An Information Theory of Aging
Is life essentially an information process driven by biochemical interactions? If so, can we simply correct any errors in that process? In this episode, renowned researcher and author David Sinclair joins Gordon to dive into the startling insights from applying information theory to aging. Topics include epigenetics, sirtuins, metabolism, and why we might not want to kill all the zombies.
Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School.
David A. Sinclair, A.O., Ph.D. is a Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School. His research has been primarily focused on sirtuins, protein-modifying enzymes that respond to changing NAD+ levels and to caloric restriction (CR) with associated interests in chromatin, energy metabolism, mitochondria, learning and memory, neurodegeneration, and cancer. The Sinclair lab was the first one to identify a role for NAD+ biosynthesis in regulation of lifespan and first showed that sirtuins are involved in CR in mammals. Dr. Sinclair is co-founder of several biotechnology companies (Sirtris, Ovascience, Genocea, Cohbar, MetroBiotech, ArcBio, Liberty Biosecurity) and is on the boards of several others. He is also co-founder and co-chief editor of the journal Aging. His work is featured in five books, two documentary movies, 60 Minutes, Morgan Freeman’s “Through the Wormhole” and other media. He is an inventor on 35 patents and has received more than 25 awards and honors.
Newest Book: https://lifespanbook.com
PODCAST EPISODE 2: David Sinclair
Most diseases on the planet — the diseases that kill us are 80, 90 percent caused by aging. It really is the cause; if you slow down aging, you don’t get sick, you don’t get those diseases. And now we have an ability to even reverse some aspects of aging. And you can treat diseases that way, and actually cure them.
None of us can escape . Like gravity it pulls on each of us. Why do some of us age gracefully and others don’t? How do our bodies and minds experience aging at the cellular level? Why do we even age to begin with? And maybe most importantly, “Can we do anything about it”? My name is Gordon Lithgow and here at the Buck Institute in California my colleagues and I are searching for – and actually finding answers to – all these questions and many more… On this podcast we discuss & discover the future of aging with some of the brightest scientific stars on the planet.
We’re not getting any younger… yet.
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Hi, everyone. Welcome to the show. I’m absolutely delighted to be speaking with a friend and colleague today. An amazing scientist, David Sinclair, professor of genetics at Harvard Medical School and also the host of a podcast, Lifespan, with David Sinclair. And today, David’s going to be on the other side of the microphone, and I’m going to be asking him about his amazing career and where the aging field is today. I think you’re going to find this absolutely fascinating.
Gordon: Well, hello, David. It’s delightful to see you. And thank you so much for taking time out of your day to do this. I actually don’t think we’ve seen each other for a couple of years, right? Certainly not since your book was published. Lifespan: Why We Age and Why We Don’t Have To which was a New York Times best seller. Congratulations on that. I really like this book for a number of reasons. One is that you explain the biology of aging in a way that is understandable to just about any reader. Secondly, you describe your own personal journey getting into aging, which is fascinating. And then and then thirdly, I think you set up the social context for where this field is today. And I really would like to talk to you about that.
David: Thanks, Gordon. Yeah, it’s been too long since we spoke last. We have a lot to talk about. And, yeah, thanks for saying those kind things about the book. The field has exploded, and I was very lucky to have written a book just at the right time.
Gordon: You know, I think that there’s — as Eric Verdin here at the Buck says, there’s an inflection point on aging research, and the inflection point is really how do we communicate this to the rest of the world that something incredible has happened, and is happening? And how do we ensure that the resources are there to make it happen? So yeah, we’ve got lots to talk about. Do you mind if we go back, though, to the — to the beginnings — why did you become a scientist? And I know you, address this quite a bit in your book with your family influences, so I’d like to unpack that a little bit, if you don’t mind.
David: Oh sure. Well, I grew up in a — in a family that was filled with biology. My parents are biologists. And, they would talk about urine and feces and blood at the dinner table. so the — really, there wasn’t really much choice. I had to become a biologist.
Gordon: Was there a single moment where you kind of realized that aging was a thing that was important to you?
David: Well, since the age of 4, really, it’s been on my mind. My grandmother told me that, she was going to die, and my parents would die, and my cat would die. That was even more traumatic , at the time. And I remember falling down on the carpet. It was a very prickly 1970s polyester thing. And yeah, it shaped my life ever since. I really do think it’s quite cruel, for a species to have consciousness and know what’s coming, and I think it’s our duty to protect human life and keep people as healthy as possible. That’s what medical research is about. I just also think — and I-I’ve grown more mature about this over the years — that addressing aging is-is going to give us the biggest bang for the buck — excuse the pun — that, — you know, most diseases on the planet, especially now, in the developed world and-and-and a lot of the rest of the world now — the diseases that kills us are 80, 90 percent caused by aging, and medicine just sticks Band-Aids on the end product of those processes.
Gordon: Yeah, I’ll really let you know that I like this. I like the fact you used the word “caused” there. I think that’s something we can agree on. And but it’s something that’s, still very much not accepted by even the general biomedical community, never mind practicing physicians.
