The Peter Attia Drive - #70 - David Sinclair, Ph.D.: How cellular reprogramming could slow our aging clock (and the latest research on NAD)

Episode Date: September 9, 2019

In this episode, David Sinclair, Ph.D., a Professor in the Department of Genetics at Harvard Medical School and co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging, returns to the podcast to discuss the content of his new book, Lifespan: Why We Age - and Why We Don’t Have To. This conversation focuses on the biological mechanisms involved in what David terms the Information Theory of Aging which provides insights into the “clock” that determines our aging and to what degree it can be manipulated. Our discussion on aging of course leads us into interconnected topics of epigenetics, sirtuins, cellular senescence, as well as what compounds David is personally taking for his own longevity. Additionally, we discuss the most up to date information related to NAD and longevity by looking at the potential benefits (if any) of supplemental agents (NAD precursors, NR, NMR, etc.) that pose a promise of increasing NAD. We discuss: SIR genes and cellular identity [8:45]; Sirtuins regulate gene expression [14:30]; DNA is methylated at the deepest layer of the epigenome [17:45]; Methylation pattern and determining cellular age [20:15]; Cellular reprogramming [33:45]; Yamanaka factors to push cells "back in time”  [41:00]; Human cellular reprogramming viability [57:00]; Measuring the rate of aging [1:02:45]; Cellular reprogramming for longevity [1:14:45]; Compounds David takes for his own longevity [1:29:15] NAD precursors (NR, NMN) and pterostilbene [1:40:00]; The current field of sirtuin activators [2:03:15]; David’s artistic work [2:05:15] and; More. Learn more: https://peterattiamd.com/ Show notes page for this episode:https://peterattiamd.com/davidsinclair2/ Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peteratia-md.com.

Hey everybody, welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about, professionally, are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally and I've seen firsthand how access to information is basically all people

need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy and even before starting the podcast that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this?

As you probably know, the tried and true way to do this is to sell ads, but after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you could trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I just know myself, I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work

over time. And that is to create a subscriber support model for my audience. This keeps my relationship with you, both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at,

you will get back more than you give. So, for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I

said, we're not taking ad dollars from anyone, but instead what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all. But my hope is that many of you will find enough value in one, the podcast itself, and two, the additional content, exclusive for members, to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription.

I guess this week is Professor David Sinclair and I'll let name may sound familiar to some of you because I've already interviewed David. In fact, his first interview appeared podcast back in November, I believe, of 2018. I wanted to bring David back on the podcast for several reasons. First of all, he's always interesting to speak with, and we spend a lot of time speaking off podcasts, and I want to be able to share those discussions with people. Second, he has a new book that is coming out. In fact, we have timed the release of this podcast to coincide with the release of that book, which is tomorrow, September 10th.

And third, we wanted to revisit some of the ideas around NAD, NR, nicotine in my riboside that is, and longevity. These are still to this day among some of the questions I get asked most about. And even though truthfully, I don't believe this is even at the top three level, you know, most interesting questions in longevity for whatever reason people want to know all about it, and therefore, I wanted to provide a little bit more insight into that. So as a bit of a refresher, David's a professor in the Department of Genetics at Harvard Medical School. He's a co-director for the biological mechanism of aging program, or it's a center, actually.

He's best known for his work in understanding why we age, how to slow its effects. We talk in the very first podcast about his role in the discovery of Sir Tuen's and the treatment there of, let's see, I think, you know, you can go back and listen to his bio from that. Let's talk about what we talked about here. We talk about this idea of the information theory of aging. And this is really a big part of what David's book is all about. And I knew that David was going to be interviewed by a lot of people for the book. So I felt that it was probably going to be most helpful to listeners if I interviewed him on some

of the more technical details of that book, which deals with, again, this information theory of aging, basically what is the clock that determines our aging? What does it look like? And perhaps most importantly, can it be manipulated? There are lots of other topics that are covered in his books, such as the ethics of delaying death to significant degrees. You know, what would it mean to him and if we could live for you know, hundreds of years? Those are very important questions. I don't touch on any of them in this

interview and I suspect you'll hear a lot about that in some of the other interviews. So, if this topic is of interest to you, one, I recommend you buy the book. I really enjoyed it and I learned a lot. And that's saying something because I don't really learn a lot reading books about aging, unfortunately, anymore. The books are written at such a low level, but that's not the case here. This is really good. Secondly, I think the discussion we have around NAD and our features, some really up-to-date stuff, including a couple of papers that were published in the weeks leading up to our talk. So again, I don't think this is the final word on the subject, but I do think that you'll come away from this with an even more nuanced appreciation for the potential benefits if

there are any of supplemental agents that pose a promise of increasing NAD. So without further delay, please enjoy my second conversation with David Sinclair. Hey David, thanks for spending and bye. Thanks on me back. Congratulations, first of all, on the almost released book. Well, thank you. That's an interesting time just waiting for the thing to drop September 10th. Yeah. Yeah. Well, by the time people hear this, it will be dropping. So I kind of want to just start with the book because I think I said this

you last time when we were together, if maybe I have a couple of months ago, but once you start recording a podcast, you end up listening to podcasts a little bit differently because now you're sort of thinking about it through the lens of the interviewer as well. And similarly, once I think you're trying to write a book, all of a sudden, you have much more interest in other people writing books, not just for the content, but the actual process and things like that. So I remember we connected on this about a year ago, and I won't lie. I'm kind of secretly jealous and envious that you're done. Yeah, well, the scary thing is, as soon as you're done, yeah, you're never done. Your agent

says, what's your next book? Oh, well, that's not even what I was thinking. I was thinking the bigger issue is the moment you're done, you think, oh, wait, there's just one more thing I want to say. There is that. At some point, the editor said no more changes to David. You're done, but it's heck of a lot of work. Anybody who's written a book, real respect for those people. And you're in the throes of yours right now, right?

Yeah. So you had sent me your proposal like a year ago, maybe longer, actually, definitely longer than a year ago. And it's probably a great example of how proposals and books often differ quite a bit. I'm generally the book, I think, ends up being so much better, so much richer. Because there were things in the book

that weren't necessarily in the proposal that kind of caught me off guard, especially the first part of the book, which is kind of what I want to talk about today. I think the second part of the book where you talk about the societal implications for a longer-lived population are interesting, but I'm gonna let somebody else talk about that with you. I want to talk about sort of the biology of this, but this idea of, I mean, you introduce a very important mathematician who wrote a paper that I remember seeing in my engineering studies paper from the 1940s. So let's just start with that. Why is Shannon relevant to the story of aging? Because I certainly didn't learn anything about him as an anti-aging researcher 25 years ago.

Well, Shannon's one of the most respected guys in math, what he did in the 1940s was essentially figured out how to mathematically encode information and make sure that information gets to the receiver. It's called the information theory of communication. What it led to is what the world we have around us, the internet, TCP, IP protocols. What that has to do with aging, I wrote down in the book, it began really when I was just a postdoc in Leningradic lab at MIT, interesting Claude Shannon was at MIT too. We discovered to our surprise that what was controlling aging in yeast in part were these Sir Tuan genes. Now Sir Tuan's in science in aging, pretty famous, but what a lot of people don't know is that the word sir toin stands for gene called sir

to which in yeast we found responds to dietary restriction, heat, starvation, and it allows yeast to live about 30% longer if you operate it or put just another copy of that gene in the yeast cells and mate Kabilaine who's now a famous professor, he was a graduate student who did that experiment to put extra sir to gene into the yeast and they lived longer. So that was a massive breakthrough but what Sur stands for is really telling. It's actually been forgotten over the last 25 years but Sur is an acronym for silent information regulator. Silent information regulator. What does that mean? This is a gene that controls all the genes. It switches them on and off. It's main job is to keep gene silent. And that allows cells

to be dividing, be healthy. But what they do that is not appreciated is when the cells are stressed, too much temperature, a broken chromosome. The protein that this gene makes, this surgeon, it leaves the silent regions and it goes to repair the problem or fix the problem. So in the case of DNA breaks, what we did was we broke the chromosome of yeast. The sur enzyme protein leaves where it should be, goes to repair the DNA. And when it's all fixed, it comes back again to shut those silent genes down. And you might say that's what we had been to do as an organism. Well, this is a highly conserved process that's found in yeats cells. Just make sure, the listener know what you're saying.

You have a gene that's being silenced, that then gets broken. The thing that is silencing it leaves its silencing post to go and repair that which is broken only to come back and silenced it. So from an expression standpoint, the world outside hasn't changed. That's right.

And the reason that I think it's set up that way is that these genes that get turned on by the absence of the Sir pruning help with the problem. They turn on DNA repair, they hunker down. These are survival programs that's in every cell on the planet, I believe. And the Sir, and Simon that we're talking about, is a master regular of that survival circuit. So why does that have anything to do with information theory? Well, what I think is going on is that this program that sat down in our cells and when a yeast cell is young, or which gene should stay on, or which gene should be off,

gets messed up, it gets lost in the noise. And what's the noise? It's this constant having to go and repair DNA or respond to too much heat or some other imminent threat. Yeah. Doing it once doesn't matter. One cut to a chromosome, a broken chromosome, is not going to kill a yeast cell if it's repaired.

But what it does over time is that cells lose there, which gene should be on and off. The genes that should be kept off in the yeast cell come on. One way to think about this, a very simple analogy is hurricane Katrina. Okay, so the surprotein are the first responders. They rush down to fix the problem. They do their job, but what happens is,

most of them come back home, mow the lawn, pay the bills, and everything's good, but some of them get stuck down there. They marry someone, or maybe they get lost on the way home, they can't afford a ticket home, and they are playing. And you do that a hundred times, or in our case, in our lives, every cell is getting a broken chromosome every day. So you're doing this. How many days do we live? 30,000 days. This is a problem, I think, over time you actually end up losing that program and our cells lose their identity. And the hallmark of aging in yeast is the loss of cellular identity. They become sterile, they don't make dysfunctional. So Claude Shannon

figured out how to preserve information. You keep a repository of the original data, a hard-dressed, distraught backup. And he said, if the receiver of that information, which in his idea was the radio receiver of the signal in World War II and after, in our world, it might be our email. In aging, it's ourselves in the future. And we lose that program of keeping ourselves young, cells and cells. And what Shannon said is that there may be a repository of that information. If our cells are right, if they're doing a good job, there should be a way to reset the system to get that complete email back again. And I think there is one, we

have some early evidence from mice that we can actually find that hard disk drive and reinstall the software so that it's pristine again. And we find that we can actually improve the health quite dramatically of parts of our mouse's body. Now, to really get into this, the way you do in the book, I think we have to take a few steps back and assume for a moment that a listener doesn't know much about DNA beyond sort of the high-level stuff, but maybe doesn't understand what an epigenetic modification is, what things like methylation mean and how that occurs.

So let's go back and go through a little bit of that stuff because I think to get a firm understanding of this will enable the other things you're going to talk about to make more sense. So we could use a mouse, we could use a person, it doesn't really matter for the purpose of this discussion, but let's use a person because I think it resonates with a listener more. So you and I have lots of DNA. We've got somewhere between 20 and 30,000 genes.

These genes are made up of lots of this coding stuff, and there's coding and non-coding segments of these DNA. But basically it's a whole bunch of strung together nucleotides. Now some of them are not working at a point in time, right? They're sitting there, but they're not actually getting turned into RNA to be turned into proteins, correct? Yeah, absolutely. We don't want to turn all our genes on because then we wouldn't have any different cell types. We'd all just be a giant blob of cells, a giant tumor, probably. So when you take a piece of my skin and you take a piece of my liver or you take a piece

of my eye, nerve in the back of my eye, they all have the same DNA, right? Yeah, except for your sperm or your egg and some immune cells. I don't have any eggs, by the way, just for the record. Yeah. Okay. I can believe this. But your point is some of them are getting turned on. So the DNA that are sitting in the epithelial cells of my skin are being instructed to express

proteins in a certain way, and that's what ends up producing skin versus the nerve in the back of my eye versus my liver, et cetera. And what's interesting is the skin and the nerve, at one point, were the same cell types when you were in embryo. But the pattern, we say, pattern of gene expression, the way the cells turn on different genes allowed nerves to become nerves and hopefully stay nerves for most of your life.

But I think towards the end of your life, that's the problem. It's they're losing your identity. And reverting back to something that was more primordial more like a skin cell. And theting back to something that was more primordial, more like a skin cell. And the way the cells do that is really interesting, so that your DNA, if you stretch it out of the cell, be about six meters long.

And there are little proteins that wrap that length of DNA up inside a microscopic cell. And it's essentially like spalling a hose in your garden and then you spool those spools on top of each other. So it's a way of packaging something very long but very, very thin and tiny. But if it's packed up in a spool, it won't be read by the cell. And that's what these serprotines do. The serprotines actually maintain that structure of that spool.

