this is Jean Louise Kalman she’s a
resident or was a resident of aural and
very much a French woman for her life
until she was a hundred she rode her
bicycle every day she smoked cigarettes
until she was 117 and her family refused
to put her in a rest home up and until
the point just a few years before her
death when she somehow managed to light
her kitchen on fire now this picture
taken a year before her death at 122 zsa
was the oldest living human being in
history
now some demography published actually
just 10 days ago suggests that the 150
years we’ve had of ever-increasing
maximum and median human lifespan that
this increase has ground to a halt and
what we’re observing now is the maximal
achievable natural human lifespan now I
did not come here today to talk about
natural human lifespan rather I want to
talk about Augmented human lifespan put
another way what becomes possible if
you’re willing to disturb the universe
of naturally occurring human biology
well if nothing else I hope that if you
guys are awakened two weeks from now in
the middle of the night and asked to
recall what it was I talked about my
hope is that you’ll remember three core
ideas and the first is that aging is not
a rigid inflexible thing quite the
contrary
it’s a flexible malleable thing and
Nature has bent and twists a twisted
aging throughout eons of evolution to
change the duration of time creatures
exist now to make that possible Nature
has had to build a series of molecular
control knobs the
things which nature actually twists and
turns to change the duration that a
creature can exist and then finally we
as scientists and drug discovery
explorers are for the first time finding
ways to turn these molecular knobs
safely what this means for all of us in
this room is we are going to be enter
we’re going to be entering an era in
which there are drugs safe drugs that
change the rate at which we age now why
do I believe all of this well let’s
begin with aging as a flexible thing so
if you look across phylogenetic space
look through evolutionary history and
you look just in the class of mammals of
which we are members and you take the
shortest living mammal the tiny shrew
and the longest living mammal the
bowhead whale no one knows actually how
long one of these creatures can live the
best estimate is at least 200 and what
you see is in a group of creatures that
is mammals which are more or less
identical in their biochemistry you have
creatures that have a greater than 200
fold difference in their duration of
time they can stay alive
now if you look at a more closely
related group specifically the rodents
and you look at the field mouse and you
look at one of its closely related
family members and you the naked
mole-rat lives ten times longer and
Brandt’s bat lives as much as 12 times
longer and these are creatures not only
with identical biochemistry but that
have been quite clustered in terms of
their evolutionary history similar
creatures very different lifespans if
you go over to far away from mammals go
all the way over to mollusks like the
hard clam that’s something people eat at
a clambake can live a maximum of
approximately forty years
well it’s deep ocean dwelling relative
the Quahog this thing as far as people
know can live at least 500 years again
they live so long no one really knows
how long these can live it’s at least a
12/12/12
full difference in maximal possible
lifespan so
this tells you that Nature has bent and
twisted biology using something and what
it’s been twisting has been these
molecular control knobs now scientists
have recently figured out what some of
these knobs are and have begun twisting
them so Robert rice was able to extend
the lifespan of a worm tenfold by
modifying one gene vulture Longo
modifying two genes and reducing calorie
intake gets tenfold extension in yeast
now a little closer to home take a fly
deleting one copy of a single gene
doubles a fly’s lifespan and now let’s
get really close to home a mouse a
creature that well certainly so much
smaller and less socially interesting
than ourselves it’s a creature with the
same biochemistry mostly that we have
and modifying a single gene and reducer
in calorie intake you get a 2x increase
in lifespan think about that for
yourself imagine being able to live to
160 or 170 these are tiny changes now
this suggests that these knobs exists
but can we really turn them in a safe
way so the answer is yes
the first example historically of such
knob turning by scientists was an
accident so it was in the 1930s and a
scientist named Clive McKay working at
Cornell during the Great Depression so
one of the things about the Great
Depression that they didn’t have was
money and so he couldn’t keep his colony
of rats alive so what he had to do was
in order to keep this precious colony
alive is he realized he had to feed some
of them every other day some of them he
fed every day something very surprising
happened the ones he fed every other day
they lived longer
in fact as much as 30% longer and it was
the first time human scientists had ever
figured out this was a knob you could
turn pretty simply now flash forward to
the 1970s this picture is in fact what
you think it is these animals are litter
joined the hip surgically their bodies
have been fused one is old one is young
