Rapamycin for Longevity? with Dr. Matt Kaeberlein

I'm so delighted to have Dr Matt Kaberlein , who's a professor at the University of Washington School of Medicine . Matt , thanks for joining us today . Sure , thank you . It's a pleasure to be here . Before we dive in , maybe you could tell us a little bit about your background and how you came to be interested in this fascinating space .

So I went to MIT where I did my PhD , and during my first year at MIT I heard a seminar by a professor there named Lenny Guarente and he was talking about how his lab had , just within the last couple of years , started studying the biological mechanisms of aging .

And I don't to this day I don't really know why that resonated with me , but I was so fascinated by the idea that you could use genetics and molecular biology and biochemistry to study something as complicated as aging that I went and I talked to Lenny and ended up joining his lab for my PhD thesis and really haven't looked back .

And so you know , the specifics of what I've been studying in my own work have evolved , I would say , over the you know , the 20 plus years since I heard that seminar .

But it's all been related to the biology of aging and you know , I would say the one thing that has changed is back then I was young enough that I didn't really appreciate the sort of personal importance of this .

But I would say that as I've gone through my career and gotten a little bit older , I have also transitioned my interest into , you know , maybe a little bit more of the immediacy , of what can we do about the biology of aging in people to improve healthspan , hopefully lifespan , but really , you know , keep people healthy as long as possible by modifying the aging

process in a positive way .

Was it you guys were just especially smart guys , or was there the timing was right , or what was the magic sauce ? Do you think ?

But I knew Brian , he was still in Boston , we interacted . David was in the lab at the time . Heidi Tissenbaum , who went on to do some really important work , was in the lab at the time . Brad Johnson , who went on to do really important work , was in the lab at the time .

So there are all these really creative and smart people in this environment that was , you know , a little bit competitive , very supportive as well , and it was that mix . I think that really had an impact on me .

And it was also a time in the field when , you know , the field was growing rapidly , new tools had come online that , for the first time , really allowed people to do true mechanistic molecular work and identify some of the foundational mechanisms around the biology of aging .

So I think it was a combination of all of those things that you know that allowed several of us to really become immersed in the field and go on and have successful careers and , I hope , my careers .

I would like to think that maybe my biggest successes aren't behind me , but I think it was a combination of all of those things that allowed several of us to make a mark . But I think we also , because of that environment and because of where the field was at at the time , we got hooked and stayed in the field .

I think oftentimes you'll see people as graduate students who go on and do something completely different when they get to their postdoctoral research and their independent careers . Several of us who were in Lenny's lab around that time stayed in the field and didn't go work on something else , and so that's probably part of it as well .

I truly wish I was 25 , 30 years younger and coming into the field now , because I think the opportunities to make , you know , just amazing discoveries that are of high impact . You know they're almost unlimited right now , and so it's a really , really exciting time to be a young person coming into the field and doing science around the biology of aging .

And it's very interesting because there's no clear consensus from the experts . Everybody has a slightly different take on it .

I think it's important to recognize that , that , that the word aging means different things to different people , and so oftentimes I think it's important to recognize that the word aging means different things to different people , and so oftentimes I think the disagreements that come up around is aging a disease ? What is aging Really ?

You can track that back to how the individual person is defining aging right . So I try to be precise in my language and talk about biological aging , because that's the way I think about it . You know there's chronological aging , which is just the passage of time that's pretty easy definitionally to agree on .

But biological aging is something different and I think of biological aging as the physiological processes , molecular biochemical processes that result in at least a permissive physiology as we get older , for all of the different functional declines and diseases that go along with old age . And again , I've tried to be precise .

I'm not saying necessarily that biological aging causes cancer , alzheimer's disease , heart disease . I think it does to some extent mechanistically , but you can argue about that because we really haven't proven that I don . It does to some extent mechanistically , but you can argue about that , because we really haven't proven that .

I don't think you can argue about whether or not biological aging creates a permissive physiology for all of those functional declines and diseases . And given that , I would say that biological aging is really where we should be focusing our attention if our goal is to keep people healthy as long as possible . So that's kind of the way I think about aging .

Now , what are the mechanisms of aging that ? I think the reason why there's so much disagreement or difference of opinion is we really are still figuring that out right . So I think it's important to appreciate .

