Unlocking the Secrets of Age Reversal | David Sinclair Returns!

This episode dives into the latest developments in anti-aging research, focusing on David Sinclair’s innovative approaches and discoveries in reversing age-related deterioration.

1. Aging can potentially be reversed by maintaining the integrity of DNA and reprogramming it through epigenetics.
2. Lifestyle choices and specific supplements recommended by Sinclair, such as NMN and resveratrol, play a significant role in slowing the aging process.
3. Sinclair’s research suggests that there are backup copies of youthful biological information in every cell, which can potentially be reactivated.
4. Experimental therapies in animals, such as gene therapy in the eyes of mice, have shown promising results in reversing age-related degeneration.
5. The implications of Sinclair's research are vast, suggesting future possibilities where aging can be significantly delayed or even reversed through medical interventions.

1. Introduction

James Altucher introduces the episode and guest David Sinclair, setting the stage for a discussion on groundbreaking anti-aging research. James Altucher: "I want to reverse my aging. I don't really care about being able to run a mile or anything like that. I just want to reverse my brain aging."

2. The Science of Aging

Sinclair explains the information theory of aging and how genetic and epigenetic factors contribute to the aging process. David Sinclair: "The aging process isn't just wear and tear. We're more like computers, and there's information that we get from our parents, both genetic and epigenetic."

3. Advances in Gene Therapy

Discussion on recent advancements in gene therapy, including potential treatments that could reverse aging in human eyes by next year. David Sinclair: "If we can restore blindness in mice and now monkeys, why don't we do that already in humans? Well, we'll do it next year."

4. Ethical and Regulatory Considerations

The conversation shifts to the ethical implications and regulatory hurdles in applying new aging therapies in humans. David Sinclair: "What society has evolved to do is that, unfortunately, not everybody is well informed and can be convinced that something is safe and useful by, you know, who knows who could be a doctor, could be some snake oil salesman."

5. Personal and Broader Implications

Sinclair discusses how personal lifestyle choices and broader societal impacts could change with these anti-aging discoveries. James Altucher: "Why do they try next year? Well, the regulatory authorities want to see safety first before you stick a gene therapy into the eye of a human."

1. Consider adopting lifestyle changes recommended by aging experts, such as improved diet, regular exercise, and sufficient sleep.
2. Research and possibly integrate supplements like NMN and resveratrol under medical guidance to potentially slow aging.
3. Stay informed on the latest scientific advancements in anti-aging to understand future therapeutic options.
4. Evaluate the ethical implications and safety of experimental treatments before participation.
5. Engage with ongoing discussions and studies related to anti-aging to better understand the evolving landscape of medical science.

A Note from James:
I particularly want to reverse my aging. I'm not concerned about being able to run a mile or anything like that; I just want to reverse the aging of my brain. I feel there's a definite difference between my brain now and when I was younger. By the way, culturally, we acknowledge that the brain ages. Not only medically, but culturally, you have to adapt to being the wise older person rather than the sharp young person.

We had a great conversation with Arthur Brooks about this. He wrote an excellent book, which I can't recommend enough, called "From Strength to Strength." That podcast with Arthur Brooks changed my life in how I view my brain aging. Additionally, several podcasts with David Sinclair about the aging process have also been life-changing.

I have used the supplements he recommended and made the lifestyle changes he suggested back in 2019. David has conducted a lot of research in the five years since his book "Lifespan" was released, and I wanted to see what the current state of his research was. So, he came on the podcast.

I'm very grateful; he doesn't do many podcasts. He shared some incredible discoveries and new information, giving me real insight. We discussed everything related to what he's doing in anti-aging and what he's discovered since the last time I had him on. At the special request of our listeners, I also asked him about testosterone.

Towards the end of the podcast, I asked him about that, and his answer was very interesting. Here’s David.

Episode Description:

Today, James discusses personal motivations for wanting to reverse aging, specifically targeting brain aging. The conversation moves into the broader cultural and scientific understandings of aging, touching on insights from Arthur Brooks and David Sinclair's research. Sinclair's work on anti-aging, including lifestyle changes and supplement use recommended by him, is highlighted, mentioning his book 'Lifespan' and the progress in his research over the past five years. Key discussions include the information theory of aging, the role of DNA and epigenetics in aging, and the concept of age reversal through maintaining or restoring the epigenome's integrity. The episode covers the potential of using Yamanaka factors for age reversal, the challenges in translating these findings from mice to humans, and regulatory considerations for human trials. Sinclair also touches on his ongoing work in developing chemical cocktails for age reversal, comparing lifestyle changes to these scientific advances.

People

David Sinclair, James Altucher, Jay Yow

Companies

Leave blank if none.

Books

"From Strength to Strength" by Arthur Brooks

Guest Name(s):

David Sinclair

Content Warnings:

None

James Altucher

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James Altucher

I want to reverse my aging. I don't really care about being able to run a mile or anything like that. I just want to reverse my brain aging. I feel there's a definite difference between my brain now and my brain when I was younger. By the way, culturally, the brain we know ages not only medically, but culturally.

You have to kind of get used to being the wise older person as opposed to the sharp young person. And we had a great conversation with Arthur Brooks about this. He wrote the very excellent book, I cannot recommend it enough. It's called from strength to strength. That podcast we did with Arthur Brooks changed my life, about how I viewed my brain aging, but also my prior podcast, several podcasts with David Sinclair about the aging process, has also changed my life.

I have used the supplements he recommended. I have made the lifestyle changes he recommended. This was back in 2019, but I knew David has done a lot of research in the past five years since his book Lifespan came out, and I wanted to see what the state of his research was. So he came on the podcast. I'm very grateful he doesn't do a lot of podcasts.

