153: T Cells, Aging, and Extreme Life Extension

Dr. Derya Unutmaz joins Dr. Buck Joffrey to discuss the critical role of T cells in the immune system, their changes with aging, and the implications for chronic diseases.

He emphasizes the importance of thymus regeneration and the microbiome's influence on health.

The discussion also covers advancements in engineering immune cells for cancer treatment and the potential of AI in revolutionizing aging research and drug discovery.

Unutmaz expresses optimism about the future of aging research, highlighting the need for a shift in how aging is perceived in the medical community.

Learn more about Dr. Derya Unutmaz:
https://www.jax.org/research-and-faculty/faculty/derya-unutmaz

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Transcript

Disclaimer: This transcript was generated by AI and may not be 100% accurate. If you notice any errors or corrections, please email us at phil@longevityroadmap.com.

  Biology, uh, has evolved to evade the, the entropy. Like, if it doesn't, you will age immediately. You will not survive.

Welcome everybody. This is Buck Joffrey with, uh, longevity Roadmap and, uh, today really interesting conversation with Dr. Derya Unutmaz. This is a, a very interesting guy who's really, um. Known for his, uh, groundbreaking research on, uh, the immune system and T cells. Um, you know, how, how they relate to aging and, um, all of the things, a lot of the things that we've sort of referenced in the past.

Um, when you listen to this conversation, the first, I'd say the first half of this interview really dives into the nuts and bolts of the role of T cells and, um, aging. And I wanna warn you upfront that gets into quite a, you know, gets into the weeds. And so if you're not super excited or that interested in a lot of the basic science, you may want to forward that.

But what I don't want you to do is to miss the last half of the interview, which is, um, really interesting conversation on the concept of, of aging in general and, uh, his particular view. This concept of longevity, um, uh, escape velocity, and ultimately the ability to completely reverse the aging process is, uh, not only possible, but inevitable, uh, in, in as short as, uh, 20 years from now.

Anyway, don't miss it. Really interesting conversation. Really smart and interesting guy who, who thinks not only, uh, at, at the level of. Um, you know, behind the bench, uh, in the lab, but also at a very, very big, uh, big picture on aging. When we come back, we'll have that interview with Dr. Derya Unutmaz. Hey, longevity enthusiast.

It's time to take it to the next level. I've been fine tuning my longevity regimen for years, and I look better and feel better than I did a decade ago. In fact, my blood work is even better than it was back then, and it's all because of my data-driven regimen. And it's inspired me to create a course and community just for you.

It's called the Longevity Roadmap, and I urge you to check it out. If you're tired of your belly fat, tired of being tired, or just wanna optimize yourself for the next 50 years, visit longevity roadmap.com. That's longevity roadmap.com. Welcome back to Longevity Roadmap, everyone. And uh, today I have had the pleasure.

Of having Dr. Derya Unutmaz, a distinguished immuno immunologist and professor at the Jackson Laboratory for Genomic Medicine. His research is centered on the role of T cells in regulating immunity, aging, chronic disease. Uh, he's recognized as a pioneer in the field of immune resilience, uh, and is advancing innovative strategies to promote health and combat disease.

Uh, welcome. How are you? Thank you so much. Thank you very much. Great to be here. Well, I, you know, I think just to, to begin, I wanna make sure that we have a little bit of a reminder for our folks, um, as we, we start this conversation on T cells. Just generally speaking, sort of a, uh, a reminder on the role of the T cells in, within the immune system.

Uh, well, I've been studying T-cells for the past 35 years, so I might be a little bit biased about their role. Um, uh, but I do think, uh, I think most immunologists would agree, um, they have a very critical role because, um, they're sort of like the, the generals of the immune system, they control, regulate, um, um, variety of things.

In fact, um, you know, we know this, uh, from HIV infections, HIV targets, uh, a subset of, uh, T cells called CD four T cells. These are sort of the, they used to be called helper cells, but you know, they, they actually secrete cytokines. They help for macrophages, B cells, other cytotoxic cells. And so when virus deplete these cells, um, you get severe immunodeficiency and you die.

So it's clear that they're, they're very, very important. Um, and I think, uh, one thing that's not. Uh, maybe as much appreciated, not, not maybe for your audience, but in general. Um, they're also very dangerous cells. Um, so they have to self-regulate. In fact, we studied a subset of these cells called regulatory T cells.

Uh, I call them the, the bureaucrats of the immune system. Um. Uh, we've made some, some discoveries about that. And their function is to actually suppress and control, uh, the other subset of, uh, T cells because they're very dangerous and probably play a role in many chronic, uh, inflamma inflammatory diseases in some of the autoimmune diseases.

Um, so, uh, yeah, they're, they're important. Yeah. For good, bad, and maybe the ugly. So when we think about them, um. As sort of both defenders and regulators of the immune system, how do they change as we age? Yeah, that's a great question. Uh, I think, um, immune aging is, is very important and something that I'm obviously very interested in, um, because it impacts, um, uh, a lot of the aging related to diseases.

And, uh, I think if you wanna reverse aging eventually, uh, or extend human lifespan, we, we need to focus on the, the immune system. And, uh, t cells are, um, are critical there because, uh, these are long lived cells. Uh, for example, uh, obviously macrophages, neutrophils, other immune cells also. Play a very important role, but they, they can constantly re uh, regenerate new ones, uh, uh, come out from, from the bone marrow and other places.

