Matt Kaeberlein

Except it's a concept. It's a qualitative concept. I think we should try to make it to where we can't actually come up with a way to measure whether we call it healthspan or not. That doesn't really matter. I kind of agree with Rich. Like, I agree with what you're saying, except I think it's a really useful term as a concept.

Except it's a concept. It's a qualitative concept. I think we should try to make it to where we can't actually come up with a way to measure whether we call it healthspan or not. That doesn't really matter. I kind of agree with Rich. Like, I agree with what you're saying, except I think it's a really useful term as a concept.

I think it's a really useful way to communicate to a broader audience what one of the goals is, which is to increase the healthy period of life.

I think it's a really useful way to communicate to a broader audience what one of the goals is, which is to increase the healthy period of life.

health for that i have a way that helps you out with your health and you don't see maybe it's pretend you can define it as a number but i think we all could agree there's a period of life where you are in relatively good health and then there's a period of life where you aren't and so i think the idea that we're trying to increase that component of life is really important so i don't think we're actually disagreeing on much other than whether we like the word

health for that i have a way that helps you out with your health and you don't see maybe it's pretend you can define it as a number but i think we all could agree there's a period of life where you are in relatively good health and then there's a period of life where you aren't and so i think the idea that we're trying to increase that component of life is really important so i don't think we're actually disagreeing on much other than whether we like the word

Yeah.

Yeah.

For lack of a better way to... Yeah. So, I mean, I think both of the points that Steve and Rich raised are part of the equation. I mean, I think it's a convergence of all of these factors and maybe a few others. I do think... The science has matured to the point where more people are believing that we can actually modulate the biology of aging.

For lack of a better way to... Yeah. So, I mean, I think both of the points that Steve and Rich raised are part of the equation. I mean, I think it's a convergence of all of these factors and maybe a few others. I do think... The science has matured to the point where more people are believing that we can actually modulate the biology of aging.

I think the concept of biological aging has become popularized through a variety of mechanisms, including some influencers, individuals who I personally think often err on the side of being a little bit less scientific than they should be, but I think they've helped popularize the concept. So I think it's been a combination of these factors. and why it has taken so long.

I think the concept of biological aging has become popularized through a variety of mechanisms, including some influencers, individuals who I personally think often err on the side of being a little bit less scientific than they should be, but I think they've helped popularize the concept. So I think it's been a combination of these factors. and why it has taken so long.

I mean, I just think that's the pace that science moves and the rate at which these concepts can sort of permeate the public sphere. So it's frustrating in a sense that it's moved so slowly. I also wonder, because you sort of said, are we at a longevity bubble? I don't know.

I mean, I just think that's the pace that science moves and the rate at which these concepts can sort of permeate the public sphere. So it's frustrating in a sense that it's moved so slowly. I also wonder, because you sort of said, are we at a longevity bubble? I don't know.

I think maybe we're still kind of in the early days of this hockey stick moment where you're getting this exponential increase in attention. My hope is As we go forward, it will become more scientific and less snake oily. And it's a spectrum. There's this huge gray area in the field right now of what's real and what's not real.

I think maybe we're still kind of in the early days of this hockey stick moment where you're getting this exponential increase in attention. My hope is As we go forward, it will become more scientific and less snake oily. And it's a spectrum. There's this huge gray area in the field right now of what's real and what's not real.

And I think none of us at this table actually can really define exactly where in that gray area that line is or is there a line.

And I think none of us at this table actually can really define exactly where in that gray area that line is or is there a line.

I think it's hard to say it. And I mean, NIH is a moving target. And as we all know, there's going to be a lot of change coming in the near future. So cautiously optimistic, I would say if you look historically, it's been really pretty terrible. The percent of NIH budget that goes to biology of aging, I think is still probably around half of 1%.

I think it's hard to say it. And I mean, NIH is a moving target. And as we all know, there's going to be a lot of change coming in the near future. So cautiously optimistic, I would say if you look historically, it's been really pretty terrible. The percent of NIH budget that goes to biology of aging, I think is still probably around half of 1%.

Not NIA. No, no, I understand. Within NIA, there's a sub fraction that goes to biology of aging, right? Yes, yes, yes. Yeah.

Not NIA. No, no, I understand. Within NIA, there's a sub fraction that goes to biology of aging, right? Yes, yes, yes. Yeah.

It was about $350 million a few years ago. It might be a little higher than that, but I don't think it's ticked up any more proportional to the increase in NIH budget since then. So it reaches about half of 1%. Wow.

It was about $350 million a few years ago. It might be a little higher than that, but I don't think it's ticked up any more proportional to the increase in NIH budget since then. So it reaches about half of 1%. Wow.

I agree completely. And I think as well, the reputation of the field has hindered that transition as well. So historically, the field was viewed as not very mechanistic, kind of phenomenological, became much more mechanistic starting around the time of Cynthia Kenyon's work and since then, but has continued to have a reputation problem as not being as rigorous as other areas of research.

I agree completely. And I think as well, the reputation of the field has hindered that transition as well. So historically, the field was viewed as not very mechanistic, kind of phenomenological, became much more mechanistic starting around the time of Cynthia Kenyon's work and since then, but has continued to have a reputation problem as not being as rigorous as other areas of research.

So I think it is absolutely a turf war. And there's this overcoming the reputational problem, which makes it harder for scientists serious people in funding and policy circles to give it the attention it deserves, in my opinion.

So I think it is absolutely a turf war. And there's this overcoming the reputational problem, which makes it harder for scientists serious people in funding and policy circles to give it the attention it deserves, in my opinion.

It could, although how much of that is actually going to biology of age? I think it's still an open question. You mentioned Calico and Altos, right? We don't know exactly. I actually agree with Steve. I don't think what Rich and I were communicating is opposed to what Steve was communicating. There are a lot of opportunities right now.

It could, although how much of that is actually going to biology of age? I think it's still an open question. You mentioned Calico and Altos, right? We don't know exactly. I actually agree with Steve. I don't think what Rich and I were communicating is opposed to what Steve was communicating. There are a lot of opportunities right now.

And again, this is sort of what I was alluding to is, are we at the beginning of this hockey stick moment? And I think Steve's right. There are real opportunities for more resources to be focused on the scientific side and hopefully less focused on the non-scientific aspects of what are going on.

And again, this is sort of what I was alluding to is, are we at the beginning of this hockey stick moment? And I think Steve's right. There are real opportunities for more resources to be focused on the scientific side and hopefully less focused on the non-scientific aspects of what are going on.

And you asked the question of, can we shift resources from the more consumer facing, maybe not as rigorous stuff and into the more rigorous stuff? I'm not a fan of that stuff at all, but maybe you need that stuff to kind of move the needle and get people's attention. And at least people are talking about longevity now.

And you asked the question of, can we shift resources from the more consumer facing, maybe not as rigorous stuff and into the more rigorous stuff? I'm not a fan of that stuff at all, but maybe you need that stuff to kind of move the needle and get people's attention. And at least people are talking about longevity now.

Yeah. And I didn't actually get to give you my spiel here, but what I started to say about the NIA budget is if you look at the major causes of death and disability, and again, we talked about how it's hard to define health spend. So if we just look at causes of death, if you look at the top 10 causes of death in the United States,

Yeah. And I didn't actually get to give you my spiel here, but what I started to say about the NIA budget is if you look at the major causes of death and disability, and again, we talked about how it's hard to define health spend. So if we just look at causes of death, if you look at the top 10 causes of death in the United States,

Nine of them have biological aging as their greatest risk factor, and it's not even close. Yet, half of 1% of the research budget that's supposed to be focused on improving human health goes to study that risk factor.

Nine of them have biological aging as their greatest risk factor, and it's not even close. Yet, half of 1% of the research budget that's supposed to be focused on improving human health goes to study that risk factor.

I mean, I think it is extremely frustrating to all of us sitting at this table that that hasn't changed, but there's reason to be optimistic that maybe it will change in the near future.

I mean, I think it is extremely frustrating to all of us sitting at this table that that hasn't changed, but there's reason to be optimistic that maybe it will change in the near future.

Yeah, I think that's important. I mean, I think the reactive disease care component is still going to be there. Even if we're insanely successful at slowing aging, people are still going to get sick. But I think Steve's point is really important. Like Peter, you've been a leader in helping people recognize the need to shift the medical approach from reactive to proactive.

Yeah, I think that's important. I mean, I think the reactive disease care component is still going to be there. Even if we're insanely successful at slowing aging, people are still going to get sick. But I think Steve's point is really important. Like Peter, you've been a leader in helping people recognize the need to shift the medical approach from reactive to proactive.

I think what a lot of people don't realize is that mentality goes all the way back to pharmaceutical research, biomedical research, basic science. That is ingrained all the way through. And I think one of the challenges with getting funding for aging research is that mentality on the basic science world and how deeply ingrained it is.

