Sauna Heart Health and Longevity: Evidence First | Vitruvian

Video·Peter Attia MD·9 min read·January 27, 2025

A roundtable on why longevity has gone mainstream, what healthspan really means, and where the science separates from the marketplace.

Longevity Meets the Mainstream

Longevity has entered the public square with unusual force. A word that once lived at the edge of aging research now appears in search trends, product claims, investor decks, and private conversations about the future of health. The signal is clear: people are no longer asking only how to live longer. They are asking whether aging itself can be shaped with intention.

For scientists who spent decades studying aging, that shift carries tension. Many once avoided the word longevity because it sounded like a promise to extend frailty. The concern was precise and human. No one is served by more years if those years are marked by loss of function, dependence, and narrowing possibility.

The field wanted a better frame. Healthspan became the preferred language because it pointed toward vitality, not duration alone. It made space for the outcome people actually care about: more time with strength, cognition, independence, and participation intact. The aim was not simply to delay death. The aim was to preserve the capacity to live well.

Let's not even say the word longevity, let's say healthspan.

The new interest comes from several directions at once. Older adults are thinking directly about their own future, often with more knowledge and more tools than previous generations had. Technology entrepreneurs see aging as a large, complex problem worthy of investment. A broader culture, unsettled by chronic disease and the visible cost of late-life decline, is looking for a more deliberate path.

That attention has value. Public curiosity can move research, attract funding, and make serious science easier to discuss outside specialist circles. It can also blur the line between disciplined discovery and commercial theater. When a market grows faster than evidence, confidence becomes a product, and the consumer carries the risk.

This is the central tension of the moment. Aging science has made real progress, and the public is right to notice. At the same time, the marketplace has learned to sell the language of longevity before the science has finished its work. The promise is powerful; the protocol must remain grounded.

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is aging a disease is that even a relevant question call me calling me relevant question call me calling me calling me so calling aging a disease is calling me so calling aging a disease is a fundamental oror the question itself a fundamental oror the question itself is incorrect I agree completely I think is incorrect I agree completely I think it's the wrong question I I I agree but it's the wrong question I I I agree but how do we Define health span I haven't how do we Define health span I haven't seen anything to make me believe that seen anything to make me believe that you can separate healthspan and lifespan you can separate healthspan and lifespan my own personal answer to that is it's a my own personal answer to that is it's a useless term a state of your physical useless term a state of your physical being that you can do the things you being that you can do the things you like to do the United States has the like to do the United States has the lowest life expectancy that's because lowest life expectancy that's because the United States has by far far the the United States has by far far the greatest rate of death in middle age and greatest rate of death in middle age and I mean the reality is the research flows I mean the reality is the research flows from where the dollars are going this from where the dollars are going this has been seen over and over and over at has been seen over and over and over at NIH maybe it's because the public NIH maybe it's because the public doesn't understand this but those people doesn't understand this but those people answer to the public cuz I'm in the mood answer to the public cuz I'm in the mood to see you get spicy can we just talk to see you get spicy can we just talk about sence for a minute there's no about sence for a minute there's no evidence as far as I know that it either evidence as far as I know that it either has an anti-aging effect or removes has an anti-aging effect or removes siness and cells let's do the closest siness and cells let's do the closest thing that a group like this could do in thing that a group like this could do in terms of a speed terms of a speed round hey everyone Welcome to the live

round hey everyone Welcome to the live podcast I'm your host Peter podcast I'm your host Peter [Music] AA gentlemen this is a lot of fun I am excited to be sitting down with with you excited to be sitting down with with you guys today um where do we want to begin guys today um where do we want to begin I mean I let me start by saying the I mean I let me start by saying the following uh the the term longevity following uh the the term longevity someone sent me something the other day someone sent me something the other day that was like list of you know I don't that was like list of you know I don't know whether it was how many times the know whether it was how many times the word longevity was searched on gole word longevity was searched on gole Google or something like that but it it Google or something like that but it it literally looks like Bitcoin if you I literally looks like Bitcoin if you I mean it's yeah so we are clearly at Peak mean it's yeah so we are clearly at Peak longevity in terms of public interest longevity in terms of public interest which um for all of you who have kind of which um for all of you who have kind of devoted decades plural to this um I just devoted decades plural to this um I just want to kind of get a reaction from you want to kind of get a reaction from you each of you on on what that means why each of you on on what that means why you think it's happening and uh uh maybe you think it's happening and uh uh maybe even extending the metaphor a little bit even extending the metaphor a little bit is is there a bubble going on uh so is is there a bubble going on uh so we'll start with you Steve yeah well I we'll start with you Steve yeah well I it's a surprise to me that longevity has

it's a surprise to me that longevity has become so big because for a long time we become so big because for a long time we sort of try to move away from that in sort of try to move away from that in the Aging field because we were worried the Aging field because we were worried that people were thinking of longevity that people were thinking of longevity as well we're going to keep frail feeble as well we're going to keep frail feeble old people alive longer that's what old people alive longer that's what longevity me when really what we were longevity me when really what we were trying to do is extend health and so I'm trying to do is extend health and so I'm kind of surprised but I think it's kind of surprised but I think it's because uh there are certain people of a because uh there are certain people of a certain age who've started to think certain age who've started to think about their own longevity and then I about their own longevity and then I think there's a whole new generation think there's a whole new generation of of of tech of of of tech unur that really feel like this is a unur that really feel like this is a problem that will allow them to live problem that will allow them to live healthily for several decades at least healthily for several decades at least longer than they are now so I think it's longer than they are now so I think it's a combination it's a multigenerational a combination it's a multigenerational thing that that kind of surprises me and thing that that kind of surprises me and you haven't seen this before to be clear you haven't seen this before to be clear so 30 years ago you didn't see glimmers so 30 years ago you didn't see glimmers of this no 30 years ago I would have of this no 30 years ago I would have said let's not even say the word said let's not even say the word longevity let's say healthspan um but um

longevity let's say healthspan um but um that's changed quite clearly as more and that's changed quite clearly as more and more people have been you know from the more people have been you know from the outside they're sort of peing in at the outside they're sort of peing in at the field I don't think the people in the field I don't think the people in the field itself have changed the way they field itself have changed the way they talk that much but the people talk that much but the people eavesdropping on the field certainly eavesdropping on the field certainly have rich is that your experience well I have rich is that your experience well I think there are two aspects that that I think there are two aspects that that I would want to emphasize in response both would want to emphasize in response both to your question and to what Steve said to your question and to what Steve said um in response to the question I think um in response to the question I think the reason that people are now people the reason that people are now people have always been fascinated for have always been fascinated for Millennia on things they could do to Millennia on things they could do to stay alive and healthy as long as stay alive and healthy as long as possible but there were actually possible but there were actually scientific discoveries in the 90s uh scientific discoveries in the 90s uh that showed that it could be done and that showed that it could be done and then in the last 20 years there's then in the last 20 years there's evidence that it can be done at least in evidence that it can be done at least in mice with pills so that naturally should mice with pills so that naturally should lead to speculation that there could be lead to speculation that there could be pills you could give to people that pills you could give to people that would postpone poor health for a would postpone poor health for a substantial amount of time uh 20 to 30% substantial amount of time uh 20 to 30% is what we're seeing in mice and 20 to

is what we're seeing in mice and 20 to 30% would be very important for people 30% would be very important for people so I think that is a part of it the so I think that is a part of it the other part is that um there are now other part is that um there are now people who are are making a lot of money people who are are making a lot of money by selling stuff that is untested to be by selling stuff that is untested to be polite about it or is useless to be less polite about it or is useless to be less polite about it to gullible customers polite about it to gullible customers and so uh people who want to make a lot and so uh people who want to make a lot of money have finally found that there's of money have finally found that there's a impetus that will allow them to sell a impetus that will allow them to sell stuff even if there's no evidence that stuff even if there's no evidence that it works that they they control an it works that they they control an enormous amount of advertising dollars enormous amount of advertising dollars both formal and informal uh uh that's a both formal and informal uh uh that's a a big part of the difference the one a big part of the difference the one comment I wanted to make with regard to comment I wanted to make with regard to to something Steve said has to do with to something Steve said has to do with the the alleged balance between Health span and alleged balance between Health span and lifespan the it's become fashionable for lifespan the it's become fashionable for the last 20 or 30 years to imagine that the last 20 or 30 years to imagine that you get one or the other that you have you get one or the other that you have to make a choice it's a decision uh and to make a choice it's a decision uh and that if you give up

that if you give up on lifespan that allows you to extend on lifespan that allows you to extend health span I think that's ridiculous health span I think that's ridiculous and controverted by all the available and controverted by all the available evidence that is all of the drugs at evidence that is all of the drugs at least that extend lifespan in mice and least that extend lifespan in mice and could potentially do so in people do so could potentially do so in people do so by postponing diseases both the diseases by postponing diseases both the diseases that will kill you that's why they that will kill you that's why they extend lifespan and the diseases that extend lifespan and the diseases that won't kill you but which will annoy you won't kill you but which will annoy you and make you very unhappy to be old and make you very unhappy to be old so which is true by the way of so which is true by the way of non-molecular tools as well that's true non-molecular tools as well that's true exercise absolutely that's a good point exercise absolutely that's a good point not being insulin resistant I agree with not being insulin resistant I agree with you so the notion it's time to put you so the notion it's time to put behind us and to make fun of the notion behind us and to make fun of the notion that I'm not interested in lifespan that I'm not interested in lifespan don't put me on that boat I am don't put me on that boat I am interested in health span because they interested in health span because they are linked together and they go up and are linked together and they go up and down together getting people disabused down together getting people disabused of that false metaphor the Seesaw of that false metaphor the Seesaw metaphor is probably an important goal metaphor is probably an important goal for sort of the public interface between

for sort of the public interface between longevity scientists aging scientists I longevity scientists aging scientists I just want to push on one thing though um just want to push on one thing though um you you talked about obviously the you you talked about obviously the discoveries of molecules you've been discoveries of molecules you've been personally Central to that work um but personally Central to that work um but there was still a lag Rich right I mean there was still a lag Rich right I mean it it was 16 15 years ago the first ITP was was 16 15 years ago the first ITP was published showing the published showing the overwhelmingly surprising and positive overwhelmingly surprising and positive results of results of those results were repeated so why why those results were repeated so why why why a decade let's be generous and and why a decade let's be generous and and charitable and call it a still decade charitable and call it a still decade long lag from that and by the way I'll long lag from that and by the way I'll throw one more thing in there if you go throw one more thing in there if you go back to Cynthia kenyon's work which may back to Cynthia kenyon's work which may have been the thin end of the wedge into have been the thin end of the wedge into the idea that lifespan was malleable the idea that lifespan was malleable albe it through a genetic manipulation albe it through a genetic manipulation in a less relevant model yeah there's in a less relevant model yeah there's still a lag and and and again do do you still a lag and and and again do do you sort of do you buy Steve's argument that sort of do you buy Steve's argument that it's a confluence of Technology Tech

it's a confluence of Technology Tech entrepreneurs let me answer your entrepreneurs let me answer your question first question first um why the lag I think there's a whole um why the lag I think there's a whole batch of reasons and they're important batch of reasons and they're important and they're easy to spell out one is and they're easy to spell out one is that the prevailing attitude is that that the prevailing attitude is that aging is there there's nothing you can aging is there there's nothing you can do about it I'm gonna uh not be able to do about it I'm gonna uh not be able to outwit aiding though I may be able to be outwit aiding though I may be able to be maybe healthier in my older years the maybe healthier in my older years the notion that aging is is not malleable notion that aging is is not malleable though wrong and provably wrong is still though wrong and provably wrong is still the overwhelming opinion even of the overwhelming opinion even of reasonably educated scientists and reasonably educated scientists and certainly of the of the lay public then certainly of the of the lay public then commercially there are companies that commercially there are companies that make a ton of money selling stuff that make a ton of money selling stuff that doesn't work by pretending with a wink doesn't work by pretending with a wink and a nod and and a lawyer that it might and a nod and and a lawyer that it might slow the aging process down um and since slow the aging process down um and since they can make a lot of money they don't they can make a lot of money they don't actually have to spend valuable actually have to spend valuable marketing dollars on doing you know marketing dollars on doing you know research and stuff to prove that it

research and stuff to prove that it works some of the drugs that at least in works some of the drugs that at least in the hands of our Mouse group the ITP the hands of our Mouse group the ITP interventions testing uh program some of interventions testing uh program some of the drugs are the patent is owned by the drugs are the patent is owned by another company or they're out of patent another company or they're out of patent or it's a natural natural product none or it's a natural natural product none of that says take me to whoever owns a of that says take me to whoever owns a big pharmaceutical firm um and also even big pharmaceutical firm um and also even if you do it right and you really want if you do it right and you really want to do it and you've got a very large to do it and you've got a very large budget it's not an overnight kind of budget it's not an overnight kind of thing anyone drug a leading agent that thing anyone drug a leading agent that like Rapa M which you mentioned and the like Rapa M which you mentioned and the half a dozen others that we've shown half a dozen others that we've shown work at least in mice finding something work at least in mice finding something in that same family that works really in that same family that works really well that is safe for people that's the well that is safe for people that's the member of the that 20 conjurers member of the that 20 conjurers conjurers of that drug that's best and conjurers of that drug that's best and most potent and safest that's not at all most potent and safest that's not at all trivial that takes a long time and it trivial that takes a long time and it takes a commitment of money and time and takes a commitment of money and time and effort and and intellectual resources um

effort and and intellectual resources um we're at the on the place where we can we're at the on the place where we can start to make an argument that that's a start to make an argument that that's a good idea but making an argument that good idea but making an argument that that's a good idea to people who that's a good idea to people who actually have the resources to carry it actually have the resources to carry it out as a has not so far been enormously out as a has not so far been enormously successful unfortunately can can I push successful unfortunately can can I push back a little on what rich said about back a little on what rich said about health span versus lifespan there health span versus lifespan there several papers that have come out several papers that have come out recently showing that the gap between recently showing that the gap between Health span and lifespan in in people is Health span and lifespan in in people is actually increasing and it's increasing actually increasing and it's increasing the fastest in the United States and the fastest in the United States and it's increasing faster among women than it's increasing faster among women than men so in humans this is a very real Gap men so in humans this is a very real Gap and it's a growing Gap and I think one and it's a growing Gap and I think one of the advantages of the kind of of the of the advantages of the kind of of the geroscience the stuff that we do is that geroscience the stuff that we do is that rich is right we don't see this in our rich is right we don't see this in our experimental systems so this to me experimental systems so this to me emphasizes the fact that we need to emphasizes the fact that we need to change the focus I think one of the change the focus I think one of the reasons that the Gap exists as we're reasons that the Gap exists as we're getting better and better and better at getting better and better and better at treating heart disease and cancer and treating heart disease and cancer and all these things and keep keeping people

all these things and keep keeping people alive when they wouldn't have been alive alive when they wouldn't have been alive 10 years ago but but this is a really 10 years ago but but this is a really important factor I think about thinking important factor I think about thinking of Public Health globally it's important of Public Health globally it's important to see ex go ahead I was gon to say I to see ex go ahead I was gon to say I think you're both right I think you're think you're both right I think you're looking at it from different angles so looking at it from different angles so Steve you're pointing out that you can Steve you're pointing out that you can make people live longer when they're make people live longer when they're sick I think what rich is saying which I sick I think what rich is saying which I agree with and hopefully I'm going to agree with and hopefully I'm going to paraphrase you correctly which is if we paraphrase you correctly which is if we target the biology of Aging I haven't target the biology of Aging I haven't seen anything to make me believe that seen anything to make me believe that you can separate Health span and life you can separate Health span and life Anan meaning that I haven't seen things Anan meaning that I haven't seen things that slow aging increase lifespan don't that slow aging increase lifespan don't increase health span I don't actually increase health span I don't actually think that's plausible no and I think think that's plausible no and I think that's and I think that's an important that's and I think that's an important point that if we target aging we're point that if we target aging we're doing something different than with the doing something different than with the way that medicine is operating now which way that medicine is operating now which is targeting individual diseases after is targeting individual diseases after they occur right this is a very they occur right this is a very important Point um it came up in a important Point um it came up in a recent podcast that I did with Sam recent podcast that I did with Sam sutaria talking about healthcare costs sutaria talking about healthcare costs and in that discussion one of the things

and in that discussion one of the things that emerged um which I think most that emerged um which I think most people are sadly familiar with this people are sadly familiar with this statistic today is that among the oecd statistic today is that among the oecd Nations the United States has the lowest Nations the United States has the lowest life expectancy which is ironic given life expectancy which is ironic given that we are spending on average about that we are spending on average about 80% more and in some cases double what 80% more and in some cases double what most other developed Nations spend on most other developed Nations spend on Healthcare so how do you reconcile this Healthcare so how do you reconcile this well s made a very interesting point well s made a very interesting point which is that's aggregate life which is that's aggregate life expectancy but why is that the case expectancy but why is that the case that's because the United States has by that's because the United States has by far the greatest rate of death in middle far the greatest rate of death in middle age right so when you look at maternal age right so when you look at maternal and infant mortality were horrible when and infant mortality were horrible when you look at gun violence and suicide and you look at gun violence and suicide and homicide were horrible and most of all homicide were horrible and most of all when you look at overdoses were horrible when you look at overdoses were horrible right so when you kill a whole bunch of right so when you kill a whole bunch of people in their 40s and 50s you cannot people in their 40s and 50s you cannot have a very high life expectancy have a very high life expectancy understood but what s pointed out was understood but what s pointed out was once an American reaches the age of and once an American reaches the age of and I forget the exact age I think it was I forget the exact age I think it was about 65 all of a sudden they jump to about 65 all of a sudden they jump to the top of the

the top of the list that was very interesting to me in list that was very interesting to me in other words if you look at the Blended other words if you look at the Blended life expectancy we're we're not doing life expectancy we're we're not doing very well but if you look at life very well but if you look at life expectancy just in measured as years expectancy just in measured as years alive once you escape those big causes alive once you escape those big causes of death in middle age we actually do of death in middle age we actually do quite well and it comes down to what quite well and it comes down to what you're saying which is we get very good you're saying which is we get very good at delaying death in chronic disease at delaying death in chronic disease that's that's the what I call the that's that's the what I call the medicine 2.0 machine at its absolute medicine 2.0 machine at its absolute finest we are going to keep you along an finest we are going to keep you along an extra 6 months once you have cancer we extra 6 months once you have cancer we are going to get you through that third are going to get you through that third revascularization procedure and so now revascularization procedure and so now the question is does that because my the question is does that because my intuition is where yours is Steve I intuition is where yours is Steve I don't think we're getting any healthier don't think we're getting any healthier even if we're incrementally figuring out even if we're incrementally figuring out ways to extend life in the face of ways to extend life in the face of chronic disease I don't see it being a chronic disease I don't see it being a quality of life now part of this might quality of life now part of this might be how do we Define health span yeah so be how do we Define health span yeah so let me I agree with you and and um I let me I agree with you and and um I think it's even worse though than the think it's even worse though than the way you laid it out so if you look at

way you laid it out so if you look at the statistics if you accept that 60% of the statistics if you accept that 60% of Americans have at least one chronic Americans have at least one chronic disease and the median age in the United disease and the median age in the United States is 38 point something and then States is 38 point something and then you think about how long are people you think about how long are people living on average that would suggest if living on average that would suggest if you say that and again this is what you say that and again this is what you're getting at with the definition of you're getting at with the definition of Health span I would not Define health Health span I would not Define health span as ending once you have your first span as ending once you have your first chronic disease but that's the chronic disease but that's the definition most people would use if you definition most people would use if you use that definition most people are use that definition most people are spending three decades or more in the spending three decades or more in the absence ofal Health span right or in absence ofal Health span right or in sick span so I mean the situation is sick span so I mean the situation is even in the United States where life even in the United States where life expectancy is relatively short compared expectancy is relatively short compared to other nations a big chunk of that to other nations a big chunk of that life expectancy is not spent in good life expectancy is not spent in good health and it's exactly for this reason health and it's exactly for this reason but the they're two different issues but the they're two different issues that are being confused here in the discussion one is the issue of whether you can help middle-aged people live you can help middle-aged people live longer and everybody's agreed that we're

longer and everybody's agreed that we're getting better at that we're pretty good getting better at that we're pretty good at it and that certainly contributes to at it and that certainly contributes to whatever you think Health span might whatever you think Health span might mean that's an mean that's an issue however that is quite different issue however that is quite different from what a concoction that slows aging from what a concoction that slows aging sure do so by extending Health span sure do so by extending Health span those both have the word Health Span in those both have the word Health Span in them but they are different and them but they are different and shouldn't ever be confused with one shouldn't ever be confused with one another the other point and this another the other point and this question you asked was what is the is question you asked was what is the is Health span my own personal answer to Health span my own personal answer to that is it's a useless that is it's a useless term that is because no one can Define term that is because no one can Define it it's not because no one is smart it's it it's not because no one is smart it's because the term itself is vacuous and because the term itself is vacuous and nebulous if you have somebody that gets nebulous if you have somebody that gets a certain chronic disease here and then a certain chronic disease here and then another one and then they fall down and another one and then they fall down and bump their head and by the way they go bump their head and by the way they go to the hospital and with Co etc etc to the hospital and with Co etc etc defining when in that broad over that 20 defining when in that broad over that 20 to 30e period perod they flicked the

to 30e period perod they flicked the switch now they have gotten to the end switch now they have gotten to the end of the health spin is impossible and of of the health spin is impossible and of no interest the general notion that no interest the general notion that people are interested in is whether that people are interested in is whether that you can do stuff to keep people healthy you can do stuff to keep people healthy for a long time either without changing for a long time either without changing their life expectancy or by changing their life expectancy or by changing their life with changing their life their life with changing their life those are interesting but you don't have those are interesting but you don't have to assign a number but couldn't we get to assign a number but couldn't we get away because I agree with you completely away because I agree with you completely rich I I don't like the medical rich I I don't like the medical definition of Health span which I definition of Health span which I believe is quote the period of time in believe is quote the period of time in which an individual is free of which an individual is free of disability and disease I find that to be disability and disease I find that to be a very unhelpful definition because it a very unhelpful definition because it be but part of the reason it's awful is be but part of the reason it's awful is it's binary yeah and silly but if we it's binary yeah and silly but if we made it analog instead of digital right made it analog instead of digital right I'm not saying that makes it easy it's I'm not saying that makes it easy it's still very challenging but now it allows still very challenging but now it allows us to start talking about things right us to start talking about things right as a person except it's a concept it's a as a person except it's a concept it's a qualitative concept right I mean I I I qualitative concept right I mean I I I think we should try to make it to where think we should try to make it to where we can actually come up with it to we can actually come up with it to measure some whether we call it

measure some whether we call it healthspan or not that doesn't really healthspan or not that doesn't really matter but I I I I kind of agree with matter but I I I I kind of agree with Rich like I agree with I agree with what Rich like I agree with I agree with what you're saying except I think it's a you're saying except I think it's a really useful term as a concept I think really useful term as a concept I think it's a really useful way to communicate it's a really useful way to communicate to a broader audience what the what one to a broader audience what the what one of the goals is Right which is to of the goals is Right which is to increase the healthy period of Life yeah increase the healthy period of Life yeah I I kind of like the term health for I I kind of like the term health for that I have a way that helps you out that I have a way that helps you out with your health and you don't have to with your health and you don't have to maybe it's you can Define it as a number maybe it's you can Define it as a number but there is a period of I think we all but there is a period of I think we all could agree there's a period of life could agree there's a period of life where you are in relatively good health where you are in relatively good health and then there's a period of life where and then there's a period of life where you aren't and so I think the idea that you aren't and so I think the idea that we're we're trying to increase that we're we're trying to increase that component of life is really important so component of life is really important so I I don't think we're actually I I don't think we're actually disagreeing on much other than whether disagreeing on much other than whether we like the word well I also think we like the word well I also think there's an individualization of this there's an individualization of this that we're missing to me health is a that we're missing to me health is a state of your physical being that you state of your physical being that you can do the things you like to do and can do the things you like to do and therefore if you like to climb mountains

therefore if you like to climb mountains your health span is going to be your health span is going to be different than if you like to play golf different than if you like to play golf for instance and and a lot of this is for instance and and a lot of this is personal you know if you if if you can't personal you know if you if if you can't run a marathon anymore some people will run a marathon anymore some people will say oh my health is you never pay say oh my health is you never pay attention to the mental health piece at attention to the mental health piece at least the biologist don't right I have a least the biologist don't right I have a question for you Ste what is my health question for you Ste what is my health span I mean I I would only be able to span I mean I I would only be able to ask you that well so so we do this ask you that well so so we do this exercise guys cuz I completely agree exercise guys cuz I completely agree with you Steve we call it the marginal with you Steve we call it the marginal decade exercise okay so we say to every decade exercise okay so we say to every one of our patients um and I write about one of our patients um and I write about this a lot in the book right everyone this a lot in the book right everyone will have a marginal decade which I will have a marginal decade which I Define as the last decade of your life Define as the last decade of your life so obviously by definition everyone has so obviously by definition everyone has a marginal decade most people do not a marginal decade most people do not realize the day they enter it but most realize the day they enter it but most people have a pretty good sense when people have a pretty good sense when they're in it right okay so the exercise they're in it right okay so the exercise we do is we go through with the patient we do is we go through with the patient and we say what are the things that are and we say what are the things that are most important to you to be able to do most important to you to be able to do in your marginal decade and they

in your marginal decade and they generally fall into three buckets with a generally fall into three buckets with a sub bucket physical cognitive emotional sub bucket physical cognitive emotional social the physical bucket we kind of social the physical bucket we kind of divide into um activities of daily divide into um activities of daily living and recreational activities so living and recreational activities so that's where again most people obviously that's where again most people obviously in it that boy I would really not be in it that boy I would really not be happy if I couldn't take care of myself happy if I couldn't take care of myself if I couldn't get out of bed get dressed if I couldn't get out of bed get dressed shave cook like that would be shave cook like that would be disappointing to me but then of course disappointing to me but then of course you have different levels of ambition you have different levels of ambition within the rec ation side and yeah I've within the rec ation side and yeah I've got patients who say when the day comes got patients who say when the day comes that I can't ski I'm going to be that I can't ski I'm going to be devastated and other people are like I devastated and other people are like I just want to be able to Garden right so just want to be able to Garden right so that's that is going to create a very that's that is going to create a very different standard on the cognitive side different standard on the cognitive side you have people who say I want to be you have people who say I want to be able to run my hedge fund and still make able to run my hedge fund and still make money and make really important money and make really important investment decisions and other people investment decisions and other people are like I want to be able to do crossw are like I want to be able to do crossw word puzzles and read the newspaper and word puzzles and read the newspaper and that's my standard and and again we can that's my standard and and again we can go to so so this is why it's very I go to so so this is why it's very I agree with you it's you can't Define it agree with you it's you can't Define it but doesn't mean we shouldn't try to

but doesn't mean we shouldn't try to personalize personalize it okay but I want to come back to you it okay but I want to come back to you Matt with the original question yeah the Matt with the original question yeah the original why are we at a point original why are we at a point where I I don't you know again why is where I I don't you know again why is longevity gone mainstream yeah yeah for longevity gone mainstream yeah yeah for like better way yeah so I mean I think I like better way yeah so I mean I think I think both of the points that that um think both of the points that that um steveen Rich raised um are part of the steveen Rich raised um are part of the equation I mean I think it's a equation I mean I think it's a convergence of of all of these factors convergence of of all of these factors and and maybe a few others um I do think and and maybe a few others um I do think the science has matured to the point the science has matured to the point where more people are believing that we where more people are believing that we can actually modulate the biology of can actually modulate the biology of Aging I think the concept of biological Aging I think the concept of biological aging has become popularized through a aging has become popularized through a variety of mechanisms including you know variety of mechanisms including you know some um influencers individuals who I some um influencers individuals who I personally think often um air on the personally think often um air on the side of being a little bit less side of being a little bit less scientific than they should be but I scientific than they should be but I think they've helped popularize the think they've helped popularize the concept so I think it's been a concept so I think it's been a combination of these factors um and it combination of these factors um and it has taken so long I mean I just think

has taken so long I mean I just think that's the pace that you know science that's the pace that you know science moves and and and the rate at which moves and and and the rate at which these Concepts can sort of permeate the these Concepts can sort of permeate the public sphere um so it's frustrating in public sphere um so it's frustrating in a sense that it's moved so slowly but um a sense that it's moved so slowly but um I do feel and and I I also wonder I do feel and and I I also wonder because you sort of said are we at a because you sort of said are we at a longevity bubble I don't know I also I longevity bubble I don't know I also I think maybe we're still kind of in the think maybe we're still kind of in the early days of this sort of hockey stick early days of this sort of hockey stick moment right where you're getting this moment right where you're getting this exponential increase in attention My exponential increase in attention My Hope is as we go forward it will become Hope is as we go forward it will become more scientific and less you know snake more scientific and less you know snake oily and it's a spectrum right there's oily and it's a spectrum right there's this huge gray area in the field right this huge gray area in the field right now of what's real and what's not real now of what's real and what's not real and I think none of us at this table and I think none of us at this table actually can really Define exactly where actually can really Define exactly where in that gray area that line is or is in that gray area that line is or is there a line so to that point Matt what there a line so to that point Matt what is the collective wisdom of the group on is the collective wisdom of the group on um the funding appetite for that because um the funding appetite for that because I agree with you completely like if we I agree with you completely like if we could Channel this could Channel this exuberance away from kind of the highly

exuberance away from kind of the highly commercial uh speculative grifting commercial uh speculative grifting towards the budget increasing legitimate towards the budget increasing legitimate investigative that would be awesome what investigative that would be awesome what is the appetite right now of Ni with is the appetite right now of Ni with respect to this I think it's hard to say respect to this I think it's hard to say it and I mean ni NIH is a moving Target it and I mean ni NIH is a moving Target and as we all know that there's going to and as we all know that there's going to be a lot of change coming in the near be a lot of change coming in the near future so um cautiously optimis I would future so um cautiously optimis I would say if you look historically it's been say if you look historically it's been really pretty terrible right the the really pretty terrible right the the percent of NIH budget that goes to percent of NIH budget that goes to biology of Aging I think is still biology of Aging I think is still probably around half of 1% even though probably around half of 1% even though biology of Aging is the Sor just to put biology of Aging is the Sor just to put numbers in perspective I don't do you numbers in perspective I don't do you know these ni gets how what percent of know these ni gets how what percent of Ni within ni there's a subf fraction Ni within ni there's a subf fraction that goes to biology of Aging right but that goes to biology of Aging right but I'm saying how there are 17 groups of I'm saying how there are 17 groups of NIH ni being one of them gets what NIH ni being one of them gets what fraction of NIH budget roughly I think fraction of NIH budget roughly I think it's roughly 3% 3% of NIH budget is NI

