this is the auto transcription for this episode. It is 95% accurate, and has some errors, but even with the errors you can still make out what is being said pretty much perfectly.
0:00:00 – Lowell
Welcome everybody to Learn With Will. Today we’re joining with Dr Matt Kaverline, phd from MIT, expert in Fundamental Mechanisms of A Jane. Some companies projects he’s involved in is just a little list The dog A Jane project, optospan Adventures and Auro Biomedical. There’s also a lab that he’s run for about 20 years And on the website right now, if you go to it and click the homepage, it says live long or die trying Matt, welcome to the show and thank you for taking the time to be here today. Thank you, it’s a pleasure Jumping into Rapamycin and so a lot of people ask questions about this and we’re gonna layer them in throughout, but on a high level, for people who are just coming into this very new what is Rapamycin? And then let’s talk about your relationship with it, but on a high level what is it and what’s interesting?
0:00:40 – Matt Kaeberlein
Sure. So Rapamycin is a small molecule. It’s actually a natural product that was first discovered on Easter Island, or Rapanoons, another name for Easter Island. That’s actually where the drug Rapamycin gets its name from. It’s produced by a bacterium that’s found in the soil there And it’s probably I think most people believe that the reason those bacteria produce Rapamycin is as an antifungal. So it sort of allows the bacteria to compete with fungal species that are in the soil there. So that’s probably the primary biological mechanism of Rapamycin is it impairs fungal growth. Now it was discovered 25, 30 years ago now maybe more than that, in these soil samples, And when people realized it had this antifungal, antiproliferative activity, people started studying it for that property.
So they were thinking it might be a useful antifungal, might be a useful anti-cancer right. So cancer cells are cells that divide uncontrollably. If you had a drug that impairs cell division, that might be useful as an anti-cancer drug. So people started studying it for those purposes. It ultimately ended up being first approved for clinical use as an immunosuppressant, And so it’s been approved now for more than 20 years by the FDA to prevent organ transplant rejection, First, I think, for kidney transplants, and then it’s been more broadly used for heart transplants and some other kinds of transplanted organs. So that’s how most people in the clinical community will know about Rapamycin. It actually also goes under the name Cyrilumus, same molecule. I don’t know why they decided it needed two names, but it’s got two names And it’s been used for many, many years as an organ transplant medication.
The reason why I sort of explicitly mentioned that is, I think that some of the concepts that we may get into around Rapamycin and its potential effects on aging and longevity get complicated by the fact that it was actually first developed as an immunosuppressant. So at high doses, there’s no question Rapamycin can prevent the immune system from rejecting transplanted organs. It’s always used in combination with other strong immunosuppressants, But in that context there is a side effect profile that is very different from what we see when we use it at lower doses in healthy animals potentially people, to have an impact on health span and lifespan, And so I just think it’s useful for people to understand the history here so that you can appreciate that some of what we think we know about Rapamycin in the clinical context may not actually apply in a different context, right In organ transplant patients versus healthy people. So I think that’s important.
The reason why I got interested in Rapamycin really stemmed from work that I was doing when I was a postdoctoral fellow at the University of Washington, where we were looking for new genes that affected lifespan, And so at this time this was the early 2000s, 2003, 2004, that was really something that a lot of people in the field were interested in, Cause we didn’t know a lot about the genetics of aging back then. So lots and lots of different labs were doing what are called genetic screens to figure out what are the genes that influence lifespan in different animal and organismal models, And so that was one of the things I was working on And we found from an unbiased genetic screen meaning we didn’t go looking for it we found that a gene called Tor, which actually stands for target of Rapamycin, TOR, when we turned it down, extended lifespan, And so I didn’t know anything about Rapamycin at this point, but we found Tor, And so I went and looked in the literature and realized there’s a drug out there that inhibits Tor. So we found that, genetically, turning down Tor could extend lifespan. There was a drug that pharmacologically could turn down Tor, And so it made sense to test whether Rapamycin could affect lifespan, given that connection, And so that was my introduction to Tor and Rapamycin.
And it was one of these sort of interesting things that happens in science sometimes where there were four labs actually I was one of the people but then three other labs independently also sort of converged on Tor within this same one or two year period And so in different animal models.
So you know, this was one of those nice situations where, through happenstance to some extent, multiple groups independently landed at the same spot, figured out that Tor was a really important regulator of longevity across many, many different organisms, And then we all also got interested in Rapamycin about that time.
And so since then, now you know, there has grown to be a massive body of literature showing that either genetically inhibiting Tor or pharmacologically meaning with a drug inhibiting Tor with Rapamycin can increase lifespan and improve a whole bunch of health span metrics in every model organism where this has been studied, all the way from very simple single celled budding yeast up to mice, which are relatively complicated mammals, and even some data now in dogs and a little bit of data in people, all supporting the idea that when you turn down Tor with Rapamycin you can attenuate the biological aging process, increase health span metrics and potentially increase lifespan, Certainly in the laboratory models. All of that is rock solid. I think you know where we’re kind of at today is we don’t know with 100% certainty to what extent will Rapamycin positively impact lifespan and health span outside of the laboratory, And that’s kind of the next frontier, I would say for the field, at least in this area, to learn to what extent is that the case.
0:06:39 – Lowell
It’s interesting to hear that you know Easter Island bacteria in the soil and then you know we’re able to use that for organ transplant and we’re finding these other uses as well. It always makes me wonder what all thing, what all does the earth have in store that we don’t even know yet, And you know especially Easter Island where everyone died off. I mean, it’s kind of like there’s like some weird symmetry there, especially considering like it might have life expansion related properties for Rapamycin when you apply it to the different species. Is it like a normal distribution of benefit relative to the species Like? is there like a? so like 15% to 20% like? is there like to that species for applied across the board Or-.
0:07:25 – Matt Kaeberlein
Yeah, i understand what you’re asking, yes, so a couple of things I would say there. One is we don’t really know what the optimal level of lifespan extension we can achieve is in different organisms. Okay, so I think it’s fair to say that there has not been a comprehensive dose response, so to speak, for Rapamycin in terms of its effects on lifespan, certainly not in mice, probably not in flies or C elegans or yeast, which are the other three major model organisms that are typically used in the field. So I don’t know that I can answer your question. I think the question you’re asking and this is an important one stems from the observation that for things like caloric restriction, which is much more, it’s been studied for much longer than Rapamycin. In this context, it seems to be the case that the magnitude of lifespan extension, in terms of percent lifespan extension, is larger in the simpler, shorter lived model organisms. In other words, maybe you’d get a 100% effect on lifespan in worms and a 30% effect on lifespan in mice, and worms live about 10 times shorter than mice do. So the question is, i think, or one question is, as we start to try to extrapolate these interventions to longer and longer lived species, humans being sort of at the far end of that distribution, would we predict that the magnitude of effect is going to get correspondingly shorter, at least in terms of percent lifespan extension?
I don’t think we know the answer to that question yet. I think it’s a reasonable expectation and certainly, if somebody forced me to say what would you predict, matt, given what we know today, what would you predict? My prediction is that indeed, the absolute or, sorry, i should say, the relative effect in terms of like percent effect compared to average, will be smaller in humans compared to mice. So if rapamycin, let’s say if we could optimize it, could have a 40% effect on lifespan in mice, maybe we’re talking a 10%, 15% effect in humans. But again, i think it’s important to just say that’s really an educated guess and it’s no more than that. The answer is we don’t know.
0:09:46 -Lowell
And even if it’s a small percentage, like I think sometimes people hear like 10%, they think, oh, that’s not that big 10% when people can live to about 100 years old, 100 years, you know, I mean that’s an extra 10 years, that’s pretty significant Yeah actually let me expand on that for just a second, because I think this is actually that’s a really important point, And I also think it’s important to differentiate between lifespan, life expectancy and potential effects on quality of life, health span, health span metrics.
0:10:16 – Matt Kaeberlein
My intuition as well and again, admittedly, this is a guess My intuition is that in humans in particular, it’s going to be much easier to move health span metrics than it is to move sort of maximal species lifespan, So I actually think it’s a relatively easy lift to get most people a decade of extra health span. I actually think we can do that today with primarily lifestyle interventions. So if we could actually get most people to practice a relatively healthy lifestyle, I think they would regain that lost decade. That’s what I call it a lost decade. Most people are giving up at least a decade of high quality life by practicing poor lifestyle choices in developed countries. I don’t think too many people would argue with that, So I actually think that’s important. If you know, like you said, decades of that’s actually a pretty long time.
