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so I'm gonna ask is anti-aging total BS
or is there something here oh it's it's
absolutely not total BS there's there is
a real
um science of Aging that has made I I
think immense progress in the last 20
years and understanding what the biology
of Aging is and I think all of our hopes
everybody in the field hopes that as we
continue to gain that understanding that
provides opportunities to actually
modify that biology in a way that will
increase lifespan and health span and
there's no question we can do that in
laboratory animals so it's it's actually
pretty much yeah well depends on the
organism but if we if we talk about
rodents mice is what most people use
today it's a fairly routine to be able
to increase lifespan by 10 to 15 percent
some things can do better so the the
most effective intervention in
increasing lifespan in laboratory
rodents is caloric restriction
has been for decades and you know it can
get up to about 60 percent increase in
average lifespan is is the biggest
effect that's ever been published
so uh
one just a caloric restriction for
people that don't you're just starving
these poor little things and as somebody
no no what do you mean this is important
so it's it's actually
um more properly referred to as caloric
restriction in the absence of
malnutrition so the idea here is to
restrict caloric intake but ensure that
all of the vitamins micronutrients are
at appropriate levels so it's actually
not starvation and I actually think
that's an important point to clarify
um but it is you know in the case of
where 60 lifespan restriction was
reported a significant reduction in
total calories of about 60 percent it's
a it's this weird sort of relationship
reduction from what they would normally
eat if they could eat what they wanted
yes okay so you and I Define the word
starving very different to me as
somebody that did probably yes 25 clerk
restriction and that might be generous
maybe it was a little bit less than that
but ballpark math is pretty close to
that yeah and it was miserable right I
lost a lot of fat I got lean as hell I
looked awesome I loved being naked it
was really cool but my business partners
pulled me aside and my wife and said you
no longer have a personality oh yeah and
so but it was on the back of I'd heard
like hey the one thing that can be
replicated across every species caloric
restriction and so I was like word now
to be honest I was doing it because I
really wanted to get lean and I just
thought that that was going to be the
way to do it but it did not hurt my
feelings that I was like oh and this is
going to have life extension benefits
now as I've gotten older I've gotten
more interested in the life extension
but 25 percent
was brutal and let's say that I'm
overestimating and it was more like 20
or 15 percent that was so unpleasant I
can't imagine 60 so there's a huge
amount of nuance to him to unpack here
right one one thing I think we should be
clear on is mice aren't people so we
don't know does 60 in a mouse translate
to 60 reduction in calories in people we
don't know would 60 lifespan extension
in a mouse translate to 60 lifespan
extension and people we don't know my
intuition is probably not yeah why not
though because mine's the same but I'm
way less well so so it is so there's a
couple of a couple of uh reasons why I I
would guess that one is there seems to
be a trend that
um the ability from these kinds of
simple interventions like caloric
restriction to increase lifespan the
magnitude of the effect is shorter in
longer lived organisms so you can go so
like in the laboratory we commonly use
yeast which is single-celled nematode
worm called C elegans fruit flies and
mice those are the four most common and
they live very different absolute
lifespans so
um a nematode will live about a month
fruit flies will live about three months
mice in the lab will live about three
years and the magnitude of of effect you
can get from interventions like caloric
restriction decreases as you go to the
longer lived organisms now whether that
will hold when you go from something
like mice to dogs to people we don't
know but I think it's a reasonable
expectation that the percent effect at
least probably gets smaller as you go to
longer lived species there's also some
people who argue that um
the processes by which humans evolved
long lifespan and other long-lived
animals to some extent put them into a
state that is already you've already
kind of gotten the benefits that you
would get from evolutionarily optimized
for that already and so adding to that
might be much smaller yeah that's really
interesting and I was going to ask you
what the hypothesis was there
uh okay so that makes a lot of sense we
don't know if it's going to transfer
from mice but we see some early signs
that caloric restriction Works
incredibly well on rodents have we seen
anything in humans so let me take a step
back because this is where I think the
common perception and the way it gets
presented
um often doesn't quite match up to
what's in the literature so it is
absolutely true that caloric restriction
is the most robust way to increase
lifespan in terms of magnitude of effect
it's probably also the intervention
that's been tested the most number of
times so it's it's highly reproducible
in a sense that many many different labs
and many many different settings have
shown you can extend Lifetime with
caloric restriction what often is not
talked about is there appears to be a
pretty significant genetic component to
whether or not or how big the benefits
are going to be and the best study
that's ever been done was a study of 41
different lines of mice so these are all
genetically inbred but genetically
different from each other and what they
saw was that in about one-third of the
lines you got this big lifespan
extension about maybe a little bit more
than one-third you get a big lifespan
extension there's some where there's no
effect and the thing that I find
fascinating and also a cautionary tale
is there's about 25 percent to one third
of the lines where lifespan is actually
shortened from our floor restriction
