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Unpacking Longevity and Cellular Health: A Conversation with Dr. Jon Brudvig - Part One · Hardiness with Dr Paul Taylor

0:08
Speaker 1: Doctor John Brudwick. Welcome to the podcast.
0:10
Speaker 2: Thanks Ball, thanks for having me.
0:13
Speaker 1: This is take three. I think this kind of used
0:16
Speaker 1: to this because of issues with recording software, and I've
0:21
Speaker 1: now defaulted to good old zoom, so we'll see this case.
0:29
Speaker 1: Yeah zoom, Jim, just one right, which is the good thing,
0:33
Speaker 1: So give on this. So, actually, the reason that you're
0:36
Speaker 1: on is that I read a LinkedIn post of yours
0:41
Speaker 1: and it was on plastics and microplastics and really interesting,
0:45
Speaker 1: and I thought, I don't read a lot of stuff
0:48
Speaker 1: on LinkedIn, but I read your article right today and
0:50
Speaker 1: then I started looking at some other articles you posted
0:52
Speaker 1: and went, this is an interesting cat. I've got to
0:55
Speaker 1: get them on because you're interested in the stuff that
0:58
Speaker 1: I'm interested in. But you're actually in the field quite
1:02
Speaker 1: a bit, and I think you're probably jugged deeper into
1:05
Speaker 1: it than I have. So we're going to talk about
1:07
Speaker 1: all things the science of egen. But tell our listeners
1:12
Speaker 1: what your PhD was in, what your backgrounds in, what
1:16
Speaker 1: you do now, and how that sparked your interest in
1:19
Speaker 1: this field of longevity.
1:21
Speaker 2: Absolutely.
1:22
Speaker 3: Yeah, So in my background and my PhD or podical science,
1:26
Speaker 3: I did a neuroscience PhD looking at a really nitty
1:31
Speaker 3: gritty detail of molecular development of the brain, the forebrain.
1:36
Speaker 3: So this was like really basic science, really interesting, but
1:40
Speaker 3: very different from what I do now. But while I
1:43
Speaker 3: was doing that sort of another project I got to
1:46
Speaker 3: help with was developing these gene therapies for rare.
1:49
Speaker 2: Lysisolmal storage diseases.
1:51
Speaker 3: These are diseases where you have mutations in a gene
1:56
Speaker 3: that's important for the function of your lysism which is
1:58
Speaker 3: like the cellular recycling center, and if you have these
2:03
Speaker 3: genetic mutations, your lysismes can't work and it's completely devastating.
2:07
Speaker 3: They you know, depending on which tissue is most affected
2:11
Speaker 3: by the specific gene that's absent.
2:15
Speaker 2: You know, they're devastating diseases. You lose function of that
2:19
Speaker 2: organ or tissue.
2:20
Speaker 3: In many cases you face premature death, really severe disability.
2:25
Speaker 3: So these devastating disorders that we were trying to cure
2:28
Speaker 3: with genetic based therapies had a lot of success there.
2:34
Speaker 3: But as I got deeper into that space, I started
2:37
Speaker 3: of making these connections to all the longevity stuff that
2:40
Speaker 3: I was reading on the side, which was you know,
2:43
Speaker 3: a long standing interest of mine, and realizing that these
2:49
Speaker 3: diseases of lysosomal dysfunction. They're really just severe examples of
2:54
Speaker 3: what's happening to all of us as we get older.
2:58
Speaker 3: Your cells and my cells don't look the same as
3:01
Speaker 3: they did when we were twenty They're not going to
3:03
Speaker 3: look the same in twenty years from now, and a
3:06
Speaker 3: big part of the reason why is that our lycisms
3:08
Speaker 3: aren't functioning as well as they used to. So, you know,
3:11
Speaker 3: we don't have these genetic deficiencies, we don't have these
3:14
Speaker 3: severe issues that result in disease, thankfully, but they're certainly
3:20
Speaker 3: not working as well as they used to, and it's
3:22
Speaker 3: a major driver of a lot of the cellular damage
3:24
Speaker 3: that characterizes aging and decline. So that kind of brings
3:29
Speaker 3: it all together, you know, in terms of how I
3:31
Speaker 3: got here and why I'm interested in now and what
3:34
Speaker 3: my sort of angle is in this longevity space. It's
3:38
Speaker 3: really understanding how all of these different interventions impact our
3:42
Speaker 3: cellular health, largely through our lysism, sometimes through other pathways.
3:47
Speaker 3: And then of course in my professional career, I developed
3:49
Speaker 3: drugs for these diseases with amarchist therapeutics and with some
3:54
Speaker 3: academic partners. Yeah, so it's sort of a nice link
4:00
Speaker 3: between my professional and personal interest.
4:03
Speaker 1: Yeah, and look, the cellular stuff is where it's all
4:05
Speaker 1: that really when it comes to eating and disease.
4:08
Speaker 2: That if you're a so biologist, it is, yes.
4:11
Speaker 1: Yes, absolutely, and yeah, my daughter would be in violent
4:14
Speaker 1: agreement because she is studying now biomedicine and loves everything
4:18
Speaker 1: to do with sales and cellular biology. But and lysisols
4:22
Speaker 1: presumably they have a major role in autopogy. Absolutely, yeah, yeah,
4:30
Speaker 1: can you just explain for our listeners autoplogy and why
4:35
Speaker 1: it is so important at a cellular you know, and
4:38
Speaker 1: at an overall function level.
4:40
Speaker 3: Absolutely so so ourselves. I think a good bonology maybe
4:44
Speaker 3: is a house or a car. You know, we have
4:48
Speaker 3: all of these different components that have to function together
4:51
Speaker 3: in a really intricate and complex way, but they don't
4:55
Speaker 3: last forever. Stuff wears out right, So that's true of
4:58
Speaker 3: every cellular component, every cell in your body. Nothing lasts forever.
5:02
Speaker 3: It accumulates damage. When we talk about reactive oxygen species
5:07
Speaker 3: and ultraviolet light.
5:09
Speaker 2: You know, different sources of damage.
