The Melanie Avalon Biohacking Podcast Episode #168 - Dr. Morgan Levine

TRANSCRIPT

Melanie Avalon: Hi, friends. Welcome back to the show. I am so, so, thrilled about the conversation that I'm about to have. So, little backstory on everything. We discuss a lot of health-related topics on this show. But as you guys know, my obsession is longevity and anti-aging and all of the diet, lifestyle, genetic, environmental factors that go into that. So some of my favorite episodes I've had on this show have been surrounding that and have been with guests who actually work with today's guests. So you guys might have heard my episodes with David Sinclair and Dr. Valter Longo and recently a new book came out called True Age: Cutting-Edge Research To Help Turn Back The Clock. The book came on my radar, I knew I had to read it. I knew I had to interview the author and then the author's probably publicist, or agent or publisher or somebody reached out and connected us. I was so, so, thrilled to have the guests on the show. I got the book, I read it, it was everything I am obsessed with and I know you guys are as well. It dives deep, deep, deep into the concept of aging, the difference between chronological and biological age, all of the factors that go into that and the concept of actually, measuring it. As well as very approachable diet and lifestyle factors that affect it. We will dive deep into all of that but I am here with Dr. Morgan Levine. 

She is the assistant professor of pathology at Yale University School of Medicine and again the author of this new book, True Age, and she's been everywhere. I had actually, seen her work back in 2020 on the Goop series on Netflix that had Dr. Valter Longo in it and they actually used some of her work in that, so that was super cool. She's also been on CNN and The Guardian and TIME and BBC and everywhere. And you guys have probably heard her because she's been on a lot of podcasts related to these topics. So that's why I'm so excited. Dr. Levine, thank you so much for being here.

Morgan Levine: Thank you for having me, Melanie, I'm excited to be here.

Melanie Avalon: And so, okay, I hope you don't think this is super strange. I do follow you on Instagram and you posted a while back about how your dad was an actor and then you mentioned it in your book as well and the post you had posted. So I'm a huge Star Trek fan. Some of the posts you posted was about one of the episodes he was in, so I actually watched that last night in honor of this interview today. I'm obsessed with the original series. So, I was like I should watch this as like a little get ready for tomorrow. So, your dad was awesome, by the way.

Morgan Levine: Thank you, he's only in that episode I think for the tiniest amount of time and I haven't seen it in forever but yeah it is exciting.

Melanie Avalon: He had the honor of getting the Vulcan-- like Spock took him out with his Vulcan, like pinch thing, that is the honor of all honors. In any case, I'm thrilled to be here with you today. There's so much I want to ask you about, but I am curious about your personal story, which you do talk about in True Age, which is super amazing but what got you interested in longevity? Were you always interested in it? Did you have an epiphany one day? I mean, what led you to where you are today? I know you do a lot with data and programming and all of that stuff. So, what's your story?

Morgan Levine: Yeah, speaking of my dad, I think, if I really had to think back and come up with when did I actually started getting interested in this field, it's probably at a really early age. I don't remember the exact moment, but my father was in his mid-50s when I was born, so I was very aware from a young age that there was an aging process and people do grow older and lose some of the functional abilities that they had and are more at risk of disease and ultimately more at risk of death. So, I was very concerned about my parent's aging process and potential mortality, but it probably wasn't until I think I was a senior in undergrad that I actually discovered there was a whole science around this and I was very interested in health and started premed and undergrad and thought I was going to do something in kind of the health sphere and then really stumbled upon this. Everything kind of fell into place from there and I kind of devoted all of my training and interest to trying to understand the aging process and figure out if there is actually any way to intervene in it.

Melanie Avalon: I love it. And I have so many questions. Okay, I guess stepping back a really broad general question, but it must be asked, and it's just the question of why do we age and in particular, because you talk about in the book about how aging appears in different species and how different species have different rates of aging. Like the honeybee, it's different by gender and then we have jellyfish that are potentially immortal. And then last night, I was looking through PubMed and all of your-- well, you have so many studies, read a lot of your research and one of your recent ones was on the naked mole rat and how it doesn't even display, I guess, externally signs of aging, which kind of blew my mind not compared to epigenetically because that's what you're talking about. But in any case, and then there are humans. So why do we age? And why is it different between species?