so the blood of the young flows into the
old animal the blood of the old animal
flows into the young this procedure
which is deemed by some to be grotesque
turns out you can extend the life span
of the old animal by as much as 15%
suggesting there are things present in
then there’s this molecule rapamycin was
discovered on Easter Island and it’s a
natural product made by soil bacteria
and this molecule got developed
ultimately as a drug for transplant
rejection or to prevent the rejection of
transplants it’s an immunosuppressive
but one of its interesting side effects
is that properly dosed animals can live
as much as 30% longer you may ask why
aren’t we all taking this well quick
answer is that you wouldn’t want to it’s
got a bunch of untoward side-effects
that no one would want to have but the
key message is that a single molecule
dosed can change profoundly the lifespan
of a mammal if only you could figure out
how to do it safely so what have we
learned from looking at all of these
animals in these experiments well I’d
say a few key principles the first is
that very similar creatures can have
very different lifespans secondly tiny
biological changes single gene changes
can give rise to big lifespan changes
and last that there are multiple
distinct mechanisms it seemed to
regulate how long we live things like
you saw with calorie restriction or
factors that are present in young blood
so with that as some background I want
to tell you about something very cool
that my group unity it’s been working on
for the last five years and if you
accept the premise that there are
multiple aging mechanisms in operation
things like the loss of stem cells
things like direct metabolic control
like you saw with calorie restriction or
with rapamycin loss of circulating youth
factors and then there’s this wealth of
biology that we have just yet to
discover well there’s this corner of
aging biology that we’ve worked on for
the last half decade called cellular
senescence now it’s not the only reason
we age we know this is because when we
perturb this biology animals continue to
age they just age more slowly and they
age differently but what’s cool about
this is it’s the single most druggable
biology we’ve seen to date for
perturbing aging and it works like this
this is you at consume okay this is you
at conception you’re a single cell so
you divide ultimately about 50 times at
which point there is an emergency break
that gets pulled in every cell in your
body and cells stop dividing forever and
cells that pull this emergency break are
said to be senescent cells now this is a
very important emergency break you do
not want to mess with it
pharmaceutically we know this because in
mice if we genetically perturb this
system mice are born normally but wind
up full of tumors before reaching
reproductive age so do not mess with the
emergency brake however as we age these
cells with the pol emergency brake begin
to accumulate in our bodies so my son
who’s just turning eight has no
detectable senescence cells in his body
whereas my stepfather who died from
Alzheimer’s at 87 was full of these
cells now before our work no one knew if
these accumulated senescence cells were
good for you bad for you or neither and
so what my group did collaboratively
with yawn vendors in this group at the
Mayo Clinic and Judy Campisi’s group at
the buck Institute is we genetically
engineered multiple strains of mice
which we could clear these senescent
cells from the bodies of mice whenever
we wanted and for the first time we were
in a position to ask what happens well
this is what happens these mice are
siblings they’re born within seconds of
each other from the same mom and they’re
genetically inbred such that they’re
mostly genetically identical and to give
you a sense of the age of these animals
they’re about 70 years old
assuming you were a mouse now if you
look at this picture which one do you
want to be so this guy on the left is
blind osteoporotic and frail this one on
the right lives 35 percent longer but I
think more importantly than living
longer it is a profound extension of
what we call health span this is the
duration of time in which this animal
lives free of chronic diseases of Aging
things like osteoporosis osteoarthritis
kidney disease imagine getting old
without getting old now this is the
picture that I carry around on my iPhone
so when anyone ever asked me what I do I
just whipped this picture out and people
immediately start to wonder you know
when will I get to try these and I’ll
get to that just in a moment now since
we started this work five years ago
we’ve discovered more than 20 effects
positive effects on health span that
happened when we clear these senescent
cells from the bodies of mice and I’ll
just show you a few of these effects so
these are the skeletons of mice with and
without senescence cells and it allows
us to examine a variety of details that
you cannot see with just simply crude
examination of the anatomy so if you
look at the femurs of these mice the
femur is the longest and strongest bone
in all of our bodies and you look down
the central axis of this femur what you
see is this profound thickening about a
25% thickening of the wall of the femur
so and this isn’t an animal that’s
equivalent to an 80 year old person and
what you see is bone that looks like