He came on the podcast. He's had some incredible discoveries and new information to report on and gave me some real insight. We talked about everything related to what he's doing on anti aging, what he's discovered since the last time I've had him on. And we had a special request from people that I also asked him about testosterone. So towards the end of the podcast, I asked about that and his answer was very interesting.

And here's David.

This isn't your average business podcast, and he's not your average host. This is the James Altager show.

David Sinclair

But, yeah, this is a. Can you see this one, James? This one here is. Do you recognize those guys? I don't.

Okay, so here are their signatures. Francis Crick and Jim Watson. Okay. The founders of DNA. Or the discoverers of DNA.

Yeah. Yeah. So they're my inspiration every day. Well, it's interesting because one of the things I want to talk about is a recent paper you published, the information theory of aging, where you discuss how DNA, essentially, it's an interesting model of aging. You basically discuss how DNA loses information about who we were the moment we were born.

James Altucher

And that's what basically triggers the aging process. And if somehow we could keep that information intact or reprogram the DNA through the epigenetics, if we can keep that information intact, we could reverse aging. Am I at a 20,000 foot level? Am I summarizing the paper? Okay.

It's a very complicated paper. Yes. You did a great job. You're welcome to come work in my lab if you want. Can you give me an honorary PhD?

I'll do it. If you can give me an honorary PhD. Sure. I can write you up one. I'm not sure Harvard would like me, but we can have something for you.

David Sinclair

But, yeah. The information theory of aging has really developed since we last talked. It was about a couple of years ago. What we were proposing doing is that the aging process isn't just wear and tear. We're not just like cars that run out of gas or break down.

We're more like computers. And there's information that we get from our parents, both genetic and epigenetic. So genetic is the DNA, and the epigenetic is the control of the DNA. Because, of course, every cell is different. They need to turn the genes on in different ways.

That's the epigenome. And what I'm proposing is that in the information theory of aging, or ItoA. ITOA is that it's the loss of this control system that's the main problem during aging. And what happens is, over time, through various insults to the cells or bad living, bad lifestyles, that program that controls the DNA gets lost over time, and cells forget how to work. They become old, dysfunctional, and we get diseases and die.

A corollary of the hypothesis that's, I think, the most exciting is that unlike mutations in DNA, which are largely irreversible, the epigenome is malleable. And we believe there's a backup copy of that information in every cell that can be flipped, like a reset switch. To reinstall this epigenetic software in the body. And therefore, that would be true age reversal. And that's your theory, that there's this backup copy?

James Altucher

And what I mean, I guess the idea of DNA is that every piece of DNA contains all the information about who you are. And so somewhere there's DNA that hasn't been kind of lost information. So somewhere there's a backup that has all the correct DNA for you. That's right. And the control systems, that's the important thing.

David Sinclair

So some of the evidence that this is true or could be correct, is that we can clone animals, even monkeys, from old cells. You take a skin cell from an old monkey, you can generate a new monkey, and that monkey starts out life fresh. It's new, it's rejuvenated, and it goes on to live a normal, healthy lifespan. That tells us that the information to be young is still in cells and that, yes, we have mutations. There's no question that we lose some of the DNA, but largely the information is intact.

James Altucher

Can I ask, how would you be able to tell if it wasn't intact? So, like, let's say you took some skin cells from an old monkey and cloned it. Meaning, you know, put it in an egg, and, I don't know, how did some monkey give birth to it? I don't know, actually, what cloning really does. But how would you know that the information wasn't sorted there?

Cause the monkey would be born old or what would happen? Exactly. Exactly. The lineage of monkeys that have been cloned would eventually die out, because you'd get older and older monkeys, and the monkeys would age prematurely. But they don't.

David Sinclair

They live normally. So that, to me, says that the information is still there. You just need to reset the software. And so there's two things. One is basically, what are the habits or lifestyles that increase this information loss on the controls?

James Altucher

So it no longer kind of manages the DNA correctly, and we get diseased and die. So what are the bad habits? And then what are the ways to restore things so that. Or can you restore things so that the controls basically reset the cells if they're diseased and we're youthful again? Yeah, well, some of my colleagues get upset when I talk about age reversal in my lab.

David Sinclair

There's no doubt that we can do this. We can see that cells and even tissues as complex as the eye can be reset permanently. We can restore blindness in mice and now monkeys. If we can do that in monkeys, why don't we do that already in humans? Well, we'll do it next year.

James Altucher

Why do they try next year? Well, the regulatory authorities want to see safety first before you stick a gene therapy into the eye of a human. But it looks like we'll be able to do that next year if all goes well. But can I ask about that? Like, shouldn't I, as a human, be allowed to decide about what I want to do with my eyes, as opposed to saying, oh, well, the FDA says I'm not allowed to try this yet.

I'm going to listen to the FDA. Do you listen to the post office worker about how to live your life, or do you listen to yourself? Well, yeah, I have libertarian streaks myself. I think that everybody should have a right to do to their body what they want as long as it doesn't hurt someone else, including suicide. So as long as you're mentally stable.

David Sinclair

So I'm with you on that. What society has evolved to do, the way it's engineered now, is that, unfortunately, not everybody is well informed and can be convinced that something is safe and useful by, you know, who knows who could be a doctor, could be some snake oil salesman. And so those laws are there to protect people who don't have enough information or don't have enough education to make those decisions. Some people disagree. I just heard this morning that there's a group, I think they said it was in South America, that is establishing an area of the planet where you can do more extreme things that are not yet approved by governments.

But I'm not involved in that. I've still got my sights set on getting these medicines tested for safety and approved through regular methods. The other problem, James, is that the methods that we have right now to reverse aging, like the one I'm talking about for the eye, not anybody can just make this in their garage. Just making the material for the human trial is costing the company $10 million. So this is not cheap yet, but I am working on that.

