The Peter Attia Drive - #112 - Ned David, Ph.D.: How cellular senescence influences aging, and what we can do about it

Episode Date: June 1, 2020

Ned David is the co-founder of Unity Biotechnology, a company developing senolytic medicines—molecules that target and destroy senescent cells in the human body. In this episode, Ned explains the science of cellular senescence and how it impacts the aging process. Ned discusses how senolytics may delay, prevent, treat, or even reverse age-related diseases, including cancer, cardiovascular disease, and neurodegenerative disease. As a serial entrepreneur, Ned also provides advice on how to transform a simple idea into the creation of a company.   We discuss: Defining longevity and the principles of aging [2:50]; The control knobs of aging and how we can turn them [15:10]; Role of cellular senescence in aging and cancer [27:00]; History of senescence in scientific study [40:30]; The cellular senescence paradox [46:00]; Developing medicines that target cellular senescence [52:15]; Ned’s lessons on risk analysis in business [1:05:15]; The search for a molecule that could eliminate senescent cells [1:15:15]; Senescent cell elimination example in osteoarthritic knees [1:30:30]; Extending lifespan by removing senescent cells [1:45:00]; Senolytic molecule example in macular degeneration reversal [1:52:30]; The future of senescent cell targeting [1:58:30]; The role of cellular senescence and metabolic syndrome [2:01:30]; The role of cellular senescence and brain health [2:03:30] What prepared Ned to start Unity Biotechnology [2:05:45]; Advice for someone deciding between business and academics [2:08:50]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode:  https://peterattiamd.com/neddavid Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll 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 peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. My guess this week is Ned David. Ned is the president of Unity Biotechnology, a company that he co-founded in 2011. In this episode, we're going to 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 found that part of the discussion was interesting, and I think you'll know what I'm talking about when we get to that part of the episode, because I found that exercise that he and his co-founders went through between about 2011, 2015, to be some of the most interesting thinking around this idea of company creation.

Ned is a prolific innovator. I think when he was about 30, he was named to the top 100 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.

Ned David David. Ned, awesome to see you today. Thank you for coming by. Oh, thank you for having me. I feel like I haven't seen you in person in way too long. This is true. We tried to get you to come to dinner. Oh god, I feel horrible about that. Yes, sorry.

Yeah, you were distracted. It's all good. No, you know what I was doing? You were doing a podcast. I was doing a podcast. Yeah. That I thought would take two and a half hours. It ended up taking six hours.

That must have been an intense experience. It was a very intense experience. And I felt horrible after I'm sorry. So I owe you an apology for that. It's okay. We love you. There's so much I want to talk 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 it was sort of reproduce at 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 what you're doing today. Is that about right?

Yeah, that's about right. It was 2011 towards the end. Yeah, actually, we're in December now, so it's actually been somewhat more than eight years. 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 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? Well, longevity for me would be being able to live without the indignities that I've witnessed, we all witnessed in our lives. All of these features of aging that seem to be inescapable.

So my father, for example, he has profound degenerative disease, which makes him functionally immobile. It defines his life. My stepfather died of Alzheimer's at 87. That defined the final chapter of his life. So I've been up close to these things and other people. In addition, we all, and you and I are now a little older than you. I'm in my 50s now, we are witnessing these changes in ourselves. And for me, longevity would be the ability to use what I know how to do, just 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 sort of began as a dream, but now we're generating human data that says this we can actually do this. So I remember when this started, Ned, circa 2011, 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 I saw this paper and it's 10 years old But it was it was almost like you were going through a second post-doc or something getting up to speed in this I've always liked the way you sort of explained your evolution of thought there Do you want to maybe for the listeners give them a sense of how you developed a framework around this about sort of aging Biology. Yeah, why do we age? And what can you do about it, ultimately?

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 always talk about these sort of three principles, that if you remember nothing else from listening, if you're awakened two weeks from now, 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 is done this with these control knobs. These are sort of biochemical systems that nature twists, and these systems

are now something we're learning in the sticks of the third principle, to turn as people that do drug hunting like us. And so it's these three principles that nature is flexible, or that aging is 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 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 clam bake. If you don't eat it, it will live about 40 years.

And it has a deep ocean dwelling relative called a Quohog that lives at least 500 years. And these are very similar creatures. They look very much the same. And no one really knows how long this Quohog lives. This 500 year thing was just because that was what the age of the wreck off of which it was pelt was. So these are very similar creatures on the order of 12-fold different lifespan. Similar story if you flip over to, let's say, the order of rodents.

Actually, let's not even go to rodents here. Let's just talk about mammals, because 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, 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. So the estimate is at least 200 years. So again, you've got this 200-fold 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, Now, if you flip over to rodents, it's the same phenomenon. 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 it doesn't die of some trauma. And again, these are in the same order. And so these are closely related creatures

of very, very different lifespans. So nature has clearly gone to town on this and created these marvelous examples of disparate lifespan, but sort of the same creature or the same biochemistry. So this kind of takes us to this idea of the nature of done this. How? It's a done this and it's done it with these control knobs. And I walk through why we thought there 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. elegance.

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 wild result. Because 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 a total mind warp 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, 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 in the animal, and you can double its lifespan. That's like you or me living to 160, 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. 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 DAF2 and DAF16 and project them forward to mammals, I don't think we've seen the same magnitude of reduction with attenuation of those, have we?

No. And maybe it's worth, rather, you explaining it than me, do you want to tell folks what DAF2 and DAF16 do just to bring them along for the ride? These were genes that were discovered in Cynthia's screen as receptors and transcription factors associated with what we now talk about as the IGF1 receptor signaling pathway. So this is something that now has been explored in great detail and in mice, for example. And the analogous knockdowns and 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 on near barzoli and actually Pedro Beltran, who I work with now, with an antibody that antagonizes the

IGF for some reason. 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. It 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 to 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.

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, right? It was this thing is malleable. Yeah, and to me at the time to your point, it was a proof of concept, right? It was, this thing is malleable. Yeah. And to me, at the time, it was just like, it was, it was a masked tip 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 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 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 thisd cornedel named Clive McKay and yet a colony of rodents and this is shortly after the Great Depression and his lab didn't have a ton of money. And in efforts 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 he's ever got experimentally demonstrated, albeit by accident. And for me, that was the first time that scientists had sort of set out, I'll say it 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 is making a decision about the rate at which you are aging. Now, flash forward several decades, a molecule is discovered on East Ireland made by a soil bacteria. It's one of your favorite molecules, rap and mason. Now the aging effects of rapimicin were not figured out until about 2003. And then the awesome work of David Sapteini eventually linked this color restriction

observation from decades and decades earlier to rapimicin. And it turns out that rapimicin and color 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 biology, so there's this complex called mTOR, which is this megadult and 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 that rapamysin and chyrosdriction and restriction of various other things like methionine, is the single best validated biology across labs, across species, and one of my co-workers, 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? Rabbimis and chirostriction definitely have that feature. It works in all these labs. Do you know that I tried to get a personalized license plate for Rapa Mison and I got rejected by the DMV in California

because Rapa Mison is a drug and you can't have a license plate that's a drug? So then I tried, again, in vain, to get Rapa log as a license plate and I got thwarted again Because apparently someone at the DMV was smart enough to Google Rapa log and figure out that it's an analog of Rapa Mison which is also a drug and I got the same rejection letter from the DMV. I would just assume knowing you would have done Rapa man Which sounds vaguely like a super villain? Okay, But now we didn't go, you stopped there. I'll tell you over dinner what I eventually went with.

Okay, I gotcha. So anyway, there's this M-Tore thing, which is the best-valid control knob. The next knob that got turned is this thing with young blood. So this is something that's sort of popularized if you watch things like Silicon Valley, but this goes back 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 old blood would be bad for you, so 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%.