I think what a lot of people don't realize is that mentality goes all the way back to pharmaceutical research, biomedical research, basic science. That is ingrained all the way through. And I think one of the challenges with getting funding for aging research is that mentality on the basic science world and how deeply ingrained it is.

I would. And I mean, the reality is the research flows from where the dollars are going. This has been seen over and over and over at NIH. You shift resource allocation to a certain area and the scientists will follow and they will submit grants. to get grants in the place where the funding line is the highest.

I would. And I mean, the reality is the research flows from where the dollars are going. This has been seen over and over and over at NIH. You shift resource allocation to a certain area and the scientists will follow and they will submit grants. to get grants in the place where the funding line is the highest.

So if somebody came along and said, we're going to go from 0.5% to 50% of NIH budget is going to go to biology of aging, you'd have no shortage of people. I mean, it'd be kind of messy at first, but you'd have no shortage of people applying for grants and becoming experts in the biology of aging.

So if somebody came along and said, we're going to go from 0.5% to 50% of NIH budget is going to go to biology of aging, you'd have no shortage of people. I mean, it'd be kind of messy at first, but you'd have no shortage of people applying for grants and becoming experts in the biology of aging.

I agree completely. I think it's the wrong question.

I agree completely. I think it's the wrong question.

It also creates a negative feeling about the field in some people as well. So I think that should be considered. The other point that people often raise, though, is we have to call aging a disease in order for FDA to approve a drug for aging, which I think is a fundamental misunderstanding of how FDA operates.

It also creates a negative feeling about the field in some people as well. So I think that should be considered. The other point that people often raise, though, is we have to call aging a disease in order for FDA to approve a drug for aging, which I think is a fundamental misunderstanding of how FDA operates.

But that is the other argument you will often hear among proponents of the idea that aging is a disease. Very interesting.

But that is the other argument you will often hear among proponents of the idea that aging is a disease. Very interesting.

I got to talk because I think I disagree fundamentally. I'm surprised, but this will be an interesting conversation. So I agree that the idea of a kit that you can buy to measure biological age, first of all, the stuff that's out there doesn't work. And we can and should talk about that.

I got to talk because I think I disagree fundamentally. I'm surprised, but this will be an interesting conversation. So I agree that the idea of a kit that you can buy to measure biological age, first of all, the stuff that's out there doesn't work. And we can and should talk about that.

But also, I sort of agree with the idea that reducing it to one number, while conceptually I think it's possible, I think in reality is going to be really, really difficult to do. But do I believe that there is a biological aging process that is different from chronological aging? Absolutely.

But also, I sort of agree with the idea that reducing it to one number, while conceptually I think it's possible, I think in reality is going to be really, really difficult to do. But do I believe that there is a biological aging process that is different from chronological aging? Absolutely.

Well, it sounded like you guys were both saying no.

Well, it sounded like you guys were both saying no.

There's two things that kind of make me feel pretty confident in this idea. One is, and this is the example I use a lot among the general public, is just look at dogs compared to people. Everybody's familiar with the idea that one human year is about seven dog years. What does that mean? means that dogs age about seven times faster than people do.

There's two things that kind of make me feel pretty confident in this idea. One is, and this is the example I use a lot among the general public, is just look at dogs compared to people. Everybody's familiar with the idea that one human year is about seven dog years. What does that mean? means that dogs age about seven times faster than people do.

But of course, chronological time is the same between dogs and people. It's the biological aging process. And so you can look across the animal kingdom and see this. And dogs get almost all of the same diseases and functional declines that we do at the tissue and organ level, but also the whole body level.

But of course, chronological time is the same between dogs and people. It's the biological aging process. And so you can look across the animal kingdom and see this. And dogs get almost all of the same diseases and functional declines that we do at the tissue and organ level, but also the whole body level.

We also know now there are single genes that significantly modulate what I would call the rate of aging. Now, maybe we have a different meaning to what we mean that.

We also know now there are single genes that significantly modulate what I would call the rate of aging. Now, maybe we have a different meaning to what we mean that.

So the fact that that's possible, DAF2, we talked about DAF2 a couple of times, TOR, we can turn these things up, turn them down, and animals across the evolutionary spectrum seem to age at different rates by modulating single genes. So I don't know of any other explanation other than that there is this process that which we call biological aging, that can be changed.

So the fact that that's possible, DAF2, we talked about DAF2 a couple of times, TOR, we can turn these things up, turn them down, and animals across the evolutionary spectrum seem to age at different rates by modulating single genes. So I don't know of any other explanation other than that there is this process that which we call biological aging, that can be changed.

And the rate can be sped up or slowed down. Can it be reversed? That's an interesting question. Maybe we'll get to that. But I think the process is real. I think it's just really, really complicated. And we probably only understand 5% of it at this point.

And the rate can be sped up or slowed down. Can it be reversed? That's an interesting question. Maybe we'll get to that. But I think the process is real. I think it's just really, really complicated. And we probably only understand 5% of it at this point.

But what if you were to come up and then you probably do this in your head. You come up with some sort of composite. You probably don't sit down and wait each of those things and come to one number. But you come up with some sort of composite picture of health based on all of those things. That's a different biological aging clock. I think sometimes we conflate.

But what if you were to come up and then you probably do this in your head. You come up with some sort of composite. You probably don't sit down and wait each of those things and come to one number. But you come up with some sort of composite picture of health based on all of those things. That's a different biological aging clock. I think sometimes we conflate.

And in part, this is because of the way that irresponsible people in the field and marketers have done this. We conflate the epigenetic tests. with biological aging clocks. There are all sorts of flavors of biological aging clocks, including things like frailty indices or metrics of a whole bunch of functional markers. So I think those probably are pretty good readouts of biological age.

And in part, this is because of the way that irresponsible people in the field and marketers have done this. We conflate the epigenetic tests. with biological aging clocks. There are all sorts of flavors of biological aging clocks, including things like frailty indices or metrics of a whole bunch of functional markers. So I think those probably are pretty good readouts of biological age.

Again, can you combine them all to get to one number that's meaningful for every person? That's much harder to do.

Again, can you combine them all to get to one number that's meaningful for every person? That's much harder to do.

Yeah, in fact, we exchanged emails at one point about doing this and each coming up with different names. So what I did was I tested four different direct-to-consumer biological age kits. They were all epigenetic biological age tests, four different companies. And I did duplicates of each kit. And it was from the same samples collected on the same day. Really tried to put my scientist hat on.

Yeah, in fact, we exchanged emails at one point about doing this and each coming up with different names. So what I did was I tested four different direct-to-consumer biological age kits. They were all epigenetic biological age tests, four different companies. And I did duplicates of each kit. And it was from the same samples collected on the same day. Really tried to put my scientist hat on.

I only had two replicates. I didn't have three replicates, but it's about the best I could afford at that point. And it was kind of expensive. So anyways, sent those in, got the results back. And they were, to me, very informative, fundamentally sort of changed my views on these epigenetic age tests. So they ranged from 42 to 63. I was 53.75 years at the time I did the test.

I only had two replicates. I didn't have three replicates, but it's about the best I could afford at that point. And it was kind of expensive. So anyways, sent those in, got the results back. And they were, to me, very informative, fundamentally sort of changed my views on these epigenetic age tests. So they ranged from 42 to 63. I was 53.75 years at the time I did the test.

And the standard deviation, I can't remember, was either seven or nine. So mean of my chronological age, standard deviation of seven or nine, which I look at that data. I'm not a statistician, but I know enough statistics to say that's completely useless. They converged on my chronological age, but with a huge variation. So that varied between the tests.

And the standard deviation, I can't remember, was either seven or nine. So mean of my chronological age, standard deviation of seven or nine, which I look at that data. I'm not a statistician, but I know enough statistics to say that's completely useless. They converged on my chronological age, but with a huge variation. So that varied between the tests.

So I think three of the four were reasonably close to each other. Three of the four companies, the duplicates were reasonably close to each other, but the individual tests were far apart. And one of the companies, the individual replicates was 20 years apart.

So I think three of the four were reasonably close to each other. Three of the four companies, the duplicates were reasonably close to each other, but the individual tests were far apart. And one of the companies, the individual replicates was 20 years apart.

And I have no idea who to believe or if any of them are actually giving accurate data. I know some of the people at some of the companies and I have my personal feelings about who's trying to do it right and who's sort of a charlatan. But across the industry, it's really hard to know. The last thing I'll say on this is where I've sort of landed is I think these are really good research tools.

And I have no idea who to believe or if any of them are actually giving accurate data. I know some of the people at some of the companies and I have my personal feelings about who's trying to do it right and who's sort of a charlatan. But across the industry, it's really hard to know. The last thing I'll say on this is where I've sort of landed is I think these are really good research tools.

I think the direct-to-consumer component has gotten way ahead of itself. And I think I align with what you were saying about the way you think about these tests. I don't think there's a lot of value in clinical practice right now because we don't know precision or accuracy. And I don't think you can make actionable recommendations based on these tests.