We're working in my lab on small molecules, so chemicals that you could take as a pill, they could reverse aging, we hope, or at least slow it and do it for $10. Now, when that happens, imagine there's a drink that you can get at the gas station that truly rejuvenates you. That would be quite an interesting world. That's the one that I'm working on right now. That's the forefront of work in my lab.

James Altucher

Okay, so I know, for instance, we've talked before about NMN and resveratrol. I don't know how to say it. You just said it right. Yeah. And NR, which you're not as believer in.

But it's interesting, the guys at Thorn are big believers in NR because they figure as a precursor to NMN. We've talked about all this on other podcasts, so I won't dive too into it, but there's various debate about what supplements are anti aging, NMN, NR, resveratrol. Uh, uh, uh. Then we also spoke, spoke about Yamanaka. Factors which seem to be very likely to reduce aging, but might have side effects that are dangerous, like cancer, for instance, which would increase aging.

And, uh. Uh. So, so I don't know where you are right now with, with all this research. Maybe, maybe you can give me an update on, on that. Oh, yeah, sure.

David Sinclair

So the, the NR and the NMN story, that debate is. I'm not really, I'm not in that debate. There's a lot of people online who are pumping that up as though it's a controversial. I'm a believer in NAD and the precursors of any sort. Now, I've put a stake in developing medicines based on a whole variety of NAD precursors, both natural and synthetic, and have been working to raise money to make those into medicines for the last ten years.

So I think NR is a very interesting molecule. More studies need to be done. So the controversy, just to be clear, is not what it seems. And I'm certainly not out there promoting one thing or another. And I don't sell anything on the Internet.

Just also to be clear, if anyone sees my name on a website selling something like NMN, it's not with my permission. In fact, I spend more money than I want to each year on legal action to try and curtail that activity. Really? People are trying to sell stuff saying, David Sinclair recommends you take this every day. There's something I get alerted to.

It's constant. Yeah. Wow. I take all of them. I take NMN.

James Altucher

Well, I take NMN and I take Thorne's resveracel, which I guess is resveratrol. Well, I do something similar. I still take resveratrol in my yogurt in the morning, a teaspoon, and then the NMN, up to a gram of that. And I'm still researching it in my lab as well, trying to see what the upside downsides are, how it works. We're about to submit a paper that pinpoints how resveratrol works in the mouse, how it's really acting.

David Sinclair

But, yeah, I'm a strong believer in those two molecules. You can think of NMN or Nr as the, as the gas. So the gas that you fill up the car with the petrol for those in the commonwealth, and then the accelerator pedal is the resveratrol. So they work together on the enzymes that control aging that I work on, called the Sirtuins, and those sirtuins control the epigenome. And so it's all linked as part of this information theory of aging by taking resveratrol and nmN.

My hope, I haven't proven it yet, but my hope and belief is that it's activating my Sirtuin defenses, turning on those enzymes, giving them gas, giving the accelerator pedal a push, and keeping me younger for longer. What I can tell you so far is it hasn't hurt me. I do measure my blood work every few months, and my blood work looks fine, but clearly it's an experiment in progress. I hope one day to. To perhaps outlive my critics.

That would be a nice thing. That's the best revenge. Yeah, we'll see. And there are a fair number of those, but really, I'm just trying to keep my head down, focus on the research. And you asked me, what's the latest thing?

Because the NMN research that we did, we're still doing a bit of it. We just are about to publish. Not publish a. Submit a paper showing that NMN extends lifespan in. In mice, especially female mice.

And so that's coming. Most of my research now has been directed at understanding the software of the body. Beyond the sirtuins, what else is involved in causing aging to occur, and how do you reset that? And we had a paper published in cell in January last year that showed. That showed evidence that changes to the epigenome can drive aging.

We made a mouse. It took us 13 years to do this research, made a mouse, where we could disrupt the epigenome. We did this by creating cuts to the DNA when the mice were young. As far as we can tell, that didn't disrupt the DNA. The DNA just got put back together quite easily, but the epigenome got disrupted.

And we know that damage to cells disrupts the epigenome over time, and we'll get to this. But stopping damage to your cells is one good way to slow down aging, because it slows down epigenetic changes, slows down the software corruption. But this paper, what it showed was that we could drive aging forwards by disrupting the epigenome. And we could also use three of the Yamanaka factors. There are normally four used, but a particular subset of three was able to safely reverse aging in those mice.

James Altucher

So you disrupted the epigenome by damaging the DNA and then using three of the Yamanaka factors, which I'll ask you to explain again. But by using these, it brought the epigenome back to start again. Yeah, well, not fully. We look at how the genes are switched on and off, and we can measure all of the genes and we can see whether the majority go back to an earlier youthful pattern. And we saw that it was highly significant.

David Sinclair

But did they go back to being age zero? No. And in fact, we wouldn't want them to because age zero, as you said, is cancer. So the trick for us was we definitely are standing on the shoulders of the great Shinya Yamanaka, who discovered that the four genes, that four particular genes that are normally turned on by embryos, if you put them into adults cells in the dish, they become stem cells going back to age zero. But you don't want to do that because that's a cancer cell.

So the trick for us was to find a combination of those genes that were safe. And even though theoretically we might be causing cancer, that's a concern. But in practice, we have not seen any negative effects in our treatments in mice or in monkeys so far, which bodes well. We still need to do more work. But using three instead of four seems to be the magic recipe.

James Altucher

Why three instead of four? How did you find out which three did you try? All combinations. And why does bringing back the age of a cell to zero cause cancer? Both excellent questions.

