Promise and Controversies: State of the State of Longevity Science with Matt Kaeberlein, PhD

It’s important to me to include a variety of voices in the sphere of aging and longevity, and Matt Kaeberlein PhD is certainly one that I appreciate for his tempered and rational arguments. I value his insights and his work with other scientists who are tussling with the challenging questions and research interpretations in this field. We are at this extraordinary inflexion point where scientists are debating the very definition of aging itself, which has important implications for how we then measure and study it. Dr. Kaeberlein shares his thoughts on this as well as the latest on longevity interventions such as rapamycin, metformin, intermittent fasting, and caloric restriction. Find out why he thinks we’ll always hit a wall with moving the needle on lifespan, and why healthspan is such an important target. I think you will find this conversation illuminating and useful.

An additional note for any of my listeners/readers who have been tracking the various discussions around the utility of epigenetic clocks and other measures of aging: I personally very much believe in epigenetics, even as the field continues to evolve. The foundation of this traces back to my beginnings in this field, working under my mentor Richard Lord PhD, who taught me that as scientists and clinicians we have no choice but to embrace uncertainty. No laboratory tests are as precise as many of us would like to think they are – microbiome, organic acid, nutrient testing, those foundational tools of functional medicine that we are very comfortable using, included. This applies to standard labs too –  I recently received a notification from one of the two biggest labs in the US stating that, due to a change in the testing instrument used, values for red cell indices (the oldest tests on the planet!) would be altered compared to prior results. As clinicians we have to grapple with uncomfortable uncertainty in medicine every single day – from that reality we still have to move forward and make the best clinical decisions we can. Epigenetic age testing is simply another tool in the mix that can add value to understanding a patient’s picture, and we can use it even as we interpret it with a similar acknowledgement of uncertainty. If you would like to add your thoughts to this discussion, please share below. And you might want to take a look at some of the other conversations on this topic here and here . ~DrKF

Promise and Controversies: State of the State of Longevity Science with Matt Kaeberlein, PhD

In this episode of New Frontiers, Dr. Kara Fitzgerald sits down with Dr. Matt Kaeberlein, a leading expert in the biogerontology field, for a comprehensive discussion on the latest in aging research. Together, they explore groundbreaking topics, including the differences between biological and chronological aging, reliable biomarkers for measuring aging, and the potential of longevity interventions like rapamycin, metformin, and fasting. They also delve into the challenges of defining and measuring healthspan, insights from Blue Zones, and Dr. Kaeberlein’s thoughts on supplements and current trends in the longevity space. Packed with actionable insights and evidence-informed perspectives, this conversation offers clinicians and health enthusiasts alike a deeper understanding of the evolving science of aging and how it may impact their practice and patients.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. Today is no exception. If you’re with me on YouTube, you can see that I am sitting next to the extraordinary Dr. Matt Kaeberlein. For any functional medicine people out there who haven’t encountered his work yet I’m really thrilled to bring him to our community. Let me give you his background, and we’re going to jump right in because we’ve got a lot to cover today. Dr. Kaeberlein is the Chief Executive Officer at Optispan, Affiliate Professor of Oral Health Sciences at the University of Washington. He’s the co-founder of the Dog Aging Project and the Dog Aging Institute. Dr. Kaeberlein’s research seeks to define biological mechanisms of aging and to facilitate translational approaches that promote healthspan and improve the quality of life for people and companion animals. I also want to add that he is a fellow of the American Association for the Advancement of Science, the American Aging Association, and the Gerontological Society of America.

Dr. Kara Fitzgerald: He’s published more than 250 papers in peer-reviewed literature on longevity, and he’s received a zillion different awards, which if you want to read through them, it’s really impressive. It’s over on our show notes. I’ve been following your work, Matt, for a long time now, and I appreciate—as I mentioned offline—your voice of reason. I think, more and more, we need rational, thoughtful leaders. It seems like you take a breath before you respond. I really look to you to guide where we’re going. It’s funny, I didn’t actually anticipate starting with this, but in this guidance, you’re part of the Biomarkers of Aging Consortium. You’re right in the middle of getting the language down and the biomarkers defined for what aging is. You’ve spent your entire career studying the mechanisms of aging.

Dr. Kara Fitzgerald: I want to talk about all of it. So, let’s start with what you think aging is. Then, I’d like to jump into how we’re thinking about measuring it, the language, and all of that.

Dr. Matt Kaeberlein: Sure. Well, first of all, thank you for that kind introduction. I do try my best to be precise in language. I think that’s one of the things that becomes especially important in a field like aging or longevity because definitions matter. In this space, not everybody has the same definitions, so I’m glad you actually started with, “What is aging?” When I think about aging, my training, since I was a graduate student, has really focused on the biology of aging. I immediately approach it through the lens of biological mechanisms. My training is in biochemistry, molecular biology, and genetics, so that’s the way I think about aging.

Dr. Matt Kaeberlein: What are the biological processes that contribute to all the functional changes and, in general, functional declines that go along with the aging process. Just to start from a foundation, it’s useful to differentiate between chronological age and biological age. I immediately gravitate toward biological age because that’s what I think about. Chronological age, of course, is what most people think about, which is just the number of birthdays you’ve had—the length of time you’ve been alive. What’s important to appreciate is that those two things don’t necessarily have to be equal. In other words, some individuals will age biologically faster or slower than the population average, so your chronological age can be different from your biological age. Some animals will age faster or slower than others. I always like to point to dogs because I’m a dog person, and I’ve studied aging in dogs. But also because everybody gets this idea that one human year is about seven dog years. All we’re saying is dogs age biologically about seven times faster than people do.

Dr. Matt Kaeberlein: So I think it’s important to differentiate between what we’re talking about. When I talk about biological aging, I’m referring to the biological, molecular, and biochemical processes that lead to the functional declines that go along with aging, which in turn lead to exponentially increasing risks for almost all the major causes of death and disability in developed countries—cancer, heart disease, dementia, kidney disease. You can go down the list. It turns out that nine of the top ten killers in the United States have this relationship that they are largely driven by biological aging. So, I think where you were going with the Biomarkers Consortium is, how do we measure that? That’s one of the big outstanding questions in the field these days: What are the right biomarkers we can use to actually measure biological aging? We could get into a deep discussion about this. I think I’ll just stop here by saying many people tend to gravitate toward molecular markers. That’s where the epigenetic tests come in, but you can use all sorts of different biomarkers of aging.

Dr. Matt Kaeberlein: It turns out that AI, just based on facial images, can do a pretty good job of estimating biological age. So, there’s nothing intrinsically special about epigenetic molecular marks versus metabolomic molecular marks, versus functional measures, versus imaging measures of skin age. I believe they are all different reflections of biological aging. I’d also say, I don’t think we, as a field, have a consensus definition for how to measure it or even necessarily what biological aging is. I think we’re still figuring it out.

Dr. Kara Fitzgerald: Yeah, all right. And then we can talk about what actually reversing or slowing it down means, especially if we don’t have it defined or measured yet. But before we do, I just wanted to mention that 2016 paper that I’m sure you’re probably familiar with, that identified that we can visually see people who are aging at a faster rate. It’s like we’re evolutionarily or biologically hardwired to see folks who might be weaker, which I think is kind of cool. It’s logical, but also sort of extraordinary.

