Measuring Longevity: Latest Bio Age Research with Dr. Morgan Levine

As a longevity aficionado, I am so excited to be talking to Dr. Morgan Levine in this episode of New Frontiers! Renowned for her research on the science of biological aging, Dr. Levine specifically uses bioinformatics to quantify the aging process. She’s played a vital role in developing and retraining several well-published bio age clocks, including the PhenoAge and Horvath clocks, making them much more reliable. Needless to say, I’m a big fan! Morgan and I dive into the fascinating science behind her new book, True Age: Cutting-Edge Research To Help Turn Back The Clock, and cover loads of important topics such as vetting bio age clocks, the role of the DNA methylome, how standard labs such as CBCs and CMPs can be used to calculate bio age, the controversial debate around immortality, challenges of applying the Yamanaka factors in clinical practice, how racial disparities affect biological aging – and believe me, so much more! I hope you’ll enjoy this thrilling conversation as much as I did, and please give me your feedback wherever you listen to New Frontiers – DrKF

Measuring Longevity: Latest Bio Age Research with Dr. Morgan Levine

Is longevity science taking us closer to immortality? And what’s the role of diet and lifestyle in all of this? In this episode of New Frontiers, we are joined by Dr. Morgan Levine, renowned scientist and researcher in the field of biological aging, assistant professor of pathology at Yale University School of Medicine, and author of the book True Age: Cutting-Edge Research To Help Turn Back The Clock. In this exciting conversation, Dr. Levine discusses the science behind measuring biological aging, DNA methylation as a universal factor in the aging process, how to use standard labs such as CBC to calculate bio age online for free, why exercise, diet and lifestyle have the upper hand over aggressive anti-aging interventions such as the Yamanaka factors and rapamycin, and much more.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine, and of course, today is no exception. I am so excited to be talking to Dr. Morgan Levine. I’m fan-girling in a pretty big way today. Let me tell you about her, and we’ll jump right in, and I know that you’re going to be as thrilled about this conversation as I am. Morgan Levine is an assistant professor of pathology at Yale University School of Medicine, and she’s author of the book, True Age: Cutting-Edge Research To Help Turn Back The Clock. Her research focuses on the science of biological aging, specifically using bioinformatics to quantify the aging process and test how lifestyle and pharmaceutical interventions alter the rate of aging. We’re going to dive into this big time. As a leading voice in the field of aging and longevity science, she has been featured in media outlets, such as CNN, the Guardian, Time, Newsweek, BBC, and many, many more.

She was just on a docuseries by Netflix, which was released in 2020. I want to just add to this bio that Morgan really sits at the epicenter, no pun intended, of epigenetics and biological aging. Like, she’s smack in the middle of figuring out how we measure bio aging and what kind of interventions will influence biological aging. In fact, I don’t know, maybe, perhaps other than Steve Horvath, who really developed the first clock that has been widely used. I don’t know if anybody else is as in the middle of this world as much as Morgan is. So, Dr. Levine, welcome to New Frontiers.

Dr. Morgan Levine: Thank you. I’m excited to be here.

Dr. Kara Fitzgerald: Let me actually, let’s just touch a little bit on your own journey. Your journey is interesting. It sort of, it reminds me a little bit in a very different way of my own, like coming to study aging. Can you just give us a little bit of a background on how you got into this?

Dr. Morgan Levine: Yeah, I mean, as far back as I remember, I’ve been very interested in aging, and I think it probably has to do with the fact that my father was actually quite a bit older than the average father when I was born. So, he was in his mid-fifties, and I was always just very concerned about the aging process. It’s something I could actually see in my dad. Whereas, I think a lot of kids aren’t really contemplating their parents growing old or potentially losing them. It was something that kind of consumed me, and then, at some point, I got exposure to this whole field of aging and the realization that it’s not something fully out of our control, and actually the biological aging process is something potentially malleable, that if we can scientifically figure out how to do that, we could potentially extend our what we call health-span and lifespan.

Dr. Kara Fitzgerald: Right. Yeah. I became a mom at 50, and so similar. That’s my Isabella. You can see on that Zoom, that’s my daughter. So, similarly, but from the other side of the equation, I feel a really intense commitment to living the best life that I can, and hopefully favorably influence that, and support others to live their best lives. Chronological age and biological age, just speak to the difference and then we’ll dive in.

Dr. Morgan Levine: Yeah. So, I think whenever we think of aging or our age, we always think of chronological age, which as everyone knows, is just measured in units of times since you’re born so, years, you can measure it in days, however you want, what unit you want to do. We usually associate our age with an increased risk of developing diseases or an increased risk of dying, but it’s actually not the chronological time itself. It’s not as if we’re rolling a dice every year and just the probability’s increasing. But what we think is happening is that our bodies are undergoing these very profound changes over our life course.

It’s that process that is actually driving all of the things that we associate negatively with aging, and this is what we consider your biological age. So, not everyone accumulates these changes at this same rate, so someone who’s lived 50 years could look very different than another person who’s lived 50 years. So, this is the idea of can we actually measure the degree of change a body’s undergone, and we like to think of that as the biological age of a person.

Dr. Kara Fitzgerald: So, even though when we look at aging as being the biggest risk factor, and you point out in your book, sort of the mind-boggling statistic that it’s, that smoking isn’t the biggest risk factor for lung cancer. In fact, age, is. It isn’t again, the chronological age, even though that’s how the data have always been presented. It’s in fact, the rate of aging.

Dr. Morgan Levine: Yeah. Because just this chronological time is very correlated with these biological changes, and chronological time is easy to measure. So, it’s always been kind of this easy proxy, but yeah, it’s actually all of these biological changes, which are not happening at a constant rate like chronological aging is.

Dr. Kara Fitzgerald: I don’t know if you happen to notice there was a, you probably did, there was a study published maybe in this past week showing that American life expectancy has gotten another hit. Of course, we can point our fingers at COVID, but it looks like we’re aging faster biologically in this country than elsewhere.

