Targeting Biological Aging: A New Paradigm For 21st Century Medicine with Dr. Matt Kaeberlein

Metformin is often thought of as this really safe drug. It's really safe for diabetics, but I think there are probably some side effects that haven't been appreciated because, you know, we weren't really worried about testosterone if you were concerned about diabetes. You might be worried about testosterone if you're taking metformin to optimize other aspects of your life. What does it take to do the impossible? What does it take to level up your game like never before? What does it take for individuals, organizations, for even institutions to achieve paradigm-shifting Nothing is ever the same again. Breakthroughs.

Our mission is to decode the neurobiology of flow and cognitive peak performance. Access the minds of maverick scientists, groundbreaking innovators, and world-leading experts to understand what it takes to achieve ultimate human performance so you can feel your best, perform your best, and accomplish your boldest goals. I'm your host, Ryan Dorris, and together with bestselling author Steven Kotler, I present to you Flow Flow Research Collective Radio. Dr. Matt Kaberlein, welcome to Flow Research Collective Radio. Really great to have you here.

Thanks, pleasure to be here.

Yeah, I've been really excited for this discussion. Before we dive into the specifics, I'm going to read your entire bio here, which is a long— please don't, I'll skim it, I'll skim it. Uh, you, um, yeah, you've done lots of very incredible, impressive things, so let's, let's take a swing through it. So You are the Chief Science Officer at OptiSpan, Geroscience, and a professor of laboratory medicine and pathology at the University of Washington. I know you're based up near Seattle there, and you have adjunct appointments in genome sciences and oral health sciences with research interests focused on understanding biological mechanisms of aging in order to facilitate translational interventions that promote healthspan. And improve quality of life for people and companion animals. You've published over 250 scientific papers and been recognized by several prestigious awards, including Young Investigator Awards from the Ellison Medical Foundation and the Alzheimer's Association and a number of other very impressive institutions. You've also been awarded fellow status with the American Association for the Advancement of Science, the AAAS, uh, the American Aging Association and the Gerontology Society of America. And you're currently the CEO and chair of AGE, past president of AGE, and have served on the board of directors for the Federation of American Societies for Experimental Biology. And you are also the founding director of the University of Washington Healthy Aging and Longevity Research Institute. The director of the NIH Nathan Shock Center of Excellence in the Basic Biology of Aging, also at UW, and the director of the Biological Mechanisms of Healthy Aging training program, which we're going to be talking a little bit about. And then the founder and co-director of the Dog Aging Project, which we're definitely going to be talking a little bit about as well. And you received a BS in biochemistry and a BA in mathematics from Western Washington University in the late '90s, and then a PhD in biology from MIT in 2002. And you've been with the University of Washington since 2006. So hopefully that wasn't too painful. Lots of impressive accolades there. And yeah, I mean, it's impressive that you've managed to just make the time to do all of those things.

I was going to say, the one thing I learned from that is I'm wearing way too many hats. But thank you for that.

Lots of, lots of roles. Very impressive indeed. So before we started recording, I asked you if there was anything that you didn't want to talk about that you found a little bit boring or were getting asked about a lot, and you were polite and, and said there was nothing. But I'm worried my first question may fall into that category because I wanted to actually start by asking you about rapamycin, which I know that a lot of people have been talking about in the longevity space. It seemed like metformin was the big thing and then rapamycin became the big thing, at least in terms of what is popularly referenced on the podcasts and things like that, which may be, you know, there's different strains of the longevity space as well. There's what's popular within kind of consumer information, and then there's what's popular within the research worlds, which they don't necessarily map.

I think you nailed it, right? I mean, I think both metformin and rapamycin are still actively studied in the scientific realm of geroscience or longevity science. Certainly, I think In terms of what gets out of the scientific world and into the podcast scene or the popular sort of media, that tends to not really closely track with, I think, what people who are in the research world are really focused on and excited about. I would say that rapamycin For me personally, I think for a long time has really been, if I had to pick a single drug or intervention that I'm most enthusiastic about the potential applications in people and in companion dogs, as we'll talk about, for a long time it's been rapamycin. I think, you know, it's been clear to me that that really is the most effective and reproducible drug for, increasing lifespan broadly, improving healthspan in laboratory animals for many, many years. I think what we're seeing now is that more people are comfortable talking about rapamycin on popular podcasts or in the media. And that has had sort of a follow-on effect of it gaining more attention. I think part of it is that we're starting to learn a lot more. For a long time, we've known that in laboratory animals, this drug was really very effective at increasing lifespan and healthspan. We're starting now to get the first hints that there may be some similar kinds of effects in the real world. And I think that's also contributing to the increase in— I don't really like the word popularity, but maybe recognition outside of the scientific community that this is something that's interesting and we should pay attention and we should be studying in greater depth the potential positive impacts that rapamycin or some other similar acting drug might be able to have for healthy longevity in dogs and potentially in people as well.

Could you speak a little bit, Matt, to what has been found in animal studies with rapamycin and then what the mechanism of action is and thus the reason there may be similar carryover effects for humans?

