLOTTING OR
HEMOSTASIS, AND IT HAS
REFLECTIVE RECEPTORS, C3
REFLECTORS AND COMPLEMENT THREE
RECEPTORS AND SEVERAL
ACTIVATION MARKERS LIKE PSGL-1
AND ACTIVATION OF LYGONE
RECEPTORS, INTERESTING
COMPONENTS IN FACT THEY THEY
EXPRESS THE COMPONENTS OF
NF-KB, EVEN THOUGH THERE IS NO
TRANSCRIPTION WE KNOW OF IN THE
CELLS PRESUMABLY.
THERE IS EVIDENCE THAT THIS IS
IMPORTANT FOR OPTIMAL PLATE
ACTIVATION AND HOW IT DOES THIS
IS NOT CLEAR. REASONABLY
THROUGH A NONCANONICAL
ACTIVATION, ALSO EXPRESSED IS
STEP 1, STEP 3, NOTHING TO
TRANSLOCATE. IT IS DIFFERENT AS
WE START TO UNDERSTAND THIS.
I WILL GIVE YOU AN EXAMPLE OF
THIS INTERFACE BETWEEN
HEMOSTASIS AND INFLAMMATORY
RESPONSE ASSOCIATED WITH AN
INFECTION. THIS IS A PAPER
PUBLISHED MANY YEARS AGO, NOT
THAT LONG AGO, FIVE YEARS AGO
IN THE NEW ENGLAND JOURNAL OF
MEDICINE. IT LOOKED AT
ADMINISTRATIVE DATA FROM
ONTARIO CANADA, AND LOOKED AT
THE RISK FOR MYOCARDIAL
INFARCTION, HEART ATTACK CAUSED
BY CORONARY ARTERY THROMBOSIS
FOLLOWING INFLUENZA AND THE
RISK WAS ESTIMATED TO BE SIX
FULL HIGHER IN THE SEVEN DAYS
AFTER AN INFLUENZA DIAGNOSIS
COMPARED TO THE 51 OTHER WEEKS
OF THE YEAR. THIS IS STILL AN
ELEVATED RISK FOR RSV AND EVEN
FOR UNDIFFERENTIATED
RESPIRATORY INFECTION WITHOUT A
SPECIFIC VIRUS IDENTIFIED. AN
INTRIGUING SUGGESTION TO US AND
IT CAUSED US TO LOOK INTO THIS
CAREFULLY.
THIS WORK WAS LED IN MY LAB I
RESEARCH SCIENTIST SUBHASIS
MOHANTY WHO WORED WITH ANNA
KONSTORUM.
WHAT WE DID WAS RECRUIT A
POPULATION OF YOUNG AND OLDER
ADULTS AND OLDER ADULTS
RESIDENTS OF A SKILLED FACILITY
OR NURSING HOME AND EVERYBODY
RECEIVED THE SEASONAL INFLUENZA
VACCINE WE EVALUATED, AND I
WILL SHOW YOU SOME DATA ON THE
BASAL EXPRESSION OF SOME
ACTIVATION MARKERS. THIS IS
ONE OF THE FEW TALK THAT IS NOT
GOING TO HAVE ANY SINGLE CELL,
THE REASON FOR THIS IS THAT
THIS IS STILL A TECHNOLOGICAL
BARRIER IN PLATELETS.
IF YOU THINK ABOUT IT THE
TYPICAL RNA CONTENT OF THE
PLATELET IS ABOUT TWO
PHENTOGRAMS. AND SHOULD THIS
BECOME A POSSIBILITY, IT WILL
BE GREAT TO HAVE OUR HANDS
AROUND THIS BUT IT CAN BE BOTH
(INDISCERNIBLE).
LET ME MAKE ANOTHER COMMENT.
THAT WE ALSO EVALUATED FOLKS
FOR THE GERIATRIC SYNDROME OF
FRAILTY IN THE STUDY, THAT
REFLECTS A STATE OF DIMINISHED
(INDISCERNIBLE), AND DECREASED
STRESS RESISTANCE WELL
VALIDATED FOR A RISK OF
MORTALITY IN THE NURSING HOME,
BEING AT INCREASED DISABILITY
AND RISK FOR FALLS AND THE
LIKE. WE USED TO MEASURE
DEVELOPED BY -- THAT HAS A
MEASUREMENT BY GAIT SPEED AS
WELL AS SELF-REPORTS OF
UNINTENTIONAL WEIGHT LOSS,
EXHAUSTION AND DECREASED
PHYSICAL ACTIVITY USING
VALIDATED INSTRUMENTS AND IF
YOU HAVE THREE OUT OF THE FIVE
CRITERIA CONSIDERED FRAIL AND
ONE OR TWO YOU ARE CONSIDERED
PRE-FRAIL, ZERO YOU ARE
NON-FRAIL.
THE REASON I BRING THIS UP IS
THAT ONCE YOU LOOK AT THE ORDER
GROUP OF COMMUNITY DWELLING
INDIVIDUALS, MOST OF THEM WERE
NON-FRAIL WITH A FEW PRE-FRAIL.
NEARLY ALL OF THE RESIDENTS IN
NURSING HOMES MET THE CRITERIA
FOR PRE-FRAIL. GIVEN THE
OPPORTUNITY TO DO SOME
CORRELATIONS AS WELL.
LET ME SHOW YOU SOME OF THE
DATA. WE SAW THE EVALUATION OF
THE BASELINE, THERE WAS
SUBSTANTIAL EXPRESSION OF RNA
ASSOCIATED WITH PLATELET
ACTIVATION AND IT WAS
UPREGULATED IN PLATELETS FROM
OLDER INDIVIDUALS, COMMUNITY
DWELLING OLDER AND FURTHER
UPREGULATED IF ONE LOOKED EVEN
IN NURSING HOMES VERSUS OLDER
INDIVIDUALS. THESE ARE THE
PARTICULAR PATHWAYS THAT WERE
UPREGULATED FOR SIGNALING
PATHWAYS, EMULATION PATHWAYS
AND THE LIKE.
IF YOU LOOK AT THIS COMPONENT
ANALYSIS, THEY SEPARATE OUT
PRETTY WELL PARTICULARLY THE
NURSING HOME GROUP IN BLUE AND
THE GREEN IS A YOUNG
INDIVIDUALS. IF YOU LOOK AT
THIS PC1 AXIS IT EXPLAINED
ABOUT 72% VARIATION WHICH IS A
SUBSTANTIAL AMOUNT AND
SOMETHING WILL COME UP A BIT
LATER, THE PRIMARY BOUNDARY
REGULATING GENES-- NOT GENES,
RNAS-- WERE MEDIATING
TRANSLATION LIKE ELONGATION,
CHROMOSOMAL DROPPINGS AND CIS
DOWN REGULATE IN PLATELETS IN
OLDER ADULTS, AND ADULTS IN
NURSING HOME POPULATIONS AND I
SHOULD ALSO MENTION, FOR WHAT
IT'S WORTH, WE SAW AN H
ASSOCIATED INCREASE IN THE
BASAL EXPRESSION OF
MITOCHONDRIAL GENES. PLATELETS
TO HAVE ABOUT 4-5 MONO CHONDRIA
PER PLATELET.
AS MANY OF YOU KNOW THE
PRINCIPAL DNA-DEPENDENT RNA
POLYMERASE IS A (INDISCERNIBLE)
ENCODED IN THE GENE.
THEORETICALLY, WE DO SEE A
BASAL UP REGULATION PLATES.
WE DO SEE SOME EVIDENCE FOR
DYNAMIC REGULATION FOLLOWING
VACCINATION IN HERE WE SEE THE
METHOD THAT ANNA KASTORUM AND
-- USED ESSENTIALLY A
DECONVOLUTION OF METRICS,
INCLUDING PARTICULAR GENES OR
GENE SETS, AND THE ASSOCIATION
WITH A PARTICULAR GROUP, WITH A
VECTOR IN THIS CASE OF TIME.
THIS ALLOWS US TO ALSO RANK
ORDER, TO WHAT EXTENT CERTAIN
GENES ARE ASSOCIATIVE WITH
MEMBERS IN A CERTAIN GROUP AND
USING THIS KIND OF APPROACH WE
WERE ABLE TO IDENTIFY SOME
COMPONENTS THAT WERE
OVERLAPPING, AND IN THIS CASE
CONSISTED OF RNAS THAT
MEDIATING ACTIVATION, SHOWING A
DIFFERENTIAL MODULATION
POST-VACCINATION.
I DON'T KNOW IF YOU CAN SEE IT
BUT THIS IS IN RICH GREEN HERE,
COMPONENTS ENRICHED IN THE
YOUNG INDIVIDUALS THAT SHOWED
THIS PARTICULAR PATTERN OF UP
REGULATION, PLATEAU IN THE
NURSING HOME COHORT. WITH THE
ENRICHMENT OF THIS PARTICULAR
PLATELET ACTIVATION RNAS THAT
ARE DOWN REGULATED AND THEN IN
OLDER ADULTS SHOWING A LITTLE
INTERMEDIATE.
WE ALSO SAW SOME SUBCOMPONENTS
THAT ALSO MODULATED THOSE
TRANSLATION SIGNATURES THAT I
MENTIONED. THE QUESTION CAME
UP, THAT WE SEE ANYTHING
RELATED TO VACCINE RESPONSE? WE
DID NOT IN THE CASE OF OLDER
INDIVIDUALS BUT FOR THE YOUNG
VACCINE RESPONDERS WE ACTUALLY
DID SEE A COMPONENT AGAIN, WITH
RNAS ASSOCIATED WITH PLATELET
ACTIVATION THAT WERE DOWN
REGULATED BUT ONLY A DAY 28.
SO THE TYPICAL HALF-LIFE OF A
PLATELET OR THE LIFESPAN OF
HUMAN PLATELET IS ABOUT A WEEK
TO 10 DAYS. THIS IS FAR BEYOND
WHAT WE WOULD EXPECT.
THIS SPEAKS TO THE LIKELIHOOD
FOR NON-PLATELET AUTONOMOUS
FACTORS THAT CONTRIBUTE TO THIS
EVIDENCE OR ASSOCIATION WITH
INFLUENZA VACCINE RESPONSE.
ANOTHER QUESTION WE TRY TO
ANSWER WAS THE ISSUE OF UP
REGULATION OF SOME OF THESE
ACTIVATION MARKERS. MANY OF
THEM RESIDE IN PRE-FORM
GRANULES, OFFER GRANULES WITHIN
THE PLATELET TRANSPORTED TO THE
SURFACE LIKE LIGAND OR
PIECE-SELECTING.
IS THE EXPRESSION OF RNAS
MATTER? NOT SUCH AN EASY
QUESTION TO ANSWER. WITH A
START TO EVALUATE THIS USING
FLOW CYTOMETRY. YOU CAN DO THIS
ON PLATELETS AND WHAT WE FOUND
IS THAT FOR SOME MARKERS THERE
WAS AN ASSOCIATION BETWEEN GENE
EXPRESSION, FOR THE P-SELECTING
GENE CALLED THE CELL. IF ONE
LOOKS AT DAY TWO TO DAY SEVEN
TO NORMALIZE EXPRESSION RELATED
TO DAY ZERO, THEY ARE SIMILAR
PATTERNS OF EXPRESSION OF
HIGHEST IN THE NORMALIZED
EXPRESSION THE YOUNG GROUP AT
THE SEVEN WE SEE SOMETHING
SIMILAR IN ONE SEPARATE
EXPRESSION PROVIDED BY FLOW
CYTOMETRY.
AND FOR LIEGAND WE DID NOT SEE
ASSOCIATION. IF WE LOOK AT THE
OVERALL EXPRESSION OF PLATELET
ACTIVATION MARKERS HAD DAY TWO
AND DAY SEVEN OF POST VACCINE
WE SEE EXPRESSION OF LOVE IS
ACTIVATION MARKERS.
SURPRISINGLY IN THE NURSING
HOME GROUP THIS WAS MODULATED.
WITH ONE EXCEPTION. WE DON'T
TOTALLY UNDERSTAND THIS. THERE
HAVE BEEN SOME REPORTS IN THE
LITERATURE OF MODULATED
EXPRESSION, THINGS LIKE ROS IN
VERY OLDER INDIVIDUALS, THERE
IS WORK FROM-- OUR COLLEAGUE AT
YALE-- AND WE SAW THE
EXPRESSION OF THE TRANSLATION
PIECE THAT IS LOWEST IN THE
NURSING HOME GROUP, WHERE THAT
IS CONTRIBUTING.
I WILL SAY WE ARE LOOKING AT
-- EXPRESSION OF THESE
ACTIVATION GENES AND WE DO SEE
EVIDENCE THAT FOR SEVERAL
(INDISCERNIBLE) -- FOR WHAT
IT'S WORTH-- THE NURSING HOME
INDIVIDUALS HAD THE HIGHEST
EXPRESSION OF INFLAMMATORY
PHENOTYPE, IF ONE LOOKS AT EX
VIVO SIMULATION.
SO THIS IS A SUMMARY OF WHAT I
DISCUSSED. SO WE THINK THAT
THERE IS EVIDENCE FOR AN AGE
ASSOCIATIVE ENHANCEMENT IN
PLATELET ACTIVATION, MEDIATED
BY RNA EXPRESSION AND THEIR
DISTINCT TRAJECTORIES OF POST
VACCINE RESPONSE THAT TALKS
ABOUT PLATELET EXIT AND
INTRINSIC FACTORS.
THERE IS AN INTERESTING
VIROLOGY POTENTIAL ANALYSIS OF
WHAT RNAS ARE TRANSLATED AS
EVIDENCED BY THIS MODULATION A
BASAL ACTIVATION PHENOTYPE. WE
DO THINK THAT THERE IS GENERAL
EVIDENCE FOR AN ENHANCED
THROMBO INFLAMMATORY MILIEU IF
YOU WILL THAT CONTRIBUTES TO
PLATELET CHRONIC INFORMATION.
WE ARE REAUTHORIZING HOW SMALL
AND MIGHTY THEY ARE, THEY HAVE
LIKE 2W10 TO THE FIFTH PER
MICROLITER BLOOD. MAYBE I'M
GOING TO FINISH WITH MY FUTURE
QUESTION SLIDE.
WE ARE INTERESTED IN THE
BIOLOGY. WHAT IS GOING ON? HOW
IS IT THAT THE PLATELET HAS NO
POTENTIALLY (INDISCERNIBLE) TO
SPEAK OF YET? WE SEE
SEGREGATION IN TERMS OF
FUNCTIONAL APPEARING RNAS. WE
CAN TALK ABOUT THAT.
FOR THIS SESSION I AM GOING TO
TALK ABOUT A COUPLE OF OTHER
QUESTIONS IN THE AREA OF
GENERAL VACCINE RESPONSE, NOT
SO MUCH ABOUT T-CELLS BECAUSE
YOU ARE SUCH EXPERTS. BUT I
WILL SAY THAT MOTIVATED BY THE
CLINICAL QUESTIONS, WHAT IS THE
MECHANISM FOR INCREASED
DURATION OF ANTIBODY RESPONSES?
WE ALL KNOW FOR EXAMPLE THERE
IS ACCELERATED DECAY IN
NEUTRALIZING ANTI SAR-COVID-2
ANTIBODIES AND THIS HAS BEEN
DOCUMENTED. IT REFLECTS THE
GENERAL RESPONSES BUT IT IS
INTERESTING TO UNDERSTAND WHAT
IS GOING ON. CAN WE HAVE
PLEASE BE LESS EFFECTIVE? IT IS
THE RELEVANT CLINICAL QUESTION
FOR (INDISCERNIBLE). PERHAPS--
WE'LL TALK ABOUT THIS BUT I
ALWAYS WONDERED IF OTHER
CERTAIN ADJUTANTS THAT CAN
BYPASS THE -- I MENTIONED --
THE COMPONENT IN THE ZOSTER
VACCINE THAT SHOWS NO
DIFFERENCE AS FAR AS WE CAN
TELL IN AGE EFFECTIVENESS. JUST
AS EFFECTIVE IN EIGHT-YEAR-OLDS
AND 60-YEAR-OLDS.
AND AT LEAST IN THE SHORT TERM
THE NANO PARTICLE RNA PLATFORM
WORK PRETTY WELL; IT SAVES A
LOT OF OLDER ADULTS WHEN IT
FIRST CAME OUT ALTHOUGH WE KNOW
THAT THE MECHANISMS OF THE
--ACCELERATED. THE LAST THING
IS THAT MUCOSAL IMMUNOLOGY SUCH
A BROAD FIELD NOT JUST TALKING
ABOUT SECRETORY
(INDISCERNIBLE), BUT ALL OF IT
SHOULD BE STUDIED AS A BARRIER,
AS A MUCUS BARRIER NOT WELL
UNDERSTOOD IN THE CONTEXT OF
AGE PARTICULARLY IN HUMANS. BUT
THAT IS FOR LATER I GUESS.
AND JUST TO THANK THE FOLKS
WHO HAVE DONE THIS WORK. AGAIN
SUBHASIS IN MY LAB AND WE
COLLABORATED WITH -- FORMER
POSTDOC IN MY LAB. STEVE -- LAB
AND -- AND -- AT THE UNIVERSITY
OF UTAH TELLS US ALL ABOUT
PLATELETS. IN THE PROGRAM ON
AGING BY TOM GILL, AND A GREAT
NURSE RESEARCHERS AND OUR
FUNDERS THANK YOU SO MUCH.
>>THAT WAS REALLY
INTERESTING. PLATELETS
(INDISCERNIBLE). HOW MUCH-- I
DO EXPRESS A LOT OF THESE
THINGS AND RNAS AND
(INDISCERNIBLE). HOW MUCH OF
THIS DO YOU THINK IS A PLATELET
ITSELF VERSUS (INDISCERNIBLE)?
>>IT IS A GREAT QUESTION. I
DON'T THINK IT IS WELL STUDIED.
YOU BRING UP THE TWO
POSSIBILITIES ABOUT WHAT IS
GOING ON. IS SOMEHOW
PARTITIONED IN SOME NONRANDOM
WAY? OR POTENTIALLY THERE ARE
FACTORS THAT REFLECT RNA
COLLECTIBILITY THAT SOMEHOW
MODULATE EXPRESSION SOME WAY.
WE DO NOT KNOW THE ANSWER TO
THAT. WE WOULD LIKE TO GET AN
IDEA ABOUT WHICH RNAS ARE
ACTUALLY TRANSLATED IN THEIR
WAYS TO DO THAT THROUGH THE
FOOTPRINT AND THE LIKE. IT IS
A GOOD QUESTION. YEAH?
