Podcast Host (3:36)

I think also you have to couple that with the amount of people that are fed from fear mongering. You know, I think people are really interested in longevity because people are scared they're going to die because they've got, they've had glyphosate on their oats.

Dr. Matt Capelan (3:49)

Yeah, I mean, I think certainly there is a lot of fear mongering and, and I don't even want to say that that's necessarily intentional. Like, I think there are some reasons where, you know, we should be a little bit worried about our environment and what we're being exposed to. Again, unfortunately, that gets taken to extremes and people can get clicks by scaring people. I mean, we, we see this in politics, we see it all over the place that that's one way to get people to pay attention. I think, I think what really is most challenging for me is the fact that, you know, it's so easy to get clicks or to get people to follow you by either, like we, we just said, scaring people or by giving people, you know, easy answers that maybe aren't very based in fact. And what I think we need more of are honest voices speaking from a place of integrity and helping people understand, you know, there are lots of things you can do to improve your health, but you don't have to go down the rabbit hole of taking 50 supplements and, you know, having this really complicated protocol first thing in the morning where you do all sorts of silly stuff. I think there's an 80, 20 to be had here where you can get 80% of the benefit from doing the things that really matter.

Podcast Host (5:03)

Well, why don't we start with some of the false claims that are out there and maybe you can clear some things in the air. And I'll ask you the first question, and I want to know the truth behind NAD without going so deep into the education behind it. Maybe not even touching on the Krebs cycle. I think there is a lot of people out there capitalizing on NAD IVs. I'd love to understand NR, NMN, and then NAD.

Dr. Matt Capelan (5:27)

Sure. So, okay, so let's start with that. So NAD is central cofactor for life. Lots and lots of different chemical reactions in every cell in our bodies, in every animal cell on this planet. And it's, you know, probably on the order of thousands of different chemical reactions that NAD participates in. So, super important, the NAD molecule has several precursors that during the synthesis of nad, are used to make nad. And that's where things like nmn, nicotinamide mononucleotide, nr, nicotinamide riboside. There's also niacin and nicotinamide are the other two cofactors that can be taken orally. Idea is if you take those as pills, you will increase the level of NAD in your body. It'll get into circulation, get turned into nad, get into your cells, and you'll have more NAD to carry out these reactions. So that's the concept we can talk about, you know, how important is it to get more NAD in your body? That's one question, I think. But then another way to do it is these NAD drips. And the reason why you would do NAD as an IV as opposed to orally is because NAD itself, the molecule, is not bioavailable. So. So that's why you would take the precursors if you wanted to take a pill, or you could go into a clinic and by iv, get NAD put directly into your circulatory system. But the goal is the same. The goal is to increase NAD levels available for your cells to use for these chemical reactions. So all of this relies on the idea that that's a good thing, that we need more nad, and that I think, you know, there's some science to support that in certain people in certain cases. But there are also lots of questions whether or not that's true for everyone. And this is where I think we also need to be clear whether we're talking about longevity per se. So when I think of longevity, I use sort of the literal definition Are we talking about trying to increase lifespan and. Or health span? So I'll include health span in that. And most of the time when we're talking about that, we're talking about doing that by targeting the biology of aging, the biological mechanisms that underlie the aging process. So it is a hypothesis that has gotten a lot of traction that with age, NAD levels decline. If that's true, then increasing NAD levels might have some benefits. I think. I say if it's true because it's not clear at all that that's generally true. It's sort of become dogma and gotten amplified. But it's not really clear that NAD levels always decline with age in every animal or certainly not in every person. So my sort of personal feeling is that NAD precursors or NAD drips could be beneficial for some people, probably not beneficial for all people. And when you look at the literature, it's a really real mixed bag in the sense that there have been some studies that report NAD can increase lifespan in laboratory animals, have some health benefits in people. Other studies that failed to replicate those initial studies. So it's really hard to know with a lot of confidence how solid is this? I put it in a. I'd say it's a solid maybe right now. I'm not saying there's no value to NAD precursors. I'm not saying that NAD isn't important for aging. I think it probably is. But it's a very complicated situation. And I don't think there's much evidence that just taking an NAD precursor or getting an NAD drip is going to generally be a positive thing for most people. The last thing I'll say on this, there's a lot of confusion about the different precursors that are out there. So again, nmn, nr, niacin, nicotinamide. There's also nicotinic acid, riboside, but that's less common. They'll all do the same thing. You can take them as pills. They probably all get broken down into nicotinamide or niacin by the gut microbiome, get taken up that way, and then get resynthesized back to nad. So there are people who will sell you very expensive NMN and NR pills. Not much evidence that if taking an NAD precursor is valuable, that that's a better way to do it than taking the very cheap nicotinamide or, or niacin. And I don't really know a lot about the NAD drips. I've heard, again, anecdotal stories, but I. I haven't seen anything that makes Me really believe they are, you know, particularly beneficial. I haven't tried it myself, so I can't say from experience one way or the other.

