September 5, 2025 • 40 mins
In a fascinating and insightful discussion, I sat down with Dr. Jon Brudvig, a medical scientist and expert in neuroscience and drug development. Together, we explored the science of aging, the critical role of cellular recycling, and the practical steps anyone can take to improve their healthspan. Jon Brudvig shared his journey from rare disease research to longevity science, offering actionable insights into how our daily choices impact the aging process. Such a good conversation, I have split it into two parts.
What You'll Learn:
The Cellular Foundation of Aging:
Discover how Dr. Brudvig’s research into lysosomal storage diseases led him to understand the universal decline in cellular recycling (autophagy and lysosomal function) as a key driver of aging.
Autophagy Explained:
Learn why autophagy—the body’s process of breaking down and recycling damaged cellular components—is essential for health, and how modern lifestyles can disrupt this natural cycle.
The Fundamentals of Longevity:
Understand why exercise, diet, sleep, vitamin D, omega-3s, and real-life social connections are the true building blocks of a long and healthy life.
Mouse Models and Human Longevity:
Gain perspective on the limitations of animal studies in longevity research, and why findings in mice don’t always translate directly to humans.
The mTOR Pathway and Protein Intake:
Explore the debate around the mTOR pathway, protein consumption, and how balancing periods of growth and rest may be the key to optimal aging.
Healthspan vs. Lifespan:
Reflect on the difference between living longer and living better, and why increasing your years of good health (healthspan) is a more realistic and valuable goal than chasing extreme longevity.
Key Takeaways:
- Aging is cellular: The decline in lysosomal and autophagy function is a core driver of aging and disease.
- Autophagy matters: Fasting, exercise, and periodic stressors help trigger the body’s natural recycling processes.
- Master the basics: Exercise, a balanced diet, quality sleep, and strong social ties are the most effective longevity interventions.
- Be cautious with quick fixes: Not all supplements or drugs that work in mice will work in humans—focus on proven fundamentals first.
- Balance is key: Intermittent activation of growth pathways (like mTOR) through meals and exercise, balanced with periods of rest, supports healthy aging.
- Protein quality counts: Mix your protein sources and prioritise whole foods for optimal health outcomes.
Connect with Dr. Jon Brudvig for more insights into longevity and health:
LinkedIn: Jon Brudvig
Substack: https://jonbrudvig.substack.com/
00:53 Dr. Brudvig’s Background and PhD Focus
01:22 Gene Therapy and Lysosomal Storage Diseases
02:45 Connecting Rare Diseases to Aging
03:10 Lysosomal Function and Aging
03:40 Professional Work in Drug Development
04:01 The Link Between Professional and Personal Interests
04:22 The Role of Lysosomes in Autophagy
04:40 What is Autophagy?
04:54 Why Autophagy Matters for Cellular Health
05:07 The Recycling Analogy: Cells as Master Recyclers
05:26 Evolutionary Importance of Autophagy
06:14 Autophagy, Fasting, and Modern Lifestyles
07:07 The Impact of Modern Comfort on Health
07:28 Social Media, Longevity, and Biohacks
08:00 The Interventions Testing Program Explained
08:42 Mouse Studies and Their Limitations
09:32 The Importance of Fundamentals: Exercise, Diet, Sleep
10:22 Omega-3s and Social Networks for Longevity
11:00 The Hallmarks of Aging
11:40 Homeostasis and the Aging Process
12:20 Healthspan vs. Lifespan: Which Matters More?
13:07 The Two Camps in Longevity Science
13:51 Promising Interventions: SGLT2 Inhibitors and Rapamycin
14:45 Rapamycin: Hype, Dosing, and Human Application
15:53 mTOR Pathway, Protein Intake, and Longevity
17:00 Balancing mTOR Activation and Autophagy
18:00 Practical Protein Advice: Whey, Collagen, and Plant-Based Sources
18:45 Final Thoughts: Eat Real Food and Mix Protein Sources
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:08):
Doctor John Brudwick. Welcome to the podcast.
Speaker 2 (00:10):
Thanks Ball, thanks for having me.
Speaker 1 (00:13):
This is take three. I think this kind of used
to this because of issues with recording software, and I've
now defaulted to good old zoom, so we'll see this case.
Yeah zoom, Jim, just one right, which is the good thing,
(00:33):
So give on this. So, actually, the reason that you're
on is that I read a LinkedIn post of yours
and it was on plastics and microplastics and really interesting,
and I thought, I don't read a lot of stuff
on LinkedIn, but I read your article right today and
then I started looking at some other articles you posted
and went, this is an interesting cat. I've got to
(00:55):
get them on because you're interested in the stuff that
I'm interested in. But you're actually in the field quite
a bit, and I think you're probably jugged deeper into
it than I have. So we're going to talk about
all things the science of egen. But tell our listeners
what your PhD was in, what your backgrounds in, what
(01:16):
you do now, and how that sparked your interest in
this field of longevity.
Speaker 2 (01:21):
Absolutely.
Speaker 3 (01:22):
Yeah, So in my background and my PhD or podical science,
I did a neuroscience PhD looking at a really nitty
gritty detail of molecular development of the brain, the forebrain.
So this was like really basic science, really interesting, but
very different from what I do now. But while I
(01:43):
was doing that sort of another project I got to
help with was developing these gene therapies for rare.
Speaker 2 (01:49):
Lysisolmal storage diseases.
Speaker 3 (01:51):
These are diseases where you have mutations in a gene
that's important for the function of your lysism which is
like the cellular recycling center, and if you have these
genetic mutations, your lysismes can't work and it's completely devastating.
They you know, depending on which tissue is most affected
by the specific gene that's absent.
Speaker 2 (02:15):
You know, they're devastating diseases. You lose function of that
organ or tissue.
Speaker 3 (02:20):
In many cases you face premature death, really severe disability.
So these devastating disorders that we were trying to cure
with genetic based therapies had a lot of success there.
But as I got deeper into that space, I started
of making these connections to all the longevity stuff that
(02:40):
I was reading on the side, which was you know,
a long standing interest of mine, and realizing that these
diseases of lysosomal dysfunction. They're really just severe examples of
what's happening to all of us as we get older.
Your cells and my cells don't look the same as
(03:01):
they did when we were twenty They're not going to
look the same in twenty years from now, and a
big part of the reason why is that our lycisms
aren't functioning as well as they used to. So, you know,
we don't have these genetic deficiencies, we don't have these
severe issues that result in disease, thankfully, but they're certainly
not working as well as they used to, and it's
(03:22):
a major driver of a lot of the cellular damage
that characterizes aging and decline. So that kind of brings
it all together, you know, in terms of how I
got here and why I'm interested in now and what
my sort of angle is in this longevity space. It's
really understanding how all of these different interventions impact our
(03:42):
cellular health, largely through our lysism, sometimes through other pathways.
And then of course in my professional career, I developed
drugs for these diseases with amarchist therapeutics and with some
academic partners. Yeah, so it's sort of a nice link
between my professional and personal interest.
Speaker 1 (04:03):
Yeah, and look, the cellular stuff is where it's all
that really when it comes to eating and disease.
Speaker 2 (04:08):
That if you're a so biologist, it is, yes.
Speaker 1 (04:11):
Yes, absolutely, and yeah, my daughter would be in violent
agreement because she is studying now biomedicine and loves everything
to do with sales and cellular biology. But and lysisols
presumably they have a major role in autopogy. Absolutely, yeah, yeah,
can you just explain for our listeners autoplogy and why
(04:35):
it is so important at a cellular you know, and
at an overall function level.
Speaker 3 (04:40):
Absolutely so so ourselves. I think a good bonology maybe
is a house or a car. You know, we have
all of these different components that have to function together
in a really intricate and complex way, but they don't
last forever. Stuff wears out right, So that's true of
every cellular component, every cell in your body. Nothing lasts forever.
(05:02):
It accumulates damage. When we talk about reactive oxygen species
and ultraviolet light.
Speaker 2 (05:09):
You know, different sources of damage.
Speaker 3 (05:10):
What that really means is it means that the components
that make.
Speaker 2 (05:14):
Up your cells are deteriorating.
Speaker 3 (05:17):
You know, it's at the molecular level, the molecules that
make up our cells degrade, and of course our cells
have evolved ways to deal with We don't want to
have this broken machinery sticking around any longer than it
needs to. Autophogy is the process by which it's one
of the processes by which cells take that material, break
(05:39):
it back down into the nails and boards and all
of the different raw materials, and then reuse it again
to build things fresh. So autoplogy literally, it's it's the
process it's self eating, that's what the word means. And
it's it's taking those cellular components, chopping them up and
this all list building blocks that the cells can make,
(06:02):
which could be amino acids or sugars or other metabolites,
and then using them as a fuel source again, using
them to make new new materials that don't have these
problems with damage and they can function better. And and
this is something that's happening all of the time in
every cell in your body.
Speaker 2 (06:21):
The link between autopogy and the lysisome.