>>I WAS REALLY INTERESTED IN
YOUR PLOT THAT YOU SHOWED,
WHERE YOU HAVE THE NURSING
ELDERS THE PC 101 SITE AND THE
YOUNGER, AND THE COMMUNITY
OLDER INDIVIDUALS. IS THAT A
REFLECTION OF BIOLOGICAL AGE OR
IS THERE HETEROGENEITY OF OLDER
INDIVIDUALS?
>>I THINK FOR SURE THERE IS
HETEROGENEITY. WE ARE NOT
PARTICULARLY RESTRICTIVE ABOUT
ENROLLING FOLKS. WE EXCLUDE
THINGS LIKE THAT WOULD CAUSE
OBVIOUS IMMUNOSUPPRESSION LIKE
CANCER THERAPY AND CIRRHOSIS
AND END STAGE KIDNEY DISEASE.
BY DIABETES AND THINGS LIKE
THAT WERE ALL INCLUDED I THINK
THEY ARE HEALTHY COHORT THAN
THE NURSING HOME POPULATION,
THAT IS FOR SURE. BUT THERE IS
A LOT OF HETEROGENEITY. I DON'T
KNOW IF WE HAVE A LOT OF
NUMBERS TO DIG DOWN INTO IT.
GOOD QUESTION.
>>REALLY NICE WORK. I WAS
CURIOUS DRILLING DOWN ON YOUR
LAST COMMENT A LITTLE MORE, HOW
HARD IS IT TO CONTROL FOR
DIAGNOSES OR MEDICATIONS THAT
AFFECT PLATELETS AND DIAGNOSIS
OF PLATELET DEFECTS?
>>SO WE ALLOW PEOPLE TO BE ON
MEDICATIONS THAT COULD CAUSE
ALTERATIONS IN PLATELETS. THIS
WOULD INCLUDE A VARIETY OF
THINGS: ASPIRIN, PLAVIX, A
VARIETY OF THINGS. MOST OF
THESE WOULD HAVE INHIBITORY
EFFECTS ON PLATELET FUNCTION.
WE DID NOT SEE-- ADJUSTING FOR
THIS-- DID NOT SEE A
SUBSTANTIAL EFFECT OF THE
PLATELET ACTIVE MEDICATIONS ON
THESE OUTCOMES WHEN WE SAW A
SMALL EFFECT OF -- BUT NOT A
LARGE ONE WE EVALUATED IT.
THERE ARE A LOT OF THINGS THAT
COULD AFFECT PLATELET FUNCTION.
>>
>>HLA LOGICAL AND PLATELETS. I
DON'T KNOW THE ANSWER. I WILL
HAVE TO LOOK IT UP. THERE ARE
A NUMBER WACKY THINGS THAT ARE
IN PLATELETS THAT SUGGEST KIND
OF POSSIBLY LONG AND I DON'T
KNOW THE ANSWER.
>>IF I MIGHT BE ABLE TO HELP,
IN MY LIMITED CLINICAL
EXPERTISE, THEY ARE EXPRESSIVE
PLATES.
>>OKAY.
>>OKAY. OUR NEXT SPEAKER, IS
DR. MICHELLE LINTERMAN, GROUP
LEADER AT ROTHERHAM INTO THE
CAMBRIDGE AND THANK YOU FOR
COMING. THE TITLE OF HER WORK
IS HOW AGING CHANGES TO IMMUNO
RESPONSE.
>>HI EVERYONE IT IS A PLEASURE
TO BE HERE. I HAVE ENJOYED IT
IMMENSELY THANK YOU AL FOR
HIGHLIGHTING THE
(INDISCERNIBLE) AN
UNDERSTANDING HOW AGE IS A KEY
AREA BECAUSE THAT IS WHAT I'M
GOING TO TELL YOU ABOUT. FOR
THOSE OF YOU WHO DO NOT KNOW,
THE BEAUTIFUL STRUCTURE OF THE
GERMINAL-- PROLIFERATE IS IN
BLUE AND THE (INDISCERNIBLE).
AND WHAT I WOULD LIKE TO
HIGHLIGHT FOR THE STAFF, IS
AWARE THAT I'M GOING TO PRESENT
WAS DONE BY A VILLAGE. THESE
ARE ALL THE WONDERFUL PEOPLE
THAT MAKE THE MAGIC HAPPEN. ON
THE QUESTION THAT WE REALLY
WANTED TO ADDRESS IS, WHAT IS
THE FUNDAMENTAL BIOLOGY THAT
UNDERPINS FOR ANTIBODY RESPONSE
IN AGING?
I TAKE YOU BACK TO THE
GERMINAL CENTER. THE RESPONSE
IS THE CELLULAR COURSE OF
LONG-LIVED HUMAN IMMUNITY.
FOLKS APPRECIATE THAT-- YOU MAY
NOT APPRECIATE IT BUT IT IS MY
FIRST LOVE, PROBABLY NOT
YOURS-- THE GERMINAL CENTER IS
INITIATED AT THE INFECTION FOR
IMMUNIZATION WHEN B CELLS
CLONES MOVING TO THE B CELL
FOLLICLE. ONCE IN THE B CELL
FOLLICLE THEY MULTIPLY. DURING
THE DIVISION PROCESS THEY
UNDERGO TARGETED MUTATION OF
THE GENES ENCODING THE BASAL
RECEPTORS.
SO THIS IS KNOWN AS
METACOGNITIVE MUTATION.
AFTER THIS MUTATION PROCESSES
THEY MOVED TO THE OPPOSITE POLE
OF THE GERMINAL CENTER CALLED
THE LIGHT ZONE, POPULATED BY
FOLLICULAR DENDRITIC CELLS, AND
DESPITE THEIR NAME THESE ARE
(INDISCERNIBLE) CELLS.
THIS IS ALSO FILLED WITH
FOLLICULAR B CELLS AND
FOLLICULAR (INDISCERNIBLE).
YOU SEE CXCR5 MIGRATION. YOU
CAN SEE THE NEWLY MUTATED B
CELL RECEPTOR TO SEE THEY CAN
BIND. IF THEY CAN AN
INVITATION PROCESS THAT'S THE B
CELL RECEPTOR FUNCTIONAL, THEY
CAN TAKE OF THE ANTIGEN AND
PROCESS IT AND PRESENTED TO
FOLLICULAR -- HEALTHY
POPULATIONS OF -- AND THE IDEA
IS THAT B CELLS COMPETE WITH
EACH OTHER IN THE GERMINAL
CENTER FOR T-CELL HELP. IT IS
OFTEN CALLED EVOLUTION IN
MINIATURE.
YOU HAVE THIS MUTATION PROCESS
AND THEN YOU NEED SELECTION TO
GET THE FITTED B CELLS WHO ARE
ABLE TO MIGRATE BACK TO THE
DARK ZONE WHERE THEY CAN DO THE
WHOLE PROCESS AGAIN SOME MORE
MUTATION AND MORE SELECTION.
OR EXIT THE GERMINAL CENTER AS
PLASMA CELLS THAT HARM THE BONE
MARROW AND THEY SET OUT THIS
LONG-TERM SOURCE OF ENERGY
PRODUCING CELLS AND CONNECTED
AS MEMORY B CELLS, THAT UPON
RESTIMULATION CAN RAPIDLY
DIFFERENTIATE INTO ANTIBODY
SECRETING CELLS.
NOW, WHILST IT HAS BEEN KNOWN
FOR A LONG TIME TO THE GERMINAL
CENTER RESPONSES MORE IN AGING,
ONE THING THAT REALLY HAD NOT
BEEN INVESTIGATED WAS HOW ITS
STRUCTURE CHANGES AND WE WERE
CAPTIVATED BY THIS QUESTION
AFTER A BIG CLINICAL STUDY WAS
DONE ON THE COVID-19 VACCINE.
YOU DON'T HAVE TO BE A
GERMINAL CENTER EXPERT TO LOOK
AT THESE TWO IMAGES AND SEE
THAT THE GERMINAL CENTER ON THE
TOP LOOKS NICE AND RUNNING
HOPEFULLY YOU CAN SEE THE TWO
FUNCTIONALLY DISTINCT ZONES,
LIGHT ZONE AND DARK ZONE.
BUT THE GERMINAL CENTER AT THE
BOTTOM LOOKS A BIT WEIRD. SO
WE WANTED TO QUANTITATIVELY DO
IMAGING STUDIES TO UNDERSTAND
WHETHER THIS
COMPARTMENTALIZATION OF THE
GERMINAL CENTER WAS CHANGED,
AND WHETHER THE POTENTIAL
CHANGE COULD LEAD TO A CHANGE
IN FUNCTION.
SO HERE WE ARE USING -- --
THIS IS A POINT OF CONTROVERSY
AT THIS MEETING. WHAT I AM
SHOWING YOU HERE IS H -- AGED
(INDISCERNIBLE) AND AGED MICE.
THE BLACK IS MALE, THE -- IS
FEMALE. BUT I AM ALSO SHOWING
USED ARE NOT JUST ACROSS
GENETIC BACKGROUNDS BUT ALSO
EFFECTS.
WHAT WE NOTICED IN OUR AGED
MICE WAS THAT BY LOOKING AT THE
GERMINAL CENTERS YOU CAN SEE
THAT THE LIGHT ZONE LOOKED A
BIT WASHED.
WE MERGE MULTIPLE GERMINAL
CENTERS PER MOUSE AND USE THE
AVERAGE -- THE AGE DOT IS A
BIOLOGICAL REPLICATIVE, MADE UP
OF MULTIPLE GERMINAL CENTERS
AND YOU CAN SEE THE OVERALL
THERE IS A SMALLER FOLLICULAR
CENTRIC. WE HYPOTHESIZE THIS
MIGHT MEAN THAT THERE IS LESS
ANTIGEN IN B CELLS TO CAPTURE.
THE OTHER THING WHEN SHE WAS
LOOKING UNDER THE MICROSCOPE IS
THAT THE T-CELL LOOK LIKE THEY
WERE IN THE WRONG PLACE AND IF
YOU READ AND REVIEW THE
GERMINAL CENTERS, INCLUDING
ONES AUTHORED BY ME, THEY WILL
TELL YOU THAT THE
(INDISCERNIBLE).
WHAT WE NOTICE IS THE
POLARIZATION OF THE TFH CELL
WAS LOST AND AGING IN YOU COULD
ASK WHAT PROPORTION OF THE
DIESELS ARE IN THE DARK ZONE.
WE HYPOTHESIZE THIS WOULD MEAN
THAT THE HELP IS NOT WHETHER B
CELLS NEEDED IT. THEY ARE NOT
ABLE TO ACCESS HELP.
ALSO I WOULD LIKE TO ADD THAT
IT APPEARS THAT THESE ARE TWO
INDEPENDENT EFFECTS OF AGING
AND FIRST CHOSE TO INVESTIGATE
THE LOCATION OF B CELLS.
NOW, WE WANTED TO UNDERSTAND
WHY THE B CELLS MIGHT BE LOST
IN THE DARK ZONE IN AGING. IN
THE SIMPLEST HYPOTHESIS IS THAT
THEY WOULD EXPRESS AS
(INDISCERNIBLE), BECAUSE THE
THERMAL IN THE DARK ZONE
EXPRESSES CXCL12, AND THE UP
AND DOWN REGULATION IS WHAT IS
USED TO MIGRATE BETWEEN THE TWO
ZONES. AND WHAT WE COULD SEE
THAT THE FREQUENCY OF THE TFH
CELL THAT EXPRESSES THIS IS AN
INCREASED IN AGED MICE AND IF
YOU TAKE THOSE TFH CELLS, YOU
CAN SEE THE INCREASED
EXPRESSION THAT LEADS TO MORE
MIGRATION.
WE WANTED TO KNOW WHY TFH
CELLS EXPRESS MORE. THAT IS
NOT AN EASY QUESTION TO ANSWER.
REGULATION OF CXCR4 IS QUITE
COMPLICATED ONE THING THAT DOES
HAPPEN IS YOU GET LIGAND
INDEPENDENT (INDISCERNIBLE).
WHAT WE CAN THEN DO IS ASK IS
IF THE TFH MIGRATION WAS
(INDISCERNIBLE). AND THE AGED
TFH CELLS WERE LESS
INDEPENDENT, AT HIGH
CONCENTRATIONS OF LIGANDS THEY
CAN DO IT, BUT THEY ARE NOT AS
CAPABLE AS THE T CELLS FROM
YOUNGER MICE.
WE ALSO WANTED TO CHECK
WHETHER THIS REGULATION OF THE
EXAMPLE, WAS CONFERRED ACROSS
SPECIES AND WHY WE DON'T HAVE
ENOUGH SAMPLES TO LOOK AT TFH
FROM LYMPH NODES FROM YOUNGER
AND OLDER PEOPLE WOULD CONSIDER
IN THE PERIPHERAL BLOOD OF
OLDER PEOPLE THAT THEY TENDED
TO HAVE A HIGHER EXPRESSION OF
CXCR4. WE THINK THAT IS
SOMETHING THAT IS RELEVANT TO
HUMANS AS WELL.
BUT WE BASICALLY SAW IS THAT
IN AGING, THIS TENDS TO BE
SMALLER AND YOU HAVE THIS
LOCALIZATION OF TFH CELLS THAT
WE THINK IS DEPENDENT ON THE
EXPRESSION OF CXCR4, BUT YOU
KNOW THAT REALLY DOES BEG THE
QUESTION OF WHETHER CXCR4 DOES
INDEED CONTROL THE EFFECTS OF
GLOBALIZATION. AND WHETHER THE
LOCATION OF THF CELLS ACTUALLY
MATTERS TO THE GERMINAL CENTER.
AND IF IT DOES, CAN BE
CORRECTED BY SUPPLYING T-CELLS
THAT ARE LOCALIZED.
AND SO WE WANTED TO THE
QUESTION OF WHETHER CXCR4 CAN
MEDIATE THE CHANGE IN LOCATION
OF THE TFH CELLS. WITH THE
QUANTITATIVE IMAGING. WHAT WE
SAW IS THAT WHEN T-CELLS LACK
CXCR4 THERE IS NO CHANGE, THAT
WE DO SHIFT ALMOST ALL OF THE
T-CELLS INTO THE LIGHT ZONE.
WHAT WE FOUND THAT WE
ABSOLUTELY DID NOT EXPECT, IS
WHEN WE PUSH THE T-CELLS INTO A
LIGHT ON YOUR EXPANDED THE
NETWORK. THERE IS SOMETHING
ABOUT THE LOCATION OF
(INDISCERNIBLE), WHICH MAY MEAN
THAT THOSE TWO DEFECTS WE
OBSERVED ORIGINALLY IN AGING
MAY ACTUALLY BE LINKED
BIOLOGICALLY.
SO CAN WE DO THE OPPOSITE
EXPERIMENT? CAN WE GENETICALLY
FINO COPY AGING BY SHIFTING
T-CELLS TO THE DARK ZONE? TO DO
THIS WE MADE THE T-CELLS CXCR5,
WHICH IS MADE BY THE FOLLICULAR
DENDRITIC CELLS IN THE LIGHT
ZONE. AND WHEN THESE BLACK
CXCR5, YOU SHIFT OUT OF THE
LIGHT ZONE INTO THE DARK ZONE,
VERY SIMILAR TO AGING.
SO WHAT HAPPENED TO THE
GERMINAL CENTER? THE GERMINAL
CENTER IS SMALLER, SIMILAR TO
THE RESULTS YOU SEE IN AGING.
I THINK, YOU CAN SEE HERE THAT
THE NETWORK REALLY LOOKS
SQUASHED LIKE IN AGING, AND IF
YOU ENUMERATE THAT YOU CAN
NICELY SEE THAT IT SHIFTS THE
T-CELLS AWAY FROM THE NETWORK.
THE NETWORK IS SMALLER.
AND SO WE THINK THAT WHAT THIS
SHOWS IS THE LOCATION OF TFH
CELLS WITHIN THE GERMINAL
CENTER INFLUENCES THE RESPONSE
OF THE TFH CELLS. WE SHOULD BE
ABLE TO CORRECT THE DEFECTS IN
THE GERMINAL CENTER SIZE BY
SUPPLYING T-CELLS THAT ARE
LOCALIZED CORRECTLY.
WE DID A TRANSFER WHERE WE
TOOK T-CELLS FROM YOUNGER
ANIMALS AND TRANSFER THEM INTO
(INDISCERNIBLE), AND HOW IT
LOOKED 10 DAYS LATER. AND WHAT
YOU CAN ACTUALLY SEE IS YOU GET
IS BEAUTIFUL EXPANSION OF THE
FDC NETWORK QUALIFIED HERE, AND
YOU CAN ENHANCE THE SIZE OF THE
GERMINAL CENTER AND LIKEWISE
THE NUMBER. YOU REALLY ARE
BOOSTING THE AGE GERMINAL
CENTER BY GIVING IT YOUNG
T-CELLS.
WHAT WE REALLY WANTED TO
UNDERSTAND WAS, IS IT THE
LOCATION OF THE T-CELLS? NOT
THE EFFECT THAT WE HAVE GIVEN
THESE YOUNG MICE T-CELLS. CXCR5
IS REQUIRED FOR THE
LOCALIZATION AND REPEATED THE
EXPERIMENT BY TRANSFERRING
T-CELLS LACKED CXCR5 OR LACK
CONTROLS AND WHEN YOU GIVE THEM
-- YOU DON'T HAVE THIS INCREASE
GERMINAL CENTER AREA. YOU DO
NOT INCREASE THE FDC NETWORK
AND THE PROPORTION OF GERMINAL
CENTER T-CELLS.
SO TO SUMMARIZE WHAT I TOLD
YOU, WHAT WE THINK WE HAVE SEEN
IS THAT THERE IS SPECIAL THIS
RELATION OF THE GERMINAL
CENTER IN AGING AND THAT IS
POTENTIALLY CAUSED BY THE MISS
LOCALIZATION OF TFH TO THE
THOSE DARK ZONE BECAUSE THEY
EXPRESS CXCR4, MOST LIKELY
BECAUSE THEY HAVE IMPAIRED
INTERNALIZATION OF THIS
RECEPTOR.
WHAT WE HAVE DISCOVERED HERE
IS THAT TFH LOCATION ALTERS THE
FDC RESPONSE. THIS IS A REALLY
NICE EXAMPLE OF HOW STUDYING
THE RESPONSE TO AGING WE
ACTUALLY UNDERSTAND MORE ABOUT
PHYSIOLOGY IN GENERAL. THIS IS
THE INTERACTION THAT HAS NOT
BEEN REPORTED PREVIOUSLY.
AND I THINK IMPORTANTLY,
SUPPLYING T-CELLS THAT CAN
LOCALIZE TO THE LIGHT ZONE CAN
CORRECT THESE DEFECTS IN AGING.
AND SO I WANTED TO FINISH WITH
RESEARCH GAPS AND
OPPORTUNITIES. QUITE LIKE THIS
IS A WAY OF THINKING ABOUT
RESEARCH. ON THIS AXIS, IT IS
ASKING THE QUESTION, ARE YOU
JUST ADVANCING HUMAN KNOWLEDGE?