David: Well, it’s true. We’ve separated aging out as something distinct, when it’s completely not the case. It really is the cause. Some of the tests you can do for that is if you slow down aging, you don’t get sick, you don’t get those diseases. And now we have an ability to even reverse some aspects of aging.
David: And you can treat diseases that way, and actually cure them. And so, for example, we can now reverse the age of a mouse’s brain and it regains its ability to learn. So, these are pointing or screaming at us, saying: Aging is the root cause of these diseases. And if you stay young, they don’t occur, typically.
Gordon: Fantastic. And I definitely want to get into your research and some of your terrific recent papers, and unpack some of that. But I also want to go back to the beginning. Tell me about Robert Mortimer.
David: So, Robert Mortimer, who’s now no longer with us, was a giant in the yeast-aging field, he was a generous, buoyant, warm guy, who I looked up to as a — as a kid when I was learning yeast genetics, in my late teens, early 20s. And, I got to know him because I needed some yeast strains, some types of yeast for my PhD. and I wrote to him and I said, “Could I have some yeast?” And he would just — he and his lab would put them in the mail, and mail them out. And that’s the way science used to be done. These days, it’s a lot more complicated. Typically you have to sign documents, and there’s all sorts of approvals. But in those days, people would just share their science and just be happy that they were spreading goodwill to the community. and I got to meet him just once when I went to Vienna for an international conference. I think I was 22 at the time. And, that was a life changing experience. I’d never been to an international conference before. And there were probably a thousand people who were working on this little organism.
David: This little yeast cell. And it was probably the best time to have gone to a yeast conference, because the-the organism was becoming extremely famous within scientific circles, and we were just discussing — well, they were discussing, and I was listening about reading the entire yeast genome, and the mind boggled because–
David: — just to read one gene in those days took months of work. And, it was hazardous. There were dangerous chemicals. There was glass and electricity involved. And to have the knowledge of the complete yeast genome — that really only took another few years to complete — was a total revolution that preceded, and-and really just showed the world what it was going to be like in a world where we knew the genome of hans, as well.
Gordon: Yeah, I was actually working on yeast, for my PhD around about the same time, and one thing — I don’t think we’ve ever talked about this — is that, my undergraduate mentor was Johnnie Johnston. And Johnnie Johnston was the co-author with Bob Mortimer on a very famous paper in Nature in, — I guess it was 1959. So, six years after Watson, Crick, Franklin, published the structure of DNA, this paper appears in Nature, which I’m sure you know very well.
David: Right, yeah. Mortimer and Johnson; , they were the first to show that yeast cells get old, in a [formal] way. And that was the basis of my postdoctoral work at MIT with Lenny Guarente, dissecting yeast cells. I guess it was a small world in those days. So, it’s not surprising we’re connected that way.
Gordon: Yeah, well — so, so Johnny Johnston had this dream life. He had six months in Scotland teaching us kids some genetics. And then he would have six months in Berkeley working with Bob. And, and I thought that was just the-the perfect existence. But the question I had for you is: 1959. Why wasn’t yeast aging, genetics, or the biology of aging happening through the ’60s and ’70s, and really it took until the ’80s before things started to take off?
David: Well, my guess is that people didn’t believe that yeast were relevant to han biology.
David: They don’t get cancer, they don’t get Alzheimer’s disease. So, how could you possibly learn about something so complicated as aging from a little, tiny yeast cell? , and then, it really just became clear through the 1970s and ’80s that you could actually learn about han biology from yeast. There are a number of Nobel prizes awarded such as, the folks that discovered how the cell cycle is controlled. Paul Nurse is, you know, a name that comes to mind.
David: And so, that really showed that, “Hey, if we can understand the cell cycle, and it can win Nobel prizes, then, you know, maybe aging is something that might be relevant, too.”
Gordon: Your book is in some ways a thesis on the idea that aging is about information, the information theory of aging. And, I guess we do go back to your early experiments with yeast and the discovery of sirtuins as modulators of lifespan in this single-celled organism. tell us about sirtuins.
David: Yeah. Well, again, They deserve credit for finding a mutant strain of yeast that was resistant to starvation. and it also happened to live about 30 percent longer, based on the number of divisions that the mother cells could do. And I arrived on the scene then, and the question was: Well, what is that gene, and what is it doing? , and the gene mutation at the time was in SIR4, silent information regulator number four.
Gordon: Oh, right. Yeah.