5:10
Speaker 3: What that really means is it means that the components
5:13
Speaker 3: that make.
5:14
Speaker 2: Up your cells are deteriorating.
5:17
Speaker 3: You know, it's at the molecular level, the molecules that
5:20
Speaker 3: make up our cells degrade, and of course our cells
5:24
Speaker 3: have evolved ways to deal with We don't want to
5:27
Speaker 3: have this broken machinery sticking around any longer than it
5:31
Speaker 3: needs to. Autophogy is the process by which it's one
5:35
Speaker 3: of the processes by which cells take that material, break
5:39
Speaker 3: it back down into the nails and boards and all
5:43
Speaker 3: of the different raw materials, and then reuse it again
5:45
Speaker 3: to build things fresh. So autoplogy literally, it's it's the
5:51
Speaker 3: process it's self eating, that's what the word means. And
5:54
Speaker 3: it's it's taking those cellular components, chopping them up and
5:59
Speaker 3: this all list building blocks that the cells can make,
6:02
Speaker 3: which could be amino acids or sugars or other metabolites,
6:07
Speaker 3: and then using them as a fuel source again, using
6:09
Speaker 3: them to make new new materials that don't have these
6:14
Speaker 3: problems with damage and they can function better. And and
6:16
Speaker 3: this is something that's happening all of the time in
6:19
Speaker 3: every cell in your body.
6:21
Speaker 2: The link between autopogy and the lysisome.
6:25
Speaker 3: The lysosome is the terminal destination of everything that's going
6:28
Speaker 3: through autopogy. So gotcha, when the cell autopogy, you could
6:33
Speaker 3: think of like the collecting process the garbage truck. Garbage
6:37
Speaker 3: truck going out picking up all of the waste and
6:40
Speaker 3: then it's delivering it to the lysosome. The lysosome is
6:42
Speaker 3: the dump or the recycling center is a better analogy.
6:46
Speaker 3: So it's you know, they're really two ends of the
6:49
Speaker 3: exact same process. You can't talk about one without talking
6:52
Speaker 3: about the other. Autopogy is more of a buzzy word.
6:54
Speaker 3: They get the lot more attention, yes, but it's it's
6:58
Speaker 3: it's really you know, the lycism is is why we
7:02
Speaker 3: have autoplogy. It's to bring things to the lysisme. So
7:05
Speaker 3: I think it's it's just as important to look at
7:07
Speaker 3: that side of things.
7:08
Speaker 1: Too, and from us at a cellular perspective, we are
7:12
Speaker 1: just master recyclers, aren't we, Like our salves do much
7:16
Speaker 1: better than we do as as species as humans in
7:19
Speaker 1: terms of recycling.
7:21
Speaker 2: Oh, it's incredibly efficient.
7:22
Speaker 3: We have to be I mean it's it's you can't
7:25
Speaker 3: be taking every nutrient you need all the time, right,
7:30
Speaker 3: some things are only available periodically, it's and we have
7:33
Speaker 3: to be able to get those materials from somewhere. To
7:36
Speaker 3: keep all of the cellular processes functioning the way they
7:39
Speaker 3: need to. So yeah, I mean it's it's evolutionarily very ancient,
7:44
Speaker 3: and it's widespread throughout all the kingdoms of life, and
7:48
Speaker 3: it's it's an essential process. If you stopped doing that,
7:52
Speaker 3: you'd be dead very very quickly. Yeah.
7:55
Speaker 1: They It is really interesting, isn't that? The stuff that
8:00
Speaker 1: evolutionarily conserved is this stuff that is core, absolutely core
8:07
Speaker 1: to to life. Really whenever you see it across species
8:11
Speaker 1: and a cross timelines, you go, this is a fundamental
8:15
Speaker 1: trick of nature, right.
8:17
Speaker 2: WHOA absolutely yeah.
8:18
Speaker 3: And it can be interesting to look at the species
8:20
Speaker 3: differences sometimes too. I think, you know, maybe we'll talk
8:24
Speaker 3: about male studies in longevity later, but you know, lysosomes
8:30
Speaker 3: and autopogy, they're they're different between species two and sometimes
8:34
Speaker 3: that can offer hints into you know.
8:37
Speaker 2: What might be some of the drivers of disease.
8:39
Speaker 3: But yes, very very conserved, and that hints at the
8:42
Speaker 3: importance just like other pathways like like insulin or you know,
8:47
Speaker 3: any longevity, these are all deeply conserved pathways.
8:50
Speaker 1: Yeah. And I think the people who would be most
8:54
Speaker 1: familiar with satophogy would be people who've engaged in intermittent
8:58
Speaker 1: fasting and particularly prolonged fast. I mean, a lot of
9:03
Speaker 1: the research is saying I mean, at least my understanding
9:06
Speaker 1: of it is that some of the benefits, particularly if
9:09
Speaker 1: you get into the four day plus water fast, is
9:13
Speaker 1: that autophogy or ramps up massively, and not only within
9:19
Speaker 1: the cells or the mitochondria as well. So we've got
9:22
Speaker 1: mitophogy within our mitochondria and then we've got cellular stuff
9:25
Speaker 1: in it. Basically, the way I explain it is that
9:29
Speaker 1: you go through a complete spring clean in your body
9:33
Speaker 1: and eat up dysfunctional cells and just recycle it. It's very
9:38
Speaker 1: very clever, isn't it that in times of poor food
9:42
Speaker 1: availability that our body would go right, well, now I'm
9:47
Speaker 1: going to do this cellular spring clean that has a
9:49
Speaker 1: double advantage. Number One, I'm going to remove damage celles
9:53
Speaker 1: that our sinesseenor could become cancerous. But secondly, I'm actually
9:57
Speaker 1: going to get a whole heap of energy from that
9:59
Speaker 1: recycle process.
10:00
Speaker 4: It's pretty freaking colon, absolutely, and I think it's it's
10:05
Speaker 4: important to think about it too in terms of evolution
10:08
Speaker 4: and where we've been as a species and where we
10:10
Speaker 4: are now.
