29: The Truth About Biological Age – What Really Slows Aging with Dr. Matt Kaeberlein

This is the last interview in a three part series on longevity where we actually go very deep and we go deep with the people leading these discoveries. So I went straight to the scientists and researchers who are digging in and finding out transformational information and we're talking to them right at the source. So if you've missed the other two, you should totally tune in. Today's interview is with Dr. Matt Kaeberlein, who is the chief executive officer at Optispan Inc. An affiliate professor at the University of Washington and a co founder of the Dog Aging Project. He's deeply committed to advancing human and animal health by targeting the biological processes underlying aging and age related disease. So this is a fascinating conversation with an absolutely brilliant man. So I'm excited to dig in. Welcome to Modern Thyroid and Wellness, the podcast that explores the intricate dance between health, wellness and thyroid, unraveling the threads that weave our vitality together. I'm your host, McCall McPherson, and I'm so thrilled to guide you on this journey to optimal wellness. So I am so incredibly grateful to have this conversation. I have been following your work for a while now and am excited to share it and all of your knowledge with our listeners. So I kind of wanted to start by laying the groundwork a little bit and building the foundation that we can take people through the journey on. So I wanted you to tell me a little bit about the concept of biological aging. How does it differ from what we think of as age and give us a little, any, any foundational aspects that you think are important.

Sure. So yeah, and I, I'm glad you use that word concept. Cause I think it's important for people to understand that right now at least, biological aging really is more of a concept than something that we can measure with any level of precision. And I think again, we can talk more about what I mean by that, but conceptually I think most of us understand that different people seem to age at different rates. Certainly different animals seem to age at different rates. Dogs are a really, I think, useful example here. Everybody's sort of familiar with the idea that one human year is seven dog years. All that really means is dogs age biologically about 7 to 10 times faster than people do. And so there's this, this differentiation between chronological age, which is just passage of time, number of birthdays. If you think about your dog, your three year old poodle is that's three human years. Right. Chronologically. But your three year old poodle is biologically more like 20 or 25 in human biological agents. So that's the concept of biological aging, that there is a. An aging process that is biological in nature, meaning it is controlled by genes and environment, and that it's different in different people or different animals. And I think it's useful for people to understand that the science of studying that biology of aging has matured a lot in the last two to three decades, to the point now where we understand something about how that biology works, what the genes are that are involved. And excitingly to at least the start of how to manipulate that in the laboratory. Using medications or gene therapy to slow the biological aging process can also speed it up. Probably not very useful from a clinical perspective. We wouldn't want to do that in people, but to manipulate that biology and that the impact of doing that is very profound. I think this is the other piece here that's really important for people to appreciate. If we're successful at slowing biological aging, I guess I should say when we're successful because we can now do this in laboratory animals. We, at the same time that we increase lifespan, we slow the onset and progression of pretty much every age related functional decline and disease at the same time. And that's sort of obvious when you say it, but it's really important for people to appreciate. This is fundamentally a different approach than what has been done traditionally in medical practice, Biomedical research, pharmaceutical drug development. For the last hundred years, we've really been focused on individual diseases in isolation, usually trying to cure those diseases. Targeting the biology of aging is fundamentally different because it's about keeping people and animals healthy by slowing the progression and onset of all of these diseases at the same time.

So cool. And I want to put a pin in that a little bit because I think people think about medicine in, let's say, America as. And I'm a. I mean I'm a licensed healthcare provider, I'm a pa, so I'm invested in medicine. Right. And the approach. But our medical system in America will never actually make people healthy. We are not really proactively trying to do a whole lot for that. We are exactly as you said, we are treating disease. And so when the disease shows up, our medical system's really pretty darn good at treating it. But it's a different concept than trying to keep people healthy and prevent disease, which I'm really invested in as well, obviously. So I love that. So cool. Tell me how I know you're. You study deep into this. Tell me how you look at signs of aging in, in your research. Like what are the hallmark signs?

Sure. So again, I think it's useful to kind of set the framework and say that, that there are lots and lots of ways to quote, unquote, measure biological aging. Right. Again, very simplistic. Humans are really good at this just looking at each other. Right. We can, within bounds of precision, we can do a pretty good job of estimating.

I'm 25, you're 32. Right?

