[MUSIC PLAYING]
DAVID SINCLAIR:
Welcome, everyone.
I'm not sure I'm going to tell
you how to live forever today,
but I'm going to tell you that
we understand how to do it.
And so thanks, Sanders,
thanks for inviting me,
and thank you all for coming.
There's a few people here that
helped make this book possible.
I want to thank them all
personally, and also for Nick
Platt for making this possible.
And also, Matt LaPlante,
who also helped
write the book in a very big
way, and he's here somewhere.
Raise your hand, Matt.
Yay.
Yeah, so this has been
a long journey for me.
I'm going to talk
for about 25 minutes
and leave time for a
fair number of questions.
So yeah, write those down.
I'm a fairly open book,
so ask me any question
and I'll do my best
to answer it honestly.
OK, so I've been working at
Harvard for, well, since 1999,
so about 20 years now.
I was 29 at the time, so I
had no idea what I was doing.
So I just turned 50,
which is good and bad.
The good part is that I
now know what I'm doing.
The bad part is that I'm
a lot closer to being
towards that edge
where we all drop off
in physical health and
mental health as well,
and we're all facing that.
Now, some of you are
very young, and it's
easy to pretend that
that's a long way off.
But it will happen.
All of us will get old,
and we will all die.
And it's a terrible thought.
It's also terrible to think
that our parents and everybody
we love will also face this.
Now, dying isn't the
point of all this.
I mean, the point
is to actually try
to prevent people from
being sick for the last 10
years of their life.
And the hope is
that our generations
will be able to
expect to live till 90
and play tennis, and
even make it to 100
and still have a
career, a second, third,
or fourth career, second, third,
or fourth partner, if you want.
But the important
point here is that this
isn't about living forever,
it's about changing
the way we treat people in
terms of health care, medicine.
Right now, aging is not
considered a medical condition.
Does anyone have any
idea why we don't
call aging a medical condition?
Just think about it.
Why don't we?
So the medical
definition of a disease
is something that
happens over time
that causes you to lose
function and become disabled.
Sounds pretty much
like aging, right?
The reason that aging
isn't a medical condition
yet is because it
happens to more than 50%.
But what we argue in the book
is that just because something
affects 51% or 50.1%
of people doesn't
mean it's any less important
than a rare disease.
In fact, I would argue
that it's more important.
And I hope that after you have
a chance to read the book,
you come away realizing that it
has been insane to regard aging
as something that is separate
from a disease or a disorder.
Now, the World
Health Organization
has declared aging for the
first time as of this year
as a medical condition.
It's really quite amazing to
see a large institution declare
aging as a condition.
And what we hope is that it
will soon change the way doctors
look at aging.
I don't know if we have any
doctors in the audience,
but where I work over at
Harvard Medical School,
doctors are taught,
in part by me,
that there are certain
pathologies and diseases,
and if it happens to
less than 50% of people,
we address it aggressively.
We do medical research to stop
that disease and treat it.
And just because something
is common like aging,
we don't really do
anything about it.
We accept it as natural.
But I put it to you to
look around this room.
What part of this room,
with maybe the exception
of the wooden--
no, it's carpet, it's
not even a wooden floor.
Nothing about our
lives is natural.
Maybe oxygen we're
breathing is natural,
but everything
else is unnatural.
It's human-made, it's man-made,
and we change our environment.
And tackling diseases and
tackling aging is also natural.
That's what we do as humans.
We don't accept
misery and frailty
as natural ways of life.
We should not be doing
that for any disease,
and we should not be doing
it for old age, either.
So I want to do a quick survey
before I get into some slides
here.
How many of you would like to
live to 80, but not beyond, not
beyond 80?
Is 80 enough for
anybody in the audience?
A few.
There's a few hands.
80 is enough.
I don't know if anyone's
80 in the audience,
but you probably don't
like that answer.
What about to 120?
Who would like to live
to 120 and then die?
Yeah, what, that's
about half of you.
How many of you would
like to live forever?
OK, so there's a few people
who didn't put up their hands,
so it's somewhere in
between 120 and immortal
that they're looking for.
Rather wide gap.
Maybe let's say
150 for that group.
But that's really
interesting, right?
We don't all want to live
the same amount of years.
But what if I told
you that you could
be just as happy and healthy
and satisfied as you are today
at age 120?
How many of you would like
to have a life like that?
Exactly.
That's most of you, if not all.
The point is, and
in the book you'll
see that the point
about all of this
is that we have the technologies
to be able to be healthy much,
much longer into later in life.
So it's not about
living forever,
and it's not about just
pushing out how long you live.
It's about how well you live.
Stopping us from getting sick,
stopping cancer, heart disease,
Alzheimer's, frailty,
and diabetes.
And you might say, David,
how is that possible?
We can't even solve cancer.
How are you going to do that?
Well, what I'm going
to tell you today,
if you don't already
know about it,
is that we have a
new understanding
of what causes aging and
even how to slow it down.
And early glimpses in some
experiments I'll show you,
they're actually resetting
the aging clock of the body.
All right, so to
really understand
how to delay diseases
and live longer--
and turns out, guess
what, if you're not sick,
you tend to live longer, that's
what we're all about here--
you need to really
understand how it works, why
it happens in the first place.
We can debate why
aging has evolved.
That's not really the
point for this talk.
But really, why does it
happen at the nanoscale,
at the molecular level,
and I think we finally
have an answer to why we age.
And it's not because
of free radicals,
and it's not going to be stopped
by antioxidants, though that
hasn't stopped marketers
building about $150
billion industry every year.
But what's different in
the book and my research
is that we've got a new
idea about why we age
and why we may not have to.
