19. Biological Aging Clocks, mTOR & Rapamycin: A Reality Check with Dr. Matt Kaeberlein

Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:04):
Welcome to MD Longevity Lab, where we're playing the long
game. This is a podcast where science
meets real life, with expert insights, practical tips, and
real world tools to not only live longer, but live better.
Our aim is to radically change the way medicine is practiced
and enable individuals to age gracefully, maintaining health,

(00:24):
span and vitality well into their later years.
We're your host doctor, Nisha and Dr. Vikas Patel, physicians,
partners in life, and parents, balancing work, Wellness and
everything in between. Let's dive in.
Welcome back to the MD LongevityLab podcast, Playing the long

(00:46):
game. I'm Doctor Nisha Patel.
And I'm Doctor Vikas Patel. Today is a special one because
we're joined by somebody who hasprobably influenced every
longevity conversation happeningtoday, at least to some degree,
whether people realize it or not.
He's a scientist whose work has shaped how we think about aging,
health, span, mtor, and maybe one of the most misunderstood

(01:10):
medications in the longevity space, rapamycin.
We are talking about none other than Doctor Matt Cabeline.
He is a world leading scientist in the biology of aging.
He notably completed his PhD from MIT in a mere 4 years and
three months. I think at the top of this
class, he's also the founder of Opti Span, which is a health

(01:34):
span and longevity focused clinic, a very similar to what
we do at MD Longevity lab focused a lot on preventive
medicine. He is the former director of the
Healthy Aging and Longevity Research Institute at the
University of Washington. His research work has really
shaped much of our modern understanding of a few things

(01:56):
that we'll get into in the podcast today, including mtor,
Rapamycin, just translational geoscience.
And he did some of this work initially starting at MIT while
identifying some of the genes responsible for aging in yeast.
He is also notably the Co founder of the dog aging Project

(02:16):
and I believe parent to three dogs currently.
And then something that we, Nisha and I, have really enjoyed
is that he's really a scientist who's known for nuance,
integrity, and really elevating evidence over the hype and the
longevity space, which is a common pitfall or trap that we

(02:37):
see quite frequently. You are one of our favorite
people because you tell the truth even when it's
inconvenient. And so we are so excited to dive
into longevity through the lens of someone who really
understands the science. Matt, thank you so much for
being here. Well, thank you for that kind
introduction that that was that was really nice and appreciated.

(02:58):
And it's a pleasure to be able to join you today.
I'm looking forward to it. So we're going to get started
with a couple basics here. I wanted your take on what you
think the biggest shift is goingto be and how we define and
measure health span in the coming decades.
Sure. I mean, I think maybe the way I

(03:21):
would start the conversation is that I think of health span as a
really useful concept. I'm not really sure that we
should try to measure health span.
And what I mean by that is I think even to some extent when
we talk about trying to measure health span, the word itself is
a little bit problematic becausebecause of that span piece,

(03:41):
right? It implies that there is a time
or a length to health, which implies that before an
individual health goes from something you have to something
you don't have overnight. And of course, that's not the
reality for anyone, right? So I think maybe the way we
should think about it is that health span is multifactorial.
It's made-up of lots of different aspects of function

(04:05):
and emotional health and molecular biomarkers that we
are, I think becoming better able to assess each of each of
those individually and understand what they mean and
then more importantly, what whatto do about it.
So I think the way that I see health span changing going
forward, and I think we're already starting to see this is,

(04:26):
is #1A better, a more widespreadrecognition of how important it
is to take a proactive approach to health, right?
And to get ahead of health and not wait until people are sick
before we try to do anything about it.
So proactive preventative approaches, I think are going to
continue to become an emphasis going forward.
And then I think also as the tools become better developed

(04:50):
and as AI gets integrated, we'regoing to continue to see real
opportunities for personalized approaches to health span
extension or health promotion. And I think this is something
that a lot of people have been excited about for a long time,
the idea of personalized medicine to date that has really
been fairly rudimentary. And we don't have a lot of

(05:11):
concrete examples of how this can be done well.
But I think, you know, with the new AI tools that are coming
online and with the sort of plethora of, of new diagnostics
that we have at our disposable at our disposal that there are
real opportunities for true, we're starting to get towards
personalized approaches to, to preventative healthcare.

(05:32):
So I think that's that's probably the, those are the
obvious things that are going tocontinue to get better and
become widely implemented in thenext 3-5 years looking forward.
One thing I wanted to pick your brain about, there's so many of
these direct to consumer biological age tests with no
oversight, no medical oversight.We have our opinions on those,

(05:55):
but I would love to hear your take on it.
Sure. Yeah, I'm very opinionated about
this topic. I will say, you know, I was just
talking about the new tools, thenew diagnostics that we have at
our disposal to assess differentaspects of health.
I think the biological age testssort of overlap with that, that
set of of diagnostics in the sense that in the research world

(06:16):
there has been a lot of progressat first of all understanding
what are some of the things thatwe can measure that tell us
about health, which is correlated to biological age,
right? So there's been a lot of
advances and I think the development of these biological
aging clocks is what most peoplecall them has been an important
research advance for sure in thefield.
So first of all, it might be useful to just appreciate what a

(06:38):
biological aging clock actually is fundamentally.
So biological aging clocks are just a collection of individual
biomarkers of aging and a biomarker of aging is just
something that changes in a predictable way across the
population with chronological age.
OK. So there are tons of those like

(06:58):
skin wrinkles, graying hair, testosterone levels in men, VO2
Max, grip strength. You can see these things at
molecular levels as well. Metabolites that change with
age, proteins that change with age.
All the clocks are is taking a bunch of those and using
complicated math and usually machine learning to pick a

(07:21):
subset of biomarkers, anywhere from a few dozen to a few 100.
And then creating a linear equation where you weight each
biomarker differently to give you a correlation to something
that's associated with health. And that can either be
chronological age, those are thegeneration one clocks, or it can
be risk of dying, mortality risk, or risk of developing a

(07:44):
age-related disease. Those are generation 2 clocks.
So you're using a collection of biomarkers to create a
predictive algorithm, a correlation to something of
interest, chronological age, your birthday or your likelihood
of dying or your likelihood of getting sick.
That's what aging clocks are. And just for a little bit of
nuance, there is a different flavor of aging clocks, which

(08:04):
some people call generation 3 clocks, which instead of
predicting chronological age or your risk of dying, predict the
likelihood that your health is going to change over the next
five years, 10 years. Those are called pace of aging
clocks. So they're predicting the rate
of change in health. OK, So these are conceptually
really fascinating. I think in the research world

(08:27):
have taught us a lot about the biology of aging and will
continue to teach us a lot aboutthe biology of aging.
And they work pretty well at thepopulation level.
If you have data from 100,000 people, you can develop really
good correlations. Where they don't work so, so
well even in the research world,is at the individual level.
So every measurement has some error associated with it.
The best clocks have an error of, you know ±5 years, maybe a

(08:52):
little bit less than that, maybea little bit more than that.
So that means the standard deviation from the true value
for whatever they're estimating chronological age or risk of
dying is going to be 5 years. So 2/3 of the time it'll be less
than that, 1/3 of the time it'llbe more than that.
OK, so that's useful to understand.
That's in the research world. Perfect conditions.
The problem we've got is we've had a bunch of direct to

(09:13):
consumer companies start sellingthese tests, marketing them to
people. They're not doing these things
under the most perfect conditions, and in fact, we have
no idea what the error rates are.
I mean, there are lots of problems with the direct to
consumer test, but to my mind, that's the fundamental problem.
You can't use them because you don't know what the error is.
Period. Full stop.