In the last 20 , 30 years , scientifically we've learned a lot about the mechanisms of aging again molecular , biochemical , genetic mechanisms , but we've also really only scratched the surface . So we've gotten to the point where we can put some names to these things .

I'm sure many of your listeners are familiar with the hallmarks of aging , and really the hallmarks of aging are just sort of a set of nine or 10 , depending on who you talk to conserved processes that seem to be related to the biology of aging in every animal where we've looked , and so we can put names on these things .

These are things like DNA damage , telomere shortening , epigenetic changes , senescent cells .

Those are aspects of biological aging , but there's a lot that we don't understand underneath the hallmarks and , I would argue , also outside of the hallmarks of aging still yet to be figured out , and I think that's why you get differences of opinion or disagreements over what is aging , what causes aging , and that leads to some of the different theories that you

alluded to , like hyperfunction , rate of living theory . Right Again , I think we don't know enough to really be able to say with a high degree of confidence you know , why did aging evolve , how did aging evolve and what are all of the underlying mechanisms that are associated with biological

aging ? There's a lot to be learned . The last thing I will say on that , though , is we don't have to understand everything about biological aging to be able to have an impact on it .

I think we know enough today that we can start to develop and test interventions that modify the biology of aging in a way that we predict will keep human beings and , potentially , companion animals , healthier longer by targeting the biology of aging , slowing it , maybe even partially reversing some of the aspects of aging , so I don't think we have to understand the

whole thing in order to be able to have an impact on it .

If we come up with interventions to improve longevity and aging , we should expect to see those interventions applied not only to the phenotypes of aging and improvement , but also by the chronic diseases that determine longevity . So and we'll talk about that in a moment- as we get into one of the drugs here .

So there's really shouldn't be any debate about whether the biology of aging exists and whether it's modifiable . We already know you can do that . You can do that through exercise , you can do that through nutrition , right . So so I think it's , it's . It's .

There's a little bit of a disconnect and and and some people just want to argue , right , but but I don't think we need to argue about this . This is a this is a solved question whether or not there is a biology of aging .

I think the other way to think about it is you can also just look across the animal kingdom If you're at all skeptical that there is an underlying biology that regulates the rate at which animals age . Just look at dogs , right ? Everybody is familiar with the idea that , you know , one human year is about seven dog years .

All that means is dogs age about seven times biologically faster than people do . They get all of the same diseases of aging that we do . They're all age-related . In dogs they get all of the same functional declines that we do . It just happens about seven to 10 times faster in dogs than it does in people , and that seven to 10 depends on body size .

So there's clearly this biology of aging and it is determined by genetics and environment . And if we can understand what those genetic and environmental factors are , we can modify them in ways that will improve aging trajectories , keep people healthier longer , probably alive longer as well .

Mtor M-T-O-R actually stands for mechanistic target of rapamycin , so they named the protein after the drug . So rapamycin inhibits mTOR . So I think really the question to answer is what is mTOR and why is it important ? So mTOR plays this fundamental role in every eukaryotic cell that we know of .

So , again , for people who maybe haven't taken biology for many , many years , there are bacteria , which are typically prokaryotic cells , and then there are eukaryotic cells , which are all the cells in our bodies and in all animals .

So every eukaryotic cell that we know of has mTOR , and mTOR plays this fundamentally important role , or one of its roles is in sensing the environment and then helping the cell or the organism make a decision about whether the environment is suitable for growth and reproduction , and one of the main things that mTOR senses is nutrient availability in the environment ,

and so , from an evolutionary perspective , this is really important . Every organism that has ever existed , has had to do this , has had to sense the environment , sense how much food is available , and then make a decision is it a good time to grow and reproduce or not ?

And when there's lots of food around , from an evolutionary perspective that's usually the successful strategy is to grow as fast as possible , develop , reproduce because you want to have babies when you have food to give them . The flip side of that is , when there's not much food around , it's a bad decision to have babies .

And so what mTOR does is it senses the amount of food in the environment and then , when there's lots of food around , mtor gets turned on and that tells the cell in the organism okay , now's a good time to grow and reproduce . Mtor gets turned down and that tells the cell and the organism okay , we need to shut down growth and become stress resistant .

