Show Notes
Aging is not a fixed sentence. It is biology, and biology can be moved. We may not be able to stop or reverse aging, but the science says we can absolutely slow it down, and the biggest levers cost nothing.
In this episode, Dr. Ravi Kumar sits down with Dr. Matt Kaeberlein, one of the world’s foremost researchers on the biology of aging, who has spent more than 25 years studying why we age and how we might slow it down. What makes this conversation so valuable is how grounded it is. Dr. Kaeberlein is one of the most informed voices in longevity, and also one of the most honest. There is no hype here, just a clear-eyed look at what the science actually supports.
The conversation starts at the foundation: aging is a biological process, not just something that happens to you. There are genes and environmental factors that influence how fast different people and different animals age. Dr. Kaeberlein explains the geroscience reality that biological aging is the underlying driver of most chronic disease, which is why nine of the top ten causes of death in the United States share the same single greatest risk factor, how old you are. Slow the aging process, and you slow the onset and progression of nearly all the diseases that come with it.
From there, they get practical. Dr. Kaeberlein lays out the four pillars of healthspan he keeps deliberately simple: eat, move, sleep, connect. These free lifestyle levers influence the same aging biology that supplements and drugs are chasing, which is exactly why they matter more than anything you can buy in a bottle. They dig into what quality nutrition, resistance training and cardiovascular fitness, real sleep, and genuine social connection are actually doing at the cellular level.
The back half of the conversation takes on the harder questions. They cover body composition and biomarkers, why a DEXA scan and a continuous glucose monitor can change behavior in ways nothing else does, and how very lean people can still be metabolically unhealthy. Then they turn to the longevity marketplace: the heavily marketed supplements with thin human evidence, and a careful, honest discussion of rapamycin, the most promising longevity drug we have, including dosing, the importance of enteric coating, the PEARL trial, and the real side effect picture. They close on the Dog Aging Project and a reminder that the journey itself is the reward.
Episode Resources
- Dr. Ravi Kumar on LinkedIn
- Dr. Matt Kaeberlein on Instagram and LinkedIn: @mkaeberlein
- Longevity Science with Matt Kaeberlein (new podcast on YouTube @mkaeberlein and Spotify)
- The Dog Aging Project: dogagingproject.org
In this episode, you will discover:
- Aging is biology, and biology can move: Aging is a biological process shaped by genes and environment. Different people and different animals age at different rates, which means the aging process can be measured, understood, and potentially slowed
- The geroscience reality: Biological aging is not just correlated with age-related disease, it actively drives it. Nine of the top ten causes of death in the United States share the same single greatest risk factor, how old you are
- Slow aging, slow the diseases: In laboratory animals, lifestyle interventions like caloric restriction and small molecules like rapamycin slow biological aging and slow the onset of multiple diseases at once, sometimes even reversing functional declines when started in middle age
- The four pillars of healthspan: Dr. Kaeberlein keeps it deliberately simple with four words: eat, move, sleep, connect. Diet, exercise, sleep, and relationships influence health precisely because they influence the same underlying aging biology
- Free beats a bottle: The biggest levers we have cost nothing. Whole foods, resistance training and cardio, protected sleep, and real social connection do more for healthspan than almost anything you can purchase
- Body composition over the scale: A DEXA scan reveals muscle mass and visceral fat that body weight and BMI hide. Very lean people, often women, can still carry a real metabolic problem you would never guess from the outside
- The CGM as a teacher: A continuous glucose monitor, paired with the right educational context, is one of the most powerful behavior-changing tools available. You cannot unlearn what it shows you about the food you eat
- The longevity supplement reality: Many heavily hyped and heavily marketed supplements have thin human evidence behind them. The honest answer is usually that we do not have the large randomized data to know
- The truth about rapamycin: Rapamycin is the most promising longevity drug we have, but the human data is limited. Dosing, enteric coating, and absorption matter enormously, and the PEARL trial likely under-dosed because the compounded drug was not enteric coated
- Rapamycin safety, honestly: At six milligrams once a week, roughly 15 to 20 percent of people get mouth sores. There are directional but not statistically significant signals for some risks. Anyone taking it off-label should monitor glucose, insulin, and lipids quarterly
- The journey is the reward: You do not pursue healthspan only to reach ninety-five. You do it because you feel better right now, and hopefully for many years after
Key Takeaways
- Aging is a biological process, not an unchangeable fate. Genes and environment both influence how fast we age, which means the process can be studied and slowed
- Biological aging is the upstream driver of most chronic disease. Slowing it slows the onset and progression of nearly all the conditions that come with getting older
- The four pillars of healthspan are eat, move, sleep, connect. They work because they act on the same aging biology that drugs and supplements are chasing, and they cost nothing
- Quality nutrition, both resistance training and cardiovascular fitness, protected sleep, and genuine social connection are not separate health tips. They are levers on the same underlying biology
- Body composition tells the truth that weight and BMI hide. A DEXA scan and a continuous glucose monitor, used with the right context, can change behavior in ways nothing else does
- Most heavily marketed longevity supplements lack strong human evidence. Skepticism is warranted, and the honest answer is often that the data simply is not there yet
- Rapamycin is the most promising longevity drug we have, but it is still off-label and under-studied. Enteric coating and dosing matter, and biomarkers should be monitored quarterly if you use it
- The goal is not just a longer life but a healthier one. The journey itself, feeling better today and for years to come, is the reward
Transcript
[00:00:00 –> 00:03:15] Dr. Ravi Kumar: Welcome to the Dr. Kumar Discovery. My name is Dr. Ravi Kumar. On today’s episode, I’m sitting down with Matt Kaeberlein, one of the world’s leading experts on the biology of aging. Now, when most of us hear the word aging, our minds go into one of a few places: gray hair, wrinkles, aches and pains, and underneath all of that, this quiet assumption that aging is just something that happens to you, something you live with, something you really can’t do anything about. But that assumption is actually wrong. Aging is a biological process. There are genes that influence how fast you age, and environmental factors that influence how fast you age as well. And once you understand that the aging is biology, you can start to ask the most important question in medicine, and that’s: Can we slow it down? Dr. Kaeberlein has spent more than 25 years of his career trying to answer that exact question. And honestly, he’s not only one of the most informed researchers on longevity, but he’s also one of the most honest. The information he gives us in this episode is sober, skeptical, and realistic. By the end of this episode, you’re gonna understand what aging actually is at the cellular level, and why four free lifestyle changes that Dr. Kaeberlein outlines in the episode matter more than anything that you can buy in a bottle. You’ll understand the truth behind longevity supplements that have been heavily hyped and marketed, and what the real science says about rapamycin, which is the most promising longevity drug out there. So for anyone interested in not only living longer, but also with better health and vitality, this show is an informational gem. So one thing before we dive in is a quick disclaimer. I’m a doctor, but I’m not your doctor. This show is for informational purposes only. Everything you learn from my conversation with Dr. Kaeberlein is meant to empower you. So take this knowledge, ask better questions with this information, and work with your own doctor to build a more informed, healthier life. That’s what I want for you. And just to be clear, this show is also separate from my role as assistant professor at UNC. All right, let’s get into it. My name is Dr. Ravi Kumar. I’m a neurosurgeon in search of the causes of human illness and the solutions that help us heal and thrive. I want you to join me on a journey of discovery as I turn over every stone in search of the roots of disease and the mysteries of our resilience. The human body is a mysterious and miraculous machine with an amazing ability to self-heal. Let us question everything and discover our true potentials. Welcome to the Dr. Kumar Discovery Dr. Kaeberlein, thanks so much for joining us on the show. I’m really excited to talk to you. You are an expert in aging, and our audience likely thinks that aging is just something that happens, and you got to live with it, and there’s nothing you can do about it. Well, is that true? And can you tell us actually what aging is from, you know, a scientific definition?
[00:03:15 –> 00:05:43] Matt Kaeberlein: Sure. Well, first of all, thank you for having me on, and it’s a great question. I think I’m a biologist by training, a scientist by training, and I’ve been studying the biology of aging for a long time now. And I think that’s the lens that I like to try to frame this through, is to first just state that it, there is a biology of aging. And what I mean by that is that there are genes that influence the way we age, and there are environmental factors that influence the way we age, and that different people age at different rates, different animals age at different rates. And so I think if that’s, if that’s not intuitive, one way to appreciate this is just to consider dogs. Everybody’s familiar with the idea that one human year is about seven dog years. Now, obviously chronological time isn’t different in people and dogs. What we really mean is dogs are aging biologically about seven to 10 times faster than people are. And so once you appreciate that, then you can appreciate that we can use the scientific method to understand that biology, to figure out what are the genetic and environmental factors that influence why different animals age at different rates and why different people age at different rates. And if we can understand that biology, we have the opportunity to modulate that biology in a way that will slow the biological aging process and thereby increase lifespan and healthspan. And that’s really what I’ve devoted my scientific career to, is understanding that biology and trying to develop new therapies, new interventions that can modulate aging in a way that increases healthspan and, and lifespan. So I think just appreciating that we have the opportunity to actually influence the way that we’re aging, influence our future health, is really important. And that the last piece that I’ll talk about there is the role that lifestyle factors play in this aging process, because I think a lot of times people don’t recognize that diet and exercise and sleep and mindfulness and relationships, we all know they’re important for health. The reason they’re important for health is because these things influence the way that we are aging biologically. There’s a reason why eating a quality diet and exercising regularly and getting good sleep and having friendships influences not just one disease of aging, but all of them. It’s because these things are in fact influencing our aging biology.
[00:05:43 –> 00:05:43] Dr. Ravi Kumar: Yeah.
[00:05:43 –> 00:06:03] Matt Kaeberlein: And we understand some of the mechanisms. So that’s maybe the last thing I’ll say is we have an imperfect understanding of aging biology. We’re still in the early days of this field of science, but we understand enough that we’re starting to have opportunities to actually influence the way that we age and the way that our companion animals age.
[00:06:03 –> 00:06:48] Dr. Ravi Kumar: That’s really interesting because, you know, there is some biological process behind aging. We all know it. Uh, you know, we see, you know, dogs, like you said, you know, die s- at a faster rate than us. We see fruit flies die very quickly, you know. They live their whole lifespan in a few days. But when we think of dying as a human being, where our life ends It’s almost always from a disease, right? I mean, it’s not, we’re not, no one almost ever says they died of old age. They either died of heart disease or cancer or neurodegenerative diseases or some, some infectious process or something. Now, could some of these diseases that usually take us out of this world be related to aging, and is aging somehow at the foundation of all these?
[00:06:48 –> 00:09:44] Matt Kaeberlein: Absolutely. And so one thing I want to say is you’re right. We very rarely say somebody died of aging, although you do hear people say, you know, died of old age. But more often than not, somebody died of cancer or heart disease or kidney disease, and they also died with declining heart function, declining kidney function, declining bone density, declining muscle mass. So we have all of these other age-related changes that are happening in all of us. Almost nobody dies with only one functional decline. We show functional declines across all of our tissues and organs as we get older. And if we live long enough, you will have functional declines across many, if not all, of your tissues and organs. It’s just that there’s one that ends up being the proximal cause of death. So, so absolutely what you said is correct, that it is the underlying biology of aging that not only creates a permissive environment for all of these functional declines and diseases but actually drives these functional declines and diseases. And in fact, if you look at the, the top ten causes of death in the United States, nine of them have the same single greatest risk factor, how old you are. So I mean, from that perspective, it should be obvious that these things are age-associated, and I think the important nuance here is that they’re not only associated with biological aging, they are caused by biological aging. And this brings us to a concept that people may have heard of before, this idea of the geroscience hypothesis. I don’t even like that word hypothesis because it’s not a hypothesis. A hypothesis means that, that it’s an idea you have that you need to test. So I would call it the, the geroscience fact that aging biology is what is driving, at least at a molecular and cellular level, the factors that influence and cause age-related functional decline and disease. And so then the correlate of that is if we can understand that biological aging process and slow it down, we will slow the onset and progression of most, if not all, of the functional declines and diseases that go along with aging, and we actually have experimental evidence that this is possible. So at least in laboratory animals, it’s pretty routine now to use interventions, either lifestyle interventions like caloric restriction or small molecules like rapamycin, to slow the biological aging process. When we do that, not only do the animals live longer, but they live healthier longer. The functional declines in diseases of old age are slowed down. And in some cases, we can actually reverse functional declines in an aged animal if we start the treatment in middle age. And so again, I just want to emphasize this is happening at the molecular level, at the cellular level, at the tissue level, at the organ level, at the whole animal level. We can see evidence that it is possible to slow biological aging and thereby increase both lifespan and health span.
[00:09:44 –> 00:10:11] Dr. Ravi Kumar: Yeah. So these diseases that we see that take, usually take us out of the world or, or cause pain and suffering are rooted in this biological aging process, which you’ve talked about reversing or slowing. You’re actually talking about slowing it in animals. Why, why are we aging? Why do animals age? Why do we age? Is there a, a biological reason for it?
[00:10:11 –> 00:11:22] Matt Kaeberlein: Yeah. So I mean, there’s different ways you can sort of approach this question. One is, is sort of philosophical, like why do we need to age? And I would say probably the best way to think about that is through the lens of natural selection and evolution, right? So again, evolution is really all about, and natural selection in particular, is really all about strategies that are going to most effectively pass genetic information on to the next generation. So it’s about reproduction and then survival of the offspring. And so from that perspective, aging intuitively you might ask, well, well why wouldn’t natural selection or evolution cause us to not age, right? ‘Cause theoretically that should be possible. If you put enough energy into a biological system, it should be possible in principle to at least dramatically slow the aging process, if not stop it altogether. So why wouldn’t evolution do that? And the answer is probably that once you have passed your genes on to the next generation, evolution doesn’t care about you anymore, right? You’re, you’re, you’re expendable at that point. So there is no reason for evolution to select necessarily for slower aging or longer life. And what we see-
[00:11:22 –> 00:11:22] Dr. Ravi Kumar: Right…
[00:11:22 –> 00:11:41] Matt Kaeberlein: if we look across the animal kingdom is a bunch of different strategies that, that natural selection has taken, all of which are successful depending on the environment, the niche that that organism occupies from an evolutionary perspective with wildly different rates of aging. And so I think that’s the explanation for why we don’t live forever or why we age-
[00:11:41 –> 00:11:42] Dr. Ravi Kumar: Yeah…
[00:11:42 –> 00:11:57] Matt Kaeberlein: is because from the perspective of natural selection and evolution, once you’ve done your job reproductively, as long as your kids survive, you don’t, you don’t need to be around anymore.
[00:11:57 –> 00:11:57] Dr. Ravi Kumar: Yeah.
[00:11:57 –> 00:13:20] Matt Kaeberlein: And then I think the other way to think about this is, you know, what are the actual mechanisms, the molecular causes of aging? And this is where the field has made a lot of progress over the last 25 years or so since I, since I started studying aging, in really understand, starting to understand what are the molecular mechanisms of aging, what are the genes that in- influence the aging process. We have sort of coalesced as a field around something called the hallmarks of aging. There are, depending on who you ask, between 12 and 15 of these hallmarks. By and large, these are evolutionarily shared, and by that I mean across the animal kingdom, molecular processes that seem to contribute to the biological aging of different organisms. It’s an incomplete list, it’s an imperfect list, but it’s a start. And these include things like telomere shortening, which a lot of people may have heard of, epigenetic dysregulation, senescent cells, mitochondrial dysfunction. You know, you could give me a test, and I could probably name 10 of the hallmarks of aging off the top of my head. Um, but again, these are all different processes that seem to be fundamentally important to biological aging. And one of the implications is, as we understand those processes better, we can start to target them therapeutically. And if we do that successfully, we should have a positive impact on, on health outcomes and potentially lifespan in animals and in people.
[00:13:20 –> 00:13:36] Dr. Ravi Kumar: Yeah. That’s really interesting ‘cause the way you describe it, aging almost seems intentional. Like evolution and natural selection said, “Listen, we’re gonna come up with 12 to 15 biological mechanisms to take you out of the world, basically, to-”
[00:13:36 –> 00:13:37] Matt Kaeberlein: Yeah…
[00:13:37 –> 00:13:50] Dr. Ravi Kumar: “… cause you to age and then to have a disease of aging and, and die .” Because like you said, you know, once you reproduce, your job’s done. But also I think if you keep reproducing the ch-change stops, right? I mean, ‘cause there has to be this experimentation with successive generations.
[00:13:50 –> 00:13:56] Matt Kaeberlein: The adaptation, I think, is what you’re referring to, yeah.
[00:13:56 –> 00:14:41] Dr. Ravi Kumar: Yeah, adaptation. Natural selection and adaptation. If your offspring aren’t adapted or successful in the world, they’re, they’re out too, you know? And so if you have one organism that just keeps reproducing forever or keeps living forever, that experimentation cycle essentially stops. And so, you know, biology said, hey, the ones who pass on their genes to their offspring, leave the world and let that successive experimentation cycle continue through the generations, they’ll be the most biologically successful from a reproductive and evolutionary standpoint because they did what they needed to do. They weren’t evolutionarily selfish, essentially, you know? So, so what you’re, what you’re referring to is a hypothesis that, that some people subscribe to called programmed aging, the idea that-
[00:14:41 –> 00:14:42] Matt Kaeberlein: Right…
[00:14:42 –> 00:14:46] Dr. Ravi Kumar: natural selection acted to actively select for a biological aging process.
[00:14:46 –> 00:16:01] Matt Kaeberlein: There are cases that you can point to where that’s clearly true. Salmon that spawn and then go through the senescence process is a clear programmed aging, or leaf senescence is another clear programmed aging, like the, the leaves that turn color in, in autumn. It’s a little bit harder to argue, in my opinion, strongly for programmed aging in animals like people or dogs or even mice. I can’t rule it out, but I don’t think you have to argue for that because, again, in order to prevent aging, that would be such an energetically costly process that you would really have to have a very, very strong selective pressure in order for that to evolve. And so I think it’s probably sufficient to say there’s just not enough value in doing that for evolution to go down that path.