Morgan Levine: Yeah, I think the actual question is, why do we not age faster? I think people can think, in a nonliving system. So think of a car or a building, we know what happens with time. There's deterioration, you have these things that are beautifully intricately designed, go from order to disorder. And this is kind of the whole concept around the second law of thermodynamics and entropy. But the amazing thing about living systems, which humans are, or all these other animals are, is that we actually can to some degree slow that decline and slow that dysregulation. I think the difference between different species is the degree to which that dysregulation is actually opposed and this probably comes down to some evolutionary selections. So certain species, in order to continue and have high fitness, they had to slow that down for longer to actually, be able to reproduce and have offspring that can reach fecundity.

And other species that may be live in a more predatory environment. They reproduce really quickly, have lots of offspring. They don't need to have this really prolonged lifespan. And their fitness Gamble is live fast, die young.

Melanie Avalon: Like the jellyfish that are, potentially "immortal". Are they reproducing?

Morgan Levine: Yeah, I think the jellyfish and there're some other kind of examples of this, too. I don't know whether they-- I will be honest, I don't know a ton about jellyfish kind of lifecycle. But yeah, I think they can almost rejuvenate themselves. So, I don't actually, know how much reproduction is going on in them. 

Melanie Avalon: Oh, I'm going to have to look that up.

Morgan Levine: Yeah, I actually, need to look that up now that you've brought it up.

Melanie Avalon: That'd be really fascinating. Is that pretty consistent? Like in the whales, and the sharks that live so long? Do they not reproduce until they're like 100 years old, or something?

Morgan Levine: Yeah, or the other thing is the number of offspring that each animal will have at a given kind of time, so with each pregnancy. So, longer-lived animals also tend to have fewer offspring at any time and those offspring actually take longer to develop. So there's more, if you think about it, you have to extend the time the parental animal is alive to make sure that you have enough progeny to optimize fitness. Whereas an animal that is probably not going to survive more than a few years because of predation or something, they need to just have lots of offspring really quickly, can't put too much parental investment in them and so there's probably not as much opposition molecularly in terms of offsetting aging.

Melanie Avalon: I have two follow-up questions to that because you talk about the role of gender and aging and the fascinating paradox with women. You mentioned how in every single society, women always live longer, and you have these really cool analogies that make it really approachable. So listeners go ahead and get the book, but I'm super curious if fertility is involved in that and just what we were just speaking about with different species having offspring. So does the body like in humans, I mean, I know it knows when it has a baby, but say a woman has a baby, and then she's had the baby. Does the body know like, Okay, I've had my baby, I'm done? And if so, does that mean that women who don't have children live longer?

Morgan Levine: Yes, so actually a lot of people I think were interested in this question. I haven't seen any concrete data that really shows that not having children extends longevity but we do know that menopause seems to accelerate longevity. So, perhaps there's also this kind of signal that happens that as women transition into menopause, there seems to be, at least when we look epigenetically, an acceleration of the aging process. And then going back to the animals, the other interesting observation is that people have compared this male-female longevity advantage and for most species, the females outlive the males, although the gap tends to be much bigger in species in which there's more maternal versus paternal investment in offspring. So it goes back to this idea, if the fathers are actually not contributing that much to the offspring's survival, they're a little more disposable.

Melanie Avalon: They die sooner.

Morgan Levine: Yeah, exactly. But this is probably on a species level. I don't know if individually there's some signal going on, it's probably just something they get genetically selected for it at the species level.

Melanie Avalon: Oh, that's really fascinating and then related to that, have humans always sort of societally taking care of offspring? Like now, for example, if there's an orphan, society takes care of that child, presumably, I don't-- I'm not making-- I'm not we're not making like broad, but that concept exists, at least that concept has that always existed in our species, do you know?

Morgan Levine: Yeah, I think so, humans tend to be more social, a more social species and we tend to be more in groups rather than kind of individuals off on their own. These are a little bit things I'm not totally familiar with, but monogamy when that kind of arose and where that came from, I think too will dictate some of this as well. But yeah, I think there's always been this kind of communal aspect in human societies and people talk about this idea of the grandmother hypothesis, which some people say might be why women live longer because the grandmothers need to survive to help their sons and daughters care for their offspring. That's kind of a theory, I don't know if it's ever been proven. But yeah, there is this kind of idea that the community also helps raise children.