(09:33):
So when researchers have some sort of intervention and one way
of doing these aging clocks are methylation tests for DNA and
they seem to imply that their technology their when they have
introduced some sort of intervention and they're
tracking methylation trends on DNA that it does actually give

(09:54):
them true insight. But then when we look at the
consumer grade methylation test,it's kind of all over the place.
Yeah. So a couple things to say there.
Number one, yes, I think in the research world, there are are a
small number of quality studies that have looked at the way
these methylation clocks. And again, I know it's getting a

(10:14):
little bit in the weeds, but it's probably worth
appreciating. The epigenetic clocks or
methylation clocks are just one flavor of aging clocks.
They're the ones that were sort of first popularized and they're
the ones that have been used themost in the research world.
But you can develop comparable, maybe even more precise aging
clocks using other types of biological data, chromium,

(10:36):
metabolome, transcriptome, microbiome, maybe even or
functional measures like I was alluding to grip strength and
VO2 Max and body composition. So the epigenetic or methylation
clocks are just one flavor, but they are the most common flavor.
So you're right, there are studies that have been
published, many studies that have been published that
correlate changes in these epigenetic clocks to

(10:57):
interventions. They could be lifestyle
interventions, drugs to major life events, pregnancy,
menopause to environmental exposure.
Some of those studies are high quality.
The vast majority are low quality in my opinion.
But there are lots of them out there and it's hard, I think for
the average person. Certainly it's hard for me as a
scientist, it takes me time to dive into the studies and really

(11:18):
look at them to know which are high quality and which are low
quality. So all of that is being said is
that I think at the population level, when done well, these
clocks can actually tell you something about how and
environmental change, a major life event, stressful event,
maybe even medications or lifestyle interventions are

(11:40):
impacting the underlying aging biology.
But it's an indirect estimate ofaging biology.
I think that's the other thing that's worth appreciating.
If you ever hear anybody say, and I guarantee if you stay in
the space long enough, you will you ever hear anybody say I
measured biological age using this test, They either A, don't

(12:01):
understand how the test works orB, they are intentionally
telling you something that is not true and you can consider
how you feel about that. I know how I feel about that.
Biological aging clocks do not measure biological age.
They measure either average methylation state at a subset of
sites or protein, protein abundances or transcript
abundances or whatever it is they're measuring.

(12:23):
It's not biological age. And those are correlated to what
they're estimating, which is also not biological age.
It's chronological age or mortality risk or risk of
developing cancer. So there's a lot of, I think,
sloppy language and misunderstanding around what
these tests actually do, how they work and whether or not you
can you can rely on them. Again, my biggest concern is

(12:47):
that in the direct to consumer space, all bets are off because
we just don't know what the error rate is for what the tests
are supposed to be estimating. Most of the direct to consumer
tests are estimating mortality risk.
Those are the algorithms that they use, which is fine.
If we had it, if we, if we knew what the error rate was, if we
knew that was ±5 years, then we could put statistical bounds on

(13:10):
the test and we could say, OK, with a 66% probability, a change
of more than five years is meaningful, right?
But we don't know what the errorrates are.
My intuition based off of some evidence is that the error rates
are much greater than five years.
And for people who are interested, like if you're a, if
you're a data nerd, I would justsuggest if you want to, if you

(13:31):
want to do an interesting thought experiment, because a
lot of people are say buying these tests quarterly and taking
them quarterly, right? If you want to do an interesting
thought experiment, whatever your age is, think about your
age. Put that into ChatGPT and say
give me a set of 10 series of four numbers based off of a
normal distribution at whatever your age is.
Let's say you're 50, around 50 with a standard deviation of

(13:54):
five. That's the result you would get
by chance if you did these testsfour times quarterly, right?
And you're you did everything right, your biological age
didn't move. And look at the look at the
distribution. You're going to look at that and
then think about what you would think if you got those results
back from your biological age test.
It's all over the map. These things in my view are

(14:16):
completely useless at this pointand that's the best case
scenario. I guarantee you the error rate
is more than five years on any direct to consumer facing
biological age test today. You.
Know you did the methylation test on yourself the same day,
right? Same company?
And what were your results? Yeah.
So I mean, it's complicated the way I did the experiment.

(14:36):
But basically what I did was I did 4 different companies.
I did each test in duplicate andit was same sample, same days.
Some of the companies use saliva, some of these them use
blood, which makes it more complicated.
But it was the same samples and the results were, I think,
interesting and informative. For three of the companies, the
two replicates were relatively close together within five years
of each other. When you look across the four

(14:57):
companies, the spread was more than 20 years and for one
company the spread was almost 20years.
It was like 15 years for the tworeplicates.
So again, first of all, it's not, it's not a large enough
set, like 2 replicates isn't a large enough set for me to say
anything other than there's a lot of noise in the system.
And when you look across the industry, it's a complete

(15:19):
freaking mess. It's my take home from that
experiment. I think in some ways that
experiment was good because it brought attention and can people
can point to it. But it's also a little bit
distracting in that you don't even need to do the experiment.
But if you're at all quantitatively inclined, that
sort of mathematical thought experiment I just laid out, if
you just, if you understand whata normal distribution is and

(15:39):
what a standard deviation is, and that the magnitude of effect
we're talking about, even in thevery best case scenario, like
the Horvath clock, the gold standard has an error of 3.6
year. That's the very, very best
you're ever, ever, ever, ever going to get and it's still 3.6
standard deviation. So if you understand that and
you model it, you will very quickly realize how useless

(16:02):
these tests are right now at theindividual level.
Because I'm telling you in the direct to consumer space, the
error rate is at least three times what it is for the
Horvath. I think that's reassuring and
it's a good number for our patients that you just can't
panic over a single number that you get from these things.
I think we feel a couple phone calls or inquiries every week on

(16:25):
a patient who specifically asks us, do we run these tests?
And then we have to go into thislengthy explanation, as you just
behaved about why this may not be a test that's worth us, worth
your time. And there's so many more useful
tests, right? VO2 Max you're.
Absolutely. Dexapan.
So I think that's really the important message, right, is

(16:46):
that we have really informative and actionable biomarkers.
Of course people want to get to a single number.
I understand the desire for that.
But I think it's just, it's not nearly as useful as looking at a
collection of of health related biomarkers that span the
different systems of health. So you can really get a feel
for, for where the biggest opportunities are.

(17:06):
It might be worth saying the theone type of aging clock I'm
relatively bullish on right now are these clinical chemistry
clocks like Lin age 2 or Enable age that use things that we can
measure from blood or urine and go to to reference laboratories
like LabCorp or Quest. I think those are quite
powerful. They're trained on mortality.

(17:28):
And what you can get is you can get from that a picture of for a
given individual, which biomarkers, if you can move them
are most likely to move the riskfor mortality.
And that makes the assumption, of course, that these things are
faithfully representing mortality risk.
But when the biomarkers are directionally consistent with

(17:51):
what we've learned from decades of clinical practice, it makes
sense, right? If you take the Lineage 2 test
and it tells you that for you, you're going to get the biggest
effect on mortality risk. If you get your blood pressure
under control and your A1C, those are the things you can
focus on right away. And so there I think those tests

(18:12):
are potentially valuable becausethey give you actionable
insights that are potentially also behavior modifying.
You can talk to a patient and say, look, this algorithm is
telling us that for you, it's most likely if we fix these
things, you're going to have a big impact on your risk of dying
or your risk of developing cancer.
What whatever the case is that those are the kinds of tests I
like because number one, we do know what the error is because

(18:34):
we know what the error rate is for each of those individual
measurements. Those reference laboratories are
required by regulatory bodies tobe within a certain tolerance
for error. So, so they're clinically
validated, we know the error rates and they're actionable.
And I think those are the two pieces we need to get in place
for the other aging clocks before they can reliably be used

(18:54):
in a clinical setting. I think that's exciting.
I think leveraging AI, which we'll talk a little bit about
later by feeding at these biomarkers and figuring out
because we do have data on, hey,if your hemoglobin A1C is 8.3,
right, from a mortality standpoint, what does that mean
for you? How much, how much higher

(19:16):
mortality rate do you have at that A1C versus that 6.0?
And I, so I think that's where these tests are looking
promising. And it's very interesting what
you bring up. I'd like to get into a little
bit more of things that you specialize in, and this may be a
little bit new to some of the listeners, but I'd like to see
if you could explain to them what mtor is and why it's so

(19:40):
central to aging biology. Sure.
So I think from a very high level, you can think of mtor as
sort of a gatekeeper for the cell and and and in terms of
sensing the environment and making the fundamental decision,
is the environment appropriate for growth and reproduction.

(20:00):
OK. Mtor is a protein that that
helps the cell makes make that decision and it's one of the key
players in that decision. And that's a really important
decision if you think about evolutionary time scales.
Every Organism that has ever existed has had to make that
decision since the environment and then determine is it a good
time to grow and reproduce or isit better to shut down growth
and become stress resistant and wait for the environment to

(20:22):
improve. And then if you think about what
in the environment helps inform that decision, it's a pretty
small number of key factors thatinform that decision.
Temperature is going to be important.
If it's an oxygen consuming Organism with mitochondria,
oxygen abundance is going to be important and food is going to
be important. And Tor senses all of those, but

(20:43):
it is mostly interested in food.So it's a lot of people will
call it a nutrient responsive sensor.
So when nutrient levels are high, Tor gets active invaded
and that tells the cell, OK, this is a good time to have
babies because you have lots of food to feed them.
When nutrient levels are low, that turns down Tor and that
tells the cell, OK, let's shut down growth and reproduction.

