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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 so
he's able to throw a lot of money at his
body and so he spends something like two
million dollars a year trying to reverse
aging
now this gets into measure what matters
are the clocks real are they not are we
looking at the right things but when I
sat across from him he looks like an elf
from The Lord of the Rings and so he
looks great and I had interviewed him
probably five years earlier and he looks
better now than he did then now that
doesn't mean he's reverse staging
um but how do we begin to like parse out
like you believe in this enough that
you're doing a gigantic trial you've
dedicated a huge portion of your
professional life to seeing if it works
in dogs presumably not just for dogs but
for humans and so what should we be
measuring and what like path are we
actually going to go down because Brian
has a blueprint protocol that I'm about
to do and based on this discussion it's
like either I go maybe we're not able to
measure the right things yet maybe you
know it's it's the hype has gotten a
little ahead of itself or maybe it's
worth a shot so I again I think this is
there's a there's a ton that we could
talk about to unpack here and it it
again is super nuanced but um so one
thing I would say is I'm I'm not so sure
that exercises and and nutrition are
fundamentally different from rapamycin
exercise hits the Hallmarks of Aging
right it affects by logical aging so so
I don't put those in different buckets I
actually think about them in my own mind
as different ways to tweak that Network
and and again this gets back to I think
that there are certain interventions and
ultimately probably combinations of
interventions that get us closer to
tweaking that Network in in a way that
optimizes functionality or health or
Vitality or youthfulness right I'm again
and I'm also not so sure that at least
in my own head I have a bundle of things
that I would say I associate with youth
that are fundamentally different from
what I would put more in the bucket of
sort of overall health span or healthy
longevity I mean being able to function
at a high level the way that you want to
um fits into both buckets the wound
healing is an interesting one because
absolutely there is an age-related
decline in wound healing our ability to
heal from wounds it's very individual
not everybody experiences it at the same
rate and you can modify it by knocking
down inflammation right so and you can
do that by fasting for example so these
things are tied together I'm not sure
that it's fundamentally different
rapamycin is in in any in any sense
fundamentally different from some of the
things that we can do with
non-pharmaceutical approaches it's just
that most people can't do them in a in a
consistent way so the blue I think is
really interesting
um
so so my take is that
I probably 90 of that is just diet and
exercise and and 10 of it is everything
else and there are a couple things I
would say first of all I think I mean I
think I I think I have a lot of um
respect for the uh intensity and level
of detail at which he's approaching this
right I mean I think that that's great I
um
I do worry a little bit about the
markers being used I don't think I don't
think that they are necessarily telling
us uh about biological age or biological
Aging in any comprehensive way are you
guys checking markers in the dog are you
just like let's just see how we are no
we are we are um so we are looking at
the epigenetic changes that happen in
blood we're looking at
um metabolism in the blood microbiome
fecal microbiome people built clocks off
all of those things
um we're also looking as best we can at
functional measures so you know activity
levels cognitive function heart function
neurological function
um uh and lifespan so I think you can
start to paint a picture when you put
all of those things together if you're
seeing the arrow going in the right
direction
for most of them that you've you've had
an impact on the biology of Aging some
of these are exploratory though like I
talked about the epigenetic metabolism
microbiome those are not things where
people should have a high degree of
confidence that they're actually
measuring biological aging and in my
view I'm much more interested in
functional outcomes and disease you know
if I can if I can
not have any diseases and be able to
lift as much weight as I want and do the
things I want to do I'm I'm much happier
about that than if my biological age
test tells me that I'm 35 right or vice
versa so I'm I so I again I don't I
don't put a lot of faith in those those
tools at this point I think there needs
something to steer by or maybe the
average person does I don't know because
maybe in your field you don't but like
at some point and I think I'm speaking
for Brian and that is a mistake he
should speak for himself but if I had to
guess he's like I need something I can
look at to see if this intervention that
will only play out over the next 50
years am I going in the right direction
or not I agree with that I think the
problem is you're not going to know
until it plays out so it's sort of a
best yeah even directionally you don't
dance well it depends on the test right
so I think there are there are certain
um certain blood-based parameters that
we know with certainty are highly
correlated with specific diseases and
with mortality over time right so you
know if you have a high level of like
glucose or hba1c right that that's a bad
thing and it's it's you're likely at
higher risk for diabetes and early
mortality same thing with lipid profiles
that are outside of the the normal range
so those are biomarkers right they're
you know no different in that sense from
the epigenetic clocks it's just that we
have a lot more evidence behind them
telling you that yeah this is kind of
where you want to be we aren't going to
know on the epigenetic clocks for a
while so most of these clocks have been
built off of in humans have been built
off epidemiological studies spanning 10
20 30 years and so there's there's and
so you can you can show that you can
identify patterns that are in that
context predictive of
three five ten year mortality risk right
what you can't show is that that's going
to be relevant for you or me or any
other individual and what's often not
appreciated is many of those samples
were taken 20 years ago in a specific
population whose environment has changed
dramatically just think about our
environment 20 years ago right so are
those same parameters going to be
relevant in our environment today we
don't really know so this is where I
think we just have to have so it depends
a little bit on your your level of so
how much certainty do you need if you're
if you're just looking for what's the
best out there and let me take a take a
best guess based on what we know today I
kind of like what what what he's doing
in terms of the comprehensive biomarkers
um so but but I I love the uh the sort
of sharing of data I think that
absolutely the approach of you know
measure intervene measure again
intervene measure again that's exactly
what we should be doing that's the only
way you ever get to personalize
interventions so I think think that's
that's really commendable so if we're
going to do measure intervene measure
intervene uh and what do you care what
in terms of your own life outcome what
do you care most about your kids doing
well what what's that thing like your
deepest like I need this to happen and I
will have been a good man it'll make
sense in a second so uh so what do I
