Hey everyone, welcome to the Pia Tia Drive. I'm your host, Peter Itia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher-quality, more fulfilling life.
If you enjoyed this podcast, you can find more information on today's episode and other topics at piaetiamd.com. In this podcast, I'll be speaking with Matt Koeberlin at the University of Washington. I met Matt about a year and a half, maybe two years ago, through David Sabatini, who some of you may be familiar with, just based on all of his remarkable work around Emtor and Rapimysen. Matt's recognized globally for his research in the biology of aging.
He got his PhD from MIT in the lab of Lenny Garante, who's produced a number of notable folks in this field. He went on to his post-hoc at the University of Washington, and after completing his post-doc, he has remained there and continues to run a fantastic lab. In this episode, we're going to talk about his experience as the director of the Dog Aging Project, which, as its name suggests, focuses on the animal model of dogs for its research. Now, of course, this is really interesting because, well, fruit flies and yeast and mice are interesting.
Dogs are obviously much closer to us, and of course, these dogs, because they're pets, generally, have something really unique to us that virtually no other research animal has, which is they share our environment. This puts them in a pretty unique spot that even the Reese's Monkeys studied in the NIA Wisconsin project didn't have going for them. Now, if you haven't already done so, I recommend listening to the podcast that I did with David Sabatini because that will get you some of the background on Emtor and Rapimysen. I think we got a little technical in this podcast, but I suspect it's something that if you've listened to that other one with Sabatini, you'll have the background to follow.
We talk about other things that people seem to be interested in as well beyond Rapimysen and we also talk about NAD, probably get into Sertuins a little bit. The other thing I really enjoyed about speaking with Matt, and I had discussions with Matt over meals and stuff where I think to myself after, man, I wish that was recorded because one, I want to be able to hear it again, and two, it's the kind of stuff that people are always asking me, and I think Matt just has such an amazing way of thinking about this stuff. Matt's work is really remarkable because it's actually focusing on health span. It's easier in some ways to study health span because you can study over a shorter period of time, and in particular, when you look at the cardiomyopathy model, meaning it's a type of heart failure that dogs experience, and you look at how Rapimysen can improve ejection for action, you can get these answers in a really quick period of time, in fact, much quicker than I think Matt even expected.
So, if you're interested in Rapimysen, if you're interested in M-Tor, if you're interested in longevity, I think you're going to find this interview very interesting. It was actually recorded initially in December 2017 as part of the interview series I was doing for my book, and we may at some point throw up the video as well. You can find a lot more information in the show notes, of course, and without further delay, here's my conversation with the remarkable Matt Caprilet. Matt, thank you so much for being here.
It's really fantastic to be able to talk with you in this format. I've been a huge fan of your work for many years now. Obviously, I know quite a bit about your background, but I think it'd be great for listeners to get a sense of, what did you study in college? How did you end up doing your PhD?
Where did you do it? And most of all, why did I get you where you are? Sure. So, I got undergraduate degrees in biochemistry and mathematics at Western Washington University, and then I went to graduate school at MIT, the biology department there.
And my background up to that point had been in biophysical chemistry, so I really went to graduate school thinking I was going to work on structural biology or extra crystallography or something like that. And I heard a seminar by Lenny Grenti who I ended up doing my PhD thesis with during my first semester at MIT where he started talking about how his lab had begun working on the genetics of aging and trying to understand what are the factors that influenced the rate of aging. And this was in yeast. That's what his lab worked on at that point.
And it was really almost like an aha moment where it just clicked with me that it was really fascinating that you could use genetics and molecular biology and biochemistry to study something as complicated and fundamental as the biology of aging. And so I got fascinated by the topic and ended up going and talking to Lenny and then subsequently doing my thesis research with him. So, it was really that moment of hearing him talk, my first year in graduate school, that got me interested in aging. And that's what I've been fascinated by and passionate about since then.
So, then I went on and did a postdoc with Stan Field at the University of Washington, also working on aging, and then ultimately started my own lab. So, it's been almost two decades now that I've been working on this problem. If my memory starts me correctly, when you were in Lenny's lab, who's obviously no stranger to probably people who are listening to this, you worked on sirtuans, correct? Yeah, so my thesis work was actually the work that first showed that if you activated or overexpressed a sirtuan, in this case it was sirtu, the founding member of the sirtuans in yeast that you could extend lifespan and slow aging.
And obviously, we were very excited about that, especially when a postdoc who was in the lab at that time, Heidi Thissenbaum, about a year later, showed that you could also over-express the worm version of sirtuan and extend lifespan and celigans. And so, that was really the first example of a conserved genetic modifier of lifespan across two widely evolutionary and divergent organisms. Because it was a relatively similar version of sirtu. Yeah.
So, more different than the daft stuff that we saw in C. elegans versus the IGF that we would see in some of the higher mammals. Right, so at that time, we knew that daftu could extend lifespan and celigans. Don't think we knew it was similar.
That's right. That's right, yeah. Now, I think one of the things that makes your work so interesting is that you work on dogs. Right.
How did you end up doing that? Yeah, so that's relatively new in my career. It was about four years ago when Daniel Promislow moved from the University of Georgia to the University of Washington. And Daniel had started thinking about dogs as a model to understand genetic and environmental factors influence the aging process.
And I'm a dog person. I've always had dogs. I have three dogs now. That qualifies.
Yeah, right. And I had never really made the connection between dogs as companion animals and dogs as a model for understanding aging until I talked with Daniel about this. And through those conversations, it occurred to me that not only could we understand genetic and environmental modifiers of aging, but our pets could actually serve as a transformative next step in testing some of these things that we know work in laboratory mammals like mice, but have never yet been taken outside of the laboratory. And so it was really that sort of connection in my mind about three years ago that propelled me to really move forward with the dog aging project.
One major goal of which is to actually do this, to take some of the interventions that we know extend lifespan and slow aging in the laboratory and test whether they have that effect in the real world. In a larger mammal that's also very socially relevant, I think that that's an important aspect of this. People love their dogs if we can actually slow aging in people's pets. That's going to have a huge impact both on the quality of life for the pets and the owners, but also the way that people think about the biology of aging.
They're going to believe it a lot more if they see that their dog is living longer and aging more slowly than just reading an article in the New York Times or wherever. Right. And it's, you know, I sort of, when I talk about this, I generally talk about these four classes if you carry out going from yeast to flies, worms and mammals, but usually when we talk about mammals, we're talking about mice. Absolutely.
And there's a couple of problems at least. Right. One problem is they're generally, especially if they're inbred, I mean they're homozygous, all low-sized. Right.
