#112 – Ned David, Ph.D.: How cellular senescence influences aging, and what we can do about it

1. 0:00 – 0:11

   Intro

   1. PAPeter Attia0:01

      [upbeat music]

2. 0:11 – 4:50

   Setting the stage: Ned David, Unity Biotechnology, and why senescence matters

   1. PAPeter Attia0:11

      Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn more now, head over to peterattiamd.com/subscribe. Now, without further delay, here's today's episode. [upbeat music] My guest this week is Ned David. Ned is the president of Unity Biotechnology, a company that he co-founded in two thousand eleven. In this episode, we're gonna talk a little bit about Unity, but more importantly, we talk about the science upon which Unity is developed, and that is the science of senescence or cellular senescence. We begin this episode by putting that into context. I think if you're interested in the space of longevity, you're listening to this podcast, you've undoubtedly heard the term senescence, but it might not mean much to you. And I think what Ned does a great job of here is explaining not just senescence, but where it fits in the overall lattice, if you will, of all of the different cellular processes that occur during aging. So where does it fit in with the role of mTOR inhibition, caloric restriction, mitochondrial dysfunction, stem cell exhaustion, methylation of DNA, and epigenetic change, all of these sorts of things. We also talk quite a bit about Ned's background as a serial entrepreneur in biotechnology. Ned is at least partly responsible for the development of a number of FDA-approved compounds, and he talks openly about what he learned, good, bad, and indifferent along the way, and how that helped him at the beginning of this process of creating this company, Unity, define sort of the jugular questions that needed to be addressed as sort of a proof of principle. In fact, I, I found that part of the discussion most interesting, and I think you'll, you'll know what I'm talking about when we get to that part in the episode, because I found that exercise that he and his co-founders went through between about two thousand eleven, two thousand fifteen to be some of the most interesting thinking around this idea of company creation. Ned is a prolific innovator. Uh, I think when he was about 30, he was named to the top one hundred innovators in the world by MIT Technology Reviews. He holds a PhD from Cal Berkeley, and he got his undergrad degree in molecular biology at Harvard. So without getting into too much more of the details of this, please enjoy my discussion with Ned David. [upbeat music] Ned, awesome to see you today. Thank you for coming by.

   2. NDNed David2:58

      Oh, thank you for having me.

   3. PAPeter Attia2:59

      I feel like I haven't seen you in person in way too long.

   4. NDNed David3:02

      This is true. We tried to get you to come to dinner.

   5. PAPeter Attia3:05

      Oh, God. I feel horrible about that.

   6. SPSpeaker3:06

      Yeah.

   7. PAPeter Attia3:06

      Yes. Sorry.

   8. NDNed David3:07

      Yeah. You were distracted. It's all good.

   9. PAPeter Attia3:10

      No, you know what I was doing?

   10. NDNed David3:11

       You were doing a podcast.

   11. PAPeter Attia3:12

       I was doing a podcast-

   12. NDNed David3:13

       Yeah

   13. PAPeter Attia3:13

       ... that I thought would take two and a half hours. It ended up taking six hours.

   14. NDNed David3:18

       That must have been an intense experience.

   15. PAPeter Attia3:21

       It was a very intense experience, and I felt horrible after. I'm sorry. So I owe you an apology for that.

   16. NDNed David3:26

       It's okay. We love you.

   17. PAPeter Attia3:27

       [chuckles] There's so much I want to talk with about you. In fact, I've been bugging you for about a year to come on the podcast because what I was hoping we could do, and we can never do it when there's a microphone in front of us, but was sort of reproduce a dinner conversation that we would have ordinarily, which would be pick some topic and we go way off on a tangent about it. And it could be energy, it could be biotech, it could be whatever. But some of the most interesting discussions we've had over the past five years have been around longevity, something that we both share an interest in. And God, it's been probably nine years since you talked to me about what became that which you're doing today. Is that about right?

   18. NDNed David4:11

       Yeah, that's about right. It was two thousand eleven, towards the end.

   19. PAPeter Attia4:14

       Yeah.

   20. NDNed David4:14

       Yeah. Actually, we're in December now, so it's actually been somewhat more than eight years.

   21. PAPeter Attia4:19

       So I want to talk a lot about your work. You're always a guy who's got a lot of hats on. Right now, you're mostly wearing one hat, and that's a hat that puts you squarely at the center of a pretty big circle with a bunch of folks working at a company called Unity Biotech, which we'll certainly get to. But I think for listeners to really understand what you do today, what your company does, they need to sort of understand the journey you've gone through over the past several years and how that's sort of shaped your thinking about

3. 4:50 – 7:07

   What “longevity” means to Ned: escaping the indignities of aging

   1. PAPeter Attia4:50

      an interesting problem. You're a serial entrepreneur, and we will likely discuss some of that in your background. But let's just start with how you think about this problem that I think about, which is how do we help people live longer? How do we help people live better? How do you define that, by the way? I don't want to impose my definitions on you. What is longevity to you?

   2. NDNed David5:07

      Well, longevity for me would be being able to live without the indignities that I've witnessed, we all witness in our lives, all of these features of aging that seem to be inescapable. So my father, for example, he has profound degenerative disc disease, which makes him functionally immobile. It defines his life. My stepfather died of Alzheimer's at eighty-seven. That defined the final chapter of his life. So I've been up close to these things in other people. In addition, we all, and you and I are now, I'm a lot older than you. I'm in my fifties now. We are witnessing these changes in ourselves. And for me, longevity would be the ability to use what I know how to do, which is science and biology, and be able to change how we get to live our lives. To be free of these indignities. And I think it's something that we can do, and we are doing it. And so for me, it, it sort of began as a dream, but now we're generating human data that says [chuckles] this, we can actually do this.

   3. PAPeter Attia6:18

      So I remember when this started, Ned, circa two thousand eleven, how you really steeped yourself in this field, which at the time was kind of new. You had already done a number of interesting things in biology that had led to the development of drugs, but none quite in this space. I mean, I literally remember many nights I'd be driving home, and we'd be talking on the phone, and you would be telling me about things that you had just read about, and you, "I saw this paper, and it's ten years old," but it was, it was almost like you were going through a second postdoc or something, getting up to speed in this. I've always liked the way you've sort of explained your evolution of thought there. Do you wanna maybe for the listeners give them a sense of how you developed a framework around this?

   4. NDNed David7:02

      About sort of aging biology.

   5. PAPeter Attia7:05

      Yeah, why do we age?

   6. NDNed David7:06

      So-

   7. PAPeter Attia7:06

      And what can you do about it ultimately?

4. 7:07 – 10:39

   Aging as malleable: three principles and the “control knobs” framework

   1. NDNed David7:07

      So maybe it's helpful for me to just create some context. And so the way I think about this and the way I explain it to people that are new to this or people that aren't scientists is I, I always talk about there're these sort of three principles, that if you remember nothing else from listening, if you're awakened two weeks from now in the middle of the night, it's these three principles that I think are a good way to think about this. And the first principle is that aging's not a rigid thing, so it's this flexible, malleable thing. And nature has, throughout evolutionary history, sort of bent and twisted aging for its own purposes to create creatures that have very different lifespans. And this kind of takes us to the second principle, which is that nature has done this with these control knobs. These are sort of biochemical systems that nature twists, and these systems are now something we're learning, and this takes to the third principle, to turn as people that do drug hunting, like us. And so it's these three principles, that nature's flexible or that aging's a flexible thing, and nature has then bent and twisted control knobs to make it flexible, and that these are turnable stuff. So if you take those three principles as the context, you may ask, "Well, why do we as scientists, why do I believe these things are true?" So if you just look outside at nature and creatures across phylogenetic history, you see very similar creatures with very different lifespans. So if you take the hard clam, so this is this thing you can eat at a clambake. If you don't eat it, it will live about forty years. And it has a deep ocean-dwelling relative called a quahog that lives at least five hundred years. And these are very similar creatures. They look very much the same. And no one really knows how long this quahog lives. It's, this five hundred year thing was just because that was what the age of the wreck off of which it was pulled was. So these are very similar creatures on the order of twelvefold different lifespan. Similar story if you flip over to, let's say, the order of rodents. Actually, let's not even go to rodents yet. Let's just talk about mammals, 'cause that's us. Of course, rodents are mammals too, but we are mammals as humans. So if you look at the shortest living mammal, which is this thing called the tiny shrew, lives less than a year. And then you look at the longest living mammal, so it's called the bowhead whale. And again, no one knows how long a bowhead whale actually lives. The estimate is at least two hundred years. So again, you've got this two hundredfold difference at least in creatures that kind of have the same biochemistry. We're both mammals. Now, if you flip over to rodents, it's the same phenomenon. Okay, you can take a field mouse, which can live somewhere between two and three years, and then you find this naked mole rat, which is this very unusual looking subterranean creature that's blind and hairless. This creature lives ten times longer. Lives on the order of even more than ten times longer. Lives on the order of thirty years if, if it doesn't die of some trauma. And again, these are, these are in the same order, and so these are closely related creatures, very, very different lifespans. So nature has clearly gone to town [chuckles] on this and created these marvelous examples

5. 10:39 – 14:56

   Single-gene longevity and the IGF signaling story (DAF-2/DAF-16)

   1. NDNed David10:39

      of disparate lifespan, but sort of the same creature with the same biochemistry. So this kind of takes us to this idea of that nature's done this. How has it done this? And it's done it with these control knobs. And I'll walk through why we thought they were control knobs and how we turn them. So the first control knob that got discovered molecularly was the work of Cynthia Kenyon, and this was a paper that blew me away. I was a first year in graduate school, maybe second year. And Cynthia published a paper that was pretty heretical at the time, and the paper showed that you could knock down the function of a single gene in a worm, C. elegans, so it's about a millimeter size little worm. And when you knock down the function of this thing, it doubled the animal's lifespan. And this was a, a wild result, 'cause at the time, aging was thought of as this kind of decay process, but the notion that you could essentially break the function of something or at least make it function a lot less well and double the lifespan of a creature was just a total mind warp [chuckles] for me and other people. Just like, oh my gosh, you can dent something, and it gets better. Now, what's happened in the intervening decades is this has been repeated in flies. It's even been repeated in mice. You can knock down the function of a single gene and calorie restrict an animal, and you can double its lifespan. That's like you or me living to a hundred and sixty Okay. Because this is a creature with really similar biochemistry to ourselves. So this just said that you could take single genes, turn them, and do radical things to lifespan.