(21:05):
Let's become stress resistant and hope the environment gets
better in the future. So that's basically what Tor
does. It's a nutrient responsive
kinase is the the biochemical term.
And that just means that it putsphosphate groups on other
proteins and controls signaling.So it's a signaling molecule
that senses the environment and then signals growth versus
reproduction versus stress resistance.

(21:26):
A lot of people got interested in in Tor, you know, many years
ago as an anti cancer target because it's so involved in cell
division, right growth. And so people began studying it
for anti cancer purposes. It actually got FDA approved.
The drug that targets Tor, whichwe'll probably talk about is
called rapamycin. It's an inhibitor of Tor that
actually got approved as an immune suppressant because

(21:48):
immune cells are rapidly dividing when you get an
infection. It's used to prevent organ
transplant rejection in that context.
So that that's how Tor got studied clinically.
But sort of in parallel, severallabs around 2003 kind of
stumbled on Tor as an important target for longevity.
And I was fortunate enough to beinvolved in in those studies as

(22:09):
a postdoc where we were working in yeast.
I was working with Brian Kennedyand Stan Fields at this point,
but other people were working inC elegans and Sydney Brenner's
lab and Pankaj Kapahi were working in fruit flies.
Again, this happens in science sometimes completely
independently, completely different lines of research.
We all converged on tour as being a central regulator of

(22:32):
lifespan in each of those organisms.
And I think, you know, 4 papers came out within a year of each
other, all pointing to tour as regulating lifespan in three
different organisms that are separated by billions of years
of evolution. People paid attention because
it's like, wow, this seems to bereally important.
And what we've learned since then is that that also is seems
to be the case in mammals. So mice and rats and some

(22:54):
evidence even in non human primates that when you turn down
Tor, you slow aging, the animalslive longer.
Not only that, but they seem to be healthier.
So turning down Tor preserves function in pretty much every
tissue and organ where people have looked in mammals like mice
and rats. So it really seems like Tor is a

(23:14):
highly evolutionarily conserved,really important component of
the biological aging network. And when we turn it down, as
long as we don't turn it down too far, we can slow aging and
increase lifespan, at least in laboratory animals.
And I think obviously one of thebig questions is, is it, does it
work the same way in the real world?
Could we do the same thing in people or you mentioned I'm, I,

(23:34):
I'm part of the dog aging project.
We're interested in knowing whether we can have a positive
impact on our life lifespan and health span of our companion
animals as well. So that's kind of the unknown
and that's the frontier right now is to what extent can we
modulate them toward a slow aging outside of a laboratory.
We know rapamycin is an immunosuppressant.
If you ask most physicians, I think they're clueless when it

(23:57):
comes to rapamycin in the longevity space.
Yeah, sure. And I mean, again, absolutely,
that was the case five years ago.
I think almost every doctor I talked to was like, why would
you even think about giving an immunosuppressant to a healthy
person? That's crazy.
So now I think that's changing. People have at least heard of
it. But I think you're right.
Still, there's a lot of misperception and
misunderstanding about about rapamycin.

(24:18):
So again, rapamycin is a small molecule inhibitor of M Tor.
So rapamycin turns down M Tor and in many ways you can think
of it as tricking the cell or the Organism into thinking
there's not very much food around because when you turn,
when there's when there's low nutrients, that also turns down
M Tor. So, so rapamycin turns down M
Tor even when there's lots of food around it.

(24:38):
It inhibits growth and cell division.
As I alluded to, it was first developed clinically and FDA
approved to prevent organ transplant rejection at high
doses in people taking other immunosuppressants.
Rapamycin has immunosuppressant properties and will reduce the

(24:59):
likelihood of rejection of an implanted organ.
That's what it was approved for.It works well in that capacity.
Also in that context, there are side effects associated with
rapamycin. They're not terrible, but it's
got a black box warning. It's got some bad reputation
associated with it because of the way it was developed,
approved and used at high doses in these patients.

(25:21):
I think the most common, the most common side effect is, is
in organ transplant patients, significant mouth sores or, or
ulcers in the mouth. But it also has some concerning
side effects around what I wouldcall pseudo diabetes.
So something that looks like diabetes based on insulin
sensitivity and and glucose measurements, high lipids,
hyperlipidemia being one of the common side effects.

(25:44):
And then of course people are worried about increased risk of
infection because it's an immunosuppressant, right?
So those are the things people get concerned about when you
talk about using rapamycin in healthy people outside of the
context of organ transplant. So why would you think about
doing that? I mean, one reason is because of
all of the evidence in laboratory animals that
rapamycin can slow aging. Obviously that doesn't mean it's

(26:06):
going to slow aging in people, but everything I know about
biology tells me it's going to slow aging in people if we can
get the dose dose right, slow biological aging.
It is important to say just because something slows
biological aging in people, thatdoesn't mean it's going to make
you live longer and healthier ifthere are side effects that are
going to offset the benefits. So to me that's I think there
are two questions about rapamycin use off label at this

(26:28):
point in my mind, 1 is what is the right dose, duration,
frequency to get the beneficial effects on biological aging in
people. Again, I can't prove it slows
aging in people, but everything I know about biology tells me it
will to some extent might not beas effective as it is in mice,
but it's going to slow aging to some extent in people.
OK, so how do we do that? What's the right dose, duration,

(26:48):
all of that stuff And then are there going to be side effects
at that dose, that duration, that regimen that are so
counterproductive that it's not worth it even if you are aging
more slowly? Those are the two questions I
think we don't fundamentally know the answer to at this
point. So what has evolved is a sort of
off label use community that is centered around a certain dosing

(27:14):
schedule. But the reality is lots of
people are doing lots of different things.
We don't have a ton of, I would say high quality, certainly not
much, you know, double-blind, randomized placebo-controlled
clinical trial level data yet toreally be able to have a lot of
confidence what people should bedoing, what's effective, what's

(27:34):
not effective. Happy to talk about what we do
know. One thing I think it that is
worth noting, and this is my, you know, largest frustration
with rapamycin is unlike some other things, we don't have
great biomarkers to use to tell us for you as an individual, if
you're taking rapamycin, is it helping?
Are you taking the right dose? We don't have obvious biomarkers

(27:58):
that can tell us with a high degree of confidence that
rapamycin is working for you. And if people don't know what I
mean by that, I think as a a sort of interesting
counterexample, another drug we can talk about if you want to
are these things called SGLT 2 inhibitors, right?
These are anti diabetes drugs. I'm sure you guys are very
familiar with these drugs. Basically what they do is they
cause you to pee out more glucose.
They they reduce kidney reuptakeby by the glucose.

(28:20):
So it lowers your blood glucose because you're just getting it
all out in your urine there. We've got really good
biomarkers. We can measure fasting glucose
levels, we can measure insulin sensitivity.
So that's a case where there's adrug that also might have Jaro
protective anti aging effects where we got a great biomarker
or set of biomarkers to look at.So that to me is really the, the

(28:40):
challenge with rapamycin right now is we don't have something
like insulin sensitivity to lookat and say we know we've got you
dialed in with your rapamycin regimen.
You took rapamycin for an injury, correct?
That's right. Yeah.
So I mean, if you had asked me, that was in 2020, so we're five
years out now. But I mean, if you had asked me
seven years ago, should people be taking Rapamycin off label?