So we see aging so often
that we take it for granted,
and we see it also so
often that we don't even
do anything about it.
We accept it as a natural way
of life, but we don't have to.
So this person
has been sunburned
on one side of their
face, as you can see,
and we know that sun damage, DNA
damage, broken chromosomes make
you look older and
even accelerate aging.
If you have chemotherapy
or radiotherapy,
you won't just feel older, your
body will literally be older,
and we haven't
understood why that is.
And the old idea that came
out of the 1950s from mostly
physicists who were previously
working on the Manhattan
Project, their idea was that we
ran out of genetic information,
mutations-- and I'm sure
you've probably all heard
of the mutation
theory of aging--
that we just lose our
genetic information.
Turns out, that's
probably wrong because we
can make mice that
have a lot of mutations
and they lose a lot of
their genetic information,
but they don't age prematurely.
And there's a whole
body of research now
that has made my field
essentially throw out the idea
that we are aging because of
a loss of genetic information.
So what is it that causes aging?
So aging, I put it to you, is
simply a loss of information.
I call it the information
theory of aging.
But I just told
you that it's not
due to the loss of genetic
information, so what is it?
Well, there are two types
of information in our bodies
that are essential for life.
One is genetic, and the
other is epigenetic.
And you'll probably
recall from high school
that epigenetic is the term for
any process and structure that
governs the way the genetic
information is packaged
and read by the cell.
So here's a cartoon of what
the epigenome looks like.
We've got the DNA,
which is in blue.
That's our genome.
And the genome, I
put it to you, is
a digital form of information.
It is A, T, C, G, four bases.
This would be, instead of
a binary, a quaternary mode
of transferring information
throughout our life
between cells and across
the last 4.6 billion--
well, at least 4
billion years since we
first emerged out
of the primordium.
And we think that the inability
to preserve genetic information
is not the cause of aging.
It's important for evolution,
but over the lifespan
of our bodies, we still have a
lot of that information intact.
Digital is a great way to store
information, as you all know.
You can copy it without error.
Our cells typically
do in a large way.
So what else is the problem
potentially in aging?
And that's the
epigenome, which I'm
showing you as these green
proteins that wrap up the DNA.
Those proteins
spool up the genome
in the same way you might
spool up a garden hose.
And when you spool
them up very tightly,
package that garden
hose, your genes
in that region of that hose or
in that region of the genome
will be switched off.
And those that are
exposed in a big loop--
so your garden
hose is looped out
over the driveway-- those are
genes that will be switched on.
And that's also an essential
type of information
because it tells each cell
what type of cell it should be.
Essentially all of our
cells have the same genome,
but what distinguishes a
brain cell from a liver cell
and what allows a fertilized
egg to become a 26 billion
composite of different
cell types when it's born
is the epigenome.
And the epigenome, I believe,
is the reason that we age.
It is a loss of
analog information.
Many of you are old
enough to remember what
analog information is like.
If you ever had a record
player or a cassette tape,
it's pathetic.
You can't copy it very well.
You lose information.
It degrades over time.
It scratches.
It's the reason we converted
to digital in the late 1990s.
But we are built with an
analog system of information.
This epigenome is
useless, but it
has to be engineered that way
because the epigenome needs
to respond very quickly
to the environment.
It has to have millions
of different values
rather than very discrete ones.
And it also needs to
be ready for things
that it hasn't ever seen before.
One way of thinking
of the epigenome
is it's the software
of our cells,
and the genome is the computer
or the underlying code.
The interesting thing about
this whole analog versus digital
is it gives us a new
perspective on aging.
Now, instead of talking
about a garden hose
and wrapped up proteins,
let me show you
what it really looks like.
Again, a schematic because I
don't have a photo for you.
We don't have a microscope
that's capable of doing this.
So what we're seeing on
the left is a young cell.
And what we think is going
on is that these chromosomes,
the black lines, are
wrapped up in these loops.
We call these TADs now.
These are called Topologically
Associated Domains,
and we can now map these
with great accuracy.
Just in the last few years,
we've learned how to do this.
And right across the genome,
I could do this for your cells
pretty easily.
And what we see is
that these loops of DNA
change as we get older.
And what that leads
to, as you can
see on the cell on the
right, is that over time,
genes that should be off
come on and vice versa,
and what happens is cells
lose their identity.
That's really important.
A nerve cell in an older
person is no longer fully
a nerve cell.
It's starting to move around in
so-called Waddington landscape
space, or epigenomic
space, and it's becoming
a different type of cell.
A nerve cell in an old person
maybe partly a skin cell.
I mean, think about that.
No wonder we start to lose
the function of our retina,
no wonder we start
to forget things
if our cells don't maintain
their epigenomic information.
Question is, though,
can we slow this down,
and can we reset the system?
Is there a reboot?
Is there a backup hard
drive of this early setup
that we can access and restore
that structure that you're
looking at on the left?
I believe that it's possible.
An analogy I like to use is
this compact disc or a DVD here.
For the very young
in the audience,
we used to put music and
photos on these things that
were very useful for a moment.
But anyway, so obviously, they
store digital information,
which was what was
great about them.
But what was really
sucky about them
was that they would
get scratched.
You had to be very
careful with them.
And you can see this is
a great analogy for aging
because the cells on the
right, by this analogy,
they still have the
information to play the music,
to play the concerto that
might be encoded in those zeros
and ones or those pits
in the aluminum foil,
but the reader of that compact
disc cannot read the songs
merely because the laser is
skipping and being refracted.
But what is great
about this analogy
is it's very simple in this
situation to reset the system.
You just get a bit of polish.
It's possible you could just
get a rag with some toothpaste
and polish off those scratches.