yeah the same Paradigm this was a 40
restriction in this case now there's
lots of limitations to that study so I
think we we have to say that needs to be
redone better but the same thing has
been done in other the all of the other
model organisms that I talked about
yeast and worms and fruit flies and it's
pretty similar there's about one-third
of genetic backgrounds where there's
either no effect or a lifespan
shortening effect from a single caloric
restriction Paradigm so and I think this
is really important because humans
obviously were genetically different
from each other there are absolutely
going to be people who are harmed by the
caloric restriction protocol that you
talked about that you tried 25
restriction it's not going to benefit
everybody and we don't really have a
great understanding at this point of who
is likely to benefit who isn't likely to
benefit the and and you were talking
about loss of body fat which is really
interesting the one one of the things
that seems to correlate in the mouse
studies with beneficial effects from
caloric restriction those
genotypes that are able to maintain fat
when they're calorically restricted seem
to be the ones that get the benefit
better but able to maintain fat
interesting the point I was going to
make is the other thing that I think is
about caloric restriction that's
important to appreciate is
um humans are weird animals and there's
this whole psychological component to
restricting food right and it affects
some people
um in psychologically in ways that I
think are maladaptive right and and I
know many people who have who have
played around with different types of
caloric restriction and
um and for some people it works great
but other some other people you know
um they they really struggle
psychologically with uh
you know feeling like they're deprived
sometimes even adopting behaviors that
that I'm not a psychologist I'm not
going to diagnose anybody or
psychiatrist but appear to me like
eating disorder behaviors right and so
this this is where again I think we have
to be careful about sometimes
translating some of what these studies
from laboratory animals mice which you
know maybe they develop psychological
responses to caloric restriction but we
don't test that in the laboratory and
and they're not given a choice I think
that's part of what leads to the
psychological challenge that some people
have with food restriction is you're
constantly being presented with a choice
constantly and so it's a battle for you
know it's battle for almost anybody to
maintain 25 reduction in calories from
what they would normally eat or or even
in this case what they would eat if they
were trying to be healthy and go 25
lower than that you're constantly faced
with choices to go off of that regimen
and I think that that lead leads to this
sort of internal you know mental
struggle and different people react
differently to that so that's not often
talked about and so that's why again I I
get a little bit
um
worried when people write books saying
that everybody should go out and do
caloric restriction or intermittent
fasting or you know whatever there's not
a lot of attention paid to the fact that
we know there's a genetic risk there are
some genotypes that aren't going to
respond positively to these things and
we know there's a psychological risk to
some people and and so I'm not sure I'm
not sure we could you should be
recommending one size fits-all sort of
strategies around nutrition and diet
Beyond and I mean you know I get it I
understand why you're saying that but I
at some point people have to do
something and so it's like in the
absence of people like you saying look
there's no one-sided fits all but
probably eat like this you're gonna get
the RDA you're going to get people
eating the food I guess not the pyramid
anymore the my plate or whatever it is
and that's been a disaster right so it's
like somebody has to step up with
guidelines but really fast going back to
the first thing that you were saying so
when I went on that hyperchloric
restriction for the reasons you're
talking about I said to Lisa my wife uh
I'm giving you the keys to when I stop
this because I would make an
extraordinary anorexic and and and I say
that right but I recognize that about
myself I pride myself on that discipline
it was man it the the the exercise was
to manifest that effectively as an
eating disorder with optimal nutrition I
was trying to make sure that I had all
my braces covered but I was like this is
going to be miserable I'm gonna be
exercising like a fiend eating as little
I was eating about 1500 calories and I
would guesstimate that my maintenance is
roughly two thousand that's why I came
up with a 25 yeah so it's like it was
somewhere in that ballpark I'd lost the
weight so I know that I was in a deep
caloric deficit was also eating well but
it was like I know I can't trust myself
because I had so much body dysmorphia
that even though I had six pack abs and
they were very defined and I was leaner
than I'd ever been in my entire life
I just couldn't stop looking at that
lower back fat and I was just like God
this is crazy so anyway I do think
that's important but going back now to
we're seeing these studies the data's
coming out it's super nuanced it's very
complicated but people are grabbing onto
a narrative I kind of think they have to
and whether that's hey here's my
narrative for you to know how to eat or
here's my narrative for me to convince
somebody to give me a grant so that I
can go study this yeah so so yeah so let
me make a couple of comments on that one
is I think
um
when we talk about nutrition for people
there there's a difference between
recommending that people should practice
caloric restriction which let's just be
honest it's not going to work for almost
everybody there are very few people who
can actually do the kind of caloric
restriction that you did for a prolonged
period of time and and you know stay on
it and this experiment's been done
I've actually heard you give this
argument before your answer is kind of
interesting what do you mean so uh
should we pursue a path where we come up
with a pharmaceutical and everybody can
