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

[00:00:00] I want to reverse my aging.

[00:00:10] I don't really care about being able to run a mile or anything like that.

[00:00:14] I just want to reverse my brain aging.

[00:00:17] I feel there's a definite difference between my brain now and my brain when I was younger.

[00:00:23] By the way, culturally, the brain we know ages not only medically, but culturally you

[00:00:29] have to kind of get used to being the wise older person as opposed to the sharp young

[00:00:34] person.

[00:00:35] And we had a great conversation with Arthur Brooks about this.

[00:00:39] He wrote the very excellent book, I cannot recommend it enough called From Strength

[00:00:43] to Strength.

[00:00:44] That podcast we did with Arthur Brooks changed my life about how I viewed my brain aging.

[00:00:48] But also my prior podcast, several podcasts with David Sinclair about the aging process

[00:00:54] has also changed my life.

[00:00:56] I have used the supplements he recommended.

[00:00:58] I have made the lifestyle changes he recommended.

[00:01:00] This was back in 2019.

[00:01:02] But I knew David has done a lot of research in the past five years since his book Lifespan

[00:01:06] came out and I wanted to see what the state of his research was.

[00:01:10] So he came on the podcast.

[00:01:12] I'm very grateful.

[00:01:13] He doesn't do a lot of podcasts.

[00:01:14] He came on the podcast.

[00:01:15] He said some incredible discoveries and new information to report on and gave me some

[00:01:21] real insight.

[00:01:22] We talked about everything related to what he's doing on anti aging, what he's discovered

[00:01:26] since the last time I've had him on.

[00:01:28] And we had a special request from people that I also asked him about testosterone.

[00:01:33] So towards the end of the podcast, I asked about that and his answer was very interesting.

[00:01:39] And here's David.

[00:01:52] Show.

[00:02:03] But yeah, this is a Can you see this one, James?

[00:02:05] This one here is a recognize those guys.

[00:02:09] I don't.

[00:02:10] Okay, so that here are their signatures.

[00:02:13] Francis Crick and Jim Watson.

[00:02:15] Okay, the founders of DNA or the discoverers of DNA.

[00:02:18] Yeah, yeah.

[00:02:19] So they're my inspiration every day.

[00:02:23] Well, it's interesting because one of the things I want to talk about is a recent paper

[00:02:27] you published, the information theory of aging, where you discuss how DNA essentially

[00:02:33] lose it's an interesting model of aging.

[00:02:36] You basically discuss how DNA loses information about who we were the moment we were born.

[00:02:43] And that's what basically triggers the aging process.

[00:02:47] And if somehow we could keep that information intact or reprogram the DNA through the epigenetics,

[00:02:55] if we can keep that information intact, we could reverse aging.

[00:02:58] Am I at a 20,000 foot level?

[00:02:59] Am I summarizing the paper?

[00:03:01] Okay.

[00:03:02] It's a very complicated paper.

[00:03:03] Yes, you did a great job.

[00:03:06] You're welcome to come work in my lab if you want.

[00:03:08] Give me an honorary PhD.

[00:03:11] I'll do it if you give me an honorary PhD.

[00:03:13] Sure, I can write you up one.

[00:03:16] I'm not sure Harvard would let me, but we can have something for you.

[00:03:20] But yeah, the information theory of aging has really developed since we last talked.

[00:03:25] It was about a couple of years ago.

[00:03:29] What we were proposing is that the aging process isn't just wear and tear.

[00:03:34] We're not just like cars that run out of gas or break down.

[00:03:39] We're more like computers.

[00:03:40] And there's information that we get from our parents, both genetic and epigenetic.

[00:03:46] So genetic is the DNA and the epigenetic is the control of the DNA.

[00:03:50] Because of course, every cell is different.

[00:03:52] They need to turn the genes on in different ways.

[00:03:54] That's the epigenome.

[00:03:57] And what I'm proposing is that in the information theory of aging or ITOA, or

[00:04:01] I-T-O-A, is that it's the loss of this control system that's the main problem

[00:04:06] during aging.

[00:04:07] And what happens is over time through various insults to the cells or bad living,

[00:04:13] bad lifestyles, that program that controls the DNA gets lost over time.

[00:04:20] And cells forget how to work.

[00:04:21] They become old, dysfunctional, and we get diseases and die.

[00:04:26] A corollary of the hypothesis that's I think the most exciting is that

[00:04:31] unlike mutations in DNA which are largely irreversible, the epigenome

[00:04:35] is malleable.

[00:04:37] We believe there's a backup copy of that information in every cell that can

[00:04:41] be flipped like a reset switch to reinstall this epigenetic software in the body.

[00:04:47] And therefore, that would be true age reversal.

[00:04:49] And that's your theory that there's this backup copy.

[00:04:52] And I guess the idea of DNA is that every piece of DNA contains all

[00:05:00] the information about who you are.

[00:05:02] And so somewhere, there's DNA that hasn't been lost information.

[00:05:08] So somewhere, there's a backup that has all the correct DNA for you.

[00:05:14] That's right.

[00:05:15] And the control systems, that's the important thing.

[00:05:18] So some of the evidence that this is true or could be correct is that we can clone

[00:05:25] animals, even monkeys from old cells.

[00:05:30] You take a skin cell from an old monkey, you can generate a new monkey.

[00:05:34] And that monkey starts out life fresh.

[00:05:37] It's new.

[00:05:37] It's rejuvenated.

[00:05:39] And it goes on to live a normal, healthy lifespan.

[00:05:41] That tells us that the information to be young is still in cells.

[00:05:47] And that yes, we have mutations.

[00:05:49] There's no question that we lose some of the DNA.

[00:05:51] But largely, the information is intact.

[00:05:54] Can I ask, how would you be able to tell if it wasn't intact?

[00:05:58] So let's say you took some skin cells from an old monkey and

[00:06:03] cloned it, meaning put it in an egg and I don't know,

[00:06:08] how did some monkey give birth to it?

[00:06:10] I don't know actually what cloning really does.

[00:06:11] But how would you know that the information wasn't sort of there?

[00:06:15] Because the monkey would be born old or what would happen?

[00:06:19] Exactly, exactly.

[00:06:20] The lineage of monkeys that have been cloned would eventually die out

[00:06:26] because you get older and older monkeys.

[00:06:29] And the monkeys would age prematurely, but they don't.

[00:06:31] They live normally.

[00:06:33] So that to me says that the information is still there.

[00:06:36] You just need to reset the software.

[00:06:39] And so there's two things.

[00:06:41] One is basically, what are the habits or lifestyles that increase

[00:06:46] this information loss on the controls so it no longer kind of manages

[00:06:51] the DNA correctly and we get diseased and die?

[00:06:54] So what are the bad habits?

[00:06:56] And then what are the ways to restore things or can you restore

[00:07:01] things so that the controls basically reset the cells if they're

[00:07:04] diseased and we're youthful again?

[00:07:08] Yeah, well, some of my colleagues get upset when I talk about age

[00:07:11] reversal. In my lab, there's no doubt that we can do this.

[00:07:15] We can see that cells and even tissues as complex as the eye

[00:07:18] can be reset permanently.

[00:07:21] We can restore blindness in mice and now monkeys.

[00:07:24] If we could do that in monkeys, why don't we do it already in humans?

[00:07:26] Well, we'll do it next year.

[00:07:29] Well, the regulatory authorities want to see safety first before you

[00:07:33] stick a gene therapy into the eye of a human.

[00:07:35] But it looks like we'll be able to do that next year if all goes well.