These are 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 going to 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 rate. 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 and 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 C's in your GATC code. And when you're young, they'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 methylation where you're not supposed to have them and you're missing them in other places. And it 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 It's gonna be 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 that 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 epigenic clock are the cause of features of aging or the result of features of aging or even a little bit above. And that's going to be a super interesting area of biology.

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 scratch as one gets in a CD surface. And the question, of course, being, can you restore the CD back to its original form if you have that master template? And that's not exactly the same as the analogy you've used, but it certainly speaks to the music and the disc. Yeah, it's interesting. So I always think of CDs getting scratched because you're negligent, okay?

Right, as opposed to just putting them in the CD player and using them, yeah. And so there's a nuance, I mean, it's funny, those two metaphors may even, as you know, it 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 going to 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 going to 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 methamelom. So you do it once at conception and so a bunch of gene products get made which erase and reset your methamelom back to day zero, because 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. Yeah, so let's explain that. So when you start at conception, you have one cell. It goes through about 50 divisions. So I don't know exactly it. So are you talking about when we do the second recess? First of all, it's different in humans and mice and I apologize I don't know. But it's some relatively small number. It's a small number. It happens within,

I believe it's weeks 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 not right the second. What happens is there's a second wave of these gene products that are made, and for a second time in your life, and the only second time in your life, you will reset because now you are making germ cells for your children, and they are capped 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 what 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 called the Yamanaka factors. And these four factors, by themselves,

if you express them in cells, super inefficient, but one in every few thousand cells, you can cause to become a reset cell with a prime, you know, when did Yamanaka do this? This is in our lifetime. I mean, this is quite recent. Yeah, he got the Nobel Prize. Last, I don't have the date.

I know a lot about actually how he isolated them. I just don this is quite recent. Yeah, he got the Nobel Prize. I last 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 with John Ackadette. He initially identified genes that is 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 managed to turn on one of these embryonic genes. And he managed to weed it down to four. And he got the NOAA 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. Right, just because you don't have the methyl groups on your DNA doesn't mean they translate into the phenotype that is youth. That's correct. What I think you do when you do Yamannokta for factory programming is

it's a self-faith 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, develop mentally and participate. That's sort of different than youth.

It's a bit of a sort of cell transplantee sort of thing, although done by the delivery of genes. So, anyway, this whole question about this methyl o'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 going to be a very interesting next five years to see where this drops out. We sort of covered a bunch of things. We've talked about...

Yeah, you've got mTOR reductions slash chloric restriction, loss of the circulating youth factors, mitochondrial dysfunction, methylation clock, which sort of ties into stem cell exhaustion, and then we've got another big one. 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 know now 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 over-hype this idea, but I would do want to explain why I've dedicated a large chunk of my life on planet Earth to this, because if you look at all of these aging mechanisms and these knots 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 synesthesia 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 isn't 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 break 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 is dramatically higher. And I'll talk about that a little bit later. Children don't have these cells. No, 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 synestin cells were good for you, bad for you, or neither. And so my two co-founders, and no almost a decade of collaborators, Judy Campizi at the Buck Institute, and Jan Fender's and 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 with 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. It's litter-mate from whom we eliminated senescent cells from midlife until it dies. 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 it's similar to treated animals die, they die with many of the features of aging either absent or reduced. And that is awesome. So we're trying to do it unity, the company I work at. Now before you say something interesting you said, which is they have this knockout of senescence that only occurs in midlife. 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 senescence cells within that animal. But do you begin that administration at midlife?

And what happens if you begin that administration at birth? We have not done that experiment in large part because we don't see senescence cells at birth. 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? 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 mix in essence cells is vitally important to our survival. So if you genetically engineer a mouse that cannot mix in essence cells, the animal is born normally. It's got 10 fingers and 10 toes, but it is statistically winds up full of tumors before it's in reproductive age. So it tells you that this emergency break,

the cellular senescent system, is an anti-cancer system. And you do not want to mess with the emergency break. 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 you'd say, dude, it's like this is an anti-cancer

system and you're kind of screwing around with it. Are you sure this is okay? 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 cells DNA is damaged, presumably its first choice is, can I fix this? But if a cells 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. It still secreets factors that wreak havoc. But is that a fair assessment that I've just made of sort of using an example of SL with DNA damage? Has that sort of choice?

It does. And we don't understand how cells make the choice between the two. Yeah, I was going to ask you that. Do we have any sense of what sues that decision? 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. And known things to destroy DNA.

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 expert cell state at the time. Is there a way post-hoc to examine the DNA damage of the cells that died in compared 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. 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 salience, okay? I have a cellular Ouija board, we can, no, I'm just kidding. Yeah. Since we've been talking about this, 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. And you still don't know which direction it's gonna go? This is 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, in which we insult cells in an effort to make cells become senescent, but a portion of them choose death. There's gotta be a dozen postdocs thinking about this problem, right? Yeah, you'd have to be in a kind of hard-core popposis. The thing is, yeah, you wanna be in a kind of hardcore apoptosis. The thing is, yeah, you want to be in a sort of apoptosis lab.

I don't know who's 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 a some sort of mark of die 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 minutes of radiation three times more of the, the incorporate three times more of the die, these are the guys that chose death. You could do something like that. And so then you don't need to say once, you just need somebody, it's kind of a, I guess it's more of like a cellular death watch.

There's ways you could start to get at that. It's kind of cool. 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? 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 Campese, discovered in 2008. And 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 the features of natural aging, as well as very particular diseases of aging, is via the sacriotome called the SASP, which stands for Sinescent's Associated Secretary Fienotype. And I know it's a mouthful, but... Well, SASP is pretty cool. Yeah.

And so it's really a parachrine feature. So in medicine, we learn about endocrine versus parachrine versus exocrine features. But parachrine 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 secrete 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 going to develop into, 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. 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 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 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 Carell, 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 at this Leonard Haiflake showed up. 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 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 world view on the problem. 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 that 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. This is about a year ago, okay? So these types of things are still happening. So Hayflik turns over this 60-year belief basically. Yeah, 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. Isn't that sort of like Watson and Cricks DNA? Yeah, the thing about it does suggest a means for replication. Yeah, yeah, yeah, yeah. The most understated. Which I love these things. Here's the great story is that when I ran Indolin or Tafelic at the Portland Airport, having gotten off the plane, I pull out my phone. which I love these things. Here's the great story is that when I ran into Leonard Haiflick at the Portland Airport having gotten off the plane, I pull out my phone and I show him, he's very old now, and I show him a picture of the mice within without Sineson cells, the term that he functionally coined. And I said, this is what happened 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, and his daughter walks up who lives in Portland. And she thinks you're a costing him or something. No, it was immediately clear that we were fans. 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 one of these great moments where you get to see this person who really architected this major insight and biology confronted with the historical result, right, to his face, 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, because senescence was something that you did in plates, like plastic plates, 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, they're senescence cells. It was the first time we got to know how many there are. Right? It's not a lot. And her work really raised this larger question, which I mentioned earlier, which is how can so few cells do so much bad for so many cells? 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 secretary phenotype,

that are how these cells exert bad stuff. And it's over a hundred 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 and 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. 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? 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. 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 veg F alpha, the target of things like Lucentus and Ilya, multi-multibillion dollar drugs for the treatment of diseases of the eye, and also using cancer, but that's a sort of a separate thing. So those are both SaaS factors that are the targets of existing massive drugs. There's also some SaaS 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. Now, that's not a marketed drug yet, but it makes the same point, which is antibody. It was taking a step back from this.

I mean, let's put some broader strokes on this. Inflammation would result from SASP, right? 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 just a little counterintuitive. I totally get the, and again, this is just my need to tele-logicalize 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. My general thinking about teleological discussions.