take it and great but it could take 20
years and 100 billion dollars or do we
go hey this is the hard truth don't eat
these things reduce your calories and
only the people that are disciplined
enough are going to pull it off yeah so
that's an interesting question um so the
couple things I would say about about
that specific question and honestly I
don't remember what my answer was that I
gave before that's what we probably have
to consider the you were you weren't
like you know forget the people that are
disciplined but you were like hey we
need to be thoughtful about the fact
that the vast majority of humanity will
not be able to do that that's right and
so if we're trying to you didn't say the
words greatest good but that was like
the gist then we need to be thoughtful
at not discarding the path because the I
would say I had that interviewer's basic
stance which is I need to know what's
true yeah and and if what is true is
there's a way for me to eat and live
live that's going to extend my life even
if it's hard I would rather you put your
time and attention there versus solving
it for people that aren't going to do
anything got it so okay so here's here's
what I would say around caloric
restriction so so I think we need to
differentiate between what I would
consider Healthy nutrition and caloric
restriction so there is absolutely no
question in humans that a healthy diet
will increase your likelihood of living
longer and avoiding disease
well here's here's what I would say I
don't think there's a one-size-fits all
right so I think it's unfortunately at
this point
um largely information that most people
know right like avoiding Ultra processed
foods right staying at avoiding being
obese certainly I would actually say
avoiding being overweight and I think
actually the guidance guidelines we've
got you know for as inaccurate as BMI is
for the average person that's not a
terrible place to start get your BMI
down into what would be called normal
range even if it's muscle that's well
again that's what I'm saying I was
saying for the average person so this is
where again I think we get we need to
get nuanced if if you are a person who
appreciates the importance of body
composition if you've had a dexa for
example and you know with some level of
precision what your body composition is
absolutely you can go beyond BMI and say
okay I want to get my body fat down into
this range and then you can even get
more Nuance like you know is it visceral
adipose that you want to get rid of so I
think it really depends on what the
audience is but
um but I think again you know as a
general rule of thumb there's not you
don't I don't think we should even
necessarily try for a one-size-fits-all
nutritional strategy because it's it's
clear that's that's not going to work is
there so while they're definitely people
in my experience there's no one size do
this they're in my Layman's opinion
there is a one size don't do this yes I
think that's fair yeah and again I mean
I think it's it's
um hyper processed what about or what's
your Vibe on that so my and I think this
is I don't think too many people would
disagree with the idea that we should
avoid high levels of simple
carbohydrates complex carbohydrates in
the forms of vegetables are generally
going to be fine for pretty much
everybody I'm not like I've I've I eat I
tend to eat a pretty low carb diet
because I find for me that works really
well I'm not hungry I enjoy what I eat
you know it's not like I have to think a
lot about
how much I'm going to eat and it helps
me maintain my body weight where I want
it to be but I don't think necessarily
that's that works for everybody and I
think you know some people have very
strong opinions about
meat products versus vegetable products
my personal view is I think the science
is still a little bit unclear there and
in either direction in either direction
well I think that you can you can
certainly make the case that that a diet
that's high in
plant good quality plant-based calories
typically is going to be pretty healthy
right because you're going to be eating
a lot of vegetables even fruits you're
going to be eating a lot of fruits I'm
not again there you can get a little bit
into which fruits are high glycemic you
know so I think that's that's sort of
second level but but for the average
person you probably don't need to worry
so much about that and and really just
focused on cutting out the processed
foods I think a Whole Foods diet is
pretty good
um that and then just paying attention
to to how much you're eating but again I
think the portions more or less take
care of themselves if you're really not
eating the garbage right I think the the
the problem I mean and again I I kind of
feel silly talking about this because
it's stuff that everybody kind of has
already heard before right like this is
as somebody that records these kind of
episodes all the time the one of the
comments we get the most is pick a lane
which is it am I supposed to eat meat am
I supposed to eat vegetables like what
is it yeah and so I'm actually going to
lay out so want to to orient the
audience we're definitely going to get
more into what the the influencers are
grabbing onto that you think are
problematic and then why you're still
enthusiastic about this but I think that
it's worth
um on this idea of a healthy diet I'm
going to lay out an abstracted from what
you chew to what you're trying to
achieve level and tell me if you think
this is bang on so if you're trying to
balance performance and Longevity You're
Gonna Want to be uh optimal nutrition is
going to be the main thing so you have
to get your main building blocks which
is largely going to be an amino acid
profile so that you can build and
maintain the muscle mass that you have
keep that all-cause mortality as you get
older is so linked to muscle mass so
you're thinking about that if you're
eating a vegan diet the odds of you
being able to get that the right amino
acid profile without supplementation is
effectively zero and so you can do it
but make sure you're thoughtful about
your supplements you can do it through
red meat but red meat or meat in general
and I'll assume nose to tail so that