I was actually thinking about this just the other day because I’m trying to write something about this, But so think back. So what are we 2023? Like what was happening in 2013,. Right, And think about that length of time and all the stuff that has gone on since then Some of it good, some of it maybe not so good right, But if you could get an extra 10 years of really high quality life, that’s a big deal And I think that’s actually not a very heavy lift.
Like I said, I think we can do that today. I suspect that we could probably get 15, maybe even 20 years of extra high quality life using some of the interventions that we know about now that target the biology of aging. So I just say all that because I do think it is useful to appreciate that we’re not talking about incremental effects. Right, Most of what biomedical research and standard what I would call reactive disease care medicine does is incremental. We’re not talking about incremental effects. We’re talking about things that could really have a very, very large impact on people’s productivity, their relationships, their experiences, their overall quality of life, And I don’t think it’s very unrealistic to think that we can do that just given the knowledge that we have today.
0:12:26 – Lowell
But for the intervention that was like 15 to 20 years, is that lifestyle changes such as caloric restriction, and then therapies like adding repamycin in there or some type of senescent cell strainer? Sennilitic, yes, yes, senilitic.
0:12:45 – Matt Kaeberlein
So I think the answer is conceptually yes. I’m talking about those things that people in the field are studying today. So that would include potentially repamycin, would include potentially senilitics, might include some of these circulating factors that change with age, that seem to impact the biology of aging, would include hormones. So I would put them all sort of in that bucket. I do think it’s important to say right now we don’t have the tools to optimize all of those things for everybody at a personal level. So we may get into this, because I know people are sort of interested in like, what’s the optimal diet?
0:13:20 – Lowell
How much protein?
0:13:20 – Matt Kaeberlein
should I eat All that stuff? we can certainly talk about that, but again, i think it’s really important conceptually for people to appreciate that at the individual level we don’t really have tools to say what is optimal for you, what is optimal for me, so we’re sort of left with these population level correlative recommendations. Okay, so I just say that because I think it’s important to appreciate. But, yeah, i’m talking about lifestyle. So, first of all, i would not say caloric restriction. I actually am not a big believer in caloric restriction and we can unpack that, i would say not being obese, certainly. So appropriate nutritional intake, but I’m not a huge fan of going below that. So, and again, personal guess might or might not be right, but I do think that certainly nutrition is critical, activity is critical, right. So those kinds of things. Like I said, i think if you were to really not even necessarily optimize but just get within the healthy range for the kind of somewhat obvious lifestyle interventions diet, exercise, sleep I think most people would get a decade of extra healthy life from that, if not more. So yeah, and then on top of that and this is where it gets to be a little bit speculative So again, i also think it’s important for people to appreciate we’re talking about, to some extent, probabilistic thinking. Right, there are very few certainties when we’re trying to predict the future and in particular an individual’s future health outcomes. It’s more about risk, reward and probabilities of something happening or not happening. So we have to just appreciate that There’s not a ton of certainty here, but now we’re getting into sort of like probabilistic outcomes.
Given what we know today and the biomarkers we have available, then I think, when you start to put on top of the lifestyle interventions things like rapamycin, you might be able to get beyond that lost decade to something bigger than that maybe 15 years, maybe 20 years, what those interventions exactly are going to be for individuals.
Now we’re talking personalized approaches. That’s where I’m optimistic and I expect that the diagnostics that are available to help guide us will improve greatly over the next five years, and that would include things like the sort of currently popular biological aging tests, which aren’t really biological aging tests in my views, but they are telling us something about the biology of aging. So I think as those biomarkers and diagnostics improve, we’ll be able to start to get closer to personalized recommendations for some of these interventions, which again could include, you know rapamycin, nad precursors, autophagy activators, analytics, circulating factors related to parabiosis, anti-inflammatories, right mitochondrial boosters. So there’s a whole bunch of potential strategies to target the biology of aging, but I think we know enough about today to be thinking about targeted interventions. When you pair that with improvements in the biomarkers, i think the hope is that we’ll be able to get to more personalized recommendations.
0:16:43 – Lowell
And so working most recent. Well, at least you’re saying what you were saying. If biomarkers that you know the aging related ones that people are talking about aren’t tracking aging directly, what do you think they are tracking then?
0:16:55 – Matt Kaeberlein
Yeah.
So I think it’s important for people to appreciate that the biology of aging is immensely complicated, right? And we don’t really let me say it this way there’s more that we don’t understand about the biology of aging than we do understand. I just think people need to appreciate that Many people who have not been in this field for very long, you know, will read some of the popular stuff that’s out there and think, oh, it’s all figured out right. That’s not the case. So one way that is popular to think about the hallmarks of, or sorry, the biology of aging is through what are called the hallmarks of aging. I think most people who have sort of been around this space will have come across the hallmarks of aging at some point. So, depending on who you ask, there are like between nine and 12 of these hallmarks of aging, and all the hallmarks are is a construct that people have, scientists have created to conceptualize what appear to be conserved mechanisms of biological aging that contribute to functional declines and increased mortality risk, that go along with aging across all of the different organisms where this has been studied. So those include things like mitochondrial dysfunction, accumulation of senescent cells, dysregulated cellular communication, dysregulated nutrient response, telomere shortening. So there’s a collection of these things, right? So what is useful hopefully for people to understand is that’s a conceptual construct, right? So it is an imperfect representation of reality. Underlying that construct is this extremely complicated network of interacting genetic and environmental factors And some of the things in that network we know about, like MTOR. Some of the things in that network appear to be useful let’s just say nodes in the network to tweak, to impact that biology of aging. But there’s a whole bunch of stuff under there that we don’t understand, and what the currently existing tests are measuring is just a tiny fraction of the biology of aging.
So let me give you an example. One of the somewhere between nine and 12 hallmarks of aging is epigenetic changes, epigenetic dysregulation. So the currently most popular flavor of biological aging clocks are epigenetic biological aging clocks. That’s what most of the direct to consumer stuff that you can buy And I don’t recommend people do that other than for entertainment purposes only Most of the direct to consumer biological aging clocks that you can buy only measure epigenetic changes. So that’s one of the hallmarks of aging, of which there are somewhere between nine and 12 of which. That’s only a fraction of the complexity of the biology of aging. So I would say, all of the stuff that we can measure today, each of them will measure a different piece of the biology of aging.
None of them are capturing all of the biology of aging, and so I think the unknown at this point is which, if any of the existing tests give us useful information about future health outcomes, future disease risk and maybe, more importantly, about response to interventions. That’s an unknown. So what we do know is you can take an epigenetic aging test and you can then modify your lifestyle and come back in three months and take the test again And maybe you see a Delta on that test. Right, it changes. What we don’t know is whether that change is meaningful in terms of your future disease risk or future health outcomes.
There are people who will argue with me on that. There are people who will say but we know that some of these epigenetic tests can predict future health outcomes from long-term longitudinal studies and epidemiological studies that have already collected samples from people over many, many years, and that’s true. What hasn’t been shown is that for a given individual living in a given environment right Today, which is different than it was 10 years ago or 20 years ago, that when you take one of these biological aging tests, that at the individual level it’s actually predictive for future health outcomes.
That hasn’t been done in people, for understandable reasons, hasn’t been done in mice for not understandable reasons. It should have been done by now. So I would say there’s a disconnect at this point between what people are claiming these tests actually measure and what we know these tests actually measure, and that’s an area that the field needs to do better, in my opinion.
0:21:40 – Lowell
I’ve been reading a lot about what Brian Johnson’s been doing and he does a lot of these tests and says, hey, i gained X amount or whatever, and I have been wondering how useful are these types of things in general, specifically, and then, with what he’s doing, it sounds like he’s trying to build a case study, kind of like Phidias, gage and the railroad spike in terms of understanding, like different parts of your brain if it’s damaged. Do you think, with Brian Johnson as an example, that he’s gaining any benefit from these tests and then developing interventions, like he’s saying, oh, i’m like 10 years older than I should, so I’m doing something that makes it smaller or lower or reduces it. Is he gaining anything from spending $2 million on this way? Or is it just like healthy eating is more what he’s gaining from the things he’s doing?