I know you and I could debate this all night long, which is get over it. Yeah, because these things are not testable, any teleological explanation should be evaluated solely on its entertainment value. Okay, right. But that's not why we're here. I will say that there is an idea that is also teleological, but which I use and is a framework that I think is 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 seemed bad for the individual. Didn't evolution get a vote? Isn't that the whole point of evolution? Well, it turns out that features of aging are manifest post-reproductively. Oh, yeah. No, no, I don't think there's going to be an evolutionary explanation for this, for

exactly that reason. So is your argument that this occurred, call it stochastically, an evolution was never there to fix it or catch it, so it just ran a mock. Oh, it's actually something, it's a cooler idea. So it turns out these decisions, if you wanna call them that, the seemingly irrational decisions made by evolution. Of course, evolution doesn't make decisions.

It's a vote with the survival of the species to reproduce, or an organism to reproduce. Many of these so-called decisions are things which benefit the young. Yeah, so it's basically, let's get the post-reproductive folks out of the way to conserve resources for the young. No, I don't think anything so active or sort of sinister.

I think mostly it's, let's take cellular sinescencecence 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, I guess I'm not arguing this senescence. It's the sasp that I'm struggling with. Right. Well, so it turns out this is interesting. So it turns out the sasp does some other things that are useful. So a paper published by Judy Kempisi again and

Marco Damaria, 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 sass factors into the wound. And the question, Judy and Marco asked was, is this important? 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, wasn't just, well, the SASP, this is a role for the SASP here. It's 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. Yeah, now that's an interesting. Certainly, things that favor wound healing could be quite beneficial. Some have even argued that L.P. little A, like a protein, A.P.

like a protein little A, which is attached to an LDL, so it makes this thing called L.P. little A, has very potent pro-thrombotic 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 pro-thrombotic factor to help you in periods of trauma would far outweigh the tail effective 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. By the way, that other example, you have this alpula laze, a perfect comparator to the, whether or not either of these teleological explanations matters not. The point is, is that those are the same logic. 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 sort of, you went on this journey of thinking through final common pathways of aging. You sort of arrived at this M-tore 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, know if sands are 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, as 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? 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 for both to figure out how to do M-Tor 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 how I kind of got

involved in this was I was sitting around actually in the Calgary airport. A lot of these important things are happening in airports, okay, for some reason. And I was eating french fries, and in this 20-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 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. These are the mice you talked about earlier. Yes. And this was Jan or this was Judy, were they collaborating at the time?

They were collaborating though, Judy was not on this particular paper. And this paper was not exactly the same mice I described. So we had a very similar or the same means of senescent cell elimination, but there was a difference. This is 2011. These animals also contain the mutation where they made less, far less of a protein called Bub R1, which is an anaphaase 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

schoolmaster and it sort of says, you're not dividing until everything's lined up. And so if you don't have Bub R1, you just blow right through the checkpoint and you become polyploid and Jan van der Sinden, 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. So let's just make sure we understand why that's the case. If Bob R1 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. That's right. So if you take away your master, a lot of faulty division should follow. That's correct. So Jan's hypothesis is we either attenuate or knockout Bob R1, we should get a lot of cancer. That's right. So, Jan's hypothesis is we either attenuate or knock out Bubbar 1, we should get a lot

of cancer. That's right. Okay, what happened? 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 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 on set very rapidly and die. 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.

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 Olsde 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. 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 bubbar 1 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. 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 a whole bunch of the features of aging, for example, they're bent spines, they're

organ atrophy, they're cataracts in their eyes. These were all severely blunted when the synesons souls 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 agreed to meet and 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 Mao, and all this stuff. But to me, it really felt important.

Now it was a long way between that paper and when you could end of her credibly claim there could be a drug discovery program based on it. We spent the next four years in stealth mode asking for biological questions. I had some very patient investors who gave us a spoon fed or a dropper fed money into the company. 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 because your decision making is very high quality because every single resource decision matters. So, we had four questions we were trying to ask an 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 then kids don't. So that was a formal question that really was on our minds. 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? We don't know that. Those could be two different things. Yeah, so kids naturally nuke them. So we know kids can make them because you can do experiments in young animals, and they make some other cells, and the animals are gone.

So in effect, that is your living, breathing experiment, right? 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 want to 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? Could we find any disease? Because if you think about it, that first mouse, all the first and second mouse experiments that you'll undead, both 2008 and then 2011 publications in nature. Those weren't diseases the way.

Right, they were sort of poly-death conditions. 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 going to develop a drug for that? But your intuition was, of course, you can't study lifespan here. It has to be health span related because if you have an interest in taking this to humans, mortality is a very difficult endpoint. Yeah, it's not the way we develop drugs.

I mean, unless you're tackling conditions that kill people quickly, mortality is a reasonable endpoint for cancer and heart disease drugs. Yeah, sure. So, in fact, I would even make us even ruthlessly more practical. We want to define 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. 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?

Yeah. So, again, Jan Venderson to the rescue here. So net at this point, it's just you and Jan and Judy. So is myself, Jan Venderson, Judy Campizi, and a guy named Da Hong Jo, who helped us discover one of the early cinematic 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 first author on the paper I'm about to describe as it relates to question one, which is how did we figure out that Sinescence was driving features of natural aging. And so that was what Darren Baker and Jan Vendors and spent the next few years after 2011 doing. And that paper took five years before published in 2016. And what they did in this paper was they took natural mice, mostly natural. Okay. They contained one difference. We made it 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 want it. 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, 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-stalthing the effort and speaking openly about what we were doing. Because 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.

So you basically were processing question one and two, three, four in parallel. 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. And then we moved, and 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 in a few doors over. No pun intended. Yeah. And we essentially went to town with a small group.

It was just a few people supported very intimately by Yon'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. So I want to 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 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 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. 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. Well, that's actually that we were going to fail than succeed.

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 buy us 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, it would have had you less likely to consider it.

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? So the approach I take to a bold idea, like this idea of making drugs that eliminates an essence cells, is I try to picture, it's a simple, beautiful idea.

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 synethnic cells don't contribute to natural aging. I'll use this particular example in our back out in a second. That was a risk. They don't contribute to natural aging. They don't cause a particular disease of aging. You can never find a molecule to eliminate or eliminating them as unsafe.

Those were the four risks we came up with. You can apply this risk to a beautiful, simple idea in any technological endeavor that I've been involved in. What's nice about that is one of those is a very clear market risk. Three of those are biologic or technology risks. Your second question is actually a market risk question. In other words, if number one worked, so if number one is, this absolutely explains natural aging. If number three was true,

you could come up with a molecule that could block it. And number four was true, you could do so safely. But there was no way, there was a regulatory pathway that was gonna allow you to go from A to B, because hook spine disease was never gonna show up on the FDA's list of drugable things to think about. It's not to say that it couldn't work, but now you've taken on an enormous regulatory risk that would be almost crushing to any one company. So what I'm hearing you say is embedded in your questions was

actually a very thoughtful risk analysis that reverse engineered success. I think so. It turned out to be a good way for us to focus ourselves. How long did it take you guys to come up with those four questions? Because it was just five of you if I did my math, right? There was a few orbiting. So my long-term business partner Keith Leonard, he was at the time, we'd found it a previous company together

and he was still being the CEO of that company where I'd previously been the chief science officer But he was involved in this and a few other just very smart people that I will pull into these things I need very simple thinkers for this sort of thing because you must in a very disciplined way to still out to these primitive in a very disciplined way to still out to these primitive risks that can animate behavior over many years. They have to be durable. If you can summon the discipline and the simplicity to distill the next, say, four to five years your life down to call it two to four risks because any more than that, then your life gets too complicated. And then you can build work plans that systematically remove each of those risks or do not remove them.