No, but, but no, I mean, you get what I mean that clearly I'm older than you. We can see that looking at each other. And most people can probably put a guess on our, on our, on our ages. So that's a, that is a metric of biological age. And it turns out that people have done studies where if you, in a very controlled way use images of people's faces and artificial intelligence, the AI can actually pick up on features in the images that within one and a half, two years can usually predict chronological age very, very well. So there are features within just the way we look that are predictive of our, of our age. Right. And so now I said chronological age. One of the interesting things here is we can also often look at each other and say, oh man, that guy looks really old for his age. Or you look really young for your age. Right. So there are also features that are predictive of what we think are biological age, which is that aspect of what our eyes are picking up on. So that's one way to measure biological age. And then what has evolved, I think in the field are more molecular cellular tissue level metrics of biological age. And then the other piece, and we can talk about these biological age clocks because I'm sure lots of people have heard about them. And there's a lot of interesting science. There's. So you can look at those molecular features or you can look at functional features. So as an example, again, VO2 max, something that we can measure very precisely, we can see at the population level, it changes with age, it goes down with age. So that would be a predictor to some extent of biological age. And we also know VO2 Max is interesting because it's very highly correlated with your risk of dying three years, five years, 10 years down the line. That's what we would expect for something that is associated with biological age. It should not only change with age, but at the individual level should give you some predictive value of current health status, future health status, future risk of death. So that's really what we're looking for in these biological age people are calling. Clocks are patterns of things that we can measure, usually multiple things that we can measure that together that signature gives you some predictive value for where you're at right now and where you're going in terms of your health. I think where a lot of the confusion arises is what people are calling biological age clocks. So first of all, people are calling lots of different things biological age, and they're measuring different things and they don't always match each other. They can't all be biological age. So there's a lot of sloppiness in the use of that terminology, which is why I say it's more of a concept right now. I think what these clocks are really picking up on is health status, which is related to biological age, but not identical. You can be, again, as you're aging biologically in general, your health is going to go down, but it's going to go. It's going to be variable within some bounds as you're, as you're aging, it's going to go up and down. Just think about if you had a COVID 19 infection during the pandemic. Your health went down for a while and then hopefully it came back up. So it's not a linear function. It's not even necessarily what we call monotonic, where it's always going down over time. So I think what these clocks are really picking up on is current health status, and that is predictive. It's correlated with biological age and it's correlated with future health status. So it's a messy and complicated field right now that may have been a little bit confusing the way I answered it, but hopefully it gives people a flavor for some of the, some of the challenges right now around what people are calling biological age. It's being, I think, misused a lot even in the scientific literature. And then when you get out on the Internet, it's all bets are off.

Totally.

Right.

It's, it's almost creates too much subjectivity.

Right.

Tell me about, and I've heard you touch on this before and you kind of teased it a minute ago. Tell me about these companies that offer a measurement of your biological age. I'm uniquely invested in this because my husband is nine years older than me but is younger than me in my biological age and I refuse to accept it.

Well, again, which biological. Just take enough tests and you'll find one that it gives you the.

I like it.

So I mean, I think that. So that's the first take home. These direct to consumer tests are more noise than signal. I personally don't think there's any value to consumers other than if you get entertainment out of it. But I don't think, I don't think they're telling you anything actionable or useful at this. And I want to be careful and say that the, the, the research use of these algorithms that people are calling biological age clocks is very useful and we're learning things about the biology of aging and how these changes are associated with health outcomes in the future. I think unfortunately, in the direct to consumer space. First of all, none of these things are FDA approved or approved by any regulatory body. There's no transparency on quality control. I've done some personal experiments, I know other people have that where the noise is just it outweighs any possible signal. Which is why I feel pretty confident that, that people can't, aren't going to get useful information out of it. And then I would go a step further and say even if they worked right, which is. Which they don't. Well, there's no actionable information right now from these biological age tests. So you might get a number. It's not your true biological age. It's one thing that we can measure that's correlated with health, but it doesn't tell you what to do about it. So that's. The other piece is, I don't know, I don't think people recognize that these aren't actually giving you real tangible information on what you should do. And unfortunately the companies that are packaging these tests with supplements, there's no science supporting the fact that you should take their supplement based on the test. It's just a marketing gimmick. So we can, if you want, I can tell you like how these things work but, but that's really the take home. They're measuring specific, usually blood based or saliva based markers. These are molecular markers that are correlated with, in the research world correlated with either mortality, your risk of dying in three years, five years or 10 years or your risk of developing specific age related diseases.

Tell me like I know some of them do telomere measurement. Is that one unreliable? Two, there's just an absence of independent sort of quality control review or tell me your thoughts on that.

Sure. So the first thing to say is there's. So there's a few flavors of the common biological age tests that are being sold right now. There are actually several apps you can download on your phone that'll do that. Facial imaging, biological age metric. So if people want to do that.

Interesting.