Sure. So in terms of what we know about the effects of rapamycin, in every laboratory organism where it's been tested, rapamycin treatment has been shown to increase lifespan. And to the extent that we can measure healthspan— and I'll define that in a second— to the extent we can measure healthspan in these different organismal models to also extend healthspan. So by healthspan, what I mean is the period of life that's spent at high function, in good health, free from chronic disease and disability. And the reason why I, I'm a little bit, uh, careful in the claims that I make is the extent to which you can really measure health and healthspan differs in different laboratory animal models that you might study. So for example, the common organisms that are used in the laboratory to study longevity, uh, biology of aging are budding yeast, which are single-celled, nematode worm called C. elegans, which is about a millimeter long. You have to watch them under the microscope. Fruit flies, which everybody's probably familiar with, and rodents like mice and rats. And if you think about the way that you would measure health in those different models, it's going to be very different. You can measure activity and cognitive function and liver function and kidney function and heart function in a mouse, you can't do that in a worm. And so that's why I make that differentiation. So we measure health differently in those different organisms, but we measure lifespan the same, right? Lifespan is really easy to understand. Length of time from birth till death. The important point that I want to make, though, is in all of those systems, rapamycin increases lifespan, and again, to the extent that we can measure it, seems to preserve health later into life. So to extend healthspan. There are two things about rapamycin from mouse studies that I think are most exciting and probably relevant for translation or potential translation. One is it seems like you don't have to start the treatment until middle age. And in fact, transient treatments just during middle age in mice are enough to give you pretty much the full increase in lifespan and increase in healthspan. And that's really important when we think about doing this in people or in companion animals. You want an intervention where you can start the treatment during middle age and maybe not have to even take it for the rest of your life. The other thing that's sort of surprising to me, and I think really exciting, is at least in some tissues and organs, you can actually reverse some of the functional declines that have gone along with aging. So again, I wanna be careful. I think some of my, colleagues get overenthusiastic and talk about reversing aging. I'm not saying that we're reversing aging. You can't take an old mouse and turn it into a young mouse. But if you look at specific tissues and organs, like the heart's a really good example, by non-invasive imaging method called echocardiography, you can see declines in function of the heart with age. 8 weeks of treatment with rapamycin in a middle-aged mouse is enough to reverse those functional declines. The same thing's true with the immune system. You see a decline in immune function with age, for example, response to a vaccine in a mouse, 6 weeks of rapamycin in an old mouse is enough to restore the immune system back to a youthful ability to respond to a vaccine. So again, that to me is unexpected. If you'd asked me 15 years ago, I would have said no, the best we can do is slow the declines that go along with aging. Now we've seen you can actually reverse some of those declines. And again, that's really important if we're thinking about testing this in people or in companion animals. So that's a flavor for what we know about rapamycin. The reason why I'm enthusiastic about it in addition to that is it's the most reproducible intervention for extending lifespan, improving healthspan in laboratory animals and in mice and rats in particular. And in this field of aging research, that's important because not everything is reproducible. In fact, I think people would be surprised to learn about some of the popular interventions that have turned out not to be reproducible in this field. So rapamycin is great because it works for everybody. It's been reproduced dozens of times now by different labs. So we know it works, and it seems to work well, and it seems to work when it started in middle age. So that all gives, I think, me and many of my colleagues confidence about trying to take this out of the laboratory and into the real world and see whether or not it works the same way. Okay. So that's background on what we know. Now, how is it working? This is another nice feature of rapamycin relative to some of the other interventions like metformin, which we briefly touched on already. So rapamycin has a very specific mechanism of action. It is a small molecule that inhibits a protein called mTOR. It turns out that mTOR is actually named after the drug. mTOR stands stands for mechanistic target of rapamycin. Okay, so rapamycin is a specific inhibitor of mTOR. As far as we know, that's the only thing it does. So it's an extremely biochemically clean drug in that it seems to have one target and only one target within cells. So mTOR is a highly evolutionarily conserved protein. Every animal has mTOR. Every eukaryotic cell that we know of has mTOR. So it's present across a huge evolutionary distance from yeast all the way through to people. And its function seems to be also highly conserved. So this is getting to this point about what gives us some confidence that rapamycin might work the same way in people or in dogs as it does in mice and flies and worms and yeast. Well, the target of rapamycin works the same way in all of those organisms. So that gives us reason to believe that some of the effects that we see in the laboratory are very likely to also be shared in the real world in people and in our pets.

What is the intervention that is recommended, at least by some, to people? Is it a lifelong drug that you take for good? Is it a targeted intervention?

You mean specifically with rapamycin? Like, what would the recommended sort of treatment modality be? So the first thing I think that we have to say is rapamycin hasn't been proven to have these effects in people. I mean, it's still an experimental intervention at this point. So those studies are ongoing. There have been a couple that are highly suggestive, I would say. So there was a series of studies from a scientist named Joan Mannick and her colleagues. She was at Novartis for a while and then at a company called RestoreBio, where they were looking at It's a slight chemical derivative of rapamycin called everolimus. But I think for today's purposes, people can just think of them as identical. They function biochemically exactly the same way. So they were studying this rapamycin derivative in healthy older people. And what they found was that a 6-week treatment with everolimus was enough to boost the ability of the aged immune system to respond to a flu vaccine. So they were really interested in this idea because we knew from mouse studies that 6 weeks of rapamycin treatment was enough to restore the ability of an aged mouse immune system to respond to a flu vaccine. They were trying to do the same experiment in humans. And it turned out it seemed to work. So there were actually 2 phase 2 clinical trials that both showed a positive impact of this rapamycin derivative on immune function. So in that context, 6 weeks seem to be enough to get some benefit. But we don't have much in the way of additional large clinical trials to guide us in recommending what's the best dose, what's the best duration of treatment, what is the real side effect profile of rapamycin. And those are all pieces of information that you really want to have if you're going to go out and start recommending to people that they should consider taking rapamycin. So the other thing I can tell you is there is a I wouldn't say large, but significant number of people who are taking rapamycin, what's called off-label, meaning rapamycin's a prescription drug. So you need a physician prescription to get the drug legally. And it's FDA approved to prevent organ transplant rejection for some rare forms of cancer, for a couple of other smaller indications. But if a physician, if a drug is FDA approved, any physician can prescribe that drug for non-approved indications, and that's called off-label use. So there are, I would estimate, a few thousand people, maybe more, but at least a few thousand people taking rapamycin off-label because of this sort of accumulating body of evidence, mostly in laboratory studies, but a little bit in people suggesting that rapamycin can have positive impacts on healthspan certainly in laboratory animals and maybe outside of the laboratory. And so the challenge with that sort of a dataset is it's a collection of n-of-1 experiments, right? Everybody's doing it a little bit differently. Everybody, of course, has their own other set of things that they might be taking, their own lifestyle interventions that they're carrying out. And so it's really hard to draw strong conclusions from those kinds of collective N-of-1 studies, but we're trying. And so I'm actually involved in a project now where we've collected survey data from a few hundred people who have been using rapamycin off-label, and we're trying to just figure out, okay, what can we learn both about potential benefits and also what do the potential risks look like? So I can't answer your question because I don't know is the real— that's probably what I should have started with.