And guess what?
It's brand new.
You can read the concerto.
And if we're right
about aging, it
will be possible to essentially
do the same to our body
and allow our tissues
and our organs
to play the symphony of our
youthful lives once again.
But only if there's a backup.
We don't know if
that's true yet.
Now what the heck
is this animal?
These are two mice,
and you might want
to guess which one's older.
It's a trick question.
They're twins.
They're genetically
identical twins.
And when we read
their genomes, we
find that their genomes
are identical as well.
But what we've messed
up is their epigenomes.
We've scratched up their CD.
And you can see what
we get is not just
a mouse with gray
hair, wrinkled skin,
and if you could look
inside, organs that look old.
We haven't just
given it diabetes
or osteoporosis or dementia.
We've given this mouse aging.
And as we wrote in
the book, Matt and I,
if you can give
something, you can be sure
that you can take it away.
So that's what I'll tell
you about in a minute.
But you might ask, well, David,
how do you scratch up that DVD?
Of course, you're not taking
sandpaper to a mouse, I hope.
What we did-- and we are going
to publish this hopefully
shortly, we have manuscripts
under review at Cell--
there's a couple of
manuscripts and 10 years
of work out of my lab and 15
others from around the world
is the discovery that
broken chromosomes disrupt
the structure of those
hose reels, that DNA,
and cells start to lose
their identity so they
don't function very well.
And the ultimate outcome
of losing cellular identity
is aging.
Now what's really interesting
about this mouse is, now
that we can accelerate aging,
we can do a couple of things.
We can create a mouse that
has the equivalent of 80
years of aging, and we can
just induce these DNA cuts
in the genome as
much as we want.
We can make a
mouse 80 years old.
And we think that
these mice will
be very useful for
finding treatments
for Alzheimer's disease, which
I think ludicrously people have
been using one-year-old
mice to study
Alzheimer's disease, which, to
me, doesn't make much sense.
The other thing we can do that's
interesting about these mice
and that we've done is we can
age only part of the animal.
We've accelerated aging in
the brain of these mice,
and we're seeing
increased dementia.
But interestingly, we
can ask the question,
do other parts of the
body age faster as well
if your brain is old?
Clearly, we couldn't
do that any other way.
Now, one of the things that made
this all possible to declare
that these mice
aren't just sick,
but they're actually
biologically older,
that we've given them aging,
is that we can now measure age
with great accuracy.
This is not qualitative.
This is 100% quantitative with
machine learning, algorithms.
What I could do to
any of you right now
is take a blood sample--
please don't give me any
blood samples before I leave--
but theoretically, I could.
I could even take a
buckle swab of your mouth,
and I could go back to my lab.
I could read what's
called the DNA methylome.
It's really just measuring
which of the letter
Cs out of those A, C, T, G,
which of those have a methyl
group, a C and 4 Hs on there.
And the addition of these
chemicals over a lifetime
is a really great predictor
of your aging rate
because we see them go up in
a linear fashion with time.
And it turns out,
if you extrapolate
backwards, even a teenage
person, teenage girls
are aging.
Even young infants are aging.
Even in the womb we're aging,
according to this clock.
Now we used to think
that this clock was just
a measure of time, like
a clock on the wall.
But what we've been testing
is the idea that perhaps
if we move the hands of
the clock backwards--
in this case, the clock,
the biological clock--
does time go backwards?
Does the age and the health
of the animal go backwards?
And I'll tell you
about that in a second.
This is an example of
data from the paper
that we are hopefully publishing
soon with Steven Horvath, who
discovered this clock.
We can see that the mice
that are normal are in blue,
and they're aging
at a certain rate,
according to these DNA
methyl marks on the DNA.
But if we scratch the genome
and cause epigenomic changes,
we can age the mouse 50% faster.
And what's exciting
is that pretty
much by all measures
of these mice,
they're 50% older than
their counterparts.
But then the question arises,
if you can cause aging,
can you reverse it?
And if you do take the clock
back, does it do anything?
All right, so now I want
to tell you about one
of my favorite scientists
and mathematicians.
Many of you may
know this person.
He used to work down
the street at MIT.
He worked at Bell Labs as well,
and his name is Claude Shannon.
And if there's one
person that gave rise
to the world we live in,
the internet age, it's him.
And what he proposed in 1948
in a couple of elegant papers
called The Mathematical
Theory of Communication
are a set of diagrams
and equations
that explain how to
preserve information
between a sender and a
receiver and what to do
if there's lost information.
And he and his equations gave
rise to the TCP/IP protocol
in the internet we use today.
And you know that if we
don't get an email correctly,
if it doesn't arrive fully
with all its packets,
the internet is smart
enough to go back
to the original backup copy
and get the full message.
We used to say, oh, sorry
I didn't get your message,
it didn't arrive in my inbox.
Now you can't use
that excuse, right?
It always gets there.
And for a while,
there were a lot
of people who were caught
lying with that excuse.
Anyway, this is one of the
most important diagrams
when it comes to aging.
And I'm pretty certain
that Dr. Shannon here
didn't realize that he was
working on something just as
important as the internet,
perhaps even more so,
and that's how to reset
the age of our bodies.
And what you can see here
in his diagram from 1948
is that if you lose a message,
a signal, a radio signal,
or, say, a Morse code signal
between the sender, which
he calls the "transmitter,"
and the receiver,
if you lose some of
that information,
don't worry because there is
what he called an "observer,"
the backup copy of that
original information, which
you can use to restore
the information using
a correcting device.
If that's true in our bodies,
we could take the old epigenome
and reset it to be young again.
But we didn't know what
the correcting device
was in the cell.
The transmitter, of course,
is the fertilized egg
and us as a young child.