But at least identify them. Yeah, identify them and then build plans. Everything we did at the company for four years, everything was those four risks. That was it. And the money we raised was pretty poultry at the time. It was all budgeted around those four risks. That was it. And the money we raised was pretty paltry at the time. It was all budgeted around those four risks. And whenever I go after a new thing, I always try to just go back to that simple, beautiful idea and then say, can I write down the risks to this beautiful idea? Then you build plans from them and then you build budgets and then you

politely ask people for money, which by the way, almost no one would provide because this idea seems relatively preposterous at the time. The people that stepped forward were people like Bob Nelson from Arch, who has been a visionary across decades of biotech. And it was he who, when I explained this to him, very rapidly said, yeah, let's do this. There's some other people at Archive, Christina Burrow, who was very supportive early on. So that really was the prime anchor early on in the life

of the company and animated all of our behavior. And that was four years of my life. How long did it take you guys to define those questions now? Because the way you rattle them off, they're so logical, they're so obvious, but my guess is those were not immediately apparent to you in 2011 that those were the four things that had to be wrestled to the ground. No, we kind of did know them. Really?

Yeah, so it's funny, I recently went through the early, I was looking through some old files and I found an old PowerPoint where there are six risks and it was clear that we'd done some kind of pruning down to the most primitive because I'm kind of a tyrant when it comes down to like, we must have the simplest plan sort of thing. So there had been some pruning, but I know that we initially generated the list of a half dozen or so and then over a period of weeks I think we managed to just in a disciplined way Shear them down to this relatively streamlined plan. Now did you learn this the hard way?

Was there a time when you went down the path of trying to do something lacked this discipline and Found yourself sort of looking back sometime later thinking we wasted time, we wasted money, we didn't pursue this as linearly as we could have. Absolutely. Now, when it really taught me this, this is something I sort of learned a bit on the fly, kind of in the eras in which I was building companies like a K-Agin and K-Thera. So those were all early 2000s. So a K-Agin was 2003, K-Thera was around 2005.

My first company, which I founded, my last year of graduate school, we were strategy-free. This was a high throughput structural biology company called Syrix, and we never had any of these intellectual tools. And so these were tools that were really developed through. Feeling is though, we wasted time, which is your most valuable resource. And you wasted people's money, which was also valuable resource. And the net effect of this has been now this discipline, streamlining of idea and risk. Yeah, so it's something that just picked up over time and now it's reflexive.

And everybody in my group, everyone thinks this way. And so whenever a new thing comes up, immediately everyone goes to the board and starts writing out risks and then starts writing out, well, this is the derisking plan for this, this, and this. And okay, that means it's 18 months and this is kind of the budget. Do you think that that type of thinking is productive or counterproductive in academia? It's clearly productive in industry. If you tomorrow decided, I want to go back and start a lab and go back to Berkeley and apply for a grant, would you encourage your graduate students and postdocs to think that way or would you modify the thinking slightly?

I would be modified, but I think there is kind of a value to this. I think in any setting where you have a problem or a technological thing you're trying to solve, which is being explicit about the failure modes, even if you're an academic in an academic setting, and I'm speaking specifically of biology or something akin to it, like I can't talk to you about math or something, because I think it drives a certain degree of honesty when things are failing. So you know what to see. And so if you're looking out for this isn't working, this isn't working, and only this

is working, and all three have to work for this project to go, you can make a go-no-go decision in an academic setting and pivot to another project because there's no end of creative ideas that you could be working on. They're limitless. And so the important thing is to conserve your most valuable resource, which is your time. And so I encourage my academic friends, some of whom listen, some of whom do not, to think similarly and to take a sort of portfolio approach to academic projects, which is, it's okay to prosecute this question for 18 months, but there are certain things we want to have in 18 months,

and if you do not have them, we make a formal go-no-go decision. Meanwhile, you had two other projects going, and so what you need is only one to raise its hand and say, I'm working. Yeah. That was super helpful. Let's go back to kind of, you now have the answer of these four questions. Is it safe to say there are still a number of ways to do this? In other words, if you know that senescence is a natural part of aging, if you know that there are

specific diseases for which it plays a role, if you know that there are molecules that can be developed that can target it, and you know that it can be done safely. That third question really has many heads. You can have molecules that kill senescent cells. You could have molecules that target the factors they secrete. Presumably there are other ways you could mashenate around this.

Had you fixated early on, you alluded to it that killing cells is something we really know how to do pretty well in biology. Was that the path you guys were on from the beginning? Or was that a pivot? 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,

because 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 senesco. 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? Yeah, well, you could take the position that any antibody therapeutic against one of these pro-inflammatories in the SASP is just such an approach. But actually, I was saying something a little bit more... I understand your point, though. 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 cell sit and they're 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, we call them

scanalytic molecules. If you could make a scanalytic molecule, you could dose it once, and once you eliminate scanalytic cells, the cells are not there anymore. So these are not drugs you take every day, every week, or every month. These are might be dosed once a year, and till 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 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.

First, long as we've looked. of a senolytic medicine, eliminates pain dramatically in these humans. First, 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 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. 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. 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 nanomoles that osteoarthritis, which is the second most prevalent disease of aging and the primary reason

it hurts to be old. What's the first, by the way? Type 2 diabetes. Interesting. So what we did is we knew from animals that if we could induce surgical trauma to an animal's knee on the mouse, and we eliminated senescent cells, we could eliminate pain and actually repair cartilage in a mouse. Wait a second, that's counterintuitive.

I know, that's so cool. 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. 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. Got it. 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. 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 cheloid, 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 to many, and all of a sudden you have a different outcome than you had prior to the insult. Yeah. Coupled with everything you said. I mean, that's all of these things factor together, I suppose.

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 osteo 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. 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. That's correct. Okay. One aside question, is there a mouse model of osteoarthritis that comes from overweight or obesity? No. Is that the most common cause of osteoarthritis in humans? 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 bearing this. Interesting. So the animal model for osteoarthritis is an ACL injury, which is still true in humans, but it's... 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, the people have built for things like osteoarthritis because they're making a pain killer. So they do things like hurt the animals' need and then give it a pain killer. How relevant is that to osteoarthritis in a human, it's not. You inject iodos acetate into the joint. It hurts like hell. And then you give them pain killers.

So we had to search around for Models that happened fast because that's the way we do experiments in which senescence played a role and the ACLT model So this was work we did collaboratively with Jennifer L. A. C. F. who's a professor at Johns Hopkins of bioengineering and She was someone 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 seniletic molecules we found, we shared with her, and she had her model

in operation. And very quickly in her laboratory, we shared with her, and she had her model in operation. And very quickly in her laboratory, we were able to demonstrate the Senneletic Molecules that we 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, a 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 because we could achieve it genetically, which says it's really a synestinous 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. How does the drug actually target the senescent cell when you don't have the luxury of a genetic tag?

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 centenualitic 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 meter made 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 it's concentration in the cell goes up.

And discovered in Judy's lab by a few people, including Remi Martana Barrage, who was a postdoc in Judy's lab at the time, he discovered that when you did this to Sinescent Cells, Sinescent Cells died, preferably. By the way, is there anything on the outside of a Sinescent Cell that identifies it? There are some things on the inside, and we've been searching... But it's not like you have an antibody or anything that would render it externally identified. We are searching now, and we don't have any universal external marker of senescent cells.

We do have some that we just haven't talked about openly at in various disease states where the senescent cells in a disease state have a marker that's on the outside. We've not found in people like Ned Sharpless have been searching for over a decade for such a marker. Wow, so just to add to the complexity of the biology, and sharpness have been searching for over a decade for such a marker. 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 synescent 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. Optically no. Now, if you had a little bit of a sniffer, eyes would not be useful if you were very small. A nose, however, would be useful.

So if you could just sort of swim up the gradient of pro-inflammatory and prophybotic markers, you would find yourself. You'd find your source. Yeah. Right, so I do think that the little mini-spaceship things often very eliminated to think of a biology. I use that a lot. Your drug then targets P53?