Dr. Morgan Levine: Yeah, and I think it also probably has to do with different sections of the country. I don’t know exactly that city, but I do remember a few years ago there were studies, and it was specifically, I think showing white women seems to be losing the most in terms of life expectancy. I think at that time, they were saying it probably had something to do with obesity epidemic, but yeah, it’s this idea that it’s malleable and both in the way we’d want it to be, right? Can we slow biological aging, but there’s also factors in our environment that can accelerate our biological aging. Then the question is how many of those are things that we actually have some control over, can do something about?

Dr. Kara Fitzgerald: I think the work that you guys are doing in developing these biological age clocks has just changed the conversation on this wildly, just extraordinarily. It feels like we’re sitting at the beginning of just revamping our scientific approach to, and our medical. I mean, this will influence us in clinical practice as well. How we think about the chronic diseases of aging, because we’re able to more accurately measure biological age, and if it being the biggest risk factor for all of these chronic diseases, if we can reverse it or if we can slow it down, we should by extension be reducing risk for all of these diseases. So, can you speak to measuring biological age, and maybe a little bit of the history and the evolution of that? It’s so, so, so interesting, and where we sit today. I know we’re into second and perhaps even third- generation biological age clocks, how we measure it, and where we are right now.

Dr. Morgan Levine: Yeah. So, the idea to measure it has actually been around for decades. I think some of the first people who said we should try to measure this were, I think either in the ’80s or even earlier, but the problem was that we didn’t have the tools and resources that would actually enable this. So, there’s so much that changes within our bodies as we age, and we’re finally at a place where the science, where we can actually measure millions of different variables from just a small sample of cells, let alone an entire human being. We also have the computing power now that can help us make sense of that data. So, we’re in this kind of data boom, coupled with increasing computing power, where we can actually take all that and make informative measures. So, some of the early measures, from a few decades ago, were pretty simple, and they just looked at functional impairments or even just the number of chronic diseases a person has.

So, you can almost take a self-assessment test here. So, it’s like, how many chronic diseases do you have? Do you have trouble doing this or that? You can add that up and get a general idea. We usually call this a Frailty Index or Deficit Accumulation Index. The hard thing about that is, those are usually just manifestations of aging that we can see or feel in our bodies, and it’s hard if you are a little bit younger, because these things haven’t manifested yet. So, there’s no idea to really know where you stand, but that’s where all this new, either molecular and cellular data comes along, where either you can measure physiological parameters, or what you alluded to with epigenetic clocks, is we can measure what’s called DNA methylation, and we do this across almost a million sites in the genomes.

So, what this is, is it’s not measuring whether you have an A, C, G, or T, so it has nothing to do with the sequence, but it’s the chemical tag that gets added to these CPG sites. That’s where you have a C next to a G, and the pattern of these across your genome changes quite dramatically with age. So, we can actually measure it at all these different sites, look at the pattern and say, “You have a pattern that is indicative of someone with this chronological age,” or now with the second-generation clocks, what we’re doing is, “You have a pattern that’s indicative of someone with this mortality risk, which is equivalent to the average 60-year old or 70-year old, whatever it may be.

Dr. Kara Fitzgerald: Yeah. So, rather than identifying, okay, this individual is frail using the Frailty Index, which I know, I think it’s still being used today, and does have a place.

Dr. Morgan Levine: Mm-hmm (affirmative).

Dr. Kara Fitzgerald: We can actually get in there and look at the aging journey epigenetically and see, really fairly precisely whether somebody’s moving too fast or too slow or not, well, not too slow or slowly.

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: I don’t know if there’s a ‘too slow’ at this point.

Dr. Morgan Levine: Yeah, that’s true.

Dr. Kara Fitzgerald: All right. That’s, it’s really exciting. Can you just speak to, there’s a lot of clocks out there these days, vetting good clocks. Any tips for, there’s a lot of clinicians listening to this, but there’s also lay people listening. So, any tips for those folks wanting to measure biological age?

Dr. Morgan Levine: Yeah. So, as you said, there are tons of clocks. So, now because it’s getting easier and easier to develop these, a lot of different groups are doing that. The interesting thing that we see is that the clocks don’t all give you the same answer. So, what your biological age might be projected to be is going to be different depending on the clocks. So, I have a few criteria for what I would look for in a good biomarker of aging, so probably the most obvious is that it’s something that should correlate with age. It should change as a function of age. That’s pretty easy to make a clock that does that, and that’s what a lot of these first generation, so the famous Horvath Clock did, is there was a measure that really strongly correlated with someone’s chronological age.

But to me, the more important criteria than that is that the discordance between your predicted biological and your chronological age should have biological meaning. What I mean by that is we assess what we call the construct validity. So, there’s no way to say, are we accurately measuring biological age, because we can’t observe it. We have no ground truth to say, “Oh, how well do we actually do in our prediction?” So, we have to use other surrogates that we think biological age should be able to predict. So, we would say, among people of the exact same chronological age, so let’s say 60 years old, are those with a higher biological age, more at risk of dying in the next 20 years, or more at risk of developing a given chronic disease, or do we see that they accumulate more physical or cognitive deficits over time?

So, there are some of these epigenetic clocks are really good at capturing that, but it’s not all of them across the board. Then finally, the last criteria that I think is really important and not actually given enough attention is the idea of reliability. So, if I were to measure the same clock twice, almost even in the same sample or day to day, how much variability am I going to get? Am I going to get the same answer? Unfortunately, what we’ve actually found is a lot of the existing epigenetic clocks are actually fairly noisy. You can get differences of five to sometimes even 10 years from the exact same sample, run in the same batch. So, we’ve actually been working, and recently developed new statistical methods that actually remove all of that, not all of it, but the majority of that technical noise.

So, now you almost always get at least the exact same age, if not maybe one year difference. So, I think it’s hard for people to evaluate these, but I would say, look at the literature and if a clock’s shown to have good, what I would call, construct validity, it means it can predict outcomes and good reliability, which means it’s not noisy. Those are probably the main criteria I would use.

Dr. Kara Fitzgerald: You published, recently, a calculation. Is that, can be sort of layered on.

Dr. Morgan Levine: Mm-hmm (affirmative).

Dr. Kara Fitzgerald: I’m not a biostatistician, so I don’t know if I’m going to use correct language here, but you can, this calculation can be applied to some of the well-published clocks, like your PhenoAge Clock or Horvath’s Clock or the GrimAge, I think. So, the big, the popular first, second-generation clocks, is this what you’re referring to adding this calculation on to remove some of the noise?