   2. PAPeter Attia12:16

      Now, in fairness, with Cynthia's work in C. elegans, I always felt that it wasn't the best model to extrapolate from because of the division stopping at the germ cell, and therefore if you take DAF-2 and DAF-16 and project them forward to mammals, I don't think we've seen the same magnitude of reduction with attenuation of those, have we?

   3. NDNed David12:37

      No.

   4. PAPeter Attia12:38

      And maybe it's worth rather you explaining it than me. Do you want to tell folks what DAF-2 and DAF-16 do-

   5. NDNed David12:42

      Yeah

   6. PAPeter Attia12:42

      ... just to bring them along for the ride?

   7. NDNed David12:44

      So these were genes that were discovered in Cynthia's screen as receptors and transcription factors associated with what we now talk about as the IGF-1 receptor signaling pathway. And if you go in-- So this is something that now has been explored in great detail in, in mice, for example. And the analogous knockdowns in mice of the receptors don't produce the same degree of longevity that you can produce in a worm. Now, interestingly, a paper published somewhat recently, this was, uh, Nir Barzilai, and actually, uh, Pedro Beltran, who I work with now, with an antibody that antagonizes the IGF-1-

   8. PAPeter Attia13:25

      IGF receptor.

   9. NDNed David13:25

      Yeah. It extends life, but there's a sex difference, so it only benefits the females. And it's not something that translates perfectly, but I think that's not the interesting piece in terms of the whole kind of story of what we're learning about aging. Was to us, and to me, it was, "Oh my gosh, you can damage the function of a single gene." The fact that it still works in mammals is remarkable. The fact that it works less, it's not as cool, it's a little bit of a bummer. But to me, it was really the, it was the DAF-2/DAF-16 observation that opened up the field and said that there were these knobs that you could turn, and you could get these radical impacts on longevity.

   10. PAPeter Attia14:09

       And the additive value of DAF-16 plus caloric restriction was also very interesting in Cynthia's worms. And I actually thought that that was perhaps the most extrapolable insight to mammals. But to your point, it was a proof of concept.

   11. NDNed David14:23

       Mm-hmm.

   12. PAPeter Attia14:23

       Right? It was, "This thing is malleable."

   13. NDNed David14:26

       Yeah. And to me, at the time, it was just like it was as though the mask tipped a little bit, and you could see the face underneath. Like, oh my gosh, there's something almost programmatic going along here, as opposed to just this idea that you just decay. And that was exciting, and that paper stuck with me for several decades. It was not something that I chose to work on, although I became friends with Cynthia at some point in the early 2000s, and we continue to be friends

6. 14:56 – 18:28

   Caloric restriction, rapamycin, and mTOR: the most reproducible aging knob

   1. NDNed David14:56

      and talk all the time. But that particular biology is not-- It's more of a marker people use now, as opposed to something that people are actively trying to perturb. So going back to this question about, of knobs, this goes to our, this third principle, which is that we can turn some of these knobs. The first knob actually that got turned in a super aggressive way goes way back to the 1930s, and it was this guy at Cornell named Clive McCay. And he had a colony of rodents, and this is shortly after the Great Depression, and his lab didn't have a ton of money. And in an effort to keep portions of his colony alive, he fed some of the animals all the time, and then other animals he fed infrequently. And what happened was not what he expected. The animals that were restricted with food lived longer, and it was the first time this ever got experimentally demonstrated, albeit by accident. And for me, that was the first time that scientists had sort of set out, albeit for a very funny reason, and turned a knob that extended life. And it brought forward this idea that as we live, aging or your biology's making a decision about the rate at which you are aging. Now, flash forward several decades, a molecule's discovered on Easter Island made by soil bacteria. It's one of your favorite molecules, rapamycin. Now, the aging effects of rapamycin were not figured out until about 2003, and then the awesome work of David Sabatini eventually linked this calorie restriction observation from decades and decades earlier to rapamycin, and it turns out that rapamycin and calorie restriction are both turning the same control knob. And this is pretty wild because biology typically only invents a few ways to do things, and what was really neat was the way in which these two totally different approaches were both touching the same biology. So it's my belief that this, uh, biology-- So there's this complex called mTOR, which is this megaDalton complex. It's this master decision maker of whether or not we are choosing to divide and make more biomass because there's enough resources, or are we choosing to fight another day? And this biology, the rapamycin and calorie restriction and restriction of various other things like methionine, is the single best validated biology across labs, across species. And one of my coworkers, who's a sort of incredibly brilliant but cynical guy, always says, "If you want to know what the real biology is, it's the stuff that works in every lab no matter who's doing it." Okay? Rapamycin and calorie restriction definitely have that feature. It works in all these labs.

   2. PAPeter Attia17:48

      Do you know that I tried to get a personalized license plate for rapamycin, and it got rejected by the DMV in California because rapamycin is a drug, and you can't have a license plate that's a drug. So then I tried again, in vain, to get rapalog as a license plate, and I got thwarted again because apparently someone at the DMV was smart enough to Google rapalog and figure out that it's an analog of rapamycin, which is also a drug, and I got the same rejection letter from the DMV.

   3. NDNed David18:17

      I would just assume knowing you, you would've done rapamycin

   4. PAPeter Attia18:20

      [laughs]

   5. NDNed David18:21

      Which sounds vaguely like a super villain.

   6. PAPeter Attia18:23

      [laughs]

   7. NDNed David18:23

      Okay? But no, we didn't go... You stopped there.

   8. PAPeter Attia18:26

      I'll tell you over dinner what I eventually went with.

7. 18:28 – 23:02

   Other aging knobs: young blood, mitochondria, and the methylation clock debate

   1. NDNed David18:28

      Okay, gotcha. So anyway, so there's this mTOR thing, which is the best validated control knob. The next knob that got turned is this thing with young blood. So this is something that's been sort of popularized if you watch things like Silicon Valley, but this goes back a ways. But the first time that the lifespan effects of this were demonstrated was in the 1970s. And so what you do is you take two animals, one's young and one's old, and you literally suture them together, and their circulatory systems join. And it's not a giant mental leap to imagine that crap in old people is bad for you, so the, the old blood would be bad for the young. The awesome result was that stuff in the young was good for the old, and it could extend life by as much as 15%. And these are with animals that are sutured together, which is not exactly an optimal way to live. So that tells you that's another knob. There's stuff in young blood that is able to exert biology and do good things, and I think that's gonna be an area that will be fruitful. The next sort of control knobs we've learned about, so mitochondria age. So mitochondria are the descendants of ancient bacteria, so they have their own DNA, they have their own genomes. And mitochondria live a really hard life, and so their mutation rate of their own DNA is somewhere between 100 and 1,000-fold faster than our nuclear mutation rates. So their DNA just gets all chewed up, and as a consequence, by the time you are in your 70s, you can go into a human being and look in their colonic crypts, and on the order of half of the cells in their colonic crypts don't have functional mitochondria. They can't utilize oxygen to make energy or do all the other things that mitochondria do that are important. And so that's something that we've learned that is clearly a part of this aging story. Another thing that could be a knob, and this is an area of some intense debate these days, is this thing called the methylation clock. So this is this ever-ticking clock in which these methyl groups, this is a little carbon atom with three hydrogens around it, are attached or detached over time to the various Cs in your GATC code. And when you're young, there's essentially these five methyl Cs, these methyl groups on your DNA. It's like a crisp pegboard where everything's lined up perfectly, and you've got areas where they are and crisp areas where they are not, and gene expression is not noisy. And as we get old, it's like someone drops the pegboard, and suddenly you've got methylations where you're not supposed to have them, and you're missing them in other places. And looks as though that might, and I stress the word might, give rise to sort of noisy gene expression. And the metaphor I often think of for this is imagine you have a vinyl LP, if you're old enough to know what that is or hip enough to know what that is, because it's kind of a hipster thing now, and you play an LP a lot. The actual act of playing that LP takes the little knobs and grooves and wears them down so the LP doesn't sound as good. And it's possible that the act of being alive, and that aging actually is modifying these little methyl groups in such a fashion as to cause aging. No one knows if these changes in this epigenetic clock are the cause of features of aging or the result of features of aging, or even a little bit of both, and that's gonna be super interesting area of biology.

   2. PAPeter Attia22:00

      Yeah, I've spoken with David Sinclair quite a bit about this. He uses an analogy that's similar but has a couple differences, which is the methylation could be thought of as the scratches one gets in a CD surface. And the, the question of course being can you restore the CD back to its original form if you have that master template? And, and that's not exactly the same as the analogy you've used, but it certainly speaks to the music and the disc.

   3. NDNed David22:24

      Yeah, it's interesting. So I always think of CDs getting scratched because you're negligent, okay? [laughs]

   4. PAPeter Attia22:29

      Right, as opposed to just putting them in the CD player and using them.

   5. NDNed David22:31

      Yeah.

   6. PAPeter Attia22:32

      Yeah.

