333 ‒ Longevity roundtable—the science of aging, geroprotective molecules, & lifestyle interventions

is aging a disease is that even a relevant question call me calling me calling me so calling aging a disease is a fundamental oror the question itself is incorrect I agree completely I think

it's the wrong question I I I agree but how do we Define health span I haven't seen anything to make me believe that you can separate healthspan and lifespan my own personal answer to that is it's a useless term a state of your physical

being that you can do the things you like to do the United States has the lowest life expectancy that's because the United States has by far far the greatest rate of death in middle age and I mean the reality is the research flows

from where the dollars are going this has been seen over and over and over at NIH maybe it's because the public doesn't understand this but those people answer to the public cuz I'm in the mood to see you get spicy can we just talk

about sence for a minute there's no evidence as far as I know that it either has an anti-aging effect or removes siness and cells let's do the closest thing that a group like this could do in

terms of a speed round hey everyone Welcome to the live 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 guys today um where do we want to begin I mean I let me start by saying the following uh the the term longevity

someone sent me something the other day that was like list of you know I don't know whether it was how many times the word longevity was searched on gole Google or something like that but it it

literally looks like Bitcoin if you I mean it's yeah so we are clearly at Peak longevity in terms of public interest which um for all of you who have kind of

devoted decades plural to this um I just want to kind of get a reaction from you each of you on on what that means why you think it's happening and uh uh maybe

even extending the metaphor a little bit is is there a bubble going on uh so we'll start with you Steve yeah well I it's a surprise to me that longevity has become so big because for a long time we

sort of try to move away from that in the Aging field because we were worried that people were thinking of longevity as well we're going to keep frail feeble old people alive longer that's what

longevity me when really what we were trying to do is extend health and so I'm kind of surprised but I think it's because uh there are certain people of a certain age who've started to think

about their own longevity and then I think there's a whole new generation of of of tech unur that really feel like this is a

problem that will allow them to live healthily for several decades at least longer than they are now so I think it's a combination it's a multigenerational thing that that kind of surprises me and

you haven't seen this before to be clear so 30 years ago you didn't see glimmers of this no 30 years ago I would have said let's not even say the word

longevity let's say healthspan um but um that's changed quite clearly as more and more people have been you know from the outside they're sort of peing in at the field I don't think the people in the

field itself have changed the way they talk that much but the people eavesdropping on the field certainly have rich is that your experience well I think there are two aspects that that I

would want to emphasize in response both to your question and to what Steve said um in response to the question I think the reason that people are now people have always been fascinated for

Millennia on things they could do to stay alive and healthy as long as possible but there were actually scientific discoveries in the 90s uh that showed that it could be done and

then in the last 20 years there's evidence that it can be done at least in mice with pills so that naturally should lead to speculation that there could be

pills you could give to people that would postpone poor health for a substantial amount of time uh 20 to 30% is what we're seeing in mice and 20 to

30% would be very important for people so I think that is a part of it the other part is that um there are now people who are are making a lot of money

by selling stuff that is untested to be polite about it or is useless to be less polite about it to gullible customers and so uh people who want to make a lot

of money have finally found that there's a impetus that will allow them to sell stuff even if there's no evidence that it works that they they control an

enormous amount of advertising dollars both formal and informal uh uh that's a a big part of the difference the one comment I wanted to make with regard to to something Steve said has to do with

the alleged balance between Health span and lifespan the it's become fashionable for the last 20 or 30 years to imagine that

you get one or the other that you have to make a choice it's a decision uh and that if you give up on lifespan that allows you to extend

health span I think that's ridiculous and controverted by all the available evidence that is all of the drugs at

least that extend lifespan in mice and could potentially do so in people do so by postponing diseases both the diseases that will kill you that's why they

extend lifespan and the diseases that won't kill you but which will annoy you and make you very unhappy to be old so which is true by the way of non-molecular tools as well that's true

exercise absolutely that's a good point not being insulin resistant I agree with you so the notion it's time to put behind us and to make fun of the notion that I'm not interested in lifespan

don't put me on that boat I am interested in health span because they are linked together and they go up and down together getting people disabused of that false metaphor the Seesaw

metaphor is probably an important goal for sort of the public interface between longevity scientists aging scientists I just want to push on one thing though um you you talked about obviously the

discoveries of molecules you've been personally Central to that work um but there was still a lag Rich right I mean

it was 16 15 years ago the first ITP was published showing the overwhelmingly surprising and positive

results of those results were repeated so why why why a decade let's be generous and and charitable and call it a still decade long lag from that and by the way I'll

throw one more thing in there if you go back to Cynthia kenyon's work which may have been the thin end of the wedge into the idea that lifespan was malleable albe it through a genetic manipulation

in a less relevant model yeah there's still a lag and and and again do do you sort of do you buy Steve's argument that it's a confluence of Technology Tech

entrepreneurs let me answer your question first um why the lag I think there's a whole batch of reasons and they're important and they're easy to spell out one is

that the prevailing attitude is that aging is there there's nothing you can do about it I'm gonna uh not be able to outwit aiding though I may be able to be

maybe healthier in my older years the notion that aging is is not malleable though wrong and provably wrong is still the overwhelming opinion even of

reasonably educated scientists and certainly of the of the lay public then commercially there are companies that make a ton of money selling stuff that

doesn't work by pretending with a wink and a nod and and a lawyer that it might slow the aging process down um and since they can make a lot of money they don't

actually have to spend valuable marketing dollars on doing you know research and stuff to prove that it works some of the drugs that at least in

the hands of our Mouse group the ITP interventions testing uh program some of the drugs are the patent is owned by another company or they're out of patent

or it's a natural natural product none of that says take me to whoever owns a big pharmaceutical firm um and also even if you do it right and you really want

to do it and you've got a very large budget it's not an overnight kind of thing anyone drug a leading agent that like Rapa M which you mentioned and the half a dozen others that we've shown

work at least in mice finding something in that same family that works really well that is safe for people that's the

member of the that 20 conjurers conjurers of that drug that's best and most potent and safest that's not at all trivial that takes a long time and it

takes a commitment of money and time and effort and and intellectual resources um we're at the on the place where we can start to make an argument that that's a

good idea but making an argument that that's a good idea to people who actually have the resources to carry it out as a has not so far been enormously successful unfortunately can can I push

back a little on what rich said about health span versus lifespan there several papers that have come out recently showing that the gap between Health span and lifespan in in people is

actually increasing and it's increasing the fastest in the United States and it's increasing faster among women than men so in humans this is a very real Gap

and it's a growing Gap and I think one of the advantages of the kind of of the geroscience the stuff that we do is that rich is right we don't see this in our experimental systems so this to me

emphasizes the fact that we need to change the focus I think one of the reasons that the Gap exists as we're getting better and better and better at treating heart disease and cancer and all these things and keep keeping people

alive when they wouldn't have been alive 10 years ago but but this is a really important factor I think about thinking of Public Health globally it's important to see ex go ahead I was gon to say I think you're both right I think you're

looking at it from different angles so Steve you're pointing out that you can make people live longer when they're sick I think what rich is saying which I agree with and hopefully I'm going to paraphrase you correctly which is if we

target the biology of Aging I haven't seen anything to make me believe that you can separate Health span and life Anan meaning that I haven't seen things that slow aging increase lifespan don't increase health span I don't actually

think that's plausible no and I think that's and I think that's an important point that if we target aging we're doing something different than with the way that medicine is operating now which

is targeting individual diseases after they occur right this is a very important Point um it came up in a recent podcast that I did with Sam sutaria talking about healthcare costs

and in that discussion one of the things that emerged um which I think most people are sadly familiar with this statistic today is that among the oecd Nations the United States has the lowest life expectancy which is ironic given

that we are spending on average about 80% more and in some cases double what most other developed Nations spend on Healthcare so how do you reconcile this well s made a very interesting point

which is that's aggregate life expectancy but why is that the case that's because the United States has by far the greatest rate of death in middle

age right so when you look at maternal and infant mortality were horrible when you look at gun violence and suicide and homicide were horrible and most of all

when you look at overdoses were horrible right so when you kill a whole bunch of people in their 40s and 50s you cannot have a very high life expectancy

understood but what s pointed out was once an American reaches the age of and I forget the exact age I think it was about 65 all of a sudden they jump to the top of the

list that was very interesting to me in other words if you look at the Blended life expectancy we're we're not doing very well but if you look at life expectancy just in measured as years

alive once you escape those big causes of death in middle age we actually do quite well and it comes down to what you're saying which is we get very good at delaying death in chronic disease that's that's the what I call the

medicine 2.0 machine at its absolute finest we are going to keep you along an extra 6 months once you have cancer we are going to get you through that third revascularization procedure and so now

the question is does that because my intuition is where yours is Steve I don't think we're getting any healthier even if we're incrementally figuring out ways to extend life in the face of

chronic disease I don't see it being a quality of life now part of this might be how do we Define health span yeah so let me I agree with you and and um I think it's even worse though than the

way you laid it out so if you look at the statistics if you accept that 60% of Americans have at least one chronic disease and the median age in the United States is 38 point something and then

you think about how long are people living on average that would suggest if you say that and again this is what you're getting at with the definition of Health span I would not Define health span as ending once you have your first

chronic disease but that's the definition most people would use if you use that definition most people are spending three decades or more in the absence ofal Health span right or in

sick span so I mean the situation is even in the United States where life expectancy is relatively short compared to other nations a big chunk of that life expectancy is not spent in good

health and it's exactly for this reason 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 longer and everybody's agreed that we're getting better at that we're pretty good at it and that certainly contributes to whatever you think Health span might

mean that's an issue however that is quite different from what a concoction that slows aging

sure do so by extending Health span those both have the word Health Span in them but they are different and shouldn't ever be confused with one another the other point and this

question you asked was what is the is Health span my own personal answer to that is it's a useless term that is because no one can Define it it's not because no one is smart it's

because the term itself is vacuous and nebulous if you have somebody that gets a certain chronic disease here and then another one and then they fall down and bump their head and by the way they go

to the hospital and with Co etc etc defining when in that broad over that 20 to 30e period perod they flicked the switch now they have gotten to the end

of the health spin is impossible and of no interest the general notion that people are interested in is whether that you can do stuff to keep people healthy

for a long time either without changing their life expectancy or by changing their life with changing their life those are interesting but you don't have to assign a number but couldn't we get

away because I agree with you completely rich I I don't like the medical definition of Health span which I believe is quote the period of time in which an individual is free of disability and disease I find that to be

a very unhelpful definition because it be but part of the reason it's awful is it's binary yeah and silly but if we made it analog instead of digital right

I'm not saying that makes it easy it's still very challenging but now it allows us to start talking about things right as a person except it's a concept it's a qualitative concept right I mean I I I

think we should try to make it to where we can actually come up with it to measure some whether we call it healthspan or not that doesn't really matter but I I I I kind of agree with Rich like I agree with I agree with what

you're saying except I think it's a really useful term as a concept I think it's a really useful way to communicate to a broader audience what the what one of the goals is Right which is to

increase the healthy period of Life yeah I I kind of like the term health for that I have a way that helps you out with your health and you don't have to

maybe it's you can Define it as a number but there is a period of I think we all could agree there's a period of life where you are in relatively good health and then there's a period of life where you aren't and so I think the idea that

we're we're trying to increase that component of life is really important so I I don't think we're actually disagreeing on much other than whether we like the word well I also think

there's an individualization of this that we're missing to me health is a state of your physical being that you can do the things you like to do and

therefore if you like to climb mountains your health span is going to be different than if you like to play golf for instance and and a lot of this is personal you know if you if if you can't

run a marathon anymore some people will say oh my health is you never pay attention to the mental health piece at least the biologist don't right I have a question for you Ste what is my health

span I mean I I would only be able to ask you that well so so we do this exercise guys cuz I completely agree with you Steve we call it the marginal

decade exercise okay so we say to every one of our patients um and I write about this a lot in the book right everyone will have a marginal decade which I Define as the last decade of your life

so obviously by definition everyone has a marginal decade most people do not realize the day they enter it but most people have a pretty good sense when

they're in it right okay so the exercise we do is we go through with the patient and we say what are the things that are most important to you to be able to do in your marginal decade and they

generally fall into three buckets with a sub bucket physical cognitive emotional social the physical bucket we kind of divide into um activities of daily

living and recreational activities so that's where again most people obviously in it that boy I would really not be happy if I couldn't take care of myself

if I couldn't get out of bed get dressed shave cook like that would be disappointing to me but then of course you have different levels of ambition within the rec ation side and yeah I've got patients who say when the day comes

that I can't ski I'm going to be devastated and other people are like I just want to be able to Garden right so that's that is going to create a very different standard on the cognitive side you have people who say I want to be

able to run my hedge fund and still make money and make really important investment decisions and other people are like I want to be able to do crossw word puzzles and read the newspaper and that's my standard and and again we can

go to so so this is why it's very I agree with you it's you can't Define it but doesn't mean we shouldn't try to personalize it okay but I want to come back to you

Matt with the original question yeah the original why are we at a point where I I don't you know again why is longevity gone mainstream yeah yeah for

like better way yeah so I mean I think I think both of the points that that um steveen Rich raised um are part of the equation I mean I think it's a convergence of of all of these factors

and and maybe a few others um I do think the science has matured to the point where more people are believing that we can actually modulate the biology of

Aging I think the concept of biological aging has become popularized through a variety of mechanisms including you know some um influencers individuals who I

personally think often um air on the side of being a little bit less scientific than they should be but I think they've helped popularize the concept so I think it's been a combination of these factors um and it

has taken so long I mean I just think that's the pace that you know science moves and and and the rate at which these Concepts can sort of permeate the

public sphere um so it's frustrating in a sense that it's moved so slowly but um I do feel and and I I also wonder because you sort of said are we at a longevity bubble I don't know I also I

think maybe we're still kind of in the early days of this sort of hockey stick moment right where you're getting this exponential increase in attention My Hope is as we go forward it will become

more scientific and less you know snake oily and it's a spectrum right there's this huge gray area in the field right now of what's real and what's not real and I think none of us at this table

actually can really Define exactly where in that gray area that line is or is there a line so to that point Matt what is the collective wisdom of the group on

um the funding appetite for that because I agree with you completely like if we could Channel this exuberance away from kind of the highly

commercial uh speculative grifting towards the budget increasing legitimate investigative that would be awesome what

is the appetite right now of Ni with respect to this I think it's hard to say it and I mean ni NIH is a moving Target and as we all know that there's going to

be a lot of change coming in the near future so um cautiously optimis I would say if you look historically it's been really pretty terrible right the the

percent of NIH budget that goes to biology of Aging I think is still probably around half of 1% even though biology of Aging is the Sor just to put numbers in perspective I don't do you

know these ni gets how what percent of Ni within ni there's a subf fraction that goes to biology of Aging right but I'm saying how there are 17 groups of