[00:07:39] But can I ask about that?

[00:07:40] Like, shouldn't I as a human be allowed to decide about what

[00:07:43] I want to do with my eyes as opposed to saying, oh, well,

[00:07:46] the FDA says I'm not allowed to try this yet.

[00:07:48] I'm going to listen to the FDA.

[00:07:49] Like, like, do you listen to the post office worker about how

[00:07:52] to live your life or do you listen to yourself?

[00:07:55] Well, yeah, I'm I have libertarian streaks myself.

[00:08:01] I think that everybody should have a right to do to their body

[00:08:03] what they want as long as it doesn't hurt someone else,

[00:08:07] including suicide.

[00:08:09] So as long as you're mentally stable.

[00:08:12] So I'm with you on that.

[00:08:15] What society has evolved to do the way it's engineered now is that

[00:08:20] unfortunately, not everybody is well informed

[00:08:23] and can be convinced that something is safe and useful by,

[00:08:27] who knows who could could be a doctor, could be some snake oil salesman.

[00:08:31] And so those laws are there to protect people who don't have

[00:08:36] enough information or don't have enough education to make those decisions.

[00:08:40] Some people disagree.

[00:08:41] I just heard this morning that there's a group,

[00:08:44] I think they said it was in South America

[00:08:47] that is establishing an area of the planet where you can do more extreme

[00:08:52] things that are not yet approved by governments.

[00:08:55] But I'm not involved in that.

[00:08:57] You know, I've still got my sights set on getting these medicines

[00:09:00] tested for safety and approved through regular methods.

[00:09:05] The other problem, James, is that the methods that we have right now

[00:09:08] to reverse aging like the one I'm talking about for the eye,

[00:09:12] not anybody can just make this in their garage.

[00:09:14] Just making the material for the human trial is costing

[00:09:18] the company 10 million dollars.

[00:09:21] So this is not cheap yet.

[00:09:22] But I am working on that.

[00:09:24] We're working in my lab on small molecules

[00:09:27] or chemicals that you could take as a pill.

[00:09:30] They could reverse aging, we hope, or at least slow it

[00:09:33] and do it for ten dollars.

[00:09:35] Now, when that happens, imagine there's,

[00:09:38] you know, a drink that you can get at the gas station

[00:09:40] that truly rejuvenates you.

[00:09:42] That would be quite an interesting world.

[00:09:45] That's the one that I'm working on right now.

[00:09:47] That's the forefront of work in my lab.

[00:09:50] Well, OK, so I know, for instance, we've talked before about

[00:09:54] NMN and Resveratrol.

[00:09:59] I don't know how to say it.

[00:10:00] You just said it right.

[00:10:01] Yeah. And NR, which you're not as a believer in.

[00:10:04] But it's interesting.

[00:10:05] The guys at Thorin are big believers in NR because they figure

[00:10:08] as a precursor to NMN.

[00:10:12] You know, we've talked about all this on other podcasts,

[00:10:14] so I won't dive too into it.

[00:10:17] But there's various debate about what supplements are anti-aging.

[00:10:20] NMN, NR, Resveratrol.

[00:10:23] Then we also spoke about Yamanaka factors,

[00:10:26] which seem to be very likely to reduce aging,

[00:10:30] but might have side effects that are dangerous like cancer,

[00:10:33] for instance, which would increase aging.

[00:10:36] And so I don't know where you are right now with all this research.

[00:10:40] Maybe maybe you can give me an update on that.

[00:10:44] Yeah, sure. So the the NR and the NMN story

[00:10:50] that debate is.

[00:10:52] I'm not really I'm not in that debate.

[00:10:54] There's a lot of people online who are pumping that up as though

[00:10:57] it's a controversial.

[00:10:59] I'm a believer in NAD and the precursors of any sort.

[00:11:04] Now, I've put a stake in developing medicines based on

[00:11:08] a whole variety of NAD precursors, both natural and synthetic,

[00:11:11] and have been working to raise money to make those into medicines

[00:11:15] for the last 10 years.

[00:11:17] So I don't.

[00:11:19] I think NR is a very interesting molecule.

[00:11:21] More studies need to be done.

[00:11:23] So the controversy, just to be clear, is not what it seems.

[00:11:27] And I'm certainly not out there promoting one thing or another.

[00:11:31] And I don't sell anything on the Internet.

[00:11:33] Just also to be clear, if you see if anyone sees my name

[00:11:37] on a website selling something like NMN, it's not it's not with my permission.

[00:11:42] In fact, I spend more money than I want to each year

[00:11:46] on legal action to try and curtail that activity.

[00:11:49] Really? People are trying to sell stuff saying David Sinclair recommends

[00:11:52] you take this every day.

[00:11:54] There's something I get alluded to.

[00:11:55] It's it's constant. Yeah.

[00:11:57] Wow. But I think I take all of them.

[00:12:00] I take NMN.

[00:12:01] Well, I take NMN and I take Thorne's Reserva Cell,

[00:12:04] which I guess is resveratrol.

[00:12:07] Well, I do something similar.

[00:12:09] I still take resveratrol in my yogurt in the morning,

[00:12:13] a teaspoon, and then the NMN.

[00:12:16] Up to a gram of that.

[00:12:18] And I'm still researching it in my lab as well,

[00:12:21] trying to see what the upside downsides are, how it works.

[00:12:25] We're about to submit a paper that

[00:12:27] that pinpoints how resveratrol works in the mouse, how it's really acting.

[00:12:32] But yeah, I'm a strong believer in those two molecules.

[00:12:35] You can think of NMN or NR as the as the gas.

[00:12:39] So the gas that you fill up the car with,

[00:12:43] the petrol for those in the the Commonwealth.

[00:12:45] And then the accelerator pedal is the resveratrol.

[00:12:48] So they work together on the enzymes that control

[00:12:52] aging that I work on called the sirtuins.

[00:12:55] And those sirtuins control the epigenome.

[00:12:58] And so it's all linked as part of this information theory of aging.

[00:13:01] And so by taking resveratrol and NMN,

[00:13:05] my hope, I haven't proven it yet, but my hope and belief is that

[00:13:09] it's activating my sirtuin defenses, turning on those enzymes

[00:13:13] giving them gas, giving the accelerator pedal a push and keeping me younger for longer.

[00:13:19] What I can tell you so far is it hasn't hurt me.

[00:13:20] I do measure my blood work every few months

[00:13:23] and my blood work looks fine.

[00:13:26] But, you know, it clearly it's an experiment in progress.

[00:13:29] I hope one day to perhaps outlive my critics.

[00:13:33] That would be a nice thing.

[00:13:35] That's the best revenge.

[00:13:37] Yeah, we'll see.

[00:13:40] And there are a fair number of those.

[00:13:42] But really, I'm just trying to keep my head down, focus on the research.

[00:13:46] And you asked me what's the latest thing?

[00:13:48] Because the NMN research that we did, we're still doing a bit of it.

[00:13:51] We just are about to publish, not publish, a submitted paper

[00:13:55] showing that NMN extends lifespan in mice,

[00:13:59] especially female mice.

[00:14:01] And so that's that's coming.

[00:14:05] Most of my research now has has been directed at understanding

[00:14:09] the software of the body beyond the sirtuins.

[00:14:12] What else is involved in causing aging to occur?

[00:14:16] And how do you reset that?

[00:14:18] And we had a paper published in Cell in January last year

[00:14:23] that showed that, or showed evidence

[00:14:27] that changes to the epigenome can drive aging.