Melanie Avalon: And do you know, this is like a very vague question, but presumably there's this drive or this concept in our bodies or in our DNA, where the goal is continuing the species through offspring seems to be the goal. So is that messaging somewhere in the DNA? Because it seems like the goal could also be preserve the self, so could we change that? I mean that's a very selfish change but could that change happen on a genetic level?

Morgan Levine: Yeah, I mean, I think in some ways it is and this goes back to natural selection versus artificial selection. So, genes that make it and get continue on in a species are going to happen because of natural selection, which is solely on fitness, and fitness is defined as the number of offspring that you have that make it to actually be able to reproduce themselves. So, I feel like evolutionarily our bodies are always going to optimize that fitness and reproduction. However, I feel like as humans, we're actually going back and doing some sort of artificial selection. We're trying to actually now reoptimize ourselves for other things that are perhaps not fitness related and in the end actually, there's a decline in fertility overall. So yeah, I think perhaps we have shifted the balance to some degree.

Melanie Avalon: And I guess I wasn't thinking about this when I asked that question just now, but you do talk in the book about, like cancer cells, for example. I guess in a way are they, if you hold to the theory the adaptive oncogenesis theory, the theory that they are adapting to an environment that's not suitable to them and so they kind of go rogue and do their own thing. I mean, that in a way, is that the concept of immortality in cells are trying to be immortal?

Morgan Levine: Yeah. So, this comes back also to other kinds of concepts in evolutionary biology about group fitness versus individual fitness, which I think a little bit actually, maybe your prior question was getting at which you can also think that selections happening as a group. Even if one individual is really successful if the entire population can't survive after a while, then that selection won't happen for much longer. And that's kind of I think what happens in cancer cells. So these cells, they are what we would call reproducing really quickly. So they're proliferating and dividing and growing, but again, they end up killing their environment and the host and everyone goes down with the ship. And then the adaptive oncogenesis idea that you mentioned, which is this theory by my colleague, James DeGregori it's his idea that with aging the internal environment changes and before you know all cells had equal fitness chance but as the environment gets more what you might think of hazardous, you get this rise of these certain subclasses of cells, which tend to be maybe cancer and have this kind of advantage in terms of being hyperproliferative in these environments.

Melanie Avalon: I'm sort of embarrassed because before I read your book, they talk about in the biohacking world and the health world and all these podcasts about senescent cells and they're always posited as automatically like a negative thing like, "Oh, got to get rid of senescent cells, senescent cells are leading to aging.” Then I read your book, I didn't realize actually their purpose is to stop cancer and are they not necessarily bad in and of themselves only if they're not gotten rid of, I guess?

Morgan Levine: Exactly. So, senescent cells the reason they even exist is because they do have some functional utility in our bodies, and we see them in wound healing, there's also a wave of senescence, I think, during birth. There is definitely a utility of for senescent cells and some people have postulated that it is one kind of anticancer mechanism. If you have a cell that undergoes some damage, or some maladaptive change, the cell has a few options, one, it can try and fix that, two, it can undergo apoptosis or cell death, or the other two are it can actually undergo senescence, so that cell will no longer divide, it doesn't die, but it just sits there and people kind of refer to these as zombie cells because they're not quite alive and not quite dead. But if none of those things happen, the cell actually has the potential to go on and form cancer, which they think senescence might be the last kind of failsafe to stop a cell from dividing, so it doesn't go on and become hyperproliferative and turn into a tumor.

Melanie Avalon: And in the timeline of that senescent cell, does the body then-- properly functioning body get rid of that senescent cell or does it just hang around perpetually?

Morgan Levine: Often, I think the problem is that they do hang around, I think the body potentially has capacity to get rid of them. But like cancer cells, they also have these different mechanisms that make them immune to cell death. So, they have what we call anti-apoptotic mechanisms, so they won't undergo cell death on their own. So, most of them hang around, and then you can imagine with age, you're going to get more accumulation of them. So, there might only be a few when you're much younger, but as more and more cells kind of move into this state, which is kind of this end state, they're going to just start accumulating and the problem with senescent cells is they tend to have this very nasty phenotype where they're highly pro-inflammatory, so they're spitting out all these inflammatory cytokines and growth factors, and can actually damage their neighboring cells in turn.

Melanie Avalon: So this is a lot of stuff that obviously can go awry in the body and I just noticed, you were saying that with age this could happen. And I guess we actually, probably should define that as well. So when you say this can happen with age, do you mean, literally just the amount of time that has passed or do you mean with aging? Like the way, we think of aging?