No, that was a great answer. Very informative. One, one final rapamycin question, which may be a little bit out of left field, but I thought it was an interesting point that was raised by a regenerative medicine doctor who I have a lot of personal respect for. And she had been using rapamycin, or not, not using it, but wondering whether there was merit to using rapamycin for patients with long-haul COVID. And so I'm curious if you see any interrelation there.

So the first thing I would say is hypothetically, absolutely. I mean, this is something that I was saying a year into COVID. So there's a couple things about rapamycin that's interesting. I already talked about the evidence from these two clinical trials that short-term treatment with rapamycin can boost vaccine response potentially. It looks that way in, in people. Um, there is data that was just published last year following some of the people from the phase 3 clinical trial that they did, where it looked like people who had been taking a different mTOR inhibitor— remember, rapamycin is an inhibitor of mTOR— so in their pivotal clinical trial, they gave them a different drug, but it still was an mTOR inhibitor. People taking that inhibitor actually showed lower rates of severe outcomes from both influenza and coronavirus. Now, that clinical trial was done in 2019. So this is before COVID-19, but that family of coronavirus, people who'd taken the rapamycin derivative seemed to be protected against severe outcomes if they got an infection. So rapamycin might boost the immune system, at least short-term treatments with rapamycin might boost the immune system and help at the infection stage with COVID-19. But I think where it probably is even more effective is in the cytokine storm that some people experience after COVID-19 infection that leads to hospitalization and in many cases death. There's very good reason to believe that rapamycin would be effective at bringing down that cytokine storm. And then long COVID is super interesting because We don't know a lot about what is causing long COVID. But I think many of us who have sort of been on the peripheral— so I'm not a virologist. I'm not an immunologist. I'm somebody with a sort of high-level understanding of biological systems in general and how they interact with aging biology. But I've had this idea that long COVID is, to some extent, a chronic inflammatory state that probably is going to share mechanistic components with autoimmune disorders. And one of the places where rapamycin seems to be particularly effective is in autoimmune disorders and tamping down that what we call sterile inflammation. And so, yeah, I think many of us have speculated that that might be a place where rapamycin could be quite effective and have tried to get at least small-scale clinical trials underway. And as far as I know, nobody has really Nobody has really picked up on that and tested that. So anecdotally, I know of cases where people say that rapamycin has helped their long COVID, but I don't know of any sort of, you know, careful quantitative or certainly I don't know of any placebo-controlled clinical trials to really test that. So I think there's a lot of merit to the idea. I would love to see somebody actually, you know, do the really careful trial to test the hypothesis.

Got it. No, that's, that's really helpful and interesting, Matt. I have two questions we'll come to in a moment. One about how to measure lifespan and healthspan in, in humans. I know there's a few different forms of measurement.

Yeah.

Then I would love to hear as well about really the top 3 or top 5 longevity interventions that are out there ranked by merit or, or validity based on the research. But before we go there, on another podcast, I heard you give a really interesting breakdown for why focusing on longevity versus specific issues like cancer can have a much greater total impact. And there's a quick quote I want to read you that I really like that addresses this issue broadly. And then it'd be great if you could give a breakdown for that so people really understand the importance of this work on longevity. But this quote is from Sam Altman, who was a partner at Y Combinator and the founder now of OpenAI, CEO of OpenAI. He says the best people in both groups spend a lot of time reflecting on some version of the Hamming question. What are the most important problems in your field and why aren't you working on them? In general, no one reflects on this question enough, but the best people do it the most and have the best problem taste, which is some combination of learning to think independently, reason about the future, and identify attack vectors. And when I heard you give that breakdown on this other podcast, it struck me as a very good argument for longevity as an attack vector to overall impact on, on health. So would love to hear that breakdown on, on longevity versus focusing on something more specific like cancer or heart disease.

Sure. So I'm gonna, I'm gonna tweak this just a little bit because, because I would say, well, what I, I don't know that longevity is the right word. It's sort of a popular way of framing this area of research now, but it's possible to live a long time and not be in good health. Right. And it's possible to live a long time by, well, by definition, avoiding dying. Right. But I think probably what the way I would frame it is targeting aging biology or the biology of aging is really the core tenet of, I think, maximizing healthspan and also maximizing longevity. And I think one of the ways to appreciate this is if you think about the leading causes of death and disability, pretty much every developed nation in the world, all of them share age as their greatest, greatest risk factor. And it's not even close. So, you know, if you think about things like cancer or heart disease, most of the risk factors that people talk about are going to be things like obesity, high blood pressure. Those all increase your risk of developing those diseases by about 2 to 3 fold. If you look at the increased risk of developing those diseases, just going from 35 to 75, depending a little bit on the disease, it's anywhere from 50 fold to 500 fold. So we're talking an order of magnitude difference, at least in the relative risk associated with getting old compared to the relative risk of, you know, the kinds of lifestyle changes that we might be more familiar with. So I think you have appreciate that in order to, to understand why targeting the biology that, that changes between being young and being old can have an outsized impact on relative risk for each of these individual diseases. And if you look at the way that we have approached health and biomedical research and clinical practice over the last century, it's really been focused around individual diseases. So we focus on diagnosing what's wrong with you, whether it's cancer or diabetes or heart disease, and then trying to treat that disease. You know, we try to cure it more often. What we, what we actually end up doing is treating the symptoms. What I think we really need is a fundamental shift in the way that we approach human health towards keeping people healthy instead of waiting until they're sick. And the very best way to do that is by targeting the biology of aging, because that is the single greatest risk factor for getting sick in in the first place. The other thing I would just add to that is it's not only about disease, right? So again, our culture of healthcare is very much focused around disease. It's really disease care, I would say. But it's not only diseases. You can still have a substantial loss in quality of life without being diagnosed with cancer or heart disease or diabetes or kidney disease or whatever. We have all these functional declines that go along with aging that maybe aren't diagnosed as diseases, but that still have a really significant impact on on the quality of life and our ability to do what we want to do. And again, it's the biology of aging that's really driving those functional declines, driving the risk of disease. So if we can understand that biology, that gives us an opportunity to intervene in that biology in a way that will preserve health, maintain health much later into life. And that's where, you know, we talk a lot about longevity, but really, I think for me, it's equally, maybe more, about maximizing healthspan and really maintaining quality of life and high function for as long as possible. And again, the very best way to do that is by targeting the biology of aging.