10:11
Speaker 2: We we evolved.
10:12
Speaker 3: To function with periodic times autoplogy on a regular basis,
10:19
Speaker 3: and we don't always get that anymore. And I think
10:22
Speaker 3: it is, you know, it's it does get some attention
10:25
Speaker 3: we talk about modern lifestyles and how they're detrimental for
10:29
Speaker 3: our health, but I think this is one of the
10:31
Speaker 3: key reasons why, the fact that you know, everything evolved
10:36
Speaker 3: to function with autopogy happening at regular intervals, whether that's
10:39
Speaker 3: overnight after a number of hours of fasting, or periodically
10:43
Speaker 3: with longer fests, or whether it's for long durations of
10:46
Speaker 3: endurance exercise.
10:47
Speaker 2: It's all the stuff that we don't get anymore. So
10:50
Speaker 2: if not autopogy process isn't being triggered.
10:52
Speaker 3: To the same extent, and you know, we just talked
10:55
Speaker 3: about why it's so important, So if that's happening less,
10:58
Speaker 3: that's that's a very bad thing.
11:00
Speaker 2: And I think that's why so many.
11:02
Speaker 3: Interventions that seem to extend health span and lifespan they
11:07
Speaker 3: have a common threat of activating.
11:08
Speaker 2: Utopogy and boosting lysosomal function.
11:11
Speaker 3: And I think it's, you know, it's it's not an
11:15
Speaker 3: accident that that's the antidote to sort of the modern
11:19
Speaker 3: lifestyle we have. I think it really, really is a
11:24
Speaker 3: key driver of some of the disease and dysfunction we're
11:27
Speaker 3: seeing today. Yeah.
11:28
Speaker 1: Look, I wrote a book called Death by Comfort about
11:31
Speaker 1: why modern life is killing us and what we need
11:34
Speaker 1: to do about. And part of that is that we're
11:36
Speaker 1: not living in accordance with our genome anymore when we're
11:40
Speaker 1: in this environment of just constant comfort, which also includes
11:46
Speaker 1: constant food availability and a lot less necessity to actually
11:52
Speaker 1: move and do these sorts of things. But you touched
11:57
Speaker 1: on my studies a lot of the there's a bocket
12:02
Speaker 1: heap of research being done in the longevity space, right.
12:06
Speaker 1: So there's I think of this as two different areas. Right.
12:09
Speaker 1: There's the stuff that people will see in their social
12:13
Speaker 1: media feeds, right, And anybody who's listening who's got any
12:16
Speaker 1: interest in longevity, I'm guessing that their social media feeds
12:22
Speaker 1: are full of NMN, n R and a lot of
12:26
Speaker 1: these other molecules that are out there, or dietary interventions
12:32
Speaker 1: or hacks biohacks. Right. But there is some very serious
12:37
Speaker 1: testing going on in terms of longevity, and this is
12:42
Speaker 1: the Intervention Testing program, right, So I know you're very
12:46
Speaker 1: familiar with that program. And basically, just for the listeners,
12:50
Speaker 1: this is a multi site program, which is really important. Right,
12:54
Speaker 1: You've got a number of different research labs doing the
12:57
Speaker 1: same thing at the same time. And you mentioned mice. Now,
13:02
Speaker 1: I get really frustrated when I see these clickbit headlines
13:08
Speaker 1: about diet and then you find out that the study
13:11
Speaker 1: was done on mice, right, which are not small humans? Right,
13:16
Speaker 1: And I think it's really important for people to understand
13:19
Speaker 1: that the mice that are used in most studies are
13:24
Speaker 1: are basically interbred, genetically interbred. The mice that are essentially
13:30
Speaker 1: you're studying one individual clones there, clones, right, and and
13:36
Speaker 1: so this should be ridiculous, like doing one an experiment
13:39
Speaker 1: on you and then trying to make widespread assumptions for
13:45
Speaker 1: all of human kind iss insane And you're one of
13:47
Speaker 1: our species.
13:49
Speaker 3: Absolutely, And it's saying it's even worse than that, because
13:52
Speaker 3: it's not just that they're clones.
13:53
Speaker 2: They're clones of a very weird mouse.
13:56
Speaker 3: This is a genetically normal mouse the way they exist
14:01
Speaker 3: and have existed for many millions of years. This is
14:04
Speaker 3: a highly inbred stick mouse that has some very unique
14:11
Speaker 3: genetics and physiology.
14:12
Speaker 2: So it's yes, it's a big problem.
14:14
Speaker 1: Yeah. Yeah, Now so the Interventions testing program has addressed
14:19
Speaker 1: that because they use genetically diverse mice as well, and
14:23
Speaker 1: they do rigorous testing of a number of different molecules,
14:28
Speaker 1: and that has has really turned up some interesting candidates
14:34
Speaker 1: right for potential longevity. But before we dive into all
14:40
Speaker 1: of that, which I do want to dive into, because
14:42
Speaker 1: we I think we can, we can bounce off some
14:44
Speaker 1: of the stuff that's come out of that. I will
14:47
Speaker 1: often say to people, and I'd love to get your
14:50
Speaker 1: thoughts on this, that that.
14:53
Speaker 5: Before we get into any of this stuff, we need
14:57
Speaker 5: to get our house in order, and for me, getting
15:00
Speaker 5: your house in order, the fundamentals would be exercised.
15:05
Speaker 1: I think there's nothing comes anywhere close from a longevity
15:08
Speaker 1: perspective as extra particularly in humans so far. That is diet,
15:13
Speaker 1: And for me, the major thing a diet is controlling
15:16
Speaker 1: insulin and reducing your ultraprocessed food consumption and getting adequate sleep.
15:22
Speaker 1: And I think getting your vitamin D at a good
15:26
Speaker 1: level is really key. And the other one that I'm
15:30
Speaker 1: interested in that I think everybody should be interested from
15:33
Speaker 1: a nutritional perspective is having good Amegia three levels in
15:37
Speaker 1: your bloods and a Mega three score of e it.