The receiver is our
bodies in the future,
let's say an 80-year-old,
and we lose a lot
of that information over time.
We succumb to entropy.
But we are biological organisms.
We're not closed systems.
We're actually open systems,
so we can use energy
to reset the system.
Now, the man on the
left won the Nobel Prize
for learning how to
take an adult cell
and make it a stem cell, wiping
all of the DNA methylation
off the genome, wiping it clean
so that those cells could be
rebuilt into anything you want.
We call this the process of
induced pluripotent stem cells,
and we use what are called--
named after Mr.
Yamanaka, Dr. Yamanaka--
the four Yamanaka factors.
These four Yamanaka
factors are called
O, S, K, and M for short.
Now Yamanaka won his Nobel Prize
because it's a great discovery
to be able to take a skin cell
and turn it into a nerve cell.
It could give rise
to new treatments,
new organs that we can
put back in our bodies.
But what he probably didn't
think of, I'm guessing,
is that this is also
relevant to aging.
Now we don't want to
put the four Yamanaka
factors into our bodies and turn
us into a giant stem cell pool.
That would be the
world's biggest tumor.
You'd get a teratoma.
And some people have tried
that, and they've actually
killed mice within two days.
So that's not going to be
a therapy anytime soon,
and I wouldn't volunteer
for it if I were you.
But what we've
discovered in my lab
just recently in work that
we've put online, which you
can check out if you'd like--
it's on bioRxiv, R-X-I-V,
and this is an online upload,
we're probably going to get back
the reviewer's comments from
Nature any day now--
this paper is
something that I never
thought I'd see in my lifetime
that I think we've finally
found how to tap
into the observer
and reset our biological edge
using Yamanaka's factors,
but not all of
them, just a subset.
So what did we decide to do?
Well, I have to give credit
to a student in the lab,
Yuancheng Lu, who
features in the book.
We were fortunate to be writing
the book as we were making
these discoveries last year,
and they were basically
written almost in real time
as they were coming out,
which makes this book a
very unusual kind of book.
You're learning about science
before most people have even
digested it yet.
So here's the experiment
that Yuancheng did.
We put three of the
Yamanaka factors.
We left off the M,
which stands for MYC.
MYC is an oncogene.
You don't want to
be causing tumors.
But we used the O, S, and the
K, O-S-K, fit it into a virus,
and we put the virus
into the eye of a mouse.
And these are viruses,
they might sound scary,
but they're used all the time
in gene therapy in patients
right now.
So it's not crazy stuff.
What we did in collaboration
with a lab across the street,
Xi [INAUDIBLE]
He's lab, after we
put the virus in
the eye of a mouse,
we pinched the back
of its optic nerve.
And what normally happens is--
I'm sure you can guess--
is the nerve dies.
If we're old, even if
we're young adults,
we will not grow
back an optic nerve.
If we break our spine,
we will not grow back
a spine and a spinal cord.
But very young animals
will, and some animals
will grow new nerves.
An axolotl loses its limb,
it will regrow a limb.
This is not unheard of.
It's just that we've
lost that ability.
But we think that we know
how to regain that ability
and make cells very
young again so they
have these properties
of regrowing,
just like embryos do.
And so what you're
looking at is a stain
of the optic nerve
that's been crushed,
and you can see
where the crush ends.
That's where the orange
dye is coming down
and stops because
all those nerves have
been crushed at that point.
And a lot of the
orange dye is missing,
which is labeling healthy nerves
because the nerves have died.
But have a look
what happens if we
turn on this reprogramming,
this age reset, in the eye
after we damage it.
First of all, the nerves
don't die, and many of them
somehow wake up and start
growing back towards the brain.
If we leave this for four
weeks, that's what you see.
If we leave it for 16 weeks,
they grow all the way back
to the brain, which is
unheard of in science so far.
Now, we've done this
also in other areas.
You might say,
David, a crushed eye,
it's unlikely I'm going to
have a crushed optic nerve.
But what about glaucoma?
Many people have pressure,
and it damages their retina.
There's nothing that
will appreciably
slow glaucoma, let alone
reverse that disease
and give you your vision back.
What about old retinas?
What about old age?
I'm already 50 and starting to
have trouble reading at night.
Can we reverse vision
loss during old age?
And I can tell you
that, at least in mice,
we absolutely can.
We can reprogram a retina
of a mouse, an old mouse,
and make it see just
like a young mouse again.
Those nerves wake up.
They remember that they're
nerves, not half skin cells.
We can look at their clock.
We've measured their clock.
They get younger.
And all the genes that should
be on when they're young
come back on, and
all the genes that
should be off when they're
young get shut off.
It's magic.
Now we don't fully
understand how it's working.
We know how to tap
into the observer.
But what's behind the clock?
What are the cogs
behind the system?
We have some idea
what's going on.
I think we've found the
communicating device back
to the observer at least.
There are a couple of enzymes
called TET, TET1 and TET2.
These are enzymes that
remove those chemical
groups off the DNA as part
of that reset process.
So we found some
cogs in the wheel
that drives aging backwards,
so that's very exciting.
And just today in lab,
Matt and I were there,
and we just had final proof
that if you have a mouse that
doesn't have the TET
genes in its eye,
you cannot restore the
growth of its optic nerve.
We also know you cannot
restore its vision, either.
So this is super exciting.
For the first time,
we have the ability
to reverse the age of cells.
Now we don't know how
long this effect lasts.
It could last for a month.
We think it will probably last
for years, if not decades,
because we are
actually getting very
deep into the deep
layers of aging,
and the epigenome
is very stable.
But could you reset?
How many times can you reset?
We don't know that yet.