Dr. Morgan Levine: Yeah. So, when we discovered this noise issue, we first went back, and I retrained PhenoAge, which was a clock I helped develop, because actually that was one of the more noisier clocks of all of them. Then we decided, well, let’s do this for all of them because we shouldn’t just make PhenoAge more reliable. We should let people use all the other ones too. So, we, as you said, we did this for the original Horvath Clock. Then there’s a Horvath Skin and Blood Clock, GrimAge, Telomere length Clock, and Hannum which is one of the first blood clocks. So yeah, if you have the data, the epigenetic data, this is just an additional computation or statistical step that you insert before you output your final score, but it gives you almost the same answer, except it removes any noise or most noise.

Dr. Kara Fitzgerald: Right. Okay. Okay. So, I would just say to folks listening, because this is a little bit dense. We’ll try to pull some of these points together in our show notes, but I would say, and correct me if I’m wrong, Morgan, that we want clocks that are, that have been published on in the literature, so they’ve been used.

Dr. Morgan Levine: Mm-hmm (affirmative).

Dr. Kara Fitzgerald: They’ve been studied and published. Their algorithms, I guess, would therefore be available to other scientists to kind of kick the tires of them, and then the laboratory that we might order a test from has access to your calculations, which are freely available, I believe, and they’re applying them. So, we could maybe use that criteria and just ask the given lab, if they’re doing these things or offering this. Would that be reasonable?

Dr. Morgan Levine: Yeah. Yeah, because I think some of, there are definitely companies offering this. I only know of one company that is actually using this new statistical method, but it doesn’t mean others won’t adopt this, since this just came out recently. But yeah, I totally agree. Those are the main criteria.

Dr. Kara Fitzgerald: Okay. Okay. That’s perhaps a little bit more straight-forward, but I do, I have confronted the fact, there’s a lot of proprietary clocks out there now and I don’t, I’m not entirely sure what to do with them.

Dr. Morgan Levine: Yeah. I agree.

Dr. Kara Fitzgerald: Okay. Interesting. Well, so I want to talk about some of the interventions. We have to make sure we get there and get to your thoughts on slowing the biological age journey, and what your thoughts are. But before we do, I want to talk about DNA methylation and epigenetic changes in the aging journey as not just being surrogate markers of aging, but perhaps the drivers. So, when we get these epigenetic clocks, and I know you’re working on this, actually. I know you published recently on this. When we get these clocks, it’s not just a suggestion or a shadow that we’re either aging well or we’re aging rapidly, but what’s happening with regard to turning genes on and off, which DNA methylation is intimately involved in, is driving the aging journey.

You talk about, I think the hallmarks of aging, that, you go in your book, you go into some detail with the breakdown of the body, and what’s happening, grossly and at the cellular and molecular levels, but upstream, perhaps root cause here, and I think research out of Sinclair’s Lab and elsewhere, where they reverse aging in animal models. I mean, it suggests that the aging journey really might start with these changes to the DNA methylome.

Dr. Morgan Levine: Yeah. I think this is the major unanswered question in aging research, is there a root cause to aging, and also when it comes to these clocks, whether the methylation changes we’re capturing, whether they’re causal or they’re just a good proxy for what’s going on. To me, the reason I feel like they probably have a more important role than just being an output measure, is I like to think of the epigenome as almost the operating system of the cell. So, essentially all the cells in your body have the same DNA, aside from a few somatic mutations that arise, but what creates the diversity of all these cell types throughout your body and gives cells their state and their phenotypes and their traits and their ability to respond to stress and how fast they turnover, is the epigenome.

So, that is really dictating the differences between all the cells in your body, and as you said, and as we’ve been talking about, unfortunately, the epigenome changes dramatically with aging. So, one question is whether those changes are actually creating maladaptive cells or what we might think of as less healthy or less resilient cells, and that’s underlining everything we see in terms of tissue dysregulation and disease manifestation with aging. The other really critical evidence that you alluded to, was this idea that if you can actually, it’s slightly an indirect targeting of the methylome, but people do this cellular reprogramming using what are called the Yamanaka factors, where you can actually, we think through epigenetic changes, convert even very old, even cells from very old individuals back into what looks like an embryonic stem cell state.

Is slightly, you can slightly differentiate them, but they behave like embryonic stem cells for the most part. The exciting thing is you can even take an old cell and convert it back into a younger version of that same cell type. I think that’s where the field’s really excited. This seems to be acting through changes in the epigenome, which is a slightly more evidence that epigenetic modifications might be somewhat central to the aging process, although I don’t presume that they’re the only thing going wrong with aging.

Dr. Kara Fitzgerald: Right, right. So, we’ve got a youthful pattern that we’re able to uncover with these cocktails of Yamanaka factors, either in animals or in cells. I mean, and then if we put that next to the very, the radically different rates of aging in other mammals, well, and actually let’s throw in there, the Mammalian Clock that Steve Horvath and many others worked on recently, it seems that there’s an element of programming.

Dr. Morgan Levine: Mm-hmm (affirmative).

Dr. Kara Fitzgerald: Can you speak to that?

Dr. Morgan Levine: Yeah. I mean, I do think a lot of the epigenetic changes that we see, people talk about them as just errors or the epigenome didn’t copy over correctly, which some of it might be, but I think a lot of it isa program hypothetically gone wrong, or that just wasn’t set up to promote extreme longevity. I don’t think it’s a program that’s forcing aging, because I don’t think aging is something that needs to be … You can just do nothing, and a system will age.

Dr. Kara Fitzgerald: Right.

Dr. Morgan Levine: But yeah, it does seem to be really interesting, and the thing that actually got me so interested in epigenetics and methylations from the get go, is how universal this seems to be.

Dr. Kara Fitzgerald: Yes.

Dr. Morgan Levine: Epigenetic clocks are the only clocks that you can use this same exact one and apply it to almost any tissue type. Now, from Steve Horvath’s work, it seems like you could use the same clock across hundreds of mammalian species, and there’s something universal about this. It does track with individual’s rates of aging, differences in lifespan across species, differences in tissue aging, that I think it will be a really exciting thing to figure out what this kind of concept or phenomenon is actually capturing.