   7. NDNed David22:32

      And so, so there's a nuance. I mean, it's funny, those two metaphors may even sp- as you note, may speak to different intuitions between me and David about what's going on here. But I don't really have an intuition. I'm sort of reporting out what's sort of known and what... It's gonna be just very exciting to see when we can actually do experiments that can tease this apart and ask questions like, if you take these methylation groups away, do you in fact start making cells that are younger functionally? And that's

8. 23:02 – 27:22

   Yamanaka factors and ‘factory reset’ caution: youth vs. cell fate reprogramming

   1. NDNed David23:02

      gonna be an awesome experiment. David did an experiment recently, and I think you have to be a little cautious with interpretation. So twice in our lives we press a factory reset your methylome. So you do it once at conception, and so a bunch of gene products get made which erase and reset your methylome back to day zero, 'cause you're now an embryo, and the program is beginning again. Now, a few weeks into your life, it happens a second time, but only in a little bit of your cells.

   2. PAPeter Attia23:37

      Yeah, so let's explain that. So when you start at conception, you have one cell.

   3. NDNed David23:41

      Mm-hmm.

   4. PAPeter Attia23:42

      It goes through about 50 divisions?

   5. NDNed David23:44

      So I don't know exactly. So are you talking about when we do the second reset? First of all, it's different in humans and mice, and I, I apologize, I don't know.

   6. PAPeter Attia23:52

      But it's some relatively small number.

   7. NDNed David23:53

      Yeah. It's a small number.

   8. PAPeter Attia23:54

      Yeah.

   9. NDNed David23:54

      And it happens within, I believe it's weeks-

   10. PAPeter Attia23:56

       Yep

   11. NDNed David23:57

       ... in the human. I think it's a little over a week in a mouse. But anyone out there that works on this, and I have friends I could call, but, uh, not, not right this second. What happens is there's a second wave of these gene products that are made, and for a second time in your life, [laughs] and the only second time in your life, you will reset, 'cause now you are making germ cells for your children, and they are kept in a special spot in your sex organs until you make babies. So those are the only two times that this factory reset gets pressed. And then going back to where I was saying you have to be a little cautious with interpretation, we now know how to do this artificially. So we can express four factors called the Yamanaka factors, and these four factors by themselves, if you express them in cells, it's super inefficient, but one in every few thousand cells you can cause to become a reset cell with a prime, you know, a-

   12. PAPeter Attia24:57

       When did Yamanaka do this? This is in our lifetime. I mean, this is quite recent.

   13. NDNed David25:01

       Yeah. He got the Nobel Prize. I, alas, I don't have the date. I know a lot about actually how he isolated them. I just don't know the precise dates. But basically he did this... It was a beautiful experiment what Yamanaka did. He initially identified genes that, this candidate list of genes that were turned on in this sort of embryological state, and then he started using-- He was delivering the genes in various combinations. He ultimately wound up paired down to about two dozen, and then he then would take various pairwise combinations and figured out how few he could do and still manage to turn on one of these embryonic genes, and he managed to weed it down to four, and he got the Nobel Prize for that. And so what's happened in the intervening years is there's been some efforts to see could you actually impose features of youth because it's sort of a simple-minded leap to say, "Oh, if you look embryonic, that's young." In fact, and I think that's the little dangerous leap.

   14. PAPeter Attia26:00

       Right. Just because you don't have the methyl groups on your DNA doesn't mean they translate into the phenotype that is youth.

   15. NDNed David26:08

       That's correct. What I think you do when you do Yamanaka four factor reprogramming is it's a cell fate decision. You've entered a very unique cellular state. Now, it just so happens to have things that are in common with youth, and so I think that when you do a reprogramming event and you're able to exert something that looks like youthful biology, you may have actually just created new young stem cells that are able to somehow pick up the music developmentally and participate. That's sort of different than youth. It's a bit of a sort of cell transplanty sort of thing, although done by the delivery of genes. So anyway, this whole question about this methyl clock is something that it's an intense area of interest in the biological community. It's evolving a lot. There's a bunch of labs that are working on this, and it's gonna be a very interesting next five years to see where this drops out. Um, we sort of covered a bunch of things. We've talked about-

   16. PAPeter Attia27:09

       Yeah. You got mTOR reduction-

   17. NDNed David27:10

       Yeah. Yeah. Right

   18. PAPeter Attia27:10

       ... slash caloric restriction, loss of the circulating youth factors, mitochondrial dysfunction, methylation clock, which sort of ties into sort of stem cell exhaustion, and then we've got another big one.

9. 27:22 – 31:44

   Why senescence is Unity’s focus: the simplest mechanism to turn into medicine

   1. NDNed David27:22

      What I wanted to do is I've spent the last now just a little over eight years working on one of these last knobs that we now know how to turn, which is cellular senescence. But I wanted to place that particular knob in the context of the others because I don't want to sort of overhype this idea, but I do want to explain why I've dedicated a large chunk of my life on planet Earth to this. 'Cause if you look at all of these aging mechanisms and these knobs that I've described, they all play a role in this. We don't yet know what the sort of underlying primordial clock that ticks that makes us age. What we do know is that you have a series of these component mechanisms that work collectively, and they create this phenomenon that we call aging. And I want to talk about cellular senescence now because I work on it because of all of the mechanisms, it strikes me and struck me as the simplest mechanism to perturb and make medicines that you can use to treat human beings. And I'll get into why that is in a sec, but I'll just tell you about the knob. So we all begin life as a single cell at conception, and then over the arc of our lives, we, the single cell, will divide as many as 50 times. And on the road to 50 divisions, the cells that make us up will encounter some form of stress they cannot resolve. They will pull an emergency brake, and they will stop dividing forever. And we call this state when you do this, we call cells that do this a senescent cell. And this is something that we've-- we find these cells in all of the tissues we've examined, and these cells, they're a very small number most of the time. Typically, it's on the order of hovering around 1% or less. Now, in some disease states we have looked at, that number is dramatically higher, and I'll talk about that a little bit later. Children don't have these cells. Now, they can make them, but they don't accumulate, and we don't know why. But as we age, these cells accumulate. Now, before the work of my collaborators and my co-founders at the company I work at, no one knew if these accumulating senescent cells were good for you, bad for you, or neither. And so my two co-founders, and now almost a decade of collaborators, is Judy Campisi at the Buck Institute and Jan van Deursen at the Mayo Clinic. Both of their laboratories genetically engineered mice, where we could eliminate senescent cells from these animals whenever we wanted. And for the first time, we got to ask what happens, and what happens is pretty eye-popping. So normally, I carry this picture around on my iPhone, so I always show people this is what I work on. But essentially, by a podcast, you have to use a little bit of imagination. So imagine two animals, siblings. Born within seconds of each other from the same mom. These are animals that are 24 months old, so it's kind of equivalent to a 70-year-old person. And one of these litter mates is blind, it's osteoporotic, it's frail. It has kidney dysfunction, it has cardiac dysfunction. It looks visibly old. Its litter mate, from whom we eliminated senescent cells from midlife until it's dies, [chuckles] this animal lives on average about 30% longer, which is cool. But what's more awesome than that is that when this animal dies, and when its similarly treated animals die, they die with many of the features of aging either absent or reduced. And that is awesome. And so we're trying to do at Unity, the company I work at-

   2. PAPeter Attia31:16

      Now, before you say that, there's something interesting you said, which is they have this knockout of senescence that only occurs in midlife.

   3. NDNed David31:23

      No. What we do is we insert into every cell of that animal's body, we genetically engineer the animals, so that we can administer a drug weekly which kills senescent cells within that animal.

   4. PAPeter Attia31:34

      But do you begin that administration-

   5. NDNed David31:36

      At midlife.

   6. PAPeter Attia31:37

      And what happens if you begin that administration at birth?

   7. NDNed David31:39

      We have not done that experiment in large part because we don't see senescent cells at birth.

10. 31:44 – 40:37

    Cancer, apoptosis vs. senescence, and the toxic secretome (SASP)

    1. PAPeter Attia31:44

       I see. Is there a chance that those animals would prematurely get cancer if we eradicated their ability to create stem cells at the beginning of life? Didn't Judith have some data that suggested the importance of senescence early on as a sort of break against cancer as well?

    2. NDNed David32:02

       So you bring up a really important point that I should clarify. So whenever I tell people about this result, people often ask, "This is an important system. Why are you messing with it?" So it turns out the ability to make senescent cells is vitally important to our survival. So if you genetically engineer a mouse that cannot make senescent cells, this animal is born normally. It's got 10 fingers and 10 toes, but it statistically winds up full of tumors before it's in reproductive age. So it tells you that this emergency brake, this cellular senescence system, is an anticancer system, and you do not want to mess with the emergency brake. You have to leave it alone. And so in the experiment I described where we eliminate these cells, we don't touch the brake. We allow the brake to pull completely, and for the cell cycle to stop. We only show up after. Now, I think it's still a reasonable question to say, "Dude, it's like this is an anticancer system, and you're kind of screwing around with it. Are you sure this is okay?"

    3. PAPeter Attia33:06

       Let's take a step way back. So in medical school, we spent all this time learning about different cellular insults, and perhaps the most obvious one and the one we could use as an example is DNA damage. So when a cell's DNA is damaged, presumably its first choice is, "Can I fix this?" But if a cell's fate is such that it can't repair its DNA, that's sort of when it has this bifurcated pathway of going down the pathway of apoptosis, which means for the listener that it has a programmed form of cell death, so it basically kills itself in a programmatic structured way. Or it goes down this pathway that you've described, which is senescence, effectively saying, "I will no longer do anything. I'm still alive, but I don't grow anymore. I don't replicate. I don't reproduce anymore. My DNA is dysfunctional." As we'll talk about, I suspect it still does things. [chuckles] It still secretes factors that wreak havoc. But is that a fair assessment that I've just made of sort of using an example of a cell with DNA damage has that sort of choice?

    4. NDNed David34:11

       It does, and we don't understand how cells make the choice between the two.