But T cells, um, have a memory so they, uh, they can remember things and they can get exhausted. They can get senescent, and they just hang out there. And so that becomes, uh, a major problem, uh, during aging because. Um, especially there's not much renewal going on. Um, so, uh, as you know, the, the T cells come out from the time as, as sort of, uh, naive cells.

Um, but that process stops, um, probably during teenage years. You, you have very, very few cells. Immigrating into the periphery from the time. So the, the, the T cells have to be self-sufficient, uh, in the periphery. And in fact there is a naive pool of cells. We call them naive because they haven't seen their antigen yet.

Uh, and those cells are both very long lived and you know, they have a half life of probably six, seven years, but they can also divide occasionally so they can maintain that naive pull. In fact, uh, one of the things that's very predictive during old age for. Know, probably for all mortality is this reduction in naive T cell population.

So if your naive T cells are going down and your effector cells or memory cells are just expanding, then uh, you, you have a very high risk of dying from pretty much any condition, um, because they have to, uh, constantly renew. Um, and you know, not only when you're. Um, exposed to knee infections, but also from the regulatory aspects.

Uh, they have to, um, constantly check the ones that are, have, become effector cells. So one, when you start losing those populations, you are more susceptible to, to inflammatory diseases, uh, uh, cancer, of course, infections. I mean, we saw that during the pandemic. Most people who died were over the age of 60, 65, and that had to do with their immune system.

Uh, so, uh, yeah, there's a very tight link between the immune system and the aging process. So, you know, we call that inflammaging often, right? This construc of that's, yeah. So inflammaging, do you think largely is a T-cell phenomena then? Uh, it, it's not, uh, just T-cell phenomena. Uh, I think actually, uh, most of the mediators of, you know, inflammaging, uh, like pro-inflammatory cytokines, T-N-F-I-L sixties, are typical things that everybody knows are actually secreted from macrophages.

So I think macrophages, um, are, are a major problem both from the aspect of the secrete these pro-inflammatory cytokines, but also they don't do their function as garbage collectors. I, I would say, 'cause macrophages actually clean, uh, the environments, uh, of, of that, uh, cells or, or excess solar matrix. And so, you know, once they're, they go into the tissues and become sort of the, these semi long lived residents cent cells, they are a major source of these, uh, uh, cytokines.

But having said that, you know, uh, again, the sort of the, the commands come from the T cells. So if the T cells are not regulating those, uh, and constantly sending signals that something going wrong and, and also the, uh, the others. Cell types in the environments, uh, do contribute, uh, as well, uh, because as other cells get senescent, they also start to produce inflammatory cytokines and they will activate the macrophages.

But, uh, you know, the T cells play an important role there just to sort of calm them down. Um, and, and I think even if they're not directly, uh, contributing to the sort of the inflammatory cytokine re, um, they are definitely contributing by not controlling. Uh, uh, these, these events. But, but there are, there are subset of T cells that do directly contribute.

There's a subset called TH 17 cells, which produce this inflammatory cytokine called IL 17, and there's a subset that produce interfering gamma. So those actually directly, uh, do contribute to the inflammaging process. Well, going back to this idea that in a, in a way, there's, uh, an inevitability, inevitability.

Losing these T cells because of aging. You, you mentioned, um, that these, uh, originate from the thymus and the thymus of course starts to become, uh, degenerates over over time pretty quickly. Um, there has been a fair amount of research on the concept of, of thymus regeneration. I'm curious on your take on that.

I know we, we've had people on the show talk about various protocols involving metformin, growth hormone, things like that. What is your view on these? I think, uh, it should be possible to regenerate timeless or at least sustain it, uh, uh, a bit longer. Um, you know, it's not just a timeless, it's also, uh, some critical cytokines, for example, IL seven, uh, which is, uh, a major survival factor for these, uh, naive cells.

In fact, um, s cells differentiate they lose the IL seven receptor. So what IL seven does is that it sends these, um. Uh, signals to, um, uh, to mTOR pathway. You know, just keep the cells alive for very, very long periods of time in a sort of a pristine manner. Um, there are a couple other cytokines like that too.

The regeneration has to happen within the time ex stroma, um, because there are specialized cell types there. Um, some of them are dendritic cells, so. Time is kind of like education area, right? So like a university. So, uh, they, and the time has to very carefully select those that shouldn't go in, shouldn't graduate, because those would be dangerous guys.

They would be, um, uh, autoreactive T cells. Um, so, uh, I am not sure that could be achieved simply by, you know, thinking things like. Metformin or growth hormone because it's a, uh, it's a very complex transcriptional molecular mechanism that's going on there. There, there are certain fox genes, for example. Uh, you have to sort of regenerate and regulate other cells, not just, of course, you have to have these stem cells.

From the bone marrow coming into the time as, as sort of what we call them, double negative cells. They're precursors of CD four and CD eight T cells. So it's, it is a very fairly complex, uh, um, issue. But having said that, I think, you know, in. Various mouse experiments. If you transplant, um, thic to an old mice, you, you do generate new T cells.

So you ha you still have the machinery there, but, but it does, uh, it does get involuted. So I think, you know, one, one important question is, um. What is the evolutionary basis for that? Like, why, why is it that time doesn't survive longer? And because we have to ask these questions, there could be, there could be a cost of that, right?

So having, having too many naive cells coming out all the time, um, it may not be a great thing as well because you have limited niches. You do need to maintain a significant memory effective population. Um. This is different than B cells, for example, because B cells are constantly being made. Uh, they're much more dispensable.