Speaker 3 (06:25):
The lysosome is the terminal destination of everything that's going
through autopogy. So gotcha, when the cell autopogy, you could
think of like the collecting process the garbage truck. Garbage
truck going out picking up all of the waste and
then it's delivering it to the lysosome. The lysosome is
the dump or the recycling center is a better analogy.
(06:46):
So it's you know, they're really two ends of the
exact same process. You can't talk about one without talking
about the other. Autopogy is more of a buzzy word.
They get the lot more attention, yes, but it's it's
it's really you know, the lycism is is why we
have autoplogy. It's to bring things to the lysisme. So
I think it's it's just as important to look at
(07:07):
that side of things.
Speaker 1 (07:08):
Too, and from us at a cellular perspective, we are
just master recyclers, aren't we, Like our salves do much
better than we do as as species as humans in
terms of recycling.
Speaker 2 (07:21):
Oh, it's incredibly efficient.
Speaker 3 (07:22):
We have to be I mean it's it's you can't
be taking every nutrient you need all the time, right,
some things are only available periodically, it's and we have
to be able to get those materials from somewhere. To
keep all of the cellular processes functioning the way they
need to. So yeah, I mean it's it's evolutionarily very ancient,
(07:44):
and it's widespread throughout all the kingdoms of life, and
it's it's an essential process. If you stopped doing that,
you'd be dead very very quickly. Yeah.
Speaker 1 (07:55):
They It is really interesting, isn't that? The stuff that
evolutionarily conserved is this stuff that is core, absolutely core
to to life. Really whenever you see it across species
and a cross timelines, you go, this is a fundamental
trick of nature, right.
Speaker 2 (08:17):
WHOA absolutely yeah.
Speaker 3 (08:18):
And it can be interesting to look at the species
differences sometimes too. I think, you know, maybe we'll talk
about male studies in longevity later, but you know, lysosomes
and autopogy, they're they're different between species two and sometimes
that can offer hints into you know.
Speaker 2 (08:37):
What might be some of the drivers of disease.
Speaker 3 (08:39):
But yes, very very conserved, and that hints at the
importance just like other pathways like like insulin or you know,
any longevity, these are all deeply conserved pathways.
Speaker 1 (08:50):
Yeah. And I think the people who would be most
familiar with satophogy would be people who've engaged in intermittent
fasting and particularly prolonged fast. I mean, a lot of
the research is saying I mean, at least my understanding
of it is that some of the benefits, particularly if
you get into the four day plus water fast, is
(09:13):
that autophogy or ramps up massively, and not only within
the cells or the mitochondria as well. So we've got
mitophogy within our mitochondria and then we've got cellular stuff
in it. Basically, the way I explain it is that
you go through a complete spring clean in your body
(09:33):
and eat up dysfunctional cells and just recycle it. It's very
very clever, isn't it that in times of poor food
availability that our body would go right, well, now I'm
going to do this cellular spring clean that has a
double advantage. Number One, I'm going to remove damage celles
that our sinesseenor could become cancerous. But secondly, I'm actually
(09:57):
going to get a whole heap of energy from that
recycle process.
Speaker 4 (10:00):
It's pretty freaking colon, absolutely, and I think it's it's
important to think about it too in terms of evolution
and where we've been as a species and where we
are now.
Speaker 2 (10:11):
We we evolved.
Speaker 3 (10:12):
To function with periodic times autoplogy on a regular basis,
and we don't always get that anymore. And I think
it is, you know, it's it does get some attention
we talk about modern lifestyles and how they're detrimental for
our health, but I think this is one of the
key reasons why, the fact that you know, everything evolved
(10:36):
to function with autopogy happening at regular intervals, whether that's
overnight after a number of hours of fasting, or periodically
with longer fests, or whether it's for long durations of
endurance exercise.
Speaker 2 (10:47):
It's all the stuff that we don't get anymore. So
if not autopogy process isn't being triggered.
Speaker 3 (10:52):
To the same extent, and you know, we just talked
about why it's so important, So if that's happening less,
that's that's a very bad thing.
Speaker 2 (11:00):
And I think that's why so many.
Speaker 3 (11:02):
Interventions that seem to extend health span and lifespan they
have a common threat of activating.
Speaker 2 (11:08):
Utopogy and boosting lysosomal function.
Speaker 3 (11:11):
And I think it's, you know, it's it's not an
accident that that's the antidote to sort of the modern
lifestyle we have. I think it really, really is a
key driver of some of the disease and dysfunction we're
seeing today. Yeah.
Speaker 1 (11:28):
Look, I wrote a book called Death by Comfort about
why modern life is killing us and what we need
to do about. And part of that is that we're
not living in accordance with our genome anymore when we're
in this environment of just constant comfort, which also includes
constant food availability and a lot less necessity to actually
(11:52):
move and do these sorts of things. But you touched
on my studies a lot of the there's a bocket
heap of research being done in the longevity space, right.
So there's I think of this as two different areas. Right.
There's the stuff that people will see in their social
(12:13):
media feeds, right, And anybody who's listening who's got any
interest in longevity, I'm guessing that their social media feeds
are full of NMN, n R and a lot of
these other molecules that are out there, or dietary interventions
or hacks biohacks. Right. But there is some very serious
(12:37):
testing going on in terms of longevity, and this is
the Intervention Testing program, right, So I know you're very
familiar with that program. And basically, just for the listeners,
this is a multi site program, which is really important. Right,
You've got a number of different research labs doing the
(12:57):
same thing at the same time. And you mentioned mice. Now,
I get really frustrated when I see these clickbit headlines
about diet and then you find out that the study
was done on mice, right, which are not small humans? Right,
And I think it's really important for people to understand
(13:19):
that the mice that are used in most studies are
are basically interbred, genetically interbred. The mice that are essentially
you're studying one individual clones there, clones, right, and and
so this should be ridiculous, like doing one an experiment
(13:39):
on you and then trying to make widespread assumptions for
all of human kind iss insane And you're one of
our species.
Speaker 3 (13:49):
Absolutely, And it's saying it's even worse than that, because
it's not just that they're clones.
Speaker 2 (13:53):
They're clones of a very weird mouse.
Speaker 3 (13:56):
This is a genetically normal mouse the way they exist
and have existed for many millions of years. This is
a highly inbred stick mouse that has some very unique
genetics and physiology.
Speaker 2 (14:12):
So it's yes, it's a big problem.
Speaker 1 (14:14):
Yeah. Yeah, Now so the Interventions testing program has addressed
that because they use genetically diverse mice as well, and
they do rigorous testing of a number of different molecules,
and that has has really turned up some interesting candidates
(14:34):
right for potential longevity. But before we dive into all
of that, which I do want to dive into, because
we I think we can, we can bounce off some
of the stuff that's come out of that. I will
often say to people, and I'd love to get your
thoughts on this, that that.
Speaker 5 (14:53):
Before we get into any of this stuff, we need
to get our house in order, and for me, getting
your house in order, the fundamentals would be exercised.
Speaker 1 (15:05):
I think there's nothing comes anywhere close from a longevity
perspective as extra particularly in humans so far. That is diet,
And for me, the major thing a diet is controlling
insulin and reducing your ultraprocessed food consumption and getting adequate sleep.
And I think getting your vitamin D at a good
(15:26):
level is really key. And the other one that I'm
interested in that I think everybody should be interested from
a nutritional perspective is having good Amegia three levels in
your bloods and a Mega three score of e it.
Those who have at a Meiga three index of it live
about five years longer than people within a Meiga three
index of five. Right, I've never seen anything like that
(15:48):
in nutrition. So for me that I say, they're the fundamentals.
Get your house in order. Otherwise all of this other
stuff is all icing and no cake.
Speaker 2 (15:59):
I think that's a very way to put it. Yes,
you're gonna find agreement from me, especially on exercise and diet.
Speaker 3 (16:07):
It sounds like we view diet through a very similar lens.
An important thing to do is minimize blood sugar spikes,
and that agrees with everything we know about the longevity
and cellular health. So yeah, I mean I I can't
disagree with any of that. I'm also very interested in
omega threes. I think it's been interesting to watch that
(16:29):
field of all. As we've we've learned sort of the
relative contributions of Dha and EPA, which are two of
the major species that are in something like a fish
oil supplement. Emergen data is suggesting that it turns out
EPA is perhaps even better than DHA, which for a
(16:49):
long time you could find a lot of resources suggesting
the opposite opposite.
Speaker 2 (16:54):
Yes, but yeah, I think.
Speaker 3 (16:56):
A high EPA fish oil supplement makes a lot of sense.
And yeah, I think the one piece that that I
would add to that that there is a lot of
data on but doesn't get discussed as much, is having
a robust social network.
Speaker 1 (17:13):
Ah yeah, yeah, absolutely, hundred percent.
Speaker 2 (17:15):
Real life social network, not an online social network.