it's roughly 3% 3% of NIH budget is NI within niia how much goes to this type within niia how much goes to this type of research it was about 350 million a of research it was about 350 million a few years ago it might be a little few years ago it might be a little higher than that but I don't think it's higher than that but I don't think it's ticked up any more proportional to the ticked up any more proportional to the increase in NIH budget since then so increase in NIH budget since then so that it reaches about half of 1% wow um that it reaches about half of 1% wow um what's your level of optimism Rich what's your level of optimism Rich you're obviously very close to this that you're obviously very close to this that NIH will wake up and start to pay NIH will wake up and start to pay attention to aging research the way they attention to aging research the way they should it's near zero uh it's been near should it's near zero uh it's been near zero for 30 years now even with this as zero for 30 years now even with this as outside outside attention well it's gone up I mean they attention well it's gone up I mean they funded the ITP the interventions testing funded the ITP the interventions testing program 20 years ago and they liked it program 20 years ago and they liked it and they doubled our budget about 15 and they doubled our budget about 15 years ago so that's something uh uh and years ago so that's something uh uh and I'm very very grateful to them for that I'm very very grateful to them for that but there there's still an enormous uh but there there's still an enormous uh untapped potential for making progress untapped potential for making progress in the basic biology of aging and the in the basic biology of aging and the reason is again reason is again um a matter of of Defending Turf if you

um a matter of of Defending Turf if you are a cardiologist researcher or an are a cardiologist researcher or an oncologist researcher or an AIDS oncologist researcher or an AIDS researcher or an Alzheimer's researcher researcher or an Alzheimer's researcher anytime somebody says you know you the anytime somebody says you know you the smart play is to reduce your budget by smart play is to reduce your budget by 10% or your institute's budget by 10% 10% or your institute's budget by 10% we're going to go there faster if we we're going to go there faster if we spend money on aging and its spend money on aging and its relationship to the disease you care relationship to the disease you care about you you get uh the porcupine about you you get uh the porcupine defense you don't take any of my money defense you don't take any of my money because Alzheimer's is important little because Alzheimer's is important little kids with leukemia are important breast kids with leukemia are important breast cancer is important you go away and that cancer is important you go away and that is the predominant feeling most of the is the predominant feeling most of the people making those decisions were not people making those decisions were not trained in aging research they view it trained in aging research they view it as something interesting I read as something interesting I read something about that in Time Magazine something about that in Time Magazine the other day but they don't understand the other day but they don't understand that to actually conquer or slow down or that to actually conquer or slow down or affect or protect against the disease affect or protect against the disease they care about the smart play is to do they care about the smart play is to do aging research and so they view your aging research and so they view your suggestion which I of course agree with

suggestion which I of course agree with 100% as a uh an imposition an invasion 100% as a uh an imposition an invasion to be repelled at any cost no one in a to be repelled at any cost no one in a position of power um has had whatever it position of power um has had whatever it takes to reverse that and if he or she takes to reverse that and if he or she tried to do that Congress would even a tried to do that Congress would even a good Congress uh would smack them down good Congress uh would smack them down they always the Alzheimer's uh group has they always the Alzheimer's uh group has 100 lobbyists the cancer group has 100 100 lobbyists the cancer group has 100 lobbyists the AIDS group has 100 lobbyists the AIDS group has 100 lobbyists the Aging group has two lobbyists the Aging group has two lobbyists one who's a lawyer and one who lobbyists one who's a lawyer and one who takes the calls and it's not enough to takes the calls and it's not enough to do it can I just add something real do it can I just add something real quick to that too I I I agree completely quick to that too I I I agree completely and I think as well the reputation of and I think as well the reputation of the field has hindered that transition the field has hindered that transition as well right so historically the field as well right so historically the field was viewed as not very mechanistic kind was viewed as not very mechanistic kind of phenomenological became much more of phenomenological became much more mechanistic starting around the time of mechanistic starting around the time of Cynthia kenyon's work and and since then Cynthia kenyon's work and and since then but has continued to have a reputation

but has continued to have a reputation problem is not being as rigorous as problem is not being as rigorous as other areas of research so I think it is other areas of research so I think it is absolutely a tur for and there's this absolutely a tur for and there's this overcoming the reputational problem overcoming the reputational problem which makes it harder for serious people which makes it harder for serious people in funding in policy circles to give it in funding in policy circles to give it the attention it deserves in my opinion the attention it deserves in my opinion so I've got a different take on this I so I've got a different take on this I actually think that this is a very good actually think that this is a very good time for uh aging research funding and time for uh aging research funding and that's not because of what's going on at that's not because of what's going on at the ni but it's what's going on in the the ni but it's what's going on in the private sector there's more and more private sector there's more and more money there's even interest now in big money there's even interest now in big Pharma and that's you know that was very Pharma and that's you know that was very spotty in the past so I think if we spotty in the past so I think if we focused entirely on the National focused entirely on the National Institute on Aging we would get a false Institute on Aging we would get a false impression of what the funding climate impression of what the funding climate is in the field now and I think we need is in the field now and I think we need to we need to take advantage of that we to we need to take advantage of that we we got to make sure that it doesn't get we got to make sure that it doesn't get captured by the people who are doing the captured by the people who are doing the the flashy but bad science that concerns

the flashy but bad science that concerns me so you're saying look Calico me so you're saying look Calico Altos um you know other private Altos um you know other private companies especially within biotech and companies especially within biotech and Pharma that are looking at Pharma that are looking at geroprotective molecules building on the geroprotective molecules building on the work of the ITP yeah I think it's safe work of the ITP yeah I think it's safe to say the amount of money that's being to say the amount of money that's being spent privately probably outdoes public spent privately probably outdoes public spending I mean in a given year two to spending I mean in a given year two to one easily right it could although how one easily right it could although how much of that is actually going to biolog much of that is actually going to biolog of agent I think it's still an open of agent I think it's still an open question you mention question you mention calact I mean I I actually agree with calact I mean I I actually agree with Steve I don't think the what rich and I Steve I don't think the what rich and I were communicating is opposed to what were communicating is opposed to what Steve was communicating there are a lot Steve was communicating there are a lot of opportunities right now and again of opportunities right now and again this is sort of what I was alluding to this is sort of what I was alluding to is are we at the beginning of this is are we at the beginning of this hockey stick moment and I think Steve's hockey stick moment and I think Steve's right there are real opportunities for right there are real opportunities for more resources to be focused on this more resources to be focused on this scientific side and hopefully Less foced scientific side and hopefully Less foced on focused on the the non-scientific on focused on the the non-scientific aspects of what are going on and you aspects of what are going on and you asked the question of you know can we

asked the question of you know can we shift resources from the the more shift resources from the the more consumer facing maybe not as rigorous consumer facing maybe not as rigorous stuff and into the more rigorous stuff stuff and into the more rigorous stuff maybe maybe you need that sort of I mean maybe maybe you need that sort of I mean again I'm not I'm not a fan of that again I'm not I'm not a fan of that stuff at all but maybe you need that stuff at all but maybe you need that stuff to kind of move the needle and get stuff to kind of move the needle and get people's attention and at least people people's attention and at least people are talking about longevity now naive are talking about longevity now naive question and I'm embarrassed I don't question and I'm embarrassed I don't know the answer CU I spent more than two know the answer CU I spent more than two years working there what's the mission years working there what's the mission statement of the statement of the NIH uh it's it's it's to preserve and NIH uh it's it's it's to preserve and enhance human health I mean it's enhance human health I mean it's basically the same thing that we do that basically the same thing that we do that we're supposed to be doing yeah and I we're supposed to be doing yeah and I didn't actually get to give you my my didn't actually get to give you my my Spiel here but um what I started to say Spiel here but um what I started to say about the Nia budget is if you look at about the Nia budget is if you look at um the major causes of death and um the major causes of death and disability and it's again we talked disability and it's again we talked about how it's hard to Define health about how it's hard to Define health span so if we just look at causes of span so if we just look at causes of death right if you look at the top 10 death right if you look at the top 10 causes of death in the United States causes of death in the United States nine of them have biological aging as nine of them have biological aging as their greatest risk factor and it's not their greatest risk factor and it's not even close yet half of 1% of the

even close yet half of 1% of the research budget that's supposed to be research budget that's supposed to be focused on improving human health goes focused on improving human health goes to study that risk factor and I mean I to study that risk factor and I mean I think it it is extremely frustrating to think it it is extremely frustrating to all of us sitting at this table that all of us sitting at this table that that hasn't changed but there's reason that hasn't changed but there's reason to be optimistic that maybe it will to be optimistic that maybe it will change in the near future let's state change in the near future let's state that again because it is so profound I that again because it is so profound I want to make sure not a single person want to make sure not a single person missed that statement the top 10 causes missed that statement the top 10 causes of death in the United States are well of death in the United States are well enumerated and Incredibly predictable enumerated and Incredibly predictable and they increase by category by decade and they increase by category by decade 3 to 8% monotonically with no exception 3 to 8% monotonically with no exception point being 90% of and more than 90% on point being 90% of and more than 90% on a on an adjusted basis of what causes a on an adjusted basis of what causes death goes up with age and death goes up with age and yet a few basis points of federal R&D yet a few basis points of federal R&D goes to addressing that let me give you goes to addressing that let me give you an example of what the sort of point an example of what the sort of point that Matthew and you have have been

that Matthew and you have have been making about once every five years I making about once every five years I give a talk an invite a talk at the give a talk an invite a talk at the University of Michigan cancer center and University of Michigan cancer center and I point out that we have drugs now I point out that we have drugs now anti-aging drugs in mice and they extend anti-aging drugs in mice and they extend Mouse lifespan and they do it mostly by Mouse lifespan and they do it mostly by postponing cancer because most of our postponing cancer because most of our mice die of cancer and if you look at mice die of cancer and if you look at age adjusted cancer incidence rates our age adjusted cancer incidence rates our drugs reduce these by a factor of 10 drugs reduce these by a factor of 10 wouldn't they like to know why as cancer wouldn't they like to know why as cancer scientists we now have a batch of drugs scientists we now have a batch of drugs that postpone cancer wouldn't they like that postpone cancer wouldn't they like to study them invariably I get one call to study them invariably I get one call back from somebody who says that's back from somebody who says that's interesting maybe we should talk about interesting maybe we should talk about that and then it dies and then five that and then it dies and then five years later I'm asked to give the same years later I'm asked to give the same talk or related talk so they know how to talk or related talk so they know how to do cancer research they are cancer do cancer research they are cancer scientists that's how they know how to scientists that's how they know how to do cancer research and you certainly do cancer research and you certainly don't do it by diverting your lab's don't do it by diverting your lab's attention to age that's insane but that

attention to age that's insane but that insanity is how medical research is insanity is how medical research is organized and breaking that addiction to organized and breaking that addiction to the kinds of models you grew up on the kinds of models you grew up on because they're a better idea is not a because they're a better idea is not a trivial not an easy thing it may not trivial not an easy thing it may not even be a possible thing to do that's a even be a possible thing to do that's a major hassle well I I think this is major hassle well I I think this is because we're we think about health all because we're we think about health all wrong we think let's wait till get wrong we think let's wait till get cancer and see what we can do about it cancer and see what we can do about it that's what cancer biologists do you that's what cancer biologists do you have cancer okay how can we better treat have cancer okay how can we better treat that or could we have diagnosed it that or could we have diagnosed it earlier what rich is saying and what we earlier what rich is saying and what we can know how to do in lots of model can know how to do in lots of model organs it prevents you from getting organs it prevents you from getting cancer delay it for a considerable cancer delay it for a considerable amount of time that's a little bit amount of time that's a little bit harder to study if you're a cancer harder to study if you're a cancer biologist um because you want to see the biologist um because you want to see the cancer before you can study it I think cancer before you can study it I think that's why we need aging biologists that's why we need aging biologists rather than people focused on certain rather than people focused on certain disease that come and try to use what we disease that come and try to use what we do to pre you know if we prevented the do to pre you know if we prevented the cancers they wouldn't have they'd be out

cancers they wouldn't have they'd be out of a job I guarantee these people or of a job I guarantee these people or mice will get cancered they'll just have mice will get cancered they'll just have 10 extra years of life if they're a 10 extra years of life if they're a person or 10 extra months of life if person or 10 extra months of life if they're they'll get cancer they'll need they're they'll get cancer they'll need Specialists it'll be all right yeah I Specialists it'll be all right yeah I think that's important I mean I think think that's important I mean I think the reactive disease care component is the reactive disease care component is still going to be there right even if still going to be there right even if we're insanely successful at slowing we're insanely successful at slowing agent people are still going to get sick agent people are still going to get sick but I think Steve's point is really but I think Steve's point is really important like Peter you've been a important like Peter you've been a leader right in helping people recognize leader right in helping people recognize the need to shift the medical approach the need to shift the medical approach from reactive to proactive I think what from reactive to proactive I think what a lot of people don't realize is that a lot of people don't realize is that mentality goes all the way back to mentality goes all the way back to pharmaceutical research biomedical pharmaceutical research biomedical research basic science it's it that is research basic science it's it that is ingrained at all the way through and I ingrained at all the way through and I think one of the challenges with getting think one of the challenges with getting funding for aging research is the that funding for aging research is the that mentality on the basic science world and mentality on the basic science world and how deeply ingrained it is it's very how deeply ingrained it is it's very interesting because you don't know which interesting because you don't know which is the tail and which is the dog like

is the tail and which is the dog like I've always assumed that that the one I've always assumed that that the one leading the charge is the clinical side leading the charge is the clinical side of things right in other words the of things right in other words the engine the machine of medicine 2.0 is engine the machine of medicine 2.0 is built around the delivery of care the built around the delivery of care the delivery of care as you said Steve is delivery of care as you said Steve is built around I'm going to wait I'm going built around I'm going to wait I'm going to sit here and hang we're going to wait to sit here and hang we're going to wait when you get the disease we're ready you when you get the disease we're ready you had the heart attack fantastic you've had the heart attack fantastic you've got chest pain St elevations we got a got chest pain St elevations we got a stent for you now you have cancer we're stent for you now you have cancer we're all in all in um and then the research flows from that um and then the research flows from that mindset of course I don't know not that mindset of course I don't know not that it really matters but it might be that it really matters but it might be that it's flipped right it might be that the it's flipped right it might be that the clinical engine behaves in that way clinical engine behaves in that way because that's how the the the base of because that's how the the the base of the pyramid has been built again not the pyramid has been built again not that it necessarily matters but if you that it necessarily matters but if you could be Health Zar and fix one of could be Health Zar and fix one of them you might actually start with the them you might actually start with the research side of things I would and I research side of things I would and I mean the reality is the research flows mean the reality is the research flows from where the dollars are going this

from where the dollars are going this has been seen over and over and over at has been seen over and over and over at NIH you shift resource allocation to a NIH you shift resource allocation to a certain area and the scientists will certain area and the scientists will follow and they will submit grants to follow and they will submit grants to get grants in the place where the get grants in the place where the funding line is the highest so if funding line is the highest so if somebody came along and said we're going somebody came along and said we're going to go from 0.5% to 50% of NIH budget is to go from 0.5% to 50% of NIH budget is going to go to biology of Aging you'd going to go to biology of Aging you'd have no shortage of people I mean it'd have no shortage of people I mean it'd be kind of messy at first but you'd have be kind of messy at first but you'd have no shortage of people applying for no shortage of people applying for Grants and becoming experts on the Grants and becoming experts on the biology of Aging the system would work biology of Aging the system would work you get the best and the rightest that you get the best and the rightest that would go into that and and and and do would go into that and and and and do that so so this then begs another that so so this then begs another question that is a tired question but question that is a tired question but but I can't help but ask it at this but I can't help but ask it at this point is aging a disease is that even a point is aging a disease is that even a relevant question call me call me call relevant question call me call me call me I call me it's it's important to to me I call me it's it's important to to use words optimally and to distinguish use words optimally and to distinguish causes from effects one of the bad causes from effects one of the bad things about aging is it's a risk factor things about aging is it's a risk factor for many diseas diseases some things for many diseas diseases some things other risk factors for diseases aging is

other risk factors for diseases aging is a risk factor for disease and so saying a risk factor for disease and so saying that aging is a disease confuses that that aging is a disease confuses that discussion it makes it impossible to see discussion it makes it impossible to see that relationship so calling aging a that relationship so calling aging a disease is a fundamental error the disease is a fundamental error the question itself is incorrect I agree question itself is incorrect I agree completely I think it's the wrong completely I think it's the wrong question I I I agree but I think we have question I I I agree but I think we have that idea for marketing purposes not for that idea for marketing purposes not for scientific purpos purposes and the idea scientific purpos purposes and the idea is well the money goes to diseases let's is well the money goes to diseases let's call aging a disease because I think call aging a disease because I think what we're trying to do is we're trying what we're trying to do is we're trying to treat aging as if it were a disease to treat aging as if it were a disease even though I I would agree with both of even though I I would agree with both of you I don't think it's a disease I think you I don't think it's a disease I think that destroys the word disease if we that destroys the word disease if we include Aging in it uh but I think there include Aging in it uh but I think there was a reason that suddenly this came was a reason that suddenly this came because you thought oh maybe this will because you thought oh maybe this will get Congress to pay attention you're get Congress to pay attention you're right it's a a it's a marketing Ploy and right it's a a it's a marketing Ploy and if you think you can convince people of if you think you can convince people of the importance of Aging research only by

the importance of Aging research only by crossing your fingers and saying oh well crossing your fingers and saying oh well it's kind of a disease isn't it uh and it's kind of a disease isn't it uh and you can you think you can fool them yes you can you think you can fool them yes that's what marketing is and it's that's what marketing is and it's probably good for that I just don't like probably good for that I just don't like lying to people it also creates a lying to people it also creates a negative feeling about the field and negative feeling about the field and some people as well so so I think that some people as well so so I think that should be considered the other point should be considered the other point that people often raise though is we that people often raise though is we have to call aging a disease in order have to call aging a disease in order for FDA to approve a drug for aging for FDA to approve a drug for aging which I think is a fundamental misunder which I think is a fundamental misunder understanding of how FDA operates but understanding of how FDA operates but that is the other argument you you will that is the other argument you you will often hear among proponents of the idea often hear among proponents of the idea that aging is a that aging is a disease very interesting disease very interesting I well yeah well okay so now let's go I well yeah well okay so now let's go one step deeper on one step deeper on that how do you think about biologic that how do you think about biologic versus chronologic age in concept and in versus chronologic age in concept and in practice Yeah so so on the ride over practice Yeah so so on the ride over here rich and I were talking about that here rich and I were talking about that I don't believe there is such a thing as I don't believe there is such a thing as bio one thing as biological age I think

bio one thing as biological age I think there is potentially an age of your there is potentially an age of your heart an age of your liver an age of heart an age of your liver an age of your lungs an age of your brain but I your lungs an age of your brain but I don't see why we wouldn't simply call it don't see why we wouldn't simply call it health in other words you know I I got health in other words you know I I got one of these a epigenetic age clocks one of these a epigenetic age clocks done on me a while ago but I didn't know done on me a while ago but I didn't know what to make out of it you know I what to make out of it you know I thought is this just flattery am I I thought is this just flattery am I I want to do this so it's or did it really want to do this so it's or did it really tell me something he must have got a tell me something he must have got a good result if he thought it was good result if he thought it was flattery huh he must have got a good flattery huh he must have got a good result if he thought it result if he thought it was but you know that's uh that may be was but you know that's uh that may be the point of the whole thing right so the point of the whole thing right so I'm I'm I'm dubious about some number uh I'm I'm I'm dubious about some number uh that is different than I know I'm in that is different than I know I'm in good health you know for my age I'm in good health you know for my age I'm in very good health so I knew that already very good health so I knew that already now I have a number for it I don't put now I have a number for it I don't put much Credence in that let me agree with much Credence in that let me agree with with with and but just put it in slightly

and but just put it in slightly different terminology it's a matter of different terminology it's a matter of taking a very rich taking a very rich complex uh data set and trying to complex uh data set and trying to collapse it to a number so if someone collapse it to a number so if someone wants to know how healthy I am he or she wants to know how healthy I am he or she would need information how good is my would need information how good is my eyesight uh how good is my hearing how eyesight uh how good is my hearing how good is various kinds of cognitive good is various kinds of cognitive activities my aerobic endurance my activities my aerobic endurance my ability to my joints all of that all of ability to my joints all of that all of that is pertinent to how my health is that is pertinent to how my health is and also Al about projected future and also Al about projected future health then there's no need once you've health then there's no need once you've got that got that information which is very rich to say ah information which is very rich to say ah there's a number a single number a real there's a number a single number a real number on a point on the number line number on a point on the number line that condenses that in any useful way that condenses that in any useful way the notion 40 50 years ago that the notion 40 50 years ago that biological age was not the same as biological age was not the same as chronological age potent for a little chronological age potent for a little while was useful it emphasized that while was useful it emphasized that there might well be 60-year-old people there might well be 60-year-old people who were unusually like youthful people who were unusually like youthful people and 60-year-old people who were and 60-year-old people who were unusually like 70y old people with my

unusually like 70y old people with my drug or my genetic mutant or whatever drug or my genetic mutant or whatever help to discriminate those people or help to discriminate those people or change them in some way I can slow your change them in some way I can slow your biological aging process that's a biological aging process that's a discussion that was maybe of Interest 40 discussion that was maybe of Interest 40 years ago and has it's now time to drop years ago and has it's now time to drop the notion let alone the silly notion the notion let alone the silly notion that you can count that biological age that you can count that biological age that number which some people's too many that number which some people's too many people still think is a value you can people still think is a value you can figure out what it is by measuring figure out what it is by measuring something transcriptions or epigenetic something transcriptions or epigenetic markers or something I can do it and markers or something I can do it and give you personally your personal give you personally your personal biological age that's a waste of biological age that's a waste of everyone's time and it also distracts everyone's time and it also distracts attention from things that actually are attention from things that actually are important and need to be thought about I important and need to be thought about I I gotta talk because I think I think I I gotta talk because I think I think I disagree fundamentally and I'm surprised disagree fundamentally and I'm surprised but this will be an interesting but this will be an interesting conversation so I agree that the idea of conversation so I agree that the idea of a kit that you can buy to measure

a kit that you can buy to measure biological Age first of all the stuff biological Age first of all the stuff that's out there doesn't work and we that's out there doesn't work and we should can and should talk about that should can and should talk about that but also I sort of agree with the idea but also I sort of agree with the idea that reducing it to one number while that reducing it to one number while conceptually I think it's possible I conceptually I think it's possible I think in reality is going to be really think in reality is going to be really really difficult to do but do I believe really difficult to do but do I believe that there is a biological aging process that there is a biological aging process that is different from chronological that is different from chronological aging absolutely yes absolutely it aging absolutely yes absolutely it sounded like you guys were both saying sounded like you guys were both saying no you didn't think it was a real thing no you didn't think it was a real thing I agree with that completely so that's I agree with that completely so that's you can agree with that and not like the you can agree with that and not like the idea of a number that constitutes your idea of a number that constitutes your biological age so there's two things I biological age so there's two things I would that that kind of make me feel would that that kind of make me feel pretty confident in this idea one is and pretty confident in this idea one is and this is the example I use a lot among this is the example I use a lot among the general public is just look at dogs the general public is just look at dogs compared to people right everybody's compared to people right everybody's familiar with the idea that one human familiar with the idea that one human year is about seven dog years what does year is about seven dog years what does that mean means that dogs age about that mean means that dogs age about seven times faster than people do but of seven times faster than people do but of course chronological time is the same course chronological time is the same between dogs and people it's the between dogs and people it's the biological aging process and so you can biological aging process and so you can look across the animal kingdom and see

look across the animal kingdom and see this and dogs get almost all of the same this and dogs get almost all of the same diseases and functional declines that we diseases and functional declines that we do at the tissue and organ level but do at the tissue and organ level but also at the whole body level um and we also at the whole body level um and we also know now there are single genes also know now there are single genes that significantly modulate what I would that significantly modulate what I would call the rate of Aging now maybe we have call the rate of Aging now maybe we have a different meaning to what we mean that a different meaning to what we mean that no I agree entirely so the fact that no I agree entirely so the fact that that's possible daff 2 we've talked that's possible daff 2 we've talked about da 2 a couple times T we can turn about da 2 a couple times T we can turn these things up up turn them down and these things up up turn them down and animals Across The evolutionary Spectrum animals Across The evolutionary Spectrum seem to age at different rates by seem to age at different rates by modulating single genes so I don't know modulating single genes so I don't know of any other explanation other than that of any other explanation other than that there is this process which we call there is this process which we call biological aging that can be changed and biological aging that can be changed and and the rate can be sped up or slowed and the rate can be sped up or slowed down can it be reversed that's an down can it be reversed that's an interesting question maybe we'll get to interesting question maybe we'll get to that but but I think the process is real that but but I think the process is real I think it's just really really I think it's just really really complicated and we probably only complicated and we probably only understand 5% of it at this point understand 5% of it at this point for me the challenge is I I kind of land

for me the challenge is I I kind of land where where rich was which is if a where where rich was which is if a patient says to me hey why aren't you patient says to me hey why aren't you doing this biologic age clock on me yeah doing this biologic age clock on me yeah my response is well I know your V2 Max I my response is well I know your V2 Max I know your zone two I know your muscle know your zone two I know your muscle mass I know your visceral fat I know we mass I know your visceral fat I know we did a very complicated movement did a very complicated movement assessment on you I understand your assessment on you I understand your balance I understand uh like your lipids balance I understand uh like your lipids your insulin like I know these 50 seven your insulin like I know these 50 seven things about you and I can tell you things about you and I can tell you individually on each of them how you're individually on each of them how you're doing that doing that number doesn't tell me a single new number doesn't tell me a single new piece of information but what if you piece of information but what if you were to come up with and you probably do were to come up with and you probably do this in your head right you come up with this in your head right you come up with a some sort of composite right you a some sort of composite right you probably don't sit down and wait each of probably don't sit down and wait each of those things and come to one number but those things and come to one number but you come up with some sort of composite you come up with some sort of composite picture of Health based on all of those picture of Health based on all of those things that's a different biological things that's a different biological aging clock I think sometimes we aging clock I think sometimes we conflate and in part this is because of conflate and in part this is because of the way that irresponsible people in the the way that irresponsible people in the field and marketers have done this we

field and marketers have done this we conflate the epigenetic tests with conflate the epigenetic tests with biological aging clocks there are all biological aging clocks there are all sorts of flavors of biological aging sorts of flavors of biological aging clocks including things like Frailty clocks including things like Frailty indices or metrics of a whole bunch of indices or metrics of a whole bunch of functional markers so I think those functional markers so I think those probably are pretty good readouts of probably are pretty good readouts of biological age again can you combine biological age again can you combine them all to get to one number that's them all to get to one number that's meaningful for every person that's much meaningful for every person that's much harder to do yeah tell tell us about harder to do yeah tell tell us about your experience cuz this was I thought your experience cuz this was I thought you did you did what I wanted to do but you did you did what I wanted to do but I've been too lazy to do yeah in fact we I've been too lazy to do yeah in fact we we we exchanged emails at one point we we exchanged emails at one point about doing this and each coming up with about doing this and each coming up with different names so yeah so what I did different names so yeah so what I did was I um tested four different direct to was I um tested four different direct to Consumer biological age kits they were Consumer biological age kits they were all epigenetic biological age tests four all epigenetic biological age tests four different companies and I did duplicates different companies and I did duplicates of each kit and it was from sample the of each kit and it was from sample the same samples collected on the same day same samples collected on the same day right so really my on I only had two right so really my on I only had two replicates I didn't have three replicates I didn't have three replicates but you know it's about the

replicates but you know it's about the best I could afford at that point so and best I could afford at that point so and it was kind of it was kind of expensive um so anyways uh sent those in expensive um so anyways uh sent those in got the results back and they were I to got the results back and they were I to me very informative fundamentally sort me very informative fundamentally sort of changed my views on these epigenetic of changed my views on these epigenetic age um tests so they ranged from um 42 age um tests so they ranged from um 42 to 63 I was like to 63 I was like 53.7 years at the time I did the test um 53.7 years at the time I did the test um and the standard deviation I can't and the standard deviation I can't remember it was either seven or nine so remember it was either seven or nine so mean of my chronological age standard mean of my chronological age standard deviation of seven or nine um uh which deviation of seven or nine um uh which you know I look at that data I'm not a you know I look at that data I'm not a statistician but I know enough statistician but I know enough statistics to say that's completely statistics to say that's completely useless they converged on my useless they converged on my chronological age but with a huge chronological age but with a huge variation and even intra like so so that variation and even intra like so so that varied between the tests so I think varied between the tests so I think three of the four were reasonably close three of the four were reasonably close to each other three of the four to each other three of the four companies the duplicates were reasonably companies the duplicates were reasonably close to each other but the individual close to each other but the individual tests were far apart and one of the

tests were far apart and one of the companies the the individual replicates companies the the individual replicates was 20 years apart so to meet and and was 20 years apart so to meet and and and some people will say but but maybe and some people will say but but maybe you know the true diagnostic test is you know the true diagnostic test is great and the alysium test is terrible great and the alysium test is terrible or the tally Health test is terrible and or the tally Health test is terrible and the other one is great maybe but how do the other one is great maybe but how do we know so so my sort of take-home is we know so so my sort of take-home is that the direct to Consumer biological that the direct to Consumer biological age testing industry is a complete mess age testing industry is a complete mess and I have no idea who to believe or if and I have no idea who to believe or if any of them are actually giving accurate any of them are actually giving accurate data I know some of the people at some data I know some of the people at some of the companies and I have my personal of the companies and I have my personal feelings about who's trying to do it feelings about who's trying to do it right and who's sort of a charlatan but right and who's sort of a charlatan but across the industry it's really hard to across the industry it's really hard to know so I the last thing I'll say on know so I the last thing I'll say on this is where I've sort of landed is I this is where I've sort of landed is I think these are really good research think these are really good research tools I think the direct to Consumer tools I think the direct to Consumer component has gotten way ahead of itself component has gotten way ahead of itself and I think I align with what you were and I think I align with what you were saying about the way you think about saying about the way you think about these test is I I don't think there's a these test is I I don't think there's a lot of value in clinical practice right

