>> WELCOME TO THE DNA REPAIR
INTEREST GROUP.
TODAY OUR SPEAKER IS FROM THE
UNIVERSITY OF ROCHESTER
WILL BE SPEAKING AT THE AGING
INSTITUTE IN BALTIMORE AND
EVERYONE ELSE BE SURE TO MUTE
AND LET'S UNMUTE IN BALTIMORE
AND TAKE IT AWAY, WILL.
>>THIS IS A JOINT
LECTURE FOR THE NIA
AND INTRAMURAL PROGRAM AND FOR
THE DNA REPAIR INTEREST GROUP
AND IT'S EXTREMELY BEFITTING
THAT IT'S DONE BY VERA,
GORBUNOVA WHO IS VERY MUCH
ASSOCIATED WITH AGING AND DNA
REPAIR SO WE'RE LOOKING VERY
MUCH FORWARD TO THIS TALK.
AND VERA IS--DID HER GRADUATE
WORK IN ISRAEL, THEN WENT ON TO
DIFFERENT OTHER PLACES AS A POST
DOC AND BECAME A PROFESSOR AT
ROCHESTER UNIVERSITY
AND SHE IS NOW AN ESTABLISHED
PROFESSOR IN NEED OF AN AGING
CENTER THERE, SHE'S ALSO VERY
POPULAR SPEAKER ON MANY MEETINGS
AROUND THE WORLD THAT SOME OF
THEM I HAD THE PLEASURE TO
ATTEND AND YOU ARE ALSO ON MANY
COMMITTEES AND BOARDS AND HAVE
REALLY DONE A WONDERFUL JOB AT
THIS INTERPHASE OF AGING AND DNA
REPAIR.
VERA DEVELOPED SOME EXCELLENT
ASSAYS THAT MANY OF US ARE USING
FOR CELL ASSESSMENT OF DNA
REPAIR AND JOINING DOUBLE STRAND
BREAK REPAIR, SHE'S ALSO WORLD
ROAFING EXPERT AND WE WILL HEAR
ABOUT ALL THIS AND SHE HAS--I
HAD THE PLEASURE OF VISITING AND
SEEING THE NAKED MOLE RAT WHICH
IS A FANTASTIC CREATURE REALLY
TELLS A LOT ABOUT AGING BUT ALSO
LATELY SHE'S DONE SOME
MAJOR--HAD SOME MAJOR FINDINGS
AGAIN IN THIS INTERNATIONAL
CLASSIFICATION FACE WITH SIRT6
BEING A LONGEVITY GENE AND LINE
ELEMENTS AND OTHER THINGS THAT I
WILL HEAR ABOUT AND I WILL NOT
TAKE MORE TIME BUT JUST SAY THAT
WE ARE VERY PLEASED.
IT WAS DELAYED, THIS LECTURE
FROM WHEN WE HAVE PLANNED IT AND
NOW WE'RE VERY PLEASED THAT YOU
ARE HERE.
WE LOOK FORWARD TO YOUR TALK AND
WHEN YOU'RE DONE WITH THE TALK
WE WILL FIRST HAVE SOME
QUESTIONS HERE BEFORE WE TURN
AROUND TO THE OTHER MEMBERS OF
THE DNA INTEREST GROUP AND I
WILL GUIDE THAT AFTERWARDS.
SO THANK YOU VERY MUCH FOR
COMING.
>> THANK ARE FOR HOSTING
ME AND THANK YOU FOR SHOWING AND
UP AND SPEAKING ABOUT THIS ALL
OVER THE COUNTRY, I WILL TRY NOT
TO DISAPPOINT.
SO SINCE IT'S DNA REPAIR
INTEREST GROUP AND NOT ALL
INTERESTED IN AGING SO I BROUGHT
UP THIS SLIDE TO KIND OF
DEMONSTRATE WHAT WE ARE TRYING
TO ACHIEVE HERE,
[INDISCERNIBLE].
AND FOCUSING ON THE DNA REPAIR
OF COURSE, PEOPLE ALWAYS WANTED
TO FIND HOW THEY INFUSE AND
THAT'S HOW MAY MENTION IT IN THE
BOOK BEFORE AND NOW WE ARE DOING
IT, YOU KNOW MAYBE THROUGH MORE
MOLECULAR MEANS BUT AGAIN, THE
IDEA IS LET'S FIND SOMETHING
THAT CAN MAKE PEOPLE YOUNGER OR
MAKE THE AGING SLOWING.
THE APPROACH MY GROUP IS USING
TO THAT IS A BIOLOGY APPROACH.
SO WHAT THIS COMPARATIVE
BIOLOGY, YOU KNOW WE ALSO USE
MOUSE MODELS THAT ARE EXTREMELY
USEFUL TO ANSWER MANY
MECHANISTIC QUESTIONS, BUT TO
UNDERSTAND AGING LIMITATION IS
THAT MICE DON'T REALLY LIVE VERY
LONG.
THEY ACTUALLY LIVE EXTREMELY
SHORT.
SO THAT'S WHERE WE DECIDED TO
EXPLORE WHAT NATURE GENERATED
FOR US IN THE COURSE OF
REVOLUTION SO YOU WORK WITHIN
MAMMALIAN TRADE, YOU HAVE
SPEECHES THAT DIFFER UP TO A
HUNDRED FOLD IN THE LIFE SPAN
FROM 2 YEARS IN A SHREW TO OVER
200 YEARS IN [INDISCERNIBLE].
SO THEN THE GOAL IS TO TRY TO
FIND THE MECHANISMS THAT ARE
DIFFERENT IN THE SHREW AND IN
THE WHALE AND THEN ONCE YOU
UNDERSTAND IT THEN THERE IS A
POTENTIAL FOR SIGNIFICANT&
IMPROVEMENT, YOU KNOW
[INDISCERNIBLE] BECAUSE YOU KNOW
HUMANS ARE LONG LIVED ALREADY SO
WE REALLY NEED TO FIND SOMETHING
THAT IS PRETTY STRONG TO BENEFIT
HUMANS.
SO THERE ARE DIFFERENT
MECHANISMS OF LONGEVITY.
THEY ARE CONSERVED, THE PUBLIC
MECHANISMS SO I WILL BE TALKING
PROBABLY MOSTLY ABOUT THIS
THROUGH MY TALK TO BE ABLE TO
TALK ABOUT DNA REPAIR.
WE ALSO STUDY THOSE PRIVATE
MECHANISMS THAT ONLY APPEAR IN
CERTAIN [INDISCERNIBLE].
FOR EXAMPLE, WE DO A LOT OF
STUDIES ON NAKED MOLE RATS.
THEY ARE THE LONGEST LIVE
RODENTS, THEY LIVE OVER 30 YEARS
AND WE FIND MANY INTERESTING
THINGS ABOUT NAKED MOLE RATS BUT
THAT WOULD HAVE TO BE A
DIFFERENT SEMINAR SO I WOULD NOT
TALK TOO MUCH ABOUT NAKED MOLE
RAT.
SO LET ME START WITH CONCERNED
MECHANISM OF AGING.
SO WE'RE WONDERING WHETHER DNA
REPAIR IS 1 OF THOSE CONSERVED
MECHANISMS AND WHETHER
SHORT-LIVED SPECIES ARE LESS
GOOD AT REPAIRING DNA DAMAGE AND
WE KIND OF ALWAYS ASSUMED DNA
REPAIR IS CENTRAL TO THE AGING
PROCESS BUT MOST EVIDENCE CAME
FROM THE STUDIES OF MUTANTS THAT
THE DEFICIENT IN DNA REPAIR AND
THEN THEY SHOW PREMATURE AGING
PHENOTYPES SO THEN WE ASSUME IF
THIS IS IMPORTANT FOR LONGEVITY,
BUT WHAT CRITICS WAS SAYING THAT
WELL, YOU KNOW, YOU KNOW
JUST--YOU SCREW SOMETHING UP AND
THE ANIMALS GET SICK AND WHAT
DOES IT PROVE?
IF WE COULD PROVE ASSOCIATION OF
BETTER DNA REPAIR WITH LONGER
LIFE SPAN SO THAT THEY COULD
[INDISCERNIBLE] THINK IT IS
IMPORTANT BUT BECAUSE IT'S NOT
SO EASY TO IMPROVE DNA REPAIR,
AND SO WE TALK ABOUT LET'S START
WITH THE NATURAL COLLECTION,
MEASURE DNA REPAIR IN SPECIES OF
DIFFERENT LIFE SPAN AND SEE
WHETHER THERE IS A RELATIONSHIP.
AND THESE ARE MODEL SYSTEMS SO
WE HAVE PRIMARY CELLS FROM MORE
THAN 20 SPECIES OF RODENTS WITH
VERY DIVERSE LIFE SPANS SO
SHORTLY TO VERY LONG LIVED, AND
WE FELT OKAY.
SO THE MORE I WILL TELL YOU
ABOUT THAT WAS MOSTLY DONE BY
THIS VERY TALENTED STUDENT AND
[INDISCERNIBLE] SO THEY WERE
HOLDING CANNED WHAT.
HIS OTHER WORK WAS WITH NAKED
MOLE RAT BUT HERE HE DECIDED TO
FOCUS ON DNA REPAIR AND
THE--THERE ARE ALL KINDS OF
IMAGE DAMAGES EXTERNAL, INTERNAL
THAT GENERATE DIFFERENT TYPES OF
LESIONS THAT THEN REPAIRED FROM
THE REPAIR PATHWAYS.
SO THE FIRST PATHWAY THAT XIAO
DECIDED TO EXAMINE WAS EXCISION
REPAIR.
AND THIS PATHWAY WAS ALREADY
STUDIED HISTORICALLY DIFFERENT
[INDISCERNIBLE] THOSE PAPERS
FROM THE 70S, THE PROBLEM WAS
THAT THE RESULT IS SOMEWHAT
UNCLEAR BECAUSE THERE ARE
SEVERAL STUDIES OF
[INDISCERNIBLE], SEVERAL STUDIES
OF [INDISCERNIBLE].
