Geoff

Welcome to this week's episode of the H.V.M.N. Podcast. I'm super excited to have professor David Sinclair on the program this week. You've probably seen his work as the bestselling author of Lifespan, but beyond being a book author and if you've been tracking the space of aging in genome sequencing, you've probably seen his work over the last two, three decades really pushing and being involved in some of the most interesting discoveries in aging. So thank you for taking the time to be on this program.

[David S.

Well Geoff, it's great to be on. Thanks for having me.

Geoff

Absolutely. So as we are preparing some of the trajectory of this conversation, I think when your book first came out, it really drew my attention in terms of just seeing what is at really the cutting edge of aging. And I think it's rare in today's setting of academia to have super credentialed folks really pushing, I would say, the limits of what is possible. So from that perspective, I think it's commendable to be throwing out, I'll say like novel theories, right? I think the key insight that, or... And I think your Lifespan covered a number of topics, but I think the key insight was really describing a unified theory of aging called Information Theory of Aging. So curious to hear from your perspective in the risk reward assessment as you're developing this book, as you're coming up with this theory, putting this all out there.

[David S.

Yeah. Well I've never been known for being shy or not taking risks. I believe life is short and we all have that problem and the faster we can figure this stuff out, the better for all of us. And there's no point in us realizing at the end of our lives we were born one or two generations too early to reap the benefit. So yeah, I'm in a rush. I want the world to reach the place that I know it's going to reach. A world that is different today as, we are from a hundred years ago in terms of medicine. And so yeah, it was an interesting journey. I like to push boundaries scientifically. I think that I've read a lot of scientific history and no theory lasts forever except maybe the second law of thermodynamics. And really we're just humans trying to figure this stuff out.

And the more dialogue, discourse, new ideas, testing those ideas, the better. Right? That's how progress is made. Unfortunately, scientists being scientists tend not to like chaos. They don't like theories to be challenged because that's usually their livelihood, which is fair enough. But I'm open to new ideas all the time and that's the way I run things. So I'm also not afraid to speak my mind and if I've got a new idea, I'll put it out there. It does upset some of my colleagues, but so be it. The other thing that I do, which definitely upsets my colleagues is I speak directly to the public and I've been doing that my whole career and I feel very strongly about that. The research that's in my lab - in the big lab behind me here, about 30 of us - that's mostly paid for by the public out of taxes.

So how arrogant would that be for myself and my colleagues to learn what we learn, even personally benefit from that, and not tell the public what we're doing. And I'm excited, Geoff, that we live in an age where people like you, God bless you, are able to allow scientists like me who normally would be in an ivory tower talking to their colleagues only, because we're afraid of newspapers who typically distort the work, finally we talk to the public. Now there's public that doesn't care about science and they'd rather just hear about fashion, whatever. That's fine. But there's a growing number of people who want to hear directly from the scientist's mouth about what they think is the best. And it's a great world, I think, that we live in right now.

Geoff

Yeah. And I think if you think about what science is, it's a pursuit of truth. So I think almost in some ways you're really practicing the core intent of science, which is finding what is true and then testing those hypotheses against observations. And if it's something that is true, then one shouldn't be afraid to stand to scrutiny and questions. I think if everyone's debating in good faith, you get to the truth faster. I think broadly the internet with the decentralization of information, I think that's probably accelerated progress because more and more people can engage on these ideas and these topics.

[David S.

No doubt, and I'll get to writing the book and the information theory in a minute, but this is a really interesting thing that I'm very passionate about, which is that we've gone from a world 10 years ago where the journals would essentially ban you from a journal if you talked about work before they published it. To a world where now you can put your work out there for the world to see, your colleagues to see, sometimes a year or two in advance of them being published. And the cart now is - well actually a horses are now where they belong in front of the cart - and it's really liberating and I think it's a world that had a long time coming.

History of scientific research was that the journals dominated and controlled the path of science and they were the gatekeepers. It's not so much that way anymore and we scientists can give our work to the public for scrutiny very rapidly. Overnight we can put it online, millions of people can look at it, argue over it, debate it. As long as you recognize that peer review is still important because we have to vet the science through experts. But I love a world where we can have ideas and have experts from all sorts of fields look at work a year or two in advance of when they otherwise would have seen it.

Geoff

Yeah, that seems to directionally true as we just progressing in terms of speed and just I think the cross interdisciplinary nature of a lot of this work. Right? I think some of the work that you described with an epigenetic clock or the Horvath clock that's incorporating a lot of data science and statistical modeling to biology. I think that's an exciting future. And I think that leads a nice segue into the information theory of aging. So as I might've referenced to you, my background is a computer scientist and I actually specialize in information and information theory so it was really interesting to see you being inspired or taking some of the concepts that Claude Shannon - who was a MIT professor and invented to field of information theory - and some of the observers in different ways that state is held and how that's applied to biology.

At least from how I read the book. It seemed like a recent paper reversing aging in nerve cells in eyes, really was the evidence or data that inspired the sort of observer theory and the information theory. I'm curious from your perspective, how did all these things come together? Because I think many of our listeners have probably heard of the different, various hallmarks of aging. I think people understand that there's some notion of genetic damage, epigenetic damage, but I think articulation that you have, which defines sort of a primal root cause of all the downstream effects of aging is quite novel, right? It's the first time I've heard that articulated in such a primal way.

[David S.