it’s from
someone in their mid-50s if you look at
the spines of these animals so one of
the features of Aging that all of us
will face is the gradual disappearance
of the intervertebral discs and back
pain and ultimately slumping and all of
the features that are so such a hallmark
when you see an old person walking down
the street well when we clear senescence
cells from these animals over the arc of
their lives we see a 41% improved
preservation of intervertebral disk
space now these mice obviously look
different when you just stare at them
you can visually pick out which ones
have senescent cells and which ones
don’t but we wanted to have a way to
actually evaluate do they somehow behave
differently so we put these guys in a
box and we put a camera on top of this
box that recorded their motion for 15
minutes and this is what the data looks
like you see this pink line that’s a
young Mouse running around in a cage
running all over the place everything it
does for 15 minutes this is 15 minutes
of an old mouse actually it’s not a
particularly old mouse just middle aged
and so we wondered what would happen
where we declare senescence cells on
what would happen to this behavior and
what we saw was that as you age an
animal to mid life but you clear
senescence cells you get a preservation
of youthful running around nests
basically they run around to mid life
like a juvenile Mouse but more striking
at least for me they’re willing to go to
the center of the cage we have no idea
why this is and it’s very hard to get
the mouse to explain it and when people
see these data they they often wonder
well how does this become an
fda-approved drug and the answer is it
doesn’t this is something that we may
and mechanistically never understand but
it speaks to the power and gravity of
the biology that we’re now learning how
to perturb so
this brings us to the question of when
do I get mine and just a personal point
I suffer from osteoarthritis I have
degenerative disc disease in my back and
so every day when I wake up you know
these data mean a great deal to me
such that I won’t suffer the same fate
as my father who’s functionally unable
to move because of destruction of his
spine and this picture kind of explains
how we’re going to be getting into
people this is an old couple with
osteoarthritis clearly of the spine and
clearly of the knees and probably other
joints as well and this is a disease in
which you lose the cartilage that exists
between your bones in the 360 joints in
your body and this disease is the
primary reason it hurts to be old now
standard of care are things like
ibuprofen and aspirin and ultimately
mechanical joint replacement but the
reality is its standard of care for this
disease is acceptance you’re old that
sucks
buy a cane then deal with it that’s a
terrible answer in my view it’s almost
just unconscionably passive and so we as
scientists I believe have a moral
obligation to solve this and this is a
normal cartilage and I’ll walk you
through how this process works this is
what it looks like in a happy normal
knee for most people in this room as you
age and begin to get osteoarthritis this
is what happens you lose this
lubricating layer on the surface you
lose the bulk of your cartilage you wind
up in pain and with inflammatory
destruction of the joint and ultimately
an inability to move around functionally
one of the things we get a lot of at the
company is knees they arrive by Federal
Express five times a week you may say
where do we get knees we get them from
patients undergoing knee replacement and
we’re able to march across the knee from
where you have disease to where you
don’t and we actually actually see
senescent cells accumulating at sites
within patients where you have disease
and in mice were able to induce
osteoarthritis by cutting a ligament in
the knee and inducing osteoarthritis and
then clearing senescent cells and asking
what happens and we asked a mouse if it
hurts we put the mouse in a special box
in which it puts one foot on one scale
one foot on another and when it hurts it
goes like this
and these data here show that a mouse in
which we’ve cut the ACL but cleared
senescent cells are pain free
essentially we’ve been able to cure the
pain of osteoarthritis data I won’t show
you today is we can also do this in
tissue taken out of human knees we’re
able to regrow cartilage we’re going to
be in humans all things staying to plan
within 18 months so where are we I often
get this question in terms of our
understanding of aging biology the most
useful metaphor I can think of is this
pretend you’re a scientist and you study
a tree well you could be setting the
leaves you could be studying something
like the trunk
you could be studying something as
pivotal as the roots and we as
scientists who work on these different
aging mechanisms don’t know are we
studying leaves or studying the trunk or
studying the roots but 50 years from now
we’re going to have a complete picture
of this tree and hopefully a set of
drugs that act on each of these
mechanisms and it’s an honor to be able
to work on biology at this time that not
only do we get to benefit from but my
son’s gonna grow up in a world in which
a bunch of these diseases are things you
only read about in books thank you very
much
[Applause] [Music]