(29:03):
I would have been like, no, I don't think anybody should take
Rapamycin off label. So I was a pretty conservative
academic. Like it, that's, that's the way
a lot of academics are, which isfine.
Like the, I think there's, there's a right balance of
conservatism and being willing to, to be risky, right, and, and
figuring out that right risk reward ratio.
But I had a personal experience where I, you know, after a long
process of, of, you know, havingthis very painful shoulder

(29:26):
condition that, that, that, you know, got to the point where I
couldn't sleep, I couldn't go across the street and throw a
ball with my son. I finally, and I was a pretty
stereotypical, you know, 40 something year old man where I
was like, I'm just going to it'sI'm going to push through it.
It's going to go away. I'm not going to go to the
doctor, you know, and it didn't go away.
It got worse. I finally got to the point I

(29:47):
don't right thing. Yeah, so, so it was dumb.
I I admit it was dumb, but anyways, it had to get to the
point where I couldn't throw a ball with my son before I would
go to the doctor and and say, OK, I need to get this fixed.
Now I also like a stereotypical 40 something guy who thinks he
knows a lot. I was sure I had a torn rotator
cuff. So I go to my, I go to my
primary care doctor and I'm like, I have a torn rotator
cuff. I need you to give me a referral

(30:09):
to a specialist so I can get it fixed.
And he was like, no, I want you to go to physical therapy, blah,
blah, blah. So I did that.
That made it worse. So I went back to him and I'm
like, OK, I tried it your way. Give me the referral to the
specialist 'cause I need surgeryto get this fixed.
And so he did. And within like 5 minutes, the
orthopedic specialist was like, you don't have a torn rotator
cuff, you have adhesive capsulitis.
And I was like, what is adhesivecapsulitis?

(30:31):
It's like it's called frozen shoulder.
It's inflammation of the shoulder capsule.
You know, it usually is more common in women than in men, but
it happens in people your age. And I was like, my age, give me
that stuff. So.
And then, and then he's like, yeah, he's like, I want you to
go back to physical therapy and maybe it'll go away in a year.
And I was like, God, I can't live like this for a year.

(30:52):
So, so I, I mean, I vividly remember I'm like in the car,
I'm pissed off, I'm depressed. And I start thinking to myself,
OK, this is an age-related inflammatory condition.
At that time we were studying rapamycin in my lab.
We'd shown that you could increase lifespan in mice with a
three month treatment in old age.
And then we gone on to looking at periodontal disease, which is

(31:12):
an age-related inflammatory condition in the mouth.
And we'd shown we had this data that treating old mice with
rapamycin turned dramatically turned down inflammation in the
oral cavity in the gums. And so I'm thinking to myself,
OK, this is inflammation in the shoulder capsule.
It's probably related to inflammation in the gums.
Maybe rapamycin would work for my frozen shoulder.

(31:33):
And again, I'm very lucky in thesense that I've got access to
doctors who will work with me and were willing to prescribe me
rapamycin so I could do this self experiment coming from, you
know, a relatively informed place.
And, you know, I can't 100% ruleout placebo effect.
All I can tell you is that within 10 weeks, I was 95% range

(31:57):
of motion back and the pain was pretty much completely gone.
And so it's such a biologically plausible mechanism that I, I
really, it's hard for me not to believe that it was the
rapamycin that, that had that effect.
So that was my personal experience.
And, but again, it took me having that personal situation
to make the leap to, to try and rapamycin.

(32:18):
I think before that I, and, and to be fair, we didn't have a lot
of data on off label use of rapamycin in, you know, 2019,
early 2020. Most of it came from the studies
that Joan Manik didn't, that those might be worth talking
about if, if you'd like to go into those.
But outside of those clinical trials, we didn't have a lot of
data on off label use of rapamycin.
So we didn't really know what the risks look like at that

(32:39):
point. I think now we know the risks
when done, you know, in a way that is reasonable and that most
people are using it. The risks seem very, very low at
this point. It sounds like, and I, and I
know that this has been explained for essentially like a
lot of people even to this day, I'll get patients talk to me
about fasting and the benefits of fasting and what it does to

(33:03):
mtor. And it sounds like this is kind
of the theory behind what rapamycin is doing, and people
are trying to replicate it to some degree in these fasting
states. I, I, yeah.
So I, I think that's true. Again, fasting is a pretty
misunderstood intervention, at least when you look at what we
know from the biology of aging, right.

(33:23):
And again, when we talk about issomething a longevity
intervention we don't have, we don't have the ability to prove
definitively whether any intervention is a longevity
intervention in people right outside of the things where we
can say with a high degree of confidence, like don't smoke,
you're more likely to live longer, eat a healthy diet.
So we have to go to the animal studies.

(33:44):
And that's where I think there'sa lot of misinformation and
confusion about fasting from theanimal studies.
So fasting is a longevity intervention when it is paired
with caloric restriction. OK.
When the animals make up for what they don't eat on the
fasting days, there's little to no longevity benefit.
So at least in laboratory animals, mice and rats, fasting

(34:08):
per SE when it's isocaloric has little to no longevity effect.
Fasting will absolutely turn down M Tor and in mice that
happens pretty quickly. But I think people need to
understand a 24 hour fast in a mouse is fundamentally different
from a metabolic perspective than a 24 hour fast in a human.
I don't know exactly. I don't think anybody knows

(34:30):
exactly how the math works out, but it's probably more like a
three or four day fast in a human in many ways, not in every
way, but in many ways. So going from the animal studies
to humans when it comes to fasting, I think it's just very
risky. And it's, it's filled with a lot
of misinformation. I think this is not.
And so that's the data. My personal opinion is I would

(34:51):
not which fasting from the perspective of fasting as a
longevity intervention. I think for some people fasting
can be a really powerful way to control body weight, to control
overeating. And you need to be careful that
you are eating a high quality diet if you're going to do

(35:13):
regular fasting, right. I think that's an area where
people often make mistakes, but I would not approach it from the
perspective of longevity. And, and again, this is again
getting in the weeds a little bit, but even the terminology is
a little problematic because some people when they say
fasting mean time restricted eating, like shrinking their
meals down to 8 hours or 12 hours.
Some people mean a 24 hour fast,some people mean a multi day

(35:36):
water only fast. So those are all going to have
different biological effects andpeople need to appreciate they
are not biologically equivalent.I think all of them can be
useful for certain people in certain conditions.
Again, outside of caloric restriction, I don't think
there's a lot of evidence that fasting is a longevity
intervention. And again, this is maybe a

(35:59):
useful counter to, to even rapamycin in the sense that, you
know, I mentioned just because something slows aging in people
doesn't mean it's going to make you live longer and healthier.
I think caloric restriction, andthis is speculation on my part,
but I think caloric restriction falls into that category, at
least the levels of caloric restriction that robustly slow
aging in my 60% caloric restriction, 50% caloric
restriction. I think in people, the data

(36:21):
we've got, which is imperfect, but from things like epigenetic
aging clocks and other biomarkers seem to show that
caloric restriction slows aging in people biologically.
And I think most people, if theywere to practice that level of
caloric restriction would not live longer.
They certainly wouldn't live better.
For most people, I don't think they'd actually live longer

(36:43):
because mice in the laboratory don't die from frailty.
They don't die from falls and fractures.
They don't die from sarcopenia. But people practicing that level
of caloric restriction, unless you really have the nutrition
dialed in and you're really doing a lot of resistance
training, are going to be at higher risk for those things.
And so I think both from a quality and quantity of life

(37:03):
perspective, the, I'm just goingto call them side effects of
caloric restriction are going tooffset the benefits of slower
solar biological agings. That may be a good at least
thought experiment for why people can understand even if
you're aging more slowly biologically, that may not mean
you're going to live longer and be healthier in the long run.
So sorry that was a big tangent.Yes, fasting mimics rapamycin,

(37:28):
but they're not identical. So the other way I would think
about it is that fasting or caloric restriction is going to
have thousands of other biochemical effects that
rapamycin doesn't have. Rapamycin is a very specific
biochemical inhibitor of mtor. As far as we know it doesn't
have any other major off target effects biochemically, whereas
caloric restriction or fasting are going to completely rewire

(37:51):
metabolism in ways that rapamycin doesn't.
So I I think of them as overlapping but distinct.
Rapamycin is very clean in the biochemical sense.
Fasting and caloric restriction are very dirty in a biochemical
sense. That's not meant to be a
pejorative, it's just a sort of reflection of what's happening
at the at the biochemical level.Can you also talk a little bit?