Morgan Levine: Yeah, so that's a great question. You can imagine how as a function of time these will accumulate. But then you can also imagine that the rate of accumulation can be dictated by how fast someone's aging still how-- how much damage cells are undergoing in the body, how much inflammation is in the body. And so cells can actually-- more and more cells can actually, transition to the senescent state at a faster rate in people who might be aging faster. So yeah, it is this kind of accumulation over time but the rate of that actually can be dictated by different factors that have to do with biological aging.

Melanie Avalon: I'm just realizing-- Because reading your book, I kept hearing biological age versus chronological age. I'm just realizing right now, it should be two different words like we shouldn't have the word age to mean. I mean, those are two completely different things, like the passage of time versus the accumulation of damage. That's not even the same thing. [laughs] I'm feeling frustrated right now. Okay. So, speaking to that because there are a lot of theories and you discuss them in the book around what that second definition of aging, that accumulation of damage, or those negative changes that happen, so there are a lot of theories about why that's happening but you talk about the loss of specificity in cells. I was wondering if you could talk a little bit about that and what your theory is.

Morgan Levine: Yeah, everyone will have a different definition to what they think biological aging or aging is and I totally agree with you, I wish we had a different term because I think when you say age or aging it immediately evokes this idea of chronological ages. I do wish we could just come up with a better term, I've not been able to yet. But the way I think about biological aging, or the sexual aging process is that again, through evolutionary time, our biology has optimized this state of human living system that is really optimized for performing all the things that humans do. And through development, we reach that state and I think of aging as any maladaptive divergence away from that and it can happen-- There are so many things that go wrong with aging, you can diverge from that state in a number of different directions but is this loss of this intricately designed system?

Melanie Avalon: You talk about the different levels, from the atom, I don't have the list of them right here. But you know, from the atom, cell, organ, organism, and beyond? Where does this aging process start? Does it start at the level of the atom or higher than that?

Morgan Levine: Yeah, I haven't seen people study it at that level, but I can imagine that perhaps it does, but yeah, we usually think that it's going to start at these lowest levels of biological organization. So, you have the molecular level and then essentially cellular level, there are a few levels in between, and then tissue, organ, organ system, organism, and then it goes up from there population, etc. But we think that these are actually small changes that are happening first at the molecular level, and in specific molecules, and then once you get enough change or divergence at that level, it starts affecting the next highest level. So, let's say eventually cells are starting to dysfunction. Once there's enough dysfunction in a critical mass of cells, it starts affecting tissue function, and eventually tissue function is going to affect organ function as certain organs fail, the whole system starts to fall apart. So, this is I think why we don't "see aging till much later" because you can't see these small changes that are actually what is starting much, much earlier in our lifespan potentially before we're even born.

Melanie Avalon: And so that concept of aging starting in certain places, and then moving into certain systems, for most people, where has aging affected the majority of their organs and systems or does it tend to stay in one avenue or one lane? And I have a second question, but first just to paint that picture.

Morgan Levine: Yeah, it's usually the former because most of our systems are interconnected. As you start getting dysfunction or failure in one, it's going to also impact failure in other ones and that's why I think with age, we tend to see this increase in what we call comorbidity. So, people developing two, three, perhaps even four or five diseases simultaneously, which also makes it really hard to treat clinically. But basically, once when people die, it's what we think of as this tipping point, you've got to a point where the entire system collapses because there's kind of so much widespread dysfunction. So, most people-- we give people a primary cause of death, but it's often a lot of compounding factors that are contributing to that failure.

Melanie Avalon: And so if you put it on a graph, people who die from the one that they decide is what they died from, do younger people tend to have way less of the comorbidities? And then if you're older, and you die-- so if you die of heart disease, when you're 30 versus like, 70, are you much more likely to have a lot more comorbidities at 70 than at 30?

Morgan Levine: Yeah, I think when people have early mortality, I almost feel these are these critical events. So, it's these huge disruptors of the system. So, you have a heart attack and you can no longer deliver oxygen nutrients to the rest of your body, and that it's kind of like a, game over. But when people tend to die at older ages, it tends to be more progressive. Of course, there can be these really acute, sudden events that can "Take someone off out." I think an analogy I use in the book is this hillside and if you think of the bottom of the hillside, you kind of fall off the cliff is death, younger people are going to be towards the top of the hill but you can imagine there could be some really massive acute event, they could make them fall all the way to the bottom. It's going to take a bigger event to get them there. Whereas for an older person, they're slowly kind of making their way closer and closer to the bottom and it takes a much smaller kind of event to trigger this kind of overall failure.