Dr. Matt Kaeberlein: Yeah, I think we have to be a little bit careful, though, to recognize that we can do that as human beings, but there are error bars on it. The accuracy is not that great. AI can actually do better than the human eye can in terms of accurately predicting chronological age. This raises the question: Can we actually predict biological age, and what do we mean by that? I think the field is struggling with the question of whether we’re measuring biological age or are we measuring health or some metric of health status. And are those equivalent? They don’t necessarily have to be.

Dr. Matt Kaeberlein: Health generally declines with chronological age.It also generally declines with biological age. But is health status equivalent to biological age at either the whole-organism or the individual organ level? That’s another layer of complexity. Sorry, I keep going off on these tangents.

Dr. Kara Fitzgerald: It’s really interesting, though.

Dr. Matt Kaeberlein: It’s super important to appreciate that we’re starting to understand that at the molecular and biochemical levels, not every organ or tissue in the body is aging at the same rate. Your health status can be largely determined by whatever your rate-limiting organ is, or at least your risk of dying. So health is not necessarily equivalent to biological age. We’ll get into reversing aging—is that even a valid thing to say? But the way I think about it is, if we just leave biological aging out of the equation, no one would be surprised that you can take an unhealthy person and make them healthier, right? That’s obvious. You take a sedentary 65-year-old who’s eating a crappy diet, and you get them to start eating right, sleeping well, and exercising regularly and they’re going to get healthier. Did their biological age reverse? I don’t know, but they got healthier. And I think sometimes we mix those things up and start claiming that we’ve reversed biological age when all we’ve really done is see someone get healthier.

Dr. Kara Fitzgerald: But why don’t you know that has reversed biological age?

Dr. Matt Kaeberlein: Because we don’t know how to measure biological age. It’s a chicken and egg sort of thing. If there’s no consensus–

Dr. Kara Fitzgerald: Because they’re likely going to live longer if you’ve turned the volume down on that process.

Dr. Matt Kaeberlein: If they’ve gotten healthier, but that’s because health status generally declines with age. Again, we didn’t reverse chronological age. There’s a correlation between health status and chronological age. No one’s going to argue that we’ve made time go backwards. So, have we actually made biological age go backward or not? That’s still an open question. I don’t know the answer. I think that’s fair to say. What bothers me is when people claim they do know the answer and claim they’ve reversed biological aging.

Dr. Kara Fitzgerald: But you don’t know the answer because we don’t have the tools to measure it. So it’s not that it’s not happening—it’s just that you’re not keen on the current toolbox. Would you say that’s true?

Dr. Matt Kaeberlein: I think that’s fair. But there are two other things I’d say. First, if you’re going to make extraordinary claims, you really should have extraordinary evidence to support it. Claiming you’ve caused someone to age in reverse, to me, seems pretty extraordinary, and they don’t have the data to support it I would say. That’s number one. Number two, so far, we have yet to see anybody, no matter how healthy they are, who makes it to 85 or 90 years old without significant functional declines. If you were really reversing biological aging and in theory could keep doing that, you should, in fact, look younger in every way, function younger in every way, and in theory, be able to maintain that.

Dr. Matt Kaeberlein: I’m not saying it’s impossible. There’s nothing biological that says it’s impossible. But it hasn’t been done yet.

Dr. Kara Fitzgerald: Wow, you’re just making more questions for me. I want to ask you about the blue zones, but let’s put a pin in that because now what you’ve said circles right back to the Biomarkers Consortium and what are you guys actually working on over there?

Dr. Matt Kaeberlein: Yeah. The way I would describe this is as a collection of mostly academics and scientists grappling with the challenge of developing something closer to a consensus on what we mean by biological age and what are the tools that we have available now to measure it. Also what questions do we need to answer as a field before we feel confident that we are not only able to measure biological age in some meaningful way, but we start to move to where those tools can actually be used in clinical practice and eventually accepted by regulatory bodies to assess whether or not interventions are actually impacting the  biological aging process.

Dr. Matt Kaeberlein: The obvious case use would be a company that has a drug they believe modulates the biological aging process. They would like to get it approved by the FDA for clinical use. Right now, there’s no clear path for that company to get their drug approved beyond picking an existing disease or functional endpoint and conducting a typical clinical trial. Is there be a future where tools like epigenetic clocks or a collection of biological age metrics could be used in clinical trials where the FDA would accept those as surrogate endpoints? Meaning there’d be high level of confidence that this expected to actually improve health, reduce mortality, and improve quality of life? We’re not there yet, but I see that as a goal that is possible and starting the discussion now makes sense if we want to get to a point where regulatory bodies will have confidence in these markers.

Dr. Kara Fitzgerald: That’s awesome. And it’s such a diverse group of academics. I imagine you guys have some pretty interesting conversations over there—really fascinating dialogue. But you’re defining what the job is ahead, and then you’ll start pulling together the relevant biomarkers. Cool.

Dr. Matt Kaeberlein: And I would also say that in these kinds of discussions, you’re never going to get 100% agreement. But the conversations and the documentation that come out of them are valuable in and of themselves. It’s important to also point out where there is disagreement.

Dr. Kara Fitzgerald: For sure. And I just want to state the obvious here for anyone familiar with my publications—we’ve discussed the potential reversal of biological age, which really put the stone in some peoples shoes. I want to acknowledge that up front. I’m a clinician and was following the voice of the literature at the time, and I appreciate this conversation.

Dr. Matt Kaeberlein: I’d say again, everyone’s entitled to their opinions. I’m just sharing mine. But I’ve had similar conversations about the word “healthspan.” I’ve been guilty of using it in the past. If you look at some of my papers from 2016 and before, in the title we said we improved healthspan. Then I realized there’s no consensus on how to actually measure healthspan. It’s a useful concept; people generally know what we mean, but there’s no agreement at all in the scientific community on how to measure it scientifically. As scientists, we shouldn’t claim we’ve statistically changed something that we can’t actually measure, right? So, while we know what we mean when we say we’ve improved healthspan, but we shouldn’t claim that we’ve shown a drug or intervention improves healthspan in the scientific literature if we don’t have a consensus way to measure it. And I feel the same way about biological aging. It’s perfectly appropriate to say ‘We have reversed this metric of epigenetic age’ because we all know exactly what we’re talking about.

Dr. Matt Kaeberlein: But we don’t actually know if epigenetic age—by whatever epigenetic test or collection of tests you use—truly reflects the biological age of the entire individual or animal at this point. We just have to be careful about the way we portray ourselves, particularly in the scientific literature.

Dr. Kara Fitzgerald: I think that’s absolutely a fair criticism, and it’s nice to spend time teasing it out here. On this podcast, there are many clinicians listening who are probably aware that there’s a challenge around language but might not understand the details behind it. So your extremely clear explanation is useful. I have a couple of questions on that. Blue Zoners are clearly living longer by definition and they have a better healthspan, right? I mean, there are certain characteristics. Why isn’t this something you can dive into? Can you speak to the Blue Zones?

Dr. Matt Kaeberlein: I think there are a couple of things to say. First, the Blue Zones themselves have different levels of confidence and credibility. There have been questions raised about some of the Blue Zones. The one I feel most confident about, and this is my opinion based on what I know, is Okinawa. I think it’s the gold standard. Historically, there’s no question that Okinawan Japanese lived significantly longer than mainland Japanese, who already have a pretty long life expectancy by international standards. There’s clearly something different about that population. To the extent that we have quantitative data on healthspan metrics, they also seem to enjoy better health later into life.

Dr. Matt Kaeberlein: What are the likely explanations? The most likely explanation is caloric restriction. That’s probably not the entire answer, but it is the case that Okinawa, up until about 30 or 40 years ago, was one of the largest natural experiments in caloric restriction without malnutrition.