David: And then, SIR2 came in, because SIR2 is the one that’s in hands. SIR4 is not well-conserved. But so, SIR2 gave rise to the sirtuins, which are pretty famous in scientific circles, and increasingly , in the public eye. And, and so, in those days, we were trying to figure out what the heck was a silent information regulator, a gene regulator doing controlling aging? That made no sense. At the time, the prevailing theory was DNA damage, free radical damage was causing aging. and so, to have this gene regulator was a total shock. And what we came up was — with was the idea that the SIR4 and SIR2 proteins were, controlling an aging gene. We didn’t know what it was. It was called the Age Locus, which is really a part of the genome that you don’t have a good name for. And then, we figured out what was going on. We went onto show that SIR4 moves away from where it normally is, regulating genes involved in fertility, to a highly, unstable part of the yeast genome called the ribosomal DNA, which is very repetitive. and one of the first things I showed, was that the ribosomal DNA is an Achilles heel for that organism. and little bits of DNA pop out from that region and choke the cell and kill it. but, as part of that process, these SIR proteins leave their post and go to try and help repair the DNA that is highly unstable. And by leaving their post, you lose the silencing of genes involved in fertility and sex determination, which you’ll know as A and Alpha, which is male and female in yeast. And that’s what gives rise to the-the sterility of old yeast cells, which at the time — and I think Mortimer and Johnson may have figured this out, or it might have been Michael Jaswinski later — that old yeast cells are sterile, and that’s a hallmark of yeast aging. And that led to the whole theory of really what we still work on in my lab, which is that the changes to gene expression due to resocialization of the sirtuin proteins — and others, of course — , are a key component of the aging process.
Gordon: So, at the time — I mean, you obviously knew that these genes were conserved in mammals. But did you even dare to think that they would be relevant for mammalian aging?
David: Yeah, we were pretty arrogant in those days.
David: So, we did like to think that we were uncovering secrets of-of general biology that would be conserved in mammals, and we really did believe that, that there would be homologs of sirtuins in mammals, and that they would control aging somehow.
David: And perhaps — and I was dreaming, and we started testing in my lab when I moved to Harvard in 1999, that the main homolog of SIR2, which is SIRT1 — there are seven of them — number one was going to also silence genes and control genes involved in aging, and move to double-stranded DNA breaks or DNA instability, including the rDNA. and for the most part that turns out to be consistent with all the results that we’ve had in mammals since. But it is funny. You know, no one’s ever asked me that, Gordon, whether we really thought that we were going to change the world. But we really did. We had this — there was this energy in the lab that we could really do amazing things. And, it — I haven’t had such an experience, like that where a whole lab has this fever about it, that, you know, we’re really doing something that’s going to change the course of history. Now, we could’ve failed. It could’ve been just complete arrogance. But, we definitely had this feeling — wherever that came from, I don’t know — but fortunately, some of it was — turned out to be true.
Gordon: Okay, let’s drill down on this information theory of aging, and we’ve got to talk about epigenetics and maybe just define some-some terms here. You already talked about gene expression changes as a result of these movements of sirtuins from site to site. So, what’s epigenetics?
David: Well, “epigenetics,” , is a term that was coined, — well, in the middle of the last century — to describe the phenomenon that you can inherit characteristics from your parents and even from cell to cell that are not genetic. And, you know, the — what-what became clear was that the epigenetic inheritance was alterable. It could switch. It could change. It was alterable by, the environment, temperature, for example. And, though people at the time, they had no idea what epigenetics was at the physical level, at the molecular level, now we know that-that epigenetics is really the mechanisms that stably control gene expression, how genes are controlled. And for the most part, it refers to the inheritance of those states, though it’s become a little lax these days. Epigenetics —
David: — tends to refer to anything that controls genes, which is really not where the term originally started from.
Gordon: Right, right. So, this is modifications to both DNA and to proteins that are associated with DNA, right?
David: It is. And those proteins, then, wrap the DNA up into bundles, tight bundles, which is a process of silencing genes, as well as contacting different regions together. So, DNA is not just a string that’s flopping around. It’s actually organized into bundles and large loops. And the large loops are often genes that together are turned on, such as development genes that control your head to your tail, the Hox genes. And so it’s — think of epigenetics — I know you know it, but, listeners may not understand it. Epigenetics involves chemical modifications to the DNA and to the packing proteins, that are called histones, as well as proteins that control large-scale looping of many thousands of letters of DNA. And it’s that three-dimensional structure that turns out to be really important for whether a gene remains switched off for 100 years — you know, if someone lives that long, or is switched on and you can actually change the — whether a loop is open or closed sometimes just by, the time of day or what you eat, that these structures are either very stable in terms of, the ones that are important for aging, or the ones that control metabolism and stress responses such as heat-shock that can — that can change rapidly within seconds.
Gordon: I mean, what blows me away is the technology that we now have at our disposal to look at this. So, I mean, just des– just describe that. How many — how many sites of DNA are we talking about? How many pieces of DNA are we looking at, at any given time?