    5. PAPeter Attia34:16

       Yeah, I was gonna ask you that. Do we have any sense of what sways that decision?

    6. NDNed David34:22

       Well, I'll tell you some anecdotes. So what we do is we in the lab will irradiate cells or treat them with a DNA-damaging agent. These are both things that do exactly-

    7. PAPeter Attia34:32

       Yeah, known, known things that destroy DNA.

    8. NDNed David34:34

       Yeah, yeah. So we have a setting on our irradiator which does both. So it both causes cells to die, and then 99% of the cells that remain will enter senescence. So you know that all those cells in the dish got the same radiation, they're all the same clone of the cell, yet some of them chose death and some of them chose senescence. I think it's a really interesting question for us to try to understand about why did some die and why did some live. Presumably, it's driven by some aspect of cell state at the time.

    9. PAPeter Attia35:05

       Is there a way post-hoc to examine the DNA damage of the cells that died and compare it to the DNA damage of the cells that underwent senescence? Because presumably the actual DNA damage is going to be stochastically distributed across those cells, and even though they are the same cells receiving the same radiation, they probably undergo different degrees of DNA damage. And could it be something as simple as if you damage this portion of the DNA, you lose the ability to undergo apoptosis, but you still retain the ability to undergo senescence or vice versa?

    10. NDNed David35:36

        Yeah. I mean, you have to be a little tricky because if you're-- So the challenge with asking cells that died what happened is that it requires a bit of a cellular séance, okay?

    11. PAPeter Attia35:46

        I have a cellular Ouija board. We can-- No, I'm just kidding. Yeah.

    12. NDNed David35:49

        Since we've been talking about this is I've been thinking kind of creatively. There are these, there's moments on the order of minutes to hours after the insult happens in which the cell is kind of going through its sort of pre-death throes. [chuckles]

    13. PAPeter Attia36:02

        And you still don't know which direction it's gonna go?

    14. NDNed David36:04

        This is so not something I've ever seen studied, so this could be something that just outside of my personal experience. But I just think about what we do every day-

    15. PAPeter Attia36:12

        Mm-hmm

    16. NDNed David36:12

        ... in which we insult cells in an effort to make cells become senescent, but a portion of them choose death.

    17. PAPeter Attia36:18

        There's gotta be a dozen postdocs thinking about this problem, right?

    18. NDNed David36:21

        Yeah. You'd have to be in a kind of hardcore apoptosis... The thing is, it's, yeah, you'd want to be in a sort of apoptosis lab.

    19. PAPeter Attia36:27

        Yeah

    20. NDNed David36:28

        I don't know who is actually working on this problem. It's a pretty interesting problem, though. I think the way you'd want to get at it would be you might want to be looking quantitatively. For example, if you had some sort of mark of dye that could tell you how much DNA damage a cell got, you had some sort of high content imaging, and you could look down at a plate and say, "Oh, these guys that accumulated in the, in the minutes of radiation three times more of the ... They incorporated three times more of the dye. These are the guys that chose death." You could do something like that. And so then you don't need a seance, you just need somebody that's kind of a ... I guess it's more of, like, a cellular death watch. There's ways that you could start to get at that. It's kind of cool.

    21. PAPeter Attia37:08

        Sorry to take us off that track, but now let's focus on the guys that didn't undergo apoptosis. So you've got all these cells that have undergone some insult, and they've now committed to sort of a celibate life. They're not going to reproduce anymore. And if they just left it at that, it wouldn't be such a problem. It's this other thing they do that's problematic, which is they sort of poison the well for cells around them that are otherwise not damaged. Is that a fair assessment of senescence?

    22. NDNed David37:36

        That is. So in fact, early on in the history of this field, which we can get into in a little bit, it was a real theoretical problem. How could something that's 1% of your cells damage the function of 99% of your cells? Well, as it turns out, these cells have a very active secretome that my co-founder, Judy Campisi, discovered in 2008, and it's ... This is the means by which these cells exert bad biology. They secrete into the microenvironment around them all this crap that distorts tissue function, and that is how these cells contribute both to features of natural aging as well as very particular diseases of aging, is via this secretome called the SASP, which stands for senescence-associated secretory phenotype. And I know it's a mouthful, but [chuckles]

    23. PAPeter Attia38:28

        Well, SASP is pretty cool.

    24. NDNed David38:30

        Yeah.

    25. PAPeter Attia38:30

        And so it's really a paracrine feature. So in, in medicine, we learn about endocrine versus paracrine versus exocrine features. But paracrine is when a gland can actually secrete its hormone, and it goes directly to the tissue that it's operating on without having to even pass through the circulation and go around, like the way, for example, insulin, when it's secreted by the pancreas, becomes systemic. But this paracrine effect is to secrete it and poison your neighbor right next to you. And I guess your point now explains why if you don't have the ability to undergo senescence, that would be bad because you take all those cells that are damaged that for whatever reason don't choose the apoptotic pathway are now ... They should be celibate, but they're not, and they keep reproducing, and that's why you might be born looking normal, but as you accumulate injury and insult, boom, you're gonna develop into tumors. But that's very different from saying, "We're gonna let you undergo senescence, but we might potentially block your ability to cause toxicity after the fact," or other means of targeting those cells. I mean, there's many ways to do this, but yeah.

    26. NDNed David39:36

        Well, let me just go back to this whole thing, which is the cancer thing. So we know that if you can't make cells become senescent, you dramatically increase tumors in mice, and that's a powerful lesson about what not to do, which is that don't mess with the underlying biology here. Showing up after, however, is a pretty cool idea, and the fact that this paper, and I'll come back to how I got involved in all this, but the fact that eliminating these cells can produce a series of youth effects while not increasing cancer risk was very awesome, and was actually kind of a theoretical validation of the picture in our minds about how this was all working. So it might be useful to actually sort of at this moment sort of talk a little bit about the history of where this actually all came from, and then we'll come back to what we're doing with this now and how we're making medicines based on it. But I think it's always helpful

11. 40:37 – 47:48

    Senescence history: Hayflick’s discovery, biomarkers, and SASP evolution

    1. NDNed David40:37

       to place what you're doing in historical context. So this whole idea of cellular senescence traces itself back to the early 1960s. There was a very, uh, clever guy named Leonard Hayflick, who I've actually had the pleasure of meeting very randomly on an airplane. But at the time, in the early 1960s, it was widely believed that cells from us, from mammals, could have infinite capacity to divide. And this was made famous by Alexis Carrel, who goes back decades before that. The leaders in the field all believed this, and it turns out this was the result of the fact that the food that was being fed to these cells, which was derived from chickens, was contaminated with chicken cells. So every time cells were fed food, they were also fed other cells, and it gave this impression that these cells were dividing forever. And, uh, this Leonard Hayflick showed up and-

    2. PAPeter Attia41:38

       And for someone listening who's listening to this thinking, "How can years, decades of dogma come from such sloppiness?" It is important to understand that they're basically relying on light microscopes. Today, you wouldn't make that mistake because you'd be able to look at the DNA of the different cells and realize that, "Hey, these are chicken cells, those are mouse cells," et cetera. But it's a beautiful example of both how far biology has come, but also how the simplest mistakes can lead to catastrophic misinterpretation. I write about this in my book, this story, and I'm, I remember the first time I came across it, like you, I was sort of like ... My first thought was, "How the hell is that possible?" But then upon further reflection, you're like, you're imposing too much of your current worldview on the problem.

    3. NDNed David42:24

       Yeah, I think it's important to show a little bit of compassion, as you have, by pointing out the limitations of their technology at the time and the context that they were living in. What's funny is I will report an interesting mistake. It turns out we ordered from ATCC What we thought were mouse cells, and they were rat, and as a consequence, they weren't behaving properly. And this is, this was about a year ago, [laughs] okay? So these types of things are still happening.

    4. PAPeter Attia42:49

       So Hayflick turns over-

    5. NDNed David42:50

       Yes

    6. PAPeter Attia42:50

       ... this 60-year belief-

    7. NDNed David42:52

       Yeah

    8. PAPeter Attia42:52

       ... basically.

    9. NDNed David42:53

       And so he published this paper in 1961, and it's pretty heretical. And he coins this term. He said he calls them senescent cells, meaning cells that lose the ability to divide in culture. And he says something very prophetic. He says, "This may contribute to features of aging."

    10. PAPeter Attia43:12

        Isn't that sort of like Watson and Crick's DNA?

    11. NDNed David43:14

        Yeah. The thing about it does suggest a means for replication.

    12. PAPeter Attia43:17

        Yeah, yeah, yeah.

    13. NDNed David43:17

        Yeah, exactly. Yeah.

    14. PAPeter Attia43:18

        Just the most understated-

    15. NDNed David43:19

        Yeah, exactly

    16. PAPeter Attia43:20

        ... uh

    17. NDNed David43:20

        Which I love these things. Here's the great story is that when I ran into Leonard Hayflick at the Portland Airport, having gotten off the plane, I pull out my phone and I show him... And he's very old now. All right? And I show him a picture of the mice with and without senescent cells, the term he functionally coined. And I said, "This is what happened when, when we delete these cells that you said may cause aging." And it was just a mind warp for him. He hadn't heard of the paper. You know, at the time, the paper had been out for six years. You know, he's very old. Then his, his daughter walks up, who lives in Portland, and-

    18. PAPeter Attia43:59

        She thinks you're accosting him or something.

    19. NDNed David44:01

        No, d- it was immediately clear that we were-

    20. PAPeter Attia44:03

        You were fans.