Speaker 1 (17:18):
Yes, we are violent agreement. And actually I wrote a
chapter on that of my new book because I think
it's hugely important. I mean, I think loneliness. I think
it's as bad for your health as smoking at least
ten cigarettes today. It's just crazy. Yeah. And so look,
if we get back to the interventions testing program via
(17:39):
a little diversion, right because I think I'm talking about
the hallmarks of aging, I think it would be quite
interesting here. So some of my listeners will be familiar
with this because I've talked about it before. I say,
I can't remember. It was two and thirteen or twenty
fourteen there was a paper released on the hallmarks of aging,
and there was nine of them then, and then I
(18:00):
think the same research group at it another three recently
about a couple of years ago. And I think what
was autophagy disabled autopity is that is that in the
original one or the newer one. I'm pretty sure.
Speaker 3 (18:14):
That it's I want to say that that's in it
wasn't the original, but I'd have to go back and
check to be honest.
Speaker 2 (18:20):
Yeah, but that's the routine.
Speaker 3 (18:23):
That is being discussed a lot too, that that isn't
in that more recent update. But I think there's pretty
widespread agreement to that. That changes to the extracellular matrix,
so the the area in between ourselves, you know, that's
probably should be added.
Speaker 2 (18:38):
As a homework too.
Speaker 3 (18:39):
But yes, it's as we learn more and it's going
to continue to grow.
Speaker 1 (18:43):
Ill absolutely the whole mark. But but these are things.
These are like the major and processes I guess you
could say, are mechanisms by which we age and and
you know, some of them have proponents are like this
is the one, and then other people are like, it's
a lot a lot of them, right, and things like
telling me are shortening, stem cell exhaustion, loss of protiostasis,
(19:06):
disregulated and nutrient sensing, you know, and disabled atophogy. That
now your view, what is your I actually heard a
really interesting it was Peter A. Tia interviewing somebody who's
been in this space for decades. It wasn't Matt Kamberlin.
(19:27):
He used to work with Matt Chamberlin, and he said
that he thinks that the major driver of aging is
disturbed homeostasis and all of these hallmarks are a result
from homeostasis going wrong in the body. And I thought, wow,
that's a really interesting take. And as he described it,
(19:48):
you know, we have these homeostatic mechanisms that are very
efficient when we're younger, and as we get older, and
of sometimes we don't bounce back into home ostheesis, and
you know, we pop over a hell and that's where
we get disease or dysregulation or some of these pathways.
Have you heard anything around the gast theory and what's.
Speaker 2 (20:10):
Your calling on it.
Speaker 3 (20:13):
I think disrupted homeostasis is clearly something that is integral
to the aging process. I guess my question would be,
is what's causing that discress? Yes, And I think if
you go up a step from there, I think there's
a strong argument to be made that the aging is
the accumulation of damage.
Speaker 2 (20:34):
Yeah, it's structurally molecularly damage.
Speaker 3 (20:39):
It's you know, things that the structure not being where
it needs to be and then function follows from structure.
So if the structure is disrupted, that's you know, the
function the homeostatsis is what suffers.
Speaker 2 (20:53):
So yeah, I think this is all.
Speaker 3 (20:59):
There's not one drive of aging, and there's not one.
Speaker 2 (21:02):
Hallmark that is more important than the others.
Speaker 3 (21:05):
It really is an integrated picture where all of these
things are influencing everything else, and one key thread running
through all of that is disrupted homeostasis. Yeah, the systems
and the ways that the stell tries to keep everything
functioning properly, they break down.
Speaker 2 (21:21):
Yeah, they stop looking as well.
Speaker 3 (21:23):
And when that happens, then you start accumulating more damage
because you're not repairing it as efficiently and you're not
preventing it. And it, yes, very it's a cyclical process.
Speaker 2 (21:32):
Where everything's influencing everything else.
Speaker 1 (21:35):
Yeah, And basically it's very hard to get away from
that high level overview that aging is just a process
of to then almost inevitable process of damage. And so
to that point, it's really interesting because there seems to
be two lines of thought in this space. Right. There's
(21:57):
a bunch of people whose meage focus is on enhancing lifespan,
and then there's another bunch of people whose major focus
is on enhancing health span. What's your intuition say about
what we're going to be most successful lot, because my
(22:18):
personal one is we are going to be able to
influence health span way more than lifespan. I think live span.
These people who are talking about escape velocity and we're
going to exceed that, I think they're in l lah land.
But you might think differently.
Speaker 2 (22:37):
No, I don't like this escape velocity thing. I think
it it to me.
Speaker 3 (22:42):
It feels like all of these singularities that we talk
about across different fields that haven't come to fruition, and
I don't think. I mean, I don't know, maybe escape
velocity is real, but if it is, we're a long
ways away from it in terms of longevity.
Speaker 2 (22:58):
But yeah, I think you summed it up well. They're
they're kind of our two camps.
Speaker 3 (23:02):
There's there's one camp of very intelligent, passionate people that
are are laser focused on radical extension of human life span.
So they, you know, they want to push the maximum
life span out, which you know, that's a tough to
argue with.
Speaker 2 (23:20):
Who wouldn't want to live longer?
Speaker 3 (23:21):
If you're in a healthy state and enjoying life that
that sounds like a nice thing to most of us.
With that said, a lot of that's theoretical at this point.
It's that there's reason to believe that some of these
approaches might be successful.
Speaker 2 (23:36):
But at this point we don't.
Speaker 3 (23:39):
Have sort of the first example to point to and
say like, oh, it's working. This stuff really is going
to radically extend human life span. I think I think
we're a little ways away from it, and there's some
really good science happening there.
Speaker 2 (23:51):
But then the other.
Speaker 3 (23:51):
Piece, the other I guess you could say, the other
camp is sort of the health span camp. It's it's
people who's focused and goal is to live a healthier
life that maybe longer. You know that those tend to
go hand in hand. If you're living healthier and having
less disease, you probably will live longer on average, but
(24:12):
you're still probably going to be capped by the maximum
life span that humans as a speet, these.
Speaker 2 (24:18):
Have been dealing with for millions of years.
Speaker 3 (24:21):
I tend to get more excited about the latter camp.
I really, you know, my focus, for my personal focus
for myself is to live life as fully as I possibly.
Speaker 2 (24:32):
Can, and I need to be healthy to do that.
So I Yeah.
Speaker 3 (24:36):
I think health span is a wonderful goal to work towards,
and you're going to have life span benefits on top
of it, in terms the average life span, not probably
the maximum life span. Those are very different than decoupled.
Speaker 1 (24:50):
Yeah, yes, they're very, very, very different. I don't think
we're going to see many humans living past one hundred
and ten, one hundred and twenty and no lifetime, but
we're certainly going to see a lot more humans living
to one hundred and beyond in better health than have
been previously. I think that's the big hope in all
of this, and I think we're obviously heading that way.
(25:13):
Well maybe not as a general population, but subsets of
the population are certainly heading that way. Right. Yeah. If
we come back now to the Intervention testing program, right, so,
they have tested a number of different molecules and looking
at how they have enhanced lifespan consistently. And that's one
(25:37):
of the interesting things. What for you has been most
interesting that's come out of the interventions testing program?
Speaker 3 (25:45):
Yeah, there's a few, and I think the most interesting
one for me, I really think the data on SGLT
two inhibitors is very exciting and as close to ready
for you white spread use as anything we have. There's
a lot you know, I think when you hear people
(26:06):
talk about the Interventions Testing program, you know, wrap amin
gets a lot of attention. Yes, I think it's a
very interesting drug. It certainly does have lifespan extending properties
across every species where we have data. So I think
there's a reason to believe that it's going to be
useful in humans. But we don't know how to dose
wrap of my icein. And yes, we're just kind of
(26:27):
taking a wild guess. Maybe it's the right dose, maybe
it's gonna work great, but we don't have readouts I
can confirm that. So I find that mouse data less
exciting because it's not ready to translate yet. But the
SGLT two inhibitors, which is a different class of drugs
that we can talk about, we know exactly how to
(26:48):
dose these in humans.
Speaker 1 (26:49):
Yeah, that's that's really interesting. Let's let's just let's focus
a little bit on rap themycin, right, because because it
can consistently showed stuff in the Interventions Testing program, there's
a rocket load of people in the longevity space who
are taking rap of mouse in off leable, right, And
(27:12):
this is a lot easier to do if you live
in the United States than it is if you live
in Australia. Right, Yeah, we cannot go to a doctor
in Australia and go can I get some wrap of
mouse in for longevity? It just doesn't happen like that,
whereas in the States there's there's a lot more off
label prescription, so there's a bucket load of people taking it.
I've always I've been definitely well, I can't get it,
(27:34):
for a start, but I've been very hesitant around that.
And it was when I heard the head of the
Buck Institute, right, which you'll be familiar with. So for
our listeners, the Buck Institute probably the biggest research facility
in terms of looking at the aging now. It's a
(27:55):
massive focus on aging. It's in I think it's in
San Francisco, isn't it. But it's got all of these
brilliant scientists doing really fundamental important research and they've got
a big focus on aging. His view was really interesting,
were you know, there's this theory about body size and
(28:15):
longevity across different species, right, and so you see that
reasonably consistently that that smaller species tend to live longer.