need to have happen for me to be a good
man so it's a funny question so
absolutely I mean I think I I would love
for my uh uh probably the most important
thing is that my kids grow up and be
good people okay perfect let's take that
okay for for this we'll get to the about
in a minute so if you live to 150 your
kids will have just a glorious life and
they'll live even longer and it'll all
be amazing but it's all contingent on
you making it to 150 which is it's
that's a lot right so oldest person on
record 123 something like that yeah some
people argue whether that was even
fudged a little bit but yes 122 right
yeah okay so you're gonna have to figure
something out and you're going to be
doing this test intervene test intervene
what would you with your deep body of
knowledge and access to a gazillion
people what would you test the truth is
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description alright my friend back to
today's episode it would probably
include
um
all of the the current biological aging
clock so here's a here so you would use
here's the way I would frame it though
we don't know what they mean so it would
be more so so if again you got to play
the long game right so if we're talking
me living to 150 I got to go another
98 plus years right okay
so actually there's a there's a cool
visual I'll tell you about in a minute
if if we if I remember so
um uh so so you got it so you got to
recognize you want to capture as much
data as you can because you're going to
need to learn from that even if it's not
telling you what what you hope it is
today you've got to capture it now so
you can learn from it as you go because
you're going to be looking for patterns
absolutely yeah so I think you would
want to use what we currently know about
the Hallmarks of aging and all of these
biological aging tests are built off of
that framework right they measure
aspects of the home would you be
measuring adipose tissue absolutely so
body composition would would be part of
the story
um certainly as comprehensive a blood
panel as I could get and actually I
think that's an area where people in in
my field haven't paid as much attention
there there's there have been a couple
of um blood-based clocks built off of
you know clinical typical clinical
measures
um pheno age I think was the first first
one because they don't know what to look
for no because it's not as interesting
as epigenetics this is this is where
shiny object you know comes into play
where are they getting the epigenetic
read then I thought it was in the blood
so I'm talking about the standard
clinical stuff that you would get from a
you know CBC Cam and maybe they're not
they're not turning those results into a
club so then one has been built with
with the like 10 or 12 blood markers um
but but there's a whole bunch of blood
Diagnostics that you can do that that
are outside of the standard panel that
most General Practitioners do they tell
you important stuff about your health
right vitamin deficiencies like I
recently found out I'm vitamin D
deficient not shocking I live in Seattle
but I take a vitamin D pill and I'm
still vitamin D deficient hormonal
panels like comprehensive hormonal
panels that's gotten to the point where
you know there are a larger number of
people who get them but still
the majority of people in their 50s 60s
70s never get a comprehensive hormonal
panel would you do hormonal replacement
therapy not to derail um so so I I uh I
I would if it was appropriate and I do
believe that
um hormone replacement therapy has
gotten a bad rap so you know
um based on the literature that's out
there I think the the aversion to
hormone replacement therapy for both men
and women for different reasons
um
it doesn't make a lot of sense when you
actually look at the data but there is
this culture that you know has evolved
that that somehow docks that that
practice hormone replacement therapy are
doing sort of shoddy medicine or
whatever right and I I don't agree with
that at all so I think absolutely
there's there are certainly people who
who when you're when you're clinically
you know outside the reference range
then it's then it's clearly appropriate
but I don't see a lot of logic behind
the idea that it doesn't make sense to
try to maintain at least the key sex
hormones at youthful levels right and so
but we don't have a lot of data either
way we don't have a lot of data showing
that if you do that that it's
necessarily beneficial other than people
anecdotally report that they feel better
and they can function better and for men
they can maintain muscle mass better and
and for women
um you know I think treating the
symptoms of menopause can have huge
benefit for certain women so I'm
generally pretty positive on hormone
replacement therapy but I also recognize
there is there is a point where it can
be abused right I think there are
certainly a fair number of men out there
who just want to take testosterone
because they you know they they don't
want to watch what they eat and they
want to want to have big muscles right
so
um and I don't again I don't know I
don't know how dangerous that is because
I just don't think we have a lot of data
yet on them not fair okay so I don't
want to pin you down too hard but I'd
love to get your top three or four
clocks assuming that's what you're
looking at they can really pay attention
to because I'm looking at things like
the average person still thinks they
need to be checking their cholesterol is
that a marker like should we really be
looking at that if you're gonna hit 150
that's important yes so there's two
things I would say so and you can put
kind of put these in the bins of
um not dying and biological aging right
so rule number one of living a healthy
long life is don't die yep and so you
need to measure things like your
cholesterol I would I would say the
standard blood panel for lipids is not
good enough you want to get your
cholesterol Peak sizes you want to look
at things like LP little a and APO B
you've probably heard Peter talk about
those independent risk factors for
cardiovascular disease you want to go
get a carotid scan right or a calcium CT
scan where you can actually look at the
plaques so these are all things you
might maybe want to get a whole body MRI
and I'm not saying everybody should get
a whole body MRI but you know if you can
afford it and it's not a big deal are
you worried about the radioactive dye
well I didn't do it for that reason so
here's the thing right again there's
there is a small risk from from
radiation but if you've got a
pre-existing cancer that you can catch
early that's going to kill you so again
you kind of have to if money were No
Object how frequently would you do that
oh that's yeah that's probably above my
pay grade I haven't really I haven't
I'll just be honest and say I haven't
really thought carefully about the risk
reward and looked into the the total
exposure so I would certainly say
probably not more than once every few
years
um but uh but I don't I don't I haven't
spent a lot of time thinking about it
but I put all of those things in the bin
of you know don't die and so you've got
you've got you've got to have a set of
Diagnostics they're going to tell you as
early as possible if there's a problem
something that's going to kill you or
you know and I say that sort of jokingly
because it it makes sense right but but
it's also important from a health span
perspective is don't get sick right so
one of the things that we've done in you
know modern medicine is we've gotten
very good at keeping people alive with
one two three four age-related diseases