That makes a ton of sense. There's a really good clarification. So the biology of aging is an upstream intervention that can more effectively, you know, mitigate disease onset and other functional declines. So it's a bigger parent category.

Roughly. Yeah, absolutely. Yeah, yeah, that's right. Hmm. Got it.

Okay. Now that, that makes a ton of sense. And then let's talk through some of the big pillars of interventions or things people can do to maximize, you know, healthspan longevity or, you know, to improve the way in which they age. What do you see as really the big 3 or the big 5 that, you know, are the most interesting, uh, to you at the moment. Maybe rapamycin's in that list. Um, yeah, that's totally fine.

So yeah, so I think the first thing that, that, you know, we have to say is, um, I would put these into a couple of different buckets, right? So, so they're— the first bucket is, I think I said this just a minute ago, if you want to live a long time, you can't die, right? So, so the first thing to do is to make sure that you don't have something that's going to kill you in the next X years, right? 5 years, whatever. So I think there is an important role for preventative diagnostics in making sure that you don't have a preexisting cancer or preexisting heart disease that is going to have a high chance of limiting your longevity. So that would be one thing I would recommend for people who are able to do it. And again, this is where I think we get into inequalities and access to healthcare and things like that. Those are big problems. I recognize not everybody has access to those preventative diagnostics, but I would say everybody can certainly make sure that you're getting in for an annual checkup and to the extent that you can do more advanced diagnostics to make sure you don't have preexisting disease. That's important. That's not aging biology, that's not longevity science. But again, I think if you're going to live a long time, you want to make sure you don't have a lethal disease. That's something that I think has to be a foundation. Then I would separate out the interventions into lifestyle interventions and maybe more advanced interventions, pharmacological interventions, things like that. Again, I'm a scientist at heart. I have to say on the pharmacological intervention side, we don't have anything that we can point to with absolute certainty that we can say right now will positively impact your biology of aging and give you some X% chance of living Y% longer. That's research that is ongoing. So I think many of us in the field have our own opinions, and we believe that some things are more likely to work than others. But nothing has been scientifically proven to positively modulate the biology of aging in terms of a drug or a supplement yet. Okay, so I think that's just important for people to understand. It's all, you know, probabilities and educated guesses. Where we can say that there is some level of certainty is in the realm of lifestyle modifications, right? So, you know, I think depending on who you talk to, you'll end up with 3 or 4 big ones, but they're all going to end up being more or less the same thing, right? So diet, clearly important. People will argue religiously over what the best diet is, what the optimal longevity diet is. My personal view is, you know, what we know for sure— obesity is bad, being overweight is suboptimal, having poor glucoregulatory homeostasis is suboptimal. So those are all things that you can pay attention to, and I believe most people can optimize through dietary modifications. And so, you know, what I mean by that is glucose homeostasis in particular, I think, is, is, um, important. So I personally have found that for me, a diet low in simple carbohydrates works really, really well at optimizing glucose homeostasis. And I can tell you how I know— it's because I've got a continuous glucose monitor on. I don't have diabetes, But, but I use this periodically to learn about my own sort of physiological response to different foods that I eat and exercise and other environmental components. And so I've learned that for me, a diet low in simple sugars is, is certainly better than the diet that I used to eat. I hesitate to say it's optimal. So I think it's a continuing journey towards optimization. But it works pretty well, and that has helped me in many aspects of my life. And I would encourage everybody to really think about, you know, I'm not saying go ketogenic. I'm not saying, you know, that you have to be super extreme in it, but really think about ways that you can lower the amount of simple sugars that you are taking in. And again, it's going to be different for everybody, but I think that that's a general rule that I don't think anybody's going to be harmed by not having that super sugary coffee drink or not eating that donut at breakfast or whatever. So that's something I would say focus on. Anything you can do to get your glucose homeostasis under control, get yourself out of the obese range— if you're in the obese range, get yourself down to a normal body weight— I would say is good. And then you can worry about optimization on top of that. That's the way I approach diet. Um, physical exercise, regular exercise— I would actually put I don't know whether I would say it's equal to diet. Personally, I think it's probably even more important than diet if you're, if you're going to have a foundation of your longevity protocol, if you want to call it that. I think regular physical exercise is, is the foundation. And again, personally, I believe that resistance training is an area that too many people underappreciate in their, their exercise regimen. A couple of reasons why I think that's important. I think muscle mass, we've learned plays a, an essential role in metabolic homeostasis in terms of helping your body deal with sugar, for example. Um, so having more muscle mass in general is very beneficial from a metabolic health perspective. That also tends to mean you have less adipose, which is harmful from a metabolic health perspective. The other reason why resistance training is so important is probably the leading cause of functional decline with age is loss of muscle mass. And that leads to increased risk for a bunch of different injuries. It's also associated with loss of bone mass, which resistance training can help maintain bone density. So I think that we've seen that sarcopenia, loss of muscle mass, is a major predictor of mortality in the elderly, and it's a major predictor of loss of independence and function as you get older. So I would say, again, It's important to, to do both resistance and cardiovascular training, but I would prioritize resistance training over even cardiovascular training. I may take some heat for that, but that's my own personal sort of belief. Again though, and this is— and, and I think for a lot of people they get intimidated by the idea of resistance training. You don't have to go into the gym and be a powerlifter, right? Just do some weights 3 times a week. Don't overthink it. Once you get that foundation, then you can start to to optimize on top of that. So diet, exercise, you know, I think sleep obviously is critically important. I'm not an expert in sleep. I feel very fortunate. I sleep pretty well. So it's not something I've had to struggle with personally. So I'm not going to try to give advice to people who are having trouble sleeping. I think there are, there are people out there who are much more knowledgeable in this space than I am. But I think whatever you need to do To get adequate sleep, again, is critically important for optimal health and longevity. And all of these things, it may not sound I'm talking about the biology of aging. All of these things at a cellular molecular level tie directly into the biology of aging. So in fact, you are impacting the biology of aging when you exercise regularly, when you get adequate sleep, when you're eating a nutritious diet. All of those things impact the biology of aging in ways that we sort of understand. I would say we best understand the role of nutrition in aging biology, but there's, there's clear biological links for all of these things to aging. Um, and then the other thing that I think is, you know, often not talked about, uh, certainly among the scientific wellness community, is, you know, psychological health, mental health, positive attitude. And I think the reason why we don't talk about that so much is because it's harder to study from a hard science perspective. But again, I think from a human perspective and optimizing your healthy longevity, having emotional health, mental health, being happy, feeling like you are accomplishing something is also critically important. And it's something that I think, again, the scientific wellness community doesn't really focus on enough. So those are 4 things. And I think if you can If you can, if you can get to a place where you're, you're doing pretty good in all 4 of those, you're well on the way. You're well on the way. And then you can start to worry about optimizing on top of that. At least that's the way I would approach it.