I think the direct-to-consumer component has gotten way ahead of itself. And I think I align with what you were saying about the way you think about these tests. I don't think there's a lot of value in clinical practice right now because we don't know precision or accuracy. And I don't think you can make actionable recommendations based on these tests.

I don't think we're that far away from that. I'm going to sound like a broken record here, but you guys keep saying biological age when what you mean is epigenetic age or epigenetic. Not necessarily.

I don't think we're that far away from that. I'm going to sound like a broken record here, but you guys keep saying biological age when what you mean is epigenetic age or epigenetic. Not necessarily.

So I guess let me frame it as a question to you. So let's take the epigenetic piece out. Again, I do think we will get to a point where the technology is developed far enough and the quality control is good enough on the consumer side that these tests will be better than just chronological age. I think we can get there.

So I guess let me frame it as a question to you. So let's take the epigenetic piece out. Again, I do think we will get to a point where the technology is developed far enough and the quality control is good enough on the consumer side that these tests will be better than just chronological age. I think we can get there.

I think it's clear from the research, unless you think that all of the research that's been done on these epigenetic aging clocks is somehow flawed, it's clear that you can create algorithms that can predict specific methylation patterns that are more highly correlated with life expectancy than chronological age.

I think it's clear from the research, unless you think that all of the research that's been done on these epigenetic aging clocks is somehow flawed, it's clear that you can create algorithms that can predict specific methylation patterns that are more highly correlated with life expectancy than chronological age.

Biological age. That's what I want to get to. Yes. And I think what you are actually doing is looking at other biomarkers that have a long-term clinical history that you're using to come up with a surrogate, but really is reflecting largely biological age, maybe not completely. And this is the other point I wanted to make is I don't think biological age and health are equal.

Biological age. That's what I want to get to. Yes. And I think what you are actually doing is looking at other biomarkers that have a long-term clinical history that you're using to come up with a surrogate, but really is reflecting largely biological age, maybe not completely. And this is the other point I wanted to make is I don't think biological age and health are equal.

I think they're strongly overlapping. And certainly you can identify many ways to reduce health without accelerating biological aging. I think that's easy. We can all think of ways to do that. So let's take a minute and try.

I think they're strongly overlapping. And certainly you can identify many ways to reduce health without accelerating biological aging. I think that's easy. We can all think of ways to do that. So let's take a minute and try.

Yeah, it's a good question. So I am hopeful that epigenetic algorithms can get to the point where they can replace many, certainly not all, but many of the other biomarkers that are being measured. I think the thing that gives me hope is we know that epigenetic changes are part of biological aging.

Yeah, it's a good question. So I am hopeful that epigenetic algorithms can get to the point where they can replace many, certainly not all, but many of the other biomarkers that are being measured. I think the thing that gives me hope is we know that epigenetic changes are part of biological aging.

This, again, is a different question, but if we look at the hallmarks of aging, epigenetic dysregulation is one of the 12. Some people will argue it's the most important one. That's a different conversation, but it's at least part. So that gives me some hope that we are, in fact, measuring something that plays a causal role in the aging process.

This, again, is a different question, but if we look at the hallmarks of aging, epigenetic dysregulation is one of the 12. Some people will argue it's the most important one. That's a different conversation, but it's at least part. So that gives me some hope that we are, in fact, measuring something that plays a causal role in the aging process.

And I think what's missing, I think what would give all of us a lot more confidence is if we had a mechanistic connection to the specific methylation changes and some cause of aging or age-related disease. In other words, This change in methylation changes this particular gene's expression level, which changes the rate of biological aging. I think if we had that, we'd feel a lot more confident.

And I think what's missing, I think what would give all of us a lot more confidence is if we had a mechanistic connection to the specific methylation changes and some cause of aging or age-related disease. In other words, This change in methylation changes this particular gene's expression level, which changes the rate of biological aging. I think if we had that, we'd feel a lot more confident.

Yeah.

Yeah.

It's so conceptually beautiful. I mean, so I agree completely with Rich and he knows I do because we've talked about this before. I think the flip side is, I think the hallmarks have been immensely useful to the field. They are a very... easy way to communicate this idea of biological aging.

It's so conceptually beautiful. I mean, so I agree completely with Rich and he knows I do because we've talked about this before. I think the flip side is, I think the hallmarks have been immensely useful to the field. They are a very... easy way to communicate this idea of biological aging.

And it helps convince some of the scientific community that thought it was all just hocus pocus and snake oil, that there is some mechanistic research happening. We can point to specific things that are aging. So I think that part of the hallmarks has been actually really valuable and has contributed to the popularization of longevity.

And it helps convince some of the scientific community that thought it was all just hocus pocus and snake oil, that there is some mechanistic research happening. We can point to specific things that are aging. So I think that part of the hallmarks has been actually really valuable and has contributed to the popularization of longevity.

And at least to the extent the science of longevity has been popularized has contributed to that. And it has been extremely detrimental to the field. And the way I think about it is it just caused the field to narrow prematurely. And this goes back to what I alluded to before. I don't know if we understand 80% of biological aging or 0.005% of biological aging biologically.

And at least to the extent the science of longevity has been popularized has contributed to that. And it has been extremely detrimental to the field. And the way I think about it is it just caused the field to narrow prematurely. And this goes back to what I alluded to before. I don't know if we understand 80% of biological aging or 0.005% of biological aging biologically.

My guess is it's closer to 0.005%. And by and large, the funding to look outside of the hallmarks dried up once the hallmarks became the dominant paradigm and people stopped looking. And I think we need to go back to more discovery science and thinking outside the box. I think it's been a double-edged sword.

My guess is it's closer to 0.005%. And by and large, the funding to look outside of the hallmarks dried up once the hallmarks became the dominant paradigm and people stopped looking. And I think we need to go back to more discovery science and thinking outside the box. I think it's been a double-edged sword.

It would help. I don't know that it would help enough, but it would help. I mean, you also kind of have to change the mindset about what people call fishing expeditions. That's like a bad word in grant review panels, fishing expedition, meaning you don't really know what you're going to find, but you got to go look before you can figure out what's important.

It would help. I don't know that it would help enough, but it would help. I mean, you also kind of have to change the mindset about what people call fishing expeditions. That's like a bad word in grant review panels, fishing expedition, meaning you don't really know what you're going to find, but you got to go look before you can figure out what's important.

So I think we have to kind of change that mindset as well.

So I think we have to kind of change that mindset as well.

Drove me nuts. Almost impossible to get the important stuff funded.

Drove me nuts. Almost impossible to get the important stuff funded.

Other than it's a nice hypothesis.

Other than it's a nice hypothesis.

You're off by an order of magnitude.

You're off by an order of magnitude.

I at least internally reframe it a little bit and say, what would the experiment be? What would you need to do to convince yourself that either, broadly speaking, epigenetic dysregulation causes aging, whatever that means, or this specific epigenetic change that is associated with chronological age causes aging?

I at least internally reframe it a little bit and say, what would the experiment be? What would you need to do to convince yourself that either, broadly speaking, epigenetic dysregulation causes aging, whatever that means, or this specific epigenetic change that is associated with chronological age causes aging?

And so that's an easier way for me to think about it, because I feel like it's all a fascinating conversation, but we're never going to get to the answer until somebody actually does the experiment.

And so that's an easier way for me to think about it, because I feel like it's all a fascinating conversation, but we're never going to get to the answer until somebody actually does the experiment.

Yeah, that's right. But people are trying to do both of those things. I mean, people are using partial or transient epigenetic reprogramming and asking, can that have effects on biological aging? I'm actually cautiously optimistic it can. I don't think it's going to be a game changer, but I think you can modulate aspects of biological aging.

Yeah, that's right. But people are trying to do both of those things. I mean, people are using partial or transient epigenetic reprogramming and asking, can that have effects on biological aging? I'm actually cautiously optimistic it can. I don't think it's going to be a game changer, but I think you can modulate aspects of biological aging.

The technologies are being developed for targeted epigenetic modifications. So if we think this particular epigenetic mark at this particular location in the genome, controls aging. And I don't think it's going to be that simple, but let's say it is. You could go in, you could modify that, and then see, do you reduce disease? Do you increase lifespan? Do you improve healthspan?

The technologies are being developed for targeted epigenetic modifications. So if we think this particular epigenetic mark at this particular location in the genome, controls aging. And I don't think it's going to be that simple, but let's say it is. You could go in, you could modify that, and then see, do you reduce disease? Do you increase lifespan? Do you improve healthspan?

So those are the kinds of experiments that I think would get us to where we can have a lot of confidence. If it's the case, if somebody, let's say at Altos, publishes a paper three years from now that they have made a mouse live six years by multiple rounds of transient epigenetic reprogramming, I'll be like their biggest fan. They moved the needle.

So those are the kinds of experiments that I think would get us to where we can have a lot of confidence. If it's the case, if somebody, let's say at Altos, publishes a paper three years from now that they have made a mouse live six years by multiple rounds of transient epigenetic reprogramming, I'll be like their biggest fan. They moved the needle.