NIH ni being one of them gets what fraction of NIH budget roughly I think it's roughly 3% 3% of NIH budget is NI within niia how much goes to this type

of research it was about 350 million a few years ago it might be a little higher than that but I don't think it's ticked up any more proportional to the increase in NIH budget since then so

that it reaches about half of 1% wow um what's your level of optimism Rich you're obviously very close to this that NIH will wake up and start to pay attention to aging research the way they

should it's near zero uh it's been near zero for 30 years now even with this as outside attention well it's gone up I mean they funded the ITP the interventions testing

program 20 years ago and they liked it and they doubled our budget about 15 years ago so that's something uh uh and I'm very very grateful to them for that

but there there's still an enormous uh untapped potential for making progress in the basic biology of aging and the reason is again

um a matter of of Defending Turf if you are a cardiologist researcher or an oncologist researcher or an AIDS researcher or an Alzheimer's researcher

anytime somebody says you know you the smart play is to reduce your budget by 10% or your institute's budget by 10% we're going to go there faster if we spend money on aging and its

relationship to the disease you care about you you get uh the porcupine defense you don't take any of my money because Alzheimer's is important little

kids with leukemia are important breast cancer is important you go away and that is the predominant feeling most of the people making those decisions were not

trained in aging research they view it as something interesting I read something about that in Time Magazine the other day but they don't understand

that to actually conquer or slow down or affect or protect against the disease they care about the smart play is to do aging research and so they view your

suggestion which I of course agree with 100% as a uh an imposition an invasion to be repelled at any cost no one in a

position of power um has had whatever it takes to reverse that and if he or she tried to do that Congress would even a

good Congress uh would smack them down they always the Alzheimer's uh group has 100 lobbyists the cancer group has 100 lobbyists the AIDS group has 100

lobbyists the Aging group has two lobbyists one who's a lawyer and one who takes the calls and it's not enough to do it can I just add something real quick to that too I I I agree completely

and I think as well the reputation of the field has hindered that transition as well right so historically the field was viewed as not very mechanistic kind

of phenomenological became much more mechanistic starting around the time of Cynthia kenyon's work and and since then but has continued to have a reputation

problem is not being as rigorous as other areas of research so I think it is absolutely a tur for and there's this overcoming the reputational problem

which makes it harder for serious people in funding in policy circles to give it the attention it deserves in my opinion so I've got a different take on this I

actually think that this is a very good time for uh aging research funding and that's not because of what's going on at the ni but it's what's going on in the private sector there's more and more

money there's even interest now in big Pharma and that's you know that was very spotty in the past so I think if we focused entirely on the National

Institute on Aging we would get a false impression of what the funding climate is in the field now and I think we need to we need to take advantage of that we

we got to make sure that it doesn't get captured by the people who are doing the the flashy but bad science that concerns

me so you're saying look Calico Altos um you know other private companies especially within biotech and Pharma that are looking at geroprotective molecules building on the

work of the ITP yeah I think it's safe to say the amount of money that's being spent privately probably outdoes public spending I mean in a given year two to

one easily right it could although how much of that is actually going to biolog of agent I think it's still an open question you mention calact I mean I I actually agree with

Steve I don't think the what rich and I were communicating is opposed to what Steve was communicating there are a lot of opportunities right now and again this is sort of what I was alluding to is are we at the beginning of this

hockey stick moment and I think Steve's right there are real opportunities for more resources to be focused on this scientific side and hopefully Less foced

on focused on the the non-scientific aspects of what are going on and you asked the question of you know can we shift resources from the the more consumer facing maybe not as rigorous

stuff and into the more rigorous stuff maybe maybe you need that sort of I mean again I'm not I'm not a fan of that stuff at all but maybe you need that stuff to kind of move the needle and get

people's attention and at least people are talking about longevity now naive question and I'm embarrassed I don't know the answer CU I spent more than two years working there what's the mission

statement of the NIH uh it's it's it's to preserve and enhance human health I mean it's basically the same thing that we do that we're supposed to be doing yeah and I

didn't actually get to give you my my Spiel here but um what I started to say about the Nia budget is if you look at um the major causes of death and disability and it's again we talked about how it's hard to Define health

span so if we just look at causes of death right if you look at the top 10 causes of death in the United States nine of them have biological aging as their greatest risk factor and it's not

even close yet half of 1% of the research budget that's supposed to be focused on improving human health goes to study that risk factor and I mean I

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

that again because it is so profound I want to make sure not a single person missed that statement the top 10 causes of death in the United States are well

enumerated and Incredibly predictable and they increase by category by decade 3 to 8% monotonically with no exception

point being 90% of and more than 90% on a on an adjusted basis of what causes death goes up with age and

yet a few basis points of federal R&D goes to addressing that let me give you an example of what the sort of point that Matthew and you have have been

making about once every five years I give a talk an invite a talk at the University of Michigan cancer center and I point out that we have drugs now

anti-aging drugs in mice and they extend Mouse lifespan and they do it mostly by postponing cancer because most of our mice die of cancer and if you look at

age adjusted cancer incidence rates our drugs reduce these by a factor of 10 wouldn't they like to know why as cancer scientists we now have a batch of drugs

that postpone cancer wouldn't they like to study them invariably I get one call back from somebody who says that's interesting maybe we should talk about that and then it dies and then five

years later I'm asked to give the same talk or related talk so they know how to do cancer research they are cancer scientists that's how they know how to do cancer research and you certainly

don't do it by diverting your lab's attention to age that's insane but that insanity is how medical research is

organized and breaking that addiction to the kinds of models you grew up on because they're a better idea is not a trivial not an easy thing it may not

even be a possible thing to do that's a major hassle well I I think this is because we're we think about health all wrong we think let's wait till get cancer and see what we can do about it

that's what cancer biologists do you have cancer okay how can we better treat that or could we have diagnosed it earlier what rich is saying and what we can know how to do in lots of model

organs it prevents you from getting cancer delay it for a considerable amount of time that's a little bit harder to study if you're a cancer biologist um because you want to see the cancer before you can study it I think

that's why we need aging biologists rather than people focused on certain disease that come and try to use what we do to pre you know if we prevented the

cancers they wouldn't have they'd be out of a job I guarantee these people or mice will get cancered they'll just have 10 extra years of life if they're a person or 10 extra months of life if

they're they'll get cancer they'll need Specialists it'll be all right yeah I think that's important I mean I think the reactive disease care component is still going to be there right even if we're insanely successful at slowing

agent people are still going to get sick but I think Steve's point is really important like Peter you've been a leader right in helping people recognize the need to shift the medical approach

from reactive to proactive I think what a lot of people don't realize is that mentality goes all the way back to pharmaceutical research biomedical research basic science it's it that is

ingrained at all the way through and I think one of the challenges with getting funding for aging research is the that mentality on the basic science world and

how deeply ingrained it is it's very interesting because you don't know which is the tail and which is the dog like I've always assumed that that the one

leading the charge is the clinical side of things right in other words the engine the machine of medicine 2.0 is built around the delivery of care the delivery of care as you said Steve is

built around I'm going to wait I'm going to sit here and hang we're going to wait when you get the disease we're ready you had the heart attack fantastic you've got chest pain St elevations we got a

stent for you now you have cancer we're all in um and then the research flows from that mindset of course I don't know not that it really matters but it might be that

it's flipped right it might be that the clinical engine behaves in that way because that's how the the the base of the pyramid has been built again not

that it necessarily matters but if you could be Health Zar and fix one of them you might actually start with the research side of things I would and I

mean the reality is the research flows from where the dollars are going this has been seen over and over and over at NIH you shift resource allocation to a certain area and the scientists will follow and they will submit grants to

get grants in the place where the funding line is the highest so if somebody came along and said we're going to go from 0.5% to 50% of NIH budget is going to go to biology of Aging you'd have no shortage of people I mean it'd

be kind of messy at first but you'd have no shortage of people applying for Grants and becoming experts on the biology of Aging the system would work you get the best and the rightest that

would go into that and and and and do that so so this then begs another question that is a tired question but but I can't help but ask it at this

point is aging a disease is that even a relevant question call me call me call me I call me it's it's important to to

use words optimally and to distinguish causes from effects one of the bad things about aging is it's a risk factor for many diseas diseases some things

other risk factors for diseases aging is a risk factor for disease and so saying that aging is a disease confuses that discussion it makes it impossible to see

that relationship so calling aging a disease is a fundamental error the question itself is incorrect I agree completely I think it's the wrong

question I I I agree but I think we have that idea for marketing purposes not for scientific purpos purposes and the idea is well the money goes to diseases let's

call aging a disease because I think what we're trying to do is we're trying to treat aging as if it were a disease even though I I would agree with both of you I don't think it's a disease I think

that destroys the word disease if we include Aging in it uh but I think there was a reason that suddenly this came because you thought oh maybe this will get Congress to pay attention you're

right it's a a it's a marketing Ploy and if you think you can convince people of the importance of Aging research only by crossing your fingers and saying oh well

it's kind of a disease isn't it uh and you can you think you can fool them yes that's what marketing is and it's probably good for that I just don't like lying to people it also creates a negative feeling about the field and

some people as well so so I think that should be considered the other point that people often raise though is we have to call aging a disease in order for FDA to approve a drug for aging which I think is a fundamental misunder

understanding of how FDA operates but that is the other argument you you will often hear among proponents of the idea that aging is a disease very interesting

I well yeah well okay so now let's go one step deeper on that how do you think about biologic

versus chronologic age in concept and in practice Yeah so so on the ride over here rich and I were talking about that I don't believe there is such a thing as

bio one thing as biological age I think there is potentially an age of your heart an age of your liver an age of your lungs an age of your brain but I

don't see why we wouldn't simply call it health in other words you know I I got one of these a epigenetic age clocks done on me a while ago but I didn't know

what to make out of it you know I thought is this just flattery am I I want to do this so it's or did it really tell me something he must have got a good result if he thought it was flattery huh he must have got a good

result if he thought it was but you know that's uh that may be the point of the whole thing right so

I'm I'm I'm dubious about some number uh that is different than I know I'm in good health you know for my age I'm in very good health so I knew that already now I have a number for it I don't put

much Credence in that let me agree with with and but just put it in slightly different terminology it's a matter of taking a very rich complex uh data set and trying to

collapse it to a number so if someone wants to know how healthy I am he or she would need information how good is my eyesight uh how good is my hearing how

good is various kinds of cognitive activities my aerobic endurance my ability to my joints all of that all of that is pertinent to how my health is

and also Al about projected future health then there's no need once you've got that information which is very rich to say ah there's a number a single number a real

number on a point on the number line that condenses that in any useful way the notion 40 50 years ago that biological age was not the same as

chronological age potent for a little while was useful it emphasized that there might well be 60-year-old people who were unusually like youthful people and 60-year-old people who were

unusually like 70y old people with my drug or my genetic mutant or whatever help to discriminate those people or change them in some way I can slow your

biological aging process that's a discussion that was maybe of Interest 40 years ago and has it's now time to drop the notion let alone the silly notion

that you can count that biological age that number which some people's too many people still think is a value you can figure out what it is by measuring something transcriptions or epigenetic

markers or something I can do it and give you personally your personal biological age that's a waste of everyone's time and it also distracts attention from things that actually are

important and need to be thought about I I gotta talk because I think I think I disagree fundamentally and I'm surprised but this will be an interesting conversation so I agree that the idea of

a kit that you can buy to measure biological Age first of all the stuff that's out there doesn't work and we should can and should talk about that but also I sort of agree with the idea

that reducing it to one number while conceptually I think it's possible I think in reality is going to be really really difficult to do but do I believe that there is a biological aging process

that is different from chronological aging absolutely yes absolutely it sounded like you guys were both saying no you didn't think it was a real thing I agree with that completely so that's you can agree with that and not like the

idea of a number that constitutes your biological age so there's two things I would that that kind of make me feel pretty confident in this idea one is and this is the example I use a lot among

the general public is just look at dogs compared to people right everybody's familiar with the idea that one human year is about seven dog years what does that mean means that dogs age about

seven times faster than people do but of course chronological time is the same between dogs and people it's the biological aging process and so you can look across the animal kingdom and see this and dogs get almost all of the same

diseases and functional declines that we do at the tissue and organ level but also at the whole body level um and we also know now there are single genes

that significantly modulate what I would call the rate of Aging now maybe we have a different meaning to what we mean that no I agree entirely so the fact that that's possible daff 2 we've talked

about da 2 a couple times T we can turn these things up up turn them down and animals Across The evolutionary Spectrum seem to age at different rates by modulating single genes so I don't know

of any other explanation other than that there is this process which we call biological aging that can be changed and and the rate can be sped up or slowed

down can it be reversed that's an interesting question maybe we'll get to that but but I think the process is real I think it's just really really complicated and we probably only understand 5% of it at this point

for me the challenge is I I kind of land where where rich was which is if a patient says to me hey why aren't you doing this biologic age clock on me yeah

my response is well I know your V2 Max I know your zone two I know your muscle mass I know your visceral fat I know we did a very complicated movement

assessment on you I understand your balance I understand uh like your lipids your insulin like I know these 50 seven things about you and I can tell you

individually on each of them how you're doing that number doesn't tell me a single new piece of information but what if you were to come up with and you probably do

this in your head right you come up with a some sort of composite right you probably don't sit down and wait each of those things and come to one number but you come up with some sort of composite picture of Health based on all of those

things that's a different biological aging clock I think sometimes we conflate and in part this is because of the way that irresponsible people in the field and marketers have done this we

conflate the epigenetic tests with biological aging clocks there are all sorts of flavors of biological aging clocks including things like Frailty indices or metrics of a whole bunch of

functional markers so I think those probably are pretty good readouts of biological age again can you combine them all to get to one number that's meaningful for every person that's much

harder to do yeah tell tell us about your experience cuz this was I thought you did you did what I wanted to do but I've been too lazy to do yeah in fact we we we exchanged emails at one point

about doing this and each coming up with different names so yeah so what I did was I um tested four different direct to Consumer biological age kits they were

all epigenetic biological age tests four different companies and I did duplicates of each kit and it was from sample the same samples collected on the same day

right so really my on I only had two replicates I didn't have three replicates but you know it's about the best I could afford at that point so and it was kind of expensive um so anyways uh sent those in

got the results back and they were I to me very informative fundamentally sort of changed my views on these epigenetic age um tests so they ranged from um 42

to 63 I was like 53.7 years at the time I did the test um and the standard deviation I can't remember it was either seven or nine so

mean of my chronological age standard deviation of seven or nine um uh which you know I look at that data I'm not a statistician but I know enough statistics to say that's completely

useless they converged on my chronological age but with a huge variation and even intra like so so that varied between the tests so I think

three of the four were reasonably close to each other three of the four companies the duplicates were reasonably close to each other but the individual tests were far apart and one of the

companies the the individual replicates was 20 years apart so to meet and and and some people will say but but maybe you know the true diagnostic test is great and the alysium test is terrible

or the tally Health test is terrible and the other one is great maybe but how do we know so so my sort of take-home is that the direct to Consumer biological