lot of value in clinical practice right now because we don't know we don't know now because we don't know we don't know Precision or accuracy and I don't think Precision or accuracy and I don't think you can make actionable recommendations you can make actionable recommendations based on these tests furthermore they based on these tests furthermore they fail in the one thing that I think fail in the one thing that I think they're attempting to do which is and I they're attempting to do which is and I usually use this illustration with usually use this illustration with patience so if I have a 40-year-old patience so if I have a 40-year-old patient who says I really want to do one patient who says I really want to do one of these tests I say if if the answer of these tests I say if if the answer comes back and says you're 20 is your comes back and says you're 20 is your expectation that you will live another expectation that you will live another 70 years conversely if the answer comes 70 years conversely if the answer comes back and says 60 is it your expectation back and says 60 is it your expectation that you will live another 30 years in that you will live another 30 years in other words is this number predictive of other words is this number predictive of future years of life because right now future years of life because right now we have this thing called chronologic we have this thing called chronologic age that is the single best predictor of age that is the single best predictor of future years of life so do we think future years of life so do we think biologic age as determined by these biologic age as determined by these tests is better as a predictor of future tests is better as a predictor of future years of life which by the way would be years of life which by the way would be very testable like how many people have very testable like how many people have contacted you to get ITP sample data to

contacted you to get ITP sample data to say can we predict how much longer these say can we predict how much longer these mice we're going to live the answer to mice we're going to live the answer to the question the question is obvious and very welln you can tell is obvious and very welln you can tell if you have a your 40-year-old patient if you have a your 40-year-old patient and he or she is fat doesn't exercise and he or she is fat doesn't exercise eats mostly cheeseburgers you know that eats mostly cheeseburgers you know that their life expectancy is probably not as their life expectancy is probably not as good as the 40y old patient in your your good as the 40y old patient in your your next waiting room that next waiting room that has extremely healthful habits and whose has extremely healthful habits and whose parents live to be 100 so it's and parents live to be 100 so it's and there's tons of I don't need a biologic there's tons of I don't need a biologic right that's what I'm saying there are right that's what I'm saying there are tons of things you can measure on tons of things you can measure on individuals four or five of them or all individuals four or five of them or all you really need to ask of a 70y old yeah you really need to ask of a 70y old yeah metti does this really really really metti does this really really really well because their money's on the line well because their money's on the line there they're they're running life there they're they're running life insurance policies right so it's not at insurance policies right so it's not at all hard to just to figure out a very all hard to just to figure out a very small set of tests that tell you how small set of tests that tell you how long a seven-year-old is likely to live long a seven-year-old is likely to live there nothing to do there nothing to do with methylation clocks or things me

with methylation clocks or things me that's the gold standard when life that's the gold standard when life insurance companies start using biologic insurance companies start using biologic clocks as the Cornerstone of their clocks as the Cornerstone of their Actuarial algorithms I'll start to be Actuarial algorithms I'll start to be far away from that though again I I want far away from that though again I I want to I want to I'm going to sound like a to I want to I'm going to sound like a broken record here but you guys keep broken record here but you guys keep saying biological age when what you mean saying biological age when what you mean is epigenetic age or epigenetic test not is epigenetic age or epigenetic test not necessarily and we should explain to necessarily and we should explain to people that there is a difference cu the people that there is a difference cu the so so some of these clocks use solely so so some of these clocks use solely epigenetic measurements all not all most epigenetic measurements all not all most of the direct to Consumer ones are of the direct to Consumer ones are epigenetic test some of these tests use epigenetic test some of these tests use a Litany of biomarkers inclusive of a Litany of biomarkers inclusive of epigenetics so they'll say we have we epigenetics so they'll say we have we we've sampled your methylation pattern we've sampled your methylation pattern but we also looked at your vitamin D but we also looked at your vitamin D level your glucose level your level your glucose level your cholesterol level and a whole bunch of cholesterol level and a whole bunch of other you know things and we compressed other you know things and we compressed all of that into a number as well so I all of that into a number as well so I guess let me frame it as a question to guess let me frame it as a question to you right so let's take the epigenetic you right so let's take the epigenetic piece out again I I do think we will get piece out again I I do think we will get to a point where the technology is

to a point where the technology is developed far enough and the quality developed far enough and the quality control is good enough on the consumer control is good enough on the consumer side that these tests will be better side that these tests will be better than just chronological age y um but so than just chronological age y um but so you've got just you're saying I think we you've got just you're saying I think we can get there I think I think that's a can get there I think I think that's a big statement I don't know that I'm big statement I don't know that I'm disagreeing with you I just want to make disagreeing with you I just want to make sure it's clear from the research unless sure it's clear from the research unless you think that all of the the research you think that all of the the research that's been done on these epigenetic that's been done on these epigenetic agent CL clocks is somehow flawed it's agent CL clocks is somehow flawed it's clear that you can create algorithms clear that you can create algorithms that can predict specific methylation that can predict specific methylation patterns that that are more highly patterns that that are more highly correlated with life expectancy than correlated with life expectancy than remain than chronological remain than chronological age but I think the big butt here is age but I think the big butt here is that even if that's the case they would that even if that's the case they would not be as good as what Peter would not be as good as what Peter would predict after all the tests that you run predict after all the tests that you run your biological AG that's what I want to your biological AG that's what I want to get to yes and I think what you are get to yes and I think what you are actually doing is looking at other actually doing is looking at other biomarkers that have a long-term biomarkers that have a long-term clinical history clinical history that you're using to come up with a

that you're using to come up with a surrogate but really is reflecting surrogate but really is reflecting largely biological age maybe not largely biological age maybe not completely and this is the other point I completely and this is the other point I wanted to make is I don't think wanted to make is I don't think biological age and health are equal I biological age and health are equal I think they're strongly overlapping and think they're strongly overlapping and certainly you can identify many ways to certainly you can identify many ways to to reduce Health without accelerating to reduce Health without accelerating biological aging right I think that's biological aging right I think that's easy right we can all think of ways to easy right we can all think of ways to do that so let's let's take a minute and do that so let's let's take a minute and try yeah so try yeah so let's think about this for a let's think about this for a second I have seen very impressive data second I have seen very impressive data where we can look at tissue samples of where we can look at tissue samples of organs and we can tell okay I'm going to organs and we can tell okay I'm going to show you a sample of show you a sample of nephrons and we just based on nothing nephrons and we just based on nothing but the methylation pattern we know that but the methylation pattern we know that if I just said to you one of these is a if I just said to you one of these is a 20-year-old one of these is a 20-year-old one of these is a 50-year-old and one of these is a 70y 50-year-old and one of these is a 70y old it's very easy to predict based on old it's very easy to predict based on the methylation pattern which nefron the methylation pattern which nefron came from which person completely agree came from which person completely agree with that yeah I mean things there are a

with that yeah I mean things there are a lot of things that change with age the lot of things that change with age the literature has 25,000 things that change literature has 25,000 things that change with age a average amount of methylation with age a average amount of methylation at these 10 spots is number 11,47 of at these 10 spots is number 11,47 of those so great you've got another thing those so great you've got another thing that changes with age so that's the that changes with age so that's the question that's not enough right so do question that's not enough right so do you believe that all of the research you believe that all of the research we're seeing on the epigenetic clocks is we're seeing on the epigenetic clocks is going to be the 78 going to be the 78 variable that we would include in our variable that we would include in our Gestalt of I don't know yeah it's it's a Gestalt of I don't know yeah it's it's a good question so I am hopeful that um good question so I am hopeful that um epigenetic algorithms can get to the epigenetic algorithms can get to the point where they can replace many point where they can replace many certainly not all but many of the other certainly not all but many of the other biomarkers that are being measured I biomarkers that are being measured I think the thing that gives me hope is we think the thing that gives me hope is we know that we know that epigenetic know that we know that epigenetic changes are part of biological aging changes are part of biological aging this again is a different question but this again is a different question but if we look at the Hallmarks of Aging if we look at the Hallmarks of Aging epigenetic disregulation is one of the epigenetic disregulation is one of the 12 right some people will argue it's the 12 right some people will argue it's the most important one that's a different

most important one that's a different conversation but it's at least part so conversation but it's at least part so that gives me some hope that we are in that gives me some hope that we are in fact measuring something that plays a fact measuring something that plays a causal role in the aging process and I causal role in the aging process and I think what's missing I think what would think what's missing I think what would give all of us a lot more confidence is give all of us a lot more confidence is if we had a mechanistic connection to if we had a mechanistic connection to the specific methylation changes and the specific methylation changes and some cause of Aging or age related some cause of Aging or age related disease in other words this change in disease in other words this change in methylation changes this particular methylation changes this particular Gene's expression level which changes Gene's expression level which changes the rate of biological aging right I the rate of biological aging right I think if we had that we feel a lot more think if we had that we feel a lot more confident yeah you and I spoke about confident yeah you and I spoke about this very briefly at the end of our last this very briefly at the end of our last podcast and I want to come back to it podcast and I want to come back to it with all of us in this table right which with all of us in this table right which is because there's so much in what you is because there's so much in what you just said Matt that I'm going I'm going just said Matt that I'm going I'm going to lay out a broad question and then we to lay out a broad question and then we can start attacking it in different ways can start attacking it in different ways so one of the things I want to address so one of the things I want to address is do we believe that it's possible that is do we believe that it's possible that of the Hallmarks of Aging epigenetic of the Hallmarks of Aging epigenetic change is the most important another change is the most important another topic I want to address do we believe topic I want to address do we believe that the epigenetic changes that we

that the epigenetic changes that we observe over time which are undeniable observe over time which are undeniable are causal in the arrival of other are causal in the arrival of other states everything from the arrival of states everything from the arrival of senescent cells the increase in senescent cells the increase in inflammation the reduced function of the inflammation the reduced function of the organs which really is the Hallmark of organs which really is the Hallmark of aging and if so does that mean that aging and if so does that mean that reversing the epigenetic phenotype will reversing the epigenetic phenotype will undo the phenotype of interest and Rich undo the phenotype of interest and Rich where I'm going that you and I left off where I'm going that you and I left off was what about the proteome what about was what about the proteome what about the metabol so you made three statements the metabol so you made three statements there broad General statements and I there broad General statements and I think each of the three deserves think each of the three deserves careful careful amendment to be polite about it um the amendment to be polite about it um the first has to do with Hallmarks of Aging first has to do with Hallmarks of Aging which I think set the field back which I think set the field back dramatically um I I think when you are dramatically um I I think when you are officially branded a Hallmark of Aging officially branded a Hallmark of Aging by two people sitting alone at their by two people sitting alone at their computers and writing a review article a computers and writing a review article a Hallmark of Aging wait they weren't I Hallmark of Aging wait they weren't I thought they were walking around a pond

thought they were walking around a pond when they came up with this all right when they came up with this all right okay okay um means that somebody once okay okay um means that somebody once said you know I'm interested in aging said you know I'm interested in aging that's kind of important isn't it let's that's kind of important isn't it let's put it on our list you can't tell if put it on our list you can't tell if someone is a Hallmark something is a someone is a Hallmark something is a hmark of Aging does that mean it goes up hmark of Aging does that mean it goes up with age it goes down with age you can with age it goes down with age you can change it in a way that will extend change it in a way that will extend lifespan you can kill a mouse or a worm lifespan you can kill a mouse or a worm by removing it um basically it's by removing it um basically it's something that somebody thought might be something that somebody thought might be of interest to aging and the downside of of interest to aging and the downside of that is once you're officially branded that is once you're officially branded as a Hallmark of Aging anyone who wants as a Hallmark of Aging anyone who wants to write a a a grant on that doesn't to write a a a grant on that doesn't have to prove that their fundamental have to prove that their fundamental cause and effect model has any Merit cause and effect model has any Merit because it's a Hallmark of Aging I don't because it's a Hallmark of Aging I don't have to prove that anymore someone I have to prove that anymore someone I don't know who or on what grounds has don't know who or on what grounds has decided it's important my reviewers know decided it's important my reviewers know it's important because they've read the it's important because they've read the Hallmark of Aging paper so I don't have Hallmark of Aging paper so I don't have to think about whether it's important to think about whether it's important the negative side of that coin is that

the negative side of that coin is that there are lots of things that didn't there are lots of things that didn't make it into the Hallmark list and I make it into the Hallmark list and I really think it's premature to close really think it's premature to close thought off on some of those it's easy thought off on some of those it's easy to come up with a dozen things that to come up with a dozen things that ought to be investigated but if you want ought to be investigated but if you want to investigate it and it's not on the to investigate it and it's not on the Hallmarks list what are you wasting so Hallmarks list what are you wasting so deciding which of the Hallmarks is the deciding which of the Hallmarks is the Big Daddy Hallmark or whatever strikes Big Daddy Hallmark or whatever strikes me as not the correct thing to talk me as not the correct thing to talk about in the Hallmarks about in the Hallmarks Arena the second question so maybe we Arena the second question so maybe we should talk about that before we go should talk about that before we go through all there's a lot to remember through all there's a lot to remember the other ones if you guys could afford the other ones if you guys could afford to give me a little piece of paper and a to give me a little piece of paper and a pen then I'd be able to write down I pen then I'd be able to write down I think the Hallmarks as a list a kind of think the Hallmarks as a list a kind of arbitrary list not completely arbitrary arbitrary list not completely arbitrary because they had some reasons for being because they had some reasons for being there and I don't think any of us would there and I don't think any of us would say that those 12 things are not say that those 12 things are not involved in aging but that's a very involved in aging but that's a very little interest any of us want to Rattle little interest any of us want to Rattle them off being that I'm the only one them off being that I'm the only one that's got the list in front me we we that's got the list in front me we we could do a game where we each name one could do a game where we each name one and see who see if we get to all 12 um

and see who see if we get to all 12 um but certainly in that list I I would not but certainly in that list I I would not I would not consider epigenetics as the I would not consider epigenetics as the the key Hallmark assuming there are such the key Hallmark assuming there are such things I consider it to be an things I consider it to be an interesting list it became biblically interesting list it became biblically sacran almost immediately and I've never sacran almost immediately and I've never understood why but for some reason it understood why but for some reason it did so I agree with Rich so conceptually did so I agree with Rich so conceptually beautiful I mean so I agree completely beautiful I mean so I agree completely with Rich and he knows I do because we with Rich and he knows I do because we we've talked about this before and I we've talked about this before and I think the flip side is I think the think the flip side is I think the Hallmarks have been immensely useful to Hallmarks have been immensely useful to the field they are a very easy way to the field they are a very easy way to communicate this idea of biological communicate this idea of biological aging and it helps convince some of the aging and it helps convince some of the scientific community that thought it was scientific community that thought it was all just Hocus Pocus and snake oil that all just Hocus Pocus and snake oil that there are that there is some mechanistic there are that there is some mechanistic research happening we can point to research happening we can point to specific things that are aging so I specific things that are aging so I think that part of the Hallmarks has think that part of the Hallmarks has been actually really valuable and has been actually really valuable and has contributed to the popularization of contributed to the popularization of longevity and at least to the extent the

longevity and at least to the extent the science of longevity has been science of longevity has been popularized has contributed to that and popularized has contributed to that and it has been extremely detrimental to the it has been extremely detrimental to the field and the way I think about it is it field and the way I think about it is it just caused the field to narrow just caused the field to narrow prematurely and this goes back to what I prematurely and this goes back to what I alluded to before I don't know if we alluded to before I don't know if we understand 80% of biological aging or understand 80% of biological aging or 0.005% of biological aging my guess is 0.005% of biological aging my guess is it's closer to it's closer to 0.005% and by and large the funding to 0.005% and by and large the funding to look outside of the Hallmarks dried up look outside of the Hallmarks dried up once the Hallmarks became the dominant once the Hallmarks became the dominant Paradigm and people stopped looking and Paradigm and people stopped looking and I think we need to go back to more I think we need to go back to more Discovery Science and and thinking Discovery Science and and thinking outside the box so I think sword Happ outside the box so I think sword Happ would that happen automatically if we would that happen automatically if we could wave that magic wand and increase could wave that magic wand and increase funding it would help I don't know that funding it would help I don't know that it would help enough but it would help I it would help enough but it would help I think you I mean you also kind of have think you I mean you also kind of have to change the mindset about you know to change the mindset about you know what people call fishing Expeditions what people call fishing Expeditions that's like a bad word in Grant review that's like a bad word in Grant review panels fishing Expedition meaning you panels fishing Expedition meaning you don't really know what you're going what don't really know what you're going what what you're going to find but you got to

what you're going to find but you got to go look before you can figure out what's go look before you can figure out what's important so think we have to kind of important so think we have to kind of change that mindset as well one can change that mindset as well one can usefully concretize this this discussion usefully concretize this this discussion I imagine that one of this I don't don't I imagine that one of this I don't don't read these papers because they upset me read these papers because they upset me but I imagine inflammation is on one or but I imagine inflammation is on one or more of these I'll bet so chronic more of these I'll bet so chronic inflammation okay good chronic inflammation okay good chronic inflammation so so what that does if you inflammation so so what that does if you say I'm I'm interested in chronic say I'm I'm interested in chronic inflammation so I'm doing good stuff huh inflammation so I'm doing good stuff huh but but what could be happening is this but but what could be happening is this particular set of cyto kindes might be particular set of cyto kindes might be overexpressed by some gal cells and that overexpressed by some gal cells and that leads to loss of cognitive function leads to loss of cognitive function whereas this other overlapping set of whereas this other overlapping set of cyto kindes produced by the macras in cyto kindes produced by the macras in your fat may lead you more prone to your fat may lead you more prone to diabetes or metabolic syndrome whereas diabetes or metabolic syndrome whereas this particular set of lymphocytes are this particular set of lymphocytes are necessary to repel covid and that's why necessary to repel covid and that's why you are more susceptible to covid so you are more susceptible to covid so learning what changes within the learning what changes within the extremely broad generic idea of

extremely broad generic idea of inflammation what changes in what cell inflammation what changes in what cell types in what people under what types in what people under what pharmacological or genetic changes how pharmacological or genetic changes how they are interacting with other aspects they are interacting with other aspects of pathology that's marvelous to do but of pathology that's marvelous to do but to say oh inflammation that gets bad to say oh inflammation that gets bad when you're old is a way of avoiding the when you're old is a way of avoiding the labor of thinking and that's why I'm labor of thinking and that's why I'm against it and I think M brought up a against it and I think M brought up a really important point and the and we really important point and the and we scientists are to blame is the way that scientists are to blame is the way that research gets reviewed and for lazy research gets reviewed and for lazy reviewers having these 12 Hallmarks is reviewers having these 12 Hallmarks is really helpful oh this has got one of really helpful oh this has got one of the Hallmarks in it this must be good the Hallmarks in it this must be good stuff I do think reviewers need to be stuff I do think reviewers need to be more open more open to new ideas and new approaches I mean to new ideas and new approaches I mean everybody knows that NIH grants are everybody knows that NIH grants are approved if they're incremental approved if they're incremental if they're really breakthrough they if they're really breakthrough they don't get approved fact very famous

don't get approved fact very famous biologist eio Wilson told me years ago biologist eio Wilson told me years ago he said don't ever include your best he said don't ever include your best ideas in a grant they won't get funded ideas in a grant they won't get funded do it standard stuff save your best do it standard stuff save your best ideas for projects that you do on the ideas for projects that you do on the side yeah and that's one of the reasons side yeah and that's one of the reasons I left Academia it's just drove me nuts I left Academia it's just drove me nuts almost impossible to get the important almost impossible to get the important stuff stuff funded H so what's your funded H so what's your go back so the second of your of your uh go back so the second of your of your uh multipartite question was does multipartite question was does epigenetic change what what are the epigenetic change what what are the results of is it causal causal effect results of is it causal causal effect and the third which we may get to is can and the third which we may get to is can you reverse it and would that be a good you reverse it and would that be a good thing so let's talk about the second thing so let's talk about the second element here is it causal and the here element here is it causal and the here the defin the problem is what it means the defin the problem is what it means there are some changes that occur in there are some changes that occur in this particular set of 40 cells in the this particular set of 40 cells in the pineal and there are other changes that pineal and there are other changes that occur in these cells in the bone marrow occur in these cells in the bone marrow and there other cells that change in the

and there other cells that change in the gut and villis lining cells and the gut and villis lining cells and the Crypt cells so they are all epigenetic Crypt cells so they are all epigenetic in some they are caused by some things in some they are caused by some things and we don't really know which if any of and we don't really know which if any of these count for aging if someone says these count for aging if someone says I'm going to prove that an epigenetic I'm going to prove that an epigenetic change is responsible for aging they change is responsible for aging they haven't begun to come to grips with the haven't begun to come to grips with the nitty-gritty nitty-gritty uh people always ask just as you hinted uh people always ask just as you hinted does your drug change does your drug change epigenetic things and unfortunately epigenetic things and unfortunately that's where they stop thinking if we're that's where they stop thinking if we're always willing to give people tissues always willing to give people tissues from our drug treated mice if they are from our drug treated mice if they are keen on epigenetic changes that affect keen on epigenetic changes that affect neuron regeneration excellent their neuron regeneration excellent their experts will send them the brains and experts will send them the brains and they can do that stuff it's important they can do that stuff it's important I'm not making fun of it but the general I'm not making fun of it but the general notion that that's aging vaguely thought notion that that's aging vaguely thought of is due to epigenetic change more of is due to epigenetic change more vaguely thought of doesn't really get vaguely thought of doesn't really get you anywhere that's my sort of skeptical

you anywhere that's my sort of skeptical View and is is part of the issue that View and is is part of the issue that you're saying well what's causing the you're saying well what's causing the cause no it's just that the the concept cause no it's just that the the concept of epigenetic change encompasses of epigenetic change encompasses thousands of changes in hundreds of cell thousands of changes in hundreds of cell types under hundreds of influences of types under hundreds of influences of course some of that causes other stuff course some of that causes other stuff agreeing to that assenting to that agreeing to that assenting to that notion that epigenetic IC change is notion that epigenetic IC change is causal for all sorts of age related causal for all sorts of age related pathologies everyone can agree to that pathologies everyone can agree to that but it does it's meaningless because but it does it's meaningless because what counts is to say this specific what counts is to say this specific change is really important in this change is really important in this disease let's go back to the example an disease let's go back to the example an epigenetic alteration or this specific epigenetic alteration or this specific broadspectrum change in multiple broadspectrum change in multiple tissues causes something good or bad you tissues causes something good or bad you have to Define what it is before let's have to Define what it is before let's so let's use a specific example when you so let's use a specific example when you look at a patient with type 1 diabetes M look at a patient with type 1 diabetes M and you look at their beta cells in and you look at their beta cells in their pancreas they look different

their pancreas they look different epigenetically than the beta cells of an epigenetically than the beta cells of an AG matched person without type 1 AG matched person without type 1 diabetes and we also know that their diabetes and we also know that their beta cells don't function so they're so beta cells don't function so they're so they they've lost function so the so they they've lost function so the so let's ask that question as a specific let's ask that question as a specific example what do you believe or what example what do you believe or what confidence would would you assign to the confidence would would you assign to the notion that the epigenetic change on the notion that the epigenetic change on the beta cells of the type 1 diabetic are beta cells of the type 1 diabetic are indeed causal to the loss of function of indeed causal to the loss of function of the beta cell right so my my last uh the beta cell right so my my last uh exposure to the causes of type 1 exposure to the causes of type 1 diabetes was I in medical school which diabetes was I in medical school which is more than five years ago but if I I is more than five years ago but if I I vaguely remember it was an autoimmune vaguely remember it was an autoimmune disease right so if your poor little disease right so if your poor little helpless beta cells are being attacked helpless beta cells are being attacked by antibodies and macrophases and things by antibodies and macrophases and things those stress reactions are going to those stress reactions are going to cause epigenetic change and whether cause epigenetic change and whether those epigenetic changes contribute to those epigenetic changes contribute to some extent to the ill fate of the beta some extent to the ill fate of the beta cells it's possible and if I were an cells it's possible and if I were an expert on Diabetes pathogenesis I'd

expert on Diabetes pathogenesis I'd really want to know that it doesn't have really want to know that it doesn't have anything to do with aging but an anything to do with aging but an interesting question it's a way to interesting question it's a way to address causality yeah but you might address causality yeah but you might equally say no no it's the mitochondria equally say no no it's the mitochondria that have changed why would yeah why that have changed why would yeah why would why Mark of diabetes yeah or it's would why Mark of diabetes yeah or it's the it's the it's the glycated proteins the it's the it's the glycated proteins misfolded Pro there's a ton of things in misfolded Pro there's a ton of things in it there's no reason in the world at it there's no reason in the world at this stage I think to actually give this stage I think to actually give epigenetics Primacy over anything it's a epigenetics Primacy over anything it's a nice hyp nice hyp diabetes is you can formulate these diabetes is you can formulate these questions because a lot is known about questions because a lot is known about type one diabetes and I understand 05% type one diabetes and I understand 05% of the biology of is is I was giving of the biology of is is I was giving you're off by an order of magnitude you're off by an order of magnitude who's raising You by a I thought your who's raising You by a I thought your One log off so so it formulating the One log off so so it formulating the questions in exactly the way Steve did questions in exactly the way Steve did makes it clear how difficult it is to makes it clear how difficult it is to evaluate the concept that epigenetic evaluate the concept that epigenetic change contributes to pathogen gen is in change contributes to pathogen gen is in type 1 diabetes and we know more or less type 1 diabetes and we know more or less what is going on in type we don't know

what is going on in type we don't know what's going on in aging we don't even what's going on in aging we don't even know what part of the body it's going on know what part of the body it's going on or parts more likely of the body I I I or parts more likely of the body I I I at least internally reframe it a little at least internally reframe it a little bit and say you know what what would the bit and say you know what what would the experiment be what would you need to do experiment be what would you need to do to convince yourself that either broadly to convince yourself that either broadly speaking epigenetic disregulation causes speaking epigenetic disregulation causes aging whatever that means or this aging whatever that means or this specific epigenetic change that is specific epigenetic change that is associated with chronological age causes associated with chronological age causes aging right and so that's an easier way aging right and so that's an easier way for me to think about it because I feel for me to think about it because I feel like this is all it's all a fascinating like this is all it's all a fascinating conversation but we're never going to conversation but we're never going to get to the answer until somebody get to the answer until somebody actually does the experiment and or actually does the experiment and or decides that it can't be formulated decides that it can't be formulated because it's too complicated and gives because it's too complicated and gives up yeah that's right but people are up yeah that's right but people are trying to do both of those things I mean trying to do both of those things I mean people are using you know partial or people are using you know partial or transient epigenetic reprogramming and transient epigenetic reprogramming and asking can that have effects on asking can that have effects on biological aging I'm actually cautiously biological aging I'm actually cautiously optimistic it can I don't think it's optimistic it can I don't think it's going to be a GameChanger but I think going to be a GameChanger but I think you can modulate aspects of biological you can modulate aspects of biological aging and then people are you know the

aging and then people are you know the Technologies are being developed for Technologies are being developed for targeted epigenetic modifications so if targeted epigenetic modifications so if we think this particular epigenetic Mark we think this particular epigenetic Mark at this particular location in the at this particular location in the genome controls aging and I don't think genome controls aging and I don't think it's going to be that simple but let's it's going to be that simple but let's say it is you could go in you could say it is you could go in you could modify that and then see do you reduce modify that and then see do you reduce disease do you increase lifespan do you disease do you increase lifespan do you improve health span right so those are improve health span right so those are the kinds of experiments that I think the kinds of experiments that I think would get us to where we can have a lot would get us to where we can have a lot of confidence if it's the case if of confidence if it's the case if somebody let's say at Altos publishes a somebody let's say at Altos publishes a paper three years from now that they paper three years from now that they have made a mouse live six years by have made a mouse live six years by multiple rounds of transient epigenetic multiple rounds of transient epigenetic reprogramming I'll be like their biggest reprogramming I'll be like their biggest fan they moved the needle that convinces fan they moved the needle that convinces me that that strategy modulates me that that strategy modulates biological aging nobody's done that yet biological aging nobody's done that yet what about something far less impressive what about something far less impressive but but but still um worth worthwhile so but but but still um worth worthwhile so consider you know if we could get to the consider you know if we could get to the point where we could locally deliver point where we could locally deliver vectors that would epigenetically change

vectors that would epigenetically change condra sites so that you could take condra sites so that you could take osteoarthritis in the knee and just osteoarthritis in the knee and just regenerate cartilage regenerate regenerate cartilage regenerate cartilage regenerate useful by changing cartilage regenerate useful by changing the EPO but is that biological aging the EPO but is that biological aging right I wouldn't be convinced that's right I wouldn't be convinced that's modulating the biological aging process modulating the biological aging process I would be convinced that's a clinically I would be convinced that's a clinically useful strategy for people who benefit useful strategy for people who benefit from that therapy I guess it kind of dep from that therapy I guess it kind of dep depends on why we think an individual depends on why we think an individual would be experiencing osteoarthritis would be experiencing osteoarthritis right how much of that is right how much of that is sence how much of that is infl trigger sence how much of that is infl trigger here before we go down that path is it here before we go down that path is it the s word or what yeah yeah let's talk the s word or what yeah yeah let's talk about sesses but before we think if you about sesses but before we think if you think uh ostearthritis of the knee think uh ostearthritis of the knee requires a knee joint replacement and requires a knee joint replacement and that's going to help your patient you that's going to help your patient you are not are not rejuvenating it's perfectly possible to rejuvenating it's perfectly possible to do great things with technology do great things with technology including con condra site including con condra site regeneration without having to decide