[00:14:30] So we made a mouse.

[00:14:32] Took us 13 years to do this research.

[00:14:34] Made a mouse where we could disrupt the epigenome.

[00:14:38] We did this by creating cuts to the DNA when the mice were young.

[00:14:43] As far as we can tell, that didn't disrupt the DNA.

[00:14:45] The DNA just got put back together quite easily.

[00:14:48] But the epigenome got disrupted.

[00:14:50] And we know that damage to cells disrupts the epigenome over time.

[00:14:55] And we'll get to this, but stopping damage to your cells

[00:14:57] is one good way to slow down aging because slows down

[00:15:01] epigenetic changes, slows down the software corruption.

[00:15:05] But this paper, what it showed was that we could drive aging forwards

[00:15:09] by disrupting the epigenome.

[00:15:10] And we could also use three of the Yamanaka factors.

[00:15:13] There are normally four used, but a particular subset of three

[00:15:18] was able to safely reverse aging in those mice.

[00:15:22] So you disrupted the epigenome by damaging the DNA

[00:15:27] and then using three of the Yamanaka factors,

[00:15:30] which I'll ask you to explain again.

[00:15:31] But by using these, it kind of brought the epigenome back to start again.

[00:15:37] Yeah, well, not fully.

[00:15:38] We look at how the genes are switched on and off.

[00:15:42] And we can measure all of the genes and we can see whether

[00:15:46] the majority go back to an earlier youthful pattern.

[00:15:49] And we saw that it was highly significant.

[00:15:51] But did they go back to being age zero?

[00:15:55] No. And in fact, we wouldn't want them to because age zero, as you said, is cancer.

[00:15:59] So the trick for us was we definitely are standing on the shoulders

[00:16:03] of the great Shinya Yamanaka, who discovered that the four genes

[00:16:07] that four particular genes that are normally turned on by embryos.

[00:16:11] If you put them into adult cells in the dish, they become stem cells

[00:16:15] going back to age zero.

[00:16:16] But you don't want to do that because that's a cancer cell.

[00:16:18] So the trick for us was to find a combination of those genes that were safe.

[00:16:23] And even though theoretically we might be causing cancer, that's

[00:16:27] a concern.

[00:16:29] But in practice, we have not seen any negative effects

[00:16:33] in our treatments in mice or in monkeys so far, which bodes well.

[00:16:39] We still need to do more work.

[00:16:40] But using three instead of four seems to be the magic recipe.

[00:16:44] Why three instead of four?

[00:16:45] How did you find out which three did you did you try all combinations?

[00:16:49] And why does bringing back the age of a cell to zero cause cancer?

[00:16:55] Both excellent questions.

[00:16:57] So the first is we tried for two years.

[00:16:59] And by we, I mean my students.

[00:17:00] Wan Cheng Liu is the student who deserves the credit.

[00:17:03] And he almost quit because it was so hard and he kept causing cancer cells

[00:17:07] instead of reversing aging.

[00:17:10] Well, why did he almost quit?

[00:17:11] Like, was he did he come into your office crying and said,

[00:17:14] Dr. Sinclair, I'm going to quit.

[00:17:16] It was it was David and it was yeah, he was pretty weepy.

[00:17:19] He was resigned to failure.

[00:17:22] And, you know, Harvard students set a high bar for themselves.

[00:17:25] And after two years of failure, it's pretty tough.

[00:17:27] You know, these are students that have never failed a test in their life.

[00:17:30] And my job these days is mainly to just make sure they don't quit.

[00:17:34] And so I said to Wan Cheng, look, I've got a really good feeling.

[00:17:38] You got to trust me.

[00:17:38] I've been doing this for 25, 30 years now.

[00:17:41] I've got a good feeling.

[00:17:42] Let let's keep going.

[00:17:44] Let's do a killer, a really good experiment and see what happens.

[00:17:47] And his suggestion was to leave out one of the Yamanaka factors

[00:17:50] that is known to cause cancer.

[00:17:53] It's called MIC, M.I.C.

[00:17:56] And in retrospect, it's obvious, right?

[00:17:58] You leave out the gene that is causing problems.

[00:18:01] But we hadn't tried that yet because we thought it.

[00:18:03] And most people thought dogma was that you need it.

[00:18:07] But we thought, let's just leave it out and see if it still works.

[00:18:09] And what happened was his cells went back in age

[00:18:11] but stopped at about 75 percent return and didn't go back 100 percent to zero.

[00:18:17] And what happens when cells hit zero is they become a stem cell

[00:18:20] and stem cells grow wildly.

[00:18:23] They don't know how to differentiate and become a tissue unless you coax them.

[00:18:29] And when you do that in animals, you get what are called teratomas,

[00:18:32] which are horrible masses of cells and it kills the animal.

[00:18:36] So we don't want to make cells zero because they'll just keep growing.

[00:18:41] Take a quick break.

[00:18:42] If you like this episode, I really, really appreciate it.

[00:18:45] It means so much to me.

[00:18:46] Please share it with your friends and subscribe to the podcast.

[00:18:50] Email me at Altature at Gmail dot com and tell me why you subscribed. Thanks.

[00:19:04] So when someone gets a stem cell transplant,

[00:19:07] let's say a leukemia patient needs has gone through chemo successfully

[00:19:11] now needs a stem cell transplant to really get rid of the leukemia.

[00:19:15] Are they getting cells like that that are age zero

[00:19:19] or are they aged a little bit, those stem cells?

[00:19:23] They're aged a bit.

[00:19:24] They're they're they're not pure stem cells.

[00:19:27] They're not pluripotent stem cells injected.

[00:19:29] As far as I know, nobody's doing that.

[00:19:31] That would be dangerous.

[00:19:32] They they differentiate them.

[00:19:34] They turn them into a cell type and then they put them back in

[00:19:36] so that the cells don't have runaway growth.

[00:19:39] I see they take the stem cells and they maybe maybe make them a blood

[00:19:43] cell stem cell.

[00:19:44] And so now they can replace blood as opposed to just being

[00:19:48] the sort of epigenome doesn't tell the new stem cells, look, new guy.

[00:19:52] You're the new guys on in the camp.

[00:19:54] Here's what you do.

[00:19:56] The epigenome is not strong enough to take pluripotent stem cells

[00:20:00] and tell them what to do.

[00:20:01] It is, but it needs the right signals.

[00:20:03] And if the cells aren't in the right niche, in the right part of the body,

[00:20:07] they don't get the chemical signals and then they just grow

[00:20:10] in absence of any control factors.

[00:20:12] But if you implant stem cells into the right part of the body,

[00:20:15] let's say the lining of the gut or into the brain, they will get the right signals

[00:20:19] and they may even trigger the epigenetic

[00:20:23] control systems that are that are OK.

[00:20:26] But if you inject it, inject stem cells into your blood,

[00:20:29] they can just keep growing and you'll die from from that.

[00:20:34] But the epigenome is very, very powerful.

[00:20:35] It's it's been neglected for a long time because we didn't have

[00:20:38] the tools to study it.

[00:20:39] We could read DNA, but we couldn't read the epigenetic

[00:20:42] code that's laid on top.

[00:20:44] But we finally have those tools now.

[00:20:45] And what we're realizing is that the epigenome is king.

[00:20:50] You know, and this might be too much in the weeds for my listeners,

[00:20:52] but I'm really curious. Where is the epigenome?

[00:20:56] Like we know that every cell's got DNA and RNA and all this stuff.

[00:20:59] What's where's the there's now there's this third thing.