So until these therapies
are ready for prime-time--
and we're hoping to
treat our first patient
in about two years from now
that suffers from glaucoma--
what can we do in
our daily lives?
I hear you ask.
Well, besides reading part
three of the book, where
a lot of it's talked about,
there are some other things
we can do.
We found a chemical
that exists in our body
that we lose as we
get older that's
really important for
stabilizing our genome
and preventing the scratches.
It's called NMN.
And you can see the mice on
the left were drinking NMN.
They recover pretty quickly.
Actually, Jeremy, let's
switch to the other one.
See if you can guess which
old mouse in this video
is drinking the NMN.
[MUSIC PLAYING]
All right, I think we've
seen enough, Jeremy.
So if you guessed the
mouse on the right,
you would be correct.
What we found and we
published about a year ago
in the journal
"Cell" was that NMN
turns on a longevity
pathway that we've
worked on for many years.
These are stabilized
of the [INAUDIBLE],,
and they also control our
cells' survival and defenses
against aging.
And what's exciting is that we
have inbuilt longevity pathways
that we can activate with
these molecules, like NMN.
There are others
that are out there.
One is called metformin, which
is a diabetes drug, which
is exciting because it's been
seen in tens of thousands
of patients to at least
seemingly slow down
the effects of aging and
protect against diseases.
There's another one
that's more toxic.
I wouldn't recommend it,
but it's called rapamycin.
But there are things out
there that we already
have run into that
actually may work.
But what else can
you do in your life?
What can you do if you
don't want to go to a doctor
and ask for metformin,
a diabetes drug?
Well, one of the
things that I do,
one of probably the
best thing I could
tell you having read thousands
of scientific papers,
is eat less often.
Now that's not malnutrition,
it's not starvation,
but it does mean going
hungry for part of the day.
What I do is I skip breakfast.
I eat a late lunch,
sometimes I miss lunch,
and eat a normal dinner.
What does that do?
That turns on these
longevity pathways.
It raises the NAD levels in our
body, which NMN will do also,
and it will mimic
exercise and hunger.
Well, hunger will, of
course, mimic hunger,
but NMN and hunger work through
these same longevity pathways.
And you might find
that by exercising
a bit like these mice,
getting yourself puffed
a few days a week on a treadmill
just for 10 minutes is enough
and being hungry for a
few days out of the week,
you'll find you feel
remarkably better,
and you'll be a lot
fitter because of it.
And perhaps when you're
80, 90, and even 100,
you'll be able to continue
doing all the things you always
have wanted to do late in life.
Start a new career, if you
want, start a new company,
leaving a legacy.
We have clinical
trials in progress
with a molecule-related NMN.
So this isn't future
stuff, this is
stuff that's actually
going on just
across the street from my lab
at Harvard Medical School.
So we know that this
molecule can raise NAD levels
at least two-fold in people.
We haven't seen any
negative side effects yet.
And we're going to be doing
clinical trials in patients
next year, but not for aging
because it's not a disease.
We're going to be treating a
rare disorder, most likely--
at least the plan
if all goes well--
is to treat a rare condition
called Friedreich's ataxia,
which is considered a
mitochondrial disorder,
a lack of energy.
But imagine a
future where you can
have an injection
of a virus and then
have a course of antibiotics,
like our mice are given,
and turn on reprogramming
for a few weeks.
You'll start to look younger.
Your hair might change color.
It might regrow, we don't know.
But your organs
should be improved.
You should get your vision
back if you've lost it.
And that might
last for a decade.
And after you've
aged for a decade,
you come back for a reset.
And all you need to do is to get
a prescription for antibiotics
that turn on these genes again.
Now again, we don't know how
many times you can reset.
It might be three,
it might be 3,000.
And if you can reset
your body 3,000 times,
then things get
really interesting.
And I don't know if any of you
want to live for 1,000 years,
and I also don't know if
it's going to be possible,
but these other
questions we have
to start thinking about because
it's not a question of if, it's
now a question of when.
And finally, I'd like to talk
about my father, who's a role
model for all of us, I think.
So he's been on a combination
of NMN and metformin
and some other things
that are written down
in part 3 of the book.
I don't like to talk a lot
about supplements and things,
so it's all in there, and I
have a newsletter as well.
But let's talk about my father.
Now, this is not
a clinical trial.
It's what we'd call an N-of-1,
or if you include my wife
and I, an N-of-3.
Not very well controlled.
It's not placebo controlled.
But my father was
heading downhill.
He was not very energetic.
He was pretty depressed.
His wife had died.
He was just thinking,
OK, I'm done for.
But he's realized that his
health isn't declining so far,
and we don't know if it's
because the molecules
or because of the
exercise he's been doing
or the intermittent
fasting that he's trying.
But nevertheless, he's a
beacon of hope for all of us
that we can live a life like
his, where, in his late 70s,
he's started a new career
and he travels the world.
And we just got back from
Uganda, where he went hiking
with his three
grandkids up a mountain
and was the oldest person
to ever do that And for him,
it was a breeze.
He's literally stronger and
fitter than I am at age 50
and probably when
I was 30 as well.
So I want to end by
saying thanks for coming.
I'm happy to answer any
questions as honestly
and as openly as I can.
And I hope that
you not just begin,
but continue this
conversation because it's
one of the most important
things we can do for the planet
to save on health care, to
save billions of dollars,
eventually trillions, that
can be put to other causes,
such as global warming
and species extinction.
And I want to really thank
you for taking time out
of your day for
coming to listen.
Thanks.
[APPLAUSE]
AUDIENCE: So you've
mentioned metformin
and intermittent fasting.
Can you talk about the role of
insulin in the aging process?