[00:16:01 –> 00:16:01] Dr. Ravi Kumar: Right.
[00:16:01 –> 00:16:19] Matt Kaeberlein: But again, this is one of these things that it’s, it’s, it’s hard to do those kinds of very rigorous experiments to test or disprove the idea of programmed aging, and there may be some subtle selection for aging, but it’s probably just not at the level of being able to select strongly for a true aging program. In humans.
[00:16:19 –> 00:17:24] Dr. Ravi Kumar: Hey guys, if you’re enjoying this podcast or it’s helping you, please help me get it out to the rest of the world. All you need to do is rate and review it on Apple Podcasts. Share it with a friend, post it on Facebook, and that’s basically it. The algorithm rewards engagement. Every review, every mention puts this show in front of someone who’s looking for clear, no-nonsense health information, the type of information that I’m putting in these podcasts. So thanks so much, and let’s get back to it. Yeah. So, okay, so we’ve got these age, biological mechanisms of aging that you talked about, the 12 to 15, and yeah, that makes sense to me that, like, maybe, um, there wasn’t enough pressure or enough that the experimental environment wasn’t right to go through this full selection process to force aging. So that, that does make sense. But a- as far as these mechanisms go, that you guys are actually applying experimental biology to modify, you’re not talking about stopping any of them, right? I mean, it’s still a train that keeps going. You’re just trying to slow it. Is that right?
[00:17:24 –> 00:19:57] Matt Kaeberlein: Well, here’s, here’s what I would say. Again, I think one thing to appreciate about the hallmarks of aging is that they are interconnected. So, so I think of it more like there is a network of proteins and metabolites and mRNA in a very, very complex biological system that is becoming dysregulated with age. And how that manifests itself is the hallmarks of aging. That’s what we see as the types of dysregulation and damage that are most prevalent. And then at the, at the whole organism level, those hallmarks of aging manifest themselves as the functional declines in diseases that end up ultimately causing mortality. So in some ways it’s a, you know, it’s like peeling the layers off an onion. You can always find a, a layer underneath. One of the things that I have thought a lot about, and I’m still not in my own head confident where I land because there’s always more data coming in, is, is there truly one biology of aging? In other words, can we get to a single root cause that all of the hallmarks of aging arise from, and then all of the diseases and functional declines of aging arise from? I’m less optimistic about that now than I was 20 years ago or 25 years ago when I started in the field. I think one reason to be optimistic that there is something at least approaching a root cause is we know in every animal where we’ve looked that we can find single genes, individual unique genes that we can modify to substantially slow the aging process. Not stop, so you asked about stopping. Nobody has created a, an immortal anything, but we can dramatically slow the aging process, so we can control the rate of aging at the level of individual genes. And so to me, that suggests there’s, there’s something more fundamental than the hallmarks of aging that we don’t understand yet. But I don’t think we’re ever gonna find a single drug or a single gene that completely arrests aging. And then I do wanna touch on this idea of reversing aging because this has become, I think, talked about a lot, I think abused a lot in, in the field, the way people talk about reversing aging. So what is possible is reversing aspects of aging, age-related changes, age-related phenotypes. In some sense, this should be obvious, right? If I wanted to, I, I’ve got gray hair here, I could go, I could dye that gray hair black. This is age-related. I didn’t have this gray hair when I was 20. I could dye that hair black, and I will have reversed a phenotype of aging. Most people lose muscle mass as they get older. You can-
[00:19:57 –> 00:19:58] Dr. Ravi Kumar: Right.
[00:19:58 –> 00:20:47] Matt Kaeberlein: exercise and regain muscle mass. You have reversed a phenotype of aging. You can get healthier. But you didn’t reverse every aspect of biological aging, and there is no evidence, none, zero, zilch, that that is possible. I’m not saying it’s impossible. Nobody has done it, and there is no reason to believe that we are close to doing that. The closest I would say we have come is in the realm of epigenetic reprogramming. So the epigenome are chemical marks that go on top of DNA that influence the way that genes are expressed. We know that there are hundreds of thousands, millions of these marks on our genome that change in response to environment and in response to aging. There is a early-stage technology called epigenetic reprogramming using things called the Yamanaka factors, these are transcription factors-
[00:20:47 –> 00:20:48] Dr. Ravi Kumar: Yeah…
[00:20:48 –> 00:21:11] Matt Kaeberlein: that influence the epigenome, that can revert the epigenome back to an embryonic state, to a pluripotent state. And when you do that, you appear to reverse most, if not all, of the epigenetic changes that go along with the aging process. This is in part why when a sperm and an egg come together to make a baby, you don’t have an aged baby because you are reversing the epigenome of, uh-
[00:21:11 –> 00:21:12] Dr. Ravi Kumar: Right…
[00:21:12 –> 00:21:52] Matt Kaeberlein: of that organism, right? So we can do that at the cellular level, and that seems to have a positive effect on other types of age-related damage. But it doesn’t fix all age-related damage. It doesn’t fix mutations to the DNA that have happened, which by the way, is one of the hallmarks of aging, DNA damage. It doesn’t fix the extracellular matrix that’s outside of the cells. So when you hear people talk about reversing aging using epigenetic reprogramming, they are not telling you the truth, and some people know better. It is a marketing effort, unfortunately, that is not scientific. So it is very interesting technology that, that could have great benefits for-
[00:21:52 –> 00:21:52] Dr. Ravi Kumar: Mm-hmm…
[00:21:52 –> 00:21:56] Matt Kaeberlein: for humans. Well, uh, time will tell, and I’d be happy to talk about-
[00:21:56 –> 00:21:56] Dr. Ravi Kumar: Right…
[00:21:56 –> 00:22:09] Matt Kaeberlein: kind of where that’s at if you’d like later on. Unfortunately, I think there are scientists who should know better who are intentionally misleading the public and investors to make them believe something that isn’t true. We are not close to reversing aging. I’m not-
[00:22:09 –> 00:22:09] Dr. Ravi Kumar: Right…
[00:22:09 –> 00:22:15] Matt Kaeberlein: again saying it’s not hypothetically possible, but where the science is at, we are a long, long way away.
[00:22:15 –> 00:22:33] Dr. Ravi Kumar: Yeah. No, I think that’s, that’s brutal honesty, right? I mean, we’re running against a billion-year-old freight train of biology that’s designed systems that are so complex that, you know, our ability to grasp them and manipulate them is still in its infancy.
[00:22:33 –> 00:23:34] Matt Kaeberlein: Yeah, and, and part of the reason why I, I try to be very clear about this is because I think when people start setting expectations that are way beyond where the science is at, what that does is it minimizes what’s actually possible, right? What’s actually likely to happen, which is a big deal. Like, I think we know enough today, mostly around lifestyle, but not exclusively, to give people fifteen years of health span, the average person fifteen years of added quality life. That’s a big freaking deal. And I think we’re not too far away from having therapies that can make it through the FDA process that can probably add another decade on top of that. That’s a big deal. That’s, that’s bigger than any advance in biomedical science in the last fifty years. So I think when we, when we start setting expectations that are unrealistic, it minimizes what is actually possible and what is actually likely. So, And that’s where I would like to see people spend more of their time. Yeah. Okay.
[00:23:34 –> 00:23:46] Dr. Ravi Kumar: Well, let’s talk more about that. What are the reasonable expectations for increasing lifespan and increasing health span? Which, if you could please, uh, define that for everybody.
[00:23:46 –> 00:23:46] Matt Kaeberlein: Sure.
[00:23:46 –> 00:23:47] Dr. Ravi Kumar: And, like, what are the techniques that we can do that are out there that are being developed to try to achieve these goals?
[00:23:47 –> 00:25:53] Matt Kaeberlein: Sure. Yeah, so lifespan and health span, maybe that’s a, a good place to s- to start. Lifespan is unambiguous. It’s, it’s quantitative, just length of time from birth till death, right? I, I think everybody gets, gets that piece. Health span is a little bit of a trickier term. I prefer to think of health span as a concept, not a quantitative variable. And, and let me tell you why. So the word health span implies a beginning and an end if you, if you treat it like a quantitative variable. And the problem is health is not binary. We don’t go from having a hundred percent health to zero health overnight, most people, right? Health is continuous. Health goes up and down. It’s dynamic. And s- and so trying to say there is an end, your health ended on this date, um, just doesn’t make sense, right? But that’s the way it often, often gets used. So I prefer health span as a concept, and conceptually, I think we all get it. Health span is the period of your life where you are functioning at a high level, able to do the things that you wanna do. I think that’s pretty reasonable. Again, that may not end overnight. It’s gonna, it, it, it’s gonna be a gradual decline for many people. But our goal should be to maximize the amount of life that people spend functioning well, being able to do what they wanna do. And so that’s really what we’re talking about when we’re talking about maximizing healthspan. And the one important thing to appreciate is the things that limit healthspan for most people are things that are driven by biological aging. So if we can successfully slow or reverse aspects of biological aging, we can thereby improve healthspan. And one of the goals of geroscience, longevity medicine, however you wanna frame it, healthspan medicine is a term that I, I, I’ve started using just because that word longevity unfortunately has been co-opted by s- by some questionable actors. Um, but the goal there is really to push the functional declines in diseases of aging back as late into life as possible and maximize healthspan. Sure, we all would like to increase lifespan as well, and I’m all for that, as long as the added lifespan is spent with good health, spent with high f- high function.
[00:25:53 –> 00:25:54] Dr. Ravi Kumar: Exactly. Yeah.
[00:25:54 –> 00:28:15] Matt Kaeberlein: And so this is a concept called compression of morbidity, compress the diseases and functional declines of aging back as late into life as possible. That should be a goal everybody can get behind. I don’t, I can’t imagine why people wouldn’t want to compress morbidity and maximize healthspan. And again, I believe the best way to do that is by slowing biological aging. That’s the most effective way to do that. So what, what, what can be done? What’s realistic today? This is kind of where I’ve spent the last four years of my professional life, and much of my personal life as well, is in really trying to think about w- what do we know? What can we do? What are the biggest levers we can pull? Turns out, not surprisingly, that, that a lot of this comes down to adopting healthy lifestyle. As I alluded to earlier, lifestyle factors fall under the bucket of environment. So first of all, maybe it’s worth just stating explicitly, all of biology is genes and environment. Pr- people have probably heard gene-by-environment interactions. All of biology is genetics and environment and how those interact. Okay. Under your environment are the foods you eat Your physical activity, the things that influence how well you sleep, right? The relationships you have, the stress that you experience. So all of that is your environment impacting the way you’re aging. And there are things we can do to minimize the negative impact that your environment is having on your aging process. Also, the, the pollution you’re exposed to. Things in your environment that are toxic can influence the way that you are aging. And so those are the levers that I think we have the, First of all, we have the best human data on because many of these things, we’ve got decades of epidemiology to guide us. Those are the levers we can pull that have the biggest impact. So that’s why I say, I think when you take the average American, and again, I don’t wanna, I don’t wanna get bogged down in depressing statistics, but one of the statistics that really I find striking is the CDC tells us that about sixty percent of Americans have at least one chronic disease, and the vast majority of chronic diseases are driven by biological aging. So if that’s true, if sixty percent of Americans have at least one chronic disease, the median age in the United States is thirty-eight point eight or something like that. The median life expectancy is about seventy-eight.
[00:28:15 –> 00:28:15] Dr. Ravi Kumar: Right.
[00:28:15 –> 00:29:14] Matt Kaeberlein: So the math here is really easy. There are lots and lots of people who are living many decades with one or more chronic diseases. And I think we can fix that largely. I’m not suggesting that chronic disease is gonna go away, but I think we can push those diseases back a lot further, primarily by adopting healthier lifestyle habits. And that’s where I get, I honestly think when I say 15, some people think that’s like, “Oh, that’s crazy .” I actually think that’s an underestimate of what’s possible on average at the population level if we could actually figure out how to help people not only understand what the most effective lifestyle interventions are, but actually adopt those in a meaningful way. And I’m not at all somebody who’s an, I mean, I’m not an optimizer. I know some people will be surprised by that. I don’t think you have to be optimal. I think you just gotta, you know, directionally be heading where you wanna get to, right? You don’t have to be perfect-
[00:29:14 –> 00:29:14] Dr. Ravi Kumar: No…
[00:29:14 –> 00:29:34] Matt Kaeberlein: by any stretch of the imagination. Believe me, ask my wife, I’m not perfect. But I have adopted healthier lifestyle habits in the last five years that have had a huge impact on, on, on my health, and I can tell that in a variety of ways. So that’s where I think we wanna spend a lot of our time. Now, there are other things. There are pharmaceuticals. There’s a limited set of supplements that I think can, can play in here that, that can have a meaningful impact. And then there are the things that are, at this point, I would say unproven in humans, but where we have lots of data in laboratory animals that these things can slow biological aging. And we’re starting to gather more data in companion animals living in the real world and in people that I would say are directionally encouraging. Things like-
[00:29:34 –> 00:29:34] Dr. Ravi Kumar: Yeah…
[00:29:34 –> 00:30:35] Matt Kaeberlein: rapamycin, which I know we’re gonna talk about, that may have an impact on biological aging in people. There are some prescription medications that are used for specific indications that in laboratory animals seem to slow aging. SGLT2 inhibitors are a really interesting class of medications. These are, these are anti-diabetes drugs, but we’re starting to see they have beneficial effects on kidney and cardiovascular disease. Oh, and by the way, they slow biological aging in mice. So I, I, That doesn’t mean they slow biological aging in people, but it’s intriguing, right? It’s directionally consistent. So I think there are reasons to be optimistic that some of those types of interventions, we will be able to use them in, in people on an individual basis to increase health span, potentially also increase lifespan.
[00:30:35 –> 00:31:01] Dr. Ravi Kumar: Yeah. No, I think you raised some really good points. I wanna just jump back to them real quick. This compression of morbidity is the goal for increasing health span and, and this whole s- you know, geroscience and study of longevity, because we’ve gone from dying in our 40s and 50s in the, you know, 18th and 19th century to living into our 70s and 80s now. But there hasn’t been this improvement in health span really. It, it may, There may be some, but it’s not significant, right? We spend twice as the amount of time alive-
[00:31:01 –> 00:31:01] Matt Kaeberlein: Yeah…
[00:31:01 –> 00:31:30] Dr. Ravi Kumar: and then that whole s-second part is unhealthy. You know, that’s okay. I mean, some people would take that. A lot of people, when you say, “Hey, do you wanna live to 120?” They’re like, “No, I don’t wanna live to 120 because I’ll be sick or I’ll be decrepit or I won’t be able to, I’ll have mobility issues or, you know, my kids won’t wanna take care of me.” And that’s a real consideration because, you know, if you’re talking about increasing lifespan But having reduced health span or longer years of chronic disease and illness-
[00:31:30 –> 00:31:30] Matt Kaeberlein: Yeah…
[00:31:30 –> 00:32:10] Dr. Ravi Kumar: and suffering. Yeah. A lot of people don’t want that, and that’s not what you want, and that’s not what everyone who’s trying to push this field along wants. They want you to be 110 and still going and walking miles per day and, you know, socializing and eating and doing all these fun things that, that make your life rich. And, uh, so that, that I think, is a very important point. Now, you also mentioned that there’s a lot of just natural lifestyle habits that can come before any of the supplements or the pharmaceuticals, and these lifestyle and diet habits actually have more evidence than anything else out there, really.
[00:32:10 –> 00:32:10] Matt Kaeberlein: Yeah.
[00:32:10 –> 00:32:20] Dr. Ravi Kumar: Right. Can you talk about what those are? And I think most people know ahead, before you even say it, what they are, but tell us what they are and actually what they do to our longevity and our health span.
[00:32:20 –> 00:32:56] Matt Kaeberlein: Sure. Yeah, and I mean, there are various, you know, buckets that people put lifestyle in, and some people call them pillars of health, or I call them pillars of health span. I sort of put them in four and, you know, we can have four to, to twelve. Again, it’s kind of like the hallmarks, depending on how you want to break it out. I like things simple. So I use eat, move, sleep, connect. So eat is nutrition, move is exercise, sleep is sleep, and connect includes both mindfulness, personal sort of strategies around minimizing stress, and human relationships. And I would not suggest that one is more important than the other. I think it-
[00:32:56 –> 00:32:57] Dr. Ravi Kumar: Right…
[00:32:57 –> 00:33:11] Matt Kaeberlein: it’s individual, where each person may have the biggest opportunities for improvement. They’re all important, and so I wouldn’t want to minimize in any of them. I think as biologists, we tend to d- neglect the connect pillar ‘cause it’s harder to study, right?
[00:33:11 –> 00:33:11] Dr. Ravi Kumar: Yeah.
[00:33:11 –> 00:33:23] Matt Kaeberlein: But it’s super important. And so then, you know, then you can say, well, once you get, Okay, so everybody’s like, “Okay, that’s sort of obvious. We, we understand that .” Some people are surprised that human relationships are important, so…
[00:33:23 –> 00:33:24] Dr. Ravi Kumar: So important.
[00:33:24 –> 00:33:27] Matt Kaeberlein: It’s really important. Pay attention. There’s lots of good data on this.
[00:33:27 –> 00:33:32] Dr. Ravi Kumar: Yeah, being socially disconnected is, like, the equivalent of smoking as far as morbidity goes.
[00:33:32 –> 00:33:45] Matt Kaeberlein: Yeah. In fact, the one hallmark that’s been added, so there were, there were three hallmarks added last year, I think, hallmarks of aging, and the one that, that is unlike all the rest of them, but I think it’s actually a good thing that it, that it’s been added, is psychosocial isolation, right? Because it is so important.
[00:33:45 –> 00:33:46] Dr. Ravi Kumar: Yeah.