[00:21:01] I learned the two things when I was in elementary school,

[00:21:04] but I didn't know about the epigenome.

[00:21:06] Yeah, it's like where is the matrix?

[00:21:08] What is the matrix?

[00:21:10] The epigenome are the control systems

[00:21:13] that tell gene A to be switched on and gene B is switched off.

[00:21:18] And the way the cell does that in a simplistic sense

[00:21:21] is it wraps up the DNA or loops it out in a loop

[00:21:26] that's accessible to the cell and the machinery of the cell, the proteins.

[00:21:30] And so what the DNA isn't just a flailing strand

[00:21:33] of the long chemical six foot long in a cell.

[00:21:35] It's actually mostly bundled up with little loops

[00:21:38] where the genes can be accessed.

[00:21:40] But most of it's bundled up tightly so it cannot be accessed.

[00:21:43] That system is called the epigenome.

[00:21:46] And it changes depending on how you live and how old you are and how

[00:21:49] how much stress and biological accidents happen.

[00:21:55] But most when you're born, basically, you've got these beautiful

[00:21:59] patterns of bundles and loops of DNA.

[00:22:01] That's the epigenome.

[00:22:03] Now, what was tricky was to, first of all,

[00:22:06] show that those loops and bundles become untangled.

[00:22:09] And that's causing aging.

[00:22:10] That was this paper I was telling you about.

[00:22:12] That's what we think is going on.

[00:22:14] And then the next challenge was, how do you take

[00:22:17] that DNA strand that's now lost that pattern of bundles and loops

[00:22:21] and might now be all mostly loops and now the cells just reading the wrong genes?

[00:22:25] How do you possibly get those structures to go back to where they came?

[00:22:30] And that was why it was it was almost ludicrous

[00:22:34] to suggest that it was possible.

[00:22:36] Even today, I get criticized from colleagues saying age reversal.

[00:22:39] How can that be possible?

[00:22:41] Well, what we're looking for in my lab

[00:22:43] are is information that tells the cell which genes to bundle up again

[00:22:48] that have become opened up over time.

[00:22:51] And that is going to be the source of the the backup copy.

[00:22:56] Exactly how that is arranged.

[00:22:59] You might say, well, what is what is that?

[00:23:01] What is the information that tells the cell how to be young again?

[00:23:05] I don't know what it is.

[00:23:06] I just can tell you I know that it's there because we can tap into it.

[00:23:11] With our experiments using the Yamanaka factors and some chemicals now.

[00:23:15] So Yamanaka factors, are they like an epigenome to the epigenome?

[00:23:19] Like like they because they were there at in the embryo.

[00:23:23] Right. And they were basically telling the initial cells,

[00:23:27] hey, this is how you be a human.

[00:23:29] And and are you suggesting that, OK, if we get some

[00:23:35] these three Yamanaka three out of the four Yamanaka factors

[00:23:38] that essentially act like those initial stem cells

[00:23:41] that tell us how to be human, how to build an epigenome.

[00:23:44] Is that what's happening?

[00:23:46] Well, we think the process is different than what Yamanaka did.

[00:23:50] It's related, but it's different in that what Yamanaka did was

[00:23:55] to erase the identity of the cells, basically strip all those bundles

[00:23:58] and loops and start again that that we're not doing.

[00:24:02] We're actually doing the opposite.

[00:24:04] We're we're telling the cell how to remember how to behave,

[00:24:07] not losing its complete memory and identity.

[00:24:11] And, you know, if I draw it, if you're just listening,

[00:24:13] what I'm drawing is a an inverted U shape.

[00:24:16] There's an optimum that we're trying to reach where the cells go back in time.

[00:24:20] Remember their identity.

[00:24:21] And the higher it is, the better identity they have and better function.

[00:24:25] If we go too far, then you lose it again.

[00:24:27] And that was what Yamanaka was doing to make his stem cells.

[00:24:29] And you're right that the Yamanaka factors of the epigenome to the epigenome,

[00:24:32] they are the trigger that sets forth a cascade of events

[00:24:36] that we're now elucidating that.

[00:24:41] Tells other proteins how to go and rearrange those loops of DNA

[00:24:45] somehow back to what they were before.

[00:24:47] And it involves enzymes that take chemicals off DNA called methyls.

[00:24:52] There are enzymes that are involved in putting chemical tags on

[00:24:55] the packaging proteins called histones.

[00:24:57] It's very complicated downstream of these three factors.

[00:25:01] And they seem to be the trigger.

[00:25:03] Now, what's interesting is why would it work in an old

[00:25:07] mouse or an old monkey or even an old human?

[00:25:10] Why would this be true?

[00:25:12] Why is the system still in existence?

[00:25:15] You know, we don't need to reverse aging, right?

[00:25:18] It's why isn't it being lost to evolutionary time?

[00:25:22] The reason I think it still exists in us is that

[00:25:25] parts of our body regenerate, right?

[00:25:27] If we cut our liver in half, take it out.

[00:25:29] It'll grow back to a normal sized liver.

[00:25:32] Cut the arm off a salamander, it'll grow back back to an arm.

[00:25:38] I hypothesize in the information theory of aging

[00:25:41] that this reset of the body.

[00:25:45] Through the three Yamanaka factors isn't used normally in nature.

[00:25:49] Not to get younger, but to regenerate lost body parts

[00:25:52] and damaged body parts, which we as humans don't really do very well.

[00:25:55] But of course, other species continue to do much better than us.

[00:25:58] I see. So because we're all sort of evolved from the same,

[00:26:03] you know, cells a billion years ago, there's some part of us

[00:26:07] that still contains that ability.

[00:26:09] And that might be encoded in the Yamanaka factors.

[00:26:11] Yeah. Remnants of this rejuvenation,

[00:26:15] rebuild kind of like a a Deadpool kind of system

[00:26:19] that is in us, but we just don't turn it on, whereas other species do.

[00:26:24] But now hopefully we have the tools to turn this on

[00:26:26] and repair ourselves like we were young again.

[00:26:29] Now, would it would another approach be like if we if we were really

[00:26:34] excellent at gene editing, like far more than we are now,

[00:26:37] and we're getting better and better every year in terms of genomics.

[00:26:40] If we were excellent gene editing, could we rebuild these DNA loops

[00:26:44] and not need the Yamanaka factors or?

[00:26:47] Yeah, if we were good enough.

[00:26:48] I just I prefer to take the approach that biology knows best.

[00:26:52] We've had more than a billion years of evolution

[00:26:55] and we tap into what the cells like like to use.

[00:26:59] I think cells are smarter than us.

[00:27:01] This has been my philosophy my whole career.

[00:27:04] That said, theoretically, if we knew which genes needed

[00:27:06] to be reset in each cell type, we could do that.

[00:27:09] It's an extremely difficult engineering problem because even adjacent cells

[00:27:14] that are microscopic distance apart might behave differently.

[00:27:17] And trying to target that that system to each different cell

[00:27:20] is an overwhelmingly complex problem.

[00:27:23] Now, that doesn't mean that we couldn't say target nerve cells

[00:27:26] in the brain specifically to reset some of those.

[00:27:30] But I think a whole body reset currently is is beyond my imagination

[00:27:34] for engineering, though never say never.

[00:27:38] But these Yamanaka factors, what they do when you when you inject them

[00:27:41] in these three out of the four is they essentially like a disease

[00:27:46] spread through the body or the body part where you inject it.

[00:27:49] And and all these bundles that are loose fritters of DNA now,

[00:27:55] they kind of get this wake up call.