but living that way is very different
than living without any age-related
diseases and so you want to make sure
you you maintain you know your health as
long as possible and so I think these
same Diagnostics can help you catch
age-related disease like metabolic
disease early and then modify
appropriately and that may involve
prescription drugs that may involve
lifestyle changes so so I think that
sort of comprehensive baselining is
super important
um and then the biological age tests
again you know I hesitate to point to
any I'm not going to point to any of the
specific commercial
um ones but as general classes like you
can you can you can develop you can use
existing clocks and they're they keep
coming out on on comprehensive blood
chemistry so the clinical stuff what
you're going to measure over here
anyways
um epigenetic profiling is is the most
common and that's where people get a
little bit confused because there are
literally
probably dozens of different epigenetic
clocks now but they all come from the
same technology so you can measure the
epigenetic marks in your blood
um
comprehensively and then apply different
clocks and that's what a lot of the
companies are doing is just applying
different clocks so from a measurement
perspective doesn't matter you just get
the most comprehensive epigenetic
profile that you can get from blood
there's a couple others there's a a
blood glycans which are a different kind
of chemical moiety in the blood that are
thought to re reflect biological age or
some aspect of biological age
and then I think you'd want to you'd
want to think about doing some what we
would call sort of exploratory endpoints
so high dimensional proteomics and
metabolomics that just means measuring
proteins so that sounded super fancy
yeah I know
so it's it's um you know old technology
that has gotten gotten a lot better
where you basically quantify you know
thousands of proteins in your blood
um at any given time and and
metabolomics is a is a it's a different
kind of Technology but can conceptually
the same you're looking at the level of
hundreds sometimes thousands depending
on you on how you do it of metabolites
which come from your microbiome right
they get absorbed they come all over the
place so they come from your own cells
some of them come from the microbiome
yeah interesting it's a picture of
everything else kick off metabolism all
your cells are constantly giving out all
sorts of organic uh molecules yeah and
those are all they all fall under
metabolites yes learn something yeah I
mean there's there's proteins there's
metabolites and RNA and then you could
get to a little bit more exotic stuff
but those are the big three so you can
also measure
um RNA from blood which tells you about
gene expression so all of these things
can be measured with with tools that are
available today in in pretty high
dimensionality the problem is again
we're still very early in building the
clocks from them but the earlier you get
your own samples you can always go back
to that data so once you've measured it
and digitized it it's always there right
and so as the clocks get better you can
look backwards in time time and see the
state that you were in back then and be
informed by how that state changed based
on what you were doing in the
intervening time so let me give you an
example of why I am uh
a little bit worried that that that the
epigenetic clocks have gotten ahead of
themselves so there's an emerging
I think pretty significant question
about what the epigenetic clocks have
been measuring that has yet to be
resolved but but it's there's emerging
evidence
um from a couple of different Labs that
one of the major signals that comes out
of these epigenetic clocks is the
composition of the types of immune cells
in your blood at a given point in time
so there are multiple types of different
immune cells in our in our blood and
they all have their own type-specific
epigenetic profile but when you're
measuring these epigenic clocks what
you're measuring really is a you know
all of that at the same time on top of
each other right and all of those cells
are probably aging your body's whole
body is aging but
um you can get changes in the
composition of the immune cells like
what percent are you know different
types of immune cells at a given time
very quickly you get an infection the
composition of your immune system is
going to be very different than it was
before you got that infection and then
it's going to change as you clear out
that infection that I would speculate
will greatly change these epigenetic
clocks and make it look like you are
aging rapidly or reversing aging rapidly
no what you really did was you got
infected you had the appropriate
response and you cleared that infection
and so they are
they have been built
um to predict usually mortality based on
samples that were available and those
usually come from blood samples that
were collected across thousands of
people as part of these large
epidemiological studies the problem is
we don't always understand what the
potential artifacts are involved in
building these kinds of tools
because we haven't really thought
carefully about what the what the
population was that samples came from
and so we may find out that most of what
these early phase epigenetic clocks were
really telling us about were immune
status right how healthy is your immune
system which is a part of biological
aging but it's probably not the whole
thing and so
um it and they may actually be telling
us more about whether you have a
pathogen or how well your immune system
is functioning or how inflamed you are
at that given snapshot in time this is
what and I actually I actually think
that there's going to be some truth to
this because to me that's how you
explain these sort of very rapid changes
in these clocks that some people have
claimed right some people have claimed
that they can reverse their epigenetic
age by 10 years and in a period of a
couple of months
um or five years in a period of a couple
months and biologically it just doesn't
make a lot of sense I mean it's possible
I can't rule it out but it's it does
make a lot of sense that you can remodel
your immune system in that time frame
because it's such a high turnover system
absolutely right
um that's one thing I will give Brian
credit for is he said if somebody's
really asking me my biological age I
have hundreds of Ages it's yeah tissue
dependent and everything's going to be
different some are harder to measure
than others yeah and and there is still
this open question of do all tissues age
at the same rate no they don't they all
there's some coordinating principle
that's causing all of our tissues to age
but you look at the the female ovary I
mean that's a really good example of a
place where aging is greatly accelerated
right
um so so clearly no they don't all age
at the same right you may hate this
question because it's just speculation
do you have any guess why women stop
being able to reproduce so young is it
that they're getting to frail they're
more likely to pass on genetic mutations
like you have to assume that Evolution
tried it where women stayed fertile
forever yeah that's a good that's a good
question so this is getting a little bit
outside my area of expertise I think um
I think
there's certainly this school of thought
that that menopause has evolved like it
was selected for specifically
um and and actually you know what you
said is kind of interesting which is
that Evolution must have tried it so
it's certainly in our close primate
ancestors they don't undergo a similar
kind of menopause