Podcast Host (9:32)

Yeah, I, I, I've, I've heard a mixed bag of reviews. I've heard that it doesn't penetrate the cell. I've heard that if you have NR or nmn, you can increase NAD levels intracellularly. So it just, it's just so it doesn't make sense to me. I hear it and then you look at all the different specialties amongst physicians and there's a lot of fertility doctors who are actually telling people to take a lot of women who are having problems with fertility or even with low amh, low egg reserve to do nad. And I hear reports of they've increased, they've increased their egg count, which I also thought didn't exist. So I just hear so many different differing opinions.

Dr. Matt Capelan (10:16)

Yeah. And I mean, I think there is a little bit of evidence from animal studies, this is in mice now that at least in certain situations, NAD precursors can boost fertility in female mice that are going through the normal aging process. Same thing's true with rapamycin. I don't know if we'll talk about rapamycin. So again, the idea here is if you are effectively targeting the biology of aging, you might have a positive impact on the natural decline in fertility. I'm not aware of any evidence in people and I think one of the things we see in this space right now is a, a very low threshold to go right from a single animal study into humans, especially with something like a supplement that isn't regulated. There are, there seem to be lots, well, definitely there are lots of companies that will sell you these products. But there seem to be a growing number of medical professionals who in my view are taking a pretty cavalier approach and going right from a single mouse study to prescribing these to their patients without any, any way of really knowing whether or not these therapies are beneficial, potentially harmful, you know, what, how it's all going to wash out in the end.

Podcast Host (11:25)

Yeah, I mean it's, it's one thing to actually see the results like increasing cellular nad, but it's another thing to know if it's actually having a positive effect.

Dr. Matt Capelan (11:34)

Well, even that, I think most of the time people aren't measuring cellular nad. You know what they will typically do? I mean, I guess maybe if you talk about blood cells, but what they'll typically do is take a blood sample and measure NAD levels directly from blood. Even that's non trivial. So I think there is a technical component here that people don't always appreciate, which is that there's, there's the total amount of nad, but there's a reduced version of NAD called nadh. And so the, that what you're actually often measuring. Right. Is not the total amount of those two molecules, but only the nad. But depending on how you process the sample, you can, you can dramatically change that ratio because it's just an oxidation reaction. So all I'm saying is it's not, it's not trivial to do a good job of measuring quantitatively NAD levels. And so even when people say that they see a change in nad, it's not always the case that we really know how accurate that is.

Podcast Host (12:28)

And it's going to be a while until we have the true randomized control trials to back it up.

Dr. Matt Capelan (12:33)

Yeah, I mean, there have been a few very small trials, sometimes randomized, sometimes not, but none of them are. I mean, they're all designed to really be safety trials and none of them are really designed to show efficacy. So it doesn't have to be a long time, but it probably will be a long time simply because, you know, there's no profit motive really because these are, these are generally recognized as safe molecules. Anybody, any supplement company can sell them. There's really no motive to do the very well controlled large scale clinical trial. I will say there have been a couple, mostly around things like Parkinson's disease that look intriguing. Again, not definitive, but like I said, intriguing early results. I think those are with nicotinamid riboside primarily. So I think we'll have to wait and see. If I had to guess, I would guess there probably are certain conditions where you have particular types of mitochondrial dysfunction where supplementing with an NAD precursor could be beneficial. I'm pretty. And so that could be something like Parkinson's disease or other disorders where you have specific types of mitochondrial dysfunction. I'm pretty skeptical that for the typical person, supplementing with an NAD precursor is going to do much. It might do a little bit, but it's probably not going to really move the needle.

Podcast Host (13:49)

I mean, what we're essentially doing then is improving the mitochondria if we talk about aging. Right. Is that what we're like with, with all of the available supplements now? It is pretty much improving the efficiency of the mitochondria to work better.

Dr. Matt Capelan (14:04)

I mean, that's, that's a, that's, it's easy to say. That's a tricky thing to measure or prove. Right. I mean, again, what do we even mean when we say improving mitochondria. Like mitochondria do a lot of different things in the cell. I mean, they're typically talked about as the powerhouses of the cell. Right. They make ATP, which is the energy currency of our cells, but they also do a lot of other stuff. Right? They're important for, you know, redox homeostasis, making iron sulfur clusters. Right? They do, they do a whole bunch of things. And so when we say we're improving the mitochondria, it's not even really clear what that means or how you would go about showing that in a, you know, quantitative way if you were trying to measure it in a laboratory. So I think, unfortunately, that's, that's one of these phrases that non science, non scientific people like to use because it sounds great, but it doesn't actually mean a whole lot because we don't really have a good way to measure. So I think what I would say is there are a few ways that NAD precursors could be working. One of the things that happens when you have certain types of mitochondrial dysfunction is you actually get an imbalance in NAD to nadh, and it's a little bit complicated, but that's because you need the mitochondria basically to take the NADH and turn it back into nad. So oxidize the NAD so you can continue to do central metabolism. So if you have certain types of mitochondrial disorders, you get too much nadh, not enough nad. You could imagine supplementing with NAD in that context could be beneficial, but there are other things that go along with that. You also tend to get too much lactate. Right. And so there's a lot of complexities here where it's not even completely clear that just supplementing with an, with an NAD precursor would be enough to fix the problem. But you're right in the sense that if we look at interventions that are effective at increasing lifespan and improving health span in laboratory animals, one of the common themes is we preserve metabolic function and mitochondrial function later into life. So maintaining mitochondrial function. So, so let's. Two things to say mitochondria become damaged with age, there's an accumulation of damaged mitochondria, and maintaining healthy mitochondrial function goes along with healthy longevity. But again, you know, I say that and then I'm like, but we don't really know exactly what that means at the mechanistic level.