But then there are these kits that you can buy. Usually they'll range from 300 to $600 that you either do us a prick your fingers and put blood on the card or. Or put saliva in a tube. So those are usually measuring something called epigenetics, or specifically DNA methylation, which is a specific type of epigenetic mark. So first of all, just kind of definitional epigenetic just re. Just really means on top of the genome. So it's not sequencing your DNA that's 23andMe, or some of these other companies that will tell you your DNA. What this is doing is looking at specific chemical modifications to the DNA methylation, in this case, that influence which genes are turned up or turned down, turned on or turned off. So it's a control regulatory point on top of your genome. Okay, so what people have done, and there are hundreds of thousands of methylation marks in each of our genomes, and they're changing with time, and they're influenced by your environment, what you eat, what you breathe, and they control which genes are turned on or turned off. And so there's hundreds of thousands of these marks. And what scientists have done is asked, if we look at all the hundreds of thousands of these marks, is there a subset in the dozens that are most correlated with your risk of dying in 10 years? And the way they've done this is because we have what are called biobanked samples from people 10 years ago, 20 years ago, some of those people are no longer alive. So we can do this on their samples from 10 years ago and say, okay, these 25 methylation marks at specific places in the genome are strongly correlated with your risk of dying in 10 years, or at least their risk of dying in 10 years in these biobank samples. And it turns out when you do that, you can get these patterns that are pretty good at predicting chronological age or risk of dying or risk of developing specific diseases. That's what these tests are measuring that works in the scientific literature because people are. Have quality control and they're doing these things, replicating them. And we know what the statistics are on the error associated with the measurement itself. The problem is now these companies don't do. They don't at least tell us what the quality control is. And when people try to independently validate it, it doesn't. It doesn't work. So, okay, so that's how these tests work. They will then give you a number, and that's pretty much it. And so then the question is, is that number real? Does it mean anything? Is that really telling you about your current health status or your current biological age relative to your husband? Again, my feeling is like, maybe is the best answer, like, maybe it's telling you something, but we don't know because there's so much noise in the system. And I can just say I did an experiment where I tested four different companies. I did two replicates of each company and I got results. And I was I think 50, 53 and a half or so. When I did the experiment, the results ranged from 42 to 63. Right. Like 20 year difference.

What about the same company with the two samples? Did you get different numbers at the time?

They were pretty close together, but in at least one case they were 20 years apart.

Interesting. Fascinating. I'm so glad you did that. Way to, way to take it into your own hands. I like it. Okay, well, I. You touched on this a little bit earlier, but epigenetics basically, again is like is. Is how our lifestyle or life influences the expression of our genes, basically. Or what's called our phenotype. You would say that's accurate.

Fairly. I mean again, environment is one thing that can influence epigenetics. And. Sorry, I just realized I didn't answer your question about telomeres. So let me just say it's useful to just clarify. So epigenetics is one of what people now call the 12 Hallmarks of Aging. The hallmarks of aging are just our sort of current way of categorizing things that we think are associated with, probably causal for the biology of aging. So that includes epigenetic dysregulation, telomere shortening, mitochondrial dysfunction. I could probably name at least eight of them, but we won't go through the whole list. So these are just useful categories that we can put out there and say this is what the literature and all the research tells us is important for aging. It's somewhere between 5 and 80% of biological aging. We don't know how much we're missing, but it's a good place to start. It's also useful to understand those hallmarks now, give us opportunities to go in with lifestyle interventions, with drugs, maybe with supplements, target those things specifically to then reduce slow biological aging. And by measuring these hallmarks in principle, we're measuring part of biological aging. So telomere shortening is one of the things that, that people have built these clocks on. Those are less common in the direct to consumer space because the technology for measuring telomeres is, is even more noisy than the technology for measuring epigenetic changes. And it's more expensive. But in principle, and people have done this in the research world, you can build clocks that measure individual hallmarks or clocks that even actually measure Multiple hallmarks at the same time. It's also maybe useful for people to appreciate then if epigenetic changes is only one of the 12, the idea that only measuring one of the 12 tells you everything about biological age clearly is incomplete. Right. So, so again, this is where I think just the sloppy use of terminology has misled people. It's a, it's, it's part of, it's associated with biological age. But the number you would get even if we could measure these epigenetic changes perfectly. Right. So if there was no noise in the system, which again, I don't know how much the average person appreciates this, that's impossible. There's always going to be some, some noise, some variation statistically in anything you measure. But even if we could do it perfectly, these epigenetic clocks are only one of the 12 hallmarks of aging. And so at best, it's part biological aging. It's not a true measurement of your biological age. There's a lot more that would go into it if, if we could actually get a true measurement of your biological age.

Interesting. Okay. And switching gears a little bit to our ability, right, to influence our longevity, our biological age, and what role we can play in that. I would love for you to take me through. Let's talk about first, like even lifestyle, outside of supplements, like lifestyle modifications that you found that can influence this potentially.