(38:13):
I know this is not part of your expertise, but just a little bit
because we hear so much now about what Klotho is and how it
might relate to mtor. Sure.
Yeah. So there there's definitely a
so, So I think first of all macro level, I think of the
biology of aging as a network ofinteracting proteins and

(38:35):
metabolites and RNAs. And so there's this network of
of factors that seem to modulatethe rate of biological aging and
the read out of that are the hallmarks of aging.
Again, for that's an oversimplification, but for lack
of a, you know, better way of saying it in, in a concise
framework, the the action of that network is affecting the

(38:58):
hallmarks of aging, which is what we perceive as biological
aging. So Klotho and M4 are both in
that network and they're, they both seem to be important, what
I would call nodes in that network and also useful nodes.
A useful node in the network is something we can target from an
intervention perspective and we see that it has changes that we
can measure on biological aging.Those changes being lifespan,

(39:18):
health span metrics, epigenetic aging clocks, things like that.
So Klotho is interesting. So, so Klotho, I think we know a
lot less about Klotho and how it's working from a biochemical
perspective to affect aging biology.
It's what's called a transmembrane Co receptor for
something called FGF 23, fibroblast growth factor 23.
And it regulates a bunch of stuff including oxidative

(39:40):
stress, IGF, one signaling, inflammation, all the things you
would expect it to regulate if it's regulating biological
aging. But I don't think we really
understand how the data here is interesting.
And and I think it's interestingthat there's a lot, a lot of
excitement about Klotho in the longevity community.
But there's a lot less known about how it's working than
there are for things like Rapamycin or AMP kinase or, you

(40:01):
know, some of the other common players in in that network.
So what we do know in mice is ifa mouse is lacking Klotho, so
you knockout Klotho in a mouse, it gets sick early, it dies
early, and it seems to show some.
Phenotypes of accelerated aging.So it's consistent with the idea
that the mouse are are aging more rapidly and if you over
express Klotho, the mice live longer.

(40:22):
And this hasn't been looked at as extensively as it has with
Emperor and rapamycin seem to behealthier across at least a few
of the major organ and tissue systems, particularly brain,
heart function things like that where people have done sort of
deep dive. So that's certainly is
consistent with the idea that Klotho is regulating biological
aging. And we can move, you can change
ageing either direction in laboratory animals.

(40:44):
I think the cool thing about cloth though, is there's there's
compelling human evidence that Klotho probably plays a role at
least in health span and maybe in longevity in people.
So lots of correlative studies showing that circulating Klotho
levels are associated with health outcomes, cardiovascular
disease, cognitive function, kidney disease.
And there are people who have a variant of Klotho KLVSI think is

(41:09):
the the. The the.
The the variant designation thatleads to higher levels of
Klotho. So people who are heterozygotes
for that variant, so they have higher levels of Klotho seem to
also be protected against cardiovascular disease,
dementia, and in a, in a couple of studies might even live a
little bit longer. So that gives us an indication

(41:31):
that Klotho may be important forhuman aging.
So this has led to excitement around Klotho gene therapy,
things like that. I think it's intriguing.
I think we're getting pretty farahead of the data to be talking
about Klotho gene therapy at this point.
And one of the cautionary notes is that there's at least some
evidence that people who have two versions of this Klotho
allele. So very high levels of Klotho

(41:52):
might actually have shorter lifespan.
So there's probably a sweet spot.
And until we know what the sweetspot is, I'd be careful about
putting in extra cloth though, you know, for the idea that it
might have some, some benefited people.
Again, super interesting research question.
There are at least a couple of companies that are looking at
ways to modulate Klotho activity, Klotho expression.

(42:12):
So I think we'll start to see those things make their way
through, you know, more traditional pipeline of
intervention or drug developmentrelationship to mtor.
They interact with each other. You can find evidence both ways.
So you can find evidence that more Klotho leads to inhibition
of mtor, higher autophagy, whichis one of the things that that
mtor regulates. And also find some evidence that

(42:34):
turning down mtor, at least the higher levels of circulating
cloth, though. So again, I think at this point,
my feeling is they're interacting with each other in
this network, but we don't really understand the the the
details of that interaction wellenough to say a lot about
exactly how that's working. I want to talk a little bit
about big picture zoomed out andwhat actually moves the needle.

(42:57):
You know, rapamycin is a prescription therapy that we're
excited about in the longevity space.
Patients are excited about supplements, but what actually
moves the needle with health span?
Yeah. So I think there's not a lot I
would say outside of the kind ofcore that we can say for for the
vast majority of people is goingto move the needle.

(43:17):
And so by the core, of course, we're going to start with
lifestyle factors. I think about it and, and and
Opti span, we sort of created this framework of four pillars
of health span, but you can have568 however you want to break it
down. But but essentially it boils
down to we use active words. So eat, move, sleep, connect.
So nutrition, high quality diet,not necessarily caloric

(43:38):
restriction, but high quality, not over nutrition, move
exercise again, there's a lot tounpack in each of these and
there's not A1 size fits all solution, but appropriate
amounts of resistance training so you can maintain muscle mass,
lean body mass, metabolic health.
Also, you want to have cardiovascular training and
biomarkers there like VO2 Max I think are really useful for for

(44:01):
estimating where you're at. So exercise, sleep quality, sort
of obvious on the surface, but that's a very individual thing.
And I think, you know, some people don't struggle with
sleep. A lot of people do.
And with age, sleep quality seems to decline.
Making sure you're getting adequate sleep and it's
sufficient quality sleep. Super important.
And then connect encompasses in my mind both sort of personal

(44:24):
sense of purpose, mindfulness, but also the really important
human relationship component. And I would say I think
companion animals can play a role here too in terms of your
feeling of connection to other beings, right?
I think that's the one that scientists like me tend to
underestimate the importance of.And I have completely done a 180

(44:45):
on the connect pillar in the last three years compared to
where I was as an academic. But I think a lot of people tend
to underestimate the importance of that aspect of human
relationships and feeling like you got a sense of purpose, like
there's a reason why you're doing what you're doing.
I think it's really important. Stress, of course, weaves
throughout all of those pillars of health.
Span and stress management is huge as a as a lever that can

(45:09):
have a huge have an impact on, on your health.
So outside of that, there are a few things that I would put as
major levers for a lot of people, maybe most people
dependent on on life stage. I would definitely put hormones
in there. I think hormone, I'm going to
use the word optimization. The problem is we don't really
know what optimal is, but makingsure your hormones aren't

(45:30):
sufficiently dysregulated that it's leading to emotional or
physical problems is hugely important.
And that that is a big lever that a lot of people can pull
and need to pull. In my opinion, once you get into
to middle age. And obviously it's different in
women and men and women have this thing called menopause,
which as far as I know, it is 100% penetrant.

(45:52):
Like every woman is going to getit.
Men are different in that it's alot.
I mean, women are variable in menopause, don't get me wrong.
But men I think are a lot more variable and what it looks like
when you go through these hormonal changes that happen
later in life, but super important for both men and and
women. I blame everything on
perimenopause. I think we're starting to learn,

(46:13):
I mean, not everything, but I think we're starting to learn
that there's a lot, a lot going on there in terms of accelerated
health risks. And again, it's, it's sloppy
terminology because we haven't proven it.
But I think there are certainly a lot of arrows pointing to the
idea that perimenopause and menopause lead to accelerated

(46:34):
biological aging in in women. So, yeah, it's again way, way,
way understudied, but people arestarting to pay attention.
And I think I'm encouraged that there's a lot of movement at
least in the right direction. I think that the hardest thing
for me about the the the female hormonal health situation is
just that, you know, because of the Women's Health initiative

(46:57):
and what happened as a result ofthat, we just kind of lost a
generation of experts, right? And so now people are paying
attention, but we'd be so much further ahead on understanding
this if that hadn't happened. But it's good to see that things
are starting to go the right direction there.
And the, and I think the FDA removing the black box warning
on hormone therapy for women is a step in the right direction as
well. So I think there's reason for

(47:18):
optimism, but yes, to me, that is the biggest lever most people
can pull outside of the the lifestyle factors that the the
pillars of health. And then I would say, you know,
avoiding risky behaviors, not smoking, making sure you aren't
drinking too much alcohol, sort of obvious, but but worth
saying. And then I would say being
proactive in your approach to health using the diagnostics
that we have available. And again, this is where I think

(47:41):
we obviously get into healthcaredisparities, you know, but I do
think there's a lot that the average person can do for one to
$200 a month in the realm of proactive preventative medicine.
I think that's about the 8020 right now.
And people should do that because that's a big lever you
can pull to make sure that you don't get sick or if you're on

(48:01):
the path to disease, that you catch it early enough and you
can take steps to get off that path.
So those are the big levers thatI can think of.
I'm sure there are others, but but I guess the other place I
would point that we tend not to think a lot about is mental
health, right? And again, just evaluating,
that's a big part of health and obviously it ties to physical
health, but we kind of put it inthis other bucket.
So if you have mental health challenges, whether it's