David: Well, so, we’re looking at, — these days, you can look at the entire genome, so billions of letters, in a single day for a couple of hundred dollars; which used to cost about a couple of billion dollars and take a few years, and a few buildings and countries involved. so that’s where we’ve come. So now you can do it really in your home, what used to require governments to do. And what we can do now is not just read the letters, but to look at how they’re modified by chemical changes such as methylation, which is a carbon and three hydrogens; , but you can also look now at what boggles my mind is we can look across the genome at how it’s structured in three dimensions — and then in time, four dimensions — and see what parts are talking to other parts. And that’s very important, because there are things called enhancers which are regions of DNA that loop around and touch genes and make them get turned on. And that’s very important, too. And so, you shouldn’t think of DNA just as a — as a string. It’s actually a, a three-dimensional, chemical that moves and vibrates and bundles, and it opens up and touches other regions, and, — and so, chromosomes are really dynamic, when you really drill down. But getting at the technology — my head spins when I see how fast this changes, that the price comes down and how many experiments we can do. just to give one-one sense of it, what took me three months to do in my PhD, which was to read three genes, you could do a million of those experiments in-in just a day as a graduate student now.
Gordon: Easy. Amazing. okay. So, the information theory is the idea that this complex machine you’re describing degrades in different ways with age. I guess in your book you used this analogy to DVDs. You might have to explain to some of our listeners what DVDs are. [Laughs] But, you — [laughs] — you do use this analogy between a sort of — , the difference between a broken DVD and a scratched DVD. Can you — can you relate that to chromatin and epigenetics?
David: Right. So, there’s two main types of information that, is carried in our cells. We inherit, of course, the DNA, the genome from our parents — which is pretty stable throughout most of our life. We have mutations, but not a great deal. we can clone animals from skin cells, so clearly it’s not all completely messed up. and we can grow new organs from-from iPSCs derived from human cells. So, we do know that the genome is pretty stable. In fact, you can read a Neanderthal’s DNA, or, 20 thousand years’ old DNA. It’s a pretty strikingly stable chemical. Now, the other part of information in a cell is the epigenome, and the epigenome is really far less stable than DNA, and it’s p– in part because it’s not just digital — there are some digital components, such as methylation — but these loops are analog. They are vibrating structures. they move. they can be deformed. They can –And-and trying to maintain analog information is very difficult over time, as anyone who is over the age of 30 will attest, who might’ve used a cassette tape or a record. I guess some young people now use records still.. , so these forms of analog storage are really poor at copying. You lose information every time you copy a cassette tape or a record. and, and so, the analogy actually — what I-I like to use is, is a DVD, which contains digital information, which represents the DNA — so, the music or the movie that you read, the little ones and zeros, represent the DNA. And then, the reader of the genes would be that little laser that moves around and reads-reads the disk. and what I like to think of aging as is, scratches on the disk, so that the reader cannot fully access the genes at the right time in the right place. And similar to aging, what we think is happening is that genes are beautifully read at the right time when we’re young, but over time the systems, the epigenetic systems that read those, become, — well, they malfunction — in the same way a scratched CD or DVD would, skip, and the music starts to sound horrible, our genome is read in a horrible way as we get older. but, it’s interesting that if you have a scratched DVD, you can actually polish it and allow that movie or that music to be played beautifully again, as opposed to if you break the DVD, it’s — then you’ve got no chance, because you’ve lost the information. but I don’t think that’s what aging is. I think that aging is surprisingly reversible, and that the epigenome turns out to have a reset switch in the same way that we can polish the scratches off.
Gordon: So, and this gets to your work on, generation and reversibility of aging in certain tissues. And, first of all, give us an insight into how that’s even possible, and then maybe describe, you know, one of — one of your major discoveries in doing that?
David: Yeah. Well, I’ve been inspired by Claude Shannon, who came up with the mathematics that led to the Internet. And his paper in 1948, called “The Mathematical Theory of Communication,” came up with the idea that you should have a back-up copy of your — of your, message. And if it doesn’t make it to the sender perfectly, you can go back and retrieve some of that information. and it dawned on me, back in 2014, that it-it’s a good analogy for aging, that if the — we definitely lose information, right? We-we know some of the noise that leads to the loss of the ability to read the genome. Double-stranded DNA breaks is one. Genomic instability in yeast, I was mentioning, is a major cause of that. We now know that just crushing a nerve will accelerate its age, so that’s another way to do it. but what Claude Shannon did brilliantly was to say, “Let’s create a back-up copy.” And so, what I dreamt of was maybe there is a back-up copy of a youthful epigenetic state. Maybe we can polish the scratches without destroying the actual original information. Now, we know that it’s possible to reset the age of the cell of an adult cell back to zero. This is what Shinya Yamanaka won the Nobel prize for in 2016. He found a set of four genes that, when you turn them on in an adult cell, will reset its age — erase all the epigenetic marks, get rid of the DNA methylation, and, and start again. But that’s not going to be useful for resetting aging. That would just be a great way to cause tors, which is not what we’re about. And so, I dreamed of maybe there’s a way to partially reset the epigenome. Maybe there’s a, a storage of what the epigenome used to look like when we were young, when a cell was young, that could be accessed, and retrieve that information, like Claude Shannon said, and allow the cell to function and read the genes like it did earlier, without going back to being a stem cell, a pluripotent stem cell. And we didn’t know that that was possible until about three years ago, when we did a critical experiment where we found a combination of genes, three genes from the Yamanaka set that safely reset the epigenome and brought gene expression back to a state that was much younger, without transforming it into a cancer cell.