    21. NDNed David44:04

        Yeah, exactly. Yeah, we were fanboys. And I show her the picture, and I said, "This is where your dad's work went." She was like, "Oh, my God." And then she, like turns to her dad and said, "Dad, you realize what this is, right?" And so there was this moment, it was at one of these great moments where you get to see this person who really architected this major insight in biology confronted with the historical [laughs] result right to his face-

    22. PAPeter Attia44:30

        Wow

    23. NDNed David44:30

        ... and watching him trying to process it all. It was pretty neat. Anyway, so that's the kind of backstory of where this all came from. Now, flash forward decades. Now, Judy Campisi was the first individual to find a marker that we could look at in vivo. This is about 1995. So you could actually figure out, 'cause senescence was a, something that you did in plates, [laughs] like in plastic plates out in an incubator. But it was Judy who figured out the first biomarker where you could go into a living creature, into a tissue and say, "Aha, there are senescent cells." It was the first time we got to know how many there are, [laughs] right? It's not a lot. And her work really asked, it raised this larger question, which I mentioned earlier, which is how can so few cells do so much bad for so many cells? [laughs] And it wasn't until 2008 when Judy described for the first time this thing that I mentioned earlier called the SASP, the so-called senescence-associated secretory phenotype, that are how these cells exert bad stuff. And it's over 100 factors that have been characterized that these cells make, now, that drive their negative biology. Now, it turns out that a lot of what we know about the SASP was all figured out in cell culture in plastic. And what we've been working on the last eight years is doing a lot of this more in vivo, and it turns out the SASP is very different in different tissues. It turns out to be very different from different cells within those tissues in different disease states.

    24. PAPeter Attia46:00

        Give folks some of the... I mean, I know there are so many of the SASPs, but what's a handful of things that they have in their playbook? How do they sort of wreak this havoc on their peers?

    25. NDNed David46:11

        So if you look at the, sort of the totality of the SASP, everything that's been labeled a SASP factor, what you will see are kind of usual suspects of badness. [laughs] Okay? So things like TNF alpha, which is the target of the most successful drug in the world today. You know, Humira, it's an anti-TNF drug. You see a factor like VEGF alpha, the target of things like Lucentis and Eylea, multi-multibillion-dollar drugs for the treatment of diseases of the eye, and also used in cancer, but that's a sort of a separate thing. So those are both SASP factors that are the targets of existing massive drugs. There's also some SASP factors that have been clinically validated, so there's one called CTGF, which if you make an antibody against that, you have efficacy in a rare lung disease that's pro-fibrotic, that we now know is driven by senescence. That's not a marketed drug yet, but it makes the same point, which is antibody-

    26. PAPeter Attia47:08

        So taking a step back from this, I mean, let's put some broader strokes on this. Inflammation would result from SASP, right?

    27. NDNed David47:15

        Yeah.

    28. PAPeter Attia47:15

        So there's lots of things that go out there that basically tell immune cells, "Hey, let's recruit you to this area." You mentioned fibrosis. What other types of broad destructive categories of things go on out there? And I'm fascinated by this work because it's, it's just a little counterintuitive. I totally get the... And again, this is just my need to teleologicalize everything, if that's even a word, but it totally makes sense why senescence exists. It's a little harder for me to accept the breadth of its destructive capacity to its peers.

12. 47:48 – 53:48

    Why SASP exists at all: tradeoffs, wound healing, and aging as a side effect

    1. NDNed David47:48

       My general thinking about teleological discussions-

    2. PAPeter Attia47:51

       I know. You and I could debate this all night long-

    3. NDNed David47:53

       Well-

    4. PAPeter Attia47:53

       ... which is, get over it.

    5. NDNed David47:54

       Yeah. Because these things are not testable, any teleological explanation should be evaluated solely on its entertainment value.

    6. PAPeter Attia48:01

       [laughs]

    7. NDNed David48:02

       Okay? Right? But that's not why we're here. I will say that there's an idea that is also teleological, but which I use and is a framework that I think's helpful. So many things that we see in aging biology in particular, they're kind of head scratchers. Like, why is the system doing this? This seems bad for the individual. Didn't evolution get a vote? [laughs]

    8. PAPeter Attia48:25

       Yeah.

    9. NDNed David48:25

       Isn't that the whole point of evolution? Well, it turns out that features of aging are manifest post-reproductively.

    10. PAPeter Attia48:33

        Oh, yeah. No, no, I don't think there's gonna be an evolutionary explanation for this for exactly that reason.

    11. NDNed David48:38

        Right.

    12. PAPeter Attia48:38

        So is your argument that this occurred call it stochastically, and evolution was never there to fix it or catch it, so it just ran amok?

    13. NDNed David48:47

        No, it's actually something-- It's a cooler idea. So it turns out these decisions, if you want to call them that, these seemingly irrational decisions made by evolution. Of course, evolution doesn't make decisions. It's, it votes with the survival of a species to reproduce or an organism to reproduce. Many of these so-called decisions are things which benefit the young.

    14. PAPeter Attia49:13

        Yeah. So it's basically let's get the post-reproductive folks out of the way to conserve resources for the young?

    15. NDNed David49:17

        No, I don't think anything so active or sort of sinister. I think mostly it's... Let's take cellular senescence, for example. It's a awesome mechanism to block tumor formation in young reproductively competent organisms. So if you can make more of those organisms to make more babies-

    16. PAPeter Attia49:36

        Yeah, I guess I'm not arguing the senescence. It's the SASP that I'm struggling with.

    17. NDNed David49:40

        Right. Well, so it turns out this is interesting. So turns out the SASP does some other things that are useful. So a paper published by Judy Campisi again, and Marco de Maria, who is a professor in the Netherlands now, they got interested in wound healing, and what they demonstrated was that if you make a wound in an animal, a week or two after you make a laceration wound, at the wound site, you will see an accumulation of senescent cells, and they're dumping SASP factors into the wound. And the question that Judy and Marco asked was, "Is this important?"

    18. PAPeter Attia50:17

        Mm-hmm.

    19. NDNed David50:17

        And so in this experiment, they went in, and they eliminated senescent cells in the course of wound healing, and what they saw was that the wound closed less well and more slowly. And it suggested that the SASP had another role. It wasn't just-- Well, the SASP, this is a role for the SASP here. Its role was to facilitate wound closure, which if you think about it, for most organisms in a naturally evolving ecosystem, is super freaking important. And so essentially, senescence got co-opted into suppressing tumors in one case, and in a very different case, was co-opted into helping heal wound. And so I think that what you see in these diseases of aging is often the sort of unintended consequences of a system that was absolutely awesome for the young at the expense of the old. One metaphor for this that I sort of like is that, let's say you innocently write a computer program to fill your bathtub. It also unintentionally becomes a computer program designed to overflow your apartment. It wasn't why you wrote it, but it is the net effect.

    20. PAPeter Attia51:23

        Yeah. No, that's an interesting point. Certainly, things that favor wound healing could be quite beneficial. Uh, some have even argued that Lp (a) , lipoprotein, apolipoprotein little a, which is attached to an LDL, so it makes this thing called Lp (a) , has very potent prothrombotic properties. And even though it's wildly atherosclerotic, you could argue, well, frankly, that's a very favorable phenotype to carry for most of our evolution. It's only recently that we need to concern ourselves with atherosclerosis, but there was certainly an era where having a prothrombotic factor to help you in periods of trauma would far outweigh the tail effect of knocking off a few elders who managed to survive and die of aortic stenosis or atherosclerosis. So that's an interesting tidbit with respect to the wound stuff. I wasn't aware of that.

    21. NDNed David52:11

        By the way, the other example, this Lp (a) , is a perfect comparator to the-- Whether or not either of these teleological [chuckles] explanations matters not. The point is, is that those are the same logic.

    22. PAPeter Attia52:23

        So let's go back to something you said at the outset, which you've now given us enough to put in context. You said, look, you, you sort of... You went on this journey of thinking through final common pathways of aging. You sort of arrived at this mTOR CR thing probably matters a whole heck of a lot. In fact, it seems to be the only one that works across organisms, across labs, no ifs, ands, or buts. You've got this loss of circulating youth factors. Clearly, something is happening to mitochondria as we age that is very problematic. We clearly see this observation of methylation, whether it's causal or not is, is unclear. We get a sense of what's happening to stem cells exhausting and senescent cells. Your view, which you very briefly touched on, is the first four things I mentioned are probably harder to drug than the last one. Is that a fair summation of how you kind of arrived at this?

    23. NDNed David53:18

        Yeah. That's how I wound up focusing the last eight years of what myself and my colleagues have been working on was that. It was, how do we make medicines that target a fundamental mechanism of aging? I was not clever enough or knowledgeable enough, or both, [chuckles] to figure out how to do mTOR and CR. I mean, there are a lot of people who are trying that by trying to get more and more selective molecules. But it was not an area where I had anything creative to add. But the backstory

13. 53:48 – 59:07

    The 2011 breakthrough and Unity’s founding: BubR1 mice and a drug-like idea

    1. NDNed David53:48

       of how I kind of got involved in this was I was sitting around actually in the Calgary Airport. A lot of these, these important things are happening in airports, okay, uh, for some reason. And I was eating french fries, and in this twenty-minute interval of french fry consumption, five different people sent me the same PDF, and they were subject lines like, "Holy shit, you have to read this. This has to be your next company." [chuckles] And I opened up the paper, and right on the front page was a figure showing these two animals, siblings, one of which had senescent cells, the other one-

    2. PAPeter Attia54:23

       These are the mice you talked about earlier.

    3. NDNed David54:25

       Yes.

    4. PAPeter Attia54:25

       Now, this was Jan, or this was Judy? Were they collaborating at the time?

    5. NDNed David54:29

       They were collaborating, though Judy was not on this particular paper, and this paper was not exactly those same mice I described. So it had a very similar or had the same means of senescent cell elimination, but there was a difference. This is 2011. These animals also contained a mutation where they made less, far less of a protein called BubR1, which is an anaphase checkpoint protein. So this is a protein that makes sure that your chromosomes line up on the spindle, and it sort of is like a bit of a school master, and it sort of says, "You're not dividing until everything's lined up." And so if you don't have BubR1, you just blow right through the checkpoint, and you become polyploid. And Jan van Deursen, my other co-founder and long-term collaborator, he created this animal thinking this animal was going to get tons of cancer, because he was a cancer researcher.