Well, actually the theory began when I was a 26 years old. I'm now 50. So it wasn't just last year that I came up with this idea, but it's been evolving over time and I've been wanting to write down the theory in a scientific journal in a formal way, but I've just been too busy working on the science out there in the lab and doing other things. It turns out just through lack of time that the book was the best way for me to express my ideas and it's unusual. We were talking before we went on air about how rare it is that a scientist puts their work out in public, their theory, in a book before it's actually totally crystallized and written down in a scientific paper and vetted, and that's just how history happened in my case. But the idea has began really with yeast cells.

We were studying yeast cells and the silent information regulators, these SIR proteins that we've been working on that word, information has been there since the beginning going back 25 years ago. And how is information tied into aging itself? Well in yeast, it didn't take long to figure out that epigenetic changes as we call them, the informational noise was a major cause of aging and yeast, but it's taken us, oh, the better part of two decades to test, to understand whether that was true for us and while you can do a yeast experiment in a week, a mouse experiment, the ones that we just put up online, not the reprogramming one, but a couple of others. They took us 10 years, those two papers, and I felt like we were at a point where we had enough evidence from our research and increasingly other people who are working in this area that this hypothesis was going to come out anyway, kind of like Charles Darwin would have gotten scooped if he hadn't written origin of the species. So he rushed it out.

The same thing was happening to me. I spent 10 years going, "Haha. No one else is thinking this way in terms of information." But then the epigenome exploded in the aging field. The Horvath clock, the epigenetic clock came out and I thought, well, I'd better get this out, or I'll really regret it for the rest of my life. And so it all spilled out on the pages quite beautifully, I think, thanks to my coauthor who's a really great writer and together we produced something that was far better than we could have produced alone. But what I've been very encouraged by is the reaction of my colleagues that for many of them, it just makes perfect sense. If you distill down biology to its essence and ask why don't organisms live forever? Why isn't life permanent? It's got to be information loss. There's nothing else it could be.

Geoff

Yeah, I mean it makes sense in terms of a lot of analogies that people make on biological contracts, right? One can make the analogy that we are evolution algorithm for biological information that's fit for survival or through natural selection. And I think what does that mean? It's an encapsulation and dissemination of information, right? So I think one thing that I think is especially compelling about this theory is that you're making a interesting claim around this existence of an observer that stores a youthful epigenetic state one and then two, if you could reverse an aging cell back to the epigenetic state, can you arrest aging? Can you reverse aging? I think that's probably the most important, most compelling testable hypothesis that your theory would predict, right? If you're going from a scientific method, this is a theory, a hypothesis, and there's some smoking evidence around that this can be done.

And I think what would really nail the coffin here is describing exactly the mechanism of how this observer works. And I think that is, I think probably the most exciting, most novel part of the book for me, and it seemed like it was just at the cutting edge of what was known because just like looking at some of the surrounding literature, this was really just the bleeding edge. When the book came out in, I think in September, this was really at the cutting edge of what was even known. So I guess if science is moving really quickly, anything to update or tease at over the last couple of months in a mechanism or testable hypotheses of how this might be implemented in our genome.

[David S.

Oh right. So there were three papers that we're revising now. Two are at cell and one is at nature. And they'll probably come out next year. And I was actually worried that by publishing the book I was going to scoop myself, which is not what you want to do first as a scientist, but it seems to be fine. The journals are happy with it. But those studies, even though they took a long time - some of them 10 years, as I mentioned - the pace of research now has exploded. We can now look at the epigenome in four dimensions very quickly. Millions of data points coming in every day into the lab. We've had to build our own servers just to, not just analyze it, but store the information. And we've got bioinformaticians in the lab that are working on a whole range of things. And so what's happening in the lab is that every day I come in when I'm not traveling and there's some new exciting development.

So we first made the, well let me take one step back. We first show that aging is likely to be the loss of epigenetic information in yeast going back 20 years ago. But we really had no sense that this was true in terms of cause and effect in mammals. And so we took a mouse, we engineered a mouse strain, where we could disrupt the epigenome and if we were right... Well, let's start with if we were wrong, lots of bad things could have happened, the mouse could have died, the mice could have contracted cancer. And it's possible nothing happened, if you disrupt the epigenomes, no big deal. And I think most people would have said, there's a one in a thousand chance that you'll get what you're looking for, which is aging. But that's what we got. We got aging in these mice, which was pretty good result.

And when you surprise yourself, how good it looks, is usually you're on the right track. But what that said was we had to think differently about our wheel of fortune, these hallmarks of aging. Now I'm not coming out and saying the hallmarks are wrong, not by any means, but what I'm saying is that just having a laundry list of problems doesn't explain why things occur in the first place. So it's not a full unified theory.

Geoff

Right. There are secondary symptoms of aging, right? I think what you are describing is a primal singular cause, which I think is interesting.

[David S.

Yeah. That's really what every field is hoping for is, not just a list, but a real cause... You could distill down aging into an equation if this information theory is right, but what's exciting is that this mouse where we disrupted the epigenome, it didn't just get to look old and it didn't just get diseases of aging. These hallmarks of aging also occurred, so a loss of mitochondria. Mitochondrial function, loss of STEM cells, inflammation, senescent cells. All of these hallmarks occurred, so that tells you likely that the epigenome is what I would say is upstream. Is the dam upstream and these others are tributaries, which is pretty exciting.