[00:33:46 –> 00:34:11] Matt Kaeberlein: And it is something that not everybody experiences as they, as they get older, but a lot of people do, right? For obvious reasons. Your spouse dies, your friends are passing away, you’re less active, you become socially isolated, and Buttressing yourself against that is, is really important. So, you know, then we can talk about like what do you actually do there? And this is where-
[00:34:11 –> 00:34:12] Dr. Ravi Kumar: Right…
[00:34:12 –> 00:34:27] Matt Kaeberlein: I think, I think we can give some fairly general pretty good advice for each pillar, but it, it also becomes individual very quickly. Like what works best for you. Because it’s not only what is optimal for, for your biological or biology of aging, but it’s what actually works for you. What works for you might not be optimal, right? And that’s okay.
[00:34:27 –> 00:34:27] Dr. Ravi Kumar: Right.
[00:34:27 –> 00:34:36] Matt Kaeberlein: Like, I don’t think we have to, we, I don’t think we have to spend all of our time trying to optimize when that detracts from quality of life. So -
[00:34:36 –> 00:34:37] Dr. Ravi Kumar: Yeah…
[00:34:37 –> 00:35:03] Matt Kaeberlein: I prefer sort of simple, you know, structures that we can put in place around the pillars. So for eat, like one of the things I’ve done, and again, I’ve been, I’ve been learning and practicing this now, you know, for not that long, five years maybe. Like I studied it. It’s not that I didn’t necessarily know what I should be doing, but I wasn’t actually living it. And so it’s a, it’s an ongoing learning process, but kind of where I’ve settled is around eat like whole foods and cut out added sugars. Like you do that, you’re most of the way there.
[00:35:03 –> 00:35:04] Dr. Ravi Kumar: Yeah, it’s the truth.
[00:35:04 –> 00:35:24] Matt Kaeberlein: Make sure you aren’t over consuming alcohol. You do that, you add that on there, you’re 95% of the way there. And then we can get into like, what do we mean by whole foods? I don’t get bogged down in meat versus no meat. I like meat. I think a lot of the negative data on red meat comes in the context of people eating an otherwise low quality diet and also eating too much, right?
[00:35:24 –> 00:35:24] Dr. Ravi Kumar: Mm-hmm. Yeah.
[00:35:24 –> 00:36:27] Matt Kaeberlein: There, it, there’s no doubt red meat has negative impacts. I think if you’re eating a high quality diet and you’re not overfed, there’s not a lot of evidence that red meat is a big negative. So if you like red meat and that’s sustainable for you, great, have a steak. So that’s sort of where I land on, on eat. Move, do a variety of exercises. Do both resistance training and cardiovascular exercise. Find what works for you. My wife is an avid hiker. I love getting outdoors with her and going hiking. That works well for us. I like lifting weights. That works well for me. So find what works for you, but don’t neglect muscle mass, right? So I think this is where just, just having some general principles is really important. Sleep is very individual. First of all, you need to know Are you sleeping well? Do you have sleep apnea? There are tools you can use. There are trackers you can use. Use them. Find out what your sleep quality’s like, and if it is poor, figure out why it’s poor. For a lot of people, it’s poor. They might have sleep apnea, they might have a lot of stress, they might be doom scrolling right before they go to bed. They might have hormonal imbalances. They might be drinking alcohol right before you go to bed.
[00:36:27 –> 00:36:27] Dr. Ravi Kumar: Mm-hmm.
[00:36:27 –> 00:37:06] Matt Kaeberlein: Figure out why your sleep is being perturbed and take steps to fix it. And then in connect, this is also very personal, right? You have to be honest with yourself about how you are experiencing stress. What are the things in your life that are causing you stress? For some people, meditation works really well. Breathwork is great if you’re experiencing stress. Learning how to use it. And then prioritizing relationships, quality relationships. Again, I think for me personally, and I think this is true for, especially for a lot of men in their 30s, 40s and 50s, we get into our careers, we’re trying really hard to be super successful in our careers. We wanna provide for our families. We wanna have good relationships with our kids, and we stop hanging out with our friends.
[00:37:06 –> 00:37:06] Dr. Ravi Kumar: Yeah…
[00:37:06 –> 00:37:32] Matt Kaeberlein: if that’s you, figure it out. Learn how to prioritize having real friendships and make an effort there. So those, That’s kind of the way I think about, I think about lifestyle. And then you can get as into the optimization game as you want to, but you don’t have to. If you really think about the, the kinds of things that I just talked about and you prioritize those, that’s 90, 95% of the game, and the last 5% is incremental. If you wanna, if you wanna spend time on that, great, but I don’t think you have to.
[00:37:32 –> 00:37:48] Dr. Ravi Kumar: Yeah, that is a fantastic framework for thinking about it. I mean, those four pillars, I mean, without those, I mean, those are these pillars that are essential to even just being human, right? We’ve always socially interacted.
[00:37:48 –> 00:37:48] Matt Kaeberlein: Yeah…
[00:37:48 –> 00:38:03] Dr. Ravi Kumar: ate whole foods. We’ve always moved. There’s no human in the history of mankind that hasn’t had to move throughout the world to maintain optimal health. And then sleep, same thing, you know? Sleep is a, a modern problem. We always just slept, you know -
[00:38:03 –> 00:38:04] Matt Kaeberlein: Yeah…
[00:38:04 –> 00:38:15] Dr. Ravi Kumar: when we, when we were tired. And so I think that’s a fantastic way to think about it. There’s some other things that I would say even before going on to supplements as well that you should think about, and that’s, you know, taking out the things that hurt you too.
[00:38:15 –> 00:38:15] Matt Kaeberlein: Mm-hmm.
[00:38:15 –> 00:38:16] Dr. Ravi Kumar: Like, you know -
[00:38:16 –> 00:38:18] Matt Kaeberlein: Yeah. Reduce the alcohol…
[00:38:18 –> 00:38:21] Dr. Ravi Kumar: like smoking, alcohol, stress. I mean, stress is one that we-
[00:38:21 –> 00:38:21] Matt Kaeberlein: Yeah…
[00:38:21 –> 00:38:34] Dr. Ravi Kumar: we don’t, like, address in this country especially. But yeah, I mean, I don’t know where those fall on your progre- when you’re advising people, do you say, “Hey, you gotta get these out before you start supplements,” or are you saying, “Work on that-”
[00:38:34 –> 00:40:35] Matt Kaeberlein: Well, again, I think it really depends on the person. So, so yes, it is absolutely good advice if you’re s- if you’re still smoking, to stop smoking. If you are drinking too much alcohol, to reduce your alcohol consumption. Stress, I don’t, Some people create stress as, their own, as, as its own pillar, and I think that, that’s perfectly reasonable. I don’t do that because stress weaves throughout all the other pillars, right? Stress influences how you sleep. Exercise can reduce your stress. If you’re eating a l- a, a, a highly processed food diet, that’s going to contribute to the effect that stress has on, on your body. And if you don’t have any friends, you’re gonna be more stressed out. Now, sometimes your friends can cause you stress, but a-all things being equal, you’re gonna be better able to manage stress if you have strong relationships and people you can turn to. So stress is kind of in all of that. And without exception, in my experience, if people take steps to optimize their lifestyle pillars, their ability to manage stress gets better. And I do think it’s important to use that phrase, manage stress. There are cases where you can identify things in your life that are causing you stress and remove those, and you should do that when you can. But in, in our world today, it’s just the reality that, that most of us can’t remove all of the things that are causing us stress. And so we need to be able to manage that stress as, in as healthy a way as we can. I think understanding what’s causing the stress is part of that, but also eating well, exercising regularly, that’s going to also help you, help you manage stress. But I say it’s individual because I don’t want to pretend that everybody’s experience when it comes to addictive substances is the same. It’s not. And so, you know, we sort of demonize smoking and alcohol, but this is true with food as well, right? Everybody experiences appetite and the relationship with different types of food differently. And so we need to recognize it’s not always the case that it is trivial to say, “Stop drinking alcohol,” right? That may not work for everybody. And in fact, I drink alcohol once in a while.
[00:40:35 –> 00:40:35] Dr. Ravi Kumar: Mm-hmm.
[00:40:35 –> 00:40:57] Matt Kaeberlein: I drink a lot less than I used to, but I’m not somebody who says you have to be a teetotaler in order to be healthy. I don’t think that’s true. And in fact, if you look at the actual data, you can make a reasoned argument that moderate consumption of alcohol, at least for all-cause mortality, is where the minimum is. Now, other people will say, “Yeah, but that’s because of artifacts and the way the data was analyzed .” Maybe, maybe not. They don’t know. I don’t know.
[00:40:57 –> 00:40:57] Dr. Ravi Kumar: Yeah.
[00:40:57 –> 00:41:18] Matt Kaeberlein: But if you look at the data, the data are pretty clear. Moderate consumption of alcohol has a lower all-cause mortality than drinking no alcohol at all. So -
[00:41:18 –> 00:41:18] Dr. Ravi Kumar: I agree with you. Yes. It’s good advice.
[00:41:18 –> 00:41:18] Matt Kaeberlein: Yeah. And if that, if that isn’t going to work for you, that’s okay. There are other things we can do.
[00:41:18 –> 00:41:35] Dr. Ravi Kumar: Yeah, totally. I mean, you know, monism or, like, just being monastic is never the way to go in life, honestly. You know, they’ve been working-
[00:41:35 –> 00:41:35] Matt Kaeberlein: Unless that’s right for you. For some people it might be. That’s not me.
[00:41:35 –> 00:41:35] Dr. Ravi Kumar: Yeah. And, and yeah, there, there are I mean, obviously there’s monks, and there’s been monks for thousands of years.
[00:41:35 –> 00:41:35] Matt Kaeberlein: Yeah.
[00:41:35 –> 00:41:43] Dr. Ravi Kumar: And in, uh, this, you know, longevity and biohacking communities, there’s tons of monks. You know, people who are only eating meat or only doing this-
[00:41:43 –> 00:41:44] Matt Kaeberlein: Yeah…
[00:41:44 –> 00:42:01] Dr. Ravi Kumar: or only doing that or taking, you know, fistfuls of pills every day. And, and those are extremes, and oftentimes the, the answer is right in the middle. And, you know -
[00:42:01 –> 00:42:02] Matt Kaeberlein: Yeah…
[00:42:02 –> 00:42:21] Dr. Ravi Kumar: with alcohol, from a biological standpoint it’s just not good for you. It’s a neurotoxin. You know, a yeast or a fungus made it to prevent animals from using that, that carbohydrate resource. But When our bodies are extraordinarily resilient and we’re able to tolerate certain amounts of toxins, and even small amounts of toxins can be good for you. It’s called, you know-
[00:42:21 –> 00:42:22] Matt Kaeberlein: Yeah…
[00:42:22 –> 00:42:23] Dr. Ravi Kumar: Zeno Hormesis, you know?
[00:42:23 –> 00:42:24] Matt Kaeberlein: That’s right. Yep.
[00:42:24 –> 00:42:33] Dr. Ravi Kumar: And so what happens, you know, when people drink alcohol? Well, they, they are inducing a small injury, but they often do it in the presence of friends and family and-
[00:42:33 –> 00:42:34] Matt Kaeberlein: That’s right…
[00:42:34 –> 00:42:49] Dr. Ravi Kumar: social interaction. And so I think there is this therapeutic effect from moderate alcohol intake when you’re doing it with people who have meaningful connections with you. And that’s why we see these communities of centenarians, and they almost all drink, you know?
[00:42:49 –> 00:42:51] Matt Kaeberlein: Right. That’s right.
[00:42:51 –> 00:42:53] Dr. Ravi Kumar: But they drink with friends and family. So -
[00:42:53 –> 00:42:54] Matt Kaeberlein: Yeah…
[00:42:54 –> 00:43:11] Dr. Ravi Kumar: I agree with you. Being monastic is, is likely not the way to go for optimal happiness in a lot of these things. And also, I think mentally it bothers us too. When we’re so tuned in on this concept that if I have any of that, it’s gonna-
[00:43:11 –> 00:43:11] Matt Kaeberlein: Right…
[00:43:11 –> 00:43:15] Dr. Ravi Kumar: kill me or it’s gonna hurt me, that, that affects your biology.
[00:43:15 –> 00:43:15] Matt Kaeberlein: Yeah.
[00:43:15 –> 00:43:24] Dr. Ravi Kumar: You know, that mental thought process. And when you fail to, to reach that ideal you’ve set in your head, that has effects on your self-esteem and the way you talk about-
[00:43:24 –> 00:43:24] Matt Kaeberlein: Yeah…
[00:43:24 –> 00:44:01] Dr. Ravi Kumar: yourself internally. So yeah, I think absolutely. Again, it, it depends on you, but most people who I know, and certainly for myself, I think moderation in these things is important. And, and, and, you know, I view this very much as a journey. A- and this is something I think that has worked really well for me and other people who I’ve helped guide, you know, on their health span journey, is, um, recognizing that while you may have a goal, like, I think the idea that, that, that, you know, think about what you wanna be able to do when you’re 90 or 95, and then backtrack from there to figure out where you need to be now. That’s a, that’s a reasonable framework. It’s not one that I subscribe to, but it’s a reasonable framework.
[00:44:01 –> 00:44:15] Matt Kaeberlein: But getting to 95 isn’t the goal. The goal is to feel really good right now and to continue feeling good going forward. And, and so-
[00:44:15 –> 00:44:16] Dr. Ravi Kumar: Yeah…
[00:44:16 –> 00:44:31] Matt Kaeberlein: I really like the framework of the journey is the reward. If y- if you really start to invest in your health, you’ll feel better. You will have more energy. You will have better relationships. You will enjoy your life more now and tomorrow and the next year, and hopefully 25 years from now Yeah.
[00:44:31 –> 00:44:36] Dr. Ravi Kumar: No, I totally agree with you. I mean, you gotta, you gotta enjoy the ride else-
[00:44:36 –> 00:44:36] Matt Kaeberlein: Yeah…
[00:44:36 –> 00:44:59] Dr. Ravi Kumar: you know, you come to the end of it and you f- you missed it. Right. So, okay, so we talked about the pillars, and I think that’s a really important point here is that if you haven’t done the pillars, you start there. Now, if you’ve got someone who’s invested and interested in longevity and they’ve done the pillars, what are the first steps they can take in improving their health span and lifespan?
[00:44:59 –> 00:45:21] Matt Kaeberlein: Yeah. Well, something we didn’t yet talk about is making sure that you also are doing the, I’m gonna use the word diagnostic work. Diagnostics has sort of taken on a, you know, d- means different things to different people. Blood work is part of it, but that’s not everything. But, but doing the diagnostic work to figure out where you’re at. And the diagnostic part is also a, a, a self-evaluation of your pillars. So it’s, in my view-
[00:45:21 –> 00:45:22] Dr. Ravi Kumar: Right…
[00:45:22 –> 00:46:16] Matt Kaeberlein: if we talk about just like what’s the 80/20 here for, for, for health span medicine, you know, there’s blood work, 100 or so blood-based biomarkers and urine-based biomarkers. Body composition, super important. I think everybody should get a whole body DEXA periodically so you know what your muscle mass is, your bone density, your, your visceral adipose. Strength, mobility, agility, kind of know where you’re at in that domain. Cognitive, kind of know where you’re at in that domain so you can baseline. A few other bells and whistles, but I’m not, I’m not suggesting everybody needs to get a whole body MRI or everybody needs to do a Galleri cancer test. I think those things have value, but you don’t have to do them in order to get a pretty good picture of where you’re at. So that’s really important in order to understand two things. One, do I have a broken leg? And, and not literally, but what I mean is if you’ve got a problem that, that needs medical care, like find out and get it fixed.
[00:46:16 –> 00:46:16] Dr. Ravi Kumar: Right.
[00:46:16 –> 00:46:47] Matt Kaeberlein: And get it fixed, yeah. And then two, where am I gonna get the biggest bang for the buck? Because again, I think a lot of people, you know, decide they wanna start focusing on their health, and then they try to do everything all at once and, and it doesn’t work, right? It’s, it’s overwhelming. So figure out where are you gonna get the biggest bang for your buck and focus on that first. And follow those biomarkers. Again, maybe it’s quarterly, maybe it’s every six months, maybe it’s every year. Depends on your goals and how fast you’re moving. And make sure you’re going in the right direction, right? And again-
[00:46:47 –> 00:46:47] Dr. Ravi Kumar: Right…
[00:46:47 –> 00:46:53] Matt Kaeberlein: I think this is where body composition is a really useful thing to follow over several months. Because-
[00:46:53 –> 00:46:53] Dr. Ravi Kumar: Mm-hmm…
[00:46:53 –> 00:47:07] Matt Kaeberlein: almost everybody, if you have been, if you’ve had a relatively typical American lifestyle and you adopt a healthier lifestyle, you’re gonna see changes in your body composition that are, are significant. And it’s very-
[00:47:07 –> 00:47:07] Dr. Ravi Kumar: Yeah…
[00:47:07 –> 00:47:17] Matt Kaeberlein: reinforcing to, to be able to see those changes. So I don’t wanna minimize the idea that we need to be looking at the biomarkers to understand where you’re starting from and to confirm-
[00:47:17 –> 00:47:17] Dr. Ravi Kumar: Right…
[00:47:17 –> 00:47:21] Matt Kaeberlein: that your trajectory is going the direction that you want it to go.
[00:47:21 –> 00:47:23] Dr. Ravi Kumar: So you need data. You need data-
[00:47:23 –> 00:47:23] Matt Kaeberlein: Yeah.
[00:47:23 –> 00:47:26] Dr. Ravi Kumar: so you can make objective, targeted interventions. So for example-
[00:47:26 –> 00:47:56] Matt Kaeberlein: And wearables can play a role too. Like I, I’m not somebody who uses five wearables, but I do think they, I do think they play a role, and they can play a role for different people at different times. Like as an example, you know, we talked about sleep. There, there are different wearables you can use for sleep. I used an Oura Ring for about six months, maybe nine months. It was very useful for me to be able to track my sleep and understand what was perturbing my sleep . during that time period. I don’t use an Oura Ring anymore because I learned what I needed to learn from that tool. So being-
[00:47:56 –> 00:47:56] Dr. Ravi Kumar: Right…
[00:47:56 –> 00:48:03] Matt Kaeberlein: willing to adapt and collect different types of data as appropriate, I think is valuable as well.