So you have to question their applicability to us in terms of their susceptibility to disease. But then the second point which you alluded to, which I think the dogs might be the first quote unquote laboratory study that gets out of this is they don't live in our environment. Right? The mice that is.
Right. So the dog truly lives in the environment you and I live in, which at least in theory should be the environment we care most about preventing aging in. That's right. I think that environmental variation is hugely important.
The genetics is also important. And dogs are, so there's a couple of things that are worth mentioning. Dogs have some of that same genetic homogeneity if you look within individual purebred breeds. But we also have many purebred breeds that are widely divergent, both genetically and morphologically.
All you have to do is look at a chihuahua and a great day to see that divergence. But we also have this really interesting and complex mixed breed population that's a combination of all these different genetic variants that each breed has. So we have kind of the best of both worlds in the sense that if you want to do a study in a relatively genetically restricted background, you can do it in a specific breed or set of breeds. But if you want to capture that genetic variation, all you have to do is look at the mixed breed dogs.
But the environmental part of this I think is probably the most important from a, what are we going to learn from dogs that we can't learn from mice perspective? As you said, dogs really share our environment to a greater extent than any other animal, maybe with the exception of cats. And so they're drinking the same water. In fact, may not even be drinking the same water.
Most people, maybe drink it worse. Right. Are not going to give their dog bottled water. Right.
But they're breathing the same air. If you smoke, they're experiencing that or someone in the house smokes, they're experiencing that second hand smoke. So they really do capture most of our environment. The diet is about the only place where dogs don't quite have the same sort of nutritional diversity that people do.
But the exception of diet is the environment is pretty close. And we have a pretty good idea of how we die. Right. I could actually map out how you and I are going to die based on our age and a bunch of other factors.
Again, it's probably an oversimplification because of this species diversification. But it's a general rule. How do dogs die? Yeah.
So I'll make one quick comment on that. First of all, I think you're right that we do know what diseases most often kill people. And that's important information. I'm not sure it's the most important information because what people die from does not always equate to what they die with, especially today.
Most people are dying with multiple comorbidities. Right. So you may die from heart disease. It doesn't mean that you didn't have kidney disease or something moving towards kidney disease or diabetes.
I think it's important to appreciate that you can have multiple diseases and only one of them is probably the way to kill them. Having said that, it is useful to think about do dogs die from and with the same age related diseases that people do. And the answer is in general, the equivalency is pretty good. So dogs get all of the same age related diseases that people do.
They don't get them at the same frequency necessarily. So one big difference is in dogs there's actually relatively little vascular disease, which is a major killer in people. So specifically atherosclerosis, whether it be peripherally or cardiovascular disease, doesn't seem to be as prevalent. There's not seem to be as prevalent.
But there are breeds that die from heart disease and certain forms of heart disease. Cancer is probably the most common cause of death in dogs. And big dogs tend to get more cancers than small dogs, but across all dogs, cancer is probably the number one cause of death. Kidney disease is a major cause of death in dogs.
Is the etiology of that kidney disease related to blood pressure? Is it related to some other nephrotic syndrome that's otherwise unidentified? I don't know the answer to that. Yeah.
I don't have the veterinary background to answer that. One of the things that's interesting in dogs is that there's, it seems to be a little bit of a debate whether dogs really get Alzheimer's disease. They clearly get dementia, some dogs do, and they clearly show cognitive decline. It's not completely clear whether they get what would be clinically diagnosed as Alzheimer's disease and people.
Apparently they do accumulate a beta in the brain, whether they get the plexentangal still seem to be a little bit up in the air and there are people studying that. But at least at the level of cognitive dysfunction and dementia, it's clear that dogs experience that with age as well. So for the most part, they do develop the same age-related diseases. The increase in risk for those diseases goes up essentially exponentially just like in people.
But the relative prevalence of specific diseases is not always the same and can also be breed dependent. So it is certainly the case that within purebred dogs, different breeds have different predispositions to certain diseases, which is exactly what you'd expect based on the genetics. So basically they're probably getting a little more cancer, significantly more renal failure as a proximate cause of death as opposed to dying with renal insipiciency, which you're pointing a lot of humans do. They're getting a lot of heart disease, but it sounds like it's more cardiomyopathy and or valvular disease but not atherosclerotic or ischemic disease.
And they unfortunately die of accidents just as humans do, which would probably be in the top four for humans and dogs I'm guessing. Yeah. And actually that's an interesting point. You're right.
What I haven't seen great data on is the age distribution of death due to trauma. I suspect it's going to be mostly younger dogs, but I don't know for sure. So that's actually an interesting question. It is absolutely true.
The other thing that is worth noting about dogs is it's actually the case that most pet dogs don't die from an age-related disease. They die from euthanasia, which is a difference between us and people. That's a great point. Well, let's turn the discussion now to what you do about this.
I've been a big fan of Rapa Myson and Tor in that entire pathway for several years now it's become almost an obsession for one to have an obsession that's not pathological. And I think what attracted me to your work a couple of years ago probably David Sabatini pointed me in your direction. So maybe three years ago it was actually after the Mac paper came out in 2014. Yeah, right.
It was the first really interesting look at the human data. I want to come back to that paper as it relates to immune function and stuff, but maybe give us a sense of how you decided that the next logical staff was to actually test the God molecule as I was talking about Rapa Myson in this context. In dogs. Yeah.
So again, this was all happening about three years ago when I first sort of made the leap to thinking that we could test interventions in dogs. And actually that's not, at least for me, was not an immediate, it wasn't immediately obvious to me that we should. So you really have to think as soon as you start talking about bringing trial of a drug out of the lab and into the real world, whether it's the human clinic or the veterinary clinic, in the context of aging, you really have to start to think about safety and side effects, right? Because there is a very low tolerance for side effects when you're talking about treating a healthy person or dog.
That was the first thing that I had to really come to grips with this. Could we do this safely and a special time? Because you were thinking we're not going to take dogs that are already sick. That's right.
We were going to take healthy dogs. That's somebody who is fundamentally interested in the biology of aging. The intent is to slow aging in people before they get sick, right? To keep them healthy longer.
So in many ways, it's the opposite of traditional medical approach, biomedical research, right? Where normally, historically, we wait until people are sick and then we try to cure their disease. This is the reverse of that, right? So that's right.