15:40
Speaker 1: Those who have at a Meiga three index of it live
15:43
Speaker 1: about five years longer than people within a Meiga three
15:46
Speaker 1: index of five. Right, I've never seen anything like that
15:48
Speaker 1: in nutrition. So for me that I say, they're the fundamentals.
15:53
Speaker 1: Get your house in order. Otherwise all of this other
15:56
Speaker 1: stuff is all icing and no cake.
15:59
Speaker 2: I think that's a very way to put it. Yes,
16:01
Speaker 2: you're gonna find agreement from me, especially on exercise and diet.
16:07
Speaker 3: It sounds like we view diet through a very similar lens.
16:11
Speaker 3: An important thing to do is minimize blood sugar spikes,
16:16
Speaker 3: and that agrees with everything we know about the longevity
16:20
Speaker 3: and cellular health. So yeah, I mean I I can't
16:24
Speaker 3: disagree with any of that. I'm also very interested in
16:26
Speaker 3: omega threes. I think it's been interesting to watch that
16:29
Speaker 3: field of all. As we've we've learned sort of the
16:33
Speaker 3: relative contributions of Dha and EPA, which are two of
16:38
Speaker 3: the major species that are in something like a fish
16:40
Speaker 3: oil supplement. Emergen data is suggesting that it turns out
16:45
Speaker 3: EPA is perhaps even better than DHA, which for a
16:49
Speaker 3: long time you could find a lot of resources suggesting
16:53
Speaker 3: the opposite opposite.
16:54
Speaker 2: Yes, but yeah, I think.
16:56
Speaker 3: A high EPA fish oil supplement makes a lot of sense.
17:01
Speaker 3: And yeah, I think the one piece that that I
17:05
Speaker 3: would add to that that there is a lot of
17:08
Speaker 3: data on but doesn't get discussed as much, is having
17:12
Speaker 3: a robust social network.
17:13
Speaker 1: Ah yeah, yeah, absolutely, hundred percent.
17:15
Speaker 2: Real life social network, not an online social network.
17:18
Speaker 1: Yes, we are violent agreement. And actually I wrote a
17:22
Speaker 1: chapter on that of my new book because I think
17:25
Speaker 1: it's hugely important. I mean, I think loneliness. I think
17:28
Speaker 1: it's as bad for your health as smoking at least
17:31
Speaker 1: ten cigarettes today. It's just crazy. Yeah. And so look,
17:36
Speaker 1: if we get back to the interventions testing program via
17:39
Speaker 1: a little diversion, right because I think I'm talking about
17:43
Speaker 1: the hallmarks of aging, I think it would be quite
17:46
Speaker 1: interesting here. So some of my listeners will be familiar
17:49
Speaker 1: with this because I've talked about it before. I say,
17:52
Speaker 1: I can't remember. It was two and thirteen or twenty
17:54
Speaker 1: fourteen there was a paper released on the hallmarks of aging,
17:57
Speaker 1: and there was nine of them then, and then I
18:00
Speaker 1: think the same research group at it another three recently
18:04
Speaker 1: about a couple of years ago. And I think what
18:07
Speaker 1: was autophagy disabled autopity is that is that in the
18:11
Speaker 1: original one or the newer one. I'm pretty sure.
18:14
Speaker 3: That it's I want to say that that's in it
18:18
Speaker 3: wasn't the original, but I'd have to go back and
18:19
Speaker 3: check to be honest.
18:20
Speaker 2: Yeah, but that's the routine.
18:23
Speaker 3: That is being discussed a lot too, that that isn't
18:26
Speaker 3: in that more recent update. But I think there's pretty
18:30
Speaker 3: widespread agreement to that. That changes to the extracellular matrix,
18:33
Speaker 3: so the the area in between ourselves, you know, that's
18:37
Speaker 3: probably should be added.
18:38
Speaker 2: As a homework too.
18:39
Speaker 3: But yes, it's as we learn more and it's going
18:42
Speaker 3: to continue to grow.
18:43
Speaker 1: Ill absolutely the whole mark. But but these are things.
18:46
Speaker 1: These are like the major and processes I guess you
18:51
Speaker 1: could say, are mechanisms by which we age and and
18:54
Speaker 1: you know, some of them have proponents are like this
18:57
Speaker 1: is the one, and then other people are like, it's
18:59
Speaker 1: a lot a lot of them, right, and things like
19:02
Speaker 1: telling me are shortening, stem cell exhaustion, loss of protiostasis,
19:06
Speaker 1: disregulated and nutrient sensing, you know, and disabled atophogy. That
19:13
Speaker 1: now your view, what is your I actually heard a
19:17
Speaker 1: really interesting it was Peter A. Tia interviewing somebody who's
19:24
Speaker 1: been in this space for decades. It wasn't Matt Kamberlin.
19:27
Speaker 1: He used to work with Matt Chamberlin, and he said
19:30
Speaker 1: that he thinks that the major driver of aging is
19:35
Speaker 1: disturbed homeostasis and all of these hallmarks are a result
19:40
Speaker 1: from homeostasis going wrong in the body. And I thought, wow,
19:45
Speaker 1: that's a really interesting take. And as he described it,
19:48
Speaker 1: you know, we have these homeostatic mechanisms that are very
19:52
Speaker 1: efficient when we're younger, and as we get older, and
19:57
Speaker 1: of sometimes we don't bounce back into home ostheesis, and
20:01
Speaker 1: you know, we pop over a hell and that's where
20:03
Speaker 1: we get disease or dysregulation or some of these pathways.
20:07
Speaker 1: Have you heard anything around the gast theory and what's.
20:10
Speaker 2: Your calling on it.
20:13
Speaker 3: I think disrupted homeostasis is clearly something that is integral
20:18
Speaker 3: to the aging process. I guess my question would be,
20:21
Speaker 3: is what's causing that discress? Yes, And I think if
20:25
Speaker 3: you go up a step from there, I think there's
20:29
Speaker 3: a strong argument to be made that the aging is
20:31
Speaker 3: the accumulation of damage.