Dr. Matt Kaeberlein: They ate—I don’t remember the exact amount—but it’s around 15% fewer calories than mainland Japanese. They had a very healthy diet: lots of seafood, lots of complex carbs, if they’re eating carbs. They also exercised regularly. Not like the American “weekend warrior” or going to the gym, but just as part of their natural daily lives—lots of walking. They also have strong social connections. Again, it tends to come back to what most people agree defines a healthy lifestyle: lots of natural foods, plenty of vegetables, if you’re eating a lot of meat it’s typically richer in seafood than red meat. Although we could talk about red meat too—that’s an interesting topic as well. Regular exercise, strong social connections, and a relatively low-stress lifestyle—those seem to be the commonalities that come out of the Blue Zones.

Dr. Matt Kaeberlein: I think what makes Okinawa interesting is that they ate less, and there could also be a genetic component as well. Those seem to be the commonalities in my view of what people attribute to the Blue Zones, and that fits pretty well with what most agree are the hallmarks in general are the themes of healthy lifestyle. These practices would likely benefit people in the U.S. if we could get them to actually do that.

Dr. Kara Fitzgerald: Right, right. What about diving into the UK Biobank data? Could you tease out healthspan from that massive, super interesting dataset?

Dr. Matt Kaeberlein: Sure. People are starting to conduct these large-scale epidemiological studies, but we need to be careful, for obvious reasons, with these types of correlative studies because the analysis can go wrong in many ways. For example, who are you comparing to? Here’s an interesting example, and it’s not just with the UK Biobank. You see a lot now about alcohol consumption, right? The question is whether moderate alcohol consumption is good for you or not. A recent study from the UK Biobank examined this, which is what made it pop into my head. When you’re thinking about challenges with the way you do these studies, the consensus, or at least popular opinion, seems to be shifting towards “no alcohol is optimal.” Right?

Dr. Kara Fitzgerald: Yeah.

Dr. Matt Kaeberlein: The problem is, the data hasn’t really changed; the issue lies in who you’re comparing to. The data is pretty clear that a low to moderate, depending on how you define moderate, level of alcohol consumption gives you the lowest all-cause mortality – the least likelihood of dying. When you compare to those who abstain from drinking, it turns out that moderate alcohol consumption is  beneficial. If you move what you call “zero” (non-drinkers) to something that’s not zero then it’s no longer beneficial. But it’s because you’ve changed the comparison group, not because the data has changed. Interpretation of those types of studies can be very dependent on the population you’re comparing to.

Dr. Matt Kaeberlein: This is where I was going with red meat. I think it’s another example where if you compare people who eat a lot of red meat and also have an unhealthy diet overall, then yes, red meat looks bad. Protein is bad. If you compare people who eat a lot of protein and eat a crappy diet but are overweight, then high protein is bad. But when you compare those who eat a healthy diet overall, those negative trends around red meat and protein consumption tend to disappear, making the impact less clear. We just need to be cautious with how we interpret these correlative, observational studies.

Dr. Matt Kaeberlein: So yeah. There’s a lot that can be done with this data, but I feel like it gets misinterpreted more often than it gets interpreted properly. Honestly, sometimes I just throw my hands up when I see this stuff show up on CNN.

Dr. Kara Fitzgerald: Right, right. That’s fair.

Dr. Matt Kaeberlein: The UK Biobank is interesting for a variety of reasons because you can do all sorts of analyses, all of which have these risks associated with them. But if done properly, you can tease out interesting signals. There was a study that looked at prescription medications. They looked at all of the prescription medications that have been prescribed to about a thousand people and tried to compare people who got those medications to health-matched individuals. They asked, “Is there a relationship between the medication itself and all-cause mortality?” Most medications led to higher mortality, as expected, but for a few, mortality actually decreased. And it’s a really interesting list because several medications overlapped with those that increased lifespan in mice, like SGLT2 inhibitors and estrogens. So, it’s suggestive that perhaps there was a biological aging signal there because those same medications have independently been shown to increase lifespan in lab animals. I do think there are cool opportunities with the UK Biobank data, as it’s rich and has been made widely available to the research community.

Dr. Kara Fitzgerald: Yeah, there are studies coming out all the time, and to your point, they’re not always useful—like the fish oil and AFib study.

Dr. Matt Kaeberlein: Exactly, we have to be cautious. And this is one of the challenges in this space: figuring out what to trust. I even struggle with what to belief sometimes. How does someone who can’t dive into the literature, doesn’t have that medical background, etc. know which sources are credible—even the credible voices get it wrong occasionally. It’s a real challenge. My advice would be never take one study as gospel, no matter how strong it seems, especially if it’s a purely epidemiological study. One study should never be the gold standard. We need reproducibility, optimally across different populations, or at least line up with other evidence pointing in the same direction.

Dr. Kara Fitzgerald: Yeah, I think that’s fair. That leads me to another question, but I’ll hold off and bring us back to the main point because I want to ask you more about defining healthspan and biological aging. And actually, what you said really ties into that.

Dr. Kara Fitzgerald: We’re at an extraordinary inflection point in science and medicine in general, where we can measure and observe things that were once unimaginable. It’s so exciting and incredible, especially now that we’re starting to layer AI on top of it. This means that biological aging and healthspan are becoming moving targets, so grappling with definitions and keeping your eyes open, moving intentionally is important. It is really very exciting, but I can see why we need the consortium. We need folks like you cutting the path for  us. So, back to defining biological age and healthspan, it seemed like it wasn’t a safe thing to talk about–biological aging as being a programmed phenomenon, as there being two tracks. So there’s aging, and I think what…  humans can max out around 120 years, while species like Greenland sharks can live for 450 years, and naked mole rats live up to 30 years, which is nuts. Or a fruit fly which doesn’t hang around very long.

Dr. Kara Fitzgerald: There are these very different and reliable lifespans that we have, and there’s reason to think that it’s programmed or hardwired. And this would make identifying and measuring biological age difficult, because then we have the exposomic aging, which is all of the environmental inputs like smoking, diet, and so on. So you might have someone who’s hardwired to age to year X, but they’re smoking, etc, etc. There’s these two trajectories that add to it and I want to get your thoughts on that.

Dr. Matt Kaeberlein: Sure. I think the first thing to say is most of the discussion around programmed aging in the scientific community comes down to definitions. When people talk about programmed aging, I think where the disagreement arises is technically, that means that natural selection acted to cause a certain rate of aging. Most people who understand the biology of aging don’t believe that’s true. By and large, natural selection is acting on the factors that will influence whether or not you reproduce at the right time and in the right number optimally because then you can outcompete your competition. It doesn’t have anything to do with how long you live. There may be rare cases but by and large, evolution and natural selection is not controlling the rate of aging. That doesn’t mean that aging is not genetically controlled. It just means these genes weren’t selected for that. They still control aging, and that’s why we see this coupling of development with longevity—things like mTOR, insulin signaling, IGF-1–

Dr. Kara Fitzgerald: Yamanaka factors

Dr. Matt Kaeberlein: Yeah. Right. They were selected for something else but they do control aging. So in that sense, if that’s what you mean by there is a program, yeah, aging and longevity are under genetic control to some extent. I think that when we compare across species—like anything else, the differences in maximal life expectancy across species, which is what you were referring to– like flies, dogs, humans, or clams that live for 500 years—that’s going to be a whole bunch of genes. It’s not a single gene that determines those differences. Which I think is why we haven’t been able to recapitulate that level of lifespan difference in the laboratory, where we can manipulate one gene or a few genes at a time. And it’s not going to be primarily the environment that’s controlling those species-level differences.