But what that also meant was that this the field that was really just focusing on longevity genes to slow one or more of these hallmarks. That's what we've been doing for the last 20 years. My lab certainly is involved in that through activation of sirtuins. What it also said was that if epigenetic change and noise is the upstream cause, then if we address that and reverse it, all these other symptoms of aging, hallmarks and diseases, should either be prevented or if we're really lucky, can be reversed. So we didn't know if there was an observer, which you can also refer to... We refer to as the backup hard drive of the youthful information in the cell.

We didn't know there was such a thing, but in 2014 I became very interested in Claude Shannon's work and I read all of it, some of the most beautiful papers I've ever read, and I was trying to find the observer. And so we were giving cells a whole bunch of factors that we thought might reverse their age by tapping into the observer. We didn't know where the observer was if it existed, we killed a lot of cells, but we had a breakthrough about two years ago where we put in set of three genes and it looked like we managed to find the zip code of the observer and the observer woke up and reset the age of the cells. And when we did it in a mouse, it reset the age of the mouse and old mice that lost their vision, got their complete vision back again. And that's the paper that we posted online a couple of months ago.

Geoff

So this is the Yamanaka factors. And this is the paper published on Bio Archive around essentially restoring vision of crushed nerve cells in induced glaucoma. You're able to reverse essentially those disease states that are associated with aging

[David S.

And aging itself.

Geoff

Right. Okay. Yeah. And then I think the third one was aging itself. So I wanted to get your thoughts on alternate explanations. Right? Because I think there's two parts that I want to explore. One is, this could be described with an observer and then if that is the case, then what would be the mechanism of action? I think you've referenced potentially something with methylation, but that seems to be probably not complete or overly simple. And I think there's been more and more research around. I think you've recently shared a paper on Twitter about lactylation. I know that there's acetylation and then I know there's colleagues and friends that are looking at betahydroxybutyralation, where betahydroxybutyrate actually binds and affects gene expression as well.

So it seems like there's more and more new science around how the epigenome is actually modified. So do you have some sense of describing that mechanism that would be the observer? And then the second part of the question is, I think where my mind goes is that, is there explanation that this also describes the behavior that you've saw that doesn't require the observer, right? I think that's an open question. Or maybe you have some better results or data that suggests why this can't be explained without an observer.

[David S.

That is a really good questions. So the first is about how complex is the man behind the curtain, the machine behind the clock. And there is no doubt that it involves more than DNA methylation, but you have to start somewhere. And we've only been working on this for a couple of years now, but we are, I've gone from a lab with just one person in my lab working on reprogramming to now probably most of the people in my lab work on it. So we're working really hard. One thing that's interesting is so we can measure DNA methylation, age of the animal and the cells, the neurons in the eye. And we could see that the Yamanaka factors, three of them, three that are seemingly safe. We're looking at mice today. We found that in terms of an update you're asking me, we find that these Yamanaka factors, the way we deliver them and the combination doesn't cause cancer, doesn't have any untoward effects in the animals.

Even if we look very carefully, histologically, which is great news. That's hot off the press. But to your point, the machine is complex, but the reason that I'm excited about the DNA methylation clock is because I think that it's a very deep layer of aging. We can change superficial things. For example, we can go for a run today and change some transcription factors and change gene expression, but that's not permanent. That's just going to change temporarily your cells and they'll take up more glucose, etc. There's a deeper level where we've been working on some epigenetic factors such as sirtuins and trying to activate them, but even then, if you stop giving these molecules that activate the system, the animal will revert back to being healthier and maybe longer lived. But it's not that you've really reset the clock. You just made things a little bit more youthful looking. But the deep layer is the actual information that tells you your age, and that's how cells really understand what type of cell they are and how old they are. And we think that this is partly driven by DNA methyl.

[David S.

And we think that this is partly driven by DNA methylation, but we thought up until our paper that the methylation age, these chemical marks on the DNA, were an indicator of biological age though it's just basically the crust on the genome, the plaque on your teeth so to speak. Plaque doesn't do much, right? It's just accumulating. Same, we thought about the methyls, but what we decided to do was to knock down or knock out, we've done it both ways, a set of genes called TETs, T-E-T, and there are three of them. And if we got rid of at least number one or number two, we haven't studied three yet, we didn't get the vision restoration and we didn't get the clock reversal. So what does that say? These enzymes are the enzymes that remove the methyl off the DNA, the pick that removes the plaque off your teeth.

If you don't have plaque remover, you don't get shiny teeth anymore and you don't get to look younger, your dentist can't do a good job. So that's what the results are telling us is that part of the reset of the clock. It's not just an indicator of age as if you move a clock hand and nothing really changes except the appearance, but what it says is that perhaps you move the clock back and it actually changes time, but to move that clock back, you need to remove the DNA methylation. Now, of course that that's not sufficient. We don't think we're testing whether it is sufficient, but we do know it's necessary for the age to go back. And then the second thing you asked me, Geoff, was about does this prove the existence of an observer? And one of the experiments that convinced me was the following.

So we can look at all the patterns of gene expression, which genes are on and off, in these neurons and can look at every gene in the cells. And what we found was that genes that go down a little bit with aging in terms of getting switched off, when we reprogram those cells, they go back up to normal, but just the right amount to where they were when they were young. If a gene goes all the way, way down then the animal's old. It goes way up when we reprogram them. Remember, we're not telling them which genes to turn on and off and at what level, the cell somehow knows that for the whole program.

Geoff

Right.

[David S.