Podcast Host (16:24)

All right, well, something else that's actually boggling me. Okay, so back in January, I got a biological age test and I've heard you, you're a, you're one of the best aging scientists. I mean, I should say scientists focusing on aging, not the aging scientist.

Dr. Matt Capelan (16:41)

Right. I'm both, I, I, yeah, both are happening.

Podcast Host (16:46)

Is measuring our biological age an actual thing?

Dr. Matt Capelan (16:51)

Yeah. So I want to be a little bit careful here, to be precise. So here's what I would say. We cannot quantitatively measure biological age. It just can't be done. Right now what we can do is we can measure things that are correlated with biological age. So what I mean by that is, you know, there are lots and lots of things that change as we get older. Right. If they change in a predictable way across the population, they're going to be correlated with biological age. The color of your hair, the wrinkles on your skin. But we can look internally, the function of your organs, we can look at molecular changes, we can look at epigenetic changes, which is what many of these biological age clocks are measuring. So what they're actually measuring are those specific things. So in the case of the epigenetic age clocks, they're measuring specific molecular changes, methylation patterns on DNA, they're not measuring biological age. And those epigenetic patterns are correlated with either chronological age or your risk of dying, mortality, or your risk of developing one or more age related diseases. None of them are even directly correlated with biological age. But those things, chronological age, mortality, your risk of developing one or more age related diseases is correlated with biological age. So in reality, these things are a correlation to a correlation to biological age. And again, maybe that doesn't matter. Like that doesn't mean they're not useful. I think it's useful to be able to have something you can measure that is going to predict with some degree of accuracy whether you're going to get sick, whether you're going to die. Because in principle, if it's accurate, you could then do something, measure it again, and know if your risk of dying went up or down or your risk of getting sick went up or down.

Podcast Host (18:40)

So I did a biological age test and it came back 10 years younger than what I actually am. What does that mean?

Dr. Matt Capelan (18:47)

It depends on which test it was. But what it probably means is that the specific methylation patterns that were measured suggest that your risk of most likely dying, so you're probably three or five year risk of dying, is that of somebody who in the population would be 10 years younger than you. In other words, whatever your chronological age is, if we look across the population, people who are 10 years younger than you have some risk of dying in the next 10 years. And that that's what your risk is. Maybe approximately. Now, again, it's a, I understand that some people are like, you're just being pedantic. It doesn't matter. That's biological age. I, I, I, I see that viewpoint, but it, but I think it is important because at least as scientists, like any random person wants to go out there and sell a biological age test, like they can do that. But science scientists should not be claiming that we can measure something we can't measure. That's just, that's not the way.

Podcast Host (19:47)

Oh, God. That would kill the entire supplement industry. And social media probably wouldn't. The health on social media probably would be very different.

Dr. Matt Capelan (19:54)

Well, maybe again, I think, you know, it's, it's a little bit of a complicated concept, but I think most people can get it. And most people probably could see the value of a test that gives them some likelihood that they're going to get sick in the next five years. Right. Like, I think there's value there, but that's not biological age. That I think is the important point. And again, I recognize that there is value in popularizing this concept of biological age. I'm totally all for that. And so even though I push back a little bit against claiming these things are measuring biological age, I think there's been a lot of good done by sort of popularizing the idea for people that there is this thing called biological age. And, you know, it is different in different people. And we can speed it up or slow it down by what we eat and how much we exercise and how much sleep we get. So I think that's all valuable. I'm almost okay with it in the, the social media realm. But where I feel like it's problematic is when it gets in the scientific literature and that and it has and that I think that just creates sloppy thinking among the scientists. And as soon as a field starts, you know, being sloppy in the way they're thinking, they start to make mistakes. And there have been a lot of mistakes, I think, made in the field of geroscience because of this sort of sloppy terminology and sloppy thinking. And at some point, you know, people forget that we can't measure biological age. Or you have a whole generation of graduate students who believe that we're actually measuring this thing that we're not measuring because we don't understand what biological age actually is in any sort of, you know, mechanistic detail right now.

Podcast Host (21:26)

So then what do you think about Brian Johnson?

Dr. Matt Capelan (21:31)

That's a complicated question. I mean, look, I think he's Done a lot of popularization for again, the concept of longevity. I have some, some challenges with what I would call a lack of accuracy or honesty in the way that he has presented himself. I think he, you know, it's become clear that he doesn't always share all of the data and he selectively shares data. And I think again, as somebody who claims to be scientific, that's not the way. I mean, if a scientist did that, we would call that fabrication of data. Right. That's like the worst thing a scientist can do. So he's not a scientist and he should not be perceived as a scientist. He's in many ways an entertainer. And I think if people view him as an entertainer, that's fine. I get concerned when people start taking medical advice from him or if they view what he says as in any way representative of the real science of the field.