20:34
Speaker 2: Yeah, it's structurally molecularly damage.
20:39
Speaker 3: It's you know, things that the structure not being where
20:44
Speaker 3: it needs to be and then function follows from structure.
20:47
Speaker 3: So if the structure is disrupted, that's you know, the
20:50
Speaker 3: function the homeostatsis is what suffers.
20:53
Speaker 2: So yeah, I think this is all.
20:59
Speaker 3: There's not one drive of aging, and there's not one.
21:02
Speaker 2: Hallmark that is more important than the others.
21:05
Speaker 3: It really is an integrated picture where all of these
21:08
Speaker 3: things are influencing everything else, and one key thread running
21:12
Speaker 3: through all of that is disrupted homeostasis. Yeah, the systems
21:16
Speaker 3: and the ways that the stell tries to keep everything
21:19
Speaker 3: functioning properly, they break down.
21:21
Speaker 2: Yeah, they stop looking as well.
21:23
Speaker 3: And when that happens, then you start accumulating more damage
21:26
Speaker 3: because you're not repairing it as efficiently and you're not
21:28
Speaker 3: preventing it. And it, yes, very it's a cyclical process.
21:32
Speaker 2: Where everything's influencing everything else.
21:35
Speaker 1: Yeah, And basically it's very hard to get away from
21:39
Speaker 1: that high level overview that aging is just a process
21:43
Speaker 1: of to then almost inevitable process of damage. And so
21:47
Speaker 1: to that point, it's really interesting because there seems to
21:52
Speaker 1: be two lines of thought in this space. Right. There's
21:57
Speaker 1: a bunch of people whose meage focus is on enhancing lifespan,
22:04
Speaker 1: and then there's another bunch of people whose major focus
22:08
Speaker 1: is on enhancing health span. What's your intuition say about
22:15
Speaker 1: what we're going to be most successful lot, because my
22:18
Speaker 1: personal one is we are going to be able to
22:22
Speaker 1: influence health span way more than lifespan. I think live span.
22:28
Speaker 1: These people who are talking about escape velocity and we're
22:31
Speaker 1: going to exceed that, I think they're in l lah land.
22:34
Speaker 1: But you might think differently.
22:37
Speaker 2: No, I don't like this escape velocity thing. I think
22:40
Speaker 2: it it to me.
22:42
Speaker 3: It feels like all of these singularities that we talk
22:46
Speaker 3: about across different fields that haven't come to fruition, and
22:49
Speaker 3: I don't think. I mean, I don't know, maybe escape
22:52
Speaker 3: velocity is real, but if it is, we're a long
22:54
Speaker 3: ways away from it in terms of longevity.
22:58
Speaker 2: But yeah, I think you summed it up well. They're
23:01
Speaker 2: they're kind of our two camps.
23:02
Speaker 3: There's there's one camp of very intelligent, passionate people that
23:07
Speaker 3: are are laser focused on radical extension of human life span.
23:12
Speaker 3: So they, you know, they want to push the maximum
23:14
Speaker 3: life span out, which you know, that's a tough to
23:19
Speaker 3: argue with.
23:20
Speaker 2: Who wouldn't want to live longer?
23:21
Speaker 3: If you're in a healthy state and enjoying life that
23:23
Speaker 3: that sounds like a nice thing to most of us.
23:27
Speaker 3: With that said, a lot of that's theoretical at this point.
23:31
Speaker 3: It's that there's reason to believe that some of these
23:34
Speaker 3: approaches might be successful.
23:36
Speaker 2: But at this point we don't.
23:39
Speaker 3: Have sort of the first example to point to and
23:41
Speaker 3: say like, oh, it's working. This stuff really is going
23:44
Speaker 3: to radically extend human life span. I think I think
23:47
Speaker 3: we're a little ways away from it, and there's some
23:48
Speaker 3: really good science happening there.
23:51
Speaker 2: But then the other.
23:51
Speaker 3: Piece, the other I guess you could say, the other
23:53
Speaker 3: camp is sort of the health span camp. It's it's
23:58
Speaker 3: people who's focused and goal is to live a healthier
24:04
Speaker 3: life that maybe longer. You know that those tend to
24:06
Speaker 3: go hand in hand. If you're living healthier and having
24:09
Speaker 3: less disease, you probably will live longer on average, but
24:12
Speaker 3: you're still probably going to be capped by the maximum
24:15
Speaker 3: life span that humans as a speet, these.
24:18
Speaker 2: Have been dealing with for millions of years.
24:21
Speaker 3: I tend to get more excited about the latter camp.
24:24
Speaker 3: I really, you know, my focus, for my personal focus
24:28
Speaker 3: for myself is to live life as fully as I possibly.
24:32
Speaker 2: Can, and I need to be healthy to do that.
24:35
Speaker 2: So I Yeah.
24:36
Speaker 3: I think health span is a wonderful goal to work towards,
24:40
Speaker 3: and you're going to have life span benefits on top
24:43
Speaker 3: of it, in terms the average life span, not probably
24:47
Speaker 3: the maximum life span. Those are very different than decoupled.
24:50
Speaker 1: Yeah, yes, they're very, very, very different. I don't think
24:54
Speaker 1: we're going to see many humans living past one hundred
24:57
Speaker 1: and ten, one hundred and twenty and no lifetime, but
25:00
Speaker 1: we're certainly going to see a lot more humans living
25:02
Speaker 1: to one hundred and beyond in better health than have
25:06
Speaker 1: been previously. I think that's the big hope in all
25:09
Speaker 1: of this, and I think we're obviously heading that way.
25:13
Speaker 1: Well maybe not as a general population, but subsets of
25:17
Speaker 1: the population are certainly heading that way. Right. Yeah. If
25:22
Speaker 1: we come back now to the Intervention testing program, right, so,
25:26
Speaker 1: they have tested a number of different molecules and looking
25:31
Speaker 1: at how they have enhanced lifespan consistently. And that's one
25:37
Speaker 1: of the interesting things. What for you has been most
25:40
Speaker 1: interesting that's come out of the interventions testing program?