[00:48:03 –> 00:48:06] Dr. Ravi Kumar: I mean, a perfect example also is a CGM. You know?
[00:48:06 –> 00:48:07] Matt Kaeberlein: Yeah, exactly.
[00:48:07 –> 00:48:36] Dr. Ravi Kumar: It’s a continuous glucose monitor you put on the back of your arm. And, you know, I, I’ve used them, and I, I don’t have one on right now, but sometimes I will. And it’s when I need a ca- recalibration, when I need to know, okay, hey, what are these things again that really cause my blood pressure to spike or stay elevated for longer periods of time? And having that data, I mean, cognitively changes your habits. It just does, you know? You know that if you, you know, eat this certain type of food, you’re going to have elevated blood pressure or sugar-
[00:48:36 –> 00:48:36] Matt Kaeberlein: Yeah.
[00:48:36 –> 00:48:40] Dr. Ravi Kumar: sorry, for two hours, three hours. You don’t eat it. You pick at something different.
[00:48:40 –> 01:07:47] Matt Kaeberlein: I agree completely. Yeah. The only thing I’d say about CGM is I think it’s important, especially the first time you use a CGM, that it’s accompanied by appropriate educational material. I think un- unfortunately, continuous glucose monitoring oftentimes gets rolled out to consumers without that educational piece, and there’s a lot of misinformation about what it means. I think a lot of people get anxiety because they get a glucose spike, or their glucose- Yeah … goes low at night and the low alarm goes off, right? So I think when accompanied with the appropriate information, it’s one of the most powerful educational and behavior modifying tools. As you said, you know, you really can’t unlearn what you learn from a CGM, and it will have an impact on decisions that you’re making about food you put in your body in the future. And I do exactly what, what you do. Most people I know who use CGM do exactly what you describe, which is what I do. I maybe use a CGM once a year now, but I always learn something new, and it’s always reinforcing for things that I already knew, and I find it very valuable. Yeah. You know, those, If you look at those pamphlets, they’ll say, “Hey, there’s plus or minus 20 milligrams-” Yeah. per deciliter of glucose," you know? So they’re- Yeah, yeah, yeah … they’re, they’re not the most accurate tools in the world, that’s for sure. No, but they tell you directions, you know? They tell you- Yeah … time periods and quantities per, you know, input. So it’s, it’s data that you can make targeted decisions. So, I mean, one of the biggest Things with metabolic health and one of the, you know, the targets for these drugs you’re gonna talk about is, is basically metabolic efficiency and- Right you know, building versus, you know, investing in recycling and all that. And so I think having optimal metabolic health is a huge initial target that can make a massive difference in your health span. 100%. I, I, I agree completely. And again, that’s where the core sets of biomarkers can really be informative, right? ‘Cause a lot of the blood work will inform you, If you get the right blood work, will inform you about- Yeah … metabolic health much earlier than, you know, fasting glucose or A1C. Right. Right? You can see a perturbation earlier on, and the body composition will tell you a lot about- Yeah … it, or at least it can help you understand the biomarkers, right? If you have impaired insulin sensitivity, right, oftentimes that’s gonna be accompanied by higher visceral adipose and/or lower muscle mass. And so there are people who can be, you know, from a BMI perspective, in the overweight or obese category, but seemingly metabolically healthy And you look at their body composition, oftentimes they’re pretty well-muscled, and they don’t have very much visceral adipose. Right. So you can sort of understand what those biomarkers mean. The flip side, which I think is more informative from a health perspective, is you will often see very, very lean people, not always, but often women who are very lean. You would not look at them and guess this is somebody with pre-diabetes or diabetes, right? Right. You put the CGM on them and you see, oh my gosh, there’s a, there’s a metabolic issue there. Yeah. You do a DEXA on them, you see they’re under-muscled and sometimes have a lot of visceral adipose for their total body fat. Yeah. So I think that’s where these different types of biomarkers can converge to help you identify problems before they become chronic age-related disease, and understand those things so you know what the strategy should be to address it. Yeah. Okay. Yeah. So I see that all the time. A patient that looks slim comes into my office, and they’ve got a A1C of six point five, which is diabetic. Right. And, you know, it’s, this is something that’s very important. You have to have more muscle and less fat, and the fat- Yeah … around your organs is more metabolically inhibitory of insulin sensitivity. So I think the scan you’re talking about, the DEXA scan, which most people think about for bone mineral density- Right … you can do it on the whole body and get the amount of fat, muscle, and also still your bone density just from one scan. Yeah. And it’s fairly cheap, and it’s very low dose radiation. That’s right. Yeah. And they’re, they’re pretty widely available. Like any major city now, you can find a provider for a whole body DEXA. So yeah, the only thing I would say is, again, it’s important to appreciate oftentimes these, these companies that provide the whole body DEXAs, they’re direct to consumer, so there is no doctor in the loop. A lot of times- Yeah … it’s kinda like the CGM. You don’t really get the nuance in the interpretation. So it’s important just to realize there’s noise in the measurement, particularly for bone density. I wouldn’t really trust a whole body DEXA. I think it can be used as a screening tool, but you’re gonna wanna get the dedicated bone density DEXA before you diagnose yourself- Yeah with osteopenia or osteoporosis. But I think for muscle, positional muscle mass, and for visceral adipose, there’s a little bit of noise in the visceral adipose measurement, but it’s pretty close. And so you can at least bucket people into low, medium, high buckets for visceral adipose using the whole body DEXA. That’s a tool that I recommend, as I said earlier. I think everybody should get a whole body DEXA. You know, I don’t know if you need them annually. I like to do it annually or even more than annually. But you wanna get one, figure out where your baseline’s at, understand your body composition, and then if your body composition is changing rapidly, maybe even every six months, maybe even every three months. It really depends on your goals and, and, and what’s motivating and reinforcing for you. And these 80 to 100 biomarkers that you’re talking about, blood biomarkers or urine, wherever you’re looking. Where do people get those? Is there a list published somewhere? Can they take it to their doctor, or do they have to go to a specialty provider to get those? Yeah. So it’s a, it’s a good question. I should just put the list out that I do. I just need to do that. Yeah. Um, so here’s what I would say. I think there are, there are companies out there that will sell you, you know, their, their health panels, right? And, uh, again, I don’t have any affiliation with Function Health. I’m not even really a fan of Function Health. I, I think that the fact that they just give people data without healthcare is really a disservice to patients, and particularly now that they bought a supplement company, I’m like, “I don’t want anything to do with those guys.” Having said that, their basic panel is pretty good, so that’s a pretty good place to start. And if you look at the, the folks who are doing, you know, what I would call pretty good health span medicine, longevity medicine, it’s gonna be an overlapping set of blood and, and urine-based biomarkers. So the urine piece, I think a standard urinalysis, you don’t have to do anything, anything fancy there. And then for the blood work, you know, it’s gonna be the common stuff, so CBC, chem. I think in, fasting insulin is an important metric. HSCRP is something most people aren’t gonna get. There’s some inflammatory markers you probably, you probably wanna look at that aren’t gonna be in the s- the standard panel. I like to look at vitamin D and omega-3 index, um- Okay … because I think those are things we can measure and actually take action if you’re outside the optimal range. Maybe once a year or once every few years, getting the common toxic metals, mercury, things like that measured. Um, you know, we would see maybe 5% of people have pretty high mercury levels. This is Pacific Northwest, so common culprit is seafood, sushi. Yeah. But if you’ve got high mercury levels, you wanna know. There are things you can do to fix it, and you can, you can take steps. Mercury toxicity is a, is a real thing, right? So those are kind of the core factors that I, that I would put in there. Um, I think a, I think a more sophisticated lipid panel than just HDL and LDL, look at particle sizes, ApoB, Lpare very informative. The other thing, you know, we haven’t touched on, and I’m not gonna suggest this is something everybody should get Although I, I think most people could benefit from a cardiac scan with contrast when you get in your forties or fifties, especially if your lipids are, are outside the normal range. What’s that gonna tell you? It’s gonna tell you your soft and hard plaque burden, right? Your calcified plaque and your soft plaque. A lot of people will get the calcium score and think that’s sufficient, and then, you know, they’ll die from a widow-maker because they had a bunch of soft plaque, right? So I think actually knowing what your cardiovascular disease state is, is important, and that can help guide how aggressive you’re gonna be if you need to be on lipid-lowering medications. So I think that’s worth, you know, at least mentioning explicitly. That’s a little bit more expensive procedure. But if you have a family history or if you have lipid levels that are concerning then I would prioritize that. The other piece is, is getting a good genetics test. Um, again, it’s still a little bit limited what we can do with genetics, but that gets more and more powerful as time goes on. And there are some high-risk genetic polymorphisms that if you’ve got, can help guide how aggressive you are in targeting certain areas of your health. ApoE is a good example of a, of a high impact polymorphism, right? If you have the ApoE4 allele, one allele, you’re about fivefold higher risk of dementia and cardiovascular disease. Two alleles, it goes up to about twentyfold. So if you are an ApoE4 carrier or homozygote, then you really wanna pay attention to an abnormal lipid profile or anything happening on the cognitive side. And again, it doesn’t really change what you do, but it will change how aggressive you are in many cases at ap- at approaching these lifestyle factors, and in some cases, things that are more experimental. So again, ApoE4 is a really nice example. There’s emerging evidence for two, what I would call experimental therapies, rapamycin and therapeutic plasma exchange, that, that these potentially could be beneficial in humans, particularly in people who are at higher risk of dementia from ApoE4. So it’s a personal decision. Have a conversation with your doctor. But if you’re an ApoE4 carrier or ApoE4 homozygote, you might want to be more aggressive at trying some of these experimental therapies that aren’t yet proven in people where we’ve got pretty good safety data. The risk-reward calculation changes, I guess, is what I’m saying. The upside is higher if you have a twentyfold increased risk of developing Alzheimer’s disease. Yeah, you know, ApoE4 is very interesting because it’s, I mean, it’s essentially a, a lipid transport molecule, and it, it basically delivers lipids inefficiently compared to ApoE3 and ApoE2. But there’s a reason it’s in our gene pool still, you know? I mean, it would, If it was so, so catastrophic, uh, it would’ve been wiped out a long time ago. And, you know, the argument against that is that, “Hey, you’ve already reproduced. It doesn’t matter,” you know, at that point. Most of, most of the deficits of the ApoE4 carrier show up later in life. Right. But yeah, presumably there is some selected value. It wouldn’t have been selected into the gene pool and maintained if there wasn’t some benefit in certain contexts to having that allele. Yeah. Yeah, yeah. And, and there are populations, you know, um, that have high levels of ApoE4 that don’t show- That’s right … the same late life neurodegeneration as Europeans do. Environment or other genetic factors. And this is where- Yeah … you know, one of the areas with genetics that’s still emerging, but, but even already can be informative, is this idea of polygenic risk analysis, where instead of looking only at ApoE4, you look at a few dozen genetic variants that have been associated with Alzheimer’s disease or cardiovascular disease or whatever the condition is that you’re interested in, and you try to come up with a summary score based on all of your variants that we think are important for that condition. It’s a moving target. The science is evolving. I don’t take any polygenic risk score as the gospel, but again, I think it can be, especially if it lines up with other biomarkers or other things in that person’s experience, it can tip the scales, move the needle towards being more aggressive at treating or preventing optimally a certain condition. Yeah, totally. And I think, you know, the lifestyle foundational pillars that you already talked about, I mean, those hit a lot of these potential genetic risk factors, you know, like ApoE4, Lp. You know, if you are living a metabolically unhealthy life, you’re not, you’re not moving, you’re not exercising, you’re smoking, all those risk factors that, you know, genetic potential risk factors we talked about, they become, they come into play much more severely, especially later in life, than they would if you lived a healthier life. The one thing I would caution listeners is that, you know, you find out you have ApoE4 or you have high Lplevels, you know, they get scared and then they become reactive because there’s people out on the internet saying you should push your LDL below thirty, which doesn’t exist in human biology. You know, it’s a completely artificial condition. And they think, “Hey, okay, I’m gonna outsmart this billions of years of evolution with a new technology.” And I just, I think people just have to be careful. I’m not arguing against pushing down, you know, um, uh, LDL levels or with medications. If that’s in the cards, then fine, but, like, you gotta be careful. Your, your biology was there for a reason, and there are certain things that you have to work with because we live in a mismatched world from our evolutionary origins, you know? And so you have to try to match up what you’re doing with the way you were designed, and some people are higher risk for living in a mismatched world, for sure. Sure. Yeah, and I, again, I think the other thing to appreciate is that having two alleles of ApoE4 is not a diagnosis or a guarantee that you’re gonna get Alzheimer’s disease or cardiovascular disease. We can modify the environment in ways that will greatly reduce that risk. And I, and I think, you know, there’s emerging now consensus that Alzheimer’s disease, I’m not gonna suggest it can be reversed. I’m not even gonna suggest that, that we can stop the progression for most people, but we can slow it down. And again, most of that is gonna fall back into these lifestyle factors that we talked about. There are maybe some select supplements that can work Preferentially in people who have certain types of Alzheimer’s disease. There may be some medications that can be used. There are strategies though that can greatly slow the process, and if you identify the risk early enough, can greatly reduce the, that 20-fold increase that you get from having two copies of APOE4. Maybe even bring it back to where it would be if you didn’t have any copies of APOE4. So there are things you can do, and it involves a spectrum of approaches centered first around lifestyle. Yeah. Okay. So let me, let’s jump back to aging. And there’s, there’s… Before we talk about rapamycin, which is the real highlight of this whole show with you, is I wanna talk about three other supplements/medications that- Okay a lot of people are using. Yep. And just get your thoughts on them, because these are things that, you know, the marketing world has told us will reduce our, or slow aging, stop aging. So the first one is one that’s really widespread. It’s nicotinamide, uh, riboside or nicotinamide mononucleotide, and which is NR or NMN, and they’re focused on basically increasing our NAD levels, which- Right basically is a electron donator in the electron transport chain, so it potentially increases our energy, and it helps with cellular repair and things like that. Now- Yeah … studies have shown that NAD goes down throughout our life, and the thought is, if you take these supplements to increase NAD your repair and your energy metabolism will be better. Does that hold up, and should people be paying 50 bucks a month for a NR supplement? So these are NAD boosters as you sort of alluded to. For me, NAD boosters are tier three supplements. So tier one is what do I do, tier two is there’s some science behind it that seems legitimate and, you know, I’m, I’m, I haven’t put it on my stack, but it’s reasonable that people might, might wanna do it. Tier three is a big maybe where the science is, is mixed and a lot of it’s not very good, and that’s where I put the NAD boosters. So actually you said something there that I think is important to clarify. There are people who claim that it is established that NAD levels decline with age. That is not true. That is a myth that this is established. I’m not saying it’s not true that NAD levels decline with age in some people or in sub- some tissues, but at the population level, it is far from established that NAD levels decline generally with age, nor is it established that NAD levels decline with age in mice or flies or worms or any other organism. Hmm. That is something that has been largely propagated by a small number of high-profile scientists who write a lot of reviews and don’t have very much primary data to actually back up that position. There was a study that just came out, I think it was published in Nature Aging, Nature Metabolism, that was probably the best study that’s been done in humans looking at NAD levels across the life course. This is in blood, and the answer is it doesn’t decline with age in blood across human populations. There’s another study that was published, I think it’s still in a pre-print, uh, last year that found the same thing. So- Which totally destroys the supplement’s whole purpose for being, you know? If that’s true, you know? Well, so let’s, let’s double-click on that because you can make an argument that it doesn’t completely rule out the possibility that supplementing with NAD is, is beneficial, but it certainly undercuts the, the primary rationale which, which, which was propagated, which is that NAD becomes limiting during aging. We can measure its decline, and if we bring it back up, it’s gonna be, gonna be beneficial. Now, look, the NAD proponents will argue, “Yeah, but blood isn’t the right place to measure it. We need to look in muscle or brain or kidney or liver.” And I’m like, “Yes, you do, and you need to show that data before we talk about whether whether the hypothesis is real.” They haven’t done that yet. So good scientists seek to disprove their models. Bad scientists make excuses for data that don’t fit their model. Mm-hmm. And so ignoring the data that doesn’t fit your model is not usually a recipe to get to the right answer at the end of the day. So I think we have to kind of take the NAD case now and ask, it is still possible that NAD precursors, NMN, NR, by the way, niacin, nicotinamide will do exactly the same thing. If you really want an NAD precursor, those are about 100 fold less expensive than NR and NMN. So the question is, do these NAD precursors have any health benefits Across the general population or for certain conditions, certain individuals. I 100% believe… So NAD is really important. As you alluded to, it is not only involved in the electron transport chain, it’s involved in tens of thousands of chemical reactions in our cells. It is a fundamentally important biomolecule metabolite in all living organisms. For that reason, we have evolved quite sophisticated mechanisms to maintain NAD levels within a very narrow range, because when it gets outside that range, bad things happen. So it seems unlikely to me that NAD levels drift that much in general with age in the average person. People who have severe mitochondrial disease, maybe people who have Parkinson’s disease, in that context, yes, NAD metabolism may be perturbed and NAD precursors could very well be beneficial. So I do believe that there are situations of severe metabolic stress. Usually, it’s got to be really severe where NAD boosters could be beneficial, and there’s hints in the human clinical data, maybe for Parkinson’s disease, that NAD boosters could have a, a beneficial effect there.
[01:07:47 –> 01:08:07] Dr. Ravi Kumar: Is it gonna cure the disease? No, no way. Could it be beneficial? Sure. Possibly. Heart failure, maybe. That’s a, that’s an energetic crisis. Maybe NAD boosters could be beneficial there. I think we would know by now if NAD boosters were having a significant effect on aging biology because it would be apparent, right?