David Sinclair

So the first is we tried for two years, and by we, I mean my students won. Cheng Lu is the student who deserves the credit. And he almost quit because it was so hard. And he. He kept causing cancer cells instead of reversing aging.

James Altucher

Why did he almost quit? Like, did he come into your office crying and said, doctor Sinclair, I'm gonna quit? It was David. And it was. Yeah, he was pretty weepy.

David Sinclair

He was resigned to failure. And, you know, Harvard students set a high bar for themselves. And after two years of failure, it's pretty tough. You know, these are students that have never failed a test in their life. And my job these days is mainly to just make sure they don't quit.

I said to won Cheng, look, I've got a really good feeling. You got to trust me. I've been doing this for 25, 30 years now. I've got a good feeling. Let's keep going.

Let's do a really good experiment and see what happens. His suggestion was to leave out one of the Yamanaka factors that is known to cause cancer. It's called Myc M Y C. And in retrospect, it's obvious you leave out the gene that is causing problems. But we hadn't tried that yet because we thought, and most people thought dogma was that you need it.

But we thought, let's just leave it out and see if it still works. And what happened was his cells went back in age but stopped at about 75% return and didn't go back 100% to age zero. And what happens when cells hit zero is they become a stem cell, and stem cells grow wildly. They don't know how to differentiate and become a tissue unless you coax them. And when you do that in animals, you get what are called teratomas, which are horrible masses of cells and it kills the animal.

So we don't want to make cells zero because they'll just keep growing. Take a quick break. If you like this episode, I'd really, really appreciate it. It would mean so much to me. Please share it with your friends and subscribe to the podcast.

James Altucher

Email me@altuchermail.com and tell me why you subscribed. Thanks.

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So when someone gets a stem cell transplant, let's say a leukemia patient needs, has gone through chemo successfully, now needs a stem cell transplant to really get rid of the leukemia. Are they getting cells like that that are age zero or are they aged a little bit? Those stem cells, they're aged a bit. They're not pure stem cells. They're not pluripotent stem cells injected.

David Sinclair

As far as I know that nobody's doing that. That would be dangerous. They differentiate them, they turn them into a cell type and then they put them back in so that the cells don't have runaway growth. I see. They take the stem cells and they maybe make them a blood cell stem cell.

James Altucher

And so now they can replace blood as opposed to just being so the epigenome doesn't tell the new stem cells. Look, new guy, you're the new guys in the camp. Here's what you do. The epigenome is not strong enough to take pluripotent stem cells and tell them what to do. It is, but it needs the right signals.

David Sinclair

And if the cells aren't in the right niche in the right part of the body, they don't get the chemical signals and then they just grow in absence of any control factors. But if you implant stem cells into the right part of the body, let's say the lining of the gut or into the brain, they will get the right signals and they may even trigger epigenetic control systems that are okay. But if you inject stem cells into your blood, they can just keep growing and you'll die from that. But the epigenome is very, very powerful. It's been neglected for a long time because we didn't have the tools to study it.

We could read DNA, but we couldn't read the epigenetic code. That's laid on top. But we finally have those tools now. And what we're doing, realizing is that the epigenome is king, you know? And this might be too much in the weeds for my listeners, but I'm really curious, where is the epigenome?

James Altucher

Like, we know that every cell's got DNA and rna and all this stuff. What's. Where's the. There's. Now there's this third thing.

I learned the two things when I was in elementary school, but I didn't know about the epigenome. Yeah, it's like, where is the matrix? What is the matrix? The epigenome are the control systems that tell gene a to be switched on and gene b to switched off. And the way the cell does that, in a simplistic sense, is it wraps up the DNA or loops it out in a loop that's accessible to the cell.

David Sinclair

And the machinery of the cell, the proteins, the DNA isn't just a flailing strand of a long chemical, six foot long in a cell. It's actually mostly bundled up with little loops where the genes can be accessed, but most of it's bundled up tightly so it cannot be accessed. That system is called the epigenome, and it changes depending on how you live and how old you are and how much stress and biological accidents happen. But most of when you're born, basically you've got these beautiful patterns of bundles and loops of DNA. That's the epigenome.

Now, what was tricky was to, first of all, show that those loops and bundles become untangled and that's causing aging. That was this paper I was telling you about. That's what we think is going on. And then the next challenge was, how do you take that DNA strand that's now lost, that pattern of bundles and loops, and might now be all mostly loops, and now the cell is just reading the wrong genes. How do you possibly get those structures to go back to where they came?

And that was why it was almost ludicrous to suggest that it was possible. Even today, I get criticized from colleagues saying age reversal. How can that be possible? Well, what we're looking for in my lab is information that tells the cell which genes to bundle up again, that have become opened up over time, and that is going to be the source of the backup copy. Exactly how that is arranged.

You might say, well, what is that? What is the information that tells the cell how to be young again? I don't know what it is. I just can tell you. I know that it's there because we can tap into it with our experiments using the Yamanaka factors and some chemicals.

James Altucher

Now, so the Yamanaka factors, are they like an epigenome to the epigenome. Because. They were there in the embryo and they were basically telling the initial cells, hey, this is how you be a human. And are you suggesting that, okay, if we get these three out of the four Yamanaka factors that essentially act like those initial stem cells that tell us how to be human, how to build an epigenome, is that what's happening? Well, we think the process is different than what Yamanaka did.

David Sinclair

It's related, but it's different in that what Yamanaka did was to erase the identity of the cells, basically strip all those bundles and loops and start again. That we're not doing. We're actually doing the opposite. We're telling the cell how to remember, how to behave, not losing its complete memory and identity. And if I draw it, if you're just listening, what I'm drawing is an inverted u shape.

