(upbeat music)
- [Announcer] Coming up on this episode.
- So the nerves we see regenerate
are the original nerves,
'cause we tagged them with a dye,
so we don't see them being replaced.
So we can say,
"Yeah, they're not being
replaced by STEM cells."
And in the case of the old eye,
we're not damaging anything,
this is just natural aging.
And there, we can reprogram those retinas.
Those retinas don't look any different,
they haven't changed,
they haven't multiplied,
there are no new cells,
but the nerve cells,
now we put an electrode
in the back of the eye,
and those nerves are now functioning
with electrical signals
like they were young again,
and then we test the vision of the mice
and they can see again.
- [Announcer] Welcome to the HVMN Podcast.
What we do with our bodies today
becomes the foundation
of who we are tomorrow.
This is "Health Via Modern Nutrition".
(rock music)
- Welcome to this week's
episode of the HVMN Podcast.
And I'm super excited to have
Professor David Sinclair
on the program this week.
You've probably seen his work
as the bestselling author of "Lifespan",
but beyond being a book author
and if you've been tracking
the space of aging in gerontology,
you've probably seen his work
over the last two, three decades,
really pushing and being
involved in some of the most
interesting discoveries in aging.
So thank you for taking the
time to be on this program.
- Well Geoff, it's great to be on.
Thanks for having me.
- Absolutely.
So as we are preparing
some of the trajectory
of this conversation,
I think when your book first came out,
it really drew my attention
in terms of just seeing what is at
really the cutting edge of aging.
And I think it's rare in
today's setting of academia
to have super credentialed
folks really pushing,
I would say, the limits
of what is possible.
So I think from that perspective,
I think it's commendable
to be throwing out pretty,
I'll say like novel theories, right?
I think the key insight that, or,
and I think your "Lifespan"
book covered a number of topics,
but I think the key insight
was really describing
a unified theory of aging
called "Information Theory of Aging".
So curious to hear from your perspective
in the risk reward assessment
as you're developing this book,
as you're coming up with this theory,
putting this all out there.
- Yeah.
Well I've never been known
for being shy or not taking risks.
I believe life is short
and we all have that problem,
and the faster we can
figure this stuff out,
the better for all of us.
And you know, there's
no point in us realizing
at the end of our lives
we were born one or two
generations too early
to reap the benefit.
- Yeah.
- So yeah, I'm in a rush.
I want the world to reach the place
that I know it's going to reach,
a world that's as different today
as we are from a hundred years
ago in terms of medicine.
And so yeah, it was an
interesting journey.
I like to push boundaries scientifically.
I think that I've read a
lot of scientific history
and no theory lasts forever,
except maybe the second
law of thermodynamics.
And really, we're just humans
trying to figure this stuff out.
And the more dialogue,
discourse, new ideas,
testing those ideas, the better, right?
That's how progress is made.
Unfortunately, scientists being scientists
tend not to like chaos.
They don't like theories to be challenged
'cause that's usually their livelihood,
which is fair enough.
But you know, I'm open
to new ideas all the time
and that's the way I run things.
So I'm also not afraid to speak my mind
and if I've got a new idea,
I'll put it out there.
It does upset some of my
colleagues, but so be it.
The other thing that I do,
which definitely upsets my colleagues,
is I speak directly to the public,
and I've been doing that my whole career
and I feel very strongly about that.
The research that's in my lab,
in the big lab behind
me here, about 30 of us,
that's mostly paid for by
the public out of taxes.
So how arrogant would that be for myself
and my colleagues to learn what we learn,
even personally benefit from that,
and not tell the public what we're doing?
And I'm excited, Geoff,
that we live in an age
where people like you,
God bless you,
are able to allow scientists like me,
who normally would be in an ivory tower
talking to their colleagues only,
'cause we're afraid of newspapers
who typically distort the work,
finally, we talk to the public.
Now there's public that
doesn't care about science
and they'd rather just hear
about fashion or whatever.
That's fine.
But there's a growing number of people
who wanna hear directly
from the scientist's mouth
about what they think is the best.
And it's a great world, I think,
that we live in right now.
- Yeah, and I think if you
think about what science is,
it's a pursuit of truth.
So I think almost in some ways,
you're really practicing
the core intent of science,
which is finding what is true
and then testing those
hypotheses against observations.
And if it's something that is true,
then one shouldn't be afraid
to stand to scrutiny and questions.
I think if everyone's
debating in good faith,
I mean, you get to the truth faster.
I think broadly the internet,
with the decentralization of information,
I think that's probably
accelerated progress
because more and more people can engage
on these ideas and these topics.
- No doubt, and I'll
get to writing the book
and the information theory in a minute,
but this is a really interesting thing
that I'm very passionate about,
which is that we've gone
from a world 10 years ago
where the journals would
essentially ban you
from a journal if you talked about work
before they published it,
to a world where now,
you can put your work out
there for the world to see,
you know, all your colleagues to see,
sometimes a year or two in advance
of them being published.
And the cart now is,
well actually the horses are now
where they belong in front of the cart,
and it's really liberating,
and I think it's a world
that had a long time coming.
The history of scientific research
was that the journals dominated
and controlled the path of science
and they were the gatekeepers.
It's not so much that way anymore,
and we scientists can give our work
to the public for scrutiny very rapidly.
Overnight, we can put it online,
millions of people can look at it,
argue over it, debate it.
As long as you recognize that
peer review is still important
because we have to vet the
science through experts.
But I love a world where we can have ideas
and have experts from all sorts of fields
look at work a year or two in advance
of when they otherwise would have seen it.
- Yeah, that seems to directionally true
as we just progressing in terms of speed
and just, I think the cross
interdisciplinary nature
of a lot of this work, right?
I think some of the
work that you described
with an epigenetic clock
or the Horvath clock
that's incorporating a lot of data science
and statistical modeling to biology.
And it's, I think that's
an exciting future.
And I think that leads a nice segue
into the information theory of aging.
So as I might've referenced to you,
my background is a computer scientist
and I actually specialize
in information and information theory,
so it was really interesting
to see you being inspired
or taking some of the
concepts that Claude Shannon,
who was a MIT professor
and invented the field
of information theory,
and some of the observers
and different ways that state is held
and how that's applied to biology.