um and so I think it's likely that it
was an evolved trait as we went down the
the hominid lineage why it evolved I
think you know that that's again it's
it's become speculative but it you know
there is speculation around the
um the idea that and certainly there's
evidence that egg quality declines with
age that you're much more likely to get
um severe birth defects and uh things
like that as as a woman is older and so
um it's probably easier to evolve
ovarian senescence than it is to try to
evolve mechanisms that would fix that
that problem of egg quality going down I
don't find that super satisfying it's
just a little bit hard for me to think
about how you get enough
um selective pressure to evolve a
process specifically for senescence of
the ovary just from that but the real
answer is I don't know I mean like you
said it's it's very speculative and I
don't I don't know that we have a good
answer but I do think what what I do
think is more interesting and more clear
is that that process in women of ovarian
senescence and menopause then has
add-on effects throughout the rest of
the body right that accelerate aging we
think I guess I should be a little
careful accelerate the onset of Aging
phenotypes in other other parts of the
body interesting and so these again
these tissues and organs are all
talking to each other and I don't think
that's at all selected I think it's a
it's a byproduct though of the whole
process of menopause
um and then just to give you one more
sort of tidbit which I think is pretty
cool going back to rapamycin one of the
places where it's been pretty surprising
to me to see is in mice you can actually
reverse ovarian degeneration with
rapamycin so that's another place where
rapamycin has a regenerative process
will the rats start ovulating again
right yep so you can you can take a
mouse out of uh being their infertile
their post menopausal and bring them
back into uh yeah I should be careful
mice don't go through menopause they go
through a I don't remember the word
there's a different word for it so it's
a different biological process in a
sense but they do become infertile and I
should be a little careful because I
don't think any of these papers have
been published yet this is all from what
I've heard at meetings so but yes I've
seen data showing at meetings where they
show that the mice that got rapamycin
are able to reproduce
Mica didn't get rapamycin are no longer
able to reproduce okay so now this is
late onset so now we have to start
because I said I'm getting excited again
about rapamycin
um I've gotten very excited about
metformin and was like I'm not going to
take this the number of people that uh
not everyone so I'll leave everyone to
speculate but the number of people that
I've had on the show that off camera are
like yeah you should take metformin and
I know a guy that's a very high level
surgeon and he was like oh yeah you
should take my form and I take metformin
and I'm just like I am always tense
about taking exogenous substances sure
and just because who knows the balance
like take vitamin D I'm just convinced
that the sun falling on your skin does
more than just trigger the production of
vitamin D so I'm like if you're avoiding
the Sun and supplementing vitamin D the
odds that you're getting exactly what
you need are basically zero so I'm a
little sketched out so I didn't take
metformin and now it's starting to come
out well maybe metformin isn't as good
for you as we originally thought so as I
get excited about rap myosin okay yeah
no I think I think I think it's a
totally legitimate uh perspective and
and I I maybe don't go quite that far
but uh but I'm pretty skeptical of
supplements and I've been public about
that for that reason like it's like
there's not a ton of evidence most of
the time and you never know what the
consequences might be so one thing I'll
say about rapamycin is rapamycin is
interesting because it started with a
bad reputation because of the way it was
clinically developed so if you go to
almost any physician who doesn't know
anything about rapamycin they're going
to look up the side effect list and
they're gonna be like this is an organ
transplant drug you shouldn't take this
why would you take this right so it
started from the bad reputation place
um do you want to talk about metformin
because metform is pretty interesting so
so I'm I I'm I'm definitely in the camp
that uh people who don't have glucose
homeostasis uh challenges probably
shouldn't take Metformin for aging so
the evidence there in mice is actually
pretty weak metformin does
either does not increase lifespan in
mice or it increases lifespan by like
five percent so you know caloric
restriction rapamycin metformin in terms
of magnitude of effect and in the one
study where it it was tested and it
showed that five percent extensional
lifespan they tested two doses this
isn't talked about but the other dose
shorten the lifespan by 10 so the
evidence that metformin really is a
potent longevity drug
not so great
um now certainly in people it's a very
good
anti-diabetes drug and there's a little
bit of evidence that now has turned out
I think there's been contradictory
evidence there was there was an initial
paper that showed that diabetics taking
metformin they lived much longer than
diabetics not taking metformin and maybe
even a little longer than non-diabetics
not taking metformin that's the data
that gets pointed to in people is the
best evidence that metformin might have
an impact on longevity in humans that
sense is not replicated at least in one
other study I don't know I don't know
what the answer is there but um
but did you ever take Metformin no I've
never taken it so there was something
there enough that made you go probably
not but rap on my sin yeah I've heard
you do take at least occasionally yeah
yes that's right the other thing I want
to say about metformin though because
most people don't appreciate this and I
didn't actually know this until recently
is that
um in men a significant fraction of men
taking metformin it actually has a
negative impact on testosterone and it's
not clear to me whether that's
reversible or not whoa so yeah so I
would just
think about that in the whole context of
science no here's the problem with
metformin Nobody Knows the mechanism
it's a super dirty drug so it's dirty
meaning it it impacts a lot it's a bunch
of stuff yeah so it's talked about as an
amp kinase activator definitely is an
mitochondrial inhibitor so it inhibits
the electron transport chain probably
has 10 or 12 other targets so we don't
really know exactly how metformin's
working and we don't know if it's the
same Target for the different effects of
metformin so anyways that that's why I
wouldn't take it
um uh so rapamycin
um
has a much better track record in terms
of
actually reproducibly and robustly
impacting the biology of aging and it's
not just lifespan so we talked a lot
about lifespan but you know as we've
alluded to in mice at least you can
either delay functional declines or in
at least four different organs and
tissues now reverse those functional
declines
giving it to mice in older age so the
potential upside I see from arapomycin
again purely speculative that it's going
to work in people the same way but the
potential upside is so much greater than
it is for metformin just based on the
pre-clinical work that that goes in the
you know risk reward that goes in the
potential reward pile so then the
question is what are the real risks and
um we've gotten a lot more data in The
Last Five Years on what the risk profile
of sort of non-organ transplant lower