AND THEN THIS IS LIKE, IS THERE
AN IMMEDIATE APPLICATION FOR
THAT? UNASHAMEDLY, THIS
RESEARCH THAT WE ARE DOING IS
VERY MUCH IN THE FUNDAMENTAL
RESEARCH QUADRANT. I THINK WE
ABSOLUTELY NEED TO DO THAT.
BUT THE MAIN GAP IS HOW DO WE
MOVE THIS TYPE OF RESEARCH INTO
THE IMMEDIATE APPLICATION?
BECAUSE THERE IS AN URGENT NEED
FOR US TO MAKE VACCINE TO DO
WORK BETTER IN ALL THE PEOPLE.
AND I GUESS THE BIG QUESTION
IS, HOW? I HAVE SOME IDEAS. I
HAVE NOT DELIVERED ON ANY OF
THIS BUT MAYBE SOME OF YOU IN
THE ROOM WILL.
THE FIRST AND MOST OBVIOUS IS
THE VAX ANALOGY APPROACHES.
THANKS AGAIN TO AL YOU
HIGHLIGHTED A COUPLE OF
EXAMPLES, CHANGING THE
FORMULATION TO MAKE VACCINES
WORK BETTER FOR OLDER PEOPLE.
BUT I THINK WE CAN BE MORE
INNOVATIVE IN THE CLASSIC
VACCINOLOGY APPROACHES,
POTENTIALLY THINKING ABOUT
TARGETING SOME OF THE HALLMARKS
OF AGING IN THE CONTEXT OF
VACCINE MEDICINE AND THERE IS
BEAUTIFUL WORK FROM-- WHICH HE
HAS USED A COMPOUND THAT
MODULATES AUTOPHAGY TO IMPROVE
HUMERAL IMMUNITY IN AGED MICE.
BY TARGETING THE HALLMARKS OF
AGING, SOMETHING THAT
NECESSARILY SPECIFIC TO VACCINE
RESPONSE, YOU CAN REALLY IMPACT
THIS. AND POTENTIALLY AN
APPROACH WHICH ALSO USES
EVIDENCE FOR UNDERSTANDING WHAT
ARE THE SPECIFIC MOLECULES THAT
ARE CHANGED WITHIN CELLS ON THE
GERMINAL CENTER RESPONSE? AND
HOW THEY CHANGE IN AGING AND
TARGETING THOSE? THERE IS A
NICE PRESIDENT FROM -- -- WHERE
THE NOTED THAT TFH FROM AGED
MICE HAD INCREASED EXPRESSION
OF PD-1 AND BY BLOCKING THE
RECEPTOR THAT COULD ENHANCE THE
GERMINAL CENTER RESPONSE IN
AGING. I THINK THE GOOD THING
IS THAT WE HAVE LOTS OF
OPTIONS, AND THE CHALLENGE FOR
US IS REALLY TO IMPLEMENT THEM
IN A MEANINGFUL WAY.
WITH THAT I WOULD LIKE TO SAY
A BIG THANK YOU TO ALYSSA
SILVA-CAYETANO POSTDOC WHO DID
THE MOST WORK AND THANK YOU FOR
YOUR ATTENTION.
>>(INDISCERNIBLE) WHAT HAPPENS
TO THE T-CELL? WHAT HAPPENS TO
MEMORY FORMATION? IS THIS A
RESPONSE TO MAKE SURE THAT GETS
(INDISCERNIBLE)?
>>YOU ARE OFF THE MOON HOT.
WHEN YOU PUSH THE TFH INTO THE
LIGHT ZONE YOU GET ENHANCED
AFFINITY MATURATION, WHAT WE
SEE IN AGING WHICH TO BE HONEST
I WAS NOT EXPECTING BECAUSE THE
DOCUMENT IN THE LIGHT ZONE THEY
COMPETE FOR T-CELLS. SO IF YOU
COMPETE THE TFH THE LIGHT ZONE
IT SHOULD RELAX THE COMPETITION
HAVE A LOWER AFFINITY. BUT THAT
IS NOT WHAT WE SEE. THAT EITHER
TELLS YOU THAT OUR MODELS ARE
MISSING SOME INFORMATION WHICH
OBVIOUSLY IS OFTEN REQUIRES TFH
IN THE DARK ZONE. WE ARE
MISSING IT BECAUSE ALL OF YOU
SAY THE (INDISCERNIBLE) ARE IN
THE LIGHT ZONE.
WHEN YOU SHIFT THE OTHER WAY,
YOU HAVE A MORE GERMINAL CENTER
RESPONSE THAT AFFINITY IS NOT
AFFECTED. THERE IS AN
INTERESTING BOUNDS OF WHAT IS
GOING ON WITH IT. (CORRECTION)
INTERESTING BALANCE OF WHAT IS
GOING ON WITH IT.>>I WAS
WONDERING IF THERE IS AN
EXPANDED (INDISCERNIBLE), ARE
THESE MISLOCALIZED THAT YOU
ALSO FIND?
>>HONESTLY IT HAS BEEN
COMPLICATED BY THE FACT THAT
TFH IS CHANGED BY THE FLOW
(INDISCERNIBLE). IF YOU INCLUDE
THE TFH PRECURSOR WHICH IS THE
(INDISCERNIBLE) INTERMEDIATE
GATE, IT SEEMS THAT THOSE
ACCUMULATE IN AGING. THIS IS
WHAT WE HAVE FOUND THIS AND
LAURA ALSO DESCRIBED IT. IT
-- INTO THE (INDISCERNIBLE).
WE ALSO ENUMERATED -- BY
IMAGING. THAT ULTIMATELY IS
WHAT YOU CARE ABOUT. IF YOU
NORMALIZE THE SMALLER GERMINAL
CENTER YOU DON'T HAVE A DEFECT
IN THE T-CELL NUMBER IN THE
GERMINAL CENTER THEY TEND TO BE
FEWER BECAUSE THE GERMINAL
CENTER IS SMALLER BUT THE TFH
IS NOT AFFECTED. IT JUST SEEMS
LOCATION THAT WAS CHANGED.
>>ONE MORE POINT MAY BE
TOTALLY UNRELATED. WITH AGE,
THE -- (INDISCERNIBLE) THAT
OCCURS IN SPAIN THAT THAT
CONTRIBUTE TO THE MISS
LOCALIZATION OF FORMATION OF
THE GERMINAL CENTER?
>>WE HAVE LYMPH NODE WORK WITH
A CONSCIOUS DECISION TO MAKE
SURE WE WERE AS CLOSE TO THE
HUMAN SITUATION AS POSSIBLE.
BECAUSE WANTED TO IMMUNIZE
PEOPLE (INDISCERNIBLE).
>>TWO THINGS. ONE IS HAVE YOU
CHECKED THE ROLE OF -- IN T
REG, WHICH IS INCREASED IN
AGING?
>>WE DID THE MOST EXPENSIVE
AND BORING EXPERIMENT. WE MADE
T-CELL 5 BLOCKS, WITH A 50%
REDUCTION OF TFR CELLS IN THE
GERMINAL CENTER AND WE THINK
THAT THE. INCREASED NUMBER OF
TFR CELLS WAS LIMITING. SO
HALVING THE NUMBER OF T-CELLS
IN AGED MICE MADE NO
DIFFERENCE.
>>OLDER DATA FOR SIGNALING,
WHEN IT (INDISCERNIBLE) IN HIGH
CONCENTRATION IT CAN BE
REPELLED. ACTUALLY IT CAN CAUSE
INSTEAD OF CHEMOTAXIS, IT CAN
CAUSE -- VERY OLD DATA FROM
CHEMOTAXIS STILL.
>>WE QUANTIFIED -- BY LOCAL
IMAGING AND WE DID NOT SEE THE
DIFFERENCE IN AGING, THAT WE
THINK IS A PREDICTOR OF
(INDISCERNIBLE) LIGANDS.
>>FINAL QUESTION. WONDERFUL
WORK. MY NAME IS MICHELLE--
DREXEL UNIVERSITY IN
PHILADELPHIA, AND WORK WITH
VACCINES. AS I WATCHED YOU
WORK, SO WONDERFUL THE TOOLS
AND WHAT YOU HAVE SHOWN YOU
HAVE A SENSE OF WHAT IS GOING
ON (INDISCERNIBLE) WITH T-CELL
DEFICIENT IN THE GUT?
POTENTIALLY AGING IS A MAJOR
RISK FACTOR FOR C DEF
(PHONETIC), IT IS RELATED
PERHAPS OF NET LYMPH NODES, DO
YOU SEE THIS IN THE MUCOSAL
SITES?
>>WE DID LOOK AT THE GERMINAL
CENTER THERE. THEY ARE LIKEWISE
REDUCED; WE HAD AN INTERESTING
SURPRISE IN THAT --
TRANSPORTATION CAN REVERSE THAT
EFFECT. I THINK I THE GUT YOU
SEE THE SAME THING BUT THE COOL
THING ABOUT THAT IS IT IS VERY
BUT THE COOL THINGS THAT YOU
SEE AN OPPORTUNITY IF YOU GIVE
IT A STRONG --.
>>(INDISCERNIBLE).
>>THE ONLY THING WE LOOKED WAS
A HIGH-LEVEL DATA. WITH NOT
SEE ANY CHANGES. BUT WE HAVE
NOT DONE LIKE A BORDER SURVEY.
I WOULD LOVE TO THINK THAT WHAT
WE HAVE SEEN IS ACTUALLY
SOMETHING THAT REQUIRES MARKER
FOUR DYSREGULATION. I DON'T
HAVE THE DATA TO BACK THAT UP.
>>SO OUR NEXT SPEAKER IS
DOCTOR -- DIRECTOR OF THE--
PRGORAM AND SENIOR PHYSICIAN IN
PEDIATRICS AT BOSTON CHILDREN'S
HOSPITAL, ALSO PROFESSOR AT THE
(INDISCERNIBLE). THE TITLE OF
THIS TOPIC IS DEVELOPMENT OF
ADJUVANT FOR IMPROVING COST IN
RESPONSE. HE WILL BE GIVEN THE
TALK VIRTUALLY VIA ZOOM. DR.
LEVY?
>>THANK YOU FOR THE
OPPORTUNITY TO SPEAK TODAY AT
THIS REALLY WONDERFUL
CONFERENCE. AND I SALUTE NIA
FOR PUTTING TOGETHER THIS
IMPORTANT TOPIC. CAN YOU HEAR
ME OKAY?
>>YES WE CAN HEAR YOU.
>>AS MENTIONED MY NAME IS OFER
LEVY, A PHYSICIAN SCIENTIST
BASED AT BOSTON CHILDREN'S
HOSPITAL WHERE A DIRECTOR
POSITION VACCINES PROGRAM, I AM
ALSO PROFESSOR OF PEDIATRICS AT
HARVARD MEDICAL SCHOOL. AND I
AM ALSO A PART-TIME EMPLOYEE OF
US FDA WHERE I SERVE ON THE
VACCINE AND RELATED BIOLOGICAL
PRODUCTS ADVISORY COMMITTEE
ALTHOUGH MY COMMENTS TODAY WILL
BE MY OWN PERSONAL OPINION.
I WILL TALK TO YOU TODAY ABOUT
POSITION ADJUVANTS TO IMPROVE
VACCINE IMMUNOGENICITY IN OLDER
ADULTS.
AS WE KNOW TRADITIONALLY
VACCINE DEVELOPMENT WAS PURSUED
OVER THE PAST 100 YEARS AS A
ONE-SIZE-FITS-ALL ENDEAVOR,
THAT THE VACCINE PIPELINE WAS
DEVELOPED THE SAME WAY
TRADITIONALLY, REGARDLESS OF
THE TARGET POPULATION WHETHER
IT WAS MALE OR FEMALE OR
WHETHER YOUNG INFANT OR AN
OLDER ADULT OR WHETHER THE
VACCINE IS GIVEN IN ONE SEASON
OR IN ANOTHER, GIVEN ALONE OR
WITH ANOTHER VACCINE. GIVEN IS
ONE TYPE OF PLATFORM LIVE
ATTENUATED SUBUNIT MRNA OR
ANOTHER OR GIVEN IN ONE PART OF
THE WORLD OR ANOTHER.
OF COURSE ONE-SIZE-FITS-ALL IS
THE MOST PRACTICAL APPROACH
FROM A PUBLIC HEALTH
PERSPECTIVE FOR VACCINES. BUT
A LOT OF HIGH QUALITY RESEARCH
HAS COME OUT AND CONTINUES TO
COME OUT TO INDICATE THAT ALL
OF THESE FACTORS AND
DEMOGRAPHIC FEATURES,
ESPECIALLY AGE WHICH WE WILL
FOCUS ON TODAY, CAN HAVE A BIG
IMPACT ON VACCINE
IMMUNOGENICITY AND EVEN
PROTECTION.
WITH THESE CONSIDERATIONS IN
MIND AND 2015 BOSTON CHILDREN'S
HOSPITAL CREATED THE POSITION
VACCINES PROGRAM, AN ACADEMIC
PROGRAM WITH ITS GOALS TO
DEVELOP VACCINES FOR VULNERABLE
POPULATIONS. WE HAVE A
PROCESSION VACCINES NETWORK OF
INDIVIDUALS ACROSS THE GLOBE.
THE SLIDE IS A LITTLE BIT
OUTDATED BECAUSE WE HAVE
SEVERAL HUNDRED COLLABORATORS
ACROSS THE GLOBE, SUMMONED THE
LEAD AND SOME IN SUPPORTIVE
ROLES. WE BRING CERTAIN MR.
TECHNICAL BIOINFORMATICS
ORGANIZATION LEGAL AND GRAPHIC
CAPABILITY FOR VACCINE PROJECT
AND FOR THOSE WHO DO TWITTER WE
ARE @PRECVACCINES.
SO WHAT DO WE MEAN BY
PRECISION VACCINES? AS WE KNOW
IN 2008 THE COUNCIL REFER TO
PRECISION VACCINE IS TAILORED
TO THE INDIVIDUAL
CHARACTERISTICS OF THE PATIENT
UNNECESSARILY MEANING SEPARATE
ROW FOR EACH INDIVIDUAL BUT
RATHER ABILITY TO DEFINE
SUBPOPULATIONS THAT MAY BENEFIT
IN THIS CONTEXT PRECISION
VACCINOLOGY IS INTO TAYLOR
IMMUNIZATION FOR VULNERABLE
POPULATIONS WITH THAT THE
COMMUNITY SUCH AS INFANTS,
ELDERS, AND IMMUNOCOMPROMISE
POPULATIONS.
THIS GRAPHIC IS MEANT TO
DEPICT SOME OF THE SEVERAL
APPROACHES WE TAKE IN
DEVELOPING PRECISION VACCINES.
WE TRY TO BASE OURSELVES IN
TARGETED CLINICAL TRIALS OF
DIVERSE POPULATIONS, INCLUDING
DIVERSE BY AGE. AND TYPICALLY
IT WE WILL ACQUIRE BIO SAMPLES
BEFORE AND AFTER IMMUNIZATION
THAT WE CAN THEN SUBJECT TO A
SMALL SAMPLE BIG DATA OF
STANDARD OPERATING PROCEDURE WE
HAVE DEVELOPED TO ALLOW US TO
EXTRACT MULTI-OHMIC
INFORMATION, TRANSCRIPTOMICS
EPIGENETIC ETC. WITH LESS THAN
HALF AN ML OF BLOOD, AND
UNDERSTANDING VACCINE INDUCED
CHANGES IN CELLULAR AND
MOLECULAR SIGNATURES.
AND MOST IMPORTANTLY WHETHER
THOSE EARLY EVENTS AFTER THE
VACCINE, AS MEASURED BY SYSTEMS
BIOLOGY, CORRELATE WITH
SOMETHING WE CARE ABOUT
CLINICALLY LIKE A PROTECTIVE
IMMUNE RESPONSE, AN ANTIBODY T
CELL OR OTHER IMMUNE
CORRELATIVE PROTECTION.
THAT IS A POWERFUL EXERCISE
BUT IT IS A HYPOTHESIS
GENERATING EXERCISE. IT IS AN
ASSOCIATION. WITHIN TRY TO GET
INSIGHT INTO MECHANISMS OF
ACTION IN DISTINCT POPULATIONS,
USING OUR HUMAN IN VITRO
MODELING, A PARTICULAR STRENGTH
OF OUR PROGRAM.
WE HAVE A RANGE OF HUMAN IN
VITRO PLATFORMS APPROXIMATELY
EIGHT OF THEM AS SIMPLE AS
WHOLE BLOOD ASSAYS TO MORE
SOPHISTICATED TISSUE-ENGINEERED
PLATFORMS, AND A NUMBER OF
FACULTY THAT DEVELOPED THESE.
THESE INDIVIDUAL SYSTEMS ARE
BASED ON HUMAN BLOOD DRAWS FROM
DIVERSE POPULATIONS. WE CAN
MODEL INFANT IMMUNE RESPONSES,
ELDER AND IMMUNOCOMPROMISED
COMORBID AND ADAPTATION TO
ADJUVANT AND ADJUVANT VACCINES
MANY TIMES CORRESPONDING TO
DIFFERENCES THAT HAVE BEEN
SHOWN IN VIVO.
SO THIS IN VITRO SYSTEM IS
VERY POWERFUL AND ALLOWS US TO
BENCHMARK NOVEL AGENTS, TO
LICENSE OR APPROVE VACCINES
THEREBY CONTEXTUALIZING THE
INFORMATION WE GENERATE AND
ALLOWING US TO SELECT LEADS
TARGETED TO A PARTICULAR
VULNERABLE POPULATION. AND THEN
CLOSE THE CYCLE OF INNOVATION
BY SELECTING APPROPRIATE ANIMAL
MODELS.
OF COURSE ADJUVANTS ARE
MOLECULES THAT BOOST AN IMMUNE
RESPONSE COMING FROM THE LACK
OF ADJUVAR TO HELP OR AID IN
THE TOP DEPICTION AND ANTIGEN
IN BLACK IS A TRIANGLE GIVEN
ALONE AND YOU CAN GET MODEST
ACTIVATION OF ANTIGEN PRESENT
CELLS AND MODEST IMMUNE
RESPONSES THAT WANE RAPIDLY,
REQUIRING RAPIDLY MULTIPLE
BOOSTER DOSES.
IN THE BOTTOM PICTURE THE
ADJUVANT IS ADDED, FOR EXAMPLE
ANTIGEN PRESENTING CELLS MAY
HAVE MORE PROFOUND ACTIVATION
AS THESE APCS, AND MORE
PROFOUND ACTIVATION OF
LYMPHOCYTES, B CELLS, ETC., AND
GET MORE HIGHER AND DURABLE
IMMUNOGENICITY.