Gordon: I remember that experiment David. Fascinating. Tell me more about how that experiment worked out.
David: My brilliant, student at the time, Yuancheng Lu, was, was about to quit. He’d been trying for two years different combinations of, res– of age resetting, potential factors, and he was going through genes that would normally be turned on during embryogenesis. Because we reasoned that embryos stay young when they’re first formed, so why couldn’t we do that? But he kept turning on oncogenes…
David: He was getting pretty frustrated. He almost quit. And, it’s a true story. He was nearly in tears, saying, “I have — I can’t do this anymore. I don’t think I can finish my PhD.”
David: Which is the moment that most graduate students go through before they have a big breakthrough. And, so we decided to try one experiment, which was to leave out one of the Yamanaka genes, and try the experiment again, which was, — we left out an oncogene called cMyc — , “M” for short — , and he tried it again in cells. Still, we hadn’t tested any mice. and it worked. The cells went back in age. They became youthful. They functioned nicely. They didn’t become senescent. we delayed senescence. and it was — it was a Eureka moment. But then, we wanted to know: Can you do this in a living organism? Which would be something quite different. And we chose the eye as an experimental system. We chose the eye for a nber of reasons. one is that if you damage your optic nerve when you’re old or even just an adult, it doesn’t regrow — but a very young animal will. we also chose the eye because gene therapy works in hans, is-is permitted by the Food & Drug Administration, and so we thought if-if it worked, we could actually treat blindness. and then the third, Yuancheng Lu, the student, had a passion for the eye. So, all of that — I said, “Yeah, go ahead. Let’s do that.” And the experiment was to, blind a mouse by damaging its optic nerve, and then putting in those three Yamanaka genes to see if we could reverse aging —
David: — and allow them to grow back. and that was a turning point in my lab, where, Yuancheng texted me an image of nerve cells regrowing back to the brain.
David: And it was a — it was a Eureka moment, for sure.
David: And Yuancheng said, “Do you see what I’m seeing?” And I said, “Yeah, I see the future.” , and, and it was. It really was a turning point. My lab now, for the most part, works on reprogramming, and the role of sirtuins in DNA damage and DNA methylation and clots. So, yeah, we really — that was a leap forward. Later we went on to show that gene expression, the patterns of genes on and off, were much more youthful. And genes that went down a little bit with aging, went up a little bit with reprogramming. But interestingly, genes that go down a lot, come back up a lot with reprogramming. And vice versa. Up, down; up, down.
David: So, what-what that tells us is, it’s not just that the cell re-remembers which genes to fix in terms of, you know, just changing the expression, but by how much. There’s a place and a rheostat. And we don’t know where that back-up information is stored, how it’s stored. I would love for somebody to figure that out. We’re trying. But, yeah. That’s one of the big questions, is how-how does a cell know which are the genes that need to be reset to-to be able to restore its identity, but not become so young that it loses its ability to function?
Gordon: Yeah, no, it’s incredible. And I prese that you’re doing this in different tissues and, different disease models?
David: Oh yeah. So, we’re doing the brain. We’re growing little mini han brains in mice. We’re resetting the age of the old brain and seeing that they regain their ability to learn tasks again, which is cool. We’re trying to figure out if you regain lost memories. That would be fun to see.
David: Important for dementia. we’re testing muscle and we’ve got skin as a project now. There’s a lot of people interested in the regrowth of hair and, and hair color. —
Gordon: Tell me about it.
David: — yeah, so we [unintelligible] — [laughs] — yeah. So, we-we’ll try that. We got little skin organoids. Karl Koehler’s lab at Harvard grows these little balls of skin, and they’re quite disgusting. The hair actually grows inward.
David: , we now have the ability to age those. We can make them 60, 70 years old. Remember, to make a skin organoid, you actually have to go through a stem cell stage, Yamanaka reprogramming.
David: So, they have to go back to age zero. And then, what we do is we age them, and now we’re de-aging them. so it’s a lot of fun. We have really good, precise control over organs and tissues now, in organoids in a dish and also in the animal.
Gordon: Yeah, s– you mentioned senescence. So, we’re going to be speaking with Judith Campisi about her work in senescence. where do you see cellular senescence fitting in with this worldview of reprogramming that you have?
David: Well, it’s part of the whole hypothesis, part of the continu of epigenetic noise. The end product of the loss of cellular identity is that the cell just says, “I give up. I check out of the cell cycle.” And we can see that when we accelerate epigenetic noise. and during normal aging, cells will check out of the cell cycle. Sometimes it’s caused by telomere loss, but not always. Sometimes it’s just that the cell forgets what it is and says, “I think I’m a bit dangerous for the organism. I’m going to check out.” And so, what we’re doing is we’re now inducing senescence of course in mice, but also in these skin organoids, and in-in flat cultures across the dish with skin fibroblasts. and we’re looking at whether we can reverse the senescence state using reprogramming. Now, dogma would tell you that that’s dangerous, that these cells are terminally checked out of the cell cycle for a good reason.