dose rapamycin looks like and we haven't
published it yet but um we hopefully
will be in the next we'll probably
submit it the next couple of weeks we
did a survey-based study of about 330
333 people who've been using rapamycin
off label we compared them to about 150
kind of age match demographically
matched people who've never used
rapamycin and looked at a whole bunch of
stuff and so it looks like the side
effects from from you know off-label use
of rapamycin the ones that are real are
mouth sores for about 10 of the people
that's a known side effect of rapamycin
um and then it probably does increase
risk of bacterial infection by maybe
twofold so you can look at that and be
like oh my God or you can look at it and
be like two times a small number is a
small number right so but it probably
does increase risk of infection by about
two full bacterial infections
is it um okay so going back to we're
lowering the immune response got it
here's the thing though it actually
seems to enhance resistance to viral
infections because it turns up antiviral
gene expression through mechanisms that
aren't understood okay that's come out
of some clinical trials and that seems
to be in our group and one of the things
we looked at in our group was covid-19
so this was actually you know fortuitous
time that we had just come through this
whole covid-19 pandemic and so we were
able to ask people you know are you
vaccinated did you get infected if you
did get infected what was your infection
like was it mild so less than a week
more than a week
or did you have to go to the hospital
and then are you still experiencing
symptoms or did you experience symptoms
that look like long coveted okay and
here's the thing where again these are
all fairly small numbers I told you the
size of the group right but so it's not
like I want to put a a huge amount of uh
certainty behind this but but I've been
in this business long enough to kind of
look at data and I know what looks like
questionable and what I think is
probably real
the one thing I think that's probably
real that came out of this is the the
people who took rapamycin continuously
so before during and after their
covid-19 infection had a much lower risk
of anything other than a mild infection
whoa so almost nobody had a moderate
infection and none of them had a severe
infection had to go to the hospital none
of them got long covered am I just not
remembering people talking about this or
are you like a lone voice in the
wilderness I'm telling you some
unpublished data right now there have
been people talking about rapamycin for
covid
um uh it hasn't gotten as much attention
as it probably should
um one one place where where people I
think they tried to do a clinical trial
and it just never got off the ground was
for for uh uh severe covet infections
when you get the cytokine storm yeah
using rapamycin to knock that down but
um Joan manik did a clinical trial she
did two clinical trials with a drug
called everolymus which is a derivative
of rapamycin so for this conversation
you you can just think of it as like
rapamycin it works exactly the same way
where they showed that you could improve
flu vaccine response in healthy elderly
people through six weeks of ever
alignments
before the vaccine so short-term
treatment and then you give them the
vaccine then you get a better response
to the vaccine do we know how long it
lasts no because these these trials were
all just one-offs yeah but it kind of
makes sense what the mouse Rejuvenation
part right so you you you restore
homeostasis and then you give the
vaccine you're going to do better than
if you give the vaccine when you've got
too much self and not enough you know
appropriate response right so that part
makes sense what was interesting there
was was they went back after the fact
and looked at
um number of infections those people got
in the next I think it was either six
months or a year and it didn't protect
against everything but the people who
got the mtor inhibitor had lower risk of
subsequent flu vac flu infection or
coronavirus infection this was done in
2019 so this was before covid-19 nobody
knew about covid-19 but that was one of
the particular viruses where it seemed
to have this protective effect so
basically it may have a protective
effect against your sort of basic cold
viral yes viral yeah I assume most colds
are viral yeah what I think of as a
traditional head cold right that's huge
uh
uh this is an organ transplant drug
though so is this this is one of those
if I go to my doctor hey prescribe me
rapamycin he's gonna be like dude no
first of all he's not even gonna know
what rapamycin is because it's called
serolimus in the clinical
same drug two different words yeah so
but yes if you went to him and said you
know I want to start taking sir all of
us
um if he knows anything about it he he
would probably say you know there's a
long list of side effects it's risky
it's going to suppress your immune
system why would you want to do that and
you know I mean again as I said I think
it probably is a real effect it's not
it's not a strong immune suppression but
it probably does slightly increase risk
of bacterial infections which is why
some people have started cycling like
they'll take rapamycin for six weeks or
ten weeks and then stop for several
months and then start again and
um and I I I kind of I kind of like that
approach first of all I should say I'm
not suggesting anybody start taking
rapamycin I'm not an MD this is not I'm
sure you have a disclaimer but but I
need I want to be careful because I I'm
I'm very
um excited about the data that we've got
so far but I also want to be clear that
we don't know that this is going to work
for everybody we don't know it's going
to slow aging
um and and we're still figuring out what
the side effects are so I'm certainly
not suggesting people should run out and
start taking rapamycin
um but it kind of makes sense that you
would get that slight uptick in risk of
bacterial infection
um because you're knocking down
inflammation and I think that's how most
of the beneficial effects of rapomycin
that people experience where you they
and I've had several people tell me like
I feel so much better after taking it I
think it's really the people who have
high levels of sterile inflammation
they're the ones who notice the effects
um so but it's not probably not going to
benefit everybody in that context
because and the other thing I think I
should say is you know rapamycin is not
so different from fasting fasting hits
mtor rapamycin hits mtor fasting knocks
down inflammation rapamycin knocks down
info formation so they overlap a lot in
their biological effects they're not
identical but they overlap a lot in
their biological effects but people
don't always appreciate that that also
means that most of the side effects for
mapomycin are also side effects for
fasting but we think about dietary
interventions as you know safe right and
pharmaceuticals is dangerous and you
know there's this that is my rough
analysis yeah like if I can get the
exact same effects am I better off just
doing the faster sometimes yeah fasting
again is a dirty drug rapamycin is a
clean drug right so fasting hits
thousands of metabolic pathways
rapamycin is pretty specific so but what
does that mean you know in terms of
benefit and risk reward and all of that
I don't know very interesting very
interesting so I want to close the loop
on this idea you've talked about
homeostasis as one of the things you
could look at for whether your Prime
condition youthful condition whatever
you want to think about how rapidly are