    6. PAPeter Attia55:19

       So let's just make sure we understand why that's the case. If BubR1 is there to make sure your spindles line up, it means that you should not be able to divide until all your chromatin is perfectly aligned, everything is in perfect tip-top order, and you're ready to undergo mitosis.

    7. NDNed David55:34

       That's right.

    8. PAPeter Attia55:34

       So if you take away your master, a lot of faulty division should follow.

    9. NDNed David55:40

       That's correct.

    10. PAPeter Attia55:41

        So Jan's hypothesis is we either attenuate or knock out BubR1, we should get a lot of cancer.

    11. NDNed David55:47

        That's right.

    12. PAPeter Attia55:48

        Okay. What happened?

    13. NDNed David55:49

        That wasn't what happened. The animals were super polyploid, meaning that they wound up with super weird numbers of chromosomes, too many, too few, all that good stuff. The animals aged quickly. So the animals wound up full of senescent cells. Okay? So there was something about become-- having very wrong numbers of chromosomes and all of the effects of that that caused the animals to be full of senescent cells and to age very rapidly, have features of aging that were onset very rapidly, and die.

    14. PAPeter Attia56:23

        So it accelerated the speed with which the record played, but it didn't change the music. In other words, they didn't die sooner because they got cancer. They just died sooner because they sped up their aging.

    15. NDNed David56:34

        We don't know the answer to that. So these animals are extremely sick animals, so trying to make a larger statement, I think it's too much to say with an animal like that of the whole record metaphor. What I can say with, I think, conviction is that clearly a whole bunch of things that go along with being old happen very quickly in these animals, and these animals die very quickly. They look visibly old. For me, it was an experiment that suggested that it was consistent with the notion that the senescent cells were actually driving these features of aging. And what's so cool about this paper and why it caught so many people's attention, even though there was a somewhat earlier paper that Jan also did, that for many allowed one to draw the same inference, but it just didn't smell like a drug. I won't get into that paper today. But what was so compelling was that you added senescent cells through this mutation that gave rise to the production of less BubR1 protein, and then you eliminated those cells or a subset of those cells with this insert into the DNA of every cell of that animal. And you could ameliorate a subset of the effects of senescent cells. Now, you didn't get rid of all the senescent cells. For-- By the way, interestingly, the animals don't live longer in that particular mutant because it's so sick when you eliminate the cells. But whole bunch of the features of aging, for example, their bent spines, their organ atrophy, their cataracts in their eyes, these were all severely blunted when the senescent cells were eliminated. And when I saw this paper, I thought, "This feels like a drug." You just eliminate cells that are driving bad things. And so I contacted Jan and Mayo Clinic, and 72 hours later, we had agreed to meet, and a little time after that, I set up the company. But this was a observation in a mutant animal, and I remember the sort of early blogosphere talking about how this paper didn't mean anything, and this was exaggerating the role of senescence in humans, and it's a mouse, and all this stuff. And-- But to me, it, it really felt important. Now, there was a long way between that paper and when you could ever credibly claim there could be a drug discovery program based

14. 59:07 – 1:16:11

    Stealth-mode de-risking: the four questions that determined whether Unity could exist

    1. NDNed David59:07

       on it. And we spent the next four years in stealth mode asking four biological questions. And I had some very patient investors who gave us... Sort of they spoon fed or dropper fed money into the company.

    2. PAPeter Attia59:23

       Mm-hmm.

    3. NDNed David59:24

       We did not have lots of excess resources. But I will confess that some of the best times in my life have been under resource constraint, 'cause your decision-making is very high quality 'cause every single resource decision matters. So we had four questions we were trying to ask and answer. And the first question, and none of this stuff got answered in the first 2011 paper, was: Do senescent cells contribute to natural aging as opposed to some genetically contrived mouse? Second question: Could we find a disease, any human disease, that we could model in an animal where we could eliminate senescent cells and take that disease and either stop it or even better send it backwards? Third question: Could we find a molecule that could trigger the elimination of senescent cells from a living creature safely? And last question, which is: Was getting rid of these cells safe? We know that kids don't have them, but that doesn't mean that getting rid of them from an adult... Like, what if adults need them for some reason and kids don't? So that was a formal question that really was on our minds.

    4. PAPeter Attia1:00:35

       Now, today, I look at question four and realize that it's not an equivalence between children and adults because of the following reason We know that if you prevent kids from being able to make them, horrible things happen. We don't know that if kids make them and you nuke them, horrible things happen, which is what you're trying to do with adults, correct?

    5. NDNed David1:00:57

       We don't know that-

    6. PAPeter Attia1:00:58

       Those could be two different things.

    7. NDNed David1:00:59

       Yeah. So kids naturally nuke them. So we know kids can make them, 'cause you can do experiments in young animals, and, uh, they make senescent cells, and then the senescent cells are gone. So in effect, that is your living, breathing experiment right there.

    8. PAPeter Attia1:01:12

       That's right. The superpower of kids is the ability to make them, which prevents the replication of a cell that shouldn't replicate, and then it has the good sense to get rid of it before it harms anyone. The adult retains the ability to make it, but keeps it around. I wanna go back to your second question. It seems obvious now... Your second question, just for the listener, if I recall, was could we find the right disease in which to study this?

    9. NDNed David1:01:35

       Could we find any disease? Because if you think about it, that first mouse, or the first and second mouse experiments that Jan did, both 2008 and then 2011 publications in Nature, those weren't diseases the way-

    10. PAPeter Attia1:01:50

        Right. They were sort of polydeath conditions.

    11. NDNed David1:01:52

        Well, they were sort of like, this animal has these features of being old. They weren't things that the FDA would label a disease. Like a bent spine. Like, who's gonna develop a drug for that?

    12. PAPeter Attia1:02:02

        But your intuition was, of course, you can't study lifespan here. It has to be healthspan related, because if you have an interest in taking this to humans, mortality is a very difficult endpoint.

    13. NDNed David1:02:16

        Yeah. It's not the way we develop drugs.

    14. PAPeter Attia1:02:17

        I mean, unless you're tackling conditions that kill people quickly, mortality's a reasonable endpoint for cancer and heart disease drugs, but-

    15. NDNed David1:02:23

        Sure. So in fact, I would even make us even ruthlessly more practical. We wanted to find very diseases of being old. Diseases, things that the FDA has regulatory paths for, and endpoints that you can get drugs approved on. And so we wanted to do that, and that's what we did.

    16. PAPeter Attia1:02:41

        So tell me about number one. Number one, again, we take that for granted today, but it was a very reasonable question eight years ago, right?

    17. NDNed David1:02:48

        Yeah. So again, Jan van Deursen to the rescue here.

    18. PAPeter Attia1:02:52

        So Ned, at this point it's just you and Jan and Judy?

    19. NDNed David1:02:58

        So it was myself, Jan van Deursen, Judy Campisi, and a guy named Dahong Zhou, who helped us discover one of the early senolytic molecules. Also, Darren Baker, who's a professor at Mayo Clinic, was also instrumental. He was first author on the 2011 paper, and he also was the, um, first author on the paper I'm about to describe as it relates to question one, which is how did we figure out that senescence was driving features of natural aging.

    20. PAPeter Attia1:03:29

        Right.

    21. NDNed David1:03:29

        And so that was what Darren Baker and Jan van Deursen spent the next few years after 2011 doing, and that paper took five years before it published in 2016. And what they did in this paper was they took natural mice. Mostly natural [chuckles] okay? They contained one difference, was we mated into natural mice that same construct, that piece of DNA that was wound up in every cell of their body, so we could eliminate senescent cells whenever we wanted. And so now we got to do that in a very slow, multi-year experiment. But these were naturally aging creatures. And that paper took as a, you know, half decade to happen. And when we got that result, which was in 2016, we'd managed to also ask the other three questions by then. But that was really the trigger for us de-stealthing the effort and speaking openly about what we were doing. 'Cause if it didn't contribute to natural aging, and it didn't cause a particular disease of aging, and we couldn't find molecules, there was no company.

    22. PAPeter Attia1:04:32

        So you basically were processing question one, and two, three, four in parallel.

    23. NDNed David1:04:37

        That's correct. We had a small team. It was relatively virtual. For a few years we were just living at Arch, the venture fund [chuckles] . And then we moved, when we got too big, we moved up to the Buck Institute. So we were camped out right over Judy's lab, or a floor up and a few doors over.

    24. PAPeter Attia1:04:54

        No pun intended.

    25. NDNed David1:04:55

        Yeah [chuckles] . And we w- essentially went to town with a, a small group. It was just a few people, supported very intimately by Jan's group, with Darren's support, and with Judy's group. And so we had this sort of virtual research group, where every week we'd get together and review all the data for each of the four questions. And we had work streams for each of questions one through four. And it was a great time.

    26. PAPeter Attia1:05:17

        So I wanna kind of pause on this journey and take a parallel or orthogonal journey for a moment, because I suspect that at least one person listening, and, and likely more, also have some sort of entrepreneurial bent in them. And as it pertains to biology or biotechnology, I think I'd love to figure out a way to extract from you some of the lessons that you've learned along the way. You've done this over and over and over again in many companies, and I'm just sort of wondering what... Well, let's start with a broad question. You already alluded to the fact that you enjoyed that period of time, right? It was a, it was really less of a company and more of a lab at that point. It was sort of a virtual postdoc that you guys were doing.

    27. NDNed David1:05:57

        Yeah. It was a coalition of the willing doing an incredibly hard project, and it was far more likely that we were gonna fail than succeed.