regeneration without having to decide that that's related to aging people that that's related to aging people don't age because they fail to have don't age because they fail to have titanium knee joints or something and titanium knee joints or something and one way I think about this and again one way I think about this and again this this may be completely wrong but it this this may be completely wrong but it but it's a useful way for me to think but it's a useful way for me to think about it is I think about age related about it is I think about age related disease as the sort of Downstream effect disease as the sort of Downstream effect of biological aging and then in for most of biological aging and then in for most diseases there becomes a point where the diseases there becomes a point where the pathology of that disease pathology of that disease mechanistically is no longer the same as mechanistically is no longer the same as biological Aging in which case very good biological Aging in which case very good you should listen to him in and one of you should listen to him in and one of the implications of that is the the implications of that is the interventions that slow biological aging interventions that slow biological aging may not work once you get past that may not work once you get past that point but things that do work for that point but things that do work for that disease may have nothing to do with disease may have nothing to do with biological aging does that make sense biological aging does that make sense yeah go go deeper on that idea though yeah go go deeper on that idea though let's use let's use the example yeah let's use let's use the example yeah well I think um so let's just I mean well I think um so let's just I mean what's your favorite disease my favorite what's your favorite disease my favorite disease let's talk about is an easy one disease let's talk about is an easy one right we know with cancer in many right we know with cancer in many cancers the process is you have one or

cancers the process is you have one or more mutations which then often lead to more mutations which then often lead to additional mutations you get genome additional mutations you get genome instability eventually you get an enco instability eventually you get an enco gen that gets activated and that leads gen that gets activated and that leads to uncontrolled cell division there to uncontrolled cell division there messor that gets deactivated yeah right messor that gets deactivated yeah right so at and if we accept that immune so at and if we accept that immune surveillance is one important surveillance is one important anti-cancer mechanism we know that anti-cancer mechanism we know that immune surveillance declines with age so immune surveillance declines with age so early on we're clearing a lot of our early on we're clearing a lot of our cancers as our immune system declines cancers as our immune system declines these cancers are going to escape immune these cancers are going to escape immune surveillance they're going to accumulate surveillance they're going to accumulate all these mutations they're eventually all these mutations they're eventually going to go into uncontrolled cell going to go into uncontrolled cell division that uncontrolled cell division division that uncontrolled cell division at that point you can treat the cancer at that point you can treat the cancer right but uncontrolled cell division is right but uncontrolled cell division is not biological aging right it's not a not biological aging right it's not a normal part it's not a part of the normal part it's not a part of the normative aging process right so the normative aging process right so the treatment there so the mechanism now is treatment there so the mechanism now is fundamentally different from normative fundamentally different from normative aging and the treatment let's just say aging and the treatment let's just say the treatment in this case is

the treatment in this case is chemotherapy might benefit the chemotherapy might benefit the cancering right and I think romy's a cancering right and I think romy's a good example here where we I think we good example here where we I think we all believe that rapy and inhibiting all believe that rapy and inhibiting mtor slows biological mtor slows biological aging at least in up to mice hopefully aging at least in up to mice hopefully in dogs hopefully in people yeah so it's in dogs hopefully in people yeah so it's a a fundamental node in the network that's fundamental node in the network that's the way I think about the Hallmarks of the way I think about the Hallmarks of Aging it's a node in the network that Aging it's a node in the network that underlies the Hallmarks of Aging so we underlies the Hallmarks of Aging so we can manipulate mtor with Ramy slow aging can manipulate mtor with Ramy slow aging ramy's a pretty good anti-cancer drug ramy's a pretty good anti-cancer drug until the cancers have evolved to ignore until the cancers have evolved to ignore the mtor break and then rapy doesn't the mtor break and then rapy doesn't work anymore and we know ramyon doesn't work anymore and we know ramyon doesn't work for most cancers that's an example work for most cancers that's an example tested we know this yeah absolutely um tested we know this yeah absolutely um and it's because the cancers evolve to and it's because the cancers evolve to bypass the mtor break or to bypass the bypass the mtor break or to bypass the ability of Rapa to inhibit mtor so ability of Rapa to inhibit mtor so that's a case where the intervention that's a case where the intervention that's a really good point that we all that's a really good point that we all take for granted that I think is worth take for granted that I think is worth noting rapamycin can be unsuccessful as noting rapamycin can be unsuccessful as a chemotherapeutic agent and can yet be

a chemotherapeutic agent and can yet be very successful as a cancer preventive very successful as a cancer preventive agent absolutely and it's exactly for agent absolutely and it's exactly for that reason and I think this also that reason and I think this also illustrates why traditional illustrates why traditional disease-based medicine is not about the disease-based medicine is not about the biology of Aging it's about something biology of Aging it's about something that the biology of Aging is distinct that the biology of Aging is distinct and it needs to be uh investigated in a and it needs to be uh investigated in a different way and we know that in the different way and we know that in the Aging field but the people in the cancer Aging field but the people in the cancer field in the Cardiology field and the field in the Cardiology field and the neurology field neurology field I don't think they understand that well I don't think they understand that well so this gets to what I wish I if I were so this gets to what I wish I if I were Health Zar this is what I would do Health Zar this is what I would do because you know it comes back to what because you know it comes back to what rich said at the outset which is why is rich said at the outset which is why is this a zero sum game like I mean you this a zero sum game like I mean you didn't ask it that way but that's didn't ask it that way but that's effectively the problem you're dealing effectively the problem you're dealing with right which is why can't we study with right which is why can't we study Cardiology oncology and neurology and Cardiology oncology and neurology and aging without everybody feeling like aging without everybody feeling like they're taking my way of saying that in they're taking my way of saying that in Peter terms is we need to have medicine Peter terms is we need to have medicine 2.0 and Medicine 3.0 in parall 2.0 and Medicine 3.0 in parall because the tools of the medicine 2.0 because the tools of the medicine 2.0 scientist and physician which we see on

scientist and physician which we see on display today are putting the stent in display today are putting the stent in giving the chemotherapy lowering the giving the chemotherapy lowering the cholesterol all of these things the the cholesterol all of these things the the medicine medicine 3.0 toolkit looks different different 3.0 toolkit looks different different science you're going to use WAP a mice science you're going to use WAP a mice in here you're not going to use it over in here you're not going to use it over here because it's too late and instead here because it's too late and instead of saying one or the other why isn't it of saying one or the other why isn't it both like why wouldn't we want both of both like why wouldn't we want both of these running in parallel well well we these running in parallel well well we would but of course um the Zero Sum game would but of course um the Zero Sum game uh is a pretty good analogy for what's uh is a pretty good analogy for what's actually going on the amount of research actually going on the amount of research dollars at least available to NIH is not dollars at least available to NIH is not infinitely expansible it's set by infinitely expansible it's set by complex political process and then um complex political process and then um there's a separate Downstream process there's a separate Downstream process that allocates it amongst uh that allocates it amongst uh institutions so saying that it would be institutions so saying that it would be a good idea to have more funds everyone a good idea to have more funds everyone I agree with you and I'll bet these two I agree with you and I'll bet these two guys do as well yeah I think ioke it guys do as well yeah I think ioke it will be a it will be a portfolio will be a it will be a portfolio reallocation but it will be worthwhile

reallocation but it will be worthwhile because the burden of this disease will because the burden of this disease will be lower so in other words it's okay be lower so in other words it's okay it's sort of like saying right now I it's sort of like saying right now I spend spend $100,000 a year on the barrier to my $100,000 a year on the barrier to my house to prevent anybody from breaking house to prevent anybody from breaking in yes and I spend $100 a year in yes and I spend $100 a year patrolling the neighborhood to make sure patrolling the neighborhood to make sure there aren't too many bad guys in the there aren't too many bad guys in the neighborhood there's a scenario where if neighborhood there's a scenario where if your total budget is $100,000 and $100 your total budget is $100,000 and $100 maybe you could spend $80,000 in total maybe you could spend $80,000 in total by spending more money patrolling the by spending more money patrolling the neighborhood less money generally agree neighborhood less money generally agree with you that having a greater with you that having a greater proportion of available research dollars proportion of available research dollars uh both private and public going into uh both private and public going into the biology of aging and its uh impact the biology of aging and its uh impact on late Life Health is would be a good on late Life Health is would be a good thing I don't think you're going to get thing I don't think you're going to get an argument here but I also think you're an argument here but I also think you're going to get a huge argument from going to get a huge argument from anybody in the Cardiology field the neur anybody in the Cardiology field the neur Alzheimer that's the Alzheimer's field Alzheimer that's the Alzheimer's field that's um their money only in but but

that's um their money only in but but wouldn't some of those people as the wouldn't some of those people as the funding dollars move towards the Aging funding dollars move towards the Aging side also want to move and say look I'm side also want to move and say look I'm going to study this through the Aging going to study this through the Aging lens I was on the council for the lens I was on the council for the national aging Institute for three years national aging Institute for three years and if at any point I can swear to this and if at any point I can swear to this from personal testimony somebody would from personal testimony somebody would say something like I wonder if maybe a say something like I wonder if maybe a few percent of the Alzheimer's budget few percent of the Alzheimer's budget might instead go to studying how slow might instead go to studying how slow aging models would have an impact on aging models would have an impact on late life neurod degenerative disease late life neurod degenerative disease the next day the director of the Aging the next day the director of the Aging Institute would get a call from two or Institute would get a call from two or three Congress people who were on the three Congress people who were on the Appropriations Committee stating that Appropriations Committee stating that this will not be happening because there this will not be happening because there was an Alzheimer's Association person was an Alzheimer's Association person who got the call from the ni staff who got the call from the ni staff member in charge of Alzheimer's saying member in charge of Alzheimer's saying tell the congressman to call the tell the congressman to call the director and let's put a stop to that director and let's put a stop to that Reckless idea so they're they're tied in Reckless idea so they're they're tied in to the political process in ways that

to the political process in ways that well we just need to go maybe one step well we just need to go maybe one step further because those Congress people further because those Congress people have a have a boss they report to somebody too who who boss they report to somebody too who who would that be at this stage yeah no I would that be at this stage yeah no I mean come on maybe it's because the mean come on maybe it's because the public doesn't understand this those public doesn't understand this those people answer to the public these are people answer to the public these are these are our dollars that's right these are our dollars that's right they're going to work but Alzheimer's they're going to work but Alzheimer's Association I mean that's a patient Association I mean that's a patient advocacy group right so that is that is advocacy group right so that is that is the public the public yes although let's ask the question what yes although let's ask the question what have they done for those patients lately have they done for those patients lately that's a different question but I mean that's a different question but I mean I'm just reinforcing what you said I I'm just reinforcing what you said I think I think part of this is educ if think I think part of this is educ if you if you know somebody who's suffering you if you know somebody who's suffering from Alzheimer's disease you know very from Alzheimer's disease you know very well that the only thing we've got going well that the only thing we've got going for us right now is prevention right we for us right now is prevention right we don't have too many silver bullets in don't have too many silver bullets in the treatment gun despite massive the treatment gun despite massive spending massive spending on I was once spending massive spending on I was once in Congress trying to Lobby in Congress trying to Lobby with about six people from the with about six people from the Alzheimer's Association in the in the Alzheimer's Association in the in the same room and I was totally ignored by

same room and I was totally ignored by the staffers that were in there I mean I the staffers that were in there I mean I I like I'm I agree with all of this I I like I'm I agree with all of this I agree with all of this I think again agree with all of this I think again though we I mean we should be careful though we I mean we should be careful not to demonize people for wanting to not to demonize people for wanting to cure Alzheimer it's a good thing it's a cure Alzheimer it's a good thing it's a good goal I think the communication good goal I think the communication piece is about the fact that it's going piece is about the fact that it's going to be much more efficient and effective to be much more efficient and effective to keep people from getting it in the to keep people from getting it in the first place this goes back to the the first place this goes back to the the idea that once you've outpaced the idea that once you've outpaced the biology of Aging with the pathology of biology of Aging with the pathology of the disease it gets a lot harder a lot the disease it gets a lot harder a lot harder to do anything about it and so I harder to do anything about it and so I think that communication part I don't think that communication part I don't know why we've been honestly I don't know why we've been honestly I don't know why we've been so unsuccessful know why we've been so unsuccessful because I think a lot of us have been because I think a lot of us have been out there trying to communicate this out there trying to communicate this message for a long time but it's message for a long time but it's starting to permeate again this is we're starting to permeate again this is we're at that moment I think where people are at that moment I think where people are starting to get it that aging biological starting to get it that aging biological aging is a thing it's malleable we don't aging is a thing it's malleable we don't really know for sure what Works in really know for sure what Works in people and what doesn't work yet but people and what doesn't work yet but we're getting there so I think I think we're getting there so I think I think it's going to take a little while but

it's going to take a little while but but there's reason to be optimistic and but there's reason to be optimistic and there's also the private sector is there's also the private sector is another reason I think to be optimistic another reason I think to be optimistic so let's go on record right now I think so let's go on record right now I think when we if we defeat Alzheimer's disease when we if we defeat Alzheimer's disease it's going to be because of the biology it's going to be because of the biology of Aging it's not going to be because of of Aging it's not going to be because of the drugs that get rid of you know the drugs that get rid of you know absolutely yep probably absolutely yep probably cancer probably heart disease although I cancer probably heart disease although I think Peter's more optimistic we can think Peter's more optimistic we can prevent heart disease through other prevent heart disease through other other mean medicine 2.0 if you took the other mean medicine 2.0 if you took the tools of medicine 2.0 and just applied tools of medicine 2.0 and just applied them 30 years earlier we wouldn't have them 30 years earlier we wouldn't have ascvd that's the one place where it's ascvd that's the one place where it's work but again that's because the work but again that's because the mechanism of action is so well mechanism of action is so well understood with ascvd compared to understood with ascvd compared to Alzheimer and cancer a lot of infectious Alzheimer and cancer a lot of infectious disease a lot of liver disease a lot of disease a lot of liver disease a lot of kidney disease all of those things can kidney disease all of those things can be be improved dramatically by targeting the improved dramatically by targeting the biology of Aging you know if I were to biology of Aging you know if I were to write my book again I would add a fifth write my book again I would add a fifth Horsemen because I talked about these Horsemen because I talked about these four horsemen of ascvd cancer neurod

four horsemen of ascvd cancer neurod degenerative and dementing diseases and degenerative and dementing diseases and metabolic disease but I would actually metabolic disease but I would actually add a fifth sort of Hallmark of it's not add a fifth sort of Hallmark of it's not really a Hallmark of disease but it's really a Hallmark of disease but it's kind of the fifth thing that brings life kind of the fifth thing that brings life to an a bad close which is immune to an a bad close which is immune dysfunction right and and I don't think dysfunction right and and I don't think I gave that enough attention in the book I gave that enough attention in the book because of course as you said it factors because of course as you said it factors in very heavily to in very heavily to oncogenesis um but also I mean as Co oncogenesis um but also I mean as Co showed us like what a risk factor it was showed us like what a risk factor it was to be old yeah and you know I'm reminded to be old yeah and you know I'm reminded of this when I see people my age get of this when I see people my age get brutal brutal pneumonias and like two months later pneumonias and like two months later they're okay and you realize and you they're okay and you realize and you look I mean you know one of my patients look I mean you know one of my patients two of my patients actually in the past two of my patients actually in the past six months have had really bad six months have had really bad pneumonias where you're looking at the pneumonias where you're looking at the CT of their chest and you cannot believe CT of their chest and you cannot believe they're alive but of course they're fine they're alive but of course they're fine 3 months later four courses of antibio 3 months later four courses of antibio iotics later they're fine and you iotics later they're fine and you realize you do that to a 75y old it's realize you do that to a 75y old it's over and it's simply comes down to how

over and it's simply comes down to how their B cells and T cells work and so their B cells and T cells work and so that's an area that again I you know that's an area that again I you know that to me is an area where I'd love to that to me is an area where I'd love to see more attention which is what would see more attention which is what would it take to rejuvenate the immune system it take to rejuvenate the immune system as as a proactive statement right well as as a proactive statement right well that's part of the of the X prise that's part of the of the X prise healthspan challenge of course um I healthspan challenge of course um I think that that's a perfect example think that that's a perfect example influenza pneumonia is never fallen out influenza pneumonia is never fallen out of the top 10 causes of death in the US of the top 10 causes of death in the US you know it used to be number two but you know it used to be number two but still now it's number eight or nine but still now it's number eight or nine but it's always there it's always there because you can't really do anything because you can't really do anything about the late life immune dysfunction about the late life immune dysfunction so so what to shift gears to and so one so so what to shift gears to and so one can just to follow this up and so if can just to follow this up and so if magically you become in charge and magically you become in charge and you're able to uh double the amount of you're able to uh double the amount of research being done on the biology of research being done on the biology of Aging fundamentally then we can afford Aging fundamentally then we can afford to do let's give some mice to start with to do let's give some mice to start with a batch of anti-aging drugs and see if

a batch of anti-aging drugs and see if it makes them more resistant to it makes them more resistant to infectious illnesses including infectious illnesses including pneumonias but but viral infections as pneumonias but but viral infections as well and many others I'd love to know well and many others I'd love to know the answer to that and no one has the answer to that and no one has actually really looked in a serious way actually really looked in a serious way because the um we we the ITP has enough because the um we we the ITP has enough money to just measure lifespan and we're money to just measure lifespan and we're hoping that everybody else is now going hoping that everybody else is now going to look at the brain and the lungs and to look at the brain and the lungs and the infection and the the sensory the infection and the the sensory systems that really ought to be done and systems that really ought to be done and it's not being done because of a lack of it's not being done because of a lack of money you said something a while ago money you said something a while ago Rich that I think is is is timely now Rich that I think is is is timely now which is with each generation of these which is with each generation of these drugs they get more efficacious and less drugs they get more efficacious and less toxic not yet but that's the hope well toxic not yet but that's the hope well no no but I'm going to use another no no but I'm going to use another example the gp1s are the best example of example the gp1s are the best example of this right so you go back to the very this right so you go back to the very very first generation of gp1 agonists very first generation of gp1 agonists barely lost any weight horrible side barely lost any weight horrible side effects right you generation two about

effects right you generation two about 10 years ago a little bit better weight 10 years ago a little bit better weight loss side effects so so fast forward to loss side effects so so fast forward to semaglutide quite a bit better efficacy semaglutide quite a bit better efficacy still really bad side effects Next still really bad side effects Next Generation tepati better efficacy side Generation tepati better efficacy side effects are almost effects are almost gone now why haven't we been able to do gone now why haven't we been able to do that with these geroprotective drugs so that with these geroprotective drugs so we have this one study using everus that we have this one study using everus that show that gives us a hint that says hey show that gives us a hint that says hey this might actually enhance immune this might actually enhance immune function in people in their mid-60s but function in people in their mid-60s but we need the follow-up study the followup we need the follow-up study the followup drug imagine what the fourth generation drug imagine what the fourth generation of that drug can do where it's tuned to of that drug can do where it's tuned to get better and better and few commercial get better and better and few commercial motivations you know you're going to motivations you know you're going to sell a lot of the uh uh obesity drugs sell a lot of the uh uh obesity drugs they're very strong commercial they're very strong commercial motivations to do those studies over and motivations to do those studies over and over and over again until you find one over and over again until you find one that works better and they're good that works better and they're good pre-clinical models that you can use so pre-clinical models that you can use so that you're not wasting too much of your that you're not wasting too much of your time on clinical time on clinical trials um that could be done for

trials um that could be done for anti-aging drugs as well although anti-aging drugs as well although testing anti-aging drugs in people is a testing anti-aging drugs in people is a whole separate set of tangle of whole separate set of tangle of difficulties we I don't want to talk difficulties we I don't want to talk about that right now but the I I'm about that right now but the I I'm saying it won't be quite as easy as it saying it won't be quite as easy as it was for anti-obesity medications but no was for anti-obesity medications but no one's doing even the first level of one's doing even the first level of research to to find the uh optimal research to to find the uh optimal compounds for efficacy without side compounds for efficacy without side effects or even to begin to see if they effects or even to begin to see if they have desirable effects on Aging rate have desirable effects on Aging rate indicators in people that's that's kind indicators in people that's that's kind of a cheap and easy study and no one has of a cheap and easy study and no one has really tackled that yet well I just really tackled that yet well I just heard that there are over 80 cytic heard that there are over 80 cytic studies in early clinical anti-aging studies in early clinical anti-aging drugs yeah it's a joke it's a joke it's drugs yeah it's a joke it's a joke it's a joke it's a joke we have to go back to a joke it's a joke we have to go back to this are any of them are any of them this are any of them are any of them powered for anything other than safety powered for anything other than safety this is I think phase one at exactly so this is I think phase one at exactly so but they're underpowered they're almost but they're underpowered they're almost useless in my opinion well until they useless in my opinion well until they get to phase two phase three if they get

get to phase two phase three if they get how many years have we been having phase how many years have we been having phase one analytic trials now I I don't know one analytic trials now I I don't know at least a decade God has it been that at least a decade God has it been that long first one I remember was 2017 so long first one I remember was 2017 so yeah a decade easily because I probably yeah a decade easily because I probably wasn't paying attention in 2014 2015 so wasn't paying attention in 2014 2015 so yeah anyways there's a lot there's lots yeah anyways there's a lot there's lots of complicated issues here I think end of complicated issues here I think end points for clinical trials are are points for clinical trials are are really challenging but solvable so so really challenging but solvable so so there are two places I wanted to go next there are two places I wanted to go next and I'm going to let Rich decide because and I'm going to let Rich decide because he's going to have the strongest point he's going to have the strongest point of view can we talk about sence or can of view can we talk about sence or can we talk about what biomarkers would be we talk about what biomarkers would be necessary to help us study Aging in necessary to help us study Aging in humans as we translate from your work humans as we translate from your work and Matt's work I know what I want to and Matt's work I know what I want to talk about and it's the second of those talk about and it's the second of those two okay um I don't want to spend the two okay um I don't want to spend the next three or four hours explaining why next three or four hours explaining why sence is silly and anti- senolytics are sence is silly and anti- senolytics are untested at best talking about that very untested at best talking about that very well let's go on to item number two um well let's go on to item number two um and I think the clear the most important

and I think the clear the most important thing is to make a clear distinction thing is to make a clear distinction between biomarkers and aging rate between biomarkers and aging rate indicators so a please explain the indicators so a please explain the difference to people please okay I I'll difference to people please okay I I'll do my best so a biomarker allegedly and do my best so a biomarker allegedly and in real life uh is something that in real life uh is something that changes with age so if you have some changes with age so if you have some drug that slows aging the biomarkers drug that slows aging the biomarkers many of them in the different cell types many of them in the different cell types and in the blood will change more slow and in the blood will change more slow slowly they are a good way of looking at slowly they are a good way of looking at whether you're slowing it'll work in the whether you're slowing it'll work in the dogs long long lived dogs and shortlived dogs long long lived dogs and shortlived dogs will have differences in the rate dogs will have differences in the rate of change of biomarkers very established of change of biomarkers very established part of the literature and valuable but part of the literature and valuable but you have to wait till somebody's old you have to wait till somebody's old whether it's a dog or a mouse or a whether it's a dog or a mouse or a person because only when they're old has person because only when they're old has the biomarker of Aging the surrogate the biomarker of Aging the surrogate marker for biological aging changed very marker for biological aging changed very much so in a clinical trial certainly in much so in a clinical trial certainly in a a human situation no one wants to wait a a human situation no one wants to wait 20 years to see whether the biomarkers 20 years to see whether the biomarkers have changed and a one year is such a

have changed and a one year is such a tiny fraction of a human lifespan that tiny fraction of a human lifespan that you don't really anticipate detectable you don't really anticipate detectable change with a appropriately powered change with a appropriately powered study a it's like aging rate indicators study a it's like aging rate indicators which are much less well studied and which are much less well studied and much less well established in principle much less well established in principle are things you can measure that tell you are things you can measure that tell you whether you're in a slow aging state or whether you're in a slow aging state or a normal State can I just make some make a normal State can I just make some make a point for the listeners so they a point for the listeners so they understand kind of the challenge of what understand kind of the challenge of what talking about y when we study blood talking about y when we study blood pressure drugs or cholesterol drugs the pressure drugs or cholesterol drugs the biomarkers change so rapidly and we know biomarkers change so rapidly and we know the relationship between the biomarker the relationship between the biomarker and the disease state so if your blood and the disease state so if your blood pressure is 145 over 90 on average pressure is 145 over 90 on average before I give you this ACE inhibitor and before I give you this ACE inhibitor and 3 months later 6 months later n9ine 3 months later 6 months later n9ine months later a year later your blood months later a year later your blood pressure is averaging 119 over pressure is averaging 119 over 74 I know I've done something well now I 74 I know I've done something well now I will still probably in the phase three will still probably in the phase three in fact I will in the phase three have in fact I will in the phase three have to make sure that I also reduce some

to make sure that I also reduce some event in you but generally by the phase event in you but generally by the phase two I know that this drug is not toxic two I know that this drug is not toxic and that it's predictably lowering your and that it's predictably lowering your blood pressure that's that's really blood pressure that's that's really really valuable a biomarker generically really valuable a biomarker generically is something that's easy to measure that is something that's easy to measure that you is informative about something you is informative about something that's hard to measure a classical that's hard to measure a classical example famous example is you want to example famous example is you want to know how many cigarettes somebody smokes know how many cigarettes somebody smokes a day they'll lie to you but if you a day they'll lie to you but if you measure cine in their blood that's a measure cine in their blood that's a byproduct of nicotine you don't have to byproduct of nicotine you don't have to ask them you can find out how many ask them you can find out how many cigarettes they had in the last couple cigarettes they had in the last couple of days by measuring blood coat that's a of days by measuring blood coat that's a biomarker of of cigarette consumption is biomarker of of cigarette consumption is it a marker of nicotine or carbon it a marker of nicotine or carbon monoxide I don't know the answer that monoxide I don't know the answer that yeah I wasn't sure so in principle a yeah I wasn't sure so in principle a biomarker of Aging is measuring there biomarker of Aging is measuring there many of them and they are measuring many of them and they are measuring biological aging processes and they're biological aging processes and they're useful in that regard but they don't useful in that regard but they don't tell you how fast you're aging the tell you how fast you're aging the analogy I love to use is an odometer is analogy I love to use is an odometer is like a biomarker of Aging of your car it like a biomarker of Aging of your car it tells you how many miles your car has tells you how many miles your car has gone but it doesn't tell you how fast

gone but it doesn't tell you how fast the car is going the speedometer tells the car is going the speedometer tells you how fast your car is going and so you how fast your car is going and so what we need and what I think we're just what we need and what I think we're just beginning now to to document is things beginning now to to document is things like the speedometer aging rate like the speedometer aging rate indicators that reliably discriminate indicators that reliably discriminate slow aging myor people from regular old slow aging myor people from regular old Meer people we have now a dozen or so Meer people we have now a dozen or so things that change in the fat in the things that change in the fat in the blood in the liver in the brain and in blood in the liver in the brain and in the muscle that are always changed in the muscle that are always changed in any slow aging Mouse whether it's drug a any slow aging Mouse whether it's drug a drug B drug C calor restriction diet or drug B drug C calor restriction diet or single gene mutations we've looked now single gene mutations we've looked now at five different single gene mutations at five different single gene mutations and this whole set of 12 or roughly 12 and this whole set of 12 or roughly 12 aging rate indicators always changes in aging rate indicators always changes in every slow aging Mouse and it does so in every slow aging Mouse and it does so in youth which is the key point so if it youth which is the key point so if it does so quickly after an anti-aging drug does so quickly after an anti-aging drug is administered is administered that's the transition that's the bridge that's the transition that's the bridge you need for clinical studies in people you need for clinical studies in people if you want to know whether metformin or

if you want to know whether metformin or Kagen or something slows Aging in people Kagen or something slows Aging in people and you don't want to wait 20 years but and you don't want to wait 20 years but you've got things that tell you whether you've got things that tell you whether they're in a slow aging State how fast they're in a slow aging State how fast they are aging versus normal and that's they are aging versus normal and that's a big if we don't yet have evidence we a big if we don't yet have evidence we can do that we just have hope we can do can do that we just have hope we can do that then that allows you quickly to that then that allows you quickly to with quickly being within six months to with quickly being within six months to a year to know whether your anti-aging a year to know whether your anti-aging manipulation alleged anti-aging manipulation alleged anti-aging manipulation has moved them to a manipulation has moved them to a physiological status which is associated physiological status which is associated with slower aging that allows that can with slower aging that allows that can be done a lot of that can be done in be done a lot of that can be done in mice with drugs with mutants and are mice with drugs with mutants and are these all proteins Rich no no some of these all proteins Rich no no some of them are changes in the fat uh different them are changes in the fat uh different classes of macras is the classes of macras is the pro-inflammatory macrophages the bad pro-inflammatory macrophages the bad ones go away the anti-inflammatory ones go away the anti-inflammatory macras is the good ones go up macras is the good ones go up uh you cp1 I recall from1 uh goes up in uh you cp1 I recall from1 uh goes up in every one of our 10 different kinds 11

every one of our 10 different kinds 11 now of slow aging mice does it go up in now of slow aging mice does it go up in any of the mice that did not receive a any of the mice that did not receive a successful drug well we compare them to successful drug well we compare them to controls and the question you're asking controls and the question you're asking is really important that's what we're is really important that's what we're doing in the next five years we just got doing in the next five years we just got to Grant to do that we're going to take to Grant to do that we're going to take mice and give them either a good drug or mice and give them either a good drug or a different drug that doesn't work yep a different drug that doesn't work yep and then make those comparisons a really and then make those comparisons a really important thing to prove so far our only important thing to prove so far our only control has been untreated my at at some control has been untreated my at at some point in this I have I had to bring this point in this I have I had to bring this up but let's imagine that rich is up but let's imagine that rich is incredibly successful at finding these incredibly successful at finding these things that is a very very long way from things that is a very very long way from assuming that it's going to be the same assuming that it's going to be the same in people most things that clinically in people most things that clinically work in mice do not work in people it work in mice do not work in people it might be and that would be wonderful but might be and that would be wonderful but I think ultimately we're going to have I think ultimately we're going to have to find this for people and my thought to find this for people and my thought is the kind of a the kind of evaluation