Dr. Matt Kaeberlein: I think that one of the interesting questions is, within species, we have a pretty good handle on what the fundamental network of genes and proteins are that modulate the rate of aging that determines the difference between a person who is going to age and die at 65 versus 105. We understand this pretty well in mice, flies, and worms, though there’s still much to learn but we can put names on it and we know a lot of the players. We know some of the genes to tweak to change lifespan by 25-50% in laboratory animals.

Dr. Matt Kaeberlein: What we don’t understand are the biological differences that go across species by an order of magnitude, or two orders of magnitude. One really interesting question is whether those are fundamentally different mechanisms than what controls from within a species rate of aging. I think they are, and I think we have no understanding of what those mechanisms are right now. But what’s also interesting is that what seems to controls within a species rate of aging seems to be highly shared– from nematode worms to fruit flies, mice, dogs, and probably humans. Insulin signaling, mTOR, IGF-1… We have data across all of those species that those things regulate the differences in rate of aging in individuals within the same species. That seems pretty clear. We haven’t proven it in people, but there are enough arrows… We were talking about if there’s enough arrows all pointing in the same direction. There’s enough arrows pointing in the same direction that I think in people it’s probably true that the same pathways that modulate aging in mice, worms, and flies, to some extent, also modulate human aging.

Dr. Matt Kaeberlein: One of the implications is that we’re probably not going to do better than 20% at best in people by tweaking that network. So that’s about what we can do pretty easily in mice. So, we’re probably not talking about doubling or drastically increasing lifespan because we just don’t fully understand those mechanisms. You mentioned Yamanaka factors earlier and we can talk more about that. That’s the one area that people have thought may give us much larger effects on health and longevity. I don’t know. But I think the early data suggests we may still be hitting that same 25% wall or effect on lifespan, even with repeated partial epigenetic reprogramming. But it’s still early days, so we’ll see how it evolves.

Dr. Kara Fitzgerald: What makes you think there’s a wall or limit? What leads you to that opinion?

Dr. Matt Kaeberlein: Recently, at a panel discussion—Ii think it was at the Aspen Institute event—where Rick Klausner from Altos Labs, which is a company that’s doing some of the leading work in epigenetic reprogramming, mentioned that they’ve been able to partially epigenetically reprogram mice multiple times in the lab. These mice seem to have greatly improved healthspan, but they’re not doing any better than 25% on lifespan. That’s unpublished and I haven’t seen the data, so take it for what it’s worth. But that fits with what little is in the literature regarding partial epigenetic reprogramming, which is not even as good as rapamycin. So far, no one has been able to break past that barrier. The only thing that has gotten past that 25% marker in mice is extreme caloric restriction. I’m being sloppy in my terminology because percent is not the best way to look at these numbers, but for the sake of simplicity, let’s say 25%.

Dr. Matt Kaeberlein: The only thing that really does better than rapamycin is extreme caloric restriction in mice. In fact, the only experiment I’m aware of that extended mouse lifespan beyond 25% was done in the 1990s by Rick Weindruch and Roy Walford, where mice underwent 65% caloric restriction and got about a 65% increase in lifespan. No one has done better than that in over 30 years. Again, I  think we should ask the question why and one interpretation would be that we’ve bumped up against the best we’re going to do by tweaking the same network. We really need to understand what else is acting at the level across species if we want to do better than that upper limit. That’s speculation on my part, but so far all the data supports that.

Dr. Kara Fitzgerald: That’s really interesting. So, we’re not hitting “escape velocity” anytime soon.

Dr. Matt Kaeberlein: There’s no data to support the idea that longevity escape velocity is getting closer. If you want to believe something in the absence of data, that’s called faith, and that’s fine. I have nothing against faith, but it’s not science.

Dr. Kara Fitzgerald: I had a really fun podcast with Vittorio Sebastiano, who you’re in the consortium with and your familiar with his work. I thought that his comments around focusing on specific organ rejuvenation using Yamanaka interventions was compelling. In women, ovarian rejuvenation strikes me as extraordinary. If we can keep our ovaries younger for a little while longer we will influence the brain, bone health, heart health, not to mention the obvious reproduction as well if we choose to go in that direction. What are your thoughts on these kinds of interventions, especially as they relate to healthspan, which we’re still defining?

Dr. Matt Kaeberlein: And they’re tied together and I agree completely. When I talk about the partial epigenetic reprogramming and I’m saying I don’t think we’re going to double lifespan, that’s not at all meant to suggest that it’s not a potentially powerful therapeutic approach. I think there are lots of potential applications. We’ll see. There are also some challenges, but I’m very enthusiastic about the idea that these approaches can have significant effects on a whole bunch of health conditions and improving healthspan. It turns out that there’s a whole body of literature, certainly starting with the heterochronic parabiosis. These are the studies where you take an old circulatory system and hook it up with a young circulatory system and you can get positive benefits on the old animal and negative effects on the young animal.

Dr. Matt Kaeberlein:  So there are circulating factors that influence whole-animal health as we age. Again, you bump up against the same limit in terms of effect on lifespan with heterochronic parabiosis. You can also do that by taking young ovaries and putting them into old mice. Again, you bump up against the same limits. So yeah, you can have effects on healthspan and lifespan at the individual organ level, and also potentially at the whole body level by rejuvenating certain tissues or organs. I haven seen nothing that makes me think that approach  is going to get us past the same sorts of limits you bump up against so far, at least in mice with rapamycin, caloric restriction or reducing IGF-1 signaling. But yeah. I think there are lots of opportunities from a therapeutic perspective, especially as we’re starting to learn about differences in aging rate in different organs, in different people. For example, if my kidneys are aging rapidly, if we could have a therapy that could go in and take care of that it would be fantastic and could significantly increase my individual longevity and healthspan. I think there are lots of applications there.

Dr. Kara Fitzgerald: It’s really exciting. I mean, it almost more satisfying to look at that level instead of trying to add another 30 years to lifespan. It just makes more sense.

Dr. Matt Kaeberlein: It’s funny, because I sometimes get branded by the extreme life extension people as a pessimist, but I’m not at all. I think there are huge opportunities to make large impacts on healthspan and potentially longevity for a lot of people. It’s just that I think adding 20 years of extra health is a big deal, and I don’t think we should minimize it just because there’s no evidence that we’re going to get 200 extra years of health. I think we have to set our expectations in a realistic way and not mislead people or turn people off by talking about stuff that sounds more like science fiction, and in many ways is science fiction, when science itself is actually pretty darn exciting right now.

Dr. Kara Fitzgerald: It is. It’s extraordinarily exciting. The quality of life in the U.S. as we age is pretty terrible overall. It’s not a fun place to be by and large.

Dr. Matt Kaeberlein: Yeah, the statistics are pretty daunting. I was actually pretty surprised when I looked into this. The CDC says that 60% of Americans suffer from at least one chronic disease. The median age in the U.S. is around 38. So if 60% of the people have at least one chronic disease and half the people are younger than 38, and the average life expectancy is in the mid-70s, that means that most people are living 3-4 decades with at least one chronic disease. So, healthspan is harder to define, but if we define ‘sickspan’ as the period of life with at least one chronic disease, that’s a pretty big chunk of life spent dealing with illness. I don’t think most people realize the impact that has on not just the quantity of their life, but the quality of their life and much of that time people can reclaim.We have tools available right now that can help people regain that time. That’s where we should be focusing our attention, in my view.