Podcast Host (22:25)

Yeah, I think some of the, the claims that he makes is wildly overestimated and he does have a large popularity and people following him, which has now breeded this entire new industry of so called longevity experts. I think to myself, what does that mean? What is a longevity expert? If you've never been to college or university, how could you claim to be a, how could you actually claim. How do you have the audacity to claim yourself as a longevity expert? Are they just watching your podcast or Peter Atia's podcast and just maybe putting into ChatGPT and then relaying that back to people? I mean, to have an actual understanding of longevity, you have to understand cell biology at, at the, at the very least.

Dr. Matt Capelan (23:16)

Yeah, I tend to agree. Again, I'm, I'm not against, like, I think people can, can gain expertise in all sorts of things in a variety of way. So I'm not somebody who says you have to have spent, you know, years doing primary research and published a bunch of papers. That helps for sure. I mean, you're going to gain a much deeper knowledge and understanding of the topic, especially I think the science of, of longevity. And that's where I feel like the term longevity has become such a catch all these days that you could mean all sorts of different things. Right. Is understanding, you know, how to work out, well, being a longevity expert. Well, I mean, maybe that's part of it, right. Is understanding what a good quality diet is, being a longevity expert. Maybe that's part of it, but it's not the science of longevity, which is where I spend most of my time. Right. So I think, I guess what I would say is I'm not so worried about People who are enthusiastic about the topic, who do their homework, who understand, you know, some of the nuances and the probabilistic nature of this stuff. And there isn't a one size fits all for everyone. I think there are lots of good communicators out there. And then there are lots of people who just want to, you know, become popular, get clicks and, you know, just put bad information out there. And so it's just, again, it's just the reality of the world we live in. I've seen so many people who call themselves longevity experts these days that I'm almost immune to it. Like, I'm just like, okay, you're another one. Add it to the group. Right? I mean, yeah. And the last thing I would say is, look, there are people who have, you know, very impressive scientific credentials who spread a lot of misinformation as well in the longevity. So, you know, credentials aren't everything.

Podcast Host (24:51)

That's true. No, I definitely agree on that. Well, why don't we move on to something else that you think. And I'll let you take this one that you think is getting a lot of spotlight right now that doesn't deserve to be. Is there anything, whether it's a tool or a supplement or an activity.

Dr. Matt Capelan (25:07)

So here's what I would say. I don't know that I would say doesn't deserve the spotlight. I would put it more in. And I'm gonna. I'm not gonna talk about the science. I could talk about the science. Like, areas of the science, I think are getting a little bit more attention than they probably deserve. But for now, I'm gonna talk more about the popular stuff that gets presented up there. I think of it more as in buckets of, like, what really matters and what might be incremental and what probably doesn't matter at all. And so I think, you know, when you get outside the realm of what really matters, there's a whole bunch of stuff that people are talking all the time about that may or may not have any incremental effects or might even be harmful in some cases, but is not really going to move the needle for most people. And most of the. It seems to me, again, I was really being honest when I said I don't pay that much attention to social media because it just annoys me. But it seems to me what I do see, most of the stuff in the in that gets a lot of attention is in that bucket at best, is probably incremental. So I put, essentially, I don't want to say all supplements, but Almost all supplements in that bucket.

Podcast Host (26:09)

Even Coq 10?

Dr. Matt Capelan (26:11)

Yeah, absolutely. I don't think that is going to move the needle for most people by a large amount. I could be wrong. Again, this is just my opinion, but there are so many supplements out there that it's really hard to know what's in the. You know, people should really pay attention to this versus what's just being marketed like crazy. So I would say there are some things you can measure. Right. And you should probably supplement if you're deficient. I think creatine, again, that might be overhyped, but it probably has some benefits for lots of people. Again, that's probably incremental, but it probably has benefits. We could have a discussion about Coq10. I don't have a strong opinion about Coq10. I'll just say. But in the longevity space and again, this is where I think Coq10 is interesting. Right. So if you look at it from the perspective of biology of aging, a very mixed bag, whether there's anything there or not in terms of does it actually impact the biology of aging when you look in the laboratory studies, not convincing at all. And of course that's my background, so that's where I started from. There's not a lot in the supplement space that you can say with any level of confidence moves the needle in terms of the biology of aging, now does that? That doesn't mean people don't get benefit from it or some people don't get benefit from it. So anyways, I would put almost all supplements in the bucket of not going to have a big effect for most people. I would put things like cold plunge and sauna and hyperbaric oxygen therapy and all of those things in that bucket. Like I don't see a lot of evidence that these are things that everybody should be doing. What should everybody be doing? You should be eating a healthy diet. You should be moving regularly. Right. You should maintain sufficient muscle mass. So pay attention to your body composition. You should be getting good sleep and you should go out and have fun with other human beings. Have some relationships. Like those are the things that really move the needle.

Podcast Host (27:56)

Yeah. I always say that. Everyone on the podcast knows that. I always talk in terms of a pyramid. If you are doing mother Nature's gifts, everything else is maybe 0.1%. I'm going to move the needle forward. But sadly, the world sees it a different way. You know, they feel like they can ice bath their way out of a good diet.

Dr. Matt Capelan (28:16)

Yeah. I mean, again, I don't know how many people actually believe that, but people really want to believe.

Podcast Host (28:20)

Yeah, the placebo effect is real.