At least from how I read the book,
at seemed like a recent
paper reversing aging
in the nerve cells in eyes,
really was the evidence or data
that inspired the sort of observer theory
and the information theory.
I'm curious from your perspective,
how did all these things come together?
Because I think many of our listeners
have probably heard of the different,
various hallmarks of aging.
I think people understand
that there's some notion
of genetic damage, epigenetic damage,
but I think articulation that you have,
which defines sort of a primal root cause
of all the downstream effects of aging
is quite novel, right?
It's the first time I've
heard that articulated
in such a primal way.
- Well, actually the theory began
when I was 26 years old.
I'm now 50.
So it wasn't just last year
that I came up with this idea,
but it's been evolving over time
and I've been wanting
to write down the theory
in a scientific journal in a formal way,
but I've just been too
busy working on the science
out there in the lab
and doing other things.
So, it turns out just through lack of time
that the book was the best way for me
to express my ideas and it's unusual.
We were talking before we went on air
about how rare it is
that a scientist puts their work
out in public, their theory,
in a book before it's
actually totally crystallized
and written down in a
scientific paper and vetted,
and that's just how history
happened in my case.
But the idea has began
really with yeast cells.
We were studying yeast cells
and the silent information regulators,
these sirA proteins that
we've been working on,
that word, information, has
been there since the beginning
going back 25 years ago.
And how is information
tied into aging itself?
Well in yeast, it didn't
take long to figure out that
epigenetic changes as we
call them, the noise of,
informational noise
was the cause of aging,
and major cause of aging in yeast,
but it's taken us,
oh, the better part of
two decades to test, and,
to understand whether
that was true for us.
And while you can do a
yeast experiment in a week,
a mouse experiment,
the ones that we just put up online,
not the one, not the reprogramming one,
but a couple of others.
They took us 10 years, those two papers.
And I felt like we were
at a point where we had
enough evidence from our research
and increasingly other people
who are working in this area
that this hypothesis was
going to come out anyway,
kind of like Charles Darwin
would have gotten scooped
if he hadn't written
"Origin of the Species",
so he rushed it out.
The same thing was happening to me.
I spent 10 years going,
"Ha ha, no one else is thinking this way
"in terms of information."
But then the epigenome
exploded in the aging field.
The Horvath clock,
the epigenetic clock
came out and I thought,
"well, I'd better get this out,
"or you know, I'll really regret it
"for the rest of my life".
And so it all spilled out on the pages
quite beautifully, I think,
thanks to my coauthor who's
a really great writer.
And together we produced something
that was far better than we
could have produced alone.
But what I've been very encouraged by
is the reaction of my colleagues that
for many of them, it
just makes perfect sense.
If you distill down biology to its essence
and ask, "Why don't
organisms live forever?
"Why isn't life permanent?"
It's got to be information loss.
There's nothing else it could be.
- Yeah, I mean it makes sense
in terms of a lot of analogies
that people make on
biological constructs, right?
One can make the analogy that we are
a evolution algorithm for
biological information
that's fit for survival or
through natural selection.
And I think, "Well, what is that?"
Anyway, it's an encapsulation
and dissemination of information, right?
So I think one thing that I think is
especially compelling
about this theory is that
you're making a interesting claim
around this existence of an observer
that stores a youthful
epigenetic state, one,
and then two, if you could
reverse an aging cell
back to the epigenetic
state, can you arrest aging?
Can you reverse aging?
I think that's probably the,
the most important, most compelling,
testable hypothesis that your
theory would predict, right?
If you're going from a scientific method,
this is a theory, a hypothesis,
and there's some smoking evidence around
that this can be done.
And I think what would really
nail the coffin here is,
describing exactly the mechanism
of how this observer works.
And I think that is,
I think probably the
most exciting, the most,
you know, the most novel
part of the book for me.
And it seemed like it was just
at the cutting edge of
what was known, because
just like looking at some of
the surrounding literature,
this was really just the bleeding edge
when the book came out in,
I think in September.
This was really at the cutting edge
of what was even known.
So I guess if science is
moving really quickly,
anything to update or tease at
over the last couple of
months in a mechanism of,
or testable hypotheses
of how this might be
implemented in our genome.
- Right.
So there were three papers
that we're revising now.
Two are at "Cell" and one is at "Nature".
And they'll probably come out next year.
And I was actually worried that
by publishing the book I
was gonna scoop myself,
which is not what you wanna
do first as a scientist,
but it seems to be fine.
The journals are happy with it.
But those studies,
even though they took a long time,
some of them 10 years as I mentioned,
the pace of research now has exploded.
We can now look at the
epigenome in four dimensions
very quickly,
millions of data points coming
in every day into the lab.
We've had to build our
own servers just to,
not just analyze it, but
store the information and
we've got
bioinformaticians in the lab
that are working on a
whole range of things.
And so what's happening in the lab
is that every day I come in
when I'm not traveling
and there's some new exciting development.
So we first made the,
well, let me take one step back.
We first show that aging is likely to be
the loss of epigenetic information
in yeast, going back 20 years ago.
But we really had no
sense that this was true
in terms of cause and effect in mammals.
And so we took a mouse.
We engineered a mouse strain,
where we could disrupt the epigenome.
And if we were right,
well, let's start with if we were wrong,
lots of bad things could have happened.
The mouse could have died,
The mice could have gotten,
contracted cancer.
And it's possible nothing happened,
if you disrupt the
epigenomes, no big deal.
And I think there's, you know,
most people would have said,
"There's a one in 1000 chance
"that you'll get what you're
looking for," which is aging.
But that's what we got.
We got aging in these mice,
which was pretty good result.
And when you surprise
yourself how good it looks,
is usually you're on the right track.
But what that said was we had to
think differently about
our wheel of fortune,
these hallmarks of aging.
Now I'm not coming out and saying
the hallmarks are wrong, not by any means,
but what I'm saying is that
just having a laundry list of problems
doesn't explain why things
occur in the first place.
- [David] Right.
- So it's not a full unified theory.
- Right, there are secondary
symptoms of aging, right?
I think what you are describing
is a primal singular cause,
which I think is interesting.
- Yeah, that's really what
every field is hoping for is,
not just a list, but a real cause.
You could distill down
aging into an equation
if this information theory is right.