0:22:28 – Matt Kaeberlein
Yeah. So I’m a little bit hesitant to talk too specifically about what Brian Johnson is doing. Definitely he’s gained attention for himself. That’s one thing, that’s for sure. But beyond that it’s hard to know. So again, i think there are aspects of what he’s doing that I really like. I like the fact that he’s sharing data. I like the fact that he’s being honest about the fact that he’s experimenting on himself. I worry a little bit about the way it gets presented. So, as an example, i actually just saw a tweet from him today about how.
he said something about I measured rapamycin in my blood and I’m right, in the optimal dose range, and my response is you have no way of knowing if you’re in the optimal dose range, because nobody knows what the optimal dose range is, because science hasn’t figured it out yet. So I worry a little bit that he and his team do not understand the biology of aging sufficiently to be able to be commenting with any sort of authority on what the results he’s getting actually are telling us, and I worry that that’s being misinterpreted by the general population, or at least the people who are paying attention to what he’s doing. So that’s my big concern there. I do think that many of these biomarkers and the panel of biomarkers, at least from my understanding that he’s looking at, makes sense. Like, i don’t have not saying that he’s doing it wrong, but I think that many of these biomarkers are the best biomarkers that we have currently And it is a reasonable expectation that when you move those biomarkers in what we think is a positive direction, that your health has improved and that your risk of developing specific diseases, of aging or dying go down.
There’s no certainty there. So again, this gets back to what I was saying before. This is all probabilistic, right, and so we can make a probabilistic expectation of future health outcomes based on what we think we know today about these biomarkers. But we have to accept, first of all, there’s no certainty He could get run over by a bus tomorrow, right? If we’re talking about mortality, that has nothing to do with the biomarker, so there’s no certainty there. He could just have bad luck, get his mutation in a cell that is highly prone to cancer right, and suddenly he’s got metastatic cancer right. So there is a stochastic component that the biomarkers simply don’t pick up on. And then, secondly, the biomarkers that we know about today are imperfect. Right, we have an imperfect knowledge base.
Is it better than it was 50 years ago, sure. Will it be better than it is today 50 years from now? Absolutely, so we’re making predictions based on what we know today, which is limited, and so our predictions are only as good as that limited knowledge base. And I think what, again, many people who haven’t spent enough time really thinking deeply about this biology don’t appreciate is how little we actually know. So I don’t know whether or not Brian is biologically younger or biologically his age is aging more slowly than he was before he started this. My guess is he probably is, although I worry a little bit that these sort of very, very extreme intervention protocols have hidden costs, right. And so one way to appreciate that that’s pretty easy is caloric restriction. So we know, if you calorically restrict too much, that’s going to be detrimental for longevity, right. There is a sweet spot where you get the optimal benefit for lifespan, and if you go past that with caloric restriction, you’re going to shorten lifespan, and that’s probably true with almost any intervention that you think about. That’s going to be true for rapamycin. I would guess that you can’t just keep taking more and more rapamycin and get more and more benefits, right. So I worry a little bit that these very extreme intervention protocols and I would certainly put his protocol in the bucket of extreme have hidden costs or they’re beyond the sort of point of optimal return. Now it’s my understanding that he’s trying to guide the optimal return based on the biomarkers that his team has told him are important, but I worry that there are hidden costs.
I also think something that’s not often talked about by scientists in the field because we don’t really you know, most of us are biologists we don’t really think about it are the psychological risks associated with these sort of extreme lifestyle interventions.
And again, i think caloric restriction is a good example here. I know many people who have dabbled with flavors of caloric restriction, and I’m not a psychiatrist, i’m not a psychologist, but I can absolutely tell you some of those people had significant psychological consequences from their dabbling with caloric restriction, and so I don’t think we really pay a lot of attention to some of the potentially adverse events that are more on the psychological, mental wellness side of things. Just because humans are super complicated animals right, we’re funny animals And we live in this, you know, social construct. That is very different from studies that are carried out in mice, say, in the laboratory, and we don’t really appreciate some of the consequences of these sort of extreme lifestyle or interventional protocols that people are thinking about and the impact that that can have on psychological health and mental well-being. So I also worry a little bit about things like that when you see people start to try to advocate for these again what I would call extreme lifestyle interventions.
0:28:24 – Lowell
And with Brian in particular, i think to some extent it sounds like it could be like a game of telephone. that’s the issue. You know, he has this scientist translating it to him and then he’s translating it to the public and there’s not someone like checking the sweets to make sure it’s accurate, because if the research hasn’t been done then how do you know it’s optimal In terms of the psychological effects? looking at caloric restriction, i have read that there’s a link between the gut biome and your psychology, like how well you’re doing. Is that what you think is causing that psychological harm?
0:28:58 – Matt Kaeberlein
Oh, it could be part of it.
I certainly don’t think that’s all of it So certainly it could be the case that some of the what we would lump under psychological consequences of nutrient deprivation, caloric restriction, some of that certainly could be related to signals coming from the microbiome. Again, the biology here. And first of all let me say I know much less about the biology of the microbiome and how it interacts with the rest of our physiology than I do about the biology of aging. So now I’m speaking from a non-expert perspective, but I know something about it and I certainly know something about biological complexity, and so I feel confident saying that our understanding of the microbiome and how it talks to the rest of the body for lack of a better way of saying that is even less well characterized than our understanding of the biology of aging. So absolutely do.
I believe that our food, our dietary consumption, not just caloric restriction, but sort of overall what you eat, whether you’re restricted or overeating, or the composition of the diet that has a huge effect on our physiology And that’s at a bunch of different levels. It could be at the hormonal level, it could be at the effect on brain chemistry. So all of those things could go into impacting your psychological state And so it wouldn’t surprise me if that’s part of it. But I also think again, this is sort of what I was more alluding to is human beings live in this really complicated social environment And so much of our behavior is around our interactions with other people, and diet plays a huge role in that, and so people who practice sort of extreme dietary interventions, they change that social interaction And so that can have impacts as well, and being hungry impacts your outlook on life.
I mean I think anybody who’s ever been hungry, really, really hungry, recognizes that impacts all sorts of stuff. It impacts your emotional well-being, it impacts the way you interact with other people, and so that’s why I say I think that those are things that the scientists who study caloric restriction or fasting or time-restricted feeding they don’t really pay attention to that because particularly in laboratory animals, that’s not part of the equation We’re looking at how long do they live and what are their biomarkers of health look like. We’re not paying attention to social interactions in general, and I’m not even sure you can really study those kinds of social interactions in the laboratory. So that’s more what I was alluding to, but absolutely I think you can layer on top of that the interaction between the microbiome and the diet and the rest of our physiology, and that’s going to have an impact as well.
0:32:06 – Lowell
Then Delving in more to caloric restriction. Before this call and read about you, i wouldn’t have like caloric restriction would have been one of those like temples. If people say, yeah, do that, that’s good for longevity of a health span, so what are you saying that says the opposite. And then I guess maybe we could steal man why we could be wrong on this. There’s a lot of people saying yes, that is good. You’re saying there’s concerns and doubts, especially if you go too low. So if you could just expand on that.
0:32:37 – Matt Kaeberlein
So there’s several reasons why I am hesitant to suggest that we should extrapolate from laboratory studies to humans in the specific context of caloric restriction. But I also think it’s worth simply stating the data because, again, the people who are arguing that caloric restriction always extends lifespan in mice and therefore we should recommend it to people either don’t know the data or they’re intentionally ignoring the data that suggests otherwise. The actual, real data in the literature tells us that indeed, caloric restriction in rodents, mice and rats can increase lifespan quite significantly. I think the largest effect that I’ve seen is about a 60% increase in average lifespan from about a 60% reduction in calories. That work was done in the 1980s by Roy Walford and Rick Weindrich and others. So, absolutely, caloric restriction can increase lifespan And along with that, caloric restriction can improve a whole bunch of health span metrics. Okay, that’s rock solid. What’s also rock solid is that only is true in certain genetic backgrounds, and if you look in other genetic backgrounds you can get the same caloric restriction paradigm. You can get no effect on lifespan or you can get shortening of lifespan. So that’s true in mice, that’s true in fruit flies, that’s true in nematode worms and that’s true in budding yeast All of the model organisms that people routinely study in the biology of aging in the laboratory. The effect of a given caloric restriction paradigm on lifespan is strongly genetically dependent In all of those systems. It’s a little bit, you know. We don’t know the exact frequency, but it’s roughly one third of the genetic backgrounds tested have their lifespan shortened by a given caloric restriction paradigm. That will extend lifespan and other genetic backgrounds. Okay, that also is a fact. So it seems to me that it would be irresponsible to recommend to people an intervention that shortens lifespan in about 30% of the genetic backgrounds where it’s been tested in the laboratory.