DAVID SINCLAIR: Of insulin?
AUDIENCE: Yes.
DAVID SINCLAIR: Right.
What you want to
be to live longer,
based on everything we
know in mice and humans,
is to be really
insulin sensitive,
and that means having a
lot of insulin receptor,
not having your blood
glucose levels go high.
And actually, the best
predictor of your longevity
is your blood
glucose levels, which
is why you want to be exercising
and why metformin probably
is, in part, working.
So insulin is key.
There's also an insulin-like
growth factor molecule
that's also important.
And when you have
lower levels of that,
it also extends
lifespan in animals
and seemingly in people.
And what's downstream
of those pathways
are what's called FOXO, our
transcription factors which
control our defenses
against aging and disease.
And so we want to
keep those active.
Now, if we're always satiated,
if we're always eating
protein bars and
never hungry and if we
sit around all day listening to
pompous academics give talks,
those transcription factors
are not going to be active.
In fact, they stay
out of the nucleus
where they don't do any good.
And so what we want
to do is make sure
the insulin signaling
pathway is active
and that they stimulate those.
There's another thing that also
goes, which is the TOR pathway.
So TOR is also controlled by the
insulin-signaling growth factor
pathway, and you want to
have less of that signal.
And then mTOR is an active.
So what's mTOR?
As you'll read in the book--
I talk a lot about it--
the mTOR censors how many
amino acids you're eating,
and you don't want a
lot of mTOR activity.
And the more protein
you eat, think
about those protein bars--
I just had one--
if you eat a lot of
steak, your mTOR pathway
will be always active, always
telling your cells to grow
rather than fighting
disease and hunkering down.
And so that's why
I have actually
switched from a regular diet
to a mostly plant-based diet
because the amount of amino
acids that I was getting
was overloading my mTOR pathway.
And so I'm trying to
keep that down as well
and give my body
the best chance,
and I'm also trying to
help the planet as well.
But very good question.
AUDIENCE: Thank you.
Good talk.
The reason I got into
computational biology
was that I read some
exciting things out
of Aubrey de Grey maybe 20
years ago, and I was like, oh,
interesting.
So one thing that
I'm curious about
is we have these other more
macroscopic, I suppose,
mechanisms around aging.
We have the rate of
cellular division,
and we have accumulation of
junk both inside and outside
of cells.
So is the management
of those processes
assumed to be downstream
of the mechanisms
where you're making
your intervention.
DAVID SINCLAIR: They are.
They are.
So we've declared as
a field, as you said,
that there are eight or
nine hallmarks of aging,
and some of them are
telomere shortening,
mitochondrial dysfunction, loss
of stem cells, senescent cells.
And so it's great to say, OK,
plant a flag in the ground,
we understand aging, we've
got seven or eight things that
cause aging, but that doesn't
explain why they happen.
Is there an upstream, as you
say, cause of all of those?
Or are we building seven
dams on seven tributaries?
And the information
theory of aging
proposes and can explain how
epigenetic aging, the loss
of gene expression as we get
older, loss of that information
can explain all of
those hallmarks as well.
And in fact, if we
look at those mice,
even though we've just
disrupted the epigenome,
they have all of
those hallmarks,
from mitochondrial dysfunction
through to senescent cells,
senescent cells being
the ultimate expression
of a scratched CD.
But yeah, I'm excited
about this theory
because it can explain the
last 100 years of observations.
Now, all theories eventually
succumb to a paradigm shift.
And I'm not saying this
is the be all and end all,
but I think it's a great
way to think about aging,
and it brings up a lot
of testable hypotheses,
such as these mice I showed you.
What are the chances we
get an old mouse when
you cut the genome like that?
One in 1,000, I'd
say, and it worked.
So we'll continue
to test this theory,
but so far, it seems
to explain, in my view,
all the observations
over the last 100 years.
AUDIENCE: Is oxidative damage
upstream or downstream or
separate from what you're
talking about here?
DAVID SINCLAIR: It's both.
It's part of the
positive feedback loop.
So this is what we think is that
oxidative stress in the nucleus
will exacerbate
the genetic damage,
so you'll get a
broken chromosome.
So there are a lot of things
that cause epigenetic change,
including to scratch the
DVD, but the most potent one
that we found is a
broken chromosome.
And oxidative stress,
free radicals,
can cause a DNA
break, but it's not
the only cause of DNA breaks.
They're happening all the time--
cosmic rays, CT scans, X-rays.
And actually, free radicals
are beneficial in biology,
so you don't want
to swap those out.
It's been shown if you
take a lot of vitamin C
and even mega
doses of vitamin E,
you can blunt the effects of
a healthy diet and exercise.
So I'm not saying
they're not part of it,
and that's why I was saying I'm
excited about this theory is
it can fit all of
these observations in.
You might be asking, well,
why don't antioxidants
work as well as we hoped?
Well, one of the main
reasons is that we
think that there are
other causes of DNA
damage besides free radicals and
that you need more than that.
But the other thing that's
interesting to think about
is that we've discovered that
the molecules that you ingest
when you drink one
of those drinks that
have the antioxidant
properties, what's
more than likely happening is
that those molecules aren't
directly mopping
up free radicals,
but we've learned that they bind
to receptors and enzymes that
sense the environment
and they turn
on our body's
natural antioxidant
defenses, such as
catalase, an enzyme that's
necessary for mopping those up.
Now we have a theory for that.
We call it xenohomesis--
xeno meaning "from other
species" and homesis
meaning "anything
that doesn't kill you
will make you stronger."
The idea is that plants make
these antioxidants, what
we call antioxidants, but
they're actually [INAUDIBLE],,
we call them, that are helping
the plants survive and hunker
down through their
genetic survival pathways,
and that by ingesting our plants
when they're stressed out,
we get the same benefits.