And so it's not mimicking an age reset, it's actually fully resetting the program at the gene expression level, at one level, and the very deep level, which is the DNA methylation level. Now, there are a lot of things we don't know. We don't know how many times can you reset. Is it once? Which we've done or is it a hundred times? And we don't know what tells the TET enzymes which methyls to remove and which ones to keep. Now, unlike our teeth and plaque, well teeth, we can get rid of all the plaque and there's no problem. If we remove all the plaque off our DNA, all methyls, our cells will lose their identity completely and we would become the biggest pool of STEM cells, it would basically be a tumor. That's not what's happening: we don't have mice that have tumors in their eyes, we have mice that can see again. So it's as though... Now, another analogy would be a pianist playing 20,000 different genes and that pianist makes some mistakes, but now we bring in a new pianist and they can play just the right notes.

Geoff

Right.

[David S.

And we're not stripping all the notes off, we're not ripping the piano off or the keys off the piano. So the observer in my mind has to exist, but exactly how the observer knows which of those changes to make to go back to restore the gene expression, we don't know that at all. I think there's probably a Nobel Prize up for grabs if someone wants to figure that out. Now we're giving it our best shot. But in terms of philosophically, where would this lie? Where would the observer be? So it could be, and I'll tell you some of my best ideas, it could be a new type of DNA modification, so it's on the genome.

Geoff

Yep.

[David S.

It could be a protein that's binding to the genome when we're young that stays there for 80 years, or it could be some quantum state that I hope not because that's going to take us a little longer to figure out, but it's quite possible.

Geoff

Yeah, it'd be interesting to see how you would even measure from a quantum level because I think that's the orders of magnitude even smaller than DNA. I think that's a good evidence where methylation is not just a symptom, I think the devil's advocate could say, "Okay, your methylation is a correlate of aging, but if you knock it out, you don't get the reversal." That definitely brings it much more closer to a causal or part of the causal path of aging, which I think is interesting. And the second part, I guess when you have the Yamanaka factors, you kind of reverse into a pluripotent STEM cell. Could one explain or have an alternate hypothesis where these STEM cells are still nearby other healthy nerve cells and just mimicking the healthiest versions of the cells around them? And I think, this is me just speculating, I have no evidence or data suggest that this is the right or wrong path, but in terms of an alternate explanation that doesn't require an observer, what do you make of that?

I mean, I think when people just kind of generically inject STEM cells into their bloodstream for anti-aging effect, and I think that's very, very spurious. No data suggests that method even works, but there are biohackers who do that. I think the most generous mechanisms of action for that is that these STEM cells somehow bind to areas that are somehow damaged and they mimic and build up this healthy tissue there. So to me that doesn't require necessarily an observer, it was just mimicking nearby healthy cells and maybe there's inflammation factors like cytokines on kind of the more damaged cells and somehow that the STEM cells just kind of mimic the ones that are a little bit more healthier. Your thoughts of why that's wrong.

[David S.

Because we've tested it. We can reprogram cells to reverse the clock and survive damage in the Petri dish where there's just one type of cell. And in the eye, we can take those retinas out and we can look at the cells and actually measure what's going on inside those cells, those neurons, and the neurons themselves have reset their age and their gene expression. It's what we would call a cell autonomous effect. So it cannot be that the eyes are relying on the STEM cells because the viruses that we deliver, the gene therapy, goes to the neurons and only those neurons that get the gene therapy are the ones that get rejuvenated. In your theory or your challenge to me, what we should see is that it shouldn't work in the dish just with neurons and it does. And we should see that nerve cells that don't get the virus should be equally rejuvenated, but they don't rejuvenate unless they get the treatment into their nucleus.

Geoff

I see. So you're saying that in the treated neurons, essentially all of them get reversed, not just the pluripotent STEM cells that differentiate themselves into a nerve cell?

[David S.

Right. So two adjacent nerve cells in the retina, if one gets the treatment, the virus, which we can see, we can stain it, and another one doesn't, only this one will rejuvenate and survive and grow, and this one won't.

Geoff

So you're saying that even if the pluripotent STEM cell tries to mimic the existing nerve cell, right? Because you have a STEM cell that wants to differentiate. You're saying that the mechanism that the STEM cell wants to mimic the nerve cell wouldn't work because...

[David S.

Well, we don't see any replacement of cells. We can look in the eye and all of the cells that were there before are still there after the treatment. They haven't been replaced, they haven't been substituted by STEM cells. It's the actual old cells that have been rejuvenated and they have to get those genes into them, into each cell, for them to get younger.

Geoff

I see. I see.

[David S.

So it cannot be an influence or replacement by other cells.

Geoff

So the existing cells that weren't injected by the virus that induces the Yamanaka factors also rejuvenate as well?

[David S.

No, they have to get the Yamanaka factors. Cells are not talking to each other or replacing each other. Each cell acts as though it's its own individual and we reprogram them individually.

Geoff

Right.

[David S.

Because our treatment doesn't infect every neuron in the retina. I think we're getting about half of them.

Geoff

Okay.

[David S.

So you can very easily see that those ones that didn't get the treatment will die off or they're not the ones that become youthful again.

Geoff

Yes, so the infected or the Yamanaka induced nerve cells. You're saying that... I would agree that those are the ones that end up being healthy, but I guess the nuance is that the challenge would be that for some reason these pluripotent STEM cells differentiate to the healthiest surrounding nerve cells and that might be signaled through some sort of intracellular communication. And that kind of differentiates all those pluripotent STEM cells that look like the healthiest of the existing older nerve cells-

[David S.