resident or was a resident of aural and
very much a French woman for her life
until she was a hundred she rode her
bicycle every day she smoked cigarettes
until she was 117 and her family refused
to put her in a rest home up and until
the point just a few years before her
death when she somehow managed to light
her kitchen on fire now this picture
taken a year before her death at 122 zsa
was the oldest living human being in
history
now some demography published actually
just 10 days ago suggests that the 150
years we’ve had of ever-increasing
maximum and median human lifespan that
this increase has ground to a halt and
what we’re observing now is the maximal
achievable natural human lifespan now I
did not come here today to talk about
natural human lifespan rather I want to
talk about Augmented human lifespan put
another way what becomes possible if
you’re willing to disturb the universe
of naturally occurring human biology
well if nothing else I hope that if you
guys are awakened two weeks from now in
the middle of the night and asked to
recall what it was I talked about my
hope is that you’ll remember three core
ideas and the first is that aging is not
a rigid inflexible thing quite the
contrary
it’s a flexible malleable thing and
Nature has bent and twists a twisted
aging throughout eons of evolution to
change the duration of time creatures
exist now to make that possible Nature
has had to build a series of molecular
control knobs the
things which nature actually twists and
turns to change the duration that a
creature can exist and then finally we
as scientists and drug discovery
explorers are for the first time finding
ways to turn these molecular knobs
safely what this means for all of us in
this room is we are going to be enter
we’re going to be entering an era in
which there are drugs safe drugs that
change the rate at which we age now why
do I believe all of this well let’s
begin with aging as a flexible thing so
if you look across phylogenetic space
look through evolutionary history and
you look just in the class of mammals of
which we are members and you take the
shortest living mammal the tiny shrew
and the longest living mammal the
bowhead whale no one knows actually how
long one of these creatures can live the
best estimate is at least 200 and what
you see is in a group of creatures that
is mammals which are more or less
identical in their biochemistry you have
creatures that have a greater than 200
fold difference in their duration of
time they can stay alive
now if you look at a more closely
related group specifically the rodents
and you look at the field mouse and you
look at one of its closely related
family members and you the naked
mole-rat lives ten times longer and
Brandt’s bat lives as much as 12 times
longer and these are creatures not only
with identical biochemistry but that
have been quite clustered in terms of
their evolutionary history similar
creatures very different lifespans if
you go over to far away from mammals go
all the way over to mollusks like the
hard clam that’s something people eat at
a clambake can live a maximum of
approximately forty years
well it’s deep ocean dwelling relative
the Quahog this thing as far as people
know can live at least 500 years again
they live so long no one really knows
how long these can live it’s at least a
12/12/12
full difference in maximal possible
lifespan so
this tells you that Nature has bent and
twisted biology using something and what
it’s been twisting has been these
molecular control knobs now scientists
have recently figured out what some of
these knobs are and have begun twisting
them so Robert rice was able to extend
the lifespan of a worm tenfold by
modifying one gene vulture Longo
modifying two genes and reducing calorie
intake gets tenfold extension in yeast
now a little closer to home take a fly
deleting one copy of a single gene
doubles a fly’s lifespan and now let’s
get really close to home a mouse a
creature that well certainly so much
smaller and less socially interesting
than ourselves it’s a creature with the
same biochemistry mostly that we have
and modifying a single gene and reducer
in calorie intake you get a 2x increase
in lifespan think about that for
yourself imagine being able to live to
160 or 170 these are tiny changes now
this suggests that these knobs exists
but can we really turn them in a safe
way so the answer is yes
the first example historically of such
knob turning by scientists was an
accident so it was in the 1930s and a
scientist named Clive McKay working at
Cornell during the Great Depression so
one of the things about the Great
Depression that they didn’t have was
money and so he couldn’t keep his colony
of rats alive so what he had to do was
in order to keep this precious colony
alive is he realized he had to feed some
of them every other day some of them he
fed every day something very surprising
happened the ones he fed every other day
they lived longer
in fact as much as 30% longer and it was
the first time human scientists had ever
figured out this was a knob you could
turn pretty simply now flash forward to
the 1970s this picture is in fact what
you think it is these animals are litter
joined the hip surgically their bodies
have been fused one is old one is young
so the blood of the young flows into the