We also need to hunker
down if our food
supply is going to run out.
So that was five different
answers hopefully answered
your question.
AUDIENCE: Well, I
was in particular
wondering about non-nuclear
oxidative damage.
DAVID SINCLAIR: All right.
Yeah.
Well, you mean in
mitochondria, for example?
AUDIENCE: Or I think
collagen and even just
extracellular things.
DAVID SINCLAIR: Right.
Well, so we need to
figure out in tissues
that have a lot of
collagen, whether it's
fibrotic lungs or
fibrotic liver,
is that reversible
or irreversible.
That's a start.
Is reprogramming going to
get rid of those problems,
or are they there
with us for life?
Hopefully not, but
we'll have to see.
But the oxidation of
collagen is a part of aging.
But what I'm proposing is
that by resetting the cell
and making it behave as
though it's young again,
it can rid itself of those
oxidized and damaged proteins
through a process of autophagy.
And there are a few
different types,
but one of the
most important one
is called chaperone-mediated
autophagy that
is really deep cleaning
the cell of getting
rid of these kind of proteins
that have accumulated.
And the best way to turn that
on besides chemicals we're
working on is actually
to not eat for two days,
and that's thought to clear
out even oxidized collagen,
for example.
AUDIENCE: So a few
months, maybe a year ago,
a doctor who was a [INAUDIBLE]
from the World Health
Organization came and
gave another talk.
And I read his book, and
it suggested like M&M
as using that help,
and a bunch of doctors
are actually secretly giving
themselves these treatments
because they see it works and
the data seems fairly good.
Why is intermittent fasting
something that really helps?
Why is there no published
studies about aging?
If doctors seem fairly
agreed that this looks good,
it's useful, there
should be more trials.
And I don't like going
to random websites
on the web to try
and see these things.
That's just kind of sketchy.
Why is there no
real clinical data
and backed up support all on
these anti-aging techniques
that even doctors
seem to agree on?
DAVID SINCLAIR: All
right, first of all,
I don't recommend eating M&M's.
I know you misspoke.
At least not if you
want to live longer.
But yeah, I know
what you mean, NMN.
There's a few answers in there.
One is that there are published
studies, and many of us
are working very hard to
try these, as I pointed out.
But trials are expensive.
Each patient's $10,000, so you
can see how quickly it adds up.
But now that we have
the clock to measure,
I think things will
move much quicker.
Because otherwise, it's going
to be a very long trial.
There are probably 15
to 20 trials with NMN
and related molecules
in progress,
so they will come out.
There are some so far
that have been published.
There's one with
NR that actually
showed there was no
improvement in blood sugar,
so that one was
a negative trial.
Then there was one
also that came out
from affiliated
with a lab at in MIT
that showed ALS patients did do
better with a combination of NR
and pterostilbene,
which is related
to resveratol and [INAUDIBLE].
So yeah, bottom line is, I see
it as my role as an educator,
communicator now, and
with this platform that's
come with the book,
to be able to sort out
which is BS from reality, and
there's a lot of BS out there.
But there are
really good studies
that are coming out all the
time and a body of literature
that nobody has time to
read or to sort through,
and that's what I hope
to do for everybody.
AUDIENCE: Hi.
DAVID SINCLAIR: Hi.
AUDIENCE: I was a
little bit confused
by your discussion of
epigenetics being analog
in nature because
I always thought
there was both digital
and analog parts of it.
So like the folding
of the chromosomes
as a topological
[INAUDIBLE] were
very analog, but
methylation I'd always
thought of as
being very digital.
That C is either a
methalyzed or it isn't.
And so first of all, I was just
wondering if I was confused.
And then second,
whether your research
has indicated so far which
parts of the epigenetics,
where there's more
the methylation
factors or other things
that are the most important
in the biological clock.
DAVID SINCLAIR: Yeah.
So there are digital parts of
the epigenome, but most of it
is not digital.
The methyl, as you
point out, is digital.
But we think that the methyl
is not the main component
of the epigenome.
It's part of it, but there
are other marks on histones
and others that don't occur in
discrete ways, but it's a haze.
And part of the problem
of measuring the epigenome
is that it's not digital,
that you get probabilities
rather than discrete units.
But I'll grant you that.
You're right that the
methyl is digital.
But the loops, the loops
are moving all the time,
that you can't say there's
a loop because it's gone
by the time you measure it.
And so what's
interesting is the field
is right now moving
away from describing
a TED as a discrete thing
to a probability, which
is a whole different
mathematical challenge.
What else didn't I answer?
You had a second
part to the question.
AUDIENCE: Just whether
any of your research
indicates which epigenetic
factors it's based on.
DAVID SINCLAIR:
Yeah, good question.
So we're searching for the
deep observer, what that is.
It's not just methyl.
It clearly cannot
be just methyl.
There are proteins that
probably bind to those methyls
to say that's a youthful
methyl and this other one has
come later, so get rid of it.
So we need to find that.
But also, there are proteins
that control the TADs.
So there's proteins called CTCF.
You might know as a biologist
then that they are controlling
the loops, the spooling,
and we see changes
in the distribution of those
proteins throughout the nucleus
as we age those
cells in the dish.
But it's early days.
I've got 35 people in my
lab, and about half of them
are now trying to
figure this all out.
And a year ago, only one
person was working on it.
So we'll get there.
And there's a few other labs
in the world working on this,
but I think in a few years,
they'll be probably 50 to 100.
In terms of the
levels, the way I
think about it is that there's
a superficial level which
is transcription factors, which
just by holding your breath,
you can change them
and they move around
and they control genes.