So because we are talking about intervening in a healthy person or a dog, the tolerance for side effects from a regulatory perspective or even just public perception is very low when you're talking about a healthy person. Now, you know, the way I view that, first of all, I think that is we need as a society, you know, and within the scientific community to have a discussion about this because I think that we need to recognize that a healthy 70 year old is not the same as a healthy 30 year old, right? And we know what's going to happen if we don't do anything about aging. So my personal view is that there should be a tolerance for some level of risk if the outcome is going to be 10%, 20%, 30% more time spent in good health.
That's a discussion that we haven't had either at the regulatory level or at the society wide level that I think we need to have. So I digress a little bit. But I had to go ahead. I think that's one of the most important points you could make.
And I sort of think a lot about this because my colleague and I were discussing this the other day, which was, you know, you take this oath at the end of medical school, the first thing you learn to say is first do no harm. And I think the spirit of that is excellent, but I also think it's highly impractical in a world where it forces you into binary thinking, which is we will only undertake interventions that are guaranteed to have no harm. And otherwise, we will do nothing regardless of the outcome, which of course is not practical. We live in a probabilistic world where the probability of harm is not zero or one, but rather it's a continuum between zero and one.
And you really need to take a risk adjusted approach to outcome. So I mean, I think that's an excellent one. So I had to kind of go through that process in my own head though, and especially thinking about moving into pet dogs where because of the way that many people feel about their pet dogs, you have to be as sure as you can that you're not going to hurt anybody's pet. They like them more than their friends.
Yeah, absolutely. Right. Yeah, people love their dogs. A lot of people feel similarly about their dogs as they do about their kids.
Right. So you kind of think that's kind of the way I thought about it is could we do this in somebody's child? And so with RapidMison, there is a perception out there that I don't share, but there's a perception out there that RapidMison has lots of side effects based mostly on the human clinical literature, which to be clear is generally in transplant patients. Transplant patients taking high doses and taking lots of other drugs.
Yeah, so sick people taking a high dose of RapidMison in combination with other medications. Right. And it does have side effects. There's no question about that.
But one of the things that's come out of my own research and other research in the field is that both the benefits and the side effects are strongly linked to dose. So one question was, is there a dose of RapidMison that will have beneficial effects in the context of healthy aging without significant side effects? That wasn't unknown. I think that we're getting to the point where we're pretty sure that that's the case.
At least you can get some of the benefits of RapidMison. We can talk more about the data that support that. But at that point, it really wasn't clear. When you say the dose, do you think that the peak or the trough play a bigger role in toxicity?
Yeah, so that's still an unknown. But I think the data that are out there suggest that the trough levels are most strongly correlated with side effects. Now what is most strongly related to health span or lifespan? There's no data as far as I know.
And this is an area where I think there's a lot of work that could be done and should be done exploring more broadly, even in laboratory animals in mice, the sort of dose response and dose timing space for where do you get the biggest effects on lifespan or specific measures of health? And don't you get any effects? Can you uncouple say the improvements in heart function from the improvements in immune function by changing the dose for the timing? That really has been very little done on that.
Now maybe for the listener who's not familiar with the pharmacokinetic discussion, let's explain maybe trough and peak. How do we think about those doses? Yeah. So when you give a medication, say a RapidMison pill, when a person takes a RapidMison pill, there will be a rapid increase in the levels of the drug and the blood.
And if they don't take another dose, then the drug will start to get cleared and it will go down. And so if you're taking a pill every day, as soon as you take the pill, blood levels go up, and then it starts to get cleared, and then the next day you take the pill, it goes up and then it starts to get cleared. So if you were to take the pill every other day, it would go down further before you get that spike again. So the spike, the top of the spike is the peak level, the bottom before you take the next dose is the trough.
And so the little bit of data that's available, and again, there's not much data for different doses of RapidMison in people who are not also taking other drugs. So the combination here is both dose and RapidMison as a monotherapy. And so really the only study that I know of that looked at this really at all actually didn't even use RapidMison. They used a derivative of RapidMison called Rad001, whatever alimus that's the manic study we talked about.
There's really no good data in people on different doses of RapidMison as a monotherapy in healthy people. So we're kind of stuck looking at the data that we have. So in Joan's study with Everalimus or Rad001, they gave the medication to healthy elderly people and they tested three dose and delivery combinations. So one of them was, I believe, 20 milligrams, one of them was five milligrams a week, and one of them was one milligram a day.
Right. And this was looking in the context of immune function as measured by a flu vaccine response. So the outcomes were that I think at all three doses, they saw evidence for improved vaccine response, which was consistent with prior data in mice that immune function is improved by RapidMison. Pause for a moment.
That's still a bit counterintuitive to the lay person. When I say the lay person, I mean like the lay person who still thinks about RapidMison. Or actually lots of physicians. Sure.
Because we think of this as an immune suppressant. And yet they took this drug in monotherapy under a different dosing schedule than a transplant patient would take it. And we saw improvement in their T cell function, the same cells that we tend to knock out in a transplant patient. Right.
Yeah. So let's come back to that. Just to come back to the trough levels and side effects. So they saw evidence for efficacy with every delivery method.
Although they got, I think the best efficacy at the five months. Five months a week. But they also had the lowest side effects. And the five effects were the ones every day or the 20s once a week.
I think it was the 20s once a week. But I can't remember. It was pretty comparable. So the first thing to say is none of the side effects were bad by clinical standards.
None of the people dropped out of the study because they were taking the drug, which is I think a pretty good indication for how tolerable the drug is. So even though they did detect some side effects, they really were not serious. They weren't even serious enough that they were uncomfortable and people stopped taking the drug. So I think that that's really the only evidence that we have that I know of that it's really the trough levels that drive side effects.
So I kind of think that's probably true, but I'm not confident. And I really think we need more data to know for sure. It's certainly true in other classes of drugs. I mean, you look at Gentha Mysin, for example, in the ototoxicity or nephrotoxicity.
It's a trough problem, not a peak problem. Right. That's why you have to make sure the patients clear it before you read those. Right.
So there are other reasons to believe that. Yeah. So now coming back to this immune function. There's a couple of things again there to consider.
So the data suggesting that Rapa Mysin can act as an immunosuppressant again is almost exclusively based on very well, I shouldn't say very high doses, higher doses than were tested in the Novartis study in people who are also taking other drugs that probably are true immunosuppressants. Typically at least two if not three other drugs. So it's really not clear to what extent Rapa Mysin as a monotherapy in healthy people has immunosuppressive properties. And the data in mice, I would say is mixed.