age testing industry is a complete mess and I have no idea who to believe or if any of them are actually giving accurate data I know some of the people at some of the companies and I have my personal

feelings about who's trying to do it right and who's sort of a charlatan but across the industry it's really hard to know so I the last thing I'll say on this is where I've sort of landed is I

think these are really good research tools I think the direct to Consumer component has gotten way ahead of itself and I think I align with what you were saying about the way you think about

these test is I I don't think there's a lot of value in clinical practice right now because we don't know we don't know Precision or accuracy and I don't think

you can make actionable recommendations based on these tests furthermore they fail in the one thing that I think they're attempting to do which is and I

usually use this illustration with patience so if I have a 40-year-old patient who says I really want to do one of these tests I say if if the answer

comes back and says you're 20 is your expectation that you will live another 70 years conversely if the answer comes back and says 60 is it your expectation

that you will live another 30 years in other words is this number predictive of future years of life because right now we have this thing called chronologic

age that is the single best predictor of future years of life so do we think biologic age as determined by these tests is better as a predictor of future years of life which by the way would be

very testable like how many people have contacted you to get ITP sample data to say can we predict how much longer these mice we're going to live the answer to

the question is obvious and very welln you can tell if you have a your 40-year-old patient and he or she is fat doesn't exercise

eats mostly cheeseburgers you know that their life expectancy is probably not as good as the 40y old patient in your your next waiting room that has extremely healthful habits and whose

parents live to be 100 so it's and there's tons of I don't need a biologic right that's what I'm saying there are tons of things you can measure on individuals four or five of them or all

you really need to ask of a 70y old yeah metti does this really really really well because their money's on the line there they're they're running life insurance policies right so it's not at

all hard to just to figure out a very small set of tests that tell you how long a seven-year-old is likely to live there nothing to do with methylation clocks or things me

that's the gold standard when life insurance companies start using biologic clocks as the Cornerstone of their Actuarial algorithms I'll start to be

far away from that though again I I want to I want to I'm going to sound like a broken record here but you guys keep saying biological age when what you mean is epigenetic age or epigenetic test not necessarily and we should explain to

people that there is a difference cu the so so some of these clocks use solely epigenetic measurements all not all most of the direct to Consumer ones are

epigenetic test some of these tests use a Litany of biomarkers inclusive of epigenetics so they'll say we have we we've sampled your methylation pattern but we also looked at your vitamin D

level your glucose level your cholesterol level and a whole bunch of other you know things and we compressed all of that into a number as well so I guess let me frame it as a question to you right so let's take the epigenetic

piece out again I I do think we will get to a point where the technology is developed far enough and the quality control is good enough on the consumer

side that these tests will be better than just chronological age y um but so you've got just you're saying I think we can get there I think I think that's a big statement I don't know that I'm disagreeing with you I just want to make

sure it's clear from the research unless you think that all of the the research that's been done on these epigenetic agent CL clocks is somehow flawed it's clear that you can create algorithms

that can predict specific methylation patterns that that are more highly correlated with life expectancy than remain than chronological age but I think the big butt here is

that even if that's the case they would not be as good as what Peter would predict after all the tests that you run your biological AG that's what I want to get to yes and I think what you are

actually doing is looking at other biomarkers that have a long-term clinical history that you're using to come up with a surrogate but really is reflecting

largely biological age maybe not completely and this is the other point I wanted to make is I don't think biological age and health are equal I think they're strongly overlapping and

certainly you can identify many ways to to reduce Health without accelerating biological aging right I think that's easy right we can all think of ways to

do that so let's let's take a minute and try yeah so let's think about this for a second I have seen very impressive data

where we can look at tissue samples of organs and we can tell okay I'm going to show you a sample of nephrons and we just based on nothing

but the methylation pattern we know that if I just said to you one of these is a 20-year-old one of these is a 50-year-old and one of these is a 70y old it's very easy to predict based on the methylation pattern which nefron

came from which person completely agree with that yeah I mean things there are a lot of things that change with age the literature has 25,000 things that change

with age a average amount of methylation at these 10 spots is number 11,47 of those so great you've got another thing that changes with age so that's the

question that's not enough right so do you believe that all of the research we're seeing on the epigenetic clocks is going to be the 78

variable that we would include in our Gestalt of I don't know yeah it's it's a good question so I am hopeful that um

epigenetic algorithms can get to the point where they can replace many certainly not all but many of the other biomarkers that are being measured I think the thing that gives me hope is we

know that we know that epigenetic changes are part of biological aging this again is a different question but if we look at the Hallmarks of Aging epigenetic disregulation is one of the 12 right some people will argue it's the

most important one that's a different conversation but it's at least part so that gives me some hope that we are in fact measuring something that plays a

causal role in the aging process and I think what's missing I think what would give all of us a lot more confidence is if we had a mechanistic connection to the specific methylation changes and

some cause of Aging or age related disease in other words this change in methylation changes this particular Gene's expression level which changes the rate of biological aging right I

think if we had that we feel a lot more confident yeah you and I spoke about this very briefly at the end of our last podcast and I want to come back to it with all of us in this table right which

is because there's so much in what you just said Matt that I'm going I'm going to lay out a broad question and then we can start attacking it in different ways so one of the things I want to address

is do we believe that it's possible that of the Hallmarks of Aging epigenetic change is the most important another topic I want to address do we believe that the epigenetic changes that we

observe over time which are undeniable are causal in the arrival of other states everything from the arrival of senescent cells the increase in

inflammation the reduced function of the organs which really is the Hallmark of aging and if so does that mean that reversing the epigenetic phenotype will

undo the phenotype of interest and Rich where I'm going that you and I left off was what about the proteome what about the metabol so you made three statements

there broad General statements and I think each of the three deserves careful amendment to be polite about it um the

first has to do with Hallmarks of Aging which I think set the field back dramatically um I I think when you are officially branded a Hallmark of Aging

by two people sitting alone at their computers and writing a review article a Hallmark of Aging wait they weren't I thought they were walking around a pond when they came up with this all right okay okay um means that somebody once

said you know I'm interested in aging that's kind of important isn't it let's put it on our list you can't tell if someone is a Hallmark something is a hmark of Aging does that mean it goes up

with age it goes down with age you can change it in a way that will extend lifespan you can kill a mouse or a worm by removing it um basically it's

something that somebody thought might be of interest to aging and the downside of that is once you're officially branded as a Hallmark of Aging anyone who wants

to write a a a grant on that doesn't have to prove that their fundamental cause and effect model has any Merit because it's a Hallmark of Aging I don't have to prove that anymore someone I

don't know who or on what grounds has decided it's important my reviewers know it's important because they've read the Hallmark of Aging paper so I don't have to think about whether it's important

the negative side of that coin is that there are lots of things that didn't make it into the Hallmark list and I really think it's premature to close thought off on some of those it's easy

to come up with a dozen things that ought to be investigated but if you want to investigate it and it's not on the Hallmarks list what are you wasting so deciding which of the Hallmarks is the

Big Daddy Hallmark or whatever strikes me as not the correct thing to talk about in the Hallmarks Arena the second question so maybe we should talk about that before we go

through all there's a lot to remember the other ones if you guys could afford to give me a little piece of paper and a pen then I'd be able to write down I think the Hallmarks as a list a kind of arbitrary list not completely arbitrary

because they had some reasons for being there and I don't think any of us would say that those 12 things are not involved in aging but that's a very little interest any of us want to Rattle

them off being that I'm the only one that's got the list in front me we we could do a game where we each name one and see who see if we get to all 12 um

but certainly in that list I I would not I would not consider epigenetics as the the key Hallmark assuming there are such things I consider it to be an

interesting list it became biblically sacran almost immediately and I've never understood why but for some reason it did so I agree with Rich so conceptually beautiful I mean so I agree completely

with Rich and he knows I do because we we've talked about this before and I think the flip side is I think the Hallmarks have been immensely useful to the field they are a very easy way to

communicate this idea of biological aging and it helps convince some of the scientific community that thought it was all just Hocus Pocus and snake oil that there are that there is some mechanistic research happening we can point to

specific things that are aging so I think that part of the Hallmarks has been actually really valuable and has contributed to the popularization of longevity and at least to the extent the

science of longevity has been popularized has contributed to that and it has been extremely detrimental to the field and the way I think about it is it just caused the field to narrow

prematurely and this goes back to what I alluded to before I don't know if we understand 80% of biological aging or 0.005% of biological aging my guess is

it's closer to 0.005% and by and large the funding to look outside of the Hallmarks dried up once the Hallmarks became the dominant

Paradigm and people stopped looking and I think we need to go back to more Discovery Science and and thinking outside the box so I think sword Happ would that happen automatically if we

could wave that magic wand and increase funding it would help I don't know that it would help enough but it would help I think you I mean you also kind of have to change the mindset about you know

what people call fishing Expeditions that's like a bad word in Grant review panels fishing Expedition meaning you don't really know what you're going what what you're going to find but you got to go look before you can figure out what's important so think we have to kind of

change that mindset as well one can usefully concretize this this discussion I imagine that one of this I don't don't read these papers because they upset me but I imagine inflammation is on one or

more of these I'll bet so chronic inflammation okay good chronic inflammation so so what that does if you say I'm I'm interested in chronic

inflammation so I'm doing good stuff huh but but what could be happening is this particular set of cyto kindes might be overexpressed by some gal cells and that

leads to loss of cognitive function whereas this other overlapping set of cyto kindes produced by the macras in your fat may lead you more prone to

diabetes or metabolic syndrome whereas this particular set of lymphocytes are necessary to repel covid and that's why

you are more susceptible to covid so learning what changes within the extremely broad generic idea of inflammation what changes in what cell

types in what people under what pharmacological or genetic changes how they are interacting with other aspects of pathology that's marvelous to do but

to say oh inflammation that gets bad when you're old is a way of avoiding the labor of thinking and that's why I'm against it and I think M brought up a

really important point and the and we scientists are to blame is the way that research gets reviewed and for lazy reviewers having these 12 Hallmarks is

really helpful oh this has got one of the Hallmarks in it this must be good stuff I do think reviewers need to be more open

to new ideas and new approaches I mean everybody knows that NIH grants are approved if they're incremental if they're really breakthrough they

don't get approved fact very famous biologist eio Wilson told me years ago he said don't ever include your best ideas in a grant they won't get funded

do it standard stuff save your best ideas for projects that you do on the side yeah and that's one of the reasons I left Academia it's just drove me nuts almost impossible to get the important

stuff funded H so what's your go back so the second of your of your uh

multipartite question was does epigenetic change what what are the results of is it causal causal effect and the third which we may get to is can you reverse it and would that be a good

thing so let's talk about the second element here is it causal and the here the defin the problem is what it means there are some changes that occur in

this particular set of 40 cells in the pineal and there are other changes that occur in these cells in the bone marrow and there other cells that change in the gut and villis lining cells and the

Crypt cells so they are all epigenetic in some they are caused by some things and we don't really know which if any of

these count for aging if someone says I'm going to prove that an epigenetic change is responsible for aging they haven't begun to come to grips with the

nitty-gritty uh people always ask just as you hinted does your drug change epigenetic things and unfortunately that's where they stop thinking if we're

always willing to give people tissues from our drug treated mice if they are keen on epigenetic changes that affect neuron regeneration excellent their experts will send them the brains and they can do that stuff it's important

I'm not making fun of it but the general notion that that's aging vaguely thought of is due to epigenetic change more

vaguely thought of doesn't really get you anywhere that's my sort of skeptical View and is is part of the issue that you're saying well what's causing the

cause no it's just that the the concept of epigenetic change encompasses thousands of changes in hundreds of cell types under hundreds of influences of

course some of that causes other stuff agreeing to that assenting to that notion that epigenetic IC change is causal for all sorts of age related pathologies everyone can agree to that

but it does it's meaningless because what counts is to say this specific change is really important in this disease let's go back to the example an

epigenetic alteration or this specific broadspectrum change in multiple tissues causes something good or bad you have to Define what it is before let's

so let's use a specific example when you look at a patient with type 1 diabetes M and you look at their beta cells in their pancreas they look different

epigenetically than the beta cells of an AG matched person without type 1 diabetes and we also know that their beta cells don't function so they're so they they've lost function so the so

let's ask that question as a specific example what do you believe or what confidence would would you assign to the notion that the epigenetic change on the beta cells of the type 1 diabetic are

indeed causal to the loss of function of the beta cell right so my my last uh exposure to the causes of type 1 diabetes was I in medical school which is more than five years ago but if I I

vaguely remember it was an autoimmune disease right so if your poor little helpless beta cells are being attacked by antibodies and macrophases and things those stress reactions are going to

cause epigenetic change and whether those epigenetic changes contribute to some extent to the ill fate of the beta cells it's possible and if I were an

expert on Diabetes pathogenesis I'd really want to know that it doesn't have anything to do with aging but an interesting question it's a way to address causality yeah but you might equally say no no it's the mitochondria

that have changed why would yeah why would why Mark of diabetes yeah or it's the it's the it's the glycated proteins misfolded Pro there's a ton of things in it there's no reason in the world at

this stage I think to actually give epigenetics Primacy over anything it's a nice hyp diabetes is you can formulate these

questions because a lot is known about type one diabetes and I understand 05% of the biology of is is I was giving you're off by an order of magnitude

who's raising You by a I thought your One log off so so it formulating the questions in exactly the way Steve did makes it clear how difficult it is to

evaluate the concept that epigenetic change contributes to pathogen gen is in type 1 diabetes and we know more or less what is going on in type we don't know what's going on in aging we don't even

know what part of the body it's going on or parts more likely of the body I I I at least internally reframe it a little bit and say you know what what would the

experiment be what would you need to do to convince yourself that either broadly speaking epigenetic disregulation causes aging whatever that means or this

specific epigenetic change that is associated with chronological age causes aging right and so that's an easier way for me to think about it because I feel like this is all it's all a fascinating

conversation but we're never going to get to the answer until somebody actually does the experiment and or decides that it can't be formulated because it's too complicated and gives up yeah that's right but people are

trying to do both of those things I mean people are using you know partial or transient epigenetic reprogramming and asking can that have effects on biological aging I'm actually cautiously optimistic it can I don't think it's

going to be a GameChanger but I think you can modulate aspects of biological aging and then people are you know the Technologies are being developed for targeted epigenetic modifications so if

we think this particular epigenetic Mark at this particular location in the genome controls aging and I don't think it's going to be that simple but let's say it is you could go in you could

modify that and then see do you reduce disease do you increase lifespan do you improve health span right so those are the kinds of experiments that I think would get us to where we can have a lot

of confidence if it's the case if somebody let's say at Altos publishes a paper three years from now that they have made a mouse live six years by multiple rounds of transient epigenetic

reprogramming I'll be like their biggest fan they moved the needle that convinces me that that strategy modulates biological aging nobody's done that yet

what about something far less impressive but but but still um worth worthwhile so consider you know if we could get to the point where we could locally deliver