Okay, that just. I mean. I don’t quite understand the disconnect here. Where for people who are saying caloric restriction, go do it right. It just doesn’t make sense because we don’t really understand what it is about those genetic backgrounds that are harmed by caloric restriction, why they’re harmed, right, so we can’t really predict in humans. And that’s again not even considering the psychological consequences of caloric restriction approach in people. So that’s one reason why I’m not super bullish about caloric restriction.
The other is that there is a bunch of misinformation out there around intermittent fasting and time restricted feeding. So intermittent and I would I’m going to define those this way, because I know that there’s some lack of clarity around what those terms actually even mean. So I’m going to say intermittent fasting is a fast of 24 hours or more, so at least one full circadian sort of cycle. Time restricted feeding is limiting the hours within a given 24 hour cycle in which you eat, to say eight or 10 or 12, whatever the flavor of time restricted feeding you’re talking about. Okay, so there is this again misperception. I would actually take it as far as to say a misinformation campaign that time restricted feeding and intermittent fasting clearly have health benefits in people. Okay, i don’t think that’s actually been shown. I think it’s true for some people, but on average I don’t think that’s been shown.
What we know in mice is neither of those interventions significantly increase lifespan unless they are paired with caloric restriction. In other words, if you time restricted feed or intermittent fast but the animals end up eating the same amount over, say, a month or years, the effect on lifespan is essentially zero. There might be a very, very small three, four, 5% effect on lifespan from intermittent fasting. That’s isocaloric. That is a little bit unclear in the literature but it’s nowhere near the magnitude of effect you get from caloric, true caloric restriction. So that often gets, unfortunately, ignored when this now is talked about in the sort of popular sphere. So intermittent fasting in the absence of caloric restriction, even in laboratory animals very little evidence that it targets the biology of aging in any really meaningful way I would say. So I think it’s fair to say, frustrated by the way that this is misrepresented for the general public in the non-academic sphere. Even in academic review papers it’s misrepresented. So that’s partly what’s leading me to maybe push back on caloric restriction, intermittent fasting, a little bit stronger than I otherwise would, because I feel like I’m kind of battling a misinformation campaign that’s out there by people who really want to advocate for this kind of a dietary strategy. So here’s what I would say And again, this is just my opinion, right, take it for what it’s worth.
My opinion is that intermittent fasting and time-restricted feeding can be useful tools for some people not for everybody, but for some people to maintain a healthy body weight. So there are some people who find it easier to maintain a healthy body weight and not overeat by practicing intermittent fasting or time-restricted feeding. I don’t see much evidence for benefits in people outside of that. It doesn’t mean there aren’t any Because we don’t have a lot of data to support that. The other thing I’d say is I have some real personal concerns around intermittent fasting in particular and the negative effects that that can have on body composition. So I said that intermittent fasting and again let’s just take a simplistic version of intermittent fasting So two days a week you don’t eat anything, right? Some people do this. I think that can help those people to maintain a healthy body weight because they then don’t feel like they have to restrict themselves on the non-fasting days. They can eat more on those days than they burn.
But I worry about the long-term effects of that sort of a strategy on body composition for two reasons.
One is we know that a prolonged fast will preferentially degrade lean mass over fat mass.
Both will come down for sure, but you’re going to lose lean mass, muscle mass, which is a bad idea in general. Secondarily, this is just my own sort of people that I know who do this, and again, i know a lot of people who’ve tried a lot of these different things. People who I know who’ve tried intermittent fasting tend not to focus as much on the quality of their diet on the days they’re not fasting. Now, that’s not going to be true for everybody, but I think, unfortunately and this is maybe a psychological thing I think there’s a psychological relaxation of your dietary quality because you think well, i’m fasting two days a week, so on the other days I can eat whatever I want. Again, i think from an overall health perspective, that’s counterproductive. You’d be better off, in my view, eating a nutritious, high-quality diet most of the time, and maybe taking a cheat day once in a while if you want to, than fasting two days a week and eating garbage the other five days of the week.
And unfortunately, i think some people fall into that sort of psychological trap of thinking that the two days of fasting is going to make up for the five days of eating a typical Western diet and it doesn’t, in my view. So I know that was sort of a long digression, but I think this is unfortunately a really complicated topic that a lot of people are confused about and they want somebody to tell them this is what you should do. And so it’s very easy for a talking head to get up there and say use my intermittent fasting protocol guaranteed to promote longevity, which is BS.
0:40:51 – Lowell
So for the differential, go down it helps versus herd. and would it be useful to study no-transcript like, maybe like a genetic test of some kind to differentiate, like how it would affect different people? So then we could say, hey, if you’re looking for to increase your lifespan and you fall within this marker with this test, this will most likely be more useful to you to make it more like granular.
0:41:16 – Matt Kaeberlein
I think if we had the information to know what to look for in a genetic test, yeah, absolutely, I mean that’s where we would love to get to. I would also say it’s probably not. It’s probably not even primarily genetic. It’s partly genetic, I would guess, in humans. So again, this is where you really have to differentiate between what’s been done in the laboratory and what the real world is like, right? So in the laboratory we’re controlling the environment. So the studies where people have looked across genetic backgrounds and say mice though all of those mice were kept in a very controlled, homogeneous environment, meaning it was the same across all of the different strains. People aren’t like that, right, We’re genetically complex, but we’re even more environmentally complex. So, again, this is my speculation, because nobody’s ever done the experiment in laboratory animals, but it’s my speculation that the environmental diversity in humans will have as much, if not more, of an impact on individual response to dietary restriction than the genetic component. Both are gonna be important, Maybe they’ll both be equal, but my speculation is environment’s gonna be even more important. So what I would say we really need and again we’re kind of going back to the topic we touched on already are quantitative biomarkers that are predictive for biological aging, future health outcomes, mortality risk. And then what you would do if you had those that you were very confident in is you would titrate the nutritional strategy that you wanna take to those biomarkers. And again, that’s kind of what people like Brian Johnson are doing. The question is, do they have the right set of biomarkers, and is the protocol that’s being implemented too extreme? That we can’t really answer right now, But conceptually that’s the approach right. You’ve got biomarkers that you believe in and you titrate your nutritional strategy to those biomarkers Now again.
Then this is where I think it’s maybe a mistake to focus too much on caloric restriction or even just on diet. Is all of that’s in the context of the rest of your life, right? So the optimal nutritional strategy is gonna depend somewhat on your activity level, your exercise regimen, right? And it’s gonna depend somewhat on the quality of your sleep, And it’s gonna depend also on your family and home life and social environment and all of that stuff. So trying to think about these things in isolation in the human situation, I think can lead to obviously oversimplification but also some misinterpretation or misguidance in giving people information that’s actually detrimental to their long-term health.
So again and this is my personal view I wouldn’t spend much time worrying about dietary restriction or caloric restriction per se. I would try to focus on maintaining a healthy body weight, eating a high quality diet right, And again, you can get as into the weeds on what a high quality diet is as you want to. You can get too far into the weeds in my view but in general, cut out the highly processed crap, cut out the food that’s high in sugar, eat whole foods. That’s a really good place to start And then try to maintain a healthy body weight And then I would say, rather than calorically restricting, put on top of that strength training regimen. So exercise is important. I think both cardiovascular exercise and resistance training is important, but I think where most people fall down is in the strength training to build and maintain lean mass. My personal view is that’s a much more likely to be successful strategy for most people right now than cutting out physical activity and trying to intermittent, fast or calorically restrict.
0:45:10 – Lowell
Now I was recently talking to a OBGYN and she almost like shook me when we talked about the subject, because for her patients who are primarily yeah, they’re all female because she’s OBGYN that they’re just told to just run, but there’s a plateau where you’re not gonna have any benefit, and so she’s been having. She’s noticed that if people just build muscle, they’ll burn fat and maintain their healthy lifestyle much easier, and so she’s trying to get more people on it. She was like they’ve been lying to me my whole life.