But he said, mice, And he said they should live
a lot longer than they actually do. So they're underperformers,
whereas way as humans are over performers in terms of
(28:39):
how long we live. We're outliers, we're outliers, right, And
he's saying that that we're outliers one way and mice
are outliers another way. And so maybe because if we
take a step back, rapamus and was basically it was
used for people getting I think it was initially when
(28:59):
they got organ donations and they would get that the
organs rejected and it was an immune suppressant, and so
it suppressed the immune system. And it's like, well Jesus,
some of those mice were on small doses and some
of them were on big doses and they all lived longer,
like and and how do you reconcile that with suppressing
of the immune system? Right? And so any any thoughts
(29:24):
on on that stuff and the difference between humans.
Speaker 2 (29:27):
There's a lot of we could unpack there.
Speaker 3 (29:30):
So I think, first to your point about the immune suppression,
keep in mind, all these mice are living, you know,
they're they're not in sterile environments. They are exposed to bacteria,
but there.
Speaker 2 (29:43):
These are pambered mice.
Speaker 3 (29:45):
They're they're living in stages, they're you know, once a while,
they're not the wines right there. So the need for yeah,
I mean that the ability to tolerate some immune suppression
is probably higher in these mice than it's going to be.
Speaker 2 (29:58):
A you or I correct, So I think that's.
Speaker 3 (30:02):
Part of the reason why we don't see a negative
impact of immune suppression there. But yeah, the difference due
to body size and physiology between mice and humans, that's
really important to consider lab mice especially, think about how
these lab mice were created for the purposes we use
them for today. People bread these mice to rapidly grow
(30:24):
and reproduce and make as many pups as they can
so we can run our experiments quickly and efficiently.
Speaker 2 (30:29):
Having a short generation time is important.
Speaker 3 (30:33):
Being really robust and resilient and resistant to disease, that's important.
Speaker 2 (30:37):
So these mice, these are growth machines.
Speaker 3 (30:40):
Yes, they are programmed to grow as fast and robustly
as possible.
Speaker 2 (30:46):
So that probably means a lot of m tour activity.
M tour being the.
Speaker 3 (30:50):
Target of the drug wrap device and the target that
we're inhibiting. So if you have a lot of m
tour because you're growing and reproducing as rapidly as possible,
and that the trade off for rapid growth and reproduction
is more damage, Right, That's what happens when we're growing
and activating those growth pathways. It kind of makes sense
(31:12):
that inhibiting them and putting the brakes down of the
little bit is going to be good for longevity. That
is going to make that mouse live longer and healthier.
Speaker 2 (31:19):
Is the same true in humans?
Speaker 1 (31:22):
I don't know. Mm mmmm.
Speaker 2 (31:24):
There's there's reason, I think to believe that it could
be beneficial, but it's not.
Speaker 3 (31:29):
It could be that there's a difference between lab mice
and humans that we haven't fully wrapped our heads around
such that the interventions we find in mice are always
going to be biased towards slowing.
Speaker 2 (31:41):
That growth, crazy growth, Yeah, putting the brakes in that.
Speaker 1 (31:45):
Yeah.
Speaker 3 (31:46):
And if you look at most of the drugs that
in the interventions testing program, most of the best drugs
in one way or another, they're kind of doing them,
you know, they are more catabolic drugs that are putting
the brakes on that a little bit.
Speaker 2 (32:00):
So I think there could be something to that.
Speaker 1 (32:02):
Yeah. Yeah, for me. The interesting thing on wrap the
mice and is the stuff that Matt Kamberland's doing on dogs, right, Yes,
will be will be out reasonably soon. Right, So if
it jumps from mice to dogs, that becomes really interesting.
And then it becomes much more interesting when they do
(32:22):
it on primates. Right. People listening might go, why don't
they just do this stuff on primates because they're closer
to us. Well, they live a shit liat longer, so
it's so much Yeah, it's much more expensive and it's
just going to take decades and decades and decades. Was
the mice ones you can do quite quickly, But to
your point, there has to also be a what's the
(32:44):
mechanism here? And is it a plausible mechanism or something
that's repeated in humans that is a similar process that
we can then inhibit in humans, which is why the
SDL twos come in. Right, But just before we put
the wrap a mouse and story better, I think that's
kind of morphed into the m tour story. And you
(33:05):
will see quite a lot of proponents of longevity saying
that we need to suppress m tour, right, and so
we should be on a low calorie diet, or we
should be doing lots and lots and lots of fasting,
or we should be reducing our protein. And I'm like, ohoh,
my spider sense is tingle around that, because we know
one of the best ways to increase your risk of
(33:28):
death is to have low muscle mass whenever you're an
older adult, right, So those two are kind of incompatible.
My I'm not sure if you have a formed view
on the whole M tour pathway. The view that I'm
developing is that we need to switch M tour on,
(33:49):
but we need to switch it on intermittently, and we
shouldn't have it on continuously. And the best way to
do that is to have plenty of protein in your
three meals, but not eight five, six seven meals a day,
not be constantly eating because protein gets a bad wrap
in this cride. But also carbohydrates actively at M tour
(34:12):
as well. Inchil An activits M tour correct and so
anytime you're eating food, you're going to be stimulating M tour.
Speaker 3 (34:20):
Yeah, and M tour's not bad, it's you know, it's
doing a lot of good things for us. Like you said,
muscle mass is a great example frailty is one of
the worst predictors of longevity. You don't want to be
frail as you age, and maintaining adequate muscle mass is
an important way to combat that. But even beyond that,
(34:41):
I mean m tour is doing a key regulator of
growth and cell division and all of these essential processes
that we need for life.
Speaker 2 (34:50):
You don't want, we don't want to shut.
Speaker 1 (34:52):
All of that off.
Speaker 2 (34:53):
So I would agree, yes, it's it.
Speaker 3 (34:55):
There is good rationale for having lower MT or activity
than what many of us have as we age, and
maybe periodically changing that either with you know, a pulsed
wrapomycin is is the rationale for why people are using
that or periods of fastating exercise, you know those exercise
kind of it both inhibits and activates them toward Its interesting. Yeah,
(35:21):
I did want to just mention too. On the protein
side of things. Yeah, this is something I've been very
interested and in reading a lot about because I being
an exerciser and someone who likes to try to build
my strength over time and a high protein diet. It
scared me for a while because you know, there is
(35:41):
this association between a high amino acid intake and.
Speaker 2 (35:46):
Some decreased health outcomes.
Speaker 3 (35:48):
But if you really dig into that literature, what you
find is that different amino acids, which are the building
blocks of proteins, they have different relationships with health outcomes,
with longevity and leucine, which is actually the key amino
acid that activate them tour. Leucine doesn't appear to be
bad increase. Leucine intake is good across many different organisms,
(36:13):
and it even extends lifespan in some organisms, whereas other
amino acids like methionine and several others, they appear to
be the bad guys. So what that suggests to me
is that the relationship between protein and health and longevity,
it's not necessarily an M tour thing. It's probably probably
(36:34):
other pathways that mediate that negative relationship between protein intake
and some health outcomes.
Speaker 2 (36:42):
So all of that to say, yes, M tour isn't bad.
Speaker 3 (36:46):
I think during periods of recovery from exercise, we obviously
want to be activating M tour get that muscle growth
and tissue repair.
Speaker 2 (36:55):
But the important thing is that it's not on all
the time.
Speaker 3 (36:57):
And this comes back to the top g discussion that
we were having earlier that when M tour is active,
your cells are not doing autopogy, they can't that down.
And also the pathways that build your lysisomes are also
shut down. So it's important to have periods where you
you let up on that and you kind of hit
(37:18):
the brakes on mTOR, which then relieves the inhibition on
autophagy and lysosomal biogenesis and and kind of lets those
pathways have a turn.
Speaker 2 (37:27):
So, yes, I think it's absolutely about alternating.
Speaker 1 (37:30):
Yeah. Cool, So so how do you not take that
knowledge all the stuff that you just talked about so
eloquently and and what does that mean for John?
Speaker 3 (37:41):
Yeah? And how do you mean to write an article
about this about the amino acid thing? Because I think
there are some interesting ways that you can sort of
apply that knowledge. Let's let's say I'm right and that
leucine is essentially good for us and that other amino
acids like methionine and cysteine are actually the bad ones.
(38:05):
You know, it can be as simple as just varying
the source of your protein supplement intake if you use
protein supplements, So, for example, Way protein.
Speaker 2 (38:18):
Has a lot of leucine.
Speaker 3 (38:19):
It is associated with good health outcomes and a lot
of very high quality studies it appears to be good
for us, but you probably don't want to just be
slamming way protein all day long and getting a large
amount of your protein intake from that because it does
have a lot of methionin, and it has a lot
of cysteine. It also has isoleucine and other amino acids
(38:42):
that maybe don't have the same positive association with health outcomes.