There's an optimum that we're trying to reach where the cells go back in time, remember their identity. And the higher it is, the better identity they have and better function. If we go too far, then you lose it again. And that was what Yamanaka was doing to make his stem cells. And you're right that the Yamanaka factors of the epigenome to the epigenome, they are the trigger that sets forth a cascade of events that we're now elucidating that tells other proteins how to go and rearrange those loops of DNA somehow back to what they were before.

And it involves enzymes that take chemicals off DNA called methyls. There are enzymes that are involved in putting chemical tags on the packaging, proteins called histones. It's very complicated downstream of these three factors, and they seem to be the trigger. Now what's interesting is why would it work in an old mouse or an old monkey or even an old human? Why would this be true?

Why is the system still in existence? We don't need to reverse aging. Why hasn't it been lost to evolutionary time? The reason I think it still exists in us is that parts of our body regenerate. If we cut our liver in half, take it out, it'll grow back to a normal sized liver.

Cut the arm off a salamander, it'll grow back to an arm. I hypothesize in the information theory of aging that this reset of the body through the three Yamanaka factors is used normally in nature not to get younger, but to regenerate lost body parts and damaged body parts, which we, as humans, don't really do very well, but, of course, other species continue to do much better than us. I see. So because we're all sort of evolved from the same cells a billion years ago, there's some part of us that still contains that ability and that might be encoded in the Yamanaka factors. Yeah.

Remnants of this rejuvenation rebuild. Kind of like a. A deadpool kind of system that is in us, but we just don't turn it on, whereas other species do. But now, hopefully, we have the tools to turn this on and repair ourselves like we were young again. Now, would another approach be like, if we were really excellent at gene editing?

James Altucher

Like, far more than we are now, and we're getting better and better every year. In terms of genomics, if we were excellent at gene editing, could we rebuild these DNA loops and not need the Yamanaka factors or. Yeah, if we were good enough. I just. I prefer to take the approach that biology knows best.

David Sinclair

We've had more than a billion years of evolution, and we tap into what the cells like. Like to use. I think cells are smarter than us. This has been my philosophy my whole career. That said, theoretically, if we knew which genes needed to be reset in each cell type, we could do that.

It's an extremely difficult engineering problem because even adjacent cells that are microscopic distance apart might behave differently. And trying to target that system to each different cell is an overwhelmingly complex problem. Now, that doesn't mean that we couldn't, say, target nerve cells in the brain specifically to reset some of those, but I think a whole body reset currently is beyond my imagination for engineering. They would never say never. But these Yamanaka factors, what they do when you inject them in these three out of the four is essentially like a disease spread through the body, or the body part where you inject it.

James Altucher

And all these bundles that are loose fritters of DNA. Now they kind of get this wake up call. Hey, you used to be a loop. Better get back there. That's right.

David Sinclair

And how that works, we don't know. We think there are little flags on the genes that tell the cell this gene needs to be reset by two fold in a negative direction, or another gene would be five fold in a positive direction. There's some information in there. We're looking for it. We have some breakthroughs just last week that I can't yet talk about.

I think we may have found the information where and how it's stored. That tells the cell where to go and what to do, and it's a whole new biology. So I'm crossing my fingers for my students that we're on the right track. What the Yamanaka factors are, they're not that mysterious. These are proteins that engage DNA.

They find a sequence of letters in DNA. They're called transcription factors, and they find them, they stick to the DNA, and then they set off the activation of other genes. So these are genes that regulate other genes. That's all they are. But they're like a domino.

Those three dominoes get set and then the rest follows, and then the complexity ensues. But there's got to, in my view, there's got to be a program in the form of software, one dimensional software, just like DNA, but probably not DNA, that records the youthful epigenome and allows the cell to reengage and create these original structures of folding of the DNA so the cell can not just behave like it's young, but literally be young again. So if there were no regulatory hurdles, what would you personally do right now? Would you inject these three Yamanaka factors into yourself, or would you drink them? Or, like, what would you do?

James Altucher

Like, what do you see as happening? Let's say, after the regulatory hurdles, and let's say all your tests go well, what do you see happening? Yeah, well, one is hypothetical, one is reality. The reality is that we put the three genes inside a domesticated virus called an aav, and we inject it into the eye, and it infects the nerve cells and reverses the age of the optic nerve in those animals and hopefully people next year. And theoretically, you could inject it into your vein and have it infect your entire body.

David Sinclair

And that way you could see what happens when you reverse aging or turn on these factors in most of your cells. That is doable today. It'd be fairly expensive, it'd be fairly risky, but it is doable today. Would I do it hypothetically? Probably not.

I think we need a bit more safety work. But I can imagine a day where, and it's not too far away, depending on the regulator's opinion, where somebody could be flooded with these viruses. And what we've got, James, which I want to mention is, from the outset of this study, going back to 2017, we engineered or won. Cheng, my student, engineered the system to have an on off switch so that we could turn it off after we finished with it and turn it back on if we needed it again. And the way we did it, way he did it, was we just give the antibiotic doxycycline, which some people take from malaria.

The antibiotic isn't acting as an antibiotic in this context. It just acts as an on off switch for our virus. And so in the future, you could be flooded with the virus. It's in every cell, or almost every cell, but you don't turn it on until you need it. So let's say you get injured or you start to get old or you lose your eyesight, your hearing.

Then you take doxycycline for two months. In theory, if it works, you get younger, you look younger, you feel younger, your organs function better, you stop the antibiotic, and you repeat that process every five years. So I guess every organ or part of the body ages differently. Like, with eyesight, it could be your cornea, it could be the nerves in the eye, it could be the brain cells that regulate vision. With your stomach and digestion, it's another set of cells would you need.