But if a cell needs to read the gene, they remove the serprotines, and now that bundle can open up and the gene can be read. And there are different layers of the epigenome. There's the superficial layer where the sir proteins are, and there are other proteins going around turning genes on and off. But there's a really deep layer. The deepest layer is what's called DNA methylation, and cells, can permanently, for decades, mark a gene to be silent by putting these chemical groups called methyals next to or in a gene. And that tells the cell spooled it up as tight as you can and never, unless I tell you to,

reveal it again. And that's the reason our brain doesn't turn into a liver one morning when we wake up. Now, let's define methylation only because it's such a buzz term right now. I think everybody in their brother is reading about, oh my God, am I a bad methylater? Am I a good methylater? Do I have an MTHFR mutation? But let's sort of demystify all this stuff. A methyl group is a carbon group with three hydrogens on it. So we're talking a very basic molecule in the broader architecture of organic chemistry. And you're saying that when you put one of those methyl groups, when you attach one of the carbons on that methyl to literally a carbon on one of the ends of DNA, you have the ability to program it to not carry out the function of

expressing itself. Is that a safe way to say that? It is. This is the underlying code that tells us sell what type it is. And there's a guy called Conrad Warrington from the 1950s who didn't know that there were these methyl groups. So what he imagined was the embryo or the fetalized cell is at the top of a hill, and it rolls down the hill. And if it lands in one valley, it's a nerve cell. It stays in the valley. But if it rolled into another valley,

it's a skin cell, and stays a skin cell. And that's a great metaphor for how an embryo and then eventually a baby is formed out of 27 billion cells that a baby is made of. Whartington didn't think about as much, if at all, was what happens after that baby's born? What happens 80 years later to his Whartington landscape? What happens to those valleys and those hills? And what I think is happening is that we're having not just a what happens to those valleys and those hills. And what I think is happening is that we're having not just erosion of those hills

so that the cells don't stay where they should, but they're getting jostled by these DNA breaks and this reorganization of the serp roting and others, so that cells start to migrate up over the valley into other new valleys. And now your neurons in your brain, your nerve cells are starting to behave a little bit like skin cells or liver cells.

And I think that's what's underlying many, if not all, of the aspects of aging that we eventually will succumb to. And what role does entropy play in this? Because when you think about these hills and valleys, there's a place where things want to settle out. There should be a place where things settle and stay put. But the figure you have in one of your talks, which shows this projection right into

the future, it starts to get blurry at the end. In other words, it starts to look like there's more chaos in the system. Is that just the natural drive of entropy within our systems? Is that the way it's expressed, I guess, is what I'm asking? Right. So mathematically, it appears very much like a loss of information and introduction of noise because these methyl groups that are laid down in a pristine precise fashion when we're young, there are other metals that accumulate over time in different places, what appears to be randomly, so it's a loss of the original pattern and that's why we talk about entropy. Now anyone who's familiar with the second law of thermodynamics says, okay, we're screwed.

We're never going to be young again because you've lost information, similar to falling into a black hole. You never coming out. Or even, let's think of more obvious examples. Like, you can't unfrien egg. Once proteins become denatured, once the clear part of the egg becomes white, you don't get to make it clear again. Yeah, or even worse, if your genome is a compact disc or DVD, you scratch that up and you can't read it again, or even worse, you break it piece off, that information is lost

if you throw it in the trash. But what I think exists in cells we have some evidence is that like Shannon suggested for the internet or information, is that if you have a backup copy and now going back to the genome, there seems to be something in cells that tells them these methyl groups, the program that was laid down when you were a baby, is still there and cells can access that somehow to say, all these other things that have happened since you were born or since you were a teenager, that's just noise, that's crap. Ignore that.

In fact, when I tell you, and in my lab, we can reprogram ourselves to go young again, to read the right pattern, there's a process that we're just beginning to understand that says, this stuff is noise. Get rid of that. Ignore that. Get rid of it. But these other methyl signals, these little flags on the genome that have been there since we were babies. That's the good stuff. Keep that. And in that way, these spools of the hose, the DNA loops that have become untangled and messed up as we've gotten older reset back to being young again. So let me make sure I understand that. If you could take the version of David Sinclair that was born

and you could look at every single piece of methylation across every single strand of DNA on every single gene in every single chromosome. And you had a picture of that, and you knew what that always looked like. Fast forward 50 years, some of those methyl groups are gone. You've lost methylation in some places,

and presumably in many more places, there are now methyl groups added that were not present. So you've had both an addition and subtraction of methyl groups, and that now looks like a different picture. Are you suggesting that at least to the first order, if you restored the methylation status to what it looked like when you were born, you'd have a younger phenotype? That's exactly what I'm saying. That wasn't like a canned question.

I wasn't even asking that rhetorically because on one level, that seems really complicated. But on one level, it actually seems kind of simple. You know what I mean? That's sort of what's weird about it. What's amazing about it is that we didn't even understand how it fully works yet. We just know that there is this backup copy

that we can access. At least we have early evidence of it. So we have this manuscript that says that if we turn on a few key genes in the body of a mouse or in a cell, it will quite literally not just act younger and turn on young patterns of genes. When you measure its age by counting these methyl groups where they are. It is young again. And so this backup copy exists. But what warps my mind, it blows my mind, is that there is something in the cell that we've had all along in our lives that allows the cell to reset.

Can I ask a question? Tell me if this is the right time to answer this question. A lot of what you're saying sounds like, hey, isn't that quote-unquote a stem cell? It's very much like that. Because what we've done in the field is we've taken the knowledge from the reprogramming field, which is using what are called Yamunaga genes, and they're used in the field right now by scientists, by companies, to take an adult cell. I could take your skin cell, for example, grow it in my lab, and I could make a stem cell out of that. How does that work?

It strips pretty much all of the methyl groups off the DNA, and that's a reset, not back to being young, but by being primordial, by being pre-embryonic. In other words, methylation by definition implies an aging in some level of a cell. So technically, your most primordial cell had no methyl groups on its DNA. Right, right. Very few. And as we get older, and it's not so what we've discovered as a field is what again, a few years ago, I wouldn't have believed it, but it is true. Is that this clock starts aging from conception. So even as we're growing in the womb, our DNA is accumulating these chemical changes, these metals. and that extends throughout life forever. And if you gave me a sample of an embryo or a baby or a teenage girl or an 80-year-old

eye and some other lives in the world, you can read that DNA. And by the pattern, I could tell you exactly the age of that cell or that tissue. It's almost like you're describing carbon dating of a cell for lack of a better word. No, that's perfect. That's the best way I've heard it described yet. And I didn't realize that the fidelity was as great as you've just described it. I understood that you could look at methylation and tell the difference between a baby and a 50-year-old, but if I heard you correctly, you're saying that if you took a fetus

at one month of development versus a newborn, a full eight months later, you would actually be able to distinguish those on the basis of methylation. I mean, obviously phenotype and many things would give that away. We would. And in fact, the pace of change is very rapid and nimble. What is the fidelity of this when you look at one, two, three, four, five year olds? Is it literally that precise that it can measure the age of DNA within a year?

Oh, I don't know what the latest statistics are. For a human blood sample, it was 95% accurate for chronological age, but what we've realized is that the clock actually changes depending on how you live your life. Well, I was just about to say, this is not that interesting if there's nothing you can do about it. It's just one more reminder of your birth certificate. It's only relevant if either things speed it up, which we'd like to know what those things are to avoid them, or things can slow it down, or even, as you said, reverse it, although

that seems too good to be true, right? Well, it's even more important than your birth certificate. Your birth certificate just tells you when you're born. This clock tells you how fast you're aging. And a few labs, Steve Horvath, is one of the inventors of the clock. We actually call it the Horvath clock. He is able to estimate not just how old you are, but predict when you're going to die with high accuracy. And that's really scary, that we are predestined based on our lifestyle up to that point, how long we're going to live. And there are

some things that slow it down. Exercise is one good thing. Calorie restriction. Smoking does the opposite. So right now, at this moment, having not eaten in a couple of days, I am slowing my clock. You are. So there are probably mechanisms, actually, we know of mechanisms that are turning on sort of two and so your NAD levels go up when you're fasting and sort of two and do a better job of both repairing the DNA and keeping it. You have more substrate now to do their job. Right. And just like in yeast, our cells need to do both at the same time repair DNA and keep

the genes silent. That should be silent. But if we're lazy and we eat a lot of food and we don't exercise, those programs that are designed to keep the clock from accelerating don't aren't as active. So that's what we think is going on, and that's why if you have smoked a lot of your life, or you don't exercise, your clock will, on average, and for most people that are tested,

will be older than your actual age. And so the only thing that you can do is either slow that down. Right now we don't have to reverse it in humans, but in mice, we're getting glimpses of how to actually literally make a cell half its age that it once was. And how does this clock work in its prediction relative to other things that get a lot of

attention such as the length of the telomeres of a cell and maybe define for the listener what telomeres are since some people might not be familiar? Our chromosomes, all 46 of them, are linear DNA molecules. So they have Ns, two Ns, each chromosome. And those Ns need to be protected. And those Ns are called telomeres. And good analogy of... It's like the hard piece of a shoe string. Exactly.

That's what an agglot is. But as we get older, they get chewed back and eventually they become so afraid that the cell recognizes the end of a chromosome as though it would be a broken piece of DNA and they shut the cell down trying to repair it and try to stick it together with another piece and you end up with a bunch of genetic chaos. One thing that cells do to prevent from becoming a tumor is they shut themselves down

and they become senescent. And that's a whole other problem for the body once you've got a zombie cell that's not dividing and is in panic mode. But telomeres do a road as we get older. the body once you've got a zombie cell that's not dividing and is in panic mode. But Tila Mears do a road as we get older. So they've served as a pretty good clock. But what happens is that cells can divide faster in different tissues. Some tissues don't even divide. So it's not like a universal clock, like the one that I just described that Horvath and

others discovered. There was a paper that came out maybe six months ago in science after, remember that you had the twin astronauts, one astronaut was at the space station for a year, the other, his twin brother was on earth for the same period of time, of course. And the paper was interesting in that, and there were two actually, I'm trying to remember,

there was one of the two papers I read. So it's possible, I'm going to misrepresent this because I don't have all of the data. But what I remember struck me as interesting enough that I was surprised nobody else was talking about it or if they were, I was somehow missing it, was they made a big deal about the fact that a lot of changes occurred in space. And certainly some of these were very obvious and predictable. You could imagine bone density going down, muscle mass, things like that.

But they talked about how there was this dramatic difference in the length of the telomeres of these two twins who presumably would have I assume they had measured pre and post so it wasn't. But what was really interesting was within something like two to three days of being back on Earth, the twin that was in space had a complete reversion to what his brother was when he was back on Earth. And maybe I'm just skeptical, but that made me a little less interested in telomeres as a particularly relevant metric of the age of an individual. Would you interpret that differently?

No, I agree with that, but something that can change within days is less interesting as a clock compared to something that seems to be immutable and ticking every day of your life. That's the holy grail, and it looks like we may have had something like that in the field. And Horowitz is a pretty young guy. Yeah, he's younger than me, so he's in his 40s, I think. And he's a mathematician? He is. You see a lot. He needed to be a mathematician because to find the clock, you can't just read all the methodful groups. You actually need

to train a computer that uses machine learning to find out which are the ones that change with age and those others that just randomly change. I know I've read a tiny bit about this enough to be dangerous, right? So Horath used the data from like Illumina or something like that. There was publicly available data. He had maybe 8,000 samples to study and presumably enough of it was longitudinal. In other words, he must have had some samples of the same people. That would give you one piece of data. But I guess if he knew the age of the person, you could train a machine, as you're saying,

I guess, to see how much methylation is occur. I guess I apologize if this question goes beyond your level, like it's on this subject. It sounds like he's someone I should interview as well. Is he able to or are you able to in your lab look at methyl groups and know if they've been there for a long period of time, if they're new, if they are additions, or if they basically they were largely inherited. I mean, do you have that capacity? We do.

That works because we know from building the clock that at age, five years of age, this is the pattern that was likely there for an average human. And this is the pattern of an 80 year old and holding between. But that would be true at a macro level. But I'm saying at the level of a given gene, are you actually able to infer that? Yes. So Corvaz clock is built, there were a number of clocks. His latest one is built on a few hundred sites on the genome. They're very specific. And for reasons that he doesn't't understand and I think we are beginning to understand those are the ones that are sensitive to age and that tick along and some tick differently in different tissues but he recently published a universal clock and another group at Harvard

published a universal clock for mice which means it doesn't matter if I give you a blood sample or skin sample or brain sample, by looking at that precise location on the genome next to the gene X and you look at 300 of them or so, then you can actually say exactly what age that mouse is independent of what part of that mouse you're given. That's kind of amazing when you consider the fact that if you didn't know that a priori, you had to start with all of the genes and look at all of the potential sites of methylation. I agree. But just be a unbelievable problem.

When Horvath and Hannum Zialogah did this, when those papers came out, it was really hard to believe. Because for the last 50 years, we've been dreaming of a clock, but the evolution of biologists said, not it's just organisms wasting away, like a car breaks down, lack of selection for longevity. There's no way there's gonna be a clock because aging is not considered a genetic program. And it isn't, there isn't a program that tells us we must age,

no one I know in the right mind believes that. But there were processes like I was describing about the movement of these surprotines in yeast and movement in mammals like us that leads to a predictable change on our genome that changes the way genes are switched on and off as we age in very precise locations. But what truly blows my mind is that the cell somehow knows which are the young ones and which are the old ones. And when we tell it to it can reset the cell back to the old ones. And when we tell it to, it can reset the cell back to what it was. But you don't want to go too far. Your point about

stem cells is well taken. If you push it too far, and some labs have done that, one color spell montait, the salt and stewed chode, you turn on this reprogramming, you can actually cause tumors in a mouse, or actually turn them on really fast and they'll die within two days. You can push those balls up that landscape from the valleys far too quickly. The cells don't just regain their identity, they go all the way back to being basically an embryo. That's not going to help anybody if we kill people after two days. In my lab, we do what's called partial reprogramming.