Sure. So a couple things I will start with. I think whenever we're talking about longevity, there are really two places to look for evidence on what works and what doesn't. There's the basic research, and I'm talking about laboratory animals in the laboratory things where we have studied it to say this causes obesity, this increases lifespan, this prevents disease. That's really powerful. But obviously we don't know whether those things are going to work exactly the same way in humans. It's powerful because we can actually get really rock solid information where with a hundred percent certainty, we know for a fact caloric restriction increases lifespan and health span in mice. In mice. Okay, so that's one type of data. Then the other type of data is we try to look at information we've got in humans. And that's messy, always messy, always tough. And we really, really have to be careful about confounding factors that can influence our ability to have competence. So all of that is to say everything I'm going to say, and I think everything anybody on this topic of nutrition or exercise or sleep or connectedness, those are the four pillars I think about. It's all probabilistic Some of them were 95% sure it's right, some of them were 5% sure it's right. But anybody who tells you with a hundred percent certainty you should do this, everybody should do this, is at least overstating the case, I would say so. There are a few things though that I think are generally good advice that, that the vast majority of people are going to benefit from. And so again, if we can start with, maybe start with nutrition. So the way I think about it is the sort of. There's a couple ways that I kind of frame this. One is you can really ask three questions. What's most important, what you eat, when you eat or how much you eat. Right. I put how much you eat and what you eat really close together. Really, really important. I put when you eat way down the list. And I think when you. And when, by when you eat, I mean things like fasting, intermittent fasting, stuff like that. I think for some people those are really good strategies to the extent that they help you control what you eat and how much you eat. Independent of that, there's really not much evidence in the literature that fasting or intermittent fasting has benefits in and of itself if, if you're not changing the composition of the diet or the total amount being eaten. So hopefully that's clear. But there's a lot of confusion out there about the idea that fasting is this miracle thing and you can eat whatever you want and you can make up for the amount you, you didn't eat when you were fasting. That might be true. There's just no real evidence in the scientific literature to support that. So, so that's sort of one way I frame it. The other way is when you think about what you eat and how much you eat. So how much is tricky, right? This is where if we look at the literature in laboratory animals, the answer would be everybody should be eating about 700 calories a day for their entire life. That's in mice. That's the level of caloric restriction ballpark that gives the biggest effect on lifespan. The problem is these mice are in a very sterile, not sterile, but pathogen controlled environment, temperature control, very cushy living. And mice don't typically die from loss of bone density, frailty, loss of muscle mass in people. We know that's really important as you're getting older, right? We know that, that if you fall down when you're in your 60s and 70s and break your hip, that's really, really bad. So frailty, loss of bone density is really important. So I don't think even if caloric restriction slows biological aging in people, I think there are other deficits that will be uncovered from that level of caloric restriction that would offset any, any benefits. So that's where we really need to look at the human data in my view. I think somewhere in the middle range of body weight. So again, BMI is not a great tool, but it, it's, it's a crude tool. That's okay. You want to be towards the lower end of normal for most people. I think body composition is a much better way to gauge if you're eating too much. And really looking at your especially visceral adipose, lean mass and bone density. Again, if you don't eat enough, if you're under, if you're undernourished, you're gonna probably struggle to have adequately mass and you're gonna have low bone density and you're gonna have hormonal problems and other things going on. And if you're overnourished, you might have fine bone density, but you're gonna have a lot of visceral adipose. I think that's a pretty good way to, to kind of gauge how much you eat and then what you eat. And this is really, I think the critical and these things are tied together, of course, but what you eat is really probably the easiest lever for most people to pull here. And again, from a general perspective, I think avoiding highly processed foods, especially foods with lots of added sugars, I'm not saying anything probably people haven't heard before, but maybe it's nice to just reinforce. I've gotten religious at reading labels and I'll say I personally have cleaned up my diet a lot in the last five years. I think it's amazing to me what the food companies do and what they put in. I mean, it's just ubiquitous and it's terrible. So you really have to take matters into your own hands. Learn how to read labels, look for added sugars, avoid those things. Again, shopping around the outside of the grocery store, like really, really good idea. So I do that and then I go down the coffee aisle and sometimes the frozen fruits and vegetables aisle.

That's it, exactly.

If you can do that, you're pretty, you're, you're pretty well set. So anyways, and then I think protein. So avoiding overconsumption of alcohol, again kind of obvious. I put that in the eat nutrition bucket. And then protein, I think is one where I don't actually know the answer. I can, I know what I do and I know what works for me. This is where I think the literature's a little bit still mixed, right? Is low protein good? So again if we go back to the laboratory animals, that's where you see lifespan extension in people. Probably lower risk of cancer, but also probably higher risk of low bone density, low lean mass, metabolic perturbations. Maybe. Is high protein better? Again, I haven't seen much evidence that high and by high protein, let's just say one one gram per kilogram up to one gram per pound of body weight. So that, you know, pretty big range. But let's just call that high protein. Some people will say, well that puts you at higher risk for cancer. That's true. It's not a big effect and it's really, as far as I can tell, only been documented in people who are eating a low quality diet. So people who are overnourished, eating a low quality diet, eating high protein, that does seem to be associated with higher risk of cancer and maybe some other negative health outcomes in a population of people who are not overnourished and eating a high quality diet. I haven't seen anything that, that convinces me that again for most people that a relatively high protein diet has any negative consequences. And I think like many people, I personally find it to be more satiating. So it's just I'm not hungry all the time. It's easier not to, to overeat. So that's kind of the framework that I take to, to nutrition and, and then I think you just have to kind of find what, what works for you. I, I personally don't think trying to subscribe to a specific diet, keto or whatever, carnivore or vegan, I mean again, you can do that if that works for you. I don't think any of those work for a large swath of the population. If you really want to have a diet like the one where there's the best evidence would be Mediterranean diet for sure.