[00:27:56] Hey, you used to be a loop.

[00:28:00] Better get back there.

[00:28:02] That's right. And how that works, we don't know.

[00:28:04] We think there are little little flags on the genes that tell the cell

[00:28:08] this gene needs to be reset by two fold in a negative direction.

[00:28:13] Or another gene would be five fold in a positive direction.

[00:28:15] There's some information in there. We're looking for it.

[00:28:17] We have some breakthroughs just last week that I can't yet talk about.

[00:28:22] I think we may have found the information where and how it's stored

[00:28:27] that tells the cell where to go and what to do.

[00:28:29] And it's a whole new biology.

[00:28:31] So I'm crossing my fingers for my students that were on the right track.

[00:28:35] What what the Yamanaka factors are, they're not that mysterious.

[00:28:38] These are proteins that engage DNA.

[00:28:42] They find a sequence of letters in DNA.

[00:28:46] They call transcription factors and they find them.

[00:28:48] They stick to the DNA and then they they set off

[00:28:54] the activation of other genes.

[00:28:56] So these are genes that regulate other genes.

[00:28:59] That's all they are.

[00:29:00] But they're like a domino.

[00:29:01] Those three dominoes get set and then the rest follows.

[00:29:05] And then the complexity ensues. But

[00:29:09] it's got it. In my view, there's got to be

[00:29:12] a program in the form of software, one dimensional software,

[00:29:17] just like DNA, but probably not DNA

[00:29:21] that records the youthful epigenome and allows the cell to reengage

[00:29:26] and create these original structures of folding of the DNA.

[00:29:30] So the cell can not just behave like it's young, but literally be young again.

[00:29:35] So if there were no regulatory hurdles,

[00:29:38] what would you personally do right now?

[00:29:40] Would you inject these three Yamanaka factors into yourself?

[00:29:45] And or would you drink them or like, what would you do?

[00:29:49] Well, what do you see is happening, let's say, after the regulatory hurdles

[00:29:52] and let's say all your tests go well.

[00:29:54] What do you see happening? Yeah.

[00:29:58] Well, you know, one is hypothetical, one is reality.

[00:30:04] The reality is that we we put the three genes inside

[00:30:08] a domesticated virus called an AAV and we inject it into the eye

[00:30:13] and it it infects the nerve cells and reverses the age of the optic nerve

[00:30:17] in those animals and hopefully people next year.

[00:30:21] And and theoretically, you could inject it into your vein

[00:30:25] and have it infect your entire body.

[00:30:30] And and that way you could,

[00:30:33] you know, see what happens when you reverse aging

[00:30:35] or turn on these factors in most of your cells.

[00:30:38] That is doable today.

[00:30:42] It would be fairly expensive.

[00:30:43] I'd be fairly risky, but it is doable today.

[00:30:47] Would I do it hypothetically?

[00:30:49] Probably not.

[00:30:50] I think we need a bit more safety work.

[00:30:54] But I can imagine a day where

[00:30:58] and it's not too far away, depending on the regulator's opinion,

[00:31:02] where somebody could be flooded with these viruses.

[00:31:06] And what we've got, James, which I want to mention is

[00:31:10] from the outset of this study going back to 2017,

[00:31:13] we we engineered or one chain my student engineered

[00:31:16] the system to have an on off switch so that we could turn it off

[00:31:19] after we after we finished with it and turn it back on if we needed it again.

[00:31:23] And the way we did it, where he did it was we just give

[00:31:27] the antibiotic doxycycline, which some people take from malaria.

[00:31:32] We didn't. The antibiotic isn't acting as an antibiotic in this context.

[00:31:36] It just acts as an on off switch for our virus.

[00:31:39] And so in the future, you could be flooded with the virus.

[00:31:42] It's in every cell or almost every cell.

[00:31:45] But you don't turn it on until you need it.

[00:31:47] So let's say you get injured or you start to get old

[00:31:49] or you lose your eyesight, your hearing.

[00:31:51] Then you take doxycycline for two months.

[00:31:54] In theory, if it works, you get younger.

[00:31:57] You look younger, you feel younger.

[00:31:58] Your organs function better.

[00:31:59] You stop the antibiotic and you repeat that process every five years.

[00:32:04] So I guess every organ or part of the body ages differently.

[00:32:09] Like with eyesight, it could be your cornea, it could be the nerves in the eye.

[00:32:14] It could be the brain cells that regulate vision with your,

[00:32:20] you know, stomach and digestion.

[00:32:22] It's another set of cells would you need.

[00:32:25] But I guess if you're putting the Yamanaka factors in each organ specifically,

[00:32:29] it'll know what to do.

[00:32:30] It'll kind of like, you know, figure out the subculture of that organ.

[00:32:36] You know, get acclimated, make friends and then do its job accordingly per organ.

[00:32:42] Yeah. James, I love the way you think.

[00:32:45] It's deep thinking.

[00:32:47] The answer is yes.

[00:32:47] Somehow the Yamanaka factors know how to reset

[00:32:53] different types of cells.

[00:32:54] We haven't yet seen a cell type that does not respond to the reprogramming.

[00:32:59] And each cell type is different.

[00:33:01] Of course, a brain cell is very different in terms of the packaging

[00:33:05] that it needs compared to a muscle cell.

[00:33:08] And so, yeah, there is a culture within the cell.

[00:33:10] Perhaps it's this system that we're trying to figure out,

[00:33:14] which is this backup copy that is specific to each cell.

[00:33:18] And so the cell individually, they know what they need to go back to.

[00:33:22] And it's perhaps different literally for every cell in the body,

[00:33:26] the pattern that needs to go back to.

[00:33:29] And we don't even know yet how and when that is laid down.

[00:33:34] Is it when the baby is born?

[00:33:36] Is it when your teenager is a different for different organs?

[00:33:40] Does your liver become set in youth at two and your brain at 20?

[00:33:45] These are really interesting questions that we want to address.

[00:33:49] So what does that determine?

[00:33:50] How much you need to age the stem cells basically for each organ or?

[00:33:56] Well, so let's say that the backup copy of youth

[00:33:59] is a chemical that gets added to.

[00:34:03] To DNA, just hypothetically, that might be the method.

[00:34:06] And so there's an enzyme that puts a chemical on DNA that says this gene

[00:34:12] needs to stay at this level to be young.

[00:34:15] But over time, it drifts away, it becomes unraveled,

[00:34:18] and now it's causing problems.

[00:34:21] There's a detector of that chemical on the DNA that the Yamanaka factors

[00:34:25] cause to go there.

[00:34:27] And then it uses that chemicals tag to say, all right, this this gene,

[00:34:34] even though it's unraveled, this little chemical tag says

[00:34:37] it actually should be bundled.

[00:34:38] So let's bundle it up.

[00:34:39] And that happens 22000 times across the entire genome,

[00:34:44] allowing the cell to repackage its DNA earlier.

[00:34:49] And what I'm saying is maybe these little chemical tags on the DNA

[00:34:53] get laid down at different times during development.

[00:34:58] Or maybe it's all you know, you wake up on your 12th birthday

[00:35:01] and suddenly you've got all these tags on your body

[00:35:03] and that's your your reset stage.

[00:35:06] We don't know that. It's just speculation.

[00:35:18] You know, I'm curious about like the brain in particular,

[00:35:22] like the other day.

[00:35:24] So this is a specific example.

[00:35:26] The other day I learned how to ski for the first time,

[00:35:28] went skiing for the first time.