Collagen is actually one source of protein that is very
low in methionine, so that can be a good way
to sort of balance out that intake. Of course, whole
food protein sources are excellent in the best way to
get it, but personally for the you know the I
(39:03):
think if you're shooting for the higher end of protein
intake for recovery, it can be tough to get that.
Speaker 1 (39:09):
It is difficult to get it just from Holford. I
totally agree, YEP.
Speaker 3 (39:16):
So what I even do is I've I've switched to
using collagen largely as a protein source with a little
bit of.
Speaker 2 (39:21):
Lucine at it on top.
Speaker 3 (39:24):
I have a tub of collagen, a tub of lucine,
and I'll take the collagen. I'll throw a little a
gram or two of loucine on top and you know it, Uh,
if nothing else, it makes.
Speaker 2 (39:35):
Me feel better about when managing my protein intake. There's
no data to say that this is superior.
Speaker 1 (39:41):
Is something that's effect the fact that it makes you
feel better about it? Right? Yeah, right, yep, yeah, so
it would.
Speaker 2 (39:48):
Be an interesting thing to test. But yeah, people have
at that.
Speaker 3 (39:51):
They've tested collagen collagen supplemented with lucine and compared it
to weigh protein. Way protein is superior for building muscle. Yeah,
but you know, maybe you're getting enough of that with
the collagen.
Speaker 1 (40:03):
Yeah, and maybe just just mix it up. I think
it's probably the take home on this one, and don't
have too much of it. Eat real food, eat real food.
Speaker 2 (40:12):
Yes, absolutely. And there's also I should mention a lot
of good data.
Speaker 3 (40:16):
To suggest that plant based protein is associated with good
health outcomes. Things like pea protein can be a really
good supplemental source of protein.
Speaker 2 (40:27):
Get course, there's
Speaker 3 (40:27):
Also like soy and stuff, but there is good data
to suggest that those are very healthy
Doctor John Brudwick. Welcome to the podcast.
Speaker 2 (00:10):
Thanks Ball, thanks for having me.
Speaker 1 (00:13):
This is take three. I think this kind of used
to this because of issues with recording software, and I've
now defaulted to good old zoom, so we'll see this case.
Yeah zoom, Jim, just one right, which is the good thing,
(00:33):
So give on this. So, actually, the reason that you're
on is that I read a LinkedIn post of yours
and it was on plastics and microplastics and really interesting,
and I thought, I don't read a lot of stuff
on LinkedIn, but I read your article right today and
then I started looking at some other articles you posted
and went, this is an interesting cat. I've got to
(00:55):
get them on because you're interested in the stuff that
I'm interested in. But you're actually in the field quite
a bit, and I think you're probably jugged deeper into
it than I have. So we're going to talk about
all things the science of egen. But tell our listeners
what your PhD was in, what your backgrounds in, what
(01:16):
you do now, and how that sparked your interest in
this field of longevity.
Speaker 2 (01:21):
Absolutely.
Speaker 3 (01:22):
Yeah, So in my background and my PhD or podical science,
I did a neuroscience PhD looking at a really nitty
gritty detail of molecular development of the brain, the forebrain.
So this was like really basic science, really interesting, but
very different from what I do now. But while I
(01:43):
was doing that sort of another project I got to
help with was developing these gene therapies for rare.
Speaker 2 (01:49):
Lysisolmal storage diseases.
Speaker 3 (01:51):
These are diseases where you have mutations in a gene
that's important for the function of your lysism which is
like the cellular recycling center, and if you have these
genetic mutations, your lysismes can't work and it's completely devastating.
They you know, depending on which tissue is most affected
by the specific gene that's absent.
Speaker 2 (02:15):
You know, they're devastating diseases. You lose function of that
organ or tissue.
Speaker 3 (02:20):
In many cases you face premature death, really severe disability.
So these devastating disorders that we were trying to cure
with genetic based therapies had a lot of success there.
But as I got deeper into that space, I started
of making these connections to all the longevity stuff that
(02:40):
I was reading on the side, which was you know,
a long standing interest of mine, and realizing that these
diseases of lysosomal dysfunction. They're really just severe examples of
what's happening to all of us as we get older.
Your cells and my cells don't look the same as
(03:01):
they did when we were twenty They're not going to
look the same in twenty years from now, and a
big part of the reason why is that our lycisms
aren't functioning as well as they used to. So, you know,
we don't have these genetic deficiencies, we don't have these
severe issues that result in disease, thankfully, but they're certainly
not working as well as they used to, and it's
(03:22):
a major driver of a lot of the cellular damage
that characterizes aging and decline. So that kind of brings
it all together, you know, in terms of how I
got here and why I'm interested in now and what
my sort of angle is in this longevity space. It's
really understanding how all of these different interventions impact our
(03:42):
cellular health, largely through our lysism, sometimes through other pathways.
And then of course in my professional career, I developed
drugs for these diseases with amarchist therapeutics and with some
academic partners. Yeah, so it's sort of a nice link
between my professional and personal interest.
Speaker 1 (04:03):
Yeah, and look, the cellular stuff is where it's all
that really when it comes to eating and disease.
Speaker 2 (04:08):
That if you're a so biologist, it is, yes.
Speaker 1 (04:11):
Yes, absolutely, and yeah, my daughter would be in violent
agreement because she is studying now biomedicine and loves everything
to do with sales and cellular biology. But and lysisols
presumably they have a major role in autopogy. Absolutely, yeah, yeah,
can you just explain for our listeners autoplogy and why
(04:35):
it is so important at a cellular you know, and
at an overall function level.
Speaker 3 (04:40):
Absolutely so so ourselves. I think a good bonology maybe
is a house or a car. You know, we have
all of these different components that have to function together
in a really intricate and complex way, but they don't
last forever. Stuff wears out right, So that's true of
every cellular component, every cell in your body. Nothing lasts forever.
(05:02):
It accumulates damage. When we talk about reactive oxygen species
and ultraviolet light.
Speaker 2 (05:09):
You know, different sources of damage.
Speaker 3 (05:10):
What that really means is it means that the components
that make.
Speaker 2 (05:14):
Up your cells are deteriorating.
Speaker 3 (05:17):
You know, it's at the molecular level, the molecules that
make up our cells degrade, and of course our cells
have evolved ways to deal with We don't want to
have this broken machinery sticking around any longer than it
needs to. Autophogy is the process by which it's one
of the processes by which cells take that material, break
(05:39):
it back down into the nails and boards and all
of the different raw materials, and then reuse it again
to build things fresh. So autoplogy literally, it's it's the
process it's self eating, that's what the word means. And
it's it's taking those cellular components, chopping them up and
this all list building blocks that the cells can make,
(06:02):
which could be amino acids or sugars or other metabolites,
and then using them as a fuel source again, using
them to make new new materials that don't have these
problems with damage and they can function better. And and
this is something that's happening all of the time in
every cell in your body.
Speaker 2 (06:21):
The link between autopogy and the lysisome.
Speaker 3 (06:25):
The lysosome is the terminal destination of everything that's going
through autopogy. So gotcha, when the cell autopogy, you could
think of like the collecting process the garbage truck. Garbage
truck going out picking up all of the waste and
then it's delivering it to the lysosome. The lysosome is
the dump or the recycling center is a better analogy.
(06:46):
So it's you know, they're really two ends of the
exact same process. You can't talk about one without talking
about the other. Autopogy is more of a buzzy word.
They get the lot more attention, yes, but it's it's
it's really you know, the lycism is is why we
have autoplogy. It's to bring things to the lysisme. So
I think it's it's just as important to look at
(07:07):
that side of things.
Speaker 1 (07:08):
Too, and from us at a cellular perspective, we are
just master recyclers, aren't we, Like our salves do much
better than we do as as species as humans in
terms of recycling.
Speaker 2 (07:21):
Oh, it's incredibly efficient.
Speaker 3 (07:22):
We have to be I mean it's it's you can't
be taking every nutrient you need all the time, right,
some things are only available periodically, it's and we have
to be able to get those materials from somewhere. To
keep all of the cellular processes functioning the way they
need to. So yeah, I mean it's it's evolutionarily very ancient,
(07:44):
and it's widespread throughout all the kingdoms of life, and
it's it's an essential process. If you stopped doing that,
you'd be dead very very quickly. Yeah.
Speaker 1 (07:55):
They It is really interesting, isn't that? The stuff that
evolutionarily conserved is this stuff that is core, absolutely core
to to life. Really whenever you see it across species
and a cross timelines, you go, this is a fundamental
trick of nature, right.
Speaker 2 (08:17):
WHOA absolutely yeah.
Speaker 3 (08:18):
And it can be interesting to look at the species
differences sometimes too. I think, you know, maybe we'll talk
about male studies in longevity later, but you know, lysosomes
and autopogy, they're they're different between species two and sometimes
that can offer hints into you know.
Speaker 2 (08:37):
What might be some of the drivers of disease.