vectors that would epigenetically change condra sites so that you could take osteoarthritis in the knee and just regenerate cartilage regenerate

cartilage regenerate useful by changing the EPO but is that biological aging right I wouldn't be convinced that's modulating the biological aging process I would be convinced that's a clinically

useful strategy for people who benefit from that therapy I guess it kind of dep depends on why we think an individual would be experiencing osteoarthritis right how much of that is

sence how much of that is infl trigger here before we go down that path is it the s word or what yeah yeah let's talk about sesses but before we think if you

think uh ostearthritis of the knee requires a knee joint replacement and that's going to help your patient you are not rejuvenating it's perfectly possible to

do great things with technology including con condra site regeneration without having to decide that that's related to aging people

don't age because they fail to have titanium knee joints or something and one way I think about this and again this this may be completely wrong but it but it's a useful way for me to think

about it is I think about age related disease as the sort of Downstream effect of biological aging and then in for most diseases there becomes a point where the

pathology of that disease mechanistically is no longer the same as biological Aging in which case very good you should listen to him in and one of the implications of that is the interventions that slow biological aging

may not work once you get past that point but things that do work for that disease may have nothing to do with biological aging does that make sense yeah go go deeper on that idea though

let's use let's use the example yeah well I think um so let's just I mean what's your favorite disease my favorite disease let's talk about is an easy one

right we know with cancer in many cancers the process is you have one or more mutations which then often lead to additional mutations you get genome

instability eventually you get an enco gen that gets activated and that leads to uncontrolled cell division there messor that gets deactivated yeah right

so at and if we accept that immune surveillance is one important anti-cancer mechanism we know that immune surveillance declines with age so early on we're clearing a lot of our

cancers as our immune system declines these cancers are going to escape immune surveillance they're going to accumulate all these mutations they're eventually going to go into uncontrolled cell division that uncontrolled cell division

at that point you can treat the cancer right but uncontrolled cell division is not biological aging right it's not a normal part it's not a part of the

normative aging process right so the treatment there so the mechanism now is fundamentally different from normative aging and the treatment let's just say the treatment in this case is

chemotherapy might benefit the cancering right and I think romy's a good example here where we I think we all believe that rapy and inhibiting mtor slows biological

aging at least in up to mice hopefully in dogs hopefully in people yeah so it's a fundamental node in the network that's the way I think about the Hallmarks of Aging it's a node in the network that

underlies the Hallmarks of Aging so we can manipulate mtor with Ramy slow aging ramy's a pretty good anti-cancer drug until the cancers have evolved to ignore

the mtor break and then rapy doesn't work anymore and we know ramyon doesn't work for most cancers that's an example tested we know this yeah absolutely um and it's because the cancers evolve to

bypass the mtor break or to bypass the ability of Rapa to inhibit mtor so that's a case where the intervention that's a really good point that we all take for granted that I think is worth noting rapamycin can be unsuccessful as

a chemotherapeutic agent and can yet be very successful as a cancer preventive agent absolutely and it's exactly for that reason and I think this also illustrates why traditional

disease-based medicine is not about the biology of Aging it's about something that the biology of Aging is distinct and it needs to be uh investigated in a

different way and we know that in the Aging field but the people in the cancer field in the Cardiology field and the neurology field I don't think they understand that well

so this gets to what I wish I if I were Health Zar this is what I would do because you know it comes back to what rich said at the outset which is why is this a zero sum game like I mean you

didn't ask it that way but that's effectively the problem you're dealing with right which is why can't we study Cardiology oncology and neurology and aging without everybody feeling like

they're taking my way of saying that in Peter terms is we need to have medicine 2.0 and Medicine 3.0 in parall because the tools of the medicine 2.0

scientist and physician which we see on display today are putting the stent in giving the chemotherapy lowering the cholesterol all of these things the the

medicine 3.0 toolkit looks different different science you're going to use WAP a mice in here you're not going to use it over here because it's too late and instead

of saying one or the other why isn't it both like why wouldn't we want both of these running in parallel well well we would but of course um the Zero Sum game

uh is a pretty good analogy for what's actually going on the amount of research dollars at least available to NIH is not infinitely expansible it's set by

complex political process and then um there's a separate Downstream process that allocates it amongst uh institutions so saying that it would be a good idea to have more funds everyone

I agree with you and I'll bet these two guys do as well yeah I think ioke it will be a it will be a portfolio reallocation but it will be worthwhile because the burden of this disease will

be lower so in other words it's okay it's sort of like saying right now I spend $100,000 a year on the barrier to my

house to prevent anybody from breaking in yes and I spend $100 a year patrolling the neighborhood to make sure there aren't too many bad guys in the

neighborhood there's a scenario where if your total budget is $100,000 and $100 maybe you could spend $80,000 in total by spending more money patrolling the

neighborhood less money generally agree with you that having a greater proportion of available research dollars uh both private and public going into the biology of aging and its uh impact

on late Life Health is would be a good thing I don't think you're going to get an argument here but I also think you're going to get a huge argument from

anybody in the Cardiology field the neur Alzheimer that's the Alzheimer's field that's um their money only in but but wouldn't some of those people as the

funding dollars move towards the Aging side also want to move and say look I'm going to study this through the Aging lens I was on the council for the national aging Institute for three years

and if at any point I can swear to this from personal testimony somebody would say something like I wonder if maybe a few percent of the Alzheimer's budget

might instead go to studying how slow aging models would have an impact on late life neurod degenerative disease the next day the director of the Aging

Institute would get a call from two or three Congress people who were on the Appropriations Committee stating that this will not be happening because there was an Alzheimer's Association person

who got the call from the ni staff member in charge of Alzheimer's saying tell the congressman to call the director and let's put a stop to that

Reckless idea so they're they're tied in to the political process in ways that well we just need to go maybe one step further because those Congress people have a

boss they report to somebody too who who would that be at this stage yeah no I mean come on maybe it's because the public doesn't understand this those people answer to the public these are these are our dollars that's right

they're going to work but Alzheimer's Association I mean that's a patient advocacy group right so that is that is the public yes although let's ask the question what have they done for those patients lately

that's a different question but I mean I'm just reinforcing what you said I think I think part of this is educ if you if you know somebody who's suffering from Alzheimer's disease you know very

well that the only thing we've got going for us right now is prevention right we don't have too many silver bullets in the treatment gun despite massive

spending massive spending on I was once in Congress trying to Lobby with about six people from the Alzheimer's Association in the in the

same room and I was totally ignored by the staffers that were in there I mean I I like I'm I agree with all of this I agree with all of this I think again though we I mean we should be careful

not to demonize people for wanting to cure Alzheimer it's a good thing it's a good goal I think the communication piece is about the fact that it's going to be much more efficient and effective to keep people from getting it in the

first place this goes back to the the idea that once you've outpaced the biology of Aging with the pathology of the disease it gets a lot harder a lot harder to do anything about it and so I

think that communication part I don't know why we've been honestly I don't know why we've been so unsuccessful because I think a lot of us have been out there trying to communicate this message for a long time but it's

starting to permeate again this is we're at that moment I think where people are starting to get it that aging biological aging is a thing it's malleable we don't really know for sure what Works in

people and what doesn't work yet but we're getting there so I think I think it's going to take a little while but but there's reason to be optimistic and there's also the private sector is

another reason I think to be optimistic so let's go on record right now I think when we if we defeat Alzheimer's disease it's going to be because of the biology

of Aging it's not going to be because of the drugs that get rid of you know absolutely yep probably cancer probably heart disease although I think Peter's more optimistic we can

prevent heart disease through other other mean medicine 2.0 if you took the tools of medicine 2.0 and just applied them 30 years earlier we wouldn't have ascvd that's the one place where it's work but again that's because the

mechanism of action is so well understood with ascvd compared to Alzheimer and cancer a lot of infectious disease a lot of liver disease a lot of kidney disease all of those things can

be improved dramatically by targeting the biology of Aging you know if I were to write my book again I would add a fifth Horsemen because I talked about these

four horsemen of ascvd cancer neurod degenerative and dementing diseases and metabolic disease but I would actually add a fifth sort of Hallmark of it's not really a Hallmark of disease but it's

kind of the fifth thing that brings life to an a bad close which is immune dysfunction right and and I don't think I gave that enough attention in the book because of course as you said it factors

in very heavily to oncogenesis um but also I mean as Co showed us like what a risk factor it was to be old yeah and you know I'm reminded

of this when I see people my age get brutal pneumonias and like two months later they're okay and you realize and you look I mean you know one of my patients

two of my patients actually in the past six months have had really bad pneumonias where you're looking at the CT of their chest and you cannot believe they're alive but of course they're fine 3 months later four courses of antibio

iotics later they're fine and you realize you do that to a 75y old it's over and it's simply comes down to how their B cells and T cells work and so

that's an area that again I you know that to me is an area where I'd love to see more attention which is what would it take to rejuvenate the immune system as as a proactive statement right well

that's part of the of the X prise healthspan challenge of course um I think that that's a perfect example influenza pneumonia is never fallen out of the top 10 causes of death in the US

you know it used to be number two but still now it's number eight or nine but it's always there because you can't really do anything

about the late life immune dysfunction so so what to shift gears to and so one can just to follow this up and so if magically you become in charge and

you're able to uh double the amount of research being done on the biology of Aging fundamentally then we can afford to do let's give some mice to start with

a batch of anti-aging drugs and see if it makes them more resistant to infectious illnesses including pneumonias but but viral infections as well and many others I'd love to know

the answer to that and no one has actually really looked in a serious way because the um we we the ITP has enough money to just measure lifespan and we're

hoping that everybody else is now going to look at the brain and the lungs and the infection and the the sensory systems that really ought to be done and it's not being done because of a lack of

money you said something a while ago Rich that I think is is is timely now which is with each generation of these drugs they get more efficacious and less

toxic not yet but that's the hope well no no but I'm going to use another example the gp1s are the best example of this right so you go back to the very very first generation of gp1 agonists

barely lost any weight horrible side effects right you generation two about 10 years ago a little bit better weight

loss side effects so so fast forward to semaglutide quite a bit better efficacy still really bad side effects Next Generation tepati better efficacy side

effects are almost gone now why haven't we been able to do that with these geroprotective drugs so we have this one study using everus that show that gives us a hint that says hey

this might actually enhance immune function in people in their mid-60s but we need the follow-up study the followup drug imagine what the fourth generation of that drug can do where it's tuned to

get better and better and few commercial motivations you know you're going to sell a lot of the uh uh obesity drugs they're very strong commercial motivations to do those studies over and

over and over again until you find one that works better and they're good pre-clinical models that you can use so that you're not wasting too much of your time on clinical trials um that could be done for

anti-aging drugs as well although testing anti-aging drugs in people is a whole separate set of tangle of difficulties we I don't want to talk about that right now but the I I'm

saying it won't be quite as easy as it was for anti-obesity medications but no one's doing even the first level of research to to find the uh optimal

compounds for efficacy without side effects or even to begin to see if they have desirable effects on Aging rate indicators in people that's that's kind

of a cheap and easy study and no one has really tackled that yet well I just heard that there are over 80 cytic studies in early clinical anti-aging drugs yeah it's a joke it's a joke it's

a joke it's a joke we have to go back to this are any of them are any of them powered for anything other than safety this is I think phase one at exactly so but they're underpowered they're almost

useless in my opinion well until they get to phase two phase three if they get how many years have we been having phase one analytic trials now I I don't know at least a decade God has it been that

long first one I remember was 2017 so yeah a decade easily because I probably wasn't paying attention in 2014 2015 so yeah anyways there's a lot there's lots of complicated issues here I think end points for clinical trials are are

really challenging but solvable so so there are two places I wanted to go next and I'm going to let Rich decide because he's going to have the strongest point

of view can we talk about sence or can we talk about what biomarkers would be necessary to help us study Aging in humans as we translate from your work

and Matt's work I know what I want to talk about and it's the second of those two okay um I don't want to spend the next three or four hours explaining why sence is silly and anti- senolytics are

untested at best talking about that very well let's go on to item number two um and I think the clear the most important thing is to make a clear distinction

between biomarkers and aging rate indicators so a please explain the difference to people please okay I I'll do my best so a biomarker allegedly and

in real life uh is something that changes with age so if you have some drug that slows aging the biomarkers many of them in the different cell types and in the blood will change more slow

slowly they are a good way of looking at whether you're slowing it'll work in the dogs long long lived dogs and shortlived dogs will have differences in the rate of change of biomarkers very established

part of the literature and valuable but you have to wait till somebody's old whether it's a dog or a mouse or a person because only when they're old has the biomarker of Aging the surrogate

marker for biological aging changed very much so in a clinical trial certainly in a a human situation no one wants to wait 20 years to see whether the biomarkers

have changed and a one year is such a tiny fraction of a human lifespan that you don't really anticipate detectable change with a appropriately powered

study a it's like aging rate indicators which are much less well studied and much less well established in principle are things you can measure that tell you whether you're in a slow aging state or

a normal State can I just make some make a point for the listeners so they understand kind of the challenge of what talking about y when we study blood

pressure drugs or cholesterol drugs the biomarkers change so rapidly and we know the relationship between the biomarker and the disease state so if your blood

pressure is 145 over 90 on average before I give you this ACE inhibitor and 3 months later 6 months later n9ine months later a year later your blood

pressure is averaging 119 over 74 I know I've done something well now I will still probably in the phase three in fact I will in the phase three have

to make sure that I also reduce some event in you but generally by the phase two I know that this drug is not toxic and that it's predictably lowering your blood pressure that's that's really really valuable a biomarker generically

is something that's easy to measure that you is informative about something that's hard to measure a classical example famous example is you want to know how many cigarettes somebody smokes

a day they'll lie to you but if you measure cine in their blood that's a byproduct of nicotine you don't have to ask them you can find out how many cigarettes they had in the last couple

of days by measuring blood coat that's a biomarker of of cigarette consumption is it a marker of nicotine or carbon monoxide I don't know the answer that yeah I wasn't sure so in principle a

biomarker of Aging is measuring there many of them and they are measuring biological aging processes and they're useful in that regard but they don't tell you how fast you're aging the analogy I love to use is an odometer is

like a biomarker of Aging of your car it tells you how many miles your car has gone but it doesn't tell you how fast the car is going the speedometer tells

you how fast your car is going and so what we need and what I think we're just beginning now to to document is things like the speedometer aging rate

indicators that reliably discriminate slow aging myor people from regular old Meer people we have now a dozen or so things that change in the fat in the

blood in the liver in the brain and in the muscle that are always changed in any slow aging Mouse whether it's drug a drug B drug C calor restriction diet or single gene mutations we've looked now

at five different single gene mutations and this whole set of 12 or roughly 12 aging rate indicators always changes in

every slow aging Mouse and it does so in youth which is the key point so if it does so quickly after an anti-aging drug is administered

that's the transition that's the bridge you need for clinical studies in people if you want to know whether metformin or Kagen or something slows Aging in people