[00:35:30] And at one point, the instructor and I were walking

[00:35:35] and we passed these little kids and they waved hi to the instructor.

[00:35:38] And I said, oh, did you give lessons to those kids?

[00:35:42] And they said, oh, I'm not going to do that.

[00:35:44] I'm going to do it.

[00:35:45] I said, oh, did you give lessons to those kids?

[00:35:48] And he said, yeah.

[00:35:50] Three weeks ago, I gave him a couple of lessons.

[00:35:53] And I said, what do you mean?

[00:35:54] They're they're they're on the line for the Black Diamond Hill.

[00:35:57] Like they're going like I would.

[00:35:59] I'm not going to be able to do that in three weeks.

[00:36:00] They're going down the hardest hill on this mountain

[00:36:04] just three weeks after you're giving lessons.

[00:36:05] And I watch them and they're just like effortless.

[00:36:08] You know, they're not it's almost like they're not using any muscles.

[00:36:11] They're just cruising on down.

[00:36:13] They're going as fast as possible.

[00:36:14] They're they're fearless.

[00:36:16] And I don't believe the example, the cliche that, oh,

[00:36:20] they don't have as far enough fall.

[00:36:22] So they're not that worried about falling like they were literally doing it

[00:36:25] differently because of their brain and mindset than I would do it.

[00:36:29] And what is happening in there's something in the aging process,

[00:36:33] but a difference between me and those kids.

[00:36:36] Like what has happened to the brain?

[00:36:38] Yeah. Oh, well, yeah, you're right.

[00:36:40] The the young brain has is very plastic.

[00:36:43] Learns very quickly.

[00:36:44] Old brains don't we know that the reason I believe

[00:36:48] that happens is your your aging due to epigenetic changes.

[00:36:52] So your nerve cells are starting to turn on genes

[00:36:55] that shouldn't be turned on in the brain.

[00:36:57] So your your nerve cells might be starting to behave a bit like skin cells,

[00:37:01] which is not going to help you learn.

[00:37:03] It's not going to help you remember things well.

[00:37:06] And that's why we did a study in mice where we aged the mice

[00:37:10] and they they were hard of learning.

[00:37:14] You know, you could say they had dementia.

[00:37:16] And then we we could reverse the age of the brain in those old mice

[00:37:20] and we could ask the question, can they learn like they were young again?

[00:37:23] And the answer is yes, they can.

[00:37:26] So I really think that the inability to learn is just a matter of epigenetic

[00:37:29] aging. So like and you were able to reverse this using the

[00:37:34] three out of four Yamanaka factors as part of those experiments.

[00:37:37] Yeah. Is there OK.

[00:37:39] And I'm just asking selfishly, like I want to reverse the aging in my brain right

[00:37:43] now. I want to learn like when I was a kid again, what can I do?

[00:37:47] Well, until we have viruses that are safe for

[00:37:52] for injection into your your veins, which is a while away,

[00:37:57] what we're working on are chemicals that will do the same thing

[00:38:01] so that it could be swallowed or put on the skin or injected.

[00:38:04] And we published a paper when was it?

[00:38:07] July last year, the first proof of concept study that we could find

[00:38:11] chemical cocktails that.

[00:38:14] Reverse the age of cells and and restored that epigenome.

[00:38:18] And we've come a long way since then.

[00:38:21] It's not published yet, but we are down to some really exciting

[00:38:25] chemicals that could theoretically be put into a

[00:38:29] a drink and consumed that may rejuvenate the body,

[00:38:34] improve memory, for example.

[00:38:36] I think don't get me wrong, I'm not going to be putting this into a drink just

[00:38:40] this year. But I think if the animal studies work out and we do some human

[00:38:44] studies, then that's you know, it's a goal worthy of my attention.

[00:38:49] And and I'm not trying to figure out the chemicals just so I could go

[00:38:54] to the store and buy these.

[00:38:56] But is it like NMN related or is it Yamanaka related?

[00:39:00] Like what what types of chemicals are these?

[00:39:02] Yeah. So these are vitamin D, vitamin K.

[00:39:05] It's not that simple.

[00:39:08] There's there's there's cocktails, so there isn't just one answer.

[00:39:13] But we're at a point where we now have it down to one chemical that can

[00:39:17] reverse the age, ostensibly reverse the age of cells in the dish,

[00:39:21] can treat human cells, make them younger, make them grow, even if they

[00:39:25] stop dividing senescent cells.

[00:39:27] And, you know, barring any safety issues, which, of course,

[00:39:32] you can't ignore.

[00:39:35] It could be made available.

[00:39:36] So right now, could you go out and buy some of these?

[00:39:39] Well, I I do know that some people have looked at our publication

[00:39:44] from July and have started taking those chemicals or surrogates

[00:39:50] of those.

[00:39:52] But they're doctors. You need prescription.

[00:39:54] So it's not that simple. You can't just go out and buy it.

[00:39:56] And it's not just a vitamin. It's a bit more complicated than that.

[00:39:59] But but, you know, just trust that I'm I'm now laser focused on making

[00:40:04] this come true if it's possible, if it's safe.

[00:40:08] It's not here yet, but it will be if I can do anything about it.

[00:40:12] You know, when when you last came out to talk about this, I did

[00:40:15] follow a lot of your advice, like in terms of intermittent fasting,

[00:40:21] you know, occasional high intensity exercise, of course, sleep

[00:40:26] and the various supplements you take, I take.

[00:40:31] And how much of these lifestyle factors are sufficient

[00:40:37] to compare with this chemical cocktail that you're putting together?

[00:40:42] We haven't put them side by side, but I don't think anything

[00:40:46] that is out there compares to this.

[00:40:49] We don't see the usual suspects, rapamycin, NMN doing this research.

[00:40:55] Doing this reset there.

[00:40:58] They might assist in the process, but these chemicals are in a different

[00:41:02] league of their own.

[00:41:04] And so I think this is probably why people are skeptical

[00:41:07] about my use of the term age reversal, because they're not seeing

[00:41:11] the results that I see in my lab.

[00:41:13] And we clearly see that aging is reversible

[00:41:16] and these new discoveries are really, really powerful,

[00:41:20] more powerful than anything I've seen before.

[00:41:22] So reversible in the sense like let's take an extreme example.

[00:41:25] And this is something we almost I believe we briefly talked about

[00:41:29] back in 2020 or 2019.

[00:41:33] Can a mouse, can a female mouse who has reached menopause, reverse menopause?

[00:41:39] We did that.

[00:41:41] And by we, I mean, my team in Australia, Lindsay Wu was the first author.

[00:41:45] Yeah. So we gave them old mice

[00:41:49] the equivalent age, a human age of 70,

[00:41:53] 65, maybe we gave them NMN.

[00:41:56] And it was just a month later that they were able to produce

[00:42:00] viable eggs and had normal offspring.

[00:42:03] And that, as far as I am aware, is the only known

[00:42:06] or at least it was the first known way to reverse what we call mouse pause.

[00:42:12] So that's incredible.

[00:42:14] But that's not what you're talking about with this new chemical cocktail

[00:42:16] you're talking about reversing aging with.

[00:42:19] It's different.

[00:42:20] What worked in the mice was we stabilized their DNA.

[00:42:23] And that's the main problem with infertility in females, the eggs

[00:42:27] trashed their chromosomes.

[00:42:28] And there was a protein, one of the sirtuins that actually was the problem.

[00:42:32] And by raising NAD, we could make sure the chromosomes

[00:42:35] were nicely packaged in the egg.