And the mechanisms are pretty well known for how this works , but fundamentally that's kind of the important gatekeeper role that TOR plays

. So rapamycin is this drug that tells TOR to get turned down , to sort of ignore the nutrient sensing cues and get turned down regardless of how much food is around , and what we and many other people in the field sort of found out many , many years ago .

This was back in the early 2000s when several of us sort of independently and in our case , accidentally discovered that when we turn down TOR we increase lifespan .

And at that point Brian Kennedy and I were working in yeast , pankaj Kapahi was working in flies , a couple of other labs were working in C elegans , and all of us independently found out that mTOR was this really potent regulator of lifespan in all of these different cellular and animal models .

And then , around 2009 , a study from the Interventions Testing Program showed that turning down mTOR in mice and in that case they used rapamycin was enough to increase lifespan in mice .

So this picture emerged that across a very wide range of different organisms , from single single cell budding yeast all the way up to mammals like mice , you could turn down mTOR and that was enough to increase lifespan and in mice .

What we've learned since then is you can do this starting in middle age which is really interesting and we can talk more about that and that you're not only increasing lifespan , but in pretty much every tissue and organ where scientists have looked , you can improve function during aging .

So it's not only that they're living longer , but you're actually maintaining function of tissues and organs much later in life , and what's really exciting to me is that in at least some cases you can reverse functional declines that have already happened with old age .

So in my lab we've shown this in the oral cavity , we can reverse periodontal disease with rapamycin in mice . Others have shown that you can reverse immune dysfunction age-associated immune dysfunction in mice . Others have shown you can reverse ovarian dysfunction . Others have shown you can reverse cognitive decline .

So and I keep saying others this is the other great thing about rapamycin and mTOR it's not one lab , it's not only one lab doing this work .

There are dozens of different labs around the world who all get the same answer , and so that provides a lot of confidence that this is a real and robust effect that is highly reproducible , and you know , having been in this field for a long time , I'll just say that's often not the case .

With a lot of what gets popular attention , it turns out to not be highly reproducible . Everybody agrees mTOR and rapamycin is a robust and reproducible target to modify the aging process in a positive way .

And so other things in that nutrient and growth promoting network include things like insulin , like growth factor , one growth hormone , insulin , foxo , transcription factors . There's a bunch of important factors in this pathway . It just turns out that some of them seem to be more amenable to modification in ways that have a positive impact on healthspan and lifespan .

And mTOR seems to be a particularly good node in this network to tweak , to positively impact healthspan and lifespan . And mTOR seems to be a particularly good node in this network to tweak , to positively impact healthspan and lifespan , at least in laboratory animals . Now you're asking why wasn't it discovered ?

Or at least in the context of aging , wasn't discovered till the early 2000s , and even before that was sort of understudied , you know , in the sort of broader biological world I mean , sometimes that's just the way these things evolve , right ?

So part of the reason why mTOR became highly studied and we learned a lot about mTOR , was because of this accidental discovery of rapamycin , right ?

So again , and people I think a lot of times the general public doesn't appreciate how much of science is serendipity , right , it's not so much that we are really smart a lot of the times and go find the answer , it's that you know we're doing experiments and something unexpected happens , and it's those unexpected things that then lead to the big discoveries .

And so this molecule , rapamycin , was discovered . Nobody knew how it worked , but what was observed was you put it on cells and they stopped growing . And so people thought oh , that might be a really useful anti-cancer drug or a really useful antifungal . I wonder how it works .

And so people started doing biochemistry and genetics to figure out , when we put rapamycin on these cells , why do they stop growing ? And that's how people identified TOR . And then , once TOR was identified , then many , many labs started studying it and we learned a lot about how it interacts with all the other players in that network .

And the same thing was true with discovering that TOR and rapamycin were important for aging biology . You know , at least in our case we were doing what's called an unbiased genetic screen for factors that influence lifespan . So it's not like Brian and I went into this thinking , oh , tor must be really important for aging .

It was because we had a tool that allowed us to look one by one at individual genes in the genome and ask which genes affect lifespan . And we got lucky that in the first 500 that we looked at , tor was there . If it wasn't , it would have taken us longer to figure it out , but TOR happened to be in that first set of 500 .