you able to get back to Baseline is
there I mean do you just look at that in
terms of like colds Cuts scrapes like
yeah exercising to your heart rate back
to normal again yeah I don't I mean I
don't think there's a right answer to
that question I think you know this idea
of resilience has gained a lot of
attention in the field as a as a
phenotype of Aging or in some ways it's
a biomarker right how quickly are you
able to return to Baseline
um I think there are lots of different
ways you can you can look at it in some
ways it probably depends a little bit on
your bias again I tend to put a lot more
faith in functional measures like wound
healing because that's important I mean
that is you know that that that's that's
important to your quality of life but
it's also telling you something about
your likelihood if you get a serious
wound of being able to recover from it
right so so I think I think those are
good measures I think you can look at
you can look at at performance measures
like you know uh heart rate variability
and things like that or recovery from
exercise those are probably telling you
the same
type of information I just don't think I
don't I don't know if we have enough if
we have as much data on those kinds of
measures and how they're integrating
into the biology of Aging I mean clearly
they're integrated I just don't know if
we have as much data on on that
um
so yeah so I I guess I don't know how to
answer your question in in great detail
other than to say that I think there are
you you could look at you know
um I guess to some extent glucose
response is is kind of a similar kind of
metric so you know when you you could do
a glucose tolerance test and actually
that's probably not a bad idea we're
going back to the kind of what would you
measure yeah I think a glucose tolerance
test is kind of that kind that sort of a
measure where you greatly perturb the
system and then you look at how quickly
is it able to respond that's another
measure of resilience of your your
metabolic system yeah that's why I found
this interesting I'd never heard anybody
talk about homeostasis is a big signal
to you
and you know also just thinking about
long covet as potentially one of these
where it's it is a mechanism of not
being able to get back to homeostasis
and I wish I knew what was hap I mean
obviously lots of people wish they knew
what was happening with long covet right
but my I speculate that it is a sort of
again chronic inflammatory reaction to
the initial infection and so to me it
makes sense that rapamycin and other
things like rapamycin might have
beneficial effects there yeah this is
why getting to the underlying
um
what it what is the organizing principle
of this thing that's happening so what
are the the nine Hallmarks of Aging have
in common what a driving actually
because you said it in that context I
want to come back to something you said
before which is that you know one of my
sort of guiding principles is around
inflammation and that's kind of true I
mean I think in in mammals this increase
in chronic or sterile inflammation is
driving a lot of the functional declines
that go along with aging but I have to
say you know I was very late to the
inflammation game and I actually don't
think that's uh the fundamental feature
of biological aging and the reason why I
don't is you know I talked earlier about
how mtor and rapamycin came initially
out of studies in invertebrate models in
yeast and c elegans and fruit flies
yeast don't have an immune system
they're a single celled organism yeah
rapamycin works there mtor works there C
elegans have an extremely rudimentary
innate immune system uh but there's not
a lot of evidence that that inflammation
is driving much around Aging in those
organisms and yet mtor inhibition works
there rapamycin works there so it's hard
it's possible that rapamycin and mtor
evolved to affect aging by completely
different mechanisms and mammals than it
did in invertebrates but that's to my
mind very difficult to to credit I think
it's much more likely that there's an
underlying principle that's shared in
all of these species for how mtor and
rapamycin are affecting aging and it
just turns out that
this increase in sterile inflammation is
a downstream consequence of mtor
hyperactivation that leads to many of
the the at least the functional and
health declines that that we notice the
most the aches and pains that go along
with aging the debilitating changes that
go along with aging and probably the
increased risk of cancer at least to
some extent because your immune system
isn't clearing the cancers anymore the
reason I think that kind of thinking is
so important having an organizing
principle is it allows you to create a
narrative which I'll say is just another
word for a hypothesis I think things are
working in this way and for my
non-scientifically minded people once
you have the hypothesis it'll make
predictions so if this is true then this
also has to be true and now I can go
test that thing I have found that really
useful in my life for one make sure I
understand somebody oh if you're saying
this and it predicts this did it yes
okay cool then I actually understand and
then two how I filter what I try and
what I don't try because hey it'll make
a prediction either
if this is true and that's true I'm not
interested right but you're now starting
to get some of the answers to these
predictions with the dogs and so I know
the study's not done yet but I've heard
you say that you are starting to get
some pretty interesting insights out of
what's happened so so what I can tell
you and and I mean it's been
frustratingly slow to get to this point
um what I can tell you is we've done two
short-term clinical trials that gave
some preliminary results that are
encouraging right so the the things that
seem Rock Solid is we really have no
evidence for any significant side
effects uh from rapamycin in dogs which
is important for a clinical trial in
people's pets right I think of this very
much like a pediatric clinical trial so
you really want to make sure that it's
safe the the other things that are in
potentially interesting in terms of
improvements
um uh we found some evidence for a
reversal of age-related heart decline a
specific
component of the heart or chamber of the
heart the left ventricle we were able to
measure that is potential improvements
and that was based on Mouse work so we
we basically measured exactly the same
parameter respecting it well because we
had a we had a hypothesis right that it
that that if this is conserved if it
works in mice then it will work in dogs
right and so that's why we've measured
that
um uh and the evidence looked like it
did so you know a small study short term
but but it looked um looked pretty real
and then the other things that I think
are interesting is in both of the the
the short-term trials the owners and
they were blinded this is double blind
placebo-controlled self-reported that
their dogs were more active and so that
makes sense again you know the way I
think about this is dogs just like
people as we get older you get a you get
you get a you get more uh sterile
inflammation autoimmunity that leads to
a lot of the aches and pains and Joints
rheumatoid arthritis is an autoimmune
disorder right and so if rapamycin is
sort of
generally tamping that down you might
see that as a decline in pain which
would then be translated to an increase
in activity in an old dog so that's
speculative but it kind of fits with and
it also fits with you know what I know
from my own personal experiences and
from talking to lots of people about