Oh, that's right. Yeah, so P53 goes up in these cells. So it doesn't target P53, it actually binds on the MDM two side. Thereby, kick and make it. Relieving. Yeah, yeah, it's okay. And then so P53 goes up in concentration, the Cinescent Cells die selectively. And then, and this turned out to work very well in our trauma osteoarthritis models. And another very cool result. This is something else that Jennifer did wound up in our nature paper or nature medicine paper in 2017 was Jennifer got knees from patients undergoing total knee arthroplasty. So these are

people that don't need their knees anymore because they're getting a metal one. And she would take the cartilage at the site of the osteoarthrothritic lesion, and she would digest out the extracellular matrix, and she would take the cells. The cells would actually make your cartilage. And she would grow them in 3D culture, and she would either expose those little blobs of baby cartilage to either vehicle or our drug that's now in phase 2 clinical trials in humans. And she observed something awesome, which is that exposure to the drug eliminated senescent

cells that were very prevalent from the site of damage. You talked earlier about how you might see one to two percent senescent cells in an organism, but when you talk about a very local spot of damage like that, how highly concentrated were they? So it's a little hard because I'll tell you a slightly different number because the cartilage stuff, so basically it's very, there are a lot of them at the site where you have the osteoarthritic injury and you go millimeters away and then it drops way down.

So it's got more punk to it in that setting. If you look to the synovial membrane, which is I'll talk to you about another study, we didn't humans where we actually counted synescent cells in patients with osteoarthritis. The number of hovers around 1 to 2% even in patients with osteoarthritis, but it scales with, you have more synescent cells when you have more disease. And when you say, do you mean synovial fluid? Like if you did a joint aspiration on somebody with osteoarthritis, you're saying 1 to 2% of the cells in the

synnovial fluid is an essence. So we actually did, I'll come back to this a little bit later. Okay. Let me just finish up and then we'll immediately flip to that. Sorry. Okay. Is that we did this experiment where we soaked the cartilage from the patients that had osteoarthritis in our drug.

And eliminated synosin cells, but a really cool thing is they started growing cartilage in the plastic dish. So these are cells that came from the sick person's knee. They had the capacity to make cartilage, but they just didn't. But once you eliminated the cells, all of a sudden they were producing cartilage again. And so that was super cool. We have yet to prove in a human being

that this drug can grow cartilage when it's still in your knee. But that experiment is kind of cool, because it suggests that you have this innate capacity if you are unburdened by the cells and their bad stuff they're making. So this next question about how many senaten cells do you have in the disease? I'll tell you why I'm asking the question, which is not just general curiosity,

it's really to get a question of how difficult is it to target these things in vivo? Are they ubiquitous enough that you can whack these things within injection? Because obviously when you're doing this in a person, you're not gonna have the luxury of taking their knee out to do it. That's sort of the ideology of my question. So I'll tell you a person, you're not gonna have the luxury of taking their knee out to do it. That's sort of the etiology of my question.

So, I'll tell you a little bit of what we've done in the clinic. So, in human beings, we have eliminated senescent cells from patients' knees with a single injection of this drug, and we can not only eliminate, or dramatically reduce pain, but we can also eliminate factors that senescent cells are making. So the quick answer to your question is that this molecule is safe enough,

selective enough, and potent enough, that we can do it. So it doesn't just work in a plastic dish, but it works actually within the knee of a patient suffering from osteoarthritis. So this was your phase one trial with your first agent. This is the 101. Yeah, that's right. Mm-hmm. I've seen the phase one data, maybe explain a little bit of what was done. Phase one for people who aren't familiar with drug studies is mostly to ensure safety,

but sometimes you'll see efficacy. Sometimes you'll see that the drug actually does something beneficial, and that's a bonus if you can see both efficacy and safety. But you're typically escalating the dose, and again, you want to see if more drug leads to more toxicity. But if there's efficacy and the efficacy improves with dose, that makes you a bit more confident that it's not the placebo effect or not the effect of the vehicle that you use to deliver the drug. That's correct. So the experiment we did, and this was all the result of what we saw in animals, the result of what we saw in a phase zero study in which we went into patients with osteoarthritis, no drugs, but we biopsy little bits of their sonovial membrane and counted senescent cells,

and we saw that the more senescent cells they had, the worse osteoarthritis they had, the more bone deformation they had in the knee, the more pain they had. So, in bolden by these results, we then took the drug to humans. And, as you noted, phase one studies are typically for safety. We realized though that we couldn't really do the right safety study in patients that didn't have a senescent cell burden. Because if you're asking the question, is it safe to eliminate senescent cells from an osteoarthritis knee, you need to have the cells to eliminate. And so that was our kind of logic in the design. And so the way we did the study was 48 patients, where we did a 3-to-1 randomization, meaning

three people would get drug versus one person giving placebo. And as you noted, we stepped up in dose, and it was a single dose of the drug that day zero injected into the knees of patients with pain-philososter arthritis. And we then followed these patients for three months, and we checked in with them every week, and they checked in with themselves every day on a little iPhone device, and we monitored their pain.

And the investigators were blinded as well? Oh, yes. It's called a double blind study, which means nobody knows who's got drug, who's got placebo, or what dose of drug you are on. So there's 12 placebo's, 36 treatments, treated patients, and those 36 treated patients were about six per dose.

They were six per dose, yeah. So we had six dose levels, and so they were marched up from essentially a group of a series of doses, three of them, which we based on some modeling we did in cell culture, we thought would be sub-pharmacologically active doses. So we thought they'd be semi-inactive or inactive entirely. And then we moved into the dose range where we thought we'd be doing biology and then we saw what happened. And we asked the

patients, they had once a week meetings with their physician where they answered questionnaires about their pain, about their functional state. Then every day they would go and they'd enter on a little iPhone device and answer one question, which is how much pain am I in on a scale of one to 10? What we saw when we unblinded the data was that there was a dose dependent, meaning as you go up and dose, you get more and more pain reduction, and durable impact in pain. For as long as we looked, when we got to three months, the pain is not returning. It's completely flat. Do you remember what the placebo group experienced? How much of a reduction in pain did they achieve relative to their baseline? It depends on which of the end points we're using,

but I'll just summarize by saying that injections into the knee, placebo effect is a big deal. In fact, if you did not see a placebo effect that looked like other clinical trials, you would scratch your head and wonder what's wrong. We saw a very similar placebo effect to what is seen with the injection of steroids into the knee, and that was actually good.

Meaning if you do a trial with steroids and with saline, for example, you saw the same placebo effect. You didn't see the same effect as you saw with steroids. Correct. You see, the placebo groups in a steroid trial had comparable effects. Yeah, it looked like the placebo effect in our trial. And that is something that one must, the placebo effects in pain studies is absolutely important. But what we saw was that we vastly exceeded anything

looking like the placebo effect. So, in fact, at our highest dose of drug, again, because it's a phase one study, the N number of patients was small at the highest dose. We saw patients who were entering, so this is this scale of one to 10 thing, okay? It's actually zero to 10 patients were entering on average at about a 6.2 and at the highest dose They were dropping to just over one is that comparable to what patients experience with steroids I know it's not apples to apples and by the way the reason is not apples to apples that I actually learned on this clinical study

The reason you don't compare across studies is that different studies in world different, patients, different inclusion, exclusion criteria, even if you use the very same clinical instrument, it's really not Naples Tapples comparison. That said, okay, the effect looks very large in terms of what we are doing, in terms of approaching our highestose, getting some patients close to pain-free.

Now, I know that the Phase I trial was a three-month study. What's the average duration that patients have now been since their injections? I don't have the answer to that question. We are not monitoring the patients in that study going forward because we didn't consent them for that. What we are doing now is we're actively dosing patients in our phase two study.

So presumably the duration will be extended in phase two. That's right. So because we only went three months in the phase one study and we didn't consent patients to keep watching them, we really wanted to answer this question, which is if you eliminate senescent cells from somebody's knee, how long does the pain stay away?