Dr. Matt Capelan (28:23)

And actually I think that's an interesting topic. Like so, so, you know, I do believe that some people get benefits from supplements or even off label use of medications because of the placebo effect. And part of me says, you know what, if you take it and you feel better and it's not hurting you, great, keep taking it. Right. So I do think there is some potential value to that. But again, I don't think any of those things are going to make up for living an unhealthy lifestyle.

Podcast Host (28:50)

Well, why don't we then open up the conversation about rapamycin. You, you mentioned it earlier. I want to know, is there a difference in terms of sex if we take this, like if a man takes it, a woman takes it?

Dr. Matt Capelan (29:02)

Yeah, I mean, I'm sure there are. I think we don't know a lot about what the sex specific differences are. So what I can tell you in mice is female mice, at least in a couple of strain backgrounds where this is been looked at, tend to respond to a lower dose of rapamycin. Whether it's better bioavailability or slower clearance, I'm not sure we know which. So at a given dose of rapamycin there's a higher effective concentration in females than males. But if you, if you give the males enough, they will catch up to the females in terms of magnitude of lifespan extension. So there doesn't really seem to be any sex difference in the amount of benefit you can get in mice. It just takes a higher dose in males. I don't know of any evidence in humans that that's the case. The only real data, and it's pretty weak that I'm aware of outside of potential effects on, on ovarian function, which we can talk about in humans. The only real data that is even suggestive of sex dependent effects I'm aware of was from this Pearl clinical trial, this distributed clinical trial. And it was a complicated outcome because they were, their dose was too low. Basically the bioavailability of their dose was too low. In that trial though, the only potential benefit they saw was in women for preserving muscle mass or maybe even gaining muscle mass. And in the men they didn't, they didn't see that. So we don't really, I wouldn't draw too much from that other than to say that's the only data point that I'm aware of in humans for a potential sensitivity or sex specific effect.

Podcast Host (30:33)

Well, why don't we talk about what rapamycin is doing for ovarian function. That's really interesting to me.

Dr. Matt Capelan (30:39)

Yeah. So again, I think we have to say in humans, we don't know for sure yet. So in mice, what has been seen now from multiple labs is that, you know, mice don't go through a true menopause, but they do show a decline and eventually cessation of ovarian function with age. And during that process, there's a hyperactivation of mtor. So MTOR is the protein that rapamycin inhibits. And if you treat mice with rapamycin, female mice, you can actually preserve ovarian function later in life and at least up to some point, even reverse declines in ovarian function. This is read out both through molecular markers of ovarian function and through fertility. So this actually you can see the functional outcome in terms of fertility. I haven't seen any data yet from the only clinical trial I'm aware of in humans right now testing this, which is being run out of Columbia, where women with premature ovarian failure are being treated with rapamycin. This is a randomized placebo, controlled clinical trial. So I'm not aware of any data coming out of that, except I've heard that it seems, you know, that they're having good safety, so they aren't seeing any significant adverse events. So I guess we'll have to wait and see what the outcomes are from that clinical trial to know whether or not rapamycin in that population can improve ovarian function.

Podcast Host (31:55)

Well, why don't we just go through a very low level understanding of what rapamycin actually is and how it's affecting longevity?

Dr. Matt Capelan (32:03)

Yeah, sure. So rapamycin, as I mentioned, is an inhibitor of this protein called mtor. What MTOR does is it's a key sensor of the environment that basically helps every cell sense the environment and make a decision. Is it a good time to grow and reproduce? So at the cellular level, this is cell division, or is the environment such that it's better to shut down growth and reproduction and become stress resistant? And one of the key cues in the environment that helps make that decision is nutrient availability. So how much food is around? There's not any food around. It's really bad time to have babies because, you know, everything to feed them. So MTOR is sort of that gatekeeper. And so higher MTOR activity. MTOR is stimulated by nutrients, primarily amino acids. But now we know that it can be affected also by carbohydrates and fats. So you can think of it just as sensing Cal at some level. So when there's lots of food around, MTOR gets activated. That's a signal for growth and reproduction. Again, from an evolutionary perspective, that makes sense. When there's not much food around, MTOR gets turned down. Rapamycin as a drug turns down mtor. So in some ways people would call it a caloric restriction mimetic. It mimics the state of low nutrient availability, tricks the cell or the organism into thinking there's not much food around. So what we've seen is when you treat all sorts of different animals in the laboratory with rapamycin, they live longer and it seems to delay or in some cases even reverse the functional declines that go along with aging across lots of different tissues and organs. In mice, you can even start the treatment in middle age. So these would be about the mouse equivalent of 60 to 70 year old people. Most of the benefits in terms of healthspan and at least some organs and tissues, you actually see a reversal of the molecular changes of the functional defines, including the ovaries, but also the brain, the immune system, the heart and the oral cavity. So we don't know yet whether that's also going to be true in people. But it's encouraging because you can do this in middle age and that's really what you want from a drug that you might think about testing in humans for effects on biological aging, something you can start giving to people when they're 50, 60, 70 years old. So it seems to be the most promising drug or supplement right now in terms of both magnitude of effect in mice and reproducibility. So I alluded to this earlier for, you know, I think all sorts of reasons. I mean, science in general, oftentimes you'll have results that can't be reproduced. In the longevity field in particular, especially in mouse studies, that seems to be a real challenge. There are several drugs or supplements that were initially reported to increase lifespan in mice and then could not be reproduced. Rapamycin, as far as I know, every single person who's ever tried to get it to increase lifespan in mice has been successful. So works for everyone, works across different genetic backgrounds. So far I don't think we found a genetic background, at least not a wild type genetic background where rapamycin doesn't work in mice. So it's robust, reproducible, which again is very encouraging if you want to think about something you might consider taking out of the laboratory and trying in the real world.