you're really getting all of your
vitamins macro micronutrients but the
the problem you're going to run into
there and this is going to be a big
thrust in this interview I have to
assume knowing what you know is you're
going to turn mtor on like crazy and so
if you're living in a world and mtor for
people that haven't heard that I won't
even yet tell you what it stands for but
right now just understand it tells your
body to grow so if you want to add
muscle whatever but you can imagine from
a longevity perspective if you're giving
your body the impulse to grow forever
you're probably going to end up growing
things like tumors and things like that
so you run into a potential problem and
sort of the quick punch line of where I
think your work takes us is you probably
have to do something that has some of
the same knock-on effects of caloric
restriction and so you said something
that our audience may not yet understand
which is the difference between
restricting your calories and not being
overweight yeah which is going to be an
important thing that we'll talk about
but like if I were to say for people
that are like which the [ __ ] which is it
yeah it isn't either it's you're eating
for something you're eating for an
effect now if you think about that
effect and you're willing to monitor
yourself you can actually figure out
what you as an end of one should eat
yeah I think that's super super
important so so one thing I would say
um is that you know I think again
the quite the answer to the question is
going to be somewhat different if the
goal is to optimize versus
you know just do better than we are now
because again I think the average person
is so far away from optimal that that's
where you can give these sort of General
guidelines the only way you're going to
get anywhere close to Optimal is by what
you said at the end actually measuring
your own response right because there's
because again this goes back to the the
point that I made about even something
as as blunt a tool as caloric
restriction in mice there's a
significant fraction of genetic
backgrounds that respond poorly to that
in terms of longevity and that's in a
very controlled environment those are
mice in a laboratory where we control
almost everything about their
environment you take humans in the real
world and our environment is so complex
that that on top of the genetic
variation really makes it almost
impossible to predict at an individual
level what optimal is going to be which
is why you need to measure biomarkers
and have some confidence that those
biomarkers are actually telling you what
you think they're telling you and that's
where I I think we're at a really
interesting time in the field where we
now have a plethora of biomarkers we can
measure that we think tell us something
about aging
but we don't really know for sure how
good a lot of these biomarkers are or
how comprehensive they are and so you
know when you hear people talking about
biological aging clocks or reversing
aging which is a term that I almost
despise these days because it gets
misused thought because it's not
accurate I mean well let me put it this
way
um there's no evidence that anybody ever
in a mouse or a person has
taken a biologically old organism and
biologically made it young again that
just hasn't been has not been shown to
be done there's no data but when you say
that do you say it yourself yet or are
you like um I don't think so there's
nothing there's no theoretical reason
why it shouldn't be possible to reverse
biological aging I feel like there's
still so much we don't understand about
the complexity of biological aging that
it's going to be a long time until we're
able to do that but who know I mean
again this is where you get into how
fast is technology going to progress we
don't know right um but there's so much
that we still don't know you can reboot
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my intuition is it is far more complex
than even most of the people in the
field appreciate and that the kinds of
tools that we're using today again are
still pretty blunt instruments and the
one thing that that could change that
and this is still an open question is
[Music]
whether or not
um
epigenetic changes are really sort of
this this uh primary Upstream driver of
aging and we can get into that that's
kind of getting into the weeds a little
bit but there is this
popularized concept that epigenetic
changes are are are really the uh
primary process of biological aging from
which all of the downstream molecular
changes functional declines diseases of
Aging derive if that's correct and I
don't personally think it's correct but
if it's correct then you could imagine a
technology and and people have developed
some technologies to do this that can
reverse those epigenetic changes and
thereby that would reverse much of
biological aging it's still a completely
open question though I want that to be
true yeah I would love it to be true as
well partly because it's easy to
understand yeah and so for a Layman like
me when I started understanding genetic
epigenetic reprogramming it was the
first time I was like oh wait I get it
aging boils down to the D
differentiation of cells they're no
longer an eye cell liver cell heart cell
whatever they begin to sort of lose what
am I and that is is aging
you it sounds like it's just that's one
piece maybe but there's just a whole lot
of stuff going on yeah it's pretty
interesting because if you go back
10 years now
um you know there was a pretty famous
paper written called the Hallmarks of
Aging where uh several leading
scientists in the field put together a
collection of nine processes that that
at the time and I think still today
um seemed to be particularly widely
shared across the animal kingdom are
these causes biological aging process so
that's a good question so they are for
the most part
um molecular processes that could be
causal so it's very hard to prove
causality right but but that could be
causal and they include things like
accumulation of senescent cells which we
know
yeah these are the nine that's one of
the nine DNA damage is one telomere
shortening is one epigenetic changes is