AND THEN WHAT WAS CRITICIZED FOR
THE INSEVERE MITRAL LOW WORK,
AND SPECIES WERE ALSO SPECIES
THAT WERE DISCIPLINARY URNAL AND
ARE EXPOSED TO SUN LIGHT AND
CERTAIN SPECIES THAT ARE NOCT
URNAL, SO THE CORRELATION WAS
STRONG BUT IT WAS NOT CLEAR WAS
IT BECAUSE OF LIFESTYLE OR
BECAUSE OF THE [INDISCERNIBLE]?
SO XIAO DECIDED TO USE OUR
RODENT COLLECTION WHERE WE WERE
KIND OF LESS BIASED IN TERMS OF
SPECIES SELECTIONS OF THE OLD
RODENTS.
HE USE PLASMA DIRECT DURATION
WHERE SIMPLY MUTEGENERATEDDIZE
THE CELLS AND SO THIS IS WHAT
XIAO SHOWED, DNA EXCISION REPAIR
SO THIS IS MAXIMUM LIFE SPAN,
DEFICIENCY, THERE WAS NO
CORRELATION WHATSOEVER.
NEITHER WITH THE [INDISCERNIBLE]
SO FROM THERE XAIO DECIDED TO
GROUP SPECIES DIFFERENT NOT BY
LIFE SPAN BUT BY THE AMOUNT OF
UV EXPOSURE BECAUSE NUCLEIC WAS
INDUCED IN DIMERS AND THEY
PRODUCED BY UV LIGHT FROM THE
SUN.
SO HE GREW THE SPECIES TO
NOCTURNAL AND AND THE DUSK WITH
THE SPECIES WITH THE SQUIRRELS
OR FOREST OR SPECIES
[INDISCERNIBLE] AND THEN HE
QUOTE TODAY BY SUFFICIENCY AND
WE SAW STRONG CORRELATION SO IT
WASN'T LIFE SPAN IT WAS THE--THE
PSYCHOLOGICAL NEARBY AND HOW
MUCH [INDISCERNIBLE].
AND WHEN THE ONLY FOCUS TO THIS
GROUP BECAUSE THESE 2 GROUPS, I
KNOW IT'S A MIXED BAG AND SPEND
A LITTLE MORE IN THE SIGN OF IT
THIS IS KIND OF CLEAN, SO THESE
ARE SPECEBS THAT ARE EITHER
SUBTERANNIAN OR EXTREMELY
NOCTURNAL SO THEY ARE NOT
EXPOSED.
SO IN THAT GROUP THERE WAS A
TREND THAT WAS CORRELATION TO
LIFE SPAN.
IT DIDN'T QUITE REACH
SIGNIFICANCE BECAUSE WE
[INDISCERNIBLE] SPECIES IN THE
GROUP, BUT IT SEEMS LIKE IF YOU
REALLY REMOVE THE EFFECT OF UV
EXPOSURE, THEN LONGEVITY
ACTUALLY MATTERS.
BUT THIS EFFECT IS MUCH WEAKER
COMPARED TO EFFECTIVE LIFE SPAN
SO YOU ALSO LOOK AT THE
[INDISCERNIBLE] AND THAT WAS
VERY SIMILAR SITUATION SO TO
SUMMARIZE THIS PART, WHAT WE
FOUND IS THAT LOOKING AT THE
EXCISION REPAIR DOESN'T REALLY
CORRELATE WITH LIFE SPAN, BUT IT
CORRELATES TO YOU KNOW ECOLOGY
OF THE SPECIES, THE AMOUNT OF
SATELLITE THAT THESE SPECIES
GET.
SO THEN WE DECIDED TO LOOK AT
DOUBLE STRAND REPAIR AND I THINK
THIS TYPE OF REPAIR IS
PARTICULARLY IMPORTANT TO
LONGEVITY BECAUSE MAINLY MUTANTS
IN THE GENES INVOLVED IN THE
[INDISCERNIBLE] MATURE AGING AND
PHENOTYPES, ALSO IN AGE TISSUES
WE SEE OBESE, ADVANCE LOITION
KACCTS AND EVEN MALIGNANCY IN
THE TISSUE THAT IS THE FULL MARK
BUT [INDISCERNIBLE] THEY START
TO APPEAR AND IN THIS PATHWAY IT
HASN'T BEEN [INDISCERNIBLE] THAT
MUCH WITH RESPECT TO LONGEVITY.
THERE ARE 2 MAJOR PATHWAYS OF
DOUBLE STRAND BREAK REPAIR, YOU
PROBABLY [INDISCERNIBLE] HERE
AND SO JOINING FROM COMBINATION,
WE DEVELOPED THOSE REPORTERS
THAT CAN MEASURE QUANTITATIVELY
THE EFFICIENCY OF THESE 2
PATHWAYS.
SO THEY'RE BOTH GFP BASED AND WE
CAN INDUCE THE SITE SPECIFIC
DOUBLE STRAND BREAK AND WHEN
IT'S REPAIRED YOU CAN CONSITUTE
THE ACTIVITY, AND HERE, SORT OF
SIMILAR BACKBONE BUT WE USE THIS
[INDISCERNIBLE] [INDISCERNIBLE]
WITH THE REPEAT.
SO WE INTEGRATED THESE REPORTERS
INTO PRIMARY 1 BLASTS FROM ALL
THOSE SPECIES THAT THEY SHOWED
YOU, AND EXAMINED DEFICIENCY OF
REPAIR VERSUS MAXIMUM LIFE SPAN.
AND HERE, AFTER I SHOWED YOU IN
THE [INDISCERNIBLE] QUARTERLY
THE LIFE SPAN WE CAN APPRECIATE
HOW STRONGLY IT CAN CORRELATE SO
LIFE SPAN SO THIS IS
[INDISCERNIBLE] COMBINATION AND
SAME THING FOR [INDISCERNIBLE].
BOTH OF THESE PATHWAYS ARE MUCH
MORE EFFICIENT INVOLVED WITH
THESE ISSUES AND OF COURSE THE
NEXT QUESTION WE ASKED WAS ABOUT
THE MECHANISM AND THE ENZYME
THAT WORKS BETTER FOR THE
SPECIES AND OF COURSE THERE ARE
MANY TYPES INVOLVED BUT BECAUSE
BOTH PATHWAYS SHOWED
UPREGULATION SO WE FIGURED OUT
THE TEST ASSEMBLING UPSTREAM FOR
THE [INDISCERNIBLE] OF
[INDISCERNIBLE] AND 1 GROUP
WE'VE BEEN WORKING ON AND REALLY
UPSTREAM FOR GOOD SEPARATION AND
X06 SO WEEK LOOK AT RECEPTOR 2
AND 6 AND THERE WAS ALSO
ADDITIONAL REASON WHY WE
DESIGHTED TO LOOK AT SIRT6, AND
THIS IS QUICK INTRODUCTION IN
INCLUDING 6 IT'S A HOMOLOGUE OF
2 PROTEIN THAT IS BEST KNOWN AS
ASIT LACE, IT'S PART CHROMATIN,
IT'S DEPENDENT AND THERE ARE
SEVERAL [INDISCERNIBLE], AND 6
IS THE STRONGEST BECAUSE WE HAVE
A PHENOTIP AND YOU GET MICE THAT
HAVE A SMALL STABILITY, AGED,
MATURITY, IF YOU OVEREXPRESS,
YOU HAVE MICE, MICE
OVEREXPRESSING, LEAVE ABOUT THAT
PERCENT OVER, THAT WAS ANOTHER
REASON FOR SIRT6, BECAUSE IT HAS
SOMETHING TO DO WITH LONGEVITY,
AND THIS IS AN EARLIER WORK FROM
2011 WHERE WE STUDIED THE
FRACTION OF 6 AND DOUBLE STRAND
BREAK REMARE IN HUMAN CELLS AND
WHAT WE SHOWED IS THAT IF YOU
OVEREXPRESS SIRT6, CAN YOU
STIMULATE BOTH IN HH, AND HR,
WHICH IS VERY RARE BECAUSE
TYPICALLY YOU OVEREXPRESS
SOMETHING, YOU SHIFT BALANCE
TWOON THE 2 PATHWAYS BUT SIRT6,
WE CAN DO BOTH.
SO THAT'S WHY WE FOCUS ON SIRT6,
AND THIS IS A QUICK SUMMARY OF
DIFFERENT FUNCTIONS OF 6 AND
APPEARED COMING FROM MY GROUP SO
WHAT WE SHOWED THAT SIRT 6 IS
RECRUITED TO DOUBLE STRAND
BREAKS WITHIN SECONDS AND AFTER
INDUCTION OF THE DNA BREAK, AND
WE ACTUALLY FURTHER, YOU KNOW
FINE TUNE AND EXPANDED THIS FOR
THE TIME OF RECRUITMENT WAS
COOPERATION WITH WILL'S LAB SO
WE USE THIS AMAZING SET UP WHERE
WE COULD USE THE BREAK WITH THE
SIRT6 COMING IN QUICKLY AND IT
BECOMES THE BEFORE PART 1.
AND THEN [INDISCERNIBLE] PART 1
STIMULATES ITS ACTIVITY AND THEN
IT PROMOTES RECRUITMENT
[INDISCERNIBLE] FACTORS FOR DNA
BREAK SO THAT'S WHY IT'S KIND OF
UPSTREAM OF MULTIPLE REPAIR
PATHWAYS.
SO--OKAY, SO FROM ALL THOSE
RODENTS, THAT I SHOWED AND YOU
THEN EXPRESS THEM IN MOUSE CELLS
THAT HAD THOSE INTEGRATED
REPORTERS AND LOOK AT THE LEVEL
OF STIMULATION THAT WE ACHIEVE.