And we saw that when we turned down TOR , all of a sudden the lifespan was extended . And then I was like well , what's TOR ? I didn't know anything about TOR and it turned out there was this drug , rapamycin , that inhibits TOR , and well , maybe rapamycin would have the same effect .

So you know , it's really this serendipitous sort of process that led us to discover that rapamycin could increase lifespan , and I think that's probably true for these other labs that we're looking at mTOR and rapamycin as well around the same time .

I would say again , you know there's a little bit of debate about to what extent does rapamycin mimic caloric restriction . So here's the way I think about it . They are overlapping but distinct interventions . So we know that one of the most potent things that caloric restriction does is turns down mTOR , and this gets back to what I was talking about before .

Mtor is a nutrient sensor . So when people or animals fast or are chronically calorically restricted , mtor activity goes down and we know rapamycin turns down mTOR .

The difference , I think , arises from the fact that caloric restriction does about 10 million other things in addition to turning down mTOR , from the fact that caloric restriction does about 10 million other things in addition to turning down mTOR , while rapamycin is a very specific mTOR inhibitor .

Now there are lots of effects of rapamycin that are downstream of mTOR , because mTOR regulates a bunch of stuff . But caloric restriction in some ways is what I would call a much dirtier drug . It has many , many other effects that rapamycin doesn't have and I think it's still an open question .

You know to what extent are the effects of caloric restriction on lifespan and healthspan in laboratory animals due to inhibition of mTOR versus non-mTOR effects . And then there's this interaction between these other things that caloric restriction does . That happens in the context of mTOR being turned down and that still hasn't been figured out .

I think there are a couple of things to say about caloric restriction and fasting , though , that most people don't appreciate .

So caloric restriction is definitely the most robust , and by robust I mean the largest effect size intervention for increasing lifespan , and you could argue healthspan a little bit , but I'm just going to make a blanket statement that's not completely precise that caloric restriction improves health span . In laboratory animals as well , it has the biggest effect .

I don't think anybody would argue that for non-genetic interventions you can get up to about a 60% increase in lifespan in mice if you restrict calories by 60% . What's often not talked about or appreciated is in about one third of genetic backgrounds where caloric restriction has been tested , it has no effect on lifespan or actually shortens lifespan .

So there's a genetic component to whether or not and again this is in mice whether or not caloric restriction increases lifespan . The fasting sort of myth that people don't understand is , in laboratory animals at least , fasting only increases lifespan if the animals are also calorically restricted .

If you do intermittent fasting in an isocaloric setting , the impact on lifespan is somewhere between zero and 4% , so it's tiny . So there's this idea out there , popularized by certain people , that intermittent fasting is universally going to be good for health in humans .

I think intermittent fasting is a very useful strategy for some people to lose weight or maintain weight . It's unclear whether or not intermittent fasting , in the absence of caloric restriction , does anything in laboratory animals or will do anything positive in humans . That's my personal view of the literature .

But it just unfortunately gets communicated in a very misleading way , I think often for the general public . This idea that intermittent fasting is this really potent way to target the biology of aging that's only true in laboratory animals if you also restrict calories by between 30 and 50% if you also restrict calories by between 30 and 50% .

to people using that for humans ? Obviously more work needs to be done , but why aren't more people aware of the potential of this drug ?

I think we could talk , we could probably spend an hour talking about the data around that , but we don't know for sure , right , there haven't been double-blind , placebo-controlled clinical trials , or at least very many of them , to try to answer those questions . So there are really two things , I think , that have been barriers .

One of them is that rapamycin in the clinical world it goes by the name sirolimus or rapamune has sort of a bad reputation because of the way that it was developed and approved by the FDA . So rapamycin again sirolimus is an FDA-approved drug .

It's been approved , I think , since 1997 , something like that 20-plus years and it was approved as an organ transplant drug . So at high doses drug . So at high doses , daily doses , rapamycin will help patients who have had an organ transplant in combination with immunosuppressants , not reject that transplanted organ .

So that's how it's been used and in that context , there are a long list of side effects that go along with taking rapamycin . So it has sort of a bad reputation among clinicians and it has a bad reputation at FDA as a drug that has lots of side effects .