is the kind of a the kind of evaluation that you do routinely of your patients that you do routinely of your patients if we took a group of 65 year olds and if we took a group of 65 year olds and we gave them a drug that we thought was we gave them a drug that we thought was an anti-aging drug and follow them the an anti-aging drug and follow them the next five or six years doing these next five or six years doing these evaluations I think you could probably evaluations I think you could probably safely say this is slowing aging or safely say this is slowing aging or slowing not or not slowing aging so I slowing not or not slowing aging so I don't think that it's going to be that don't think that it's going to be that easy to jump from Ice to people in this easy to jump from Ice to people in this I've always wondered if in people I've always wondered if in people the the easiest way to do it would be to the the easiest way to do it would be to take the most obvious thing that we know take the most obvious thing that we know is going to reduce the rate of Aging so is going to reduce the rate of Aging so it'd be an interesting experiment but it'd be an interesting experiment but you find someone who is overweight you find someone who is overweight diabetic and smokes and has hypertension diabetic and smokes and has hypertension you you get hundreds of these folks you put half get hundreds of these folks you put half of them on a sort of to be ethical a of them on a sort of to be ethical a plan where you try to get them to stop plan where you try to get them to stop and presumably many don't right but on

and presumably many don't right but on the in the other group you pull out all the in the other group you pull out all the stops and you don't care because the stops and you don't care because you're interested not in testing the you're interested not in testing the hypothesis does this thing help you hypothesis does this thing help you you're interested in getting them to you're interested in getting them to lose weight not have diabetes stop lose weight not have diabetes stop smoking exercise like crazy so you with smoking exercise like crazy so you with the greatest division between two groups the greatest division between two groups of individuals where we would I think be of individuals where we would I think be able to agree that this group is now able to agree that this group is now aging slower the group that we've aging slower the group that we've reconciled their diabetes quit the reconciled their diabetes quit the smoking etc etc and then I'd love to see smoking etc etc and then I'd love to see riches 12 line up in that in that riches 12 line up in that in that population that would be great let me population that would be great let me just say that I think that people that just say that I think that people that study animals myself included always study animals myself included always underestimate how well we can evaluate underestimate how well we can evaluate Health in people with a very very Health in people with a very very thorough evaluation because we don't do thorough evaluation because we don't do that in our experimental animal why do that in our experimental animal why do you think that is Steve why is it that you think that is Steve why is it that because I was going to ask about because I was going to ask about parabiosis later on in the discussion we parabiosis later on in the discussion we might as well talk about it now right might as well talk about it now right parabiosis seems to actually kind of

parabiosis seems to actually kind of work in certain Mouse models do we have work in certain Mouse models do we have any reason to believe it's going to work any reason to believe it's going to work in humans and if not why not why are in humans and if not why not why are mice so different from people well wait mice so different from people well wait a minute I wouldn't say that just a minute I wouldn't say that just because we don't have evidence that it because we don't have evidence that it works in humans means mice are different works in humans means mice are different from people first of all when it comes from people first of all when it comes to parabiosis right I mean that's a to parabiosis right I mean that's a different discussion but I I actually different discussion but I I actually have a little bit I agree that most if have a little bit I agree that most if you look at the attempts to cure cancer you look at the attempts to cure cancer or or other diseases in mice and or or other diseases in mice and translation to people most have failed I translation to people most have failed I actually think that's because those are actually think that's because those are artificial Mouse models where they tried artificial Mouse models where they tried to give young mice an age related to give young mice an age related disease I'm more optimistic I don't know disease I'm more optimistic I don't know thises have those mice I know I'm I'm thises have those mice I know I'm I'm more optimistic that biological aging or more optimistic that biological aging or normative aging is going to be much more normative aging is going to be much more likely to translate to people both likely to translate to people both interventions and biomarkers than the interventions and biomarkers than the specific disease interventions I might specific disease interventions I might be wrong I don't know answer I'm just be wrong I don't know answer I'm just more op we would hope that's the case so more op we would hope that's the case so I I don't I don't I don't think we I I don't I don't I don't think we should rule out the mice as a useful

should rule out the mice as a useful model in fact I think there's reason to model in fact I think there's reason to be optimistic that it will I actually am be optimistic that it will I actually am kind of bullish on parabiosis as like I kind of bullish on parabiosis as like I think it will work to some extent in think it will work to some extent in people it's not a pragmatic approach for people it's not a pragmatic approach for population gerpe but I'm just wondering population gerpe but I'm just wondering like why it wouldn't be as efficacious like why it wouldn't be as efficacious how do we know it's not yeah right I how do we know it's not yeah right I this is something that I mean aren't this is something that I mean aren't there six or eight clinical trials going there six or eight clinical trials going on right now variant on right now variant that yeah yeah so I I haven't seen them that yeah yeah so I I haven't seen them I've seen the one that's looking at I've seen the one that's looking at um well there's the one that it's not um well there's the one that it's not really a parabiosis study but it's really a parabiosis study but it's looking at plasma FIS for Alzheimer's looking at plasma FIS for Alzheimer's but that's I consider that a little bit but that's I consider that a little bit different but but fair enough okay different but but fair enough okay because they're just using Albin I think because they're just using Albin I think aren't they right but there's also aren't they right but there's also studies going on of young young blood studies going on of young young blood yeah right but if you think of yeah right but if you think of parabiosis as both you know taking away parabiosis as both you know taking away the bad stuff that accumulates with age the bad stuff that accumulates with age and adding in the good stuff that's in and adding in the good stuff that's in young some sort of of plasma exchange young some sort of of plasma exchange hits at least half that equation right hits at least half that equation right MH okay let's go I want to come back to

MH okay let's go I want to come back to this but but so so so my question this but but so so so my question was why the why the difference you're was why the why the difference you're saying Matt uh the difference is saying Matt uh the difference is probably Amplified in disease specific probably Amplified in disease specific cases like heart disease cancer and cases like heart disease cancer and Alzheimer's disease probably less Alzheimer's disease probably less relevant when you're talking about aging relevant when you're talking about aging because even a flawed Mouse model still because even a flawed Mouse model still ages in fact it's designed to age in a ages in fact it's designed to age in a certain way yeah and I mean I think certain way yeah and I mean I think normative aging looks very similar again normative aging looks very similar again if we look from mice to dogs to people if we look from mice to dogs to people just sort of broadly speaking the just sort of broadly speaking the process looks pretty similar so I'm process looks pretty similar so I'm cautiously optimistic that these things cautiously optimistic that these things are going to translate I think the the are going to translate I think the the reason that not to pay too much reason that not to pay too much attention to Steve's pessimism on this attention to Steve's pessimism on this point although he's completely right of point although he's completely right of course most things that do have a an course most things that do have a an important effect in my fail in human important effect in my fail in human clinical trials and it's for a variety clinical trials and it's for a variety of reasons sometimes humans are of reasons sometimes humans are different from mice sometimes the drug different from mice sometimes the drug has side effects that are tolerable in has side effects that are tolerable in my is not tolerable in people Etc but I my is not tolerable in people Etc but I always like to look at the other side of always like to look at the other side of the coin that is if your goal is to

the coin that is if your goal is to develop um a drug that blunts pain in develop um a drug that blunts pain in people uh uh and you screen 40 or 50 people uh uh and you screen 40 or 50 drugs and you find a couple that inhibit drugs and you find a couple that inhibit pain in mice that's a really good start pain in mice that's a really good start it doesn't guarantee they're going to it doesn't guarantee they're going to work in people but it gives you this work in people but it gives you this category of of snail based uh category of of snail based uh neurotoxins let's make 40 of those from neurotoxins let's make 40 of those from 40 different different snails we'll find 40 different different snails we'll find one that actually in people works uh can one that actually in people works uh can be made by a scalable process and be made by a scalable process and doesn't produce serious side effects so doesn't produce serious side effects so the the mice are not a it's not a the the mice are not a it's not a onetoone mapping it works in mice it onetoone mapping it works in mice it doesn't it works in people but it's an doesn't it works in people but it's an important critical First Step which important critical First Step which usually succeeds in in finding a set of usually succeeds in in finding a set of drugs of related families or with drugs of related families or with related targets at least that are related targets at least that are efficacious in people most drugs that efficacious in people most drugs that are used in people uh had useful are used in people uh had useful rodent-based research somewhere in their rodent-based research somewhere in their pedigree but and I absolutely agree with

pedigree but and I absolutely agree with that rich and nobody saying that 100% of that rich and nobody saying that 100% of things that work in mice do not work but things that work in mice do not work but I think there's a critical difference I think there's a critical difference with aging research was it takes four with aging research was it takes four years to do one of these and in mice years to do one of these and in mice right and so if we have to do 40 to find right and so if we have to do 40 to find one or two that work that's why I like one or two that work that's why I like aging rate indicators speed things up so aging rate indicators speed things up so let me ask a question I'm going to take let me ask a question I'm going to take you I'm going to take I'm sorry I'm you I'm going to take I'm sorry I'm stepping on your toes Peter but the stepping on your toes Peter but the question I always come back to I agree question I always come back to I agree we need these a rate indicators when do we need these a rate indicators when do we how do we get to the point where we how do we get to the point where we're confident that they actually work we're confident that they actually work in people and maybe more importantly how in people and maybe more importantly how do we get to the point that FDA is do we get to the point that FDA is confident that they works that's the confident that they works that's the only way you're going to be able to use only way you're going to be able to use them in a clinical trial and I don't see them in a clinical trial and I don't see a path in the short term well I don't a path in the short term well I don't know that we need that to tell you the know that we need that to tell you the truth so I went to the FDA to try to get truth so I went to the FDA to try to get them to to to to approve a a trial of them to to to to approve a a trial of met foreman and we didn't couch it in met foreman and we didn't couch it in aging cuz you're right as soon as you aging cuz you're right as soon as you mention aging their eyes glaze over and mention aging their eyes glaze over and they're not interested anymore but we they're not interested anymore but we did it in terms of multimorbidity and

did it in terms of multimorbidity and they were fine they were fine with that they were fine they were fine with that but that's a different Endo to your but that's a different Endo to your question is that you've you've merged question is that you've you've merged two different difficult problems problem two different difficult problems problem a can we find drugs that's slow Aging in a can we find drugs that's slow Aging in people problem B can we surmount the people problem B can we surmount the legal and political barriers to getting legal and political barriers to getting them that's not what I was asking I was them that's not what I was asking I was asking how do we get to the point that's asking how do we get to the point that's what I'm okay what I'm saying is that what I'm okay what I'm saying is that you were focused on something I don't you were focused on something I don't have any answers to basically which is have any answers to basically which is how do we get the FDA to develop an an how do we get the FDA to develop an an approved clinical trials I was more approved clinical trials I was more interested in a step before that we' be interested in a step before that we' be nice to have some drugs that actually do nice to have some drugs that actually do work to slow Aging in people but you work to slow Aging in people but you have to trust the biomarker of Aging have to trust the biomarker of Aging rate before you can be confident that rate before you can be confident that the drug that moves the biomarker of the drug that moves the biomarker of Aging rate works in people that's like Aging rate works in people that's like that's what that's fundamentally what that's what that's fundamentally what I'm asking how do we get to the point I'm asking how do we get to the point where even let's just take FDA out of where even let's just take FDA out of the equation the four of us would sit the equation the four of us would sit look at the data and I'll be like yep look at the data and I'll be like yep well that's sort of my thought well that's sort of my thought experiment right I would have to take an experiment right I would have to take an example in humans that is so egregious

example in humans that is so egregious that nobody with a straight face could that nobody with a straight face could say one group isn't now aging slower say one group isn't now aging slower than the others sure would that convince than the others sure would that convince you though so let's say we do that let's you though so let's say we do that let's say I it would make me worry it it say I it would make me worry it it wouldn't wouldn't be yeah it would only show you the be yeah it would only show you the positive signal it wouldn't show you it positive signal it wouldn't show you it would show you the specificity and not would show you the specificity and not the sensitivity of the test that's the the sensitivity of the test that's the problem sorry well I'm just gonna say it problem sorry well I'm just gonna say it it you might miss the signal if you it you might miss the signal if you found a a proteomic genomic epig like if found a a proteomic genomic epig like if you found a multimodal signal that you found a multimodal signal that detected a rate of detection a detected a rate of detection a difference in rate of Aging between difference in rate of Aging between those two very extreme sets you might those two very extreme sets you might miss it with a geroprotective drug which miss it with a geroprotective drug which wouldn't be as dramatic as that change wouldn't be as dramatic as that change so what if I told you that there are so what if I told you that there are people who claim there there are people who claim there there are epigenetic signatures that do that that epigenetic signatures that do that that that that correlate quite well they that that correlate quite well they claim with health outcome 10year claim with health outcome 10year mortality 5year mortality threeyear mortality 5year mortality threeyear mortality in mortality in people and um are measuring the rate of

people and um are measuring the rate of biological aging because it's out there biological aging because it's out there I mean it's in the literature I mean I I mean it's in the literature I mean I would look I mean this is not perfect would look I mean this is not perfect but it would be one thing I would but it would be one thing I would immediately think of which is I would immediately think of which is I would take a really good biobank that would take a really good biobank that would have enough samples that I could you have enough samples that I could you know sample a bunch of human stuff and know sample a bunch of human stuff and use an unbiased sample and a biased use an unbiased sample and a biased sample so I would determine an algorithm sample so I would determine an algorithm based on one and see how well it based on one and see how well it predicted on another based on enough predicted on another based on enough samples I mean that would be I would samples I mean that would be I would have to have that would have to be true have to have that would have to be true at a minimum yeah I think it is I mean at a minimum yeah I think it is I mean again I think at least it depends on how again I think at least it depends on how much Faith you put in in these these much Faith you put in in these these research studies but I mean people have research studies but I mean people have published epigenetic algorithms denen published epigenetic algorithms denen pace is the one that most people are pace is the one that most people are going to talk about right that that going to talk about right that that correlate seemingly pretty well at least correlate seemingly pretty well at least with mortality and with metrics of with mortality and with metrics of Health span to for lack of a better way Health span to for lack of a better way of framing it so so um so that exists of framing it so so um so that exists and Denine pace is using something and Denine pace is using something besides epigenetic or is it only besides epigenetic or is it only epigenetic I think it uses something

epigenetic I think it uses something else it was trained it was trained off else it was trained it was trained off of other biomarkers and then they found of other biomarkers and then they found epigenetic marks that correlate with epigenetic marks that correlate with those other biomarkers so it's a those other biomarkers so it's a correlation to a correlation but there's correlation to a correlation but there's still a still a correlation what do you think Rich well correlation what do you think Rich well I wanted to go back to the example you I wanted to go back to the example you gave where you took a lot of people and gave where you took a lot of people and gave them intense uh exercises and gave them intense uh exercises and dietary changes to improve their health dietary changes to improve their health out likely Health outcomes and that's a out likely Health outcomes and that's a good good place to start a discussion good good place to start a discussion because you you said every sensible because you you said every sensible person would see the treated group as person would see the treated group as aging more slowly and I would want to aging more slowly and I would want to ask before I agreed to that do they also ask before I agreed to that do they also have improved cognition how are they have improved cognition how are they doing in cataracts how are they doing in doing in cataracts how are they doing in hearing what happens when you give them hearing what happens when you give them a flu shot do they have a great flu shot a flu shot do they have a great flu shot so the things you've pointed to are so the things you've pointed to are really important for really important for um both overall health and for um both overall health and for cardiovascular risk and and the things cardiovascular risk and and the things linked to that so it's nice to know but

linked to that so it's nice to know but to convince me that you now have a slow to convince me that you now have a slow aging group of people you need to go aging group of people you need to go beyond the risk factors for specific beyond the risk factors for specific common human common human diseases um if you could show that then diseases um if you could show that then for the first time I would be convinced for the first time I would be convinced you had an effective anti-aging you had an effective anti-aging manipulation in people currently I don't manipulation in people currently I don't know that there is any know that there is any effective anti-aging manipulation in effective anti-aging manipulation in people if your people if your approach got there that would be a approach got there that would be a terrific research model well but now terrific research model well but now we're getting we're getting into the definition of Aging a little into the definition of Aging a little bit which is would you agree that the bit which is would you agree that the approach I'm approach I'm describing would produce a longer life describing would produce a longer life it's easy to produce a longer life if it's easy to produce a longer life if you happen to have a clinical condition you happen to have a clinical condition where you're tied to a railroad track where you're tied to a railroad track and there's a train coming you can and there's a train coming you can extend that woman's life enormously by extend that woman's life enormously by simply uh giving her a knife and cutting simply uh giving her a knife and cutting the bonds and letting her walk away from the bonds and letting her walk away from the track longevity promoting

the track longevity promoting interventions are not % of people died interventions are not % of people died as a result of trains on trained tracks as a result of trains on trained tracks that might be a worthwhile example but that might be a worthwhile example but given that 80% of people die from these given that 80% of people die from these four chronic diseases all in favor all four chronic diseases all in favor all in favor of protecting people against in favor of protecting people against chronic diseases that's good thing and chronic diseases that's good thing and I'm glad that people are doing that no I'm glad that people are doing that no question about it now talking about the question about it now talking about the biology of Aging there are all sorts of biology of Aging there are all sorts of things that also happen when you get things that also happen when you get older that are not part of those chronic older that are not part of those chronic diseases and to make a case that you've diseases and to make a case that you've got an anti-aging manipulation you need got an anti-aging manipulation you need to show that those are changed too but to show that those are changed too but do all of them have to change or just do all of them have to change or just most of them I mean I think don't enough most of them I mean I think don't enough have to change that you increase the have to change that you increase the length and quality of your life and and length and quality of your life and and if you if you still get a cataract at if you if you still get a cataract at the same rate I'm not sure that should the same rate I'm not sure that should be disqualifying right but the important be disqualifying right but the important thing I think about what rich said is thing I think about what rich said is all the stuff that he pointed out could all the stuff that he pointed out could be easily done in humans wouldn't be be easily done in humans wouldn't be hard to measure here the nice thing hard to measure here the nice thing about like the dog examples where we've about like the dog examples where we've got well-known famous long and slow got well-known famous long and slow aging uh uh dog breeds and it's true for

aging uh uh dog breeds and it's true for horses too it's certainly true for mice horses too it's certainly true for mice is that more or less everything slows is that more or less everything slows down together the tiny dogs that are are down together the tiny dogs that are are very long lived it's not just that they very long lived it's not just that they have a delay of cancer they have a delay have a delay of cancer they have a delay in neurod degenerative disease of delay in neurod degenerative disease of delay and digestive diseases and Joint and digestive diseases and Joint diseases aging has been slowed in those diseases aging has been slowed in those dogs dogs and if the dogs did your we might not and if the dogs did your we might not have an intervention that does that to have an intervention that does that to your point Rich I'm saying I'm saying we your point Rich I'm saying I'm saying we might not have a non-pharmacologic might not have a non-pharmacologic method that does that it's not clear method that does that it's not clear that even though exercise clearly that even though exercise clearly extends lifespan it's not clear that extends lifespan it's not clear that it's doing so by slowing aging those are it's doing so by slowing aging those are two different things to your point it's two different things to your point it's not clear but it's an interesting not clear but it's an interesting question like do you believe exercise question like do you believe exercise slows aging exercise healthy diet sleep slows aging exercise healthy diet sleep I have no idea I think so would be my my I have no idea I think so would be my my intuition is I think so but I can't intuition is I think so but I can't point to the evidence that tells me so point to the evidence that tells me so well there's evidence to support it but well there's evidence to support it but it's not the question is does it rise to

it's not the question is does it rise to the level of evidence that would the level of evidence that would convince rich I don't know like I I convince rich I don't know like I I believe it probably does too but I'm not believe it probably does too but I'm not going to you know say with 100% going to you know say with 100% certainty I I think here's where we get certainty I I think here's where we get back into Health span versus lifespan back into Health span versus lifespan the effect of exercise on longevity is the effect of exercise on longevity is pretty small its effect on quality of pretty small its effect on quality of life is enormous so much depends on life is enormous so much depends on where you start and it also depends on where you start and it also depends on the I I've always found these to be a the I I've always found these to be a little bit problematic because I don't little bit problematic because I don't think that defining it by the input is think that defining it by the input is as valuable as defining it by the output as valuable as defining it by the output in other words to say you exercise this in other words to say you exercise this many minutes a week versus that many many minutes a week versus that many minutes a week is a little dirty because minutes a week is a little dirty because intensity matters what you do matters intensity matters what you do matters sometimes the output is what matters sometimes the output is what matters more how strong you are how high your V2 more how strong you are how high your V2 Max is those tend to be more predictive Max is those tend to be more predictive uh because that's the integral of the uh because that's the integral of the work that's been done but but your point work that's been done but but your point is I it's well taken like the impact on is I it's well taken like the impact on health span is what I tell my patients health span is what I tell my patients if this if this amount of exercise if this if this amount of exercise didn't make you live one day longer the

didn't make you live one day longer the quality in which your life would improve quality in which your life would improve would justify it now fortunately we can would justify it now fortunately we can move past this sort of semantic uh move past this sort of semantic uh discussions uh because there's now discussions uh because there's now molecular ways of checking this exercise molecular ways of checking this exercise as I'll bet all of you know increases an as I'll bet all of you know increases an enzyme called enzyme called gd1 in the blood of exercise people and gd1 in the blood of exercise people and in mice and sv's lab has shown that if in mice and sv's lab has shown that if you elevate gld1 it does great things to you elevate gld1 it does great things to your brain more neurogenesis and more your brain more neurogenesis and more brain derived protective factors brain brain derived protective factors brain derived neurotropic factors I also goes derived neurotropic factors I also goes up in humans and in mice after exercise up in humans and in mice after exercise it does great things for your fat at it does great things for your fat at least least CL let's leave that up for a moment oh CL let's leave that up for a moment oh boy oh boy I'm striking all the nerves boy oh boy I'm striking all the nerves here today all right you may be quite here today all right you may be quite right I just don't I wanted to stick right I just don't I wanted to stick with the gld1 and I to make the point with the gld1 and I to make the point that they also go up in in all of the that they also go up in in all of the slow aging mice that is all the slow aging mice that is all the anti-aging drugs the Cal restricted diet anti-aging drugs the Cal restricted diet the isoline restricted diet and five

the isoline restricted diet and five different single Gene mutants that different single Gene mutants that extend L Bane and mice they all Elevate extend L Bane and mice they all Elevate gld1 17 Alpha estradiol yes Cana floen gld1 17 Alpha estradiol yes Cana floen uh both SE well this is the key question uh both SE well this is the key question in uh for what I recent um is sex in uh for what I recent um is sex specific specific gld1 is in both sexes but this is this gld1 is in both sexes but this is this is how one begins to answer that that is how one begins to answer that that question this is the exact kind of question this is the exact kind of question one has to ask so if you are question one has to ask so if you are interested in the idea that exercise interested in the idea that exercise regimes have an a benefit beyond the regimes have an a benefit beyond the obvious exercise link physiological obvious exercise link physiological declines of age do they improve declines of age do they improve cognition and if so how these molecular cognition and if so how these molecular changes are the things you need to begin changes are the things you need to begin to investigate and the anti-aging to investigate and the anti-aging studies in mice show that the anti-aging studies in mice show that the anti-aging drugs at least the ones we've looked at drugs at least the ones we've looked at so so far increase the same things that far increase the same things that exercise does is Rich have you done this exercise does is Rich have you done this experiment with a CO with an ITP cohort

experiment with a CO with an ITP cohort where you run in addition to a drug where you run in addition to a drug parallel n you know what I'm going to parallel n you know what I'm going to ask well you're G to ask if we re ask well you're G to ask if we re exercised our mice right yes yeah we've exercised our mice right yes yeah we've never done that so you haven't done a never done that so you haven't done a sedentary versus exercise have not done sedentary versus exercise have not done that you haven't done a obesogenic that you haven't done a obesogenic versus fasted we we never use obesogenic versus fasted we we never use obesogenic diets and I mean it's worth doing it diets and I mean it's worth doing it that the ITP doesn't do we don't have that the ITP doesn't do we don't have the resources we have enough resources the resources we have enough resources to test about five drugs a year but if to test about five drugs a year but if we wanted to test them in exercise we wanted to test them in exercise versus non- exercise we got to get to a versus non- exercise we got to get to a budget increase because that will now budget increase because that will now get to this question because now we get to this question because now we could look at the solu yeah maybe it could look at the solu yeah maybe it would maybe it wouldn't so I'm I'm very would maybe it wouldn't so I'm I'm very in in mice I'm very agnostic about what in in mice I'm very agnostic about what we can learn from exercising mice we can learn from exercising mice because mice are basically kept in a because mice are basically kept in a jail cell something the size of a jail jail cell something the size of a jail cell their entire life if you took a cell their entire life if you took a bunch of people and put a exercise wheel bunch of people and put a exercise wheel in a gel cell that would use it would in a gel cell that would use it would that be the same would that substitute

that be the same would that substitute for people that walk around to go inside for people that walk around to go inside they go outside they go to the gym that they go outside they go to the gym that do this it wouldn't substitute for all do this it wouldn't substitute for all of it no no question so to me it's a of it no no question so to me it's a very very low of of exercise if you didn't see low of of exercise if you didn't see anything from it then that Ru you anything from it then that Ru you wouldn't rule it out right wouldn't rule it out right good so their molecular testable good so their molecular testable molecular hypotheses that link the molecular hypotheses that link the biology of Aging to anti-aging drugs and biology of Aging to anti-aging drugs and to exercise and teasing out how those to exercise and teasing out how those are are interrelated uh and whether which of interrelated uh and whether which of your exercise regimes say increase iin your exercise regimes say increase iin increase gld1 and increased neurogenesis increase gld1 and increased neurogenesis right right that's a research agenda that could be that's a research agenda that could be very valuable then if you want to screen very valuable then if you want to screen drugs in people to see which ones drugs in people to see which ones deserve expensive long-term testing the deserve expensive long-term testing the ones that rais gld1 irin and some aspect ones that rais gld1 irin and some aspect of uh neurobiological function in of uh neurobiological function in addition to the good the good stuff

addition to the good the good stuff they're doing for the muscles that's an they're doing for the muscles that's an approach right I I I agree completely approach right I I I agree completely and this gets back to what we were and this gets back to what we were talking about before with the epigenetic talking about before with the epigenetic changes is if you had a mechanistic changes is if you had a mechanistic connection which is what rich is drawing connection which is what rich is drawing there yes not only this is correlated there yes not only this is correlated with out with this outcome but here's with out with this outcome but here's why we all feel a lot more confident why we all feel a lot more confident that that this is real right that it's that that this is real right that it's important and especially that important and especially that mechanistic connection is preserved in mechanistic connection is preserved in people good do any of you believe that people good do any of you believe that glp1 agonists are gero protective oh I'm glp1 agonists are gero protective oh I'm super interested in that question I I super interested in that question I I think we need to find that out it's it's think we need to find that out it's it's they look good I think there's two parts they look good I think there's two parts though are they jerop protective from a though are they jerop protective from a caloric restriction effect or are there caloric restriction effect or are there caloric independent effects that could caloric independent effects that could potentially be asking the second potentially be asking the second question I'm taking the first as a given question I'm taking the first as a given okay well I yeah that's different okay well I yeah that's different question is is chronic caloric question is is chronic caloric restriction beneficial in normal weight restriction beneficial in normal weight people but most people taking gp1 people but most people taking gp1 agonists aren't normal yes and I think

agonists aren't normal yes and I think it's impossible at this point because it's impossible at this point because the studies are all done in obese and the studies are all done in obese and type and patients with type 2 diabetes type and patients with type 2 diabetes that we can't disentangle them so we that we can't disentangle them so we will just say that for that patient will just say that for that patient population the caloric restriction population the caloric restriction appears to be gero protective but yes appears to be gero protective but yes you're right I'm technically asking the you're right I'm technically asking the second question which is in an second question which is in an individual who is metabolically healthy individual who is metabolically healthy but but overweight where there's actually no overweight where there's actually no evidence that weight loss per se is evidence that weight loss per se is necessary outside of maybe some edge necessary outside of maybe some edge cases and Orthopedic stuff um is there cases and Orthopedic stuff um is there is there a geroprotective nature to this is there a geroprotective nature to this and where it's most talked about is in and where it's most talked about is in dementia prevention right now that's dementia prevention right now that's where it's at least most complicated to where it's at least most complicated to tease that out so what do you guys think tease that out so what do you guys think and it clearly has neurological effects and it clearly has neurological effects there's effects on addiction right so there's effects on addiction right so the dementia connection is not it's the dementia connection is not it's crossing the blood brain crossing the blood brain barrier I mean Rich this is one for you barrier I mean Rich this is one for you to tell ITP tested this yet rich is it to tell ITP tested this yet rich is it because the oral ones are just not because the oral ones are just not strong enough and we want to yeah can strong enough and we want to yeah can you break your protocol and do an ITP

you break your protocol and do an ITP with an with an injection why because it's enormously injection why because it's enormously laborious to do weekly in that sounds laborious to do weekly in that sounds like an I need more money problem and like an I need more money problem and also you need a separate control group also you need a separate control group because need you get sham injections and because need you get sham injections and our yes if you increase our budget our yes if you increase our budget dramatically I think it's a worthwhile dramatically I think it's a worthwhile experiment but what we're waiting for um experiment but what we're waiting for um is oral drugs that work that that you is oral drugs that work that that you don't have to to do um uh injections of don't have to to do um uh injections of drug I mean there is an oral semaglutide drug I mean there is an oral semaglutide formulation that's taken daily submitted formulation that's taken daily submitted to us this year okay um the detailed to us this year okay um the detailed protocol however is again technically protocol however is again technically very laborious each Mouse has to be food very laborious each Mouse has to be food deprived for six hours then the material deprived for six hours then the material is administered and then they have to is administered and then they have to have a a a change in their water balance have a a a change in their water balance for the next 2 hours it is technically for the next 2 hours it is technically not an injection y but it is not any L not an injection y but it is not any L laborious and in addition you have to laborious and in addition you have to have your own separate control group have your own separate control group that gets all of those different that gets all of those different manipulations with a sham injection

manipulations with a sham injection could you do three instead of five next could you do three instead of five next year and make that one of them year and make that one of them reallocate some funding well I'm not in reallocate some funding well I'm not in charge it's a heavy lift yeah but I charge it's a heavy lift yeah but I would I I'd vote against it I I would would I I'd vote against it I I would vote for waiting about a year until vote for waiting about a year until somebody comes up with a pill that you somebody comes up with a pill that you can just mix into Mouse food or water can just mix into Mouse food or water and give it to the mice and it'll work and give it to the mice and it'll work and these are going to be mice that are and these are going to be mice that are an incredible amount of stress from all an incredible amount of stress from all the handling the injection yeah that's the handling the injection yeah that's why the control group is necessary but why the control group is necessary but what what it it the companies are what what it it the companies are putting so much money into this they putting so much money into this they understand why people don't like to understand why people don't like to inject themselves I I'm reasonably sure inject themselves I I'm reasonably sure I mean I know nothing about it but I'm I mean I know nothing about it but I'm reasonably sure that in a year or two reasonably sure that in a year or two there'll be some agent that works when there'll be some agent that works when you put it in the food of a mouse or the you put it in the food of a mouse or the the poppet as a pill as a person those the poppet as a pill as a person those would be enormously important to test do would be enormously important to test do we know if tepati for instance were we know if tepati for instance were given to people of normal body weight do given to people of normal body weight do they also lose 15% of their body weight