rapamycin in humans so that seems like
it's probably real
um the one thing I will say though is
because it's owner reported we really
want to get the quantitative activity
monitor so like you know little collar
trackers that we can actually look at
the data yeah whether it actually is or
not yeah but uh but I you know I felt I
felt pretty good about the quality of
the honor reported data that we've
gotten not just for the rap mice and
trial but in the larger dog aging
project it seems more accurate than I
than I would have thought
um going in people pay a lot of
attention to their dogs and can actually
report the data yeah no I heard you
mentioned that for some people because
you always refer to them as companion
yeah and companion are sort of
interchangeable it's just that the word
pet you know has sort of a connotation
that that some people don't appreciate
it so yeah companion is it's probably a
better word the only reason I don't use
that word all the time is because some
people when I say companion dog think of
service dog that's exactly what I
thought yeah but then when I heard you
clarify that you know a lot of people
think of their Pet Companion Animal as
one of their children and I was like oh
yeah that's me yeah and that's when I
realized oh you just you're just giving
a warm name to pet dog right got it and
so that is I'm really intrigued and if
this ends up and I'm assuming you did it
on dogs because it's just such a faster
life cycle you can learn more than if
you're trying to do it on humans
and because dogs share our environment
so again if you think about what we know
in a laboratory is in this very sterile
controlled environment and whereas
companion dogs with the exception of
food and even depends on the depends on
the household sometimes even the food
they share pretty much every aspect of
the human environment so it's a it's a
way to capture environmental complexity
the other is the genetic diversity so
dogs are sort of unique in this
um breed structure that humans have have
created right through selection we've
got purebred breeds but then on top of
that we've got this this mixed breed
genetic architecture which is very
interesting and Powerful but can match
to some extent the diversity of the
human population so you know I don't
know if we're going to be powered enough
to really get to True sort of
personalized outcomes in our trial but
in the larger dog aging project where we
have 44 000 dogs now we actually do have
enough power to actually say okay in
these in these breeds you know there is
this genetic component to this
aging process or to this interaction
between aging and diet and things like
that
it's incredible I want to talk about
obesity so you made a really interesting
distinction between weather caloric
restriction is actually the thing that's
having the benefit or if it's just not
being fat yeah talk to me about fat as
an organ why does that hypothesis bring
to mind
so so I think I think the question of
whether in laboratory animals where we
know caloric restriction can extend
lifespan is purely an anti-obesity uh
response is a valid response because of
the way that we maintain animals in the
laboratory they do become obese with age
they are overfed
um and I've heard people criticize that
by saying well that means it's not going
to work in humans well look around I
mean you know oh yeah sure so so I don't
think that's a good argument for saying
that caloric restriction is not going to
work in in humans I do think it is an
important question whether uh obesity is
just on the same Spectrum with respect
to biological Aging in other words is is
you know are we going if from this is
very simple I don't believe it's true
but let's just make it simple you know
if you're calorically restricted you're
aging the slowest if you're at a normal
weight you're aging at a rate in the
middle and if you're obese you're Aging
in an accelerated way
I think conceptually there's probably
some truth to that and in fact we see
that obesity is associated with you know
higher risk for a whole bunch of
different are you aging faster if this
is accurate are you aging faster because
you're just eating more things and
you're asking your body to process it or
is it actively holding the fat whether
it's the hormonal signal that fat kicks
off or it's the compression of the
organs I mean it's probably it's
certainly some of it is that some of it
is driven by adipose itself right we
know that adipose gives off uh
inflammatory coming back to inflammation
that's what I'm saying inflammatory
signals right so so absolutely uh the
fat itself can contribute I think also
the you know you you I think you're
alluding to this the the physical
um effect of gravity just being heavier
wears down your your joints and your
organs and so I think that probably
plays a role as well
um that's something we don't really
think about in the biology of Aging very
much is the impact of
of gravity
on our bodies right and and that's
actually maybe important it might mean
that some of the stuff we do if we
reverse biological aging is only going
to be so effective because we're not
going to change gravity unless we go
with Elon and go to Mars right you know
so so uh so that probably is important
in the context of Adipose though there
is this physical
component there but I don't think that's
all of it I mean I think I think some of
it uh is probably just from enhanced
metabolism and the impact of that
enhanced metabolism on other tissues and
organs on your liver you know which is
kind of the first pass for all this
stuff on your kidneys which have to
detoxify all the stuff you're taking in
on your circulatory system so that all
is going to affect the Aging of the rest
of your body not only because of of the
adipose itself
super interesting yeah that's one of the
things when I think about our modern
diet and I think about organizing
principles so what's the underlying
cause and effect yeah
um we're ah God is it we're extending
life but not Health span or is this the
first generation that's going to live
less time either way it's remains to be
seen yeah no it really remains to be
seen what's going to happen to life
expectancy going forward but yeah I mean
obviously a huge swath of the population
in pretty much every developed country
is unhealthy and I don't so so a couple
things I would say I don't think you can
argue that uh we have been successful at
keeping sick people alive longer I think
you can have a debate about how much of
the life expectancy over the last 30
years is better health and how much of
it is poor health but I think it's clear
a significant fraction is poor health
and then you put on top of that these
cultural and societal forces which have
led
the vast majority of people to eat an
unhealthy diet and become sedentary
um and that's just you know compounding
the whole thing and yeah it's you know
it's um we'll see where it goes I mean I
I think
I'm not super optimistic that medicine
is going to be the solution
um you know I think we've we've had a
couple of uh exciting developments in
anti-obesity drugs and we'll see how how
effective they are over the long term
and whether American is ever able to you
know be be used widely right
um so there's a few so I think I think
the um the newest ones are actually
mostly inhibiting uh appetite so they
kind of make you nauseous so you don't
want so you just don't want to yeah the
thing I've heard though and I haven't
read the study so don't don't don't
quote well I guess you can't quote me on
this I'm gonna say it but we will quote
you as you say don't quote us Fair yeah