That convinces me that that strategy modulates biological aging. Nobody's done that yet.

That convinces me that that strategy modulates biological aging. Nobody's done that yet.

But is that biological aging? I wouldn't be convinced that's modulating the biological aging process. I would be convinced that's a clinically useful strategy for people who benefit from that therapy.

But is that biological aging? I wouldn't be convinced that's modulating the biological aging process. I would be convinced that's a clinically useful strategy for people who benefit from that therapy.

You're going to trigger Rich here before we go down that path. Is it the S one? Yeah, yeah. Let's talk about senescence.

You're going to trigger Rich here before we go down that path. Is it the S one? Yeah, yeah. Let's talk about senescence.

And one way I think about this, and again, this may be completely wrong, but it's a useful way for me to think about it, is I think about age-related disease as the downstream effect of biological aging. For most diseases, there becomes a point where the pathology of that disease mechanistically is no longer the same as biological aging.

And one way I think about this, and again, this may be completely wrong, but it's a useful way for me to think about it, is I think about age-related disease as the downstream effect of biological aging. For most diseases, there becomes a point where the pathology of that disease mechanistically is no longer the same as biological aging.

And one of the implications of that is the interventions that slow biological aging may not work. Once you get past that point, but things that do work for that disease may have nothing to do with biological aging. Does that make sense? Yeah. Go deeper on that idea though. Let's use the example. I mean, what's your favorite disease?

And one of the implications of that is the interventions that slow biological aging may not work. Once you get past that point, but things that do work for that disease may have nothing to do with biological aging. Does that make sense? Yeah. Go deeper on that idea though. Let's use the example. I mean, what's your favorite disease?

Cancer's an easy one. We know with cancer, in many cancers, the process is you have one or more mutations, which then often lead to additional mutations. You get genome instability. Eventually, you get an oncogene that gets activated, and that leads to uncontrolled cell division. Or a tumor suppressor gene that gets deactivated. Yeah, right.

Cancer's an easy one. We know with cancer, in many cancers, the process is you have one or more mutations, which then often lead to additional mutations. You get genome instability. Eventually, you get an oncogene that gets activated, and that leads to uncontrolled cell division. Or a tumor suppressor gene that gets deactivated. Yeah, right.

And if we accept that immune surveillance is one important anti-cancer mechanism, we know that immune surveillance declines with age. So early on, we're clearing a lot of our cancers. As our immune system declines, these cancers are going to escape immune surveillance. They're going to accumulate all these mutations. They're eventually going to go into uncontrolled cell division.

And if we accept that immune surveillance is one important anti-cancer mechanism, we know that immune surveillance declines with age. So early on, we're clearing a lot of our cancers. As our immune system declines, these cancers are going to escape immune surveillance. They're going to accumulate all these mutations. They're eventually going to go into uncontrolled cell division.

That uncontrolled cell division at that point You can treat the cancer, but uncontrolled cell division is not biological aging. It's not a part of the normative aging process. So the treatment there, so the mechanism now is fundamentally different from normative aging.

That uncontrolled cell division at that point You can treat the cancer, but uncontrolled cell division is not biological aging. It's not a part of the normative aging process. So the treatment there, so the mechanism now is fundamentally different from normative aging.

And the treatment, let's just say the treatment in this case is chemotherapy, might benefit the cancer, but it's not going to slow normal aging. And I think rapamycin is a good example here where I think we all believe that rapamycin and inhibiting mTOR slows biological aging. at least in up to mice, hopefully in dogs, hopefully in people. Yeah. So it's a fundamental node in the network.

And the treatment, let's just say the treatment in this case is chemotherapy, might benefit the cancer, but it's not going to slow normal aging. And I think rapamycin is a good example here where I think we all believe that rapamycin and inhibiting mTOR slows biological aging. at least in up to mice, hopefully in dogs, hopefully in people. Yeah. So it's a fundamental node in the network.

That's the way I think about the hallmarks of aging. It's a node in the network that underlies the hallmarks of aging. So we can manipulate mTOR with rapamycin, slow aging. Rapamycin is a pretty good anti-cancer drug. Until the cancers have evolved to ignore the mTOR break, then rapamycin doesn't work anymore. And we know rapamycin doesn't work for most cancers. That's an example.

That's the way I think about the hallmarks of aging. It's a node in the network that underlies the hallmarks of aging. So we can manipulate mTOR with rapamycin, slow aging. Rapamycin is a pretty good anti-cancer drug. Until the cancers have evolved to ignore the mTOR break, then rapamycin doesn't work anymore. And we know rapamycin doesn't work for most cancers. That's an example.

Yeah, absolutely. And it's because the cancers evolve to bypass the mTOR break or to bypass the ability of rapamycin to inhibit mTORs.

Yeah, absolutely. And it's because the cancers evolve to bypass the mTOR break or to bypass the ability of rapamycin to inhibit mTORs.

That's a good example. These are our dollars that are going to work. But Alzheimer's Association, I mean, that's a patient advocacy group. That is the public.

That's a good example. These are our dollars that are going to work. But Alzheimer's Association, I mean, that's a patient advocacy group. That is the public.

I agree with all of this. I agree with all of this. I think, again, though, we should be careful not to demonize people for wanting to cure Alzheimer's. It's a good goal. I think the communication piece is about the fact that it's going to be much more efficient and effective to keep people from getting it in the first place.

I agree with all of this. I agree with all of this. I think, again, though, we should be careful not to demonize people for wanting to cure Alzheimer's. It's a good goal. I think the communication piece is about the fact that it's going to be much more efficient and effective to keep people from getting it in the first place.

This goes back to the idea that once you've outpaced the biology of aging with the pathology of the disease, it gets a lot harder, a lot harder to do anything about it. So I think that communication part, honestly, I don't know why we've been so unsuccessful because I think a lot of us have been out there trying to communicate this message for a long time, but it's starting to permeate.

This goes back to the idea that once you've outpaced the biology of aging with the pathology of the disease, it gets a lot harder, a lot harder to do anything about it. So I think that communication part, honestly, I don't know why we've been so unsuccessful because I think a lot of us have been out there trying to communicate this message for a long time, but it's starting to permeate.

We're at that moment, I think, where people are starting to get it, that biological aging is a thing. It's malleable. We don't really know for sure what works in people and what doesn't work yet, but we're getting there.

We're at that moment, I think, where people are starting to get it, that biological aging is a thing. It's malleable. We don't really know for sure what works in people and what doesn't work yet, but we're getting there.

Yep. Probably cancer. Probably heart disease, although I think Peter's more optimistic we can prevent heart disease.

Yep. Probably cancer. Probably heart disease, although I think Peter's more optimistic we can prevent heart disease.

A lot of infectious disease. a lot of liver disease, a lot of kidney disease, all of those things can be improved dramatically by targeting the biology of aging.

A lot of infectious disease. a lot of liver disease, a lot of kidney disease, all of those things can be improved dramatically by targeting the biology of aging.

We have to come back to this. Are any of them powered for anything other than safety? This is, I think, the problem. No, it's all phase one. Yeah, exactly. So they're underpowered. They're almost useless, in my opinion. Well, until they get to phase two, phase three. How many years have we been having phase one senolytic trials now? I don't know. At least a decade.

We have to come back to this. Are any of them powered for anything other than safety? This is, I think, the problem. No, it's all phase one. Yeah, exactly. So they're underpowered. They're almost useless, in my opinion. Well, until they get to phase two, phase three. How many years have we been having phase one senolytic trials now? I don't know. At least a decade.

there's lots of complicated issues here. I think endpoints for clinical trials are really challenging, but solvable.

there's lots of complicated issues here. I think endpoints for clinical trials are really challenging, but solvable.

Why are mice so different from people? Wait a minute. I wouldn't say that just because we don't have evidence that it works in humans means mice are different from people. First of all, when it comes to parabiosis, right? I mean, that's a different discussion. But I agree that if you look at the attempts to cure cancer or other diseases in mice and translation to people, most have failed.

Why are mice so different from people? Wait a minute. I wouldn't say that just because we don't have evidence that it works in humans means mice are different from people. First of all, when it comes to parabiosis, right? I mean, that's a different discussion. But I agree that if you look at the attempts to cure cancer or other diseases in mice and translation to people, most have failed.

I actually think that's because those are artificial mouse models where they tried to give young mice an age-related disease. I'm more optimistic. But riches are not. I don't know this. Rich doesn't have those mice. Yeah, I know.

I actually think that's because those are artificial mouse models where they tried to give young mice an age-related disease. I'm more optimistic. But riches are not. I don't know this. Rich doesn't have those mice. Yeah, I know.

I'm more optimistic that biological aging or normative aging is going to be much more likely to translate to people, both interventions and biomarkers than the specific disease interventions. I might be wrong. I don't know the answer. We would hope that's the case. That's fair. I don't think we should rule out the mice as a useful model.