But what's exciting is that
this mouse where we
disrupted the epigenome,
it didn't just get to look old
and it didn't just get diseases of aging,
these hallmarks of aging also occurred,
so a loss of mitochondria,
mitochondrial function,
loss of STEM cells,
inflammation, senescent cells.
All of these hallmarks
occurred,
so that tells you likely
that the epigenome is
what I would say is upstream,
is the dam upstream and
these others are tributaries,
which is pretty exciting.
But what that also meant was that this
the field that was really just
focusing on longevity genes
to slow one or more of these hallmarks,
that's what we've been
doing for the last 20 years.
My lab certainly is involved in that
through activation of sirtuins.
What it also said was that
if epigenetic change and
noise is the upstream cause,
then if we address that and reverse it,
all these other symptoms of aging,
hallmarks, and diseases,
should either be prevented
or if we're really lucky,
can be reversed.
And, so we didn't know
if there was an observer,
which you can also refer to.
We refer to as the backup hard drive
of the youthful information in the cell.
We didn't know there was such a thing.
But in 2014 I became very interested
in Claude Shannon's work
and I read all of it,
some of the most beautiful
papers I've ever read.
And it just,
I was trying to find the observer.
And so we were giving cells
a whole bunch of factors that
we thought might reverse,
their age by tapping into the observer.
We didn't know where the
observer was if it existed.
We killed a lot of cells,
but we had a breakthrough
about two years ago
where we put in set of three genes
and it looked like we managed to find
the zip code of the observer
and the observer woke up and
reset the age of the cells.
And when we did it in a mouse,
it reset the age of the mouse
and old mice that lost their vision,
got their complete vision back again.
And that's the paper that we posted online
a couple of months ago.
- So this is the Yamanaka factors,
and this is the paper
published on Bio Archive
around yeah, essentially restoring vision
of crushed nerve cells
in induced glaucoma.
You're able to reverse those,
essentially those disease states
that are associated with aging.
- And aging itself.
- Right, okay yeah.
And then I think the third
one was aging itself.
So I wanted to
get your thoughts on
alternate explanations, right?
'Cause I think there's two
parts that I wanna explore.
One is,
this could be described with an observer.
And then if that is the case,
then what would be the
mechanism of action?
I think you've referenced
potentially something with methylation,
but that seems to be maybe,
probably not complete or overly simple.
And I think there's been more
and more research around,
I think you've recently
shared a paper on Twitter
about lactylation.
I know that there's acetylation,
and then I know there's
colleagues and friends
that are looking at
betahydroxybutyralation,
where betahydroxybutyrate
actually binds in
and affects gene expression as well.
So it seems like there's more and more
new science around how
the epigenome is actually modified.
So do you have some sense
of describing that mechanism
that would be the observer?
And then the second part of
the question is, I think,
you know, sort of where
my mind goes is that,
is there a explanation
that this also describes
the behavior that you've saw
that doesn't require the observer, right?
'Cause, I think,
and that's just, I think
that's an open question.
Or maybe you have some
better results or data
that suggests why this
can't be explained through
without an observer.
- That, these are really good questions.
So the first is about how complex is the,
"the man behind the curtain"?
- Right.
- The machine behind the clock, and,
there is no doubt that it involve
more than DNA methylation,
but you have to start somewhere.
And we've only been working on this
for a couple of years now,
but we are, I've gone from a lab with
just one person in my lab
working on reprogramming
to now probably most of the
people in my lab work on it,
working on it, so we're
working really hard.
One thing that's interesting is
we can measure DNA methylation age
of the animal and the cells,
the neurons in the eye.
And we could see that the
Yamanaka factors, three of them,
three that are seemingly safe.
We're looking at mice today.
We found that in terms of
an update you're asking me,
we find that these Yamanaka factors,
the way we deliver them
and the combination
doesn't cause cancer,
doesn't have any untoward
effects in the animals,
even if we look very
carefully histologically,
which is great news,
that's hot off the press.
But to your point, the machine is complex,
but the reason that I'm excited about
the DNA methylation clock
is because I think that it's
a very deep layer of aging.
We can change superficial things.
For example, we can go for a run today
and change some transcription factors
and change gene expression,
but that's not permanent.
That's just going to change
temporarily your cells
and they'll take up
more glucose, et cetera.
There's a deeper level
where we've been working on
some epigenetic factors such as sirtuins
and trying to activate them,
but even then, if you stop giving
these molecules that activate the system,
the animal will revert back to being
you know, healthier and maybe
longer term, longer lived,
but it's not that you've
really reset the clock.
You just made things a little
bit more youthful looking.
- Right.
- But the deep layer
is the actual information
that tells you your age,
and it's how cells really understand
what type of cell they
are and how old they are,
and we think that this is partly
driven by DNA methylation,
but we thought up until our
paper that the methylation age,
these chemical marks on the DNA,
were an indicator of biological age,
they were just basically
the crust on the genome,
the plaque on your teeth so to speak.
Plaque doesn't do much, right?
It's just accumulating.
Same, we thought about the methyls,
but what we decided to do
was to knock down or knock out,
we've done it both ways,
a set of genes called TETs, T-E-T,
and there are three of them.
And if we got rid of at least
number one or number two,
we haven't studied three yet,
we didn't get the vision restoration
and we didn't get the clock reversal.
So what does that say?
These enzymes are the enzymes
that remove the methyl off the DNA,
the pick that removes the
plaque off your teeth.
If you don't have plaque remover,
you don't get shiny teeth anymore
and you don't get to look younger,
your dentist can't do a good job.
So that's what the results are telling us
is that part of the reset of the clock,
it's not just an indicator of age
as if you move a clock hand
and nothing really changes
except the appearance,
but what it says is that perhaps
you move the clock back and
it actually changes time,
but to move that clock back,
you need to remove the DNA methylation.
Now, of course that's not sufficient.
We don't think, we're testing
whether it is sufficient,
but we do know it's necessary
for the age to go back.
And then the second thing
you asked me, Geoff,
was about does this prove
the existence of an observer?
And one of the experiments
that convinced me
was the following.
So we can look at all the
patterns of gene expression,
which genes are on and
off in these neurons,
and can look at every gene in the cells.