And so the phase two study goes out to six months, so it's 24 weeks, and we're trying to replicate the phase one study as much as we can. So we're using the same clinical instruments to measure pain and function. We're similar dose levels, so we're doing placebo,-meg, two-meg, four-megs, okay, which was the highest dose that we explored in the phase one study. And it's 45 patients per dose level, as opposed to six. So we should have sufficient statistical power to really see this, really clearly. And in terms of the criteria, the patients that are coming in, they have to have painful osteoarthritis of the knee. And so there is a score, this thing called the NIRS,

which is this numerical rating scale. This is this 0 to 10, so it's an 11 point scale. And you have to be between a four and a nine. And are these patients that typically have already tried corticosteroids and only achieved limited or short-term response. Like I'm trying to understand clinically, somebody listening to this, who should and shouldn't be excited about this type of work on the horizon. So I think all of us should be excited about this work, because not only is this a solution, so if our phase two replicates the phase one, and which we all hope and believe it ought to,

not only is this a means to treat the primary reason it hurts to be old, but it's a read-through to this whole idea of medicine, which is could you treat diseases of aging by eliminating these cells at sites of disease? This is just the beginning of something. Well, let me go back and make sure I understand a few things because I'm already doing what you're doing, I think, which is sort of extrapolating to the what it means.

Is radiographic evidence a way, because you can certainly look at a person's knee on an x-ray and examine the loss of cartilage and appreciate an osteoarthritic knee. You could do the same thing on an MRI. Do you know if the reverse is true? Do you know if the level of cartilage that's making its way back into the knee as a result of the loss of senescent cells is radiographically evident as well? Or is it possible that some of the amelioration of pain is due to the reduction of the circulating factors there, but not so much an increase in the structural integrity of the knee.

So what we saw in terms of the speed of pain resolution in the phase one was that within two weeks of the injection, you achieved most of your pain reduction. So it seems pretty implausible to me that that is the result of a structural change to your joint. It seems far more likely that this is the result of getting rid of factors that are driving pain acutely. And it's possible, like my questions are probably so ignorant, and I'm sure there's some orthopedic surgeon listening to this cringing.

We would assume that some of the pain that people experience in osteoarthritis is due to the structural part of this, but your evidence would suggest that at least part of the pain that people experience in osteoarthritis is due to the structural part of this, but your evidence would suggest that at least part of the pain is not. It's consistent with that idea, but who's to say? So we're going to know, because we're also doing MRI and X-ray in the Phase II study, and so we're going to be able to not only follow pain, but we will follow structure as well. But we have no idea if you will see improvements in the structure of the joint. Over what time scale you would see changes and improvements to the structure of the joint.

This is the cool thing about doing cutting edge biology in clinical science. I mean, I would love to take a group of patients. If resources were no object, then we could continue to be absolutely sure of the safety of this. You know, you imagine to take a bunch of people our age. You do a bunch of T2-rated images, MRIs of their spine, and you look at these signal loss, L4, L5, L5, S1 discs. Many people are age, myself certainly, have these blown out blackened discs that just aren't taking up water. Yeah, I have them. Yeah. It would be very interesting

to note if you did directed injections of synthetic agents like this, if you could restore this signal, could you by eradicating enough senescent cell, create an environment where the existing cell could proliferate into a healthy enough place where it takes up water. Something as simple as that, that again, it's a slippery slope in the spine to go after indications because it's not as clean as the knee, I don't think. But again, just a great proof of concept. Yeah, I will say that I suffer from degenerative disease. Well, everyone does at some point, but it's particularly prevalent in my family.

There was a result I did not mention earlier from mice. But when we eliminate senescent cells from mice from midlife until death and we do x-ray on their spines, we see a 41% improvement in the maintenance of the intervirtuebral disc volume. Now, do you see a restoration or a reduction in decline? We only measured reduction in decline, so we do not know if you could see a restoration. So that's still an unknown question in the Cinescent Space.

Absolutely. So it's possible you, me, and all the other folks that are in the senior category here, won't necessarily reap the benefits nearly as much as the people like your kid and my kid right now, where you figure this out and when you're 20 you start to prophylactically take these things to reduce the glide rate of decline. That might be true structurally but I would say that what we saw on our phase one study was you can take people with frank, painful osteoarthritis of the knee, dose them and two weeks later they have profound pain reduction at the highest dose. So that tells you that you are taking a big feature of that disease, the one that you get to feel

on a minute to minute basis, and you are sending it backwards. Now whether or not that becomes a structural change is something we hope to understand in the phase two study. The other thing we don't understand, and it might take even more than a phase two study, to understand is with corticosteroids, we have problems, which is excessive use of corticosteroids is not a viable option. They themselves become destructive and or potentially lose efficacy over time. And so they're a great once in a while tool, but not a great maintenance tool. It will be interesting to know if you become tacky, phallactic to this,

or if the efficacy increases with use as you start to increase the amount of cartilage-laying tissue that exists and you tip the battle in favor of the condra site over the Cinescent cell. Yeah, that would be the prediction one would make from the zero-order prediction. Would be that, I think. Is there an example in bio-pharmacology where the good guy ends up winning with progressive dosing? Oh, I would say oncology. If you think about cancer as a gain of function. Only in the cancers that don't spread, though. But that sort of, that almost seems binary, doesn't it? I guess you're right. I guess you could say that.

So because if you think of cancer as a sort of pitted battle between you, the organism, and cancer, which is sort of a gain of function, separate organism based on you, living in you, but not you, when you successfully treat cancer through the elimination of those cells, the good guy won. Yeah, I guess. I guess that's true some of the time, but most of the time that's not true. It's sort of a totology, right? It's true when it's true, but when it's not, it's not.

But most of the time it's not true is the problem. But it could certainly be the case here. There's certainly a case. But even if the worst case scenario is you need a drug injected every six months or every 12 months. It's certainly interesting. Let's go one step further because this is obviously a critical piece of health span. In fact, you could argue that along with cognition, there's no more important piece of health span

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? These are the atherosclerosis, cancer, or other diseases that actually shorten life? Well, we know, atherosclerosis, cancer, or other diseases that actually shorten life. Well, we know that atherosclerosis is another disease in which, since 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 360 joints in your body, we treat the local version of the disease with local therapy. Atharosclerosis is about a systemic as it gets. And Jan Vendorzen, at Mayo Clinic, published a paper,

actually, is Jan Vendorzen, the guy named very excellent young scientist named 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, and it showed these plaques are full of senescent cells. And if you eliminate those cells. What are the cells that have become senescent? What's their origin?

So they appear to be macrophage in origin? I see, so it's not the endothelial cell. Well, no, there's three cell types. It's basically there's a senescent endothelium. There is a myofriboblastic type of cell that's in there. And then there are macrophages. 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. 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 got to wonder

what is that really saying about the pathophysiology of the human disease. But there is this phybrotic cap that forms on the surface of an atherosclerotic plaque, and one of the ideas in the literature is if 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 in with drug that he can thicken the plaques of atheroscopic plaques in a mass.

That would seem to counter the idea that you could lessen plaque volume. Do you have to pick between one of those two strategies? Because typically if you thicken the plaque, wouldn't you likely increase the volume? No. So if you look at the sort of relative partitioning of how much of the plaque volume is the cap, and then how much is this bulk lipid deposit with macrophages in it, eyeballing it, it's 90% is this lipid-like macrophage blob, and then there's this thin little veneer on top that is the cap. And so the thickening of that cap

doesn't dramatically contribute to the overall volume of the atheroscleric plaque, at least in a mouse. But both are happening. You're thickening the cap and reducing the subendithelial portion of the reducing the foam solenoid. So the 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 is given rise to relatively moderate uptake of those drugs. Good argue, that's just due to the cost of the drug.