NOW WHILE IT IS WELL KNOWN
THAT ACTIVATING PRRS CAN
ENHANCE NOT JUST INNATE BUT
ADAPTIVE IMMUNE RESPONSE, WHAT
HAS BEEN LESS APPRECIATED IS
THEIRS AND ONTOGENY TO HUMAN
NOTE RECEPTOR RESPONSES IN
OTHER WORDS A TYPE AND PATTERN
OF CYTOKINE PRODUCTION AFTER
STIMULATING. THIS GRAPHIC IS A
DEPICTION OF HER REVIEW THAT I
WROTE IN THE JOURNAL OF
COMMUNITY A FEW YEARS AGO ON
THE Y-AXIS IS THE CYTOKINE
INDUCTION AND THE X AXIS IS THE
INFORMATION FROM LABS ACROSS
THE WORLD SHOWING DIFFERENT
PATTERNS OF IMMUNE ACTIVATION
WITH IMPAIRED TH-1 ONE
RESPONSES AND LATER IN LIFE THE
PHENOMENON ALLUDED TO IS
INFORMATION DISCUSSED IN THIS
CONFERENCE OF LOW-LEVEL TONIC
ACTIVATION OF INNATE IMMUNITY
ASSOCIATED WITH THIS REGULATED
OR IMPAIRED RESPONSE
IMMUNIZATION OR INFECTION.
AND BECAUSE OUR TEAM IS REALLY
INTERESTED IN ADJUVANT
DISCOVERY AND DEVELOPMENT, I
WILL MENTION THE 2018 NIAD
STRATEGIC PLAN FOR RESEARCH ON
VACCINE ADJUVANT WHICH IS
PUBLICLY AVAILABLE. YOU CAN
GOOGLE IT AND IT IS A PDF. YOU
CAN SEE FROM THE COVER ART THAT
IT IS ANTICIPATED THAT ONE
MIGHT HAVE DIFFERENT DISTINCT
VACCINE FORMULATIONS,
ADJUVANTED VACCINE FROM
RELATIONS DEPENDING ON THE
TARGET POPULATION: INFANT,
ELDER, MALE-FEMALE, ETC.
OF COURSE WHEN THE CORONAVIRUS
PANDEMIC BROKE OUT IT WAS
RAPIDLY EVIDENT THAT ELDER
INDIVIDUALS WERE PARTICULARLY
SUSCEPTIBLE, AND ESPECIALLY
ELDERLY MEN, AND THAT BECAME A
FOCUS FOR US TO TRY TO
UNDERSTAND WHAT IS THE
LANDSCAPE OF ADJUVENTATION IN
HUMAN ELDERS AND WHAT IS KNOWN
AND NOT KNOWN?
SO THE RATIONALE FOR THE
VACCINE IN OLDER ADULTS IS THAT
IT CAN ENHANCE RESPONSE TO
VULNERABLE POPULATIONS AND
THERE IS A PLOT OF PROOF OF
CONCEPT INCLUDING YOUNG, THOSE
WITH COMORBIDITY AND OTHERS AND
CAN BROADEN EPITOPE SPECIFICITY
WHEN YOU HAVE VIRAL VARIANTS
SPECIFICALLY.
ADJUVANTED VACCINES AND THOSE
DEMONSTRATE TRANSIT
CIRCUMVENTION OF FEATURES OF
ELDER IMMUNITY ENABLE
GENERATION OF ROBUST
IMMUNOGENICITY.
WHAT IS THE LANDSCAPE? WHAT
ARE CURRENTLY USED VACCINES IN
OLDER ADULTS? MULTIPLE
ADJUVANTS HAVE BEEN INCLUDED.
OLDER ADULTS, ALUM IS THE MOST
COMMONLY USED ADJUVANT AN
EXAMPLE IS THE PNEUMOCOCCAL
CONJUGATE. AN OIL AND WATER
EMOTIONS INCLUDING MF59, THE
FLU VACCINE EFFECTIVE IN ELDERS
IS ADJUVANT WITH MF59. IN FACT
IT'S AUTHORIZATION AND USE
APPROVAL IN THE UNITED STATES
IS BASED ON HIS EFFICACY IN
ELDERS.
ADJUVANTATION SYSTEM OR AS03.
AND TLR AGONISTS ARE USED AND
AUTHORIZED AND APPROVED
VACCINES AND AS01B, WITH THE
SUPPONENT QS21, USED TO PROTECT
ELDERS AGAINST VARICELLA,
ZOSTER.
THE ADJUVENTATION SYSTEM IS
KEY TO THE HIGH ADVOCACY, IT
HAS A 95% VACCINE EFFICACY.
I SAW THE HEADLINES YESTERDAY
OF SENATOR FEINSTEIN WHO
SUFFERED FROM SHINGLES I HOPE
SHE IS RECUPERATING.
I WAS IN THE COMMITTEE THAT
HELPED APPROVE THAT VACCINE IN
TWO DOSES OF THE TLR9
ADJUVANTED VACCINE SHOWED
HIGHER IMMUNOGENICITY IN ELDERS
AND THREE DOSES OF THE
CONVENTIONAL ALUM-ADJUVENATED
VACCINE ON THE BASIS OF THE
EFFICACY DATA THAT WAS
APPROVED.
WE DID A LANDSCAPE ANALYSIS
HERE AT THE POSITION VACCINE
PROGRAM. WHEN I SAY WE, ETSURO
NANISH, A BRILLIANT AND
HARD-WORKING POSITION ON OUR
TEAM AND PARTNER WITH OUR --
WITH THE USE OF ADJUVANT IN
OLDER ADULTS AND AGED ANIMALS
IN GLOBAL LITERATURE. AND WITH
STRUCTURED LITERATURE SEARCHES.
WE FOUND THAT IF YOU LOOK AT
PANEL A, THE GOOD NEWS IS THAT
THERE IS INCREASING INTEREST IN
THIS TOPIC. AS WE GO ACROSS
TIME ON THE X AXIS WE ARE
SEEING MORE PUBLISHED ARTICLES
IN HUMANS AND ANIMALS LOOKING
AT ADJUVANTS FOR AGED
INDIVIDUALS.
AND PANEL B, YOU SEE THAT MOST
STUDIES LOOK AT ONE OR AT MOST
TWO ADJUVANTS. VERY FEW STUDIES
COMPARE MULTIPLE ADJUVANTS.
THAT IS AN ISSUE BECAUSE WE
WANT TO UNDERSTAND HOW THE
ADJUVANTS COMPARED TO EACH
OTHER, ESPECIALLY AS A PIPELINE
OF ADJUVANTS IS GROWING. THAT
IS PART OF THE RATIONALE FOR
THE IN VITRO SYSTEMS AS WELL.
AND THEN IN PANEL C, THE
DIFFERENT ADJUVANTS EVALUATE
WHETHER IT IS ALUM, ETC. AND
YOU CAN SEE THE BREAKDOWN THERE
AND WE ALSO COMPARED ACROSS
PUBLISHED STUDIES TO SHOW THE
NON-ALUM ADJUVANT MAY BE MORE
EFFECTIVE THAN ALUM ADJUVANTS.
AND WE SEE IN PANEL C, ANIMAL
STUDIES AND IN PANELS A AND B
YOU CAN SEE MULTIPLE STUDIES,
THE STUDIES AS STATED ABOVE. IN
THE ANIMAL STUDY AND YOU SEE
THE ADJUVANT MAKES A BIG
DIFFERENCE VERSUS NEOADJUVANT
AND CAN MAKE THE AGED ANIMAL
LOOK LIKE A YOUNG ANIMAL WHEN
YOU ADD AN ADJUVANT. SO A LOT
OF INTERESTING DATA IN THIS
REVIEW ARTICLE BY NANISHI AND
CLINICAL INFECTIOUS DISEASES,
SUPPLEMENT TO THE PRECISION
VACCINES CONFERENCE..
WE PARTNERED WITH TRYING TO
DEFINE WHETHER WE CAN DEVELOP
AN ADJUVANTED VACCINE THAT
COULD WORK WELL IN OLDER LIFE
AND WE PARTNERED WITH -- AND WE
OBTAINED BLOOD FROM ELDER
ADULTS IN THE BOSTON AREA
INCLUDING MY SYNAGOGUE WHO CAME
AT THE HEIGHT OF THE PANDEMIC
AND DONATED BLOOD FOR SCREENS.
THESE WERE INDIVIDUAL 65 YEARS
OF AGE AND OLDER. WE SCREEN IN
VITRO FOR MOLECULES THAT WOULD
BE EFFECTIVE AT ACTIVATING TH-1
TYPE IMMUNITY IMPORTANT FOR
ANTIVIRAL DEFENSE AND WE NOTICE
THE CPG WITH OR WITHOUT ALUM
WAS A SYSTEM THAT PARTICULARLY
ACTIVATED ELDER IMMUNITY IN
VITRO.
THIS ARTICLE WE PUBLISHED IN
SCIENCE TRANSLATIONAL MEDICINE
ABOUT AN ALUM HYDROXIDE, CPG
ADJUVANT AND ENHANCING
PROTECTION BY TWO RECEPTOR-
BINDING VACCINES AND AGED MICE
AND WE ACQUIRED AGED MICE WHICH
ARE EXPENSIVE AND ARE MORE
SUSCEPTIBLE ALSO TO CORONAVIRUS
AND DEMONSTRATED NOT JUST HI
IMMUNOGENICITY OF THE
ADJUVANTED PRODUCT BUT ALSO
PROTECTION.
THIS WORK LED TO AND
CONTRIBUTED TO THE INTELLECTUAL
BASIS FOR THE CORBID (PHONETIC)
VACCINE AUTHORIZED, NOW GIVEN
TO HUNDREDS OF MILLIONS OF
PEOPLE.
THIS IS SOME DATA FROM THAT
ARTICLE. YOU SEEING WITH THE
STAINING YOUNG VERSUS THE AGED
OF THE NODES, THE LYMPH NODES
AND AT THE BOTTOM RIGHT YOU CAN
SEE THE ALUMINUM HYDROXIDE TBD.
YOU SEE THAT IN AGED ANIMAL YOU
CAN GET ROBUST GENERATION OF
GERMINAL CENTERS WHEN YOU ADD
THE FULL ADJUVANT AGENT SYSTEM.
THE ALUM PLUS THE CPG, WHICH
YOU CANNOT GET UNDER THE GPS OR
ALUM CONDITIONS ALONE AND ON
THE RIGHT YOU CAN SEE SOME OF
THE IMMUNE CORRELATES WHETHER
GERMINAL CENTER B CELLS OR
(INDISCERNIBLE) -- AND SEE THE
EFFECT OF THE ADJUVANTATION
SYSTEM IN OTHER WORDS AND
PURPLE WHEN YOU COMBINE THEM
YOU GET THE MOST ROBUST
IMMUNOGENICITY.
ANOTHER THING IS WE WORK WITH
A COMPANY IN THE NOTHINGNESS
CALL THE LITEVAX AND THEY HAVE
A SOFTWARE ADVOCATE DEPICTED
THERE. IT INDUCES TH1
RESPONSES, IT SHOWS SYNERGY
WITH ONLY WATER TO INDUCE
(INDISCERNIBLE) AND ENHANCED
RBD NANO PARTICLE ANTIBODIES
AND TH1 IN T CELLS AND PROTECT
AGED ANIMALS PUBLISHED IN --
MAGAZINE.
WE COMPARED HUNDREDS OF HUMAN
MOLECULES, COUNTER SCREEN
AGAINST ELDER PBNCS TO FIND
MOLECULES THAT WERE
PARTICULARLY EFFECTIVE IN
ACTIVATING VIRAL IMMUNITY AND
BYRON BROOK, HELPED US WITH THE
-- SMALL MOLECULE THAT HAS
GREATER ACTIVITY AGAINST ELDER
NUCLEAR CELLS AND ADULT HUMAN
PBMCS ON THE BOTTOM RIGHT WITH
TNF AS THE READER TO REDISCOVER
THE MARKET PARTICULARLY ACTIVE
IN ELDERS. NOW WE HAVE TO BE
WORKING ON THE MECHANISM OF
ACTION. WHY IS THIS MOLECULE
MORE ACTIVE?
TO CONCLUDE ADJUVANT TATIAN
VACCINES IS A PROMISING
APPROACH AND HAS
IMMUNOGENICITY, DURABILITY AND
PROTECTION. GROWING PIPELINE
OF CANDIDATE ADJUVANTS.
WE THINK OUR COLLABORATORS
AROUND THE GLOBE AND FOR NIA
THE GENEROUS SUPPORT AND YOU
ARE ALL INVITED TO OUR NEXT
PRECISION VACCINES PROGRAM
CONFERENCE IN ROME ON OCTOBER 5
AND 6. I'M HAPPY TO TAKE ANY
QUESTIONS.
>>QUESTIONS?
>>THANKS FOR THE TALK. YOU
GOING TO BE INCORPORATED
PRECLINICAL TESTING ON AGED
MICE AS PART OF YOUR PIPELINE
ROUTINELY?
>>I'M SORRY THE QUESTION IS,
CAN YOU REPEAT THE QUESTION?
>>SURE. WILL YOU BE INCLUDING
PRECLINICAL TESTING OF VACCINES
FOR ADJUVANT CANDIDATES IN AGED
MICE ROUTINELY?
>>I WILL NOT SAY ROUTINELY. I
WOULD SAY DEPENDING ON THE
DECISION WANT TO PROTECT
AGAINST. IF IT IS A DISEASE OF
PARTICULAR HITS ELDERS HARD,
THEN YES WE WOULD INCORPORATE
THAT BUT AN IMPORTANT APPROACH
WE TAKE IS WE FIRST PUT THINGS
INTO THE HUMAN IN VITRO SYSTEM.
SO WE PREFER NOT TO SPEND A LOT
OF TIME ON ANIMAL SYSTEMS IN
VIVO UNTIL WE CONFIRM THE
MOLECULES WE ARE STUDYING ARE
GOING TO BE ACTIVE, NOT JUST
TOWARDS HUMANS BUT ALSO HUMANS
OF THE TARGET POPULATION,
DEPENDING ON THE DISEASE ARE
VACCINE AND WHAT THE TARGET
WOULD BE, WHETHER INFANTS OR
ELDERS, WHETHER SOMEBODY WITH
CANCER OR OTHER COMORBID
CONDITIONS LIKE DIABETES. WE
BELIEVE IN TAILORING IT AND
THEN MOVING THROUGH THE
PIPELINE.
>>THANK YOU.
>>I WOULD ADD THERE IS GREAT
MECHANISTIC DATA PRESENTED
YESTERDAY AND TODAY WE HAVE A
LOT TO LEARN WE DISCOVER A
SMALL MOLECULE LIKE TBP 180
THAT WORKS WELL IN ELDERS WE
WELCOME COLLABORATION TO
UNDERSTAND THE MECHANISM OF
ACTION WHY A GIVEN MOLECULE
MIGHT WORK PARTICULARLY WELL
INACTIVATING INNATE IMMUNE
RESPONSES THROUGH PATTERN
RECOGNITION RECEPTORS IN ELDER,
MONONUCLEAR CELLS. THERE IS A
LOT OF MECHANISTIC WORK AHEAD
OF US AND WE ARE HAPPY TO
PARTNER WITH OTHER LABS TO SORT
THAT OUT.
>>THANK YOU VERY MUCH DOCTOR
LEVY. WE HAVE FIVE MINUTES
BREAK. WE WILL CONTINUE WITH
-- WE HAVE THREE MORE SPEAKERS.
>>THANK YOU DOCTOR LEVY.
>>GOOD AFTERNOON AND THANK YOU
FOR THE INVITATION. YESTERDAY
DURING HIS PRESENTATION I
INTRODUCE THE SUBJECT ON--
IMMUNOLOGICAL RESILIENCE IN
THIS CASE COVID-19.
SO MARK IS NOT HERE BUT THE
INSPIRATION OF THE WORK BEGAN
FROM THE PAPER I WROTE IN 2006,
MOST OF THE ADVANCES CITED
INCORPORATING INTO STANDARD
MEDICAL PRACTICES SPECIALIZED
TO AN EXTENT (INDISCERNIBLE)
YOU MIGHT AND DON'T JUST THROW
YOU OUT BE OFFERED A WHITE CELL
BLOOD COUNT. ASK ABOUT BLOOD
LIPIDS YOU WILL BE GREETED WITH
WARM SMILES, MORALITY TALES
ABOUT GOOD AND BAD CHOLESTEROL,
AND HE GOES ON TO CONCLUDE THAT
ALTHOUGH THE MOUSE MODEL HAS
BEEN SPECTACULARLY SUCCESSFUL
IN ADVANCING OUR UNDERSTANDING
OF BASIC IMMUNOLOGICAL
MECHANISMS THIS RECORD IN
FORMULATING CLINICALLY USEFUL
PROTOCOLS IS MUCH LESS
IMPRESSIVE.
SO WE HAD IN THE MIDDLE
OVERACTIVE AND UNDERACTIVE.
AND WE HAVE THESE MARKERS THAT
ONE COULD POSSIBLY USE TO
DEFINE HEALTH. WE CAME UP WITH
THE CONCEPT OF IMMUNE
RESILIENCE, WHICH WE CATEGORIZE
NOW AS OPTIMAL, SUBOPTIMAL AND
NONOPTIMAL AND HOW WE CAN
MONITOR THEM.
I'M GOING TO DESCRIBE TO YOU
THE CONCEPT OF IMMUNE
RESILIENCE WHICH IS SEXUALLY
DIMORPHIC, MODIFIABLE TRADE
ASSOCIATE WITH SUPERIOR
IMMUNITY DEPENDENT HEALTH
OUTCOMES AND LONGEVITY.
SO THE MODEL SYSTEM AND GOING
TO SHOW YOU IS ABOUT LONGEVITY
BOTH YOUNG FEMALES HAVE
SURVIVAL ADVANTAGE BUT EVEN
AMONG YOUNG PEOPLE THERE IS A
WIDE VARIATION IN THE SURVIVAL
RATES AMONG YOUNG PEOPLE,
BETWEEN 40-66 AND AMONG THEM
THE SURVIVAL RATES ARE
DIFFERENCE.
THIS IS A NUN WHO SURVIVED
COVID, THE OLDEST LIVING PERSON
IN EUROPE AND SHE JUST GOT
COVID. AND UP THE STREET THERE
IS DOCTOR COSTA, CHIEF OF ICU
IN BALTIMORE WHO DIED A YOUNG
INDIVIDUAL AT OUR INSTITUTION.
WHAT ARE THE IMMUNE FEATURES
THAT DETERMINE SUSCEPTIBILITY
RESISTANCE TO DEVELOP
PROGRESSIVE COVID-19 REGARDLESS
OF THE AGE? CAN THESE FEATURES
BE USED FOR PROGNOSTICATION.