And what we found was that genes
that go down a little bit with aging,
in terms of getting switched off,
when we reprogram those cells,
they go back up to normal,
but just the right
amount to where they were
when they were young.
If a gene goes all the way,
way down when the animal's old,
it goes way up when we reprogram them.
Remember, we're not
telling them which genes
to turn on and off and at what level,
the cell somehow knows
that for the whole program.
- Right.
- And so it's not
mimicking an age reset,
it's actually fully resetting the program
at the gene expression
level, at one level,
and the very deep level,
which is the DNA methylation level.
Now, there are a lot of
things we don't know.
We don't know how many
times can you reset.
Is it once, which we've done,
or is it a hundred times?
And we don't know what
tells the TET enzymes
which methyls to remove
and which ones to keep.
Now, unlike our teeth and plaque,
where our teeth, we can
get rid of all the plaque
and there's no problem.
If we remove all the plaque
off our DNA, all the methyls,
our cells will lose
their identity completely
and we would become the
biggest pool of STEM cells,
it would basically be a tumor.
That's not what's happening.
We don't have mice that
have tumors in their eyes,
we have mice that can see again.
So it's as though,
now, another analogy would be
a pianist playing 20,000 different genes
and that pianist makes some mistakes,
but now we bring in a new pianist
and they can play just the right notes.
- Right.
- And we're not stripping
all the notes off,
we're not ripping the piano
off or the keys off the piano.
So the observer in my mind has to exist,
but exactly how the observer
knows which of those changes to make
to go back to restore the gene expression,
we don't know that at all.
I think there's probably
a Nobel Prize up for grabs
if someone wants to figure that out.
Now we're giving it our best shot.
But in terms of philosophically,
where would this lie?
Where would the observer be?
So it could be,
and I'll tell you some of my best ideas,
it could be a new type
of DNA modification,
so it's on the genome.
- Yep.
- It could be a protein
that's binding to the genome
when we're young that
stays there for 80 years,
or it could be some quantum
state that I hope not,
'cause that's gonna take us a
little longer to figure out,
but it's quite possible.
- Yeah, it would be interesting to see
how you would even measure
from a quantum level,
'cause I think that's
the orders of magnitude
even smaller than DNA.
I think that's a good evidence
where methylation is not just a symptom,
I think a devil's advocate could say,
"Okay, your methylation
is a correlate of aging,
"but if you knock it out,
"you don't get the reversal."
That definitely brings it
much more closer to a causal
or part of the causal path of aging,
which I think is interesting.
And the second part,
I guess when you have
the Yamanaka factors,
you kind of reverse into
a pluripotent STEM cell.
Could one explain or have
an alternate hypothesis
where these STEM cells
are still nearby other healthy nerve cells
and it just mimicking
the healthiest versions
of the cells around them?
And I think, this is me just speculating,
I have no evidence or data suggests
that this is the right or wrong path,
but in terms of an alternate explanation
that doesn't require an observer,
what do you make of that?
I mean, I think when people just
kind of generically inject STEM cells
into their bloodstream
for anti-aging effect,
and I think that's very, very spurious.
No data suggests that method even works,
but there are biohackers who do that.
I think the most generous
mechanisms of action for that
is that these STEM cells
somehow bind to areas
that are somehow damaged
and they mimic and build up
this healthy tissue there.
So to me, that doesn't require
necessarily an observer,
it was just mimicking nearby healthy cells
and maybe there's inflammation factors
like cytokines on kind
of the more damaged cells
and somehow that the STEM
cells just kind of mimic
the ones that are a
little bit more healthier.
Your thoughts of why that's wrong.
- Because we've tested it.
- Right.
- We can reprogram cells
to reverse the clock
and survive damage in the Petri dish
where there's just one type of cell.
And in the eye,
we can take those retinas out
and we can look at the cells
and actually measure what's going on
inside those cells, those neurons,
and the neurons themselves
have reset their age
and their gene expression.
It's what we would call
a cell autonomous effect.
So it cannot be that the eyes
are relying on the STEM cells
because the viruses that we
deliver, the gene therapy,
goes to the neurons and only those neurons
that get the gene therapy
are the ones that get rejuvenated.
In your theory or your challenge to me,
what we should see is
that it shouldn't work
in the dish just with neurons and it does.
And we should see that nerve cells
that don't get the virus
should be equally rejuvenated,
but they don't rejuvenate
unless they get the treatment
into their nucleus.
- I see.
So you're saying that
in the treated neurons,
the overall, essentially
all of them get reversed,
not just the pluripotent STEM cells
that differentiate
themselves into a nerve cell?
- Right.
So two adjacent nerve cells in the retina,
if one gets the treatment, the virus,
which we can see, we can stain it,
and another one doesn't,
only this one will rejuvenate
and survive and grow,
and this one won't.
- So you're saying that even
if the pluripotent STEM cell
tries to mimic the
existing nerve cell, right?
'Cause you have a STEM cell
that wants to differentiate.
You're saying that the mechanism
that the STEM cell wants
to mimic the nerve cell
wouldn't work because--
- Well, we don't see any
replacement of cells.
We can look in the eye
and all of the cells
that were there before
are still there after the treatment.
They haven't been replaced,
they haven't been
substituted by STEM cells.
It's the actual old cells
that have been rejuvenated
and they have to get
those genes into them,
into each cell, for them to get younger.
- I see, I see.
- So it cannot be
an influence or
replacement by other cells.
- So the existing cells that
weren't injected by the virus
that induces the Yamanaka factors
also rejuvenate as well?
- No,
they have to get the Yamanaka factors.
Cells are not talking to each
other or replacing each other.
Each cell acts as though
it's its own individual
and we reprogram them individually.
- [Geoff] Right.
- Because our treatment doesn't infect
every neuron in the retina.
I think we're getting about half of them.
- Okay.
- So you can very easily
see that those ones that
didn't get the treatment
will die off or they're not the ones
that become youthful again.
- Yes, so the infected,
or the Yamanaka-induced nerve cells,
you're saying that,
I would agree that those are the ones
that end up being healthy,
but I guess the nuance is that,
my, the challenge would be that
for some reason these
pluripotent STEM cells
differentiate to the healthiest
surrounding nerve cells
and that might be signaled through
some sort of intracellular communication.