Podcast Host (35:14)

And why isn't it readily available?

Dr. Matt Capelan (35:16)

I mean, it is in the sense that it's a prescription drug, so it's been FDA approved. You need a doctor to prescribe it for you. There are, you know, lots of people, I don't know what lots is. Tens of thousands of people now probably taking it off label. And I expect that number will continue to increase as we start to get more and more hints that first of all it can be done safely. I mean, obviously that's really important if you're considering taking a drug for the possibility it might have benefits, because we don't know yet. And I think we're starting to get early evidence for at least some conditions that rapamycin can have benefits in a subset of people. So the things that I think a lot about are chronic inflammatory diseases where there have been lots of anecdotal reports there, there are now again multiple pieces of evidence. None of them rise to the level of the, you know, thousand person randomized controlled clinical trial. So just get that out of your head if you want that. You're not going to get it with rapamycin right now. But what we're starting to see are multiple small studies, multiple case reports for chronic viral infections. So again, this is probably long term inflammation caused by severe viral infections. So long Covid would be one example of this where rapamycin seems to be beneficial. There was actually a paper that just came out on chronic fatigue syndrome. Turns out many cases of chronic fatigue syndrome are post viral infections. So probably again a long term inflammatory response to a severe viral infection. I think it was something like 3/4 of the people in that study responded well to rapamycin. These are real world patients being prescribed rapamycin off label. And then there are some interesting hints in people who are at high risk of dementia because they carry the ApoE4 allele. So there have been a couple of again, very small studies recently with ApoE4 heterozygotes with rapamycin. Two studies, I think both of them looked at cerebral blood flow and saw an improvement and one of them saw an increase in brain volume in the hippocampus and caudate nucleus in the people taking rapamycin. So, you know, it's like, I wish we had the gold standard data to point to. We don't. So we're sort of stuck with these, you know, small studies. But if you see enough arrows all going in the right direction, you start to have a little bit of confidence that there's probably something real there.

Podcast Host (37:37)

I noticed that, unless I noticed wrong, that you went through plasma exchange.

Dr. Matt Capelan (37:45)

Yeah, just tried that recently.

Podcast Host (37:47)

So I'm that Really interests me in the area of brain health, longevity, because I think I've read where you can eliminate a lot of the toxins that are built up and throughout your body over the many years. Eliminate them. What I'm not too bullish on is the fact that you have to repeat it, I think like three or four times in a year. So plasma exchange is real. It's a. It's a real. Like there is benefits to it.

Dr. Matt Capelan (38:15)

Are you asking me?

Podcast Host (38:16)

I'm asking you because it's so expensive. I don't know if you. I don't know where you got it done. And this is for the average person, it's around $10,000.

Dr. Matt Capelan (38:23)

Yeah, it depends on where you go. But yeah, it can be anywhere from 5,000 to up to 15,000. Yeah. So I don't know. I mean, so here's what I would say. I did it, you know, in part because I like to try these things myself before I develop opinions around them. I think one of the reasons why I believe that plasma exchange probably has benefits. So there's actually two reasons. One is based on the, you know, pre clinical literature on heterochronic parabiosis. The idea that you hook the circulatory system of an old mouse up to a young mouse. The old mouse does better, the young mouse does worse. So the idea is there are factors in circulation that accumulate with age that are detrimental. And if you can dilute those out, there can be some beneficial effects. That makes sense. We know that chronic inflammation is one thing that happens across the population with aging. So it could be as simple as just diluting out these inflammatory cytokines and other other factors there. But I think there's more to it. And lots of other people have tried to identify other factors with mixed success. So that makes sense. And then the other part that makes sense is, you know, we are learning, we've known for a long time that we get exposed to all sorts of environmental toxins that accumulate in our cells, our tissues with age. Heavy metals are one example. And of course now there's a lot of concern about microplastics, but there's all sorts of stuff in our environment. Right. And it is intuitive to me that diluting those out, you know, is not going to be a bad thing. And there's probably going to be some benefits that goes along with diluting those factors out as well. So it makes sense. Like you said, though, probably in order to do that effectively, it requires multiple rounds of therapeutic plasma exchange. And you know, really to get the full benefit you probably have to do it for the rest of your life, maybe every three months, like we really don't know. So is it practical, pragmatic right now? No, it's especially for most people because of the cost. It absolutely is not. And again, you know, we can talk about things that are going to have a big effect and things that are going to have a small effect. I guess I, and I don't know the answer to this. If I had to guess, I'd probably put therapeutic plasma exchange in the small effect bucket, but towards the higher end of that, right? Again, I don't think it's going to be as good as, you know, if you're sedentary, starting to exercise regularly. But, you know, if you think about all the things you can do that might have small effects, again, it's a guess. But to me it's very plausible that diluting out these toxins could have a benefit for lots of people. And I think the microplastics, you know, in particular is really interesting because we don't know yet how bad that's going to be. Right. I think there's no question that we're all being exposed to these microplastics all the time and they accumulate in our bodies. We, in some people, they contribute to plaque development and probably other pathological conditions. We don't know if that's true for most people or a small fraction of the population. And we don't know how much you can modify it by modifying your environment, but it's probably not a good thing. And so diluting out the microplastics probably going to help. We just don't know how much it's going to help. So again, I don't think it's something that everybody needs to do and certainly it's not within the affordability range for lots of people. But I think that, you know, as we learn more about how large the benefit is and, and perhaps as this technology becomes more widely distributed, the cost will come down.