old animal the blood of the old animal
flows into the young this procedure
which is deemed by some to be grotesque
turns out you can extend the life span
of the old animal by as much as 15%
suggesting there are things present in
then there’s this molecule rapamycin was
discovered on Easter Island and it’s a
natural product made by soil bacteria
and this molecule got developed
ultimately as a drug for transplant
rejection or to prevent the rejection of
transplants it’s an immunosuppressive
but one of its interesting side effects
is that properly dosed animals can live
as much as 30% longer you may ask why
aren’t we all taking this well quick
answer is that you wouldn’t want to it’s
got a bunch of untoward side-effects
that no one would want to have but the
key message is that a single molecule
dosed can change profoundly the lifespan
of a mammal if only you could figure out
how to do it safely so what have we
learned from looking at all of these
animals in these experiments well I’d
say a few key principles the first is
that very similar creatures can have
very different lifespans secondly tiny
biological changes single gene changes
can give rise to big lifespan changes
and last that there are multiple
distinct mechanisms it seemed to
regulate how long we live things like
you saw with calorie restriction or
factors that are present in young blood
so with that as some background I want
to tell you about something very cool
that my group unity it’s been working on
for the last five years and if you
accept the premise that there are
multiple aging mechanisms in operation
things like the loss of stem cells
things like direct metabolic control
like you saw with calorie restriction or
with rapamycin loss of circulating youth
factors and then there’s this wealth of
biology that we have just yet to
discover well there’s this corner of
aging biology that we’ve worked on for
the last half decade called cellular
senescence now it’s not the only reason
we age we know this is because when we
perturb this biology animals continue to
age they just age more slowly and they
age differently but what’s cool about
this is it’s the single most druggable
biology we’ve seen to date for
perturbing aging and it works like this
this is you at consume okay this is you
at conception you’re a single cell so
you divide ultimately about 50 times at
which point there is an emergency break
that gets pulled in every cell in your
body and cells stop dividing forever and
cells that pull this emergency break are
said to be senescent cells now this is a
very important emergency break you do
not want to mess with it
pharmaceutically we know this because in
mice if we genetically perturb this
system mice are born normally but wind
up full of tumors before reaching
reproductive age so do not mess with the
emergency brake however as we age these
cells with the pol emergency brake begin
to accumulate in our bodies so my son
who’s just turning eight has no
detectable senescence cells in his body
whereas my stepfather who died from
Alzheimer’s at 87 was full of these
cells now before our work no one knew if
these accumulated senescence cells were
good for you bad for you or neither and
so what my group did collaboratively
with yawn vendors in this group at the
Mayo Clinic and Judy Campisi’s group at
the buck Institute is we genetically
engineered multiple strains of mice
which we could clear these senescent
cells from the bodies of mice whenever
we wanted and for the first time we were
in a position to ask what happens well
this is what happens these mice are
siblings they’re born within seconds of
each other from the same mom and they’re
genetically inbred such that they’re
mostly genetically identical and to give
you a sense of the age of these animals
they’re about 70 years old
assuming you were a mouse now if you
look at this picture which one do you
want to be so this guy on the left is
blind osteoporotic and frail this one on
the right lives 35 percent longer but I
think more importantly than living
longer it is a profound extension of
what we call health span this is the
duration of time in which this animal
lives free of chronic diseases of Aging
things like osteoporosis osteoarthritis
kidney disease imagine getting old
without getting old now this is the
picture that I carry around on my iPhone
so when anyone ever asked me what I do I
just whipped this picture out and people
immediately start to wonder you know
when will I get to try these and I’ll
get to that just in a moment now since
we started this work five years ago
we’ve discovered more than 20 effects
positive effects on health span that
happened when we clear these senescent
cells from the bodies of mice and I’ll
just show you a few of these effects so
these are the skeletons of mice with and
without senescence cells and it allows
us to examine a variety of details that
you cannot see with just simply crude
examination of the anatomy so if you
look at the femurs of these mice the
femur is the longest and strongest bone
in all of our bodies and you look down
the central axis of this femur what you
see is this profound thickening about a
25% thickening of the wall of the femur
so and this isn’t an animal that’s
equivalent to an 80 year old person and
what you see is bone that looks like
it’s from
someone in their mid-50s if you look at