So I think that's been one of the real barriers to people even psychologically thinking about rapamycin as a drug that healthy people or healthier people , people who are aging normally maybe let's say not organ transplant patients might take to modify their biology of aging in a positive way .

There's a lot of pushback against that because the gut reaction is that's a dangerous drug , right ? So I think that's one . That's one thing .

The other thing is that it's really , you know , in the timeline of scientific discovery , fairly recent , that we've learned about these effects of rapamycin on healthspan and lifespan , even in laboratory animals like mice , right . The first study for lifespan was 2009 .

I think the first study showing that you could increase lifespan with a short-term transient treatment with rapamycin came from my lab and that was in like 2000, . I should remember this 2016 maybe , when that was published . So you know , in the timeline of science , this is all happening really , really recently , so it's only started to become appreciated .

You know how widespread , the effects are in different tissues and organs and that you don't necessarily have to start taking the drug as a teenager if you were a person , and we extrapolate from mice to get some of these effects .

So we're learning a lot in the last few years and there are probably now you know somewhere between a thousand and 10,000 people around the world , I would guess , who are taking rapamycin off label for potential effects on healthspan and lifespan , and I know you've been involved in trying to collect information from some of these people .

I've been involved in that as well to start to try to learn Anecdotally it's going to be imperfect data but start to try to learn . What are the real side effects look like ? What do maybe the real benefits look like for people who are taking rapamycin with the idea that it might have a positive impact on their health span ?

I think that's what's really important , so I would put those in the category as well . How well are you functioning ? And there's a variety of different organ functional measures that you can do . There's physical functional measures , so I think the answer to your question , though , is , conceptually , yeah , these things can be really useful .

What we don't know yet is what are the best set of biomarkers to put into what I think we all would really like , which is an integrative clock that is telling us overall how well is somebody aging at the moment and maybe , more importantly , how well are they going to age in the future ? So it's pretty early days with these clocks .

I'm not convinced yet that we have biological aging clocks that are actionable , and by that what I mean is what I would really like is a test that I could take on myself or give to someone else and say if you take rapamycin and it moves the needle on this test up or down , that's a good sign and you should keep taking rapamycin .

If it doesn't do that , that's a bad sign and you should stop taking rapamycin . That's what we really want , right ? We want actionable tests that will allow us to make personalized recommendations for people to get them , on the , you know , something closer to their optimal aging trajectory .

I don't think we have that yet and I think , you know , in some ways the marketing has gotten ahead of the science . Where you can , there's a bunch of these direct to consumer biological aging tests that people can go buy . I don't have a lot of faith in any of them right now that they're actually telling you information that's useful .

I think we'll get there , but I think it's a little . I think if we're still a little bit early to know which of these tests are going to be most informative .

That's something I'm working on right now , and I'll probably be working on it for the next couple of years , is trying out some of these different biological aging tests and trying to get closer to some sort of you know integrated signal that I feel confident about .

I guess acute stress can be good for longevity , but chronic stress shifts our bodies from growth to protection and that seems like that's opposite of what we want to do with mTOR . Does that ring any bells for you ? It's a little bit off topic but I think so .

of different things . So when we talk about rapamycin and turning down mTOR , inducing a stress-resistant state , what we really mean is that , at least for certain types of acute stress , it makes cells , organs , tissues , less likely to be damaged by the stress , right ? So stress itself isn't a bad thing .

It's the consequences of stress and the damage that it does to organs and tissues and cells that lead to the functional declines and diseases that we associate with chronic stress .

And so I think that we have to appreciate that turning up protective mechanisms that make cells more resistant to stress is part of the chronic stress response , but it's not the only thing that's happening , right ?

So when you have , for example , you know you're constantly exposed to radiation let's just say you get exposed to radiation your body , your cells are immediately going to turn on a protective response that helps keep those cells , to the best of the cell's ability , from being damaged by that radiation .

But if you keep being exposed to more and more radiation , eventually you're going to overload those protective responses and then you're going to accumulate damage . So the stress itself ultimately is what's going to drive the damage . But it's only when you overload the protective responses .

Rapamycin in some ways turns up the protective responses , but you don't necessarily have the stress itself driving that response . So one way to think about it is you're preconditioning maybe the cell and the tissue to be more resistant if it gets hit by the damage , before the damage gets there .