David: , and it would be very dangerous and also very difficult to restore them to normal. but preliminary results in my own lab say that it might not — might not be that difficult or that dangerous.
Gordon: And do you think this is a better strategy than simply removing those cells with senolytic drugs or other approaches?
David: It could be. I mean, senolytic drugs are really promising, and I think they’re really simple. It’s a simple solution. But you don’t want to kill off senescent stem cells. You don’t want to kill off senescent, if there are those things. And so, I think that ultimately it’d be great if we could preserve the cells that we need, even if they become senescent. But for now, of course, we get rid of them, and that’s the best we can do. Ultimately, you know, I think I liken senescent cells — another analogy would be that these are zombies. And, you know, it’s okay to go crazy with machine guns, shoot all the zombies. Until, you know, one of those zombies is your — is your family member. You might want to figure out a cure for the zombies instead.
Gordon: I just want to go back to metabolism and, you know, you and others have clearly made inroads into understanding how to modulate epigenetic, fate and, — through changes in energy metabolism. So, can you say something about that?
David: Yeah. So, metabolism is one of the easiest things to correct, actually. The-the changes to the epigenome in metabolism are already really dynamic. And, many others bes-besides my lab have shown that, restricting calories, and also when calories are consumed, is able to, greatly improve metabolism and there’s increasing evidence that that’s also a way to slow down ticking of the epigenetic clock. But yeah, you know, the reason that I fo– my lab is focused on muscle and fat and metabolism — and glucose metabolism — is that it’s super easy to reverse. But I do like metabolism as-as a starting point for understanding why we age and-and how to reverse aspects of it. And, it’s been really fruitful, actually, for the field, I think, to focus on metabolism. And a lot of the genes that came out early in the days, when you were — , one of my heroes was, — well, you still are, but when I first came upon your work was to understand cell-to-cell signaling. and of course, in C. elegans, the insulin-signaling pathway was f-front and foremost — and also in flies. And that is a major controller of metabolism. It’s what — you know, what is insulin? And it’s like a growth factor, if it’s not controlling metabolism and cell growth. And so, yeah, and that’s where the field began, really. And it taught us a lot about the relationship between-between calories, between hormones and-and the aging process at the cellular level.
Gordon: Yeah, we’re trying to learn metabolism. yeah. We-we recently showed that, for keto growth rate, the TC cycle metabolite was having a — it’s always been — that’s been known for many years. [Unintelligible] Lab published the extended lifespan in C. elegans in the worm, but it-it seems to also extend lifespan in the mouse. But more importantly, it seems to — it seems to compress morbidity. You’ve talked a lot about healthspan. Did-did you have a sort of — a-a goal there in thinking about, you know, developing drugs?
David: I’ve wanted to compress morbidity and extend han health as my life’s goal, and then I-I work back from there how to do that. You know, get a PhD, do a postdoc, get a lab. So you know, if you understand that, you see why I develop drugs, because that’s the next logical step to achieve what I’m trying to do before I die. And so commercialization is a big part of that. Most ideas will die if you don’t have a champion. And the scientist is typically that champion. You’ve got to be that person, because there’s just too many ideas, and there’s too many distractions, and there’s not enough money to go around. and so, what I-I’ve done in my career is to take the best findings from my lab, and-and those that I’ve seen around the world, and direct money towards it in-in a way to, improve human health and-and extend healthspan. It’s — I’m not i– I’m not interested in-in making people live longer if it’s not, a healthy life and an enjoyable life. I mean, that-that’s what modern medicine is. It’s keeping people alive while their brains get old. I have no interest in doing that.
Gordon: Just a final point about the societal change that-that this-this science could engender. And I know you think about this. And I know the first thing that people say to us when we talk about healthspan, lifespan extension, is what are you doing to the planet? Do you want to just close on a couple of thoughts on that?
David: Yeah. Oh, I’m sad that we have to end. I-I do want to — I’ll-I’ll-I’ll talk about that, yeah. but remind me to get back to some of your research, because I do want to ask you a question. so societal ef-effects. So, the-the — a lot of people are worried about what happens when you make people live longer. We’ve always worried about that, you know?
David: I’m sure when antibiotics were invented, people were wondering, “What are we going to do with all these people that survive?” , and we’ve been trained — especially those that-that grew up, in the era of Paul Ehrlich and his books about the end of the world and population growth — we-we were worried that we’re all going to starve to death. That’s not going to happen. We have more food than we could eat. Twice over the whole planet, really. We know how to grow food. It’s a question of environmental degradation that’s the problem.