NOT JUST IN COVID AND
SARS-COV-2, IT SHOWS THAT 47%
OF YOUNG PEOPLE AND
(INDISCERNIBLE).
ON THE OTHER HAND YOU ALSO
HAVE THE OTHER SPECTRUM WHERE
YOU HAVE LIKE SARS, PEOPLE GET
EXPOSED BUT NOT INFECTED. HERE
IS A WOMAN WHO HAS HAD
UNPROTECTED SEX WITH UP TO 2000
INFECTED MEN, AND REMAINS HIV
UNINFECTED. YOU HAVE SIMILAR
EXAMPLES OF OTHER VIRUSES WHICH
EVEN INSTEAD YOU PEOPLE BETWEEN
30-50% OF PEOPLE WHO EITHER
HAVE SEASONAL INFECTION OR
REMAIN UNAFFECTED OR A
SYMPTOMATIC.
SO MY VIEW IS THAT THERE ARE
INFLAMMATORY STRESSES THAT WE
EXPERIENCE, ALONG OTHER
CHALLENGES LIKE AGING, AND WE
CONVERT THAT TO LOW IMMUNO
COMPETENCE HIGH INFLAMMATION
STAGE, AND YOU SEE SOME
ABBREVIATIONS LIKE THAT.
THERE ARE INDIVIDUALS THAT
PRESERVE OR RAPIDLY RESTORE
HIGH IMMUNOCOMPETENT, LOW
INFLAMMATION STAGE AND I
DEFINED THIS AS OPTIMAL IMMUNE
RESILIENCE. AND I WILL SHOW YOU
THIS IS MORE IN FEMALES THAN IN
MALES WITH ASSOCIATED LONGER
LIFESPAN.
THIS IS AN UPCOMING PAPER THAT
SHOULD APPEAR PROBABLY IN ABOUT
TWO WEEKS FROM NOW. THE TITLE
IS IMMUNE RESILIENCY DESPITE
INFLAMMATORY STRESS PROMOTES
LONGEVITY AND FAVORABLE HEALTH
OUTCOMES INCLUDING RESISTANCE
TO INFECTION.
WE ALL KNOW THAT SOME PEOPLE
REMAIN HEALTHY THROUGHOUT LIFE
THAN OTHERS BUT WE DON'T REALLY
KNOW WHY. WE HYPOTHESIZE THE
DISADVANTAGES ATTRIBUTABLE IN
PART TO OPTIMAL IMMUNE
RESILIENCY DEFINED AS THE
CAPACITY TO PRESERVE AND
RAPIDLY RESTORE IMMUNE
FUNCTIONS THAT PROMOTE DISEASE
RESISTANCE I.E. IMMUNO
COMPETENCY AND CONTROL
INFLAMMATION, AND INFECTION
DISEASES AS WELL AS OTHER
CAUSES OF INFLAMMATORY STRESS.
OPTIMAL IR IS HIGH IMMUNO
COMPETENCY. WHAT WE ARE
INTERESTED TO UNDERSTAND IS
WHEN A PERSON EXPERIENCES
INFLAMMATORY STRESS, HI
INFORMATION HERE, AND THEN
DURING THE REPAIR PROCESS IT
GOES TO SOME SORT OF BASELINE
AND CURRENTLY THERE IS A DROP
IN IMMUNO COMPETENCY, AND THEN
HE GOES BACK TO SOME BASELINE.
HOWEVER DURING AN ACUTE
CHRONIC OR DURING AGING
OTHERWISE WE EXPERIENCE
MULTIPLE BOUTS OF THIS UP AND
DOWN CYCLE THAT I SHOWED YOU
HERE. SOME PEOPLE RESIST ANY
CHANGE. THOSE ARE THE ONES WHO
HAVE OPTIMAL IR, COMPARED TO
THOSE WHO HAVE A GRADUAL
INCREASE OR DEGRADATION FROM
THE STATE TO THE STATE VERSUS
THOSE WHO ARE IN THE EXTREME
STATE CALLED NONOPTIMAL. THOSE
WHO ARE HERE HAVE BETTER
COMMUNITY DEPENDENT MODELS.
THE CONCEPT IS WE
EXPRESS A LOT OF
(INDISCERNIBLE). DEPENDING
ON WHETHER WE REMAIN IN OPTIMAL
STATE OR SHIFT TO SUBOPTIMAL
AND AN OPTIMAL AND WITH THE
ADJUVANT STIMULATION EVAPORATES
IT CAN GO BACK TO THE STATE NOT
ALWAYS BUT IN MANY CASES.
AND IN THIS CASE, THIS IS
MOST COMMON IN FEMALES
ASSOCIATED WITH HIGH IMMUNO
CONFIDENCE LOW INFLAMMATION AND
SOME PEOPLE RESIST THIS
DEPRIVATION, AND THERE ARE
PEOPLE WHO ARE SUSCEPTIBLE.
WE DEVELOP MARKERS WHICH I
WILL DESCRIBE TO YOU ASSOCIATED
WITH OPTIMAL IR, IMMUNE HEALTH
GRADES AND SURVIVAL ARE
ASSOCIATED GENE SIGNATURES. WE
APPLY THEM SO THE SEVERAL
COHORT, ASSOCIATED WITH THESE
KINDS OF OUTCOMES AND WE
STARTED OVER 50,000 PEOPLE,
NONHUMAN PRIMATES AND MICE,
THAT WILL DESCRIBE THE STUDY TO
YOU.
WE DEVELOPED TWO METRICS ONE
IS WHAT WE CALL IMMUNE HEALTH
GATES DEFINED WITH THE CD8 CD4
PROFILE AND WE DEVELOP
TRANSCRIPTOMIC PROFILES AS WELL
AS ASSOCIATED MORTALITIES.
IN A LARGE STUDY IN IMMUNO
MEDICINE WE ESTABLISH THE
MEDIAN CD4 CONFIDENCE ABOUT
50,000 HIV-INFECTED WHICH IS
ABOUT 800, AND THEN WE USE THE
CD4 CD8 RATIO. GREAT ONE IS
THE BEST FOR PEOPLE HAVE BOTH
OF THESE CONDITIONS AND IS
ASSOCIATED WITH RESTRAINT CD8
CELLS WITH HIGHER LEVELS OF CD4
COUNTS.
OF THE OTHER HAND YOU HAVE
PEOPLE WITH LOWER CD4 COUNTS
BUT A HIGH RATIO WITH RESTRAINT
CD8 BUT LOWER CD4 COUNT AND ON
THE OTHER HAND YOU HAVE
INDIVIDUALS THAT HAVE AN
INVERTED PATIENT WITH HIGH
CD4S, INDIVIDUALS WITH CD8
EXPANSION, AND THOSE WITH
NEITHER WITH HIGH CDH AND LOW
CD 4 COUNTS.
THESE ARE ABOUT 3000 PEOPLE WE
HERE AT THE BOTTOM. SO THIS
GROUP OF PEOPLE WITH GRADE 1,
YOU CAN SEE HERE THEY HAVE 1100
CD4 CELLS; THIS GROUP GRADE III
HAS 900 CD4 CELLS, THIS IS
ASSOCIATED WITH LOWER CD8
COUNTS, AND THIS IS ASSOCIATED
WITH NEARLY TWICE THE AMOUNT.
AND THIS GROUP IN GRADE II AND
GRADE IV, THIS IS ASSOCIATED
WITH CDC EXPANSION COMPARED
THIS GROUP.
SO WE ARE GOING TO USE -- TO
DERIVE THESE GRADES. THIS IS
ABOUT 3000 PEOPLE FROM STARTING
A COHORT AGE 15 TO 90+ GREEN IS
GRADE III, BLACK IS GRADE IV.
THIS IS A GROUP OF YOUNG
INDIVIDUALS WHO HAD A
SUSCEPTIBILITY TO DEGRADE THE
IR, COMPARED TO THIS GROUP OF
PEOPLE WHO ARE OVER WHO DESPITE
THE ADVANCED STAGE MANAGED TO
PRESERVE IHG-1.
HERE YOU SEE THAT MORE FEMALES
THAN MALES PRESERVE THE BLUE
COLOR. WITHIN EACH AGE GROUP
YOU CAN SEE THERE IS THIS LEVEL
OF HETEROGENEITY, SO THE GRADES
THAT I WILL SHOW YOU IN A
MINUTE DIFFERENCE BY AGE OR
SOME OLDER PEOPLE ALSO HAVE
RESISTING IHD DEGRADATION.
I'M GOING TO USE THESE PROXIES
HERE FOR IMMUNOGENIC LOAD. THE
OTHER HERE ARE CHILDREN WHO ARE
FIVE YEARS OLD LOOKING AT --
AND THE AMOUNT OF -- COUNTS IN
THE URINE FROM 99 TO MORE THAN
500, PROGRESSIVE DEGRADATION IN
THE IR, HAVING GRADE IV.
HERE ARE THE SAME SEX WORKERS
FROM NAIROBI. YOU CAN SEE THE
SEX ACTIVITY AND THERE IS A
DECREASE IN PROPORTION AND BLUE
OR THE (INDISCERNIBLE).
THIS IS HIV-POSITIVE PEOPLE.
THE CAPACITY AT THE PRESERVE--
THE CLIENT AND THESE ARE AN
ELITE GROUP OF PEOPLE WHO WERE
THERAPY NAïVE WHO HAVE
LONG-TERM NON-PROGRESSION,
CONTINUES TO CONTROL THE VIRUS.
YOU CAN SEE THE PRESERVE A
FAIR AMOUNT OF (INDISCERNIBLE).
SO WE USED COVID IS AN
EXPERIMENT TO TEST THE CONCEPT
OF IR, BECAUSE WE COULD MONITOR
OF PATIENTS DAILY WITH HIS
GRADES. WE STARTED OVER 90,000
MEASURES OF BIOMARKERS. WILL
FOLLOW PEOPLE FROM THEIR
PRESENTATION TO MORE THAN 2.5
YEARS, AGE AND SEX MATCHED
THEM AND CONTROL THE EFFECTS OF
(INDISCERNIBLE), AND COMPARED
TO OTHER CONDITIONS SO WE HAVE
A LOT OF OUTCOMES WE COULD
EXAMINE. WE HAD A STANDARD OF
CARE PANEL OF SOME 7 OR 8
BIOMARKERS THAT WE EVALUATED
IN OUR PATIENTS EVERY DAY AND
THEN WE HAVE VIRAL LOAD IN GENE
EXPRESSION. WE ALSO DEVELOPED
A VACCINE COHORT.
THE BASIC THESIS IS THIS.
THIS IS A GROUP OF PEOPLE
NORMALLY PRESENT IN THE HUMAN
POPULATION, BLUE BEING GREAT
ONE, BROWN TWO, GREEN 3, BLACK
4.
THERE WILL BE PEOPLE WHO GO
FROM GRADE 1 TO GRADE 1 AND
THEY WILL DO WELL IN THOSE FROM
GRADE 1 TO BROWN OR 4 DO WORSE
AND GROUP 2 TO WORSE 4, ARE THE
ONES WHO DO WORSE.
TO QUANTIFY THIS BEFORE WE
SECULARIZE THIS GRADE 2 AND
GRADE 4 BASED ON THE CD4
COUNTS, WE HAVE
(INDISCERNIBLE), AND GRADE 4
SIMILAR FASHION.
AND THIS IS THE VACCINE
CONTROL COHORT. NOTED THAT 56%
OVER HERE. NONE OF THE PEOPLE
HAVE LESS THAN 200 HERE. THESE
ARE SOME OF THE OTHER CONTROL
COHORTS, WHEN PEOPLE GET COVID
THERE IS A MARKED SHIFT IN THE
DECLINE, AND A MASSIVE SHIFT
BETWEEN GRADES 2 C AND 4 C, AND
UPON RECOVERY THIS GOES AWAY.
IF YOU COMPARE IT TO ACUTE HIV,
BASICALLY YOU CAN SEE THAT
LESSON 200 IN THE GRADE 2 C
CATEGORY IN HIV-POSITIVE
PEOPLE, ALL APPEAR IN THE GRADE
4 CATEGORY AND FOUND THAT
APPROXIMATELY 18% OF COVID
PATIENT PRESENTED WITH AN ACUTE
AIDS LIKE DEFICIENCY, SAME
POLYMORPHISM PROGNOSTIC AND
ASSOCIATED WITH A STRONG RISK
FOR DEVELOPING SEVERE COVID.
SO BASICALLY IN SUMMARY OF OUR
WORK WE FOUND THAT THOSE WHO
PRESENT GRADE 1, WHICH IS ABOUT
21% COMPARED TO THOSE WHO ARE
AGING ARE THE ELITE GROUP
COMPARED TO THE VULNERABLE
GROUP. THIS IS OPTIMAL IR VS.
NONOPTIMAL IR. THESE PEOPLE
HAVE THE SAME BUT THE REVERSE
AS WELL AS LOW NK SALES AND
INCREASED CRP AND -
ANTIBODIES-, WHEN WE LOOK BACK
AT THIS INDIVIDUAL WILL FIND
THAT INDIVIDUALS WHO CAME WITH
GOOD GRADES AFTER CONTROLLING
FOR AGE A LOWER PRE-EXISTING
COMORBIDITY COMPARED TO THIS
GROUP OF PEOPLE WITH HIGH
LEVELS OF PRE-EXISTING
COMORBIDITY. AND THIS PEOPLE
HAD GOOD OUTCOMES DURING ACUTE
AND POSTACUTE SEQUELAE, WHETHER
THESE PEOPLE HAD BETTER
OUTCOMES. BASICALLY IT TAKES
NEARLY 7 YEARS FOR PEOPLE TO
DEVELOP A LEVEL OF CD4 FOUND
THE PRESENTATION WITH COVID.
COVID IS HIGHLY
IMMUNOSUPPRESSIVE.
AND WE LOOK AT PEOPLE THAT
HAVE HIGH OR LOW COMORBIDITY WE
FIND A RESTRICTION OF
(INDISCERNIBLE), WHEREAS THOSE
WHO COME WITH HIGH
COMORBIDITIES AGAIN WITH THE
ELITE -- RESTRICTIVE AMOUNT OF
INFLAMMATION THAN PEOPLE COMING
WITH THE BAD VULNERABLE TRADE.
WE LOOK ACROSS AGE WE FOUND,
EVEN THOUGH THERE ARE CHANGES
OF AIDS ALWAYS THERE IS A GROUP
OF PEOPLE WHO MANAGED TO
PRESERVE GRADE 1 WILL DO THE
BEST.
AS AN EXAMPLE HERE IS THE
OVERALL COHORT. THERE IS A
SEXUAL DIMORPHISM THAT
REAPPEARS HERE; PEOPLE WHO ARE
NOT HOSPITALIZED IN GRADE 1
COMPARED TO THE REST OF THE
GROUPS THAT SURVIVOR WHO WERE
HOSPITALIZED, NOT SURVIVORS.
EVEN THOUGH THE RATE OF
HOSPITALIZATION INCREASES OF
RAGE, 35% IN THE 21-39 GROUP
AND 86% IN THE AGE 70 GROUP WE
FOUND THAT EACH GROUP -- YOU
CAN SEE MORE BLUE LESS BLUE,
MORE AND LESS.
ACROSS AGE GRADE ONE IS THE
BEST IN THIS IS A 30-YEAR-OLD
WITH -- PROBABILITY OF BEING
HOSPITALIZED ACROSS THE AGENT
DOES NOT MATTER.
SO THOSE ARE THE
(INDISCERNIBLE). YOU CAN
MEASURE WHATEVER YOU FEEL LIKE
IN THIS GROUP OF PEOPLE. THEY
ARE INDEPENDENT OF AGE, SEX,
BIOMARKER PROFILES.
THIS IS A PATTERN WHICH YOU
WILL FIND OF THE NON- IHG ONE
GREAT IT WHEN THE NORMAL
CONTROL POPULATION AND MORE
MALES PRESERVE THIS, NON-IHG
COMPARED THE FUMES AND THIS IS
SHIFTED LEFTWARDS FOR PEOPLE
WITH ACUTE COVID.
BIOMARKERS CAN GO UP WITH AGE
BUT THERE WILL LEAVE THIS GROUP
OF PEOPLE. THIS IS WHAT MY
MOOD LOOKS LIKE WHEN I WAS
MONITORING PATIENTS EVERY DAY
WITH THE GRADES. THE
NEUTRALIZING ANTIVIRAL TITERS
ACROSS PEOPLE OVER A PERIOD OF
TIME AND PEOPLE WHO PRESERVE
THE BEST GRADE IN THE STUDY
ABOUT THOSE WHO HAD GOOD
GRADES.
WHEN WE IDENTIFIED A CORE SET
OF SIGNATURES THAT -- AS WELL
AS HOSPITALIZATION, ETC.,
RELATED TO B CELLS AS WELL AS
TO (INDISCERNIBLE).
IMPORTANT TO RECOGNIZE THAT
THE IMMUNE TRAITS ASSOCIATED
ARE CONTEXT DEPENDENT. THIS IS
4000 PEOPLE WITH
IMMUNOPHENOTYPE. WE CAN
CATEGORIZE THE IMMUNE TRADES
THAT CATEGORIZE ONLY TO THOSE
GRADES, ONLY TO AGE, RATES IN
NATURE NEITHER. I DON'T HAVE
TIME TO GO THROUGH THIS.
THE FINAL THING I WANT TO GO
THROUGH, AS WOMEN INCREASE
THEIR SEX ACTIVITY THE
PROPORTION OF BLUE GOES DOWN.
MOST OF THE RISK OF ACQUISITION
APPEARS IN THIS GROUP. WHEN
WOMEN STOP HAVING SEX, OR STOP
USING CONDOMS YOU CONSIDER OVER
TIME THEY ARE BACK TO NORMAL
AND EVEN AMONG PEOPLE WITH
AIDS, ALSO PRESERVE THE BEST
GRADE (INDISCERNIBLE).
WE IDENTIFIED A CORE SET OF
GENE SIGNATURES ASSOCIATED WITH
SECURITY IN THE COVID COHORT,
ASSOCIATED WITH HIGHER
EXPRESSION AND ASSOCIATIVE
MORTALITY AND THIS IS
ASSOCIATED WITH ASSOCIATIVE
SURVIVAL AND WE OVERLAID THIS
ON TOP OF THE FRAMINGHAM
COHORT, WE IDENTIFIED SOME
SIGNATURES COMMON TO BOTH SO
THIS RECORD SIGNATURE MEANS
ONLY PRESENT IN THE COVID
COHORT BUT THE SIGNATURES IN
GREEN OVER HERE FOR EXAMPLE,
HIGHER EXPRESSION OF THE
DEFENSE RESPONSE, BACTERIUM
SIGNATURE ASSOCIATED WITH
MORTALITY BOTH IN THE COVID
COHORT AND IN THE FARMING HAVE
COHORT AND PRE-IMMUNIZATION
RECEPTORS, HIGHER EXPRESSION
ASSOCIATED WITH SURVIVAL.