And that kind of differentiates
all those to look,
all those pluripotent STEM cells
to look like the healthiest
of existing, like older nerve cells--
- Okay so you're saying that--
- Versus, yeah.
- A STEM cell could insert
itself into the retina
and replace a retina,
and grow all the way back to the brain
and fuse and be functional,
and then get rid of all the other cells
so that now the retina looks identical,
but it's actually replaced itself.
- Yeah, the STEM cells that
go into the damaged area
and then mimic the healthier,
the healthiest surrounding nerve tissue.
- So the nerves we see regenerate
are the original nerves,
'cause we tagged them with a dye,
so we don't see them being replaced.
So we can say,
"Yeah, they're not being
replaced by STEM cells."
And in the case of the old eye,
we're not damaging anything.
This is just natural aging.
- Okay.
- And there,
we can reprogram those retinas.
And those retinas don't
look any different,
they haven't changed,
they haven't multiplied,
there are no new cells,
but the nerve cells now,
we put an electrode in
the back of the eye,
and those nerves are now functioning
with electrical signals
like they were young again.
And then we test the vision of the mice
and they can see again.
- Yeah, I mean, I don't doubt that
you're definitely
rescuing function, right?
I think that is very, very clear.
I think the question would be around
exactly the mechanisms.
And it sounds like you're at the forefront
of teasing what that could look like
and I think a smoking gun clue
would be around methylation,
but it's probably necessary
but not sufficient
definition of an observer.
- Well we,
we can reverse aging in the dish.
So we grow human neurons,
and we can look at whether
they are rejuvenated
and they survive.
And we don't have STEM cells in the dish,
but those nerve cells with the treatment,
the Yamanaka treatment are,
respond to reprogramming.
- Okay.
- So it doesn't require
STEM cells for it to work.
- Yeah, so I think one of
the interesting things that,
you know, moving off of
just on the information
theory of aging here
in the nerve cell experiments
is around the Horvath
clock or epigenetic clocks
more broadly.
But, before you answer that question,
let's take a quick break.
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Thanks, Chrissy.
- Horvath clock or epigenetic
clocks more broadly.
So it's a very interesting tool
that differentiates chronological age
with biological age, right?
And I think that's like,
an interesting effect
and I think there's
probably a few markers that
researchers use for this, right?
There's no functional markers like VO2 max
or functional muscle
strength as predictors
for health span or longevity, right?
These are, you know,
perhaps a little bit more
intuitive functions, right?
The more VO2 max,
that correlates or associates
very well with longevity.
And where I think we're
seeing emerging research
for epigenetic clock could be
used as a similar predictor.
Right, there's a certain
pattern in the epigenetic clock
or Horvath clock that does the same thing.
Have you seen this work in all tissues?
Some of my conversations
with researchers suggest that
like they've been looking
at lean muscle tissue
and they date, they
didn't see, for example,
the epigenetic clock work
on that specific tissue.
Is there tissue specific differences here
or does it work for
universally all types of cells?
- Well, no one can answer that question,
'cause no one's tested all types of cells.
- Fair enough.
- But in my lab,
we've tested many different
tissues in the mouse
and Steve Horvath's tested
a bunch of cells in humans.
I can speak about my
own research, of course,
with more confidence.
We've been able to make a
clock every time we've tried,
whether it's something as
easy as muscle,
skeletal muscle, lean muscle mass,
a liver, blood.
More challenging was the retina,
build a retina clock out of
very small samples in a mouse.
You can imagine you only get
10,000 cells out of that,
but it worked.
Now there are a lot of
ways to screw it up,
and I'm not suggesting those
researchers you refer to
screwed it up, but it wasn't easy.
And there are, especially if
you have low amounts of cells,
you definitely have to boost
the signal to noise ratio.
For example,
you can zoom in on a part of the genome
that is highly repetitive and
get stronger signals that way,
100 fold,
and that's what we used in the
eye to be able to boost that.
But yeah, I was skeptical of the clock,
you know, because most things in aging
are more variable
than we want them to be,
varying between month to month
or individual to individual,
and, but the clock has
turned out to be surprisingly
stable and reliable.
You know, I'm happy to see negative data.
That would be useful.
I'm unaware of that problem.
What I've heard,
and you know again,
I probably shouldn't talk about hearsay,
but it's interesting,
'cause we've talked
about the atomic level.
If you go down to the single cell level,
I'm told that you lose the clock,
which makes perfect sense actually,
because the clock is an
average of the methylation.
You know, in the same
way you can't predict
where plaque accumulates
on someone's tooth,
but if you measure a million teeth,
you can have a pretty good idea
of where it tends to
accumulate, same thing here.
And so that could be
an issue going forward,
that the fewer cells you have,
the less clock you're able to see.
And it's gonna be similar I think to
trying to map the position of an electron,
where if you really try to pinpoint it,
you end up with basically a
probability and that's about it.
- Right.
- And trying to observe it
doesn't really help you,
in fact it makes it worse.
So taking an average has
been very productive.
I think the guys that developed the clock
have really led to a great
advance in the field,
and what I think is
probably driving the clock,
and we have a couple of papers
that we're working on on this,
is that the disruption of the epigenome,
and then it's
reconstitution, is a problem.
If you do it once, it's not a problem,
if you do it a thousand times
over a period of a decade,
then your epigenome is
going to be structured
informationally different than it did,
than it was when you were young.
- One of the, I would say, the most,
I guess hyped or exciting interventions
that reflect one of these pathways
is the AMPK pathway and Metformin.
There's been a couple of
New York Times articles
describing upcoming clinical trials
and some positive and
interesting data around
the use of Metformin,
which is typically a diabetes drug,
for anti-aging use cases.
So I think one of the interesting things
that I've been trying
to unpack here is that,
well, I would say that
it's not super well known,
but I'm curious if you
have a stronger opinion
on how Metformin works?
But one of the most popular
explanations of why it works
is that it inhibits Complex 1,
which is part of the
electron transport chain
of the mitochondria.
And the explanation there is that
it somehow disrupts the Complex 1,
which makes the mitochondria
a little bit less efficient
and that activates AMPK,
because now you have a
higher AMP to ATP ratio.
You're producing ATP a
little bit less efficiently.