It really seems to be the case that for some forms of immune challenge at high doses, Rapa Mysin can enhance susceptibility to infection or other forms of immune challenge and enhance this function. But again, those studies are almost always done at very high doses of the drug that are even much higher than you would give to a person. So it's an unknown. Now what seems to be the case, both in mice and people is that short term treatment with Rapa Mysin in an old mouse or an old person followed by a two week washout where they stop taking the drug.
When you then test immune function, at least as measured by a vaccine response, you get a better response. So one model would be that the treatment with Rapa Mysin is restoring immune function in an aged animal, probably through enhanced stem cell function, although I think that that hasn't really been demonstrated clearly. And you might need that washout period. If there is an immunosuppressive effect, you might need that washout period to be able to see that rejuvenation in immune function.
Again, that's really speculative though, because nobody's done. In Jones paper, did they do, I'm sure they didn't actually know what I think about it. They didn't have enough people in the study. It would have been very interesting to have seen the immune challenge without the washout.
Yeah, they knew that. No, I was just going to say nobody's done it in either mice or in people. That actually would be a fairly easy experiment to do in mice. The problem is you would never get an NIH study section to fund that experiment, because we already know the answer that Rapa Mysin works.
It wouldn't be viewed as, even though it's really important from a translational perspective, it wouldn't be viewed as innovative or important enough for somebody to fund a grant to do it. So it's an unknown and I don't know how long it will be until we actually get the answer to that question. Now bringing it back to the dogs, one of the challenges, of course, in leaping from mice to dogs is mortality becomes difficult to study. You have an animal that lives a lot longer, whereas mice, you can get a longevity answer in months if you select them correctly.
And dogs, if you want to study them for true, hard outcome of death. So you pick a proxy. Well, you can. Yeah, I'm saying I'm saying the shortest path would be let's look at organ function or something else.
Right. So what we did, so we've done one study where it was a 10-week study of Rapa Mysin in middle aged, healthy companion dogs, and we chose heart function as our short-term measure. And that again was based on mouse data where two different, actually three different labs now have shown that if you take 24-month-old mouse, that's maybe the 40-year-old. That's more like a 60-65-year-old person, that if you just look at the heart of a 24-month-old mouse compared to, let's say, a six-month-old mouse, you can see declines in heart function just like you can in people.
And the parameters that have been studied with respect to Rapa Mysin specifically are mostly measures of left ventricular function, so ejection, fraction, fractional, shortening, things like that. And this is done by echocardiography, so it's relatively non-invasive. So you can see a decline in function with age. And what has been seen now in three independent studies is that six to 10 weeks of treatment with Rapa Mysin is enough to cause those measures of heart function in the old mouse to go back about halfway to what you would see in a young mouse.
So it doesn't bring you all the way back to a teenager, but it gets you back to, you know, maybe a 35-year-old heart if you're doing this sort of mouse to human equivalence. And just to be clear, that was how many weeks? So the studies have varied. It's between six and 10 weeks.
All of them saw improvements. It's not clear whether you get bigger improvements by longer treatments, so it's kind of in that range. And did these animals also require a washout to see the benefit? No, no washout.
So these are measures of heart function taken while the mice are still on the Rapa Mysin. And these animals were dosed daily? So yes, all three of those studies used the encapsulated Rapa Mysin in the diet, so they were getting the drug daily. And it was not.
And this is where it gets a little bit complicated because I'd say 85% of the studies on aging or age-related functional measures in mice with Rapa Mysin have been done with an encapsulated form of Rapa Mysin in the diet called ERAPA. And so that's different from a pill, right? Because mice are going to eat throughout the night. So they're probably not experiencing exactly the same pharmacokinetics that you would experience from a pill or the other kinds of experiments that people have done in mice have been injections, where you get this rapid peak in the drug and then a pretty steep drop off as the drug starts to be delivered.
And nobody's ever done the 24-hour measures of Rapa Mysin blood level on the mice getting ERAPA. So I don't know how different it is, but it's probably different in the sense that it's probably a more stable level of Rapa Mysin in the blood for a longer period of time. I mean, I would expect that the ERAPA animals are going to have lower peaks and higher troughs. I mean, that would be the expectation.
That would be the expectation, yes. But I don't know that anybody's ever really carefully looked at that. So having said that, I think all three of the studies that looked at heart function in mice used the ERAPA. And it was a pretty low dose of the...
How many milligrams per kilogram? It's 14 parts per million in the food. I don't remember off the top of my head what that works out to a milligrams per kilogram. I feel like it's in about the two range.
Wow, but much. Well, yeah, but again, you have to keep in mind that you can't translate the dosing across species very well. So the dosing across species is not going to be the same as the dosing in the dosing. Or the dosing.
Because the dogs and the humer's eye suspect are probably a lot closer than the... You would think so, although I don't know that there's actually good evidence to support that. So certainly in terms of body size, if you're talking about a bigger dog, they're closer. In terms of metabolism of the drug though, that I imagine could very quickly...
It's hetically used to species. I don't know, that's a good question. I'm pretty sure it's not right from the P450. Yeah, it's the scene that's supported.
It's going to be in the liver. So how did you ultimately come up with both a dose and a schedule of delivery for your first trial? So this again goes back to this question that I was asking myself about, can we do this safely? I'm not going to endog on Rapamycin at all.
And just like in people, there's almost none on Rapamycin as a monotherapy in healthy animals. So I started basically digging and talking to as many veterinarians as I could to find out what was known. And I was very fortunate to actually be able to get in touch with a veterinary group at the University of Tennessee who was studying Rapamycin in dogs who had had Hemangiosarcoma of the spleen. And so they had done the pharmacokinetics and had developed a dosing strategy that they feel is extending life expectancy in dogs who have had Hemangiosarcoma of the spleen.
And where they weren't seeing side effects. And they had some of their dogs on Rapamycin for more than a year. So we were pretty confident, or I was pretty confident after talking to them, that if we took their dosing strategy that we're unlikely to see any significant side effects over a 10-week period. And so I said that cardiac function was the functional endpoint that we were using.
Really the goal of that 10-week study though was to confirm. So phase one basically. Yeah, that we could do this and we could get people to participate. They would actually give their dog the medication and that we didn't see any significant side effects.
So I was pretty confident that based on their dosing and delivery protocol, we at least wouldn't see any severe side effects in a 10-week period. And I had fun that study? And then IH money because we have one of these Nathan Shocks Centers of Excellence in the Biology of Aging. And we had a small amount.
It was on the order of a few tens of thousands of dollars left over from the prior year. And so I asked Felipe Sierra, who's the head of the Division of Aging Biology at NIH, if we could use that surplus specifically for this project. And he was kind enough to agree to that. But we didn't write a grant.