We push them a little bit so that they regain their youth, but they don't lose their identity. Let me think about this for a second. So when you go back to the analogy of Shannon, which is you've got receiver operator trying to communicate through a signal, through an electrical signal, there's a loss of fidelity in the signal. So the receiver operator pair have to be able to compare this transmitted signal to a master signal. When you bring that analogy down into our DNA, is it the expectation that within every cell resides a master copy or not necessarily within every cell? It appears to be within every cell because when we reprogram the animal and currently we're

choosing to reprogram the retina and restore eyesight in all mice. The cells that get the reprogramming signal from the three genes we put in, those cells will survive, will regrow, will restore their function back to being young again. And if a cell next door doesn't get the reprogramming signal, it doesn't regenerate, so it appears to be intrinsic for each cell. We can also do that in the dish. We can grow human cells, grow nerve cells, mini brain in the dish. We can reprogram those to be young

again and survive a stress such as chemotherapy and regrow, as though they were young embryonic cells again. So let's talk about what this reprogramming means. What I mean by reprogramming is that we can means. What I mean by reprogramming is that we can use technology that we use now to generate stem cells, but to partially reprogram them so that they turn on the youthful pattern of genes that we once had, that we know we lose. There's no question as we get older, our cells don't turn on the genes that they once did we know young and genes that should be on when you young get switched off. So we lose that, that's that noise. It's a genetic noise, I call it. Reprogramming somehow resets that pattern. In terms of the hose and the spalling of the DNA, what's actually going on is that genes

that were once tightly bundled up by the sore proteins and by methylated DNA are coming undone as we get older. This noise. Reprogramming. Somehow tells the cell that region of the genome, package that up again, get the sore proteins to go back there, get the methyl back there, or remove them, and get that gene to switch off again because that gene has no business being on in the retina. You might need it somewhere else and somehow, somehow a liver cell knows that that gene shouldn't be silenced.

Maybe it should come on. But there's a repository. So in Shannon Parlens, he calls it the observer. His backup disk is called the observer. And the observer keeps a signal, keeps the original signal until it's needed. And if the receiver of the signal does the check sum, you know what a check sum is, I think, oh, you'll listen as we'll know that every time a signal is sent, we know that it is complete because it all the math adds up. If that doesn't add up, that's a signal that says there's been a transmission error. Right. And instead of going back to the original sender, it goes to the observer

who keeps a copy of the original signal and gets the rest of the data. So if you're sending a photo to Instagram, often you're in the subway or it doesn't make it half of the picture will make it, but Instagram computers will say, hey, I only got half this picture, it didn't add up, the check sum didn't make any sense. Please resend the rest of that signal. It may be stuck in Denmark. It may be stuck in Highsland somewhere, but the system set up that way and that's what I think is going on in every cell in our body is that information is still There our DNA is largely intact. We haven't lost the genes

Dutamutations that was the old idea in the 1950s that information is there We just don't access it because the cells don't know whether to spool up the DNA and hide it What will expose it to turn on the right genes. And I'm still just kind of blown away by this notion that you can, you shared really once a story about how the Horbath Clock was accurate enough that you could even predict how much a person had smoked. Yeah, this paper recently came out. They had the records of Pax Poday that were accurate based on medical records.

And then they also asked these patients, how much do you think you were smoking over your lifetime? And they made up some number based on what they remembered. The clock matched what the medical record said and not what the person said. So I'm sure they weren't lying. No, of course not, because they would have had to have told the medical record in the first place. But presumably it's easier over time to tell,

like if you ask a person every year, how much they're smoking, you'll get a more accurate response of the aggregate smoke versus at the end of. That's exactly right. What it tells us is that this clock, there's no lying here. Your DNA doesn't lie.

Your clock records probably every good activity and every bad activity that you've had in your life. You talk about the ultimate wearable. Could you imagine? We love our rings and our CGMs and all of these things, but imagine you had a little whore of Athe clock, you could stick into your interstitial fluid. It's coming. If you gave me your DNA, I could tell you how old you are biologically. I would love to do that. In fact, it would be fun. Let's do a longitudinal sample. We'll stress the system a little bit. We'll do, here's some DNA, and then we'll do a fast.

I'll go a week without eating or something like that, because that's a pretty extreme stress. A week of fasting should do it. In fact, we should do this with rapamycin dosing. I'm curious as to whether the pulsatile dosing of rapamycin that I take does that have an impact. In other words, you start to wonder, are there final common pathways that so many of these higher level interventions impact? I think level is the right word. The spooling of the DNA, this epigenome, there were various levels. The superficial level are these transient proteins. We call them transcription factors that jump across to genes and tell them to be red.

Another level down are these sertuins that we work on. They actually chemically modify the spalling proteins. We call them histones. And then the deepest level, the third level down, is this methylation clock, which is very hard to reverse. As far as I know, the only way to really do it is using a stem cell technology, this reprogramming factors, Yamannaka.

In other words, your belief is, I'm gonna come back to that, because I actually like that level system you just put forward, but the reason you're saying that is the best your evidence suggests in the lab today, outside of using a vector to actually insert new DNA or something is is you can change the rate but you can't change the direction. Is that sort of what you're seeing?

Yeah, that's the summary of now hundreds of papers on this topic. It's a scary thought. All of these interventions, Rappamyson, NAD boosters, midform and all the data's not in, of course, we need to do more but the first studies have said that they have relatively little impact on this very deep clock. And they slow it down, that's fine. They stop the models, the balls from jumping too far across valleys. But they don't get the balls to go back into the valleys that they will once win we're young, which makes sense. You can't take rapper Mison or any de-brew storm at format and restore vision in a mouse like we are with reprogramming

factors. So let's talk about that. That's obviously now we're entering the future. So talk about that experiment. Well, so what we did was we took three of the Yamunaka genes that I used to make stem cells and we packaged them into what's called an AAV, adenine associative virus. There's a virus by the way, as you already used by many companies. There are a number of products on the market. Some are used actually to fix eye diseases, genetic diseases. So this isn't some crazy, super science fiction story. This is medical FDA-approved drug development.

We take these vectors, the viruses. We package these three genes in, which is not easy, because they don't hold much. So we whittled this down, we gave it an on-off switch, which is important because you don't want to become a stem cell, you don't want your eye to develop a tumor, if it might. We did another trick, which is important, which is we left off the fourth Yamannaka factor called Mick. Now Mick is a well-known oncogene, gene that causes cancer. That didn't take a genius to leave that off. But what was surprisingly rewarding to see was that the MEC gene was superfluous. We didn't

need it to reprogram cells to be partially young again. How did you program the on-off switch? That's really interesting too. This is in the field we use a system where we can feed a cell or a mouse doxocycline and it's just an antibiotic. And antibiotic. So my daughter who had Lyme disease will tell you, it's not great for long-term use, but just for a week or a month that's fine, we've given it to mice for their whole life. They seem to be okay. We set it up so that what's called a doxocycline responsive gene. And so now when we have the virus in the stomach.

So you can silence the gene with doxie, basically you use something inert that has a trigger. Yeah, we could have used a bunch of different chemicals, but we use this one because it's... You understand it well and it's pretty benign. And the FDA would likely approve it because we know a lot about it. We didn't reengineer it so it was extremely tight.

So we don't want any leaky gene if we don't want it. And we also made its levels very low because we don't want to blow the system out. So we made this new version of the virus and delivered it. And then adenovirus for folks who might not know what that term is, these are very common viruses. Or many of us have been exposed to these already. Presumably everybody has. I mean, it'd be hard to not be exposed when adenovirus at some point, but unless you live in a bubble.

And there's so many different ones, yeah. And remind me, is an adenovirus at some point, but unless you live in a bubble. And there's so many different ones, yeah. And remind me, is an adenovirus a DNA virus or an RNA virus? I can't even remember. Yeah, I can't remember either. I used to know that. Okay, so it's a basically, and how much DNA can you pack into it? I'm pretty sure it's a DNA virus, so we pack a DNA in there. You can pack a 5.4 thousand base pair of DNA.

5.4, okay. All right. And you go back to these mice, and the phenotype of the mouse is what at this point? It's an old mouse, middle-aged mouse. Well, we've done three crazy things, door mouse, to test. The first thing we did was we crushed the optic nerve. So you took a normal mouse,

and you crushed its optic nerves, and now it can't see. Yeah, and only very, very young mice will retro nerves. You break your spine, you're not going to walk again. And so we thought maybe if we turn the age of those cells back to being extremely young, they'll grow back. And there's nothing that works to grow all the way back. Healthy optic nerve.

So we did that. I won't reveal the punchline yet. We also, these are wrong collaborations, I should credit my collaborators. She gang here at the Children's Hospital in Boston and a Bruce Cassandra's lab did this experiment and I'm going to tell you about glaucoma. So he puts pressure in the eye, pressure is one of the large drivers of glaucoma and disrupts the vision. And then the third experiment was to take just regular old mice. There were two years of age and reprogrammed those. Actually, they were 12 months of age. We didn't go too far. But by 12 months of age, mouse has lost a lot of its vision about it.

Interesting, because that's only about 35-year-old human, right? Yeah. You're 40. Okay, it's about 40-year-old. But those mice, we thought even that's an old mouse. So most people can't restore vision in anything. We have now treated it much older mice, we thought even that's an old, so most people can't restore vision in anything. We have now treated much older mice and we do see some partial effects. Okay, so let me recap that. So you've got the first group are young mice, but they've had their optic nerve surgically traumatized or traumatized through compression. You have a second group,

I don't recall the age, but you increased interocular pressure to mimic glaucoma, and then the third group you just took relatively old mice that had a natural decline in their vision. Right, and there are two ways that Bruce's live measures vision in mice. One is you expose, well, you show it a TV screen with moving lines, and the lines can be thick or thin, and you've got really good vision, you can see the thin lines and you can watch the mouse turn its head. And if it blind or it can't see it, it obviously won't move its head. Now that's partially subjective, it's not bad, but you want something completely objective. You can't measure the electrical signal in the occipital cortex.

So we stick an electrode in the back of the eye and measure the signals that come like an electrocardiogram for the retina. And that doesn't lie. You want both to agree with each other, but that one we can measure before and after treatment. And there we can see what the virus is doing. Now one thing that I haven't mentioned, which your listeners may be interested in, is when do we turn on the virus? And because we want to treat patients, we're not just doing this for fun, we turned on these Yamunaka genes in the virus after the treatment, not before. Because if you've got glaucoma or you've damaged your optic nerve or you're old, you need to be able to reverse that, not just prevent the damage. And so we did that. So these results that we've put

out there actually show that in all three experiments, regenerate nerves and in the case of glaucoma and old mice they get their vision back. So let's go through actually technically how you do this. So the adenovirus vector now contains the modified stem cell basically. The genes of a modified stem cell is that a safe way to describe it? Well a better way would be that these are genes that specify us during embryogenesis. So it tells the cells. But you took it back to, yeah, I was trying to figure out where you, so you basically have the methylated pattern of the gene that mouse would have had during development.

Well, we think so. We've measured the clock in no cells after reprogramming, and they are younger. Steve Hoverth helped us with that. But what's also interesting is we can look at which genes are on and off. And if we look at the young mouse and the old mouse and look at which genes are on and off, we can see that we've got noise now. Genes that shouldn't be on are coming on, such as genes that are involved in stress responses. And other genes that interestingly are coming on that shouldn't be in the eye in a young mouse. And those are very interesting. Some of those are, think about, 80 of them are taste receptors, meaning proteins stick

out of cells and smell. Actual taste receptors in a mouse or homologues to other animals. Well they're predicted to be taste receptors or smell receptors. They're called olfactory receptors. But what they're doing in the back of the eye and why they change with aging is so far a complete mystery. I could speculate that they're important for signaling chemicals that have nothing to do with smell.

Has this been identified, for example, in humans? Do we know that humans also have olfactory nerves in their eyes? I don't believe so. I think we were the first to figure that out. But there are sporadic accounts of it because it's so weird for a few people of paid attention to it. But anyway, the end of the story is that when we reprogram the retina, those genes that were coming on during aging get turned off and vice versa. How many genes are we talking about, David? In this particular process. Just hundreds, hundreds of genes. In terms of statistical significance, depends where you want to draw the line. So I think it might be a few hundred that are really significant. But the thing that blows

my mind about this result is that the genes that went down with aging just a little bit, when reprogrammed come up a little bit, and those genes that went way down with aging when you reprogram a way up. So it's as, the cell knows that this gene should be put back to where it was. And I have some ideas, but I have no evidence how that actually happens. Sorry to interrupt, but does that correlate to how much methylation is on the gene? In other words, you talked about this gene was down a little bit, and it corrected to going up a little bit. This one was down a lot, and it corrected to going up a little bit. This one was down a lot and it corrected to go up a lot.