And this is described as a formatic
or positive effect, right?
Typically, when you make
something less efficient,
you would think that this
is a negative effect,
but we explain that this could be positive
because of hormesis.
But I think on the other hand,
if you look at some of the
other literature around,
for example, Parkinson's,
Complex 1 inhibition seems
to be one of the targets of
targeting Parkinson's.
So to me,
it seems like there's a degree
of how much you wanna inhibit
and how much you wanna activate.
And I think on one hand if you,
and maybe this is because
it's like, squishy or fuzzy,
and it's like, not well quantified,
but how do you think about
when hormesis is a good thing for when,
or when it's actually inhibiting something
that's actually bad?
And I think that's
something that I think is
perhaps missing the nuance
when people talk about,
"Oh, Metformin works through
Complex 1 inhibition.
"We want to inhibit all the time.
"Simple story."
I think it's a little bit
more complicated than that.
Curious to hear your
thoughts on that topic.
- Geoff, it's clear that you think
more deeply than most people about it.
So hormesis is,
you know, I think it's a wonderful thing.
I like to call it,
"Whatever doesn't kill you,
"makes you stronger and longer lived."
But that doesn't mean at all
that we want to always be
under the same condition.
And the more we learn from studies,
what we realize actually is that the body
can even get used to hormesis, right?
You wanna be changing things up
in your daily life, in,
probably in supplements.
And,
it's no surprise to me
that it gets confusing,
because we have this standard model
and a lot of books written about it
that if something works,
you know, to take it in the morning.
If you take it three times a
day, it'll work even better,
and that's not true.
When you take it, how much you take,
in terms of the day, and
whether you're exercising,
whether you've eaten,
all of these things play in
and it's extremely complicated.
And if anyone says they know the answer,
they are lying,
or they're delusional,
'cause we don't know at all really
what the best combination
of these supplements is
and also in combination
with diet and time of day.
Now, I don't want listeners
to think that we know nothing, right?
We know a fair bit.
There's a whole 30 years of
research on this, even more.
But I think as a general theme,
what guides my research, and also,
you know, what I hesitate to
call self experimentation,
is the theory
and the belief, actually that,
that our bodies want to be challenged
and that's what wakes up these sirtuins,
the AMPK, the mTOR,
the insulin IGF-1, which
is controlling mTOR.
And because some of the experiments
that we do in the lab, have seen that,
I'll give you a good
example, resveratrol, right?
Everyone dumb that down.
Let's just drink lots of red
wine and we'll all live longer.
That's not true.
For a start, you need to
have a lot of resveratrol,
but the other thing that's
missed even by scientists,
particularly those
scientists who, you know,
want to challenge my research,
is that they miss the fact
that we also published
with Rafael de Cabo down at NIH,
that
resveratrol given on a high
fat diet will extend lifespan.
Resveratrol given on a lean diet
did not extend lifespan.
By the way,
the amount they got into the
body of those lean animals
was about five fold less
than what you'd get if
you'd have a fatty meal.
But what did work that
is almost always ignored,
or intentionally or otherwise,
is that if we gave
resveratrol to those lean mice
every other day with their food,
okay, so you're giving pulsing
food and pulsing resveratrol,
out of all the mice,
out of all the groups,
those were the ones
that lived the longest,
even longer than if you
just gave resveratrol
or intermittent fasting alone.
So what does that tell me?
It's very likely that
it's not just what you eat.
It's when you eat, and
in certain combinations.
And so I'm at that point actually where
I'm trying
to discover things in my lab,
discover things with my own body
to try and figure out when's
the best time to take things.
Metformin is a good example.
There's one study that says,
"People on Metformin
"are likely to be protected
from diseases of aging."
And then studies that come out,
which I think are really
over hyped in a negative way,
is that,
"Taking Metformin will
inhibit the benefits of"--
- Exercise.
- Exercise.
But I was gonna qualify,
'cause it's not all exercise,
it's weight lifting.
But if you drill down into the data there,
actually, that all groups,
Metformin or without, gain muscle mass.
Now we're all just as strong,
but there was a slight difference
in the size of the muscles.
Okay, fine.
If all you care about is
the size of your muscles,
don't take Metformin.
If you want to be just as strong
and potentially be protected against
cancer, or heart disease, frailty,
and of course diabetes,
then you know, take a
good look at Metformin.
But does that mean that
you should take Metformin
on the same day that you exercise?
Maybe not.
And that's what I'm trying in my regimen.
- Yeah, I think this notion of
pulsing or cycling or
periodization I think,
is really interesting because,
I would say that around
half of our conversations in this podcast
talk about longevity, health span,
but the other half really
talks about optimization
and elite athletics and sports.
And it's really interesting to me because
if you talk to elite physiologists
and sports physiologists,
they often put their athletes
through cyclical training blocks
in periodizing their diet
against their exercise.
And I think we see this manifest
into potentially better
performance on the athletic side.
But I think, it just,
that theme just rings true to me here
on the health span, longevity side,
where there's this notion of
hormesis at the right time,
the right cycling and periodization of it.
And it sounds like
we're still figuring out
exactly what those protocols might be
for which types of folks and
which types of baselines.
But I would agree with you that,
that seems to be the direction to explore.
You know, there's probably not likely,
they're just like one magic formula
that works for every single person
on every single lifestyle.
Another interesting, I would say,
a hyped up or a commonly discussed
pathway or compound
is mTOR and Rapamycin.
And I wanna just do like a
quick blaze through of that
in the sense that
there was a recent news for
a company called resTORbio
that was testing an mTOR inhibitor
that's like a very close
analog to Rapamycin
that, unfortunately,
you know, didn't make
its Phase III endpoint.
So I'm curious from your perspective,
I don't know if you have chance
to really dive into the data,
but just for me, just
looking from the outside,
obviously, mTOR inhibition
was like a big exciting area
that a lot of people have been looking at
as like potentially a way to halt aging.
The endpoint on respiratory
illness didn't quite pan out.
Are you more or less neutral on Met-,
or mTOR, and Rapamycin as a,
or Rapalogs as a path
to explore given this,
you know, fairly recent
new data point here?
- It's not as bad as it seems.
It's certainly bad for
resTORbio, no question.
Their stock dropped 90, 89%.