(48:25):
depression or anxiety, taking steps to get help and deal with
that is another big lever that you can pull.
And a lot of people do. And again, our culture is sort
of creating this, you know, situation where just because of
the nature of social media and what's happening in the world,

(48:45):
you know, anxiety is an epidemicfor sure.
And so if you're struggling withthat, there are lots of steps to
take. That's getting to an area that
I'm not an expert in. I've learned a lot, but there
are lots of smart people who have advice on how to deal with
anxiety and depression and othermental health challenges that
people face. Being aware and taking action

(49:06):
there I think is another big lever that people can pull.
And then, and so those are the big things.
And then we get into the incremental stuff.
And there are some things that have incremental value, some
supplements that I put in that bucket, particularly
deficiencies that you can fix through supplementation, vitamin
D, omega-3, that might even be in the, it's not a big lever for
most people in my view, but it'ssort of something, it's a no

(49:27):
brainer. You should do it if you can
measure it and you know that you're deficient.
But then when we get into other supplements, there are some
things I think have value, but Idon't think they're going to
really move the needle for for most people.
And there are some things that are going to be individual.
Like I said, rapamycin for me had a big effect.
It had a big effect on my quality of life.
I don't know if I'm going to live longer, but it had a big

(49:48):
effect on my quality of life. I think there are people with
things like rapamycin, SGLT, 2 inhibitors, things like that,
where that becomes much more individual.
It can have a big effect for that individual.
But I don't think there's anything else, at least in the
Jaro protective realm that I would point to that we should
talk about for everybody at this.
Point kind of in that vein, whatare your pet peeves in the this

(50:09):
field? What are the things that I think
can get a lot of crap or get a lot of social media attention
that really don't move the needle?
Yeah, I mean, well, so we already talked about clocks.
Clocks are one of my pet peeves,mostly because of the
misinformation and, and the factthat they're being presented to
people in a, in a way that isn'thonest.

(50:30):
I think honestly, the things that, that, that bother me the
most tend to be the, the, the, the things that are being
dishonestly represented to people and could be harmful to
people, harmful being economic damage or health damage.
So supplements are a big, big, big challenging space.
Like I said, there are some supplements that I believe in.

(50:50):
There are a lot of supplements where I'm just like, I don't
know, maybe, maybe not. The problem in the supplement
space, I think is the deceptive marketing.
And I have yet to find a companythat is selling longevity
supplements that is not lying toconsumers in my view, or at
least deceiving them, intending to make them believe something
that isn't true, even if the words themselves don't say

(51:12):
something that isn't true. So deceptive marketing around
supplements, I think is really, really problematic in this
space. And most people are not equipped
to be able to evaluate that. Related to that, I I am very
concerned about academic scientists who are involved in
selling biological age tests or supplements.

(51:33):
I think that the general public will assume that somebody who
has an affiliation at Harvard orMIT or pick your favorite
university is giving credibilityto the supplement or the test
that they are selling. And then when that is
deceptively marketed to consumers, in my view, that is

(51:53):
unethical and a real problem from that perspective, but also
because it makes the field look bad and and it creates A
credibility problem for the field.
So that's. Credibility as a whole when that
happens, and I think that's we have to answer to patients when
they've kind of been deceived bythis supplement.
I was told this would save my life.
I saw this on TikTok so I boughtit at 3:00 AM and.

(52:18):
You know, in the academic world,I totally get it.
We're not on the academic side. But there's plenty of physicians
who have become spokespeople forvarious things, and they don't
have any real evidence to back up what they're claiming, which
makes it really tough for us to say no.
I'm a doctor too, believe me, right?

(52:41):
Yeah, no, I agree it is it's a real challenge.
And I think obviously I don't have the answers for how you for
how you have those conversations.
I think helping people to recognize what is and isn't
known and where the uncertainty begins and ends.
I think is is probably the best we can do and then try to let
people make their own decisions.But but also, I think pointing

(53:03):
out when people, whether it's, you know, an academic, medical
professional and influencer say things that are demonstrably
untrue, pointing that out and then simply, you know, making
the point, if somebody lies to you once, they're probably going
to lie to you again. Why would you trust this person?
And then it's up to people like they want to continue to trust
these folks. That's on them in my view.

(53:25):
Yeah, I, I think you're right. We touched a little bit earlier
and you'd mentioned something about AI in this space and I
wanted to get back to that. I know we've been leveraging it
a little bit in how we do the work UPS on our patients and how
we analyze the data that comes out of those work UPS.

(53:46):
What are you most excited about,I guess, moving forward on how
AI is going to change things forus?
Because I think there is, I mean, there's broader
implications on just healthcare in general and reducing red tape
and stuff, but I mean specifically in the jurorscience
field. Yeah.
So there's lots of ways I think AI is going to impact

(54:07):
geroscience, just like there's lots of ways it's going to
impact every aspect of life. There are two that I think a lot
about right now. 1 is on the research side, which is more
around how these tools can enable us to interpret these
very, very large data sets to identify either novel
signatures, novel novel patternsor maybe even be hypothesis

(54:28):
generating. And the clocks are an obvious
example of this. This was before, you know that
the the current batch of LLMS and how we see how powerful
those are, but that's how the clocks were developed.
It was was using AI tools to pick out the best in, in the
Horvath clock case, 353 methylation sites out of
3,000,000. That's a clear example there.

(54:49):
Even tools from 10 years ago were useful in identifying these
novel predictive signatures for chronological age in that point.
So those are going to just be continue.
And as we start to generate larger human data sets from
these large population studies, we need those AI tools to be
able to interpret that data and identify correlations and
signatures that would be really hard for individual human beings

(55:12):
to to identify. So that's going to be 1 area,
you know, intervention prediction, maybe using AI to,
to look at what we know about the biology of aging and predict
new drugs or other targets to goafter to slow aging.
That's gotten a lot of attention.
So far I have not seen a single case where an AI predicted
intervention proved out. Doesn't mean it's, it's not

(55:32):
going to happen. I haven't seen any data.
And my concern there is that theintervention set we're working
with right now is so small and limited.
If you put in, you know, rapamycin and SGLT 2 inhibitors
and metformin, you're going to get out things that look like
rapamycin. So we're going to find things
that we already know about. I don't know yet that AI is

(55:53):
going to be super powerful there.
On the clinical side, the area that I I think about a lot and,
and, and we're working on as areothers is much what you
described, right. So using these tools,
particularly the advanced large language models to help us both
integrate the data we're collecting from a whole bunch of

(56:13):
different tests and diagnostics in the context of what's already
clinically established to identify patterns and then
report it back to the doctor andat some point the client in a
way that is useful for them. I am, you know, we've been doing
that for 18 months now since the, you know, the first sort of

(56:34):
iteration of ChatGPT came out internally.
We're not rolling this out to patients, at least initially.
They weren't even close to beingready.
But I have been. And you, this is probably your
experience, too. I have been amazed at how good
the tools have gotten. They're really, really good.
They're not perfect, but human beings aren't perfect.
So I definitely see a time in the pretty near future where we

(56:55):
will have what I call AI Healthspan agents that can do
exactly that, can take all of your data from the different
diagnostics. Optimally, it'll be longitudinal
data you've had over many monthsor years, integrate it, build in
the wearables, the trackables, the real time data and give you

(57:17):
feedback. And so again, this is where I
think we kind of have to wait and see how the regulatory
landscape evolves, how comfortable people are with the
AI tools, how well the AI tools perform, to what extent will
these tools be allowed to give medical recommendations?
Right. At first, they're not going to
be. And I think that's appropriate.
They shouldn't be allowed to at first.

(57:37):
I very much believe right now doctor in the loop is the only
way to go. I am actually concerned about
some of these direct to consumercompanies that sell diagnostics
to people and then don't give them any, any help after that.
So that's a different topic. But I think there will come a
time, and I don't know if it's five years from now, 10 years
from now, two years from now, where people feel really, some

(58:00):
people feel really, some people feel really comfortable with
these tools now. I mean, I'm sure.
I mean, I've put all my data into ChatGPT and said, hey, tell
me what this means, right? So some people just take it as
granted that ChatGPT is going togive you the right answer.
You shouldn't do that right now.But there will come a time when
it's pretty good. And so I don't know what that
looks like, but I can see us getto a point where pretty pretty

(58:20):
quickly, again, two years, five years, we've got these very
powerful AI health span agents that can give you 24/7, 365
feedback and we'll give you recommendations that are
designed hopefully in partnership with your physician
to optimize your health span. I don't think I, I see that path
clear as day where that's going to happen.