You have very few long-lived memory, uh, B cells that make antibodies. Um, so, uh, but, but I think, uh, it, it's at least in a, in, its. Limited manner, we probably should, uh, try to regenerate, uh, the times. Uh, I don't know whether that's gonna require genetic, uh, engineering or uh, uh, other more sophisticated methods that should definitely help for, for the aging process of the, of the immune cells.

But we have to think it in combination with also getting rid of these sort of, the troublemakers, effector cells that are. Not really scent. They're terminally differentiated. They are very pro-inflammatory. They just stick it around. So if they stick around, you can't have the new cells coming out. Um, they're not gonna leave their, uh, niches.

And that's, that's a major problem. It's, it is a major problem in other organs like skin and other places as well. Uh, the, the, we gotta get rid somehow. Figure out to get rid of them. So, um, we know that obviously T cells play a big role in fighting infections. They have a role in, I guess, um, preventing or even accelerating chronic diseases, right?

Heart disease, diabetes, Alzheimer's. Um, do you see any, any potential opportunities, uh, sort of at an organ specific or, or disease specific, um, level. Yes, definitely they play an important role in those inflammatory conditions. Uh, but I don't think, you know, we, we have to discriminate that from an autoimmune condition, right?

So in an autoimmune disease like type one diabetes, there, there are, uh, t cells that specifically recognize, uh, individual peptides or antigens. Just like they ever recognize a virus, but just happens to be a self, uh, self peptide. Um, so there, uh, you know, you, you kind of know the targets and you can try to interfere with them.

But in a, in a chronic inflammation, uh, uh, there is, as far as I know, there isn't, uh, a sort of a, a self trigger, like a molecule that these cells are, I mean. Uh, with very few exceptions, it's mostly the cells feel that there is a constant threat. You know, whether that threat is disruption of the microbiome or, uh, uh, hemostatic mechanisms or not sufficient regulation.

This, the cells are under constant alert, and, and that's actually the, the pillar of immune system that it, it acts, uh, according to the dangers. So we call it the danger theory. So if there's, there's no danger, immune systems does, doesn't really care. But at the same time, I think that's also, uh, could be a way to, uh, interfere with that in a more generic way, not just looking at specific T cells, but how can we sort of lower that trigger that causes, you know, like th 17 cells or th one cells to produce these cytokines, stimulate macrophages, and so on and so forth.

I and I, I, I will point out to microbiome a lot because, um, you know, some of our research and many others show that, you know, that is, that is a major source of this, uh, this trigger. Yeah. Talk a little bit about that, a little bit more about that. We're curious. 'cause you know, we, we have on this show talked much about the role of the microbiome, uh, and, you know.

So how much do T cells interact with the microbiome? Could you explain why gut health ultimately seems so tied to aging? It's definitely very tied to aging, and not only aging, but I think it's tied to many of these chronic, uh, conditions. Quite a few of the autoimmune diseases as well, because it's very tightly linked to the immune system as well as the nervous system actually.

Um, and the reason for that, we're beginning to understand, um, you know, uh, imagine you have these, I don't know, uh, close to a hundred trillion foreign. Organisms that you have to make peace treaty with, right? So they live in your gut. Quite a few of them are very useful for us. You know, they, they digest our food, they produce all these metabolites that are necessary for us.

You know, uh, like right before, and vitamin B two is purely made by the bacteria. Yeah. Um, so the immune system has a challenge. Um, what do I do with that? Right. So, and then some of them are potentially dangerous bacteria. Um, they could be pathogenic if they find the, uh, the opportunity. So there's constant, uh, communication.

There's constant, um, uh, treaties being made and broken and uh, and occasionally the immune system responds to it. But at, at the same time, if you look at it from the perspective of the bacteria there, they wanna live there. So they have adapted evolutionarily to control the immune system. And so they produce lots of, um, metabolites, which, which in turn, um, uh, actually regulate the immune system.

But that turns out to be actually useful. Because, you know, under, um, chronic inflammatory condition, you want that, you want those bacteria, you know, I'll give you an example. You know, those bacteria that produce, uh, butyrate or short chain fatty acids? So it turns out that brate actually could be a negative regulator of certain pro-inflammatory, um, immune cells, especially T cells, or, uh, treat defined metabolites.

They could also act as, um, as sort of suppressor. So they, both of these systems have kind of, uh, in a synergistic manner or opportunistic manner. They adapt it, you know, okay, we can use that to regulate excessive immune function. And then, okay, you can use this so that we don't attack you kind of a, a thing.

But when that breaks down, when what we call dys, dysbiosis happen, when there's sort of the. Uh, let's call them the more pathogenic bacteria that live there, increase. Uh, and then actually we start to, to learn the, the sort of the pH, these, um, uh, you know, like bacteria, this and, uh, fmic cuts and things like that.

So there's like thousands of strains. Uh, and, um, some of them, uh, starts to, to break that balance. So they don't produce enough butyrate. So if they don't produce enough butyrate, then the immune system becomes a bit more active. Then they produce other things that will trigger more inflammatory, uh, reactions.

Um, and then, you know, all of that is also linked to your diet. Because you can actually manipulate, uh, the bacteria using, uh, changing your diet habits. Certain bacteria likes meat, others like, you know, vegetables and, and so on. Um, so there, there's still lots of gaps in that because they produce, um, thousands of metabolites.