Speaker 3 (08:39):
But yes, very very conserved, and that hints at the
importance just like other pathways like like insulin or you know,
any longevity, these are all deeply conserved pathways.
Speaker 1 (08:50):
Yeah. And I think the people who would be most
familiar with satophogy would be people who've engaged in intermittent
fasting and particularly prolonged fast. I mean, a lot of
the research is saying I mean, at least my understanding
of it is that some of the benefits, particularly if
you get into the four day plus water fast, is
(09:13):
that autophogy or ramps up massively, and not only within
the cells or the mitochondria as well. So we've got
mitophogy within our mitochondria and then we've got cellular stuff
in it. Basically, the way I explain it is that
you go through a complete spring clean in your body
(09:33):
and eat up dysfunctional cells and just recycle it. It's very
very clever, isn't it that in times of poor food
availability that our body would go right, well, now I'm
going to do this cellular spring clean that has a
double advantage. Number One, I'm going to remove damage celles
that our sinesseenor could become cancerous. But secondly, I'm actually
(09:57):
going to get a whole heap of energy from that
recycle process.
Speaker 4 (10:00):
It's pretty freaking colon, absolutely, and I think it's it's
important to think about it too in terms of evolution
and where we've been as a species and where we
are now.
Speaker 2 (10:11):
We we evolved.
Speaker 3 (10:12):
To function with periodic times autoplogy on a regular basis,
and we don't always get that anymore. And I think
it is, you know, it's it does get some attention
we talk about modern lifestyles and how they're detrimental for
our health, but I think this is one of the
key reasons why, the fact that you know, everything evolved
(10:36):
to function with autopogy happening at regular intervals, whether that's
overnight after a number of hours of fasting, or periodically
with longer fests, or whether it's for long durations of
endurance exercise.
Speaker 2 (10:47):
It's all the stuff that we don't get anymore. So
if not autopogy process isn't being triggered.
Speaker 3 (10:52):
To the same extent, and you know, we just talked
about why it's so important, So if that's happening less,
that's that's a very bad thing.
Speaker 2 (11:00):
And I think that's why so many.
Speaker 3 (11:02):
Interventions that seem to extend health span and lifespan they
have a common threat of activating.
Speaker 2 (11:08):
Utopogy and boosting lysosomal function.
Speaker 3 (11:11):
And I think it's, you know, it's it's not an
accident that that's the antidote to sort of the modern
lifestyle we have. I think it really, really is a
key driver of some of the disease and dysfunction we're
seeing today. Yeah.
Speaker 1 (11:28):
Look, I wrote a book called Death by Comfort about
why modern life is killing us and what we need
to do about. And part of that is that we're
not living in accordance with our genome anymore when we're
in this environment of just constant comfort, which also includes
constant food availability and a lot less necessity to actually
(11:52):
move and do these sorts of things. But you touched
on my studies a lot of the there's a bocket
heap of research being done in the longevity space, right.
So there's I think of this as two different areas. Right.
There's the stuff that people will see in their social
(12:13):
media feeds, right, And anybody who's listening who's got any
interest in longevity, I'm guessing that their social media feeds
are full of NMN, n R and a lot of
these other molecules that are out there, or dietary interventions
or hacks biohacks. Right. But there is some very serious
(12:37):
testing going on in terms of longevity, and this is
the Intervention Testing program, right, So I know you're very
familiar with that program. And basically, just for the listeners,
this is a multi site program, which is really important. Right,
You've got a number of different research labs doing the
(12:57):
same thing at the same time. And you mentioned mice. Now,
I get really frustrated when I see these clickbit headlines
about diet and then you find out that the study
was done on mice, right, which are not small humans? Right,
And I think it's really important for people to understand
(13:19):
that the mice that are used in most studies are
are basically interbred, genetically interbred. The mice that are essentially
you're studying one individual clones there, clones, right, and and
so this should be ridiculous, like doing one an experiment
(13:39):
on you and then trying to make widespread assumptions for
all of human kind iss insane And you're one of
our species.
Speaker 3 (13:49):
Absolutely, And it's saying it's even worse than that, because
it's not just that they're clones.
Speaker 2 (13:53):
They're clones of a very weird mouse.
Speaker 3 (13:56):
This is a genetically normal mouse the way they exist
and have existed for many millions of years. This is
a highly inbred stick mouse that has some very unique
genetics and physiology.
Speaker 2 (14:12):
So it's yes, it's a big problem.
Speaker 1 (14:14):
Yeah. Yeah, Now so the Interventions testing program has addressed
that because they use genetically diverse mice as well, and
they do rigorous testing of a number of different molecules,
and that has has really turned up some interesting candidates
(14:34):
right for potential longevity. But before we dive into all
of that, which I do want to dive into, because
we I think we can, we can bounce off some
of the stuff that's come out of that. I will
often say to people, and I'd love to get your
thoughts on this, that that.
Speaker 5 (14:53):
Before we get into any of this stuff, we need
to get our house in order, and for me, getting
your house in order, the fundamentals would be exercised.
Speaker 1 (15:05):
I think there's nothing comes anywhere close from a longevity
perspective as extra particularly in humans so far. That is diet,
And for me, the major thing a diet is controlling
insulin and reducing your ultraprocessed food consumption and getting adequate sleep.
And I think getting your vitamin D at a good
(15:26):
level is really key. And the other one that I'm
interested in that I think everybody should be interested from
a nutritional perspective is having good Amegia three levels in
your bloods and a Mega three score of e it.
Those who have at a Meiga three index of it live
about five years longer than people within a Meiga three
index of five. Right, I've never seen anything like that
(15:48):
in nutrition. So for me that I say, they're the fundamentals.
Get your house in order. Otherwise all of this other
stuff is all icing and no cake.
Speaker 2 (15:59):
I think that's a very way to put it. Yes,
you're gonna find agreement from me, especially on exercise and diet.
Speaker 3 (16:07):
It sounds like we view diet through a very similar lens.
An important thing to do is minimize blood sugar spikes,
and that agrees with everything we know about the longevity
and cellular health. So yeah, I mean I I can't
disagree with any of that. I'm also very interested in
omega threes. I think it's been interesting to watch that
(16:29):
field of all. As we've we've learned sort of the
relative contributions of Dha and EPA, which are two of
the major species that are in something like a fish
oil supplement. Emergen data is suggesting that it turns out
EPA is perhaps even better than DHA, which for a
(16:49):
long time you could find a lot of resources suggesting
the opposite opposite.
Speaker 2 (16:54):
Yes, but yeah, I think.
Speaker 3 (16:56):
A high EPA fish oil supplement makes a lot of sense.
And yeah, I think the one piece that that I
would add to that that there is a lot of
data on but doesn't get discussed as much, is having
a robust social network.
Speaker 1 (17:13):
Ah yeah, yeah, absolutely, hundred percent.
Speaker 2 (17:15):
Real life social network, not an online social network.
Speaker 1 (17:18):
Yes, we are violent agreement. And actually I wrote a
chapter on that of my new book because I think
it's hugely important. I mean, I think loneliness. I think
it's as bad for your health as smoking at least
ten cigarettes today. It's just crazy. Yeah. And so look,
if we get back to the interventions testing program via
(17:39):
a little diversion, right because I think I'm talking about
the hallmarks of aging, I think it would be quite
interesting here. So some of my listeners will be familiar
with this because I've talked about it before. I say,
I can't remember. It was two and thirteen or twenty
fourteen there was a paper released on the hallmarks of aging,
and there was nine of them then, and then I
(18:00):
think the same research group at it another three recently
about a couple of years ago. And I think what
was autophagy disabled autopity is that is that in the
original one or the newer one. I'm pretty sure.
Speaker 3 (18:14):
That it's I want to say that that's in it
wasn't the original, but I'd have to go back and
check to be honest.
Speaker 2 (18:20):
Yeah, but that's the routine.
Speaker 3 (18:23):
That is being discussed a lot too, that that isn't
in that more recent update. But I think there's pretty
widespread agreement to that. That changes to the extracellular matrix,
so the the area in between ourselves, you know, that's
probably should be added.
Speaker 2 (18:38):
As a homework too.
Speaker 3 (18:39):
But yes, it's as we learn more and it's going
to continue to grow.
Speaker 1 (18:43):
Ill absolutely the whole mark. But but these are things.
These are like the major and processes I guess you
could say, are mechanisms by which we age and and
you know, some of them have proponents are like this
is the one, and then other people are like, it's
a lot a lot of them, right, and things like
telling me are shortening, stem cell exhaustion, loss of protiostasis,
(19:06):
disregulated and nutrient sensing, you know, and disabled atophogy. That
now your view, what is your I actually heard a
really interesting it was Peter A. Tia interviewing somebody who's
been in this space for decades. It wasn't Matt Kamberlin.