WE DEVELOPED THESE FINISHES
REMAIN ASSOCIATIVE SIGNATURES
ONE BY MARK DAVIS GROUP IN
ANOTHER RECENT IS SENMAYO AND
ANOTHER IS ESSENTIALLY JUST
CAME OUT FROM THE HARVARD GROUP
AND THE SIGNATURES BASICALLY--
HERE IS A LONGEVITY SIGNATURE
FROM THE HARVARD IMMUNE ASSAY.
YOU CAN SEE THE MAS-1 CLUSTER
HERE AND THE (INDISCERNIBLE).
IF YOU HAVE HIGH IMMUNO
COMPETENCY SIGNATURE WOULD
LOWER INFORMATION PEOPLE LIVE
LONGER. THOSE WHO ARE
(INDISCERNIBLE) DIE QUICKLY.
PEOPLE WHO HAVE THEIR DOUBLE
GRADE, HI IMMUNO CONFIDENCE AND
NO INFORMATION PROFILE ARE THE
PEOPLE WHO GOT GREAT ONE. THIS
IS A CORE FROM SLE THIS IS
FROPM ACUTE COVID-19.
AS LONG AS THEY HAVE GREAT ONE
THEY HAD ENRICHED SURVIVAL
PROFILE. THE MORTALITY PROFILE
SIGNATURE (INDISCERNIBLE).
THE QUESTION ARISES, DOES IT
HAVE ANYTHING TO DO WITH
INFLUENZA? THIS IS A COHORT OF
NATURAL SEASONAL INFECTION AND
THIS IS A SAMPLE OF BLOOD A FEW
MONTHS BEFORE THEY HAD THE
SEASONAL FLU. AND THEN THEY
ZERO, 2, 6, 6, 21 DAYS. AND
YOU CAN SEE IS THAT NEARLY ALL
PEOPLE WHO DEVELOP ACUTE AND
YOU CAN SEE IS THAT NEARLY ALL
PEOPLE WHO DEVELOP ACUTE
RESPIRATORY INFECTION DURING
THE NATURAL SEASON ALL
DEVELOPED AS MORTALITY PROFILE
OVER TIME THEY WERE CONSTITUTED
(INDISCERNIBLE).
PEOPLE WHO WERE MORE
SYMPTOMATIC WE EXAMINED THE
GENE PROFILE HERE AND HERE.
THOSE WHO BECAME SYSTEMATIC
TURN ON THE MORTALITY PROFILE
AND THEY CAN SEE THE YELLOW
FROM HERE TO HERE AND THOSE WHO
ARE ASYMPTOMATIC YOU CAN SEE
THE INCREASE THE AMOUNT OF
BLUE, SO THEY REMAIN A
SYSTEMATIC SO THE SURVIVAL
PROFILE (INDISCERNIBLE) THIS IS
PURE INFLUENZA CHALLENGE COHORT.
YOU CAN SEE THAT THOSE WHO
WORK SYSTEMATIC ALL WERE IN THE
YELLOW AND THOSE WHO WERE
ASYMPTOMATIC WERE IN BLUE.
I DESCRIBED TO YOU A
MONITORING SYSTEM TO MEASURE
THE IMMUNOLOGICAL RESILIENCY OF
PEOPLE IN HERE OF PEOPLE DURING
40-50, YOU CAN SEE THIS GROUP
OF PEOPLE HERE SOME OF THEM,
25%, IN1 AND 45% ARE IN BLUE.
HE IS THE NUMBER GOES UP AND
YOU CAN SEE THE HETEROGENEITY
GO UP.
SO WHAT I WANT TO DESCRIBE
WITH YOU IS A PROCESS FOR
IMPLANTING STRESS UPPERS IN
VARIOUS CONDITIONS AND THOSE
WHO MANAGED TO PRESERVE THE
SUBOPTIMAL IR, BETTER IN MALES
AND FEMALES IN THIS IS
ASSOCIATED WITH GOOD OUTCOMES.
I WAS ASKED TO SAY SOMETHING
ABOUT CHALLENGES. THE FIRST
CHALLENGE OF COURSES ARE THERE
DISTINCT FORMS OF
IMMUNOSENESCENCE? WHAT IS AN
FROM TORY STRESS ASSOCIATED AGE
INDEPENDENT IMMUNOSENESCENCE.
AND THE OTHERS CHRONOLOGICALLY
IS DEPENDENT IMMUNOSENESENCE.
RESEARCH CHALLENGES IS THERE A
WAY TO RECONSTITUTE THE
RESILIENCE? THIS IS SOME OF THE
PEOPLE WHO DID THE WORK. VERY
BIG TEAM, NATHAN AND JUSTIN THE
BIOINFORMATICS AND I THANK YOU
VERY MUCH.
>>
WE CAN HAVE A VERY SHORT
QUESTION/ANSWER. >>>>WHAT
HAPPENS IN TERMS OF
(INDISCERNIBLE)?
I WANT TO START WITH THE
PARADOX. IT HAS BEEN KNOWN FOR
QUITE SOME TIME, MAYBE 10 YEARS
OR SO, THAT T-CELLS ARE LESS
RESPONSIVE TO (INDISCERNIBLE).
A NUMBER OF DIFFERENT REASONS.
ONE IS A HAVE IMPAIRED
(INDISCERNIBLE), YOU CAN SEE IN
THE UPPER -- IT ACHIEVES
(INDISCERNIBLE) --
-- YOU WOULD EXPECT THE MEMORY
T-CELLS TO (INDISCERNIBLE).
IF YOU LOOK AT THE
CONSCRIPTION FACTOR, WE STARTED
THIS ABOUT FIVE YEARS AGO, AT
THE PEAK OF THE T-CELL
RESPONSE, THE PROFILE OF -- NOT
SURE WHY -- THE LOW EXPRESSION
OF THE -- YOU HAVE THE
PHENOTYPE OF THE RECEPTOR CELL
IN SPITE OF THE TCR. IT WAS
INTERESTING CAN YOU ACTUALLY
GET ACUTE RECEPTOR STIMULATION
WITH THE ABDOMINAL EFFECT OF
THE PHENOTYPE. AND IT PEAKED
IN THE FIRST 48 HOURS, IT
COMBINED WITH THE-- AND HERE IS
THE DATA AND THE
(INDISCERNIBLE).
WHAT THAT MEANS IS ESSENTIALLY
WE TRIED TO IDENTIFY ALL SITES
THAT ARE DIFFERENTIALLY -- --
CLASS THEM INTO A TIME KLUSTER,
ARRANGED AST C1 THROUGH C6.
THIS IS A (INDISCERNIBLE) THIS
PARTICULAR CLUSTER. BOTH THE
OLD AND YOUNG LOOK SIMILAR. IN
SPITE OF THE TCR ADULATION THE
OLDER -- HAS (INDISCERNIBLE) --
SO NOT FRAIL PEOPLE. THERE ARE
TINY DIFFERENCES. THERE IS
ONLY ONE CLUSTER WHICH APPEARS
TO BE IN YOUNG PEOPLE; DOES NOT
APPEAR TO BE IN OLDER PEOPLE.
THERE ARE SUBTLE CHANGES. IF
YOU LOOK AT THE DIFFERENT
MOTIFFS THROUGHOUT THE
ACTIVATION, YOU SEE THAT -- YOU
SEE THAT THERE ARE A NUMBER OF
DIFFERENT MOTIFFS THAT ARE
GETTING MORE ACCESSIBILITY.
CERTAINLY NOT THE CASE WHERE
YOU HAVE INCREASED MOTIF EXPECT
ABILITY IN THE YOUNG. A MOTIF
HERE IS RED OR BROWN COLOR AND
INTERMEDIATE IS YELLOW,
NON-ACCESSIBLE IS BLUE-COLLAR.
YOU SEE THAT PRETTY MUCH ALL
CHROMATIN OPENING HAPPENING IS
MORE PRONOUNCED IN OLDER
INDIVIDUALS.
SO IF YOU SEE ALL DIFFERENT
(INDISCERNIBLE), YOU HAVE A
FOCUS ON THE SLIDE THAT IS
DIFFERENTIALLY ACCESSIBLE
BETWEEN YOUNG AND OLD. YOU
ESSENTIALLY GET THE SAME STORY.
THIS IS PASSED IN 10 DIFFERENT
CLUSTERS. YOU CAN SEE THE
OPENING ACTIVATION. THE PLUS
AND DOWN, CLOSING ACTIVATION.
YOU SEE THE YOUNG PEOPLE ON THE
LEFT SIDE, DIFFERENT TIME
POINT, OPENING LEFT
(INDISCERNIBLE).
IN PARTICULAR FOR THE SECOND
CLUSTER, WHICH CONSTRICTION
MOTIFFS ARE NOT IN THIS
PARTICULAR CLUSTER, ARE STATED
ON THE LEFT SIDE.
YOU SEE THE ATF3 AND STAT,
MORE ACCESSIBLE IN OLD AGE.
YOU CAN CONFIRM IF YOU FOLLOW
IT UP WITH EXPRESSION DATA. WE
FOCUS ON THIS PARTICULAR
CLUSTER TOOL. AND LOOKED AT
THE DIFFERENT COMPONENTS AND
THE AVERAGE INCLUDED STAT5 OR
NPHGS, WE USE TWO DIFFERENT
LEVELS OF ACCUMULATION, LAW
ACCUMULATION, HIGH
RECOMMENDATION YOU SEE YOUNG
PEOPLE ON THE LEFT SIDE AND THE
OLDER PEOPLE IN THE RIGHT.
IF YOU LOOK AT THE RIGHT LOWER
CORNER, INHIBITED STAT 5
PHOSPHORYLATION, WE CAN
INCREASE IN (INDISCERNIBLE).
IF YOU FOLLOW THAT UP,
FOCUSING ON A FEW -- WITHIN THE
FIRST 24 HOURS, LOOKING AT
FEWER TRANSCRIPTION FACTOR
MOTIFFS THE UPPER ONE SHOW GENE
EXPRESSION IN THE LOW IS THE
STABILITY, (INDISCERNIBLE) MORE
ACCESSIBLE THE LAST CLUSTER.
IF YOU LOOK AT THE YOUNG SIDE
AGAIN YOU HAVE LESS EXPRESSION.
LESS ACCESSIBILITY
(INDISCERNIBLE).
PRDM1 -- FACTORS OF
DIFFERENTIATION. YOU CAN SEE
THE INFORMATION (INDISCERNIBLE)
-- AND IN ONE CLUSTER. AND
ACCESSIBILITY IS EVEN MORE,
MUCH MORE EVIDENT EARLY IN THE
T-CELL ACTIVATION CLUSTER.
THIS SUMMARIZES WHAT I
MENTIONED.
YOU HAVE REDUCED --
PHOSPHORYLATION -- THE
PHOSPHORYLATION FACTOR IS
(INDISCERNIBLE). YOU CAN HAVE
OLDER NAïVE, YOU HAVE THE
EQUATION OF TWO RECEPTORS IN
THE REASON FOR THIS EXPRESSION
IS A LOTS OF DIFFERENT
(INDISCERNIBLE) AND IT HAS A
TRANSCRIPTION FACTOR DOMINATED
BY BATF AND IRF4. DIMINISHED
AND TRANSCRIPTION FACTORS LIKE
TCF 1 AND BACH2 IMPORTANT FOR
MEMORY DIFFERENTIATION.
T-CELLS IN OLDER DIFFERENTIATE
INTO -- CELLS, FAILURE TO
DIFFERENTIATE (INDISCERNIBLE).
I THINK I MENTIONED ALREADY IN
THE INITIAL SLIDE, THE FINAL
TRANSCRIPTION FACTORS. IT IS
ALSO IMPORTANT FOR MEMORY
DIFFERENTIATION. FOX01.
IS SLIGHTLY DIFFERENT TERMS OF
THE MECHANISM. FOX01 RAPIDLY
DEGRADES AFTER ACTIVATION.
ESSENTIALLY WITHIN 2-3 DAYS.
IT IS REALLY UNDETECTABLE. AND
THEN IT SLOWLY RECOVERS,
RECOVERS MORE IN YOUNG THAN IN
OLD PEOPLE. YOUNG PEOPLE ARE
MORE RESILIENT IF YOU THINK OF
THE LAST TALK.
THE REASON FOR THIS ONE IS
SUSTAINED (INDISCERNIBLE) AND
-- ACTIVATION ALSO
(INDISCERNIBLE) AND THEN IT'S
DEGRADED.
ONE OF THE INTERESTING PARTS
OF FOX01 IS IT EVENTUALLY
IMPAIRS LYSOSOMAL BIOGENESIS.
IN THE ABSENCE OF FOX01 YOU
CANNOT GENERATE NEW ISOZYMES.
A NUMBER OF DIFFERENT
TRANSCRIPTION FACTORS
(INDISCERNIBLE), MANY OF THE
ENZYMES THAT ARE IN LYSOSOME --
IN THE ABSENCE OF FOX01 YOU
HAVE REDUCED EXPRESSION. AND
YOU CAN SEE ON THE LEFT SIDE,
YOU CAN SEE YOUNG AND OLD, OLD
IN BLUE, YOUNG IN RED, THE
EXPRESSION OF THESE ENZYMES IS
DECREASED. ALL LYSOSOME GENES
DISAPPEAR-- YOU SEE THAT PRETTY
MUCH THE EXPRESSION OF LYSOSOME
GENES (INDISCERNIBLE).
LYSOSOMES-- BASED ON -- IF YOU
FOUND A CERTAIN MECHANISM OF
HOW ACTUALLY LYSOSOMES GENESIS
HOW IT IS AFFECTED, THIS HAS TO
DO WITH TCF1, REDUCED
EXPRESSION IN OLDER INDIVIDUALS
AND TCF1 WE HAVE TRANSCRIPTION
FACTOR, IT IS VERY MUCH CONTEXT
DEPENDENT. MANY GENES ARE
REPRESSED BY TCF1
(INDISCERNIBLE), AS YOU CAN SEE
HERE IN THE PLOT, WHICH
COMPARES TCF1 POSITIVE COMPARED
TO NEGATIVE. TCF1 INDUCES THE
CELL (INDISCERNIBLE) --
CONSCRIPTION FACTOR IS IN 1 --
ESSENTIALLY REPRESSED BY
T-CELLS (INDISCERNIBLE).
WE WERE INTERESTED IN ONE
PARTICULAR GENE CALLED
(INDISCERNIBLE) ALSO THE FIRST
TCF1.
YOU CAN SEE ON THE RIGHT SIDE,
IF YOU SILENCED TCF1, IT'S
ABOUT 50% REGULATION ENDED UP
REGULATES AND YOU GET HERE.
THE ULTIMATE EXPRESSION IS THAT
IT INCREASES.
-- IS ONE OF THE DOMINANT
GENE THAT CAME UP, ESSENTIAL IN
THE FIRST SET AND ON THE LEFT
SIDE YOU SEE THE PLOT OF GENES
THAT ARE DOMINANTLY CHANGING
WITH AGE. THE SIZE OF THE --
INDICATES ACCESSIBILITY. THE
COLOR INDICATES THE EXPRESSION
LEVEL. YOU SEE THE PRETTY MUCH
KISH (PHONETIC) HAS A
RELATIVELY LARGE SIZE. THE
KISH CHANGE AND THE DATA
PREDICTS THAT THE CHANGE IS
HIGHLY (INDISCERNIBLE) IN ALL
INDIVIDUALS.
WHAT KISH DOES IS THE MOLECULE
THE TARGETS OTHER MOLECULES. IT
FUNCTIONS AS A PLATFORM, ONE OF
THE MOLECULES THAT IS
(INDISCERNIBLE) WHY KISH IS
HGPS 1A. YOU CAN SEE THAT ON
THE LEFT SIDE. (INDISCERNIBLE).
COMPARED TO THE CONTROL. WHEN
YOU LOOK FOR ATPASE, LOOK FOR
THE EXPRESSION IN YOUNG VERSUS
OLD, AND YOU SEE IT EXPRESSED.
SO AGAIN ATPASE T 1 A, THIS IS
BASED ON OLD PEOPLE AND YOU SEE
-- -- IN THE ELECTRON
MICROSCOPY AND I SHOW ONE
PICTURE OF AMPHISOMES
(PHONETIC), GENERATING INFUSION
OF PHAGOSOMES.
YOU SEE A YOUNG EXPRESSION OF
THE (INDISCERNIBLE), IT IS
SILENCE ATPASE YOU HAVE MANY
MORE (INDISCERNIBLE).
IT SPITS OUT ALL DIFFERENT
THINGS INCLUDING MITOCHONDRIA
--. IF YOU LOOK OUT RESPONSES
WHAT WE SEE IS, IN THE POWER T
CELL RESPONSE, WE SEE AN
INCREASE THE CREATION OF
(INDISCERNIBLE) RDNA IN ALL
PEOPLE VERSUS YOUNG PEOPLE.
IF YOU LOOK AT THE PLOT ON THE
RIGHT SIDE TO SEE THE VARIANCE
IN YOUNG INDIVIDUALS. IT CAN
COME DOWN TO A DNA
(INDISCERNIBLE) WE SEE IN YOUNG
PEOPLE THE INCREASE -- OF
(INDISCERNIBLE).
WE FOLLOW IT UP WITH A
HEMOSTAT STATUS USING CD4 --
WE SILENCED THE T-CELLS. IF
THERE IS A HUGE INFECTION, WE
WOULD SEE AN INCREASED IN
MITOCHONDRIAL DNA. THE
INCREASE IN MITOCHONDRIAL DNA,
SHOWS AN ACUTE INFECTION. WE
CAN SIGNIFICANTLY REDUCE THE
KISH. WE CAN ALSO
(INDISCERNIBLE) THE
(INDISCERNIBLE) AT THE TIME OF
THE PEAK OF THE IMMUNO
RESPONSE. YOU CAN SEE THAT THE
T-CELLS OF THE (INDISCERNIBLE)
ARE IN THE END, RESPONSIBLE FOR
THE SECRETION OF MITOCHONDRIA
DNA.
THE INCREASE OF MEDICAL DNA IS
A SYSTEMIC RESPONSE. YOU CAN
SEE THIS BECAUSE OF THE LEVELS
OF (INDISCERNIBLE).
THE SUMMARY OF MY LAST SLIDE,
I HAVE DISTINCT ACTIVATION THAT
LEADS TO (INDISCERNIBLE) WHICH
IMPAIRS CLASSICAL BIOGENESIS,
GENERATION OF MITOCHONDRIAL
BODIES AND INCREASED EXPRESSION
OF -- EXPRESSION, WHICH
DEGRADES THE EXISTING LYSOSOMES.