Hey, it's Joshua with the production team. Thanks for listening to Flow Research Collective Radio. Before we dive back into our conversation, there's something to consider. It may be that today we are under-challenged. We're drowning in comfort.

Comfort.

Now, in his book Antifragile, statistician Nassim Taleb pointed out something that's of key importance. Quote: "Undercompensation from the absence of challenge degrades the best of the best. The best horses lose when they compete with slower ones and win against better rivals." Now, put another way, who we could be, or our highest potential, is squandered by safety, coddled by comfort. If you want to train with us at the Flow Research Collective, it require boldness, but what's life without a little adventure, right? To learn more about how you can get more flow in your life and achieve your professional and personal goals in less time and with more ease, go to getmoreflow.com. If you're a good fit, we'd love to train with you.

All the best.

And then let's assume some of the listeners at least are, are pretty locked up on those and on our, you know, edging towards a 9 outta 10 on those categories. What are some of the interesting things within the long tail of optimization that you are curious about or that you see others in the space experimenting with? I'm, you know, assuming fasting for example is, is one, but I'm curious if there's any even less commonly talked about examples of, yeah, long tail interventions.

Yeah. So, so a couple things I would, I would say on that. I mean, I don't know that I would even necessarily put fasting into that long tail. I I think things like fasting, time-restricted feeding, there's a couple things to say about them. One is it's not really clear that those are potent longevity interventions, but I think they can certainly be potent interventions for helping people get to and maintain, you know, a healthy, healthy weight. I think they can be important parts of a nutritional strategy. They're not going to work for everybody, but they can work, work for a lot of people. Um, the other thing I would say is I'm not I'm probably not the guy to come to for how do we optimize in terms of diet, exercise, things like that. Personally, I really like Peter Attia. I think he's probably, in my view, he's the master at optimization in those categories. So I would recommend people check out his podcast. I'm sure most of your listeners are familiar with Peter, but if they're not, check out his podcast because he's the guy who really does a deep dive on how people can optimize those aspects of their, their life and their performance. I think what I can maybe comment on is in the longevity intervention space, what are some of the interventions that have some potential? And again, with the caveat that these are experimental and that we don't know for sure exactly how beneficial these things are going to be, and we don't completely know what the risk profile looks like for these things. So personally, I would put rapamycin at the top of the list. So I've been public in talking about the fact that I use rapamycin cyclically myself. I've had personal benefits from rapamycin. And again, I've talked about the fact that I was diagnosed with a condition called adhesive capsulitis or frozen shoulder, which is inflammation of the shoulder capsule. I wasn't able to go across the street and throw a football with my son. It was that painful. And I believe that taking rapamycin cured me of that condition, which makes sense with the biology. All of that is just to say, you know, this is based on my own personal experience in addition to, you know, my knowledge of the biology of aging and rapamycin. But it's also, I think, to say that, you know, my belief about rapamycin being beneficial is influenced by my personal experience, which is going to be the case for, for anybody you ask this question to who's in this field. So I would put rapamycin at the top of the list. I think what we're learning is is that for some people, rapamycin can be very effective at tamping down the age-related increase in chronic inflammation that everybody has. But, but, but different people have different degrees of, of this, uh, chronic inflammatory state with age. So things like frozen shoulder are caused by chronic sterile inflammation. Things like autoimmune disorders are caused by chronic sterile inflammation. A lot of the aches and pains that go along with aging are caused by chronic sterile inflammation. So I think people who have a high burden of sterile inflammation, rapamycin can be quite effective for. What I would say though is rapamycin's a prescription drug. It's not FDA approved for that. I think I'm obligated to say, you know, people, if they're going to experiment with rapamycin, should absolutely do it under the care of a physician. We're learning more as we go, and honestly, we don't know what the risk profile associated with rapamycin is. We're trying to figure that out. Personal opinion, it's not very high, but it's an unknown. So I would put rapamycin at the top of the list for some people to try. And I think you're not going to know until you try it. So the other area that I think is really interesting and exciting is this area of senolytics, which some of your listeners have probably heard of. The idea behind senolytics is with age, we have an accumulation of what are called senescent cells. These are cells stop doing what they're supposed to. They don't die. So when— one way to think about it is when a cell in your body, you know, walks off the job, it's like, okay, I'm done, I'm out of here, not working this job anymore. There are a couple of things that cell can do. It can die, it can go down the process of what's called apoptosis, or apoptosis. It's a programmed cell death pathway. That's okay, that's fine, it's not going to cause any problems if it does that. It can turn into cancer which is a problem. And so that's where most of our cancers come from. Or it can go down this pathway called senescence, which means it stops dividing. It doesn't turn into cancer, it doesn't die, it just hangs out. And if that was all it did, that's not really a big deal. The problem is it hangs out and starts sending out signals that cause other cells to stop doing their job. And that's what's called this SASP or senescence-associated secretory profile. So it's really the SASP that is the problem with senescent cells because they give off all these other signals that then tell the cells around them to become dysfunctional. Particularly stem cells seem sensitive to the SASP. So then you've got these senescent cells which are causing your stem cells to stop doing their job, and that seems to contribute to many of the degenerative declines that go along with old age. Okay, so senolytics are a class of drugs that people are developing that will go in and kill senescent cells selectively, not the cells that are doing their job, just the senescent cells. And so there are what I would call first-generation senolytics that are out there, like dasatinib, visidin, quercetin, that people have studied. They seem to have some beneficial effects in mice. Some people are taking them. Personally, I'm not super convinced that these senolytics are all that effective in humans, the first-generation ones. I think the second-generation ones that are being studied and developed right now will be more effective. And part of the reason why I don't personally take any senolytic strategies in, in my own lifestyle is because rapamycin, as it turns out, is a very potent what's called senomorphic. So it doesn't kill the senescent cells, but it shuts off that SASP. So I think if you're taking rapamycin, you probably don't need to worry so much about senescent cells. Um, then I think there are things like metformin. So metformin obviously is something that a lot of, you know, biohackers are are currently taking. My view on metformin is that it's nowhere near as potent as rapamycin at affecting the biology of aging in laboratory animals. I don't think anybody would argue with that. That data is, is pretty clear. What metformin seems to be very good at in humans is helping if you have glucoregulatory problems. So if you're diabetic, pre-diabetic, um, metformin I think can be an important, uh, aspect of, of, uh, helping maintain glucose homeostasis. I'm not convinced that for people who don't have any glucoregulatory issues that metformin is a good idea. And, and the reason for that is there is accumulating evidence that metformin can interfere with the, at least some of the, what are thought to be the positive responses to exercise. And so if exercise is an important part of your optimization regime, you, you might not want to take metformin unless you have diabetes or you're pre-diabetic or you have some other reason to think that your glucoregulatory regulatory system is not functioning exactly the way that you want it to be. So I'm not personally a big fan of metformin for everyone. The other thing that— and I didn't actually— it's funny, I've been in this field for a long time. I didn't actually know this until about a month ago. Turns out one of the side effects of metformin in many men is a reduction in testosterone. And so again, you know, part of the— we know that there's a reduction in testosterone with age. We know that's a concern for many men. You might not want to be taking metformin if you're concerned about your testosterone levels, or at least you might want to get your testosterone tested if you're taking metformin. So there are some— metformin, it's interesting because metformin is often thought of as this really safe drug. It's really safe for diabetics, but I think there are probably some side effects that, that haven't been appreciated because, you know, we weren't really worried about testosterone if you were concerned about diabetes. You might be worried about testosterone if you're taking metformin optimize other aspects of your, of your life. So again, that's all to say, I think metformin's the right choice for some people, but it's probably not right for everybody. And again, metformin's a prescription drug, even though there's this perception that it's a really safe prescription drug. If you're going to take it, you should do it under the supervision or at least the knowledge of your primary physician. Okay, so then, you know, I would put the other prescription drugs that are potentially out there in the much more experimental category and maybe maybe not worth spending a lot of time talking about now. There's, there's these new classes of, uh, anti-obesity drugs or anti-diabetes drugs that people are just starting to really study in the context of aging, um, but there's not as much evidence. Again, the only thing I would say there is if you're obese and taking prescription drugs help you get down to the normal weight range, I think that's, that's a beneficial thing to do. If you're not obese Personally, I don't think the data is there to suggest that you might want to start experimenting with those.