the spines of these animals so one of
the features of Aging that all of us
will face is the gradual disappearance
of the intervertebral discs and back
pain and ultimately slumping and all of
the features that are so such a hallmark
when you see an old person walking down
the street well when we clear senescence
cells from these animals over the arc of
their lives we see a 41% improved
preservation of intervertebral disk
space now these mice obviously look
different when you just stare at them
you can visually pick out which ones
have senescent cells and which ones
don’t but we wanted to have a way to
actually evaluate do they somehow behave
differently so we put these guys in a
box and we put a camera on top of this
box that recorded their motion for 15
minutes and this is what the data looks
like you see this pink line that’s a
young Mouse running around in a cage
running all over the place everything it
does for 15 minutes this is 15 minutes
of an old mouse actually it’s not a
particularly old mouse just middle aged
and so we wondered what would happen
where we declare senescence cells on
what would happen to this behavior and
what we saw was that as you age an
animal to mid life but you clear
senescence cells you get a preservation
of youthful running around nests
basically they run around to mid life
like a juvenile Mouse but more striking
at least for me they’re willing to go to
the center of the cage we have no idea
why this is and it’s very hard to get
the mouse to explain it and when people
see these data they they often wonder
well how does this become an
fda-approved drug and the answer is it
doesn’t this is something that we may
and mechanistically never understand but
it speaks to the power and gravity of
the biology that we’re now learning how
to perturb so
this brings us to the question of when
do I get mine and just a personal point
I suffer from osteoarthritis I have
degenerative disc disease in my back and
so every day when I wake up you know
these data mean a great deal to me
such that I won’t suffer the same fate
as my father who’s functionally unable
to move because of destruction of his
spine and this picture kind of explains
how we’re going to be getting into
people this is an old couple with
osteoarthritis clearly of the spine and
clearly of the knees and probably other
joints as well and this is a disease in
which you lose the cartilage that exists
between your bones in the 360 joints in
your body and this disease is the
primary reason it hurts to be old now
standard of care are things like
ibuprofen and aspirin and ultimately
mechanical joint replacement but the
reality is its standard of care for this
disease is acceptance you’re old that
sucks
buy a cane then deal with it that’s a
terrible answer in my view it’s almost
just unconscionably passive and so we as
scientists I believe have a moral
obligation to solve this and this is a
normal cartilage and I’ll walk you
through how this process works this is
what it looks like in a happy normal
knee for most people in this room as you
age and begin to get osteoarthritis this
is what happens you lose this
lubricating layer on the surface you
lose the bulk of your cartilage you wind
up in pain and with inflammatory
destruction of the joint and ultimately
an inability to move around functionally
one of the things we get a lot of at the
company is knees they arrive by Federal
Express five times a week you may say
where do we get knees we get them from
patients undergoing knee replacement and
we’re able to march across the knee from
where you have disease to where you
don’t and we actually actually see
senescent cells accumulating at sites
within patients where you have disease
and in mice were able to induce
osteoarthritis by cutting a ligament in
the knee and inducing osteoarthritis and
then clearing senescent cells and asking
what happens and we asked a mouse if it
hurts we put the mouse in a special box
in which it puts one foot on one scale
one foot on another and when it hurts it
goes like this
and these data here show that a mouse in
which we’ve cut the ACL but cleared
senescent cells are pain free
essentially we’ve been able to cure the
pain of osteoarthritis data I won’t show
you today is we can also do this in
tissue taken out of human knees we’re
able to regrow cartilage we’re going to
be in humans all things staying to plan
within 18 months so where are we I often
get this question in terms of our
understanding of aging biology the most
useful metaphor I can think of is this
pretend you’re a scientist and you study
a tree well you could be setting the
leaves you could be studying something
like the trunk
you could be studying something as
pivotal as the roots and we as
scientists who work on these different
aging mechanisms don’t know are we
studying leaves or studying the trunk or
studying the roots but 50 years from now
we’re going to have a complete picture
of this tree and hopefully a set of
drugs that act on each of these
mechanisms and it’s an honor to be able
to work on biology at this time that not
only do we get to benefit from but my
son’s gonna grow up in a world in which
a bunch of these diseases are things you
only read about in books thank you very
much
[Applause] [Music]
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