Is the a little versus a lot correspond closely to the extent of methylation? We don't know that yet. You're right at the cutting edge of the work in my lab. One prediction would be that those chemical changes map to those genes that we see change, but we haven't overla overlap those data sets yet. But it's the next exciting possibility. One thing that we do see is that if we stress a cell out, let's say we break its chromosome for a day, the cell actually has these hypersensitive regions

that will open up and stay open. And that's evidence for epigenetic noise. And so what I think is going on is that cells in their daily response to broken DNA and other things, like UV damage when we go to the beach, don't wear sunglasses, that back and forth of, oh, we got to go put out that fire, we got to go repair that chromosome,

has led to these regions of the chromosome that are sensitive to opening up. And once they're open up and the methyl groups have removed or been added in the wrong place, they stay that way. Unless we reprogram them, somehow the cell knows, oh, that one screwed up. Let's go back to being young again. So let's play devil's advocate for a moment. In clinical medicine, we're actually 20 years almost exactly to the first time someone used one of these adenovirus factors to treat a patient. Wasn't it 20 years ago at Penn, Jesse? I don't even remember his last name now.

It begins with a G, I believe, blanking on this. But basically a patient died, right? And that sort of really, really changed the trajectory of genetic engineering. And I always thought that as tragic as that death was, it was a little bit of a distraction from what I always took to be was a much bigger issue, which was how penetrant can you get these vectors, how ubiquitous can you get these vectors? Let's use an example. If somebody had the belief that apoe forgene was predisposing them to Alzheimer's disease, which it is, right? It's a predisposition.

It's not a fate of complete. The likelihood that you could engineer a vector to swap every copy of apoe4 with a new copy of apoe2, for example, seems very improbable. If you're doing that once they're an adult, I mean, if you're gonna have a shot at doing that as there's reports of this in China,

I haven't really followed this, but there's all this talk about these crisper babies where they're engineering out LP little A and things like that in embryos. But how technically difficult is this to do in a complex organism like a mouse or ultimately a human where you need to change enough of the gene to actually put the right program.

And I'm blanking on what the analogy is going back to Shannon's observer. Because that looks sort of binary. It's sort of like receiver, operator, observer. Okay, but here it's like, don't you have to get enough of the corrected version of the gene in to actually get the optic nerve back? I don't know if my question makes sense, by the way. It is binary in the sense that if a cell doesn't get the virus, it's not going to be reprogrammed. So the current limit to technology right now is getting it into the system. How many of the cells can actually get the virus?

That's really what I mean. Yeah. At the cellular level, it's binary, but it's sort of analog across all the cells, right? Yeah, it is. And that's the problem we face. That's why it's going to take a while to reprogram an entire human being. These viruses like the liver, for example, and you don't want to give yourself liver cancer, just trying to reprogram your nose or whatever.

That wins the Darwin award, right? If the person who does that. I cured my wrinkles, but I died of teratoma. I would predict that at some point people are going to try and use this for cosmetic effects as well. We don't know what we can rebuild, we know we can restore retina, we can regrow optic nerves. We don't yet know how much we can reprogram an entire animal, little alone, and entire human. But one thing that has held us back in my lab is that we can't deliver these AAVs, the viruses to every cell in a mouse. Now, the good news is we may not have to. Maybe we only need to reprogram a quarter of them and we get to be a lot healthier and younger.

We don't know that yet. But in the eye, the reason we chose the eye as well, besides the fact that we really like a challenge, is that the eye has drugs approved for viral delivery. It's relatively insensitive to the rest of the immune system. So even if you've got anti-acidins, it's protected organ. And then we've got the fact that we can deliver a lot of virus and in fact about half of the optic nerves in the back of the eye. Can I get a vote on the next tissue to work on here? Sure. You have a lot of the similar features. You have a very immune privileged location. Every single man will get prostate cancer in his life. What we can't figure out is which ones are going to die of it.

Imagine you could take the prostate gland of a man who's 50. So a 50-year-old has, I don't know, something like a 40% chance of already having prostate cancer. Again, fortunately most of those will not go on to kill. But the prostate causes a lot. There's really no need for your prostate gland once you get beyond a certain point. But rather than eradicated, imagine just restoring it back to a young prostate and getting rid of the cancer and getting rid of some of the hypertrophy and the other things that come along with it. I mean, it just strikes me as a very discrete immune protected organ that you could go after. I'm sure there's

10 problems I haven't thought of that a urologist is listening to this sort of. Yeah, I think it makes sense except from a business standpoint where diseases that have much more need than long-term effect. So you're saying that loss of vision is acute enough that there's a reason to do something about it immediately as soon as you're saying that loss of vision is acute enough that there's a reason to do something about it immediately as you're experiencing visual loss. Exactly. Or you're having heart failure. Got no other choice but to try this. Or you're going to die. Those are the early low-hanging fruit that to help people. We need to figure out is this safe. There's some risk, right? There's no risk-free drug, except for fish oil, which we don't know anymore if that's highly effective. a fish oil, which we don't know anymore if that's highly effective. So there are risks and with this technology that we don't yet know what those risks are, we're going for

the eye because it's not likely to cause any problem. We've gone long-term studies in the mice, many months, no effect on anything negative. If it was perfectly safe, I think the prostate would make a lot of sense. If we had a drug on the market, a doctor could try that in clinical trial off label. But I think the future looks bright if we can get one tissue or one organ B-RU program. So cardiac myocytes, how technically challenging will that be? And do you have a mouse model for that yet? A heart failure or a mouse model? We have hypertrophy. That's the best model we have in my lab. They may be better ones. Oh, the problem with hypertrophy is they retain contractility, right?

So it's sort of, you almost want a mouse model where they've lost some of the contractility. That strikes me as it, I don't know, I can be wrong, but that strikes me as the easiest place to try to figure this out. All right. Yeah, I need to research this. I wonder if Jackson would be one way to go. Right. Yeah. I need to research this. I wonder if to Jocson would be one way to go. Interesting. So what steps exist between this proof of concept in mice to an actual human clinical trial, even in phase one? Well, the good news is about an eye study is that you go straight to phase two. Because you have enough other adenoviral vectors out there that they give you your safety in phase one?

Well, my understanding is that in the eye, it's a special condition where healthy volunteers don't want their eye injected with virus. Ah, of course. So you're not going to do a dose escalation. And but, although sometimes they make you do dose escalation in a diseased population, for example, with cancer drugs, a lot of times the phase one is still done in cancer patients.

All right. Well, the advice that I've been given is that we could go to a phase two immediately. And so the obstacle is surprisingly not getting into patients doing the trial, actually making enough virus. There's such a gold rush and interest in gene therapy that making these adenoviruses can take a year. And it's about twice as much as it cost a couple of years ago. Gene therapy has gone from... Wow, so that's kind of the opposite of what you think of with Moore's Law on the sort of transistor side where more interest, more technology should get cheaper. It will, but we're in that uptake of supply versus demand, and the demand is huge. And it's probably because it's the

hottest thing now, being able to edit the genome, correct genetic diseases, and now reprogram the body. This is a massively interesting area that holds huge amount of promise. And presumably profit if there's promise. Well, otherwise, you're not going to get people to put their hard-earned money behind it unless they're very philanthropic. The point is that I think you raised this earlier, I know you raised it earlier, that the gene therapy used to be the pariah of medical treatments because it was thought to be dangerous, risky, probably won't work.

That's gone at 180. And now, if you have a gene therapy company, there've been a few that have been sold in the billions recently. These are extremely hot. Everything that's new, breaking new ground, investors are all over it. How did the vectors today differ from the vectors 20 years ago?

And I don't even remember the story, particularly well, of when this boy died. Presumably he died of sepsis or something sort of related to, but not the direct, proximate result of the gene therapy. My understanding is these were different types of viruses that could integrate into the genome and cause mutation, and that led to problems Not least with standing up. I could look at a lot too much. The viruses today don't cause cancer

They don't integrate and they don't have any negative side effects other than immune reaction How is that possible that this is not putting? Sorry, you're saying it the problem used to be that it was putting its DNA in as well as a package DNA that it was carrying with it. Yeah, that's my recollection that they had a propensity to integrate into the genome. So where is gene therapy today with things like sickle cell and some of the really obvious, like if you're thinking about what's the poster child

for gene therapy, it's sickle cell, it's thalassemia, it's cystic fibrosis, like you can rattle off 20 diseases that are tailor-made for this because they're single-known gene mutations. Well, people who are interested in this should Google it. ClinicalTrials.gov. ClinicalTrials.gov has a bunch of these. Oh, yeah. Many, many.

This is a great example of how I sleep at the wheel I am. It's like my day job to pay attention to medicine, but you get siloed into one thing that I'm interested in and my knowledge of gene therapy is 18 years old. It's kind of embarrassing, I'm embarrassing myself as I, the more I'm talking, the more I'm embarrassing myself. Don't be so hard on yourself. Even I can't keep up.

My head is spinning, and this is my day job. I have a double out of this because of osmosis, I'm at meetings and whatever, but every day I have to read, or at least skim, 50 papers just to keep up and in my area Little learn someone else's so there's no way you are certainly anyone who's not following this for a living Can keep up so you're saying that right now there are active clinical trials ongoing for people with these really obvious candidate genes Sickle cell is a company that looks really promising has clinical trials I believe in progress So yeah, I think it won't be long, maybe just a few years before these diseases are correctable. Now they cost a lot, and this is probably a topic we shouldn't jump into because it's

a complete diversion, but because they're one shot, then to recoup the cost that it cost, these are extremely expensive. The spark therapeutics drug that treats a type of retinal degeneration, it's one or two injections, I think it's two injections, but it's in the high hundreds of thousands per treatment. That's a lot of money and some politicians are up in arms about that. So companies are getting more innovative in how this might play out and I'm aware of one biotech that said, if in five years you're not cured, you don't have to pay for the treatment. It's interesting. I've also heard of models, this

one's even more controversial, where the cost of the treatment is basically taken out as future earnings of an individual whose health is restored. So you're sort of tying it back to a gain in productivity. So if someone who can't see as their vision restored, well, they're going to presumably be able to make more money or do XY and Z in a more productive fashion over the remainder of their life. And a portion of that gets paid back to remunerate the cost. I mean, I gotta say I am really glad that that's

not the problem I have to solve because I can really empathize with both sides of these debates. I don't, it's very difficult for a drug company to sort of find the motivation to do these things without some clarity around how these things can be priced and at the same time it seems criminal to say it's going gonna cost a couple hundred thousand dollars for someone who's born with sickle cell anemia to be free of sickle cell anemia. I mean, I'm glad that smarter people than me get to figure that one out.

I wanna go back to this thing because I'm still sort of wrapping my mind around this idea of the Horvath clock. So, too totally unrelated to thoughts. The first is, in the short term, can we use this as a way to measure our progress with the interventions we have at our disposal? So remember a few months ago, you and me and Near were sort of hanging out in Boston. I don't even remember what we were doing. We were just

sort of talking about some stuff, but I made this argument that we already have some pretty amazing quote unquote, drugs out there. There's the really obvious ones like rapamysin that are actual drugs, but then there are other quote unquote drugs like exercise. Exercise is a very potent drug. Fasting is a very important drug if you want to use that terminology loosely. But we still don't really know how to dose these drugs

that well. And again, with the case of rapamysin, I talked a little bit about my use of it. My reading of the literature says, pulsatile use of rapamysin, probably the right way to do it, constitutive use, probably not. But truthfully, it shouldn't be pulsed every three days, every five days, every seven days, every ten days,

at what dose. Not really sure. Fasting, you and I have talked about this all day long, could come up with an infinite number of permutations and combinations for how one should fast. And my fear is we won't get really good answers in these because one, the biomarkers we have today are far too crude to really tell you what's going on, even slapping a continuous glucose monitor on 24-7 doesn't come close to giving you this insight. Looking at IGF, in my opinion, certainly doesn't give

you this insight. We need something deeper to your point, right? We need to go deeper, deeper, deeper. And because these interventions are not essentially profitable, there's really no great incentive for the biomedical community to be studying them. But yet, those are some of the best interventions we have. And for many of us, we'll never have the opportunity to have an adenovirus shoved down our retinal cavity to fix our eyes. It's going to be, hey, how do we eat? How do we sleep? How do we exercise?

And how do we take drugs that are currently available? So do you think there's an opportunity to do this, to use these clocks to look at the extent of methylation and epigenetic change within our DNA? To, as you said, even though none of these things are likely to reverse it the way the intervention that you described is, if we study rates of change, that could be a great first order proxy.

Right, but it's still not gonna tell you within a month of what you've just done is working. If every year a person had a look at their clock, and you could say, hey, David, I'm sort of making this up, but David, since I saw you last year, your genetic clock sped up nine months relative to the 12 months of chronologic aging that you've undergone. Keep up the good work. I can't tie it to what you've done, but would I be able to at least directionally say whatever you've done in the last year has been directionally correct versus if you showed up after the following year and it said, oh gosh, David, you've aged two years epigenetically. Something's not good. Now, you might say, yeah, I got a divorce and got fired.