Is semaglutide one of those?

Yeah, that's exactly right. So I would put that in that category where, you know, it's interesting because there's a lot of excitement right now, but I don't think we have a lot in the way of experimental data yet to really make informed decisions on something like semaglutide. But again, you know, this is all going to also fall into where every individual sort of, you know, risk-reward calculus places them.

And something like semaglutide, from what I'm aware of at least, only has an acute effect. It doesn't necessarily have enduring lasting effects. It works while you're on it, in other words.

That's right. Yeah. And so again, that, and, and that's, you know, I would say that's something we don't have a lot of understanding for many of these interventions, right? So I talked about rapamycin. Certainly in mice, we know that a single or cyclical rapamycin treatment can have have prolonged persistent effects after you stop. Same thing's true with senolytics. And again, that makes sense. I laid out how senolytics are working. They, at least in theory, are killing the senescent cells. So you do that once, and then it takes a while for the senescent cells to come back. So for those kinds of interventions, the biology makes sense that you might take it, and then there's a period where you stop, and, and then you wait for the, the problem to come back, and then you take it again. But yeah, certainly some of these interventions you have to continuously— I would probably guess metformin falls in the category where you've got to be taking it continuously to get the persistent glucoregulatory benefits. And if you stop taking it, you're going to lose those benefits. So then there's this whole world of supplements which we haven't really talked about. And I tend personally not to dive into the supplement world because I don't feel like there's much there that we can put a lot of confidence into, especially in the aging realm. So there's this whole realm, obviously, of longevity supplements. And my opinion is that varies from pure snake oil to questionable. But there's nothing that I feel like— there's enough data at this point to say, yeah, people should go out and really, really do this. I think you could put things like NAD boosters, NAD precursors, nicotinamide riboside, nicotinamide mononucleotide towards the— I would put that towards the questionable end of the spectrum in the sense that there's conflicting evidence in, in animal models that these things can have some benefits in the context of aging, but there's some positive evidence, uh, um, and they're unlikely to hurt you, right? So again, we're thinking about the risk-reward calculus. There's probably not a lot of downside to taking NAD precursors, although some people have speculated on cancer risk, um, but there's probably not a lot of harm associated with them. So you might get a little benefit probably not a lot of harm. I would say it probably depends on where you are on the economic spectrum because, you know, money from your bank account could be harmful depending on where you're at. But when you get to the other stuff that's in the supplement realm, you know, there's not a lot out there that I have a lot of confidence in. And, you know, part of this is there's a long track record in this field of really, really bad bets that were made and bad information that got out of the general public. And it takes a really long time to clean that up. Up. And, and so I'm really hesitant to feed into that, that aspect of, of the, of this field. So I have a hard time with supplements. I feel like we've been burned.