[00:42:38] An old egg, by the way, the chromosomes are all torn apart.

[00:42:41] It's quite terrible.

[00:42:42] There's no way you're going to produce an offspring for one of those.

[00:42:45] But it's different.

[00:42:46] It's different. This new age reset isn't just for eggs.

[00:42:49] It seems to work on every cell type.

[00:42:52] And you don't just go back a little bit, seem to go back a lot,

[00:42:56] you know, 50 percent, 75 percent in age and reset

[00:43:00] the pattern of what we call gene expression.

[00:43:04] And what's interesting is it's not just a temporary reset.

[00:43:07] We've co-published a paper recently that when we.

[00:43:13] It's essentially cure glaucoma in a mouse

[00:43:16] and turn off the Yamanaka factors, the effect.

[00:43:20] Continues, right?

[00:43:22] It's not that you need to keep the factors on.

[00:43:24] It's truly a reset.

[00:43:26] And then the mouse gets old again and then you just can't keep resetting.

[00:43:30] We know we can reset the body at least twice.

[00:43:34] I'm not sure there's actually a limit to it other than

[00:43:38] in these experiments, the mice got old and died,

[00:43:40] but their eyes were beautiful at the end of the experiment.

[00:43:43] But yeah, so it's you know, I'm looking forward to us getting better

[00:43:47] at reprogramming the body of mice so we can make them live longer.

[00:43:51] There was a recent study that was published, not from my lab,

[00:43:54] but a group that used our system and they gave it to old mice.

[00:43:59] They put the Yamanaka virus into the vein instead of the eye.

[00:44:03] And those mice were very old and their remaining

[00:44:06] lifespan was doubled, 109 percent extra life.

[00:44:10] Which, you know, is a good beginning.

[00:44:12] But I would love to be able to make a mouse that could live

[00:44:15] for two or three times.

[00:44:18] But the technology is not really there yet.

[00:44:20] The biggest obstacle is getting the virus into all the cells evenly.

[00:44:24] And viruses like to pile up in the liver and a few other places.

[00:44:29] And so what people are doing, not me, but people who have the skill

[00:44:32] in viruses, they may engineering viruses and even other types

[00:44:36] of delivery vehicles like nanoparticles that can evenly spread across

[00:44:40] the body and deliver genes.

[00:44:42] So so let's say there's someone like you and a lab like yours in China.

[00:44:49] And I'm assuming there must be labs working in China on similar things.

[00:44:55] Maybe I'm wrong, maybe I'm not.

[00:44:56] But, you know, they have no ethical barriers to what they're trying.

[00:45:01] Wouldn't they already be injecting humans with this?

[00:45:03] And we would start to know what what results they're getting.

[00:45:08] I mean, possibly, possibly.

[00:45:12] I haven't heard about it.

[00:45:14] It wouldn't surprise me, though, if

[00:45:17] if some people in South America started doing this.

[00:45:21] I've heard that people are doing gene therapy on themselves already down there.

[00:45:25] So, you know, this is not too far from that.

[00:45:28] And for you like to prove OK, so so first step is you proved,

[00:45:33] oh, there's some effect in mice.

[00:45:36] How do you then prove safety in humans?

[00:45:37] Like, do you have to get humans to agree to the risks

[00:45:41] and get injected with small amounts or what happens?

[00:45:45] Yeah, so that's been my work with the company that I co-founded.

[00:45:50] It's called Life Biosciences here in Boston.

[00:45:54] They've been working since 2018 on this.

[00:45:56] And so you do a lot of studies in mice to see what the mice can tolerate.

[00:46:01] You turn it on for the rest of their life, see if they get cancer.

[00:46:03] The answer is no.

[00:46:05] You inject it in the whole body.

[00:46:06] Do they can't get cancer?

[00:46:07] The answer is no so far.

[00:46:09] And then what we did, the company did, I shouldn't say we,

[00:46:12] but the company did studies in monkeys.

[00:46:15] So they injected the virus and turned it on in

[00:46:18] the retinas of monkeys that had poor vision and their vision improved.

[00:46:22] And there was no issue with safety, seemingly.

[00:46:26] And so they're doing some more of those studies.

[00:46:28] And then with that data, our plan is to go to the FDA.

[00:46:33] Who are we're already talking to?

[00:46:35] So they're aware of our plans and giving us some advice

[00:46:40] or at least pointers.

[00:46:41] I don't know if they're allowed to give advice,

[00:46:42] but they definitely give feedback about what we need to do

[00:46:46] for them to approve a human study in the US.

[00:46:50] And things look good.

[00:46:51] I don't see any obstacle currently why we shouldn't be

[00:46:55] asking for volunteers who are blind as early as this time next year.

[00:47:01] And they have to be volunteers.

[00:47:02] Of course, it's a clinical trial.

[00:47:04] But if you wake up blind, which can happen,

[00:47:06] you get a stroke in the back of the eye.

[00:47:08] You know, what have you got to lose?

[00:47:12] I know if I did, if I was blind, I would try it.

[00:47:15] Is it is it kind of a not to use the word here,

[00:47:18] but is it a double blind trial in the sense that

[00:47:21] some people will get the cure and some people will not.

[00:47:26] And again, you don't know who is who.

[00:47:28] Well, the plan is that everybody will get the treatment just at different stages.

[00:47:32] So some people will get it early.

[00:47:33] Some people will get the antibiotic later.

[00:47:36] And so each person can be their own control.

[00:47:39] But yeah, we don't currently plan to leave anybody out of this trial.

[00:47:43] And then and then how long does it take to determine safety?

[00:47:47] Do they have to live out their lives and then, you know, it's safe?

[00:47:50] No, I don't think so.

[00:47:52] So, you know, you're so it's beyond my area of expertise.

[00:47:55] My understanding, though, is because there's no current treatment for blindness

[00:48:01] and you can't reverse glaucoma currently,

[00:48:04] the FDA and regulators around the world look more favorably on treatments,

[00:48:10] but there's nothing else you can do.

[00:48:12] So my hope actually is that those studies, if they're successful,

[00:48:15] we do another large scale study,

[00:48:17] and that would be sufficient for the drug to be approved.

[00:48:22] It's really fascinating.

[00:48:23] And then I guess once it's safe, I don't know what phase that is.

[00:48:26] Phase one or phase two.

[00:48:28] Then you then you start see what's the next phase after that.

[00:48:33] So phase one is safety.

[00:48:35] This is different because it's the eye.

[00:48:37] You get the safety and the efficacy.

[00:48:40] The results in the same trial.

[00:48:43] So this is a phase one slash two study.

[00:48:46] So then. If all goes well, you know, fingers crossed,

[00:48:51] what you're left with is a phase three study, which is expanding it into

[00:48:55] hundreds of patients, maybe thousands to see how safe it is.

[00:49:02] Given that gene therapy,

[00:49:03] probably the number of patients will not be in the thousands

[00:49:07] like something like a diabetes trial would.

[00:49:09] So I think that a phase three probably would take one to two years.

[00:49:13] That's typically what they take.

[00:49:15] So if you want to know when is this available on the market

[00:49:18] to everybody in the US,

[00:49:22] you know, we're still a few years away.

[00:49:24] And I always say a few years away and it ends up being more so.

[00:49:28] But we will see.

[00:49:30] What's exciting to me is the eye is a much faster path

[00:49:34] than than something like diabetes, where you need to be testing it

[00:49:37] for a long time for safety.

[00:49:39] And you have to spend a couple of years

[00:49:42] testing it before you can even see if it works.