0:45:40 – Matt Kaeberlein
Yeah, that’s a really good point And I think you nailed it. Unfortunately and I don’t know all the reasons for this, because I haven’t honestly haven’t really been paying attention to a lot of the recommendations in that sphere around exercise for the general public, but it is absolutely the perception and I see this all the time. In fact, my wife was telling me today about a list that she’s on where and again, i think it’s mostly women, but I think this is true for men as well But on the list, the recommendations that people were giving to each other were well, just go out and walk, just go out and walk, right.
0:46:18 – Lowell
Which is good.
0:46:18 – Matt Kaeberlein
I mean, it’s not bad advice but you really need to pair it with a strength training regimen to build and maintain muscle mass. And that has sort of gotten lost, i think, in the messaging that has gotten out to the general public, broadly speaking. And I think particularly and again I could be wrong on this, but it’s my impression that particularly for people in their 40s, 50s, 60s, it may be even more skewed that way, where the messaging has really been more around get out and walk, 3,000 steps a day, 5,000 steps a day, maybe run or ride a bike, which is all good advice. But I think again, this is my personal feeling if you’re only gonna do one type of exercise, i would say strength training, resistance training is probably more important for that demographic than just getting out and walking. Obviously I think you should do both, and for a whole bunch of reasons, and I don’t know how much you wanna get into it.
But what you alluded to is correct muscle as a tissue, lean mass, is immensely powerful from a metabolic perspective at promoting and maintaining health, particularly as we get older. And the only way you’re gonna build and maintain lean mass is to use your muscles And the best way to do that is, by strength or resistance training. And so, yeah, i agree, i think from a if there’s one message that would be really useful from a health perspective to get out there to the average person it’s like don’t believe what you’ve been told about only walking, do some resistance training. The other thing I’d say is there are lots of different ways you can do resistance training. If you don’t wanna go to the gym and use barbells and dumbbells, you can do body weight exercises in your home. Like you don’t have to pick only one type of resistance training to effectively build and maintain lean muscle mass.
0:48:18 – Lowell
And you can, depending on where you are financially. You can retool old milk jugs to fill that up with water And it gets quite heavy.
0:48:27 – Matt Kaeberlein
There’s all sorts of ways to tackle this, for sure.
0:48:31 – Lowell
Yeah, and I think something to add to that is the fact that muscle works for you when you’re trying to do these things, where if you’re using, like if you’re just doing an aerobic exercise or whatever, you’ll burn during that time, but then you go back to doing nothing. Muscle, just like it’s a very needy tissue. So it’s kind of like the nice thing that we’re talking about It’s like one way I think about it. It’s like I can build muscle and And eat more.
0:48:59 – Matt Kaeberlein
I mean, there is some truth to that. Right, you’re right. If you are the same body weight and you have more muscle, probably your basal metabolic rate is gonna be higher and your caloric consumption to maintain body weight is also gonna be higher. That’s absolutely true. I would say. Equally, probably more important than that is, again, when people get in, especially in their 50s, 60s, 70s, having a higher lean mass. Clearly, no question about it.
Like I think the epidemiology is clear on this, when you normalize for body weight, having a higher proportion of lean mass is associated with a whole bunch of good stuff lower mortality, lower risk of injury, lower risk of a whole bunch of different age related diseases. Maintaining function again, i don’t know about you, but for me, as I’m getting older, for me, maintaining function and being able to do what I wanna do as long as possible is really, really important. And having being strong, having muscles that actually work for you, is a big part of that right. Avoiding injury, having the ability to go out and do what you wanna do, being strong, is really important for that, and so I think this is another reason why focusing on building and maintaining lean mass is really important.
And I just wanna I wanna mention something specific here because you will see I don’t know why You will see people sometimes grossly misinterpret the data that’s out there around lean body mass and health outcomes from epidemiological studies. So simply appreciate this Obese people have higher lean mass. There are many reasons for that, one of them being they’re carrying around more body weight, so their muscles have to be bigger. Okay, if you correlate just lean body mass to health outcomes, you can find cases where more lean body mass is associated with poorer health outcomes. That can, as far as I can tell, that can all be attributed to the fact that those people who have high lean body mass but poor health outcomes are obese.
When you normalize it to body composition, which is really what we’re talking about, having higher lean body mass in general, i’m sure there’s a point where it becomes suboptimal Body builders we could talk about. That’s a complicated situation with drug use and all of that. But in general, unless you’re on the extreme end of the lean body mass body composition index, having a higher lean body mass, lower fat mass, is generally a good idea, at least into your 60s. Once we get into 70s and 80s there’s some evidence that having a little bit more fat also is associated with positive health outcomes. But certainly into your 60s, do everything you can to build and maintain lean body mass would be my recommendation.
0:52:00 -Lowell
What does fat do when it clicks over in your 60s that it doesn’t do during lower periods of time? Yeah, that’s a good question.
0:52:07 – Matt Kaeberlein
I don’t think we really know at this point. I have seen hypotheses around the idea that as we age, a lot of stuff goes wrong. One of the things that goes wrong is the ability of our organs and tissues throughout our body to efficiently utilize energy sources, and so maybe having a fat store is somewhat beneficial from that perspective, could also be somewhat mechanical. I mean, i think and again we’re not talking about people who are morbidly obese, we’re talking about within the normal to slightly overweight body range. Having a higher percent fat mass is associated again, correlation causation we have to be a little bit careful is associated with reduced risk of mortality and some age-related diseases. It could also be and this is pure speculation on my part, but that having a little bit of padding isn’t a bad thing. We know that getting injured once you get into your 70s and 80s is a big risk factor for mortality, and so maybe just having a little bit more padding is actually beneficial. You bump against something, you fall down. It’s a big difference when you’re in your 70s if you trip and fall down and you get up with a bruise, versus you break your hip right. If you break your hip, your mortality risk goes through the roof over the next six months If you get up and you just have a bruise. No big deal, right, you’re okay. So that could be part of it as well. Honestly, i don’t know.
There is one interesting tidbit I’ll just mention. I have no idea what the mechanism is, but you know how we were talking about those caloric restriction studies across a bunch of different genetic backgrounds. Some get the benefit, some get harmed, some are right in the middle, some are right in the middle, so that’s a big difference. I don’t know if that’s a good thing. I don’t know if that’s a good thing. No effect. One thing that correlate, anti-correlated, i guess I should say, with let me see, yeah, anti, no, the correlated sorry, correlated with the lifespan benefit was the ability of the animals to maintain body fat under caloric restriction.
In other words, the genetic backgrounds that maintained more body fat when calorically restricted were the ones that got the bigger benefit, and the ones that were not fat when calorically restricted the most were the ones that were harmed. That’s not a perfect one-to-one, but there was a significant correlation there. So again, there could be some connection here between the network that underlies the biology of aging and ties into metabolism and how that impacts fat storage versus fat metabolism.
0:54:34 – Lowell
That we just don’t understand yet I think one if you were to summarize a little bit, but thus far it’s basically on one level.
Humans are really really complex. There’s so many different things going on And it sounds unbelievably complex and almost stressful to imagine trying to piece out one little aspect. And so I’m wondering, as a thought exercise, if we gave you a Bell Labs and limited funding and just an army of people to research the fat biomarker or anything like that or any of these different things that could reduce the dark matter in terms of longevity and health span that currently exists in these fields, as we’ve discussed, what would be some of the areas that you’d want to push for. I mean, that’s a really, really big thing, so I’m trying to limit it as much as I can, but it’s so complicated. It feels like there would be some benefit in researching out some really esoteric stuff so that you could then build up and have a better sense of how things work. And so it’s, to some extent, it’s like if you’re building a solid foundation, if we don’t have the full foundation yet.
0:55:41 – Matt Kaeberlein
Yeah, I mean, it’s a really good question. So I’ll tell you three areas. If I had unlimited resources that I would focus more on than the field is Okay. One is human clinical trials. I think that you’re right. The system is immensely complex, but the only way we are really ever going to find out what the impact is in humans of a given intervention is to test the intervention in humans. I don’t think anybody would disagree with that. We can argue back and forth about Rapa Mycin and Metformin and NAD precursors, and do they work? do they don’t work? It’s just going to be arguing back and forth until we actually get the data. So I would invest substantially in well-controlled, well-designed human clinical trials, not for lifespan, because I don’t think that’s pragmatic, and plus I don’t want to wait 20 years to get the result, but looking at a multitude of functional and molecular measures of function that we believe are important, and I think we know enough about functional declines that go along with aging and people right now to do that. So I think it’s all doable And so that would be area number one, and I think that would be extremely expensive.