But they reset.
If you change those,
of course, you're
not going to permanently
go back 10 years.
A different layer are the
epigenetic modifications
on histones, and those are
fairly stable, but still quite
transient.
They won't last for a long time.
But those DNA methyl marks
are the third very deep layer
that last for years,
even decades, and that's
the very deep layer.
And that's why I'm
excited about what
we're working on because
we finally penetrated
that deep layer.
But how the cell gets
to that deep layer
and then knows which
parts of it to reprogram
and reset and reorganize,
that's the challenge.
AUDIENCE: So I was wondering
about the experiment
with the twin mice.
So aside from showing all
these symptoms of aging,
does the mouse with the
scrunched-up genome,
does it actually end up
living a shorter life?
Or do they still keep
the same life span?
DAVID SINCLAIR: So
they live shorter,
but we didn't have enough mice
to be able to statistically
tell you that with certainty.
In a small group, I
think we had 10 and 10.
The ice mice died
younger on average,
but it wasn't
statistically significant
because you typically need
about 40 to 50 per group.
But yeah, it looks like they
die from regular mouse diseases.
They're not riddled
with cancer more
than a normal mouse would be.
So it's a good question.
They should live
shorter, and they are.
We can also measure
their frailty,
and we've used
machine learning to be
able to use frailty measures
to predict longevity.
And based on those
measures, it's
also consistent with those
mice aging and dying younger.
AUDIENCE: So you have a
promising technology .
Five years from now, you find
that the treatment that works.
5 to 10 years later,
the FDA approves it,
and now you're going through
the insurance system.
Clearly, this is like a
blockbuster drug of our time.
Do you have any
thoughts on how that
will be handled
when suddenly you
can, say, go to your
doctor, go back 10 years?
DAVID SINCLAIR: Yeah,
that's the thing.
That's the thing we
need to talk about,
what happens when this happens.
And I don't know if it's
going to be five or 10 years.
I mean, the NMN stuff
is here already.
You can go buy that.
But the reprogramming
early days,
we don't think it's
dangerous, in mice at least.
We put it into the mice for over
a year, and they're healthy.
They're not a giant tumor.
But yeah, let's talk about
what happens when this comes,
hopefully within our lifetimes.
What does the world look like?
So first of all, let's
say it's for glaucoma.
This is where the first
trials will be done.
We have a company called
[INAUDIBLE],, full disclosure.
So you can treat glaucoma, OK?
Glaucoma patients,
if all goes well,
get their vision back
within a few weeks.
But the world will know
that this is a reset.
What's to stop a doctor
in Costa Rica giving
this IV to their patients?
Nothing.
Nothing.
That's where it will begin,
how it'll spread if it works.
Hopefully, those people
will not be sick from it.
But then project
another 20 years,
will people be banging down
the doors of their doctors
saying, give it to me or else?
Probably what will
actually happen
is that there are doctors that
are more willing than others
to prescribe things.
And with the case
with metformin,
you can find doctors that
have read the literature
and they're OK with it.
But yeah, I think it's going to
be an interesting world where
you can at age 30 say, I
don't want to get any older.
Yeah.
A lot of ethical things.
One of the things that
Matt and I put in the book
was, for all those
people who say,
whoa, this is way too
much, I don't want this,
we write, we don't want
you to live any time longer
than you want to, either.
So we're not forcing
this on anyone.
But if you have a
choice, that's great.
We also say we both
believe that you
should have the choice to
die when you want to as well.
So it's important
to balance it out.
Thanks.
Good question.
AUDIENCE: NMN versus NR.
DAVID SINCLAIR: OK, so NR
is nicotinamide riboside,
which is similar to NMN
without a phosphate group.
NMN and NR, NR is
cheaper than any NMN.
As a professor at
Harvard Medical School,
I don't recommend
anything and I certainly
don't talk about
supplements and I don't work
with any supplement companies.
That's my disclaimer.
If you ask why would I take
NMN and why did my father,
partly it's availability.
We have a stash of
it that we've tested,
but that doesn't help you.
What I think would help you
is go to the website that I've
got on the book.
Honestly, I'm not promoting it.
I've written down
everything that I
can say about NMN and NR.
I can also tell you that NMN
is more stable on the shelf.
And if NR gets a little bit
wet or is out for too long,
it'll degrade into nicotinamide.
And I wouldn't take high
doses of nicotinamide.
It may have the opposite effect.
But that's the main reason.
Now in mice, they've both
shown remarkable effects
to protect the body
of those animals,
and clinical trials are
ongoing with both molecules.
So at this point, I
really couldn't say
one is better than the other.
AUDIENCE: What does the M
factor that you're not using do?
DAVID SINCLAIR: Sorry?
AUDIENCE: The stem cell
M transmission factor
that you're not using.
DAVID SINCLAIR: Oh, MYC, c-MYC.
AUDIENCE: Yes.
DAVID SINCLAIR: Yeah,
so c-MYC is a gene that
controls cell proliferation.
And if you turn it
on in normal cells,
they will be partway towards
a tumor, hence its name
as an oncogene.
And it's very useful if you want
to reset the age of a skin cell
to zero, but it's
not so helpful if you
want to reset the retina
partway back towards youth.
Thanks.
We were just lucky that
worked without MYC,
but you got to swing
for the fences.
If I can give you any
advice about careers,
you got to take some risks.
Not everything will work.
When they fail, just keep going.
You'll eventually get there
if you focus on a dream.
And my dream has been
to figure out why we age
and see if we can live an
extra 10 healthy years of life.
Any more questions?
I think that's it.
Sanders, thank you.
[APPLAUSE]