[01:08:07 –> 01:09:06] Matt Kaeberlein: Right. And I think people will point to early studies in animals. There have been, There’s, there was one study that reported that nicotinamide riboside increased lifespan in mice. There was another one that reported that NMN increased lifespan in mice. Those have not been reproducible. And in fact, when you look at the initial studies, it’s pretty obvious that those mouse experiments were not high-quality experiments because the control animals were very short-lived. This is a common theme we see in mouse longevity studies. When the control animals are very short-lived, there was something about the environment they were housed in, the intervention increased lifespan back to where the control should have been in a well-done experiment. Those typically can’t be reproduced when other people do well-controlled mouse experiments. That’s what we’ve seen with NR and, and NMN for longevity. Having said that, the people who want you to believe that NAD boosters are beneficial and want to sell them to you will point to the original studies that aren’t reproducible and say, “Yeah, but this increases lifespan in mice.” Again, these are people who largely ignore the data that doesn’t fit the narrative that they, they want you to believe.
[01:09:06 –> 01:09:30] Dr. Ravi Kumar: So I’m at a point with NAD precursors where there’s smoke, right? And there’s a metabolically plausible reason why in certain situations NAD precursors could be beneficial. There isn’t much fire. Like, I have not seen a signal in either the preclinical literature or the, or the human data to suggest that these things have robust beneficial effects in the typical person.
[01:09:30 –> 01:11:20] Matt Kaeberlein: I’m not saying it’s not possible. I’m not ruling it out. But I am saying, you know, if you wanna make fantastic claims, you should have fantastic data to back it up, and there just isn’t fantastic data on NAD precursors right now. Right. Yeah, I mean, that is a common story, unfortunately, with supplements and science. You know, I mean, there’s this, especially in the United States, you know, the capitalistic pursuits are tied to scientific discoveries, and human beings are biased, and they want money, you know, and they want success, and they want notoriety, and they want to feel like they’re having an impact, and that can override the whole point of scientific discovery, which is to find the truth. So yeah, I think you’ve cast this in a really good light. We don’t know, but the evidence is not convincing right now. Right. Yeah, I think that’s exactly a fair statement. And, I mean, marketing is effective, and, and again, this gets to, you know, the incentive structures around supplements. And, like, I know people who are in the supplement space. I like some of them as individuals. I think some of them are well-intentioned. But the reality is the incentive structure of that business model requires people to make claims that go beyond the data. If you’re gonna be successful, you have to stretch the truth in that space, which is partly why I want nothing to do with the direct-to-consumer space as for me personally, ‘cause I’m not comfortable lying to people. Well, thank you for that. Okay, so NAD out. Um, let’s, let’s go on to the next one. So can you talk about metformin? Because this is… I mean, everyone’s heard about this now. Even there was, you know, a longevity expert who was talking to Jeffrey Epstein about metformin, so it’s all over the news, you know? And the question is Does metformin increase longevity?
[01:11:20 –> 01:11:41] Dr. Ravi Kumar: What does the data say so far, and what are the downsides? ‘Cause I know they’re real. Yeah. Can you talk a little bit about that? Sure. So, so metformin, of course, is, I believe it’s still the most widely prescribed anti-diabetes drug in the world. It’s an effective drug for diabetes. We don’t really know the mechanism of action for metformin, so, so it isn’t, It’s what’s called an AMP kinase activator.
[01:11:41 –> 01:20:44] Matt Kaeberlein: So AMP kinase- Right … is an energy sensor. And so when you, when you put metformin on cells or give it to animals, you will see an increase in, in AMP kinase. That has the effect of, you know, I’m gonna use an imprecise term, but boosting mitochondria to make more ATP. That’s essentially what AMP kinase is supposed to do, sense the amount of ATP and then tell the cell to make more ATP when it, when it needs to. And so metformin does that, but exactly how it’s activating AMP kinase is still a little bit of a mystery. It is definitely an electron transport chain inhibitor, so one of the ways you can reduce the amount of ATP is to inhibit the electron transport chain, which is used to make ATP. That’s probably its primary mechanism of action, but it affects the microbiome. There are people who microbiome effects are involved in, in, in its anti-diabetes function, so we don’t really know. Metformin is a pretty dirty drug, meaning biochemically it has lots of potential targets it could be acting on. Um, people got interested in metformin as a longevity drug from, I think the first studies were done by this, this Russian scientist named Anisimov. Again, I was talking about the short-lived mice. So he used a cancer-prone strain of mice that was very short-lived, not even really clear it was aging in, in the normal aging sense that we would think about, and he showed that metformin was effective at increasing lifespan in those mice. And I don’t think the mechanism there was ever fully understood, except that it did seem to be affecting cancer incidence in those mice. Hmm. And so that got picked up more broadly. People did studies in C. elegans and fruit flies. The data there is a little bit more mixed, but metformin can increase lifespan in C. elegans, and it activates AMP kinase, and we know that activating AMP kinase is sufficient to increase lifespan in C. elegans. So now fast-forward, you know, ten years or so, and metformin was tested by what is really the highest quality mouse lifespan program out there, called the NIA Interventions Testing Program, had no effect on lifespan. There was another study that was done by Rafa de Cabo at NIA that tested metformin at two doses. At one dose, it increased lifespan by a whopping three percent And at the other dose, it shortened lifespan by ten percent. The title of that paper actually was something about how metformin increases lifespan and healthspan in mice, which is more marketing than actual science, given that the biggest effect was a shortening of lifespan by ten percent. Nonetheless, taken together, I think we can be pretty confident that metformin does not robustly increase lifespan in mice, probably has no effect on lifespan in mice. Does not seem to broadly improve healthspan in mice, although it probably does have a positive effect on glucose, uh, or insulin resistance in mice, which is an age-associated phenotype, which is what we would expect for a diabetes drug. Okay, that’s the preclinical literature. Meh, probably not an effective longevity drug. The human data is also interesting and mixed. There was a study probably ten years ago now looking at people using metformin, comparing them, so these are diabetics on metformin, comparing them to diabetics not taking metformin. There, there’s a big effect, a reduction in mortality. Diabetics taking an anti-diabetes drug do better than diabetics who are not taking an anti-diabetes drug. That makes sense. That paper also made the claim that the diabetics taking metformin had lower all-cause mortality than non-diabetics not taking metformin. That was pretty exciting, and a lo- and that, that fit with the narrative that metformin might slow aging in people. And at this time, people still were somewhat optimistic about metformin in mice and, and other laboratory animals. Unfortunately, that study has not been reproducible. There, I think, have been two or three studies now, one of which went back and looked at the way the data was analyzed in the original study and found pretty serious flaws in that. And then studies looking in other human populations have not been able to find a signal that diabetics taking metformin live longer than non-diabetics not taking metformin. In fact, they seem to live shorter. So I would say the human data is also relatively weak for the idea that metformin is broadly slowing aging biology I think there are some hints that metformin potentially can have some benefits for maybe certain types of cardiovascular disease, maybe certain types of dementia. My intuition is those effects are starting from the metabolic improvements. Right. Because those diseases are also associated with impaired metabolic health. But it is possible that metformin has impacts on certain age-related diseases independent of its ability to improve insulin sensitivity and, and glucose handling. That’s kind of where I land on metformin. And if the question is should non-diabetics take metformin because it might slow their aging process for all of the reasons I just went into, my opinion is no, that’s not a good idea. And I think we’re starting to get some signals that metformin may not be as benign as people thought it was, that there may be costs to taking metformin if you are non-diabetic, um, including potentially attenuating the benefits of exercise- Yeah reducing testosterone in men. So things like that, you know, to me, the, again, the, the cost-benefit analysis doesn’t favor benefit at this point. No. Metformin’s a great diabetes drug. I mean, it’s a fantastic diabetes drug. But, you know, take, when you take it, like you said, you inhibit complex one of the mitochondrial, uh, electron sh- transport chain. Right. And y- so you’re not making energy a- as well, and that’s why you have this increase in- Right … in AMP kinase ‘cause you want to actually make more ATP. Your body’s trying to tell you to do this. So it’s like you’re choking off mitochondrial efficiency, and that’s one of the tenets of aging, right, is mitochondrial- Like the hallmarks, yeah dysfunction? Yeah. And so you’re, I mean, I see it as you’re actually putting a spike in your shoe, you know? You’re tr- you’re not able to run your mitochondrial- chondria efficiently. And then the fact that you don’t put on muscle mass, I mean, tho- that study was pretty convincing that- Yeah … you know- Yeah … if you were taking metformin and you exercised, your thigh circumference and your muscle mass just did not increase the same as someone who was not taking metformin. I mean, that, that to me, I don’t see why people want to take it despite that data and the, the weakness of the other data. I agree with you. Again, I think it’s a different situation if you’re a diabetic and metformin helps you manage, manage your disease. Having said that, there are other good diabetes drugs that don’t seem to have some of these potential downsides of, of metformin, so there, there may be options there as well. But I also want to say, like, I agree 100% with the way you characterized it. And as we alluded to before, there are examples in the literature where a subtle mitochondrial stress, a subtle heat shock can actually be beneficial. So I don’t want to rule out the possibility that if you could titrate the metformin exactly right- Mm-hmm create just enough mitochondrial stress that it would have a, what, what people would call a mitohormesis effect that would be positive. I don’t think we know enough about how to do that. And so again, I always try to put this in the context of a risk-benefit or risk-reward. And given the limitations on, on our knowledge of if that’s even possible how to do it, what we understand about the likelihood of benefits for metabolically healthy people from metformin and the likely downsides, to me it clearly skews To the risk side and the rewards aren’t, aren’t that high. I agree with you. Um, and I, and I want to differentiate that because, um, you know, I think there’s the SGLT2 inhibitors that I alluded to before as well, which are also anti-diabetes drugs, where again, I’m not suggesting everybody should start taking an SGLT2 inhibitor. But if I had to pick like one that’s likely to have a gerotherapeutic or a benefit for aging, the SGLT2 inhibitors are really pretty high. Like they’re really interesting drugs from that perspective. And so if you’re gonna take a diabetes drug and you don’t have diabetes, I would take an SGLT2 inhibitor. I’m not, That’s not medical advice. I’m not suggesting that you necessarily do that. Not medical advice, yeah. Just saying. No, but that’s, that’s great. I mean, a-and that, you know, looking, looking at the available drugs we have and seeing how they might be applied to different situations is very important. I know you’re doing that in a, on a big scale, so we can maybe talk about that later, but okay. The next thing I want to ask you about is senolytics, because this is something that’s very interesting and probably something that most of my listeners have not heard of. Like- Okay. So can you tell us what a senescent cell is, why they’re bad- Yeah … and what these compounds that might kind of clean them out are doing and how they might help us, and if you recommend them at all? Sure, yeah. So senescent cells are cells that exit the cell cycle, right? So most cells are dividing or can divide. Senescent cells exit the cell cycle. They become what’s called senescent as opposed to quiescent. So quiescent is if you exit the cell cycle, but you can reenter at some point. Okay. Senescence is at least thought to be an irreversible exit from the cell cycle, and it is thought to be an evolved mechanism to prevent cancer.
[01:20:44 –> 01:21:03] Dr. Ravi Kumar: So what’s cancer? Cancer are cells that divide uncontrollably, right? So there are two ways, basically, that our bodies can prevent uncontrolled cell division, at least at that initial phase. One is cell death. That’s called apoptosis or necrosis. The other is senescence. And so what that does is it prevents a cell from becoming cancerous.
[01:21:03 –> 01:28:19] Matt Kaeberlein: There are lots of ways that cells can become senescent, lots of types of damage, radiation, oxidative stress, proteostatic stress, so a bunch of misfolded proteins can cause cells to become senescent. And so you can think of it like a protective mechanism. The problem is that because these cells don’t die, they accumulate with age. And even that wouldn’t be an issue, but instead of just hanging around and doing nothing, they seem to give off signals that are counterproductive to tissue homeostasis in the area that the senescent cells are accumulating. These signals also get into circulation and can cause problems throughout the body. Mostly these are inflammatory signals, but not exclusively. So this has been called the senescence-associated secretory phenotype, or SASP, the signals that senescent cells give off. So some people call these things zombie cells because kinda like zombies, they don’t die, and they can turn other cells into zombies. That’s, that’s the idea there. Okay. So this is, this is true. There’s a lot of, I think, work right now happening in the field to understand how important is senescence, how many senescent, you know, to what level do senescent cells accumulate with aging, which tissues and organs have a burden of senescent cells, what environmental stressors can cause a high level of senescent cells. I think you’ll get different opinions in the field about how important senescence is as a driver of aging. I’ll just say it’s one of the hallmarks. Do I think it’s the most important hallmark? Probably not. Do I think senescent cells contribute to chronic inflammation with aging? Yeah, I do believe that’s true. And depending on you, if you’re exposed to a lot of radiation or you’re exposed to, you know, an environmental stressor that can induce senescence, you could have a very high senescent cell burden. Okay, so that’s senescent cells. Now, senolytics are Drugs or other types of therapies that can kill senescent cells. That’s what the seno-senescent lytic kill. So the first of these were things like dasatinib plus quercetin. So if you’ve ever heard of DNQ, that’s sort of the classic senolytic molecule cocktail to clear senescent cells. So why do we think senolytics would be beneficial? There were a couple of studies done in mice, one using a genetic construct to clear senescent cells, and then another using DNQ, treating mice with these interventions, seeing that senescent cell burden goes down, seeing that lifespan is increased a little bit, it’s not a big effect, and that multiple health span metrics seem to be improved from clearing senescent cells. The lifespan data has been sort of questioned. I don’t know how reproducible that is, but pretty consistently people can see improvements in age-related health metrics from different types of senolytic strategies. One thing to appreciate about senolytics, though, especially the small molecule approaches, is none of them are perfect. None of them clear all senescent cells, and none of them only kill senescent cells. So you’ll get some death of healthy cells with any senolytic, at least that we have right now. So I would put senolytics in the category of an intriguing class of drugs that we don’t yet have, you know, real class leader that is particularly effective at clearing senescent cells and avoids killing non-senescent cells. There are lots of people working on developing these. So I don’t personally take anything as a senolytic, and I don’t, I don’t think we’re there yet in terms of the specificity of these drugs. But they’re a very interesting class of therapeutics that, that people are working on. And then the other thing that’s probably worth saying is there is another class of interventions called senomorphics that don’t kill the senescent cells but reduce the SAS. So basically shut off their ability to send out these, these detrimental signals. Rapamycin, as an example, is a potent senomorphic. It doesn’t kill the senescent cells, but it does turn down or turn off the SAS in a majority of senescent cells. It’s probably one of the reasons why when we treat animals with rapamycin, we see a very rapid blunting of the chronic sterile inflammation that goes along with aging. I think those are interesting classes of drugs to be thinking about as well, and it might be easier from a drug development perspective to create a specific senomorphic ‘cause that’s an, that’s an aberrant response in senescent cells as opposed to a very specific and potent senolytic. But time will tell as to, to, you know- Right which approach turns out to be more potent. Maybe one more thing to add, our immune system is very capable of surveilling cancers. It’s also capable of removing senescent cells. Okay. When we’re young, I think the thought is one of the reasons we don’t accumulate very many senescent cells, ‘cause they’re, they’re happening in our bodies all the time, is because our immune system is effective at clearing senescent cells. But as we get older, in part because of this chron- increase in chronic inflammation, our immune system becomes less able to surveil cancer, less able to clear senescent cells. It becomes sort of a vicious cycle where the inability of the immune system to clear senescent cells allows more secretion of the SAS, allows more chronic inflammation, further reduces the immune system’s ability to clear senescent cells. So strategies for resetting immune homeostasis in aging are likely to be indirectly senolytic because then the immune system can actually go in and do what it’s supposed to with senescent cells. Yeah, that’s very interesting. So what about fasting to induce autophagy? Mm-hmm. Yeah. First, tell us what autophagy is, and then tell us about, like, how, if that plays any role in senescent cells. So autophagy is commonly referred to as the recycling center of the cell. It is, uh, a, a biological response mostly to nutrient deprivation, where you turn up production of these subcellular vesicles that can encapsulate macromolecules, including even whole mitochondria in some cases, inside of these vesicles. It targets them to the lysosome, where they are degraded and recycled back into building blocks, nucleotides and amino acids and things like that. The idea is conceptually that when a cell or an organism is under nutrient stress, there’s not very much food around, first, one thing you wanna do is shut off unnecessary production. So you don’t, you don’t need to make all the, the stuff that is not essential for cellular function and, and, and growth. So you wanna focus on the basics, which is a good idea when there’s not very much food around, and you wanna have lots of the building blocks you need to make the basics. So you break down either damaged components of the cell or components of the cell that are not essential for life, and you recycle those back into the building blocks. So that’s what autophagy does. One of the key gatekeepers, probably the most important key gatekeeper for autophagy, is mTOR, the mechanistic target of rapamycin. This is the protein that rapamycin inhibits. So when you treat cells with rapamycin, one of the most robust things you see is an upregulation of autophagy. Um, and so fasting also is effective at turning up autophagy because fasting turns down mTOR. So there may be other effects of fasting on autophagy, but most of the ability of fasting or caloric restriction to turn up autophagy is because you turn down mTOR. So then the question is, you know, what effect does that have on cell health?
[01:28:19 –> 01:28:42] Dr. Ravi Kumar: What effect does it have on, on aging? What effect does it have on senescent? So I think the effect of fasting on senescent cells, l- that’s a little bit less clear. My intuition is if fasting is cl- is effective at reducing senescent cell burden, it’s more because of the reduction in chronic inflammation, which allows the immune system reset as opposed to direct effects of killing senescent cells.