I'm more optimistic that biological aging or normative aging is going to be much more likely to translate to people, both interventions and biomarkers than the specific disease interventions. I might be wrong. I don't know the answer. We would hope that's the case. That's fair. I don't think we should rule out the mice as a useful model.

In fact, I think there's reason to be optimistic that it will. I actually am kind of bullish on parabiosis as I think it will work to some extent in people. It's not a pragmatic approach for population gerotherapeutics. But I'm just wondering like why it wouldn't be as efficacious.

In fact, I think there's reason to be optimistic that it will. I actually am kind of bullish on parabiosis as I think it will work to some extent in people. It's not a pragmatic approach for population gerotherapeutics. But I'm just wondering like why it wouldn't be as efficacious.

Yeah. Okay. Okay. But if you think of parabiosis as both taking away the bad stuff that accumulates with age and adding in the good stuff that's in young, some sort of plasma exchange hits at least half that equation.

Yeah. Okay. Okay. But if you think of parabiosis as both taking away the bad stuff that accumulates with age and adding in the good stuff that's in young, some sort of plasma exchange hits at least half that equation.

Yeah. And I mean, I think normative aging looks very similar. Again, if we look from mice to dogs to people, just broadly speaking, the process looks pretty similar. So I'm cautiously optimistic that these things are going to translate.

Yeah. And I mean, I think normative aging looks very similar. Again, if we look from mice to dogs to people, just broadly speaking, the process looks pretty similar. So I'm cautiously optimistic that these things are going to translate.

That's why I like aging rate indicators, speed things up. I'm stepping on your toes, Peter. But the question I always come back to, I agree, we need these aging rate indicators. How do we get to the point where we're confident that they actually work in people? And maybe more importantly, how do we get to the point that FDA is confident that they work?

That's why I like aging rate indicators, speed things up. I'm stepping on your toes, Peter. But the question I always come back to, I agree, we need these aging rate indicators. How do we get to the point where we're confident that they actually work in people? And maybe more importantly, how do we get to the point that FDA is confident that they work?

Because that's the only way you're going to be able to use them in a clinical trial. I don't see a path in the short term.

Because that's the only way you're going to be able to use them in a clinical trial. I don't see a path in the short term.

But that's a different end point.

But that's a different end point.

But you have to trust the biomarker of aging rate before you can be confident that the drug that moves the biomarker of aging rate works in people. That's fundamentally what I'm asking. How do we get to the point where, let's just take FDA out of the equation, the four of us would sit and look at the data and I'll be like, yep, that works. Well, that's sort of my thought experiment.

But you have to trust the biomarker of aging rate before you can be confident that the drug that moves the biomarker of aging rate works in people. That's fundamentally what I'm asking. How do we get to the point where, let's just take FDA out of the equation, the four of us would sit and look at the data and I'll be like, yep, that works. Well, that's sort of my thought experiment.

So what if I told you that there are people who claim There are epigenetic signatures that do that, that correlate quite well, they claim, with health outcomes, 10-year mortality, 5-year mortality, 3-year mortality in people and are measuring the rate of biological aging.

So what if I told you that there are people who claim There are epigenetic signatures that do that, that correlate quite well, they claim, with health outcomes, 10-year mortality, 5-year mortality, 3-year mortality in people and are measuring the rate of biological aging.

Yeah, I think it is. I mean, again, at least it depends on how much faith you put in these research studies. But I mean, people have published epigenetic algorithms. Dunedin-Pace is the one that most people are going to talk about that correlate seemingly pretty well, at least with mortality and with metrics of healthspan, for lack of a better way of framing it.

Yeah, I think it is. I mean, again, at least it depends on how much faith you put in these research studies. But I mean, people have published epigenetic algorithms. Dunedin-Pace is the one that most people are going to talk about that correlate seemingly pretty well, at least with mortality and with metrics of healthspan, for lack of a better way of framing it.

It was trained off of other biomarkers, and then they found epigenetic marks that correlate with those other biomarkers. So it's a correlation to a correlation, but they're still a correlation.

It was trained off of other biomarkers, and then they found epigenetic marks that correlate with those other biomarkers. So it's a correlation to a correlation, but they're still a correlation.

But do all of them have to change or just most of them?

But do all of them have to change or just most of them?

You're right. Those are two different things, to your point. It's not clear, but it's an interesting question. Like, do you believe exercise slows aging? Exercise, healthy diet, sleep? I have no idea.

You're right. Those are two different things, to your point. It's not clear, but it's an interesting question. Like, do you believe exercise slows aging? Exercise, healthy diet, sleep? I have no idea.

Well, there's evidence to support it. The question is, does it rise to the level of evidence that would convince Rich? I believe it probably does too, but I'm not going to say it with 100% certainty.

Well, there's evidence to support it. The question is, does it rise to the level of evidence that would convince Rich? I believe it probably does too, but I'm not going to say it with 100% certainty.

I agree completely. And this gets back to what we were talking about before with the epigenetic changes is if you had a mechanistic connection, which is what Rich is drawing there, not only this is correlated with this outcome, but here's why we all feel a lot more confident that this is real, that it's important. And especially if that mechanistic connection is preserved in people.

I agree completely. And this gets back to what we were talking about before with the epigenetic changes is if you had a mechanistic connection, which is what Rich is drawing there, not only this is correlated with this outcome, but here's why we all feel a lot more confident that this is real, that it's important. And especially if that mechanistic connection is preserved in people.

I'm super interested in that question.

I'm super interested in that question.

Are they geroprotective from a caloric restriction effect, or are there caloric independent effects that could potentially be geroprotective? I'm actually asking the second question.

Are they geroprotective from a caloric restriction effect, or are there caloric independent effects that could potentially be geroprotective? I'm actually asking the second question.

Okay. Yeah, that's a different question. Is chronic caloric restriction beneficial in normal weight people? But most people taking GLP-1 agonists aren't normal. Yes, yes, yes.

Okay. Yeah, that's a different question. Is chronic caloric restriction beneficial in normal weight people? But most people taking GLP-1 agonists aren't normal. Yes, yes, yes.

I think this conversation points out, again, how constraining lack of resources are. I mean, there are probably- It's infuriating.

I think this conversation points out, again, how constraining lack of resources are. I mean, there are probably- It's infuriating.

And I mean, every time I hear Rich talk about this stuff, it just pisses me off because there's a bunch of stuff that should be tested, should have been tested by now that hasn't been tested, not because it's not a good idea, but because there just isn't any resources to do it.

And I mean, every time I hear Rich talk about this stuff, it just pisses me off because there's a bunch of stuff that should be tested, should have been tested by now that hasn't been tested, not because it's not a good idea, but because there just isn't any resources to do it.

Last estimate I saw was 38 trillion a year for every year of healthspan. Wow. That was a McKinsey report. 38? I'll send you the link.

Last estimate I saw was 38 trillion a year for every year of healthspan. Wow. That was a McKinsey report. 38? I'll send you the link.

It's a natural product, yeah.

It's a natural product, yeah.

I think they started treatment in middle age, right?

I think they started treatment in middle age, right?

But we're conflating a bunch of different issues here. We're conflating the genetic model with the drugs and do senescent cells even exist? And I feel like, I mean, I think Rich's skepticism is valid in many ways. And there's actually a large body of evidence that

But we're conflating a bunch of different issues here. We're conflating the genetic model with the drugs and do senescent cells even exist? And I feel like, I mean, I think Rich's skepticism is valid in many ways. And there's actually a large body of evidence that

Whether we agree on the definition of senescence, what people are calling senescent cells do accumulate in multiple tissues with age in mice and people. And if you get rid of them, you can see some health benefits. Am I convinced they have big effects on lifespan? No, I'm not because the data is mixed. And even that genetic model, other people haven't been able to reproduce. So it's messy.

Whether we agree on the definition of senescence, what people are calling senescent cells do accumulate in multiple tissues with age in mice and people. And if you get rid of them, you can see some health benefits. Am I convinced they have big effects on lifespan? No, I'm not because the data is mixed. And even that genetic model, other people haven't been able to reproduce. So it's messy.

But I think partly maybe start with what is the definition of a senescent cell? Because that's where a lot of this confusion comes from.

But I think partly maybe start with what is the definition of a senescent cell? Because that's where a lot of this confusion comes from.

But we do that with other things. We have mitochondrial dysfunction. There's lots of different ways to get to mitochondrial dysfunction.

But we do that with other things. We have mitochondrial dysfunction. There's lots of different ways to get to mitochondrial dysfunction.

I keep trying to purge that from my memory. I mean, the most common definition, I think, is just an irreversibly arrested cell that doesn't die and typically gives off a pattern of inflammatory cytokines and other factors. which is a catch-all for a lot of different ways to get there and a lot of different states that these irreversibly arrested cells can exist in.