(19:27):
He used to work with Matt Chamberlin, and he said
that he thinks that the major driver of aging is
disturbed homeostasis and all of these hallmarks are a result
from homeostasis going wrong in the body. And I thought, wow,
that's a really interesting take. And as he described it,
(19:48):
you know, we have these homeostatic mechanisms that are very
efficient when we're younger, and as we get older, and
of sometimes we don't bounce back into home ostheesis, and
you know, we pop over a hell and that's where
we get disease or dysregulation or some of these pathways.
Have you heard anything around the gast theory and what's.
Speaker 2 (20:10):
Your calling on it.
Speaker 3 (20:13):
I think disrupted homeostasis is clearly something that is integral
to the aging process. I guess my question would be,
is what's causing that discress? Yes, And I think if
you go up a step from there, I think there's
a strong argument to be made that the aging is
the accumulation of damage.
Speaker 2 (20:34):
Yeah, it's structurally molecularly damage.
Speaker 3 (20:39):
It's you know, things that the structure not being where
it needs to be and then function follows from structure.
So if the structure is disrupted, that's you know, the
function the homeostatsis is what suffers.
Speaker 2 (20:53):
So yeah, I think this is all.
Speaker 3 (20:59):
There's not one drive of aging, and there's not one.
Speaker 2 (21:02):
Hallmark that is more important than the others.
Speaker 3 (21:05):
It really is an integrated picture where all of these
things are influencing everything else, and one key thread running
through all of that is disrupted homeostasis. Yeah, the systems
and the ways that the stell tries to keep everything
functioning properly, they break down.
Speaker 2 (21:21):
Yeah, they stop looking as well.
Speaker 3 (21:23):
And when that happens, then you start accumulating more damage
because you're not repairing it as efficiently and you're not
preventing it. And it, yes, very it's a cyclical process.
Speaker 2 (21:32):
Where everything's influencing everything else.
Speaker 1 (21:35):
Yeah, And basically it's very hard to get away from
that high level overview that aging is just a process
of to then almost inevitable process of damage. And so
to that point, it's really interesting because there seems to
be two lines of thought in this space. Right. There's
(21:57):
a bunch of people whose meage focus is on enhancing lifespan,
and then there's another bunch of people whose major focus
is on enhancing health span. What's your intuition say about
what we're going to be most successful lot, because my
(22:18):
personal one is we are going to be able to
influence health span way more than lifespan. I think live span.
These people who are talking about escape velocity and we're
going to exceed that, I think they're in l lah land.
But you might think differently.
Speaker 2 (22:37):
No, I don't like this escape velocity thing. I think
it it to me.
Speaker 3 (22:42):
It feels like all of these singularities that we talk
about across different fields that haven't come to fruition, and
I don't think. I mean, I don't know, maybe escape
velocity is real, but if it is, we're a long
ways away from it in terms of longevity.
Speaker 2 (22:58):
But yeah, I think you summed it up well. They're
they're kind of our two camps.
Speaker 3 (23:02):
There's there's one camp of very intelligent, passionate people that
are are laser focused on radical extension of human life span.
So they, you know, they want to push the maximum
life span out, which you know, that's a tough to
argue with.
Speaker 2 (23:20):
Who wouldn't want to live longer?
Speaker 3 (23:21):
If you're in a healthy state and enjoying life that
that sounds like a nice thing to most of us.
With that said, a lot of that's theoretical at this point.
It's that there's reason to believe that some of these
approaches might be successful.
Speaker 2 (23:36):
But at this point we don't.
Speaker 3 (23:39):
Have sort of the first example to point to and
say like, oh, it's working. This stuff really is going
to radically extend human life span. I think I think
we're a little ways away from it, and there's some
really good science happening there.
Speaker 2 (23:51):
But then the other.
Speaker 3 (23:51):
Piece, the other I guess you could say, the other
camp is sort of the health span camp. It's it's
people who's focused and goal is to live a healthier
life that maybe longer. You know that those tend to
go hand in hand. If you're living healthier and having
less disease, you probably will live longer on average, but
(24:12):
you're still probably going to be capped by the maximum
life span that humans as a speet, these.
Speaker 2 (24:18):
Have been dealing with for millions of years.
Speaker 3 (24:21):
I tend to get more excited about the latter camp.
I really, you know, my focus, for my personal focus
for myself is to live life as fully as I possibly.
Speaker 2 (24:32):
Can, and I need to be healthy to do that.
So I Yeah.
Speaker 3 (24:36):
I think health span is a wonderful goal to work towards,
and you're going to have life span benefits on top
of it, in terms the average life span, not probably
the maximum life span. Those are very different than decoupled.
Speaker 1 (24:50):
Yeah, yes, they're very, very, very different. I don't think
we're going to see many humans living past one hundred
and ten, one hundred and twenty and no lifetime, but
we're certainly going to see a lot more humans living
to one hundred and beyond in better health than have
been previously. I think that's the big hope in all
of this, and I think we're obviously heading that way.
(25:13):
Well maybe not as a general population, but subsets of
the population are certainly heading that way. Right. Yeah. If
we come back now to the Intervention testing program, right, so,
they have tested a number of different molecules and looking
at how they have enhanced lifespan consistently. And that's one
(25:37):
of the interesting things. What for you has been most
interesting that's come out of the interventions testing program?
Speaker 3 (25:45):
Yeah, there's a few, and I think the most interesting
one for me, I really think the data on SGLT
two inhibitors is very exciting and as close to ready
for you white spread use as anything we have. There's
a lot you know, I think when you hear people
(26:06):
talk about the Interventions Testing program, you know, wrap amin
gets a lot of attention. Yes, I think it's a
very interesting drug. It certainly does have lifespan extending properties
across every species where we have data. So I think
there's a reason to believe that it's going to be
useful in humans. But we don't know how to dose
wrap of my icein. And yes, we're just kind of
(26:27):
taking a wild guess. Maybe it's the right dose, maybe
it's gonna work great, but we don't have readouts I
can confirm that. So I find that mouse data less
exciting because it's not ready to translate yet. But the
SGLT two inhibitors, which is a different class of drugs
that we can talk about, we know exactly how to
(26:48):
dose these in humans.
Speaker 1 (26:49):
Yeah, that's that's really interesting. Let's let's just let's focus
a little bit on rap themycin, right, because because it
can consistently showed stuff in the Interventions Testing program, there's
a rocket load of people in the longevity space who
are taking rap of mouse in off leable, right, And
(27:12):
this is a lot easier to do if you live
in the United States than it is if you live
in Australia. Right, Yeah, we cannot go to a doctor
in Australia and go can I get some wrap of
mouse in for longevity? It just doesn't happen like that,
whereas in the States there's there's a lot more off
label prescription, so there's a bucket load of people taking it.
I've always I've been definitely well, I can't get it,
(27:34):
for a start, but I've been very hesitant around that.
And it was when I heard the head of the
Buck Institute, right, which you'll be familiar with. So for
our listeners, the Buck Institute probably the biggest research facility
in terms of looking at the aging now. It's a
(27:55):
massive focus on aging. It's in I think it's in
San Francisco, isn't it. But it's got all of these
brilliant scientists doing really fundamental important research and they've got
a big focus on aging. His view was really interesting,
were you know, there's this theory about body size and
(28:15):
longevity across different species, right, and so you see that
reasonably consistently that that smaller species tend to live longer.
But he said, mice, And he said they should live
a lot longer than they actually do. So they're underperformers,
whereas way as humans are over performers in terms of
(28:39):
how long we live. We're outliers, we're outliers, right, And
he's saying that that we're outliers one way and mice
are outliers another way. And so maybe because if we
take a step back, rapamus and was basically it was
used for people getting I think it was initially when
(28:59):
they got organ donations and they would get that the
organs rejected and it was an immune suppressant, and so
it suppressed the immune system. And it's like, well Jesus,
some of those mice were on small doses and some
of them were on big doses and they all lived longer,
like and and how do you reconcile that with suppressing
of the immune system? Right? And so any any thoughts
(29:24):
on on that stuff and the difference between humans.
Speaker 2 (29:27):
There's a lot of we could unpack there.
Speaker 3 (29:30):
So I think, first to your point about the immune suppression,
keep in mind, all these mice are living, you know,
they're they're not in sterile environments. They are exposed to bacteria,
but there.
Speaker 2 (29:43):
These are pambered mice.
Speaker 3 (29:45):
They're they're living in stages, they're you know, once a while,
they're not the wines right there. So the need for yeah,
I mean that the ability to tolerate some immune suppression
is probably higher in these mice than it's going to be.
Speaker 2 (29:58):
A you or I correct, So I think that's.
Speaker 3 (30:02):
Part of the reason why we don't see a negative
impact of immune suppression there. But yeah, the difference due
to body size and physiology between mice and humans, that's
really important to consider lab mice especially, think about how
these lab mice were created for the purposes we use
them for today. People bread these mice to rapidly grow
(30:24):
and reproduce and make as many pups as they can
so we can run our experiments quickly and efficiently.
Speaker 2 (30:29):
Having a short generation time is important.