one mitochondrial dysfunction is one so
epigenetic changes are one of a
collection of Hallmarks of Aging
and they interact with each other and I
think of it as kind of a network of
interacting processes and so there's two
things I would say about that nothing
has really changed from 2000 I think it
was 2012 when that paper was written to
today to strongly suggest that
epigenetic changes are any more
important today than they were then in
the science again people have used
reprogramming and shown that you can
improve some functions in a mouse and so
for your listeners who who aren't aware
reprogramming is a technology that
allows us to change the epigenetic state
of an old cell back to what it was when
that cell was young or de-differentiate
as you said
um so people have used reprogramming now
in mice and shown you can improve
function in a few tissues you can
increase lifespan a little bit
um but not even to the extent that you
can do with rapamycin and nowhere near
what you can do with caloric restriction
so those following along we will get
into rapidmines yeah yeah sure so so the
the point being that um
we thought epigenetic changes were
important when this Hallmarks of Aging
paper was written we still think that
they're important but it's not clear
that they are any more important as some
of the other processes that that play a
role in biological aging and the real
test of that is to take an old mouse
reprogram it and make it young again and
if somebody can do that believe me I'll
be on the bandwagon I hope that happens
but I'm my intuition is it's not going
to and and I've actually
starting to think that it's it's
probably unlikely you're even going to
do as well as you can do with caloric
restriction using the epigenetic
reprogramming technology because I don't
think that that epigenetic changes are
in fact any more uh important than some
of the other
factors that we know play a role in
biological aging the last thing I'll say
on this is and this is where the field I
think unfortunately has
um become a little bit too narrow uh
because once these Hallmarks of Aging
were sort of formalized it created a
structure that limited people's thinking
and so now even though we know that's
not everything about biological aging
it's created this structure that in
order to get a grant funded you have to
frame it in the Hallmarks of aging and
so almost nobody is actually asking well
what else is there what else might be
important and how do we find those
things and so I'm I'm a little bit
concerned that the the field has
narrowed its
um
search in a way that will that's
limiting us right now you know who Eric
Weinstein is
the name sounds familiar but I can't
place it really digging so he also is a
mathematician for people that don't know
you have a very impressive background in
mathematics uh and he is saying exactly
what you just said about health and
anti-aging in uh physics yeah and he was
like string theory grabbed the hold of
people's minds and won't let go and we
now have had 50 years it's fruitless
it's led to absolutely nothing but
to be taken seriously and all that like
everybody's working within that
framework and his whole thing is like
who's going to be the person that is
like the young rock and roll researcher
that steps outside of that and is not
afraid to look crazy and it's like no
it's this thing over here it's really
interesting now as the person who can
embody the problem I will say you need
an organizing principle and so when I do
interviews like this I first write down
like what the person's theory is and
then I try to understand so one it shows
me that I understand where you're coming
from like I could I might be wrong in
some unacceptable percentage but I could
reiterate to you right now what I think
your thesis is the reason I do that is I
want to know what the predictions are
and I'm trying to do that so that I can
categorize like what's going on so for
instance you give me nine Hallmarks of
Aging my immediate question is is there
an underlying cause uh like is there one
thing that then manifests as these nine
things because because that gets
interesting now it might be a
categorical error on my part or anybody
else's part to try to Bunch everything
into the Hallmarks of Aging but for
instance when I think about aging even
your own thesis has to do with
inflammation
and so it becomes a question of
is this all like is this a game of
inflammation like if I can turn off
inflammation does that like what we
don't know what that is but like if I
identified that sort of switch of on
inflammation off inflammation if I could
somehow and obviously inflammation is a
good thing so you don't want to
eradicate it but if I could turn that
switch off whenever it wasn't doing the
job that we want it to do would that
stop aging so anyway I don't need you to
take that question seriously my thing is
there needs to be a framework well I
think that's a good good question so
um so first thing I would say is no
changing or turning off inflammation or
optimizing inflammation maybe that's a
better way to say it would not stop
aging I don't believe
um so you so you asked I think a very
interesting question that that not very
many people in the field actually I
think spend enough time thinking about
and and we don't know the answer but
we've got some Clues which is is there
an underlying principle that is
biological aging is there can we
actually boil it down to one thing right
and we don't know the answer there are
as I alluded to this there are
absolutely links between the Hallmarks
of Aging you can draw it as a network
diagram and make make connections where
we have evidence to support those
connections I think the best evidence
that there is a something fundamental
about the biology of Aging is in every
animal or organism where we've looked we
can identify single genes that
significantly increase lifespan and seem
to improve what we call Health span or
delay the functional decline single
genes so I can go in with crispr cas9
and I can edit some things there are
people trying that yes interesting yes
and we can do it in mice like again this
is fairly routine so there's there are