I keep trying to purge that from my memory. I mean, the most common definition, I think, is just an irreversibly arrested cell that doesn't die and typically gives off a pattern of inflammatory cytokines and other factors. which is a catch-all for a lot of different ways to get there and a lot of different states that these irreversibly arrested cells can exist in.

Right, but they don't always give off this pattern of signals, right?

Right, but they don't always give off this pattern of signals, right?

I mean, again, this is part of the problem. As you mentioned P16, I think even at the molecular level, the catalog of markers that people are using to define a senescent cell is changing, and it seems to change. Broadening, yeah. Yeah. Yeah. I agree with much of what you're saying. I just don't think we should throw the baby out with the bathwater here and say there's nothing to this.

I mean, again, this is part of the problem. As you mentioned P16, I think even at the molecular level, the catalog of markers that people are using to define a senescent cell is changing, and it seems to change. Broadening, yeah. Yeah. Yeah. I agree with much of what you're saying. I just don't think we should throw the baby out with the bathwater here and say there's nothing to this.

I think there is something to it. And I think there's lots of evidence that, are there enough similarities between all the different classes of senescent cells that people are studying now that they should be categorized as one thing? I think that's a valid conversation to have. It's a good discussion point. I don't think we know the answer yet.

I think there is something to it. And I think there's lots of evidence that, are there enough similarities between all the different classes of senescent cells that people are studying now that they should be categorized as one thing? I think that's a valid conversation to have. It's a good discussion point. I don't think we know the answer yet.

But I think you're both right. I think you're looking at it from different angles. So, Steve, you're pointing out that you can make people live longer when they're sick. I think what Rich is saying, which I agree with, and hopefully I'm going to paraphrase you correctly, which is

But I think you're both right. I think you're looking at it from different angles. So, Steve, you're pointing out that you can make people live longer when they're sick. I think what Rich is saying, which I agree with, and hopefully I'm going to paraphrase you correctly, which is

Maybe inefficient, but the field is making, I would say, quite a bit of progress. And I think the way you learn about the complexity is you start with a simple model, you study it, and then your model gets more complicated. So I totally get the frustration, Rich, because I get as frustrated as you are about senescent cells, about other things. But

Maybe inefficient, but the field is making, I would say, quite a bit of progress. And I think the way you learn about the complexity is you start with a simple model, you study it, and then your model gets more complicated. So I totally get the frustration, Rich, because I get as frustrated as you are about senescent cells, about other things. But

I think this is also part of the natural process here. And I think what Steve said is really important. The fraction of the NIH budget that goes to study the biology of aging through NIA has remained tiny. But senescent cells are actually a really good example of how a bunch of people in other institutes are studying aging, and they don't even know it.

I think this is also part of the natural process here. And I think what Steve said is really important. The fraction of the NIH budget that goes to study the biology of aging through NIA has remained tiny. But senescent cells are actually a really good example of how a bunch of people in other institutes are studying aging, and they don't even know it.

They're studying senescence in cancer, or senescence in Alzheimer's, or senescence in kidney disease. So it actually has had an impact in broadening the appeal and scope of the field outside of NIA in ways that I certainly didn't anticipate.

They're studying senescence in cancer, or senescence in Alzheimer's, or senescence in kidney disease. So it actually has had an impact in broadening the appeal and scope of the field outside of NIA in ways that I certainly didn't anticipate.

If we target the biology of aging, I haven't seen anything to make me believe that you can separate healthspan and lifespan, meaning that I haven't seen things that slow aging, increase lifespan, don't increase healthspan. I don't actually think that's plausible.

If we target the biology of aging, I haven't seen anything to make me believe that you can separate healthspan and lifespan, meaning that I haven't seen things that slow aging, increase lifespan, don't increase healthspan. I don't actually think that's plausible.

I mean, I think that could alleviate some of the turf war issues, but I think what you really need is the change in leadership and leaders who actually recognize why this is important. And that's where it starts. We can have a conversation about how much power does the NIH director have? How much power does the director of HHS have? But that's a place to start.

I mean, I think that could alleviate some of the turf war issues, but I think what you really need is the change in leadership and leaders who actually recognize why this is important. And that's where it starts. We can have a conversation about how much power does the NIH director have? How much power does the director of HHS have? But that's a place to start.

If you can get people in those positions who get it, it's going to have an impact.

If you can get people in those positions who get it, it's going to have an impact.

I think it's supply and demand, honestly. If there was demand, yeah, I think so. But coming back to the metformin question, I mean, I think, first of all, we don't know the answer. I mean, Rich is right. We don't know. So what are our opinions?

I think it's supply and demand, honestly. If there was demand, yeah, I think so. But coming back to the metformin question, I mean, I think, first of all, we don't know the answer. I mean, Rich is right. We don't know. So what are our opinions?

My opinion is diabetes probably accelerates biological aging and metformin is effective at reducing diabetic symptoms and probably reduces biological aging in that context, probably doesn't in people who are not diabetic. That's my intuition.

My opinion is diabetes probably accelerates biological aging and metformin is effective at reducing diabetic symptoms and probably reduces biological aging in that context, probably doesn't in people who are not diabetic. That's my intuition.

I don't know the answer, obviously. I think the question is, is the biomarker, in this case, A1C, what is that actually reflecting, right? Is that presumably reflecting some aspect of metabolic homeostasis? And so, first of all, does metformin in non-diabetics have the desired effect or the effect we would associate with reduced mortality in non-diabetics consistently? Be question number one.

I don't know the answer, obviously. I think the question is, is the biomarker, in this case, A1C, what is that actually reflecting, right? Is that presumably reflecting some aspect of metabolic homeostasis? And so, first of all, does metformin in non-diabetics have the desired effect or the effect we would associate with reduced mortality in non-diabetics consistently? Be question number one.

I don't know the answer to that. You probably do.

I don't know the answer to that. You probably do.

Well, and I would also say TAME could be successful independent of whether metformin is effective at slowing biological aging. By getting others into the field, you mean? Well, also even just hitting the endpoints, right? So the endpoint is multimorbidity or comorbidity.

Well, and I would also say TAME could be successful independent of whether metformin is effective at slowing biological aging. By getting others into the field, you mean? Well, also even just hitting the endpoints, right? So the endpoint is multimorbidity or comorbidity.

So it's quite possible that the trial will be successful, even if metformin is not effective gerotherapeutic, which is also true. It may not succeed for a variety of reasons. The clinical trials don't succeed. I sort of agree with Steve. I'm supportive of doing the trial.

So it's quite possible that the trial will be successful, even if metformin is not effective gerotherapeutic, which is also true. It may not succeed for a variety of reasons. The clinical trials don't succeed. I sort of agree with Steve. I'm supportive of doing the trial.

I also agree, I think, with probably both Steve and Rich, that it's not what I would pick if I was going to do one trial, if we could only do one trial, but we have to start somewhere.

I also agree, I think, with probably both Steve and Rich, that it's not what I would pick if I was going to do one trial, if we could only do one trial, but we have to start somewhere.

Because inhibiting mTOR increases lifespan and slows aging. I know what you're asking. Yeah, you know where I'm going. Because most people who are using rapamycin off-label have moved to once weekly or some sort of cycling like that. So I think one question is, would that increase lifespan in mice as much or more than daily? We don't effectively know the answer to that question, I don't think.

Because inhibiting mTOR increases lifespan and slows aging. I know what you're asking. Yeah, you know where I'm going. Because most people who are using rapamycin off-label have moved to once weekly or some sort of cycling like that. So I think one question is, would that increase lifespan in mice as much or more than daily? We don't effectively know the answer to that question, I don't think.

You guys do some intermittent. It can increase lifespan, but it's never been dose optimized, right? I think this is the question.

You guys do some intermittent. It can increase lifespan, but it's never been dose optimized, right? I think this is the question.

Yes, and the RAPA in the ITP study is in the food. So it's not a single dose or it's not a single- They're just chowing on it all day. Well, at least during the period of day that they're eating and have access. I'll let Rich talk about what they know about the blood levels, but it is a fundamentally way of delivering the drug.

Yes, and the RAPA in the ITP study is in the food. So it's not a single dose or it's not a single- They're just chowing on it all day. Well, at least during the period of day that they're eating and have access. I'll let Rich talk about what they know about the blood levels, but it is a fundamentally way of delivering the drug.

That the bad side effects come from mTORC2 off-target effects of rapamycin and all the good stuff comes from inhibiting mTORC1.

That the bad side effects come from mTORC2 off-target effects of rapamycin and all the good stuff comes from inhibiting mTORC1.

But even what Rich is saying is, while, I mean, really important and informative, also only a tiny piece of all the downstream things that mTOR affects. And I think the point is we just really don't have a good understanding of how rapamycin or fasting or other drugs that hit mTOR are affecting all of the things that are downstream of it.

But even what Rich is saying is, while, I mean, really important and informative, also only a tiny piece of all the downstream things that mTOR affects. And I think the point is we just really don't have a good understanding of how rapamycin or fasting or other drugs that hit mTOR are affecting all of the things that are downstream of it.