David: countries — o continents such as South America and Africa are realizing, as a whole, that educating a couple of children is the way to go. And I know this first-hand. I visited Africa a couple of years ago. And so, that means we’re going to ti– top out as a species at around 10 billion and start to decline, actually, after that. Now, if we start slowing aging, it’s not going to make a big difference. I mean, the only thing that would make a big difference is if we become immortal. And that’s not going to happen anytime soon.
David: Not within our lifetimes, that’s for sure.
David: I’m not an immortalist. I’m — , I think I’m pretty realistic about it. So, it’s going to happen slowly. People will start to live a few years longer. Those who do the right things might get a-another decade or-or even two decades, if they do all the right things. We already know that just doing five of the right things — drinking and sleeping and not smoking, and all those things — , gives you another 14 years, on average. So, it’s-it’s not crazy to think we could live that long, on average.
David: But, even if we do that, the point is that population growth isn’t going to be a problem. What do we need to do? We need to d– redirect resources into understanding how to live better on the planet, have less impact, how to recycle, how to grow crops without degrading the environment. I’ve recently given up meat, and all dairy, actually — in part because of the planet, and in part because it’s — I see a lot of signs pointing towards that being healthy, particularly for long-term health. Maybe not as much short-term. and you know, I’m-I’m — I can always debate the-the carnivores on that. But yeah, no, getting back to the main point, I think that by-by making people healthier and living longer, and being productive and spending money — rather than costing money in hospitals and in nursing homes for the last 10 years of their life — the economy is going to boom. The world is going to be a better place. My colleagues in London are — we were calculating that the cost-savings to the United States by just delaying aging by one year, would save, in the long run, $86 trillion; and if it’s 10 years- $365 trillion. That’s money that can be not wasted on sick care, which-which I call it — versus health care.
David: It can actually be put towards research and development of ways to protect the planet and allow us to exist on this rocky little ball without having to find new places to live.
Gordon: It’s stunning. It’s — , you know, and I know Jay Olshansky’s done some of these calculations in the past based on what we could achieve in-in-in mice in a lab, and these-these numbers are just astronomical. you had a question for me, David.
David: I did. So, alpha-ketoglutarate. Super exciting. I’m taking it. I’m having a look at what it does to me. I’m an experimentalist on myself, so I —
David: — I science the crap out of myself, as Matt Damon would say.
David: And I-I-I haven’t got the results yet, but I’m excited at the possibility of reversing my epigenetic age on my DNA methylation clock–
David: — which was recently shown in a paper, and also in mice. they’re — the mouse results that you guys have are just stunning. There’s very few molecules that are beneficial to healthspan and lifespan. And so, my question to you is: How did you know to test alpha-ketoglutarate? And second of all, do you think it works through the TET enzymes which do control the DNA methylation epigenetic clock?
Gordon: , yeah. So, well, we-we started looking at AKG simply because it kept turning up in screens in-in the nematode C. elegans for lifespan extension. And we were interested in combinations of natural products for commercialization reasons. We were being funded by a foundation at that point. And, it just — it seemed to play well with other molecules. And so, it was — it was always something that we thought would be a candidate to get into mouse. And, really, the-the-the results that we published were the controls, because we were actually looking for additional effects of other molecules. And you know, we’ll see if they wash out, in the end, in-in, you know, various combinations. But, no, we’re-we’re super excited about it. I mean, the-the compression mor– of morbidity was unexpected. I c– I can’t really explain it to myself quite yet. W– , Brian Kennedy, as you probably know, is doing some clinical trials in-in Singapore. We’re very excited to see what happens there. And, we get a lot of interest everywhere we go. La-last week, we were at the aging center, and then they were saying, “Let’s do some clinical trials.” So, it’s, it’s-it’s definitely, — it’s definitely a winner. It’s one of those Eure-Eureka moments you’re talking about.
David: Do you know how it’s w– slowing down the clock, or or reversing it?
Gordon: No, we don’t know. No.
David: All right. Well, I would put money on it activating the DNA demethylases, for all of those aficionados listening.
David: That’s where my money [is]. but yeah, I’m excited about the clinical trials. So, that’s where we’re at. Sometimes I speak to reporters who say, “Oh yeah, it sounds like science fiction. Maybe in a hundred years we’ll have this technology.” And I say, “No, no, no. There’s clinical trials going on right now in many different companies. Your molecule, my molecules — mi-mine are NAD boosters. We had some positive results just last week.
David: So yeah, someone is going to succeed in getting one of these drugs out onto the market that probably is f– initially for a disease, not for aging — which of course is not yet considered a disease, but it should be —
David: — in my view.
David: But yeah, we are at a t-turning point in human history. And I’m not exaggerating. I don’t feel I’m exaggerating when I say that-that we’re finally tack-tackling what we should’ve been tackling for over a hundred years now, which is the root cause of diseases that plague us, the longer we live. And the healthier we think we are, we’re actually ignoring the main cause of suffering on the planet. But finally, we — it’s not just our small band of brothers that it used to be. Remember, it was just a handful of us that’d go to conferences up in the Alps — you know, wondering, “Why doesn’t the world care?” Now the world really cares. The spotlight is on us, and billions of dollars are being put into this field. And so, that’s what’s super exciting. And that’s why I say it’s no longer an “if,” just a “when” all of this comes true.