I was going to ask that like a couple follow up questions. One is I know blue zones, right, Tend to eat lower ish protein, at least from animal sources and definitely like substitute in legumes and lentils, et cetera. Seems to be a theme. Do you feel like that extrapolates to support the median sort of middle range of protein consumption or is it something else that maybe I'm missing perhaps?

Well, I mean I, I think, I think first of all you have to be a little bit careful with the blue zones. I think there is a growing body of evidence that that may have been overstated in some cases. So I think some of them, it's clearly, clearly the case. Like Okinawa is one where this has been researched and documented, at least historically. Okinawans lived five to six years longer than mainland Japanese. That's one of the blue zones, a lot of the blue zone stuff. We'll see how, how, how that plays out. But so, but you're, you are right in that, in that population. Right. It was a relatively low, low protein diet. They were also calorically restricted by maybe 10% relative to mainland Japanese. But there's also a genetic component there where that may or may not apply in a typical cross section of America. Right. So we don't know the answer. I think what I would say is, and again, this is where I think our environment has changed so much over the last hundred years. And by that I mean not just like the things we're exposed to around pollution and microplastics, although that's a different topic. But even just the food that we're presented with and our sedentary lifestyles, I, again, that's why I'm not, I'm not really strongly advocating for a particular protein consumption. I think you really have to find what works for you. I think for a lot of people in our current environment with the food choices that we have, a low protein diet can be less satiating and makes you more prone to eating bad things, other stuff. Yeah, but again, it's gonna be different for different people. And I guess the other thing I would say is what we don't have is the compare group. If we could take Okinawans and then we could create an identical population and have them eat similar calories, similar quality diet, but high protein, what would happen? Maybe they would live shorter, maybe they live longer. We just don't have that, we don't have that group to compare to. So the real answer is I don't know. So I think we're all, and this is, I mean, I think it's good for people to recognize that sometimes you just have to figure out like pick the best information you can get, apply that to your own life and figure out what works for you. And if you're trying to eat a high protein diet and you're trying to eat a high quality diet and you find that you're hungry all the time, or you're tired all the time, try something else.

It's not working. Yeah, yeah, totally. One other follow up question. So I want to circle back to caloric restriction because I know that in mice that has a pretty Significant lifespan extension or roughly around 30% with extreme caloric restriction. Right.

A little bit more actually. So yeah, it's kind of interesting. So the, the longest, the largest lifespan extension. So I'm going to be very specific here. The largest lifespan extension from a non genetic intervention. What I mean by that is we didn't go in and change the genome and allow the mice to go through development with a different genetic makeup. So caloric restriction is a non genetic intervention. We're applying that once they're adults. The largest lifespan extension in the literature from a non genetic intervention is an experiment that was done, probably started in the 1980s where they did a range of caloric restriction and found that at the, the, the greatest level of restriction, which was about 65%, they got about a 60% increase in lifespan. And those mice were long lived. So this was a really, really big effect. This would probably be like getting people out to 130, 140 years on average and then some people would live even longer.

That's great.

So yeah, so that's the biggest effect. So it can be pretty big. It is useful for people to appreciate and this is what is often not talked the caloric restriction conversation. When people have looked at lots of different mouse strains, so different genetic backgrounds, there's somewhere between maybe 20 and 35% of genetic backgrounds actually have a negative response to a given level of caloric restriction. So took a hundred strains of mice and we put them all on 30% caloric restriction. Maybe half of them will get a lifespan extension. There would be some where there was no effect and maybe a quarter would actually have their lifespan shortened. So there is this interaction with your genetic makeup that in. And that shouldn't surprise anybody but, but there is an interaction with your genetic makeup that influences how you as an individual respond to caloric restriction or really to any dietary change.

Yeah. And then obviously like this isn't medical advice, it's it, it's extrapolated data. But would it, do you think it would extrapolate to humans with more obviously mild caloric restriction? Do you think that could promote.

So I'll tell you what I think and I will admit up front it's pure speculation.

Yeah, yeah, totally. But that's why you're here. I want, I want what you think so.

I think so. So I am confident that caloric restriction in humans engages many of the same biological changes within this network that we think is regulating aging as caloric restriction in mice. So things like turning down mtor, turning up amp kinase, reducing IGF1, those things happen in mice, they happen in people. This is well documented. That leads me to believe that caloric restriction probably slows much of biological aging in humans the same way that it does in mice.

Yeah.