Okay. So you're saying that-

Geoff

Yeah.

[David S.

A STEM cell could insert itself into the retina and replace a retina and grow all the way back to the brain and fuse and be functional and then get rid of all the other cells so that now the retina looks identical, but it's actually replaced itself.

Geoff

Yeah, the STEM cells that go into the damaged area and then mimic the healthiest surrounding nerve tissue.

[David S.

So the nerves we see regenerate are the original nerves because we tagged them with a dye, so we don't see them being replaced. So we can say, "Yeah, they're not being replaced by STEM cells." And in the case of the old eye, we're not damaging anything, this is just natural aging.

Geoff

Okay.

[David S.

And there we can reprogram those retinas. Those retinas don't look any different, they haven't changed, they haven't multiplied, there are no new cells, but the nerve cells, now we put an electrode in the back of the eye, and those nerves are now functioning with electrical signals like they were young again and then we test the vision of the mice and they can see again.

Geoff

Yeah. I mean, I don't doubt that you've definitely rescuing function. Right? I think that is very, very clear. I think the question would be around exactly the mechanisms and it sounds like you're at the forefront of teasing what that could look like and I think a smoking gun clue would be around methylation, but it's probably necessary but not sufficient definition of an observer.

[David S.

Well we can reverse aging in the dish. So we grow human neurons and we can look at whether they are rejuvenated and they survive. And we don't have STEM cells in the dish, but those nerve cells with the treatment, the Yamanaka treatment, respond to reprogramming.

Geoff

Okay.

[David S.

So it doesn't require STEM cells for it to work.

Geoff

Yeah. So I think one of the interesting things that moving off of just on the information theory of aging here in the nerve cell experiments is around the Horvath clock or epigenetic clocks more broadly. So it's a very interesting tool that differentiates chronological age with biological age. Right? And I think that's an interesting effect and I think there's probably a few markers that researchers use for this, right?

There's more functional markers like VO2 max or functional muscle strength as predictors for health span or longevity, right? These are perhaps a little bit more intuitive functions, right? The more VO2 max that correlates or associates very well with longevity. And where I think we're seeing emerging research for epigenetic clock could be used as a similar predictor. Right? There's a certain pattern in the epigenetic clock or Horvath clock that does the same thing. Have you seen this work in all tissues? Some of my conversations with researchers suggest that they've been looking at lean muscle tissue and they didn't see, for example, the epigenetic clock work on that specific tissue. Is there tissue specific differences here or does it work for universally all types of cells?

[David S.

Well, no one can answer that question because no one's tested all types of cells.

Geoff

Fair enough.

[David S.

But in my lab, we've tested many different tissues in the mouse and Steve Horvath's tested a bunch of cells in humans. I can speak about my own research, of course, with more confidence. We've been able to make a clock every time we've tried. Whether it's something as easy as muscle, skeletal muscle, lean muscle mass, a liver, blood, more challenging was the retina, build a retina clock out of very small samples in a mouse. You can imagine you only get 10,000 cells out of that, but it worked. Now there are a lot of ways to screw it up. I'm not suggesting those researchers you refer to screwed it up, but it wasn't easy. Especially if you have low amounts of cells, you definitely have to boost the signal to noise ratio. For example, you can zoom in on a part of the genome that is highly repetitive and get stronger signals that way, a hundred fold, and that's what we used in the eye to be able to boost that.

I was skeptical of the clock because most things in aging are more variable than we want them to be, varying between month to month or individual to individual, but the clock has turned out to be surprisingly stable and reliable. I'm happy to see negative data that would be useful. I'm unaware of that problem. What I've heard, again, I probably shouldn't talk about hearsay, but it's interesting because we've talked about the atomic level. If you go down to the single cell level, I'm told that you lose the clock, which makes perfect sense actually because the clock is an average of the methylation. In the same way you can predict where plaque accumulates on someone's tooth, but if you measure a million teeth, you can have a pretty good idea of where it tends to accumulate.

Same thing here. And so that could be an issue going forward, the fewer cells you have, the less clock you're able to see and it's going to be similar I think to trying to map the position of an electron where if you really try to pinpoint it, you end up with basically a probability and that's about it and trying to observe it doesn't really help you, in fact, it makes it worse. So taking an average has been very productive. I think the guys that developed the clock have really led to a great advance in the field and what I think is probably driving the clock, and we have a couple of papers that we're working on on this, is that the disruption of the epigenome and then it's reconstitution is a problem. If you do it once, it's not a problem, if you do it a thousand times over a period of a decade, then your epigenome is going to be structured informationally different than it was when you were young.

Geoff

One of the, I would say, most I guess hyped or exciting interventions that reflect one of these pathways is the MAPK pathway and Metformin. There's been a couple of New York times articles describing upcoming clinical trials and some positive and interesting data around the use of Metformin, which is typically a diabetes drug, for anti-aging use cases. So I think one of the interesting things that I've been trying to unpack here is that, well, I would say that it's not super well known, but I'm curious if you have a stronger opinion how Metformin works. But one of the most popular explanations of why it works is that it inhibits Complex 1, which is part of the electron transport chain of the mitochondria. And the explanation there is that it somehow disrupts the Complex 1, which makes the mitochondria a little bit less efficient and that activates MAPK because now you have a higher AMP to ATP ratio. You're producing ATP a little bit less efficiently and this is described as a formatic or positive effect, right?