SO EVERY DOT IS 1 SPECIES WHERE
SIRT6 VERSUS MAXIMUM LIFE SPAN
AND YOU CAN SEE AGAIN, SIRT6 AND
A SPECIES AND BETTER AT
PROMOTING THE COMBINATION AND
THOSE WHO [INDISCERNIBLE].
SO THEN ASK WHERE IS ABOUT QUINN
5, AND A LITTLE BIT BECAUSE WHEN
WE TESTED CELLS FROM DIFFERENT
SPECIES BUT IT SUGGESTS THAT
SIRT6 EXPLAINS PARTIAL
MANINNULATION, AND IN THE LIFE
SPAN, THERE ARE PROBABLY SOME
OTHER FACTORS CONTRIBUTING AS
WELL, BUT SIRT6 IS 1 OF THE MAIN
1S.
SO THEN NEXT QUESTION WAS, OKAY,
SO WHAT'S DIFFERENT ABOUT SIRT6
FROM SHORT LIVED VERSUS LONG
LIVED.
WE CHOSE THE EXTREME CASES FROM
OUR COLLECTION MODELS BECAUSE
IT'S VERY SHORT LIVED.
IT WAS AT WEEK 6 AND THEN WE
CHOSE BEAVER, IT'S LONG LIVED,
MORE THAN 20 YEARS AND MAYBE
ANECDOTALLY 50 YEARS BUT 24
YEARS THAT WAS 1 PARTICULAR
BEAVER THAT WAS [INDISCERNIBLE]
THIS ISSUE AND THEY HAD VERY
GOOD DNA REPAIR, SO WE TOOK
THOSE SIRT6 PROTEINS AND WE MADE
A LOT OF CHIMERAS SO BEAVER,
MOUSE,--THIS IS JUST A QUICK
SUMMARY OF ALL THIS MUTE O
GENESIS WORK THAT XIAO FORMED
AND HERE IT'S THE SAME IN
JOINING ASSAY BUT THEN MORE TO
FEEL THE FORMAT IF WE
OVEREXPRESS MOUSE SIRT6, IT
STIMULATES REPAIR A LITTLE BIT
BUT WITH BEAVER 6 THE EFFECT IS
MUCH STRONGER AND THEN XIAO MADE
ALL THESE SWATHS SO WE
[INDISCERNIBLE] FROM THE
C-TERMINALS UP TO HERE, UP TO
HERE IT DOESN'T MAKE A BIG
DIFFERENCE IF WE SWAP ALL THIS
REGION, WE CAN HOUSE MOUSE
RODENT QUITE A LOT AND THEN HE
DID MANY OTHER COMBINATIONS AND
HERE IS WHAT HE ENDED UP DOING
IS JUST REPLACING THIS SEGMENT
AND THAT WAS ENOUGH TO
COMPLETELY SWAMP THE ACTIVITY OF
THE MOUSE AND SO THAT WAS VERY
NICE, WE LOOKED AT THIS REGION,
THE 2270, THERE ARE 5 DIFFERENT
DIFFERENCES BETWEEN MOUSE AND
BEAVER.
WE TRIED TO MUTATE EACH
[INDISCERNIBLE] RAT AND IN VIRUS
COMBINATIONS AND AGAIN TO MAKE A
LONG STORY SHORT, WE ACTUALLY
HAD TO REPLACE ALL 5.
SO EACH 1 INDIVIDUALLY WAS GIVEN
A BIT OF AN IMPROVEMENT BUT
NEITHER OF THEM WAS ENOUGH SO
IT'S REALLY THOSE SMALL CHANGES
YOU GIVE IT.
WHICH KIND OF MAKES SENSE
BECAUSE THESE ARE 2 PROTEINS
THAT THE WILD TYPE PROTEINS BUT
1 COMES FROM A MOUSE, 1 SHORT
LIVED, ANOTHER COMES THROUGH THE
[INDISCERNIBLE] LONG LIVED SO
THEY MOVE KIND OF FUNCTION BUT
THE FUNCTION GETS ADJUSTED
DEPENDING ON THE LIFE SPAN.
SO THEN WE DID SOME INVITRO
BIOCHEMISTRY WITH THESE
PROTEINS, [INDISCERNIBLE]
ACTIVITIES, AND THESE PROTEINS
AND HISTONE H3--
>> COULD YOU PLEASE USE THE
COMPUTER MOUSE TO TELL US ABOUT
YOUR MICE IN THE LAB?
>> I WILL TRY, YES, SORRY ABOUT
THAT.
CAN YOU SEE THE ARROW RIGHT
THERE?
IT'S A BIT TRICKY.
IT'S MY LAB TOP SO I WILL BE A
LITTLE CLUMSY BUT--YEAH.
SO THIS IS--YEAH, SO THIS IS HCK
9, YOU CAN SEE THAT MOUSE
PROTEIN IS NOT VERY GOOD AT
DEACETALATING IT BUT WITH BEAVER
SUBSTITUTIONS IT BECOMES
STRONGER WITH THE ACET LACE AND
BEAVER PROTEIN IS GOOD, AND IT
GETS WORSE WITH THE MOUSE.
OH YEAH IS THIS IS KIND OF--I
DIDN'T CORRECT THIS SLIDE SO
[INDISCERNIBLE] PUBLISHED SO NOW
WE TESTED THE SECOND ACTIVITY
WHICH IS MORE SSETALATION AND
HERE WE [INDISCERNIBLE] AND THEN
THE MEASURE SELF-[INDISCERNIBLE]
CHANNEL 6 SO IT TRANSFERRED
LABEL TO ITSELF AND SO HERE
AGAIN, YOU CAN SEE THAT MOUSE IS
NOT VERY GOOD AT POSTULATING BUT
IT BECOMES MUCH BETTER WITH
BEAVER SUBSTITUTIONS AND VICE
VERSA IN WILD TYPES AND ENZYME,
BUT IT BECOMES DIFFICULT WITH
MOUSE SUBTUITIONS.
SO THIS IS THE STRUCTURE SO WE
TRY TO FIGURE OUT WHERE THOSE
ASH SIDS ARE LOCATED--ACIDS ARE
LOCATED USING HUMAN CRYSTAL
STRUCTURE, WE CAN SEE THAT THEY
ARE ALL 5OT SURFACE OF THE
PROTEIN--5 ON THE SURFACE OF THE
PROTEIN AND 2 OF THEM ARE CLOSE
TO SUBSTRATE BINDING SITE SO
THAT'S WHERE HUMAN CELL SET WAS
KRIOF THE ALTHOUGHAISED WITH H3
PEPTIDE AND THEY'RE CLOSED AND
WE--I DON'T HAVE THE SLIDE, THE
DATA SLIDES FOR IT, BUT WE ALSO
SHOWED THAT BEAVER CELL 6 HAS
STRONGER BINDING TO NUCLEOSOME
WHICH IS CONSISTENT.
THE OTHER 3 AMINO ACIDS ARE ON
THE OPPOSITE SIDE OF THE
PROTEIN, WE DON'T KNOW EXACTLY
WHAT THE IPAD DO, BUT 1 THING WE
NOTICED IN THE MOUSE THERE IS A
SOUTH BRIDGE AND IT'S ABSENT IN
THE BEAVER SO PERHAPS THAT GIVES
GREATER FLEXIBILITY TO THOSE
ALPHA HELIXES MAY BE MOVING INTO
ACTIVITY [INDISCERNIBLE].
SO TO SUMMARIZE THIS PART OF MY
STORY WHAT WE SHOWED WAS THAT
STRONGLY CORRELATES TO MAX LIFE
SPAN AND SIRT6 AND RESPONSIBLE
FOR MOST OF IT.
AND WE ALSO IDENTIFIED 5 AAMINO
ACIDS THAT WAS SUFFICIENT TO
CANNED WHAT MOUSE AND BEAVER TO
CHANGE THE ACTIVITY, WE ALSO
EXCISE NUCLEOTIDE EXCISION
REPAIR WHERE WE DIDN'T FIND
MAXIMUM LIFE SPAN.
SO HERE OF COURSE THE NEXT
QUESTION THAT COMES IN IS
WHETHER YOU KNOW WE CAN IMPROVE,
YOU KNOW BECAUSE HERE WE SHOWED
THERE IS ASSOCIATION IN TERMS OF
SPECIES THAT HAVE DIFFERENT
MAXIMUM LIFE SPANS CAN MAKE
MOUSE LIVE LONGER BY GIVING IT
THE STRONGEST CELL 6 SO THAT'S
WHAT WE ARE WORKING ON RIGHT
NOW.
WE ARE GENERATING THIS
BEAVERRIZED MOUSE WITH KRSPR,
AND THOSE 5 SUBTUITIONS SO WE
THOUGHT WE WOULD HAVE THE MOUSE
BUT IT WAS DIFFICULT WITH 5 AT
THE SAME TIME AND WE STILL
WORKING ON GETTING THE OTHER 5
AND THEN WE WILL SEE, WELL, IF
MOUSE LIVES LONGER, THEY THINK
THEY WILL REALLY IMPROVE THE
CONNECTION BETWEEN BETTER DNA
REPAIR AND LIFE SPAN.
WE ARE ALSO LOOKING AT OTHER
PAIRS OF SPECIES, YOU KNOW WHALE
FOR XMPLE IF WE MARK THOSE, IN
ESSENCE THEY'RE DIFFERENT
BETWEEN MOUSE AND WHALE SO MAYBE
WE TRY A DIFFERENT SET OF
RESIDUES THAT CAN BE MODULATED.