Speaker 3 (30:33):
Being really robust and resilient and resistant to disease, that's important.
Speaker 2 (30:37):
So these mice, these are growth machines.
Speaker 3 (30:40):
Yes, they are programmed to grow as fast and robustly
as possible.
Speaker 2 (30:46):
So that probably means a lot of m tour activity.
M tour being the.
Speaker 3 (30:50):
Target of the drug wrap device and the target that
we're inhibiting. So if you have a lot of m
tour because you're growing and reproducing as rapidly as possible,
and that the trade off for rapid growth and reproduction
is more damage, Right, That's what happens when we're growing
and activating those growth pathways. It kind of makes sense
(31:12):
that inhibiting them and putting the brakes down of the
little bit is going to be good for longevity. That
is going to make that mouse live longer and healthier.
Speaker 2 (31:19):
Is the same true in humans?
Speaker 1 (31:22):
I don't know. Mm mmmm.
Speaker 2 (31:24):
There's there's reason, I think to believe that it could
be beneficial, but it's not.
Speaker 3 (31:29):
It could be that there's a difference between lab mice
and humans that we haven't fully wrapped our heads around
such that the interventions we find in mice are always
going to be biased towards slowing.
Speaker 2 (31:41):
That growth, crazy growth, Yeah, putting the brakes in that.
Speaker 1 (31:45):
Yeah.
Speaker 3 (31:46):
And if you look at most of the drugs that
in the interventions testing program, most of the best drugs
in one way or another, they're kind of doing them,
you know, they are more catabolic drugs that are putting
the brakes on that a little bit.
Speaker 2 (32:00):
So I think there could be something to that.
Speaker 1 (32:02):
Yeah. Yeah, for me. The interesting thing on wrap the
mice and is the stuff that Matt Kamberland's doing on dogs, right, Yes,
will be will be out reasonably soon. Right, So if
it jumps from mice to dogs, that becomes really interesting.
And then it becomes much more interesting when they do
(32:22):
it on primates. Right. People listening might go, why don't
they just do this stuff on primates because they're closer
to us. Well, they live a shit liat longer, so
it's so much Yeah, it's much more expensive and it's
just going to take decades and decades and decades. Was
the mice ones you can do quite quickly, But to
your point, there has to also be a what's the
(32:44):
mechanism here? And is it a plausible mechanism or something
that's repeated in humans that is a similar process that
we can then inhibit in humans, which is why the
SDL twos come in. Right, But just before we put
the wrap a mouse and story better, I think that's
kind of morphed into the m tour story. And you
(33:05):
will see quite a lot of proponents of longevity saying
that we need to suppress m tour, right, and so
we should be on a low calorie diet, or we
should be doing lots and lots and lots of fasting,
or we should be reducing our protein. And I'm like, ohoh,
my spider sense is tingle around that, because we know
one of the best ways to increase your risk of
(33:28):
death is to have low muscle mass whenever you're an
older adult, right, So those two are kind of incompatible.
My I'm not sure if you have a formed view
on the whole M tour pathway. The view that I'm
developing is that we need to switch M tour on,
(33:49):
but we need to switch it on intermittently, and we
shouldn't have it on continuously. And the best way to
do that is to have plenty of protein in your
three meals, but not eight five, six seven meals a day,
not be constantly eating because protein gets a bad wrap
in this cride. But also carbohydrates actively at M tour
(34:12):
as well. Inchil An activits M tour correct and so
anytime you're eating food, you're going to be stimulating M tour.
Speaker 3 (34:20):
Yeah, and M tour's not bad, it's you know, it's
doing a lot of good things for us. Like you said,
muscle mass is a great example frailty is one of
the worst predictors of longevity. You don't want to be
frail as you age, and maintaining adequate muscle mass is
an important way to combat that. But even beyond that,
(34:41):
I mean m tour is doing a key regulator of
growth and cell division and all of these essential processes
that we need for life.
Speaker 2 (34:50):
You don't want, we don't want to shut.
Speaker 1 (34:52):
All of that off.
Speaker 2 (34:53):
So I would agree, yes, it's it.
Speaker 3 (34:55):
There is good rationale for having lower MT or activity
than what many of us have as we age, and
maybe periodically changing that either with you know, a pulsed
wrapomycin is is the rationale for why people are using
that or periods of fastating exercise, you know those exercise
kind of it both inhibits and activates them toward Its interesting. Yeah,
(35:21):
I did want to just mention too. On the protein
side of things. Yeah, this is something I've been very
interested and in reading a lot about because I being
an exerciser and someone who likes to try to build
my strength over time and a high protein diet. It
scared me for a while because you know, there is
(35:41):
this association between a high amino acid intake and.
Speaker 2 (35:46):
Some decreased health outcomes.
Speaker 3 (35:48):
But if you really dig into that literature, what you
find is that different amino acids, which are the building
blocks of proteins, they have different relationships with health outcomes,
with longevity and leucine, which is actually the key amino
acid that activate them tour. Leucine doesn't appear to be
bad increase. Leucine intake is good across many different organisms,
(36:13):
and it even extends lifespan in some organisms, whereas other
amino acids like methionine and several others, they appear to
be the bad guys. So what that suggests to me
is that the relationship between protein and health and longevity,
it's not necessarily an M tour thing. It's probably probably
(36:34):
other pathways that mediate that negative relationship between protein intake
and some health outcomes.
Speaker 2 (36:42):
So all of that to say, yes, M tour isn't bad.
Speaker 3 (36:46):
I think during periods of recovery from exercise, we obviously
want to be activating M tour get that muscle growth
and tissue repair.
Speaker 2 (36:55):
But the important thing is that it's not on all
the time.
Speaker 3 (36:57):
And this comes back to the top g discussion that
we were having earlier that when M tour is active,
your cells are not doing autopogy, they can't that down.
And also the pathways that build your lysisomes are also
shut down. So it's important to have periods where you
you let up on that and you kind of hit
(37:18):
the brakes on mTOR, which then relieves the inhibition on
autophagy and lysosomal biogenesis and and kind of lets those
pathways have a turn.
Speaker 2 (37:27):
So, yes, I think it's absolutely about alternating.
Speaker 1 (37:30):
Yeah. Cool, So so how do you not take that
knowledge all the stuff that you just talked about so
eloquently and and what does that mean for John?
Speaker 3 (37:41):
Yeah? And how do you mean to write an article
about this about the amino acid thing? Because I think
there are some interesting ways that you can sort of
apply that knowledge. Let's let's say I'm right and that
leucine is essentially good for us and that other amino
acids like methionine and cysteine are actually the bad ones.
(38:05):
You know, it can be as simple as just varying
the source of your protein supplement intake if you use
protein supplements, So, for example, Way protein.
Speaker 2 (38:18):
Has a lot of leucine.
Speaker 3 (38:19):
It is associated with good health outcomes and a lot
of very high quality studies it appears to be good
for us, but you probably don't want to just be
slamming way protein all day long and getting a large
amount of your protein intake from that because it does
have a lot of methionin, and it has a lot
of cysteine. It also has isoleucine and other amino acids
(38:42):
that maybe don't have the same positive association with health outcomes.
Collagen is actually one source of protein that is very
low in methionine, so that can be a good way
to sort of balance out that intake. Of course, whole
food protein sources are excellent in the best way to
get it, but personally for the you know the I
(39:03):
think if you're shooting for the higher end of protein
intake for recovery, it can be tough to get that.
Speaker 1 (39:09):
It is difficult to get it just from Holford. I
totally agree, YEP.
Speaker 3 (39:16):
So what I even do is I've I've switched to
using collagen largely as a protein source with a little
bit of.
Speaker 2 (39:21):
Lucine at it on top.
Speaker 3 (39:24):
I have a tub of collagen, a tub of lucine,
and I'll take the collagen. I'll throw a little a
gram or two of loucine on top and you know it, Uh,
if nothing else, it makes.
Speaker 2 (39:35):
Me feel better about when managing my protein intake. There's
no data to say that this is superior.
Speaker 1 (39:41):
Is something that's effect the fact that it makes you
feel better about it? Right? Yeah, right, yep, yeah, so
it would.
Speaker 2 (39:48):
Be an interesting thing to test. But yeah, people have
at that.
Speaker 3 (39:51):
They've tested collagen collagen supplemented with lucine and compared it
to weigh protein. Way protein is superior for building muscle. Yeah,
but you know, maybe you're getting enough of that with
the collagen.
Speaker 1 (40:03):
Yeah, and maybe just just mix it up. I think
it's probably the take home on this one, and don't
have too much of it. Eat real food, eat real food.
Speaker 2 (40:12):
Yes, absolutely. And there's also I should mention a lot
of good data.
Speaker 3 (40:16):
To suggest that plant based protein is associated with good
health outcomes. Things like pea protein can be a really
good supplemental source of protein.
Speaker 2 (40:27):
Get course, there's
Speaker 3 (40:27):
Also like soy and stuff, but there is good data
to suggest that those are very healthy
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