Podcast Host (41:42)

The reason I ask that is because I went and got a total tox screen where they basically it was a urine test and there's around 700 different things that they measured. And I actually surprisingly, and I blame New York City for this, it came back as high in a heavy metal that I can't pronounce, but also nickel. And I was like, where am I getting nickel from, for God's sake? And then I was interested in doing therapeutic plasma exchange to obviously eliminate that bring about look out of 700. I don't think that I Think there was only probably about 100 where I was in the green light. And so, and I'm a very healthy person. So now I'm thinking, and I want to know if this is true, am I able to eliminate some of these toxins through sweating through sauna use?

Dr. Matt Capelan (42:32)

First of all, I will say I haven't really looked into the literature deeply on this. I know that people talk about that. I don't know how clear it is that you're going to have a large effect on eliminating toxins through repeated sauna use. Again, you know, I think the evidence is on whole is pretty consistent that sauna is probably a good thing for lots of people. Again, there's going to be some nuance there and exactly how you do it, how often you do it and all of this stuff. But probably a reasonably good thing for probably a variety of reasons is eliminating toxins. One of those reasons could be one of the things that I've sort of thought about and actually tried to encourage Circulate, which is the company that I did the therapeutic plasma exchange through to do is actually, I mean, when they take the plasma out, they just discard it. I'm like, why don't you measure what's in there? Like, show people what you actually took out of their body, right? Show them all the toxins that you took out. Start to quantify this because I think that's actually really important. That's obviously hard to do with something like sauna to quantify how much you sweat it out, but, but I think it's easier in some ways to measure what's in the plasma you take out than measuring what's in the circulation. You know, when you do a blood dryer or a plow, did you feel.

Podcast Host (43:44)

Better when you did it? Like, did you actually feel better?

Dr. Matt Capelan (43:47)

So again, placebo effect, right? Who knows for sure? I, I definitely felt really good right after and I slept really, really good that night after that. I can't say anything. Like, I don't, I don't know, I didn't really notice anything one way or the other. It's not like I suddenly, you know, felt great, but I would definitely say I slept very, very solid the night afterwards. And we just got the, the blood work, the post TPE blood work back. I haven't had a chance to dive into it. So there are two of us who did it together and we want to compare to see, you know, if any of the changes were similar across both of them. So I haven't had a chance to really dive into that and then we also got a microplastics assessment before, right after and then we're going to do another one a month after. But those haven't, haven't come back yet either. So we'll, I can report back once I, once I get the data. But I mean, I, I would say, you know, it wasn't anything where I would definitely say that I noticed a big change. I should also say, I mean, I haven't done much in my life where I would say that. You know, I can say with 100% confidence this had a huge impact on my health. There are, you know, a few things that I've done that definitely did, but by and large, you know, the, the, the majority. And I've tried a lot of supplements, I've tried a lot of stuff. So I don't know if I'm, you know, resistant to placebo effect or I'm just not very observant or what. But I can't say, I can't say.

Podcast Host (45:11)

There'S a lot where, yeah, like, because I, I live a pretty healthy life. I don't smoke, I don't drink, I sleep, I exercise. It's like, what, what, what could make me feel better. I'm actually looking for that. I'm telling you, a good night's sleep, which is very hard for me right now to come by with how crazy I am in my schedule. That makes me feel bulletproof, I'll tell you that. All right, what about GLP1s? So I am on. So, you know, I'm an Alzheimer's disease researcher. I believe they are promising. I, I am all for even tirzepatide, GLP1 and GIP. I think they're promising. I even think it's promising to micro dose GLP1s. I think it's promising for the fact that one of the major risk factors of Alzheimer's disease is type 2 diabetes, obesity. If this is helping insulin resistance, if it's helping in those aspects, then of course it's beneficial. The only thing that I caution people with is make sure you're having, you know, at least 100 grams of protein a day and maintaining muscle mass. But outside of that, I think this is going to be one of those miracle drugs, right?