[00:49:44] With the same with the same drug, though, that works on the eye,

[00:49:47] have off label use for diabetes if you inject it in the gut

[00:49:52] where wherever diabetes happens.

[00:49:56] Well, I'm aware of research that I'm an author on that that.

[00:50:00] These factors help with blood pressure.

[00:50:02] I'm not aware of it helping with diabetes in a mouse yet.

[00:50:06] We haven't tested that just to address that.

[00:50:08] But it can be used off label.

[00:50:11] Well, I wouldn't condone that. Right.

[00:50:14] That said, off label use of drugs is used all the time,

[00:50:18] especially for compassionate use.

[00:50:20] And I'm just wondering, though, if the if the cocktail specific

[00:50:23] for the eye like it's pro. Oh, I see.

[00:50:28] Yeah, the type of virus is better for the eye than the whole body.

[00:50:33] You'd you'd want to re engineer it

[00:50:36] to infect the whole body.

[00:50:38] So specifically, we're using what's called an AAV number two for the eye

[00:50:43] in the mouse whole body.

[00:50:45] We use AAV nine.

[00:50:47] So probably it's not the best to use the eye version.

[00:50:52] Well, it all sounds very interesting.

[00:50:55] I am really excited about all the like you wrote the book Lifespan.

[00:51:01] What year was that? 2019 or 2018?

[00:51:04] And we spoke about that several times.

[00:51:07] And it's a fascinating read about aging and your approach to it.

[00:51:11] You know, your approach as aging as a disease rather than just something

[00:51:15] we should accept and all the different research you summarize.

[00:51:19] And it's very exciting now to see how five years later

[00:51:23] where the research has taken you.

[00:51:24] And I didn't know about any of these advances that you have.

[00:51:29] And oh, yeah, yeah, David, there was one question I wanted to ask.

[00:51:33] I had a podcast recently and OK, this started off.

[00:51:36] I was speaking at a men's group.

[00:51:38] There was several hundred men on this men's group.

[00:51:42] And I was speaking about some random thing.

[00:51:44] And suddenly everybody started talking about testosterone.

[00:51:48] I'm 56 years old and people were asking me to take testosterone.

[00:51:51] Everybody was saying you have to take testosterone,

[00:51:53] you have to take testosterone.

[00:51:55] What what's the and people were saying it's an anti aging thing.

[00:51:58] Testosterone for men.

[00:52:00] And we posted this this clip on some social media.

[00:52:05] And a lot of people are arguing against this.

[00:52:07] There was a whole battle in the comments that I was not involved in

[00:52:10] because I don't know anything.

[00:52:11] And but what's your stance on testosterone?

[00:52:16] This has nothing to do with anything you've been talking about.

[00:52:18] But I'm just curious what your stance is on this

[00:52:20] is in terms of aging and male aging and so on.

[00:52:24] Yeah. So I know a fair bit about this.

[00:52:28] One of my good friends and collaborators with the

[00:52:33] the clinical trials actually has done a lot of testosterone

[00:52:37] studies in humans.

[00:52:38] And and so I'm hearing it really from the horse's mouth here.

[00:52:43] There's a lot of data and it's dangerous to summarize.

[00:52:47] I will anyway.

[00:52:49] Testosterone is is helpful for some things.

[00:52:53] OK, built maintaining and building muscle mass.

[00:52:55] Yes. Is that good for old men? Absolutely.

[00:52:59] We lose muscle mass all the time.

[00:53:02] Does it extend lifespan?

[00:53:05] Is it true? Anti-aging, is it slowing down the process?

[00:53:09] The answer there seems to be no.

[00:53:11] So it's in between. It's useful.

[00:53:13] It's helpful during aging.

[00:53:16] But it's not an anti-aging medicine.

[00:53:19] And then the third thing I want to add is

[00:53:22] that I work with a lot of people who come to me for advice.

[00:53:26] And often it's should I take testosterone?

[00:53:29] I've seen some really good, good results.

[00:53:32] Naturally, building up testosterone levels,

[00:53:36] working on the larger muscles of the body, like your legs and your back.

[00:53:41] Tonkat Aali, for instance, is a supplement

[00:53:44] that's been shown time and time again to raise testosterone.

[00:53:48] And speaking for myself, I naturally raise my own testosterone

[00:53:52] through those means and don't have to take it.

[00:53:55] What was the song that you mentioned?

[00:53:57] Tonkat, T-O-N-G-K-A-T and then A-L-I.

[00:54:01] To South East Asian Plant Extract.

[00:54:05] And it helps actually.

[00:54:06] Jay, do you have some kind of Southeast Asian insight into this?

[00:54:10] Well, yeah, because this is what we usually take when...

[00:54:13] Oh, sorry, I'm from Malaysia, but Tonkat Aali is what we usually

[00:54:17] advise people to take in Southeast Asia.

[00:54:20] That's why I'm like, oh, I know that name. It's very familiar.

[00:54:23] These are nitric oxide donor medicines,

[00:54:26] and low dose seems to be helpful in maintaining

[00:54:32] what's called endothelial function, your blood vessels, health.

[00:54:36] And that declines with age.

[00:54:37] And it definitely will...

[00:54:39] Not definitely, but it probably will help your sex life as well.

[00:54:42] So, I think that's the key to being healthy.

[00:54:45] And I think that's the key to being healthy.

[00:54:47] And I think that's the key to being healthy.

[00:54:49] And I think that's the key to being healthy.

[00:54:51] And it definitely will help your sex life as well.

[00:54:53] The goal, though, is to keep your blood vessels youthful and flowing.

[00:54:58] And so I'm currently trying that.

[00:55:00] And it does seem to give me seemingly the benefits of exercise

[00:55:06] without having to exercise a lot.

[00:55:09] It's just my personal experience.

[00:55:12] I can't say it's a clinical trial.

[00:55:14] But I did want to mention that because I've heard it from many doctors

[00:55:17] that this is a thing that they're looking into and advising their patients.

[00:55:22] It's so funny, I can't imagine taking low dose Viagra

[00:55:26] in order to perform better at a chess tournament, for instance.

[00:55:29] It could help though.

[00:55:31] Yeah, I'm just trying it out.

[00:55:32] You know, I like to experiment to see what works and what doesn't.

[00:55:36] But yeah, that's something that, you know, it's got this stigma

[00:55:40] because it's an erectile dysfunction drug.

[00:55:42] But really, it was developed to help with blood flow in the beginning.

[00:55:46] My mother was on it, actually, because she had lung cancer and one lung removed.

[00:55:50] And I remember trying to get Viagra from my mother

[00:55:52] and getting all these pop up ads on my computer for Viagra.

[00:55:55] And I was thinking, it's not for me, but, you know, never say never.

[00:56:00] That's funny.

[00:56:01] Oh, well, OK, David, once again, thank you for spending the time

[00:56:04] while you're saving civilization and the human species.

[00:56:08] Thank you for spending the time on the podcast.

[00:56:11] I really appreciate it.

[00:56:11] I hope we could update it again at some point.

[00:56:14] And yeah, thanks for coming on.

[00:56:17] You're welcome, James.

[00:56:19] Yeah, I get asked to go on podcasts a lot, and I typically don't

[00:56:21] because I'm focused on the research.

[00:56:24] Obviously, I love what you do.

[00:56:25] People should read your books. They're awesome.

[00:56:27] Oh, I appreciate it. Thank you.

[00:56:28] Appreciate the really great questions.

[00:56:30] That's what's special about your podcast.

[00:56:33] Thank you.