Dr. Kara Fitzgerald: You need to make a slide for that. Have you noticed that there’s been a wholesale adaptation of your BioAge—

Dr. Matt Kaeberlein: Yeah, it’s nice to see. I’ve been doing this for about 15 years now, and the first time I saw one of my slides being used in someone else’s presentation, I thought, “They stole my slide!” But then I realized, that’s actually the best form of flattery, so I think it’s great.

Dr. Kara Fitzgerald: Yeah, I’m working on a deck for a nutrition group in the UK, and one of your slides is in there.

Dr. Matt Kaeberlein: Everybody, feel free to use my slides. Go for it.

Dr. Kara Fitzgerald: But create that one. It’s incredibly powerful and then one diagnosis begets another. It’s like you slide down a slope I think.

Dr. Matt Kaeberlein: Right. I think so too. Absolutely. And again, it’s maybe not surprising that one of the first chronic diseases that many people experience in the U.S. is metabolic-related, like obesity or diabetes. I think there’s pretty good reason to believe that obesity, and particularly metabolic disease, accelerates biological aging. Again, this is a little bit of speculation going back to my insistence that we don’t over-define how we define biological age. So it’s not shocking if metabolic disease is the first condition people experience, that it’s going to increase the rate of onset of other age-related diseases. That’s also why you’re starting to see headlines about GLP-1 agonists potentially reversing aging. I don’t think they’re reversing aging; I think they’re reversing an acceleration of aging.

Dr. Matt Kaeberlein: They’re slowing down that acceleration of aging. It’s an interesting hypothetical question: in normal weight people, would GLP-1 agonists reduce mortality and age-related diseases through a caloric restriction effect? I don’t know the answer to that. But I do think in people who have metabolic disease, for sure, you’re going to have a positive impact on a bunch of age-related diseases if you can reverse that metabolic disease. There are other potential downsides to GLP-1 agonists, but from that perspective, they’re incredibly powerful drugs.

Dr. Kara Fitzgerald: Super powerful and that’s another conversation that we can talk about—primarily about muscle and so forth.

Dr. Matt Kaeberlein: Muscle and bone would be the two areas I’d be most concerned about. Hormones too.

Dr. Kara Fitzgerald: Yeah. Quickly, before we dive into supplements, rapamycin, metformin, and what to do in your opinion, I wanted to ask you about the pan-mammalian clock—the Horvath pan-mammalian clock—and your thoughts on linking together some shared aging phenomena that they’re starting to tease out.

Dr. Matt Kaeberlein: Right. This is the idea that you can measure changes in the epigenome. Maybe it’s worth defining what we’re talking about at a high level. Epigenetics refers to modifications that occur on top of the DNA. You can think of it as control knobs on individual genes. We can modify the epigenome to turn genes up or down through various mechanisms, and methylation is the most common one people measure when looking at epigenetic clocks and we have tens of thousands of methylation marks in our genomes. What has been seen is that you can find a subset of those—usually in the order of a few dozen to a couple of hundred of these tens of thousands—that change in a predictable way with age. You can also find different subsets that change in a predictable way with health status or with remaining life expectancy if you have biobank samples, things like that.

Dr. Matt Kaeberlein: What has started to emerge is, first of all, you can do this at the organ or tissue level within individuals, which I find super interesting. There are different signatures for different organs and tissues. You can also look across species and find a different subset of marks that seem to correlate with aging if you take what we know about the maximum lifespan and normalize it– so we’re talking about the same relative access. In other words, an animal that lives for 100 years compared to an animal that lives one year, you would shrink it by 100. If you do that you can find a subset of epigenetic marks that seem to mark the aging process across mammals. One interpretation would be, although it runs against what I suggested before—there is a conserved biological aging process across at least all mammals, that we can measure at the epigenetic level.

Dr. Matt Kaeberlein: That might be true. But the challenge is, there’s no mechanistic connection at this point. In other words, nobody has actually gotten to the point where we can look at these specific epigenetic marks that are correlated in any of these clocks and say, mechanistically, this is causing a change in the rate of aging, or a change in the risk of dying, or a change in the risk of a specific disease. They are purely correlative at this point, and I think in the absence of a mechanistic understanding, we don’t really know what it means. I have a bit of a mathematical background—actually an undergraduate degree in mathematics although I haven’t used it in decades– which leads me to recognize that the dimensionality on the epigenome is so large, (tens of thousands of marks), you’re very likely to be able to find a subset of marks in the order of a few dozen that will correlate with anything.

Dr. Matt Kaeberlein: And so again, in the absence of a mechanistic understanding of whether that correlation is causal or responsive or just a correlation, it’s hard to have a ton of confidence to know how useful that is, both as a measurement tool and for understanding the biological process. So, it’s still an open question. Another thing worth mentioning—and Steve Horvath might have a good answer to this, I haven’t asked him—one of the things that makes me a bit cautious about the way these epigenetic clocks are being used and marketed today is in order to make predictions about mortality 10 or 20 years down the road, in the absence of doing a 20-year experiment, the only way to do that is by going back to biobank samples and making predictions based on samples from 20 or 30 years ago. Then you can know which people who have since died and you can come up with these correlations.

Dr. Matt Kaeberlein: My concern is that the environment 30 years ago is so fundamentally different than it is today that it may be a completely different set of marks that would correlate today with health outcomes than they did 30 years ago. So I’m a little worried that because we lack a mechanistic understanding, we may be misinterpreting what these clocks are actually telling us. They may not be telling us what many people believe they are telling us.

Dr. Kara Fitzgerald: That’s fair. I think that’s definitely a fair pushback. The OMICmAge clock that True Diagnostic developed with Harvard, is using currently banked specimens and they might be onto something. It’s sort of a sidebar, but I also want to throw out the polycomb repressive complex clock (PRC2), looking at the entire methylome that Sebastiano and Horvath developed, that seems to possibly be touching on a little bit more rather than an isolated set of markers correlated with aging.

Dr. Matt Kaeberlein: And I think this is both one of the exciting things about the field and one of the challenges. There are so many flavors of these clocks now. And nobody really, at least that I’ve seen, has rigorously shown how well these clocks match up to each other. Do they all give the same answers? And if they don’t, what does that mean? When they don’t, what does that mean?

Dr. Kara Fitzgerald: And I don’t think they do, actually.

Dr. Matt Kaeberlein: Okay, if they don’t, that should tell us something, right?

Dr. Kara Fitzgerald: That aging is complex.

Dr. Matt Kaeberlein: Yes. And at least some of the clocks are not being interpreted properly. So I think we just have to approach this with a fair degree of caution. My viewpoint right now is these are really great research tools and I think they have the opportunity to be useful from a regulatory perspective in clinical trials. We’re not there yet. If we want to use them in the context of a healthcare practice, they should be used in combination with more standard and traditional blood-based biomarkers and functional measures—the stuff we’re more confident about as predictors of current health status and future health outcomes, future disease risk. If the epigenetic clocks don’t match up with those other things, I’m going to put my money on those other things for now.

Dr. Kara Fitzgerald: I think that’s fair, and I appreciate that as a clinician. I’m casting a wide net of standard biomarkers. I do think there’s a place for at least some of the clocks out there, and I’m excited to pay attention to the others. For example, I would like to send our IDAT files from our original cohort to look at that polycomb clock, looking at the whole methylome.