and you don't want to wait 20 years but you've got things that tell you whether they're in a slow aging State how fast they are aging versus normal and that's a big if we don't yet have evidence we

can do that we just have hope we can do that then that allows you quickly to with quickly being within six months to a year to know whether your anti-aging

manipulation alleged anti-aging manipulation has moved them to a physiological status which is associated with slower aging that allows that can be done a lot of that can be done in

mice with drugs with mutants and are these all proteins Rich no no some of them are changes in the fat uh different classes of macras is the pro-inflammatory macrophages the bad

ones go away the anti-inflammatory macras is the good ones go up uh you cp1 I recall from1 uh goes up in every one of our 10 different kinds 11

now of slow aging mice does it go up in any of the mice that did not receive a successful drug well we compare them to controls and the question you're asking

is really important that's what we're doing in the next five years we just got to Grant to do that we're going to take mice and give them either a good drug or a different drug that doesn't work yep

and then make those comparisons a really important thing to prove so far our only control has been untreated my at at some point in this I have I had to bring this

up but let's imagine that rich is incredibly successful at finding these things that is a very very long way from

assuming that it's going to be the same in people most things that clinically work in mice do not work in people it

might be and that would be wonderful but I think ultimately we're going to have to find this for people and my thought is the kind of a the kind of evaluation

that you do routinely of your patients if we took a group of 65 year olds and we gave them a drug that we thought was an anti-aging drug and follow them the

next five or six years doing these evaluations I think you could probably safely say this is slowing aging or slowing not or not slowing aging so I

don't think that it's going to be that easy to jump from Ice to people in this I've always wondered if in people

the the easiest way to do it would be to take the most obvious thing that we know is going to reduce the rate of Aging so it'd be an interesting experiment but

you find someone who is overweight diabetic and smokes and has hypertension you get hundreds of these folks you put half

of them on a sort of to be ethical a plan where you try to get them to stop and presumably many don't right but on the in the other group you pull out all the stops and you don't care because

you're interested not in testing the hypothesis does this thing help you you're interested in getting them to lose weight not have diabetes stop smoking exercise like crazy so you with

the greatest division between two groups of individuals where we would I think be able to agree that this group is now aging slower the group that we've reconciled their diabetes quit the

smoking etc etc and then I'd love to see riches 12 line up in that in that population that would be great let me just say that I think that people that

study animals myself included always underestimate how well we can evaluate Health in people with a very very thorough evaluation because we don't do

that in our experimental animal why do you think that is Steve why is it that because I was going to ask about parabiosis later on in the discussion we might as well talk about it now right

parabiosis seems to actually kind of work in certain Mouse models do we have any reason to believe it's going to work in humans and if not why not why are mice so different from people well wait a minute I wouldn't say that just

because we don't have evidence that it works in humans means mice are different from people first of all when it comes to parabiosis right I mean that's a different discussion but I I actually have a little bit I agree that most if

you look at the attempts to cure cancer or or other diseases in mice and translation to people most have failed I actually think that's because those are artificial Mouse models where they tried

to give young mice an age related disease I'm more optimistic I don't know thises have those mice I know I'm I'm more optimistic that biological aging or

normative aging is going to be much more likely to translate to people both interventions and biomarkers than the specific disease interventions I might be wrong I don't know answer I'm just

more op we would hope that's the case so I I don't I don't I don't think we should rule out the mice as a useful model in fact I think there's reason to be optimistic that it will I actually am kind of bullish on parabiosis as like I

think it will work to some extent in people it's not a pragmatic approach for population gerpe but I'm just wondering like why it wouldn't be as efficacious how do we know it's not yeah right I

this is something that I mean aren't there six or eight clinical trials going on right now variant that yeah yeah so I I haven't seen them I've seen the one that's looking at

um well there's the one that it's not really a parabiosis study but it's looking at plasma FIS for Alzheimer's but that's I consider that a little bit different but but fair enough okay because they're just using Albin I think

aren't they right but there's also studies going on of young young blood yeah right but if you think of parabiosis as both you know taking away the bad stuff that accumulates with age

and adding in the good stuff that's in young some sort of of plasma exchange hits at least half that equation right MH okay let's go I want to come back to

this but but so so so my question was why the why the difference you're saying Matt uh the difference is probably Amplified in disease specific cases like heart disease cancer and

Alzheimer's disease probably less relevant when you're talking about aging because even a flawed Mouse model still ages in fact it's designed to age in a certain way yeah and I mean I think normative aging looks very similar again

if we look from mice to dogs to people just sort of broadly speaking the process looks pretty similar so I'm cautiously optimistic that these things are going to translate I think the the

reason that not to pay too much attention to Steve's pessimism on this point although he's completely right of course most things that do have a an important effect in my fail in human

clinical trials and it's for a variety of reasons sometimes humans are different from mice sometimes the drug has side effects that are tolerable in my is not tolerable in people Etc but I

always like to look at the other side of the coin that is if your goal is to develop um a drug that blunts pain in people uh uh and you screen 40 or 50

drugs and you find a couple that inhibit pain in mice that's a really good start it doesn't guarantee they're going to work in people but it gives you this

category of of snail based uh neurotoxins let's make 40 of those from 40 different different snails we'll find one that actually in people works uh can

be made by a scalable process and doesn't produce serious side effects so the the mice are not a it's not a onetoone mapping it works in mice it doesn't it works in people but it's an

important critical First Step which usually succeeds in in finding a set of drugs of related families or with related targets at least that are

efficacious in people most drugs that are used in people uh had useful rodent-based research somewhere in their pedigree but and I absolutely agree with

that rich and nobody saying that 100% of things that work in mice do not work but I think there's a critical difference with aging research was it takes four years to do one of these and in mice

right and so if we have to do 40 to find one or two that work that's why I like aging rate indicators speed things up so let me ask a question I'm going to take you I'm going to take I'm sorry I'm stepping on your toes Peter but the question I always come back to I agree

we need these a rate indicators when do we how do we get to the point where we're confident that they actually work in people and maybe more importantly how do we get to the point that FDA is confident that they works that's the

only way you're going to be able to use them in a clinical trial and I don't see a path in the short term well I don't know that we need that to tell you the

truth so I went to the FDA to try to get them to to to to approve a a trial of met foreman and we didn't couch it in aging cuz you're right as soon as you

mention aging their eyes glaze over and they're not interested anymore but we did it in terms of multimorbidity and they were fine they were fine with that but that's a different Endo to your

question is that you've you've merged two different difficult problems problem a can we find drugs that's slow Aging in people problem B can we surmount the legal and political barriers to getting

them that's not what I was asking I was asking how do we get to the point that's what I'm okay what I'm saying is that you were focused on something I don't have any answers to basically which is

how do we get the FDA to develop an an approved clinical trials I was more interested in a step before that we' be nice to have some drugs that actually do work to slow Aging in people but you

have to trust the biomarker of Aging rate before you can be confident that the drug that moves the biomarker of Aging rate works in people that's like that's what that's fundamentally what I'm asking how do we get to the point where even let's just take FDA out of

the equation the four of us would sit look at the data and I'll be like yep well that's sort of my thought experiment right I would have to take an example in humans that is so egregious

that nobody with a straight face could say one group isn't now aging slower than the others sure would that convince you though so let's say we do that let's say I it would make me worry it it wouldn't

be yeah it would only show you the positive signal it wouldn't show you it would show you the specificity and not the sensitivity of the test that's the problem sorry well I'm just gonna say it

it you might miss the signal if you found a a proteomic genomic epig like if you found a multimodal signal that detected a rate of detection a difference in rate of Aging between

those two very extreme sets you might miss it with a geroprotective drug which wouldn't be as dramatic as that change so what if I told you that there are people who claim there there are

epigenetic signatures that do that that that that correlate quite well they claim with health outcome 10year mortality 5year mortality threeyear mortality in

people and um are measuring the rate of biological aging because it's out there I mean it's in the literature I mean I would look I mean this is not perfect but it would be one thing I would immediately think of which is I would

take a really good biobank that would have enough samples that I could you know sample a bunch of human stuff and use an unbiased sample and a biased

sample so I would determine an algorithm based on one and see how well it predicted on another based on enough samples I mean that would be I would have to have that would have to be true at a minimum yeah I think it is I mean

again I think at least it depends on how much Faith you put in in these these research studies but I mean people have published epigenetic algorithms denen pace is the one that most people are

going to talk about right that that correlate seemingly pretty well at least with mortality and with metrics of Health span to for lack of a better way

of framing it so so um so that exists and Denine pace is using something besides epigenetic or is it only epigenetic I think it uses something else it was trained it was trained off

of other biomarkers and then they found epigenetic marks that correlate with those other biomarkers so it's a correlation to a correlation but there's still a correlation what do you think Rich well

I wanted to go back to the example you gave where you took a lot of people and gave them intense uh exercises and dietary changes to improve their health

out likely Health outcomes and that's a good good place to start a discussion because you you said every sensible person would see the treated group as

aging more slowly and I would want to ask before I agreed to that do they also have improved cognition how are they doing in cataracts how are they doing in hearing what happens when you give them

a flu shot do they have a great flu shot so the things you've pointed to are really important for um both overall health and for cardiovascular risk and and the things

linked to that so it's nice to know but to convince me that you now have a slow aging group of people you need to go beyond the risk factors for specific

common human diseases um if you could show that then for the first time I would be convinced you had an effective anti-aging

manipulation in people currently I don't know that there is any effective anti-aging manipulation in people if your approach got there that would be a

terrific research model well but now we're getting into the definition of Aging a little bit which is would you agree that the approach I'm

describing would produce a longer life it's easy to produce a longer life if you happen to have a clinical condition where you're tied to a railroad track and there's a train coming you can

extend that woman's life enormously by simply uh giving her a knife and cutting the bonds and letting her walk away from the track longevity promoting interventions are not % of people died

as a result of trains on trained tracks that might be a worthwhile example but given that 80% of people die from these four chronic diseases all in favor all in favor of protecting people against

chronic diseases that's good thing and I'm glad that people are doing that no question about it now talking about the biology of Aging there are all sorts of things that also happen when you get

older that are not part of those chronic diseases and to make a case that you've got an anti-aging manipulation you need to show that those are changed too but do all of them have to change or just most of them I mean I think don't enough

have to change that you increase the length and quality of your life and and if you if you still get a cataract at the same rate I'm not sure that should be disqualifying right but the important thing I think about what rich said is

all the stuff that he pointed out could be easily done in humans wouldn't be hard to measure here the nice thing about like the dog examples where we've

got well-known famous long and slow aging uh uh dog breeds and it's true for horses too it's certainly true for mice is that more or less everything slows

down together the tiny dogs that are are very long lived it's not just that they have a delay of cancer they have a delay in neurod degenerative disease of delay and digestive diseases and Joint

diseases aging has been slowed in those dogs and if the dogs did your we might not have an intervention that does that to your point Rich I'm saying I'm saying we

might not have a non-pharmacologic method that does that it's not clear that even though exercise clearly extends lifespan it's not clear that

it's doing so by slowing aging those are two different things to your point it's not clear but it's an interesting question like do you believe exercise slows aging exercise healthy diet sleep

I have no idea I think so would be my my intuition is I think so but I can't point to the evidence that tells me so well there's evidence to support it but it's not the question is does it rise to the level of evidence that would

convince rich I don't know like I I believe it probably does too but I'm not going to you know say with 100% certainty I I think here's where we get back into Health span versus lifespan

the effect of exercise on longevity is pretty small its effect on quality of life is enormous so much depends on where you start and it also depends on

the I I've always found these to be a little bit problematic because I don't think that defining it by the input is as valuable as defining it by the output in other words to say you exercise this

many minutes a week versus that many minutes a week is a little dirty because intensity matters what you do matters sometimes the output is what matters more how strong you are how high your V2

Max is those tend to be more predictive uh because that's the integral of the work that's been done but but your point is I it's well taken like the impact on health span is what I tell my patients

if this if this amount of exercise didn't make you live one day longer the quality in which your life would improve would justify it now fortunately we can move past this sort of semantic uh

discussions uh because there's now molecular ways of checking this exercise as I'll bet all of you know increases an enzyme called

gd1 in the blood of exercise people and in mice and sv's lab has shown that if you elevate gld1 it does great things to your brain more neurogenesis and more

brain derived protective factors brain derived neurotropic factors I also goes up in humans and in mice after exercise it does great things for your fat at least

CL let's leave that up for a moment oh boy oh boy I'm striking all the nerves here today all right you may be quite right I just don't I wanted to stick

with the gld1 and I to make the point that they also go up in in all of the slow aging mice that is all the anti-aging drugs the Cal restricted diet

the isoline restricted diet and five different single Gene mutants that extend L Bane and mice they all Elevate

gld1 17 Alpha estradiol yes Cana floen uh both SE well this is the key question in uh for what I recent um is sex

specific gld1 is in both sexes but this is this is how one begins to answer that that question this is the exact kind of question one has to ask so if you are

interested in the idea that exercise regimes have an a benefit beyond the obvious exercise link physiological declines of age do they improve

cognition and if so how these molecular changes are the things you need to begin to investigate and the anti-aging studies in mice show that the anti-aging

drugs at least the ones we've looked at so far increase the same things that exercise does is Rich have you done this experiment with a CO with an ITP cohort

where you run in addition to a drug parallel n you know what I'm going to ask well you're G to ask if we re exercised our mice right yes yeah we've never done that so you haven't done a sedentary versus exercise have not done

that you haven't done a obesogenic versus fasted we we never use obesogenic diets and I mean it's worth doing it that the ITP doesn't do we don't have

the resources we have enough resources to test about five drugs a year but if we wanted to test them in exercise versus non- exercise we got to get to a budget increase because that will now

get to this question because now we could look at the solu yeah maybe it would maybe it wouldn't so I'm I'm very in in mice I'm very agnostic about what

we can learn from exercising mice because mice are basically kept in a jail cell something the size of a jail cell their entire life if you took a bunch of people and put a exercise wheel

in a gel cell that would use it would that be the same would that substitute for people that walk around to go inside they go outside they go to the gym that do this it wouldn't substitute for all

of it no no question so to me it's a very low of of exercise if you didn't see anything from it then that Ru you wouldn't rule it out right

good so their molecular testable molecular hypotheses that link the biology of Aging to anti-aging drugs and to exercise and teasing out how those

are interrelated uh and whether which of your exercise regimes say increase iin increase gld1 and increased neurogenesis right

that's a research agenda that could be very valuable then if you want to screen drugs in people to see which ones deserve expensive long-term testing the

ones that rais gld1 irin and some aspect of uh neurobiological function in addition to the good the good stuff they're doing for the muscles that's an approach right I I I agree completely

and this gets back to what we were talking about before with the epigenetic changes is if you had a mechanistic connection which is what rich is drawing there yes not only this is correlated

with out with this outcome but here's why we all feel a lot more confident that that this is real right that it's important and especially that mechanistic connection is preserved in