they also lose 15% of their body weight question I I have not seen the data on question I I have not seen the data on that I can tell you that I can tell you anecdotally having seen patients um it's anecdotally having seen patients um it's going to be dose dependent um so as you going to be dose dependent um so as you know that drug is dosed from as low as 2 know that drug is dosed from as low as 2 and a half milligrams weekly to as much and a half milligrams weekly to as much as 15 milligrams weekly usually people as 15 milligrams weekly usually people who don't need to lose much weight you who don't need to lose much weight you know someone who says look I just want know someone who says look I just want to lose this last 10 PBS and I've you to lose this last 10 PBS and I've you know I've done all the exercising and know I've done all the exercising and dieting I can do they typically just dieting I can do they typically just lose that 10 pounds and they take a very lose that 10 pounds and they take a very low dose now to your point if they took low dose now to your point if they took the 15 milligrams would they would they the 15 milligrams would they would they become sarcopenic right uh I don't know become sarcopenic right uh I don't know but I I think you know this conversation but I I think you know this conversation points out again how constraining lack points out again how constraining lack of resources are I mean of resources are I mean we sit here and come up with 50 amazing we sit here and come up with 50 amazing questions that can't every time I hear questions that can't every time I hear Rich talk about this stuff it just Rich talk about this stuff it just pisses me off because there's a bunch of

pisses me off because there's a bunch of stuff that should be tested should have stuff that should be tested should have been tested by now that hasn't been been tested by now that hasn't been tested not because it's not a good idea tested not because it's not a good idea but because there just isn't any but because there just isn't any resources to do resources to do it well I think what's it well I think what's really frustrating as well is that these really frustrating as well is that these are the types of experiments that would are the types of experiments that would allow us to actually start to allow us to actually start to economically model the impact of these economically model the impact of these drugs outside of just kind of a disease drugs outside of just kind of a disease State um for example if if if drugs like State um for example if if if drugs like these are indeed geroprotective and these are indeed geroprotective and people can work three years longer five people can work three years longer five years longer because they're healthier years longer because they're healthier think of the impact on that uh over at think of the impact on that uh over at om right what does that mean to tax take om right what does that mean to tax take what does that mean to delaying Medicare what does that mean to delaying Medicare what does that mean to reduce Health what does that mean to reduce Health Care spending at the time when it is Care spending at the time when it is most expensive so boy there's last most expensive so boy there's last estimate I saw was 38 trillion a year estimate I saw was 38 trillion a year for every year of health for every year of health span wow that's that was a McKenzie

span wow that's that was a McKenzie report that 38 I'll send you the link report that 38 I'll send you the link not 3.8 NOP 38 that's analysis by Andrew not 3.8 NOP 38 that's analysis by Andrew Scott who British Economist that's Scott who British Economist that's bigger than I would have guessed wow bigger than I would have guessed wow um can we just because I'm in the mood um can we just because I'm in the mood to see you get spicy can we just talk to see you get spicy can we just talk about sence for a minute about sence for a minute sent cells he means Rich you know the sent cells he means Rich you know the things that drive aging oh tell me more things that drive aging oh tell me more what do you what do you mean you want you want me to to talk mean you want you want me to to talk about sess and cells okay yes I'll be about sess and cells okay yes I'll be glad to do that it's a it's a terrible glad to do that it's a it's a terrible historical accident um Leonard hylick historical accident um Leonard hylick way back found that human cells would way back found that human cells would only divide 50 times and stop one of his only divide 50 times and stop one of his colleagues a a guy named Victoria colleagues a a guy named Victoria defendi made a joke at lunch and said to defendi made a joke at lunch and said to him hey Lynn maybe they're getting him hey Lynn maybe they're getting old and Lenn did not understand it was a old and Lenn did not understand it was a joke uh he thought it was a serious joke uh he thought it was a serious scientific hypothesis it's clearly nuts scientific hypothesis it's clearly nuts because we don't uh get old in a way

because we don't uh get old in a way that is modeled by having lung embryonic that is modeled by having lung embryonic lung fiber blasts stop growing but it at lung fiber blasts stop growing but it at the time the hottest technique in modern the time the hottest technique in modern medicine was you could grow cells in medicine was you could grow cells in culture that was really so cool you culture that was really so cool you could do stuff with them so all the cell could do stuff with them so all the cell biologists who really wanted to use the biologists who really wanted to use the coolest new toys wanted to have a way of coolest new toys wanted to have a way of studying aging without all these mess studying aging without all these mess messy mice and rats and having to wait messy mice and rats and having to wait and stuff they could do it in vitro and stuff they could do it in vitro because this was inv vitro aging this is because this was inv vitro aging this is inv vitro inessence and the field to inv vitro inessence and the field to skip 30 or 40 years the field um went skip 30 or 40 years the field um went ahead with this metaphor without ever ahead with this metaphor without ever questioning it it's now such an industry questioning it it's now such an industry that the people who review these grants that the people who review these grants and and papers uh and advise papers uh and advise billionaires um and advise startup billionaires um and advise startup companies they all were trained in Labs companies they all were trained in Labs that just Essence for a living so they that just Essence for a living so they never stopped to question one of the never stopped to question one of the most famous and best scientists in this most famous and best scientists in this area is a woman named Judy cesy who

area is a woman named Judy cesy who recently passed away died last year she recently passed away died last year she and I were assistant professors together and I were assistant professors together at Boston University and I she and I at Boston University and I she and I were going to send in a program project were going to send in a program project with a third person Barbara gilchrest uh with a third person Barbara gilchrest uh I was going to study IM immunity and I was going to study IM immunity and aging Barbara was going to study skin aging Barbara was going to study skin cells we talked Judy you want to study s cells we talked Judy you want to study s in essence so she read the literature in essence so she read the literature she sing came back to us and she said she sing came back to us and she said this has nothing to do with aging I me this has nothing to do with aging I me it's good cell biology it's good about it's good cell biology it's good about cancer biology but of course it's cancer biology but of course it's nothing to do with aging and we told nothing to do with aging and we told Judy of course it has nothing to do with Judy of course it has nothing to do with aging we understand that but the aging we understand that but the reviewers think it is aging so if you reviewers think it is aging so if you can just keep a straight face for the can just keep a straight face for the three hours of the site visit pretend three hours of the site visit pretend you think it has to do with aging you'll you think it has to do with aging you'll get a great score and that's what get a great score and that's what happened she got a great score we got happened she got a great score we got the program project when she moved to the program project when she moved to Berkeley she took her Grant with her and Berkeley she took her Grant with her and after a year or two she had a apparently after a year or two she had a apparently convinced herself that it was aging it convinced herself that it was aging it was close enough to aging so the notion was close enough to aging so the notion that aging is due to ccent cell

that aging is due to ccent cell accumulation is bad for two reasons it's accumulation is bad for two reasons it's it's a grotesque oversimplification the it's a grotesque oversimplification the evidence for this is awful but even evidence for this is awful but even worse it again cuts off productive worse it again cuts off productive thinking there almost certainly are thinking there almost certainly are changes that occur in some gal cells in changes that occur in some gal cells in the brain so that as you get older they the brain so that as you get older they start making bad cyto kinds B for your start making bad cyto kinds B for your brain there probably are changes in some brain there probably are changes in some bone cells or some cells in the lineage bone cells or some cells in the lineage that leads to the beta cells in the that leads to the beta cells in the pancreas that lose the ability to divide pancreas that lose the ability to divide and that's bad for you and finding out and that's bad for you and finding out how it happens is really important but how it happens is really important but once you've convinced yourself that's once you've convinced yourself that's all the same thing this cyto kind this all the same thing this cyto kind this also proliferation this change in uh also proliferation this change in uh ability to make specific fibrous ability to make specific fibrous connective tissue let's call that sence connective tissue let's call that sence it's the same thing you've lost what you it's the same thing you've lost what you need to think of good careful need to think of good careful well-defined experiments with well-defined experiments with well-defined endpoints if you say that

well-defined endpoints if you say that ccent there is a thing called a ccent ccent there is a thing called a ccent cell the thing that's happening in this cell the thing that's happening in this glea and in this marrow cell and this glea and in this marrow cell and this pancreas it's due to the senescent cell pancreas it's due to the senescent cell accumulating you've blocked off accumulating you've blocked off productive generation of research productive generation of research hypothesis the last point I'll mention hypothesis the last point I'll mention in this rant has to do with in this rant has to do with um cenotic drugs so the ITP was asked to um cenotic drugs so the ITP was asked to test an allegedly senolytic drug called test an allegedly senolytic drug called fistin it was given to us by someone who fistin it was given to us by someone who is using this now for clinical trials is using this now for clinical trials and who has a company that's interested and who has a company that's interested in senolytic drugs so we gave it to mice in senolytic drugs so we gave it to mice it had no beneficial effect it had no beneficial effect whatsoever at the what's the mechanism whatsoever at the what's the mechanism of this Drug's action oh it has no of this Drug's action oh it has no action okay has no action or had no effect what is it supposed to or had no effect what is it supposed to supposed to kill C ccent cells or supposed to kill C ccent cells or something okay um so we told this guy

something okay um so we told this guy sorry it had no effect he said well sorry it had no effect he said well let's prove that whether it had any let's prove that whether it had any change inessence cells so we gave him change inessence cells so we gave him blind tissues from each of the treated blind tissues from each of the treated and untreated mice and he tried a test and untreated mice and he tried a test and there were no changes in sessen and there were no changes in sessen cells by his marker he tried six cells by his marker he tried six different markers there were no changes different markers there were no changes and senescent and senescent cells so then he said well send the cells so then he said well send the brain and the liver and the muscle maybe brain and the liver and the muscle maybe the senescent cells have been changed in the senescent cells have been changed in the brain so we blind sent blind samples the brain so we blind sent blind samples to a colleague of his there were no to a colleague of his there were no changes in sessen cells by any of the changes in sessen cells by any of the markers that these folks looked at so markers that these folks looked at so this drug which is now being marketed in this drug which is now being marketed in clinical trials and you can buy it I'm clinical trials and you can buy it I'm sure as an an natural sure as an an natural product um there's no evidence as far as product um there's no evidence as far as I know I know that it either has an anti-aging effect that it either has an anti-aging effect or removes siness and cells but once or removes siness and cells but once you've got a commercial company pushing you've got a commercial company pushing this stuff and your whole brand your

this stuff and your whole brand your whole Lab your whole program project and whole Lab your whole program project and all the people who are reviewing you are all the people who are reviewing you are convinced the nest and cells exist convinced the nest and cells exist there's they're bad and drugs can kill there's they're bad and drugs can kill them it's it's a snowball rolling them it's it's a snowball rolling downhill and uh a rant of the sort I've downhill and uh a rant of the sort I've just delivered has no impact on the just delivered has no impact on the field so can I give a counter example field so can I give a counter example cuz there's good experimental data that cuz there's good experimental data that there that these things can be at least there that these things can be at least partially eliminated and when you do partially eliminated and when you do that there's an improvement in health that there's an improvement in health and this has been done both in a genetic and this has been done both in a genetic treatment which genetically uh which treatment which genetically uh which they Prime these cells to be genetically they Prime these cells to be genetically killed and it's also been done with uh killed and it's also been done with uh you know with with drugs not with fan I you know with with drugs not with fan I hasten to say so I think there's strong hasten to say so I think there's strong evidence that getting rid of these p16 evidence that getting rid of these p16 positive cells which is really what it's positive cells which is really what it's all based on can have an improvement in all based on can have an improvement in health and in longevity is the vanerson

health and in longevity is the vanerson paper you're talking about in which they paper you're talking about in which they were allegedly depleted yeah let me tell were allegedly depleted yeah let me tell you about that because I was on the you about that because I was on the program project my job in that program program project my job in that program two papers okay one was with was with two papers okay one was with was with the short live mice and one okay so I'm the short live mice and one okay so I'm talk about the one that is not the short talk about the one that is not the short live mice there's a paper a famous paper live mice there's a paper a famous paper by vanerson Kirkland and several other by vanerson Kirkland and several other colleagues Darren Baker Baker are these colleagues Darren Baker Baker are these the guys at the guys at Mayo I remember this they they've left Mayo I remember this they they've left two of them have left but yes uh they two of them have left but yes uh they alleged that they could remove senescent alleged that they could remove senescent cells by taking genetically modified cells by taking genetically modified mice giving them a drug all the ccent mice giving them a drug all the ccent cells would go away and the mice lived cells would go away and the mice lived longer according to this was on the longer according to this was on the cover of nature it was on the cover of cover of nature it was on the cover of nature I remember this one I was a part nature I remember this one I was a part of the program project so was Judy cesy of the program project so was Judy cesy and my job was to do the lifespan and my job was to do the lifespan experiment we got the mice from uh experiment we got the mice from uh Kirkland and V person we got Camp's mice Kirkland and V person we got Camp's mice we got the drugs from them and we gave we got the drugs from them and we gave the drugs to the mice at 18 months and the drugs to the mice at 18 months and you know they had no effect on sessen

you know they had no effect on sessen cells not one we tried seven times to cells not one we tried seven times to show depletion of sessen cells by in show depletion of sessen cells by in their mice using their drug and and went their mice using their drug and and went zero for seven we then took the tissues zero for seven we then took the tissues blinded and sent them to Judy's lab Judy blinded and sent them to Judy's lab Judy C's lab so she could measure p16 cells C's lab so she could measure p16 cells but she didn't know which ones were from but she didn't know which ones were from treated and which ones were untreated treated and which ones were untreated when we undid the code there was no when we undid the code there was no effect on sess and cells whatsoever so I effect on sess and cells whatsoever so I remained somewhat skeptical I asked remained somewhat skeptical I asked vanerson had he measured the number of vanerson had he measured the number of senescent cells in his treated mice no senescent cells in his treated mice no we're planning to do that but what was we're planning to do that but what was the phenotypic change in the mice when the phenotypic change in the mice when you did this experiment oh when I I you did this experiment oh when I I could I didn't want to do an expensive could I didn't want to do an expensive Lipan experiment with with an alleged Lipan experiment with with an alleged anti anti-colitic drug until I knew that anti anti-colitic drug until I knew that it was depleting sessen so how long did it was depleting sessen so how long did you treat for I used their protocol and

you treat for I used their protocol and we I asked them I asked Darren Baker how we I asked them I asked Darren Baker how what is the dose how long do you treat what is the dose how long do you treat the mice and how long after you add the the mice and how long after you add the the drug should you wait before you the drug should you wait before you detect the removal of senescent cells detect the removal of senescent cells and his answer astonishingly was we and his answer astonishingly was we don't know we've never looked at that don't know we've never looked at that but the nature mice were treated for how but the nature mice were treated for how long long they were a long time long time they they were a long time long time they were yeah treated I think they started were yeah treated I think they started treatment in middle age right and I mean treatment in middle age right and I mean in the published papers they do show a in the published papers they do show a reduction in p16 positive cells and reduction in p16 positive cells and you're saying you couldn't replicate you're saying you couldn't replicate that in your lab is that but we're that in your lab is that but we're conflating a bunch of different issues conflating a bunch of different issues here we're conflating the genetic model here we're conflating the genetic model with the drugs and do so essent cells with the drugs and do so essent cells even exist and I I I feel like I mean I even exist and I I I feel like I mean I think Rich's skepticism is valid in in think Rich's skepticism is valid in in many ways um and there's a actually a many ways um and there's a actually a large body of evidence that that whether large body of evidence that that whether I think whether we agree on the I think whether we agree on the definition of syence what people are definition of syence what people are calling ccent cells do accumulate in

calling ccent cells do accumulate in multiple tissues with age in mice and multiple tissues with age in mice and people and if you get rid of them you people and if you get rid of them you can see some health benefits am I can see some health benefits am I convinced they they have big effects on convinced they they have big effects on lifespan no I'm not because the data is lifespan no I'm not because the data is mixed and even that genetic model other mixed and even that genetic model other people haven't been able to reproduce so people haven't been able to reproduce so it's messy um but I think partly maybe it's messy um but I think partly maybe start with what is the definition of a start with what is the definition of a ccent cell because that's where a lot of ccent cell because that's where a lot of this confusion comes from right that's this confusion comes from right that's what I was saying that there it's there what I was saying that there it's there is no satisfactory definition there are is no satisfactory definition there are many things that satisfactory to you I many things that satisfactory to you I mean is your issue Rich that there we mean is your issue Rich that there we talk about it like it's one cell but talk about it like it's one cell but inity big part of it you can't think inity big part of it you can't think about it clearly if you imagine that about it clearly if you imagine that these many many different kinds of cell these many many different kinds of cell intrinsic changes with potential intrinsic changes with potential pathological impacts are all aspects of pathological impacts are all aspects of the same phenomenon but we do that with the same phenomenon but we do that with other things we the mitochondria other things we the mitochondria dysfunction there's lots of different dysfunction there's lots of different ways to get to mitochondrial dysfunction ways to get to mitochondrial dysfunction so the NIH has just put about $600 so the NIH has just put about $600 million into a network of researchers to

million into a network of researchers to study self and Essence and I'm on The study self and Essence and I'm on The Advisory Group for that and to the Advisory Group for that and to the extent that rich is saying these are extent that rich is saying these are many many different things all many many different things all pretending to be the same thing that's pretending to be the same thing that's clearly true they're but they're coming clearly true they're but they're coming up with bigger and bigger and broader up with bigger and bigger and broader definitions of what a ccent cell is um definitions of what a ccent cell is um but on the other hand there also coming but on the other hand there also coming up with more and more interesting things up with more and more interesting things that those senescent cells do in either that those senescent cells do in either in in tissue culture which I don't put in in tissue culture which I don't put much or in mice so you know I don't much or in mice so you know I don't think the NIH would put that kind of think the NIH would put that kind of money into something if they didn't feel money into something if they didn't feel there was a valid basis I think part of there was a valid basis I think part of this is we're is we're calling it sence this is we're is we're calling it sence and I think none of us to me that's and I think none of us to me that's stolen a really good word out of the stolen a really good word out of the vocabulary cuz sin Essence just means vocabulary cuz sin Essence just means aging and it used to be you could talk aging and it used to be you could talk about calendar aging you could talk about calendar aging you could talk about syence which is what we now think about syence which is what we now think of as aging and now you can't use this of as aging and now you can't use this anymore because anytime you do they

anymore because anytime you do they think you're talking about these cells think you're talking about these cells that it's an easy analogy is this what that it's an easy analogy is this what they call the zombie cell I keep they call the zombie cell I keep forget I keep trying to purge that from forget I keep trying to purge that from my memory I mean the most common my memory I mean the most common definition I think is just an definition I think is just an irreversibly arrested cell that doesn't irreversibly arrested cell that doesn't die and typically gives off a pattern of die and typically gives off a pattern of inflammatory cyto kindes and other inflammatory cyto kindes and other factors and which is a catch all for a factors and which is a catch all for a lot of different ways to get there and a lot of different ways to get there and a lot of different states that these lot of different states that these irreversibly arrested cells can exist in irreversibly arrested cells can exist in yeah but even neurons they're not yeah but even neurons they're not considering ccent neurons and neurons considering ccent neurons and neurons are you know they're post they're post are you know they're post they're post mitotic but they don't always give off mitotic but they don't always give off this pattern of signals right that's I this pattern of signals right that's I mean again this is part of the problem mean again this is part of the problem is you mentioned p16 I think the even at is you mentioned p16 I think the even at the molecular level the the catalog of the molecular level the the catalog of markers that people are using to define markers that people are using to define a cell is changing and it seems to a cell is changing and it seems to changeing yeah so I I agree I agree with changeing yeah so I I agree I agree with much of what you're saying I just don't much of what you're saying I just don't think we should throw the baby out with think we should throw the baby out with the bathwater here and say there's

the bathwater here and say there's nothing to this I think there is nothing to this I think there is something to it and I think there's lots something to it and I think there's lots of evidence that are are there enough of evidence that are are there enough similarities between all the different similarities between all the different classes of senescent cells that people classes of senescent cells that people are studying now that they should be are studying now that they should be categorized as one thing I think that's categorized as one thing I think that's a valid conversation to have it's a good a valid conversation to have it's a good discussion point I don't think we know discussion point I don't think we know the answer yet and they discussed this a the answer yet and they discussed this a lot in the s lot in the s because even the sasp even these things because even the sasp even these things that are oozing out of the cells varies that are oozing out of the cells varies quite a bit depending on the nature of quite a bit depending on the nature of the cell that's the problem of course the cell that's the problem of course you you referred to it as almost anyone you you referred to it as almost anyone would as the sasp the setup inessence would as the sasp the setup inessence Associated proteins secretory proteins Associated proteins secretory proteins and once you think of it as the sasp and once you think of it as the sasp you've lost because the key point is not you've lost because the key point is not to do that the key point is here's a set to do that the key point is here's a set of cyto kindes that this cell has begun of cyto kindes that this cell has begun to make that's really interesting here's to make that's really interesting here's another set overlapping probably they another set overlapping probably they make it when you've made them stop make it when you've made them stop dividing for a separate reason that's dividing for a separate reason that's interesting we should study that but to

interesting we should study that but to think you've proven something about this think you've proven something about this cell type when you've actually been cell type when you've actually been looking at this cell type because the looking at this cell type because the sasp has been changed but do you think sasp has been changed but do you think it's possible that a drug such as rapy it's possible that a drug such as rapy has part of its effect on Aging through has part of its effect on Aging through a broad inhibition of a subset of the a broad inhibition of a subset of the sasps by a bizarre coin ents we have oh sasps by a bizarre coin ents we have oh oh sorry oh sorry um I think it's very likely that Romy um I think it's very likely that Romy changes cyto production by many changes cyto production by many different cell types and that some of different cell types and that some of those changes would probably have health those changes would probably have health benefits I would like to know what it benefits I would like to know what it does to the cyto production from the does to the cyto production from the macrofagos in the fat and the gal cells macrofagos in the fat and the gal cells in the brain and cells that are in in the brain and cells that are in charge of protecting you from infe viral charge of protecting you from infe viral infections but the mistake is to say yes infections but the mistake is to say yes it's affecting the sasp it's affecting the sasp it's easy to see um an an analogy if if it's easy to see um an an analogy if if I said here's a drug and it it helps you I said here's a drug and it it helps you because it affects neurons you'd laugh because it affects neurons you'd laugh at me because what you really want to

at me because what you really want to know is is it motor neurons sympathetic know is is it motor neurons sympathetic neurons parasympathetic neurons neurons neurons parasympathetic neurons neurons uh in your hypothalamus what part of the uh in your hypothalamus what part of the hypothalamus the ones that control hypothalamus the ones that control appetite and I said no no no it affects appetite and I said no no no it affects neurons I've got a drug that affects neurons I've got a drug that affects neurons but I mean people are aware of neurons but I mean people are aware of these complications and are studying these complications and are studying these complications it seems to me that these complications it seems to me that it's the terminology that you object to it's the terminology that you object to and I can appreciate that thinking that and I can appreciate that thinking that I object to you the terminology is I object to you the terminology is problematic because it makes people stop problematic because it makes people stop thinking about the important details and thinking about the important details and start imagining that they've had a start imagining that they've had a thought when they say I have a drug that thought when they say I have a drug that removes sessen cells it the the problem removes sessen cells it the the problem is that the words trap you into patterns is that the words trap you into patterns of thought that are in this case of thought that are in this case nonproductive and misleading maybe nonproductive and misleading maybe inefficient but the field is making I inefficient but the field is making I would say quite a bit of progress and would say quite a bit of progress and and and I think the way you learn about and and I think the way you learn about the complexity is you start with a the complexity is you start with a simple model you study it and then your simple model you study it and then your model get gets more complicated so I model get gets more complicated so I totally get the frustration Rich because totally get the frustration Rich because I get as frustrated as you are about I get as frustrated as you are about siness and cells about other things but

siness and cells about other things but I think this is also part of the natural I think this is also part of the natural process here and I think what Steve said process here and I think what Steve said is really important um yeah the the the is really important um yeah the the the the fraction of the ni budget that goes the fraction of the ni budget that goes to study the biology of Aging through to study the biology of Aging through Nia has remained Tiny But senescent Nia has remained Tiny But senescent cells are actually a really good example cells are actually a really good example of how a bunch of people in other of how a bunch of people in other institutes are studying aging and they institutes are studying aging and they don't even know it don't even know it they're studying they you know they're they're studying they you know they're studying sence in cancer or syence and studying sence in cancer or syence and Alzheimer's or sence and kidney disease Alzheimer's or sence and kidney disease um so it actually has had an impact in um so it actually has had an impact in kind of broadening the appeal and scope kind of broadening the appeal and scope of the field outside of Nia in ways that of the field outside of Nia in ways that I don't I certainly didn't anticipate do I don't I certainly didn't anticipate do you think that going back to the meta you think that going back to the meta problem at the beginning of our problem at the beginning of our discussion do you think that's um maybe discussion do you think that's um maybe a better way to think about allocating a better way to think about allocating funds so for example the NCI obviously funds so for example the NCI obviously received the most funding within NIH received the most funding within NIH maybe some of the NCI funding goes to maybe some of the NCI funding goes to the NCI to study cancer prevention the NCI to study cancer prevention through Jiro protection right if if the

through Jiro protection right if if the turf war is what matters that's a good turf war is what matters that's a good idea no no no we've idea no no no we've actually a group of us who are lobbying actually a group of us who are lobbying the the Congress have actually asked the the the Congress have actually asked the NIH to tell us exactly this how much NIH to tell us exactly this how much work in geroscience is going on in all work in geroscience is going on in all these other these other of they're going of they're going have to minimize that or maximiz it or have to minimize that or maximiz it or but at least it will give us an idea but at least it will give us an idea right now we have no idea how much of right now we have no idea how much of the NCI budget is going to this or niddk the NCI budget is going to this or niddk or anything else so they already have or anything else so they already have produced a report that told us how much produced a report that told us how much they were spending in the Nia but we they were spending in the Nia but we already knew that we wanted to know how already knew that we wanted to know how much they're spending in the other much they're spending in the other institutes I mean I think that could institutes I mean I think that could alleviate some of the turf war issues alleviate some of the turf war issues but I think what you really need is you but I think what you really need is you know the the change in leadership and know the the change in leadership and and leaders who actually recognize why and leaders who actually recognize why this is important and that's where it this is important and that's where it starts I mean we can have a conversation

starts I mean we can have a conversation about how much power does the NIH about how much power does the NIH director have how much power does the director have how much power does the director of HHS have but that's a place director of HHS have but that's a place to start if you can get people in those to start if you can get people in those positions who get it it's going to have positions who get it it's going to have an impact let's talk a little bit about an impact let's talk a little bit about met Foreman um Rich do you think met Foreman is guro protective in humans I know it's is guro protective in humans I know it's yeah doesn't appear to be in your yeah doesn't appear to be in your mice I I think uh the evidence is UN mice I I think uh the evidence is UN certain there's a famous paper from certain there's a famous paper from banister yes that alleged that uh banister yes that alleged that uh diabetics on Metformin had lower diabetics on Metformin had lower survival low lower mortality risks you survival low lower mortality risks you don't listen to my podcast do you I do don't listen to my podcast do you I do occasionally when when actually no you occasionally when when actually no you know what it was a different it was a know what it was a different it was a different podcast I did a very lengthy different podcast I did a very lengthy treaties in a journal Club comparing the treaties in a journal Club comparing the banister paper to the Keys paper good banister paper to the Keys paper good and came to the conclusion that the and came to the conclusion that the banister paper had too many methodologic banister paper had too many methodologic flaws to be valid that's exactly what I flaws to be valid that's exactly what I was going to say and as a matter of fact was going to say and as a matter of fact Keys Christensen who's the senior member

Keys Christensen who's the senior member of the group and I have just written a of the group and I have just written a review article which says exactly that review article which says exactly that you just that's the title of uh it's you just that's the title of uh it's under review so yes so you know exactly under review so yes so you know exactly what I was going to say and I agree what I was going to say and I agree completely uh the question is to we completely uh the question is to we metformin would be geroprotective that metformin would be geroprotective that is a non diabe slow in a non-diabetic is a non diabe slow in a non-diabetic Inhumans I think is interesting Inhumans I think is interesting unanswered it's not the drug I I would unanswered it's not the drug I I would have looked at myself if I had a big set have looked at myself if I had a big set of dogs for instance and I wanted to of dogs for instance and I wanted to give them a drug that uh modified their give them a drug that uh modified their glucose homeostasis I would probably glucose homeostasis I would probably start with something like start with something like canagan that uh actually does work in canagan that uh actually does work in mice and which is known to be safe over mice and which is known to be safe over the long term in people metformin is the long term in people metformin is safe over the long term in people but I safe over the long term in people but I don't think there's much evidence that don't think there's much evidence that it's it's anti-aging uh leaving aside how great it anti-aging uh leaving aside how great it is for diabetics and pre-diabetic what is for diabetics and pre-diabetic what do you think Steve I think it's very do you think Steve I think it's very promising you know I'm skeptical because promising you know I'm skeptical because I'm always skeptical in the absence of