[01:28:42 –> 01:32:35] Matt Kaeberlein: That, that’s my intuition, but that’s a, that’s a to-be-determined scientific question. Okay. I think does fasting slow aging is an, is an interesting, important question. Caloric restriction definitely in laboratory animals slows aging. That’s the gold standard. The biggest effects you get, the most reproducible and robust effects on lifespan and healthspan metrics come from caloric restriction in laboratory animals. Fasting, when it is accompanied by caloric restriction has that effect. You see increases in lifespan and health span. In fact, if you go back and look at the classic literature on caloric restriction, they were all intermittent fasting experiments. So people would typically feed mice seven days a week, but, you know, the people who wanted to do the caloric restriction experiments, it was just easier for them to say, “We’re gonna only feed the mice two days a week or three days a week.” So they were doing intermittent fasting. In that context, they lived longer and were healthier. When you control for caloric intake, in other words, if you allow the mice to double up, let’s just say you feed them every other day, and you allow them to double up on the calories on the day they’re being fed, that lifespan extension pretty much goes away. There may be a teeny-tiny, you know, single-digit percent effect, if that. I don’t find that compelling at all. But the vast majority of the benefits go away. So that doesn’t mean fasting doesn’t have other physiological effects that are independent of caloric consumption, but the longevity effects seem to be largely, if not exclusively, due to caloric restriction, not due to fasting. So this puts us in an interesting space where I think in people, we don’t have a lot of quality data that intermittent fasting in an isocaloric context has significant health benefits. But I think for lots of people, intermittent fasting is a useful strategy for reducing caloric consumption or maintaining a healthy caloric consumption. And so in that context, I’m like, “Yeah, all for it. Go do it if that works for you.” I don’t know there’s much evidence for intrinsic value in intermittent fasting or time-restricted eating if you are also over-consuming calories. There might be, but I just haven’t seen much compelling data at this point. Right. Yeah. So if you’re fasting for 16, uh, hours and eating for eight, but you’re eating, you’re still eating 3,000 calories in eight hours, there’s no benefit there because you’re still, the nutrient overload is still there. Yeah. What I would say is I am not convinced there’s benefit there. I don’t want to rule out the possibility, ‘cause again, I, I try to be rigorous in the way I, I think about and talk about this stuff, but I haven’t seen any compelling evidence that you’re gonna get a benefit from 16/8 or even two days of fasting a week if you’re eating a low-quality diet and you’re eating too many calories. Yeah. I haven’t seen anything to make me believe that’s the case. No, my view of the literature is the same. Yeah, I, I think that it can be a useful tool to help you reduce caloric intake. There’s also nutrient composition, which is a- another big one people can work on. Of course. Yeah, but, uh, no, I agree with you there. Okay, so let’s move on to rapamycin. And, you know, I think a lot of people have heard of it. You know, they’ve heard the name and they’ve seen it in The New York Times or in some popular news media, but most don’t know what it does. They don’t know how it was discovered, which is a really cool story, and how it was originally used, and now how you guys are Exploring its use in inhibition of mTOR. So can you kind of start from the beginning and, uh, we’re, we’re also gonna have to tell people what mTOR is. You know, I think a lot of people have heard that, but they- Yeah … they don’t know exactly what it’s doing. So give us, give us the story here on rapamycin. Sure. Maybe I’ll start with mTOR. Again, from a, a conceptual level, we can get into the biochemistry, you know, as much as you want to, but conceptually, you can think of mTOR as really the gatekeeper of the cell or the organism when it needs to make really the fundamental evolutionary decision, “Should I have babies or not?”
[01:32:35 –> 01:32:49] Dr. Ravi Kumar: Right? Because as we talked about before, that’s what natural selection cares about, passing your genes on to the next generation. And then the second part of that is not only do you have to have babies, your babies have to grow into adults who can then pass their genes on to the next generation. That’s what mTOR does.
[01:32:49 –> 01:37:17] Matt Kaeberlein: It, is it helps the cell be successful at that. And if you think about every organism that’s ever existed, there’s a fundamental decision point when it comes to having babies or not. You need to sense the environment and ask yourself, “Is this a good time to have babies?” Right? Like in, in our own lives, you know, if you’re unemployed and you’re in debt and you can’t feed yourself, probably bad idea to have kids, right? And every cell and every organism has to make that decision too. And so if you think about the environment, what are the important factors in the environment that help inform, is this a good time to reproduce? Temperature, if you’re an oxygen-consuming organism, oxygen levels, and food. And mTOR senses all of those things. It’s probably most adept at sensing nutrient levels. And so when there’s lots of food around That’s a pretty good time to have kids ‘cause you can feed them, they can grow, and they can develop. If there’s not very much food around, it’s a probably a bad idea to reproduce. And so when there’s lots of food around, mTOR activity gets turned up. That’s a signal for the cell to divide, for the organism to grow and get bigger and become sexually mature. When there’s not very much food around, mTOR gets turned down. That shuts down that growth and reproduction process and turns up stress resistance. And so one of the things that’s been observed is that when we turn mTOR down and we go into this low, slower growth, higher stress resistance state, aging is slowed and organisms live longer and, and again, seem to, to, to age biologically at a slower rate. Okay. So rapamycin is a drug that specifically turns down mTOR. And so one thing I wanna say, mTOR is not an on-off switch. Think of it like a volume dial. Rapamycin doesn’t turn off mTOR. You need mTOR to live, but it turns it down, and it kinda tricks the cell or the organism into thinking there’s less food around. That slows growth and reproduction, reduces hypertrophic signals, increases stress resistance, seems to slow aging. Okay. So now let’s talk about rapamycin. Rapamycin, as you mentioned, super interesting backstory. It was discovered on Easter Island as part of an expedition there to take soil samples. So Easter Island is, of course, also Rapa Nui. That’s where the drug gets its name from. And the reason the expedition went there was because it had been observed that natives on the island went barefoot typically and didn’t get tetanus. And so people thought there might be something in the soil that would be effective at preventing tetanus. So they went and they got soil samples, brought it back to the, to the lab, I, It was either Canada or the United States, and started studying it. And it was found that there were bacteria in the soil called Streptomyces hygroscopicus that produced this molecule, rapamycin. And they found that if they put rapamycin on cells, it would cause the cells to stop dividing. Nobody knew about mTOR yet. As you, as you might be able to, to reason, mTOR was actually named after the drug, so they used the drug to find mTOR and understand mTOR biology. But they could see that they put it on cells, cells would slow down, their cell division eventually stopped. So people got excited. They thought, “Hey, maybe this would be a potent antifungal,” or, “Maybe this would be a great anticancer drug,” and started studying it in that context. It ended up being clinically developed as an immune suppressant, and so that’s the pathway it went down for FDA approval. And I’ve left out a bunch of really interesting steps here. People should go check out the, the story of rapamycin, my- rapamycin. This guy, Suresh Sehgal, the scientist involved, who when the pharmaceutical company shut down the research, he, like, took it home and hid it in his freezer and brought it across the border. And it’s a cool story. Go, go look it up. But- Yeah … through a series of twists and turns It ended up getting FDA approval for organ transplant rejection, kidney transplant rejection, and that’s how it became clinically used. And so the good news there, and this was, I don’t know, 20 plus years ago, 25, 30 years ago now. So the good news is we know a lot about rapamycin use in humans because it’s been FDA approved for so long. The bad news is it was developed as an immune suppressant, and that’s the way it has been used clinically, and there it’s a very, you know, sick patient population in many cases. It’s used at very high doses that will in fact have a, have a blunting effect on immune function. So people are very concerned about the side effects of rapamycin in that context. It’s also used in combination with other strong immune suppressants. So we don’t actually know a lot from that human clinical literature about rapamycin monotherapy by itself at, at lower doses. We’re starting to get that information.
[01:37:17 –> 01:37:46] Dr. Ravi Kumar: Okay. But we don’t have very much good data on that. Okay. So why do we think rapamycin’s important for aging? How did that evolve? And this is, again, I, I’m very fortunate. I’ve been lucky in my career a few times to be in the right place at the right time. So between like 2003 and 2005, four different labs independently working in three different organisms sort of converged on mTOR, not rapamycin the molecule, but mTOR the protein or the gene as a regulator of aging biology.
[01:37:46 –> 01:42:01] Matt Kaeberlein: I was working with, with Brian Kennedy at the time, and we were doing a genome-wide screen for genes that affected lifespan, and we happened luckily to land on mTOR. And, you know, so it was lucky. I wish I could say I was smart enough to be like, “Oh yeah, mTOR is gonna be really important. We should go study that.” But we were at least smart enough to do the unbiased screen and say, “We need to figure out what’s out there.” So we hit mTOR. We found that if we turned down mTOR genetically, we could increase lifespan. I immediately went to the literature. I didn’t know anything about rapamycin at this point, but I found out there was this drug, rapamycin, that’s an inhibitor of mTOR. We were turning down mTOR genetically. It made sense that the drug might have the same effect on lifespan, which we then published in 2006. So that was the first study showing that rapamycin could increase lifespan in any organism. This was actually in, in budding yeast, believe it or not. But the cool thing was, as I said, three other labs at the same time we were finding mTOR in yeast found that genetically turning down mTOR in worms or in flies also increased lifespan. And so that was something that I think, you know, those of us who think about biology through the lens of evolutionary conservation, we realize this is interesting. This suggests that mTOR across two billion years of evolution has been functioning to regulate the rate of aging. And that doesn’t prove it’s going to be the same in mice or in people, but there’s a pretty good bet that it’s going to be sh- that function is going to be shared even further into the, when we go up in more complexity in the evolutionary tree. So then in 2009, the Interventions Testing Program, which we, we touched on briefly, which is this NIH-funded program to test interventions for lifespan in mice, showed that you could increase lifespan with rapamycin in mice. And I think that was the turning point where people really believed, okay, we’ve gone from yeast to worms to flies. Now we’re in a mammal, and this drug increases lifespan in a mammal. We need to start paying attention to this. Um, the other thing about that ITP study that’s worth mentioning is by a happy accident, they, um, they weren’t able to actually formulate the rapamycin in a way that it had bioavailability, uh, until the mice were 20 months old. So the mice didn’t actually start getting the drug. This wasn’t d- by design. It was, it was by accident. Um, they didn’t actually start getting the drug until they were middle-aged, uh, about the mouse equivalent of a 60, 65-year-old person. Um, but it still increased lifespan pretty robustly in both males and females. And that I think was a paradigm shifting moment, it, now that we look back, for the field because that was really the first demonstration that you could have a big impact on lifespan Starting in middle age. Before that- Yeah … with the caloric restriction studies, the dogma was sort of you had to start early to get the full benefit. Now we know from studies of other interventions through the ITP and other, other investigators that it is possible to start the treatment in a middle-aged animal, still see robust effects on lifespan and multiple healthspan metrics. And so that, that was 2009. Rapamycin since then has been tested in dozens of labs. It always increases lifespan to the best of my knowledge. Highly reproducible. The biggest effects we’ve ever gotten from a drug on lifespan in preclinical studies come from rapamycin, about a 30% increase in, in mean lifespan. You can start treatment in middle age, as I alluded to. Seems to slow the progression of functional decline and molecular changes associated with aging in every tissue and organ where it’s ever been looked at in mice. And in at least some cases, you can reverse the functional declines that have happened during aging. So this is best demonstrated in the heart, the immune system, the ovary, and the oral cavity. You can take old mice where there’s already been significant declines in function, significant pathology. You can start treatment with rapamycin, and within between six and 10 weeks, see partial or full reversal of these functional declines back to a, a youthful state. So that’s highly encouraging from a translational perspective- Yeah … because it’s much easier to think about doing clinical trials if you can take a functional endpoint. You’re not gonna do lifespan in people, but you can take a functional endpoint where there’s age-related decline, and you can show an improvement.
[01:42:01 –> 01:42:18] Dr. Ravi Kumar: Right. So talking about mTOR, which stands for mammalian target of rapamycin, correct? Yeah. It actually now stands for mechanistic target of rapamycin. Oh, mechanistic. And, and we changed, we changed the M- Okay … because mTOR is present in yeast and worms and flies, which are not mammals. So we felt like- They’re not mammals, exactly
[01:42:18 –> 02:10:37] Matt Kaeberlein: we wanted to be, you know, we wanted to have appropriate recognition for the diversity of life- And keep, and keep the acronym at the same time, right? You didn’t want to change the acronym, so. That’s right. Okay, so mTOR is basically like this sensor, and y- I like how you describe it as a dial. It goes up, which spurs growth and cell division, and it goes down, which spurs basically kind of like a saving on energy resources and recycling of and repair- Yeah of the structures and machines that are there. If you’re treating an animal with rapamycin, wouldn’t they start to… I mean, if you’re completely catabolic, which is the opposite of anabolic, isn’t that a less healthy state? I mean, ‘cause people are constantly trying to, hey, they want to take growth hormone, they want to take TRT because they don’t want their body to be in a catabolic state. They want to be robust and- Right … have good integrity to their tissues. How is rapamycin playing a role in that? ‘Cause it sounds like it would be taking you in the opposite direction. Yeah. So, so it’s a complicated question, and I mean, I think the fair answer is we don’t completely understand all, all of the nuance here. Okay. But a, a few things seem pretty well established. So one is you don’t wanna be always catabolic. You’re gonna get cancer, you’re gonna get hypertrophy, you know- Yeah … which isn’t great in the heart, for example, right? Yeah. So you don’t wanna always be catabolic all the time everywhere. You don’t always wanna be anabolic or, sorry, I had that around, I had that backwards. You wanna always wanna be anabolic everywhere all the time everywhere, or catabolic all the time- Right … everywhere, right? You wanna have appropriate balance between new synthesis growth and repair and recycling. And- Right … that’s partly why I s- I made the point TOR is not an on/off switch. TOR activity is going up and down throughout the day, um, in response to when you eat a meal. It’s going up and down in different tissues in a sort of continuous manner. One of the things that seems to be the case, though, is that with age, there becomes an imbalance between TOR activity and some of the downstream processes that TOR regulates. So we see a gradual increase in TOR activity, not everywhere with age, and again, this is best established in mice. It’s harder to do in people. In m- in several tissues and organs, there seems to be an age-related increase in TOR activity that does not m-match the downstream consequences on protein synthesis- Right … inflammatory state, things like that. So there seems to be a dysregulation between TOR activity and how it’s interacting in this overall network of- Okay longevity factors. Yeah, ‘cause the phenotype of an old person is like they’re cachectic, right? They’re, they’re lower muscle mass, and they’re not- Yeah … as robust. And often, often resistant to signals that would turn up TOR, like- Yeah … eating protein, right? Yeah. So that’s exactly the idea is that TOR is no longer appropriately sensing and responding to the signals that it would respond to in a youthful state. Okay. And so the other piece of information that I think is useful here is sometimes you just y, So, so what you said is absolutely right. We would expect if you took a high dose of rapamycin, you would lose muscle, you would loon, lose bone density ‘cause mTOR is required for muscle synthesis. That’s exactly what people thought would be the case in mice with rapamycin. People were like, “Well, this is, this will never work ‘cause you’re gonna induce sarcopenia and muscle loss.” Sometimes you just gotta do the experiment. Yeah. The experiment’s been done. Mice on, and rats on rapamycin actually preserve muscle mass with age. They do. So I think it’s more about the dose is really important. I absolutely believe if we gave a high enough dose of rapamycin, we would induce muscle loss, we would induce immune suppression to the point where cancer would take over If you push it hard enough, you will absolutely cause problems. That’s true with almost any drug. But also it can be the case that a low dose of rapamycin or an appropriately timed inhibition of mTOR may be cyclical, can reset that mTOR balance, can reset the chronic inflammatory state, and that will then allow the normal functioning of tissues and cells once you have brought down that, that chronic inflammation, maybe transiently induced autophagy to break down misfolded proteins, other damaged macromolecules in the cell. It’s kinda like the conceptual idea behind intermittent fasting. You transiently turn up these processes, clean up the cell, reduce inflammation, and then you can sort of reset. Right. And then for a while, the system will function more like it’s supposed to. So that’s pretty speculative. Again, the data we’ve got is that in mice, in rats, very consistently across a pretty wide dose range, rapamycin increases lifespan, seems to slow many if not all of the- Yeah functional declines and molecular changes that go along with aging In people, there’s directional evidence, but certainly nothing that I would say rises to the level where I’m confident that I can say rapamycin slows aging in people and we know how to use it effectively in that regard. So what data do we have in human beings for rapamycin? Yeah. So it’s messy, it’s incomplete, it’s unsatisfactory. There have been a few randomized clinical trials. That’s obviously the gold standard. That’s what we would like to see are large randomized clinical trials. There haven’t been very many. The, the best clinical trials that I’m aware of that we have for rapamycin were done by a scientist clinician known as Joan Mannick, fantastic scientist. She did this work, this was in like 2014, 2018, testing a derivative of rapamycin called everolimus, so it’s what’s called a rapalog. I think for this conversation we can think of them as, as identical molecules. Biochemically- Okay … they’re identical, slightly different pharmacokinetics and tissue distribution. So she was testing everolimus in healthy older people looking at immune function, and this was based off of mouse work from Pan Zheng’s lab at Michigan, where they had shown in mice six weeks treatment with rapamycin could completely restore the ability of the aged mouse immune system to respond to a flu vaccine- Hmm and protect mice against influenza. So Joan was asking whether the same thing might be true in people. So they enrolled healthy older adults, 65 to 85, gave them a six-week course of everolimus. They tested three different doses. They had a placebo. And what they were able to show was that indeed you got better, uh, antibody titers after the vaccine in the people who’d seen everolimus. It seemed to work in all the dosing protocols that they used, but they got the best efficacy to side effect ratio at five milligrams once a week. And in fact, in that group, the side effects were, were statistically no different from placebo. So- Okay … a couple things, and these were, you know, there were a few hundred people in the study. It was a reasonably sized clinical trial. They went on and did an additional clinical trial, and they showed that not only do you get better vaccine response, you have better, uh, lower lab-laboratory confirmed infections over the next season. So it seems to not only enhance antibody titers, but provide some degree of functional benefit. Okay. Yeah. That’s the best data. There are lower quality data sets, often