people good do any of you believe that glp1 agonists are gero protective oh I'm super interested in that question I I think we need to find that out it's it's

they look good I think there's two parts though are they jerop protective from a caloric restriction effect or are there caloric independent effects that could

potentially be asking the second question I'm taking the first as a given okay well I yeah that's different question is is chronic caloric restriction beneficial in normal weight

people but most people taking gp1 agonists aren't normal yes and I think it's impossible at this point because the studies are all done in obese and type and patients with type 2 diabetes that we can't disentangle them so we

will just say that for that patient population the caloric restriction appears to be gero protective but yes you're right I'm technically asking the second question which is in an

individual who is metabolically healthy but overweight where there's actually no evidence that weight loss per se is necessary outside of maybe some edge

cases and Orthopedic stuff um is there is there a geroprotective nature to this and where it's most talked about is in dementia prevention right now that's where it's at least most complicated to

tease that out so what do you guys think and it clearly has neurological effects there's effects on addiction right so the dementia connection is not it's crossing the blood brain

barrier I mean Rich this is one for you to tell ITP tested this yet rich is it because the oral ones are just not strong enough and we want to yeah can you break your protocol and do an ITP

with an injection why because it's enormously laborious to do weekly in that sounds like an I need more money problem and

also you need a separate control group because need you get sham injections and our yes if you increase our budget dramatically I think it's a worthwhile

experiment but what we're waiting for um is oral drugs that work that that you don't have to to do um uh injections of drug I mean there is an oral semaglutide formulation that's taken daily submitted

to us this year okay um the detailed protocol however is again technically very laborious each Mouse has to be food deprived for six hours then the material

is administered and then they have to have a a a change in their water balance for the next 2 hours it is technically

not an injection y but it is not any L laborious and in addition you have to have your own separate control group that gets all of those different manipulations with a sham injection

could you do three instead of five next year and make that one of them reallocate some funding well I'm not in charge it's a heavy lift yeah but I would I I'd vote against it I I would

vote for waiting about a year until somebody comes up with a pill that you can just mix into Mouse food or water and give it to the mice and it'll work and these are going to be mice that are an incredible amount of stress from all

the handling the injection yeah that's why the control group is necessary but what what it it the companies are putting so much money into this they understand why people don't like to

inject themselves I I'm reasonably sure I mean I know nothing about it but I'm reasonably sure that in a year or two there'll be some agent that works when

you put it in the food of a mouse or the the poppet as a pill as a person those would be enormously important to test do

we know if tepati for instance were given to people of normal body weight do they also lose 15% of their body weight

question I I have not seen the data on that I can tell you anecdotally having seen patients um it's

going to be dose dependent um so as you know that drug is dosed from as low as 2 and a half milligrams weekly to as much as 15 milligrams weekly usually people who don't need to lose much weight you

know someone who says look I just want to lose this last 10 PBS and I've you know I've done all the exercising and dieting I can do they typically just lose that 10 pounds and they take a very

low dose now to your point if they took the 15 milligrams would they would they become sarcopenic right uh I don't know

but I I think you know this conversation points out again how constraining lack of resources are I mean we sit here and come up with 50 amazing

questions that can't every time I hear Rich talk about this stuff it just pisses me off because there's a bunch of stuff that should be tested should have been tested by now that hasn't been tested not because it's not a good idea

but because there just isn't any resources to do it well I think what's really frustrating as well is that these are the types of experiments that would

allow us to actually start to economically model the impact of these drugs outside of just kind of a disease State um for example if if if drugs like

these are indeed geroprotective and people can work three years longer five years longer because they're healthier think of the impact on that uh over at

om right what does that mean to tax take what does that mean to delaying Medicare what does that mean to reduce Health Care spending at the time when it is

most expensive so boy there's last estimate I saw was 38 trillion a year for every year of health

span wow that's that was a McKenzie report that 38 I'll send you the link not 3.8 NOP 38 that's analysis by Andrew

Scott who British Economist that's bigger than I would have guessed wow um can we just because I'm in the mood to see you get spicy can we just talk

about sence for a minute sent cells he means Rich you know the things that drive aging oh tell me more what do you

mean you want you want me to to talk about sess and cells okay yes I'll be glad to do that it's a it's a terrible historical accident um Leonard hylick way back found that human cells would

only divide 50 times and stop one of his colleagues a a guy named Victoria defendi made a joke at lunch and said to him hey Lynn maybe they're getting old and Lenn did not understand it was a

joke uh he thought it was a serious scientific hypothesis it's clearly nuts because we don't uh get old in a way

that is modeled by having lung embryonic lung fiber blasts stop growing but it at the time the hottest technique in modern medicine was you could grow cells in

culture that was really so cool you could do stuff with them so all the cell biologists who really wanted to use the coolest new toys wanted to have a way of studying aging without all these mess

messy mice and rats and having to wait and stuff they could do it in vitro because this was inv vitro aging this is inv vitro inessence and the field to

skip 30 or 40 years the field um went ahead with this metaphor without ever questioning it it's now such an industry that the people who review these grants and

papers uh and advise billionaires um and advise startup companies they all were trained in Labs that just Essence for a living so they never stopped to question one of the

most famous and best scientists in this area is a woman named Judy cesy who recently passed away died last year she and I were assistant professors together at Boston University and I she and I were going to send in a program project

with a third person Barbara gilchrest uh I was going to study IM immunity and aging Barbara was going to study skin cells we talked Judy you want to study s in essence so she read the literature

she sing came back to us and she said this has nothing to do with aging I me it's good cell biology it's good about cancer biology but of course it's nothing to do with aging and we told Judy of course it has nothing to do with

aging we understand that but the reviewers think it is aging so if you can just keep a straight face for the three hours of the site visit pretend you think it has to do with aging you'll

get a great score and that's what happened she got a great score we got the program project when she moved to Berkeley she took her Grant with her and after a year or two she had a apparently

convinced herself that it was aging it was close enough to aging so the notion that aging is due to ccent cell

accumulation is bad for two reasons it's it's a grotesque oversimplification the evidence for this is awful but even worse it again cuts off productive

thinking there almost certainly are changes that occur in some gal cells in the brain so that as you get older they start making bad cyto kinds B for your brain there probably are changes in some

bone cells or some cells in the lineage that leads to the beta cells in the pancreas that lose the ability to divide and that's bad for you and finding out

how it happens is really important but once you've convinced yourself that's all the same thing this cyto kind this also proliferation this change in uh

ability to make specific fibrous connective tissue let's call that sence it's the same thing you've lost what you need to think of good careful

well-defined experiments with well-defined endpoints if you say that ccent there is a thing called a ccent cell the thing that's happening in this

glea and in this marrow cell and this pancreas it's due to the senescent cell accumulating you've blocked off

productive generation of research hypothesis the last point I'll mention in this rant has to do with

um cenotic drugs so the ITP was asked to test an allegedly senolytic drug called fistin it was given to us by someone who is using this now for clinical trials

and who has a company that's interested in senolytic drugs so we gave it to mice it had no beneficial effect whatsoever at the what's the mechanism

of this Drug's action oh it has no action okay has no action or had no effect what is it supposed to supposed to kill C ccent cells or

something okay um so we told this guy sorry it had no effect he said well let's prove that whether it had any change inessence cells so we gave him

blind tissues from each of the treated and untreated mice and he tried a test and there were no changes in sessen cells by his marker he tried six different markers there were no changes and senescent

cells so then he said well send the brain and the liver and the muscle maybe the senescent cells have been changed in the brain so we blind sent blind samples to a colleague of his there were no

changes in sessen cells by any of the markers that these folks looked at so this drug which is now being marketed in clinical trials and you can buy it I'm

sure as an an natural product um there's no evidence as far as I know that it either has an anti-aging effect or removes siness and cells but once

you've got a commercial company pushing this stuff and your whole brand your whole Lab your whole program project and all the people who are reviewing you are convinced the nest and cells exist

there's they're bad and drugs can kill them it's it's a snowball rolling downhill and uh a rant of the sort I've just delivered has no impact on the

field so can I give a counter example cuz there's good experimental data that there that these things can be at least partially eliminated and when you do

that there's an improvement in health and this has been done both in a genetic treatment which genetically uh which they Prime these cells to be genetically

killed and it's also been done with uh you know with with drugs not with fan I hasten to say so I think there's strong

evidence that getting rid of these p16 positive cells which is really what it's all based on can have an improvement in health and in longevity is the vanerson

paper you're talking about in which they were allegedly depleted yeah let me tell you about that because I was on the program project my job in that program two papers okay one was with was with

the short live mice and one okay so I'm talk about the one that is not the short live mice there's a paper a famous paper by vanerson Kirkland and several other colleagues Darren Baker Baker are these the guys at

Mayo I remember this they they've left two of them have left but yes uh they alleged that they could remove senescent cells by taking genetically modified mice giving them a drug all the ccent cells would go away and the mice lived

longer according to this was on the cover of nature it was on the cover of nature I remember this one I was a part of the program project so was Judy cesy and my job was to do the lifespan

experiment we got the mice from uh Kirkland and V person we got Camp's mice we got the drugs from them and we gave the drugs to the mice at 18 months and

you know they had no effect on sessen cells not one we tried seven times to show depletion of sessen cells by in

their mice using their drug and and went zero for seven we then took the tissues blinded and sent them to Judy's lab Judy C's lab so she could measure p16 cells

but she didn't know which ones were from treated and which ones were untreated when we undid the code there was no effect on sess and cells whatsoever so I

remained somewhat skeptical I asked vanerson had he measured the number of senescent cells in his treated mice no we're planning to do that but what was

the phenotypic change in the mice when you did this experiment oh when I I could I didn't want to do an expensive Lipan experiment with with an alleged anti anti-colitic drug until I knew that

it was depleting sessen so how long did you treat for I used their protocol and we I asked them I asked Darren Baker how what is the dose how long do you treat

the mice and how long after you add the the drug should you wait before you detect the removal of senescent cells and his answer astonishingly was we

don't know we've never looked at that but the nature mice were treated for how long they were a long time long time they were yeah treated I think they started treatment in middle age right and I mean

in the published papers they do show a reduction in p16 positive cells and you're saying you couldn't replicate that in your lab is that but we're conflating a bunch of different issues here we're conflating the genetic model

with the drugs and do so essent cells even exist and I I I feel like I mean I think Rich's skepticism is valid in in many ways um and there's a actually a

large body of evidence that that whether I think whether we agree on the definition of syence what people are calling ccent cells do accumulate in

multiple tissues with age in mice and people and if you get rid of them you can see some health benefits am I convinced they they have big effects on lifespan no I'm not because the data is

mixed and even that genetic model other people haven't been able to reproduce so it's messy um but I think partly maybe start with what is the definition of a ccent cell because that's where a lot of

this confusion comes from right that's what I was saying that there it's there is no satisfactory definition there are many things that satisfactory to you I

mean is your issue Rich that there we talk about it like it's one cell but inity big part of it you can't think about it clearly if you imagine that these many many different kinds of cell

intrinsic changes with potential pathological impacts are all aspects of the same phenomenon but we do that with other things we the mitochondria dysfunction there's lots of different ways to get to mitochondrial dysfunction

so the NIH has just put about $600 million into a network of researchers to study self and Essence and I'm on The Advisory Group for that and to the

extent that rich is saying these are many many different things all pretending to be the same thing that's clearly true they're but they're coming up with bigger and bigger and broader

definitions of what a ccent cell is um but on the other hand there also coming up with more and more interesting things that those senescent cells do in either

in in tissue culture which I don't put much or in mice so you know I don't think the NIH would put that kind of money into something if they didn't feel

there was a valid basis I think part of this is we're is we're calling it sence and I think none of us to me that's stolen a really good word out of the

vocabulary cuz sin Essence just means aging and it used to be you could talk about calendar aging you could talk about syence which is what we now think of as aging and now you can't use this anymore because anytime you do they

think you're talking about these cells that it's an easy analogy is this what they call the zombie cell I keep forget I keep trying to purge that from my memory I mean the most common

definition I think is just an irreversibly arrested cell that doesn't die and typically gives off a pattern of inflammatory cyto kindes and other

factors and which is a catch all for a lot of different ways to get there and a lot of different states that these irreversibly arrested cells can exist in yeah but even neurons they're not

considering ccent neurons and neurons are you know they're post they're post mitotic but they don't always give off this pattern of signals right that's I mean again this is part of the problem is you mentioned p16 I think the even at

the molecular level the the catalog of markers that people are using to define a cell is changing and it seems to changeing yeah so I I agree I agree with much of what you're saying I just don't

think we should throw the baby out with the bathwater here and say there's nothing to this I think there is something to it and I think there's lots of evidence that are are there enough similarities between all the different

classes of senescent cells that people are studying now that they should be categorized as one thing I think that's a valid conversation to have it's a good discussion point I don't think we know the answer yet and they discussed this a

lot in the s because even the sasp even these things that are oozing out of the cells varies quite a bit depending on the nature of

the cell that's the problem of course you you referred to it as almost anyone would as the sasp the setup inessence Associated proteins secretory proteins

and once you think of it as the sasp you've lost because the key point is not to do that the key point is here's a set of cyto kindes that this cell has begun to make that's really interesting here's

another set overlapping probably they make it when you've made them stop dividing for a separate reason that's interesting we should study that but to think you've proven something about this

cell type when you've actually been looking at this cell type because the sasp has been changed but do you think it's possible that a drug such as rapy

has part of its effect on Aging through a broad inhibition of a subset of the sasps by a bizarre coin ents we have oh oh sorry

um I think it's very likely that Romy changes cyto production by many different cell types and that some of those changes would probably have health benefits I would like to know what it

does to the cyto production from the macrofagos in the fat and the gal cells in the brain and cells that are in charge of protecting you from infe viral

infections but the mistake is to say yes it's affecting the sasp it's easy to see um an an analogy if if I said here's a drug and it it helps you

because it affects neurons you'd laugh at me because what you really want to know is is it motor neurons sympathetic neurons parasympathetic neurons neurons

uh in your hypothalamus what part of the hypothalamus the ones that control appetite and I said no no no it affects neurons I've got a drug that affects neurons but I mean people are aware of

these complications and are studying these complications it seems to me that it's the terminology that you object to and I can appreciate that thinking that I object to you the terminology is

problematic because it makes people stop thinking about the important details and start imagining that they've had a thought when they say I have a drug that removes sessen cells it the the problem

is that the words trap you into patterns of thought that are in this case nonproductive and misleading maybe inefficient but the field is making I would say quite a bit of progress and and and I think the way you learn about the complexity is you start with a

simple model you study it and then your model get gets more complicated so I totally get the frustration Rich because I get as frustrated as you are about siness and cells about other things but I think this is also part of the natural

process here and I think what Steve said is really important um yeah the the the the fraction of the ni budget that goes to study the biology of Aging through Nia has remained Tiny But senescent

cells are actually a really good example of how a bunch of people in other institutes are studying aging and they don't even know it they're studying they you know they're studying sence in cancer or syence and