I'm always skeptical in the absence of evidence but the observational evidence evidence but the observational evidence ignoring the banister paper just the ignoring the banister paper just the observational the consistency of the observational the consistency of the observational data that it reduces observational data that it reduces dementia cancer cardiovascular disease dementia cancer cardiovascular disease suggest to me there's enough smoke there suggest to me there's enough smoke there to look to see if there's if there's the to look to see if there's if there's the keys article and then you can rethink keys article and then you can rethink that okay but but sorry Steve you're that okay but but sorry Steve you're saying it does all of those things in saying it does all of those things in diabetic well most the studies have been diabetic well most the studies have been done in diabetics absolutely and and how done in diabetics absolutely and and how much of that is just much of that is just because you're curing the diabetes is an because you're curing the diabetes is an open question but I think it's and and open question but I think it's and and how much of that is a selection for how much of that is a selection for people in diabetes that are progressing people in diabetes that are progressing much less slowly because they're the much less slowly because they're the ones that stay on a single agent as ones that stay on a single agent as opposed to the ones that progress opposed to the ones that progress into right but but which is why you have into right but but which is why you have to do the study you know the question to do the study you know the question where is tame in the world of um tame is where is tame in the world of um tame is in a very preliminary State there's now in a very preliminary State there's now enough money to get it started

enough money to get it started previously so it has not it has not previously so it has not it has not enrolled anything yet it's enrolling enrolled anything yet it's enrolling right now okay previously they didn't right now okay previously they didn't want to start it until they had enough want to start it until they had enough money to do the whole thing but it's money to do the whole thing but it's been impossible to get that there's now been impossible to get that there's now a small amount of money enough to get it a small amount of money enough to get it started at a small scale with the hope started at a small scale with the hope that that will sort of uh uh start the that that will sort of uh uh start the pot rolling but um yeah it's been around pot rolling but um yeah it's been around for eight years now and I was in on the for eight years now and I was in on the original discussion about do we do Rapa original discussion about do we do Rapa mice and do we do met foran and and it mice and do we do met foran and and it was all about cost and safety that was was all about cost and safety that was the whole thing I went in strongly the whole thing I went in strongly advocating for Rapa M about I came out advocating for Rapa M about I came out saying okay there are these cost issues saying okay there are these cost issues and I think it was important because and I think it was important because when we went to the FDA we want didn't when we went to the FDA we want didn't want them to think that we were trying want them to think that we were trying to make a bunch of money with this trial to make a bunch of money with this trial and um nobody's going to get rich from and um nobody's going to get rich from met foran why is generic is so

met foran why is generic is so expensive still I think it's supply and expensive still I think it's supply and demand honestly I think they just Haven demand honestly I think they just Haven there's no need yeah I think so but um there's no need yeah I think so but um coming back to the Met Foreman question coming back to the Met Foreman question I mean I I think um first of all we I mean I I think um first of all we don't know the answer I mean Richard is don't know the answer I mean Richard is right we don't know uh so what what are right we don't know uh so what what are our opinions my opinion is diabetes our opinions my opinion is diabetes probably accelerates bi biological aging probably accelerates bi biological aging and Metformin is effective at reducing and Metformin is effective at reducing diabetic symptoms and probably reduces diabetic symptoms and probably reduces biological Aging in that context biological Aging in that context probably doesn't in people who are not probably doesn't in people who are not diabetic that's my intuition um and let diabetic that's my intuition um and let me push back on that for a second which me push back on that for a second which is diabetes is diabetes is um is an artificial diagnosis in that is um is an artificial diagnosis in that we just make a cut off we say your we just make a cut off we say your hemoglobin A1c is 6.5 you have type two hemoglobin A1c is 6.5 you have type two diabetes if your hemoglobin A1c is 5.9 diabetes if your hemoglobin A1c is 5.9 you don't but there are data that we've you don't but there are data that we've looked at that suggest looked at that suggest a monotonic Improvement in all cause a monotonic Improvement in all cause mortality as average blood glucose goes mortality as average blood glucose goes down measured by hemoglobin A1c in the down measured by hemoglobin A1c in the non-diabetic range meaning people with

non-diabetic range meaning people with an A1C of five live longer than people an A1C of five live longer than people with an A1C of 5.5 live longer than with an A1C of 5.5 live longer than people with an A1C of six all of whom people with an A1C of six all of whom are D are D non-diabetic point being if metformin's non-diabetic point being if metformin's gero protection comes through the gero protection comes through the regulation of glucose in the patient regulation of glucose in the patient with diabetes does it stand to reason with diabetes does it stand to reason that even in patients without diabetes that even in patients without diabetes further attenuation of hepatic glucose further attenuation of hepatic glucose output is going to improve all cause output is going to improve all cause mortality maybe I I don't know I don't mortality maybe I I don't know I don't know the answer obviously um I think the know the answer obviously um I think the question is is the biomarker in this question is is the biomarker in this case A1C what is that actually case A1C what is that actually reflecting right is that presumably reflecting right is that presumably reflecting some some aspect of metabolic reflecting some some aspect of metabolic homeostasis right and so um first of all homeostasis right and so um first of all does metformin in does metformin in non-diabetics have the desired effect or non-diabetics have the desired effect or the effect we would associate with the effect we would associate with reduced mortality in non-diabetics reduced mortality in non-diabetics consistently be question number one I consistently be question number one I don't know the answer to that you you don't know the answer to that you you probably and I don't want to speak for

probably and I don't want to speak for near because it's been a while since near because it's been a while since we've spoken but I the last time I had we've spoken but I the last time I had near on the podcast his rationale for near on the podcast his rationale for why Matt foran was geroprotective had why Matt foran was geroprotective had nothing to do with glucose homeostasis nothing to do with glucose homeostasis and a non-diabetic it was and I know and a non-diabetic it was and I know you're going to love this I mean Rich you're going to love this I mean Rich you're really going to love this there you're really going to love this there was a figure of the Hallmarks of aging was a figure of the Hallmarks of aging and how met Foreman on each of them sure and how met Foreman on each of them sure which which is I mean but my point being which which is I mean but my point being not not not to say that that's incorrect not not not to say that that's incorrect correct or anything it's that that there correct or anything it's that that there was something much more um Primal about was something much more um Primal about met foran's actions now I here here's my met foran's actions now I here here's my push back on that metformin requires an push back on that metformin requires an organic C and transporter to get into organic C and transporter to get into cells as I've learned somewhat recently cells as I've learned somewhat recently that muscles don't have so if you look that muscles don't have so if you look at the Tracer studies metformin does not at the Tracer studies metformin does not get into muscles it gets into entos and get into muscles it gets into entos and the liver it's very concentrated in the the liver it's very concentrated in the liver gets in the gut unclear from these liver gets in the gut unclear from these Tracer studies if it's getting into Tracer studies if it's getting into immune cells so nav chandelle tells me

immune cells so nav chandelle tells me that he believes they are getting into that he believes they are getting into immune cells as well so the the question immune cells as well so the the question is at least I think we need to ask is at least I think we need to ask ourselves the question if it's working ourselves the question if it's working which cells is it working on and how and which cells is it working on and how and so the liver part's easy everybody gets so the liver part's easy everybody gets big concentration of Metformin shows up big concentration of Metformin shows up here we we sort of understand understand here we we sort of understand understand that that reduces hepatic glucose that that reduces hepatic glucose output after that I'm sort of scratching output after that I'm sort of scratching my head going I don't know how it works my head going I don't know how it works well we know it has a Target in the well we know it has a Target in the mitochondria complex one it inhibits we mitochondria complex one it inhibits we knows besides that's my point it's not knows besides that's my point it's not in the muscle that's a question and and in the muscle that's a question and and we also know that it activates amk yep we also know that it activates amk yep uh interestingly a friend of all of our uh interestingly a friend of all of our those mechanisms probably related yes those mechanisms probably related yes yes yes and that could all that could yes yes and that could all that could all that all could exp this this is why all that all could exp this this is why near points at two of the Hallmarks I near points at two of the Hallmarks I just have to tell you this but here's just have to tell you this but here's the interesting thing a good friend of the interesting thing a good friend of ours George Martin who died a couple of ours George Martin who died a couple of years ago once went through and years ago once went through and cataloged all the human diseases he

cataloged all the human diseases he could and tried to look at the could and tried to look at the similarities of their phenotypic changes similarities of their phenotypic changes relative to what happens with normal relative to what happens with normal aging he came up with diabetes as having aging he came up with diabetes as having the most similarities to accelerated the most similarities to accelerated aging of any of the groups that he aging of any of the groups that he looked at which and it makes the looked at which and it makes the glycosilation the hyper growth factors glycosilation the hyper growth factors like igf1 all these things I mean there like igf1 all these things I mean there there's there's there's logic to that there's there's there's logic to that well let me let me agree with the well let me let me agree with the emphasis you were just putting on organ emphasis you were just putting on organ specific and tissue specific changes and specific and tissue specific changes and I think it's about time to get away from I think it's about time to get away from what does metformin do to the body or what does metformin do to the body or any of these drugs for that matter and any of these drugs for that matter and start to think what does it do to each start to think what does it do to each of the interesting players and how they of the interesting players and how they talk to one another um someone in my lab talk to one another um someone in my lab has been looking at the enzymes related has been looking at the enzymes related to denovo to denovo lipogenesis and she's been looking at a lipogenesis and she's been looking at a couple of different kinds of slow aging couple of different kinds of slow aging mice and it has major effects in the mice and it has major effects in the liver and it has major effects on the

liver and it has major effects on the white and brown atopos tissue and they white and brown atopos tissue and they go in different directions and which is go in different directions and which is primary which is reactive whether any of primary which is reactive whether any of these are related to the effects of the these are related to the effects of the of the of the mutations on the muscle or of the of the mutations on the muscle or the brain is now an open question the brain is now an open question so having a diagram of Hallmarks which so having a diagram of Hallmarks which are changed by a drug is much less are changed by a drug is much less useful than asking what specific changes useful than asking what specific changes in what cell types of which organs that in what cell types of which organs that talk to each other um are being changed talk to each other um are being changed by this drug as a primary or as a by this drug as a primary or as a secondary or as a compensatory effect secondary or as a compensatory effect that's how you'll start to get into that's how you'll start to get into first mechanism but also start to be first mechanism but also start to be able to think clearly about ways of able to think clearly about ways of targeting therapy so that it has a targeting therapy so that it has a benefit with fewer and fewer side benefit with fewer and fewer side effects so let's use kagaoan as an effects so let's use kagaoan as an example yeah we've demonstrated I use we example yeah we've demonstrated I use we very liberally here yeah um you've very liberally here yeah um you've demonstrated that it reduces all cause demonstrated that it reduces all cause mortality in your mice in males in males mortality in your mice in males in males do you believe and we know exactly what

do you believe and we know exactly what kagaoan does in the kidney and we know kagaoan does in the kidney and we know that those mice live longer do you that those mice live longer do you believe that the longevity benefit came believe that the longevity benefit came through glycemic control because there through glycemic control because there was no difference in weight if I recall was no difference in weight if I recall uh they actually lost weight males and uh they actually lost weight males and females lost weight on females lost weight on kagin but the question is but was there kagin but the question is but was there a difference in weight between so was a difference in weight between so was the difference in weight statistically the difference in weight statistically significant between the long-lived males significant between the long-lived males and the less and the normal and the less and the normal males the mice treated with the drug males the mice treated with the drug were lighter in weight than controls and were lighter in weight than controls and that's true of both SE sees so the that's true of both SE sees so the weight loss wasn't necessarily lost more weight loss wasn't necessarily lost more weight in females than in males so the weight in females than in males so the question is very valid and and we do not question is very valid and and we do not know the answer sglt2 is on many other know the answer sglt2 is on many other cell types and it's quite possible very cell types and it's quite possible very plausible that kagal and had an effect plausible that kagal and had an effect principally through controlling Peak principally through controlling Peak daily blood glucose not average but Peak daily blood glucose not average but Peak and it's also possible that it had and it's also possible that it had effects on cells of Unknown Origin in effects on cells of Unknown Origin in the brain and all of these are very

the brain and all of these are very valid and I don't think anyone knows the valid and I don't think anyone knows the answer it's well worth EXA answer it's well worth EXA evaluating there are other Inhibitors of evaluating there are other Inhibitors of sglt2 and sglt1 that have differential sglt2 and sglt1 that have differential cell specificities and differential cell specificities and differential effects on different cell effects on different cell types uh and looking at those would help types uh and looking at those would help give you glimpses into this question we give you glimpses into this question we we guessed it had to do with glucose but we guessed it had to do with glucose but we might be wrong so what is your we might be wrong so what is your intuition intuition Steve well going back to Matt foran my Steve well going back to Matt foran my intuition is that it might work I you intuition is that it might work I you know I don't have a strong opinion it I know I don't have a strong opinion it I there's enough suggestive evidence that there's enough suggestive evidence that I think it's worth a trial and I I think I think it's worth a trial and I I think that if we wait until we figure out that if we wait until we figure out exactly what each drug does in each cell exactly what each drug does in each cell type it will take us forever to get any type it will take us forever to get any therapies and in medicine there have therapies and in medicine there have been many many advances that came about been many many advances that came about before we understood the mechanistic before we understood the mechanistic underpinning and if there's enough underpinning and if there's enough suggestive evidence and there's not a suggestive evidence and there's not a lot of side effects suggest me that it's

lot of side effects suggest me that it's worth digging into now because the the worth digging into now because the the benefits are so enormous you know like benefits are so enormous you know like we said one year healthy aging $ 38 we said one year healthy aging $ 38 trillion that's you know that makes you trillion that's you know that makes you know that should talk to Congress and know that should talk to Congress and nothing else does well and I would also nothing else does well and I would also say tame could be successful independent say tame could be successful independent of whether met foran is effective of whether met foran is effective at slowing biological aging right so at slowing biological aging right so those are not necess getting others into those are not necess getting others into the field you the field you mean the end points right so the end mean the end points right so the end point is multi multimorbidity right or point is multi multimorbidity right or comorbidity right so it's quite possible comorbidity right so it's quite possible that the trial will be successful even that the trial will be successful even if metformin is not a if metformin is not a effective ger effective ger therapeutic and the opposite is also therapeutic and the opposite is also true right it may not succeed for a true right it may not succeed for a variety of reasons that clinical trials variety of reasons that clinical trials don't succeed I sort of agree with Steve don't succeed I sort of agree with Steve like I'm I'm supportive of doing the like I'm I'm supportive of doing the trial I also agree I think with probably trial I also agree I think with probably both Steve and Rich that it's not what I both Steve and Rich that it's not what I would pick if I was going to do one would pick if I was going to do one trial if we could only do one trial but

trial if we could only do one trial but we have to start we have to start somewhere Matt why do you think that the somewhere Matt why do you think that the ITP studies for Rapa always worked ITP studies for Rapa always worked regardless of which which start young regardless of which which start young start old give it with met Foreman do it start old give it with met Foreman do it by itself always worked and the mice are by itself always worked and the mice are taking Rapa M every day because inhibiting mtor increases lifespan and slows aging I know what lifespan and slows aging I know what you're asking you're asking because most you're asking you're asking because most people who are using rap ay off label people who are using rap ay off label have have moved to Once weekly or some have have moved to Once weekly or some sort of cycling like that and right so I sort of cycling like that and right so I think one question is would that think one question is would that increase lifespan in mice as much or increase lifespan in mice as much or more than daily we don't effectively more than daily we don't effectively know the answer to that question I don't know the answer to that question I don't think don't you guys do some think don't you guys do some intermittent it can increase lifespan intermittent it can increase lifespan but it's never it's never been dose but it's never it's never been dose optimized right I think this is the optimized right I think this is the question right is is the metabolic rate question right is is the metabolic rate of the mouse so fast that giving the of the mouse so fast that giving the mouse daily wppa is not the same as

mouse daily wppa is not the same as giving the human daily wppa yes and the giving the human daily wppa yes and the wppa in the ITP study it is in the food wppa in the ITP study it is in the food so it's not a s it's not even a single so it's not a s it's not even a single dose or it's not a single they're just dose or it's not a single they're just chowing on it all day well at least chowing on it all day well at least During the period day that they're During the period day that they're eating and have access to I mean I'll eating and have access to I mean I'll let Rich talk about what they know about let Rich talk about what they know about the blood levels but it is a the blood levels but it is a fundamentally way why did you guys fundamentally way why did you guys decide I mean I guess in 2008 when you decide I mean I guess in 2008 when you or seven when you did the first study or seven when you did the first study maybe it wasn't clear this idea of mtor maybe it wasn't clear this idea of mtor One Versus mtor 2 and and the One Versus mtor 2 and and the constitutive dosing maybe we should ask constitutive dosing maybe we should ask how many people at this table actually how many people at this table actually believe that model yeah that's kind of believe that model yeah that's kind of where I want to go right I want to where I want to go right I want to understand what we think is true and not understand what we think is true and not true about Rapa based on this experience true about Rapa based on this experience I guess I don't understand the question I guess I don't understand the question do do we believe what model what are you do do we believe what model what are you asking that that that the bad side asking that that that the bad side effects come from M torque 2 offt Target effects come from M torque 2 offt Target effects of rapy and all the good stuff effects of rapy and all the good stuff comes from inhibiting mtor 1 I don't comes from inhibiting mtor 1 I don't know enough to say many of our slow know enough to say many of our slow aging mice actually uh mtor complex one

aging mice actually uh mtor complex one function is down in all of them but mtor function is down in all of them but mtor complex 2 is often up and it's up in an complex 2 is often up and it's up in an interesting way uh mice eat mostly at interesting way uh mice eat mostly at night and they qu more or less fast night and they qu more or less fast during the day uh in our slow aging mice during the day uh in our slow aging mice mtor complex 2 is elevated but it no mtor complex 2 is elevated but it no longer responds in the fast in the longer responds in the fast in the fasting period but it doesn't respond to fasting period but it doesn't respond to food in the same way so there're complex food in the same way so there're complex changes uh in both its Baseline state changes uh in both its Baseline state and its response to food whether these and its response to food whether these would happen in people what happen in would happen in people what happen in people taking it every other day every people taking it every other day every fifth day whether they are beneficial or fifth day whether they are beneficial or harmful or a mixture I really don't know harmful or a mixture I really don't know the mtor complex two story is is the mtor complex two story is is trickier the other thing that's un that trickier the other thing that's un that is I think important but not really is I think important but not really appreciated is that it not mtor complex appreciated is that it not mtor complex one drugs like Ramy and not only lower one drugs like Ramy and not only lower the overall effect but it also changes the overall effect but it also changes the substrate specificity so that um the the substrate specificity so that um the kinas that is susceptible to inh to

kinas that is susceptible to inh to torque inhibition that looks at a torque inhibition that looks at a ribosomal protein S6 that goes down it ribosomal protein S6 that goes down it doesn't work nearly as well it's doesn't work nearly as well it's inhibited but the kyat that for how long inhibited but the kyat that for how long um I don't know but the other aspect of um I don't know but the other aspect of tour Downstream is on a protein called 4 tour Downstream is on a protein called 4 bp1 that's involved in trans ation it bp1 that's involved in trans ation it does not change that kinas what it does does not change that kinas what it does is it changes the total amount of the is it changes the total amount of the protein so the proportion of the Protein protein so the proportion of the Protein that's phosphorated drops down but the that's phosphorated drops down but the actual kinas that adds the phosphate to actual kinas that adds the phosphate to that substrate is unchanged so whether that substrate is unchanged so whether that's important that it's having at that's important that it's having at least two different Pathways that are least two different Pathways that are being influenced in one case by changing being influenced in one case by changing the substrate and in the other Case by the substrate and in the other Case by changing the kinas no one's really changing the kinas no one's really looked at that they say it's a drug that looked at that they say it's a drug that blocks M Torin one function and blocks M Torin one function and downstream is where a lot of the downstream is where a lot of the actionist I know your lab at one point actionist I know your lab at one point was interested in cell type specific was interested in cell type specific Inhibitors of uh the tour complex one I

Inhibitors of uh the tour complex one I don't know whether everything you just don't know whether everything you just said Rich occurs in what said Rich occurs in what cell um liver Mouse liver what about cell um liver Mouse liver what about muscle well the the overall muscle well the the overall decline in F in the ratio of decline in F in the ratio of phosphorated versus substrate was also phosphorated versus substrate was also we also published that I think in muscle we also published that I think in muscle and kidney I would have to go back to and kidney I would have to go back to the papers and see whether we also found the papers and see whether we also found the elevation of the substrate the 4 the elevation of the substrate the 4 abp1 in both of those tissues I vaguely abp1 in both of those tissues I vaguely recall that it was the substrate that recall that it was the substrate that changed not the kinas in those tissues changed not the kinas in those tissues as well but I'd rather look it up before as well but I'd rather look it up before I sort of sign my name to it but even I sort of sign my name to it but even what rich is saying is is wow I mean what rich is saying is is wow I mean really important and informative also really important and informative also really only tiny piece of all the really only tiny piece of all the downstream things that mtor effects and downstream things that mtor effects and I think the point is we just really I think the point is we just really don't have a good understanding of how don't have a good understanding of how rap Ain or fasting or other drugs that

rap Ain or fasting or other drugs that hit mtor are affecting all of the things hit mtor are affecting all of the things that are Downstream of of mtor I agree that are Downstream of of mtor I agree completely let me give you an example so completely let me give you an example so Linda Partridge just published in Linda Partridge just published in bioarchive at least a nice paper Rapa bioarchive at least a nice paper Rapa mice and increased lifespan for mice if mice and increased lifespan for mice if she added an inhibitor of a different she added an inhibitor of a different kise called irk it did better it did the kise called irk it did better it did the inhibition by irk work by itself but it inhibition by irk work by itself but it actually improved on rapy so two people actually improved on rapy so two people in my lab were looking at that and it in my lab were looking at that and it turns out that the KK kinas inhibitor is turns out that the KK kinas inhibitor is working in an entirely different pathway working in an entirely different pathway it's affecting the proteome by it's affecting the proteome by increasing the uh uh degradation uh increasing the uh uh degradation uh through a Chevron mediate autophagy through a Chevron mediate autophagy mechanism which is not affected by rapy mechanism which is not affected by rapy so at least at the dose they used right so at least at the dose they used right at least at the dose they used right at least at the dose they used right that's right sorry what model was this that's right sorry what model was this this was M Mouse Li probably black six this was M Mouse Li probably black six no we never used black about the no we never used black about the Partridge it was an F1 hybrid actually Partridge it was an F1 hybrid actually um so

um so it's agreeing with and amplifying the it's agreeing with and amplifying the question there may well be multiple cell question there may well be multiple cell intrinsic Pathways some of which are intrinsic Pathways some of which are tour dependent some of which are map KY tour dependent some of which are map KY Earth dependent which can synergize as Earth dependent which can synergize as in the Partridge case for lifespan but in the Partridge case for lifespan but also potentially synergize for health also potentially synergize for health impacts yeah and here's here's I mean I impacts yeah and here's here's I mean I think an important think an important again limitation to what's been done again limitation to what's been done there are drugs out there that hit both there are drugs out there that hit both types of kineses right there are drugs types of kineses right there are drugs out there that are that are ATP out there that are that are ATP competitive Inhibitors that have competitive Inhibitors that have different affinities for different types different affinities for different types of of kinases haven't been tested for kinases haven't been tested for longevity these dual kinas Inhibitors longevity these dual kinas Inhibitors right um in fact in the in the um restor right um in fact in the in the um restor bio trial the last one the the the phase bio trial the last one the the the phase three which did not get to completion three which did not get to completion they they substituted they took the they they substituted they took the rapalog out and used an ATP competitive rapalog out and used an ATP competitive uh drug I didn't know that so what is uh drug I didn't know that so what is your belief Matt around um dosing Raa in

your belief Matt around um dosing Raa in humans then or even in your dogs you're humans then or even in your dogs you're doing it in we're doing once a week now doing it in we're doing once a week now we've moved to once a week so I mean we've moved to once a week so I mean maybe it's worth at least talking about maybe it's worth at least talking about how that evolved and this is my how that evolved and this is my understanding of of sort of how we got understanding of of sort of how we got to where we are today which is that most to where we are today which is that most people using ramyon off label for people using ramyon off label for potential Health span effects most potential Health span effects most doctors prescribing it are recommending doctors prescribing it are recommending once weekly dosing you know in the 3 to once weekly dosing you know in the 3 to six sometimes 8 10 milligram range um so six sometimes 8 10 milligram range um so the first place I'm aware of in the the first place I'm aware of in the literature where this was um shown to literature where this was um shown to have a potential benefit for anything have a potential benefit for anything related to aging was Joan manik's work related to aging was Joan manik's work when she was first at novaris and then when she was first at novaris and then at rest store bio looking at flu vaccine at rest store bio looking at flu vaccine response or sorry yeah flu vaccine response or sorry yeah flu vaccine response in elderly people um and they response in elderly people um and they were using everus so a derivative of were using everus so a derivative of Ramy and they found that um for vaccine Ramy and they found that um for vaccine response it was most effective and had response it was most effective and had the least side effects at once weekly

the least side effects at once weekly dosing at 5 milligram yeah and they dosing at 5 milligram yeah and they tested daily one or two migs five migs tested daily one or two migs five migs once a week 20 migs once a week it was once a week 20 migs once a week it was once it was a milligram a day five once once it was a milligram a day five once a week 20 once a week now I've had both a week 20 once a week now I've had both Lloyd clickstein and Joan manik on the Lloyd clickstein and Joan manik on the podcast it's been so long that I don't podcast it's been so long that I don't recall if I asked them why they designed recall if I asked them why they designed the trial with those forearms so my the trial with those forearms so my understanding is that novaris had understanding is that novaris had internal data at that point on side internal data at that point on side effects and had an internal hypothesis effects and had an internal hypothesis that if you let the trough levels bottom that if you let the trough levels bottom out that reduced side effects so that out that reduced side effects so that the side effects in organ transplant the side effects in organ transplant patients were largely driven bys High patients were largely driven bys High troughs yep and then after that they troughs yep and then after that they developed um B based off of David developed um B based off of David sabatini's work and then Dudley lamming sabatini's work and then Dudley lamming after he left David's lab a hypothesis after he left David's lab a hypothesis that chronic treatment with Romy which that chronic treatment with Romy which maybe would be equivalent to daily maybe would be equivalent to daily dosing in people this was all done in dosing in people this was all done in cells led to off-target effects on mtor cells led to off-target effects on mtor complex 2 and it was mtor complex 2

complex 2 and it was mtor complex 2 effects that were driving the side effects that were driving the side effects so that got sort of dogmatized effects so that got sort of dogmatized as um the truth and I actually don't as um the truth and I actually don't think there's a ton of evidence Beyond think there's a ton of evidence Beyond those initial papers to support the idea those initial papers to support the idea that the side effects are all through that the side effects are all through mtor complex 2 the idea is if you dose mtor complex 2 the idea is if you dose once a week you let the trough levels once a week you let the trough levels bottom out you don't get the of Target bottom out you don't get the of Target effects on mtor complex 2 you avoid the effects on mtor complex 2 you avoid the side effects again we don't have side effects again we don't have definitive data the data I've seen seem definitive data the data I've seen seem consistent with that idea people dosing consistent with that idea people dosing daily seem seem to be more likely to daily seem seem to be more likely to have side effects you know mostly things have side effects you know mostly things like bacterial infections or the really like bacterial infections or the really severe mouth sores but it's sort of severe mouth sores but it's sort of anecdotal and I don't know for sure how anecdotal and I don't know for sure how strong that data is in in people it did strong that data is in in people it did hold up in all of the restor bio hold up in all of the restor bio clinical trials that I'm aware of that clinical trials that I'm aware of that that that once weekly dosing really that that once weekly dosing really didn't show any side effects different didn't show any side effects different from from Placebo and in the dog study you're Placebo and in the dog study you're using a slow release formulation correct using a slow release formulation correct it's um it's an inic coded kind of it's

it's um it's an inic coded kind of it's a different formulation than what the a different formulation than what the ITP uses but that all of the human um uh ITP uses but that all of the human um uh Camus formulations have some way to to Camus formulations have some way to to get to the small intestine right so it's get to the small intestine right so it's not substantially different I don't not substantially different I don't think than you know rapamune or the think than you know rapamune or the generic Camus that you would let's do the closest thing that a group like this could do in terms of a speed like this could do in terms of a speed round going to go through a couple of round going to go through a couple of other ideas I just want to get the what other ideas I just want to get the what are you thinking about this can we say are you thinking about this can we say anything positive about RIS anything positive about RIS veratrol no Rich no no why does this thing not no why does this thing not die why is there still die why is there still 100 different resveratrols being sold on 100 different resveratrols being sold on Amazon why do I still get people asking Amazon why do I still get people asking me do you take RIS veratrol should I be me do you take RIS veratrol should I be taking RIS veratrol has a good PR

taking RIS veratrol has a good PR team I think it's really hard to prove team I think it's really hard to prove something doesn't work right so once it something doesn't work right so once it gets in the Consciousness as as gets in the Consciousness as as improving health I mean even in the improving health I mean even in the longevity field Jesus Christ I was longevity field Jesus Christ I was saying the Resveratrol stuff was garbage saying the Resveratrol stuff was garbage for 10 years before people believed it for 10 years before people believed it right now everybody believes it but right now everybody believes it but takes a really long time well at least takes a really long time well at least in the Aging field like I think if you in the Aging field like I think if you went like you never see you never see went like you never see you never see people studying Resveratrol in the the people studying Resveratrol in the the Aging field anymore I think if you went Aging field anymore I think if you went to a conference and asked scientists to a conference and asked scientists what do you think about Resveratrol what do you think about Resveratrol you'd get the same answer here with you'd get the same answer here with maybe one exception maybe one exception um but I think I think it takes a really um but I think I think it takes a really hard just one hard just one exception it takes a long time to exception it takes a long time to um bad ideas Don't Die Hard that's right um bad ideas Don't Die Hard that's right and that's true in the scientific lit and that's true in the scientific lit and it's and it's especially true when and it's and it's especially true when there's a profit motive to continue there's a profit motive to continue selling this stuff and like I'm not 100% selling this stuff and like I'm not 100% convinced that there are no health convinced that there are no health benefits from Resveratrol I'm pretty