Well, okay, no guff, it's not good, but that doesn't offer much help. But anyway, I'm just sort of thinking about this through purely selfish reasons. I'm gonna be completely transparent. I just wanna know what to do. Yeah, I think the clock gives us the ability to do that. We did it with telomeres, quite the filtered with telomeres,

but it wasn't as accurate as this new clock. So you could do that. You could, every year, even every six months, do your DNA meth alone, the whole life clock. And have a look at your rate of change. If you've got stored blood samples, you could go back and see what that change was back in time. Be interesting, everybody could save a blood sample

and go back in time too. Are there any companies that are doing this? There are, they just have sprung up. I can't remember their names off the top of my head, but you can find them on the internet. They'll tell you your DNA methylation age. Yeah. Interesting.

I was actually just looking at something totally unrelated to this, but equally outside of my wheelhouse the other day, which was, it was looking at something around endogenous versus exogenous AGE formation. And I was like, how has no one come up with a company to measure this? Because that's the crux of everything, right? It's not about people get so phosphorylated about how many AGEs they're eating and they don't realize it's the endogenous production of AGEs that are far bigger issue. This is like screaming commercial application.

Well, yes, so Steve Hoverth and I were approached by someone who wanted to start a company that would measure your age and then tell you what supplements to take. And he and I didn't believe that the science was rigorous enough yet to say what would correct the clock. But those experiments that you're talking about could actually do that. So the second thing I wanted to come back to on this is something I think we may have touched on very briefly in our first podcast is around Cinescent Cells. And this is one of those things where you see the picture on the front cover of science or nature and it's mind boggling.

You've got this old mouse, this old decrepit mouse sitting right next to what looks like a spry plump, young, beautiful mouse. And the punch line is, guess what, they're the same age. But in the beautiful, young one, we took this subset of cells called synescent cells, and we killed them. So maybe explain what that is at a high level and how it overlaps with or differs from everything you've just described with respect to the methylation clock.

Well, if it just, for a second, go back to the jostling of the epigenome and the noise that's introduced. What we've shown in my lab is that creating this noise and the way we do it in my lab, we like to use a broken DNA to distract the proteins. What we see is that the early stages of aging due to this epigenomic noise leads to a loss of cellular identity. The very end stage of that process is that the cells check out of the cell cycle so they don't divide anymore, but they don't die. They just sit there and they're stuck in this emergency state.

There are other things that can cause senescence. Loss of the end of the chromosomes are telomeres. We'll also cause a cell to say, well, got a real problem here, got a broken piece of DNA at the end of my chromosome. Let's shut this down before we become a tumor. And it's thought that these cells, these senescent cells are really important to prevent cancer from taking off because they shut themselves down and they stay like zombies in our tissues for decades, and they don't die. The problem is that they don't just sit there, they're actually...

Yeah, they're sort of poisoning the well. They're in a state of stress and they're saying to these cells around them, oh my god, I'm panicked, you guys should be panicked too. So they send out chemicals and proteins that stress the other cells, the other cells are now in a panicked state, and their epigenome, I believe, is getting disrupted and accelerated as well.

So if I'm hearing you correctly, you're saying the senescent cells can be part of the cause of the methylation and epigenetic interference with the non-senescent presumably dividing cell or active cell. Yeah, and so there's some evidence for that. Like I said, we can disrupt the epigenome. They get senescent. Those senescent cells you can now put next to normal cells and they will induce senescent or cancer in those cells or make them tumour-genic, we call it.

The other experiment that was beautiful was done by Jim Kirkland at the Mayo Clinic. He took some senescent cells and he implanted them a little bit in a little dab into the peritoneal cavity, the lining of the gut, under the skin. And those mice ended up having signs of premature aging, higher blood sugar and other things. So a little bit of senescent cells goes a long way. And that's what's scary because if you take fat from a young and an old mouse or a young and an old human, we can actually stain them, we can color them,

whether they're senescent or not. And when they turn senescent, we can stain them blue. There's an enzyme they make, it'll be to collect a size. If you stain young fat, it actually looks white. But if you look at middle aged, it's pale blue, and an older mouse or an older human, 50 years old, my age aged, it's pale blue and an older mouse or an older human, 50 years old my age now. It's dark blue.

It's packed with these SNS cells in the fat. And no wonder the rest of the body is in a panic state if these fat cells are now sending out the emergency screaming signal. What is the phenotypic identification of a SNS cell? Well, that's still debated at conferences, but we all agree that they turn blue, that beta collector site is. There are other genes that come on that signal DNA damage, one called P16, one called P21, these are genes that cause cells to check out of the cell cycle and stop cancer. If you lose these genes, actually it predisposes you to cancer, it makes sense. There are other issues, which is that some senescent cells don't have that

particular signature. And there are other cells that is that some senescent cells don't have that particular signature. And there are other cells that are non-senescent that do have those signatures, presumably, right? Not so many. Well, there are some, there's a mouse that was made by Ned Sharpless, who's now the head of the FDA. So he made a mouse that would floresce with a five-fly luciferase, a glowing mouse that was under the control of the P16 gene. So that P16 came on that cell or that tissue would glow green.

So we had that mouse, we found that if a cell or tissue got stressed, let's say a mouse had an infection or it got damaged or was nibbled on or for some reason was just stressed out the P16 gene that fluorescent signal came on. So that you're right, there are other things that can turn this on. So it's not definitive. There is actually no definitive way to tell senescence in a tissue versus none besides this blue stain. It seems to be pretty good. Well, going back to the third group of mice that you worked on. This was the one that was just older, mice that you worked on. This was the one that was just older, presumably at had senescent cells, it had senescent optic neuron cells.

They weren't senescent yet. I see. So you'd stain those, you knew that they weren't, you didn't have any senescent cells that were contributing to the visual deficits that were slowly accumulating. We looked because I was curious as to whether we saw that. I don't believe we saw senescence. The reason that it's also highly unlikely is that we don't know how to reverse some essence, even with reprogramming. Well, so that's exactly the question I was gonna ask,

which is if you saw them, did they change in the presence of the reprogramming or did they still stay there? That's the next experiment, actually, in my lab. We need to know if that's true. There's a postdoc listening to this who's cursing right now, because I think I rattled off a couple

of next experiments for your lab, right? Well, there's 30 people in my labs. Oh, you can split the lab. That's good. But yeah, it's an important question. But what I think is going to turn out is that if you're pre-synessent and you just lost your identity, then that's reversible. We see that in the lab, in the retina.

But if you've clicked over into this zombie state, then you're in this state that may be possibly never reversible. I would never say never, but that's a lot more difficult. So what does that mean for the future? How does that fit into your CD analogy? So if you've got a scratched CD and the scratches are being caused by a senescent actor that's out of the replicating pool, but is poisoning the well, you're telling me you can buff out the scratches in the CD, but you can't get rid of the scratcher, and you're accumulating more and more scratches over time. You are, but theoretically, it should be possible to even get a senescent cell to grow again,

because it should have all of its DNA still there. Now there are issues if it's lost its telomeres, it won't like being brought out of a senescence or it's senesced because it's full of mutations. That can also cause senescence. So there are reasons why you wouldn't want to get a senescence cell to start growing again. You might cause cancer. But there are other reasons cells check out that isn't due to loss of information. So we've got a pretty badly scratched CD that we can polish with reprogramming, but if

you've gouged it so deep that even reprogramming can't work, then we need something else probably. But I wouldn't say for sure. So this is now let's get into sort of a little bit more of the sci-fi speculation. Where do you think would be the ideal application for this clinically in terms of inhumans explicitly for the purpose of longevity and not disease treatment. So we've already talked about lots of applications on the gene therapy side. Is your belief that that is the only application that using reprogramming as an anti-aging tool is a precise tool that goes after the specific anti-aging phenotypes.

Oh, look, your skin is more wrinkly and more saggy. Boom, here's a virus. Ah, your vision is deteriorating. Boom, here's a virus. Ah, your heart muscle doesn't pump as hard. Boom, here's a virus versus a global approach that says, no, we're going to go right to the master CD and somehow we can restore your methylation pattern to that of you at your birth. Which of those two paradigms do you think is the sort of quasi-sifi, but quasi, if you had to guess, predicted approach?

Well, I think within our lifetimes, we'll see the first one. The glaucoma patients are waiting for this. We're working on starting a clinical trial, hopefully within the next 18 months. So this isn't as far away as you might think. How long before we can treat other diseases? I think that it's going to depend on the severity of the disease, the FDA. But I could imagine within this decade

that multiple diseases, heart, maybe not skin, I don't know about that, but other severe disease will be tackled either one by one. But we're not just waiting for that. In my lab, we've already dosed mice with the virus intravenously to see what would happen. The good news is that they're all still alive, they're all still happy, no evidence of that. What's the expression pattern? Well, this is the issue.

Majority is in the liver, some in the gut. That's an ad no feature, isn't it? Ad no really loves the liver. Yeah, if somebody hadn't had an ad no that got into every cell evenly We'd be set that science fiction future could be within our lifetimes where we Get a dose when we're young of ad nobirus We get to age 40 and we're starting to experience the signs of aging our eyesight isn't as good as at night We have to hold the menu a bit far away. I'm there by the way. Yeah, me too. I just, I hit it, man. I hit it at 45 and a half. I can't believe it. It happened overnight. And it's exactly the scenario you described.

It's the restaurant, tiny print, dark. Well, you're losing your vision. If you had been infected with the adenovirus, your doctor, your doctor, you could have someone prescribe a course of Dr. Ciclin for a month. And if we're right, you'll get your vision back, and you'll get who knows what back. It's amazing. It's funny. With all of these incredible, as you describe it, this huge re-uptick in the interest around gene therapy, I have to believe some of these companies are looking for better vectors as well. I mean, if the fact that I remember Adno has a predisposition for the liver that tells you it's 200 years ago's news, are there other viruses that appear more promising? Well, there are dozens in academia now.

They come with greater risk, of course, right? No, these are slight variations on what's currently used in that clinic, and different companies are using different vectors. So, Aav9 is good for muscles, so companies are going for musculoskeletistrophy with Aav9, Aav11 and 2 are good for the eye. There's a menu now of dozens. But they're basically all still adding a virus.

They are. They're slight tweaks on the proteins that tell the virus where to go in. But what I hear is that some companies, I forget if it's Rochbrett, that's my recollection, has made millions of different varieties. And if that's true, we may be able to choose any tissue we want. In other words, we're not getting away from the tissue-specific paradigm. Well, eventually we will. Why not? I mean, if it's on the market, what's going to stop somebody from trying this anyway?

Because I think it gets to a theoretical question, which comes down to, you sort of alluded to it earlier. Why do I need a new car eventually? Can I just keep replacing each individual failing part, or at some level do I need a new car? Is there some final thing that it becomes impossible to replace? Like the chassis just, especially year in Boston, like us Californians, we don't, our chassis is never rust, but at some point, you could replace the

engine, and it's not enough. What are you going to replace? The axle, place this, you're going to place that. So if you take this organ-specific approach, the skin, the eyes, the heart, the lungs, the brain, is there something else that ultimately is going to lead to our demise, or is that effectively just the accumulation of enough senescent cells that the gouges in the CD become so deep that even an organ-specific approach ultimately fails.

Where I'm really going with this is, is there even theoretically an argument for cellular immortality? Theoretically, this is as closely as we've come to finding a way to actually live for thousands of years. I don't know about immortality. I think that the problem with what I'm calling the information theory of aging, which

is what I wrote about in my book, is that we do lose information. Every cell does experience mutations. It's not perfect. Though I know I can take some of your cells and clone you, make a young version of Peter, but it doesn't work for all cells. And so ultimately, if you're a thousand years old, you may have lost a lot of the genetic information, but epigenetic information, because there's this backup drive, this observer that we have found exists in cells somehow that you can tap into.

As long as the genome, the DNA strands are still largely intact, we can reverse aging. But it's an information loss issue. So the gouging that we get may scratch some of the foil in the CD, the DVD, and you lose a little bit of the song, which you'll never get back. Now that said, if I was George Church, he's in my department, he would say, no big deal. By the time a thousand years goes by, we can replace anything. And that's probably true. Whole system, Rico bones. Why not grow a whole new heart, put it in. That's going to be doable. So what I think the future holds is the following. A lifestyle where you're monitoring yourself with devices, devices tell you what to eat, what to eat. If you

want to pay attention, you don't have to eat, what to eat if you wanna pay attention, you don't have to listen. But when there's a problem, you'll notify it. You've got a tumor somewhere in your body, we've detected it, go have that killed before it grows. That's gonna be 20 years ahead of what we can do now for patients. That'll keep you young and healthy for a lot longer.