Dr. Matt Capelan (46:14)

I certainly could be, yeah. I mean, again, I think all signs are pointing to the idea that these drugs can have a huge impact on health, broadly speaking for lots and lots of people. Right. So miracle drug. I don't know if I'd characterize it that way because, you know, we actually understand the Biology, a fair amount of why they're working, but certainly something that can move the needle for lots of people. So I think where I would say in my view there's still a question is in people who are healthy weight. Right. Or, and, or eating a healthy diet and have a healthy body composition, do you get an added value from these drugs either through even better metabolic function or through effects of the GLP1 agonists in other ways? Right. So this question of are there effects of these drugs targeting the receptor throughout the body that we don't understand anti inflammatory, maybe other, other ways. That's an open question and I think it's an interesting question. Do these drugs target the biology of aging outside of a caloric restriction effect? So again, you know, we know that improving insulin sensitivity, improving metabolic control appears to be one of the most profound ways to slow aging. But do these drugs have effects on longevity healthspan outside of that I think is a really, really interesting question. And you know, then if they do, then the question becomes, you know, do you start prescribing lower doses of these things to people who are as preventative. Right. As an anti aging drug? Maybe. So it's really, really interesting. It's exciting. I think also fair to say we, we need still to have a little bit of caution what the sort of long term consequences might be over, you know, decade plus in a large number of people. Especially if we're starting to think about giving this to people who are not significantly metabolically challenged or significantly obese. I don't think we know the answer to that yet. But I'm not trying to be a fear monger. I think we just should be to just say that we don't know for sure what that's going to look like. But I haven't seen anything yet that makes me super concerned that we're going to suddenly uncover some terrible side effect, you know, in the subset of people 10, 15 years down the road. I do think what you said though about maintaining muscle mass and making sure that especially if people are seeing significant body weight loss when on these drugs that they are also being prescribed exercise in some way that will help them preserve their lean mass.

Podcast Host (48:38)

So what is Matt Cable and excited about? What's, what's the one thing that you've come across that you think other than good nutrition, social connection, food, exercise.

Dr. Matt Capelan (48:50)

Yeah, I mean, well, so there's, so are you talking about interventions or, or in general? Yeah, yeah. I, I mean again, if this is going to bore people because if I had to point to One, I'm still pretty bullish on rapamycin. Like, I think, you know, for all that I've said that we don't have the, the gold standard randomized clinical trials. I mean, I think the GLP1 agonist I would put right up there as well. And I would say, you know, one of the studies that, that intrigued me was a study, I think it came out earlier this year, it might have been last year, where this group looked at UK biobank data and they looked at all the prescriptions that were in there and they asked a pretty straightforward question, which was at least for drugs that had been prescribed over some, some minimum threshold number of times, if you compare people taking that drug to people who are health matched but didn't take that drug, where do you see the biggest mortality benefits? And so some interesting things in there where we didn't see that, they didn't see it with metformin. So for all the talk of metformin as this really great longevity drug, it didn't come out of that particular study. What did come out though were some things that the interventions testing program had already shown. Increased lifespan in mice. And this includes SGLT2 inhibitors and a bunch of different estradiols. Right. So again, it's intriguing to me that, you know, this completely the study that had nothing to do with mice, it was all human real world prescription medication data, hit on some of these classes of molecules that independently had come out of a basic science, you know, study testing them for lifespan in mice showing the same thing, reduced mortality. So, you know, I think what we're starting to see is better evidence that the biology of aging is highly conserved going from laboratory animals to people. And some of the same drugs modulate that biology potentially in the same way. So that's very promising. And then I would say if you look at the interventions where we don't yet know what the ceiling is, I think again, this probably is going to surprise a lot of people. I think epigenetic reprogramming is really interesting. It's going to be really hard to move into the clinic using things like the Yamanaka factors. But I think this idea that we can revert some of the epigenetic changes, maybe all of the epigenetic changes that go along with aging is very promising. And the question there is to what extent do we actually impact healthspan and lifespan? And I don't know, you know, I think the low end of that is going to be comparable to rapamycin. I don't think we know what the high end is maybe we can get, you know, a much larger effect on healthspan and lifespan if we can do that in a very precise and targeted way.

Podcast Host (51:23)

But until then, stick to Mother Nature's gifts.

Dr. Matt Capelan (51:27)

Right? I mean, I think that really should be the foundation if you want, like, if you're interested in what you're. We're sure is going to work. That's where you, that's where you want to go.

Podcast Host (51:36)

Yeah, even, even that is controversial now. Like, you know, how many times a week do we exercise? Do we focus on zone two? But then we're. It's just, just move.

Dr. Matt Capelan (51:45)

Ignore the noise. Yeah, right. Again, I think, I think more important is find what is going to be sustainable for you. But yeah, just move. And the same thing with diet, like, you don't have to be perfect, you know, don't get off into all the wacky little, you know, things that, that people will tell you. One off diets that everybody should do. Focus on the basics, right? Whole foods, cut out the simple sugars, right? It's really, don't, don't overly complicate it. Get enough protein and even that, like, what does that even mean? What is, what is enough protein? What is too much protein? Right? Don't lose muscle mass. I think that's, that's where you want to be.

Podcast Host (52:20)

Well, thank you so much for clearing the air for me. I got all my questions answered, Matt, and I dare say you'll be coming back for round three, hopefully in person next time. And we can, I'll get my plasma exchange as well and we'll, we'll compare notes.

Dr. Matt Capelan (52:34)

You got to, you got to, you got to convince me me about coq. We'll have to do that next time.

Podcast Host (52:38)

Yeah, I'll definitely give you a review on that. Thank you for being part of the Neuro Experience podcast.

Dr. Matt Capelan (52:44)

All right, my pleasure.