But conceptually it’s not that hard to think about what you would actually do. You just need the resources to do it, and I think we’ve got a reasonably good list of things we could test, like rapamycin, like metformin, like NAD precursors, like autophagyactivators, like senolytics. There’s a bunch of things we could test. But the problem is, right now people are doing some of that. But the clinical trials are crap, to be honest with you, and I mean I guess I shouldn’t say that quite so bluntly, but none of them are large enough to really answer the question. So what we get are 20 person, 40 person, you know, phase one, phase two, sort of kind of that’s what they’re called clinical trials. They give a hint, but you know you’re kind of left thinking OK, maybe maybe it worked, maybe it didn’t, i don’t know. We need a bigger clinical trial. Somebody just needs to do the damn bigger trial, in my view, to answer the question. So that’d be one thing. Another thing would be expanding the research in companion dogs. So we haven’t yet talked about the dog aging project. Probably won’t have time today, but I’m happy to come on in the future if you want to talk about the dog aging project in detail. But you know, this is something that I’ve been involved with.
Is this large scale longitudinal study of aging in companion dogs, pet dogs living with their owners. And then we also have one clinical trial of rapamycin in pet dogs. The huge advantage right, there are several, but one huge advantage of doing a clinical trial like that in pet dogs is we can actually measure whether rapamycin can increase lifespan, because dogs age biologically about seven to ten times faster than people do. Meaning, if you design the trial appropriately, starting in middle age, in a three year time period, you can actually statistically determine whether or not rapamycin or a different intervention increases lifespan And improves health span metrics in pet dogs. Now let’s say you’re successful at that. Does that prove the intervention is going to work in people? No, it doesn’t prove it, but I do think it gives you a lot more confidence that it’s probably going to work in humans. Plus, you’ve extended the lifespan and health span of people’s pets. That’s a big deal in and of itself. So I would expand that. I mean people are starting to do this. I would just accelerate it. I think that there is huge untapped potential for geroscience discovery and clinical trial interventions, validation in companion animals. So that’d be area number two that I would put a bunch of resources into.
And then area number three is getting back to this idea I talked about before, which is that, you know, what we understand about the biology of aging pales in comparison to what we don’t understand, and I worry actually probably more than I should that the field has become very narrow over the last 10 years, and what I mean by that is, while there are many more people interested in the biology of aging and studying the biology of aging, the breadth of research that people are studying is actually quite small compared to what it was 20 years ago. Almost everybody and this is actually you might even attribute this somewhat to the hallmarks of aging paradigm, because it’s become difficult for people to think outside of that paradigm and think about what don’t we know. So almost everybody who’s working in the field right now, whether it’s in basic research or in the biotech community, is focusing on something related to the hallmarks of aging and targets that we already know about. And yet these that what I would call the intervention space, right. So if you think about all the possible interventions you could test for effects on aging, the intervention space is essentially infinite. So so we are. We’ve explored a tiny, tiny fraction of the intervention space, and very few people are thinking creatively about how do we look beyond what we already know. So I would put a large amount of resources into trying to encourage people to develop novel sort of innovative approaches to explore the longevity intervention space.
And there are a couple of reasons for that. One is, you know, as I’ve said a couple of times already, i believe that there’s a lot we don’t know about the biology of aging. There’s a lot that remains to be discovered And the only way we’re going to discover it is to look for it. I also believe that, given what people are studying now, it’s very unlikely we are going to find new interventions of large effect size. Ok, and we could talk about epigenetic reprogramming. That’s the only thing that I think has the potential for large effect size and the current crop of things people are studying.
But I think if you look back over the last you know 20 years, even over the last 100 years. So we talked about caloric restriction, caloric restriction. I said this earlier the most I’ve seen is a 60 percent increase in lifespan from caloric restriction, and that was a study that was done in the 1980s. We’ve known about caloric restriction since 1930s. Why hasn’t anybody done better than caloric restriction in terms of magnitude of effect in the last 100 years. Rapamycin 2009 is when rapamycin was first shown to increase lifespan in mice. Why is rapamycin still the gold standard in terms of effect size and reproducibility for longevity interventions small molecule longevity interventions.
So I think you can make a case that intervention discovery has stagnated in the field, and I would argue that’s because people have become very narrow in the way they’re thinking about the biology of aging. So I would try to blow that up. I think we need to blow up the intervention pipeline and be able to screen hundreds of thousands optimally millions of interventions to find new things that affect longevity, and that’s kind of the premise behind Aura Biomedical, which you mentioned I’m involved in. That’s a spin out from my lab. Certainly, i’m not going to argue that’s the only way to approach this problem, but it was my solution, or start towards a solution of what I viewed as a problem for the field. So Aura has developed a platform that we are now scaling to measure hundreds of thousands of interventions.
Small molecule could be genetic for effects on lifespan. We’re actually just just now sort of have gotten the technology to the point where I think we can realistically propose a million intervention study right Five years, a million interventions to find out how big of an effect can we get on longevity. Just to give people a feel for what that means, if you look in drug age, which is currently the largest database of small molecule interventions for lifespan across all organisms, there is something like 1,500 drugs that have been tested for effects on lifespan. So we go from 1,500 to a million. We’re going to find really interesting stuff. So those are the kinds of ideas that I think I would like to see more people in the field thinking about to try to help us get past what I view as sort of a bottleneck right now that’s limiting the potential of where the field can go. So that’s the other area that I would focus resources on.
1:04:17 – Lowell
To do a million interventions at a time? are you looking at something like organ, or well, i guess? in addition to this, what do you think about organ organisms on a chip to measure health, span and aging And then and then slide into how would you do a million if the best so far has been 15,000 over several years, 1500.
1:04:37 – Matt Kaeberlein
1500? Oh, wow, okay.
1:04:38 – Lowell
I added in zero. I was being generous.
1:04:40 – Matt Kaeberlein
So okay, So yeah, good question. So the first thing I would say is I’m biased towards what are called in vivo whole animals.
Right. So I think, if I think, if your goal is to find things that affect longevity and health span, you need to look in a model system where you can actually measure longevity and health span, okay. Otherwise you’re stuck using, you know, what are called surrogate phenotypes or secondary phenotypes that you think somehow correlate with longevity and health span. So that’s my bias, and so what we developed and have spun out at aura is a high throughput robotic system coupled with artificial intelligence to do whole animal lifespan and health span moderate measurements in C Elegans at scale. Okay So, and we could get into the details of all that, but it’s probably not worth it. Suffice it to say that we think we can build this pretty reasonably to a scale where you can do a million interventions over a few years.
It’s not going to be simultaneous, but we can scale it easily to the point where we can do a million interventions over a few years Okay, in whole animals. So then the question is could you do something like that in cell culture, in organized, in organoids? You could certainly develop screening platforms that screen for something in cell culture and organize or organoids that might be related to lifespan and health span. You can’t measure lifespan and health span in those systems, so you are making an assumption that you know what to measure that is going to be predictive for lifespan and health span, and I think that can absolutely work. Here’s the problem Your assumption is based on what we already know. So again, my whole starting point was there’s a bunch of stuff we don’t know that we probably shouldn’t, should find out. All of the systems that are, that are designed to use, you know, in vitro cell based assays, or systems that are using artificial intelligence to predict novel longevity interventions today. Those are all based on the knowledge base that we already have, right? So let me give you an example that I think everybody can conceptually appreciate. There are there are people who have taken approaches where they say OK, we know that rapamycin is interesting and metformins interesting and NAD precursors are interesting for their effects on aging right, based on studies and laboratory animals. So if we treat cells and culture with those molecules, we can see what happens. And let’s just say we’re looking at gene expression. We can see how gene expression changes from those molecules in cell culture, and then we can take a whole library of small molecules and try to find new molecules that you know look something like these molecules that we think are interesting in terms of gene expression, and then maybe those will be new drugs that will have an effect on longevity, right, and that’s perfectly reasonable. The problem is, only thing you’re going to find are things that act like the things you started from Rapamycin, metformin, nad precursors. Are they going to be better? Maybe, probably not.