It's also the fact that, 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 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 because now we have to, you're not using circuit markers anymore. You're using outcome studies. You're actually following people until they die

or have a serious cardiac event. Do you see an application here in oncology? I mean, it seems like there should be. Well, it's an area of interest of ours. So one of the things we saw in Yonvander's in 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 within 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 just head scratch from them. Like, what is that mean? And if I recall, you said they got a 30% lifespan extension. Yeah. So you basically created centenarians. You just phase shifted chronic disease by a third. And some of the diseases were just dramatically reduced. So the effects on kidney function, the age effects of kidney function were reduced dramatically,

cataracts were reduced dramatically. So there's a whole bunch of behavior stuff that we don't know what that means, but these animals seem to preserve features of youthful behavior. They're spinal-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. 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. 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 in situation where you could intervene in it. There's also an idea where if you could make cells

synescent, which is what chemotherapy does, in many cases, and then do a sort of two-hit strategy where you drive the cells into synescence, and then you exploit a synescent 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 driver's 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 antivagias. This is a disease that appears to have senescence associated with it. What's the distribution of those two? So people that have age associated macular generation, one in eight has the wet disease. And only that one out of eight people is treatable with the anti-vegetarian bodies. 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 centolytic 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. Do you have an animal model for that? 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 am personally attracted. First of all, I just want to say that when we talked about the four risks to find your works. Yeah. For four years, we live in a different risk set now. So if you think about it, the chapter one of this entire effort really was demonstrating a human being, that eliminating senescent cells could take a feature of aging that otherwise was untreatable and sent it backwards. Our phase one study, certainly if the phase two replicates, that was the end of chapter one. And we're sort of living in this chapter two moment where we're seeing how broad can

we make this work. And if you think about what risks live in chapter two, for me, and I think anybody, it would be that the risk is you have your biological disease hypothesis wrong. And animal models, they only ask and answer the questions they're built to ask an answer. And the only way you get to really ask and answer the question you want to ask is in the clinical setting in human beings. So the way I think about diseases of the eyes, you have a series of these untreatable diseases that make you blind, where we think senescence could play a role, and we're going to explore each of these in the clinic.

So essentially being able to ask in the relevant setting that, can we intervene in these diseases of aging using the very same approach that we took to osteoarthritis, all be it with different drugs. Now you won't be doing a real phase one here. You're gonna go directly into a phase two, right? So this is something that we haven't really talked about yet, but notionally, we're going to be going into patients because obviously your eye is something

that's super, super important and you can't mess with it. We're going to be going into a very select population first, demonstrating safety and then branching outwards into multiple diseases out of the eye. How do you deliver the vehicle? Is it an injection? Yeah, so it's very similar to clinical practice for anti-vegetarian delivery. Anti-vegetarian delivery. So it goes right into the vitrious fluid of the eye, and our drug then takes up, we actually know exactly where the drug goes into the various sub-compartments within the eye.

And we know where senescent cells are in these different diseases, and our drug gets there, and the clinical hypothesis is that one or more of these, you know, essentially progressive diseases of the aging eye, when we eliminate the cells, we'll stop. And can you speak about the drug? What is it targeting? It's not targeting P53. No. So we have two molecules that were advancing toward the clinic. Both of them are inhibitors of the BCL2 protein

family. So these are molecules that inhibit inhibitors of apoptosis. So they cause cells to enter a program to sell death. But interestingly we've shown in animals that they don't cause that to happen in normal health eyes. They only target cells that have been damaged by the disease process and the stress associated with the disease process. And so why is that? There's something about, so senescent cells, when they enter this state, do a variety of things.

They turn up proteins that are pro-apoptosis, and they also turn up proteins, in terms of our expression, that are anti-apoptosis. So what we do is we go in with a drug and just give a little shove in one direction. I see, but you're saying if you give that same shove to someone who has not up-regulated or down-regulated, either of those factors, it doesn't seem to matter too much. Yeah. And so we have a beautiful experiment in mouse where we have a disease condition, okay, and we have a normal condition. It might as our identical but for this. And we put the drug in and we can see the drug molecularly going in and engaging its target. So we cause it actually breaks up to proteins

that are stuck together. And you can see in these animals, both of them are equally engaging target. But the apoptosis program only turns on in the disease state. And it was a pretty awesome result because you can see the selectivity of the molecules in a living creature's eye. Does that same molecule work in the osteoarthritic scenario? No, so we couldn't get it to work either in the trauma models, in mice. We couldn't get it to work when we took the cartilage out of human needs, it didn't work there either. And so it never raised its hand. And-

What do you think that says about the biology? There's something about cells and their fate that determines which apoptosis vulnerability you have. And they have different Achilles heels. And we don't understand mechanistically why that is. We've sort of figured this out empirically and picked molecules based on their behavior against the cells that we find to be senescent in these human diseases. So 15 years from now or 20

years from now we will likely look back and companies like Unity and presumably there will be many like Unity. You will have an entire suite of targets. You will say, well, here's the playbook in this type of cell or this scenario going after the anti-anti-a-poptotic pathway is the way to go. In this case, we're going to go after P, and you might have a dozen of these different targets. Well, we're not sure yet. I think it's too early to say how this is gonna play out. Oh, so you don't think it's a fate of complete.

I mean, you think it might be that there's a very small number of ways to go about doing this. I doubt that. I doubt it will be dozens though. I think it's going to be a small number. I think it'll be context specific. I think it's going to be a small number. I think it'll be context specific. I think there'll be super creative ways that we and others come up with to exploit these different vulnerabilities. I don't think biology is going to have made 24 different keys to this lock.

I think it's going to make a half dozen. And we actively search for these. It's just interesting to me that you can turn And we actively search for these. It's just interesting to me that you can turn one key and get a benefit. I mean, think about how often that doesn't work. I think of the futility of that in chemotherapy, where you target this one piece of cell cycle replication, and very quickly the cell mutates away around that drug. So cancer is incredibly hard, okay? Because cancer exploits the single best tool biology has,

which is variation. Cancer cells can divide and mutate and become anything to avoid death. They live under selective pressure, particularly in the context of drug. Cinescent cells can't divide by definition. So their ability to access variation is dramatically reduced. Now that's not to say that there couldn't still be selection without division, but boy, it's way harder when you can't make a million progeny with tiny variants and test them all in parallel Which is what cancer does yeah, it's sort of funny isn't cancer is the ultimate a b-tester Yeah, we like to think of senescent cells as cancer cells that can't divide is one I've heard that said semi-humorously

But that's actually really right which is sort of funny because it's like tape the top 100 most valuable traits of cancer and take away 99 of them. Right. By the way, I was saying that in some joke. No, I understand. Yeah. Yeah. In the sense that senescent cells become senescent, well, first of all, in vivo, we don't often know why they became senescent, but one of the mechanisms by which cells can become senescent is activation of a cancer-causing gene. can become senescent is activation of a cancer-causing gene. But that could be very rare event compared to mitochondrial failure or high concentration glucose or tealimere-shortening. I mean, I was going to actually ask you exactly about that example, which is, do we have any reason to believe that the increase in age-associated type 2 diabetes could be resulting from some sort of

pancreatic senescence where beta cells become less and less robust due to senescent beta cells in the proximity. There is some data in support of senescence in that cellular niche, but it's very complicated biology and there's even some talk about compensatory mechanism where senescent cells actually may improve the function of some of those cells within the niche. It's an area of intense literature debate. The other challenge we have there is we don't have good models in animals of studying this. And so it's been hard for us to get our heads around. What I will say about type 2 diabetes in humans is that there was a

large meta-analysis of a genome-wide association studies looking for the genetic correlation between grievous illness of aging and loci. Where did these mutations map? And what you saw is that one of the very big peaks for diseases of aging maps into the control system for the establishment of cellular senescence. This P14 are flocus. And you look at, this is where this very important gene that people use for senescence all the time called P16, which is this part of the emergency break. It's gene lives in this locus. And what you see is diseases like type 2 diabetes, mutations that give rise to that,

live there. Mutations to give rise to late onset Alzheimer's, live there, frailty lives there, atherosclerosis lives there. So a whole bunch of these diseases where we saw phenotypes in mice. You see a natural genetic variation of humans also shows a kind of tie-in to senescence. And so type two diabetes caught my eye there because you see that in the GWAS studies. And lastly, what about Alzheimer's disease? We have to believe that astrocytes are losing some functionality to protect neurons, right?