Typically, when you make something less efficient, you would think that this is a negative effect, but we explain that this could be positive because of hormesis. But I think on the other hand, if you look at some of the other literature around, for example, Parkinson's, Complex 1 inhibition seems to be one of the targets of targeting Parkinson's. So to me, it seems like there's a degree of how much you want to inhibit and how much you want to activate. And I think on one hand if you... and maybe this is because it's squishy or fuzzy, it's not well quantified, but how do you think about when hormesis is a good thing or when it's actually inhibiting something that's actually bad? And I think that's something that I think is perhaps missing the nuance when people talk about, "Oh, Metformin works through Complex 1 inhibition. We want to inhibit all the time. Simple story." And I think it's a little bit more complicated than that. Curious to hear your thoughts on that topic.

[David S.

Geoff, it's clear that you think more deeply than most people about it. So hormesis is... I think it's a wonderful thing. I like to call it whatever doesn't kill you, makes you stronger and longer lived, but that doesn't mean at all that we want to always be under the same condition. And the more we learn from studies, what we realize actually is that the body can even get used to hormesis, right? You want to be changing things up in your daily life, probably in supplements, and it's no surprise to me that it gets confusing because we have this standard model and a lot of books written about it that if something works, to take it in the morning, if you take it three times a day, it'll work even better and that's not true. When you take it, how much you take in terms of the day and whether you're exercising, whether you've eaten, all of these things play in and it's extremely complicated.

If anyone says they know the answer, they are lying or they're delusional because we don't know at all really what the best combination of these supplements is and also in combination with diet and time of day. Now, I don't want listeners to think that we know nothing, right? We know a fair bit, there's a whole 30 years of research on this, even more. But I think as a general theme, what guides my research, and also what I hesitate to call self experimentation, is the theory and the belief, actually, that our bodies want to be challenged and that's what wakes up these sirtuins, the AMPK, the mTOR, the insulin IGF-1 which is controlling mTOR. And because some of the experiments that we do in the lab have seen that... I'll give you a good example, resveratrol, right? Everyone dumb that down, let's just drink lots of red wine and we'll all live longer.

That's not true. For a start, you need to have a lot of resveratrol, but the other thing that's missed even by scientists, particularly those scientists who want to challenge my research, is that they miss the fact that we also published with Ruffo Dachabo down at NIH, that resveratrol given on a high fat diet will extend lifespan. Resveratrol given on a lean diet did not extend lifespan. By the way, the amount they got into the body of those lean animals was about five fold less than what you'd get if you'd have a fatty meal. But what did work that is almost always ignored or intentionally or otherwise, is that if we gave resveratrol to those lean mice every other day with their food... Okay, so you're giving pulsing food and pulsing resveratrol, out of all the mice, out of all the groups, those were the ones that lived the longest, even longer than if you just gave resveratrol or intermittent fasting alone. So what does that tell me? It's very likely that it's not-

So what does that tell me? It's probably likely that it's not just what you eat, it's when you eat and in certain combinations. And so I'm at that point actually where I'm trying to discover things in my lab, discover things with my own body to try and figure out when's the best time to take things. Metformin is a good example. There's one study that says people on Metformin are likely to be protected from diseases of aging and then studies that come out, which I think are really over hyped in a negative way, that taking Metformin will inhibit the benefits of...

Geoff

Exercise.

[David S.

Exercise. But I was going to qualify because it's not all exercise, it's weight lifting. But if you drill down into the data there, actually, that all groups, Metformin or without, gain muscle mass. Now we're all just as strong, but there was a slight difference in the size of the muscles. Okay, fine. If all you care about is the size of your muscles, don't take Metformin. If you want to be just as strong and potentially be protected against cancer, heart disease frailty, and of course diabetes, then take a good look at Metformin. But does that mean that you should take Metformin on the same day that you exercise? Maybe not. And that's what I'm trying in my regimen.

Geoff

Yeah. I think this notion of pulsing or cycling or periodization I think is really interesting because I would say that around half of our conversations in this podcast talk about longevity health span, but the other half really talks about optimization and elite athletics and sports. And it's really interesting to me because if you talk to elite physiologists and sports physiologists, they often put their athletes through cyclical training blocks in periodizing their diet against their exercise. And I think we see this manifest into potentially better performance on the athletic side. But I think that theme just rings true to me here on the health span longevity side, where there's this notion of hormesis at the right time, the right cycling and periodization of it. And it sounds like we're still figuring out exactly what those protocols might be for which types of folks and which types of baselines.

But I would agree with you that, that seems to be the direction to explore. There's probably not likely, they're just like one magic formula that works for every single person on every single lifestyle. Another interesting, I would say, a hyped up or a commonly discussed pathway or compound is mTOR and Rapamycin. And I want to just do a quick blaze through of that in the sense that there was a recent news for a company called resTORbio that was testing an mTOR inhibitor that's a very close analog to Rapamycin that, unfortunately, didn't make its Phase III endpoint. So I'm curious from your perspective, I don't know if you have chance to really dive into the data, but just for me, just looking from the outside, obviously, mTOR inhibition was a big exciting area that a lot of people have been looking at as potentially a way to halt aging endpoint on respiratory illness didn't quite pan out. Are you more or less neutral on mTOR or Rapalogs as a path to explore given this fairly recent new data point here?

[David S.