I also believe that for most people there are other negative consequences of at least severe caloric restriction that offset those benefits. Which is why I sort of landed at low end of normal. Whatever caloric intake you need to get to be around low end of normal is probably optimal for longevity. But having said that, we're all different and I'm not at low end of normal and I feel like I'm in a pretty good place for where I want to be. And I know if I was at low end of normal, I would be hungry and miserable. So you kind of also have to figure out again what is working for you. Might I live a little longer? Maybe. But I'd rather enjoy my life now and be able to do the things I want to do. So that needs to be part of, part of the conversation. But yes, my guess is that caloric restriction does slow biological aging in humans, much like it does in mice. But for most people there are going to be offsetting detrimental consequences that would make it not worth it and might even ultimately have a shortening effect on their lifespan or health.

Spanish Interesting follow up question that you might know nothing about. I've never heard you speak to this, but I'm curious your take. So if we take significant caloric restriction off the table, but know it can influence some of these mechanisms of longevity, would something potentially like a shortish water fast of 36 or 48 hours intermittently propagate the same response without the deleterious effects?

Great question. So again, I don't know the answer because we don't have the right data to definitively answer that. What I can say is in laboratory animals, people have tried to do these experiments, so they've done short term fasting or even every other day feeding. Right. For months or years. This is often misinterpreted in the literature because when those studies are controlled for total caloric intake, again, meaning that if you're feeding the mice every other day, on the days they're eating, they're eating twice as much. There's really no effect on lifespan. Okay, so that would suggest that the, the, the overeating, let's just call it overeating on the days where they're eating, offsets the benefits you get from the fasting. So I think of fasting and time restricted eating, which would be like 16 or 816 or 12 12, whatever. I think of those as useful tools that at a minimum can help some people control how much they're eating. I think for some people it can also have a benefit on their circadian rhythm, which is a different discussion but also important for health. But if you aren't, if they, if, if you are overeating, I don't think that fasting or time restricted feeding gives you any benefits, at least based on what we know in the animal studies.

Cool. I love it. Thanks for answering that. That was a little bit of an offshoot, but I was curious your thoughts.

Okay.

I wanna switch gears a little bit so I know I'd love your thoughts in general on supplements, just briefly, whatever your thoughts are on that. And then really I just wanted to pick your brain about medications that are out and influence aging that I know you're familiar with as well.

Sure, yeah. So supplements are really tough and I, I personally, I struggle with supplements because again, there's not a lot of good data and I think the industry is very problematic, much like the direct to consumer biological age testing industry. So I, I put supplements really into two broad categories and then we can get in the subcategory for, for one of them. So one category is things that we can measure and we have at least some reasonable understanding of what is optimal or normal. So I would put things like vitamin D, omega 3B12s in that category. We can measure them. We have at least some confidence around where most people should be. So in my view that those are things that people should get measured and should supplement if they, if they're not in the optimal range or certainly if they're in the deficient range. Now people will sometimes say, yeah, but the epidemiology doesn't definitively show that supplementing vitamin D has any benefits. There are lots of problems with those studies. We could talk about it. That's bunk. If you're deficient, get yourself out of the deficient range. Would it be better to go outside and get it from the sun? Sure it would be, but some people can't do that. Many people, like where I live, even if I spent half the day outside, I wouldn't get enough sun to make enough vitamin D. So supplement if you're deficient. So measure, intervene, measure again. So that's pretty easy. Then the category are things we can't measure. We don't have definitive data, might work, might not work. We don't know what the risks are. That's almost everything else, unfortunately.

Right.

Then you have to get into this probabilistic territory of, okay, if we try to look at all of the information that's out there, take out all the garbage that's on the Internet that just isn't real, what can we conclude about the different supplements? And so some of these are gonna be what people are calling longevity supplements. And then there's a bunch of other supplements that really have no data on longevity, but certainly could impact health. Right. So to keep this from getting too far afield, let's just mostly focus on the ones that are in my wheelhouse, which would be longevity. So what would I call a longevity supplement? It would be supplement. It would be something that has been tested in laboratory animals and shown to increase lifespan and or health. Right. So it's a pretty small list of things that fit that category. And of those, most of them haven't been reproducible. So there's not a lot that we can point to and go like, yep, people should be taking that for longevity. So the stuff that people I'm sure have heard about would include NAD precursors. So NAD itself, nicotinamide, riboside, nmn, niacin, or nicotinamide. So. So NAD itself, people, you. You can take that orally, but it's not really bioavailable. So you can either get V, or there are now, I think, some sublingual formulations, and then the others are oral precursors you can take that are supposed to boost nad. The rationale here is that NAD levels decline with age. NAD is involved in a bunch of important metabolic processes, and if we supplement the NAD back up, that could be good for mitochondrial function and overall longevity. Mitochondrial dysfunction is One of the 12 hallmarks of aging, by the way. So the evidence to support that were some early studies that showed lifespan extension from NAD precursors in mice. Those have not been replicated. So it's kind of like who knows what the real answer is for longevity. But there is a growing body of evidence that there are at least some potential healthspan benefits from NAD precursors in mice. There's also a couple of warning signs that at least some NAD precursors in aged mice might cause things like kidney path, so they may not be as safe as people. So should people take NAD precursors? I don't know.

Right?