But she's wrapped this thing. Yeah, so actually I paid for this study mostly out of funds that I had gotten because I was recruited to get a job somewhere else. And as part of my retention package, the University of Washington gave me some money that I could spend on whatever I wanted to. So I thought this was a good way to spend money.
So what did that 10-week study show? Right. So first of all, I'll go back to the dosing before I... Oh, that's right.
Yeah. So I talked to this group, the University of Tennessee. And so their strategy was 0.1 milligrams per kilogram given three times a week, Monday, Wednesday, Friday. And that made sense to me in light of what we were just talking about from the manic paper, where it seems like if you give an extra day to let the trough levels get down, it made intuitive sense that I thought it was...
Yeah, so I don't know that that's the case. But it made sense. And so that was the dosing strategy that we went with for our highest dose. And then we also tested a dose that was half of that.
So we enrolled dogs into this study. This was a very small study all at a private veterinary specialty clinic in the Seattle area. And so the dogs had to be at least 40 pounds and at least six years old. And they could not have any pre-existing conditions.
So again, this is a study of healthy aging. We wanted healthy dogs coming into the study. Six years old because of that weight range, we figured that that would be roughly the human equivalent of 55 years, maybe, big dogs aged faster than small dogs. So that's why we had the weight criteria.
So we wanted to have a population where we expected there would be the potential for the some age-related functional decline, but that we wouldn't get a high proportion of dogs. You won't be too close to the age-related question. That's right. That were really sick.
So one thing we found, though, that was unexpected was that about 20% of dogs in that age and weight range actually have asymptomatic heart disease. You will see if you give them an echocardiogram, but you won't detect from a stethoscope exam. And that was in hindsight, it kind of makes sense. Again, heart function is going to go down with age.
And where you decline, like what is the clinical threshold that we call disease, it's sort of a moving target sometimes, right? If a vet with a stethoscope pecs on the other hand, it's not a good thing. It's sort of a moving target sometimes, right? If a vet with a stethoscope pecs a heart murmur and then they give the dog an echocardiogram and they see regurgitation, they'll call that heart disease.
If they don't hear a heart murmur, nobody's going to give their dog an echocardiogram. Yeah, and I'm not a cardiologist, but I can't imagine the day would ever come where using a stethoscope, I could detect a low EF to the tone of... You would not see a murmur. No, no, it's really the regurgitation that they're hearing as a heart murmur.
And that was most of the dogs that we ended up having to exclude, we had to exclude because they had a pre-existing dog- The regurgitation. That came out from the echocardiogram. But this was actually a discussion that we had to have with the cardiologist. The cardiologist initially went into the study with the feeling that if there's any regurgitation that's beyond trivial, that that's heart disease.
And so when we started to see dog after dog show up with this level of regurgitation, we had this discussion, what's normal aging versus disease, right? And so just because of the way that the protocol was written, we ended up having to exclude about 20% of dogs because they had underlying heart disease. So we had 40 dogs come into the study for their first exam, that was our target number. We ended up having 24 of them all the way through the study.
Most of those... Three groups? Three, that's the possible. So I kept not being evenly distributed.
And in part, this was because... Part of this was my first clinical trial that I'd ever done. And I didn't plan for the fact that we would have to exclude as many dogs as we did. So the way it ended up was we had eight placebo, 11 high dose, and five lower dose.
That went all the way through. We only had one dog leave the study, and that was because the owner just stopped giving their dog the medication. And we had one dog where the owner gave their dog the wrong amount of the medication, which ironically enough, he was a physician. Low.
So the dog was randomized into the high rapamycin group and ended up getting one quarter of the expected dose. Other than that, there was fantastic compliance. All of the owners did what they were supposed to do, came in for their exams. So the main outcomes of the study were one.
There was no evidence for increased side effects. So the owners filled out weekly surveys that there was a long list of... The dogs didn't film them. You never know.
There was a long list of did your dog experience any of these things? And then there were a couple of just open ended questions. Do you feel like you observed any positive changes or negative changes in health? Did a group in Tennessee see the apthosulsors in their dogs?
No. Because that seems to be... I remember as a resident we would give rapamycin to the kidney transplant patients. And the biggest complaint by far was those apthosulsors.
And we didn't, again in hindsight, we probably should have done a better job of looking, but we did not have any evidence that was happening. The only thing that initially I thought that maybe we were detecting that was because we had several owners, and this was while the study was still blinded, so I didn't know which dogs were at this point. We had several owners report that their dog was drinking a lot more water, and a couple of them actually came in for urinalysis and stuff like that. And so I thought maybe that could be a dog's response.
If they have sores on the inside of their mouth and they're uncomfortable, maybe that would be the canine equivalent of how they would talk about that. As it turns out though, when we unblinded the study, that reported observation of increased water consumption was equally spread between the placebo and rapamycin groups. So I don't know if that's happening in dogs. That's something we'll look at in the next phase.
So again, for all of the side effects though that we surveyed owners on no difference between treated and untreated, the blood chemistry showed no significant changes with rapamycin, which was actually a little bit surprising. Did you do a glucose tolerance test? Did you do any? We did not do a glucose tolerance test.
In part because we wanted to keep the number of assays that we were asking the owners to subject their dogs to as small as possible. I think it is non-invasive as possible for the animals. We did get blood chemistry before randomization at week three and at week eleven, so within one week of coming out of the study. And we saw improvements in heart function.
Now I will say it's a small cohort. They were on sort of the borderline of statistical significance. So two of the three measures that we had is our primary endpoints. The three measures were ejection fractional shortening and EDA ratio.
And again, that was just coming directly from the mouse studies. Two of those three were statistically significant. One was the value of 0.06. So I mean, you must do it underpowered on absolutely anything.
Absolutely. Yeah. It's amazing you saw it significantly. I agree.
It's about the most positive outcome that we could have hoped for. Clearly needs to be replicated, but at least the changes are going in the right direction. And interesting, a couple of interesting things when you actually look at the heart data, it very much looks like the dogs on-wrap mice and they got the biggest benefits were the ones that started with the lowest function, which is not surprising. But that also is encouraging because that's kind of what you'd expect, right?
The dogs that have undergone a greater age-related decline are likely to be the ones that are going to get the biggest benefit from a treatment that's actually affecting that. So that was really encouraging. And then we actually had one Doberman Pincher in the study. And this turned out to be interesting because Doberman Pinchers as a breed are highly prone to dilated cardiomyopathy.