In the meantime, we'll learn, thanks to guys like you and clinical trials, what to do to live live longer whether it's the perfect exercise that the perfect combination of diet But is that necessary? I mean if you really stop to think about it Couldn't you just make the case that all of this nonsense that people like me do and all of this Ridiculous effort that goes into fasting and wrap a mice in and this exercise and sleeping and all of this fun killing activity of my existence. If I could reprogram, why would I do any of this? Well, yeah, I mean, who could argue with that? I mean, like, I could literally go and get

a biggest, most beautiful pizza burger imaginable right now and not worry about any of this stuff. All right. That's if it comes true. So, so far, it's so good. You know, if you can restore vision, I'm sure you can restore a lot of parts of the body. Let's say reprogramming doesn't work that well and you say you get senescent cells, your organs eventually lose their information in the genome, then what, well, you can delete senescent cells,

you can take someone else's organs or grow your own in the dish or have a pig grow your own. With all that put down, if that all worked, I would challenge anybody to say that that wouldn't allow people to live a lot longer. There's still people out there who say we're never going to make it past on average 80, 85, they'll learn to 100, they'll learn to 120. Well, I don't know. I think it's much easier to imagine an upward Movement to a hundred for example. I mean look that's sort of my point of view right? I think genetically I'm probably engineered to stick around until I'm in my early to mid 80s I get this is just looking at my parents

Which once you get over 80 your genes become a far bigger predictor of your longevity than in your 60s through virtually uncoupled I feel like I've got a great roadmap on what it means to get to be a hundred become a far bigger predictor of your longevity than in your 60s, they're virtually uncoupled. I feel like I've got a great roadmap on what it means to get to be a hundred, which is still stochastic. There's no guarantees, but it's like, how would you stack the odds in your favorite kind of thing? But it's an entirely another animal to imagine a world where you can take individuals and even get them to be 200. That's a really big leap. And I would have said three years ago, it's impossible. What did you think three years ago would have been the

limits of our technology? And that's again, three years ago, you were thinking, I could give you more NAD, I could give you more things to activate your Sir 2-ins, I could tweak your mitochondria this way versus that way, based on that level of manipulation, what were the limits you thought we were? So my thinking was having come from the calorie restriction world, that animals that are calorie-stricted live at best, 30% longer. And they're healthy, which is great. And the CR-mometics, like RAPA-Mysin and MET-formin, they can,

depending on how sick the animal is. But let's say even RAPA in a non-sick mouse can give you 30% more life. Right, so as long as we're like a mouse, we could live 30% lower. So you know, 30% of 80. That's a big deal. That gets you 200 right there. Yeah, that's 100. That's why I thought someone who does all these things has a better chance of reaching

100 than ever before. But what I didn't take into account in those numbers, most people don't, when they think about this, is if we make it to 100, okay, so that means I'm still alive in the year 2069, what technologies do they have in 2069? Is reprogramming a common thing? Probably it will be. Yeah, so in other words, this is the optionality play. It's, if you add 20 years of life,

extending someone from 80 to 100, you have to take into account the probability that things come online during that period of time that can also impact the very variable that you're trying to manipulate. Yeah, and already every month that we stay alive, we get an extra week of life, that's how technology is going currently. Wait say that again. Extra month of existence you'll

be able to live an extra week. Come on that seems too good to be true. That's a 25% plus up. I can't be right. I'll check on it. Did I hear you right? I'll tweet that out if it's right but that's what I recall here. I'm only questioning it just based on it seems too good to be true. Every additional month of life is offering a week of additional life extension just based on the technologies associated with them. Because there's no evidence of that to date, is there? Because we really have seen a compression of life expectancy over the last two years. Haven't we actually seen so up until I think, again, I don't want to, I'm probably misquoting this, but directionally, I think this is right. Up until about 2015, life expectancy was increasing at about 0.4% per year.

That's now crested. I don't believe that in this environment that we live in. In other words, we have figured out a way to eat, stress, and not exercise our way out of all of the technological benefits that have come our way. And that's, I think, why you're seeing this sort of cresting, right? We've solved all of the infectious problems that gave us most of our longevity gains way back in the day. We figured out that you shouldn't drink out of your sewer, and we learned to wash our hands, and we've got great antibiotics. But these chronic diseases that are killing us now, the force that's driving them, which I think is basically food, sleep, lack of exercise stress, etc., etc., I feel like those

things are weighing down on us more than modern medicine is giving us tools to fight back. And at the very least, they're at a standoff. Certainly in the U.S. that's true. It's not true for all countries. That one week to a month thing might be a non-US stat then. Oh, yeah, it's a global increase in the maximum lifespan. So that might take into account, again, I don't follow this research closely enough to say it, but it might be that, well, you're getting more vaccines in the hands of people who are

otherwise unvaccinated and getting fresh water and food into people who otherwise don't have it. Is that, do you think it's not?, it's have to correct what I said, because it's very important. It's a graph of the average lifespan of the longest lived country at the time. So Japan has been leading that for the last decade or so. So that's important. It means it's average lifespan is increasing at the top end.

So if a country uses all the new technology and has good health care and people don't eat themselves to death or take opioids, that continues to march up. What doesn't seem to change, in fact if anything, is plateaued or reversed, is the maximum lifespan of humans. Which, if you believe John Colman, she was 122, people debate that, but some people have made it 117, 118, no question about it. But that seems to be our current limit. But did those people take care of themselves? Absolutely not. No, no, no. They're the opposite. Yeah, near has done great work on that topic. They smoke and drink themselves to an untimely at 117. But what if they had access to the knowledge

that we have now, which is lifestyle, some of these medicines that we think can help? Maybe they would help those people to get beyond that. But to really go beyond that, I think you need something really new. And that's why I'm a lot more optimistic than I was having seen what reprogramming has in terms of potential to be able to not just slow the clock down, which is an extrable, seemingly an extrable, but now actually get sales to go back in time. Well, I mean, it's interesting I could talk about this for a lot longer. I think at this point, I mean, I think the readers will, I think, enjoy your book greatly. I've deliberately avoided asking you, I think, some of the questions that are also on my mind about what are the implications of this. I think I get asked these questions a lot and I just defer. I just punt. I just say, look,

I'm not even trying to solve a societal defer. I just punt. I just say, look, I'm not even trying to solve a societal issue. I'm interested in the longevity of the individual. And that's a hard enough problem. So that's kind of the one that I want to think about and put all of my energy into. But in your book, you really do actually try to ask the broader question, which is, what is the implication of a society where people can live to 200? It would change a lot of things. So I'll let the readers either hear you on other podcasts to talk about that or do what's even better and just actually read the book themselves. But I want to kind of come back to some things that we touched on really briefly in our first discussion that I've had so many follow-up questions on. And so

if you still got a little, you have to go back to Boston tonight to you. Okay. So let's talk a little bit about your own personal habits around stuff. So let's start with Metformin. We've talked a little bit about Metformin. There are a couple of papers that have come out kind of recently that have suggested, hey, maybe Metformin in the, the Metabolically Healthy Person and or the Person who's exercising is either not effective or potentially blunt in the effects of that. How are you reading those papers?

Well, I thought what you wrote online was excellent. I think about the same way, which is we've known that one of Metformans main effects is to quote unquote poison mitochondria. It inhibits a group of proteins that generates energy in mitochondria. And the response of the body when it has a bit of inhibition of this is to say, wow, I'm low on energy. Let's build up those factories. So mitochondria are often called the power packs or the battery packs of the cell. They generate chemical energy. If you're young or you exercise or you calorie strict, you'll have more greater

area or activity of these mitochondria. So more is better in general for humans, while mitochondria is good. And as we get older, we lose that ability. We met Foreman slightly inhibits that activity and the response is to make more of them. Problem is that if you're constantly inhibiting those mitochondria, that's not going to be seemingly helpful with this new study for building up mitochondria after exercise. Now, you could argue that maybe you don't need to have more mitochondria after exercise, but I think you probably would benefit from more mitochondria. So what you suggested that I think makes a lot of sense, though we need to prove this, or at least test it, is that if you're exercising, don't take metformin. On the days

we do intense exercise maybe the next day after to let your body recover and build up my conrad. This leads to something that I think is a very clear theme in all the work that I've done, the work that others doing and what you've been talking about which is pulse your biological stress. Put your body in a state of anxiety or fear, adversity, but you don't want to do it all the time. Your body needs to change the recover. If you want to take a supplement, maybe you don't want to do it all the time. Your body needs to change the recover. If you want to take a supplement, maybe you don't take it every day, same with repomizing.

You don't want that on all the time. In fact, I wouldn't take repomizing, certainly if I was exercising, because it's going to tell the cell to hunker down and not grow, and you may not even heal after exercise as well with repomizing. So I think that the view that the combination of hunker down fast, but then exercise on alternative

days, take the supplement and exercise on alternative day, they make a lot of sense. Do you think anybody's going to be able to probe this? I mean, near is working on obviously getting tame funded, and that's obviously asking a slightly different question that's really going after a non-diabatic population, but is it going to be able to look at this? You think it will be able to tease out this issue that we're talking about, or does the study not going to be structured to be able to answer this question? I've not heard of anybody who's testing that directly. Usually there's just one variable. And has this changed the way you take metformin? It has, but I need to put a caveat, is that I don't take metformin regularly anyway.

I need to find the right time to take it, and before I was taking it when my stomach felt in good shape, and you can tell when your stomach feels out of whack either you've eaten a big meal the night before, or you're just not feeling right, a little bit of hotburn. Out of those cases, I don't take metformin because it does a number on my stomach, which is great if you don't want to eat, but also prefer not to always have a sore stomach. So I was already timing it. So now I just take metformin, when I know I'm going on a long trip

and I'm not gonna exercise, you know, I'm on planes and trains, that's a good time to rebuild your body. And then if I'm at home and I'm exercising a couple of times a week, I'll lay off the metformin. And then what about rapamysin? Have you ever revisited that? I did take it just as an experiment, but

haven't been taking it regularly. One of the things I do when I'm fasting is I'm not taking those things, obviously. So any period of fasting longer than a day, those things get stopped. Again, that's sort of an idea that's not sort of supported necessarily by evidence one way or the other. When we last spoke, you were taking risk of a withdrawal. You noted that you were taking it with sort of a fattier meal.

Is that still something you're doing? The evidence of a withdrawal just continues to be good. It certainly does no harm. I do take it with my tiny bit of yoghurt in the morning, which I make myself. I mean, I grow yogurt at home. I miss that. That does no harm. I don't have any negative effects.

My cardiovascular system seems great. So... Do you think that risk-vera-trol, like where do you think it ranks in certain activators? There's others on the market out there. There's other supplements even, like Terra's still being that are sold that you can buy online. You very eloquently describe the story and if people haven't listened to our first podcast, obviously, this is a great opportunity to hit pause, go back and listen to it because

you talk about sort of the novelty of risk-bearer atrol and how it was sort of the first sort of built for purpose, custom. This is what it should look like. Oh, let's go get it. That's been over 10 years, hasn't it? Wasn't that like 2006, 2007? We first showed that it activated the end time sort of one, sort of an in-east, an extended lifespan that was 2000 per day.

Geez, yeah. So do you still think Resveratrol is the best if I, because this is something I haven't done yet? I just haven't been able to convince myself that it's just one more thing I need to add to my already complicated regimen. And if I wanted to start taking certain activators, would you recommend Resveratol? If so, at what dose or would you recommend I take something different? And again, you can speak to me and you don't have to give advice to anybody else. Well, yeah, I'd never give recommendations, but I continue to take Resveratol because it's cheap, it's harmless as far as we know. But the evidence keeps tacking out that long term is beneficial.

I mean, it's not going to cure diabetes. It's not as powerful in human studies or in mice as rapid mice in no question. But does it extend the lifespan of a mouse that's eating a western diet? Absolutely. It does. That's been done many times.

It almost seems like it falls potentially into the Metformin trap, which is the Metformin data in metabolically unhealthy people. It's pretty hard to argue that metformin's beneficial. Paradoxically, the people who are most obsessed with this stuff are already doing so many of the other quote unquote, good lifestyle things that you wonder, is it possible that you're already doing

such a good job of all the other things you manage with respect to your health, that the risk for a withdrawal is neutral? Well, maybe if you're optimized like you are, I think as good as it can get, but if you're elderly and you're not exercising, wheelchair, what else are you gonna do? There is some data in my lab that I'll share with you

that we haven't published yet, but I think it's interesting to mention. And I presented it at a meeting in Rotterdam last week for the first time, to a big audience. So let me just tell the audience quickly what residual is. It's a plant molecule, get it from red wine in very small quantities, but the amount that we're giving the mice and human studies, it's a lot. It's hundreds of times more than

that. So you can't drink your way into enough resparatrol? No, but you know, a glass of wine. That hasn't stopped people from trying. Right. The molecule, I take a gram of residual in the morning, it's high dose. It's easy to define. What did the ITP study way back in the day as a human equivalent or is it too difficult to make that normalization? So, ITP showed that if you have a healthy mouse on a lean diet, it doesn't extend their lifespan. Sorry, yeah.

And then in your lab, you took obese or unhealthy mouse on crappy diet extended lifespan. Well, it depends where you start the diet. It was extensive. It was 20, 30%. Depending on how you count it. And the dose roughly was what? We did two different doses. They both worked.

One was 24 mi per kg. Another one was 240 mi per kg. It's a big difference. That's a 10x difference. Yeah. Right. And the lower dose was just as effective. What did the log higher dose do that the lower dose didn't?

It kept the mice from gaining weight. All right, so you're closer to the 24 megs per gig. No, I guess you're taking a gram, yeah. You're sort of in between those, right? Yeah, it's on the high end. But the result is the following, we had a science paper published in 2013, where we went to the effort of making a finding,

we searched for a mutation in the CERT1 gene that we had published is likely the wave resertral works. And that mutation blocked resertral's ability to activate the CERT2 and enzyme. And that's been heavily debated and highly controversial. It's one of the big controversies in my career. So we were forced, if not encouraged, to do better. So we went back, we found this mutation that blocked the activation of this enzyme.