Dr. Kara Fitzgerald: Yeah. Like, you talk about Greenland sharks. I mean, they don’t hit sexual maturation, I think you said, until 150 years old. Is that right?

Dr. Morgan Levine: I think so. Yeah. I mean, yeah. The, I mean the diversity in aging in the animal kingdom is amazing and there are people doing really exciting comparative studies in aging.

Dr. Kara Fitzgerald: And they’re built from the same ingredients. I mean-

Dr. Morgan Levine: Exactly.

Dr. Kara Fitzgerald: They’re built from the same ingredients. It’s, as you pointed out in the book, mice share 80, 95% of protein-coating genes with us, and yet we live orders of magnitude, I guess, longer than them.

Dr. Morgan Levine: Yeah. It’s just that a different arrangement of the system gives you a totally different lifespan in an organism, and it’s amazing. Yeah. We’re all built from essentially the same building blocks.

Dr. Kara Fitzgerald: It’s amazing. Yeah. So, I want to talk, so there are some people who are probably looking at it through this lens, and saying, “We can go in there.” Well, Josh Mitteldorf wrote a book called Cracking the Aging Code, and I know there’s other people who speak about immortality. I mean, that’s kind of a concept that’s rather radically sort of jaw-dropping, I guess, me coming from functional medicine and thinking, and paying attention to some of the scientists speaking about this. It’s pretty wild that there’s this expectation that this will be cracked and immortality is perhaps not far around the corner. Anything to say on that?

Dr. Morgan Levine: I mean, I would say I’m probably one of the more pessimistic people in the aging field, where I don’t think it is going to be as simple as some people think. I don’t, I would say if I was a betting person, I’d probably say, we’re never going to kind of crack immortality or “solve aging”, but of course, who knows. I don’t presume to know the future, so I am open to being shown that I’m wrong. But yeah, I think it’s going to be, there’s a lot of obstacles I think we’re going to have to overcome. Yes, there are species that seem hypothetically immortal, but they, but I think we need to understand that a lot of phenotypes and traits of an organism are connected.

So, you can’t just take one trait out of some immortal species, put it in a human and expect a human to be immortal, so it’s probably also dependent on all the other things. So, so there’s this concept called pleiotropy, so things aren’t just coding for one trait at a time. It’s kind of a manifestation of multiple things, and I personally, have no intention on becoming a hydra or a clam, or taking on any of their other traits. No, I don’t want to trade that-

Dr. Kara Fitzgerald: So, you can live a long-

Dr. Morgan Levine: Immortality.

Dr. Kara Fitzgerald: Yeah, exactly.

Dr. Morgan Levine: That’s really funny.

Dr. Kara Fitzgerald: Yeah, that’s funny, but it’s extremely exciting to see where we’ve come, and just the possibility of what we can look at now, and some suggestion that if we think about eating, living for optimal gene expression, that we may really be able to make a difference. It’s, I just, I, for me, it just seems like it’s an exciting time, just an exciting time to be on the journey and to be alive.

Dr. Morgan Levine: Yeah. I mean, it is exciting that we can decide and change the state of a cell. I think that was never something we thought was going to be possible, that we can take cells and just move them to a different state and even “a different age”, in terms of the biological aging. Yeah. So, I think it is exciting. There’s a lot that we’re going to discover over the next few decades.

Dr. Kara Fitzgerald: Yeah, absolutely. Well, let’s talk about some of the interventions that we can be doing now. So, I mean, and I just want to preface that by saying it’s, so this is another transformation, I think, that’s happening. We always thought our genes were our destiny, and I think this new sort of omics era that we’ve landed in, and again, you’re right here, demonstrating this with your research, is that in fact, our genes really largely are not our destiny, and that we are, we’re driving the gene expression car way, way, way more than we previously we thought. Talk to that, and just while you already have, but some of the interventions that we need to be thinking about and doing right now.

Dr. Morgan Levine: Yeah. Just in terms of genes being our destiny, I think when the Human Genome Project came out of, in the early 2000s there was this idea that, oh, we’re going to explain all differences in someone’s risk of getting cancer or heart disease or whatever. Actually, what we’ve discovered is you can explain very, very little of the differences between people, based on their genetics. Some of this might be, we don’t have the best models, but it even seems like things like lifespan, which I think people always thought was due to your genes, only about, genes only explain about 10, maybe if we’re being liberal, 20% of differences in lifespan. That might be different for people who live exceptionally long, so super-centenarians.

But for most of us, most of our differences in lifespan come down to these variations in our lifestyle, our behaviors, our environment. Of course, there’s a little bit of sarcastic chance thrown in there, but we have a lot of power to do, to change the rate of aging, compared to what we probably once thought we did.

Dr. Kara Fitzgerald: So, on one hand, there does appear to be some program phenomena happening, because we can see it across species, and there’s a shared aging journey, and we’re going to slide down that aging slope. You use the really interesting and sort of powerful analogy of a hill. I mean, it’s such a simple analogy, but it’s, it was impactful for me. This whole developmental journey is a massive energetic output. You’re climbing up the hill. I mean, just think about being pregnant, and the amount of calories, and just full tilt, nonstop energy into building this little human. Then, the early, early infancy, which, my daughter’s four now, and she’s still just developing, daily sprouting new skills, and understandings.

It’s such an extraordinary thing to witness, and so that happens. We climb the hill and devote so much, and then, as you say, aging is really the slippery slope. It’s the other side of the hill, and there’s a program phenomenon, like it’s going to happen, regardless of who we are and where we are. But there are choices that we can make to maybe stop at the top of the hill or, or really slow down our walk, and it’s an active, engaged process to slow that slope down.

Dr. Morgan Levine: Yeah. Yeah.

Dr. Kara Fitzgerald: So talk about that.

Dr. Morgan Levine: Yeah, we can probably, through our behaviors, change how steep our slope is, right? So, maybe there, we’re going to go down the hill, I think, unless some massive breakthrough that I can’t conceive of right now happens. But we can change how fast we go down the hill, so maybe we have a less steep hill, and we’re going to go down more slowly, and it’ll take a lot longer for us to develop all these chronic diseases we see with aging. Or you could do things that are problematic, and go down quite quickly, or some of the things are not necessarily within our control. You can have life experiences, or as we saw with COVID, things that can kind of push you a little further than maybe you wanted to.