many so so one of the cool things so
so I'll answer your question in in two
ways um one is sort of from my own
personal background I started in this
field in 1998 as a first year graduate
student
um and that was a really cool time to be
in the field because it was when the
field sort of switched over from being
observational to molecular and
mechanistic and one of the things that
allowed that to happen were the creation
of tools where you could suddenly do
very detailed genetic molecular
biochemical experiments in simple model
organisms so again I I talked about
yeast and nematodes and fruit flies
where they they age so quickly you can
do it at a time frame that's amenable to
Discovery at the same time people
created these things called genome-wide
libraries where you could look across
the entire genome at either Gene
deletion or Gene knockdown and look for
mutants that gave you whatever phenotype
you were interested in I was interested
in lifespan because I study aging so you
suddenly had the ability to look at five
thousand ten thousand genes and in a
very unbiased way ask which ones
increase lifespan when you mutate them
and so that led to the observation there
are
hundreds of genes that when you mutate
them in simple organisms will increase
lifespan now the effects are usually
pretty small on the order of 10 to 30
percent I would say a 40 percent effect
from a single Gene is is very large
that's towards the upper end any
unifying characteristic to these scenes
so they if they affect they affect the
Hallmarks of Aging that's kind of how
the Hallmarks of Aging actually evolved
was because as we learned about
different ways so was it like all
hundreds of them slot into these nine
things I don't think you could ever say
all because there's so much we don't
understand and this this gets a little
bit to how science happens right I mean
you know let's so one of the things I
did early in early-ish in my career was
one of these genome-wide screens and we
identified hundreds of genes but you
don't go study all 300 of them you pick
a few one of which was mtor so we'll
come back to mtor I'm sure
um you pick a few and those are the ones
you study and those are the ones that
you figure out the mechanism so there's
still a lot of Undiscovered Country out
there for things that people have never
really followed up on but but to answer
your question yes in general you can
point to certain Pathways or networks
that seem to be particularly important
and
work Across The evolutionary tree right
and I think that's what that's again
where a lot of the attention has been
paid if a gene in yeast affects lifespan
only in yeast that's not so interesting
but if it also affects lifespan in worms
and fruit flies and mice then we start
to think okay maybe that's going to be
really relevant in the real world and so
those are things like
um growth hormone signaling insulin-like
growth factor one igf-1 insulin
signaling mtor and things in that
network foxo is another factor in that
that interacts in that Network so so so
those are sort of to me form in my own
mind a picture of an interacting set of
very important factors that seem to
modulate the biology of Aging which
would be represented to some extent by
those Hallmarks of aging and the way I
think about it is there are certain
nodes in that Network that are
particularly amenable to
intervention in a way that will increase
lifespan in health span and that's where
something like mtor comes into play just
turns out that and for reasons that I
don't understand but I speculate have to
do with the network architecture that
particular node when you tweak it
has big effects throughout the the
network that that then lead to our
observation that you can increase
lifespan and health span and another
thing that makes certain nodes more
favorable is that you've got a a range
in which you can play before you push
things the other direction so again all
these things are going to have the
potential not only to increase lifespan
so if you think about a certain Gene
there's an optimal expression level of
that Gene for lifespan none of our genes
are intentionally optimized for lifespan
which is probably why it's so easy to
find genes that affect lifespan
um uh but some genes so that means you
can you can get it to the optimal which
would be increasing lifespan but if you
go outside that range you're going to go
the other direction and you're going to
shorten lifespan and and it's much
harder or much easier to break a system
than it is to make a system function
better so all of these things you have
to be careful because if you tweak them
the wrong way you're actually going to
go to a place we don't want to go
um have you ever asked the question did
nature have a reason and for making sure
that we die yeah I mean it's an
interesting question and there are
different people who have different
thoughts on this so the uh the the the
the collection of people who argue that
nature did
evolve us to die fall into the camp that
would be called programmed aging the
idea there is there is an evolutionary
evolutionarily selected program that
causes us to age and die and you can
come up with speculative reasons why
that might be beneficial there are some
cases where that seems to be the case so
salmon are sort of a classic example
right where they have evolved after
reproduction to undergo this rapid
senescence process and die Leafs are
another one so Leaf senescence is
another one where annually Leafs will go
through this senescence process yeah so
that's that clearly happens in select
cases my personal view is that there's a
much much easier argument and sort of
going by Occam's razor right let's just
take the easiest explanation that works
there's a much easier argument that what
what aging really is is an absence of
selection so once we do our job we from
an evolutionary perspective we pass our
genetic information on to the next
generation and we get them far enough
that they're going to be okay
natural selection doesn't really care
about us from at that point so it's a
it's a selection Shadow there's no
benefit from an evolutionary perspective
to
slowing aging at that point and making