And if we're right, then resveratrol won't work if you've got this mutation in a cell. And we found that was true. The drugs that were in development, the super potent ones, also blocked by this one mutation. What the mutation did was it made an enzyme that couldn't be moved. It had a stiff elbow, and without the bending of the protein at the elbow, residual couldn't activate it anymore. And we know this very clearly, it's been well published and cited, but here's the big experiment and it's been 10 years in the making. You take the mutation, you put it into a mouse, not just a cell, a mouse, that takes a couple of years, took us a couple of years. And now we have a mouse that not just a cell, a mouse. That takes a couple of years to cause a couple of years.

And now we have a mouse that isn't normal. It's missing one amino acid in an enzyme that renders it susceptible to respiratory. Well, worse, calciterant. It's immune to the effects of a respiratory in the test, you know, and now we could repeat our 2006 study of the high fat diet within without resveratrol and within without this mutation. And I didn't know this was gonna work. In fact, in the history of pharmacology, I don't know if anyone's ever found

one immunosid change that blocks a plant molecule in the diet. And that's very difficult because in a diet, these molecules and plants hitting probably hundreds of proteins. But we made this one change. And now we could ask the question definitively,, if you give a mouse for his virtual, which benefits still occur? Yeah, what do you attend to it?

But also, which are off target, which are working through something else? That's just as interesting. And I really don't give a damn anymore about what the answer is, I just want to know. And so we did experiment. My student pretty much definitively, I would like to hear anybody who can disagree

with this statement that Resveratrol extends lifespan by activating so on and it begs the question Can we apply that to ourselves which is during those periods of time when we are not fully dialed in would we benefit from Resveratrol? Well, that's the reason I'm taking Res veritrol is, I don't necessarily- You pulse it as well? No, unfortunately, you caught me out. I'd like to take it every morning. I found that it's been good to me. Health is great, doing fine.

It's one of the longest experiments I've have done, probably the longest, but it's ongoing. And because I'm changing other things all the time to see what works, what it doesn't, I've kept that constant. So I would love to chat about it. We've got a little bit more time here if you're willing is I still probably get more questions about nicotinamide riboside than NAD specifically than almost any other molecule that's sort of

out there. We talked about I'm writing a book now and part of that book there's an appendix in it. And in the appendix what I'm doing is writing a short section on sort of the drugs, supplements, and hormones that I think are most interesting. And so I'm including, of course, something on NAD and NR. I think I've identified 17 or 19 drugs, supplements, hormones that I want to address in this appendix. I would say that I get more questions about N NR and NAD than all other 18 put together, maybe with the exception of Metformin. So this is a topic that just continues to interest

people. I would say that my understanding of it is sort of at the six out of 10 level, which is enough to be dangerous and enough to be frustrated at the fact that it's not nine out of 10 level. And we talked about this again the first time we spoke, but let's go back for a moment and explain why do people even care about NAD or why should one care about their NAD levels? Well, I've talked a lot about certain tools today. These are the protectors of the genome and the epigenome. They lose their activity over time. They have two things they require for activity, for maximum activity. We've mentioned Resveratrol, which is an activator you can eat or take in a supplement. That's the accelerator

pedal on this enzyme family. The fuel that they also need, 100% without it, they don't work, is NAD. NAD is a molecule that's in our bodies. We require it every second of every day to exist. Our bodies use it for chemical reactions and without it everything shuts down. And we're always making more and we recycling it all the time. We have many grams of it in our body. It's probably one of the top two molecules that's important for life and one of the earliest that have ever evolved on the planet, the other ones ATP, which is chemical energy. NAD is also used to be the most boring molecule in biology. You just had to learn by wrote how it was used by the body and recycled and it was just a bunch of chemical

reactions. And it was forgotten about during the 1960s, 70s and 80s. In the 1990s, especially in the 2000s, was discovered that it also acts as the body's signaling molecule. And we think tells the body when you're exercised, when you're hungry, and is largely how calorie restriction works. So we think that in organisms like worms, flies, yeast, more anity is better. When you give them more anity, they live longer. And now the question is, is that true for humans as well?

And the idea is that by either replacing lost an AD or boosting it to levels that you would only get if you run marathons constantly, you can turn on these sort of two end defenses and other aspects like DNA repair proteins that need NAD. So again, we could almost be back in the paradigm that we potentially are with metformin and with respiratory which is it might be that the less healthy you are, the more you could benefit from supplementation or restoration, correct? I believe that because in our animal studies and other studies, the people have done the benefits of NAD and a visceral trull are seen predominantly in mice and humans that are

obese or have a disease. And so they replenish what's lost. That said, if you boost the levels in a mouse of NAD, we published a few years ago, actually no, it was a patty here ago, that raising them above normal levels in an old animal gets you back to having a young cardiovascular system, and they can run just as far as the young mouse. But when we gave NAD boosters to the young mice, they didn't run further. But they did if we exercised them and gave them the AD booster at the same time. So it was the fuel, but not the trigger?

I mean, you still needed to actually... It wasn't enough to get the expression, basically, of the behavior. You know, three-month-old, very young mouse. But in a 50-year-old, I would say that, at least speaking for myself, I already have some deficits I'm not as perfect or as healthy as I used to be, and so that may actually help more than it ever has before. All right, so let's talk about boosting it. So the first question is, David, can I just go out and buy NAD in a pill and take it?

I think people sell NAD as a pill. Let me reframe that. Is there a biological rationale for taking NAD orally? Very few people have studied taking NAD orally. What we've studied in humans and in mice extensively, maybe not as extensively as many would like, is giving precursors to NADs. Because most people take NAD intravenously,

that's sort of the typical way it's administered in this country or elsewhere. Right. Right. But there's this adage and there's some evidence that NAD doesn't directly get into cells. It's a large molecule. There's some evidence that no cells take it up. But in general, it has to be broken down first before it's taken up into cells and reconstituted inside the cell. is taken up into cells and reconstituted inside the cell. That may work fine. I've heard anecdotes that IV NAD is interesting, interesting results. Although you could argue that the placebo effect coupled with the actual physiologic responses, one might have to nicotinamide could explain the quote unquote reactions and the feelings that people have to intravenous NAD. But is it safe

to say that the, at this point in time, our scientific understanding is to intravenous NAD, but is it safe to say that the, at this point in time, our scientific understanding is that intravenous NAD is not sufficiently making it into cells and more importantly mitochondria, is that a safe assumption? Well, it gets into mitochondria because there's at least, if you believe that this literature, there's an NAD transporter that pulls it into mitochondria.

But not from the plasma. Right, that's how I would have to make it into the mitochondria. But not from the plasma. Right. That's how I would have to make it into the cell first. Yeah. I haven't seen convincing evidence yet. Now, I haven't read every paper on the planet, but I'm unaware of... Wait, you haven't read every paper on the planet? Trying to... I know.

You don't come on this show without reading every paper on the planet? Well, I'll sell my kids. The IV NAD needs a lot more clinical research. I agree with you. I'm a little skeptical on that. Okay, so then you said, okay, well, look, we've got this idea where we can orally take something like nicotinamide riboside. And I can go buy this on Amazon today.

Yeah, you can. So NR, for short, we're going to talk a lot about abbreviation. So NR becomes NAD how. Right. So NR is nicotinamide riboside. It looks actually chemically similar to how DNA is made interestingly. That's what the riboside means. Nicotinamide is vitamin B3, so it's partly a vitamin B3, partly a piece of DNA.

So that is a molecule that sells suck up through a transporter. It's well understood. They stick on a phosphate. it becomes NMN, nicotinide mononucleotide, and then the cells turn that into NAD. So it's two steps, NR into cells to NMN, to NAD. And then once it's into NAD, it's then recycled. It's turned into nicotinamide when a certain

it reacts with it. NICotinamide is abbreviated NAM. Yeah, typically. And that's a version of NICE and a vitamin B3. But many people ask me, can I just take a hydro-survitamin B3? And that there's some interesting things you can raise in AD by just taking vitamin B3, but you're missing out on the other components that the cell now has to make, which is the riboside, the sugar, DNA part, and the phosphate. So it's not surprising that other labs have shown that your goal is to raise NED in the body, at least in a mouse, it's been studied that Niasin isn't as effective as taking NR or NMN. And there's actually reasons to avoid taking high doses of nicotinamide

unless you're a cancer patient where it may help. But nicotinamide, we showed back in 2002, is a really effective inhibitor of the serotonin, which are enzymes that you want to keep on. It's the whole point of raising an AD. And so we try to avoid nicotinamide while raising an AD. And actually, I hadn't thought of this, but it would be very useful if the field had a definition, which is the ratio of an AD to nicotinotine wine, because that would give us an indication of the

boosting, the gas to the engine versus the brake. So right after you and I spoke last year, there was a paper that came out from Princeton, Joshua Bennett, which is lab, that looked at oral nicotine and myde riboside. It was a tracer study that looked at mice where they gave them oral NR. And basically the question was, what is the fate of this? Where is it going? And what that paper showed was the liver

took because this was oral, of course, so that stuff gets the NR gets absorbed out of the gut presumably, and very quickly everything in the gut makes its way to the liver first, hence it's called this first pacifect, and it was in the liver that most of that NR got turned into NAD, but the study didn't find that much NR made it out of the liver. In fact, with the study, if I recall, and now it's been so long since I've looked at it, but I think that they saw NAM, nicotinamide was up in the blood, but not nicotinamide riboside, which you presumably will still want

in some of that leaving the liver to go to get into other cells, because I'm assuming that you don't just need more NAD in the liver, correct? Wouldn't you want it also in the muscles or other cells? Well, yeah, you would, but there was a new study that came out that showed that if you give NR to people in a clinical trial, they could get NAD levels raised in muscle as well. Which study, this one was the- Just was posted on bio-acquired. Yeah, this is the one that hasn't been peer-reviewed yet, correct? And it also showed the very high, they could hit it in my levels in the blood. Yeah, yeah. Right. And so I think where the field is now is it's trying to get the NAD levels high without- Okay, yeah, that's the study that was using a very high dose of NR, correct? This is a thousand milligrams.

Right. Yep. Okay. So that's taking... On somewhat. Four times the posted dose that's given when you buy the supplements online. Yeah. It was a good study. placebo control. They had average BMI was slightly higher. I think it was in the high 20s. average age was, I think, up in the mid 50s. It was a higher age group where you'd expect some effects. So they proved at least what we had seen in mice that you can get NAD to rise beyond the liver. How do you reconcile that?

If that study demonstrated that there was an increase in NAD in the muscle, how did it get there? It couldn't have got there from the liver. The liver can't, to my knowledge, can't export NAD to the plasma to the muscle. How did it get there? It couldn't have got there from the liver. The liver can't to my knowledge, can't export NAD to the plasma to the muscle. Does that imply that the dose potentially in the Rebenoid study was not high enough for enough excess NR to leave the liver to make its way to the cells? Does it suggest as at least one author has suggested, potentially there was a methodologic error in the Rebenowitz study where through freezing the samples some of the NR was not detectable on thawing, something that by the way I've asked people on both sides of this and I'm getting

conflicting inputs on this by the way it's very difficult to sort of understand this. Again, I don't think people are bad actors here. I think it's complicated stuff and the assays don't lend themselves to necessarily working out every time, but what is your best explanation for how the thousand milligrams of oral NR in humans made its way into increasing muscle, NAD? Well, it's getting past the liver. The NR is getting past the liver. Yeah. Well, that's the simplest explanation. You've got to start hand waving and saying, oh, well, the liver then sends out an enzyme or a signal of, I think that possible, but... They didn't look in the mitochondria. We don't have the NAD made it into the mitochondria, correct? They didn't. They didn't, but there are a couple of recent studies that show that it's

very important for the NAD to go up in mitochondria, particularly. Yes, and I don't think that's been demonstrated, has it? At least not in healthy. We're going to come back to the other study in a moment. If I recall that study you're talking about showed a few improvements in certain inflammatory markers, is that correct? Right, there wasn't much change with the NR. It was, it's some inflammation went down in the muscle, and if anything mitochondrial markers of activity were lower. We're lower. That was something that didn't make a lot of sense. Although you could argue,

if the mitochondria became more efficient, perhaps you needed less activity, but you start to wonder if that becomes hand waving as well. What's your interpretation of that particular finding? I don't have a good explanation other than that's what happens and that's what we'll see with other studies I think we just need to check if other precursors do that because we don't know if it's a NR specific effect or if the whole class Of molecules will do that as well. That'll be interesting to see But what I can say is that it's a surprise because Johann Orricks who's over in Switzerland and myself and and Matt Kablein, even, who's shown in mitochondrial

disease that NMN, and in some cases NR as well, does boost mitochondrial activity. Now, these are mice, and it may be unfortunate that humans are just not mice, and that's where it ends. I don't expect that, but it's not true, but the data won't lie. We'll do the clinical trials, and we'll be blinded. We've got many trials to go, but there are differences between NMN and NR. So curious to see if NMN has the same effect in humans as well.