James Altucher

But I guess if you're putting the Yamanaka factors in each organ specifically, it'll know what to do. It'll kind of like, you know, figure out the subculture of that organ, get acclimated, make friends, and then do its job accordingly. Per organ. Yeah. James, I love the way you think.

David Sinclair

It's deep thinking. The answer is yes. Somehow the Yamanaka factors know how to reset different types of cells. We haven't yet seen a cell type that does not respond to the reprogramming. And each cell type is different.

Of course, a brain cell is very different in terms of the packaging that it needs compared to a muscle cell. And so, yeah, there is a culture within the cell. Perhaps it's this system that we're trying to figure out, which is this backup copy that is specific to each cell. And so the cell individually, they know what they need to go back to. And it's perhaps different, literally, for every cell in the body, the pattern that needs to go back to, and we don't even know yet how and when that is laid down.

Is it when the baby is born? Is it when you're a teenager, is it different for different organs? Does your liver become set in youth at two and your brain at 20? These are really interesting questions that we want to address. So what does that determine how much you need to age the stem cells, basically, for each Oregon or.

Well, so let's say that the backup copy of youth is a chemical that gets added to DNA. Just hypothetically, that might be the method. And so there's an enzyme that puts a chemical on DNA that says, this gene needs to stay at this level to be young. But over time, it drifts away, it becomes unraveled, and now it's causing problems. There's a detector of that chemical on the DNA that the Yamanaka factors cause to go there, and then it uses that chemicals tag to say, all right, this gene.

Even though it's unraveled, this little chemical tag says it actually should be bundled. So let's bundle it up. And that happens 22,000 times across the entire genome, allowing the, the cell to repackage its DNA earlier. But what I'm saying is maybe these little chemical tags on the DNA get laid down at different times during development. Or maybe you wake up on your 12th birthday and suddenly you've got all these tags on your body, and that's your reset stage.

We don't know that. It's just speculation.

Unknown

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James Altucher

You know, I'm curious about, like, the brain in particular. Like, the other day. So this is a specific example. The other day, I learned how to ski for the first time. I went skiing for the first time.

And at one point, the instructor and I were walking, and we passed these little kids, and they waved hi to the instructor. And I said, oh, did you give lessons to those kids? And he said, yeah, three weeks ago, I gave him a couple of lessons, and I said, what do you mean? They're, they're, they're on the line for the black diamond hill. Like, they're going.

Like I would. I'm not gonna be able to do that in three weeks. They're going down the hardest hill on this mountain just three weeks after you're giving lessons. And I watch them, and they're just, like, effortless, you know, they're not. It's almost like they're not using any muscles.

They're just cruising on down. They're going as fast as possible. They're, they're fearless. And I don't believe the example, the cliche that, oh, they don't have as far to fall, so they're not that worried about falling. Like, they were literally doing it differently because of their brain and mindset than I would do it.

And what is happening in. There's something in the aging process, but a difference between me and those kids, like what has happened to the brain. Yeah. Oh, well, yeah, you're right. The young brain is very plastic, learns very quickly.

David Sinclair

Old brains don't. We know that. The reason I believe that happens is you're aging due to epigenetic changes. So your nerve cells are starting to turn on genes that shouldn't be turned on in the brain. So your nerve cells might be starting to behave a bit like skin cells, which is not going to help you learn.

It's not going to help you remember things well. And that's why we did a study in mice where we aged the mice, and they were hard of learning. You could say they had dementia, and then we could reverse the age of the brain in those old mice and we could ask the question, can they learn like they were young again? And the answer is, yes, they can. So I really think that the inability to learn is just a matter of epigenetic aging.

James Altucher

So, like. And you were able to reverse this using the three out of four Yamanaka factors? It was part of those experiments, yeah. Is there. Okay.

And I'm just asking selfishly, like, I want to reverse the aging in my brain right now. I want to learn like when I was a kid. Again, what can I do? Well, until we have viruses that are safe for injection into your veins, which is a while away, what we're working on are chemicals that will do the same thing so that it could be swallowed or put on the skin or injected. And we published a paper, when was it?

David Sinclair

July last year. The first proof of concept study that we could find chemical cocktails that reversed the age of cells and restored that epigenome. And we've come a long way since then. It's not published yet, but we are down to some really exciting chemicals that could theoretically be put into a drink and consumed that may rejuvenate the body, improve memory, for example. I think, don't get me wrong, I'm not going to be putting this into a drink just this year.

But I think if the animal studies work out and we do some human studies, then that's, you know, it's a goal worthy of my attention. And I'm not trying to figure out the chemicals just so I could go to the store and buy these. But is it like NMN related or is it Yamanaka related? Like, what types of chemicals are these? Yeah, so these are vitamin D, vitamin.

K. It's not that simple.

There's cocktails. So there isn't just one answer. But we're at a point where we now have it down to one chemical that can reverse the age, ostensibly reverse the age of cells in the dish, can treat human cells, make them younger, make them grow, even if they've stopped dividing senescent cells. And, you know, barring any safety issues, which, of course, you can't ignore, it could be made available. So right now, could you go out and buy some of these?

Well, I do know that some people have looked at our publication from July and have started taking those chemicals or surrogates of those, but they're doctors. You need prescription. So it's not that simple. You can't just go out and buy it. And it's not just a vitamin.

It's a bit more complicated than that. But just trust that I'm now laser focused on making this come true. If it's possible, if it's safe. It's not here yet, but it will be if I can do anything about it. When you last came on to talk about this, I did follow a lot of your advice in terms of intermittent fasting, occasional high intensity exercise, of course, sleep.

James Altucher

And the various supplements you take, I take. And how much of these lifestyle factors are sufficient to compare with this chemical cocktail that you're putting together? We haven't put them side by side, but I don't think anything that is out there compares to this. We don't see the usual suspects. Rapamycin, NMN doing this reset.