At least at the dose they used, right?

At least at the dose they used, right?

Right. That's right.

Right. That's right.

Yeah. And here's, I mean, I think an important, again, limitation to what's been done. There are drugs out there that hit both types of kinases. There are drugs out there that are ATP competitive inhibitors that have different affinities for different types of kinases. Haven't been tested for longevity. These dual kinase inhibitors.

Yeah. And here's, I mean, I think an important, again, limitation to what's been done. There are drugs out there that hit both types of kinases. There are drugs out there that are ATP competitive inhibitors that have different affinities for different types of kinases. Haven't been tested for longevity. These dual kinase inhibitors.

In fact, in the RestorBio trial, the last one, the phase three, which did not get to completion, they substituted, they took the Rapalog out and used an ATP competitive drug. Didn't know that.

In fact, in the RestorBio trial, the last one, the phase three, which did not get to completion, they substituted, they took the Rapalog out and used an ATP competitive drug. Didn't know that.

You're doing it. We're doing it once a week now. We've moved to once a week. So, I mean, maybe it's worth at least talking about how that evolved.

You're doing it. We're doing it once a week now. We've moved to once a week. So, I mean, maybe it's worth at least talking about how that evolved.

And this is my understanding of how we got to where we are today, which is that most people using Rapamycin off-label for potential health span effects, most doctors prescribing it are recommending once weekly dosing in the three to six, sometimes eight, 10 milligram range.

And this is my understanding of how we got to where we are today, which is that most people using Rapamycin off-label for potential health span effects, most doctors prescribing it are recommending once weekly dosing in the three to six, sometimes eight, 10 milligram range.

The first place I'm aware of in the literature where this was shown to have a potential benefit for anything related to aging was Joan Manick's work when she was first at Novartis and then at Restore Bio looking at flu vaccine response in elderly patients. And they were using everolimus, so a derivative of rapamycin.

The first place I'm aware of in the literature where this was shown to have a potential benefit for anything related to aging was Joan Manick's work when she was first at Novartis and then at Restore Bio looking at flu vaccine response in elderly patients. And they were using everolimus, so a derivative of rapamycin.

And they found that for vaccine response, it was most effective and had the least side effects at once weekly dosing at five milligrams. And they tested daily one or two mg, five mg once a week, 20 mg once a week.

And they found that for vaccine response, it was most effective and had the least side effects at once weekly dosing at five milligrams. And they tested daily one or two mg, five mg once a week, 20 mg once a week.

So my understanding is that Novartis had internal data at that point on side effects and had an internal hypothesis that if you let the trough levels bottom out, that reduced side effects. The side effects in organ transplant patients were largely driven- High troughs. nitrophs.

So my understanding is that Novartis had internal data at that point on side effects and had an internal hypothesis that if you let the trough levels bottom out, that reduced side effects. The side effects in organ transplant patients were largely driven- High troughs. nitrophs.

And then after that, they developed, based off of David Sabatini's work and then Dudley Lamming after he left David's lab, a hypothesis that chronic treatment with rapamycin, which maybe would be equivalent to daily dosing in people, this was all done in cells, led to off-target effects on mTOR complex 2, and it was mTOR complex 2 effects that were driving the side effects.

And then after that, they developed, based off of David Sabatini's work and then Dudley Lamming after he left David's lab, a hypothesis that chronic treatment with rapamycin, which maybe would be equivalent to daily dosing in people, this was all done in cells, led to off-target effects on mTOR complex 2, and it was mTOR complex 2 effects that were driving the side effects.

So that got sort of dogmatized as the truth. I actually don't think there's a ton of evidence beyond those initial papers to support the idea that the side effects are all through mTOR complex 2. The idea is if you dose once a week, you let the trough levels bottom out, you don't get the off-target effects on mTOR complex 2, you avoid the side effects. Again, we don't have definitive data.

So that got sort of dogmatized as the truth. I actually don't think there's a ton of evidence beyond those initial papers to support the idea that the side effects are all through mTOR complex 2. The idea is if you dose once a week, you let the trough levels bottom out, you don't get the off-target effects on mTOR complex 2, you avoid the side effects. Again, we don't have definitive data.

The data I've seen seem consistent with that idea. People dosing daily seem to be more likely to have side effects, mostly things like bacterial infections or the really severe mouth sores, but sort of anecdotal. And I don't know for sure how strong that data is in people.

The data I've seen seem consistent with that idea. People dosing daily seem to be more likely to have side effects, mostly things like bacterial infections or the really severe mouth sores, but sort of anecdotal. And I don't know for sure how strong that data is in people.

It did hold up in all of the rest or bioclinical trials that I'm aware of that once weekly dosing really didn't show any side effects different from placebo.

It did hold up in all of the rest or bioclinical trials that I'm aware of that once weekly dosing really didn't show any side effects different from placebo.

It's an enteric-coded. It's a different formulation than what the ITP uses, but all of the human serolimus formulations have some way to get to the small intestine. So it's not substantially different, I don't think, than rapamune or the generic serolimus you would get.

It's an enteric-coded. It's a different formulation than what the ITP uses, but all of the human serolimus formulations have some way to get to the small intestine. So it's not substantially different, I don't think, than rapamune or the generic serolimus you would get.

I think it's really hard to prove something doesn't work. So once it gets in the consciousness as improving health, I mean, even in the longevity field, Jesus Christ, I was saying the resveratrol stuff was garbage for 10 years before people believed it. Now everybody believes it, but it takes a really long time.

I think it's really hard to prove something doesn't work. So once it gets in the consciousness as improving health, I mean, even in the longevity field, Jesus Christ, I was saying the resveratrol stuff was garbage for 10 years before people believed it. Now everybody believes it, but it takes a really long time.

Well, at least in the aging field, like you never see people studying resveratrol in the aging field anymore. I think if you went to a conference and asked scientists, what do you think about resveratrol? You'd get the same answer here with maybe one exception. But I think it takes a really hard- Just one exception. It takes a long time to change- Bad ideas don't die hard. That's right.

Well, at least in the aging field, like you never see people studying resveratrol in the aging field anymore. I think if you went to a conference and asked scientists, what do you think about resveratrol? You'd get the same answer here with maybe one exception. But I think it takes a really hard- Just one exception. It takes a long time to change- Bad ideas don't die hard. That's right.

And that's true in the scientific literature. And it's especially true when there's a profit motive to continue selling this stuff. And I'm not 100% convinced that there are no health benefits from resveratrol. Pretty convinced. There's no reason to believe it affects the biology of aging or is a longevity drug, but I can't say for sure that nobody would ever benefit from any dose of resveratrol.

And that's true in the scientific literature. And it's especially true when there's a profit motive to continue selling this stuff. And I'm not 100% convinced that there are no health benefits from resveratrol. Pretty convinced. There's no reason to believe it affects the biology of aging or is a longevity drug, but I can't say for sure that nobody would ever benefit from any dose of resveratrol.

Yeah, but we couldn't say that about anything. I agree.

Yeah, but we couldn't say that about anything. I agree.

Yeah.

Yeah.

I agree with you. And I think it's even worse, though, than the way you laid it out. So if you look at the statistics, if you accept that 60% of Americans have at least one chronic disease, and the median age in the United States is 38 point something, and then you think about how long are people living on average?

I agree with you. And I think it's even worse, though, than the way you laid it out. So if you look at the statistics, if you accept that 60% of Americans have at least one chronic disease, and the median age in the United States is 38 point something, and then you think about how long are people living on average?

Yeah, well, I think the way you framed that question to Steve is indicative of why it's so hard to disprove something, especially when there are people out there who have money to make who really want to make the case that you should buy this stuff. Because it's always possible that there's some way that this could be beneficial. Having said that,

Yeah, well, I think the way you framed that question to Steve is indicative of why it's so hard to disprove something, especially when there are people out there who have money to make who really want to make the case that you should buy this stuff. Because it's always possible that there's some way that this could be beneficial. Having said that,

NAD, like Steve said, central molecule in thousands of chemical reactions, really important. Good reason, I don't know about good reason, some reason to believe that NAD homeostasis declines with age like lots of many other things. So it's plausible that if you fix that, you can get benefits from it. The data is decidedly mixed, both in the literature.

NAD, like Steve said, central molecule in thousands of chemical reactions, really important. Good reason, I don't know about good reason, some reason to believe that NAD homeostasis declines with age like lots of many other things. So it's plausible that if you fix that, you can get benefits from it. The data is decidedly mixed, both in the literature.

preclinical literature and in people as to whether or not boosting NAD increases lifespan, improves health span. So I think there's lots of issues. What's the most positive data you would point to?

preclinical literature and in people as to whether or not boosting NAD increases lifespan, improves health span. So I think there's lots of issues. What's the most positive data you would point to?