25:45
Speaker 3: Yeah, there's a few, and I think the most interesting
25:49
Speaker 3: one for me, I really think the data on SGLT
25:53
Speaker 3: two inhibitors is very exciting and as close to ready
25:59
Speaker 3: for you white spread use as anything we have. There's
26:03
Speaker 3: a lot you know, I think when you hear people
26:06
Speaker 3: talk about the Interventions Testing program, you know, wrap amin
26:11
Speaker 3: gets a lot of attention. Yes, I think it's a
26:12
Speaker 3: very interesting drug. It certainly does have lifespan extending properties
26:17
Speaker 3: across every species where we have data. So I think
26:21
Speaker 3: there's a reason to believe that it's going to be
26:23
Speaker 3: useful in humans. But we don't know how to dose
26:25
Speaker 3: wrap of my icein. And yes, we're just kind of
26:27
Speaker 3: taking a wild guess. Maybe it's the right dose, maybe
26:31
Speaker 3: it's gonna work great, but we don't have readouts I
26:34
Speaker 3: can confirm that. So I find that mouse data less
26:38
Speaker 3: exciting because it's not ready to translate yet. But the
26:42
Speaker 3: SGLT two inhibitors, which is a different class of drugs
26:45
Speaker 3: that we can talk about, we know exactly how to
26:48
Speaker 3: dose these in humans.
26:49
Speaker 1: Yeah, that's that's really interesting. Let's let's just let's focus
26:54
Speaker 1: a little bit on rap themycin, right, because because it
26:59
Speaker 1: can consistently showed stuff in the Interventions Testing program, there's
27:04
Speaker 1: a rocket load of people in the longevity space who
27:08
Speaker 1: are taking rap of mouse in off leable, right, And
27:12
Speaker 1: this is a lot easier to do if you live
27:13
Speaker 1: in the United States than it is if you live
27:15
Speaker 1: in Australia. Right, Yeah, we cannot go to a doctor
27:19
Speaker 1: in Australia and go can I get some wrap of
27:21
Speaker 1: mouse in for longevity? It just doesn't happen like that,
27:24
Speaker 1: whereas in the States there's there's a lot more off
27:27
Speaker 1: label prescription, so there's a bucket load of people taking it.
27:31
Speaker 1: I've always I've been definitely well, I can't get it,
27:34
Speaker 1: for a start, but I've been very hesitant around that.
27:38
Speaker 1: And it was when I heard the head of the
27:41
Speaker 1: Buck Institute, right, which you'll be familiar with. So for
27:44
Speaker 1: our listeners, the Buck Institute probably the biggest research facility
27:52
Speaker 1: in terms of looking at the aging now. It's a
27:55
Speaker 1: massive focus on aging. It's in I think it's in
27:57
Speaker 1: San Francisco, isn't it. But it's got all of these
28:01
Speaker 1: brilliant scientists doing really fundamental important research and they've got
28:06
Speaker 1: a big focus on aging. His view was really interesting,
28:11
Speaker 1: were you know, there's this theory about body size and
28:15
Speaker 1: longevity across different species, right, and so you see that
28:20
Speaker 1: reasonably consistently that that smaller species tend to live longer.
28:25
Speaker 1: But he said, mice, And he said they should live
28:30
Speaker 1: a lot longer than they actually do. So they're underperformers,
28:35
Speaker 1: whereas way as humans are over performers in terms of
28:39
Speaker 1: how long we live. We're outliers, we're outliers, right, And
28:43
Speaker 1: he's saying that that we're outliers one way and mice
28:47
Speaker 1: are outliers another way. And so maybe because if we
28:52
Speaker 1: take a step back, rapamus and was basically it was
28:56
Speaker 1: used for people getting I think it was initially when
28:59
Speaker 1: they got organ donations and they would get that the
29:02
Speaker 1: organs rejected and it was an immune suppressant, and so
29:07
Speaker 1: it suppressed the immune system. And it's like, well Jesus,
29:10
Speaker 1: some of those mice were on small doses and some
29:12
Speaker 1: of them were on big doses and they all lived longer,
29:15
Speaker 1: like and and how do you reconcile that with suppressing
29:19
Speaker 1: of the immune system? Right? And so any any thoughts
29:24
Speaker 1: on on that stuff and the difference between humans.
29:27
Speaker 2: There's a lot of we could unpack there.
29:30
Speaker 3: So I think, first to your point about the immune suppression,
29:35
Speaker 3: keep in mind, all these mice are living, you know,
29:36
Speaker 3: they're they're not in sterile environments. They are exposed to bacteria,
29:42
Speaker 3: but there.
29:43
Speaker 2: These are pambered mice.
29:45
Speaker 3: They're they're living in stages, they're you know, once a while,
29:48
Speaker 3: they're not the wines right there. So the need for yeah,
29:53
Speaker 3: I mean that the ability to tolerate some immune suppression
29:56
Speaker 3: is probably higher in these mice than it's going to be.
29:58
Speaker 2: A you or I correct, So I think that's.
30:02
Speaker 3: Part of the reason why we don't see a negative
30:04
Speaker 3: impact of immune suppression there. But yeah, the difference due
30:08
Speaker 3: to body size and physiology between mice and humans, that's
30:12
Speaker 3: really important to consider lab mice especially, think about how
30:16
Speaker 3: these lab mice were created for the purposes we use
30:19
Speaker 3: them for today. People bread these mice to rapidly grow
30:24
Speaker 3: and reproduce and make as many pups as they can
30:26
Speaker 3: so we can run our experiments quickly and efficiently.
30:29
Speaker 2: Having a short generation time is important.
30:33
Speaker 3: Being really robust and resilient and resistant to disease, that's important.
30:37
Speaker 2: So these mice, these are growth machines.
30:40
Speaker 3: Yes, they are programmed to grow as fast and robustly
30:45
Speaker 3: as possible.
30:46
Speaker 2: So that probably means a lot of m tour activity.
30:49
Speaker 2: M tour being the.