us live longer aside from the little bit
of added benefit from further
reproduction but most of the work is
done early on and then the the benefit
that comes from slowing aging and
increasing lifespan falls off pretty
quickly and so that so the idea would be
that that biological aging to some
extent is an accident of evolution it's
an absence of selection and you know
these are fun sort of conversations to
have but you can't really test them
experimentally and so I tend to I like
to have the conversation when people
start arguing about it I tend to tune
out so I'm like this isn't interesting
anymore but you know people love to
argue so all right well I want to use a
specific example to highlight some of
the things you're talking about so
rapamycin yeah
rapamycin tied to mtor
give us a brief history so you're doing
the dog aging project the punch line is
let's see if we can extend their life
and health span by giving them rapamycin
as far as I know that's the only while
you're tracking other things that's the
only intervention that's the only
clinical trial as part of the dog aging
project okay so why why
did you think rapamycin would be the
right thing to try as a clinical
intervention to extend the life of dogs
right so I mentioned caloric restriction
was the most effective way to increase
lifespan intervention wise in a in mice
rapamycin is the second most effective
and again seems to be the most
reproducible so there's a huge body of
literature showing that genetically
turning down mtor can increase lifespan
in yeast and worms and fruit flies and
mice and then there's another body of
literature showing that
pharmacologically turning down amatory
that's what rapamycin does it's an
inhibitor of mtor can increase lifespan
in all of those organisms so and it's
been done by many many different labs
and so personally I have a lot of
confidence in in that body of work
because it's not one lab showing this
one time and then everybody gets excited
about it and then you know it may or may
not be real this has been reproduced
over and over and over again
um and then in mice there's a couple of
features of rapamycin that are
particularly I think
relevant for
potential to have an impact outside of
the laboratory one is you can start the
treatment in middle age and really that
was first that was first demonstrated
with rapamycin I think so that was done
in 2009
um before that I think most people
myself included would have been would
have would have speculated that it would
be very hard in an old animal to
actually have a significant impact on
lifespan and Healthcare but that was
shown with rapamycin you get almost the
same effect starting at about the mouse
equivalent of a 60 year old person as
you do starting at young age and so from
a we can talk about maybe why that's
happening but from a from a from a
translational perspective that all of a
sudden starts to become pretty exciting
because you can it's much easier to
imagine a drug that you would start
giving to people in their 60s 70s 80s
versus something they have to start
taking as teenagers right so yeah so so
that was and that also told us I think
something fundamentally important about
the biology of Aging like what that that
it it um that there's some plasticity
there right that at least at a
functional level you you can actually
reverse some of the functional declines
that go along with aging okay so this is
the one I want to push on so I am
scandalized scandalized by one of the
findings I've heard you talk about so
you talk about rapamycin and the effects
on
um
oral cavity degeneration just to lump it
all into one thing that okay fair enough
if rapamycin happens which again is
shocking for people to understand mtors
about growing rapamycin therefore if
it's inhibiting that would lead most
people to predict that you would get
muscle loss if you're taking rapamycin
that seems pretty logical but it doesn't
it actually seems to mean that it might
do the exact opposite and so you can
grow bone back in your teeth none of
this is scandalous once you accept that
even though it's counterintuitive all
right I'm waiting to see what scandalous
how the hell does it impact the oral
microbiome I don't understand that
that's bacteria in my mouth yeah what
the hell does something that inhibits
mtor have to do with that whether
bacteria can Thrive or not yeah I can't
wrap my head around really good question
there's actually so so the real answer
is we don't know for sure but I think
there's a pretty good speculative answer
that that's probably correct which is
that the reason you get the remodeling
of the oral microbiome
um is because of because rapamycin is
rejuvenating to some extent immune
function so most people don't realize
this right but there's a huge
interaction limiting mtor rejuvenate
okay oh wait can I guess okay these are
all your ideas I want everyone to be
very clear but I think I understand so
one of the things that I've heard you
say is you have uh senescent cells some
percentage of Aging is you get these
cells that become senescence and essent
means that they realize they're
dysfunctional so they don't keep
replicating but they kick around still
and they give off an inflammatory signal
of some kind and so you get these auto
immune responses where because of these
senescent factors the immune system is
going after them so now you have this
increased inflammation a certain type of
inflammation called sterile inflammation
meaning there's no bacteria present
that's causing it let me just so this is
interesting so I had a conversation with
somebody the other day about these terms
because I tend to use them
interchangeably chronic inflammation
sterile inflammation all sterile
inflammation really is as autoimmunity
it just means your immune system
reacting against yourself as opposed to
a pathogen so again I think I think to
be clear that's part of what's happening
to the immune system with aging is The
Chronic signals given off by these and
cells which then it's not only causing
your immune system to act against self
you know it kind of hyper activates the
immune system in general the outcome of
that is that you get higher levels of