Dr. Kara Fitzgerald: Yeah.

Dr. Morgan Levine: But, what we see now is actually behaviors have a huge effect, it seems, on our aging process, and our health-span and our lifespan. So, things like our diet, our exercise, sleeping patterns, stress, so nothing that we didn’t already know, but I think now just there’s more and more evidence showing how important these different things are.

Dr. Kara Fitzgerald: The interesting thing that you speak about too, actually, of the many cool things in your book, is that a little bit of reversal can really add up. I mean, your research suggests that a little bio-age reversal. I mean, you were speaking about the study, I think it was recently published with Valter Longo, looking at the-

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: Yeah. Go ahead. Speak to that.

Dr. Morgan Levine: Oh, sorry. No, I was just saying, those studies, I think it’s under review right now, but yeah, both little “reversals,” I don’t know if we ever revert back to an initial state exactly. But you kind of maybe go up the hill a little bit more, or the slowing can really compound. So, one could imagine mathematically, if you’re only gaining, let’s say, 0.8 years of biological age for every one year of chronological age, that’s going to compound, after 10 years of time versus thinking about it at a single given point in time. So yeah, all these little things we can do.

So, I talk a little bit about the diets that seem the most beneficial. Although, again, it’s probably going to be slightly different for everyone, and the type of diet that one person will benefit the most from may not be exactly what another person would benefit the most from.But, it seems to be whole food, plant-based diets, and with the idea of not, maybe slight caloric deprivation, but not extreme by any means, and definitely not excessive calories is the best. There are also fasting regimens that might mimic some of the caloric deprivation, or at least cause a beneficial stress response to the system that I talk a little bit about. Then probably, the biggest one I always think about is exercise. So, I argue that if you could bottle the effects of exercise, it’d probably be the biggest longevity and aging pill on the market, because it’s amazing, not just in preventing disease, it seems to be able to reverse disease.

Dr. Kara Fitzgerald: Yes.

Dr. Morgan Levine: It’s one of the only things for Alzheimer, for people who are at risk of Alzheimer’s disease, it actually seemed to delay the progression of that disease. So, yeah, I think just any way that people can have an excuse to get up and move is going to be hugely beneficial for them.

Dr. Kara Fitzgerald: Would you actually put exercise in front of diet? I mean, you really can’t, and it’s sort of, a sort of a waste of a…

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: Yeah. But I’m just curious.

Dr. Morgan Levine: It’s hard to say, because I think a lot of our data is from population data, and probably people who are exercising a lot have slightly better diets, so it’s hard to tease the two apart. I wouldn’t say that exercise can overcompensate or can compensate for a McDonald’s diet or whatever it might be. But I think it’s often not considered maybe as much as diet, especially in aging. There’s been a lot of studies on diet for what seems like a more than a century, and only recently have people really been thinking more about exercise. Even, I think the other thing about exercise is there’s never really a point in your lifespan when it’s not beneficial. So, there’s always a fear that very frail people shouldn’t do it because it’s dangerous, but actually, randomized control trials show that even individuals who are in nursing homes, or have lots of functional impairments actually still benefit from exercise, moderate exercise, under supervision.

Dr. Kara Fitzgerald: One of the coolest studies that I read, in the not so distant past, was looking at exercise and epigenetic changes, and I know more and more of this, these studies are coming out, and they’re just really cool. Like, we can see beneficial changes from limited, very limited exercise. Then we can see sort of more profound changes with practiced exercisers. You talk about the changes to the methylome as we age. One of the things that I’ve thought a lot about in my work is tumor suppressor genes are shut off, so these genes that keep us cancer-free, that take care of us, and sort of surveil a body and protect us from getting cancer are shut down in the aging journey, which to me just seems like a raw deal. Like, what the heck?

It just, and it doesn’t make entire sense to me. Then you talk about the transposons being turned on, or these potentially oncogenes are actually turned on, making us more vulnerable. So, either in cancer or in aging, we can see similar epigenetic changes, and exercise can actually turn tumor suppressor genes back on. The study that I’m thinking of showed that the older, the older folks may actually experience this benefit more powerfully than younger folks, and maybe that’s just because they have more inhibition of their tumor suppressor genes. But any thoughts on that?

Dr. Morgan Levine: Yeah. I mean, yeah. Exercise probably does so much, and actually that’s why I think if something that is so powerful is, it’s one thing thinking about interventions that are meant to target like a single gene or a single pathway, but exercise is this really dynamic thing that your entire body is responding to this mild stress.

Dr. Kara Fitzgerald: Yeah.

Dr. Morgan Levine: So, yeah, it’ll definitely get encoded, probably in the epigenome because that’s how cells have memory for how to respond, or again, how to change their state to be more adaptive to their environment, and exercise is an environmental perturbation. It changes our immune system, which also is really important in cancer detection, and prevention in our bodies. It improves our metabolic functioning. Yeah. It’s, the effects are so widespread that just overall, it seems to be a beneficial thing. I do believe that yeah, the older people who probably got a bigger benefit, and actually in our diet study, it’s a very similar thing. The worse you started, and I think also the older you were when the intervention happened, the more you improved over the course of the intervention, because like you said, you have the most to gain from it, at that point.

Dr. Kara Fitzgerald: The older you were biologically, or both biologically and chronology? Probably either, right?

Dr. Morgan Levine: Yeah. It was both. Yeah. Either one.

Dr. Kara Fitzgerald: Then another piece of this study was just showing that there may be a heritable component. So, if you’re in preconception, you might be able to hand down some of these favorable epigenetic patterns from exercise to offspring, which to me is just really … I don’t know that we’ll be handing down rock hard abs, but maybe somewhere. But it’s just, it’s just really, it’s neat, and it’s just, always just very interesting to me.

Dr. Morgan Levine: Yeah. There’s another example of that actually with the Dutch Hunger Winter, where this was in the wrong direction, where mothers who had kind of malnutrition during this space of their life actually handed down, and offspring ended up being more prone to, I think it was like metabolic disorders.