    28. PAPeter Attia1:06:05

        Well, that's actually the question I wanted to pose to you. So we don't talk enough about sort of what the graveyard looks like of these ideas gone wrong. It's quite possible that 2011 to 2016, you spent all of that time working on something, and it didn't work. In fact, that would be the expected outcome of this type of endeavor. But that said, no one goes into something with a belief that it's going to fail. Without getting too much into the rose-colored glasses that inevitably bias our ability to look back, what proof points did you look to to say there's a biological plausibility here, that if it wasn't there, would've had you less likely to consider it? And, and if you can, Ned, try to answer it in a broad enough way that it would be applicable to other endeavors that maybe don't deal with senescent cells. In other words, I'm asking this through the lens of Somebody who's considering finishing their lab or finishing their time in their lab, or even graduating from undergrad and wanting to join a company, how can they think through handicapping the odds of success, which you've done a number of times?

    29. NDNed David1:07:08

        So the approach I take to a bold idea like this idea of making drugs that eliminate senescent cells is I try to picture... It's a simple, beautiful idea, and I try to picture the end state, like what does this look like at the end? And then I say, "Okay, I can see this in my mind." And then I say, "Well, what are the existential risks to that beautiful, simple dream?" And I try to write them down in the most primitive way I can. And so those four questions, they were the four risks, which is that senescent cells don't contribute to natural aging. I'll use this particular example-

    30. PAPeter Attia1:07:49

        Yeah, sure
15. 1:16:11 – 1:19:27

    Choosing senolytics over SASP suppression: why killing cells could be safer long-term

    1. NDNed David1:16:11

       Early on, we honored the possibility that we could either eliminate the cells, because that's what was achieved genetically and was our proof of concept, but we could also come up with ways to reduce the pathological SASP that these cells were creating. It wasn't so much as a pivot, but a decision to go one way rather than the other, 'cause in the beginning, we thought you could do either. And the decision was driven by a simple idea, which is that were you to make molecules that would simply suppress the secretions of the cells but not remove the source of all of these factors, you'd have a drug you had to take all the time. And the cool thing about eliminating senescent cells-

    2. PAPeter Attia1:16:54

       And it also assumes you know all the factors. Your approach strikes me as the more logical approach, but there are companies doing the other approach, correct?

    3. NDNed David1:17:01

       Yeah. Well, you could take the position that any antibody therapeutic against one of these pro-inflammatories that's in the SASP is just such an approach. But actually, I was saying something a little bit more, um-

    4. PAPeter Attia1:17:11

       I understand your point, though

    5. NDNed David1:17:12

       ... primordial. I was suggesting if you understood, for example, the regulatory mechanism that makes the cell decide to secrete all of these factors and you targeted that, then hey, what you've done is you've shut down the secretion. The cells sitting there not dividing, how bad can it be? But what motivated us was this would be a drug you would have to take all the time. And what we thought was so neat about the idea of making a molecule that could eliminate senescent cells, which we then named, [chuckles] we called them senolytic molecules. If you could make a senolytic molecule, you could dose it once, and once you eliminate senescent cells, the cells are not there anymore. So these are not drugs you take every day, every week, or every month. These might be dosed once a year until your body makes more senescent cells. And in fact, which maybe we can talk about later, in our human clinical data, what we show is that when we eliminate senescent cells from the painful knee joint of a human being with osteoarthritis, a single administration of a senolytic medicine eliminates pain dramatically in these humans for as long as we've looked. And so the cells, we don't know if the cells have come back, but we don't think they've come back by that time. This sort of validates the notion that you can now have a drug that's far safer because what kills most drugs actually is the fact that they're unsafe. That generally is a result of treatment again and again and again. If you don't have to do that, if you can go in once, surgically eliminate the cells, I mean surgically metaphorically here. It's not surgical. You can make a safer drug, at least theoretically, and that's why we went that direction.

    6. PAPeter Attia1:18:55

       So there's another big challenge here, which is how do you identify which cells are the senescent cells in vivo when you don't have the luxury you've had in the animal lab, which is you get to label those cells, you get to put big targets on them. What was the proof of concept that you could go into an organism, and without the luxury of having the senescent cells raise their hand and say, "Here we are," metaphorically, actually send out snipers to get them.

16. 1:19:27 – 1:45:10

    Osteoarthritis: from animal models to human trials, pain reduction, and what’s next

    1. NDNed David1:19:27

       Deep profiling of human tissues for senescence exists, but it's few and far between. And so we undertook a study, and this is after we demonstrated in animals that osteoarthritis, which is the second most prevalent disease of aging and the primary reason it hurts to be old-

    2. PAPeter Attia1:19:47

       What's the first, by the way?

    3. NDNed David1:19:48

       Type 2 diabetes.

    4. PAPeter Attia1:19:49

       Interesting.

    5. NDNed David1:19:50

       So what we did is we knew from animals that if we could induce surgical trauma to an animal's knee, a mouse, and we eliminated senescent cells, that we could eliminate pain and actually repair cartilage in a mouse.

    6. PAPeter Attia1:20:03

       Wait a second. That's counterintuitive. [laughs]

    7. NDNed David1:20:05

       I know. That's what's so cool.

    8. PAPeter Attia1:20:07

       Well, it's counterintuitive because of the experiment you shared with me earlier that Judith's group did, I think it was Judith's group, that did this looking at wound healing. You would think if senescent cells were necessary for wound healing, they would be necessary for the non-pathologic healing of cartilage following surgical trauma.

    9. NDNed David1:20:25

       And they may be. So our theory about what's going on in osteoarthritis, and this is just one of the ideas we entertain here, and I can explain what data we have that supports this notion, is that senescent cells accumulate at sites of osteoarthritis. In fact, they may be trying to heal.

    10. PAPeter Attia1:20:43

        Got it.

    11. NDNed David1:20:43

        But unlike in the skin, they literally fall off in the context of healing, the cells remain and essentially continue to sound the alarm over and over and over again. And we think it could be giving a sort of flawed attempt at wound healing that could be driving the pathophysiology of disease.

    12. PAPeter Attia1:21:02

        And the margin for error, sorry to interrupt, is much smaller in a joint. In other words, you don't have to heal a wound perfectly to achieve a functional outcome that is perfect. You might not have a cosmetically perfect outcome, but functionally you could have a hypertrophic scar, you could have a keloid, you could have this, you could have that, but you've closed the barrier to the outside world. But inside of a joint, it's a very delicate balance of one cell layer too many, and all of a sudden you have a different outcome than you had prior to the insult.

    13. NDNed David1:21:33

        Yeah.

    14. PAPeter Attia1:21:33

        Coupled with everything you said, I mean, that's-- All of these things factor together, I suppose.

    15. NDNed David1:21:37

        So what we were able to show in animals was that when we induced trauma by cutting the ACL, which is known to be risk factor for human osteoarthritis of the knee, we got something that looked like osteoarthritis, and we eliminated senescent cells either genetically or with our drug, which we've now taken into human beings. We could, in this trauma-induced setting-

    16. PAPeter Attia1:22:01

        And sorry, that genetic mouse, just to be sure, that's a mouse that has a genetic tag for senescent cells that's easy to turn off.

    17. NDNed David1:22:07

        That's correct.

    18. PAPeter Attia1:22:08

        Okay. One aside question: Is there a mouse model of osteoarthritis that comes from overweight or obesity?

    19. NDNed David1:22:14

        No.

    20. PAPeter Attia1:22:15

        Is that the most common cause of osteoarthritis in humans?

    21. NDNed David1:22:18

        It's a comorbidity. I'm not aware that anyone's established causality, but it would make some sense that it could be causal because of weight-bearingness.

    22. PAPeter Attia1:22:27

        Interesting. So the animal model for osteoarthritis is an ACL injury, which is still true in humans, but it's-

    23. NDNed David1:22:32

        Well, there are a few different models for osteoarthritis. And so really one of the things we've learned is that when you attempt to model disease, there are lots of off-the-shelf models that people have built for things like osteoarthritis because they're making a painkiller, so they do things like hurt the animal's knee and then give it a painkiller. How relevant is that to osteoarthritis in a human? It's not. You inject iodoacetate into the joint. It hurts like hell, and then you give them painkillers. So we had to search around for models that happen fast, 'cause that's the way we do experiments, in which senescence played a role. And, and the ACLT model... So this was work we did collaboratively with Jennifer Elisseeff, who's a professor at Johns Hopkins of bioengineering, and she was someone, an old friend, and she'd been thinking about osteoarthritis and had the model in her lab. And I called her up one day and I said, "We have this crazy idea. We think that senescent cells could be driving this disease. Do you want to try to figure this out with us?" And she was an awesome collaborator. Some of the first senolytic molecules we found, we shared with her, and she had her model in operation. And very quickly in her laboratory, we were able to demonstrate the senolytic molecules that we'd identified at the Buck Institute in Judy's group. One of them was active in Jennifer's model of osteoarthritis. And so for the first time, we actually had a disease, a human disease, the second most prevalent disease of aging, the primary reason it hurts to be old. I can't overstate that enough. It's like being in pain sucks, and this is the reason old people are in pain mostly. And we could drive that disease backwards in a mouse. So we were just overjoyed by this 'cause we could achieve it genetically, which says it's really senescent cells, and the second thing is we could also achieve the same result with a drug-like molecule. It was the confluence of those two results that convinced us this is really cool. It seems that we got the idea right.

    24. PAPeter Attia1:24:32

        How does the drug actually target the senescent cell when you don't have the luxury of a genetic tag?