we get it so um uh I have read though
that there's now some concerns about
rebounds so when people come off the
drugs you know they rebound and that
that we know about this
setting in the brain
you know this is where I'm gonna I I
would rapidly get outside of my area of
expertise if I started commenting too
too deeply on this I think there is
absolutely uh
uh effects of many of the highly
processed foods and high calorie foods
that are easily available today on the
brain that reinforce this process I
don't think anybody really would argue
with that is it a formal addiction or
not people you know that's a word that I
think triggers some people and so I
don't I don't know that that's important
but clearly
um there are changes in brain chemistry
associated with eating certain foods
that reinforce that behavior and
contribute to the
obesity epidemic around around the world
and I mean look some of these things
were developed for that purpose right I
mean some of these these uh companies
that created these Foods put a lot of
research into figuring out how to you
know this how do we impact this what's
it called the Bliss number or something
this the scale right you know to make
the brain fire so I think there might be
something else going on as well so I'll
throw I'm just not I don't have a
scientific pedigree to protect so I'll
just pontificate
um I think that part of what might be
going on is your microbiome is adjusting
to what you eat it's sending
neurochemical signals to your brain of
like crave this crave this crave this
and then on top of that I have heard I
don't know if this is going to pen out
or not but I have heard from uh somebody
they believe it and they are very much a
scientist in FDA trials right now and
they believe that they have a mechanism
by which you can
um adjust the hypothalamuses
um basically weight fat set point set
point so that the amount of fat the body
wants adjusts and that his hypothesis is
you have a set point your body wants I
don't know if you want to put in
percentage pounds what I don't know but
it has some amount of fat that it wants
on your body and you you can dye it all
you want you'll lose the fat but as soon
as you stop dieting it goes right back
or more and until you adjust that set
point all you can hope to do is is Yo-Yo
yeah that's interesting now if you
combine that with the microbiome is
screaming out for things and you've got
the set point you're going to rock it to
that so so yeah so I mean I think
there's there's certainly some truth to
the whole set point idea and I don't
know I don't know what you're referring
to so I can't comment on likelihood that
that's going to be successful a couple
things to say so I think the microbiome
is is uh link is super interesting and
definitely there's some evidence that
that for exactly what you said which is
that the the diet you eat remodels the
microbiome and then the microbiome
indeed is sending signals throughout
your body not just to the brain
throughout your body in these
metabolites that we talked about before
so they get into your circulatory system
um and that that probably does play some
role in the I don't know whether I want
to call it habituation or changes in
brain chemistry you know whatever the
process is that's reinforcing this
desire to continue to eat that way is it
a big role is it a small role I don't
think we know enough at this point to
know
um but it it almost certainly is uh is
important
um and the microbiome interacts with
your immune system so again the the gut
is I think the largest immune organ in
the body right because of these
interactions with the microbiome and so
that's probably also driving a lot of
the changes in immune function that that
happen
um as well in response to these these
you know
low quality diets that lead to obesity
so again it's all interconnected and the
signaling is
um complicated yes it is yeah super
complicated but so interesting all right
as somebody that's going to deploy this
stuff I always find it very interesting
to see where people are in terms of if
they have kids which I know you at least
have one two boys you learn real fast
what people really believe in so what
how do you feed your kids uh would you
have them supplement anything yeah like
how does that play out yeah so so we
have always um maybe not say always so
when the kids were very young I will
admit we did take them to McDonald's
once in a while but we haven't done that
for years we've and this is a complaint
what about not going to McDonald's no
Andrew no I know but we never did it all
the time so so I should say this is this
is more my wife than me because she was
she first of all was much smarter about
diet than I was earlier so she she was
telling me things that I now am you know
saying out loud right or about 10 years
before I actually started practicing
them so so she really was the one that
drove this but but we were pretty
healthy so she uh made a strong effort
to ensure that you know we mostly Whole
Foods uh uh lots of vegetables
um and um but we're not perfect and we
never tried to be perfect and again I
think there's this you know this is
where I think it becomes very individual
and and and I think that some people can
function in a very rigid sort of
lifestyle and that works for them but I
think most people can't and so I I we
have never tried to say oh you can never
have a hamburger cheeseburger whatever
you can never have candy but try to make
sure that the day-to-day sort of uh
normal uh life at home is a healthy one
supplements
um I
vitamin D we give to our younger son
because he is also vitamin D deficient
um and probably a multivitamin and
that's about one who isn't one who isn't
well uh our oldest one has never no I
all just wanted I don't know if he's
ever been tested to be honest with you
our youngest one got tested so our
youngest one got tested our oldest one
is out of the house now so it's a little
bit different situation then but how old
were you when you had them
um
he was born in 2002 and I'm going to be
52 so yeah wow 2002 sounds like oh a
couple weeks ago yeah I know right crazy
that yeah that's a 21 year old yeah whoa
uh but but you know we're not super big
on supplements so so my wife takes a
multivitamin I don't
I I actually I've been thinking about
this I need to go get a comprehensive
vitamin uh panel I don't think I'm going
to be deficient in anything but I need
to find out but I don't I I don't like
the idea of mega dosing so you know
finding the right balance for vitamins
is important and so I want to figure out
where I'm at and then figure out what if
anything I need to supplement other than
vitamin D which I already know
so interesting man I really like the way
that you approach things where can
people follow you so
um I would suggest that people follow me
at the dog aging project which I've got
my shirt on yes dogagingproject.org and
I'll also make a plug if anybody out
there has a dog any age any kind any
size consider participating in the dog
aging project we are so they can do from
home yeah absolutely go to the website
nominate your dog and you can complete
the survey and
um it's the largest open science project
for uh canines in the world and our goal
is to increase Health and Longevity for
pet dogs so if you have a dog I'm sure
you think that's a worthwhile goal and
I'd encourage you to participate in the
project yes I do that's awesome all
right guys if you haven't already be
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and he said I thought I was gonna fail
but do you see what I'm seeing
and I said yeah I see it what are you
seeing I said the future