David Sinclair

They might assist in the process, but these chemicals are in a different league of their own. And so I think this is probably why people are skeptical about my use of the term age reversal, because they're not seeing the results that I see in my lab. And we clearly see that aging is reversible. These new discoveries are really powerful, more powerful than anything I've seen before. So reversible in the sense, like, let's take an extreme example, and this is something we almost, I believe we briefly talked about back in 2020 or 2019.

James Altucher

Can a mouse, can a female mouse who has reached menopause reverse menopause? We did that. And by we, I mean my team in Australia, Lindsay Wu, was the first author. Yeah. So we gave them old mice the equivalent age, human age of 70, 65, maybe we gave the men a man and it was just a month later that they were able to produce viable eggs and had normal offspring.

David Sinclair

And that, as far as I am aware, is the only known, or at least it was the first known way to reverse what we call mousopause. So that's incredible. But that's not what you're talking about with this new chemical cocktail. You're talking about reversing aging with. It's different.

What worked in the mice was we stabilized their DNA, and that's the main problem with infertility in females. The eggs trash their chromosomes, and there was a protein, one of the sirtuins, that actually was the problem. And by raising nad, we could make sure the chromosomes were nicely packaged in the egg. An old egg, by the way, the chromosomes are all torn apart. It's quite terrible.

There's no way you're going to produce an offspring for one of those. But it's different. It's different. This new age reset isn't just for eggs. It seems to work on every cell type.

You don't just go back a little bit, you seem to go back a lot. 50%, 75% in age and reset the pattern of what we call gene expression. And what's interesting is it's not just a temporary reset. We've co published a paper recently that when we essentially cure glaucoma in a mouse and turn off the Yamanaka factors, the effect continues. It's not that you need to keep the factors on.

It's truly a reset. And then the mouse gets old again, and then you just can keep resetting. We know we can reset the body at least twice. I'm not sure there's actual limit to it other than in these experiments. The mice got old and died, but their eyes were beautiful at the end of the experiment.

But, yeah, so it's, you know, I'm looking forward to us getting better at reprogramming the body of mice so we can make them live longer. There was a recent study that was published, not from my lab, but a group that used our system and they gave it to old mice. They put the Yamanaka virus into the vein instead of the eye. And those mice were very old, and their remaining lifespan was doubled. 109% extra life, which is a good beginning, but I would love to be able to make a mouse that could live for two, three times.

But the technology is not really there yet. The biggest obstacle is getting the virus into all the cells evenly. And viruses like to pile up in the liver and a few other places. And so what people are doing, not me, but people who have the skill in viruses, they're engineering viruses and even other types of delivery vehicles, like nanoparticles, that can evenly spread across the body and deliver genes. So let's say there's someone like you and a lab like yours in China, and I'm assuming there must be labs working in China on similar things.

James Altucher

Maybe I'm wrong. Maybe I'm not. But, you know, they have no ethical barriers to what they're trying. Wouldn't they already be injecting humans with this? And we would start to know what.

What results they're getting? Um, I mean, possibly. Possibly. Uh, I haven't heard about it. Um.

David Sinclair

It wouldn't surprise me, though, if. If some people in South America started doing this. I've heard that people are doing gene therapy on themselves already down there. So this is not too far from. That and for you to prove.

James Altucher

Okay, so first step is you proved, oh, there's some effect in mice. How do you then prove safety in humans? Do you have to get humans to agree to the risks and get injected with small amounts or what happens? Yeah. So that's been my work with the company that I co founded.

David Sinclair

It's called Life Biosciences here in Boston. They've been working since 2018 on this. And so you do a lot of studies in mice to see what the mice can tolerate. You turn it on for the rest of their life, see if they get cancer. The answer is no.

You inject it in the whole body. Do they get cancer? The answer is no, so far. And then what we did, the company did. I shouldn't say we, but the company did studies in monkeys.

So they injected the virus and turned it on in the retinas of monkeys that had poor vision, and their vision improved. And there was no issue with the safety, seemingly. And so they're doing some more of those studies. And then with that data, our plan is to go to the FDA, who we're already talking to, so they're aware of our plans and giving us some advice, or at least pointers. I don't know if they're allowed to give advice, but they definitely give feedback about what we need to do for them to approve a human study in the US.

And things look good. I don't see any obstacle currently, why we shouldn't be asking for volunteers who are blind as early as this time next year, and they have to be volunteers. Of course, it's a clinical trial, but if you wake up blind, which can happen, you get a stroke in the back of the eye, you know, what have you got to lose?

If I was blind, I would try it. Is it kind of a. Not to use the word here, but is it a double blind trial in the sense that some people will get the cure and some people will not? And you don't know who is who? Well, the plan is that everybody will get the treatment just at different stages.

So some people will get it early, some people will get the antibiotic later, and so each person can be their own control. But, yeah, we don't currently plan to leave anybody out of this trial. And then how long does it take to determine safety? Do they have to live out their lives and then, you know, it's safe? No, I don't think so.

So, you know, you're so. It's beyond my area of expertise. My understanding, though, is because there's no current treatment for blindness, and you can't reverse glaucoma. Currently, the FDA and regulators around the world look more favorably on treatments where there's nothing else you can do. So my hope, actually, is that those studies, if they're successful, we do another large scale study, and that would be sufficient for the drug to be approved.

James Altucher

It's really fascinating. And then, I guess once it's safe, I don't know what phase that is, phase one or phase two. Then you. Then you start seeing what's the next phase after that. So, phase one is safety.