Dr. Kara Fitzgerald: Yeah.

Dr. Morgan Levine: You can even experimentally show this in worms, where they can do some environmental perturbation, and they can see the effects of this for a few generations. It’s again, all encoded at the epigenetic level, which is pretty amazing.

Dr. Kara Fitzgerald: Yes. Yeah. It’s really quite extraordinary. I mean, it makes sense. Would you say that in the Dutch Hunger Winter, that was evidence of sort of a thrifty epigenome type being passed down, hanging onto every calorie, kind of thing?

Dr. Morgan Levine: Probably. Yeah. Yeah.

Dr. Kara Fitzgerald: Yep. So, a plant-forward diet, some caloric limitation, but not too crazy, exercise. There’s some suggestion if we’re overdoing it, and I always think about my own history competing. I used to get sick after every season, so I was clearly overdoing it. I would just wear myself down, and I would inevitably get sinusitis or something like that. I don’t anymore, exercising a little bit more balanced. So, I would imagine there’sa U-curve.

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: None at all, versus going way crazy, and then sleep and stress. So, talk about exercise and the U-curve, if you have any thoughts there, or anything you want to add to the diet, and then let’s talk about some of the other lifestyle components you think are really important.

Dr. Morgan Levine: Yeah. So, for exercise and actually diet as well, I think there are these U-shaped curves where a mild stressor, which we call hormesis, or some hormetic effect, is going to be beneficial. It’s going to make your system more robust, but once the stressor is too extreme, so again, in the case of people who are doing very intensive long-term exercise, so not like a short, intensive exercise, your system actually doesn’t have the ability to adapt as well to that, because it’s pushed so far out of the extreme. It’s also important to give it kind of the rest and rehabilitation part after.

Dr. Kara Fitzgerald: Right.

Dr. Morgan Levine: Where again, these things can then get encoded, and it can respond to the mild stressor you just put it through. So, they do show, I think, people who are ultra-marathon runners, it’s not that you continue to get a benefit linearly with the more exercise, but it is this U-shape where eventually there will actually be deleterious effects, and the hard thing to know is that kind of apex of where the optimal spot is, is probably different for each of us.

Dr. Kara Fitzgerald: Yes.

Dr. Morgan Levine: Yeah. There’s, it’s really hard to know where that is for ourselves. It probably also will change, as a function of our aging and our different fitness levels.

Dr. Kara Fitzgerald: Yes.

Dr. Morgan Levine: Yeah. But, and the other, I guess the other thing with exercise is, we don’t really know which exercise is best. Should I do-

Dr. Kara Fitzgerald: Right.

Dr. Morgan Levine: … mostly cardio or weight training or HIIT or whatever it is.

Dr. Kara Fitzgerald: Right.

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: Right, yes.Yeah. I wrote about that in my book, and it was just an interesting exercise, no pun intended, to go through the literature on all of these different types. But, you’re exactly right. So, there’s this individualization component that’s going to be … It is, it’s essential now, and it’s going to continue to be. My conclusion, at this point is, we’ll know, as we’re able to do serial measurements of appropriate biological age clocks, plus other markers.

I think, you talk about in the book, some of the standard chemistries that you based your PhenoAge Clock on, or your original publication before you created the PhenoAge, you were just looking at things on a complete blood count, standard panel, all of us have kicking around somewhere in our medical folders and a chem screen, really basic old-school tools. I mean, those labs were developed, I think, in the ’50s. It’s amazing to me how you’ve catapulted them into the next generation, and demonstrated them as being still useful. So, chemistry and CBC, and then a C-reactive protein, which is a little bit of a newer one, but so we can look at some of these, and I would just suggest to people to grab Morgan’s book to read about these biomarkers and where you can actually access a tool to plug your numbers in, to see your bio-age. So, that would be an easy useful tool that we can look at pretty often, as we wait for DNA methylation clocks to become cheap enough and available enough, which, so, is that logical?

Dr. Morgan Levine: Absolutely, yeah. Actually, I would say right now, for just a general health assessment, those are, they’re about on par with the epigenetic clocks. So, in terms of looking at how would they predict outcomes, not the individual clinical chemistry measures, but yeah, these composites where you kind of put them all together, and get a, again, you get like a biological age out of them, and there are free online calculators where people can plug them in. If you have a lab test with, like you said, metabolic panel, CBC, and C-reactive protein from a recent physical. For now, those are probably going to be more useful for people, because again, the methylation still costs a ton of money.

Dr. Kara Fitzgerald: Yeah.

Dr. Morgan Levine: It takes awhile to sequence. We’re still early days in really knowing what we’re capturing. Whereas, like you said, these other measures, we have a more, we have more intuition about what they represent. So, I think they’re a great thing right now, and I think in the future, the methylation’s going to be more powerful, but we aren’t there yet to where it’s really, we need to be doing … I don’t think we needed to be doing methylation over these more standard ones.

Dr. Kara Fitzgerald: We will link to one of those calculators or a couple of them. Okay, folks. So, if you just hop over to the show notes, I’ll make sure that we pop them in so you can use them.  Yeah. Super easy. Really cool. So, it’s not looking at them in an isolated, it’s looking at them within this calculator where you’re weighting them and analyzing them in the context of an individual’s chronological age. Then, you give a bio-age as outcome.  I just, I honestly, I think it’s pretty cool that these really old studies are, you’ve given them a current, an update, and they’re still very useful for us, so good job there.

Dr. Morgan Levine: Yeah. Thank you.

Dr. Kara Fitzgerald: All right. This is a long-winded way of saying that we need, this is how we, this is one way that we can individualize what we’re doing. So, people are asking me, we created a methylation diet and lifestyle program. Obviously, that I think you’re familiar with, that we published on and everybody’s asking me, well, do I stay on it forever, or do I do this? Or, how do I exercise, or do I continue? I’m sure you get those questions all of the time, and I think-

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: At this point, A, how do you feel? We can, there’s subjective questionnaires we can use. B, what do your labs look like? C, if you are measuring biological age, doing DNA methylation clocks from a good reputable lab, then what are you seeing there? It’s only those ways that we can speak to the benefit of a given protocol.