Something like 60, 65% of Doberman Pinchers will develop dilated cardiomyopathy as they get older. I wasn't really aware of this literature going into the study, but it turns out that many Doberman Pincher owners will actually give their dogs echocardiograms or electrocardiograms routinely as they're getting older to try to detect dilated cardiomyopathy as early as possible. And the owner of this dog didn't tell us this before she came into the study, had actually been aware of this and was giving her dog echocardiograms before coming into the study. That dog had low cardiac function, but it was not yet to the point where it was clinically diagnosed as dilated cardiomyopathy.
So our cardiologists in the study also not knowing the dog's history of having prior echoes did not flag the dog as needing to be excluded. So the dog was randomized. It just happened to be randomized into the higher rapamycin dose. And its function was that was one of the dogs where we saw the largest improvement in function.
What is interesting about that is the owner then after the study was over continued to get echocardiograms every three months and he shared that information with us. And so it's really, it's an end of one, but it's a really fascinating case study because you can see the dog's cardiac function declining. Then the dog comes into the study, gets rapamycin, it shoots up. It's quite a dramatic increase.
And then within about- What was the increase in EF, do you remember? I don't remember, I don't want to say the exact number. It was from the borderline of being a dilated cardiomyopathy up at least 10%. 10%.
Absolutely. It's enormous. Yeah. Well in spec into the normal range.
Has that patient or that patient, has that woman shared with you what the resulting decline in EF has been since the trial? Yeah. So I've got the data out to about six months and we're just now trying to reconnect with her to see if she has additional data that she'll share with us. By about six months out, the ejection fraction and fractional shortening were back right at the point when the dog came into the study.
And at that point, her cardiologist diagnosed the dog as a cult DCN. So clearly going down the path to dilated cardiomy. So the million dollar question in a study like that, or in a case like that is, if you had to guess, what would be the ideal way to take care of that dog to delay the onset of cardiomyopathy as long as possible? Would it be just keep this dog on that dose three times a week in perpetuity?
Would it be give the dog a 10 week holiday, 10 on, 10 off, 10 off? Right. And every six months is just a seesaw back. If everything's working the way that we think it is, yeah, my guess is that the default there would be to keep the dog on the drug unless you start to see side effects, right?
So continue to monitor by echoes every three months and unless you see side effects or unless you see something else that makes you worried that rapamycin is having a negative effect, just keep the dog on the drug. But you know, it's an unknown as to whether we would eventually see side effects at that dose because you know, as I said, the only data that I know of is that University of Tennessee Group where they did have some dogs that survived more than a year and continue to take the drug. And so as I said, had had a mangeosarcoma of the spleen, they'd had surgeries, you know, they were very sick coming into that study. And so I don't know, even if there were mild side effects that you would really be able to tease that apart from everything else that's going on with those dogs.
There are other larger mammal studies that are going on, correct? With rapamycin specifically. So there are research studies in the context of aging in marmosets, they're very small and very early, but those are being done at the University of San Antonio, yeah, Texas San Antonio, the Bar Shop Institute. And then there are a variety of cancer studies in dogs with rapamycin.
So there's a large study of rapamycin for osteosarcoma in dogs and then there are a few smaller clinical trials. But I don't know of any other large animal studies in the context of aging. Yeah. Now I want to obviously come back to the end to aging in the dogs, but on the cancer topic, there are some data that are actually suggesting that the increase in autophagy that one might see with rapamycin, which one would expect to see, at least with M-TORC1 inhibition, might be paradoxically not ideal in the active setting of cancer.
Right. So the question is, are you swayed by those data? And if so, what would be the teleologic explanation? Yeah.
So I'll say I'm not swayed much. I think that those kind of data are important to be aware of. I think one of the real challenges in the autophagy field is that not everybody can't measure it. Yeah.
But side the fact that we can't, we don't really know how to measure it. I think as a community, we really don't know what we mean when we say that autophagy is increased or decreased. Different people use different markers or measures for autophagy. So my view is that one of the things that can happen, not just for cancers, but for lots of different pathologies, is one of the ways that cells try to deal with many different forms of stress, in particular protein misfolding, but also other forms of stress is to turn up autophagy.
So I think that autophagy, some markers of autophagy going up can be a response to a pathological condition. Also what often happens is that response of turning up autophagy does not lead to productive autophagy. So you actually get an accumulation of autophagosomes because they don't ever make it all the way through the process. So depending on how you're measuring autophagy, what you really might be detecting is a block at the late stages of autophagy.
And what you're seeing is that you're measuring a backlog. So it's not necessarily the case that more autophagy is bad in that context. It's the failure to actually bring it through the completion. And again, I don't have a lot of data to support this.
My intuition is that at least for some diseases, one of the things that Rapa Meisen does, and I don't really understand the molecular biology here, it seems to alleviate that block. So you actually get productive autophagy working again. And again, I don't know exactly how that works. But that's what it seems to me is happening.
And so we have seen some evidence for this in mitochondrial disease in the brain where if we look in the brain, we can see these sort of massive autophagosomes that are trying to digest mitochondria that can't do it while the disease is progressing. Somehow Rapa Meisen fixes that. So I think you have to be cautious in interpreting an increase in autophagic markers in disease as necessarily meaning that increased autophagy is causing or contributing to that disease. And it could be the case that depending on how you activate autophagy, it could be a detrimental or it could be beneficial.
And so there's really two different questions. The first would be if you take a patient with cancer and you inhibit M-TOR, is it not helpful because the tumor has already evolved so much to be outside of M-TOR's purview? Or is it, it's actually harmful? And that's of course separate from the option that could be helpful.
Right. So my understanding of the clinical and the literature in humans is that for most cancers, once it's reached the point of diagnosis that Rapa Meisen is disappointing in its effectiveness, not particularly effective, that's not true for all cancers, but for most cancers it has not been as effective as you might expect given that we know that activation of M-TOR is common when you get high proliferation and then turning down M-TOR should stop that. Turn off the proliferative though. So I think you're probably right that at least part of the story is that one of the steps in the progression to cancer is evolving to ignore the break of turning down M-TOR.
So Rapa Meisen may not be effective there. I think it's a complicated system though because the effects of Rapa Meisen on the immune system could have beneficial effects in terms of cancer or detrimental effects. So we know that immune surveillance is probably the most important anti-cancer mechanism, certainly one of the most important anti-cancer mechanisms. And we know that immune function goes down with this.