from off-label use Suggesting benefits primarily, I would say, for autoimmune disorders. A whole bunch of case reports for different types of autoimmune disorders. Some evidence for chronic fatigue syndrome. This is actually pretty interesting. So probably two-thirds to three-quarters of chronic fatigue syndrome can be at least correlated to, uh, a recent, uh, strong viral infection. So the idea is kinda like long COVID. Often it’s Epstein-Barr, but other viruses as well. The idea is you have a very severe viral infection. There is persistent either viral replication or viral antigens that are driving a chronic inflammatory state that contributes to the chronic fatigue. A pretty compelling study last year showing that something like three-quarters of chronic fatigue syndrome patients had a robust positive response to rapamycin six milligrams once a week. So that fits with the autoimmune data. Some intriguing early data for cerebral blood flow and brain volume changes in people who are APOE4 carriers on rapamycin therapy. Some mixed data, I would say, on muscle mass and response to exercise, and that might actually be worth diving into ‘cause there was a recent, um, clinical trial that Bran Stad- Brad Stanfield funded. But I would say there the data’s unclear, right? Yeah. Whether rapamycin has a positive benefect- benefit on body composition or might slightly attenuate the increase in muscle mass in people who start an ex- so in untrained people who start an exercise regimen. Both things can be true, by the way. Yeah. We might expect that rapamycin would slow muscle gain in untrained people because we know that mTOR activation is required for building new muscle. That is not inconsistent with the idea that in the context of aging, rapamycin might have beneficial effects on muscle mass or even muscle loss. We just don’t have a ton of data- Right … in humans there. And then the other place that I find pretty interesting, there are two other areas in humans where it’s very early, but the data that I know about are intriguing. One is ovarian function. So there’s one study out of, uh, a lab in China reporting that in women who were having trouble conceiving and were doing in vitro fertilization because of early ovarian failure, you could actually improve pregnancy rates. Small study. Wow. Again, not to the level that we would want for, you know, strong conclusions. Mm-hmm. But interesting because it very much parallels what’s been seen in mice with actually reversal of ovarian failure if you start the rapamycin treatment- Wow … early enough in the female mouse lifespan. This is late life ovarian failure, so they’re, they’re heading towards menopause, and it’s… Yeah. So in mice, yes, although mice don’t get a true menopause, but, but you can think of it the same way. Yeah. Yeah. It’s, it’s ovarian failure associated with normal aging. I’ll put it that way. Okay. Yeah. The human data we’ve got, as far as I know, have all been in women who experience early ovarian failure, not like typical menopause. Now, presumably it’s underlying biological similarities, but I just don’t think we have data yet in people. There’s a clinical trial, um, that’s been completed. Again, pretty small, but it’s a well-designed trial out of Columbia. Yuxin Su and Zev Williams are running that, looking at premature ovarian failure in women and asking whether or not rapamycin, I think it was a 13-week treatment in that study, can attenuate biomarkers of ovarian failure. I don’t think they had any functional measures. Okay. So that study’s completed. I know what the data is, but I can’t tell you because Yuxin asked me not to, so- Okay … sorry. Um, but I, you know, I’m, I’m, I’m smiling, so yeah. It’ll be great to see when that data gets released. Um, and then, and then, uh, we did a study in my lab. This was work that Jonathan Ahn did when he was a graduate student with me. Jon’s a, a DDS PhD, so a dentist PhD. Um, he showed that mice during normal aging develop periodontal disease, and we could reverse three clinically defining features of periodontal disease in aged mice by starting treatment with rapamycin. We could reduce gingival inflammation, which makes sense. We could actually reverse bone loss around the teeth, which is pretty interesting. And then we could see the, the pathological changes in the oral microbiome revert back to something that looked more like a youthful microbiome composition. So Jon has been carrying on that work in people. He’s doing a clinical trial now. Again, it’s very early. He was required by FDA to do a dose escalation, so he had to start with low doses of rapamycin and is building up. But the anecdotal case reports for periodontal disease and off-label use are pretty compelling. Jon has published some of that, and the early data from his clinical trials also seems very compelling. I think periodontal disease or even normal age-related changes in the oral cavity may be a really useful clinical endpoint to evaluate rapamycin because it’s so non-invasive. Yeah. And it’s pretty prevalent. Like, almost everybody shows detrimental changes in their oral health with age. So I’m, I’m enthusiastic about rapamycin in that context as well. Yeah. Well, that’s very cool. So it sounds like rapamycin has very reproducible effects in animal models. We’re just starting to test it in human beings, and we still don’t know. We see some signs that there are beneficial effects in different organ systems with basically functional declines or structural declines that are associated with aging, but we still don’t have the big picture. There, there have been, uh, safety studies done, right? And we know it’s safe. Well, so first of all, by definition, it’s FDA approved. So I mean, some people would argue it’s safe. Yeah. Doesn’t mean it doesn’t have side effects, just means we know what the side effects are, and we know how to use it for a specific indication with an appropriate risk-benefit analysis. Having said that, so here’s m- here’s my take. Uh, uh, so we collected data on three hundred and thirty-three people who’d been using rapamycin off-label. Again, off-label means prescribed by a physician for something other than what it’s FDA approved for. Right. Um, so these are not people buying it, you know, from off the internet from, from some random source. Sure. Which unfortunately has become prevalent in the wellness space these days. That’s a different conversation. So these are people using rapamycin off-label. We compared them to a hundred and fifty or so people who’d never used rapamycin. So again, not to the level of a randomized clinical trial. We did the best we could based on survey data and, and medical reports, right? But one of the interesting things was we asked people, you know, in the last, uh, I wanna say it was three months, in the last three months, have you experienced X? And X was a long list of forty or fifty potential side effects that we thought might be caused by rapamycin or that are common among different types of prescription medication. There was only one that was statistically more prevalent in the people using rapamycin off-label, and that was mouth sores. This is a well-known side effect in organ transplant patients. In organ transplant patients, these are pretty typically severe aphthous ulcers inside the mouth. Yeah. So not fun. In the people using rapamycin off-label, I’m not suggesting it was fun, but these are more like what we would mostly think of as a normal canker sore. About 15% of people will get canker sores taking rapamycin off-label. Usually, the off-label dose is six milligrams once a week. There’s some variation around that, but that’s the most common dose. Outside of that, nothing that was statistically more prevalent in the rapamycin users compared to the non-users. There were five other things that were different, but they were all lower in the rapamycin users. So I’m not gonna try to claim those are benefits of rapamycin. Right. But again, interesting potential signal. The other thing that, that I did find, I believe it’s real, because of the timing of this study, this was 2023 that we did the study, lots of people had been taking rapamycin during the pandemic who were in our study. And so we were able to ask the question, was there any difference in likelihood of developing a COVID-19 infection, of being diagnosed, or in the likelihood of, of severity of outcome, or in the likelihood of long COVID? So no difference in likelihood of being diagnosed. The numbers were right on top of each other. Okay. So rapamycin does not seem to impact your likelihood of getting a viral infection if you are exposed. That’s actually what we would expect for rapamycin. Yeah. But the likelihood of developing a moderate or severe infection was lower statistically in the- Hmm … the group who’d been taking rapamycin versus those who had never taken rapamycin. And then it was a tiny N, but the likelihood of developing symptoms consistent with long COVID was also lower in the- Hmm … rapamycin users versus the non-users. This matches up with, with what we understand about rapamycin’s effects on chronic inflammation, also fits very well with the idea and the data that rapamycin and rapalogs boost antiviral gene expression, and it fits very well with the data I was talking about with chronic fas- fatigue syndrome post-viral infection. Yeah. So I do think that’s a real signal. So kind of where I’m at is I’m pretty confident that rapamycin, using these kinds of off-label dosing strategies that we’re talking about, six milligrams once a week ballpark, can have beneficial effects for a subset of people By and large, right now, these are people who have a high burden of chronic inflammation, and that’s leading to symptoms, you know, that they perceive as impacting their quality of life. Yeah. Outside of that, I’m intrigued by the periodontal data. I’m intrigued by the data for cerebral blood flow and brain volume, but I, it’s early, and I want to see more data before I really- Sure … feel comfortable saying I think that’s likely to be real. Again, this always comes back at the individual level to a risk-reward calculation, right? Yeah. So, you know, for an individual, if you’re in good health and you’re working hard to maintain your body composition, rapamycin’s probably not something you wanna, you wanna play around with. Like, maybe it is, but there’s no great reason to do that if you’re in, if you’re in really good health and you don’t have a lot of inflammation, especially if you’re in your twenties or thirties, right? Yeah. If you’re an APOE4 heterozygote and you’ve got some biomarkers that are concerning for dementia or even if you’re just concerned about dementia, like, I’m not gonna say don’t use rapamycin. Yeah. I probably would if I was in that boat. In fact, I have used rapamycin, so… But I mean, all this is all just say it, it comes down to the individual, given the data that we’ve got, what we think we know about the drug, what we think we know about the side effects, doing this, this informed risk-reward analysis, hopefully in consultation with a doc who is knowledgeable in the space. That’s the way I think we need to approach things like rapamycin or even off-label use of SGLT2 inhibitors or PCSK9 inhibitors or PDE5 inhibitors, right? All of the drugs where there’s some reason to believe that for certain people, they may be effective in a proactive sense as opposed to- Right … waiting until you’ve got, got a, a chronic disease. Yeah. Yeah, it’s als- all about that risk-benefit ratio. I mean, you gotta now analyze it. You need someone to help you, especially if you’re not a healthcare provider. But yeah, I, I think that’s reasonable, especially with the low risk profile of, um, rapamycin. Okay, so you’re using this, uh, based on what you’ve told us so far, you’re using this generally once a week. It’s almost like you’re going in, cleaning house, and then going back to normal metabolism throughout the rest of the week. Is that the strategy? Yeah. So, so again, I have to say this, this has evolved due to sort of cultural forces and a lack of, uh, a lot of data comparing different dosing strategies. So I mentioned Joan Mannick’s study where they found that five milligrams once a week for that specific, you know, response to a flu vaccine gave the best efficacy to, to, to side effect ratio. That’s probably the best data supporting this five to six milligrams once a week. Um, there’s a biochemical hypothesis that also supports that rationale. We know that in cells at least, if you treat with high doses of rapamycin chronically… So, so we didn’t get into mTOR complex I and mTOR complex II, but there are two mTOR complexes, mTOR complex I and mTOR complex II. For longevity, inhibiting mTOR complex I seems to be where most of the action’s at. You can genetically turn down mTOR complex I and increase lifespan. Inhibiting mTOR complex II is often associated with not so favorable outcomes, including dysregulation of glucose homeostasis being one of them. If you take rapamycin, rapamycin is a specific inhibitor of mTOR complex I biochemically. It has what’s called an allosteric mechanism of action. It binds a protein called FKBP12, and that complex of rapamycin and FKBP12 goes and disrupts mTOR complex I. It doesn’t touch mTOR complex II. Okay. So rapamycin biochemically is very, very clean, very specific for mTOR complex I. But it turns out if you have mTOR complex I low for long enough That will lead to off-target effects on mTOR complex 2. And so a hypothesis was proposed by Dudley Lamming and, and David Sabatini based on some mouse data. I’m not gonna suggest there isn’t any data to support this. There was a hypothesis proposed that the side effects of rapamycin that are seen in organ transplant patients, particularly the dysregulation of glucose metabolism and hyperlipidemia, are driven by off-target effects on mTOR complex 2. And that then was extrapolated to suggest that if you take a high dose of rapamycin, you get a big peak in, in blood and cells, that very acutely effective at inhibiting mTOR complex 1, but then you don’t take the next dose for a week, that allows the trough levels to bottom out, so you go back to zero, and that won’t have the effects on mTOR complex 2. So that’s why I say it’s a hypothesis. That piece hasn’t really been established. Okay. But that’s one of the rationales you will hear for why once-weekly dosing will have, in theory, a better efficacy to side effect ratio. Okay. Then the last piece here, which is just kind of the, the cultural piece I was talking about, there was a doctor in Long Island, New York, named Alan Green, Alan unfortunately passed away last year, who was really the first doctor to go public and start talking about prescribing rapamycin, and, and he was very much a believer that that off-label use of rapamycin would have lots of benefits for lots of people. He used it, basically reversed his hypertrophic cardiomyopathy. Uh, at least that’s what he describes, and I believe that because there’s very good evidence in mice and cats and some in people that rapamycin is effective at, at reversing at least the hypertrophic aspects of hypertrophic cardiomyopathy. So he used it for that But he became convinced that it had positive effects on biological aging in people. And so he started prescribing it to a large number of patients, and he settled on six milligrams once a week. That was just like Alan’s dose. Mm-hmm. And so it just kind of became established in the off-label world, and I’m sure you’re familiar with this. Like, a lot of the ways these experimental therapies become propagated is by doctors talking to each other or patients talking to each other. And because we don’t have the clinical trials saying that six milligrams once a week is better than three milligrams once a week or twenty milligrams every two weeks or one milligram a day- Mm-hmm it just sort of becomes the established go-to protocol. So I don’t know if it’s the best protocol. I honestly don’t know. I have no idea I mean, he was doing it once a week, right? That’s seven days. What if a week was ten days? You know what I mean? We do it once every ten days. And so, yeah, that’s- It’s convenient. It’s a convenient, yeah, way to do it, but I agree. Yeah. That’s how human beings work. You know, they- All I can say is, you know, you do bottom out the trough levels. Most people are bottomed out at six milligrams by day three. Okay. Which I think you can assume that by seven days in your cells, you’re gonna, you’re gonna bottom out. So you probably are avoiding the off-target effects on mTOR complex 2, if those were gonna be prevalent at a one milligram a day dose or not. But- Okay … here’s, here’s also my speculation. I think optimal dosing is going to depend on the indication that you are using it for. I’m, I’m confident in saying a single dose of rapamycin has different effects on mTOR in different tissues. And so if your goal is to prevent Alzheimer’s disease, you might need a higher dose of rapamycin or a more continuous dose of rapamycin to get sufficient penetration of the blood-brain barrier and inhibition of mTOR in the brain than you need if your goal is to reverse periodontal disease. We just don’t have the data yet to really know. Right. Okay. Well, what about people who are… You know, obviously, mTOR is spurring the cleanup cycle once a week based on this, you know, this dosing protocol that people are using. What about people who are using TRT or HRT to try to maintain youthful hormone levels and spur anabolism, which is a problem when you get older in life. You, you get sarcopenic. You lose muscle mass. We want to keep it. It’s, it’s a signal of optimal health and, and longevity. So how do those two work together? Can people be on TRT or HRT and rapamycin at the same time? You absolutely can, and I don’t, I don’t think that they’re mutually exclusive. I mean, again- Okay I think the goal of rapamycin in the context of aging, and again, I don’t know if rapamycin is going to slow aging, but the goal is to blunt chronic inflammation and restore immune homeostasis and mTOR homeostasis. It’s not to prevent new muscle synthesis, right? It’s not to prevent anabolic activity. So this is where the dose and the protocol really become important. I don’t see using TRT and rapamycin, though, as counteracting each other. Okay. Testosterone does a lot of stuff outside of mTOR, right? If you’re using once weekly rapamycin or if you’re doing what a lot of people do, which is cycle rapamycin, so do once weekly rapamycin say for 12 weeks and then take three months or six months off, probably you’re gonna stay on testosterone continuously. So, so I don’t see any reason why, why you can’t do both. Again, I think you want to be clear why you’re using each of those and follow the biomarkers as best you can- Yeah … to make sure that you’re not having a counterproductive effect. And I would say that’s true for any combination of things that you’re doing, right? We don’t know what the combinatorial interactions are gonna be between a lot of different pharmaceutical medications. You put supplements on top of that. So you have to be kind of be guided by are you seeing the, the changes in your blood-based biomarkers, your body composition, the way you feel to help you understand whether these things are, are working for you, right? Yeah. And so, you know, with the case of testosterone and, and rapamycin specifically, you know, I think if you’re on testosterone therapy and you have a lot of chronic inflammation and you take both and you see your inflammatory markers go down and you see your muscle mass continue to go up and you feel real good, great. Don’t mess with it. Yeah. Right. Um, but if you’re seeing evidence that your, the rapamycin isn’t effective, isn’t improving your inflammatory state or you feel like crap, right? Either you need to do something about your testosterone therapy or you need to do something about your rapamycin. Try different things until you get it, until you get it dialed in. Yeah. And, and again, I sh- I should also say like I don’t think of rapamycin and, and testosterone or hormone therapy for women equivalently. Like Hormone therapy is one of the biggest levers outside of lifestyle that, that, that many people can pull, right? Yeah. I have no doubt that when done well, that has a huge impact on quality of life. I don’t know if it’s slowing aging. I think you can make a case on women that, that hormone therapy probably is slowing aspects of biological aging. Mm-hmm. But for quality of life and health span, it can have a huge impact. Yeah. Whereas rapamycin and, I, you know, as you can tell, I’m a lot less confident in saying that this is gonna be a big lever that a lot of people can pull. Yeah. I think it can be beneficial for some people, but it’s still not anywhere near as established as, as we would like it to be. Yeah. Yeah, for sure. No, I mean, I think especially for HRT, I mean, women are, uh, essentially lose their hormones at one point in life, and they’re, In our body, all our tissues are hormonally active. They, they have hormone receptors. They, you know, the, the nucleus with all our genetic information is dependent on it, and losing that hormonal signal leads to deterioration in connective tissue and brain health and all sorts of, and vascular health. And so, yeah, uh, we’ve been scared for years about HRT. It’s coming back. People are being educated properly on it. The science is clearer now. So yeah, I think it’s very important, and I, I, I’m very happy to hear that rapamycin and hormone replacement therapy doesn’t, uh, contradict each other. I know many people who are doing both successfully. Yeah. Okay, cool. I’ll just leave it at that. Okay, so let’s talk about this dog aging project with- through the Dog Aging Institute. Yes, it’s on your T-shirt, and I, I think this is fantastic. It was, It’s actually such a good idea, honestly. That’s the first thing I thought when I read about it, is that here we’ve got these companion animals that age quicker than us, seven times faster than us. They live in our home. Sometimes they eat our food. They’re exposed to the same environmental conditions and toxins and all these other things that we are exposed to. They often get the same amount of activity as we do ‘cause they go with us when we’re active. You’re basically dosing or allowing people to dose their dogs with rapamycin to see if there’s an effect on longevity.