It's not as bad as it seems. It's certainly bad for resTORbio, no question. Their stock dropped 90, 89%. But there are a number of ways to inhibit mTOR. Rapamycin and Rapalogs is one way. And as far as I know, there are a number of companies, there's Navitor Bio that's working on that. resTORbio wasn't actually working on a Ramycin analog. They were working on an upstream pathway. Legal was an AKT inhibitor that led to downregulation of mTOR, so there were still plenty of ways to skin that cat so to speak. You know, it's never good when something fails because we're all hopeful that we're going to move forward, not backwards, but there's enough data on mTOR in people using Rapamycin that I don't think we should suddenly give up anytime soon. And it's Rapamycin is still the most potent drug we have to extend the life span of animals late in life.

If we can remove those side effects, then it would be a great thing for humanity. But what it shows you is that making a drug is not easy and you can't just extrapolate from a mouse to a human easily either. And that's why it's important that we have multiple shots on goal. And that's one of the reasons that I work with a number of companies because if I just had one idea and one company, you know that's pretty risky, but to spread that risk and hopefully one or more will make it. But mTOR I still think is one of the three main pillars of aging regulation. I do my best to optimize mTOR in my own special way. I don't take Rapamycin though. You know, if I was 95 I might, but I'm still pretty healthy. But I, I think I can activate my mTOR.

Sorry, inhibit my mTOR using other means. So one of the interesting things to remember is all of these pathways are talking to each other. If you activate sirtuins, you will inhibit mTOR. And we showed years ago that at least in yeast, if you inhibit mTOR, you'll activate sirtuins by raising NAD. So it's not necessarily, I don't think to take Rapamycin to chuck down lower your mTOR activity. And I think it also helps to not be eating a lot of branch chain amino acids as well.

Geoff

Right.

[David S.

And which is what I also do, but if there's a safe mTOR inhibitor that doesn't cost, you know, 1000 bucks a month, I'd certainly consider it.

Geoff

Yeah. And I think you touched on it, I think an important point, which is that these are all interrelated, interconnected networks, right? This is definitely a systems problem and I think the human body is so complicated that you can't just push one button and expect everything necessarily to perfectly fall in line. I mean, I think when you talk about intermittent fasting, that inhibits mTOR, that up regulates AMPK I think some of these, I would say best practices that a lot of people have been looking at affect the network of these metabolic pathways. And it kind of the right ways that you'd want them to go. Right. So I think when we were looking at specific endpoints, I think it's important to, I mean I think think it's important that you really sit with the overall network effects of how these things all work.

[David S.

Well. That's why I emphasize in my book about personalized medicine. It's not because it, you know, it's, it's a buzz word. I actually believe that the future of longevity will require devices like this. I, I love this and I'm not an investor so I think I can freely talk about it. The Oura Ring is one of those devices that is the future. The patch that I wear here for glucose monitoring is the predecessor of future little things that'll be under our skin or on a bandaid. And right now it seems weird. You know, when I go to the gym, I can't tell you the number of people. It can be a funny look because I've got this device stuck to the back of my arm.

Geoff

I'm guilty of that. I have been playing around the CGMs for the last three, four years and yeah, just an early user of the Oura ring as well.

[David S.

Yeah. People think it's a bit weird?

Geoff

Yeah. But I think people are interested, right? It's like the cyborg future is not evenly distributed.

[David S.

Well, as we get into this and we think similarly that not only is there a lot to still figure out, but individuals will respond differently in terms of how much, what, when. The only way to know what works for you or at least have an indication is to measure it. Otherwise you're flying blind like driving without a dashboard. And boy, I've learned a lot over the last two years and anyone who's actually interested in their own body and is scientifically minded or an engineer, I think they would be like, Oh, it's actually a lot of fun as well. You know, you get double bang for the buck, right? You got data that can help you be healthy. But it's also interesting. I love the idea that I wave my phone here under my arm-

Geoff

And you get your blood sugar. Yeah.

[David S.

I see what's inside my body. I've never been able to in real time graph something inside my body. And I look forward to a future when we can do that in real time and have recommendations on what we eat and what we're deficient in and if we have cancer coming on board. But without that we're just relying on clinical trials, on groups of people that may not even be in the same country with the same microbiome or the same sex as you. And you just have to hope that it's going to work. But I think that we can tailor our lifestyles and the way we live and the supplements based on biofeedback and biotracking.

Geoff

You're preaching to the choir here. I mean I think you've identified a couple of the problems, right? Like widely controlled trials and drugs. I mean it's population level medicine and that probably means that'll work for the individual, but it's by no means guaranteed going to work for you specifically if the population set that's being studied is different race, different country, different lifestyle. I mean a lot of variables there. But I think the future is going to go to that direction. We're going to have real time access to all our information, especially our biologic information. It just seems like we're in the dark ages. We'll kind of flying blindly, maybe getting our annual checkup once a year for our annual lipid panel. And like that's your check-in. Right? And like we know more continuous data about our computers, our house, our cars than our own bodies.

[David S.

Well yeah, you and I are living in the future basically. But soon the rest of the world will catch up as prices come down. But to me it seems the world we live in right now where you go for an annual checkup is medieval. It's ridiculous. And not only that, you only go to the doctor when you get sick.

Geoff

Right? Like once a year's optimistic.

[David S.