Alzheimer's or sence and kidney disease um so it actually has had an impact in kind of broadening the appeal and scope of the field outside of Nia in ways that

I don't I certainly didn't anticipate do you think that going back to the meta problem at the beginning of our discussion do you think that's um maybe

a better way to think about allocating funds so for example the NCI obviously received the most funding within NIH maybe some of the NCI funding goes to

the NCI to study cancer prevention through Jiro protection right if if the turf war is what matters that's a good idea no no no we've

actually a group of us who are lobbying the the Congress have actually asked the NIH to tell us exactly this how much

work in geroscience is going on in all these other of they're going have to minimize that or maximiz it or

but at least it will give us an idea right now we have no idea how much of the NCI budget is going to this or niddk or anything else so they already have

produced a report that told us how much they were spending in the Nia but we already knew that we wanted to know how much they're spending in the other institutes I mean I think that could alleviate some of the turf war issues

but I think what you really need is you know the the change in leadership and and leaders who actually recognize why this is important and that's where it starts I mean we can have a conversation

about how much power does the NIH director have how much power does the director of HHS have but that's a place to start if you can get people in those positions who get it it's going to have an impact 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 yeah doesn't appear to be in your

mice I I think uh the evidence is UN certain there's a famous paper from banister yes that alleged that uh diabetics on Metformin had lower

survival low lower mortality risks you don't listen to my podcast do you I do occasionally when when actually no you know what it was a different it was a different podcast I did a very lengthy

treaties in a journal Club comparing the banister paper to the Keys paper good and came to the conclusion that the banister paper had too many methodologic flaws to be valid that's exactly what I

was going to say and as a matter of fact Keys Christensen who's the senior member of the group and I have just written a review article which says exactly that you just that's the title of uh it's

under review so yes so you know exactly what I was going to say and I agree completely uh the question is to we metformin would be geroprotective that is a non diabe slow in a non-diabetic

Inhumans I think is interesting unanswered it's not the drug I I would have looked at myself if I had a big set of dogs for instance and I wanted to

give them a drug that uh modified their glucose homeostasis I would probably start with something like canagan that uh actually does work in

mice and which is known to be safe over the long term in people metformin is safe over the long term in people but I don't think there's much evidence that it's anti-aging uh leaving aside how great it

is for diabetics and pre-diabetic what do you think Steve I think it's very promising you know I'm skeptical because I'm always skeptical in the absence of evidence but the observational evidence

ignoring the banister paper just the observational the consistency of the observational data that it reduces dementia cancer cardiovascular disease

suggest to me there's enough smoke there to look to see if there's if there's the keys article and then you can rethink that okay but but sorry Steve you're saying it does all of those things in

diabetic well most the studies have been done in diabetics absolutely and and how much of that is just because you're curing the diabetes is an open question but I think it's and and

how much of that is a selection for people in diabetes that are progressing much less slowly because they're the ones that stay on a single agent as opposed to the ones that progress into right but but which is why you have

to do the study you know the question where is tame in the world of um tame is in a very preliminary State there's now

enough money to get it started previously so it has not it has not enrolled anything yet it's enrolling right now okay previously they didn't want to start it until they had enough

money to do the whole thing but it's been impossible to get that there's now a small amount of money enough to get it started at a small scale with the hope

that that will sort of uh uh start the pot rolling but um yeah it's been around for eight years now and I was in on the

original discussion about do we do Rapa mice and do we do met foran and and it was all about cost and safety that was the whole thing I went in strongly

advocating for Rapa M about I came out saying okay there are these cost issues and I think it was important because when we went to the FDA we want didn't want them to think that we were trying

to make a bunch of money with this trial and um nobody's going to get rich from met foran why is generic is so expensive still I think it's supply and

demand honestly I think they just Haven there's no need yeah I think so but um coming back to the Met Foreman question I mean I I think um first of all we don't know the answer I mean Richard is

right we don't know uh so what what are our opinions my opinion is diabetes probably accelerates bi biological aging and Metformin is effective at reducing

diabetic symptoms and probably reduces biological Aging in that context probably doesn't in people who are not diabetic that's my intuition um and let me push back on that for a second which

is diabetes is um is an artificial diagnosis in that we just make a cut off we say your hemoglobin A1c is 6.5 you have type two diabetes if your hemoglobin A1c is 5.9

you don't but there are data that we've looked at that suggest a monotonic Improvement in all cause mortality as average blood glucose goes down measured by hemoglobin A1c in the

non-diabetic range meaning people with an A1C of five live longer than people with an A1C of 5.5 live longer than people with an A1C of six all of whom are D

non-diabetic point being if metformin's gero protection comes through the regulation of glucose in the patient with diabetes does it stand to reason

that even in patients without diabetes further attenuation of hepatic glucose output is going to improve all cause mortality maybe I I don't know I don't

know the answer obviously um I think the question is is the biomarker in this case A1C what is that actually reflecting right is that presumably

reflecting some some aspect of metabolic homeostasis right and so um first of all does metformin in non-diabetics have the desired effect or

the effect we would associate with reduced mortality in non-diabetics consistently be question number one I don't know the answer to that you you probably and I don't want to speak for near because it's been a while since

we've spoken but I the last time I had near on the podcast his rationale for why Matt foran was geroprotective had nothing to do with glucose homeostasis and a non-diabetic it was and I know

you're going to love this I mean Rich you're really going to love this there was a figure of the Hallmarks of aging and how met Foreman on each of them sure which which is I mean but my point being

not not not to say that that's incorrect correct or anything it's that that there was something much more um Primal about met foran's actions now I here here's my

push back on that metformin requires an organic C and transporter to get into cells as I've learned somewhat recently that muscles don't have so if you look

at the Tracer studies metformin does not get into muscles it gets into entos and the liver it's very concentrated in the liver gets in the gut unclear from these

Tracer studies if it's getting into immune cells so nav chandelle tells me that he believes they are getting into immune cells as well so the the question

is at least I think we need to ask ourselves the question if it's working which cells is it working on and how and so the liver part's easy everybody gets

big concentration of Metformin shows up here we we sort of understand understand that that reduces hepatic glucose output after that I'm sort of scratching my head going I don't know how it works well we know it has a Target in the

mitochondria complex one it inhibits we knows besides that's my point it's not in the muscle that's a question and and we also know that it activates amk yep

uh interestingly a friend of all of our those mechanisms probably related yes yes yes and that could all that could all that all could exp this this is why near points at two of the Hallmarks I

just have to tell you this but here's the interesting thing a good friend of ours George Martin who died a couple of years ago once went through and cataloged all the human diseases he

could and tried to look at the similarities of their phenotypic changes relative to what happens with normal aging he came up with diabetes as having the most similarities to accelerated

aging of any of the groups that he looked at which and it makes the glycosilation the hyper growth factors like igf1 all these things I mean there

there's there's there's logic to that well let me let me agree with the emphasis you were just putting on organ specific and tissue specific changes and

I think it's about time to get away from what does metformin do to the body or any of these drugs for that matter and start to think what does it do to each

of the interesting players and how they talk to one another um someone in my lab has been looking at the enzymes related to denovo lipogenesis and she's been looking at a

couple of different kinds of slow aging mice and it has major effects in the liver and it has major effects on the white and brown atopos tissue and they go in different directions and which is

primary which is reactive whether any of these are related to the effects of the of the of the mutations on the muscle or the brain is now an open question

so having a diagram of Hallmarks which are changed by a drug is much less useful than asking what specific changes in what cell types of which organs that

talk to each other um are being changed by this drug as a primary or as a secondary or as a compensatory effect that's how you'll start to get into first mechanism but also start to be

able to think clearly about ways of targeting therapy so that it has a benefit with fewer and fewer side effects so let's use kagaoan as an example yeah we've demonstrated I use we

very liberally here yeah um you've demonstrated that it reduces all cause mortality in your mice in males in males do you believe and we know exactly what

kagaoan does in the kidney and we know that those mice live longer do you believe that the longevity benefit came through glycemic control because there was no difference in weight if I recall

uh they actually lost weight males and females lost weight on kagin but the question is but was there a difference in weight between so was the difference in weight statistically significant between the long-lived males

and the less and the normal males the mice treated with the drug were lighter in weight than controls and that's true of both SE sees so the

weight loss wasn't necessarily lost more weight in females than in males so the question is very valid and and we do not know the answer sglt2 is on many other

cell types and it's quite possible very plausible that kagal and had an effect principally through controlling Peak daily blood glucose not average but Peak

and it's also possible that it had effects on cells of Unknown Origin in the brain and all of these are very valid and I don't think anyone knows the answer it's well worth EXA

evaluating there are other Inhibitors of sglt2 and sglt1 that have differential cell specificities and differential effects on different cell

types uh and looking at those would help give you glimpses into this question we we guessed it had to do with glucose but we might be wrong so what is your intuition

Steve well going back to Matt foran my intuition is that it might work I you know I don't have a strong opinion it I there's enough suggestive evidence that I think it's worth a trial and I I think

that if we wait until we figure out exactly what each drug does in each cell type it will take us forever to get any therapies and in medicine there have

been many many advances that came about before we understood the mechanistic underpinning and if there's enough suggestive evidence and there's not a lot of side effects suggest me that it's

worth digging into now because the the benefits are so enormous you know like we said one year healthy aging $ 38 trillion that's you know that makes you

know that should talk to Congress and nothing else does well and I would also say tame could be successful independent of whether met foran is effective at slowing biological aging right so

those are not necess getting others into the field you mean the end points right so the end point is multi multimorbidity right or comorbidity right so it's quite possible

that the trial will be successful even if metformin is not a effective ger therapeutic and the opposite is also true right it may not succeed for a

variety of reasons that clinical trials don't succeed I sort of agree with Steve like I'm I'm supportive of doing the trial I also agree I think with probably both Steve and Rich that it's not what I

would pick if I was going to do one trial if we could only do one trial but we have to start somewhere Matt why do you think that the ITP studies for Rapa always worked

regardless of which which start young start old give it with met Foreman do it by itself always worked and the mice are taking Rapa M every day because inhibiting mtor increases

lifespan and slows aging I know what you're asking you're asking because most people who are using rap ay off label have have moved to Once weekly or some

sort of cycling like that and right so I think one question is would that increase lifespan in mice as much or more than daily we don't effectively know the answer to that question I don't

think don't you guys do some intermittent it can increase lifespan but it's never it's never been dose optimized right I think this is the question right is is the metabolic rate

of the mouse so fast that giving the mouse daily wppa is not the same as giving the human daily wppa yes and the wppa in the ITP study it is in the food

so it's not a s it's not even a single dose or it's not a single they're just chowing on it all day well at least During the period day that they're eating and have access to I mean I'll let Rich talk about what they know about

the blood levels but it is a fundamentally way why did you guys decide I mean I guess in 2008 when you or seven when you did the first study

maybe it wasn't clear this idea of mtor One Versus mtor 2 and and the constitutive dosing maybe we should ask how many people at this table actually believe that model yeah that's kind of where I want to go right I want to

understand what we think is true and not true about Rapa based on this experience I guess I don't understand the question do do we believe what model what are you asking that that that the bad side

effects come from M torque 2 offt Target effects of rapy and all the good stuff comes from inhibiting mtor 1 I don't know enough to say many of our slow

aging mice actually uh mtor complex one function is down in all of them but mtor complex 2 is often up and it's up in an interesting way uh mice eat mostly at

night and they qu more or less fast during the day uh in our slow aging mice mtor complex 2 is elevated but it no longer responds in the fast in the

fasting period but it doesn't respond to food in the same way so there're complex changes uh in both its Baseline state and its response to food whether these would happen in people what happen in

people taking it every other day every fifth day whether they are beneficial or harmful or a mixture I really don't know the mtor complex two story is is trickier the other thing that's un that

is I think important but not really appreciated is that it not mtor complex one drugs like Ramy and not only lower the overall effect but it also changes

the substrate specificity so that um the kinas that is susceptible to inh to torque inhibition that looks at a

ribosomal protein S6 that goes down it doesn't work nearly as well it's inhibited but the kyat that for how long um I don't know but the other aspect of

tour Downstream is on a protein called 4 bp1 that's involved in trans ation it does not change that kinas what it does is it changes the total amount of the

protein so the proportion of the Protein that's phosphorated drops down but the actual kinas that adds the phosphate to

that substrate is unchanged so whether that's important that it's having at least two different Pathways that are being influenced in one case by changing the substrate and in the other Case by

changing the kinas no one's really looked at that they say it's a drug that blocks M Torin one function and downstream is where a lot of the actionist I know your lab at one point

was interested in cell type specific Inhibitors of uh the tour complex one I don't know whether everything you just said Rich occurs in what

cell um liver Mouse liver what about muscle well the the overall decline in F in the ratio of

phosphorated versus substrate was also we also published that I think in muscle and kidney I would have to go back to the papers and see whether we also found

the elevation of the substrate the 4 abp1 in both of those tissues I vaguely recall that it was the substrate that changed not the kinas in those tissues

as well but I'd rather look it up before I sort of sign my name to it but even what rich is saying is is wow I mean really important and informative also really only tiny piece of all the

downstream things that mtor effects and I think the point is we just really don't have a good understanding of how rap Ain or fasting or other drugs that

hit mtor are affecting all of the things that are Downstream of of mtor I agree completely let me give you an example so Linda Partridge just published in bioarchive at least a nice paper Rapa mice and increased lifespan for mice if

she added an inhibitor of a different kise called irk it did better it did the inhibition by irk work by itself but it actually improved on rapy so two people

in my lab were looking at that and it turns out that the KK kinas inhibitor is working in an entirely different pathway it's affecting the proteome by

increasing the uh uh degradation uh through a Chevron mediate autophagy mechanism which is not affected by rapy so at least at the dose they used right

at least at the dose they used right that's right sorry what model was this this was M Mouse Li probably black six no we never used black about the

Partridge it was an F1 hybrid actually um so it's agreeing with and amplifying the question there may well be multiple cell intrinsic Pathways some of which are

tour dependent some of which are map KY Earth dependent which can synergize as in the Partridge case for lifespan but also potentially synergize for health impacts yeah and here's here's I mean I

think an important again limitation to what's been done there are drugs out there that hit both types of kineses right there are drugs out there that are that are ATP

competitive Inhibitors that have different affinities for different types of kinases haven't been tested for longevity these dual kinas Inhibitors

right um in fact in the in the um restor bio trial the last one the the the phase three which did not get to completion they they substituted they took the

rapalog out and used an ATP competitive uh drug I didn't know that so what is your belief Matt around um dosing Raa in humans then or even in your dogs you're

doing it in we're doing once a week now we've moved to once a week so I mean maybe it's worth at least talking about how that evolved and this is my understanding of of sort of how we got

to where we are today which is that most people using ramyon off label for potential Health span effects most doctors prescribing it are recommending

once weekly dosing you know in the 3 to six sometimes 8 10 milligram range um so the first place I'm aware of in the

literature where this was um shown to have a potential benefit for anything related to aging was Joan manik's work when she was first at novaris and then

at rest store bio looking at flu vaccine response or sorry yeah flu vaccine response in elderly people um and they were using everus so a derivative of