Dr. Kara Fitzgerald: So anyway, I’m going to put a pin in this because we’re getting pretty arcane and I want to circle back to some ground that people can relate to. But it’s a cool space and conversation. Let’s talk about interventions like rapamycin. You’re really bullish on rapamycin, and more studies are coming out in humans. For a long time, it was like, yeah, we have no idea, but now I think we’re on firmer ground, and you’re bullish on it. Talk to me about what’s up in the scientific community with it and why you like it.

Dr. Matt Kaeberlein: Sure. So, rapamycin—there are a few reasons why I guess I’m bullish. I mean, I still say, with complete sincerity, we don’t know the extent to which rapamycin is going to increase lifespan in people or improve healthspan for most people. I am 100% confident that rapamycin can improve healthspan for at least some people because I’m one of those people, and it had a significant impact on my healthspan, which I’ve shared and I’m happy to share again.

Dr. Matt Kaeberlein: I think the question is: to what extent is rapamycin really slowing biological aging in people? And can we start to get to a point where we can have some real rational risk-reward analysis where we can be confident—which people does the reward outweigh the risk, and what is the actual risk? Why am I bullish on rapamycin? In the preclinical studies—preclinical meaning everything in laboratory animals, mice, flies, worms, yeast, marmosets now—rapamycin always increases lifespan and always improves multiple healthspan metrics. Does it improve every age-related metric? I don’t think we know that. Probably not, but certainly most age-related health metrics in most tissues and organs in laboratory animals seem to be improved by rapamycin treatment. You can start the treatment in middle age and still get most or all of the benefits for both lifespan and healthspan metrics, at least in a mouse. We now have data in a non-human primate, in marmosets, showing lifespan extension, and at least some aspects of healthspan being improved.

Dr. Matt Kaeberlein: We have some data in dogs—similarly, evidence for improved healthspan. I think we’re learning that the side effect profile of rapamycin, which is what the biggest concerns were for a long time, at the doses that people are using off-label where some people, I believe, are seeing benefits, the side effects are pretty minimal—not significantly different than placebo in controlled studies where there’s been a placebo. The one side effect that really looks real to my eye is about a 15% likelihood of developing canker sores in people using rapamycin off-label. So, I think we can start to have some confidence around safety and there have been a few studies now in people suggestive of efficacy. We published a study last year looking at about 300-some people who’d been using rapamycin off-label and compared them to people who’d never used rapamycin. Take it for what it’s worth; there are lots of caveats with that kind of data, but it was suggestive that rapamycin had positive impacts on things like chronic pain, and maybe even things like depression.

Dr. Matt Kaeberlein: I think the strongest data was around the severity of COVID-19 infection and the potential for long COVID. Again, that lines up with other data—biologically plausible. There have been a couple of clinical trials now—these are years old now from Joan Mannick—suggesting that a derivative of rapamycin can boost vaccine response in healthy elderly people. The PEARL trial, which again has lots of issues, the biggest probably being that the dose was lower than what most people are using off-label. Again, no real evidence for side effects, and some evidence for improvements in body composition, at least in women, meaning preservation of lean mass in women taking rapamycin, or maybe even improvements. Again, that lines up with anecdotal data that many people report these positive changes in body composition when taking rapamycin. None of it is great, right? We don’t have the definitive randomized clinical trial data.

Dr. Matt Kaeberlein: Again, I should just say clinical trials get it wrong all the time so I don’t put as much faith in clinical trials as some people do. But it would be great if we had really large randomized clinical trial data giving us information to go off of. But the data we’ve got is all pointing in the same direction that, at least for a subset of people, most people using rapamycin in the once-weekly 5 or 6 mg range, plus or minus a few, can get some positive benefits. My intuition is that it tends to be people with a high chronic inflammatory burden that feel better when they’re taking rapamycin. That lines up with the biology of what we know about rapamycin. So, I think the preclinical data, which is rock solid, shows rapamycin is without a doubt the gold standard for a longevity healthspan intervention in laboratory animals. Combined with what’s starting to emerge in the clinical world, it’s pretty suggestive, in my view.

Dr. Kara Fitzgerald: That’s awesome. Okay, great. And you actually answered my questions on dosing. What about folks suggesting that one take a break? Is that something…?

Dr. Matt Kaeberlein: Right. Again, nobody knows. That’s what I do—I typically will do three months on and then some period of time off, although last time I did six months on. Again, everybody’s kind of doing their own thing. There is no right or wrong dosing. Nobody really knows. Six milligrams once a week is the most common dose. Is that too high? Too low? Should women take less than men? Nobody really knows. But I think that dose is pretty safe for most people. Should you take a break? What we know from laboratory animal studies is that, at least in mice, a single three-month treatment in middle age is enough to give a significant increase in lifespan. Is it the biggest increase in lifespan you can possibly get? Probably not. But we know that single transient treatments are enough to have a long-term effect on the biological aging process.

Dr. Matt Kaeberlein: In people where we’re working with an unknown risk and an unknown reward equation you could make a case that you’re going to reduce your risk of long-term side effects by doing repeated transient treatments with rapamycin. How long do you need to get the benefits? What I think is interesting here—and I think this comes down to the biological mechanism for how rapamycin works, which we haven’t really gotten into—but for the purposes of right now, we can just say biochemically, rapamycin is a very specific drug. It inhibits a protein called mTOR. mTOR does a whole bunch of stuff, but I think the biggest effects that most people experience are the ability of rapamycin to quite rapidly tamp down chronic inflammation. Particularly, it seems very good at tamping down age-related sterile inflammation for reasons that are complicated and that I don’t completely understand—I don’t think anybody does.

Dr. Matt Kaeberlein: In mice, you can get benefits as fast as 4 weeks; people have shown that 4 to 6 weeks is enough to get significant improvements in some things; you can go up to 12 weeks, or you can do continuous treatments. In people, we don’t have that data other than from Joan Mannick’s studies, where they used a derivative of rapamycin called everolimus—it has the exact same biochemical mechanism. They showed that six weeks of treatment in healthy older people was enough to improve their subsequent response to a flu vaccine, which perfectly matches a previous mouse study. So, even though mice are aging roughly 30 times faster than people biologically, the time frame for efficacy of rapamycin, at least for that outcome, is the same. You might only need 6 to 12 weeks to knock down that inflammatory burden that then is impacting all sorts of tissues and organs in humans.

Dr. Matt Kaeberlein: From my personal experience, the first time I took rapamycin was after being diagnosed with frozen shoulder, which is inflammation of the shoulder capsule. That’s why I took it. I couldn’t go another year with this and my doctor didn’t want to do anything for me beyond physical therapy, so I figured I had nothing to lose and I was pretty confident that it was safe, so I gave it a try. I went in planning on a 12-week course and within 12 weeks, I was 95% better. So, I think there’s reason to believe that in the 6 to 12-week time frame, rapamycin at the doses we’re talking about, is pretty effective at knocking down at least some of that chronic sterile inflammation in people with a high inflammatory burden. Does it have benefits for people without a high inflammatory burden? I don’t know.

Dr. Kara Fitzgerald: Right, right. But the safety profile seems pretty good overall, with the exception of canker sores.