We only know a small portion of that, and I think as we learn more, the nice thing is that this is actionable. Right. So if we find that certain bacteria that's lacking butyrate, well, we might be able to replace that, either the bacteria or the, or the metabolite. Um, so I'm trying to really summarize in a very genetic way, but there's, there's obviously lots of details there.

Sure. Um, in terms of therapies, so in cancer, cancer therapy, um, you know, we've, we've. Come to a point where we have learned how to reprogram patient's own immune cells in certain cases called, uh, you know, CAR T cells, uh, and a big breakthrough. Um, those, those cells can essentially, um, specifically attack tumors.

Um, can you explain sort of the process of engineering immune cells and how. If we can use it against cancer, it seems like there could be a broader application to aging. Um, just your thoughts on that. Sure. Yeah, that's a great question and something that I, that I'm very, very interested in. We actually have been working on that topic for quite some time.

In fact, uh, I think I, I was one of the first to develop, uh, what we call lentiviral vectors. Uh. Back in 1998. It's been a long time now. Um, so what Lentiviral Vector means is that it's actually a sub portion of HIV. So I used to work with HIV and we realize as well as many other labs, you know, this virus knows the T cells very well, and it actually integrates into the genome.

So it can deliver the cargo, whatever the gene you wanna send and become, uh, part of the cell. And so we and others engineered these vectors where we took out sort of the parts of the virus that makes it replication incompetence. So it cannot divide, but it can still go in and integrate into genome of the cell and then deliver the car.

So that's the principle of these CAR T cells that have to be used. It. Many, many times for genetically engineering T-cells with crispr, with expression transcription factors and all kinds of things for research purposes. And, um, and the idea was that, um, you know, T-cells have specificity. They need to recognize something which is usually a small peptide, uh, present in the virus or viral infected cells, um, that is presented by these MHC molecules.

This is very different than antibodies, right? So the antibodies will bind directly to the antigen and they will recognize the confirmation. Um, but the problem with the cancer is that, um, these are also self, uh, cells, right? So almost all of the antigens in a cancer are. Selected against in the time, you know, the T cells don't wanna respond to that.

Uh, so what do you do? I mean, you can't find, uh, what we call nail antigens. And people are doing that with mRNA, um, uh, approaches. There are mutated, uh, antigens, like P 53 gene, uh, which if you can identify that and you might be able to generate a T cell that will only recognize that peptide, but this is, um, gonna be different for every patient.

So it's not very, it's not a trivial thing to do. The alternative is that what if the T cell can recognize something on the surface of the cancer cell? That might be shared with normal cells, but it's, uh, it's either more on the cancer cell or it won't cause a major problem, even if the cells react to the normal, normal tissue.

Uh, an example of that, like in breast cancers called her two, HER two is a, is an antigen on surface of these cells. Normal breast cells have her two, but a specific set of cancers have much upregulated version of her two. Uh, because it signals the cells, uh, the cancer cells divide. So if you can engineer, um, a chimeric molecule where outside is an antibody that binds to her two molecule, so you will only recognize her two molecule.

Then the inside is a signaling domain, which mimics what would happen if the T-cell were to activate it by an antigen through their T-cell receptor. So as a couple of modules of the signaling domains. So, and then you, uh, deliver that with the lenti vector, what we call the car chimeric antigen receptor.

Uh, it's because it's a chimeric molecule, it's expressed on the cell surface, so the outside is an antibody. Recognizes this antigen on the surface of the cancer. Um, it could be CD 19 on a B-cell lymphoma or HER two, or, you know, whatever, whatever is in the cancer surface that you think you can design it to.

And once that binds to that antigen, like the her two molecule, that will send a signal to the T-cell, say, okay, get activated and kill that guy. 'cause the T-cell doesn't know whether that's a viral effect or not. So that's the principle, and it's been tremendously successful in, in cancer. Um, uh, they're, they're not easy to make, so you have to, to generate them in the lab, uh, from the patients and every time and so on.

Although we are, we are, uh, figuring out, uh, ways to do it more kind of like a off the shelf, uh, manner. So then people said, okay, well, uh, what if we use that exactly. Coming to your point, use that against. These so-called senescent cells, these cells that are supposed to retire, but they don't. And we were having difficulty getting rid of them.

Uh, and several papers were published, um, as a proof of concept. You know, if you can find, um, an antigen again, it has to be on, on the cell surface. That is more so on a senescent cell, you can generate a car molecule that will recognize it and that you can actually eliminate it. Uh, people have done it for the, for the heart muscle, uh, for, uh, skin cells.

Uh, the challenge there again, is to find something semi specific, right? So we're actually looking for that. Too many others are doing it as well. That's somewhat upregulated. On, on, uh, senescent cells. Um, uh, so you don't wanna damage the, the normal population. There is one variant to that which might be, uh, a better approach in engineering for the aging or for, for senescence actually could also be used for, for cancer.

Uh, so it's, it's a variant of what I mentioned earlier, that it's easier to find peptides that are different. Because even in senescent cells, you're gonna have mutated genes, right? Uh, if you can find a peptide that is, uh, uh, somewhat mutated or more so in a senescent cell, then one can generate an engineered TCR T-cell receptor.

Rather than trying to generate T-cells in each individual, because you may not have the right T-cell receptor to recognize that. Um, and because they're selected against it might be very difficult, but we could generate a T-cell receptor that will only recognize that peptide. And then engineer that back into the T cells.