So my view is what we really need to do is find new things, maybe combinations of things, and again, i really am biased to the idea that the only way you’re going to be successful at doing that is to do it in a system where you can actually measure what you’re interested in, which is lifespan and health span. Now, is C elegans the best system? I don’t know. We thought it was simply because we knew we could develop the technology Could, if you could do it in mice, that would be great. Do you know how much it would cost to do a million molecule longevity study in mice? We actually did the math. It’s, i think, just for the animals it’s like one and a half billion dollars. When you put personnel and facilities cost and all that on top of it, it gets to be pretty expensive. So let’s just say it’s two billion dollars to do that, that million molecule screen in mice.
We can do it in worms for probably five million, right? So you know, i think there is a pragmatic component here as well. Maybe, maybe you could do it in flies, maybe killy fish, you know, maybe planaria, i don’t know. There are options. We we figured we could build it in worms and we built it now, and so we’re pretty confident we can execute. I’m not going to argue, worms are the only place to do it, but I do believe strongly that You’re going to be much more likely to get the answer you want at the end of the day If you’re actually measuring the phenotype that you’re interested in, and from my perspective, lifespan and health span are the phenotypes that we’re interested in.
1:09:16 -Lowell
And we we touch on the subject with your dog project, But I want to expand on it because I think it’s something that people don’t talk about, which is the quality of love and how it affects people’s just health span and in your life in general. There’s many stories of people who their loved one passes and it’s like six months later and they’re gone as well And I don’t I don’t know like clinically, I don’t think they die from heartbreak, But I feel like there’s something there to the effect of, like you know, I think sometimes people say like get three hugs a day or whatever, But what are your thoughts on that correlation between you know, love, health span and having a good long life?
1:09:51 – Matt Kaeberlein
Well. So I think one thing I would say is, you know, so, first of all, i’ll dive into, like, the actual connections to health in a minute. But you know again, i’m a pretty pragmatic guy And my view is, if you’re miserable, what’s the point of living a living longer, Right? So I think, joy, happiness, love, however you want to kind of frame that, if you’re missing that piece, i would say you don’t have, certainly don’t have, optimal health span, and I would say it’s probably hard to have good health span if you’re not happy, right, if you’re miserable. So that’s kind of the first thing I would. I would say about that. But you’re absolutely right.
So you know different people have. You know a different number of pillars of health, right, but I kind of, i kind of like the idea of you know four pillars, right. So I would say nutrition, activity, which would encompass exercise, sleep, and you know. Then I don’t know what the right word is. I’ve been actually trying to think about what’s the right word for the fourth pillar. Is it, you know, wellness, is it happiness, is it joy, maybe love? I don’t know, but it sort of encapsulates for me all of that And I, and absolutely that’s very real And I think also we have to recognize these pillars are interconnected, right. So that’s easy to see. If you look at the connection between nutrition and exercise We already talked about that right The optimal nutrition is going to be different depending on what sort of exercise people are doing. It’s also easy to see with sleep.
There’s no question that sleep impacts the biology of aging. The biology of aging impacts sleep, No question. It’s a little bit less characterized, i think, when we start to get into, you know, wellness, anxiety, stress, fear. Those are sort of you know, anxiety, stress, fear, sort of the negative side of it joy, happiness, love, the positive side of it. But I would say those are all sort of touching on the same biological component, i’m guessing, at least overlapping, and it’s really. It’s clearly important. There’s been some work done on the interactions between chronic stress and the biology of aging and longevity. So we can point to, you know, molecular connections at that level, certainly some work done on brain chemistry changes with aging which are going to be impacted by anxiety, fear, stress and also impact the perception of anxiety, fear, stress. So there’s some connections there. But I think what you were getting at, which is something that is less studied, but maybe equally, if not more important is how our interactions with other humans and potentially companion animals can also impact our biology, and that’s real no question about it. I mean, there is some work showing you know, for example, that humans interacting with their pets, that can actually show a reduction in stress markers in the human. Interestingly, it also shows a reduction in the stress markers in the pet right. So there’s clearly biological connections there which are really important and I think, but I think also pretty poorly understood.
So you know at this point what I would again, i would go back to sort of my pragmatic answer to begin with, which is, you know, i think people need to think about and try to figure out, you know, what can they do in their own lives to sort of increase their joy, their happiness right, their wellness, reduce stress, reduce anxiety. I know that’s like easier said than done, but I think you have to start by thinking about it And there are lots of people who have spent much more time thinking about this than I have, who have recommendations on how to approach that. But paying attention to it is where you have to start. But absolutely I would put that up there, you know again, if I had to say from a purely pragmatic perspective if you’re not happy, the rest of the other stuff doesn’t. It matters a lot less, right? So that’s got to be. Maybe that’s where you start, i don’t know, but it should be a part of everybody’s equation here when they’re trying to think about their overall health span.
1:13:52 – Lowell
I was reading recently and I have some friends of relatives that are in high school and stuff, and that COVID has really shattered how people socialize now And so you know how people form bonds or relationships that happy component of a balanced life is for people who, like, grew up under it. Apparently it’s much harder now. So is there a person in particular that you point at, those people who are, you know, trying to? I guess everyone needs more love and more happiness in their enjoying their life. Is there a researcher out there that you recommend people check out?
1:14:25 – Matt Kaeberlein
You know that’s a good question. I don’t have an answer for you. I should. I will do some homework. I wish I did.
I mean again, i think, the specific case of COVID, right. There are certainly people who are thinking along the lines of what are the impacts of COVID on social development, particularly for younger people who went through COVID, say, when they were in high school or college, important social forming years? That’s way outside my area of expertise. What I would say, though, is, while I think it’s important certainly to pay attention to that, human beings are pretty resilient, right. So I think we went through this period of sort of extremes, all sorts of extremes the political spectrum, the social spectrum, right, And maybe we’re still in it. I don’t want to suggest that we’re out of the woods yet, but having said that, i think that there will be long lasting impacts from the pandemic. But I also think people are pretty resilient. So I think a lot of the impacts psychological impacts, social impacts will come down with time, and so I guess where I would land, again, without having thought a lot about this, is, for most of us, we’re hoping that we’ve got multiple decades of health span ahead of us, right? So I would really think about psychological well-being, emotional well-being, from that perspective. Right, you’ve got decades to go, and so what can you do in that context to optimize your emotional, psychological well-being?
And I think one thing for sure that this seems to me, that the data clearly backs up is forming strong community, social, family connections now is important for the future, And so I don’t mean again, this is going to be different for everybody.
I can say from my own personal perspective, i’ve spent more time thinking about this in the last year And I can say I’m probably pretty typical for a male in his early 50s where I didn’t spend as much time as I probably should have thinking about friends and those kinds of social connections. And so I’m making a dedicated effort to do better going forward, and I think probably most people can do that right. So forming real bonds with other human beings, i think, is a place to start. Is that going to solve all your problems? No, but it’s going to. You can think of it like exercise, like exercise for your body. This is exercise for your community, right? If you don’t exercise your community, that may be the pillar that crashes down first when you’re older, right? So paying attention to that now. I think makes a ton of sense.
1:17:26 – Lowell
And then I have a bunch of. I have some fan questions and then some just rapid fire. You can just like as quickly as you feel appropriate. But this one’s for me When you close your eyes before you, when you wake up in the morning and you look before you look in the mirror, how old do you feel mentally? Like is there an age associated with your internal feeling of age?
1:17:46 – Matt Kaeberlein
That’s a good question. I don’t know that I’ve ever thought about it. Young, i guess I would say. But I I mean, look, my wife will tell you I’m a little kid at heart, i’m a 13 year old mentally. So yeah, that’s probably about where I start.
1:18:01 – Lowell
Yeah, and then so last call 2021 says there’s a weird dichotomy of IGF-1’s role in biology of aging. Some super super centarian populations have a down-regulated IGF-1 receptors and knocking out IGF-1 receptors and mice causes them to be smaller but live longer. But there seems to be some measurable effect on the ability to maintain muscle mass as some sort of therapeutic boost of life. I’m trying to like scam this as a giant paragraph, the. Basically, they would love to hear your thoughts on the connection between IGF-1, mtor through the PI-3K forward slash ATT. Hard to give a short answer to this question, so let me I will not do it justice.