So, this is what my group works on, and it's something that animates a lot of us at the company. We know that astrocytes, or Gleea, just call them Gleeal cells. So, if you guys don't know what Gleea is, it's actually derived from the word glue. So, this is the cells that are not your neurons in your brain that seem to hold the rest of it together. Which outnumber neurons tremendously. I think the number is on the order of 10 to 1. Eight to 10 to 1 or something like that. Guys, you gotta look that number up.

But it's on that order of magnitude. And what was known before we got involved was that as human beings aged, there's a dramatic increase in senescent glial cells, specifically astrocytes and microglia, which are the sort of macrophages of the brain. And stuff we've been working on. If we've been looking at that trend in rodents, and we see a very similar trend. Now we have not talked about doing on this yet because it's still early days, but it's hard to imagine that the pro-inflammatory environment created by this vast number of

synescent glial cells is good for you. One needs to ask the question, what would happen if you could eliminate synescent glial cells? Would that enhance cognition? Would it harm cognition? And this is something that we are actively looking into. But all of the work we've done over the last eight years, everything going from the mutant animals to the wild-type animals to human data, in osteoarthritis, and now moving into human data soon within the eye.

It would just be very hard to imagine that senescence is not playing a role in aspects of cognition loss as we age. And this is something when I think about why we do what we do that is something that there could be very few greater contributions that myself and my colleagues could make than making a contribution there because it has been an unsolved problem and a scourge to humanity. I mean, do you get the sense that doing what you've done now would be very difficult for you to go

back in time and do something like Kaitera over again? And I'm not saying that to be critical or in any way, shape or form. I'm just saying like, I mean, maybe tell people what Kaitera did. That was a very successful company for you, but there's no comparing the nature of the two problems you're trying to solve. Yeah, actually, thank you for actually pulling me out of it. Otherwise, be a kind of like overly sort of sappy discussion about contribution. Okay. So Kathera is actually a total kind of opposite sort of thing.

And Kathera was a company at myself and two co-founders founded now almost 15 years ago. It's about as opposite as you can get from doing unity. And so it was basically this idea that all this biology that's been explored for oncology and inflammatory disease, taking molecules from that and applying it to the biology of aesthetics. And we did this and I had these great business partners that continue to be partners with me today. One of them is Keith Leonard, who is CEO of Unity and very close friend. And he's been my big brother for 15 years and continues as of this

morning, calling me and giving me feedback on things. And I've just grown. And the reason I did Kathera was it was sort of a cute idea, but it was mostly because of people was these guys said, hey, let's do something together. And it was a great decision because I learned so much in a sense because so the drug we ultimately got approved. We took four things into the clinic and one out of the four things worked. And it was a molecule that causes fat cells to explode. So we went from an in vitro observation all the way to a launched commercial product called kybella. You can go get it your dermatologist. And Allergan acquired the company. And it was a great learning experience of just how to

develop pharmaceuticals in something that didn't have historical resonance at all. And so it was a great learning experience of just how to develop pharmaceuticals in something that didn't have Historical resonance at all and so it was a great sort of it was a great moment where the stakes weren't as high for whether you succeeded or failed it as a consequence that allowed you to hone your skills of kind of making really high-quality decisions on risk and making drug development decisions in a way that's actually frankly a little more dispassionate. And it was a great growth experience for me.

I mean, is it safe to say that if you had not had the experience at Kaithera, because then you would have been coming from a K-Agin, right? Basically, would you have had a more difficult time doing what you and the early co-founders did at Unity. It would have been impossible. I would have none of the intellectual or emotional toolkit to do what we did. I mean, that whole risk thing. That was stuff we built. I mean, it was a little bit, and we'd do a little bit of the other occasion, but it'd become a kind of ritualized practice by the time we were doing Khythera projects, this

dimensionization of risk and creating work plans based on it. And so yeah, I would say that there would be no unity without there being Khythera. Last question, Ned. What? I actually have two questions for him. Sorry, but I think about it. First question is, what advice do you give for a person who's studying science and trying to decide between the entrepreneurial pathway that you've been on versus a more academic pathway? What would you offer them as an insider or a set of questions that they could pose to themselves to further delineate that?

Well, I would say two things. First, don't create a false choice. All right. So, I have friends that are academics that have founded as many companies as I have. And I do from time to time have career jealousy over some of the freedoms and some of the responsibilities, frankly, that they have as people who have academic appointments. There are wonderful things that you can do from the seat of academia in company creation.

If you are so lucky and so positioned to do so. So first, don't fall into this idea of a false choice. And I see people do that, I think, out of some emotional discomfort, this desire to just move and confuse action with progress. And I'd say, just slow down, take a deep breath, don't rush, you have your life. That'd be the first thing. The second thing is animate what you do with a single beautiful idea. So something that moves you, that makes your, gives you literally gives you goosebumps, that weird tingling sensation when you think about it, when you think how cool it is. And oh my god, if we could actually make this work, I mean, few things in life rival

that feeling when a hard fought battle for data that was 18 to 24 months and the experiment finally works. And you're looking at the data and you feel like the future taking root in the present, the only thing I can compare it to is love from your kids. That is the only thing that has the same emotional gravitas. Finally, third thing, learn from people that are better than you, that are more experienced than you, that will have patience with you. I mean, the chythera experience was that. I mean, good heavens, I was, may still be sort of unemployable in normal corporate settings. Yet, the people there saw that I knew how to

do certain things. And I learned from them. And I learned how to do the things that allowed us to build unity because people were patient and took time to teach. I learned from real experts and I don't claim to be an expert at much of anything, but I do claim to have a deep appreciation for learning from people who are better and more skilled than myself. So three things. Well, I'm gonna leave it at that.

I was gonna ask you another question, but I think this was the more interesting question and so we'll leave it at that. I was going to ask you another question, but I think this was the more interesting question. And so we'll leave it at that. And grateful net for the time that you've set aside today to talk about this stuff. This is, I think this is a super interesting topic. When I think about the pillars of longevity, going back to your initial framework, right, which is things that inhibit tour, things that target mitochondrial function, things that may set back the methylation clock, slow down time in that regard in this problem. It's not a zero-sum game,

and it's very likely we need to be pursuing all of these strategies in parallel. But the data so far with respect to a very tangible problem like osteoarthritis is pretty exciting. So I suspect there's gonna be a lot of people listening to this who are going to be very eager to follow the results of the technology that you guys are trying to bring to market along with presumably some others down the line. Thank you Peter. It's been really a treat and an

honor to share this with you and I always and shall always I love your questions. They're awesome. Thank you. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth, exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of this subscription. Now to that end, membership benefits include a bunch of things. One, totally kick- ass comprehensive podcast show notes that detail every topic paper, person, thing we discuss

on each episode. The word on the street is, nobody's show notes rival these. Monthly AMA episodes are asking me anything episodes, hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spills like this. The Qualies, which are a super short podcast, typically less than five minutes that we release every Tuesday through Friday, highlighting the best questions, topics, and tactics discussed

on previous episodes of the drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to everyone. Steep discounts on products that I believe in, but for which I'm not getting paid to endorse. And a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member-only benefits, you can head over to peteratiamd.com forward slash subscribe. You can find me on Twitter, Instagram, your Facebook, all with the ID, Peter Atia MD.

You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only. It does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have,

and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures in the companies I invest in or advise, please visit peteratiamd.com word slash about where I keep an up to date and active list of such companies. you.