30:50
Speaker 3: Target of the drug wrap device and the target that
30:52
Speaker 3: we're inhibiting. So if you have a lot of m
30:55
Speaker 3: tour because you're growing and reproducing as rapidly as possible,
31:01
Speaker 3: and that the trade off for rapid growth and reproduction
31:05
Speaker 3: is more damage, Right, That's what happens when we're growing
31:08
Speaker 3: and activating those growth pathways. It kind of makes sense
31:12
Speaker 3: that inhibiting them and putting the brakes down of the
31:14
Speaker 3: little bit is going to be good for longevity. That
31:16
Speaker 3: is going to make that mouse live longer and healthier.
31:19
Speaker 2: Is the same true in humans?
31:22
Speaker 1: I don't know. Mm mmmm.
31:24
Speaker 2: There's there's reason, I think to believe that it could
31:27
Speaker 2: be beneficial, but it's not.
31:29
Speaker 3: It could be that there's a difference between lab mice
31:32
Speaker 3: and humans that we haven't fully wrapped our heads around
31:36
Speaker 3: such that the interventions we find in mice are always
31:39
Speaker 3: going to be biased towards slowing.
31:41
Speaker 2: That growth, crazy growth, Yeah, putting the brakes in that.
31:45
Speaker 1: Yeah.
31:46
Speaker 3: And if you look at most of the drugs that
31:48
Speaker 3: in the interventions testing program, most of the best drugs
31:51
Speaker 3: in one way or another, they're kind of doing them,
31:54
Speaker 3: you know, they are more catabolic drugs that are putting
31:58
Speaker 3: the brakes on that a little bit.
32:00
Speaker 2: So I think there could be something to that.
32:02
Speaker 1: Yeah. Yeah, for me. The interesting thing on wrap the
32:07
Speaker 1: mice and is the stuff that Matt Kamberland's doing on dogs, right, Yes,
32:13
Speaker 1: will be will be out reasonably soon. Right, So if
32:17
Speaker 1: it jumps from mice to dogs, that becomes really interesting.
32:20
Speaker 1: And then it becomes much more interesting when they do
32:22
Speaker 1: it on primates. Right. People listening might go, why don't
32:26
Speaker 1: they just do this stuff on primates because they're closer
32:28
Speaker 1: to us. Well, they live a shit liat longer, so
32:30
Speaker 1: it's so much Yeah, it's much more expensive and it's
32:35
Speaker 1: just going to take decades and decades and decades. Was
32:38
Speaker 1: the mice ones you can do quite quickly, But to
32:41
Speaker 1: your point, there has to also be a what's the
32:44
Speaker 1: mechanism here? And is it a plausible mechanism or something
32:49
Speaker 1: that's repeated in humans that is a similar process that
32:53
Speaker 1: we can then inhibit in humans, which is why the
32:56
Speaker 1: SDL twos come in. Right, But just before we put
32:59
Speaker 1: the wrap a mouse and story better, I think that's
33:02
Speaker 1: kind of morphed into the m tour story. And you
33:05
Speaker 1: will see quite a lot of proponents of longevity saying
33:09
Speaker 1: that we need to suppress m tour, right, and so
33:12
Speaker 1: we should be on a low calorie diet, or we
33:14
Speaker 1: should be doing lots and lots and lots of fasting,
33:17
Speaker 1: or we should be reducing our protein. And I'm like, ohoh,
33:21
Speaker 1: my spider sense is tingle around that, because we know
33:25
Speaker 1: one of the best ways to increase your risk of
33:28
Speaker 1: death is to have low muscle mass whenever you're an
33:32
Speaker 1: older adult, right, So those two are kind of incompatible.
33:37
Speaker 1: My I'm not sure if you have a formed view
33:40
Speaker 1: on the whole M tour pathway. The view that I'm
33:45
Speaker 1: developing is that we need to switch M tour on,
33:49
Speaker 1: but we need to switch it on intermittently, and we
33:52
Speaker 1: shouldn't have it on continuously. And the best way to
33:56
Speaker 1: do that is to have plenty of protein in your
34:00
Speaker 1: three meals, but not eight five, six seven meals a day,
34:04
Speaker 1: not be constantly eating because protein gets a bad wrap
34:08
Speaker 1: in this cride. But also carbohydrates actively at M tour
34:12
Speaker 1: as well. Inchil An activits M tour correct and so
34:16
Speaker 1: anytime you're eating food, you're going to be stimulating M tour.
34:20
Speaker 3: Yeah, and M tour's not bad, it's you know, it's
34:23
Speaker 3: doing a lot of good things for us. Like you said,
34:26
Speaker 3: muscle mass is a great example frailty is one of
34:30
Speaker 3: the worst predictors of longevity. You don't want to be
34:34
Speaker 3: frail as you age, and maintaining adequate muscle mass is
34:37
Speaker 3: an important way to combat that. But even beyond that,
34:41
Speaker 3: I mean m tour is doing a key regulator of
34:46
Speaker 3: growth and cell division and all of these essential processes
34:49
Speaker 3: that we need for life.
34:50
Speaker 2: You don't want, we don't want to shut.
34:52
Speaker 1: All of that off.
34:53
Speaker 2: So I would agree, yes, it's it.
34:55
Speaker 3: There is good rationale for having lower MT or activity
35:00
Speaker 3: than what many of us have as we age, and
35:02
Speaker 3: maybe periodically changing that either with you know, a pulsed
35:06
Speaker 3: wrapomycin is is the rationale for why people are using
35:09
Speaker 3: that or periods of fastating exercise, you know those exercise
35:15
Speaker 3: kind of it both inhibits and activates them toward Its interesting. Yeah,
35:21
Speaker 3: I did want to just mention too. On the protein
35:23
Speaker 3: side of things. Yeah, this is something I've been very
35:27
Speaker 3: interested and in reading a lot about because I being
35:30
Speaker 3: an exerciser and someone who likes to try to build
35:33
Speaker 3: my strength over time and a high protein diet. It
35:38
Speaker 3: scared me for a while because you know, there is
35:41
Speaker 3: this association between a high amino acid intake and.