That's probably one of the reasons why most cancers are age-related. So if you can boost age-related immune function with Rapa Meisen, enhance immune surveillance, that's going to have a potent anti-cancer mechanism. And again, this is my guess. My guess is that's why we see in the studies in mice that cancers are pushed back during aging by Rapa Meisen.
On the other hand, if the dose of Rapa Meisen is high enough that you're actually inhibiting immune function, that could be... Oh, the sample size. And there's not a lot of data yet. So we did one study in my lab where we gave mice, I think it's the highest dose that's ever been given in the context of an aging study.
So it's a daily injection of 8 milligrams per kilogram. So as we call it the party dose. Yeah, right. And so this was a study where we only gave the mice Rapa Meisen for three months.
So this was from 20 to 23 months. And then we stopped the treatment. And what was interesting there was we got completely different effects in male mice versus female mice. The male mice lived 60% longer after the end of treatment.
They had better muscle function. They got less cancer. The female mice had no difference in lifespan. The mice that got Rapa Meisen didn't get Rapa Meisen.
But they died with... I want to say from, but it's hard to say for sure what a mouse dies from. They died with very different types of cancers. So the female mice that had gotten this high dose of Rapa Meisen for three months all had aggressive hematopoietic cancers.
Whereas about... I think it was about 30 or 40% of the vehicle treated mice. So in Black 6 that's not an unknown. But none of the Rapa Meisen treated mice had non-matopoietic cancers.
Whereas 60% of the mice that didn't get Rapa Meisen. Now the 2009 study that kicked all this off actually showed a greater survival benefit in the female mice, didn't it? That's right. So I think, and again, this is a guess because I actually have dated to back it up.
My guess is that because we pushed the dose so high, we might have actually taken it too far in the female. So one school of thought is that female mice at least. We don't know if this is true in any other organism. Female mice are more sensitive to Rapa Meisen.
And that could either be that they don't clear the drug as quickly or that for whatever reason in female mice the same amount of Rapa Meisen has a greater mTOR inhibitory effect. But that's one school of thought. And I kind of think that's right. So at lower doses of the drug, you see a bigger lifespan benefit in females than a male.
Did you repeat that experiment at like four makes per gig or something? We haven't. We should. We need a definite pool of money.
I agree. I agree. We need to figure out the most important questions. Yeah.
And I think the dose response is really important. We did do a lower dose for three months as well. And there we saw increases in lifespan above males and females roughly the same magnitude. So that dose was nine times higher than what the ITP tested.
So one of the things that's interesting though is as you go higher in dose, so three times higher than what they originally tested, the females still live a little bit longer. But the difference between males and females, the gap has closed quite a bit. So I think that females for whatever reason at a given concentration of Rapa Meisen are just more affected by that amount of the drug. And I think what we did in our high dose study is we just pushed it a little too far.
We pushed it to the point where Rapa Meisen did something probably to the immune system that allowed these immune cancers to escape surveillance or become hyperproliferative. Again, I'm not a cancer biologist. I'm not an immunologist. So I don't have a good feel for what the mechanism is.
I can tell you what the observation is. And that's that all of those animals had aggressive, amatopoietic cancers when they got this week months of Rapa Meisen. Just out of curiosity, more B-cell or T-cell, do you recall? I don't recall.
It's in the paper. Because there's an opportunity here to do the reverse, right? I mean, there's an opportunity to take, right now we're seeing just an unbelievable amount of activity and adaptive cell therapy. And we're even, you just talk about checkpoint inhibitors and things like that.
Like it makes you wonder, are there ways to make these things better? And I'm not sure if you could get a checkpoint is the wrong example because you might get more autoimmunity. But certainly when you talk about adaptive cell therapy, anything that could boost either CDA function or inhibit the regs or something, there might be ways, like almost once you wonder if using Rapa Meisen in a different manner in combination with immune-based therapy might make more sense. Yeah.
No, I think there's a lot that could be done there for sure. Part of the reason why we haven't explored this in more detail, one reason is, again, is I'm not a cancer biologist. So it's not the thing I'm most interested in. I think it's really interesting biology, but it's not the thing I'm most interested in.
But I also feel like because the dose that we gave was so high that, again, thinking translationally about Rapa Meisen as a drug in the context of aging, my feeling is that what we've uncovered here is not going to be relevant at the doses that we would think about giving to you now. Yeah. Yeah. So that's why I haven't really spent a lot of my time trying to figure out what's going on there.
But I think certainly in the context of cancer immune therapies, I think we do need to think a little bit more about how effective those kinds of therapies are going to be in the elderly and maybe something like Rapa Meisen could help, could actually enhance the ability of those therapies. I mean, this question you posed when David, 17E, Tim Ferriss, and Napchan, and I were in a year ago, over a year ago, this might have been our favorite mealtime discussion, which is what best explains the increase in cancer incidence with age being, in other words, would the primary driver be the reduction in immune surveillance or the length of time to accumulate mutations or the frequency of mutations? I mean, it's not an obvious answer. I don't think it has to be just one.
No, it's all this thing. It's all this way. It's all about together. Yeah.
Yeah. I certainly over the last few years have come to think that the decline in immune function is certainly more important than I had initially got. That's my time. I mean, I secretly want that to be the biggest driver because I think we have a better chance to control that than some of the other ones.
And I think it probably is. That would be my guess. And I also think it kind of makes sense that if you have an immune system that's functioning the way it's supposed to, you can actually deal with the mutation accumulation because your immune system is going to clear those before they become problems. So now let's go back to the anti-aging thesis, which is we're going to take healthy dogs, eventually healthy people.
We want to reduce the rate of decline is probably the best way to think about it, right? So we have a deterioration in organ function. So yeah, it's been surprising to me again over the last few years is the different ways that Rapamycin not only seems to delay the decline, but it seems to make things better. There clearly seems to be in at least some organs a rejuvenating function.
And I suspect that's mostly stem cell mediated, but again, the mechanisms haven't been worked out yet. So we've already talked about immune function. You can take an old immune system and make it work more like a young immune system. We've talked about cardiac function.
You can take an old heart. You make it work more like a young heart. There's some evidence from David's lab that intestinal stem cells can be rejuvenated by Rapamycin. We've recently published that alveolar bone levels, so in the mouth, the bone around the teeth, can be rejuvenated back to a more youthful level by short term treatment with Rapamycin.
So there are now multiple different places in the body, at least in mice, where you actually see functional improvements back to a more youthful state. And so I don't think Rapamycin is going to do that for everything, but at least for tissues and organs where stem cell senescence plays a big role, I suspect that Rapamycin can have not just an effect on delaying declines, but actually bring things partially back towards a more youthful functional state. What's the best available evidence for that centrally in a CNS? It's a good question.