Yeah. Oh, I'll tell you the interesting thing, I haven't told anybody. So I've been optimizing myself, particularly in the last few years as I've now turned 50 and I wish I started sooner because I can tell you I feel better than I ever have and that's fine. You know, you can see that I have no gray hair. I've got same amount of hair as I had when I was in my twenties but that's all great. You know, that could just be luck. But what I've noticed is I used to get sick, you know, at least a few times a year, either in bed, I'd be stuck in bed or I'd get a cold. I don't remember the last time I had a sniffle and I'm traveling and everyone around me is getting sick and you know, that's known to be a sign of good health and predicting longevity. And I'm really feeling it. I think that's my best bellwether. And my father too, he's always been resistant to diseases and I think that is really a good sign that we often don't talk about in this longevity field.

Geoff

Yeah. So I know that we're running a little bit out of time here, so I want to wrap with a final thought. I think a big portion of our book is articulating why it's not insane, but probably the most humanitarian thing to extend longevity, not just on productivity, but I think just like the human aspect that like there's so much experience that one accrues. I think one of the things I think about is like you just learn so much about being a human and then once you kind of figure out how to be a good person, you're like ready to go die. And I think that's like a shame because you build like decades of experience of how to be a good person and then it's time to go onto your way. So I think I'm like very much in line with your thinking that this is probably one of the highest leverage things to work on.

But I'm curious to just tease into some of the potential sociological questions that we would need to update in our governments perhaps in a future of where we're living, you know, 200 300 500 years. I mean, you know, maybe as like a final thought here, assuming that folks like yourself can solve this problem of aging, what would you be concerned about in terms of the society and culture that we build? I think one of the things that I kind of identified or was thinking about is that dying seems to just make sure that you can distribute wealth, distribute power. Right. I think the interesting thing with capitalism is that it's the winners keep accruing more and more wealth and sometimes the clock of death forces some distribution back to other people. Yeah. With trust funds and all of that. But I'm curious, you know, assuming we solve aging, which is going to be quite challenging, what would be your final thoughts on things that future humans and future political leaders to set up a society that fits this new norm?

[David S.

Oh wow. There's a lot in there. Yeah. I mean, in terms of redistribution of wealth, that's the easiest thing to solve. You know, changing the inheritance tax, the estate tax or what some people have politically called the death taxes. That's easy. You can change that in a month. Solving aging is the hard part. Right? So fair enough. Yeah. I'm not so worried about that. If you know humanity, if they can't fix taxes, then we deserve what we get. But what I think we do deserve is a chance for a healthier, longer life as we've always done. It's just this is a new approach that people haven't thought of and one that could have a much bigger impact in addressing, like what I call in the book whack-a-mole medicine, trying to treat diseases as they come up, not realizing that what's driving all of those problems is aging in the first place.

So yeah, ethically I think it's the right thing to do for us. It sounds like you agree. The other thing that most people who argue this point with me on a population scale, they'll say, Oh, we shouldn't live longer and life isn't worth it. How much would you give for an extra two months with your mother or your father? Right. And then they go, Oh, right, yeah, I really want that. Right. Well, how about another two years with your mother or your father or your grandmother who you love. Then it's oh yeah, I want that. Give it to me. But don't give it to everybody.

So when it's personal, you don't want your family to die. You don't want them to suffer. You don't want them to have to go into a nursing home and be spoonfed as most people end up doing. And so it's very different when you talk about your own family. It's going to require changes. The same way that a hundred years ago we didn't have retirement, we didn't have weekends, it was a horrible, brutish kind of world. And go back a hundred years before that, even worse, and none of us would go back to that world even though we've had to change. We've had to work on other parts of our lives. But the bonus is that you get to be healthy and relatively wealthy and you have a retirement and you have weekends because the world is wealthier when people are healthier, right? It's a virtuous cycle and when you're wealthier, you get healthier.

But health is the core of what's driven us out of the middle ages. And that's also true for the developing world where, as they become healthier vaccines and other things, antibiotics. they're having fewer children. They're not living a brutish life and I think they wouldn't want to go back to this short life either. So I think that we also have responsibility ethically to take care of ourselves. I'm not just selfishly trying to stay young and healthy. I'm a little bit more motivated because now people are watching me and seeing how I do over the next few decades and it's kind of a game. But really what makes me happy about doing that is the realization that my kids may not have to look after me in a decrepit state. And hopefully I'll die very quickly at an advanced old age and not be a burden to them and be very productive throughout my life. I don't plan on retiring anytime soon.

And then finally things that will have to change. We're going to have to change the retirement age. We're going to have to look at social security. I do believe, and I've done the calculations with an economist, that the medical healthcare costs of the country will go down enough to easily pay for social security, but we can't retire halfway through our lives, which is what we're heading towards actually. We're going to have to give people incentives to start new careers, even if it's nonprofit work. They have to be some productive members of society, taking care of grandkids or whatever. And if you've been busting roads and doing a horrible job that no one would really want to do, and there are a lot of jobs like that, we're privileged, you and I to do what we do. You know, you wouldn't want them to have to do that for even longer, but give them a chance to do what they always dreamed of. Learn guitar, learn a language, start a company, that kind of thing. And with a longer life, you can do that.

Geoff

I think we're all looking for to that future where we can have that time. That luxury to be healthy and have the time with their loved ones and our personal desires and personal ambitions and personal goals. So thank you so much for taking the time here. I know you're a busy man, so I appreciate the time and we'll have to continue that conversation at some point. I mean, I think plenty of more material to go through, but again, a wonderful conversation.

[David S.

Yeah, I enjoyed it. It was really great conversation and great questions and I'll come back on.