And we and others have done it actually in melanomas. This was one of the first, uh, trials people identified specific melanoma peptides, uh, from an anti called gp, uh, GP one 20. And so you can gen, you can make these T cells. It's like a clonal army. They all have the same T-cell receptor, uh, and you can even knock out the endogenous T-cell receptor and they will go and, and, and kill these cells.

Um, so again, you know, for, for the cancer, people are trying to do that for these neo antigens and then generate t TCRs because again, that solves a major problem that, that you don't have to start from scratch for every donor. You have already a off the shelf engineered tcell ready to, to, to wait there.

So that, that's, that's sort of, that's, uh, another alternative approach. Seems like a, a broad approach for, you know, just in general. Um. It, we're pretty far away from that in just a broad approach to, to, you know, just the aging process or that kind of thing. Of course, you know, we, we talk a lot about longevity and, and, you know, escape velocity and all these concepts here.

Um, do you see any of these, um, any of these technologies, uh, you know, coming to fruition anytime soon in terms of actually. Sort of, um, you know, battling the inevitable, um, process of, of, of aging. Uh, absolutely. Uh, I am more optimistic than ever because of ai. I think if, if AI wasn't at this point. Uh, I would be less hopeful that we will solve this in the next, I don't know, a reasonable time, like 20 years or 30 years.

Uh, it would've taken us much, much longer. Uh, but, uh, actually, I, I, my timeline, which I predicted 20 years ago, haven't changed, you know. Around the 2040s, 2040 fives, we should be able to, uh, completely regenerate the biological systems such that, you know, it's not stopping or slowing aging, but reversing aging.

And I think, we'll, do you mean, uh, the immune system in particular, or immune system? But, but I think as a, as a whole. Every organ might need to be dealt with separately. Um, uh, some could be more generics, some could be very, uh, focused, you know, because different organs have different needs. You know, the brain or the heart muscle cells don't regenerate very much.

So we we're gonna have to fix the cells that are already there. And of course, the brain neurons, you don't wanna get rid of them, uh, uh, whereas the skin, you know, you can get rid of all the senescent cells and then get, uh, new newly generated, um, uh, stem cells, um, you know, clean up the niches. The reason I'm so confident about this is that, um.

This is what biology does anyway. There's no, uh, a physical limit that you have to age and, and, uh, the system has to break down. Let, let's, let's drill down that a little bit. 'cause I think it's an interesting concept. When you say it's what biology does anyway. You're talking about the repair mechanisms, the, the things that when we're young, uh, we automatically do right.

That's right. I mean, uh, you know, take for example, the immune system, right? So we have a population of these naive cells in the periphery. That constantly repopulate and you know, as you get a lot of effector cells, they're removed. I mean, so the cells expand thousands of folds, and then once their job is done, 99% of them are, are killed.

They go undergo apop dose and and whatnot. And then you have new cells coming in. So this is happening. All the time. The, the moment you're born, uh, this process starts the same thing happening in your skin. You know, the cells divide certain time, you know, they reach what's called the hay flick limit. You know, their telaris are shortened.

They die. New cells come in, the cells in your gut. Um, they renew almost every day. Uh, there's, there's a stem cell at the very bottom of the, what we call the, you know, the Crips. Um, that's the mother stem cells that. You know, divides, I don't know, once every few months. The next one divides it once every few weeks and then so on.

So they, they constantly replace the whole, the gut, the epithelium. Um, you know, on, on a daily basis or a every few days. Um, so the point I'm trying to make is that this process is happening or you have, uh, you know, um, uh, DNA re repair mechanisms. You know, we, our DNA is under constant bombardment, which mutations, but, you know, we have, uh, genes that specifically focus on that.

They repair it. Uh, we have epigenome regulation. So epigenetic changes are very important because some of them can be irreversible, not irreversible, but they push the cells toward terminal stages. But you have mechanisms that, that control that. So all of that breaks down is, uh, um, we don't know what, why that happens.

It's, again, an evolutionary reason. You know, a a, a blue whale lives hundreds of years. Our biology is not very different. Why is it that they can keep living and we can't, for example, or a mouse lives only two, three years and they're also mammalian. And actually we do a lot of experiments with mice 'cause they're similar to us, but it's very complex 'cause there are millions and billions of parts that are, that are interacting in a, in a very network fashion.

That's where AI comes in. So AI can really see all that information. We just need to collect a lot more data and create these patterns is you can say, well, here's what you need to interfere with and let me screen a billion compounds, by the way, and then find you the exact molecule that will act there.

Or this is the peptide you need to develop your CAR T cells to, and this is the time that you need to deliver it and, and so on. So. That, that will tremendously accelerate, uh, the whole process. And, uh, and I'm, I'm very confident we're gonna get a handle to this. So, so I'm curious on your timeline. Where do you get the mid 2040 projection?

I mean, obviously, you know, we have ai now we know that accelerates things, uh, in terms of, uh, you know, a lot of things you're talking about, but tell us what you, what you think about, like the big picture here. Where's the target? I mean, obviously the immune system is a big part of it, but it seems to me that if you're talking about, you know, a, a sort of master switch or a master mechanism, do you think we've identified that?

Uh, do, do you know what I mean? I'm, I'm, yeah. So there's a two, there's a couple different ways to look at this. You know, talking to Aubrey De Gray, for example, and he talks about longevity, escape velocity, and his, his take is essentially that we are. We can essentially, uh, get to the point where we can reverse or fix the things, uh, that are wrong with us and then live long enough so that the next time we have a problem, we can, we have a solution for that as well.