I don't know. Maybe. I do believe that for some people, NAD imbalances become limiting for health and that they would benefit from NAD precursors. I don't think we have a great way right now to tell which people should be taking NAD precursors. And then there's all these questions about dosing and which one's best, and we don't really know right now. There is some interesting new approaches being taken to combine an NAD precursor with, with what's called a CD38 inhibitor. So CD38 degrades NAD. And so I'm, I'm, I mean again, I haven't seen data, so I'm certainly not suggesting people should go out and start taking these. I, I'm personally testing one of these right now. It's intriguing and the biology makes sense and so this might be a way to increase bioavailability of an NAD precursor, but I, I have no information one way or the other on, on work. So, so that was a long winded answer on NAD precursors. There are a few others that I think are interesting. Alpha ketoglutarate. I would put in the interesting, but I have no idea how beneficial it is. Thin a, I'd put in that category. Spermidine. I'd put in that category. I'm not taking any of those personally because the data in the laboratory studies is, is pretty mixed and I should say none of them are anywhere near as effective as caloric restriction in mice. But none of them are nearly as effective as rapamycin. If we can talk, we'll talk about medications today. So there's no supplement that comes anywhere near what has been shown in laboratory animals for caloric restriction or rapamycin yet. Yeah, yeah, maybe. The last thing to say is most supplements are not particularly bioavailable. So it's not even clear even if they could have the effect that, that the doses that people are taking would actually achieve the biological effects that we're looking for. If we had perfect biological age tests, those might be useful in telling us whether the supplements are working. But right now, as we've already discussed, they're not, they're not good enough to, to give you that sort of information.

Totally. Okay, tell me about rapamycin.

Sure. So, I mean, rapamycin is FDA approved drug. It was first approved to prevent organ transplant rejection. This is 25 years or so ago now. So we know a lot about human use. It's commonly sort of referred to as an immunosuppressant. It's not a true immunosuppressant, but in, when used in combination with other immunosuppressants and at high doses, rapamycin does help prevent organ transplant rejection, sort of independent of that clinical development. In the like early 2000s, multiple labs independently converged on rapamycin and the Protein that it targets, which is called mtor, sensor, mechanistic target of rapamycin as a key node in this biological aging network. And so what we've learned really since about 2004 till now, is that really, mtor seems to be one of the most powerful things we can modulate to impact the rate of aging and longevity in laboratory animals. It works in every animal where it's ever been tested. It increases lifespan in mice up to about 25% and seems to delay the onset and progression of pretty much every functional decline and disease of aging in laboratory animals. A couple of other things that are interesting and potentially important when we talk about human use for this purpose. One is you can start the treatment in middle age. And this was a study that was published in 2009 where they showed you could start treating mice with rapamycin at about the mouse equivalent of a 60 year old person. Biologically still get pretty much the full benefit. That was really the first time anything had been shown convincingly to work starting at middle age. That was really important. And now we know you can start treatment in middle age. And in certain tissues and organs where function has already declined, you can actually see improvement. So we can reverse functional declines with aging. So that's true, definitively true. In the oral cavity. So we can reverse periodontal disease in mice, in the brain, so we can actually see improvements in mouse models of dementia and normal aging in the immune system. So we can improve vaccine response with rapamycin in mice in the ovaries, which is really interesting. So can take mice that have undergone ovarian decline and actually see restoration of function. And in the heart. So there are, again, I'm not saying that rapamycin reverses all aspects of aging, but at least in some of these tissues and organs, we can see an improvement in function. So that's really intriguing when you think about testing rapamycin in humans, because it's much easier to show that you can take a system that's already declined and make it better than to show that you can increase lifespan in a population. Totally 20, 30 year study, right? So now people are starting to do clinical trials. There are trials running for muscle function, ovarian function, oral, oral disease in humans now. And so none of them are really large. But I think we'll start to get additional information. There were two pretty good sized clinical trials for influenza vaccine response done maybe 10 years ago now with a derivative of rapamycin. But it works exactly the same way. Both of them showed positive results. So at least for Immune function. It seems like the same pattern that we see in mice is probably true in people. And then now there are lots of people using rapamycin, what's called off label. So it can be prescribed by a doctor. It's not for the FDA approved label indication. That's where off label comes from. But you can get a doctor to prescribe any FDA approved medication they're legally allowed to if they believe it's in the best interest of their patient. So people are using rapamycin off label in the hope that it will improve healthspan and potentially lifespan. Collecting data from those people, I think what I feel pretty confident saying is there aren't a lot of side effects. So about 15% of people will get canker sores. But outside of that, nothing is statistically significant at this point other than some benefits that are different between non users and users. But in terms of side effects, nothing jumps out. So seems like at the doses and the strategies that people are using right now, it's pretty safe. We really don't have much data on efficacy at this point. A couple of hints around long Covid or severity of COVID 19 infection and then some specific inflammatory or autoimmune conditions where anecdotally we're seeing people report benefits.