WE GET A LOT OF THESE
(INDISCERNIBLE) THAT LEAD TO
THE SECRETION OF EXOSOMES AND
MITOCHONDRIAL DNA.
I AM FOCUSING HERE ONLY ON
WHAT WE PLAN TO DO IN THE NEXT
-- -- WE KNOW THAT TCF1
ESSENTIAL FOR GENERATION OF TFH
AND LOG OF MEMORY CELLS AND FOR
FUNCTIONAL LYSOSOMES.
WE HAVE NETWORKS UPSTREAM AND
DOWNSTREAM IN HEALTHY OLDER
ADULTS AND WE ARE PLANNING TO
USE NEAT TECHNOLOGY, SEQUENCING
AND NUCLEOPROTEIN TO ATTACK THE
(INDISCERNIBLE).
OBVIOUSLY, MORE STUDIES ARE
DONE ON (INDISCERNIBLE). THE
ASPECT OF LYSOSOME DEFICIENCY
WE DO NOT KNOW IT YET BUT THAT
MEANS. OR LONG-TERM T-CELLS
(INDISCERNIBLE).
I WILL LET THE ACKNOWLEDGMENT
SPEAK FOR THEMSELVES. ALSO MY
LAB AND (INDISCERNIBLE).
>>AGAIN IF THERE IS ONE SHORT
QUESTION OR SOMETHING ONLINE --
WE CAN -- ONE SHORT QUESTION IN
THE BACK.
>>YEAH, BEAUTIFUL. COULD YOU
CLARIFY IF YOU THINK THAT THE
ENHANCED AT 5 AGING IS BECAUSE
OF EXTRA CYTOKINES IMPLEMENTING
A RECEPTOR?
>>WE THINK IT IS AUTOPLAY. WE
FIND HELIOS IS IN HUMAN
T-CELLS, TRANSCRIPTION FACTOR
WE ONLY SEE IN TCF. HE WE LOSE
HELIOS IT STARTS TO
(INDISCERNIBLE). ALL HAVE SOME
LEVEL OF PHENOME EXPRESSION.
>>THANK YOU VERY MUCH.
>>POWERLESS PRESENTATIONS BY
DOCTOR -- IS THAT CLOSE ENOUGH?
FROM JOHNS HOPKINS AND I WILL
LET HER TAKE OVER.
>>IT'S 4 P.M. LAST LECTURE.
THANK YOU FOR THOSE WHO STUCK
WITH IT. I AM REALLY EXCITED
TO SHARE SOME OF OUR WORK WHICH
COMES FROM A DIFFERENT
PERSPECTIVE, BUT I THINK
CONNECTS A LOT OF THINGS THAT
WE HAVE HEARD.
SO, JUST TO GET SOME
BACKGROUND ABOUT THE
PERSPECTIVE I AM COMING FROM. I
WORK IN TISSUE ENGINEERING IS A
BIOMEDICAL ENGINEER, BUILDING
BIOMATERIALS TO HELP WITH
TISSUE REPAIR. AS A RESULT OF
OUR CLINICAL TRIAL, WE STARTED
TO REALIZE THAT THE IMMUNE
SYSTEM IS REALLY CRITICAL AND
BIOMATERIALS CAN BE A NICE
MODEL FOR DIFFERENT IMMUNO
ENVIRONMENT AND I WILL ALSO
SHOW YOU THE CHANGES IN AGING
AND THESE MODELS HAVE ALLOWED
US TO DEVELOP SOME BETTER
UNDERSTANDING OF
(INDISCERNIBLE) CELLS AND HOW
TO CONNECT WITH THE IMMUNE
SYSTEM. A GREAT QUESTION
EARLIER TODAY.
WE HEARD A LOT ABOUT THE
CONCEPT OF TISSUE REPAIR; A
FAIR AMOUNT IS KNOWN ABOUT
MYELOID CONTRIBUTIONS,
MACROPHAGES AND VARIOUS
GRANULAR (INDISCERNIBLE) WE
HAVE BEEN FOCUSING ON THE
ADAPTIVE IMMUNE RESPONSES IN
PARTICULAR T-CELLS, TH2, TH17.
I WILL DROP A NOTE THAT WHAT WE
HAVE SEEN WITH GAMMA DELTA
T-CELLS HAVE MADE INTERESTING
CHANGES IN AGING AND CONTRIBUTE
TO IL17 PRODUCTION AND --
ENVIRONMENT.
AND ARE VERY RESPONSIVE TO
THINGS LIKE DIET AND INFECTION.
SO OUR PERSPECTIVE COMING FROM
DIFFERENT REPAIR, FIRST TRY TO
UNDERSTAND THE IMMUNE PHENOTYPE
AND THE COMMUNICATION AND
HEALING WOUND AND COMPARE THAT
TO ONE IN A NONHEALING WOUND
CHARACTERIZED BY FIBROSIS AND
CHRONIC INFORMATION.
UNDERSTANDING THOSE DIFFERENCES
WE CAN START TO REDIRECT
HEALING.
WE HAVE BEEN USING MODEL
SYMPTOMS, MUSCLE AS AN EXAMPLE
OF TISSUE THAT CAN REPAIR
PRETTY WELL.OPPOSED TO
CARTILAGE WHICH SWITCHES DOES
NOT REPAIR. AND WE HAVE
BIOMATERIALS THAT CAN MONITOR
EACH OF THOSE ENVIRONMENTS IN
THE BIOLOGICAL SCAFFOLDS ARE IN
THE CLINIC FOR WHEN IT IS
REPAIRED AND THE ROLE OF
MACROPHAGES IN THE RESPONSE AND
PROMOTING A POSITIVE HEALING
OUTCOME HAS BEEN DEMONSTRATED.
LOOK MORE AT THE ADAPTIVE
IMMUNE COMPONENT, KAILIN IS AN
INVESTIGATOR AT NIH LOOKED AT
(INDISCERNIBLE) PRODUCTION AND
HE WOULD LOOK AT POSSIBLE
CONNECTIONS WITH THE ADAPTIVE
IMMUNE SYSTEM, YOU WILL SEE IL4
IS AN IMPORTANT COMPONENT FOR
DIFFERENTIATION.
WHAT SHE FOUND WAS THAT YOU
HAVE SOME T-CELLS IN THE
BIOMATERIAL WOUND, IMPROVING
HEALING AND IMPACTS MACROPHAGE
BEHAVIOR. WE EVEN SEE LOCAL,
REGIONAL LYMPH NODES
(INDISCERNIBLE) AND INCREASING
RICTOR KNOCKOUT AND T-CELLS THE
DID NOT HAVE THE CAPACITY TO
UNDERGO DIFFERENTIATION AND WE
SEE FUNCTIONAL REPAIR.
IF YOU LOOK AT THE FIBROSIS
AND AND -- RESPONSE TO MATERIAL
AND TISSUE DAMAGE. THAT BRINGS
UP ALSO THE CONCEPT OF
FIBROSIS. FIBROSIS IS PRESENT
IN A LOT OF AGE-RELATED
DISEASES, IPF ARTHROSIS,
ARTHRITIS, FIBROIDS, NICE MODEL
FOR NONHEALING WOUNDS AND
CHRONIC INFORMATION, AND YOU
CAN SEE HOW FIBROSIS AND TISSUE
PROBABLY INCREASES WITH AGING.
FIBROSIS IS A NICE MODEL.
FIBROSIS HAPPENS AROUND
BIOMATERIAL IMPLANT EVEN IN
YOUNG ANIMALS AGAIN AND NICE
PLACE WHERE WE CAN ENGINEER
MODELS.
SO IN LOOKING AT THE IMMUNE
CELLS AROUND THE IMPLANT,
PEOPLE KNEW THAT MACROPHAGES
PLAY AN IMPORTANT ROLE IN THAT
FORM BY THE RESPONSE WE FOUND
T-CELLS FROM IMPLANTS IN
PATIENTS AND SO WE HAVE A LARGE
GROUP OF TISSUES FROM PATIENTS
UNDERGOING EITHER PERMANENT
IMPLANT EXCHANGE AND
RESPIRATORY CONSTRUCTION, OR
WITH AN ACE IMPLANT THAT NEEDED
TO BE REMOVED.
WHAT WE FOUND IN THE T-CELLS
IS THAT WE HAVE T4 T-CELLS
EXPRESSING IL17 AND ALSO GAMMA
DELTA T-CELLS EXPRESSING IL17,
A FAIR AMOUNT OF THOSE AND THAT
WAS RATHER UNEXPECTED.
AND WILL PUT THE FACT THAT
PRECLINICAL MODELS ALSO HAD
SOME PRE-(INDISCERNIBLE). IT
WILL LOOK ON THE LEFT, CD45.1
VS. CD45.2, THE .2 BEING FROM
THE OT2 MOUSE, YOU GET IMMUNE
ACTIVATION IN BOTH OF THEM BUT
ONLY TH 17 PRODUCTION IN THE
WILD TYPE NOT IN THE OT2.
SO IT WOULD DELIVER ANTI IL17
ANTIBODIES WE CAN REDUCE
FIBROSIS BUT THEN IT THERE IS A
CONNECTION BETWEEN IL17 AND
SENESCENTS.
IN KNOCKOUT ANIMALS WE SEE
REDUCED SENESCENCE. AROUND
CHEMICAL IMPLANTS WE ALSO SAW
SENESCENT CELLS IS LABELED BY
IL17 AND A POSITIVE CORRELATION
BETWEEN 6 AND IL17.
FIBERGLASS DIVERSITY HAS BEEN
THE RESEARCH TOPIC AND MANY
STUDIES DENY MENTIONING
FIBROBLAST BECAUSE THAT IS
PRIMARILY WHAT OUR SENESCENT
COME OUT TO.
WE HAD A BEAUTIFUL
INTRODUCTION OF SENESCENT THIS
MORNING SO WE ARE LOOKING AT
SENESCENCE FROM THE TISSUE
REPAIR FIBROSIS SIDE SO WE
LEARN THAT SENESCENCE IS A
NORMAL PART OF DEVELOPMENT IN A
NORMAL PART OF TISSUE REPAIR.
(INDISCERNIBLE).
SENESCENT CELLS WERE FOUND IN
CARTILAGE OF PATIENTS
UNDERGOING TOTAL KNEE IMPLANT,
QUITE A WHILE AGO. IT IS A
NICE EARLY TARGET AND YOU HEARD
ABOUT THE SASP WHICH INCLUDES A
NUMBER OF IMMUNE FACTORS THAT
WILL TELL YOU IS QUITE
IMPORTANT FOR T-CELL
DIFFERENTIATION AND UNEXPECTED
RESULT WAS INCREASED TISSUE
PRODUCTION FOR TISSUE REPAIR
AND THE SENESCENT CELLS FOR
SERVING AS A BREAK FOR TISSUE
REPAIR IN THAT ENVIRONMENT.
AND SOME BACKGROUND. IF YOU
HAVE A SHAM SURGERY OR YOU
DON'T GET AS MUCH SENESCENCE,
FOR CHRONIC SENESCENCE YOU HIRE
INFORMATION EARLY ON BUT THEN
HE GOES AWAY. AND THE ACL
TRANSACTION A LITTLE BIT LESS
SENESCENCE BUT THE STATES
CHRONIC AND THE INTENSITY AND
TIMING OF BOTH THE IMMUNE AND
SENESCENCE RESPONSE IS
CRITICAL.
IF WE LOOK AT THE FACTORS
PRODUCED BY THE T-CELLS, IL 1
BETA, IL6, WE ARE ARTIFICIALLY
INDUCED SENESCENCE AND WHAT WE
SAW WAS IN THE PRESENCE OF TH
BETA, (INDISCERNIBLE), WITHOUT
IT IS A NICE SWITCH TO
INTERFACE GAMMA.
AT THE SAME TIME WE CAN USE
ARTIFICIALLY USE T-CELL TO
INCREASE THE PHENOTYPE AND WE
SEE HEALTHY FIBROBLAST PRESSING
MARKERS OF SENESCENCE, IL6,
OTHER FACTORS.
WE CHARACTERIZE THIS A LITTLE
MORE AND INFLAMMATORY REDUCED
SENESCENCE, LOOKING AT
PERIMETER INFORMATION AND
SENESCENCE, WE THINK THIS IS A
MORE PHYSIOLOGICALLY RELEVANT
SENESCENCE WHEN YOU HAVE IMMUNE
ACTIVATION BUT WHAT IS A
SENESCENT CELL?
YOU HEARD THAT QUESTION
EARLIER TODAY. WE ARE QUITE
INTERESTED IN THE IMMUNE
FUNCTIONS OF SENESCENT CELLS IN
CONNECTION TO THE IMMUNE SYSTEM
SO WE USE THE FBR MODEL FROM ME
AND USE OUR FIBROSIS MODEL.
IN THE PRECLINICAL MODEL
INDUCING FIBROSIS AND 6 AND TD
TOMATO. WE LOOK FOR --
INDUCTION, NOT IN THE EARLY
IMPLEMENTATION, MORE OF THE
CHRONIC SENESCENCE.
AND AS YOU SAW EARLIER I
THINK, VERY SMALL NUMBERS.
SENESCENT CELLS ARE INTERESTING
BECAUSE THEY ARE REALLY LOW IN
NUMBER BUT THEY SEEM TO HAVE A
BIG EFFECT, AT LEAST WHEN YOU
CLEAR THEM.
IT'S ONLY A SMALL PERCENTAGE,
.09%, USING A LARGE FLOW PANEL
YOU CAN SEE THAT MOST OF THOSE
SENESCENT CELLS IN THIS YOUNG
ANIMAL FIBROSIS IMPLANT MODEL
WERE CD 45 NEGATIVE, CD 49
POSITIVE AND WE HAVE SOME
MYELOID CELLS, PRIMARILY
(INDISCERNIBLE) CELLS IN THE
ANIMAL VALIDATED WITH TISSUE
AND THE (INDISCERNIBLE) ITSELF.
WE SORTED OUT THOSE TD TOMATO
POSITIVE, TC 15 POSITIVE, AND
WE DID BOTH SEQUENCING ON THIS
AND HAVE A SENESCENCE SIGNATURE
AND WHILE THE SIGNATURE IS
DETERMINED BY THAT EXPRESSION,
WE'VE GOT GREATER THAN 1000 IS
GOING UP AND DOWN. YOU CAN USE
THIS TO COMPARE TO OTHER DATA
SETS AND FIND CELLS THAT MAY
NOT BE T 16 POSITIVE EXPRESSING
SOME OF THESE MARKERS SO, WHAT
ARE THE INTERESTING PATHWAYS?
WE SAW THINGS THAT RELATE TO
ENDOTHELIAL MIGRATION. YOU CAN
SEE THE PICTURES AND THE
CONNECTION TO (INDISCERNIBLE),
MAKE SENSE WITH TISSUE REPAIR
AND TISSUE DEVELOPMENT. AND IN
THE DIFFERENTIATION, WITHOUT
THIS LITTLE STRAIN WONDERING IF
WE HAD LIGAMENT OR TENDON
CONTAMINATION BUT NO IT WAS IN
THE FIBROSIS REGION WITH A LOT
OF PROTEINS AND GLYCAN
ASSOCIATED WITH CARTILAGE WERE
IN THE FIBROSIS REGION.
SO WHICH OF THE SAME CD 49
POPULATION AND THE SINGLE CELL
WE DO NOT SEE T 16 VERY HIGH,
BUT WE HAD TO TRANSFER THE
LEARNING APPROACH AND APPLY
THAT TO THE SINGLE DATA SET TO
SEE WHICH CELLS GREATER
SIMILARITY TO THE SENESCENT
CELLS.
AS YOU MIGHT GUESS FROM THE --
CONNECTION WE RENAMED THE
CARTILAGE POPULATION FIBROTIC
BUT THERE IS A COMMON
PROGENITOR CELL THAT WE SEE
THROUGH THE RED CELLS, AND THE
FIBROTIC AND PERICYTE.
WE CAN ALSO PREDICT FACTORS
RELATED TO ANGIOGENESIS,
COLLAGEN PRODUCTION AND ALSO
INTERESTING THINGS LIKE GDF 15
WHICH COMES UP IN A LOT OF
FRAILTY STUDIES IN THE SERUM.
AND ALSO APPLIED CLINICAL SETS
AROUND ONE OF THOSE IMPLANTS,
YOU CAN SEE P15 -POSITIVE CELLS
IN PURPLE AROUND THE BLOOD
VESSEL LOOKING MORE LIKE
PARASITES AND MORE STRESSED OUT
FIBER PLASTIC LIKE P16 POSITIVE
AND YOU CAN SEE THE GENES
DRIVING SIMILARITY, WHICH ONES
WERE IN THE CLUSTERS AND WERE
IN THE SENESCENCE SIGNATURE AND
NOW WORKING WITH NEW METHODS TO
DO THE TRANSFER LEARNING USING
PROJECT R SO WE CAN START
LOOKING AT THE DIFFERENTIAL
EXPRESSION BETWEEN SENESCENCE
CELLS AND NON-SENESCENCE CELLS
IN EACH CLUSTER AND WE CAN PICK
OUT THE SENESCENCE CELLS, AND
WE THOUGHT RPF WAS INTERESTING
BECAUSE IT SUGGESTED THAT
CERTAIN EPITHELIAL CELLS WERE
SENESCENCE, EVEN THOUGH WE DID
NOT HAVE EPITHELIAL CELLS IN
ORIGINAL THE SIGNATURE.
AND THIS IS IN THE
GEREOSCIENCE PAPER. THIS IS BY
ONE OF OUR COLLABORATIVE WHO
HAS BEEN COMPARING THE VARIOUS
SENESCENCE SIGNATURES--
APOLOGIES THAT IT IS HARD TO
READ, THE FPR -- AND
ESSENTIALLY WE ARE GETTING THE
REALLY HIGH CORRELATION IN THE
FBR-DERIVED SIGNATURES WHEN
COMPARING IT TO THE OTHER
METHODS.
AS YOU COMPARE THE INDIVIDUAL
SIGNATURES PLEASE FEEL FREE TO
USE (INDISCERNIBLE).
I'M GOING TO END WITH WHAT
GOES ON WITH AGING. JIN HAN IS
HERE A SENIOR FELLOW IN THE
LABORATORY IN THE BACK OF YOUR
QUITE INTERESTED IN WHAT
HAPPENS TO THE RESPONSE WITH
THERAPIES AND HEALING WITH
AGING. AND AGAIN THE
COLLABORATOR BEEN HEALTH GROWTH
(CORRECTION) BEN HATHGROVE
(PHONETIC) A FEW YEARS AGO.