That's, that's one way to look at it. The other is a master switch, which we've discovered that this is what goes wrong and this is what ultimately. Creates this cascade that we can stop. So what is your view on these kind of ways of approaching, um, aging and, and what do you, you know, I mean, you don't have a crystal ball, but what, where do you think that answer's gonna be?

Yeah. So, uh, it's probably two questions that are, that are linked. I'll start from the second one. Um, uh, I don't think there is a, there is a master switch. Uh, it's not, uh, lemme put it this way. There's no such thing as free lunch, right? So it, it's not, it's not gonna be that, that straightforward because.

There's a lot of noise. There's a lot of stochastic events that happen, um, both at the gene level, on the protein level, on cellular level. So, uh. It's, it doesn't make sense for evolution to control such a multicellular organism with one switch, because if something goes wrong there, you're gone. Let me re, let me rephrase it because you brought up the example of the, the whales and other th you know, other organisms that live much longer than us.

Whales, of course, genetically. I mean, they're, they're not that different from us and we know that. For example, they have a lot more tuin genes. They express a lot more of these, you know, specific aging related diseases. And when I think about a switch, maybe it's not one, but maybe it's a, a dozen, uh, big picture genes that are controlling the, the, the speed at which we age.

Is that, yeah, that, that's, that's probably more reasonable. Um, uh, in fact, if you look at the developmental biology, right, so we, we can recreate ourself from a single cell, right? So you can actually reverse, you can take a skin cell. Reverse it back to what we call IPS cells, polyprotein stem cells, and you can regenerate everything that you have from that already programmed cells that that's regenerated.

So that suggests that, uh, uh, it can't be, uh, thousands of switches. As you said. There's probably, in fact, even in during dual mental stages, you know, there's things called hawk genes, for example. Uh, so the, the, this is a family of genes that's. There are kind of the orchestrator, right? So they, they give a lot of commands and then they, they create cascade, uh, events and, and feedback loops and, and so on and so forth.

So, um, uh, a lot of those things we, we also know what probably what they are, um, you know, reversing the, the cell back to an IPS. So you just need like three or four transcription factors. Uh, so, so we know those genes. Regulate a lots of other genes, they can reverse the, or reset the, the epigenome and and so on.

So my point was that, you know, there might be somewhat different. Sort of the tuners, depending on the organ. Like the brain could be a bit different than how the immune system is regulated or ages or, or regenerated versus the skin. But again, if you look at it within that system, uh, you are probably right.

I don't think there's, there's too many of those things. The, the issue is that, um, that's why I said there's no such thing as free lunch because. All of these things are also very, very tightly regulated, right? So it's easy to make something immortal, right? Cancer, so those cells don't die. We can have immortality, but that's not what we want.

So how do we make sure. You don't overdo, like going back to example of the timeless. So we probably don't want too many naive cells. We want just enough. How do we regulate that? How do we make sure that there's enough of those, um, under certain conditions and then, you know, it will, it will be different in, uh, people with different genetic backgrounds.

You know, not everybody ages the same speed. Um, some people, uh, live much longer. Women and men have very different immune systems. We, we, we beginning to understand that. I mean, women live always, uh, you know, five, six years longer than men, for example. And we think part of that, or maybe most of it, is because of the immune system differences.

So, uh, it, it needs to be, um, adapted to those environments. Again, you know, I think the key point here is not intractable problem. It is a tractable problem. And now going back to your other question, why I think this will be feasible in the next 15 years or maximum 20 years reversing, but I think we'll reach the longevity escape velocity much earlier.

My, my, my estimate is within 10 years, if not earlier, um, actually we began to, to, to achieve that. You know, I always give the example of GLP one, um, drugs. Um, you know, some estimates is that if everybody who needed GLP one used it. You probably extend lifespan by between five to 10 years, maybe even longer.

So you already, uh, added an escape velocity there. Um, so the, the time is really based on, um, how the technology is, um, is accelerating or evolving. Um, this is not just ai, of course, AI just came in the right perfect moment. Um, but before that, we developed these, uh, omics, uh, based, um, assays. When I say omics, you know, doing RNA-Seq, uh, which, uh, I think your audience would know.

Uh, basically RNA-Seq is to determine, uh, uh, the gene expression in every cell. You know, there's thousands of genes that are being turned on and off. And so if, if you wanna understand what's different in a senescent cell and normal cell, we need to look at all those thousands of different, um, genes. Now we are able to do that on a single cell level.

For millions of cells, we can say which cell has what Gene. Now because of the AI and the bioinformatic tools we have, we can also, uh, analyze those. The same thing is true for genome analysis, right? We've, we've sequenced thousands or hundreds of thousands of genomes. We know all of the mutations that happen, the SNPs, and how the, uh, epigenome changes and, and.

We know a lot about the microbiome. We've, we've sequenced, uh, thousands of these bacteria. We know a lot about the metabolites. We've identified thousands of metabolites. It's not. Finished yet. But the point I'm trying to make is, you know, the technology has advanced to a point where, uh, it's just a matter of generating more data so we have a complete picture, uh, because there are trillion parts.

We already know a hundred billion, but to get the next 900 billion is not gonna take us another 50 years because the technology is to a point where we could just do this in mass, mass scales. We are even able to now beginning to look at individual metabolism that's happening in a single cell. You know, what's, what's going on in your mitochondria and, and and whatnot.