    25. NDNed David1:24:38

        We spent the first-- Remember that was question three of the big four questions. We spent the first two and a half years of this whole effort searching fruitlessly and not finding a senolytic molecule. And the first molecule we identified followed swiftly by the second, and then a series of others that were very related to the second one. The first molecule identified was a MDM2-p53 interaction inhibitor. And so normally MDM2 is this ubiquitin ligase. So it walks around and it's like a, a meter maid who goes around marking cars with chalk for getting a parking ticket. But what MDM2 does is it walks around and it marks proteins with a little molecule called ubiquitin, and it marks them for destruction. And P53 is one of its client proteins. And so if you break up the interaction between Mdm2 and P53, P53 doesn't get marked for destruction, so its concentration in the cell goes up. And discovered in Judy's lab by a few people, including Remy Martin-Laberge, who was a post-doc in Judy's lab at the time, he discovered that when you did this to senescent cells, senescent cells died preferentially.

    26. PAPeter Attia1:25:49

        By the way, is there anything on the outside of a senescent cell that identifies it?

    27. NDNed David1:25:52

        There are some things on the inside, and we've been searching-

    28. PAPeter Attia1:25:55

        But it's not like you have an antibody or anything that would render it externally identified.

    29. NDNed David1:26:03

        We are searching now, and we don't have s- any universal external marker of senescent cells. We do have some that we just haven't talked about openly yet, uh, in various disease states where the senescent cells in a disease state have a marker that's on the outside. We've not found ... And people like Ned Sharpless have been searching for over a decade for such a marker.

    30. PAPeter Attia1:26:24

        Wow. So just to add to the complexity of the biology, if you were on a little mini nano spaceship and you were inside the joint of a person with osteoarthritis, you wouldn't be able to look out and see which of the cells are actually senescent and which ones are normal, which ones are simply injured. You wouldn't be able to make that distinction. So even if you had a special gun to shoot senescent cells, you wouldn't know which cells to shoot based on just the observation of the cell.
17. 1:45:10 – 2:15:04

    Beyond joints: atherosclerosis, oncology hypotheses, eye disease programs, and brain aging

    1. PAPeter Attia1:45:10

       piece of healthspan than the structural integrity of your body as you age. Have you, in your leisure time, had the ability to think about how this might impact lifespan vis-a-vis atherosclerosis, cancer, or other diseases that actually shorten life?

    2. NDNed David1:45:26

       Well, we know that atherosclerosis is another disease in which senescence plays a role. Now, we're not currently working on that. One of the things you may have noticed is that osteoarthritis, the way we approach the disease, even though it affects many of the three hundred and sixty joints in your body, we treat the local version of the disease with local therapy. Atherosclerosis is about as systemic as it gets. And Jan Vanderssen at Mayo Clinic published a paper. Actually, it was Jan Vanderssen and a guy named, uh, very excellent young scientist named, uh, Bennett Childs. And this is a paper in science in which he showed in rodents that senescent cells accumulate in the atherosclerotic plaques that form in a high-fat diet mouse, which is a model that can predict, say, statin efficacy to some extent, although it exaggerates it somewhat compared to the human case. And what Bennett showed, these plaques are full of senescent cells, and if you eliminate those cells-

    3. PAPeter Attia1:46:26

       What are the cells that have become senescent? What's their origin?

    4. NDNed David1:46:30

       So they appear to be macrophage in origin.

    5. PAPeter Attia1:46:33

       I see. So it's not the endothelial cell.

    6. NDNed David1:46:35

       Well, no, there's three cell types. It's basically there's a senescent endothelium. There is a myofibroblastic type of cell that's in there, and then there are macrophages.

    7. PAPeter Attia1:46:45

       So it's all three. It's basically the barrier, the immune cell that came to the rescue, and the fibroblast that attempted to repair the damage.

    8. NDNed David1:46:53

       Yeah, all of them. And when you eliminate these senescent cells, either genetically or with a drug, first of all, you can reduce plaque volume, which is cool. But what might even be cooler is that, and again, it's in a mouse, and so you just gotta wonder what is that really saying about the pathophysiology of the human disease. But there is this fibrotic cap that forms on the surface of an atherosclerotic plaque. And one of the ideas in the literature is that the thinning of that plaque gives rise to a unstable plaque that is clinically dangerous, and that interventions that can thicken that plaque might be a therapy because you could take a plaque that you have and now convert it into something clinically more innocuous. And what Jan showed was that genetically and with drug, that he can thicken the plaques of atherosclerotic plaques in a mouse.

    9. PAPeter Attia1:47:50

       That would seem to counter the idea that you could lessen plaque volume. Do you have to pick between one of those two strategies? 'Cause typically if you thicken the plaque, wouldn't you likely increase the volume?

    10. NDNed David1:47:59

        No. So the, if you look at the sort of relative partitioning of how much of the plaque volume is kind of the cap and then how much is this sort of bulk sort of lipid deposit with macrophages in it, eyeballing it, it's, you know, ninety percent is this kind of lipidy sort of macrophage blob, and then there's this thin little kind of veneer on top that is the cap. And so the thickening of that cap doesn't dramatically contribute to the overall volume of the atherosclerotic plaque, at least in a mouse model.

    11. PAPeter Attia1:48:32

        But both are happening. You're thickening the cap and reducing-

    12. NDNed David1:48:35

        Yeah

    13. PAPeter Attia1:48:36

        ... the subendothelial portion of the-

    14. NDNed David1:48:39

        Mm-hmm

    15. PAPeter Attia1:48:39

        ... reducing the foam cell also.

    16. NDNed David1:48:40

        Yeah. So athero is-- it's a very tough place to do drug development. I mean, we've seen the PCSK9 story has been a multi-billion dollar battle that has given rise to relatively moderate uptake of those drugs.

    17. PAPeter Attia1:48:56

        Could argue that's just due to the cost of the drug.

    18. NDNed David1:48:58

        It's also the fact of... Yeah, it's a relative cost issue going up against statins. So switching people and all this sort of thing, but it's not been-- It's caused a sort of downward pressure on people's enthusiasm for doing cardiovascular drug discovery, just the... Because now we have to-- You're not using surrogate markers anymore. You're using outcome studies. You're actually following people until they die or have a serious cardiac event.

    19. PAPeter Attia1:49:24

        Do you see an application here in oncology? I mean, it seems like there should be.

    20. NDNed David1:49:28

        Well, it's an area of interest of ours. So one of the things we saw in Jan van Deursen's 2016 paper was that these mice from whom we eliminated senescent cells from midlife until death, they had the same cancer prevalence. So 85% of them die of lymphoma with and without senescent cells. The difference is that when you eliminate the cells, the animals from whom these cells were eliminated get cancer 30% later in their lives. So you have to kind of s- head scratch for a moment, like what does that mean?

    21. PAPeter Attia1:50:01

        And if I recall, you said they got a 30% lifespan extension.

    22. NDNed David1:50:05

        Yeah.

    23. PAPeter Attia1:50:06

        So you basically created centenarians. You just phase shifted chronic disease by a third.

    24. NDNed David1:50:11

        And some of the diseases were just dramatically reduced, so the effects on kidney function, uh, the age effects of kidney function were reduced dramatically. Cataracts were reduced dramatically. So there, there was a whole bunch of behavior stuff that we don't know what that means, but these animals seem to preserve features of youthful behavior. Their spinal lor- lordosis looks youthful. So there's a whole set of things, but one of the things that people often ask about the experiment is, do they die of different things when you live 30% longer? And the answer is no, they die of the same thing mostly. Now, that could have to do with the fact that it's mice and these lab strains of mice.

    25. PAPeter Attia1:50:49

        Yeah, they just get cancer like crazy. And it's less interesting to me that it's how much lymphoma they get. It's more interesting to me that you could phase shift it.

    26. NDNed David1:50:56

        So we don't know why that is, but an explanation that makes some sense to me is that there is something perverse that senescent cells do to the tissue microenvironment. So this system, which is an anti-cancer system in the young, could become a pro-cancer system in the old by doing something to the tumor microenvironment that makes it more amenable to tumor genesis. And that would be consistent with what you see where the rate of tumor formation across the animal's life is unchanged, but its ability to take root is delayed. So you could imagine applications in oncology, but you would require something in which you had some sort of highly sort of tumor-prone situation where you could intervene in it. There's also an idea where if you could make cells senescent, which is what chemotherapy does in many cases, and then do a sort of a two-hit strategy where you drive the cells into senescence, and then you exploit a senescence-associated, you know, Achilles' heel. So it could be a strategy in which you deliberately are trying to drive tumor cells into senescence and then killing them. And then there are a series of cancers that we think that are age-associated that may be essentially the product of a highly senescent environment. So cancers of the skin, what if you could-- or cancers of, say, the bladder or something like this, these things that older people get. Could you go in and eliminate senescent cells and change trajectory of disease? That's an idea that's very cool that you could think about. But I would say that the most powerful read-through from our results so far in humans are these other diseases of aging for which we have no treatments. So let us take something like the dry version of macular degeneration. This is a disease for which there is no treatment, and it's eightfold more prevalent than the wet disease that you can treat with anti-VEGFs. This is a disease that appears to have senescence associated with it.

    27. PAPeter Attia1:53:03

        What's the distribution of those two?

    28. NDNed David1:53:05

        So people that have age-associated macular degeneration, one in eight has the wet disease, and only that one out of eight people is treatable with the anti-VEGF antibodies. Seven out of eight of those people are untreatable. Now, that disease, the dry disease, moves more slowly, but it makes you just as blind. And so that is an area in which senescence and senolytic medicines may play a role, but we'll have to find out in the clinic. And next year, we are going with our first molecules into the eye.

    29. PAPeter Attia1:53:36

        Do you have an animal model for that?

    30. NDNed David1:53:38

        No. So you have animal models of the wet disease, and our molecules work in that model. And so you could say that that's pretty neat. This is a giant opportunity. But I'm personally attracted-- First of all, I just want to say that when we talked about the four risks-

Episode duration: 2:15:33