1:18:52 – Matt Kaeberlein
But let me first of all just try to summarize what I think the question is asking which is in the mouse models in particular, but also in nematodes and fruit flies. Turning down insulin IGF-1 like signaling increases lifespan.
That was one of the first things that was discovered Cynthia Kenyon, tom Johnson with DAF2 and age one that’s in that pathway. So these are connected to MTOR And the common theme is these are growth promoting pathways during development. So what we know is that, all the way up through mice, mutants that have reduced growth signaling through these pathways during development live longer and they appear to age more slowly in the laboratory. There are humans that have mutations in these pathways. Some are probably moderate reduction in function that you can find enriched in centenarians, but there’s no evidence yet that that’s possible for their ability to live to a hundred or more. And then there are extreme versions, like the Lerone population.
so dwarfism right, where we have severe down regulation of growth hormone signaling and IGF-1 signaling in people. They don’t live longer, but they do seem to be protected against certain age-related diseases, some forms of cancer, things like that. So I think it is absolutely the case in humans that there is a similar relationship, meaning if you substantially reduce growth hormone IGF-1, particularly during development, your risk for many age-related diseases decreases and you may be aging biologically more slowly. However, as we’ve already talked about in this conversation, humans are funny animals.
There are complicated social consequences and probably environmental interaction consequences to being very, very small, right And in some cases maybe frail. So I think it’s unlikely that significant reductions in growth hormone and IGF-1 signaling, say in middle age, would be net beneficial, at least to a large extent, in humans. And this gets complicated really fast because there’s this weird dichotomy that we don’t completely understand, which is that reducing mTOR seems to be beneficial right, at least transiently. reducing mTOR with rapamycin seems to be beneficial for a whole bunch of health span metrics and potentially lifespan in people and dogs and certainly in mice. And yet maintaining muscle mass, maintaining strength, which is pro-promoting mTOR, at least in muscle, also is clearly beneficial in people.
And so how do we resolve that? And I think a lot of it comes down to context, but the real answer is we don’t completely understand it. I think a lot of it comes down to tissue and some of it comes down to when and how much. So I think chronic inhibition of mTOR growth hormone IGF-1, in middle-aged people from my perspective is probably a bad idea, but I don’t know for sure. I can only say that my guess is that will increase your risk of frailty. loss of muscle mass might slightly reduce the risk of cancer, but I don’t think it’s gonna lead to very large increases in longevity. So it’s just a super complicated question that probably isn’t a simple answer for right now.
1:22:17 – Lowell
Yeah, And then techno future eight. everyone has great usernames. Ask them about mesochymal stem cells.
1:22:27 -Matt Kaeberlein
Mesochymal stem cells.
1:22:28 – Lowell
From exosomes And even if just like are you aware of them And just like that would be sufficient for this person, but they’re wondering your thoughts on it. I am aware of them. Yes, they’ve linked a bunch of research. They’re very excited.
1:22:39 – Matt Kaeberlein
I think the question is around exosomes from mesochymal stem cells.
So, let me take a step back. In general, there is a lot of interest in various types of stem cell therapies for regenerative purposes, right, so you can go to clinics around the world that will inject you with stem cells and you may or may not get some regenerative benefit from that. There is emerging interest in factors that are secreted from stem cells, and exosomes are lipid bound particles that are secreted from cells that may contain the rejuvenating properties that, or some of the rejuvenating properties that you can get from stem cells. I think this is a super interesting and important area of research. There is certainly some evidence in animal models that you can get regenerative properties from stem cell exosomes. People are starting to try to study what the factors are that are maybe mediating those properties microRNAs, things like that.
Would I go out and inject myself with mesochymal exosomes today?
No, i probably wouldn’t, and in part, i would say part of the reason why I’m hesitant to really think too much about going, even for stem cell therapies, is there’s no regulation as far as I can tell at this point, which means you don’t really know what is in these preparations of stem cells that you’re going and getting at these stem cell clinics.
So that makes me nervous, and so I personally wouldn’t recommend doing that, but I do think it’s a super important area of research and there’s a lot of potential there. So I would actually like to see I know people are gonna hate me for this And honestly I’m not a big fan of FDA, if people have followed me but I would actually like to see FDA take a little stronger role, or somebody take a little stronger role in regulating these stem cell therapies that are mostly offshore right now. Maybe bring them onshore and regulate them so that we have some knowledge about purity and quality and outcomes, cause right now it just kind of feels like the wild west And I personally would be nervous about going somewhere and getting stem cell injections. And I’m not saying there aren’t reputable places that do that, i’m certainly not trying to suggest that, but how do you know? How do you know which are the reputable places? And so that would be my concern. I’d like to see more regulation so that we can have some more confidence in these sorts of offerings.
1:25:14 – Lowell
All right, and then I think this might be the last fan of question, given our time, So stoic optum. One issue in a raptomycin RCTs is the risk of unbinding due to characteristics of AEs like mouth ulcers. Have you thought about this aspect? in future human trials? This might mitigate. This might be mitigated by careful consideration of endpoints being measured. I think they have a PhD in biology, so yeah.
1:25:38 – Matt Kaeberlein
Yeah, so a couple of things I’ll say about this. So let me rephrase, just to make sure everybody’s on the same page. I think the first part of that was so you do a clinical trial. If it’s a randomized double blind clinical trial, the provider, the doctor doesn’t know who’s getting the placebo or the treatment and the person the participant doesn’t know. That’s the double blind part.
So the unbinding comment there, i think, is around the idea that one of the known side effects of raptomycin is mouth sores, mouth ulcers, and so if somebody’s in a clinical trial they don’t know if they’re getting the placebo or they’re getting raptomycin, they develop a mouth ulcer. They might conclude that they’re getting the raptomycin. That’s absolutely a possibility. There’s not a lot you can really do about that. I will say people who aren’t taking raptomycin get canker sores all the time. So it’s not like that’s a definitive you’re getting raptomycin just because you got a canker sore. And in fact there’s a study that is now accepted it should be out in gerocyanin soon where we collected data from people who’ve been using raptomycin off-label And it’s something like 4% or 5% of the non-users had mouth sores in the past three months and 15% of the raptomycin users Don’t quote me on that, that’s my recollection, something like that. So it’s not a definitive all or nothing, i would say regardless. But it is a concern that people then might conclude they’re getting raptomycin and that would affect the rest of their perception of what the drug’s doing.
Couple of things to say about that. I think, again, in a well-designed clinical trial you would also wanna look at a variety of, in addition to patient reported outcomes, a variety of more biochemical measures, functional measures that you would expect to be less susceptible to, whether the participant thinks they’re getting the medication or not, not to say that there’s no effect, because placebo effect is real, but you would expect them to be less sensitive, like blood-based parameters, grip strength, walking speed, depending on what the clinical trial’s for, echocardiographic parameters, for heart function, cognitive assessment. So things like that are, i think, the things you would wanna measure. But also, i would say, if the trial is sufficiently designed, so large enough, long enough, i think the concerns about potentially bias from people believing they’re getting the placebo or not are minimized. You can’t ever completely rule that out, but I think you can reduce it.
1:28:11 – Lowell
And then a quick bonus one is do you recommend any books people check out? It doesn’t have to be in your field, it could just be a book that you’ve enjoyed.
1:28:17 – Matt Kaeberlein
I mean one that’s pretty recent is Peter Atia’s book Outlive. I think that’s a climber that anybody who’s interested in this space should absolutely read. I think Peter nailed it.
1:28:28 – Lowell
And then I just wanna thank you, Matt, for coming out today. Everyone listening in for the fan question sorry if we couldn’t get to all of them, And if there’s one place I would guess is the best place to stay up to date with what you’re working on at your Twitter. You seem very active, but is that the best place? And then thank you for coming on the show.
1:28:42 – Matt Kaeberlein
Probably the best place for now, i will say I have a love-hate relationship with Twitter, so I have periods of activity and then periods where I don’t look at it. Although I will say I’m sure everybody else knew this already, but I only realized in the last six months or so that if I just mute the people who annoy me, it’s great because I don’t see their nonsense. So that’s been my solution to Twitter frustration is I just mute the people who annoy me?
1:29:06 – Lowell
You’re training the algorithm for what you’re looking for, but that’s simple.
1:29:10 – Matt Kaeberlein
Yeah, I know, but it’s better than getting frustrated.
1:29:12 – Lowell
No, i think that’s a good thing, that’s a good thing to do.