That's sort of hand wavy , but I think that's part of what's going on . But again , I think , and there are a variety of different types of stress response mechanisms and I certainly wouldn't want to suggest that rapamycin is turning up all of them , right ? So I think we have a lot to learn about .

You know which protective mechanisms are being affected by mTOR and which are mTOR independent . And how does that integrate with , you know , longevity and aging , with you know , longevity and aging ? There's again this goes back to what I was saying before there's a lot we don't understand , a lot to still be figured out .

And even this idea of inflammation , I think , is complicated , right ? So you know , we know that with aging there is an increased amount of what we call sterile inflammation , which I think the easiest way to think about that is your immune system reacting to stuff that it shouldn't be reacting to .

So we need our immune system , we need inflammation to respond to infections and things like that . But with age , we get this dramatic increase in sterile inflammation , which is your immune system responding to things that it shouldn't be responding to , and rapamycin is quite potent at knocking that down . So that's a good aspect of what rapamycin does .

If you have too much suppression of inflammation , though , so that's a good aspect of what rapamycin does . If you have too much suppression of inflammation , though , that's where you get into the realm of immunosuppression , which is what rapamycin is used , as in organ transplant patients .

So there is this balance and this dose response , with stress resistance and anti-inflammatory effects , where you know there's a sweet spot where we would want to be . That gives you the benefit without so much of the detriment .

But we don't know exactly where that is , and if you push it too far , you may get into the point where you're actually having negative effects in addition to the positive effects . I think that's true with inflammation and immune function . I think that's also more generally true with stress resistance .

Telomere shortening is one of the hallmarks of aging , clear evidence that people who are under high levels of psychological stress tend to have shorter telomeres .

You can find many other connections where it seems clear that psychological stress can accelerate to some extent the hallmarks of aging , which is consistent with the idea that they're biologically aging more quickly . And when you think about it , that's not shocking , right ?

Again , we know that people who are exposed or experience high levels of chronic stress throughout their lives tend to have a variety of poor health outcomes later in life , consistent with the idea that they're aging more rapidly . So there are absolutely those connections .

And then there are these connections between rapamycin and brain function that I honestly don't understand , brain function that I honestly don't understand but have fascinated me . So , and let me just put a little bit more meat on that . So we know that changes in brain function with aging right happen .

There are declines in cognitive function , changes in cognitive function that happen during aging . In some people that manifests itself as dementia or things like Alzheimer's disease , which is a subtype of dementia In animal studies . Rapamycin is very potent at reversing or preventing some of those age-related changes in brain function .

That makes sense in the context of aging biology . But then there's this whole other body of literature on rapamycin that's kind of evolved in parallel to the studies in the biology of aging , where rapamycin has potent effects on autism , for example , or on seizure-related diseases , and I don't understand that .

So let me say this Let me be careful how I say this I speculate that there are mechanistic similarities to what rapamycin is doing in the context of dementia and normative brain aging and why rapamycin has these effects in autism and seizure disorders .

But I don't know what those mechanisms are , but I speculate that they're important and probably tell us something really fundamental about how mTOR is acting in the brain that we don't currently understand .

And then there's this emerging sort of literature that I'm peripherally aware of on rapamycin in combination with some psychedelic drugs or things like ketamine , where you get these really interesting interactions . For example , there's some evidence that ketamine , that rapamycin , potentiates the effects of ketamine on things like depression or pain .

And again , I think that's going to be related to these observations that rapamycin has effects on autism spectrum disorders and seizure disorders , but I don't know what the mechanisms are yet . So I think there's a bunch to be learned there that we don't really understand . Right now .

We're kind of at the observation stage where we see that there are these effects and interactions , but we don't mechanistically really understand how they're working . At least I don't .

And if you met I mean you think , turning mTOR down just remove the glucose from the diet and switch to ketosis , you'll effectively turn mTOR down . Maybe that's a common mechanism , but who knows ? Like you say , we don't even , we're just scratching the surface .

That probably is important , but it's again , ketogenic diet is kind of like caloric restriction in the sense that it's going to hit mTOR but it's going to do a bunch of other stuff as well , and so you have to be careful not to say that all of the effects of the ketogenic diet are through mTOR . Some of them probably are .