Yeah, we often describe excessive supplementation as majoring in minor things.

It's easy to, you know, the other thing I would say, and I don't think most people have, have really thought about this, is we have very little understanding of what the combinatorial interactions are going to be. So there are a lot of people who have these stacks of supplements. And I don't have much data yet, but it's a question that I'm interested in exploring is what happens if we take 3, 4, 5, 6, 7 different interventions that individually might increase lifespan a little bit or might have a positive impact on healthspan. We put them all together, what happens? We don't have much data yet, but the little bit of data that we've collected so I think the one thing I can say with confidence is it's almost impossible to predict what's going to happen in that I have never seen yet in an experimental setting a situation where you combine more than 3 things and actually get additivity or synergy. By synergy, I mean more than additive positive benefits. I've seen several cases now where you get canceling out and even a net negative effect. Now, these are all in laboratory animals. So take it for what it's worth. But I do think that the naive assumption that taking— if one thing is good and another thing is good and another thing is good, if we combine them all, we're going to get 3 times the benefit. Biological systems are immensely complex, and predicting the combinatorial interactions is very difficult. And the other thing that I think people don't often appreciate is supplements in particular are extremely dirty drugs. So first of all, supplements are drugs. They are molecules that get into your body and have biological effects. They're just not regulated by the FDA the same way, but they're extremely dirty. So I talked before about how rapamycin has one biochemical target. It targets mTOR. These supplements that are generally recognized as safe, I, I don't want to say none of them have one target, but I don't know of any that don't at least have a dozen targets or two dozen targets. And so If these molecules are actually getting into cells and affecting, let's just say each are affecting 10 different proteins in the cell. When you combine 3 of those, now you're affecting at least 30 different proteins. It's really hard to predict what the outcome is going to be in this complicated biological system. My intuition is, when you do something to perturb a biological system, and you, and you have no a priori sort of prediction of what that— whether that's going to be good or bad, 98% of the time it's going to be bad. It's much easier to break a complex biological system than it is to make it function better. And so if you're just randomly messing with stuff, you're much more likely to do something detrimental than you are to do something positive, which I think feeds into my philosophy that we really should focus on the things that we have a level of confidence are going to be beneficial and maybe not mess around with a bunch of stuff that might be good, might do nothing, but then when we combine them all, it actually becomes detrimental.

That's a rarely made and important point about supplements being drugs and dirty. What is the threshold or distinguisher between a supplement and a drug? Or is there one?

Yeah, so I mean, there might be some formal legal definition that I don't know about. So I'll tell you the That's the way I think about it. So I kind of put supplements, and some people like the word nutraceuticals because it sounds maybe a little bit more appealing than supplements. So I kind of put those in the category of things that the FDA does not regulate as a medication because it's generally recognized as safe or GRAS. So there are a set of molecules that through a variety of ways can get into this category of being generally recognized as safe. And so if a molecule falls into that category, there are much lower restrictions on selling that molecule in a nutraceutical format or a supplement format. And the restrictions are lower, although there are still restrictions on what you can claim about those molecules in your product. So, you know, you'll see lots of people claim that this product with these three generally recognized as safe components is a longevity pill, right? Has that ever been shown to increase longevity? Probably not. But the FDA doesn't really crack down on that kind of what I would say is deceptive marketing. They don't really crack down on it, even though technically that might be against the rules. But I think the key point is if your components are all on this list of generally recognized as safe molecules, you can put that into a supplement format and sell sell it as a nutraceutical or as a supplement. That's my understanding of the system. Again, this isn't a world that I've ever been in. I've never tried to make or market my own supplement. But that's my understanding of the, the way that works.

That makes sense, Matt. Are you okay for another few minutes? I know we're just—

yeah, yeah, I'm good.

There's a couple more questions. Super. So just to close the loop on the, the aging piece, what are the, some of the ways to measure biological age. People talk about telomeres and all sorts of different, yeah, you know, epigenetic ages and things like that. I'm, I'm curious if you could paint that landscape for us and, and separate the wheat from the chaff.

Sure.

So, back to what's legit.