SOMETHING ELSE THAT'S QUITE
INTERESTING IS THAT CELL 6
ACTIVATORS THAT WILL MAP WHERE
THEY INTERACT, SO THERE WAS 1
THAT LIKE BINDS RIGHT HERE WHICH
IS CLOSE TO THOSE AND USING THIS
TO CONFER WITH THE APPROACH
AGAIN, YOU CAN USE THIS TO MAYBE
DESIGN ACTIVATE THE CELL 6, SO
WE--YOU KNOW WE MAY DISCOVER
WHICH CELL DIDN'T TAKE BUT THEY
STILL LIKE THE PICTURE.
SO YOU CAN SEE THAT IT'S KIND OF
THE [INDISCERNIBLE], PROBABLY
WILL USE THIS POINTER, SO THIS
IS THE BEAVER PREPARING DNA,
IT'S VERY GOOD AT IT, AND IT'S
PROBABLY SIRT6, AND IN MOUSE,
DOESN'T REALLY KNOW HOW TO
REPAIR DNA WELL.
THERE ARE LOTS OF BREAKS IN THE
CELL 6 IS SMALL.
SO HERE CONTINUATION OF THIS
STORY THIS IS WORK OF ANOTHER
TALENTED POST DOC MATT SIMON, HE
KIND OF TOOK OFF FROM WHERE XIAO
FINISHED AND HE ASKED THE
QUESTION, OKAY, SO WE
DEMONSTRATED THE DIFFERENT
SPECIES THAT WITNESSED
ACTIVITIES ASSOCIATE WIDE LONGER
LIFE SPAN BUT WHAT ABOUT OUR
FAVORITE SPECIES HUMANS?
SO FOR HUMANS IF WE IMPROVE
SIRT6 ACTIVITIES WILL BENEFIT US
IN EMERGING ITS OF LONGEVITY.
SO WE WERE VERY FORTUNATE THAT
WE WERE COLLABORATING AT THIS
TIME WITH [INDISCERNIBLE] WHO
DOES STUDIES OF [INDISCERNIBLE]
SO SHE WAS DOING EXOME
SEQUENCING ON ALL GENES THAT I
INVOLVE TO DNA DAMAGE AND
REPAIR.
AND SHE WAS LOOKING FOR
[INDISCERNIBLE] IN SEN
ILLEGALSEN 10AURIANS MOST OF
THEM ARE NONCODING AND FOR MANY
OF THEM IT'S DIFFICULT TO
DETERMINE THE FUNCTION BUT SHE
DID FIND THE CLOSING VARIANT AND
IT WASN'T SIRT6 SO WE WERE VERY
EXCITED.
SO SHE FOUND THESE 2 MUTATIONS
THAT ONLY APPEARED IN
CENTENARIAN AND IT'S A RARE
ITEM, AND SMALL PERCENTAGES OF
THEM HAVE IT [INDISCERNIBLE] AND
THEY ALSO APPEARED TOGETHER.
SO WE DECIDED, OKAY, LET'S TEST
WHAT IT DOES TO THE PROTEIN.
WE MADE THIS PROTEIN REDOMAIN
BIN ANTLY AND THEN WE TESTED IT
IN DNA REPAIR AND THEN THE
MUTATION AND [INDISCERNIBLE]
PULL TOGETHER LIKE
[INDISCERNIBLE].
AND THIS IS HOMOLOGOUS
COMBINATION JOINING US YOU CAN
SEE THAT CENTENARIAN IS ACTUALLY
BETTER DNA REPAIR SO THAT WAS
REALLY EXCITING.
YOU KNOW WE CAN DETECT IT.
WE ALSO LOOKED AT BASAL LEVEL OF
DNA DAMAGE SO HERE WE MEASURED
GAMMA 3 X FORSIGHT, AND CELLS
AND CELLS EXPRESSING THOSE
OBSERVATIONS OF SIRT6, AND
[INDISCERNIBLE] VARIANCES.
WE ALSO HAD THE PREVIOUS ASSAY
WHERE WE SHOWED THAT SIRT6 CAN
SHOW CELLS THROUGH P53 DEPENDENT
MECHANISM AND WHEN WE EXPRESS
CENTENARIAN PART, WE ALSO HAVE
STRONGER KILLING OF CANCER CELLS
THAN IN THE WILD TYPES.
SO NOW SOMETHING, YOU KNOW WE
THOUGHT OKAY, LET'S LOOK AT
ENZYMATIC ACTIVITY AND THAT WAS
A BIT UNEXPECTED WITH THIS, SO
WE TESTED ENZYMATIC ACTIVITY ON
THE H3 SUBSTRATE, SO THIS IS
JUST A SITUATION AND YOU SEE
THAT WELL CENTENARIANS SIRT6
INVITRO WAS WORSE OFF THAN THE
WILD TYPES AND THAT WAS VERY
STRANGE.
WE ALSO MEASURED KINEETICS AND
AGAIN WE SEE THE SAME THING,
CENTENARIAN, IS REALLY GOD ACET
LACE.
THEN WE LOOKED INVIVO IN CELLS
THAT HAVE KNOCK-IN VERSIONS OF,
YOU KNOW USING CRSPR, THEY HAVE
CELL 6 WITH THOSE MUTATIONS AND
IN CELLS WE DIDN'T REALLY SEE
MUCH DIFFERENCE SO MAYBE INVITRO
BECAUSE THESE ARE CONDITIONS
WHERE THEY'RE NOT OPTIMAL WE CAN
SEE IN THAT ENVIRONMENT IS NOT
SO GOOD AND INVIVO WE DON'T GET
THE BIG DIFFERENCE, WE ALSO HAVE
MASS SPEC ON THE CELLS TO SEE IF
WE CAN MEASURE DIFFERENCES IN
THESE HISTONE LEVELS AGAIN,
INVIVO WE COULDN'T SEE.
AND THEN HAY IMAGINED WELL, IT
WAS MUCH WORSE THAN THE WILD
TYPE DOESN'T EXPLAIN VERY MUCH
BECAUSE IT [INDISCERNIBLE] SO WE
MEASURED SIRT6 ACTIVITY, AND
THAT WAS ACTUALLY QUITE AMAZING.
IT IS MUCH BETTER
[INDISCERNIBLE] THAN THE WILD
TYPE.
SO THIS IS THE SELF-REGULATION
ASSAY, YOU CAN SEE THAT THE
EFFECT AND THERE IS ANOTHER
SCENE OF REGULATION ACTIVITY
WHERE IF YOU REMEMBER IN THE
INTRODUCTION, I SHOWED THAT CELL
6 [INDISCERNIBLE] MANIPULATES
PARTNERSHIP 1 DOUBLE STRAND
BREAK SO WE CAN USE THIS ASSAY,
SO IF WE INTERNATIONAL
CLASSIFICATION BEAUTY
INDUSTRIED, IF WE INCUBATED WITH
PARTNERSHIP 1 IN THE PRESENCE OF
BROKEN DNA SO WE CAN SEE THAT
THIS WILL COST US A LITTLE BIT
BUT RELATIVE TO LOAD SIRT6, AND
ACTIVITIES A BIT STRONGER, BUT
IF WE NOW ADD CENTENARIAN SIRT6,
IT ENHANCES ACTIVITY BY A LOT.
SO IT'S A LOT OF EVIDENCE THAT
THE UPREGULATION ACTIVITY WAS
STRONGER, SO WE ALSO TRIED TO
YOU KNOW CONNECT IT TO FUNCTIONS
SO THE STAGE WHERE WE ARE AT
RIGHT NOW SO WE LOOKED AT WHERE
THE CENTENARIAN PART INTERACTS
DIFFERENTLY WITH PROTEINS IN THE
CELL BECAUSE AS YOU NOTICE THOSE
2 MESSAGE MUTATIONS ARE IN THE
C-TERMINALS, AND THAT IS LIKELY
RESPONSIBLE FOR PROTEIN-PROTEIN
INTERACTION SO WITH THAT, WE
HAVE IMMUNE O PRECIPITATIONS AND
MASS SPEC AND LOOK THAT IF
SOMETHING IS DNCHTD BETWEEN WILD
TYPE CELL 6 AND CENTENARIAN
VARIANT SO THESE ARE SEVERAL
PROTEINS THAT CAME UP THAT
SHOWED STRONG INTERACTION WITH
CENTENARIANS IN 6 WITH THE WILD
TYPE AND I THINK THE MOST
INTERESTING HERE IS
[INDISCERNIBLE].
SO ACTUALLY IT WAS REPORTED THAT
SIRT6 INTERACTING WITH
[INDISCERNIBLE], AND WE SEE THAT
THE CENTENARIARS HAVE STRONGER
INTERACTION SO HERE CAN YOU SEE
QUANTIFICATION SO THIS IS LAMIN8
AND THIS IS WILD TYPE, SO IT'S
ABOUT 20% DIFFERENCE BUT WITH
MASS SPEC WE CAN DO IT IN A VERY
QUANTITATIVE WAY SO WE ARE
CONFIDENT THAT IT'S A REAL
DIFFERENCE.
SO THIS IS QUICK SCENARIO OF THE
CENTENARIAN PROJECT SO SIRT6
PROVIDES BETTER STIMULATION OF
DNA REPAIR BUT IT'S NOT ACROSS
SPECIES BUT WITH HUMANS THIS IS
STRONGER ASSOCIATED WITH
LONGEVITY.
INTERESTINGLY CROSS SPECIES WE
SAW THAT BOTH ENZYMATIC
ACTIVITIES WERE IN CURRENT BUT
WITH THE HUMAN CENTENARIAN
ENVIRONMENT, THERE WAS ONLY 1
REGULATION THAT WAS
[INDISCERNIBLE].
AND WE ALSO--THIS IS THE LATEST
RESULT THAT INTERACTS MOST
STRONGLY WITH THE
[INDISCERNIBLE].