35:46
Speaker 2: Some decreased health outcomes.
35:48
Speaker 3: But if you really dig into that literature, what you
35:51
Speaker 3: find is that different amino acids, which are the building
35:55
Speaker 3: blocks of proteins, they have different relationships with health outcomes,
36:00
Speaker 3: with longevity and leucine, which is actually the key amino
36:04
Speaker 3: acid that activate them tour. Leucine doesn't appear to be
36:07
Speaker 3: bad increase. Leucine intake is good across many different organisms,
36:13
Speaker 3: and it even extends lifespan in some organisms, whereas other
36:17
Speaker 3: amino acids like methionine and several others, they appear to
36:22
Speaker 3: be the bad guys. So what that suggests to me
36:26
Speaker 3: is that the relationship between protein and health and longevity,
36:31
Speaker 3: it's not necessarily an M tour thing. It's probably probably
36:34
Speaker 3: other pathways that mediate that negative relationship between protein intake
36:40
Speaker 3: and some health outcomes.
36:42
Speaker 2: So all of that to say, yes, M tour isn't bad.
36:46
Speaker 3: I think during periods of recovery from exercise, we obviously
36:50
Speaker 3: want to be activating M tour get that muscle growth
36:53
Speaker 3: and tissue repair.
36:55
Speaker 2: But the important thing is that it's not on all
36:57
Speaker 2: the time.
36:57
Speaker 3: And this comes back to the top g discussion that
37:00
Speaker 3: we were having earlier that when M tour is active,
37:04
Speaker 3: your cells are not doing autopogy, they can't that down.
37:09
Speaker 3: And also the pathways that build your lysisomes are also
37:12
Speaker 3: shut down. So it's important to have periods where you
37:16
Speaker 3: you let up on that and you kind of hit
37:18
Speaker 3: the brakes on mTOR, which then relieves the inhibition on
37:22
Speaker 3: autophagy and lysosomal biogenesis and and kind of lets those
37:26
Speaker 3: pathways have a turn.
37:27
Speaker 2: So, yes, I think it's absolutely about alternating.
37:30
Speaker 1: Yeah. Cool, So so how do you not take that
37:34
Speaker 1: knowledge all the stuff that you just talked about so
37:37
Speaker 1: eloquently and and what does that mean for John?
37:41
Speaker 3: Yeah? And how do you mean to write an article
37:45
Speaker 3: about this about the amino acid thing? Because I think
37:47
Speaker 3: there are some interesting ways that you can sort of
37:50
Speaker 3: apply that knowledge. Let's let's say I'm right and that
37:54
Speaker 3: leucine is essentially good for us and that other amino
37:59
Speaker 3: acids like methionine and cysteine are actually the bad ones.
38:05
Speaker 3: You know, it can be as simple as just varying
38:08
Speaker 3: the source of your protein supplement intake if you use
38:11
Speaker 3: protein supplements, So, for example, Way protein.
38:18
Speaker 2: Has a lot of leucine.
38:19
Speaker 3: It is associated with good health outcomes and a lot
38:22
Speaker 3: of very high quality studies it appears to be good
38:25
Speaker 3: for us, but you probably don't want to just be
38:29
Speaker 3: slamming way protein all day long and getting a large
38:33
Speaker 3: amount of your protein intake from that because it does
38:36
Speaker 3: have a lot of methionin, and it has a lot
38:37
Speaker 3: of cysteine. It also has isoleucine and other amino acids
38:42
Speaker 3: that maybe don't have the same positive association with health outcomes.
38:47
Speaker 3: Collagen is actually one source of protein that is very
38:52
Speaker 3: low in methionine, so that can be a good way
38:55
Speaker 3: to sort of balance out that intake. Of course, whole
38:58
Speaker 3: food protein sources are excellent in the best way to
39:00
Speaker 3: get it, but personally for the you know the I
39:03
Speaker 3: think if you're shooting for the higher end of protein
39:06
Speaker 3: intake for recovery, it can be tough to get that.
39:09
Speaker 1: It is difficult to get it just from Holford. I
39:12
Speaker 1: totally agree, YEP.
39:16
Speaker 3: So what I even do is I've I've switched to
39:18
Speaker 3: using collagen largely as a protein source with a little
39:21
Speaker 3: bit of.
39:21
Speaker 2: Lucine at it on top.
39:24
Speaker 3: I have a tub of collagen, a tub of lucine,
39:26
Speaker 3: and I'll take the collagen. I'll throw a little a
39:29
Speaker 3: gram or two of loucine on top and you know it, Uh,
39:34
Speaker 3: if nothing else, it makes.
39:35
Speaker 2: Me feel better about when managing my protein intake. There's
39:38
Speaker 2: no data to say that this is superior.
39:41
Speaker 1: Is something that's effect the fact that it makes you
39:43
Speaker 1: feel better about it? Right? Yeah, right, yep, yeah, so
39:47
Speaker 1: it would.
39:48
Speaker 2: Be an interesting thing to test. But yeah, people have
39:50
Speaker 2: at that.
39:51
Speaker 3: They've tested collagen collagen supplemented with lucine and compared it
39:55
Speaker 3: to weigh protein. Way protein is superior for building muscle. Yeah,
39:59
Speaker 3: but you know, maybe you're getting enough of that with
40:01
Speaker 3: the collagen.
40:03
Speaker 1: Yeah, and maybe just just mix it up. I think
40:05
Speaker 1: it's probably the take home on this one, and don't
40:08
Speaker 1: have too much of it. Eat real food, eat real food.
40:12
Speaker 2: Yes, absolutely. And there's also I should mention a lot
40:16
Speaker 2: of good data.
40:16
Speaker 3: To suggest that plant based protein is associated with good
40:20
Speaker 3: health outcomes. Things like pea protein can be a really
40:24
Speaker 3: good supplemental source of protein.
40:27
Speaker 2: Get course, there's
40:27
Speaker 3: Also like soy and stuff, but there is good data
40:30
Speaker 3: to suggest that those are very healthy