But there are a number
of ways to inhibit mTOR.
Rapamycin and Rapalogs is one way.
And as far as I know,
there are a number of companies,
there's
Navitor Bio that's working on that.
ResTORbio wasn't actually
working on a Rapamycin analog.
They were working on an upstream pathway.
I believe it was an AKT inhibitor
that led to downregulation of mTOR.
So there were still plenty
of ways to skin that cat
so to speak.
You know, it's never
good when something fails
because we're all hopeful
that we're gonna move forward,
not backwards.
But there's enough data on mTOR
in people using Rapamycin
that I don't think we should
suddenly give up anytime soon.
And it's Rapamycin is
still the most potent
drug we have to extend the life span
of animals late in life.
If we can remove those side effects,
then it would be a great,
great thing for humanity.
But what it shows you is that
making a drug is not easy
and you can't just extrapolate
from a mouse to a human easily either.
And that's why it's important
that we have multiple shots on goal.
And that's one of the reasons
that I work with a number of companies,
because if I just
had one idea and one company,
you know that's pretty risky,
but to spread that risk
and hopefully one or more will make it.
But mTOR I still think is
one of the three main pillars
of aging regulation.
I do my best to
optimize, mTOR sirtuins, and AMPK
in my own special way.
I don't take Rapamycin.
Though, you know, if I was 95 I might,
but I'm still pretty healthy.
But I think I can activate my mTOR,
sorry, inhibit my mTOR using other means.
So one of the interesting
things to remember is
all of these pathways are
talking to each other.
If you activate
sirtuins, you will inhibit mTOR.
And we showed years ago
that at least in yeast,
if you inhibit mTOR,
you'll activate sirtuins by raising NAD.
And the same is true for crosstalk
between AMPK and these others.
So it's not necessarily,
I don't think to take
Rapamycin to chuck down,
lower your mTOR activity.
And I think it also helps to
not be eating a lot of branch
chain amino acids as well.
- Right.
- And which is what I also do.
But if there's a safe mTOR
inhibitor that doesn't cost,
you know, $1000 a month,
I'd certainly consider it.
- Yeah, and I think you touched on a,
I think an important point,
which is that these are all interrelated,
interconnected networks, right?
This is definitely a systems problem.
And I think the human
body is so complicated
that you can't just push one button
and expect everything necessarily
to perfectly fall in line.
I mean, I think when you talk
about intermittent fasting,
that inhibits mTOR,
that up regulates AMPK.
I think some of these, I
would say best practices
that a lot of people have been looking at
affect the network of
these metabolic pathways
in kind of the right ways
that you'd want them to go.
Right, so I think,
I think when we we're looking
at specific endpoints,
I think it's important to, not overly,
I mean I think it's
important that you really
sit with the overall network effects
of how these things all work.
- Well, what's why I emphasize in my book
about personalized medicine.
It's not 'cause it,
you know, it's a buzz word.
I actually believe that the
future of longevity will require
devices like this.
- Yeah.
- I love this and I'm not an investor
so I think I can freely talk about it.
The Oura Ring
is one of those devices
that is the future.
The patch that I wear here
for glucose monitoring
is the predecessor of future little things
that'll be under our skin or on a bandaid.
And right now it seems weird.
You know, if I, when I go to the gym,
I can't tell you the number of people
that give me a funny look,
'cause I've got this device
stuck to the back of my arm.
- I'm guilty of that.
I've been playing around the CGMs
for the last three, four years.
And yeah, just an early user
of the Oura ring as well.
- Yeah, people think it's a bit weird?
- Yeah, but I think people
are interested, right?
It's like the cyborg future
is not evenly distributed.
- Well, as we get into
this and we're clearly get,
we think similarly that,
not only is there a lot
to still figure out,
but individuals will respond differently
in terms of how much, what, when.
The only way to know what works for you
or at least have an
indication, is to measure it.
Otherwise you're flying blind,
like driving without a dashboard.
And boy, I've learned a lot
over the last two years.
And anyone who's actually
interested in their own body
and is scientifically
minded or an engineer,
I think that they would
be like, "Oh, it's actually
a lot of fun as well."
You know, you get
a double bang for the buck, right?
You got data that can help you be healthy.
But it's also interesting.
I love the idea that I wave my phone here
under my arm.
- And you get your blood sugar, yeah.
- I see what's inside my body.
I've never been able to in real time
graph something inside my body.
And I look forward to a
future when we can do that
in real time and have,
you know recommendations on what we eat
and what we're deficient in,
and if we have cancer coming on board.
But without that we're just relying on
clinical trials on groups of people
that may not even be in the same country,
with the same microbiome,
or the same sex as you,
and you just have to hope
that it's gonna work.
But I think that we can
tailor our lifestyles,
and the way we live, and the supplements,
based on biofeedback and biotracking.
- You're preaching to the choir here.
I mean I think
you've identified a couple
of the problems, right?
Like the randomized
control trials and drugs.
I mean it's population level medicine,
and that probably means that'll
work for the individual,
but it's by no means guaranteed
gonna work for you specifically
if the population set that's being studied
is different race, different
country, different lifestyle,
I mean a lot of variables there.
But I think the future is
gonna go to that direction.
We're gonna have real time
access to all our information,
especially our biologic information.
It just seems like we're in the dark ages
like kind of flying blindly,
maybe getting our annual checkup
once a year for our annual lipid panel.
And like that's your check-in, right?
And like we know more continuous data
about our computers, our house, our cars,
than our own bodies.
- Well yeah, you and I are
living in the future basically.
But soon the rest of
the world will catch up.
- Yeah.
- As prices come down.
But it, to me it seems the
world we live in right now
where you go for an annual
checkup is medieval.
- Yep.
- It's ridiculous that,
and not only that,
you only go to the
doctor when you get sick.
- Right, like once a year is optimistic.
- Yeah.
Oh, I'll tell you the interesting thing
I haven't told anybody.
So I've been optimizing myself,
particularly in the last few
years as I've now turned 50,
and I wish I started sooner,
because you know, I can tell you I feel
better than I ever have and that's fine.
You know, you can see
that I have no gray hair.
I've got same amount of hair
as I had when I was in my 20s.
But that's all great, you
know, that could just be luck.