Dr. Matt Kaeberlein: The one thing I’m still on the fence about is whether there’s a slight uptick in the risk of bacterial infections. Again, if you look at the data across the board, you can make a reasonable argument that there’s probably an improvement in antiviral effects. Rapamycin boosts antiviral gene expression, and we’ve seen that in studies involving flu vaccines and subsequent infections with flu and coronavirus match that. But there might be a corresponding slight increase in the risk of bacterial infections. It’s not huge—it’s nothing like what we see in organ transplant patients who are taking higher daily doses of rapamycin. But it wouldn’t surprise me if there’s a slight increase in bacterial infection risk.

Dr. Kara Fitzgerald: So, more information and research is needed. But this is cool. I appreciate your synopsis of this. And everyone, we’ll make sure to grab the citations and everything Matt has referenced and include them in the show notes. What about metformin? What are your thoughts on that?

Dr. Matt Kaeberlein: Metformin is a really good diabetes drug. I think if we go back to my analogy of this network that underlies the biology of aging as we understand it today, there are a few nodes in that network that seem to be very useful for tweaking the rate of biological aging. mTOR is one. AMP kinase, which is one of the targets of metformin, is also in that network, but metformin itself doesn’t seem to be particularly good at modulating the network as a whole. What I mean by that is, if you look at animal studies, especially in mice, the data that you can significantly increase lifespan or improve healthspan in mice using metformin is really lacking. There’s not a strong body of literature and there’s actually some negative data, where researchers have been unable to replicate those results. So, I think that metformin is one of those cases where the enthusiasm was very high several years ago that generally speaking, it could modulate the biology of aging, but that enthusiasm has since waned.

Dr. Matt Kaeberlein: I think that enthusiasm was in part– we talked about the challenges with human epidemiological studies– There was a study that looked at diabetics taking metformin, diabetics not taking metformin, and non-diabetics not taking metformin and then looking at all cause mortality risk. The study concluded without question that diabetics on metformin did better and lived longer than those not taking it.  But there was a hint from that study that diabetics taking metformin might actually live a little bit longer than non-diabetics. That got people really excited about metformin as a drug that non-diabetics should be taking. Turns out that was probably wrong. Multiple studies have now tried to reproduce that and have been unable to: one was in the same population and at least one other was in a different population. So, the consensus has shifted that metformin likely doesn’t have a big effect on the biology of aging in non-diabetics.

Dr. Matt Kaeberlein: Additionally, there’s growing appreciation for some of the potential downsides of metformin that hadn’t been previously appreciated, such as potentially blunting some of the benefits of exercise. You can go back and forth on that, and I’m not making a strong case there, but I think there is some evidence to support that. There may be some effects on hormones that are suboptimal. My feeling is that if you’re diabetic and your doctor recommends metformin, it’s a great drug for diabetics. If you’re pre-diabetic it might even make sense. But if you’re not metabolically perturbed, I don’t personally see a strong rationale for taking metformin from a biology of aging perspective.

Dr. Kara Fitzgerald: Okay, cool. I have tons more questions, but we don’t have much time left. I want to talk a little about supplements. In my world I’m looking at the essential nutrients and conditionals, and I use a relatively broad swath of laboratory testing to identify what the person in front of me really needs and I create something based on that with diet and supplement interventions. But there are tons of “longevity” supplements out there with broad, overstated promises for everybody, all of the time. Patients are coming to me who are focused on longevity, often taking these stacks of supplements that are getting attention, like taurine, spermidine, nicotinic acid molecules, and resveratrol. What should we be thinking about in this space? And I’m curious what you’re taking.

Dr. Matt Kaeberlein: I don’t take a lot, actually. I take creatine every day because I do resistance training, and I think that’s one where there’s very little doubt that it has benefits in that context with very little downside. I take vitamin D and omega-3 to get myself into a reasonable range since I was deficient in both. I’ve started taking a multivitamin again—more as an insurance policy. I eat a pretty healthy diet, but there may be a little bit of evidence, pro or con on taking a multivitamin, but I don’t see much downside there. Other than that, I don’t take many supplements regularly.

Dr. Matt Kaeberlein: My rationale isn’t that I don’t believe there’s evidence for some of these supplements. Again, this is a challenge because you can find papers that will support taking just about any supplement on the market if you look hard enough. But is there a body of evidence that strongly supports an individual supplement for longevity for most people, in the absence of specific biomarkers that you can measure? I’m not convinced there is at this point. You can make a reasonable case for NAD precursors. You can make a reasonable case for calcium alpha-ketoglutarate and spermidine which you mentioned. Urolithin A looks pretty interesting. I think there is a collection of these things. The other option would be just take everything, right?

Dr. Matt Kaeberlein: Part of the reason I don’t do that is that we don’t fully understand the consequences of hitting this network in a bunch of different ways all at the same time. We don’t have combinatorial studies, even in laboratory animals, looking at the impact of taking 10 or 20 different things all at once. It might all be great—maybe synergistic—but my understanding of biological complexity leads me to believe that when you start randomly messing around with things in a biological system, you’re more likely to make things worse than better.

Dr. Matt Kaeberlein: That’s my default position. I want to be pretty confident that whatever I’m doing is either going to make things better or that I have a way to measure whether it’s making things better. That’s why none of the other supplements have reached my personal threshold yet, where I’d start taking them on a regular basis. I also feel like I’ve dialed in my diet, exercise, sleep, and stress levels pretty well. So I might be the king of person who would benefit from these types of supplements, but I think the important thing for most people to appreciate is that none of these supplements will make up for a crappy lifestyle. Those are the levers you want to pull first. The idea that you can take an NAD precursor while eating garbage and not exercising is just nonsense. It’s not going to  move the needle and I think people really need to understand that.

Dr. Matt Kaeberlein: But then you could get into each supplement and talk through the pros and cons. I think the ones I talked about are interesting, and maybe I’m making a mistake by not taking them—I don’t know. But that’s where I’m at right now. Taurine is an interesting one. I was an author on a paper, published in Science, showing it could increase lifespan in multiple different animal models when supplemented. Even though I’m an author on it, it’s just one study.

Dr. Kara Fitzgerald: And it’s in animals.

Dr. Matt Kaeberlein: Yes, it’s in laboratory animals. There was some human correlative data. Spermidine is the same way. There’s interesting correlative data in people on dietary polyamines and health outcomes. (Spermidine is of a class of molecules called polyamines.) I’ve been in this field long enough to know that some things stand the test of time, and many don’t. And even though I’m a coauthor on that paper, I want to see things replicated before I feel confident saying, “Yes, this can go into that class of ‘take it to the bank’ interventions that we’re confident modulate the biology of aging in an effective way.”

Dr. Kara Fitzgerald: And we can measure taurine—it’s easy to measure in plasma so we can see when people need it. I routinely prescribe taurine when I see individuals who don’t appear to make it well, which incidentally includes vegans and vegetarians. Taurine is conditionally essential, and for some of us, it may be an essential nutrient and we can measure it.

Dr. Matt Kaeberlein: I think that’s really important. I think, in cases where you can measure levels and know what suboptimal or deficiency looks like, absolutely, you should supplement to reach optimal levels when you can, for sure.

Dr. Kara Fitzgerald: Are you engaged in any kind of time-restricted eating structure or fasting program?

Dr. Matt Kaeberlein: Not at all. Partly because I’ve never really enjoyed fasting. Here’s how I think about fasting and time-restricted eating: the idea that those are longevity interventions is very limited. And again, I’m going to go back to the laboratory studies, because that’s the only place where we can definitively say something is a longevity intervention unless we have hundreds of years of human data, we can’t really point to it as a longevity intervention.