Gordon: So, one of the challenges that we have is-is measuring aging and-and-and also that — the challenge there is that when we have an intervention that we think might be slowing or reversing aging, how you actually measure it. And th-there’s been a lot of popularity around methylation clocks. Can you just explain what those are?
David: These DNA methylation clocks, sometimes called the Horvath clock, named after our good colleague Steve Horvath at UCLA — what they are, are they — they’re really just measuring chemical changes on the DNA that occur predictably over time. And they can be clocks of the blood, clocks of skin. In mice we do brain clocks, liver clocks. Even kidney clocks. but there are — there are these common sites, common clocks that are so-called “universal” that can be used to determine the age of any tissue. And even between species, there are clocks and — , little sites on-on the genes that change the same in sheep and bats, and even hans. And so — and even whales. And so, this — what this tells us is a couple of things. It’s not just a parlor trick. It’s not just a way to estimate your biological age. It’s actually more important than that. What it tells us is that the epigenome, which these marks are part of, is a component of aging itself, and th– some of the evidence of that is the following. When we drive aging forward in our mice, in my lab, and we give them aging — which we can do by creating some genome instability — the clock advances. We can make a mouse 50 percent older than its sibling that was born on the same day. And that involves changes in the clock, and they get aging. But I think more importantly, when we reverse aging by reprogramming those mouse tissues in the cells that we grow in the dish, if we stop the clock from being reversed — and we can do that by disrupting enzymes that are required to change those chemicals —
David: — then the cells don’t get younger.
David: And here’s the really important thing. The cells don’t function as though they’re young anymore. So, in re– the reversal of blindness, curing blindness in mice —
David: — needed the clock to be reversed, needed the — those methyl chemicals to be removed. Which tells us that the clock itself, or at least the DNA methylation patterns which the clock represents, is not just like a clock on the wall; it actually represents time itself. They’re part of the aging process and required for the reversal step, as well — which is really cool. That really brings us to a point where now we can measure our age, and you can do that — there are some tests that you can buy commercially that are somewhat accurate. and then you can also — we can also now measure if interventions such as alpha-ketoglutarate, or my NAD boosters —
David: — affect the rate of aging and even potentially reverse the rate of aging.
Gordon: Wow, terrific. So, Dav– , David, would you — I mean, if-if you were a PhD student now, would you be — would you get into aging?
David: Oh yeah, as soon as possible, right?
David: Oh yeah. It’s — as soon as possible. Right? This field is taking off. In five years, there will be so many people in it that it’ll be hard to distinguish yourself. But it’s still a really good time to get into it. There’s so much money pouring into aging research from the government, particularly also from philanthropists — in the billions of dollars — that are — you know, it’s going to lead to new jobs. There are going to be new departments. It’s — there’s never been a better time to get into aging research, right now.
Gordon: I completely agree. Fantastic. S-so, so you-you-you’ve just emerged from your PhD in some subject — maybe neuroscience or a disease model or something. And you’re-you’re-you’re seeing the excitement that you’re describing here. How do you — how do you design your first experiment? What does that look like?
David: Oh. Well, here’s my trick — and I think good scientists, yourself included, have learned this trick. you don’t look at the technology. You don’t try and figure out what you think might be the next experiment. You start with a really good question and then work back from there and figure out how you’re going to answer that question. But all of the papers that we’ve published have started with a really good question. And what you do is you ask a hundred questions. You can come up with a hundred questions. In my lab, we’re asking questions all the time. And then you pick that one that is the key question that everybody’s missed, though it’s right in front of their face. And a good question is: What drives aging? You know, for a hundred years, people didn’t even care. Another question would be: How is it possible to reset the age of the cell? Where is that information stored? That’s a really good question. How does alpha-ketoglutarate possibly delay aging or even reverse it? Great question. So, that’s where I would start. And then, you could figure out the technology, or even invent it, or — you know, get money to-to-to hire a company to do that. But-but don’t try to figure out the next step using the current state of knowledge of the current state of technology. You won’t see far enough into the future to get ahead of your colleagues unless you ask a really good question.
Gordon: Wonderful advice for those young scientists out there. Thanks again, David, for your time. You’ve been very generous.
David: It’s been a lot of fun, and great to see you.
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“We’re not getting any younger, yet!” is made possible by a generous grant from the Navigage Foundation. The Navigage Foundation is enhancing the lives of older people through the support of housing, health, education and human services. Our podcast is produced by Vital Mind Media: Wellington Bowler is here with me using sign language to keep me on course and recording the podcast. Stella, who I love spending time with talking about science, as you know, is our editor with the Creative Direction of Sharif Ezzat and the Buck Institute’s very own Robin Snyder as the executive producer.
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