But what I've noticed is,
I used to get sick,
you know, at least a few times a year,
either in bed,
I'd be stuck in bed or I'd get a cold.
I don't remember the last
time I had a sniffle,
and I'm traveling and everyone
around me is getting sick.
And you know, that's known to be a sign
of good health and predicting longevity.
And I'm really feeling it,
and I think that's my best bellwether.
And my father too,
he's always been resistant to diseases
and I think that is really a good sign
that we often don't talk
about in this longevity field.
- Yeah.
So I know that we're running
a little bit out of time here,
so I wanna wrap with a final thought.
And I think a big portion of your book
is articulating why it's not insane,
but probably the most humanitarian thing
to extend longevity,
not just on productivity,
but I think just like
the human aspect that,
like there's so much experience
that one accrues for,
I think one of the things I think about
is like you just learn so
much about being a human,
and then once you kind of figure out
how to be a good person,
you're like ready to go die.
And I think that's like a shame,
'cause you build like
decades of experience
of how to be a good person
and then it's time to go onto your way.
So I,
I think I'm like very much
in line with your thinking
that this is probably the,
one of the highest
leveraged things to work on.
But I'm curious to just
tease into some of the
potential sociological questions
that we would need to
update in our governance,
perhaps in a future of where we're living,
you know, 200, 300, 500 years.
I mean,
you know, maybe as like
a final thought here,
what,
assuming that folks like yourself
can solve this problem of aging,
you know, what would
you be concerned about
in terms of the society
and culture that we build?
I think one of the things
that I kind of identified
or was thinking about is that,
dying seems to just make sure that
you can distribute wealth,
distribute power, right?
I think the interesting
thing with capitalism
is that it just,
the winners keep accruing
more and more wealth,
and sometimes the clock of death
forces some distribution
back to other people.
Yeah with it,
with yeah, with trust
funds and all of that.
But I'm curious,
you know,
assuming we solve aging,
which is gonna be quite challenging,
what would be your final thoughts on
things that future humans
and future political leaders
to set up a society
that fits this new norm?
- Oh wow.
(Geoff laughs)
There's a lot in there.
Yeah, I mean, in terms of
redistribution of wealth,
that's the easiest thing to solve.
You know,
changing the inheritance
tax, the estate tax,
or what some people
have politically called
the "death taxes", that's easy.
You can change that in a month.
Solving aging is the hard part, right so.
- Fair enough.
- Yeah, I'm not so worried
about that.
If you know humanity,
if they can't fix taxes,
then you know, then we
deserve what we get.
But what I think we do deserve is a chance
for a healthier, longer
life as we've always done.
It's just this is a new approach
that people haven't thought of
and one that could have
a much bigger impact
in addressing, like
what I call in the book
"whack-a-mole medicine"
trying to treat diseases as they come up,
not realizing that what's
driving all of those problems
is aging in the first place.
So yeah, ethically I think
it's the right thing to do for us.
It sounds like you agree.
The other thing that
most people who argue this point with me,
that on a population scale,
they'll say, "Oh, we
shouldn't live longer.
"And life isn't worth it."
How much would you give
for an extra two months
with your mother or your father?
Right, and then they go,
"Oh, right, yeah, I really want that!"
Right, "Well, how about another two years
with your mother or your father?
"Or your grandmother who you love?"
Then it's, "Oh yeah, I want that.
"Give it to me, but don't
give it to everybody."
So when it's personal,
you don't want your family to die.
You don't want them to suffer.
You don't want them to have
to go into a nursing home
and be spoonfed as most people
end up doing.
And so it's very different
when you talk about your own family.
But it's gonna require changes.
The same way that 100 years ago
we didn't have retirement,
we didn't have weekends.
We, you know, it was a
horrible, brutish kind of world.
And go back 100 years
before that, even worse,
and none of us would go back to that world
even though we've had to change.
We've had to work longer at longer lives,
longer parts of our lives.
But the bonus is that you get
to be healthy and relatively wealthy
and you have a retirement
and you have weekends,
'cause the world is wealthier
when people are healthier.
Right?
It's a virtuous cycle,
and when you're wealthier,
you get healthier.
But health is the core
of what's driven us
out of the Middle Ages.
And that's also true
for the developing world
where, as they become healthier,
vaccines and other things, antibiotics.
they're having fewer children.
They're not, you know, living
a brutish life and they're,
I think they wouldn't wanna go back
to this short life either.
So I think that we also have
responsibility ethically
to take care of ourselves.
I'm not
just selfishly trying to
stay young and healthy.
I'm a little bit more
motivated 'cause now I'm,
people are watching me
and seeing how I do over
the next few decades.
And it's kind of a game, but really,
what makes me happy about
doing that is the realization
that my kids may not have to look after me
in a decrepit state.
And hopefully I'll die very quickly
at an advanced old age
and not be a burden to them
and be very productive throughout my life.
I don't plan on retiring anytime soon.
And then finally, you know,
things that will have to change.
We're gonna have to
change the retirement age.
We're gonna have to
look at Social Security,
though I do believe,
and I've done the calculations
with an economist,
that the medical healthcare
costs of the country
will go down enough to easily
pay for Social Security,
but we can't retire
halfway through our lives,
which is what we're
heading towards actually.
- Yeah.
- We're gonna have
to give people incentives
to start new careers,
even if it's nonprofit work.
They have to be
some productive members of society,
taking care of grandkids or whatever.
And if you've been busting roads
and doing a horrible job
that no one would really wanna do,
and there are a lot of jobs
like that, we're privileged,
you and I to do what we do.
- Yeah.
- You know,
you wouldn't want them to have
to do that for even longer,
but give them a chance
to do what they always dreamed of.
Learn guitar, learn a language,
start a company, that kind of thing,
and with a longer life, you can do that.
- I think we're all looking
forward to that future
where we can
have that time, that luxury to be healthy
and have that time with their loved ones,
and our personal desires,
and personal ambitions,
and personal goals.
So thank you so much for
taking the time here.
I know you're a busy man,
so, appreciate the time and
we'll have to continue that
conversation at some point.
I mean, I think
plenty of more material to go through,
but again, a wonderful conversation.
- Yeah, I enjoyed it.
It was really great conversation
and great questions and I'll come back on.
- Alright, thanks so much.
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