The Secret to Longevity: David Sinclair's Revolutionary Anti-Aging Insights

27:06That 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. But 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, the Yamanaka factors are 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.

27:53And 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, right? 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, right? If we cut our liver in half, take it out, it'll grow back to a normal size liver.

28:38Cut 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 Deadpool kind of system that is in us, but we just don't turn it on, whereas other species do.

29:29But 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, 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? Yeah, if we were good enough. I prefer to take the approach that biology knows best. We've had more than a billion years of evolution and we tap into what the cells like to use. I think cells are smarter than us. This has been my philosophy my whole career.

30:09That 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, though never say never. But these Yamanaka factors, what they do when you inject them in, these three out of the four, is they essentially, like a disease spread through the body or the body part where you inject it 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.

31:08That's right. 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 twofold in a negative direction or another gene would be fivefold 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.

31:44These 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 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 re-engage 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.

32:40So if there were no regulatory hurdles, what would you personally do right now? Would you inject these three yamanaka factors into yourself and or would you drink them or like what would you do like what what do you see is happening let's say after the regulatory hurdles and and let's say all your tests go well what do you see happening yeah um well you know one is hypothetical one is reality the the reality is that we 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.

33:27And theoretically, you could inject it into your vein and have it infect your entire body. 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 Chang, 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.

34:29And the way we did it, the 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.

35:05You 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, uh, you know, stomach and digestion. It's another set of cells. Would you need, 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, the cult, the subculture of that organ, you know, get acclimated, make friends and then do its job accordingly per organ.

35:47Yeah. James, I love the way you think. 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.

36:28And 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 organ? 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.

37:11And 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 chemical 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 cell to repackage its DNA earlier. And what I'm saying is maybe these little chemical tags on the DNA get laid down at different times during development.

38:04Or maybe it's all, you know, 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.

38:30you 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 high 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 going to be able to do that in three weeks.

39:07They'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, 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 fearless. And I don't believe the example, the cliche that, oh, they don't have as far enough 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, And there's something in the aging process, but a difference between me and those kids.

39:42Like what has happened to the brain? Yeah. Well, yeah, you're right. The young brain is very plastic, learns very quickly. 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.

40:22And 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. So like, and you were able to reverse this using the three out of four Yamanaka factors as 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.

41:02What 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? 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 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.

41:47But 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 chemicals. Is it 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.

42:33And, 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 a 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, you know, 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.

43:18You know, when you last came out to talk about this, I did follow a lot of your advice like in terms of intermittent fasting, you know, occasional high-intensity exercise, of course, sleep 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. They might assist in the process, but But these chemicals are in a different league of their own.

44:09And 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. And 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. 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.

44:51Yeah, so we gave them old mice, the equivalent age, a human age of 70, 65 maybe. We gave them NMN and it was just a month later that they were able to produce viable eggs and had normal offspring. And that, as far as I'm aware, is the only known, or at least it was the first known way to reverse what we call mousipores. 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.

45:34And 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. And you don't just go back a little bit, seem to go back a lot, you know, 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.

46:13We've co-published a paper recently that when we essentially cure glaucoma in a mouse and turn off the Yamanaka factors, the effect continues, right? 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 a 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.

46:57There 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.

47:48so 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 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. I haven't heard about it. It wouldn't surprise me though 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.

48:34And for you, to prove... 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. 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 or the answer is no. You inject it in the whole body, do they get cancer? The answer is no so far.

49:15And 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 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.

49:56And 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, 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 again, you don't know who is who? Well, the plan is that everybody will get the treatment just at different stages.

50:38So 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 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.

51:18So 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. 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 start seeing. What's the next phase after that? So phase one is safety. 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 slash two study. So then if all goes well, you know, 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.

52:08Given 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. 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.

52:50Would the same drug though that works on the eye have off-label use for diabetes if you inject it in the gut or 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. 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. I'm just wondering, though, if the cocktail is specific for the eye, like it's programmed for the eye. Yeah, the type of virus is better for the eye than the whole body.

53:39You'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 aav9 so probably it's not the best to use the i version well it all sounds very interesting i i i'm really excited about all the like you wrote the book lifespan what year was it 2019 or 2018 and um we spoke about that several times and it's a fascinating read about aging and your approach to it you know your your approach as aging as a disease rather than just something we should accept and all the different research you summarize and and it's very exciting now to see how five years later where the research has taken you and and i didn't know about any of these advances that that you have and oh yeah yeah david there was one question i i wanted to ask i had a podcast recently and okay this started off i was speaking um at a men's group.

54:45There 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 to 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?

55:22This has nothing to do with anything you've been talking about, but I'm just curious 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. And so 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.

56:08Does 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, you know, 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.

56:54And speaking for myself, I naturally raise my own testosterone through those means and don't have to take it. What was the supplement you mentioned? oh tongkat t-o-n-g-k-a-t and then a-l-i uh to south uh east asian plant extract and it helps actually jay do you have some kind of southeast asian insight into this well yeah because uh this is what we usually take when oh so i'm from malaysia but uh tongkat ali is what we usually advise people would take in southeast asia that's why i'm like oh i know I know that name. It's very familiar. Yeah. Well, the other thing that's becoming popular is taking low-dose Viagra or Sidenafil.

57:40These are nitric oxide donor medicines, and low-dose seems to be helpful in maintaining what's called endothelial function, your 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 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.

58:28It'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'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 for 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.

59:06That'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. I hope we can update it again at some point and yeah, thanks for coming on. You're welcome, James. Yeah, 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. Thank you. I appreciate the really great questions. That's what's special about your podcast. Thank you.

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