Yeah , I think the interactions with ket , with ketamine in particular , are fascinating area that it'll be interesting to see how this evolves .

So , um , you know , I have a colleague here in Seattle , uh , who's a psychiatrist who has been treating some of his patients with ketamine plus rapamycin , and he's told me some really profound stories about improvements in his patients .

Um , uh , particularly things like chronic pain , and it's reminiscent of what you were saying with the ketogenic diet , where sometimes people come off of medications that they've been taking for decades . Right , when they go on this combination , they don't have to take the chronic pain medication anymore . They have a strong antidepressant .

So , yeah , there's clear interactions there that are going to turn out to be really important and it's going to be fascinating to see how that evolves and also whether or not . To what extent are those related to the way that rapamycin is impacting the biology of aging ?

So what we are doing is really trying to understand the biology of aging in companion dogs , with the goal of being able to help our pets live longer , healthier lives , and so I can say I think generally maybe the way to think about it there are really two pieces to the dog aging project .

This is an oversimplification , but it's an easy way to think about it . There's an observational study which is very , very large . We have about 40,000 dogs in the observational study right now .

Any dog is eligible for the observational study , any age , any breed , any size and the goal there is to understand what are the most important genetic and environmental factors that influence healthy aging in our pets . So if any of you have dogs , I'd encourage you to go to dogagingprojectorg .

There's a little button nominate my dog up in the upper right-hand corner of the website . Join the Dog Aging Project pack and you will be part of what is one of the largest , if not the largest , community science , open science projects in the world , with the goal of helping our pets live longer .

The other piece of the Dog Aging Project is to do something about the biology of aging . So we have a smaller double blind , placebo controlled clinical trial of rapamycin in dogs . To really try to answer the question does rapamycin increase health span and lifespan in pet dogs ?

So to be eligible for the rapamycin trial , dogs have to be at least seven years old , between 40 and 120 pounds and can't have any significant pre-existing health conditions , because it's a study of healthy aging .

So if and we are recruiting for both the longitudinal study and the clinical trial , so again , if anybody's interested , please consider going and nominating your dog for the study . I'm obviously particularly excited and interested to find out , you know , to what extent does rapamycin have an impact on healthy aging in our pets ?

These are owner-reported pre-existing diagnoses of disease or conditions , and the question we asked was very simple . We thought dogs might be an interesting natural model of time-restricted feeding , because some owners feed their dog once a day , some twice a day , some three times a day .

Some actually feed their dog what's called ad libitum the dog has free access to food . So the simple question was are dogs where the owners only fed them once a day , are there any differences in the likelihood that those dogs were diagnosed with one of 10 different age-related categories of disorders ?

That included cognitive function , kidney disease , you can go down the list , and I didn't think this was going to work because I'm not a big believer in time-restricted feeding , but as it turns out , I was wrong .

So what we found was that in all 10 cases , the arrow direction of the effect was going towards dogs that were fed once a day were less likely to have been diagnosed with any of these 10 conditions , and I think in six or seven of them it was statistically significant . In a couple of cases the effects were pretty big .

So what that tells us is that you know this is now looking backwards in times had the dog been previously diagnosed with these disorders ? If the dog was fed once a day , the likelihood of a previous diagnosis was lower . Does that mean that being fed once a day caused them to not be diagnosed ? We can't answer that .

And here's where I think you do have to be careful , because there are obvious potential explanations for this correlation . One being the dog's fed once a day , compared to two or three times a day , might be less likely to be obese , and we know that obesity is a predisposition for multiple age-related comorbidities .

So we have to do more work to figure that out , but it is intriguing and it certainly may suggest that feeding your dog once a day means that it's less likely your dog's going to get any of these 10 diseases or one of these 10 diseases .

It may also suggest that this is a useful strategy in humans , or at least in some people , but I think we have to be really careful not to jump the gun . It's a hypothesis-generating observation that requires additional study to really get to definitive . I know that frustrates people , it frustrates me , but that's the reality of the situation .

We can't say that there's causality there .

I certainly again will make the plug that if you have a dog and you love your dog and you believe in science , please consider participating in the Dog Aging .