Dr. Morgan Levine: Yeah, exactly.

Dr. Kara Fitzgerald: So, sleep and stress.

Dr. Morgan Levine: Yeah. I will just say, on a personal note, these are ones I struggle the most with in my life. I think a lot of busy professionals can probably relate. So, yeah, in sleep, it seems to be, it’s not just the quantity of sleep. Again, how much sleep should we be getting is a little bit of a debated topic. I think they say somewhere between seven, maybe some people need eight hours of sleep, but again, it’s this U-shaped curve. Too little sleep is bad. Too much sleep is bad, although we’re not exactly sure why, whether those are just indicators of other things, other health problems.

Dr. Kara Fitzgerald: Yeah.

Dr. Morgan Levine: Yeah. So, these are the hard things to kind of sort out with these observational studies. But, the other thing we know is that the sleep quality, so whether you have uninterrupted sleep or versus insomnia, where you’re waking up in the middle of the night and having a hard time going back to sleep, these seem to be problematic for our health. Then the other thing is stress. Usually what we see in stress is not necessarily, people think of, oh, job stress or all these other things. But it’s actually, some of the most impactful things are things like socioeconomic status or some of these really major chronic stressors that people are going to suffer from for perhaps their entire life, if not decades and decades of their life.

To me, the most impactful studies are the ones that just show, just knowing someone’s zip code, that they were born into, how well you can predict how long they’ll live. This seems to be kind of due to differences in socioeconomic status, and neighborhood disorders, and all these other things that you can measure. But yeah, it’s something we have slightly less control over, but still important to be aware of, and probably at the policy level, something we need to do something about.

Dr. Kara Fitzgerald: Yes, and I appreciate you speaking to that. I know that you’ve published on it, I believe, on racial disparities and biological aging.

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: And that could potentially relate to zip code, et cetera, and just how it’s baked in institutionalized racism. I mean, would you say that’s a biological age driver?

Dr. Morgan Levine: Yeah. I mean, we have some studies that show where people can report discrimination, and that seems to have an impact, and definitely these things that are impacting different groups of people, in terms of their social mobility, or any of these other things are going to have major impacts it seems, on aging, and as a result on health-span and lifespan, and this is why we see these huge health disparities in the United States, and in also other countries around the world.

Dr. Kara Fitzgerald: Well, I appreciate you speaking on that, and thinking about it, and publishing on it because it’s just, it’s important to keep a constant light on it. So, we need to be tending to all of these, and some we can do easier, and more readily than others, as you just spoke to. But all of these can add up, as you stated in the beginning, and really improve  health-span, and what James Fries said, many years ago, this compression of morbidity.

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: Yeah. So, we can live well longer. Would you say that, that’s conclusive?

Dr. Morgan Levine: Yeah. I mean, yeah. The compression of morbidity, I think, is the goal of many of the people in the aging field. Some people want to live forever, but I think for most of us, we want to, even if we all have maybe 100, 110 years on this planet, can we have the vast majority of that be in fairly good health? Again, I’m not, when I talk about health-span, it’s not to exclude people who are born with certain chronic diseases. So, it’s more the accumulation of chronic diseases with aging that we’re talking about. So, it’s not like someone has a health-span of zero, if they’re born with something, but the idea is, can you push that accumulation as close to the end of life as possible? This’ll be beneficial for wellbeing. It’ll be beneficial economically. We see how much, I mean, how much money is spent in the last few decades of life, for most people, is exorbitant.

Dr. Kara Fitzgerald: Yeah.

Dr. Morgan Levine: The other interesting thing I have read about in some studies, is centenarians have much fewer healthcare costs in the last few of their life, compared to the rest of us. Again, it has to do with probably a compression of morbidity. I think we potentially have the ability to compress our morbidity. The extent to which we can do that is somewhat unknown, but I think we definitely can do it to an appreciable degree.

Dr. Kara Fitzgerald: So, as we just head to close here, I mean, just a couple, a few more questions. So, why not just suck down a Yamanaka cocktail or a little, just a little sort of Yamanaka-light cocktail, and reverse our bio age a little bit. Why isn’t this ready for prime time, even though we’re doing it in the animal studies and cell studies, and what are the issues with making us younger with something aggressive like that?

Dr. Morgan Levine: Yeah. So, since the studies on this kind of cellular programming came out, people have been very excited about this in terms of a therapeutic. I would say we’re still in the very basic science phase of this. This is not necessarily approaching translation. We’ll see, but not necessarily anytime soon. I think, there’s major hurdles we need to overcome. So, one is, too much of this can actually promote, it can push cells too far back to where they become, they lose their identity. Actually, then they actually have the potential of becoming what are called teratomas, which are these really weird tumors that have all the different cell types in them, because they don’t know what they’re supposed to be anymore. The same thing, as you don’t want to push cells too far back because, let’s say you’re doing this in your liver.

You want to have all your normal liver cells, like your hepatocytes and your Kupffer cells. You don’t want a liver full of just embryonic stem cells, because you’re not going to function the correct way. So, the few things we need to figure out are one, the dosing. How do you know how far you’re pushing a cell back, and when to stop. Also, the problem is that it’s probably going to be different for different cell types.

Dr. Kara Fitzgerald: Yeah.

Dr. Morgan Levine: The timing of this is going to be, to some degree, cell-type specific. Then I think just the delivery system is hard. So, it’s easy to do it in a dish and then also in mice, we’re using transgenic mice, but I don’t think people want us CRISPRing, and actually changing their genome just to get Yamanaka factor expression. So, how do you deliver this safely and effectively in a whole organism, is something that’s going to be challenging, but again, potentially not impossible, and exciting to kind of see where the field goes.

Dr. Kara Fitzgerald: Thoughts on some of the longevity drugs being studied, Metformin, Rapamycin. I mean, are these ready for prime time, in your opinion?

Dr. Morgan Levine: I think we’re jumping the gun if we say that they’re actually slowing the pace of aging. They might, but I think we don’t have conclusive or even like very strong data that they are. I am somewhat optimistic that they will have an impact. There’s clinical trials going on for both. So, Metformin, Nir Barzilai and others are trying to get what’s called the TAME trial up and running, where they’re going to do a randomized controlled trial to look at the effect of Metformin on delaying disease incidents. It’s among people who have a chronic disease, time to second disease. Then, same for Rapamycin. There’s some small human trials that there’s also really exciting trials being done in companion animals, almost as the first proof of principle, that I think will be exciting.