And so, uh, but the bottleneck then was how do you analyze that data? How do you put it together? That's where the AI came in. Uh, in fact, when I made this prediction 20 years ago, I said, you know, we are gonna need ai, uh, because otherwise there's no way we can, we can make sense out of this, this data. And it just happened.

Uh, and AI is, is getting better and better. Um, um, you know, I, I do a lot of tests. I, I was, uh, uh, testing, uh, you know, g PT five, uh, from open AI before they released it, you know, uh, I'll give you one example. We had, um. We were working on this disease called chronic fat fatigue syndrome. Uh, we had collected millions of bits of data, um, metabolites, immune system and so on, microbiome.

And, um, you know, it took us long time to analyze that, you know, like over a year period we had to, we had to analyze it. And so I took part of that, like the metabolites part. We had 1300 different metabolites from 200 patients and, and healthy controls. Just uploaded that to uh, GPT five. Um, you know, it took about three minutes.

Uh, it came out with almost exactly, uh, the same analysis and then also showed things that we had missed. You know, we have spent like probably months just doing that. So that now accelerated everything in an incredible manner. Uh, so at this point, all we need is a lot of data and that's why. I'm thinking the next five, maximum 10 years is gonna be spent mostly collecting this, missing links of the dataset.

After that, once we have that data, uh, finding, um, cures or finding solutions, we'll probably happen in a matter of days or weeks. We're not gonna spend, uh, years looking for that. Now there's still one bottleneck that we have to solve, and that's the clinical trials. Because you can say, well, okay, great, you found the the drug, but you're gonna test it on an old person and wait.

Yeah, okay. That's not gonna work out very well. Right? And this is true for other diseases too, right? It takes so long to do clinical trials. Uh, but there's a solution for that too. And the solution is what we call digital. So, uh, you know, we will come to a point where once you have a complete picture, all of the parts of an individual, uh, in fact, we can even personalize that, you upload that to, to ai.

The AI has a replica, biological replica of you. And so you can actually run the experiment in silico in the computer. I can say, okay, what happens if I give this drug? What will happen to the metabolite in the microbiome that will then act on this cell? Or if I kill these senescent cells, like run me the experiment, run me the scenarios.

Um, and so, so, uh, I think this is probably not far from 10 years. Uh, it might be sooner. Um, because all we need is a lot of compute, uh, probably need a thousand fold more compute than we have now. If we can run that simulation. Then you can just run the clinical trial in silico you, you, we don't have to wait, uh, 10 years, uh, for, for the finding.

Uh, or we can really restrict it to a very small subset of people for the final, uh, final validation. Um, uh, so I think this, this will revolutionize drug discovery. Uh, we, we'll be able to find drugs or, or solutions or therapeutics for pretty much every disease imaginable. And then of course, the mother of all disease is aging.

And that that might take, you know, maybe a few more years after that, uh, we will, uh, we'll definitely get there. I think people, um, are not used to this because they're not thinking exponentially. Uh, they're thinking that in the next 10 years we are gonna have an advances like the last 10 years or like 20 years.

No, next 10 years is gonna be more advances than the past a hundred years. So imagine the, the life in 1925 versus now. That's how different it's gonna be between now and, and in 10 years, in 20 years probably. And that's mostly just because of the compute element, right? The, the, the, the ai It's absolutely, because it's, it's, it's doubling every three, four months and it's capacity and compute and, and, and, and intelligence.

I mean, we see this, we are living through it. I've been using GPT since it first came out, you know, three less than three years ago. And it's unbelievable the, the advance that we had during this period, and it's, it's accelerating, uh, actually it's getting, uh, faster and faster. So, um, that's why I'm very, very excited.

I, I think it's just a matter of time. Of course, we do need quite a bit of resources. We need to invest into this. Um, you know, people are spending hundreds of billions of dollars to, to data centers, but let's spend some to collecting this biological data. There is, um. It seems like there is a lot of interest in the 18, especially, you know, you've got a lot of billionaires who are getting older, right?

Yeah. Actually Putin and the, the Chinese premier, they, they, they, I don't know if you saw that. They I did, I did. Yeah. They were, they were chatting about it. Right. And they were chatting about it. Yeah. Now we can probably coming mortal, uh. Not sure it's a great idea for them, but, uh, yeah, they're gonna put a lot of resources to this Well, right.

And then private money as well. I mean, you've got, yes. I mean, a lot of these, uh, you know, these people who made their money in dot coms and, you know, they're getting older. And are you seeing, by the way, just outta curiosity, I mean like, are you seeing a, a, a big difference from lengthy 20, 30 years ago in terms of private investments in this from, you know, large donors?

Absolutely. Yeah. Even compared to 10 years ago. Yeah. Uh, there, there's, there's, there's massive, I mean, there were some pioneers, but people, because I mean, even, uh, Sam Elman invested in an aging company. Google has, of course, uh, Amazon has their own. And so, because the tech guys now see the light at the end of the tunnel.

That this is now feasible because before it was kind of like a science fiction, you know, very few people believed in this. Um, uh, so, uh, yeah, there's tremendous interest. One thing that needs to change, uh, in terms of the, the, the policy, the government policy, which I think is also beginning to change aging was not, and still is not recognized as a, as a disease.

It's, it's seen as something natural. Like I can't write a, a grant to NIH and say I, the, the purpose of this grant is to reverse aging process. That's not gonna get accepted. That's why I'm very, um, adamant against this notion of what's called healthy aging. 'cause this is sort of used as, okay, don't touch the aging itself.