(58:41):
I just don't know how long it's going to take.
And I don't know how the regulatory environment's going
to, going to evolve. But optimally, you know, there
will be a collection of physicians who really lean into
these tools and can become the docs who can work in partnership
with these tools, with the people who want to use them that
way. The last thing I'll say on this,
and again, maybe I'm being naive, but I, I, I, I hope not.

(59:04):
I think that this is the opportunity to really deal so
with some of the major healthcare disparities that we
have right now. Because these tools are not
prohibitively expensive. Everybody in principle should be
able to have access to at least a rudimentary healthspan agent.
Now, they may not all be able tohave access to the best docs in
the world who can help them use those tools, but I think it's
going to be better than what most people get right now.

(59:26):
And then it's going to be very much up to the individual.
Do they want to use those tools and do they want to do the
things that the tool tells them they need to do to optimize
their health span? There's good obviously a huge
behavior modification piece, butI do think this is a real
opportunity to address a lot of the health healthcare
disparities that are out there. It's not going to fix everything
for sure, but I think it can, I think it can be a big help.

(59:48):
So I'm I'm really excited about the where where things can go.
I think you're right about that.Your last sentiment, it's
interesting. I mean, it's not like people
don't fundamentally understand that they should eat properly or
exercise and sleep better and cut the alcohol.
But having someone tell you exactly how to do those things

(01:00:10):
is much more valuable. And.
Why you're doing those things rather than just having the
basic knowledge that smoking is bad and I should sleep 8 hours a
night. And that's where this AI think
does get interesting because it is pretty good at at giving you
a plan. If you give it proper input
data, it spits out a plan that can be pretty evidence based,

(01:00:33):
and at least it's a good starting place for people, which
I think is pretty interesting. And it's come a long way.
We started two years ago and this, the technology, this
wasn't even around. And each month it just gets
better. Yeah, they upgrade Squad or
ChatGPT and it's like Oh my gosh, this same thing took like
2 days three months ago and now it's doing it in we.

(01:00:56):
Were like I wish it would do XY and Z and then two weeks.
Later, Boom. It heard you.
Yeah, yeah. The only thing I would add to
that, I think you're right. Most people do in general know
what they should be doing. But I think when it comes to the
specifics, like you're saying, it helps to have somebody tell
you in detail what you should bedoing.
I think when it comes to the specific, I'm still often
surprised at how many people I don't know the things that I

(01:01:19):
sort of take for granted right now that I'm, you know, I've
been in this space for for a while.
Even simple things like being able to read a nutrition label,
walk through the store and understand, you know, where are
the added sugars, right? Those are things where these AI
tools also can be quite, quite helpful.
And you know, again, depending on how you use them, potentially
could tell you in the moment like, OK, that particular

(01:01:42):
product is not aligned with yourhealth goals.
Why don't you consider this alternative, right?
Or, you know, you're in your car, you're wearable, detects
that you're blood pressure has spiked when we get, you know,
continuous blood pressure monitors.
And it's like, I can see that you seem to be stressed out.
Perhaps you should consider deepbreathing, you know, whatever

(01:02:03):
the technique is. So the sort of just like in the
moment, deescalate that sort of stress before it gets to the
point that that, you know, it creates a, a major event for
your day, or maybe even a major event in terms of a heart attack
or something like that. So I think there's all sorts of
ways this, this could evolve. People are going to be
uncomfortable. Some people are going to be
uncomfortable with the idea. Some people are going to be

(01:02:23):
uncomfortable with the idea thatthe AI might be manipulating
you. Like is it, is it controlling
your behavior to get you to calmdown?
But I would argue that's probably a good thing If it's as
long as it, I would think of it,it may be as more like emotional
tuning. So I'm just, I'm interested to
see how this evolves. But I but I think there's a lot
of opportunities here. It's a benevolent AI.
Yeah, hopefully. I always say thank you when I

(01:02:45):
use ChatGPT because when they take over the world one day, I
just want to be remembered as I was.
I was always gracious. You're on their team.
Yeah, you. Yelled it.
There's all sorts of interestinghuman psychology and behavior
that goes into to using these tools.
Every once in a while, I find myself feeling a little
embarrassed about the question Iasked ChatGPT.
And then I'm like, no, wait a minute, it's just a, it's just

(01:03:06):
ChatGPT. I'm going to need to be
embarrassed about it. There's so many different
wearables right now. Are there ones that you use?
I mean, I've used aura ring for sleep tracking.
I personally found that with aura ring, I felt like there's
about a six month value proposition there for me
personally. And then I kind of knew what I,
what I knew. I use my Apple Watch all the
time to track, you know, my workouts and, and things like
that. That's really the only wearable

(01:03:28):
that I use a lot is my Apple Watch because it just does so,
so much. But again, I think it's a very
personal thing and, and what you, what you are most
interested in, You know, I, if there was a really good, I think
continuous blood pressure monitor, I'd, I have, I don't
have blood pressure, I don't have high blood pressure.
So it's not an issue for me, butI'd want to try it.
I do like CGMI do do that periodically.

(01:03:51):
I think that's a very useful behavior, educational and
behavior modification tool. I don't think it's something
people need to do all the time, continuous glucose monitoring,
but I do it now. I do it maybe once every six
months just to kind of, you know, see where I'm at.
And I always learn something newevery time I I use CGM.
I'm kind of on the same page as you.
I also like the latest the latest Airpods.

(01:04:15):
You don't have to wear a heart rate monitor anymore because
when you're exercising they're pretty good.
I've attracted versus like a chest strap and it's almost
identical data, so it's super helpful when I'm doing zone 2
and zone 5 exercise. What other questions do you
have? Can I tell you something?
I'm going to delete this from the podcast.
I had a dream last night about not that kind of dream and I

(01:04:38):
woke up and I was like because he yelled at me in the dream and
he's like why are you so nervous?
Literally like had a nightmare. That that you yelled at her.
No, they knew that I yelled at me.
For being nervous. Or no, just in general.
It was something like, I was so worried about the technology
because we're good at seeing patients.

(01:05:00):
I would say technology's not in our wheelhouse.
Well, here you go, you can use this.
What the hell is wrong with you?That's gonna be on the intro.
That's great. I wanted to ask a little bit
just because I know this is nearand dear to your heart.
With the dog aging project with NIA funding and everything

(01:05:25):
getting messed up with the changes in government, where is
it at right now and and what arethe plans for when it's going to
be completed? Sure.
So first of all, may be useful to just define the dog aging
project and the and the overarching goal.
So there's really two parts to the dog aging project 1 is a
large longitudinal study of aging.

(01:05:46):
It's purely observational where we are just following dogs
living with their owners and collecting as much data as we
can about the dogs, mostly through owner surveys, some
through veterinary records, somethrough biological samples.
So genome, epigenome, metabolome, things like that.
And that's about 50,000 some dogs in the longitudinal study
today. Then there is the smaller

(01:06:07):
clinical trial, which is a randomized double-blind
placebo-controlled veterinary clinical trial of rapamycin that
currently is about 250 dogs. It will eventually be more than
500 dogs, half rapamycin, half placebo.
There the goal is to determine does rapamycin increase lifespan
and slow aging in dogs. So in the initial grant which

(01:06:29):
was funded in 20 end of 2018, those two parts of the project
were Co funded. They were both funded by the
large grant from from NIA. That grant ended in 2023 and was
not refunded. And you know, I have my feelings
about that. As you can imagine, I would say
lots of swear words if we talkedabout it.