RIGHT NOW WE ALMOST TRIED TO
SUBMIT THIS PAPER BUT SINCE WE
FOLLOWED THIS LAMIN 8
INTERACTION WE SHOW THAT LAMINA
IS MORE [INDISCERNIBLE] THESE
CELLS SO IT'S A LITTLE BIT
TRICKIER WITH MASS SPEC BUT I
HOPE WILL GET THE DATA WITH THE
NEXT WEEK AND THEN WE CAN SUBMIT
THE PAPER.
OKAY SO NOW, A LITTLE BIT OF
DIFFERENT FUNCTION OF CELL 6, WE
ALSO VERY INTERESTED IN GENOME
STABILITY FROM THE POINT OF VIEW
OF [INDISCERNIBLE] DNA,
COMPARATIVE DEVELOPMENTS THAT
MAKE A HUGE PORTION OF OUR
GENOMES AND WE FOUND SO THAT WAS
PUBLISHED YEARS AGO THAT CELL 6
PLAYS IMPORTANT ROLE IN
SILENCING [INDISCERNIBLE]
BECAUSE YOU KNOW AS WE GET OLDER
THESE ANIMALS BECOME DEPRESSED
SO THAT CAN LEAD TO ACTUALLY
VERY SEVERE CONSEQUENCES AND
WHEN WE ANALYZED THESE CELL 6
KNOCK OUT MICE THAT THEY MENTION
INNED BEGINNING SO BESIDES JUST
GENERAL GENOMIC STABILITY, THEY
ALSO SHOW A HUGE ACTIVATION OF
LINE 1 ELEMENTS SO LINE 1S THOSE
AUTONOMOUS RETROTRANSPOSONS THAT
CAN WRAP AROUND DNA DAMAGE AND
IF WE PUT CELL 6 BACK INTO THESE
CELLS WE CAN RESCUE THIS
ACTIVATION.
SO THAT'S WHAT WE PUBLISHED BACK
THEN.
NOW MORE RECENT WORK, WHAT WE
FOUND WAS THAT BESIDES JUST
HOPPING AROUND AND MAKING DNA
BREAKS, WHAT LINE 1S CAN DO
THAT'S ACTUALLY [INDISCERNIBLE]
PERHAPS MORE DAMAGING, THEY
GENERATE YOU KNOW A LOT OF LINE
1 DNA, IN THE CELL IS AT 50 I
DEPARTMENT KNOW WHERE THE DNA
IS, WE MEASURED IT BY PC R,
QUANTITATIVE PC R AND WE FOUND
THAT SIRT6 MUTANT CELLS AND
CELLS FROM AGE ANIMALS THAT HUGE
ELEVATION OF [INDISCERNIBLE],
AND IT WAS VERY DIFFICULT TO
UNDERSTAND BECAUSE IF YOU
IMAGINE IT'S IN THE GENOME AND
THEN HAVE YOU 10 TIMES MORE LINE
1 SO THAT MEANS WITH GENOME IS
10 TIMES BIGGER DIDN'T MAKE ANY
SENSE UNTIL WE TRIED TO FIND
WHERE THEY'RE LOCATED AND EVEN
EXTRA NUCLEUS, SO THIS IS
STAYING IN [INDISCERNIBLE].
DNA AND IT'S AROUND THE
[INDISCERNIBLE], IT'S NOT
EXCITED SO SOMEHOW THESE
TRANSPOSONS MAKE THOSE DNA
COPIES THAT FIND THEIR WAY
OUTSIDE OF THE NUCLEUS AND WE
ALSO THEN CELL FRACTIONATION AND
VERY SIMILAR RESULT IN SIRT6 IMK
OUTS ALSO IN OLD CELLS, WE SEE A
LOT OF LINE 1 DNA THAT'S IN THE
CYTOPLASM.
SO THAT'S FROM A MOUSE LONG,
MOUSE SPLEEN, THE SAME THING SO
THERE IS DNA IN THE CYTOPLASM
AND THERE IS DNA IN THE
CYTOPLASM IT'S USUALLY WHEN
YOU--[INDISCERNIBLE] BECAUSE
USUALLY DNA IN THE CYTOPLASM
MEANS IT'S AN INFECTION, A
VIRUS, SO THERE ARE THESE
NUCLEIC SENSORS IN THE CELL THAT
EVOLVE TO DETECT CYTOPLASM DNA
AND IMMUNE RESPONSE SO 1 OF
THOSE SENSORS IS PROTEIN CALLED
CGAS, IT BINDS CYTOPLASMIC DNA
AND THEN YOU GET THE RESPONSE.
SO WE MADE IP FOR CGAS AND WE
LOOKEDDA THE WHAT DNA ASSOCIATES
WITH IT AND WE FOUND IN CELL 6
KNOCK OUTS THERE WAS A LOT OF
LINE 1 DNA THAT WAS BOUND TO
CGAS.
SO IN BIND CGAS AND THEN IT ALSO
INDUCES INTERFERONS.
SO THAT WAS KIND OF A NEW WAY WE
FOUND THAT WELL BESIDES DAMAGE
IN DNA THOSE TRANSPOSONS CAN
ALSO INFUSE INFLAMMATION AND
THEN WE THOUGHT, WELL, CAN WE
SOMEHOW EXTERMINATE THEM, LIKE
THESE ARE FILE O GENOMIC PESTS,
AND THERE ARE DRUGS THAT CAN
SUPPRESS RETROTRANSPOSITIONS SO
THESE WERE DRUGS THAT WERE
DEVELOPED AGAINST HIV, THEY
INHIBIT REVERSE TRANSCRIPT ACE
OF HIV AND SOME OF THEM CLOSELY
ACT WITH LINE 1 CANNED WHAT.
SO WE TREATED OUR MICE, THOSE
SIRT6 KNOCK OUT MICE, WE TREATED
THEM WITH THESE DRUGS AND WHAT
WE OBSERVED THAT THESE MICE HAD
VERY STRONG INTERFERON RESPONSE
BUT IF WE TREAT THEM WITH THE
DRUGS WE CAN COMPLETE THE
RESCUE, INTERFERON CANNED WHAT
AND WE ALSO MAKE THESE MICE LIVE
A LITTLE BIT LONGER.
SO NORMALLY THEY'RE ALL DEAD BY
30 DAYS BUT [INDISCERNIBLE]
DRUGS WE COULD MAKE THEM LIVE
ALMOST TO 60 DAYS.
SO THESE ARE CELL 6 KNOCK OUTS
OF COURSE WHAT ABOUT THE WILD
TYPE, WE ARE VERY INTERESTED IN
THE WILD TYPE, IF WE PUT MICE,
WE TOOK FIRST, WE THOUGHT, YOU
KNOW JUST PURCHASED VERY OLD
MICE AND WE PUT THEM ON THESE
DRUGS AND THEY DIDN'T HELP THEM.
AND THEN WE THOUGHT, WELL, WE
OBSERVED SOME LIVER INFLAMMATION
SO THE DRUGS MAY BE WERE JUST
CLOSING TOXICITY IN THESE VERY
OLD MICE, SO THEY'LL BE TREATED
MIDDLE AGE MICE FOR A FEW MONTHS
AND THEN WE MEASURED THE
BIOMARKERS, SO THIS IS
METHYLATION CLOAK AND WE SEE
THAT MICE THAT WERE TREATED WITH
THE DRUGS HAD LOWER METHYLATION
AGE, WE ALSO TREATED MICE THAT
HAD THE P16 LUCIFERASE CONSTRUCT
SO P16 IS ANOTHER PROTEIN THAT'S
ELEVATED IN SENESCENSEL AND THEN
WE MEASURED LUCIFERASE SIGNAL
AND IT WAS LOWER IN THE TREATED
MICE AGAIN BUT THIS BIOMARKER WE
COULD SEE REDUCES STAGE IN THE
TREATED MICE.
SO THIS IS THE SUMMARY THAT WE
HAVE THOSE ELEMENTS OF, YOU KNOW
WAKING UP BIG PORTION OF OUR DNA
AS WE GET OLDER THEY BECOME
ACTIVATED SO THEY--THIS
DEPRESSIVE MECHANISM IS 1 OF
WHICH IS CELL 6, THEY START TO
FAIL WITH AGE ACCIDENT LINE 1S
BECOME TRANSCRIBED AND IN THE
PROCESS, THEY ALSO GENERATE THE
CYTOPLASMIC DNA THAT TRIGGERS
THE STAYING PATHWAY, AND CAN
TRIGGER [INDISCERNIBLE] SO THIS
[INDISCERNIBLE] INFORMATION FOR
THE BASIS OF MULTIPLE AGING
PATHOLOGIES.
YEAH, SOPHISTICATEDY THIS
ANOTHER PICTURE WITH MAMMALIAN,
THE JOURNAL DIDN'T LIKE,
BUT--[LAUGHTER]
--SO HERE, THIS IS YOUNG CELL
TRAZ POSEONS OF THE DOGS AND
THEY'RE SLEEPING AND SIRT6 AND
[INDISCERNIBLE] DNA SO THEY
DON'T RUN AROUND BUT IN OLD
CELLS, CELL 6 IS NOT HOLDING
VERY WELL, TRANSPOSONS GET
ACTIVATED AND START CHEWING ON
THE DNA WHICH IS BAD, BUT THE
WORSE IS THAT THEY ESCAPE IN THE
CYTOPLASM AND THEN THEY TRIGGER
THOSE SENSORS THAT DRIVE THE
[INDISCERNIBLE] THE POLICE CAR.