Actually, now there’s a lot of people self-experimenting with these drugs. I don’t, but we might have a kind of natural experiment without even attempting it, just because there’s been a lot of excitement around them. My thinking, especially for Rapamycin, is that the animal studies show that it works even quite late into life. So, for anyone who is not really worried about the clock running out, I would say you have enough time to wait and see, before jumping on that bandwagon. But I’m someone who’s lower, I’m a low risk-taker. So, to each their own.

Dr. Kara Fitzgerald: Right, right. Metformin, there’s concern around it. I know there’s an argument that it’s actually beneficial to mitochondria, that it, in its inhibition of the electron transport chain, one of those proteins, that it may have a hormetic effect on mitochondrial health. Then others argue that it’s actually perhaps toxic. Any thoughts on that?

Dr. Morgan Levine: I mean, for me, my biggest concern with Metformin is actually there’s a few studies out that say it might actually blunt the benefits of exercise.

Dr. Kara Fitzgerald: Right.

Dr. Morgan Levine: To me, that is, because unless it can completely replace the benefits of exercise, I would never want to kind of lose those benefits, especially if you’re going to take the time and energy to go out and exercise. I mean-

Dr. Kara Fitzgerald: Right.

Dr. Morgan Levine: Exercise has other benefits for endorphins and stuff, but that’s something I think really needs to be followed up, because I would imagine most of the old clinical trials, because Metformin’s a diabetes medication, is not done in highly active.

Dr. Kara Fitzgerald: Right.

Dr. Morgan Levine: … very healthy individuals. So, I think, figuring out the effect on those types of people is going to be important. So, that’s my biggest concern with it right now.

Dr. Kara Fitzgerald: Yeah. Yeah. That makes sense. I know I’ve heard people talk about toggling it between exercise-

Dr. Morgan Levine: Yeah.

Dr. Kara Fitzgerald: But what would be the optimal toggle?

Dr. Morgan Levine: Exactly. We have no idea how long … First, we don’t even know with exercise what that time is that your body is actually still getting this benefit, and same thing with Metformin. The timing of it, I think, is going to be hard to sort out.

Dr. Kara Fitzgerald: Yeah. Yeah. A lot of questions, a lot of questions. So, listen, I know you’re hopping over to Altos Labs, which rumor has, is Jeff Bezos’ baby, and he wants to crack the aging code over there. So, I want to ask you a little bit about that. Any excitement to share about what you’re going to be focusing on? I know that brings you back from here, cold Connecticut to warm California. I’m kind of envious of you in that. Then, just speaking to the future, and what you’re working on and excited about.

Dr. Morgan Levine: Yeah. So, it’s actually, so the company is not technically Jeff Bezos’s company. I think there’s a rumor he’s an investor, and this is not even something that’s been confirmed to people on the inside, but it was, it was founded. One of the main founders is Rick Klausner, who is serving as the Chief Science Officer. I think his official role, who is, he was a former Director of National Cancer Institute, and then really instrumental in GRAIL and Illumina. This is kind of his new big project, which I was not looking to move from Yale. I was very happy. My lab was very well-funded. I had lots of students and post-docs, but then kind of got this opportunity, and it seemed like a once in a lifetime thing. So, I will basically be continuing doing the same types of projects I would have done in Yale.

Although, now probably expanded, because I have an entire new set of amazing colleagues that were also recruited, and we’re going to try and do a lot of, kind of, really big team science projects. I think the other main difference, which made me excited to move to Altos is, in academia, it’s really hard to do high-risk, high-reward research, because of just the way things are funded. You have to really prove out that what you’re going to do is going to work. So, you can’t take risks and try … you have to take these incremental steps, but the ability to just try what might be, sound like a crazy thing, and just see if it works, I think is really exciting.

Because if we look back on big breakthroughs, they’re, for the most part, they come out of things that are unexpected, and just from trying tons of different things and following the science. So, that was the other thing that just made me really excited. There is kind of a rumor that also this is focused solely on this reprogramming, but I think it’s really just the basic science of understanding of what makes a healthy cell, and if we have any power to make what have become unhealthy cells, healthy again.

Dr. Kara Fitzgerald: Right.

Dr. Morgan Levine: Yeah, we’ll see.

Dr. Kara Fitzgerald: Very exciting stuff. Well, listen, Dr. Levine, it was fabulous to have you on New Frontiers. I could continue to pick your brain, but I know you’ve got a lot going on with your book launch here. So, thanks for joining me today, and having this really terrific conversation.

Dr. Morgan Levine: Absolutely. This was fun. Thank you for having me.

Dr. Kara Fitzgerald: Absolutely. All right. Good luck on your launch.

Dr. Morgan Levine: Thank you.

Dr. Kara Fitzgerald: As always, thank you for listening to New Frontiers in Functional Medicine, where our sponsors help bring the very best minds in functional medicine, and today is no exception. Not everyone can be a sponsor on my platform, and I so appreciate the good work, relentless research, and generous support from my friends at Biotics, TA Sciences, and Integrative Therapeutics. These are brands I know and trust in my own clinic and can confidently recommend to you. Visit them at BioticsResearch.com, TASciences.com, and IntregrativePro.com, and please, tell them you learned about them on New Frontiers.

If it’s not too much to ask, I would appreciate a thumbs up and a kind review wherever you listen to New Frontiers. Thanks.

Morgan Levine is an assistant professor of pathology at Yale University School of Medicine and the author of True Age: Cutting-Edge Research to Help Turn Back the Clock. Her research focuses on the science of biological aging, specifically using bioinformatics to quantify the aging process and test how lifestyle and pharmaceutical interventions alter the rate of aging. As a leading voice in the field of aging and longevity science, she has been featured in media outlets such as CNN, The Guardian, Time, Newsweek, The Huffington Post, the BBC, and many more. She also appeared in the DocuSeries by Netflix and Goop, alongside Gwyneth Paltrow, released in 2020.

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