IF YOU PUT THE SAME MATERIAL
TO PROMOTE TISSUE REPAIR IN AN
OLD ANIMAL YOU SEE A LOT MORE
FIBROSIS AND EPIGENESIS IN
THOSE OLDER ANIMALS AND WE
DON'T SUPER HAPPENING. IN
MUSCLE YOU WANT TO SEE
ESSENTIAL LOCATED NUCLEI.
WHAT HE FOUND WAS INTERESTING
DIFFERENCES BETWEEN A LYMPH
NODE AND FLAME, PRODUCE NUMBERS
BETWEEN AVON OLD AND INCREASED
RECEPTOR CELLS, AND THAT IS
DIFFERENT IN DIFFERENT PLACES.
T CELLS IN THE OLDER ANIMAL
SWITCHING TO IL17 EXPRESSION
AND CD4 T-CELLS WE GET MORE
DIFFERENT GAMMA IL17.
WE SEE INCREASED IL17 IN OLDER
ANIMALS. WE PUT IN INJURY AND
IMPLANTS WE SEE INCREASES IN
IL17 A AND F, AND IF WE LOOK
LITTLE BIT FURTHER IN THE
TRAINING LYMPH NODES, T 17 CAN
REDUCE MMPS AND VARIOUS
(INDISCERNIBLE), WE DON'T SEE
DIFFERENCES BETWEEN YOUNG AND
OLD AT BASELINE BUT THERE ARE
SEVERAL CHANGES IN THE IMPLANT
THAT IS IMPEDING THE RESPONSE.
IL4 DECREASES IN THE IMPLANT
DOESN'T IN THE TISSUE AND IN
ADDITION YOU ALSO HAVE
INCREASED IL17.
LAST FEW SLIDES. T-CELLS-SNC
COMMUNICATION.
IN THE BOTTOM WE HAVE THE
CLUSTERS ENRICHED IN THE
SENESCENT SPACE AND IN THE
SENESCENCE SIGNATURE AND THIS
MGP FIBROBLAST IS IMPORTANT.
THAT MGP FIB IN READ INDICATE
IF YOU THINK YOU LOOK AT THE
OLD ANIMAL. T-CELLS ARE DOING A
LOT MORE HERE, A LOT MORE
RECEPTORS COMMUNICATING IN A
T-CELL AND LOOK AT THOSE
SENESCENCE IN THE OLDER ANIMALS
THAT THEY ARE COMMUNICATING A
LOT MORE. SO AGAIN THE T-CELLS
SENESCENCE COMMUNICATION IS
IMPORTANT. LAST TWO SLIDES I
PROMISE.
THERE WERE FEWER NAïVE IN OLD.
YOU GET INCREASE
DIFFERENTIATION OF THE OLDER
SALES AND INCREASED PRESS STAR
3 ON YOUR Q (CORRECTION) TH 17
DIFFERENTIATION IN ORDER CELLS.
WE HAVE ALL THESE MARKERS THAT
ONE OF EXPRESSING DIFFERENTLY.
A LOT OF THINGS WERE RELATED TO
VASCULAR DYSFUNCTION IN OLDER
ANIMALS IN THE T-CELLS ARE
TRYING TO REPAIR THE DISRUPTED
VASCULATURE IN AGING.
T-CELLS ARE DIFFERENT IN OLDER
ANIMALS TOO. YOU LOOK AT THE
SIGNATURE AND THE PHENOTYPE, IS
DIFFERENT IN THE YOUNG AND OLD
AND FACTORS A DIFFERENT. METRIC
MODELS BEING EXPRESSED, AND THE
(INDISCERNIBLE) DIFFERENT
EXPRESSION AND AGAIN THE
T-CELLS AND SENESCENT CELLS ARE
DIFFERENT.
JIM WAS ABLE TO RESCUE IT BY
AN INHIBITOR. HE CAN INCREASE
THE TISSUE REPAIR, DECREASE THE
IL17, PROMOTE THE IL4 PHENOTYPE
AND DECREASE FIBROSIS,
DECREASED EPIGENESIS WITH A
COMBINATION THERAPY TARGETING
THE IMMUNE HEPATORY FACTORS IN
BLOCKING RESPONSES TO
PROGENITOR MATERIAL.
IN THIS IS TIGHTLY INTEGRATED.
SENESCENT CELLS TIGHTLY
INTEGRATE WITH THE IMMUNE
SYSTEM. SNCS PLAY A ROLE IN
REGULATED TISSUE REPAIR PROCESS
CORRELATING IMMUNE CELLS,
MATRIX PRODUCTION AND
REGULARIZATION.
AGING IS A CHRONIC, NONHEALING
WOUND IMPEDED WITH AGE SO THAT
IS ANOTHER PERSPECTIVE TO THINK
ABOUT.
THANK YOU FOR YOUR TIME AND
THANK YOU FOR STICKING AROUND
TO THE LAST LIVE TALK. I LOOK
FORWARD TO CONNECTING WITH
PEOPLE LATER BY EMAIL OR
WHATEVER.
>>SO WE CAN AGAIN HAVE ONE
QUESTION. AND THEN WE WILL GO
ON TO OUR GAPS AND KNOWLEDGE
SESSION. ONE QUESTION.
>>REAL QUICK. SO REALLY
WONDERFUL TALK. WITH THIS DATA,
COULD YOU TELL IF THE CONNECTED
MY FIBROBLAST IN THE CARTILAGE
WERE THEY COMING FROM
SENESCENCE RESIDENT FIBROBLAST
OR GAINING SENESCENCE AS THEY
WERE DIFFERENTIATING?
>>I DON'T THINK WE HAVE THAT--
WE HAVE NOT DONE THE STUDIES TO
SHOW THAT. I THINK, WELL,
REALLY IT IS THE SENESCENCE
SIGNALING SO THAT THERE IS
SOMETHING WRONG WE ALSO SEE
MECHANO RESPONSES, GENES COMING
UP. ARE THEY DIFFERENTIATING
INTO SENESCENT CELLS? THAT IS A
GREAT QUESTION. BUT THE
FIBROBLAST IS ONLY A SMALL
PERCENTAGE. THAT IS A GREAT
QUESTION. I DON'T HAVE AN
ANSWER AND I WOULD LOVE TO DO
SOME TRACKING STUDIES IF THERE
IS A WAY TO DO THAT.
>>THANK YOU VERY MUCH TO ALL
OF THE SPEAKERS. AND WE WOULD
LIKE TO HAVE THE SPEAKERS WERE
STILL HERE FROM THE SESSION,
COME UP FOR OUR NEXT SESSION
THAT IS UNDER BONNIE'S
JURISDICTION. THE GAPS.
>>SO THERE ARE FOUR OF YOU
HERE. THANK YOU FOR JOINING US
FOR THE GAPS. PERHAPS IN THE
FIELD DISCUSSION. SOME OF YOU
HAVE ACTUALLY LIFTED SOME OF
YOUR GAPS THAT YOU THOUGHT WERE
IMPORTANT TO PUT FORWARD TO
DISCUSS. BUT I WOULD GIVE YOU
THE OPTION OF DOING THAT AGAIN.
I THINK WE CAN START WITH --
PERHAPS, AND GO DOWN THE LINE.
THANK YOU SO MUCH. ANYTHING
THAT YOU WANT TO SAY ABOUT GAPS?
>>I THINK THE BIGGEST GAP IS
CONSIDERING AGE AS A CATEGORY
TO ONLY DO RESEARCH. VERY
IMPORTANT IN GETTING PEOPLE.
BECAUSE THE YOUNG PEOPLE I
SHOWED YOU TODAY WILL HAVE GENE
PROFILES THAT TRACK SURVIVAL OR
MORTALITY. SO IF YOU HAVE A
POPULATION OF SAY-- I DID NOT
SHOW THE WHOLE DATA SETS-- BUT
MAYBE 20-YEAR-OLD PEOPLE HAVE
TISSUE FOUND IN ABUNDANCE IN
ALL PEOPLE. CHARACTERIZING
PEOPLE WITH DIFFERENT RISK
PROFILES. (INDISCERNIBLE).
SO I DID NOT HAVE TIME TO SHOW
YOU. IF YOU ACTUALLY COMPARE
OLDER PEOPLE WHO HAVE THE SAME
GRADE AS A YOUNG PEOPLE, THERE
IMMUNE PROFILES ARE SHARED, AND
THEY ARE DISTINCT FROM THOSE
THAT ARE OLDER.
AND SAME WITH A IF I TOOK A
GENERAL PERSON WHO HAS A
DEGRADED IMMUNOLOGICAL
RESILIENCE AND WE GIVE THEM THE
FLU VACCINE ARE NOT RESPONSIVE.
THAT COULD HELP IN TAKING CARE
OF THE (INDISCERNIBLE) MEMORY.
THIS IS A LARGE STUDY AND
YOU'RE WELCOME TO READ IT WHEN
IT COMES OUT, BUT HE GETS TO
THE IDEA THAT IF YOU CONTROL
FOR THE HETEROGENEITY, THERE
ARE TWO PROCESSES GOING ON IN
THE CONTROL FOR THOSE PROCESSES
YOU MIGHT GET GREATER
DISTINCTION. WHY DO CLINICAL
TRIALS FAIL? THING ONCOLOGISTS
ARE VERY SMART. ONCOLOGIST ARE
WAY AHEAD OF US IN THE CONTROL
FOR HETEROGENEITY AND GENE
SIGNATURES. AND THEY TARGET
THE POPULATION IN THE SAME
THING HOLDS TRUE HERE.
IF YOU FOR EXAMPLE HAVE A
CLINICAL TRIAL WITH A SMALL
STUDY EVEN, AND YOU ARE IN
BALANCE FOR PEOPLE WHO HAVE
DIFFERENT LEVELS OF GREATER
IMMUNE SURVIVAL MORTALITY
SIGNATURES WOULD BE
(INDISCERNIBLE). YOU CAN
CONTROL HETEROGENEITY AND WE
NEED TO CONTROL IT.
>>OKAY JUST MAKE SURE THAT
EVERYBODY CAN HEAR YOU. THANK
YOU.
>>THANKS. I THINK ONE OF THE
GAPS IS MOVING FUNDAMENTAL
KNOWLEDGE AND TO SPUR MENTAL
MEDICINE TRIALS. AND HAVING
REALLY GOOD PRECLINICAL MODELS.
WE TALKED A LOT ABOUT THE
STRENGTHS AND WEAKNESSES OF
VARIOUS MODELS INCLUDING USING
ANIMALS AS MODELS.
I THINK WE NEED TO EMBRACE THE
FACT THAT AGING IS COMPLEX. WE
NEED ALL THE MODELS WE CAN GET.
AS LONG AS WE UNDERSTAND THE
LIMITATIONS, BUT ALSO THE
STRENGTHS. THAT I THINK WE
SHOULD BE USING EVERY SYSTEM WE
HAVE.
>>SO I THINK THERE IS GREAT
OPPORTUNITY IN BRINGING
TOGETHER THE COMMUNITIES THAT
WE HAVE HERE. VERY DIFFERENT
PERSPECTIVES. THERE'S A LOT OF
I WOULD SAY LOW HANGING FRUIT
CONNECTING THE TOPICS HERE.
SO WE HAVE BEEN WORKING
PREVIOUSLY ON MAPPING VARIOUS
ENVIRONMENTS, IN HEALING AND
NONHEALING WOUNDS, NOT REALLY
SHIFTING TO WHAT TRANSLATION
DOES ADDRESSING THE GAP IN
PRECLINICAL AND CLINICAL AND
AGING IS A BIG ONE.
HETEROGENEITY, YOU HAVE GREAT
MINDS IN THE SAME CONDITION AND
THEY HAVE HETEROGENEITY.
(INDISCERNIBLE).
BUT OTHER THINGS BEING, LIKE
HISTORY OF INFECTIONS IMPACTING
RESPONSES, COMORBIDITIES, AND
IT IS INTERESTING HOW YOU CAN
SEE LOCALLY AGE ENVIRONMENTS
EVEN IN A YOUNG SAY ANIMAL
MODEL BUT YOU CAN IMAGINE
ANOTHER SYSTEMS THAT YOU HAVE
THESE LOCAL ENVIRONMENTS THAT
MIGHT BE AGED INFLUENCING IN
OTHER THINGS.
AS AN EXAMPLE, I THINK CANCER
PEOPLE ARE SMART TOO. I AGREE
WITH YOU ON THAT. WE PUT
DIFFERENT TYPES OF WOUNDS WITH
TUMORS IN OTHER PARTS OF THE
BODY. ONE TYPE OF ONE WILL
INCREASE TUMOR GROWTH, INCREASE
RESPONSE AND ANOTHER TYPE WILL
INCREASE TUMOR GROWTH AND
DECREASE THERAPEUTIC RESPONSE.A
SIMPLE SYSTEM SHOWING HOW
COMORBIDITIES ARE DIFFERENT
THINGS GOING ON CAN CHANGE
RESPONSE AND ALSO THE NEED FOR
ACCOMMODATION THERAPIES. FOR
VARIOUS REASONS THAT HAVE BEEN
HARD TO INTEGRATE THAT INTO
OTHER FIELDS. I THINK THAT IS
A GOOD PLACE TO START.
>>I AGREE WITH WHAT HAS BEEN
SAID. WITH THE HUMAN STUDIES IN
THE CONTEXT OF AGE EMBRACING
HETEROGENEITY, AND USING
APPROPRIATE STATISTICAL METHOD
TO TRY TO GET TO SOME OF THAT
HETEROGENEITY, THE COVARIANTS,
NOT USING T-TESTS OF THINGS
LIKE THIS TO A BETTER MODEL OF
HETEROGENEITY IS IMPORTANT AS
YOU MOVE FORWARD.
THE POINT THAT I MADE AT THE
WERE, AND HE CERTAINLY
MOTIVATED BY SOME OF THE STUFF
WE ARE DOING WITH COOL BIOLOGY,
AIMING TOWARDS QUESTIONS OF
VACCINE RESPONSE AT THE
FOREFRONT NOW. BECAUSE WE SEE,
IT IS ACCEPTED EVEN IN THE
POPULAR PRESS, YOU WILL SAY
OH! OLDER ADULTS LOSE TITERS TO
NEUTRALIZING ANTIBODIES AND
THIS IS SOMETHING YOU WILL SEE
ON CNN AND SOMETHING LIKE THIS.
WHAT DO WE DO ABOUT THIS?
THERE IS AN URGENT NEED TO
UNDERSTAND, IS THERE A
DIFFERENCE BETWEEN MAGNITUDE,
INTENSITY OF RESPONSE? IS THERE
A DIFFERENCE BETWEEN THE
DURATION OF THE RESPONSE? DO
YOU HAVE ANY DIFFERENCE ABOUT
THE PERSISTENCE OF ANTIGENS? IS
THERE SOMETHING WE CAN DO TO
CHANGE THAT? SO THAT WE HAVE
LONGER (INDISCERNIBLE) T-CELLS
RESPONSES THAT WILL PROTECT
PEOPLE AGAINST GETTING REALLY
SICK. BUT A LOT OF THE UPTAKE
AND CONTROVERSIES THAT VACCINES
DON'T WORK AS WELL FOR THE
ACQUISITION OF INFECTION. WHAT
CAN YOU DO TO GET IT THAT?
THE QUESTION ALWAYS WONDERED
ABOUT IS, HOW DO WE COME UP
WITH NEW ADJUVANTS? SHOULD WE
DECLARE VICTORY THAT WE HAVE
SOME THAT WORK REALLY WELL? IS
IT THAT ASO 3D IS JUST REACTIVE
GENETICS BUT WE DON'T WANT TO
USE IT WITH EVERYBODY BECAUSE
THEY WILL GET SORE ARM AND
COMPLAINS. SO IT IS NOT
ONE-SIZE-FITS-ALL.
>>ARE THERE ANY OTHER COMMENTS
FROM PEOPLE THAT ARE STILL OUT
THERE?
SO -- YES?
>>THIS MORNING WE HAD A VERY
INTENSIVE PRESENTATION OF THE
RESTRICTION OF (INDISCERNIBLE).
ANOTHER IMPORTANT PRIMARY
(INDISCERNIBLE) BONE MARROW.
WE DID NOT DISCUSS
(INDISCERNIBLE) AND IMMUNE
DEGRADATION. DOES ANYBODY HAVE
ANY INSIGHT OR COMMENT?
>>WELL, GIVEN THAT I'M A B
CELL PERSON I'M GOING TO MAKE
SOME COMMENT BUT NOT TOO LONG.
BASICALLY THE BONE MARROW AND
THE GENERATION OF CELLS, IT IS
AFFECTED BY AGE. AND REALLY I
WOULD LIKE TO POINT OUT AT
LEAST THAT THERE ARE TWO
POSSIBILITIES OF LOOKING AT THE
PROBLEM. ONE PROBLEM IS, WHAT
IS CAUSING THAT?
FOR EXAMPLE THE BONE PROBABLY
HAS SOMETHING TO DO WITH BONE
MARROW FOR EXAMPLE. FOR ALL OF
OUR SYSTEMS. WHAT IS CAUSING
THAT? WHAT IS DOWNSTREAM? WHAT
IS UPSTREAM AND WHAT IS
DOWNSTREAM?
THE MORE WE CAN GET THE
DETAILS OF THAT WITH REGARDS TO
WHATEVER WE ARE TAKING ABOUT OR
WORKING ON AND WE HAVE HAD A
WONDERFUL COMPILATION OF REALLY
WONDERFUL INTEGRATION OF TOPICS
HERE. I DON'T HAVE TOO MUCH
MORE TO SAY. BUT I WILL OPEN IT
UP AGAIN IF THERE'S ANYBODY
ELSE THAT IS SOMETHING ELSE
THAT WOULD LIKE TO SAY BEFORE I
SAY MY FINAL REMARKS.
IS ANYONE ELSE IT WOULD LIKE
TO ADD SOMETHING WITH REGARDS
TO THIS TOPIC? WHICH IS
BASICALLY GAPS IN THE FIELD OR
ANYTHING ELSE THAT YOU WOULD
LIKE TO SAY? AND IF NOT, I
WOULD LIKE TO SAY THANK YOU TO
MERCY AND TO -- AND TO --,
BECAUSE THEY HAVE ORGANIZED,
AND SOME OF US HAVE HELPED A
LITTLE TINY BIT, MYSELF AND LIZ
AND OTHERS IN THE ORGANIZATION.
I REALLY WANT TO SAY I THOUGHT
THIS WAS A WONDERFUL WAY TO GET
TOGETHER. WAS REALLY EXCITED
ABOUT EVERYBODY'S TALK. I
THINK YOU ALL DID A GREAT JOB.
ANY NO ONE ELSE HAS ANYTHING
TO SAY I WILL SAY PLEASE HAVE A
SAFE TRIP EITHER TO THE NEXT
MEETING OR AT HOME OR WHEREVER
YOU ARE GOING. AND THANK YOU
EVERYONE.