Ramy and they found that um for vaccine response it was most effective and had the least side effects at once weekly dosing at 5 milligram yeah and they

tested daily one or two migs five migs once a week 20 migs once a week it was once it was a milligram a day five once a week 20 once a week now I've had both Lloyd clickstein and Joan manik on the

podcast it's been so long that I don't recall if I asked them why they designed the trial with those forearms so my understanding is that novaris had

internal data at that point on side effects and had an internal hypothesis that if you let the trough levels bottom out that reduced side effects so that the side effects in organ transplant

patients were largely driven bys High troughs yep and then after that they developed um B based off of David sabatini's work and then Dudley lamming

after he left David's lab a hypothesis that chronic treatment with Romy which maybe would be equivalent to daily dosing in people this was all done in cells led to off-target effects on mtor

complex 2 and it was mtor complex 2 effects that were driving the side effects so that got sort of dogmatized as um the truth and I actually don't

think there's a ton of evidence Beyond those initial papers to support the idea that the side effects are all through mtor complex 2 the idea is if you dose once a week you let the trough levels

bottom out you don't get the of Target effects on mtor complex 2 you avoid the side effects again we don't have definitive data the data I've seen seem consistent with that idea people dosing

daily seem seem to be more likely to have side effects you know mostly things like bacterial infections or the really severe mouth sores but it's sort of anecdotal and I don't know for sure how

strong that data is in in people it did hold up in all of the restor bio clinical trials that I'm aware of that that that once weekly dosing really didn't show any side effects different from

Placebo and in the dog study you're using a slow release formulation correct it's um it's an inic coded kind of it's a different formulation than what the

ITP uses but that all of the human um uh Camus formulations have some way to to get to the small intestine right so it's not substantially different I don't

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 round going to go through a couple of

other ideas I just want to get the what are you thinking about this can we say anything positive about RIS veratrol

no Rich no no why does this thing not die why is there still

100 different resveratrols being sold on Amazon why do I still get people asking me do you take RIS veratrol should I be taking RIS veratrol has a good PR

team I think it's really hard to prove something doesn't work right so once it gets in the Consciousness as as improving health I mean even in the longevity field Jesus Christ I was

saying the Resveratrol stuff was garbage for 10 years before people believed it right now everybody believes it but takes a really long time well at least in the Aging field like I think if you

went like you never see you never see people studying Resveratrol in the the Aging field anymore I think if you went to a conference and asked scientists what do you think about Resveratrol you'd get the same answer here with

maybe one exception um but I think I think it takes a really hard just one exception it takes a long time to

um bad ideas Don't Die Hard that's right and that's true in the scientific lit and it's and it's especially true when there's a profit motive to continue selling this stuff and like I'm not 100%

convinced that there are no health benefits from Resveratrol I'm pretty convinced it there's no reason to believe it affects the biology of Aging or is a longevity drug but I can't say

for sure that nobody would ever benefit from any dose of ratol yeah but we we couldn't say that about anything AG yeah yeah yeah now we could say that if you were force-fed the highest fat diet in

the world such that your liver approached on your lungs through your diaphragm isn't there a chance Rich that under that situation RIS veratrol might help I have no

idea wasn't that the one and only one experiment that worked yeah the famous experiment which was published as ratol the first drug ever found to extend Mouse lifespan it turns out that the

mice die because um they were on a 60% coconut oil diet and it's poisonous uh to the extent that it causes the liver to fill with fat

and compresses the thorax so that they cannot inhale three or four papers later they published as a obscure paragraph and a discussion section on a paper uh

Pearson was the the first author of the second paper that oh by the way all these mice on the coconut all dieet finally we've looked at them they're all

dying because of lung compaction due to uh expansion of the liver um so the notion that their drug had slowed aging

because on the 60% coconut our diet it temporarily extended lifespan was due to the prevention of this extremely bizarre

phenomenon I I just cannot get enough of that story and um all documented believe I know it well two separate papers all right let's have a

word on NAD NR nmn uh Steve what is your point of view on this well the current state of evidence I I'm I'm skeptical IAL it's one of those things that makes

a great deal of conceptual sense but the evidence at this point is not very compelling and we have the ITP evidence that is I think the strongest uh and

there was strongest negative evidence yes yes just to make it clear I assumed it people knew that I guess I did okay

so and is it your view Steve that well this stuff probably does not extend lifespan you know but maybe there

is some other health span benefit out there that is just not been studied the right experiment hasn't been done it hasn't been powered correct you know pick your favorite excuse I think NAD is

is is very very interesting molecule and I don't think we could throw out you know manipulating NAD as something that could be important for aging I just think the evidence is there at this point do you think if you're going to

manipulate it you would have to do it with really really high venous doses or do you think you could achieve those levels using oral precursors that I don't know I will

Express complete ignorance on that Matt what is your point of view on all of this yeah well I think the way you framed that that question to Steve is indicative of why it's so hard to disprove something especially when there

are people out there who have money to make who really want to want to you know make the case that you should buy this stuff cuz it's always possible that there's some some way that this could be beneficial having said that NAD you know

like Steve said Central molecule in thousands of chemical reactions really important good reason I know about good reason some reason to believe that NAD homeostasis declines with age like lots of many other things so it's plausible

that if you fix that you can get benefits from it the data is decidedly mixed both in the literature uh pre-clinical literature and in people as

to whether or not boosting NAD increases lifespan improves Health span um so I think there's lots of issues here what's the most positive d you would point to well for lifespan the original study by

Johan A's lab where they started treating I think at 20 months of age was published in science I believe um showed an effect that was reasonably good sized except the controls were short which is

a different issue yeah it's different issue right you see a lot of there there a number of cases where something was reported to increased lifespan when the controls were short-lived and then when

when the study was repeated and longer lived controls you didn't see an effect so I don't know why they I don't know why there was a difference between that study and the ITP but that's probably the best case you can point to there's

studies in cagans as well that were where NAD precursors increase lifespan so there's evidence out there and again it's a plausible the biolog is plausible um but then I think when you talk about

the precursors you know it's even more complicated than maybe boosting NAD could slow aging because can you get the right doses in people you talked about bioavailability is is there any

difference between nmn NR nasin nicotinamide and when you take it orally the data suggests that it all gets broken down to nin in the gut so why are

people taking you know $70 yeah why are people selling it the people who are selling it who some of them are scientists Dodge that question

I mean it's it's complicated I don't personally believe there is enough evidence to to think that NAD precursors as are being marketed today are likely

to benefit most people some people probably people who have um conditions of disregulated NAD could get a benefit I don't think there's any

difference between the the various molecules that are being marketed right now and there's at least one study in mice that giving nmn to aged mice causes kidney inflammation and potentially

kidney pathology so there's you know I'm not saying n mn's dangerous but when you try to weigh the risk reward you know if it if it causes kidney pathology in aged mice at least at high doses could it do

the same thing in dogs or people yeah it could um and it bothers me particularly in the companion animal space that people are marketing nmn for people's

pets when they know that it might cause kidney disease in people's dogs and cats that's problematic to me we talked briefly about parabiosis and plasma FIS

let's come back to it a little bit so Steve is there going to be a day when the substance found in the blood of someone much younger than you when

infused into you whilst some of your old blood is removed is going to assuming we figure out at what frequency that has to

be done impact your life yeah I I think this is an incredibly interesting question and it really deserves to be investigated in detail because if it's

true it's it's a real game Cher because we do transfusions I mean this this is not exotic medicine I think we very much need to know whether this works the same

way in people and also it would be nice to know how much of it is due to the the taking outus how much of it is getting rid of the oldwood but the evidence from

mice is very very compelling I think Steve if we could design the perfect experiments that would try to ask these questions and let's just say we started by doing the one experiment which was the full parabiosis so the putting in

the taking out we didn't try to disentangle the effect um and there was no benefit in humans MH what would be your best hypothesis as to why it would have failed assuming it was

statistically powered correctly and there was no methodologic error if if if if this was a biologic result why would you think given how favorable this has

been in mice it would not occur in humans that the products that in Ed up in the circulation of humans was a very

different nature than in mice I mean uh you know the number of things that differ between humans and mice and blood would be enormous so pinning it down

would be but I think there probably uh is some reason to suspect that it may work I mean I you know I I'm very Ian if it does work this is a an opportunity

that I mean should I mean this is not like we had the technology to do this 50 years ago right right and and it may not work in young people right but it may work in older people I think there's a

lot of drugs that could affect aging that because young people haven't aged as much might not have minimal effect you give it to somebody you know 50 years later might have a big effect I I

think that the I find myself frustrated by the question ra ra rather than by the answer because you got a horrible question ask here rich is the problem I think you are well above average but

this particular one I think is illustrative because the reason like people like parabiosis is that they've seen it in a Sci-Fi movie it sounds exactly like what you do in sci-fi and

they're sure flashing lights and it's so sexy and it's just so great and you can take the blood of young virgins virgins and give it to old people and they stand up and they can get on the I didn't

realize they had to be virgins way so but none of that is pertinent is is there something that is in the blood of old people that it would be good to

remove and if so what is it and is there something a cell a molecule a set of three molecules that's in the blood of young people or mice that would be good

for you the only purpose of the the only virtue of this parabiosis uh circus is to suggest that you know the answer might be yes there

might be something you could remove from Old Blood a cell or more or some plasma molecule and there might be something good in the blood of young individuals

so the challenge now is to find out what those things are and then you can do real life science real life science is not done by taking blood from young

people or and putting it into old people it's that's medieval science where it's a complex mixture of dozens to hundreds of potentially right but that could be

the proof of principle right in other words you might start with that and no one thinks that if you do that experiment where you literally take blood out of an old person and discard

it and take blood out of a young person and you know put it in and you get a favorable result nobody thinks that that's what's going to the FDA that is the proof of concept experiment would be

worth what experiments you have a limited amount of volunteers doctors and money what experiments are most informative and in my view by far the most informative experiments are what is

in the blood of young mice that is so good and what is in the blood of I don't know would you want to go on that fishing Expedition until you at least saw a signal in the people are doing it I mean there are companies of course

they are doing of course they are I'm asking a different question though which is yes that's the only way you can turn your idea into science well on the other hand if it has if it has a positive

effect I don't think it really matters that's something to be investigated later my thought is it's not simple it's not one thing it's not gdf11 for sure um

if it were simple there's enough people looking at it they would have figured it out my guess is some combination if if there's something there there's some combination like I mean why can't you do both I I I I think Peter and I are saying the same thing like I think would

we love to to understand the mechanism yeah absolutely do we have to understand the mechanism to figure out whether it works in in people no and if it works great that's a win too I think richest point is we only have so much money

let's spend it on figuring out the mechanism but that's a again that's a fundraising issue I yeah it's a scientific question if you have a choice

I mean the ITP loves to test in individual chemical compounds even sometimes ones where the mechanism of action is not known and that's very sensible we are very dubious about let's take a little of this and a little of

that a little of that and we're really dubious about taking let's grind up the asparagus who knows what's agree and yet you guys have tested natural products where we have no clue what the mechanism is or even metformin you pointed to

complex one inhibition yeah that's one thing metformin does and it might activate that mean say know the mechanism exactly of each drug what I'm saying is that if you have a very

complex mixture of hundreds of molecules and something happens you don't know what to do next because it could be any one or two or eight or 10

of those and you haven't really decided you you have troubles then with standard Iz ation with mechanistic tests and with transferring to a key species like my

thought is we still wouldn't be using anesthesia if we had to wait figured out how it worked yeah I I I mean I think and and it doesn't have to be parabiosis

it doesn't have to be you know taking blood from from young people and putting it into to old people right there are other variants of this that can be done clinically and there's some evidence to support things like therapeutic plasma

exchange or or things like that so should we test it I think so and my gut feeling is yeah it probably will have some benefits you can only do one

experiment would you do a plasma FIS experiment and if so what would you like would you test I

mean the simplest one is you literally just exchange old plasma for albumin right that's that's what they're typically doing in these studies yeah I mean I don't first of all I don't know

enough about this area to be confident in my answer but yeah that that's probably where I would look to start simply because it's going to be logistically easier to do from a

clinical trial perspective so but but so so scientifically then the hypothesis is it's the presence of something bad well it's both that is worse than the absence

of something good I don't know the Alum is not going to give you the young person problem with that experiment to me we don't know now we don't if it's

young blood is good old blood is bad or some combination we would automatically if we only did the plasma foris we would only be testing part of that I push back on that I think we do have reason to

believe it's a combination of both there's data in both directions so so that's why I proposed starting with I think that's again as much as anything's sure in this field it's not that's not

as sure as Rapa increases lifespan in mice but there's at least evidence to support that idea right and the last thing I'll say is you you mentioned you asked why might it fail in humans I think Steve's answer is

is is valid um it's also worth mentioning at least with the parabiosis experiments the the parabiosis experiment itself shortens lifespan in rodents and

so the parab just the the fact that you're surgically connecting these animals together so it may be that the benefit from parabiosis true parabiosis in that context is somehow related to

the shortening of lifespan due to the procedure I don't think that's the case because there's other L of evidence that argue against that but there may be something about the procedure itself

that is increases muscle repair and improves cardiac function it just seems to me that's you know I agree I'm just saying that may be an alternative explanation for something that's limiting in those

Mouse experiments just seems like there's not enough time and not enough money to do the work hopefully some of that's changing

um if we were to do another long round table next year which is problematic CU this table I mean you guys are going to have to get awfully cozy um any

nominations for folks you'd want to invite to a longevity round table next time there's so many people we could we could do this with right and I'm guessing nobody wants to give their seat

up next year to make this table bigger I think it would be good to invite VM glad because I think even though I

disagree with some of what he says I think he always has something interesting to say who's your nominee i' need some more time to think about it mat anybody jum

mean I think I think we would all agree there are tons of great people in the field I mean uh I think Brian Kennedy and I think Brian's going to be on your podcast in an upcoming date is somebody

who also thinks broadly and deeply about the science and is fantastic so he would be great to have it would be great to have some different I mean we differ sometimes on opinions but I think more

or less are aligned be interesting to have some differing voices as well all right so we think we'll do another longevity Round Table around the oval

table sure let's do it let's see where we are a year in a year from now I think there's going to be a lot of new stuff that's that's that's what's new in aging research the pr rate of progress the

derivative is very much positive you know who else I want to throw out there is Morgan LaVine I think she'd be really interesting to have because she while she is an expert in epigenetics and

biomarkers I think takes a pretty cleare eyed view of that space now is Morgan at Yale still she's at alos she's at Al okay I wasn't sure if she was there full-time got it okay yeah I would

second that that's an excellent idea all right well Rich you can get back to me on your your nominees as well I will definitely do that all right gentlemen committee onto this and I'll

get back to you thank you it was fun fun all right guys thank you [Music]