We, we should all age and we should all die, but let's just live. Few more years of healthy life. Let's fix that. Um, this includes a lot of scientists in the field. Um, healthy aging is an oxymoron. There's no such thing as healthy aging. Aging means your system is starting to get bad and bad and bad, and that's why you have 90% disease happen in the 18 and, and close to 50 million people died.

Directly or indirectly because of aging, it's a, it's a hundred percent mortality rate, right? So that's, but that's not a very healthy thing. Bring up an interesting idea, which I, I'm, I kind of, uh, you know, doing these conversations, I hear a lot of very smart people like yourself on, you know, in let's say David Sinclair or, you know, those on, on one side who really do, are, are really bullish, uh, on this concept of, you know.

Stage reversal, significantly lengthening life lifespan, uh, beyond, you know, not just a five, 10 years, but a hundred years, that kind of thing. Then there are others who are very, very smart. I mean, uh, Charlie Brenner, for example, Charles Brenner comes to mind, uh, who you, you probably know if you're following this.

And, and, and Charles is a very, we don't get along very well, you mention, yeah, probably not. I'm sure he's, uh, tag you on, on Twitter, whatever. Where do really, really smart people on this, what fundamental question are they not agreeing on? Um, honestly, uh, I don't understand. First of all, in my opinion, anyone who doesn't believe that aging can be reversed, shouldn't be in this field.

Why are you working in this field? Like, what, what is your point? Um, uh, because that creates a sort of a perception that you have other agendas, right? So let, let, let me just, uh, create something like NAD precursor and then, you know, I'll, I'll start a company and then sell it to people so they can live an extra six months or a year or something like that.

This is not, uh, uh, the reason to work on an aging, uh, process because they don't have a scientific, um, rationale to say that this is not possible, what these people say. This is too complicated. Yeah, it's too complicated. You know, uh, a hundred years ago it was extremely complicated to go to space, right?

Like, who would've imagined that we would, now we're trying to send a, a Starship to Mars. Who would've imagined a computer or AI or internet or any of these things that we have now. These are so complicated things, um, but that's why we do what we do. So we can break the complicated things apart. And now with the tools like AI put them together.

'cause if you say, okay, well, you know, there is a physical law. You cannot pass this law, like the light will not, uh, travel faster than, you know, 300 whatever thousand, uh, kilometers per per second. That's physical law, right? Um, there might even be ways to, to figure that out, but there is no such law, there's no such biological law.

People make the point of, oh, well there's entropy, there's second law of thermodynamics. Well. Biology is, uh, has evolved to evade the, the entropy, right? So it does for years. Like if it doesn't, you will age immediately. You will not survive. I mean, there's a disease called progeria, right? So it's a, it is a genetic mutation in, in one single gene, uh, that has to do with the nuclear, uh, structure and so on.

And these, these kids, they age a hundred years in a matter of, you know, few years. And they die by the age of eight or 10. Uh, um, uh, so everything gets accelerated. Uh, um, and again, you know, there are organisms that live there. There are crabs, uh, there are certain crabs that have treat. They have lived three, 400 years.

They probably could live thousands of years. They just don't age. There are other organisms that constantly you cut their head, you know, they, they, uh, they regenerate a new head, you know, uh, like certain worms or their arms or whatever. So, so biology has that capability to regenerate, to fix, to, to heal, um, to, um, to eliminate the, the, the toxic a aspects of things.

It's just that it, uh, it stops again. It's an evolutionary selection. Uh, why do veils live so much longer? There are very few threats to whales, right? Who's gonna kill a whale. Um, so they're the largest animal so they can afford, and they have plenty of food. They have, uh, the whole sea for themselves. And so they could keep living their biology didn't get selected against that.

The short answer is that I don't understand it. Uh, I don't understand what is their argument against this. So even if it was very, very, very difficult. Your job as a scientist should be to figure that out. That's why you're working in the aging field. Go work on something else. I mean, go work on, uh, you know, something that could, that could help, uh, a lot of people.

So anyway, I'm, I'm a little bit passionate about this. No, I'm good. I'm glad, I'm glad to have that, that perspective. Well, Derya, it's been, uh, it's been great talking to you. I really do appreciate your time, uh, and, uh, all of your insight, not only on. On, uh, you know, the specific stuff that you're working on in, in your lab, but also in this bigger picture.

And it's, uh, where, where could people learn more, uh, about your work? Again, you know, find more about, you know, your, your beliefs and thoughts and is there a website or anything that we can. Uh, I'm very active on, on Twitter or x you know, my, my handle is, uh, at derya, D-E-R-Y-A-T-R, under dash. Um, they can, they can find me.

I have, I have a LinkedIn, uh, page, but I don't post much there. Uh, um, I, I have a lab page, but. That's not, uh, getting updated. Um, I do go to various podcasts and talk about these things. Uh, so if I search my name on, on Google, they'll probably find things. Uh, but, but, um, Twitter or ex uh, Elon Musk will get upset with me.

Yeah. Uh, every time I say Twitter, uh, is probably the best way because I, I, I post a lot about these things, uh, yeah, on a daily basis. Thank you so much. My pleasure. It was great. Thanks for listening. A quick reminder that while I am in fact a surgeon, nothing I say should be construed as medical advice.

Now, make sure to include your physician in any medical decisions you make, and also, if you're enjoying the show, please make sure to show your support with the like, share, or subscribe.