Those studies are ongoing. We don't have any good data just yet. And do you think that NMN would be best administered through a regular oral route, or would you wanna do it through an SL route, somehow bypass the liver? Do you think that there are opportunities there with either NR or NMN to get even higher plasma concentrations, but

without this compensatory rise in nicotinamide that potentially is harmful? Well, the SL route, I'm asked about a lot, sublingual, put under your tongue, try and get it taken up by that. And let me explain why this is the case, because it might not be obvious if you're listening, because you might be saying, why would putting it under your tongue be okay, but swallowing it not. And the reason is, when a person swallows a medication, it goes through from the stomach into the jajunum and the ilium, usually in the jajunum, which is the first part of the

gut after the stomach, it gets absorbed. And that blood supply goes straight to the liver through this thing called the portal circulation. And so most drugs actually have to be designed with that in mind, either immune to the liver's metabolism or design such that their pro-drugs in the liver actually turns them into the right drug. When you're talking about putting something under your tongue, just like someone who, for example, carries around nitroglycerin, if they run their risk of getting chest pain, that drug gets directly absorbed into circulation and doesn't go through the liver.

So I just explain that for the listener to make sure they understand why that would be a potential advantage. Yeah. And also there's the complicating factor that microbiome will love to chew out that in our probably. And there's an increasing study showing that microbiome does eat up some of the molecules that we're ingesting, so that nice and part of the molecule, nicotinamide, it comes off pretty quickly, even if a molecule in your fridge gets wet, you all start to lose that nicotin

my bond and it'll break off. And in the gut, some evidence that people have published in some haven't points to the gut playing a major role in how much this actually gets into the body and how. Typically the public and are not doing this for a living, they don't see the brutal struggle for academic survival going on, but now in the days of podcasts like your speeder, the public can actually see this play out. Now that's good because the public can see what is the cutting edge of science

and make their own decisions and here experts opinion. But it's bad because it makes it look like science is on giant food fight. But that's normal. Any new field will have these disagreements about, is your essay working, is there a transport or taking it up, is the microbiome destroying it? Do we need pro drugs for liver or can we just put in a men under the tongue? And we don't have any good answers, really good answers. I'm afraid to say that right

now, but I can tell you what I see emerging. I'm happy to give my opinion. These are not facts, these are opinions. And I think we're all entitled to our own opinions, certainly not facts. My opinion is that the microbiome removes a lot of the nicotinamide from NMN and of NR, before it's taken up by the gut. There are some studies that I've seen that aren't yet available. That traced the movement of these molecules through an animal. We don't do those in humans typically because they're very expensive. You need to have isotopically labeled molecules, labeling different parts of the molecule. But then you can say, okay, where did the nicotine of my dough? Where did the sugar go? And so I've seen some of that data now. It's not all in agreement, but if I was to summarize it, I think there's a little truth in everybody's

results. I think there's truth that it makes sense not to put it all through the gut. It makes sense that if you put a lot in the gut, that's also going to work. Some of it will get through. There's some truth in that NMAN gets broken down in the gut and then taken up by the gut and remade in the body into NAD because you're basically just pulling a part of, you know, three piece of Lego set, putting it through the screen, and then reassembling it on the other side. That seems to happen too. But also, I've seen data that looks convincing that some NMN and some NR gets straight into

the body, goes to the liver, some goes beyond the liver into the muscle. And so it's messy, and there's probably never going to be one single answer to what's going on in the body with something discomplicated. But here's the way I view it, is that certainly for the members of the public, I don't think they care if there's a transporter or not. They don't care what we want to disagree about, a mass spectrometry assay for in a man. We'll figure that out, that'll come out in the wash. What's important is does it work in a human? That's really all that matters. We know it, these molecules do amazing things in mice, to health and in some cases, to longevity. Well, potentially the most important study of this is not yet out yet, which is this ITP for NR in mice, correct?

That should be the most robust analysis of NR, should it not in mice? It is, so they use mixed strains, They use a variety of labs across the country. And so that's it's considered a standard, but it's not definitive because there are plenty of ways to dose, plenty of ways to deliver it, plenty of molecules in our kit. But if it doesn't work, it's another data point. And so with ITP, we'll see. Maybe it doesn't work. Johan Oerich's over in Switzerland says, if you give in art to old mice, it does work. It took us in the last minute a little bit. We don't know about NMN.

We're running that experiment in my lab. That's no secret. So we'll see if that works or not. We'll see. I think ITP is a good start. What I find somewhat frustrating is that they've never asked me for advice on how to dose or what to give or anything. Yeah, I was surprised as well that you weren't involved in that.

Now, what you're basically saying is, look, in the end, does this stuff clinically work as all that matters? Because there's really smart people out there saying, show me the evidence that increasing intramuscular NAD matters. What if it's indifferent? What if this is true, true, and unrelated? Very recently, a paper came out looking at mega-dose of oral nicotinamide riboside with terastil bean in patients with ALS, and it was a minuscule study

that had as many dropouts as it had completers if not more, but the gist of it was that on some would appear to be subjective measurements of quality of life, there was an improvement in patients with ALS taking this very high dose of nicotinamide riboside with terastil being versus those taking a placebo. And what they measured some cardiac function as well. I think they measured one pulmonary function called forced vital capacity, yeah. So, which is how much air could you blow? Which would be a pretty important pulmonary function, which is one of the more important things that gets degraded in somebody with ALS.

So, the point is, for a very small study that obviously didn't have any hard end points, it looked like a success. But I can't help but think of what you talked about earlier. What if this is another example of something where, to see the effect, you have to be testing it in the most distressed organism.

You don't like to talk about people in that terms, but a person with ALS is under far greater distress than you are. And it's certainly possible that in somebody who is that close to the physiologic limits of survival can actually see a small benefit, which I think is what that study, assuming that study is replicated, which of course is what that study, assuming that study is replicated, which of course is, to your point, that's the nature of science. I mean, each experiment is nothing more than a way to alter a probability of something likely to be true. But this would now make that case.

But that was my reading of that study, which was interesting, but I want to see that in someone healthy. I want to see that in someone healthy. I want to see that in someone, for the same reason I want to know what Matt Foreman is doing and somebody who doesn't have diabetes. So someone really smart, I'm sure who it was on this topic once, speaking very specifically about this, there is so much smoke out there that you have to believe there's a fire, but I just don't know where it is. I think that's sort of how I feel. Well, with the resveratrol experience that I've had in my career and with NAD, it wouldn't surprise me what you said is true, which is if you're in peak condition and you're young,

you're not going to see a big effect. If you've got ALS or some other disease that gives you low NAD levels, so two ones are not working the way they should, then you'll see the benefits. That seems to be a theme that's emerging. If that's true, that's still good, because we're not always going to be super healthy, or able to run every day, there will be a comma time. And for the ALS patients, I'm sure they're rejoicing that this could be true. That study was the first real, believable hint, I'm choosing my words very carefully, but

that one looked like there may be some fire there in the ALS patients. Now, it was a p-value of 0.01 and there was some subjectivity. But if you look at the placebo versus the control, the placebo's got worse and the drug, experimental, most of them went up in improvement in terms of life measurements. You didn't have to squint to see that result, which was a nice thing. Now we'll see, I mean, again, you got to remember that they don't have pure NR in this drug. It's mixture of NR with terrestrial being. And terrestrial being is a very similar molecule to Rsevertral.

Yeah, I was going to ask you. The study was, I believe they were using 1,200 milligrams combined. So it was a thousand of NR and 200 of terrestrial being. That's six of those capsules that they sell. That's right. Now the question is, is terrestrial being milligram from milligram as potent as risk of a trawl? In other words, were those patients only taking one fifth of their dose of a certain an activator that you were taking? Yeah, they would have been. So in other words, 200 milligrams of terrestrial bean is about the same as 200 milligrams of

risk raretrol? No one knows that, but risk raretrol is just again these methyls. risk raretrol has three little arms sticking out of two rings and two of those are methyls in terrestrial bean. So it's very similar molecule to risk raretrol. Whether or not it's superior, I don't believe it is. I mean, there's some marketing that or not it's superior, I don't believe it is. And there's some marketing that says that it's better. I haven't seen any data on that. If this study were done without the tarot still being, it might be more interesting

because we could then, it's almost like you'd almost have a third arm that had either NR only or PT only, PT for the listener being tarot still being. Yeah, well that's the best way to do an experiment, but it's probably an extra few million dollars to do that.restrial, being. Yeah. Well, that's the best way to do an experiment, but it's probably an extra few million dollars to do that. Yeah.

Interesting. So, what is the current field looking like on the Sirtu and Activators? Are there others coming down the pipeline? Is your lab working on next-gen Sirtu and Activators? Well, we're pushing hard on our pro-drugs of NAD boosts. Hopefully, get around all the liabilities that we've discussed about these NAD boosters, such as better absorption, not digested by the gut bacteria, is released in the gut, doesn't fall apart in your fridge.

These are all good things, and hopefully is more potent than the natural molecule. And those have been working with a team of chemists for the last five, six years with hundreds of different molecules that have been put at least through animals and hopefully one day we'll be putting into humans. Our most advanced molecule in that class is in human studies right now at the Brigham Women's Hospital.

In what type of patient? Well, these are healthy volunteers. So this is like phase one? It's a phase one, yeah. So phase two would be, if all goes well next year. And what type of patient do you think would be most applicable? I can't divulge what the company's thinking because they're paying for it, but I can say that they're looking at diseases that are not common. And so very similar to what you're...

Sort of like this example of the... So people who are closer to the metabolic or to the sort of cliff edge. Well there are a number of reasons for doing that. One is that there are there's good animal models for some of these diseases where these molecules and relatives of them have worked. But also, there's that business reason, which is that trying to make a drug for obesity or longevity is currently no one would give you any money to do that. It'd be very difficult. And so what's hot, what people want to see is a fast track for a disease that has an unmet

need where patients are demanding something from the FDA, and that there were actually bonuses incentives that the government is putting in place to encourage people to make drugs for those diseases as well. Well, David, the last thing I want to talk about is how in the hell did you make those beautiful, beautiful drawings in your book? Oh, well. I was surprised to learn that you had actually done those. You're an actual artist.

You're an artist who masquerades as a scientist. Well my enemies would say I'm a BS artist, but I do drawing as a hobby. And it was actually a real pleasure that I was forced to do drawing. I hadn't done it since the 1980s, but I used to do a lot of drawing. I was going to be an artist or at least an architect, a paid artist. I very nearly became a computer graphic design guy before it was such a thing as Pixar. I loved biology though I ended up falling in love with lab work and but aging was the biggest thing that needed to be sold

rather than drawing pictures. But the way I ended up having to draw all these pictures, which you haven't seen the book, you can go on the website lifespanbook.com and I've got a lot of drawings up there, even now they're posted. Well, by the time people hear this, the book will be out. Well, fantastic. So unfortunately, they're reduced to the size of a poster stamp. I drew them the size of a foot by half a foot on a sketchpad. That's what makes them look so impressive, though. That's what they look like. They're drawn by a computer. They're so good. Because I'm trying to imagine you actually drawing them that small. Not that it's any less impressive that you drew them at larger scale, but the detail is unbelievable.

They actually look like photographs that were then rendered into sketches. That's how impressed I was. That's why I originally did it. And the lawyers that Simon and Shusdow say, you can't even use that. You'd have to go and get permission from everybody who took the photo that I was rendering. So I had to go back and basically make original art that I own. I had 28 days to draw 28 human faces. And so it was fun.

I really enjoyed it. I'll get home sometimes at 10 o'clock at night and have someone's face to draw And what was actually helpful was that I couldn't obsess over it because of that kind of personality of perfection and I was forced. I've only got an hour or two to draw this and I would just sketch it out. It actually wasn't that hard because at these days you can hit Control delete and or all delete and get rid of what you've just done if you don't like it. In the old days with India, ink, you make a sketch and a mistake, you forget it. So over and start again. Wasn't that hard, but really enjoyed using that other part of my brain that I usually don't use.

Well, David, thank you very much for stopping by today. Congratulations on your book. I know how much work goes into that. And I think people are really going to enjoy it, I think. It's so funny. It's actually a pretty different look at a pretty common topic. I haven't done the Google search on how many longevity books are in Amazon, but you probably need scientific notation to count it. And most of them probably aren't worth reading

to be honest with you. But yours absolutely is. I think people will really enjoy it. Well, it's a fresh look. I think from today, it's been clear that there's a lot of new stuff in there. It's a different way of looking at aging, this whole information theory idea. It's new. Nobody talks like I do about aging, very few of us I should say. And what's exciting about it actually is I was writing stuff down as it was happening in the lab. So readers won't just learn about what I do every day and what my family does and what I think the future looks like. But also, what it's like to be part of these discoveries and how it feels and for the students and the impact on, potentially impact on the world.

So, yeah, I'm pretty appreciative that you've had me on, allowed me to talk a bit about what's in the book. I'm looking forward to reading yours when it comes out to. Well, that'll be a couple of years from now, but that'll be great. We'll turn the tables. Anyway, thanks so much, David. I really appreciate it. Thanks, David. I really appreciate it. Thanks, Peter.

You can find all of this information and more at peteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peteratiamd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email, where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc.

On social, you can find me on Twitter, Instagram, and Facebook, all with the ID, Peter, Tia, MD, but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaim. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed.

The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals

for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously for all of my disclosures. The companies I invest in and or advise please visit peteratiamd.com forward slash about.