benefits from Resveratrol I'm pretty convinced it there's no reason to convinced it there's no reason to believe it affects the biology of Aging believe it affects the biology of Aging or is a longevity drug but I can't say or is a longevity drug but I can't say for sure that nobody would ever benefit for sure that nobody would ever benefit from any dose of ratol yeah but we we from any dose of ratol yeah but we we couldn't say that about anything AG yeah couldn't say that about anything AG yeah yeah yeah now we could say that if you yeah yeah now we could say that if you were force-fed the highest fat diet in were force-fed the highest fat diet in the world such that your the world such that your liver approached on your lungs through liver approached on your lungs through your diaphragm isn't there a chance Rich your diaphragm isn't there a chance Rich that under that situation RIS veratrol that under that situation RIS veratrol might help I have no might help I have no idea wasn't that the one and only one idea wasn't that the one and only one experiment that worked yeah the famous experiment that worked yeah the famous experiment which was published as ratol experiment which was published as ratol the first drug ever found to extend the first drug ever found to extend Mouse lifespan it turns out that the Mouse lifespan it turns out that the mice die because um they were on a 60% mice die because um they were on a 60% coconut oil diet and it's poisonous uh coconut oil diet and it's poisonous uh to the extent that it causes the liver to the extent that it causes the liver to fill with fat to fill with fat and compresses the thorax so that they and compresses the thorax so that they cannot inhale three or four papers later cannot inhale three or four papers later they published as a obscure paragraph they published as a obscure paragraph and a discussion section on a paper uh

and a discussion section on a paper uh Pearson was the the first author of the Pearson was the the first author of the second paper that oh by the way all second paper that oh by the way all these mice on the coconut all dieet these mice on the coconut all dieet finally we've looked at them they're all finally we've looked at them they're all dying because of lung compaction due to dying because of lung compaction due to uh expansion of the liver um so the uh expansion of the liver um so the notion that their drug had slowed aging notion that their drug had slowed aging because on the 60% coconut our diet it because on the 60% coconut our diet it temporarily extended lifespan was due to temporarily extended lifespan was due to the prevention of this extremely bizarre the prevention of this extremely bizarre phenomenon I I just cannot get enough of phenomenon I I just cannot get enough of that story and um all that story and um all documented believe I know it well two documented believe I know it well two separate papers all right let's have a separate papers all right let's have a word on NAD NR nmn uh Steve what is your word on NAD NR nmn uh Steve what is your point of view on this well the current point of view on this well the current state of evidence I I'm I'm skeptical state of evidence I I'm I'm skeptical IAL it's one of those things that makes IAL it's one of those things that makes a great deal of conceptual sense but the a great deal of conceptual sense but the evidence at this point is not very evidence at this point is not very compelling and we have the ITP evidence

compelling and we have the ITP evidence that is I think the strongest uh and that is I think the strongest uh and there was strongest negative evidence there was strongest negative evidence yes yes just to make it clear I assumed yes yes just to make it clear I assumed it people knew that I guess I did okay it people knew that I guess I did okay so and is it your view Steve so and is it your view Steve that well this stuff probably does not that well this stuff probably does not extend lifespan you know but maybe there extend lifespan you know but maybe there is some other health span benefit out is some other health span benefit out there that is just not been studied the there that is just not been studied the right experiment hasn't been done it right experiment hasn't been done it hasn't been powered correct you know hasn't been powered correct you know pick your favorite excuse I think NAD is pick your favorite excuse I think NAD is is is very very interesting molecule and is is very very interesting molecule and I don't think we could throw out you I don't think we could throw out you know manipulating NAD as something that know manipulating NAD as something that could be important for aging I just could be important for aging I just think the evidence is there at this think the evidence is there at this point do you think if you're going to point do you think if you're going to manipulate it you would have to do it manipulate it you would have to do it with really really high venous doses or with really really high venous doses or do you think you could achieve those do you think you could achieve those levels using oral levels using oral precursors that I don't know I will precursors that I don't know I will Express complete ignorance on that Matt Express complete ignorance on that Matt what is your point of view on all of

what is your point of view on all of this yeah well I think the way you this yeah well I think the way you framed that that question to Steve is framed that that question to Steve is indicative of why it's so hard to indicative of why it's so hard to disprove something especially when there disprove something especially when there are people out there who have money to are people out there who have money to make who really want to want to you know make who really want to want to you know make the case that you should buy this make the case that you should buy this stuff cuz it's always possible that stuff cuz it's always possible that there's some some way that this could be there's some some way that this could be beneficial having said that NAD you know beneficial having said that NAD you know like Steve said Central molecule in like Steve said Central molecule in thousands of chemical reactions really thousands of chemical reactions really important good reason I know about good important good reason I know about good reason some reason to believe that NAD reason some reason to believe that NAD homeostasis declines with age like lots homeostasis declines with age like lots of many other things so it's plausible of many other things so it's plausible that if you fix that you can get that if you fix that you can get benefits from it the data is decidedly benefits from it the data is decidedly mixed both in the literature uh mixed both in the literature uh pre-clinical literature and in people as pre-clinical literature and in people as to whether or not boosting NAD increases to whether or not boosting NAD increases lifespan improves Health span um so I lifespan improves Health span um so I think there's lots of issues here what's think there's lots of issues here what's the most positive d you would point to the most positive d you would point to well for lifespan the original study by well for lifespan the original study by Johan A's lab where they started Johan A's lab where they started treating I think at 20 months of age was treating I think at 20 months of age was published in science I believe um showed

published in science I believe um showed an effect that was reasonably good sized an effect that was reasonably good sized except the controls were short which is except the controls were short which is a different issue yeah it's different a different issue yeah it's different issue right you see a lot of there there issue right you see a lot of there there a number of cases where something was a number of cases where something was reported to increased lifespan when the reported to increased lifespan when the controls were short-lived and then when controls were short-lived and then when when the study was repeated and longer when the study was repeated and longer lived controls you didn't see an effect lived controls you didn't see an effect so I don't know why they I don't know so I don't know why they I don't know why there was a difference between that why there was a difference between that study and the ITP but that's probably study and the ITP but that's probably the best case you can point to there's the best case you can point to there's studies in cagans as well that were studies in cagans as well that were where NAD precursors increase lifespan where NAD precursors increase lifespan so there's evidence out there and again so there's evidence out there and again it's a plausible the biolog is plausible it's a plausible the biolog is plausible um but then I think when you talk about um but then I think when you talk about the precursors you know it's even more the precursors you know it's even more complicated than maybe boosting NAD complicated than maybe boosting NAD could slow aging because can you get the could slow aging because can you get the right doses in people you talked about right doses in people you talked about bioavailability is is there any bioavailability is is there any difference between nmn NR nasin difference between nmn NR nasin nicotinamide and when you take it orally nicotinamide and when you take it orally the data suggests that it all gets the data suggests that it all gets broken down to nin in the gut so why are

broken down to nin in the gut so why are people taking you know people taking you know $70 yeah why are people selling it the $70 yeah why are people selling it the people who are selling it who some of people who are selling it who some of them are scientists Dodge that question them are scientists Dodge that question I mean it's it's complicated I don't I mean it's it's complicated I don't personally believe there is enough personally believe there is enough evidence to to think that NAD precursors evidence to to think that NAD precursors as are being marketed today are likely as are being marketed today are likely to benefit most people some to benefit most people some people probably people who have um people probably people who have um conditions of disregulated NAD could get conditions of disregulated NAD could get a benefit I don't think there's any a benefit I don't think there's any difference between the the various difference between the the various molecules that are being marketed right molecules that are being marketed right now and there's at least one study in now and there's at least one study in mice that giving nmn to aged mice causes mice that giving nmn to aged mice causes kidney inflammation and potentially kidney inflammation and potentially kidney pathology so there's you know I'm kidney pathology so there's you know I'm not saying n mn's dangerous but when you not saying n mn's dangerous but when you try to weigh the risk reward you know if try to weigh the risk reward you know if it if it causes kidney pathology in aged it if it causes kidney pathology in aged mice at least at high doses could it do mice at least at high doses could it do the same thing in dogs or people yeah it the same thing in dogs or people yeah it could um and it bothers me particularly could um and it bothers me particularly in the companion animal space that

in the companion animal space that people are marketing nmn for people's people are marketing nmn for people's pets when they know that it might cause pets when they know that it might cause kidney disease in people's dogs and cats kidney disease in people's dogs and cats that's problematic to me we talked that's problematic to me we talked briefly about parabiosis and plasma FIS briefly about parabiosis and plasma FIS let's come back to it a little bit so let's come back to it a little bit so Steve is there going to be a day when Steve is there going to be a day when the substance found in the blood of the substance found in the blood of someone much younger than you when someone much younger than you when infused into you whilst some of your old infused into you whilst some of your old blood is removed is going to assuming we blood is removed is going to assuming we figure out at what frequency that has to figure out at what frequency that has to be done impact your life yeah I I think be done impact your life yeah I I think this is an incredibly interesting this is an incredibly interesting question and it really deserves to be question and it really deserves to be investigated in detail because if it's investigated in detail because if it's true it's it's a real game Cher because true it's it's a real game Cher because we do transfusions I mean this this is we do transfusions I mean this this is not exotic medicine I think we very much not exotic medicine I think we very much need to know whether this works the same need to know whether this works the same way in people and also it would be nice

way in people and also it would be nice to know how much of it is due to the the to know how much of it is due to the the taking outus how much of it is getting taking outus how much of it is getting rid of the oldwood but the evidence from rid of the oldwood but the evidence from mice is very very compelling I think mice is very very compelling I think Steve if we could design the perfect Steve if we could design the perfect experiments that would try to ask these experiments that would try to ask these questions and let's just say we started questions and let's just say we started by doing the one experiment which was by doing the one experiment which was the full parabiosis so the putting in the full parabiosis so the putting in the taking out we didn't try to the taking out we didn't try to disentangle the effect um and there was disentangle the effect um and there was no benefit in humans MH what would be no benefit in humans MH what would be your best hypothesis as to why it would your best hypothesis as to why it would have failed assuming it was have failed assuming it was statistically powered correctly and statistically powered correctly and there was no methodologic error if if if there was no methodologic error if if if if this was a biologic result why would if this was a biologic result why would you think given how favorable this has you think given how favorable this has been in mice it would not occur in been in mice it would not occur in humans that the products that in Ed up humans that the products that in Ed up in the circulation of humans was a very in the circulation of humans was a very different nature than in mice I mean uh different nature than in mice I mean uh you know the number of things that

you know the number of things that differ between humans and mice and blood differ between humans and mice and blood would be enormous so pinning it down would be enormous so pinning it down would be but I think there probably uh would be but I think there probably uh is some reason to suspect that it may is some reason to suspect that it may work I mean I you know I I'm very Ian if work I mean I you know I I'm very Ian if it does work this is a an opportunity it does work this is a an opportunity that I mean should I mean this is not that I mean should I mean this is not like we had the technology to do this 50 like we had the technology to do this 50 years ago right right and and it may not years ago right right and and it may not work in young people right but it may work in young people right but it may work in older people I think there's a work in older people I think there's a lot of drugs that could affect aging lot of drugs that could affect aging that because young people haven't aged that because young people haven't aged as much might not have minimal effect as much might not have minimal effect you give it to somebody you know 50 you give it to somebody you know 50 years later might have a big effect I I years later might have a big effect I I think that the I find myself frustrated think that the I find myself frustrated by the question ra ra rather than by the by the question ra ra rather than by the answer because you got a horrible answer because you got a horrible question ask here rich is the problem I question ask here rich is the problem I think you are well above average but think you are well above average but this particular one I think is this particular one I think is illustrative because the reason like illustrative because the reason like people like parabiosis is that they've people like parabiosis is that they've seen it in a Sci-Fi movie it sounds

seen it in a Sci-Fi movie it sounds exactly like what you do in sci-fi and exactly like what you do in sci-fi and they're sure flashing lights and it's so they're sure flashing lights and it's so sexy and it's just so great and you can sexy and it's just so great and you can take the blood of young virgins virgins take the blood of young virgins virgins and give it to old people and they stand and give it to old people and they stand up and they can get on the I didn't up and they can get on the I didn't realize they had to be virgins way so realize they had to be virgins way so but none of that is pertinent is is but none of that is pertinent is is there something that is in the blood of there something that is in the blood of old people that it would be good to old people that it would be good to remove and if so what is it and is there remove and if so what is it and is there something a cell a molecule a set of something a cell a molecule a set of three molecules that's in the blood of three molecules that's in the blood of young people or mice that would be good young people or mice that would be good for you the only purpose of the the only for you the only purpose of the the only virtue of this virtue of this parabiosis uh circus is to suggest that parabiosis uh circus is to suggest that you know the answer might be yes there you know the answer might be yes there might be something you could remove from might be something you could remove from Old Blood a cell or more or some plasma Old Blood a cell or more or some plasma molecule and there might be something molecule and there might be something good in the blood of young individuals good in the blood of young individuals so the challenge now is to find out what so the challenge now is to find out what those things are and then you can do

those things are and then you can do real life science real life science is real life science real life science is not done by taking blood from young not done by taking blood from young people or and putting it into old people people or and putting it into old people it's that's medieval science where it's it's that's medieval science where it's a complex mixture of dozens to hundreds a complex mixture of dozens to hundreds of potentially right but that could be of potentially right but that could be the proof of principle right in other the proof of principle right in other words you might start with that and no words you might start with that and no one thinks that if you do that one thinks that if you do that experiment where you literally take experiment where you literally take blood out of an old person and discard blood out of an old person and discard it and take blood out of a young person it and take blood out of a young person and you know put it in and you get a and you know put it in and you get a favorable result nobody thinks that favorable result nobody thinks that that's what's going to the FDA that is that's what's going to the FDA that is the proof of concept experiment would be the proof of concept experiment would be worth what experiments you have a worth what experiments you have a limited amount of volunteers doctors and limited amount of volunteers doctors and money what experiments are most money what experiments are most informative and in my view by far the informative and in my view by far the most informative experiments are what is most informative experiments are what is in the blood of young mice that is so in the blood of young mice that is so good and what is in the blood of I don't good and what is in the blood of I don't know would you want to go on that know would you want to go on that fishing Expedition until you at least

fishing Expedition until you at least saw a signal in the people are doing it saw a signal in the people are doing it I mean there are companies of course I mean there are companies of course they are doing of course they are I'm they are doing of course they are I'm asking a different question though which asking a different question though which is yes that's the only way you can turn is yes that's the only way you can turn your idea into science well on the other your idea into science well on the other hand if it has if it has a positive hand if it has if it has a positive effect I don't think it really matters effect I don't think it really matters that's something to be investigated that's something to be investigated later my thought is it's not simple it's later my thought is it's not simple it's not one thing it's not gdf11 for sure um not one thing it's not gdf11 for sure um if it were simple there's enough people if it were simple there's enough people looking at it they would have figured it looking at it they would have figured it out my guess is some combination if if out my guess is some combination if if there's something there there's some there's something there there's some combination like I mean why can't you do combination like I mean why can't you do both I I I I think Peter and I are both I I I I think Peter and I are saying the same thing like I think would saying the same thing like I think would we love to to understand the mechanism we love to to understand the mechanism yeah absolutely do we have to understand yeah absolutely do we have to understand the mechanism to figure out whether it the mechanism to figure out whether it works in in people no and if it works works in in people no and if it works great that's a win too I think richest great that's a win too I think richest point is we only have so much money point is we only have so much money let's spend it on figuring out the let's spend it on figuring out the mechanism but that's a again that's a mechanism but that's a again that's a fundraising issue I yeah it's a fundraising issue I yeah it's a scientific question if you have a choice

scientific question if you have a choice I mean the ITP loves to test in I mean the ITP loves to test in individual chemical compounds even individual chemical compounds even sometimes ones where the mechanism of sometimes ones where the mechanism of action is not known and that's very action is not known and that's very sensible we are very dubious about let's sensible we are very dubious about let's take a little of this and a little of take a little of this and a little of that a little of that and we're really that a little of that and we're really dubious about taking let's grind up the dubious about taking let's grind up the asparagus who knows what's agree and yet asparagus who knows what's agree and yet you guys have tested natural products you guys have tested natural products where we have no clue what the mechanism where we have no clue what the mechanism is or even metformin you pointed to is or even metformin you pointed to complex one inhibition yeah that's one complex one inhibition yeah that's one thing metformin does and it might thing metformin does and it might activate that mean say know the activate that mean say know the mechanism exactly of each drug what I'm mechanism exactly of each drug what I'm saying is that if you have a very saying is that if you have a very complex mixture of hundreds of complex mixture of hundreds of molecules and something happens you molecules and something happens you don't know what to do next because it don't know what to do next because it could be any one or two or eight or 10 could be any one or two or eight or 10 of those and you haven't really decided of those and you haven't really decided you you have troubles then with standard you you have troubles then with standard Iz ation with mechanistic tests and with Iz ation with mechanistic tests and with transferring to a key species like my transferring to a key species like my thought is we still wouldn't be using thought is we still wouldn't be using anesthesia if we had to wait figured out

anesthesia if we had to wait figured out how it worked yeah I I I mean I think how it worked yeah I I I mean I think and and it doesn't have to be parabiosis and and it doesn't have to be parabiosis it doesn't have to be you know taking it doesn't have to be you know taking blood from from young people and putting blood from from young people and putting it into to old people right there are it into to old people right there are other variants of this that can be done other variants of this that can be done clinically and there's some evidence to clinically and there's some evidence to support things like therapeutic plasma support things like therapeutic plasma exchange or or things like that so exchange or or things like that so should we test it I think so and my gut should we test it I think so and my gut feeling is yeah it probably will have feeling is yeah it probably will have some benefits you can only do one some benefits you can only do one experiment would you experiment would you do a plasma FIS experiment and if so do a plasma FIS experiment and if so what would you like would you test I what would you like would you test I mean the simplest one is you literally mean the simplest one is you literally just exchange old plasma for albumin just exchange old plasma for albumin right that's that's what they're right that's that's what they're typically doing in these studies yeah I typically doing in these studies yeah I mean I don't first of all I don't know mean I don't first of all I don't know enough about this area to be confident enough about this area to be confident in my answer but yeah that that's in my answer but yeah that that's probably where I would look to start probably where I would look to start simply because it's going to be simply because it's going to be logistically easier to do from a logistically easier to do from a clinical trial perspective so but but so

clinical trial perspective so but but so so scientifically then the hypothesis is so scientifically then the hypothesis is it's the presence of something bad well it's the presence of something bad well it's both that is worse than the absence it's both that is worse than the absence of something good I don't know the Alum of something good I don't know the Alum is not going to give you the young is not going to give you the young person problem with that experiment to person problem with that experiment to me we don't know now we don't if it's me we don't know now we don't if it's young blood is good old blood is bad or young blood is good old blood is bad or some combination we would automatically some combination we would automatically if we only did the plasma foris we would if we only did the plasma foris we would only be testing part of that I push back only be testing part of that I push back on that I think we do have reason to on that I think we do have reason to believe it's a combination of both believe it's a combination of both there's data in both directions so so there's data in both directions so so that's why I proposed starting with I that's why I proposed starting with I think that's again as much as anything's think that's again as much as anything's sure in this field it's not that's not sure in this field it's not that's not as sure as Rapa increases lifespan in as sure as Rapa increases lifespan in mice but there's at least evidence to mice but there's at least evidence to support that idea support that idea right and the last thing I'll say is you right and the last thing I'll say is you you mentioned you asked why might it you mentioned you asked why might it fail in humans I think Steve's answer is fail in humans I think Steve's answer is is is valid um it's also worth is is valid um it's also worth mentioning at least with the parabiosis mentioning at least with the parabiosis experiments the the experiments the the parabiosis experiment parabiosis experiment itself shortens lifespan in rodents and

itself shortens lifespan in rodents and so the parab just the the fact that so the parab just the the fact that you're surgically connecting these you're surgically connecting these animals together so it may be that the animals together so it may be that the benefit from parabiosis true parabiosis benefit from parabiosis true parabiosis in that context is somehow related to in that context is somehow related to the shortening of lifespan due to the the shortening of lifespan due to the procedure I don't think that's the case procedure I don't think that's the case because there's other L of evidence that because there's other L of evidence that argue against that but there may be argue against that but there may be something about the procedure itself something about the procedure itself that is increases muscle repair and that is increases muscle repair and improves cardiac function it just seems improves cardiac function it just seems to me that's you know I agree I'm just to me that's you know I agree I'm just saying that may be an alternative saying that may be an alternative explanation explanation for something that's limiting in those for something that's limiting in those Mouse Mouse experiments just seems like there's not experiments just seems like there's not enough time and not enough money to do enough time and not enough money to do the the work hopefully some of that's work hopefully some of that's changing changing um if we were to do another long round um if we were to do another long round table next year which is problematic CU table next year which is problematic CU this table I mean you guys are going to this table I mean you guys are going to have to get awfully cozy um any have to get awfully cozy um any nominations for folks you'd want to nominations for folks you'd want to invite to a longevity round table next

invite to a longevity round table next time there's so many people we could we time there's so many people we could we could do this with right and I'm could do this with right and I'm guessing nobody wants to give their seat guessing nobody wants to give their seat up next year to make this table up next year to make this table bigger I think it would be good to bigger I think it would be good to invite VM invite VM glad because I think even though I glad because I think even though I disagree with some of what he says I disagree with some of what he says I think he always has something think he always has something interesting to interesting to say who's your nominee i' need some more say who's your nominee i' need some more time to think about it mat anybody jum time to think about it mat anybody jum mean I think I think we would all agree mean I think I think we would all agree there are tons of great people in the there are tons of great people in the field I mean uh I think Brian Kennedy field I mean uh I think Brian Kennedy and I think Brian's going to be on your and I think Brian's going to be on your podcast in an upcoming date is somebody podcast in an upcoming date is somebody who also thinks broadly and deeply about who also thinks broadly and deeply about the science and is fantastic so he would the science and is fantastic so he would be great to have it would be great to be great to have it would be great to have some different I mean we differ have some different I mean we differ sometimes on opinions but I think more sometimes on opinions but I think more or less are aligned be interesting to or less are aligned be interesting to have some differing voices as well all have some differing voices as well all right so we think we'll do another right so we think we'll do another longevity Round Table around the oval

longevity Round Table around the oval table sure let's do it let's see where table sure let's do it let's see where we are a year in a year from now I think we are a year in a year from now I think there's going to be a lot of new stuff there's going to be a lot of new stuff that's that's that's what's new in aging that's that's that's what's new in aging research the pr rate of progress the research the pr rate of progress the derivative is very much positive you derivative is very much positive you know who else I want to throw out there know who else I want to throw out there is Morgan LaVine I think she'd be really is Morgan LaVine I think she'd be really interesting to have because she while interesting to have because she while she is an expert in epigenetics and she is an expert in epigenetics and biomarkers I think takes a pretty cleare biomarkers I think takes a pretty cleare eyed view of that space now is Morgan at eyed view of that space now is Morgan at Yale still she's at alos she's at Al Yale still she's at alos she's at Al okay I wasn't sure if she was there okay I wasn't sure if she was there full-time got it okay yeah I would full-time got it okay yeah I would second that that's an excellent idea all second that that's an excellent idea all right well Rich you can get back to me right well Rich you can get back to me on your your nominees as well I will on your your nominees as well I will definitely do that all right definitely do that all right gentlemen committee onto this and I'll gentlemen committee onto this and I'll get back to you thank you it was fun fun get back to you thank you it was fun fun all right guys thank you [Music]

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The Science Behind the Promise

The modern longevity conversation did not appear from aspiration alone. In the 1990s, discoveries in model organisms showed that lifespan was not fixed in the way many assumed. Aging could be altered, at least under experimental conditions. That insight changed the field because it moved aging from inevitability toward biology.

The next stage made the question more practical. Over the last two decades, studies in mice have shown that certain compounds can extend lifespan by roughly 20 to 30 percent. That range matters because it is large enough to command attention. If a similar effect translated to people, it would reshape how we think about prevention, disease, and the later decades of life.

These compounds matter because they point toward a different medical ambition. Instead of waiting for one disease to emerge and then fighting it in isolation, geroprotective molecules aim upstream. If aging biology contributes to many diseases at once, then slowing that biology could postpone several forms of decline together. The benefit would be broader than one diagnosis.

The source discussion is careful on this point. Evidence in mice is not evidence in humans. A compound that performs well in an animal model still has to prove that it works in people, at the right dose, with acceptable safety, over meaningful time. Translation is slow because real longevity science cannot be rushed into belief.

The lag has clear causes. Many people still assume aging is beyond influence, even though experimental work challenges that assumption. Commercial incentives also complicate the landscape. Products without strong evidence can reach customers quickly, while rigorous testing requires years, capital, and disciplined uncertainty.

There is also the practical burden of drug development. Even when a leading compound works in mice, researchers still need to identify the safest and most effective version for human use. They need funding, intellectual focus, and time. A serious protocol respects the distance between a promising signal and a reliable human outcome.

This is where calm matters. The science is neither empty nor complete. It has earned attention, but not blind trust. We can hold both truths at once: aging biology is malleable in experimental systems, and human longevity remains a demanding frontier.

Healthspan Is Not a Simple Number

Healthspan sounds simple until it meets a real life. A standard definition often treats it as the period before disease or disability appears. That frame is clean on paper and limited in practice. Human health rarely flips from whole to broken in a single moment.

The panel challenges the familiar contrast between lifespan and healthspan. The common story says we must choose between longer life and better life, as though the two sit on opposite sides of a scale. Aging biology does not support that neat division. When an intervention slows processes that drive disease, it should in theory protect both duration and function.

That distinction matters because modern medicine already extends life after disease appears. It can keep people alive through cancer, heart disease, and other serious conditions longer than it once could. That is meaningful progress. It is also different from preserving vitality before decline takes hold.

A binary definition of healthspan misses the lived texture of aging. Someone may have one chronic diagnosis and still move with strength, think clearly, maintain relationships, and participate fully in daily life. Another person may be free of a formal diagnosis and still feel constrained. Health is not only the absence of a code in a chart.

A more useful frame begins with capacity. What can you still do, physically, cognitively, emotionally, and socially. Can you rise from bed, dress, cook, travel, garden, ski, read, decide, connect, and contribute in ways that matter to you. The answer will differ from person to person, and that is the point.

The marginal decade exercise in the discussion makes this personal. Each person has a final decade of life, though few know when they enter it. The deliberate question is what abilities you want to carry into that decade. The answer becomes a compass for training, prevention, and daily ritual.

The smart play is to do aging research.

For one person, the standard may be independent living and steady cognition. For another, it may include skiing, managing complex work, or caring for family without feeling diminished. These goals are not vanity. They are definitions of dignity, expressed through action.

Healthspan, then, is not a single number to defend. It is a living measure of useful strength, clear thought, emotional steadiness, and social presence. We preserve health by preserving access to what matters. That is the more honest definition.

Medicine, Markets, and the Work Ahead

The United States shows why the longevity conversation cannot stay abstract. Among developed nations, the country has low overall life expectancy despite very high healthcare spending. The discussion points to a critical reason: high mortality in middle age. Maternal and infant mortality, gun violence, suicide, homicide, and overdoses all pull the national average down.

That pattern reveals a hard truth. Longevity is not only a question for older adults. It is shaped by the conditions that determine whether people reach older age at all. A society cannot claim mastery over lifespan while losing so many people in their forties and fifties.

Health is a state of your physical being that you can do the things you like to do.

Once Americans reach later life, the picture changes. The healthcare system becomes very good at delaying death after disease has arrived. It can extend time after cancer, support people through repeated cardiovascular procedures, and keep chronic disease managed for longer. This strength is real, but it is not the same as creating health.

Geroscience asks a different question. Instead of treating diseases one by one after they emerge, it asks whether we can delay the biology that makes several diseases more likely in the first place. That shift is subtle and profound. It moves the work from reaction to preservation.

This is where the marketplace often loses discipline. Longevity branding can move faster than human evidence, especially when companies sell compounds, supplements, or services with confident language and limited proof. The public wants agency, and that desire is valid. It also makes people vulnerable to claims that borrow the authority of science without carrying its burden.

A grounded protocol separates foundations from speculation. Exercise, metabolic health, and other established lifestyle practices belong in the center because they already connect to better function and lower disease risk. Untested anti-aging claims belong at the perimeter until evidence earns them a stronger place. Precision begins with hierarchy.

This does not make the future smaller. It makes the future more credible. The right posture is neither cynicism nor surrender, but disciplined attention. We can welcome serious progress in aging science while refusing to confuse momentum with proof.

Longevity has gone mainstream because people are ready to think more deliberately about time. The work ahead is to make that attention worthy of the subject. Life is not optimized by slogans. It is protected through evidence, ritual, and the steady pursuit of resilience before decline demands it.

Wim's Wise Words

A second take, from someone who's lived it.

If you take one thing from this, let it be hierarchy. Longevity is crowded now. Every week brings a molecule, a device, a claim, a graph, a promise. Some of it will become useful. Some of it will fade. Your job is not to chase the loudest thing. Your job is to protect the foundations that carry the most weight.

I would start with the practices that make your next decade more capable: strength, walking, sleep, food that keeps your energy steady, and deliberate recovery. Then I would place heat and cold around that center, not above it. Contrast therapy is powerful when it supports adaptation; it becomes noise when it replaces the basics.

Where I'd Start

Use sauna as a recovery ritual before you use it as a longevity claim. Twenty minutes of heat in the evening can create a clean pause between the day and the night. You breathe more slowly. Circulation rises. The nervous system gets a clear signal that the work is done. For me, that is enough reason to keep it in the protocol.

Cold is different. Cold asks for more respect. It sharpens focus because the body has to respond. Dopamine rises, breathing tightens, attention narrows. That can be useful, but only if you meet it deliberately. I like cold earlier in the day, short and precise. Long enough to build composure. Not so long that the practice becomes a contest with yourself.

If you want the broader frame for heat, cold, and adaptation, read Thermal Stress, Cellular Longevity. It sits well beside this piece because it keeps the promise close to the mechanism: small, intentional stress can train resilience when recovery is present.

What To Be Careful With

Be careful when a product asks for belief before it has earned trust. A serious longevity practice should make you more consistent, not more anxious. If a supplement, tracker, or new protocol pulls you away from sleep, training, nutrition, relationships, or time outdoors, it has lost its place in the order.

I also think you need a personal definition of healthspan. Not an abstract one. A real one. What do you want to be able to do when you are seventy, eighty, or in your final decade. Carry your own bags. Get off the floor. Walk after dinner. Think clearly under stress. Stay useful to the people you love. Those answers should shape your protocol more than any headline.

For that reason, Healthspan, Lifespan, and the Marginal Decade is worth reading next. It turns the concept into a mirror. You stop asking only what extends life and start asking what preserves access to the life you actually want.

The steady path is not passive. It is disciplined. Keep the foundations central. Use heat and cold with precision. Stay curious about the science without handing your agency to the marketplace. Longevity begins to mean something when your daily rituals protect capacity, not just time.