So there are studies on cognitive function in mice showing that you can improve cognitive function in age animals. I believe at least one of those started the treatment late in life and saw improvements in cognitive function. And then in all of the major Alzheimer's disease mouse models, the literature is a little bit mixed. There's at least evidence that you can wait until the pathology of the disease is set in.
You see the A-beta accumulated. You see the functional deficits in terms of cognitive function. You can start the treatment and you can improve things. And on postmortem, are you seeing an actual reduction in animal?
Yeah. So we haven't done this. There's a lot of other labs in the AD area. Yes.
So again, the data is a little bit mixed. There's a lot of papers out there where they see that you can get really robust benefits if you start rapamycin treatment early, but they didn't see benefits in the AD models when you started late. And then there are studies that did see declines in aggregation, increased autophagy, and functional improvements. Even when you start staggering, if you could take an animal, an alternately, of course, a human who's already accumulating AB and tau.
Yeah. And even just halting that is a big deal. There's one drug in the disease-proof. Yeah.
Now you're going right into my biggest pet peeve right now, which is why there hasn't been or isn't the current rapamycin trial for Alzheimer's disease. But I think you're right. And again, three years ago, if somebody had asked me, will rapamycin, is it likely to have any benefit in somebody who's been diagnosed with AD? I would probably said no.
I'd come around to thinking that there's at least a reasonable chance that it cannot just halt progression, but it could actually make- Well, especially if you, you know, one of our colleagues is a neurologist here named Richard Isaacson, and he runs the largest Alzheimer's prevention clinic in the country of Cornell. You know, Richard's thesis, which I think makes a ton of sense is, again, I think other people share this view is you want to catch people while they just have the first signs of myocognitive impairment. Sure. Absolutely.
And your ability to actually impact them is enormous. Why aren't those people being considered for clinical trials when we already know that these other agents aren't really doing anything? Right. Yeah, I agree.
I think that if I was going to design a clinical trial for Alzheimer's disease or dementia with rapamycin that I thought had the best chance of success, that would be the target population. Those trials are harder to do in some ways because they're longer. And not everybody moves from MCI to full-blown AD at the same rate. And we don't have, at least my understanding is we still really don't have great predicted biomarkers of how fast that's going to happen in an individual.
But that would be the study that would have the best chance of working. Having said that, I still think there's a decent chance in somebody who's already gotten to the point where they will be diagnosed as having Alzheimer's disease. Serious functional deficits. There's a chance that rapamycin could make things better.
Now, I get the practical reasons for why people don't want to try a risky clinical trial. It's expensive. If you fail, then your drug gets a bad reputation. All that.
So I understand why people are hesitant to do that trial. I think there's actually a pretty good chance of what to help you. I think you can combine it. I think Richard often talks about, and others do as well, that one of our failures in Alzheimer's is we consider it a single disease.
I agree. It says, now you've been saying, John has cancer. Oh, well gosh. That's the end of his life.
Well, don't you want to know what kind of cancer? It's the first life. Or maybe what mutation. So similarly, but broadly speaking, this is a gross oversimplification.
If you consider the metabolic version of Alzheimer's disease, the vascular version of Alzheimer's disease, and then the sort of toxin clearance impaired version of the disease, to me, I'm generally most optimistic about the metabolic one. So the variant of this disease that seems to be mostly due to a failure of energy metabolism in the brain, that also strikes me as the one that's most amenable to systemic therapies as well. If you improve insulin sensitivity, if you improve glucose disposal, if you reduce hypercordicylimia, you can actually, through nutrition, exercise, sleep, a number of other things start to modulate that. That strikes me as the one where you want to at least take your first shot at adding rapa.
I think you're probably right. Although again, with rapa mysons, because we know that it is effective at, for example, turning up autophagy, it might also be- It might work in the harder ones, but it's a harder one. I agree. I tend to agree with you.
I think that's a good point. I also want to add that I actually think the biggest problem with the way that the scientific community has thought about Alzheimer's disease, aside from considering it to be one disease, is not really recognizing that it's a disease of aging. I really think that one of the reasons why the preclinical research has been disappointing at developing therapies for Alzheimer's disease is because very rarely have people approach that from the perspective that this is a disease of aging. Something that can affect the mouse models of Alzheimer's disease when we create this disease in young mice may not work the same way in an aged person or an aged animal.
That's one of the things that also makes me optimistic about rapa mysons is we already know that it hits the hallmarks of aging. It also seems to be effective in these Alzheimer's disease models. That makes me think that it's acting as a more fundamental level to target the molecular causes of this disease. Well, especially if you can regenerate a cardiac myocyte from its stem cell, it's not an impossible thought that you can regenerate neurologic stem cells.
Absolutely. And this is again an area where- Which I mean, 20 years ago, we would have said that's impossible, but it's physically impossible. Going back to the dogs for a moment. Again, I'm not familiar with dog literature.
What does the fasting literature look like in dogs? There's not a lot that I'm aware of either. I think that makes sense. First of all, you have to differentiate the literature in.
Laboratory copies from companion dogs. There's probably not much in companion dogs. I don't know of true fasting experiments in like these- So we can't use like the fasted versions as proxies for what we would hope to see on the rapid dogs. Which is the way they sort of did in mice, right?
They sort of said, well, you know, we know that if you calorically restrict this mouse, this strain of mouse under this degree of caloric restriction can expect this much of a longevity boost. And oh, lo and behold, a rapamycin is probably even better than that. Right. Although from a metabolic perspective, I think it's still unclear even in mice whether rapamycin and caloric restriction are working through the same mechanism.
And this is actually another area where there haven't been a lot of good experiments done. And so there's a portion of the field that argues strongly that caloric restriction and rapamycin are completely different. Which to my mind is absurd. I mean, we know that one of the main things that caloric restriction does is it inhibits mTOR.
And we know that rapamycin inhibits mTOR. So they're not fundamentally different. So I think they are overlapping but distinct. Not everything that caloric restriction does is going to be mimicked by rapamycin and vice versa.
Having said that, when you look at the gene expression profile or the metabolic profile, they don't look all that similar, at least at the low doses of rapamycin. And so I think it's a little bit unclear. You're right, lifespan. They both extend lifespan.
Rapamycin might actually extend lifespan across a broader genetic background. Yeah, yeah. And caloric restriction. But when you get beyond that, I think it's still an unknown whether there are, you know, say, are there metabolic signatures that are common to both that might therefore be more likely to be causal.