SO THAT WAS RECENTLY PUBLISHED
AND NOW IN THE REMAINING FEW
MINUTES, I WANT TO SHOW YOU SOME
RECENT THINGS AS WELL,
CENTENARIAN STORIES ARE NOT
PUBLISHED YET BUT OUR DNA REPAIR
WAS PUBLISHED THIS YEAR, AND
NOW, SOMETHING ELSE INTERESTING
THAT WE ARE DEVELOPING RIGHT
NOW, SO THIS IS THE DIAGRAM OF
WHAT SIRT6 IS DOING SO WE TALKED
ABOUT DNA REPAIR, WE DISCUSSED
THE LINE 1 TRANSPOSONS AND WE
FOUND THAT THERE IS THIS
INTERESTING PHOSPHORYLATION SITE
AND 6 IT THIS WAS DONE IN
COLLABORATION WITH WILLS GROUP
AND WE SHOWED THAT THE
PHOSPHORYLATION OF THE S10 WHICH
IS DONE BY GMP IS IMPORTANT FOR
DRIVING CELL 6 TO DOUBLE STRAND
BREAKS AND WE COULD ENHANCE
RECRUITMENT WITH THIS
PHOSPHORYLATION, SO, SOMETHING
MORE RECENT AND HERE IS FINGER
FROM THE PAPER THAT WE MADE FROM
A MUTANT OF SIRT6 RECRUITMENT
AND IT WAS BETTER THAN THE WILD
TYPE DOUBLE STRAND BREAKS AND
THIS S10 AMUTANT WHICH CAN NOT
BE PHOSPHORALATED GOES A LITTLE
SLOWER SO MORE RECENTLY WE FOUND
THAT THIS MUTANT CAN ACTUALLY,
IT'S LESS GOOD FOR DNA REPAIR
BUT IT'S BETTER TO BE PRESSING
[INDISCERNIBLE] SO THIS
PHOSPHORYLATION SITE MAY BE
DIRECTING SIRT6 TO WHAT THESE
MAY FUNCTION AND IN THE MEAN
TIME SO THIS SAWLS WORK OF MARK
SIMON.
HE GENERATED CRSPR 6 MICE WITH
THESE 2 STEM MUTATIONS SO HE
MADE THIS A, CANNOT BE
PHOSPHORALATED AND IS BETTER FOR
[INDISCERNIBLE] DEPRESSION AND
HE MADE S10 E THAT IS REMIXED
CONSTITTATIVE PHOSPHORYLATION.
SO WE ARE BEGINNING TO
CHARACTERIZE THESE MICE, SO
SOMETHING VERY INTERESTING THAT
MARK FOUND.
S10 EMICE, A SUPER GOOD AT
DEALING WITH THE DNA DAMAGE SO
HE RADIATED THESE MICE, WITH 10
DEAGREE OF GAMMA RADIATION WHICH
IS SUPPOSED TO [INDISCERNIBLE]
THEM AND WHICH IT DID FOR THE
WILD TYPES BUT S10 E, ACTUALLY
MANY MICE SURVIVED SO THAT WAS
UNBELIEVABLE SO THEY'RE SO GOOD
AT DEALING WITH THE DNA DAMAGE
AND THEN WE ALSO HAVE LIFE SPAN
STUDY THAT IS ONGOING AND THAT
WAS KIND OF FIRST DIFFICULT TO
UNDERSTAND RESULT, BUT WHAT WE
SEE THAT S10 E, DOESN'T SEEM TO
BE VERY DIFFERENT FROM THE WILD
TYPE.
BUT S10A IT'S ALMOST 20%, LONGER
LIVED WHICH IS SOMETHING
UNEXPECTED SO WHAT WE THINK, YOU
KNOW MAY BE GOING ON HERE IS
THAT THERE ARE THESE 2 FUNCTIONS
OF SIRT6, 1 IN PROMOTING DNA AND
ANOTHER 1 SILENCING.
THEY ARE BOTH IMPORTANT BUT BY
PLAYING WITH THIS SIGHT WE CAN
NATURALLY CHALLENGE SIRT6, WITH
THE OTHER ACTIVITY AND
REPRESSING LINE 1 SEEMS TO MORE
IMPORTANT FOR LONGEVITY BECAUSE
THAT'S PROBABLY WHAT PREVENS
AGE RELATED INFLAMMATION SO WE
ARE NOW ALSO LOOKING AT
INFLAMMATION IN THESE MICE, SO
THIS IS AN ONGOING PROJECT AND
PERHAPS ALSO WITH SIRT6
ACTIVATORS WE CAN TRY TO, YOU
KNOW EITHER STIMULATE THIS
FUNCTION OR THAT FUNCTION.
YOU KNOW, MAYBE SOME
IMPLICATIONS THERE AND YOU KNOW
I SAID LINE 1 SILENCING BUT THIS
MAY BE ALSO CHROMATIN
MAINTENANCE IN GENERAL SO IT'S
LIKE MORE EPIGENETIC ROLE VERSUS
[INDISCERNIBLE] DNA.
SO LET ME SUMMARIZE AND WE
DISCUSSED DIFFERENT LONGEVITY
MECHANISM SO AGAIN WE DIDN'T
HAVE TIME TO TALK ABOUT
[INDISCERNIBLE] SPECIFIC
MECHANISM WE FOUND
[INDISCERNIBLE] THINGS, SO HERE
ARE DIFFERENT SPECIES THAT ARE
LONG LIVED AS OPPOSE TO TYPICAL
LABORATORY ORGANISMS SO WOO FIND
THIS SPECIFIC MECHANISM AND ALSO
CONSERVED MECHANISM THAT THE
SAME, YOU KNOW--TUNE THE SAME
WAY, NO LONG LIVED SPECIES AND
MECHANISMS WE'VE BEEN REPORTED
FOR SOMETIME THESE NUTRIENT
SENSING PATHWAYS SUCH AS
[INDISCERNIBLE] AND IGF AND MORE
THAT ARE IMPORTANT FOR LONGEVITY
AND NOW WE CAN ADD HERE, DNA
DOUBLE STRAND BREAK REPAIR SO WE
KNOW A PATHWAY IS A PATHWAY OF
LONGEVITY AND ALL SIRT6 AND BY
COMBINING, YOU KNOW SOMETHING
FROM HERE, SOMETHING FROM HERE,
YOU KNOW THEN WE HOPEFULLY CAN
DEVELOP SOME USEFUL
INTERVENTIONS FOR HUMAN HEALTH
SPOT.
SO THESE ARE PEOPLE WHO DID THE
WORK, I ACTUALLY NAMED MOST OF
THEM WHILE I WAS GOING ALONG SO
THIS IS MARK HERE, THIS IS
XIAO BEFORE HE MOVED ON TO HIS
NEXT POST DOC, ALL THIS WAS DONE
IN COLLABORATION WITH
[INDISCERNIBLE] WITH MY CO-PI ON
ALL MY PROJECTS AND WE HAVE MANY
EXTERNAL COLLABORATORS SO WE'RE
ALWAYS RIGHT HERE.
WE HAVE THESE 2 BIG PROGRAM
PROJECTS, 1 IS FOCUSED ON
COMPRATIVE BIOLOGY,
[INDISCERNIBLE] AND
[INDISCERNIBLE] PROGRAM FOR
[INDISCERNIBLE] AND I WILL BE
HAPPY TO TAKE QUESTIONS.
[APPLAUSE ]
>> THANK YOU FOR A WONDERFUL
TALK.
WE WILL START WITH A COUPLE
QUESTIONS FROM HERE BEFORE WE
MOVE,A ROUND TO THE OTHER SITES.
>> MAYBE I CAN JUST ASK YOU
WHILE THEY'RE LANGUAGING ABOUT
T6 IS INVOLVED IN BR, EVER SINCE
BR IS 1 OF THE 5, WHAT DO YOU
THINK ABOUT BR AND LONGEVITY.
>> WELL I'M ALMOST SURE IT'S
IMPORTANT AND THERE'S SO MUCH
WITH THEOXIDATIVE DAMAGE AND
DOUBLE STRAND BEPAIR BECAUSE IF
YOU ARE REALLY DESTROYED BR,
IT'S LETHAL.
MAYBE THAT'S PART OF THE REASON
THAT THERE ARE A FEW BUT THEY'RE
NOT--YOU DON'T TELL THEM WHAT
BECAUSE MOSTLY THEY WERE
MEASURING INDIVIDUAL ENZYMES
THAT DIDN'T SHOW VERY STRONG
ASSOCIATION BUT MAYBE THAT NEEDS
TO BE REVISITED AND FOR THE ROLE
OF 6, YES, IT IS ALSO INVOLVED
THEY WOULD SUGGEST THAT MAYBE
THERE IS VERY SIMILAR
ASSOCIATION FOR LONGEVITY.
>> OKAY, SO BEING SIRT6,
[INDISCERNIBLE] LINE 1
EXPRESSION, ARE WE ABLE TO LOOK
AT THIS IN THE CENTENARIANS?
>> OH YES, I DIDN'T SHOW THE
DATA.
YES, YES, WE DID.
AND CENTENARIANS SIRT6 IS BETTER
THROUGH [INDISCERNIBLE] SO IT'S
ACTUALLY DOES BOTH.
YES.
>> WILL, CAN PEOPLE USE THE
MICROPHONE TO ASK QUESTIONS
BECAUSE THEY AREN'T COMING
THROUGH ON THE BROADCAST.
>> WE WILL TRY REPEATING
QUESTIONS TOO.
>> WHAT WAS THE QUESTION?
>> [INDISCERNIBLE].
>> [INDISCERNIBLE]
>> OH YES, SO IT WAS PREPORTED
THAT CELL 6--
>> CAN YOU REPEAT THE QUESTION
PLEASE.
>> YES, YES.
SO THE QUESTION IS: IT WAS
REPORT THAD SIRT6 CAN
TRANSCRIPTIONALLY CONTROL
NFCAPPA B AND INFLAMMATION
PATHWAY SO THIS IS IMPORTANT
VERSUS EFFECT ON LINE 1 THAT WE
SHOWED IS WELL, YES WE COULD
DISASSOCIATE IT BECAUSE FOR
EXAMPLE THAT MICE SHOW IN
CONSTANT WITH THE HUMAN
RESPONSE, WE COULD, YOU KNOW IN
1 BLAST ON THESE MICE, WE COULD
JUST USE THIS HRNA TO LINE 1 AND
BE COMPLETELY APPROPRIATE
INTERFERON RESPONSE SO THIS
NFCAPPA B, PERHAP ITS PLAYS SOME
ROLE BUT WE [INDISCERNIBLE] SO
THAT IT WAS REALLY LINE 1
DEPENDENT.