Well, if you guys ever want to do a study on thyroid, thyroid function or Hashimoto's, let me know.

I mean, Hashimoto's is interesting. Right. So again, I think there is at least a couple of case reports. So I think that's again, one of the places where you might anticipate seeing a benefit from rapamycin.

How fascinating. I'll have to do some data. I've started it myself. I always do things before I offer it to like my people in our practice. So I started it myself a few months ago and yeah, I'll absolutely look for that. I was not aware that that could happen. So that's really exciting. Tell me about your work in Optispan and the role that it has in ag and longevity.

Sure. So this will go back to kind of one of the topics we touched on earlier, which is how the traditional healthcare system is very reactive. Largely, completely but largely reactive. Not really set up to assess where people are at, detect problems early and prevent problems. So Optispan is really a healthcare technology company. First and foremost, our mission vision is to enable health optimization for as many people as possible, but particularly in the context of aging. Right. Because that's really the biggest driver of declines in health and disease. So we're developing tools Technologies, protocols within the space to scale that to as many people as possible. And there are a couple of pieces there. One is to develop our own clinical programs because I think you really have to do that before you can figure out what works, what doesn't work, what are the friction points. I'm sure you're familiar with this. I wasn't familiar with it when I started because I came from an academic background. The healthcare system is full of friction. And so a big part of what prevents people from taking control of their own health is how much friction there is in the system. So that, so I felt like we needed our own clinical programs to be able to really sort of figure those pieces out. So we've got a couple of programs up and running now. One is really, if you think about the sort of high end longevity clinics, measure everything, that's really what we're doing. And again, most of these high end longevity clinics are basically doing the same diagnostics, right? There's an overlapping set of diagnostics, comprehensive blood work, ultrasound, multicancer detection, whole body MRI, DEXA, VO2 max. Right, you go down the list. So we're doing that. And again, but partly with an eye, of course, with getting people onto the best health span trajectory that they can get on our clients, but also with an eye to what works, what doesn't work, what do we change? One of the things we've changed is we're no longer recommending biological age testing or microbiome testing. It's just not using, it's not actionable at this point in, in our view. So figuring out what doesn't work as well as what does work and, and then trying to develop optimized approaches at different price points so that there's, there's gotta be an 8020 here where you can get 80% of the benefit for 20% of the cost. Figure out what that is so we can make it available to a lot more people and to the people who want to take matters into their own hands, provide enough information that allows them to do that. Now I do want to, I do want to state, well, our other program is a corporate program. So we are currently running the corporate healthcare program for a company called Sabi Corporation. That's a scaled down version and that's sort of like getting to the 80 20. What might employers want to invest in their employees, but firmly in the healthcare proactive preventative health optimization venue, not in the reactive disease care venue. And I say reactive disease care, that sounds disparaging. I'm not at all suggesting we don't need that. We do need that. People are still gonna get sick. But wouldn't it be better to keep people healthy and for as long as possible? So that's what we're doing in our clinical programs right now. Again, with an eye though, to figuring out how do we, how do we make this available to as many people as possible.

Well, thank you for that work. That's absolutely incredible. And so needed, like people need that, we need that, corporations need that. So.

Yeah. And actually one more thought that I, that I just like to add is I think so far, and I don't think this will change, we have chosen not to go the direct to consumer route. I know a lot of companies are doing that. I'm not, I'm not trying to disparage people who go that route. I think in any of the direct to consumer market right now, there are misaligned incentives and because of the regulatory environment, it makes it very difficult to actually give people medical care doing direct to consumer. So I worry a little bit, maybe maybe more, more than a little bit about the sort of proliferation of all of these companies that are offering a variety of different diagnostics to consumers, but then not giving them any further follow on care, on how to, how to interpret or act on that, and the idea that you can go get an MRI or a comprehensive blood test and then it's like, take this to your primary care doctor if something looks bad. Most primary care docs are not going to be equipped to deal with that. So I worry that that is not helping people and in fact maybe creating a lot of anxiety for people who are then put back into the reactive disease care system without the tools to navigate. To navigate it. So.

Right.

I think, I think there's. There should be an ongoing conversation about how we actually create tools that enable people to get the care that they need.

Absolutely. And that's sort of my mission, obviously in the niche of thyroid and hormones, but educating and empowering people to actually get to the finish line for sure. Not halfway there. Tell us how we can find out more about Optispan and find more details about it and follow your journey.

Sure. Our website is www.optispan life. We have a podcast channel, the Optispan Podcast. So I would definitely encourage people to check that out. It's a, it's a mix of science, of longevity and hopefully really actionable things that people can do within their own healthcare journey. And we've got quite a bit of content up there, so please check it out.

I love it. Well, thank you so much for coming today. I've been looking forward to this conversation for so long and thank you for taking the time to share your knowledge and wisdom and for all of the work that you put into helping us live more of a health span lifespan. So thanks.

Thank you. It's been a pleasure.