Yeah. So, so what I would say here is as a field, we don't have a consensus on the definition of biological age. We also don't have a consensus on the definition of healthspan. And we didn't really talk about that. But I'd say those are two terms that conceptually, we all more or less know what we mean. But when you get down to the nitty-gritty of how do you actually measure biological age or how do you actually measure healthspan, there is not consensus among the scientific community or the clinical community on either of those two terms. I think that's something that we need to work towards. As a field. I would also say I think we can get there with biological age. I don't know that we're ever going to get to a quantitative definition of healthspan that everybody agrees with. Okay, so, so how do we measure biological age right now? So I think there are a variety of approaches that you can take. You can approach it from sort of a molecular framework, and what I mean by that is there are these collections of things that people call the hallmarks of aging or the pillars of aging. The hallmarks of aging are 9 evolutionarily conserved molecular cellular processes that seem to be shared about biological aging across all animals and seem to be mechanistically involved in the aging process in the sense that they are thought to drive functional declines and diseases that go along with aging. And so those include things like telomere shortening, which you mentioned. Some of the others are senescent cells, which we talked about. Mitochondrial dysfunction, nutrient dysregulation, protein misfolding. So again, there are 9 of these things. They're interconnected, but they can be distinctly categorized. So one approach to measuring biological aging would be to measure each of those 9 things and come up with some metric that is a quantitative overarching assessment. People will have heard of epigenetic clocks. In fact, in the popular sort of podcast world and media, epigenetic aging clocks are sometimes conflated with biological aging clocks. That's sort of a pet peeve of mine. They're not the same thing at all. I shouldn't say that. They're not— they are the same thing partially, but epigenetic aging is only a single piece of biological aging. So epigenetic changes are one of the 9 hallmarks of aging. Okay, so there— people have developed these epigenetic aging clocks that measure epigenetic changes. And just quickly, for definitional purposes, not to get too far in the weeds, when we say epigenetic changes, what we mean are chemical modifications to your DNA or to the histones that package the DNA that, that regulate gene expression. So they're not mutations, they are on top of the genome, one way to think about it. Okay, so there's a pattern of these epigenetic changes, particularly methylation of DNA, that people have noticed with aging, with chronological age. And people have developed algorithms where you can measure those epigenetic changes based on blood samples or tissue samples and tell chronologically how old somebody is with some error, some precision. Those work really well, so they can measure chronological age. Then people now have gone on with second-generation epigenetic assays to try to build clocks that they think are measuring the biological age of individuals. And one way to think about this is, you know, let's just say that we've got this epigenetic clock for chronological age. So you've got your chronological age on the x-axis, right? And your epigenetic age on the y-axis. Most people are gonna fall along the line y equals x. If you're 70 years old chronologically, you're 70 years old epigenetically. Okay, that can be done. But then you've got the people who are either above the line or below the y equals x line. The hypothesis is those people are aging biologically faster or slower than their chronological age. And there's some evidence to support this. For example, people whose epigenetic age is lower tend to go, tend to go on in future years and have lower risk of death, for example, or specific age-related diseases. So people have developed now these clocks that can predict biological age. Based on the epigenome. And you will often see this referred to as biological aging in the, in the media, or, and sometimes even in the scientific literature. No, it's one aspect of biological age. It is epigenetic age. And so I, I went off on that tangent because I think it's important for people to appreciate, first of all, there's a lot of misleading use of this nomenclature out there. And secondly, if we really think about the hallmarks of aging as a mostly comprehensive picture of biological age, you really need to measure more than just one of them. You need to get some sort of holistic measure of the hallmarks of aging that takes into account all the different molecular processes that are driving biological aging. Okay, so that's how you could develop a molecular biological aging test, and people are working on that, and I think we'll get there. The other thing, of course, that's important is it's great to have this molecular biological aging test, but it darn well better match up with functional declines, disease risk, and mortality in people. Otherwise, it's not very useful. And so I think validating these biological aging tests is also going to be critically important. And that takes longer because you need to have a test that you can then follow those same people and say, yep, This guy who was 50 years old chronologically but 70 years old biologically went on to develop heart disease and die in 5 years. You need to have that kind of data to know that your test is working. And I think that's going to take longer to get there. So this is an area that's really active right now. And there's a lot of research. And I think we're going to continue to see more and more progress. But we're not there yet. There yet.

Yeah, it'll be really interesting when we do converge on something that is, uh, you know, more and more agreed upon.

Um, yeah, the other thing I would say is, you know, there are a bunch of these commercial biological aging tests right now, and it's unclear, I think, which are the best ones or how precise they are. There's a lot of noise in the system, it seems like. Um, so what I'm looking for is kind of the next generation where people are developing biological age tests that don't rely only on the epigenome. That don't rely, you know, only on immune markers, but that actually query again multiple aspects of the hallmarks of aging to see how well those things correlate. And it may be different in different tissues. I think that's another area that, you know, there's a lot of complexity that we're still trying to figure out.

Got it. The final question, Matt, is a question we ask all of our academic guests who do research, and the question is a question about a question. Um, so if you could snap your fingers and immediately have all of the research conducted to give you a conclusive answer to any big question that you find yourself pondering a lot, what would that question be?

I think, you know, one of the things that I'm most interested in is, um, and this isn't really a scientific— I don't know that it's a scientific question per se, but it's, it's what can we do to maximize or optimize healthspan for as many people as possible. I think this is a— you know, I study the biology of aging. I absolutely believe that optimizing or targeting the biology of aging is an important component of that, but I don't think it's sufficient. And I do have some concerns that it's not going to be effective for the broader population. I think we have, you know, societal structures that are in place. And I don't mean that they've been put there. I think some of them have sort of evolved culturally or through accident that make it really, really hard for the average person to optimize their health. So how do we get around that? You know, we can— in the field of, of geroscience, we can come up with interventions that people who have taken care of— you know, we talked about the lifestyle foundations— people who've taken care of diet and exercise and sleep maybe can benefit from those interventions. And those people might get 20, 30 or more years of healthy longevity. Like, I don't think that's outside the realm of possibility of where we'll be in the near future. I do, I do have real concerns that the majority of the population who haven't figured out how to, how to deal with the foundation aren't going to benefit from those interventions. So how do we actually get strategies in place that are going to help more people and hopefully most people? I'm not naive enough to think that we're going to be able to maximize healthspan for everyone, but I think we can do a better job of maximizing healthspan for most people. And this is something that I think a lot about because I have no clue. I can see the path towards targeting the biology of aging to have an impact on healthspan for some people. I really struggle with how do we put solutions in place that the majority of people are going to be able to benefit from. So I'd love to, to, to know more about that and to be able to come up— I don't know about an answer, but with some steps down that path, because I think it's going to be really, really important, especially as we go forward, because we know that most people in the United States and other developed countries, they're not getting better, they're getting sicker. And I think we have to come up with some strategies to deal with that.

Amazing. Thanks so much, Matt, for your time and wisdom and expertise. And where can people learn more about the work you're doing and support your current projects?

Sure. So one thing I would say, we actually didn't talk much about the Dog Aging Project, but if you have a dog and you love science and you want to, you want to be engaged, dogagingproject.org is the website. And there's certainly lots of information out there that you can find out about the, about the project, but, but would love to have you and your have your pup participate in that study if you're interested.

Amazing. And Stephen Kotler, who's my co-founder and who the audience knows well, actually runs a dog sanctuary for Chihuahuas that does hospice care. He's got 19 Chihuahuas with him at the moment.

Amazing.

So we have a big community of dog lovers as well. So we'll definitely send people your way. And hopefully next time we'll dive into that topic a little bit more. And again, Matt, thanks so much for your time and expertise. Really, really amazing and incredibly educational.

Absolutely, my pleasure. Thank you.

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