OKAY.
>> OKAY THEN WE'LL GO ON TO THE
CENTERS, LET'S START WITH YOU
STEVE IN OREGON, SO EVERYONE
ELSE MUTES AND 1 QUESTION PER
SITE.
>> THANK YOU VERY MUCH.
WILL YOU ACTUALLY TOOK THE
INITIAL QUESTION WE HAD HERE IN
REGARD TO THE ROLE OF V. E. R.
AND WHETHER THERE HAD BEEN
ANYTHING LOOKED AT RELATIVE TO
THE LEVELS OF OGG 1 ESPECIALLY
IN LIGHT OF DIRECT MEANS
RELATIVELY RECENT WORK SHOWING
THE NECESSITY WE'RE CREATING
THOSE BREAKS THAT WE'RE GOING TO
BE P A RT DEPENDENT SO IT SOUNDS
LIKE THAT THAT'S NOT BEEN
ADEQUATELY LOOKED AT BUT 1 OF
THE QUESTIONS CONCERNING SOME OF
THESE TRANSGENIC MICE WHERE
YOU'VE DONE SOME OF THE DOMAIN
SWAPPING ARE THERE ANY RPGHT
BEHAVIORIAL EFFECTS OR METABOLIC
EFFECTS THAT YOU SEE ASSOCIATED
WITH THOSE MICE?
>> WELL THAT'S A GOOD QUESTION.
YEAH, SO THE SWAPPING MOUSE WE
DON'T HAVE YET, SO WE HAVE THE
MICE WITH PHOSPHORYLATION SITE
MUTATION SO WE ARE
CHARACTERIZING IT.
I DON'T REALLY HAVE MUCH TO TELL
YOU RIGHT NOW BECAUSE IT'S SLOW
GOING.
WE NOTICED THAT YOUNG S10
E MICE, REPAIR THEY SEEM TO BE
MORE ACTIVE BUT OVERTIME THOSE
LINES KIND OF MEET AGAIN SO WITH
MIDDLE AGED MICE WE DON'T SEE
THE DIFFERENCE BECAUSE S10 MICE
TEND TO BE A LITTLE BIT HEAVIER,
SO AGAIN, WHEN THE ORGANISM
LEVEL, THERE ARE ALL THOSE
COMPLICATIONS SO WE'RE STILL
TRYING TO SOLVE THIS OUT.
>> I ASSUME YOU'RE JUST KEEPING
THOSE MICE ON A NORMAL CHOW DIET
AND NOT WHERE THERE WOULD BE A
REALLY RELATIVELY LOW FAT
CONTENT IN THEIR CHOW?
>> WELL, SO FAR IT'S ALL BEEN
REGULAR CHOW BUT THAT'S A VERY
GOOD IDEA TO TRY TO CHALLENGE
THEM METABOLICALLY.
INTERESTING.
YES.
>> OKAY, THANKS.
STEVEN THANKS, OREGON AND THEN
LET'S MOVE OVER TO PITTSBURGH.
EVERYBODY ELSE MUTE PLEASE?
>> HI, VERA THIS IS BEN
[INDISCERNIBLE] WE ENJOYED YOUR
SEMINAR VERY MUCH HERE IN
PITTSBURGH.
I HAD A COMMENT AND A QUESTION.
THE COMMENT IS JOHN
[INDISCERNIBLE] CAME AND GAVE A
TALK HERE RECENTLY AT THE AGING
INSTITUTE AND HE TALKED ABOUT
HIS BEAUTIFUL WORK WITH THE LINE
ELEMENTS AND THE NRTIs AND 1
CONCERN THAT PEOPLE RAISED WAS
THAT TOO MUCH OF A GOOD THING IS
A BAD THING AND THE NRTIs
COULD HURT MITOCHONDRIAL
FUNCTION BECAUSE GAMMA COULD
INSERT THEM INTO THE
MITOCHONDRIA, YOU SHOWED 1 DOSE
BUT MAYBE IT DIDN'T WORK IN
OLDER ANIMALS BECAUSE MAYBE YOU
DIDN'T GET THE DOSE RIGHT.
BUT MY QUESTION HAS TO DO WITH
MONORIEBS ONALATED P A RP AT
LISINE 521, DO YOU KNOW IF JOHN
PASCAL OR ANYBODY ELSE HAS SHOWN
THAT BINDS MORE AVIDLY TO DOUBLE
STRAND BREAKS OR A-BASIC SITES
OR IS IT JUST NOR CATALYTICALLY
ACTIVE?
>> THESE ARE ACTUALLY, THERE ARE
2 QUESTIONS RIGHT?
SO LET'S START WITH THE P A RP,
NO, WE HAVEN'T CHARACTERIZED IT
ENOUGH.
I THINK THIS WOULD BE VERY
INTERESTING TO DO SOPHISTICATED
SEE WHAT EXACTLY THAT
MODIFICATION DOES IN THE P A RP
LEVEL.
SO I THINK--I AM GOING TO GET
SOMEONE TO DID IT BECAUSE THAT
REALLY CHANGES SOMETHING WITH P
A RP, BUT WE HAVEN'T SIGNIFY
SECTIONAL ANALYSISSED IT FURTHER
AND NOW TO YOUR FIRST QUESTION
ABOUT NRTIS WHETHER IT'S A GOOD
THING OR A BAD THING, WE HAVE
ANOTHER PROJECT WHICH WOULD TAKE
ME TO ANOTHER SEMINAR TO PRESENT
WHICH I DIDN'T TALK ABOUT WHERE
WE ACTUALLY FOUND EXECUTIVE
[INDISCERNIBLE].
SOEE USED A DIFFERENT ORGANISM,
BLIND MOLE RAT THAT THEY DID
PROPERLY INTRODUCED, IT'S
ANOTHER LONG LIVED RODENT AND
USING THAT ANIMAL SO WE FOUND
THAT LINE 1S IN THE ANIMAL, ARE
IMPORTANT FOR [INDISCERNIBLE].
SO WHAT HAPPENS THERE, SAME
STORY ACTIVATED TRANSPOSONS, 3
[INDISCERNIBLE], TRIGGER
[INDISCERNIBLE], AND THAT'S WHAT
ELIMINATE PREMALIGNANT LESIONS
AND THEN IT FITS WELL BUT IF WE
COMPLETE LYE DEPRESS THOSE
ELEMENTS WE ACTUALLY CAN MAKE
ANIMALS MORE SENSITIVE TO CANCER
SO THIS IS KIND OF THIS OTHER
IDEA WE'RE DEVELOPING RIGHT NOW
THAT LINE 1S MAY BE THE DOUBLE
EDGED SWORD BECAUSE IN THE YOUNG
ANIMAL THEY PLAY TUMOR
SUPPRESSIVE ROLE BUT AS THEY GET
OLDER THEY GET ACTIVE AND LEAKY
AND THEN THAT TRIGGERS
FORMULATION AND THEN SIMILAR
PROCESS LIKE SENESCENSEL P53
WOULD BE THE YOUNG AND THEN THE
[INDISCERNIBLE] INTO THE OLD BUT
THEN IN TERMS OF DEVELOPING
THERAPEUTICS THAT MAKES YOU
THINK ALL RIGHT, IF WE JUST WANT
TO REFRESES THEM ALTOGETHER LIKE
IS IT GOING TO HURT US AT SOME
POINT.
SO WE DON'T KNOW AT THIS POINT
WE DON'T KNOW, WE GENERATED
ANOTHER MOUSE MODEL WHICH WE
HAVEN'T CHARACTERIZED BUT YET,
WE'RE--WE ARE USING SEVERAL
LINKED SHRNAs WHERE WE REPRESS
LINE 1 BY 50%.
SO I CAN TELL YOU THESE MICE ARE
ALIVE.
YOU KNOW?
SO, YOU KNOW THESE DON'T USE
LINE 1 ACTIVITY BUT HOW WE GO AT
THE CANCER AGING, WE DON'T KNOW
YET.
>> THANK YOU.
THANKS.
NOW LET'S GO TO KENTUCKY.
DAVE?
>> IS HI, REALLY ENJOYED YOUR
TALK VERA, I HAD 1 QUESTION, I
NOTICED THAT SIRT6 FROM
CENTENARIANS THAT INTERACT
STRONGLY WITH LAMINA, THAT'S
CORRECT, RIGHT?
>> YES, SO OBVIOUSLY LAMINA IS
DIFFERENT AND HAVE YOU LOOKAD
THE WHETHER THAT INTERACTION IS
ABOLISHED IN CELLS FROM
PROGERIATRICKIZATIONIA PATIENTS?
>> SO THAT IS ACTUALLY THE WORK
FROM [INDISCERNIBLE] LAB.
I THINK HE REPORTED THAT THERE
S&P INTERACTION BETWEEN
LAMINACE, AND PROGERIAN, IT
WASN'T ABOLISHED IT WAS THE
OPPOSITE, AS THE PROGENERRIAN
WAS TRAPPING IT CLOSE TO THE
MEMBRANE.
SO I THINK THATIA KIND OF WHAT
PROGERRIAN DOES, SO INSTEAD OF
LOSING INTERACTION, IT
SEQUESTERS PROTEINS IN THE
APPROPRIATE SO NOW WHAT
CENTENARIAN BINDS BECAUSE THAT
ISN'T WHAT THE WILD TYPE KIND SO
THEN IT'S KIND OF--THE CORRECT
INTERACTION AND THEN IT'S
BENEFICIAL.