Well, for lifespan, the original study by Johan Auwerx's lab, where they started treating, I think, at 20 months of age, was published in Science, I believe, showed an effect that was reasonably good-sized, except the controls were short-lived, which is a different issue. Yeah, it's a different issue, right?

Well, for lifespan, the original study by Johan Auwerx's lab, where they started treating, I think, at 20 months of age, was published in Science, I believe, showed an effect that was reasonably good-sized, except the controls were short-lived, which is a different issue. Yeah, it's a different issue, right?

That would suggest if you say that, and again, this is what you're getting at with the definition of healthspan. I would not define healthspan as ending once you have your first chronic disease, but that's the definition most people would use. If you use that definition, most people are spending three decades or more in the absence of healthspan or in sickspan.

That would suggest if you say that, and again, this is what you're getting at with the definition of healthspan. I would not define healthspan as ending once you have your first chronic disease, but that's the definition most people would use. If you use that definition, most people are spending three decades or more in the absence of healthspan or in sickspan.

There's a number of cases where something was reported to increase lifespan when the controls were short-lived, and then when the study was repeated in longer-lived controls, you didn't see an effect. I don't know why there was a difference between that study and the ITP, but that's probably the best case you can point to.

There's a number of cases where something was reported to increase lifespan when the controls were short-lived, and then when the study was repeated in longer-lived controls, you didn't see an effect. I don't know why there was a difference between that study and the ITP, but that's probably the best case you can point to.

There's studies in C. elegans as well where NAD precursors increase lifespan. So there's evidence out there. And again, it's plausible. The biology is plausible. But then I think when you talk about the precursors... It's even more complicated than maybe boosting NAD could slow aging because can you get the right doses in people? You talked about bioavailability.

There's studies in C. elegans as well where NAD precursors increase lifespan. So there's evidence out there. And again, it's plausible. The biology is plausible. But then I think when you talk about the precursors... It's even more complicated than maybe boosting NAD could slow aging because can you get the right doses in people? You talked about bioavailability.

Is there any difference between NMN, NR, niacin, nicotinamide? When you take it orally, the data suggests that it all gets broken down to niacin. in the gut. So why are people taking $70 NMN or NR? Yeah. Why are people selling it? The people who are selling it, some of them are scientists, dodge that question. It's complicated.

Is there any difference between NMN, NR, niacin, nicotinamide? When you take it orally, the data suggests that it all gets broken down to niacin. in the gut. So why are people taking $70 NMN or NR? Yeah. Why are people selling it? The people who are selling it, some of them are scientists, dodge that question. It's complicated.

I don't personally believe there is enough evidence to think that NAD precursors as they are being marketed today are likely to benefit most people. Some people, probably people who have conditions of dysregulated NAD could get a benefit. I don't think there's any difference between the various molecules that are being marketed right now.

I don't personally believe there is enough evidence to think that NAD precursors as they are being marketed today are likely to benefit most people. Some people, probably people who have conditions of dysregulated NAD could get a benefit. I don't think there's any difference between the various molecules that are being marketed right now.

And there's at least one study in mice that giving NMN to aged mice causes kidney inflammation and potentially kidney pathology. I'm not saying NMN's dangerous, but when you try to weigh the risk-reward... If it causes kidney pathology in aged mice, at least at high doses, could it do the same thing in dogs or people? Yeah, it could.

And there's at least one study in mice that giving NMN to aged mice causes kidney inflammation and potentially kidney pathology. I'm not saying NMN's dangerous, but when you try to weigh the risk-reward... If it causes kidney pathology in aged mice, at least at high doses, could it do the same thing in dogs or people? Yeah, it could.

And it bothers me, particularly in the companion animal space, that people are marketing NMN for people's pets when they know that it might cause kidney disease in people's dogs and cats. That's problematic to me.

And it bothers me, particularly in the companion animal space, that people are marketing NMN for people's pets when they know that it might cause kidney disease in people's dogs and cats. That's problematic to me.

So the situation is even in the United States where life expectancy is relatively short compared to other nations, a big chunk of that life expectancy is not spent in good health. And it's exactly for this reason.

So the situation is even in the United States where life expectancy is relatively short compared to other nations, a big chunk of that life expectancy is not spent in good health. And it's exactly for this reason.

I think Peter and I are saying the same thing. Would we love to understand the mechanism? Yeah, absolutely. Do we have to understand the mechanism to figure out whether it works in people? No. And if it works, great. That's a win too. I think Rich's point is we only have so much money. Let's spend it on figuring out the mechanism. But again, that's a fundraising issue.

I think Peter and I are saying the same thing. Would we love to understand the mechanism? Yeah, absolutely. Do we have to understand the mechanism to figure out whether it works in people? No. And if it works, great. That's a win too. I think Rich's point is we only have so much money. Let's spend it on figuring out the mechanism. But again, that's a fundraising issue.

I agree, but yet you guys have tested natural products where we have no clue what the mechanism is, or even metformin. You pointed to complex one inhibition. Yeah, that's one thing metformin does, and it might activate AMP kinase, that mechanism, but we have no clue.

I agree, but yet you guys have tested natural products where we have no clue what the mechanism is, or even metformin. You pointed to complex one inhibition. Yeah, that's one thing metformin does, and it might activate AMP kinase, that mechanism, but we have no clue.

Yeah. And it doesn't have to be parabiosis. It doesn't have to be taking blood from young people and putting it into old people, right? There are other variants of this that can be done clinically. And there's some evidence to support things like therapeutic plasma exchange or things like that. So should we test it? I think so.

Yeah. And it doesn't have to be parabiosis. It doesn't have to be taking blood from young people and putting it into old people, right? There are other variants of this that can be done clinically. And there's some evidence to support things like therapeutic plasma exchange or things like that. So should we test it? I think so.

And my gut feeling is, yeah, it probably will have some benefits in people.

And my gut feeling is, yeah, it probably will have some benefits in people.

Yeah. First of all, I don't know enough about this area to be confident in my answer. But yeah, that's probably where I would look to start simply because it's going to be logistically easier to do from a clinical trial perspective.

Yeah. First of all, I don't know enough about this area to be confident in my answer. But yeah, that's probably where I would look to start simply because it's going to be logistically easier to do from a clinical trial perspective.

I'd push back on that. I think we do have reason to believe it's a combination of both. There's data in both directions. That's why I proposed starting with that experiment. I think that's, again, as much as anything's sure in this field, that's not as sure as rapamycin increases lifespan in mice, but there's at least evidence to support that idea.

I'd push back on that. I think we do have reason to believe it's a combination of both. There's data in both directions. That's why I proposed starting with that experiment. I think that's, again, as much as anything's sure in this field, that's not as sure as rapamycin increases lifespan in mice, but there's at least evidence to support that idea.

Last thing I'll say is you asked why might it fail in humans. I think Steve's answer is valid. It's also worth mentioning, at least with the parabiosis experiments, the parabiosis experiment itself shortens lifespan in rodents. And so just the fact that you're surgically connecting these animals together. So it may be that the benefit...

Last thing I'll say is you asked why might it fail in humans. I think Steve's answer is valid. It's also worth mentioning, at least with the parabiosis experiments, the parabiosis experiment itself shortens lifespan in rodents. And so just the fact that you're surgically connecting these animals together. So it may be that the benefit...

from true parabiosis in that context is somehow related to the shortening of lifespan due to the procedure. I don't think that's the case because there's other lines of evidence that argue against that, but there may be something about the procedure itself that is- That increases muscle repair and improves cardiac function.

from true parabiosis in that context is somehow related to the shortening of lifespan due to the procedure. I don't think that's the case because there's other lines of evidence that argue against that, but there may be something about the procedure itself that is- That increases muscle repair and improves cardiac function.

I'm just saying that may be an alternative explanation for something that's limiting in those mouse experiments.

I'm just saying that may be an alternative explanation for something that's limiting in those mouse experiments.

Matt, anybody? I mean, I think we would all agree there are tons of great people in the field. I mean, I think Brian Kennedy, and I think Brian is going to be on your podcast in an upcoming date, is somebody who also thinks broadly and deeply about the science and is fantastic. So he would be great to have. It would be great to have some differing.

Matt, anybody? I mean, I think we would all agree there are tons of great people in the field. I mean, I think Brian Kennedy, and I think Brian is going to be on your podcast in an upcoming date, is somebody who also thinks broadly and deeply about the science and is fantastic. So he would be great to have. It would be great to have some differing.

I mean, we differ sometimes on opinions, but I think more or less are aligned. Be interesting to have some differing voices as well.

I mean, we differ sometimes on opinions, but I think more or less are aligned. Be interesting to have some differing voices as well.

You know who else I want to throw out there is Morgan Levine. I think she'd be really interesting to have because while she is an expert in epigenetics and biomarkers, I think takes a pretty clear-eyed view of that space.

You know who else I want to throw out there is Morgan Levine. I think she'd be really interesting to have because while she is an expert in epigenetics and biomarkers, I think takes a pretty clear-eyed view of that space.