Dr. Matt Kaeberlein: The evidence that fasting and time-restricted eating, in and of themselves, are longevity interventions, modulating the biology of aging in an effective way in the absence of caloric restriction is essentially zero. There’s a little evidence with intermittent fasting, but it’s small and hasn’t been largely reproducible. What I mean by that is, if you take a mouse and feed it every other day, but you allow it to make up for the missed calories, there’s no lifespan extension or significant improvement in healthspan. However, if you also calorically restrict them, you do see a lifespan extension and improvement in healthspan. The idea that when you eat—without considering how much you eat—is a potent way to tweak this longevity network is largely lacking.

Dr. Matt Kaeberlein: Does that mean there are no benefits to fasting and time-restricted eating? Absolutely not. For some people there are pretty big benefits. The most obvious being that for some people it’s a really useful way to control how much you eat. And if that works, great. I do think time-restricted eating for some people—especially if you are struggling with your circadian rhythm—there’s some reason to believe that if you line up when you eat with your circadian rhythm you can actually reinforce that in a positive way to improve sleep quality. So I do think there are use cases where fasting and time-restricted eating have benefits for many people, but I don’t think people should go into those things believing that they are significantly slowing biological aging in and of themselves. It’s an individual case for each of those. I could be wrong—maybe intermittent fasting does slow aging in people—but going off what we know from animal studies, in the absence of caloric restriction, there’s not much evidence to support  that.

Dr. Kara Fitzgerald: Certainly clinically, we can see people who engage in it appropriately and reap some benefits, especially if it’s prescribed to someone who is somewhere on the metabolic continuum. If they can do it. However, we also see cases of disordered eating or orthorexia, which is becoming a concern as people try extreme approaches like one meal a day. It’s a little bit of a fallout of this idea of only one meal a day. Some of these patients show up in our practice.

Dr. Matt Kaeberlein: I think that’s a really important point. The social and psychological interaction with food—Humans are funny animals, and we can’t look for this in laboratory mice, but it’s real. You see this a lot. I don’t know if you remember the group called the Calorie Restriction Society back in the early 2000s. They were a group of people who were self-practicing caloric restriction, disciples of Roy Walford’s.

Dr. Kara Fitzgerald: Yeah.

Dr. Matt Kaeberlein: They had open discussions about everything they were doing. But if you perused that discussion group, you saw a lot of what—again, I’m not a psychiatrist or psychologist—but it looked to me like disordered eating, right? Because of this whole social-behavioral connection we have with food. I think that’s something we don’t always appreciate people recommend these dietary modifications. You have to be aware of the potential psychological consequences that go along with it.

Dr. Matt Kaeberlein: And to what you were saying about time-restricted eating, intermittent fasting, and metabolic disease—I think you’re right. Certainly there are people, and maybe this is true in general, where you will see an improvement in insulin sensitivity, particularly if you’re already perturbed from these interventions. It’s an interesting question—and maybe you have a better feel for this from your clinical practice, I have not seen definitive data—whether or not those improvements in insulin sensitivity are completely independent of total calories or not. Or, is it the case that those people who are practicing intermittent fasting are also eating less. I don’t know the answer. It certainly could be the case that there are affects on insulin sensitivity independent of total caloric consumption.

Dr. Kara Fitzgerald: It would be interesting to tease that out, just like we see different dietary patterns have influence on metabolic markers regardless isocaloric structures. I did a postdoc in a clinical laboratory in the early 2000s and we looked at caloric restrictor data. There was this interesting pattern of amino acids in this population and I recall they often had hypothyroidism, or at least lower thyroid numbers. I don’t know that it matched energy. My mentor and teacher at the time, Dr. Richard Lord, a nutritional biochemist, really felt that they were healthy. He was in close contact with them and felt those thyroid numbers were appropriate for such significant caloric restriction. Whereas in another population, you’d definitely diagnose them with hypothyroidism.

Dr. Matt Kaeberlein: Right. And there are several published papers by John Holloszy, Luigi Fontana did a series of studies on individuals who were self-practicing caloric restriction. There have also been NIH-funded CALERIE trials, which are more controlled. As a whole, that data certainly points to the canonical core set of biomarkers that you’d measure at any primary care visit all going in the right direction in those practicing caloric restriction, right? Lipids look great, glucose looks great, insulin looks great, blood pressure looks great. So, based on those biomarkers, they are healthier. And I certainly believe that caloric restriction, if done properly from an overall nutritional perspective, probably can slow biological aging in people.

Dr. Matt Kaeberlein: The question is whether there will be corresponding detriments that offset the quality or quantity of life benefits you might get from slower biological aging. We’ve touched on psychological consequences. You’re also looking at things like loss of lean mass and loss of bone density, which could lead to problems in your 70s and 80s that would offset the benefits, even if at a more whole body level, you are aging more slowly. I think we just don’t know. And it’s a very self-selected group that can maintain that lifestyle, so it’s not very pragmatic approach.

Dr. Matt Kaeberlein: We may find out with the GLP-1 agonists, because now we’re starting to get this population of people who are being pharmacologically aided in caloric restriction. Over the next few decades, we may discover if there are negative consequences that more than offset the health benefits from these drugs. I don’t think they will more than offset the benefits in an obese population, but if a large number of normal-weight people start taking these drugs, we may find out.

Dr. Kara Fitzgerald: Yeah, right. There’s still so much to unfold. Well, listen, we could keep talking. I really appreciate your insights into a broad range of topics today. Thanks for joining me, Matt.

Dr. Matt Kaeberlein: You’re welcome. My pleasure.

Dr. Matt Kaeberlein is the Chief Executive Officer at Optispan, Affiliate Professor of Oral Health Sciences at the University of Washington, and Co-Founder of the Dog Aging Project and Dog Aging Institute. Dr. Kaeberlein’s research seeks to define biological mechanisms of aging to facilitate translational approaches that promote healthspan and improve quality of life for people and companion animals.

www.optispan.life

https://www.youtube.com/@optispan

Email: Matt@optispan.life

Dr. Matt Kaeberlein

Optispan

Dog Aging Project

Dog Aging Institute

Biomarkers of Aging Consortium

UK Biobank data

Study: The retardation of aging by caloric restriction: its significance in the transgenic era

Study: Antiaging diets: Separating fact from fiction

Study: Evaluation of off-label rapamycin use to promote healthspan in 333 adults

Study: Quantification of biological aging in young adults

Study: Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project

Study: An open science study of ageing in companion dogs

Study: The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery

Study: ExplaiNAble BioLogical Age (ENABL Age): an artificial intelligence framework for interpretable biological age

Study: Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study (PEARL)

CDC: Commentary on Chronic Disease Prevention in 2022

Eat Less Live Longer

Study: 2 years of calorie restriction and cardiometabolic risk (CALERIE) trial

Blog: New and Notable Studies Using Epigenetic Biological Age Clocks

Podcast: Decoding Aging: The Science Of Cellular Rejuvenation With Dr. Vittorio Sebastiano

Podcast: AI, Digital Twins, and the Future of Personalized Medicine Interventions with Dr. Nathan Price

DrKF Clinic: Patient consults with DrKF physicians including Younger You Concierge

Bio Age Lab Test

Bio Age Self Assessment Quiz

Younger You Group Program

Younger You book

Better Broths and Healing Tonics book

Interview: Past, Present, and Future of “Biological Aging” with Dr. Fitzgerald

Video Blog: Does Multivitamin Use Increase Mortality Risk?

Podcast: Decoding Aging: The Science Of Cellular Rejuvenation With Dr. Vittorio Sebastiano

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