>> SO DOES THAT ACCELERATE IN
OUR STRAND BREAKS OR INCREASED
STRAND BREAKS AND
PROGERIATRICKIZATIONIA CELLS
BECAUSE IF YOU SEQUESTER CERTAIN
6 THEN YOU--
>> YES SO--
>> TO BE REGRESSED AND?
>> RIGHT AND AGAIN FROM
[INDISCERNIBLE] WORK SO HE
MEASURED THE DNA REPAIR TO USING
OUR ASSAYS AND THERE WAS REDUCED
THAT WAS [INDISCERNIBLE], YEAH.
>> AND ALSO REDUCE THE
[INDISCERNIBLE]
>> MM-HMMEASURE.
>> OKAY, THANK YOU, DAVE.
THANK YOU GOOD TO SEE YOU AND
THEN WE GO TO GAINSVILLE,
FLORIDA.
>> HI THERE.
>> HI, THANK YOU FOR THE TALK,
THIS IS MICHAEL MCINTOSH FROM
UNIVERSITY OF FLORIDA.
I HAVE 2 QUESTIONS.
ONE HAVE YOU--
>> JUST 1 NOW.
>> SO, ALL RIGHT, I WILL--ALL
RIGHT, SO THE FIRST QUESTION I
CAN THINK OF IS THE--HAVE YOU
LOOKED AT THE SPINY MOUSE MODEL
THAT SEEMED TO BE THESE REALLY
LONG LIVED MICE.
THEY LIVE LIKE 5 YEARS INSTEAD
OF 3.
>> RIGHT WE WANT TO LOOK AT THE
SPINY MICE, SO THEY'RE NOT PART
OF OUR COLLECTION YET BUT WE
WERE PLANNING ON GETTING THEM SO
COLLABORATING WITH LAB WITH
KENTUCKY.
SOY WE DON'T KNOW YET.
SO 5 YEARSOOSE NOT SUPER LONG
LIVED RIGHT?
NAKED ROLE RATLIFFS 30 YEARS, I
THINK THEY'RE GENERATED FOR THE
MORE THAN LONGER LIFE SPAN SO
THAT'S WHY, YOU KNOW WE WILL
NOTE THE FIRST THING AND WE WILL
GET, YOU KNOW WORK IN OUR ANIMAL
COLLECTION BUT OF COURSE WE WANT
TO LOOK AT IT.
>> OKAY, WE WILL COME BACK FOR
ROUND FOR ANY FOLLOW UPS.
SO THANK YOU GAINSVILLE.
>> I WILL GET MY [INDISCERNIBLE]
>> NOW WE GO TO NIEHS.
>> HI, THIS IS MATT AT NIEHS,
CAN YOU HEAR ME?
>> YES.
>> WONDERFUL.
I WANT TO EXTEND A QUESTION THAT
STEVEN AND BEN WERE TOUCHING ON,
ON THE MICE THAT HAVE AN
EXTENDED LIFE SPAN, DO THEY DIE
OF DIFFERENT PATHOLOGIES
COMPARED TO THE UNINFECTED
MYSELF TO THE WILD TYPE MICE?
>> WELL WE DEPARTMENT SEE
ANYTHING, YOU KNOW--DIDN'T SEE
ANYTHING YOU KNOW STRIKING BUT
WE HAVEN'T REALLY DONE YET AND--
>> CHANGED THE ABILITY OF INNATE
IMMUNITY BECAUSE OF THE NRTIs,
ALL OF THAT WOULD BE INTERESTING
TO SEE IF YOU HAVE THE CHANGES.
>> THANK YOU MATT, THANK YOU.
>> THANK YOU.
>> LET'S GO TO NCI.
>> THANK YOU.
IT'S NICE WATCHING YOU DO THIS,
WILL.
IT'S REALLY VERY WONDERFUL TALK.
HERE WE ARE IN THE CANCER
INSTITUTE, COULD YOU SAY A
LITTLE MORE ABOUT THE INCREASED
OR DECREASED CANCER
SUSCEPTIBILITY WITH THE MICE FOR
INSTANCE, THE 1S WHERE CHANGED
THE AMINO ACID COMPOSITION OF
THE SIRT6?
>> YEAH, WELL, SO I DON'T HAVE
THE DATA FOR THE S10 MICE ON
CANCER.
I THINK WE STILL ARE GOING TO
FINALIZE THE PATHOLOGY AND
CANCER ACCESS, AND WE ARE 2
COHORTS THAT WILL SHOW YOU
THEY'RE NOT VERY LARGE, BUT IT
SHOULD PROBABLY BE ENOUGH TO SEE
IF THERE IS A BIG CHANGE BUT YOU
KNOW I THINK THAT COULD BE VERY
GOOD POINT TO START IT BECAUSE
IF WE--YOU KNOW IT'S KIND OF--WE
CAN EXPECT TO HAVE MORE CANCER
EITHER WITH SUFFICIENT DNA
REPAIR OR WITH [INDISCERNIBLE]
BEING OVERLY ACTIVE SO I DON'T
EVEN HAVE A HYPOTHESIS AT THIS
POINT BUT--
>> INTERESTING TO LOOK AT
[INDISCERNIBLE] IS HAPPENING.
>> I WAS MORE THINKING OF AN
INDUCED CANCER WITH RADIATION
EXPOSURE OR SOME OTHER AGENT.
>> YEH, YEAH THAT,'S SOMETHING
WE SHOULD BE DOING IT, WE ARE
DOING RIGHT NOW, THAT'S AGAIN A
WHOLE DIFFERENT STORY.
WE HAVE MICE WITH NAKED MOLE RAT
GENES AND THERE WE'VE DONE
SUSCEPTIBILITY AND WE'VE DONE
[INDISCERNIBLE] ON THOSE MICE,
AND WE CAN EFFECT DIFFERENCES
BUT YEAH, WE SHOULD DO IT ON
THOSE SIRT6 MUTANTS.
>> OKAY, THANK YOU KEN.
NOW WE WILL OPEN IT UP FOR
ANYONE WITH A QUESTION.
>> IT WAS STONY BROOK, I DON'T
THINK--
>> STONY BROOK, SORRY.
YOUR TURN.
>> YES, WE'VE BEEN WAITING
PATIENTLY, THANK YOU THERE WAS A
LOT OF INTERESTING DATA.
>> GOOD IT TO SEE YOU.
>> AND I WANTED TO ASK, GO BACK
TO THE BEGINNING ABOUT N. E. R.
SO WE USED TO HEAR A LOT ABOUT
SOMETHING CALLED THE RODENT
PARADOX WHICH THERE APPEARED TO
BE A LOT OF UNREPAIRED UV DAMAGE
LEFT IN RODENTS DNA COMPARED TO
HUMAN DNA AND I THINK THAT'S
LARGELY BEEN DESCRIBED OUT TO
DIFFERENCES IN ON GLOBAL GENOME
REPAIR AS OPPOSE TO ACTIVE GENE
TRANSCRIBED AND ACTIVE GENE
REPAIR AND IN THE ASSAY YOU'RE
SUING, I THINK YOU SEE ONLY
ACTIVE GENE REPAIR, SO AS YOU
EXAMINE GLOBAL GENE REPAIR, YOU
SEE BIGGER DIFFERENCES, SMALLER
DIFFERENCES ARE THE SAME THING?
>> WELL, WE HAVEN'T DONE THAT
AND YOU KNOW IT'S A GOOD POINT
AND PREPARE AGAIN, IT WAS
BASICALLY, I THINK LIMITED TO
CANCER CELLS.
>> THE SAME IN MOUSE
[INDISCERNIBLE]
>> SO THEY HAD GENE IN THE
KD--SALLY WAAND IS EXPRESSED AND
IT'S POSSIBLE THAT MANY OF THE
SPECIES IN OUR NOCTURNAL GROUP
AS IN THE PICTURES AND THEN I'M
PRETTY SURE THAT THE SPECIES
THAT THE OTHER END OF THE
SPECTRUM LIKE THE SQUIRRELS
THEY'RE JUST AS GOOD AS HUMANS,
SO I WOULDN'T CALL IT RODENT
REPAIR, SO MAYBE
[INDISCERNIBLE].
BUT,A BACK TO YOUR QUESTION, I
MEAN WE HAVEN'T DISSECTED IT
[INDISCERNIBLE] IN THE NER SO I
DON'T KNOW.
>> YOU SAID YOU DID SEE--YOU DID
EXAMINE?
>> WE ONLY USE THIS 1 SARKS A
THAT'S WITH THE TRANSCRIBED
[INDISCERNIBLE].
>> WHAT I'M SAYING IS YOU MIGHT
ACTUALLY MISS SOMETHING BY NOT
LOOKING AT THE REST OF IT.
>> SO IN THIS CASE, I WOULD SAY
THAT MAYBE GLOBAL REPAIR, WE
SHOW MORE APPRECIATION WITH LIFE
SPAN?
>> THAT'S POSSIBLE.
I'M NOT SURE WHAT KIND OF
PREDICTION TO MAKE BECAUSE I
WOULD THINK REPAIRING THESE
GENES IS [INDISCERNIBLE]
IMPORTANT, YOU KNOW FOR LIFE
SPAN, SO MAYBE--I DON'T KNOW IF
WE WOULD SEE ANY KIND OF
DIVERGENCE OF THESE PATHWAYS
WITH RESPECT TO [INDISCERNIBLE].
BUT THAT WAS INTERESTING TO
TEST.
>> OKAY.
THANKS A LOT EVERYONE, I THINK
WE HAVE TO FINISH HERE NOW
BECAUSE WE'RE OVER TIME.
THANKSFOR EVERYONE FOR THE
ATTENDANCE.
THANK YOU KEN AND THANKS TO THE
SPEAKER AGAIN.
GOODBYE FOR NOW!
SEE YOU NEXT MONTH.
[APPLAUSE ]