[02:10:37 –> 02:10:54] Dr. Ravi Kumar: What are you finding? Yeah. So first of all, let me, let me describe the Dog Aging Project at a higher level, right? So again, the way you described it is accurate in terms of like, why would we even think that studying aging in dogs is something worth doing, outside of the fact that people love their dogs, and if we can make dogs live longer, that’s great.
[02:10:54 –> 02:21:36] Matt Kaeberlein: I’m a dog person, so, so I fully align with that. But because they age more rapidly, they share our environment, they’ve got a very unique genetic architecture with, with pure breeds and, and mixed breeds. Those from a scientific perspective, uh, make them quite a powerful animal in which to actually study aging in the real world, right? In the laboratory, you know, we try to control the environment as much as we can, but humans, of course, live in this complicated, constantly changing, dynamic world, and dogs share that. So we decided to set up the Dog Aging Project with really two goals, right? So one of them you talked about. This is the, can we do something to slow down aging in dogs? And that’s the rapamycin clinical trial, which I’ll, I’ll talk about in a minute. But the other goal is, can we learn as much as possible about the genetic and environmental factors and how they interact in this rapidly aging animal that is socially relevant, that shares our environment, and how would we go about doing that? And so most of the Dog Aging Project from, like, the number of animals participating is that observational piece, learning as much as we can about genetics and environmental and how these factors influence health outcomes and longevity. And so we have about fifty-four thousand dogs and their owners participating in this very large open science community science project where we’re just collecting data. We’re not asking the owners to do anything different besides, you know, tell us about your dog, take a kit to your veterinarian, collect blood, collect fur, and send it to us, and we’ll do the, the molecular analyses. And so that’s been very powerful, you know, 100 plus papers published by this point, huge data set that is publicly available, so anybody in the academic or nonprofit community can get access to that data. And then there’s the clinical trial. I just want to make the point that there’s a lot more to the Dog Aging Project than rapamycin, right? Yeah. Thank you for saying that. I’m passionate about the rapamycin clinical trial, but it is a huge, very, very impactful project just from what we’re learning about aging biology. The rapamycin clinical trial is a dedicated, randomized, placebo-controlled veterinary clinical trial with the goal of answering the question, does rapamycin slow aging in companion dogs, in, in pet dogs? And so we’ve done two short term trials. One was 10 weeks, one was six months. Those were primarily safety trials. Again, you sort of have to approach a clinical trial of an experimental drug in people’s dogs the way you would a pediatric clinical trial. People feel very similarly about their dogs and their children. So safety’s got to be like the number one thing you think about. And again, I’m a dog person. I would have been devastated if we killed somebody’s dog. So- Yeah … we wanted to be very careful. We were lucky in that there were veterinary groups studying rapamycin for cancer at the time that I was starting to envision this clinical trial. And they shared with us their side effect data, their dosing, so we could go into this being pretty confident that we could start with a dose that seemed to have a hint of efficacy for cancer with a, with a favorable side effect profile. So we did a 10-week study. That was successful. We didn’t see any side effects. Again, everything’s randomized, placebo-controlled, actually triple blind if you count the dogs. So the vets don’t know, the owners don’t know, the dogs presumably don’t know if they’re getting placebo or rapamycin. So no, no side effect signal. We had some evidence, actually statistically significant evidence for improvements in left ventricular function by echocardiogram. This is normal aging. These weren’t dogs that had heart disease. And then owner reported improvements in activity and quality of, of life. And again, the owners were blinded. That, we got the same signals, a little bit different by echo, but also some evidence for improvements in some of the echo parameters, and then owner reported activity and quality of life in the second trial, which was six months. That was at Texas A&M. So that gave us confidence to be able to start on the current clinical trial. It also allowed us to get enough preliminary data that we could finally get an NIH grant to support this work. So the current clinical trial is called TRIAD, Test of Rapamycin in Aging Dogs. It’s actively enrolling. We’re about half enrolled. Once it’s completely enrolled, it’ll be 580 dogs, half rapamycin, half placebo. It’s a one-year treatment, two-year follow-up. And so that, that number of dogs combined with the entrance criteria, so the dogs have to be at least seven years old and between 40 and 110 pounds in weight, ‘cause big dogs are aging faster than small dogs. That age weight range, that number of dogs, that follow-up period, we believe gives us statistical power to detect a 9% change in lifespan, which is towards the low end of what’s been seen from rapamycin in mice. So the goal, the, the primary endpoint of this clinical trial is lifespan, and the goal is to ask the, answer the question, does rapamycin increase lifespan in dogs? Now, of course, we’re interested in healthspan. We’ve got multiple secondary endpoints looking at cognitive function, heart function, neurological function, cancer, kidney disease, activity. Um, and then we have exploratory endpoints looking at metabolome, epigenome, microbiome. So So it’s a lifespan study with the goal of also assessing does rapamycin improve health span in dogs? As I said, it’s ongoing. If people are interested and your dog, you know, fits that age weight range, I would absolutely encourage you to nominate your dog to participate, www.dogagingproject.org. If you’re not interested in the rapamycin clinical trial or your dog isn’t the right age weight category, you can still p- participate in the project in the observational part, contribute to, you know, longevity science that has the potential to improve quality and quantity of life for people and our companion animals. Yeah, no, that’s really cool. I mean, it’s just such a fantastic idea, and I’m, I’m gonna see if I can enroll my two dogs now that you, they talk about- Absolutely should. Yeah. I guarantee you, you can. Yeah. So, okay. Well, very cool. I think you already answered this, but do you take rapamycin? I cycle rapamycin, yeah. So I’m not on- Okay … I’m not on rapamycin right now. What I’ve typically done is three months on, and then anywhere between three and six months off. Okay. And again, I’m, I’m less, maybe less scientific in my approach than most people would think, but I tend to go by how I feel. And, and again, to maybe just give some context, you know, if you’d asked me 10 years ago should people be taking rapamycin off-label, I would’ve said no. Yeah. We’re not ready. So, and I think partly the data has changed, and partly my own view has changed. This is where it sort of becomes personal and the personal risk-reward analysis. And this is where I think, and this is why I appreciate that an experimental therapy that, that may not be ready for primetime or may not be ready for widespread use, for an individual, if in their specific situation they’ve got a need and there’s a reason to believe this might work and the need is extreme enough, it can be the right call. Yeah. Um, rapamycin is pretty benign, but my experience was I started developing, um, some chronic pain in my shoulder that got worse and worse and worse. It got to the point where I couldn’t sleep. This was in my early, late, late 40s, early f- right around the time I turned 50. I was a pretty typical, you know, guy, not really paying attention to my health. I didn’t go to the doctor. I’m like, “Oh, it’ll just go away. As long as I can still lift weights, it’ll be fine.” Um, it got to the point where I, We have a park across the street from, from our house, and I went out with my younger son and tried to throw a football with him, and I couldn’t do this. I couldn’t make that motion. And, you know, I had to, I’m like, “Man, sorry, bud, I can’t throw the ball.” Um, that’s what was the, the triggering event that I’m like, “Okay, I gotta get this fixed.” And I was convinced I had a torn rotator cuff. I didn’t know why. I just… That’s what I knew was the problem. So, you know, I went to my primary care doc, and I’m like, “I g- I need to go see a specialist.” He’s like, “No, no, no, you need to go, go to physical therapy.” I’m like, “I don’t wanna go to physical therapy.” He’s like, “No, you have to go to physical therapy.” So went to physical therapy. It sucked. It didn’t make it better. It made it worse. I went back to him and I’m like, “All right. I did it your way. Now give me the referral to the specialist,” which he did, and within 15 minutes, the specialist is like, “You don’t have a torn rotator cuff. You have adhesive capsulitis.” And I’m like What is that? He’s like, “It’s called frozen shoulder and, you know, it’s more common in women than in men, but it kinda happens to people your age.” But, uh, but then he explained to me that, you know, this is a, this is chronic inflammation of the shoulder capsule. Yeah. And he says, “You know, I could give you a shot into the capsule. I don’t like to do that right off the bat because there can be, you know, negative consequences there. So I want you to go back…” He says this to me. He’s like, “I want you to go back to physical therapy and it might go away in a year.” And I’m like, “I can’t live like this for a year. I can’t throw a ball with my kid. I can’t sleep well.” Then I start thinking, you know, and we were doing the, the mouse studies on periodontal disease in my lab at this point, and I’d seen the data that, you know, six weeks of rapamycin, all the inflammatory markers go down in the gingival tissue and in the periodontal bone. And I start thinking to myself, like, this is an age-related inflammatory condition Maybe it’ll work- Mm-hmm … you know, for the shoulder capsule. And so I just created this protocol based on six milligrams once a week, and I’m like, “I’m gonna give it 12 weeks and, you know, see what happens.” And again, I was fortunate. I was in a situation where I had colleagues, medical professionals I could go to who would support me in this. Right. And all I can say is the pain went away. Like, maybe it was placebo effect. Seems really unlikely given how severe- Yeah … the pain was and how limited my range of motion was. But- What about the mobility? within 10 weeks, yeah, 95% range of motion- Wow … back and pain completely gone. Within 10 weeks? Yeah. Adhesive capsulitis is self-resolving, but it’s not without a significant amount of work. Right. So for it to, you know, just you go back to normal life without extensive physical therapy, I mean, ‘cause you’re essentially pushing through scar tissue that’s formed, that’s ad- adhesing the normally mobile and lubricated areas of the shoulder. So I mean, that’s pretty fantastic, honestly. And, and mobility, there’s no placebo for mobility, by the way. Right. Well, no, again, I mean, you know, uh, uh, what I mean by placebo’s effect is I, I absolutely believe that our brain, I mean, ev- this is sort of obvious, but our, our brain has effects systemically throughout the body, right? Yeah. And so I believe that placebo effect usually involves changes in brain chemistry that can, can have systemic anti-inflammatory effects and things like that. Sure. So it could have been that. I don’t think it was, but again, my scientist mind is like, “I can’t 100% rule it out.” We need the clinical trial for frozen shoulder to- Right show us whether rapamycin actually works. Having said that, uh, you know, it got me to where I wanted to be, s- number one, so that’s great. And, and, and I, I can’t, I can only say that’s the, that’s the only time I’ve taken rapamycin where I’m like, “Yeah, this had a big effect,” no question. Since then, my perception has been that when I’m off rapamycin for, you know, 12, 14, 16 weeks, the aches and pains in my joints, wrist and elbow especially when I lift weight, come back, and every time I take rapamycin, they go away.
[02:21:36 –> 02:21:51] Dr. Ravi Kumar: Okay. So again, could it be placebo? Maybe. But it also fits with, with chronic, chronic inflammation. Yeah, sure. So that’s kind of the way I approach it. If I start to feel that chronic joint pain coming back, then I’m like, “Okay, it’s time for a course of, of rapamycin.” Yeah. Might I get better benefits if I took it all the time?
[02:21:51 –> 02:26:26] Matt Kaeberlein: Maybe. I don’t know. That’s the world we live in. We live in a world of maybes. A world of maybes. That’s a really good way to put it. So is that rapamycin compounded by a pharmacy? Is that how…? No, I, I take, I take the… So again, this is where it gets really confusing, right? ‘Cause rapamycin, if you go to a, a medical doctor is probably gonna call it sirolimus. Same compound, different word. And then there’s a brand name generic called Rapamune. So Rapamune is the one that, you know, is gonna have the pharmacokinetics for the FDA approval. Okay. Generic sirolimus should have the same pharmacokinetics as the Rapamune, and that’s, that’s what I usually take. But then the compounding piece introduces a lot of variability and bioavailability- Okay because rapamycin is unstable at, at gastric pH in the stomach. And so if you don’t have an enteric coating on your compounded rapamycin or sirolimus, you’re gonna have maybe 20 to 25% bioavailability of the Rapamune or the t- the sirolimus tablets. Okay. So that’s just something to be aware of. And in fact, you know, I was gonna say a funny story, but it’s not really funny, related to this is there was a clinical trial called the PEARL trial that enrolled, you know, 100-plus people into this placebo-controlled randomized clinical trial, distributed clinical trial of rapamycin. They were supposed to test two doses, five milligrams once a week and 10 milligrams once a week. Turns out they did not use enteric-coated compounded rapamycin. They did use compounded rapamycin, but it wasn’t enteric-coated. So the actual dosing in that study was probably closer to one milligram a week or- Wow two and a half milligrams a week. We don’t know though, because we didn’t get the pharmacokinetic data on these people. Yeah. And the results were sort of, eh, it’s hard to tell if there’s anything real there. The one thing that looked real, at least statistically, was the women in that study, I think it was the 10 milligram a week dose, so again, guessing two and a half mgs a week, had improvements in body composition over a year. This was a year-long study, so it was actually a pretty reasonable timeframe. So more muscle mass. Can’t remember if there was lower visceral adipose, but definitely more muscle mass. So that’s a signal suggestive, right? That maybe- Two to three milligrams a week for women- Yeah … might be beneficial for body composition. Very interesting. So at a very low dose, we were seeing benefits there. So, and I know that’s the trial that everyone quotes when they say, “Hey, look, rapamycin’s safe,” but it was also, you know, at a, a much lower dose ‘cause of the absorption issues. That’s right. Yeah. Yeah. I mean, I think, I think when it comes to safety, again, I’ll just tell you sort of my feeling based on all of the data that I’ve seen. The, the real answer is, again, without the randomized, the large randomized clinical trials, we’re not gonna know what the real prevalence of, of, of side effects are or what the- Okay … side effect profile looks like. For most people at six milligrams once a week, again, that’s where we have the, the best data, like I said, 15 to 20% of people are gonna get mouth sores. Yeah. I don’t know why certain people get it. I don’t know why other people don’t. The one thing that’s interesting is many people who get the mouth sores the first time they try it, if they stop and then start again a few months later, they don’t get the mouth sores. Yeah. Okay. I wish I understood that. I don’t know what it is. Outside of that, you know, there are directional but not statistically significant signals for bacterial infection, so it wouldn’t surprise me if there’s a slight increased risk of bacterial infection. Hmm. Having said that, I’m also pretty confident that there’s a benefit when it comes to not risk of viral infection, but consequences of viral infection. So the effects on immune function are mixed- Yeah … maybe is the way to say it. The things people would be concerned about, which are like impaired insulin sensitivity and glucose homeostasis or hyperlipidemia, at the population level, they’re not there. There are probably certain individuals where you will see a, a pretty significant and dramatic increase in blood lipids. And it’s probably a genetic polymorphism we don’t understand. Hmm. We’ve seen that in one dog in all of our studies. One dog showed hyperlipidemia. Yeah. Fortunately, that’s, that’s reversible. You just come off the rapamycin it goes away in people and dogs. That’s very interesting, yeah. And in dogs, dogs don’t get vascular disease really, so it’s not even as much of an issue as it would be in, in people. But- Yeah … I would say if you are taking rapamycin off-label, get your biomarkers assessed quarterly. Mm-hmm. Right? Measure glucose, measure insulin, measure lipids, and if, if it’s perturbing those things, stop taking the rapamycin. Yeah, right. Okay. So just to review, Rapamune and Sirolimus are the generic versions of rapamycin that have the same dosing and bioavailability.
[02:26:26 –> 02:26:39] Dr. Ravi Kumar: Is that correct? They should. Okay. As long as you’re getting, as long as you’re getting quality pharmaceutical grade medicine. Yeah. Okay. And in fact, you can actually tell the, the, the tablets ‘cause they’re triangular shaped. So if you just do like a Google search for Rapamune, very characteristic triangle-shaped tablets.
[02:26:39 –> 02:26:57] Matt Kaeberlein: Okay. If you get those, that’s gonna be the stuff that’s got the, the right enteric formulation. Got it. Okay. Well, this has been an amazing conversation. Honestly, Dr. Kaeberlein, you are a fount of knowledge on this, and it’s… I mean, I learned so much today just in our conversation. Yeah. Believe me, there’s a lot of stuff in here that, that, that is useless too.
[02:26:57 –> 02:27:15] Dr. Ravi Kumar: Okay. Well, that stuff’s important too, you know? How can people get ahold of you if they, or find out more about what you’re doing? Yeah. So I’m on Instagram @mkaeberlein, on LinkedIn as well @mkaeberlein, and I’ve just recently started a new podcast channel called Longevity Science- Okay … with Matt Kaeberlein.
[02:27:15 –> 02:27:33] Matt Kaeberlein: That’s YouTube @mkaeberlein, also on Spotify. So I would love it if people would check it out, and if you like the content, give me a subscribe. Yeah. I’ll definitely put all that information in the show notes. Um- Great … and I’ll start, I’ll start subscribing too. Can’t wait to hear more. Awesome. This has been great.
[02:27:33 –> 02:29:05] Dr. Ravi Kumar: I really appreciate you, and thanks for coming on the show. Thank you. It’s been a fun conversation. Okay, so I hope you enjoyed my conversation with Dr. Matt Kaeberlein. I thought it was a fantastic conversation, but I know it was a lot of information. So here’s what I want you to walk away with. Aging is not a fixed sentence. It’s biology, and biology can be moved. We may not be able to stop aging or reverse it, despite what companies with billions of dollars on the line want you to believe, but we can absolutely slow it down. And the beautiful part is the biggest levers we have cost you nothing. Eating whole foods and cutting out added sugar, moving your body with both resistance training and cardio, protecting your sleep, and connecting with other people are pillars in longevity. Dr. Kaeberlein put it simply with four words: eat, move, sleep, connect. Get those right, and you’re most of the way there. And here’s the part I loved the most. He said that the journey is the reward. You don’t do this just to get to ninety-five. You do it because you feel better right now and hopefully for many years after. So if you wanna go deeper, Dr. Kaeberlein just started his own podcast called Longevity Science with Matt Kaeberlein. Please check it out because he’s definitely one of the most honest voices in this whole space. And if you have a dog who’s at least seven years old, you can actually nominate them to be part of the Dog Aging Project at dogagingproject.org. It’s good real science, and you’d be contributing to research that could help both dogs and people live longer and healthier. I think that’s a beautiful thing. Okay, folks. So until next week, stay curious, stay skeptical, and stay healthy. Cheers.