(01:06:49):
So we shouldn't talk about it. And, and, and it took a couple
of years to get the clinical trial refunded.
That has since been refunded. So that is enrolling.
It's a five year grant. The trial will be done before
the before the grant ends. So that is going to get
completed. The longitudinal study has not
yet been refunded. The grant was submitted a month
or so ago. So fingers crossed, hopefully it

(01:07:12):
will get refunded. We managed to keep the lights on
through philanthropic funding. We have a nonprofit called the
Dog Aging Institute. It's a 5O1C3 dog
aginginstitute.org shameless plug if anybody wants to support
it. So that kept the lights on and
allowed us to keep at least the core team intact.
So hopefully, like I said, the longitudinal study will be
refunded and that will allow that project to to continue for

(01:07:34):
another five years. The other thing I'll say on this
topic and, and again, whether it's done through the dog aging
project or in the private sector, I don't, I don't really
care. I do think it is a a message I
want to communicate to people that slowing aging in our
companion animals is a solvable problem.
In five years, we know probably 20 things that slow aging in

(01:07:57):
laboratory animals and we can measure it.
We know how to measure it. We can do this safely.
We can test these things in companion animals.
I can't say with 100% certainty,because I'm a scientist, that
some of those are going to work in dogs, but some of those are
going to work in dogs. It's going to be the case.
We could solve that problem. This is just a resource
allocation problem. If people care about their
companion animals, we could do this.

(01:08:19):
I don't know how much it would take, but it would take less
than $100 million. That sounds like a lot of money.
But if you look what we spend $100 million on crazy stuff all
the time, that's a drop in the bucket.
So this is all just to say this is this is only a resource
allocation problem to increase healthy lifespan in our
companion animals by 20 plus percent.

(01:08:40):
Seems to me like it's a no brainer.
Somebody needs to do this. Some rich person needs to get
off your ass. If you care about your dog and
do this, OK, That's my message. Any rich people listening, this
is what you're going to do. Yeah, just imagine how much you
would be beloved if you slowed aging in people's companion
animals. This is worth it.
Go do it. And I don't have to be involved,

(01:09:02):
but I'm happy to tell you how todo it if you want to know.
You know, dogs age faster or have a shorter lifespan than we
do. So it's easier to track over a
period of time than it is in humans.
What other biometrics are are you going to be tracking in the
in the intervention and the and the placebo group?

(01:09:24):
Yeah. So two things to say about that.
I'll talk about all the things we're measuring in a second.
So you mentioned dogs age faster, which is absolutely
true, right? The other piece that it makes
dogs very powerful for this kindof a study is they share our
environment, which we can't. We can't, you know, recapitulate
in the laboratory. In fact, we try really hard not
to. We try to control the
environment. So that's another I think
important aspect here that makesthis informative about human

(01:09:48):
biology as well. OK.
So in the trial lifespan is the primary endpoint.
So that is what we are statistically powered for.
Again, this depends a little biton the demography.
And so that's it's a little bit of an estimate, but we believe
we are statistically powered to detect a nine percent change in
lifespan, which is towards the lower end of what's been
reported for rapamycin in mice. So that's why we have the the

(01:10:10):
size of the study and the enrollment criteria that we've
got. That's the primary endpoint.
Secondary endpoints include heart function measured by
echocardiogram. That's because in mice, several
labs have seen improvements in age-related heart function from
rapamycin treatment, neurological function measured
through a bunch of different neurological parameters,
activity, disease incidents, andthen we have exploratory

(01:10:33):
endpoints. Oh, and cognitive function as
well for secondary endpoint. Then we have exploratory
endpoints looking at things likemetabolome, microbiome,
epigenome, blood chemistry, inflammatory markers, things
like that. So we're trying to take as broad
a look as we can given the constraints of working in
companion animals and funding. So take as broad a look as we

(01:10:56):
can at at Health Span. One of the challenges people
often don't appreciate about doing these kinds of studies in
dogs is that many of the reagents, I'm talking about
things like antibodies or Elizasthat we would use for
quantitative measurements. We have them for humans and we
have them for mice, but we don'thave them for dogs.
So there are things we would like to measure that we just

(01:11:16):
can't measure in dogs because because the reagents haven't
been generated for veterinary medicine.
But the majority of things that we are interested in looking at,
we can measure in it within the context of the clinical.
That's pretty cool. I think we're going to be super
excited to see the results once you're once you're done with
full enrollment and you're getting down to that five year
mark. And Everett, who doesn't love
dogs? I mean, you would probably win a

(01:11:39):
Nobel Peace Prize for. That there's someone else vying
for. That I mean, yeah, I would just
be, I would just be happy to like be able to demonstrate we
can slow aging in ducks. And again, I mean, look,
everybody's got an ego. I would love to be the person to
do it, but honestly, I'll be happy when anybody does it.
And I think that one of the things that has been really

(01:11:59):
great is to see that the template that we built at the
dog aging project is now starting to be moved into the
private sector. So companies like Loyal that are
going through the FDA approval process for aging in dogs.
That's really encouraging and and exciting.
And so like I said, this is a solvable problem.
We'll get there. We could get there in a few

(01:12:21):
years if people would actually put a relatively modest amount
of resources towards this all. Right.
Well, this was awesome. Yeah.
Thank you so much. I.
Enjoyed it you made our day truly.
We appreciate you being such a prominent voice in the longevity
space. I think there's a lot of
charlatans and people with ulterior motives selling things

(01:12:43):
and you brought so much credibility and just truth to a
newer space and medicine and we're so grateful for that.
So if our listeners who want to learn more about you, you're
work, the Dog Aging project, want to know more, where can
they find you? Yeah, so best place is the Opti
Span podcast, which is on YouTube.

(01:13:03):
OPTISPAN, it's optimal health span just mashed together, lots
of content there. If you enjoyed this, there's
plenty more where that came from.
I'm also on Instagram at MK Rely.
I'm also on X, but I'm not very active on on X these days at MK
Rely. Dog Aging Project is Dog
agingproject.org. If you have a dog, we're still

(01:13:24):
enrolling dogs into the longitudinal study.
So I'd absolutely encourage you,if you want to participate in
Science of Longevity, nominate your dog to participate in the
study. If your dog meets the criteria
for the Rapamycin trial, we're still enrolling dogs into that
as well. So you could potentially
participate in the clinical trial as well and definitely

(01:13:45):
would encourage anybody who's a dog lover to think about doing
that. Geographically, where do they
have to be? So in the United States, that's
it, although we do have a limited number of clinical
sites, there's about 21 or 22 atthis point.
So obviously it's easier if you live close to one of the
clinical sites. So the dogs come in for the
clinical trial once every six months.
I should clarify though, that's only for dogs that are in the

(01:14:07):
clinical trial. For dogs that are in the larger
longitudinal study anywhere in the United States,
unfortunately, it's not yet international.
I wish it was. Someday we'll get there, but
right now any dog in the United States can participate in the
longitudinal study. And then there are eligibility
requirements and geographic location near 1 of the clinical
sites for the clinical trial. Awesome.

(01:14:29):
Awesome, Matt. Thank you so much.
You're welcome. We really appreciate you being
kind of the adult in the room ofthe longevity.
Spirit, I wish I could be the little kid in the room.
There are days. Well, then we wouldn't need
longevity, right? This has been awesome.
Thank you so much. Hopefully we can have you back

(01:14:50):
on at some point. Thank you, that's been a lot of
fun. All right, all.
Right, we'll let you know if Nisha has any more nightmares.
Hopefully not. I don't enjoy being in people's
nightmares. All right, take care.
Take care guys. Thank you for playing the long
game with MD Longevity Lab. You can visit us at
www.mdlongevitylab.com to learn more about how we can support

(01:15:14):
you on your journey. Stay connected with us on social
media at MD Longevity Lab for tips, updates, and behind the
scenes insights. If you enjoyed today's episode,
we'd love it if you subscribe, left us a rating, or shared it
with someone you know who's alsoplaying the long game.
Thanks for listening, We'll see you next time.

All Episodes

Episode Transcript

Popular Podcasts

Stuff You Should Know

SmartLess

My Favorite Murder with Karen Kilgariff and Georgia Hardstark

.css-15opob5{left:0;position:absolute;top:0.8rem;} All Episodes

.css-14f5ked{margin:0;word-break:break-word;display:-webkit-box;-webkit-box-orient:vertical;box-orient:vertical;-webkit-line-clamp:2;overflow:hidden;}19. Biological Aging Clocks, mTOR & Rapamycin: A Reality Check with Dr. Matt Kaeberlein

Episode Transcript

Popular Podcasts

.css-r6mb8g{margin:0;word-break:break-word;display:-webkit-box;-webkit-box-orient:vertical;box-orient:vertical;-webkit-line-clamp:1;overflow:hidden;}Stuff You Should Know

SmartLess

My Favorite Murder with Karen Kilgariff and Georgia Hardstark

All Episodes

19. Biological Aging Clocks, mTOR & Rapamycin: A Reality Check with Dr. Matt Kaeberlein

Stuff You Should Know