autoimmunity senescent cells probably
aren't the only thing causing that just
to close that Loop if I'm taking
rapamycin it goes and either addresses
those cells in some way it somehow
lowers it shuts off it shuts off what
people call the senescence-associated
secretory phenotype which is mostly this
inflammatory signal it's rapamycin is
one of the most potent interventions we
know at shutting down the the stuff that
senescent cells are giving off and stuff
we understand some mechanisms but again
it's it you know it's um it doesn't
really matter the what matters is that
it shuts the cells off but there's an
important question for me in there which
is if that's the mechanism is it
rejuvenating the immune system or just
giving it a break
probably both so here's the way I think
about it and again I've I've tried a few
times to to learn enough Immunology to
uh to at least you know be able to talk
to immunologists and I fail miserably
every time so I've come up with a very
simple way that I think about this so we
know that what happened one of the
things that happens during aging is
people talk about a decline in immune
function and that's true we are more
susceptible to pathogens we are less
likely our immune system is less likely
to catch cancers early so there's this
thing called immune surveillance of
cancer which is why I think most cancers
are strongly age Associated because as
we get older our immune system is less
able to catch those Cancers and kill
them early so then they become tumors
then they metastasize and that's that's
when it becomes a problem so immune
function does decline towards some of
the things it's it's supposed to do but
there's this other thing that happens
which is this increase in the immune
system doing what it's not supposed to
do which is autoimmunity or sterile
inflammation and I think what rapamycin
does is it it's almost like a reset I
don't know that it actually brings up
the the stuff that's that's declined
with age but I think it knocks down this
sterile inflammation to the point where
the system can re-establish homeostasis
so functionally it's a Rejuvenation and
that's where again I think you know
terms are important and and we need to
try to be precise in the words that we
use I think it's okay to say that that
we know things like rapamycin again at
least in mice can reverse some of the
functional declines that go along with
aging it can also reverse some of the
tissue pathologies that go along with
aging did it reverse aging no it didn't
make an old mouse into a young Mouse
again that the best again we've been
able to do with rapamycin tissue
specific way well that's where it it
depends a little bit on what level of
resolution you want to you want to get
to
um I I can't answer this with a hundred
percent certainty because nobody's ever
done it but I am
I'm pretty sure that if you dug deeply
you would still find accumulated damage
in pretty much any tissue that you look
at in a mouse that's been treated with
rapamycin
so it depends a little bit on how what
you look at and how How Deeply you look
and how you define it so like when I
think about anti-aging what people
really want yeah they want to go
backwards they want to feel better they
want to be able to contract muscles
harder add muscles easier look better
tighter skin that kind of stuff like
there's a very specific set of workouts
that they're looking for I mean this is
what the question right well just so
exercise does all of those things right
does exercise reverse ages your skin if
you keep your muscles get big enough yes
harder on your face again right this is
yeah no you're right but it depends a
little bit on what you're what you're
looking at this is that's that's I mean
it's a really good example because
that's exactly the point I was making I
was making it because I you know I'm a
scientist from the molecular perspective
but it's the same thing it depends on
what which which phenotypes you're
asking about you can find some where
absolutely rapamycin reverses it if you
keep looking you're going to find others
where it doesn't and I think exercise
does the same thing right certainly
functionally you can almost anybody from
where you're at now you can functionally
improve your body through exercise facts
so is that reversing aging again it
depends a little bit on how you want to
Define that's a fun way to look at it
okay so very important to get our terms
right definitely when I say
um reversing aging I don't mean
optimizing for where you're at now it's
a fun Framing and that actually is more
motivating to actually work out harder
but when I think about what I'm really
hoping happens is that we get back to
and I imagine it will be
the nine elements of Aging or indicators
of Aging
but also there's hormonal profiles
there's all kinds of things that lead
your body to not only do those things
but to do them either more efficiently
faster better whatever there is
something and I've heard I can't
remember the stat that you threw out oh
no it was you were talking to Peter uh
Peter attia Peter ortia's kid was on his
scooter whatever he falls down mashes
his face gets up blood everywhere
Peter's like how fast can I get to the
hospital and he said like a week later
he had like a minor Mark left on and he
was like if that had happened to me at
my age he's like the scar might last for
a year or more yeah and there is
some like I don't know how we Define
that if it's just efficiency if it's
that the system isn't bogged down by the
damages that you're talking about but
there there's a way to classify youth
that we're trying to get back to
whatever that bundle of things is we're
trying to get back to that now I am this
is how we started the episode I'm one of
the people that really won because I
want to live as long as I can have the
greatest Health span possible I want to
make sure I want this stuff to be real
so I have like this vested incentive
meaning I don't want to die yeah that
this becomes real so I get very
emotionally invested I get very excited
I recently had a guest on the show his
name is Brian Johnson and he I don't
think he would call himself a scientist
but he's been very successful and