David Sinclair

This is different because it's the eye. You get the safety and the efficacy, the results in the same trial. So this is a phase one, two study. So then, if all goes well, fingers crossed, what you're left with is a phase three study, which is expanding it into hundreds of patients, maybe thousands, to see how safe it is. Given that it's a gene therapy, probably the number of patients will not be in the thousands, like something like a diabetes trial would.

So I think that a phase three probably would take one to two years. That's typically what they take. So, if you want to know when is this available on the market to everybody in the US? You know, we're still a few years away, and I always say a few years away, and it ends up being more so, but we will see. What's exciting to me is the eye is a much faster path than something like diabetes, where you need to be testing it for a long time for safety, and you have to spend a couple of years testing it before you can even see if it works with.

James Altucher

The same drug, though, that works on the eye, have off label use for diabetes. If you inject it in the gut, wherever diabetes happens. Well, I'm aware of research that I'm an author on that these factors help with blood pressure. I'm not aware of it helping with diabetes in a mouse yet. We haven't tested that just to address that.

David Sinclair

But can it be used off label? Well, I wouldn't condone that. Right. That said, off label use of drugs is used all the time, especially for compassionate use. And, you know, I'm just wondering, though.

James Altucher

If the cocktail's specific for the eye. Like, it's probably.

David Sinclair

Yeah, the type of virus is better for the eye than the whole body. You'd want to re engineer it to infect the whole body. So specifically, we're using what's called an aav number two for the eye in the mouse whole body. We use aav nine. So probably it's not the best to use the I version.

James Altucher

Well, it all sounds very interesting. I'm really excited about all the, like, you wrote the book lifespan. What year was it? 2019 or 2018. And we spoke about that several times.

And it's a fascinating read about aging and your approach to it. You know, your approach as aging as a disease rather than just something we should accept. And all the different research you summarize. And it's very exciting now to see how five years later where the research has taken you. And I didn't know about any of these advances that you have, and.

Oh, yeah. Yeah. David, there was one question I wanted to ask. I had a podcast recently, and, okay, this started off, I was speaking at a men's group. There were several hundred men on this men's group, and I was speaking about some random thing, and suddenly everybody started talking about testosterone.

I'm 56 years old, and people were asking me, do you take testosterone? Everybody was saying, you have to take testosterone. You have to take testosterone. And people were saying it's an anti aging thing, testosterone for men. And we posted this clip on some social media, and a lot of people were arguing against this.

There was a whole battle in the comments that I was not involved in because I don't know anything. But what's your stance on testosterone? And this has nothing to do with anything you've been talking about, but I'm just curious about what your stance is on this in terms of aging and male aging and so on. Yeah, so I know a fair bit about this. One of my good friends and collaborators with the clinical trials actually has done a lot of testosterone studies in humans.

David Sinclair

I'm hearing it, really from the horse's mouth here. There's a lot of data, and it's dangerous to summarize. I will anyway. Testosterone is helpful for some things. Maintaining and building muscle mass.

Yes. Is that good for old men? Absolutely. We lose muscle mass all the time. Does it extend lifespan?

Is it true anti aging? Is it slowing down the process? The answer there seems to be no. So it's in between. It's useful, it's helpful during aging, but it's not an anti aging medicine.

And then the third thing I want to add is I work with a lot of people who come to me for advice, and often it's, should I take testosterone? I've seen some really good results, naturally building up testosterone levels, working on the larger muscles of the body, like your legs and your back. Tongkat Ali, for instance, is a supplement that's been shown time and time again to raise testosterone. And speaking for myself, I naturally raise my own testosterone through those means and don't have to take it. What was the song that you mentioned?

Oh, tongkat. Tongkat. And then a l I. It's a southeast asian plant extract. And it helps, actually.

James Altucher

Jay, do you have some kind of southeast asian insight into this? Well, yeah, because this is what we usually take when. Oh, so I'm from Malaysia, but Tongkat alley is what we usually advise people would take in Southeast Asia. That's why I'm like, oh, I know that name. It's very familiar.

David Sinclair

Yeah. Well, the other thing that's becoming popular is taking low dose Viagra, or sidenophil. These are nitric oxide donor medicines. And low dose seems to be helpful in maintaining what's called endothelial function, blood vessels health. And that declines with age.

And it definitely will not. Definitely, but it probably will help your sex life as well. The goal, though, is to keep your blood vessels youthful and flowing. And so I'm currently trying that. And it does seem to give me seemingly the benefits of exercise without having to exercise a lot.

It's just my personal, my personal experience. I can't say it's a clinical trial, but I did want to mention that because I've heard it from many doctors that this is a thing that they're looking into and advising their patients. It's so funny. I can't imagine taking low dose Viagra in order to perform better at a chess tournament, for instance. It could help, though.

Yeah, I'm just trying it out. I like to experiment to see what works and what doesn't. But, yeah, that's something that, you know, it's got this stigma because it's an erectile dysfunction drug, but really it was developed to help with blood flow in the beginning. And my mother was on it, actually, because she had lung cancer and one lung removed. And I remember trying to get Viagra from my mother and getting all these pop up ads on my computer for Viagra.

And I was thinking, it's not for me, but never say never. That's funny. Well, okay, David, once again, thank you for spending the time while you're saving civilization and the human species. Thank you for spending the time on the podcast. I really appreciate it.

James Altucher

I hope we can update it again at some point. And, yeah, thanks for coming on. You're welcome. James. Yeah.

David Sinclair

I get asked to go on podcasts a lot, and I typically don't because I'm focused on the research. Obviously, I love what you do. People should read your books. They're awesome. Oh, I appreciate it.

James Altucher

Thank you. Appreciate the really great questions. What's special about your podcast? Thank you.

Unknown

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James Altucher

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Unknown

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