Melanie Avalon: Okay, gotcha. We were talking before about how we have a mutual friend James Clement, and he's done a lot of work in supercentenarians. So, what's happening with that population of people? Are they just immune to all of these issues that otherwise affect other people with aging?

Morgan Levine: Yeah, so they're really interesting population. And yeah, James and there are other people who have been studying centenarians, as well, he studies supercentenarians, which are even older, so 110 and above. And they seem to just have this much slower rate of aging. They seem to be much more like you said, immune to all the things that might make everyone else age faster. And the other really interesting thing about centenarians and supercentenarians is that most of them stay healthy, for a much longer proportion of their life. So, it's not just they develop some diseases in their 80s and they're still able to survive, but they're actually what we call compressing the morbidity. So, they're extending what we call their health span and only getting disease at the very end of life. And centenarians, actually in terms of medical costs have much lower medical costs than people who are dying in their 70s or 80s or have any of the normal life expectancies.

Melanie Avalon: I've two follow-up questions from that. One is, I guess, because of their genetic profile that is allowing them to experience that and I do want to be clear because I think-- we could talk about this but I think otherwise we wouldn't say that genetics are the creme de la creme of the reason that people live long, but in this case was with the centenarians and supercentenarians, maybe it is the reason, so those genetics, are they basically doing things that we could do if we could edit our genome or make those epigenetic changes in our own genome? Or is it like an outlier-type gene situation where we can't even have that concept?

Morgan Levine: Yeah, hypothetically, we could if we could figure out what they were. So, exactly like you said, for most people genes aren't going to determine our longevity or necessarily our risk of disease unless you have very specific risk alleles. But these supercentenarians and even centenarians tend to have won the genetic lottery. So, they have the perfect permutation of genetic variants, which gives them this advantage. And there are a lot of people looking at genetics of centenarians and supercentenarians to try and figure out what genes are actually giving them this advantage and can we figure out-- even if we're not going to edit genes but how do we target those pathways? The problem is that traits like longevity tend to have lots and lots and lots of genes that are all acting simultaneously. Again, it's not that they got the one longevity gene, but they just got the perfect pattern or perfect combination of genes to get to that point. And it's not clear exactly how many genes are contributing and different supercentenarians or different centenarians might actually have different combinations. So, there might not even be the single magic version, but hypothetically if we can start figuring out maybe what these are, we could try and optimize for that but it's a little more complex I think than people originally had hoped.

Melanie Avalon: I was actually thinking about that last night when I was reading the naked mole rat study because I feel there are a lot of key genes that people even like me and my audience, so non-scientists who are not familiar with SIR2 and okay, maybe I'm just going to think of SIR2, but there are a few key genes that people think of, but then I was just reading through some of your research, and I was like, "Oh, there are so many genes." So, I was actually wondering I guess talking about something like SIR2 because you talk in the book and this blew my mind and I would love to hear a little bit more about it. You talked about some research. Was it your research that you conducted in yeast and the two aging phenotypes?

Morgan Levine: Oh, no, yeah, that's not mine. I love that study. It's such a beautiful study.

Melanie Avalon: I am fascinated by-- because you're talking about how they are doing research in yeast. And basically, at least in the beginning, there were two and correct me if I'm wrong, but two general phenotypes of aging, one that involved the mitochondria, and one that involves the nucleolus in the cell, and there was an influence of genes in that and it all involved lifespan. But what was really interesting-- I just spat out a lot of words. So, I'd love to hear your thoughts and just the concept of the study. But what really caught me was, you're talking about how it seemed to be determined early in the lifespan about which profile the yeast would exhibit that led to their aging rate. Yeah, so what's going on there? And is that happening in humans?

Morgan Levine: Yeah, that was this really beautiful elegant study also because the way yeast, "reproduce" I think it made it feasible. They had the mother cells in these microfluidic devices that is fixed and then they could watch as the daughter cells or yeast bud off, so the next cell just buds off and then falls off. And they could capture these and actually track the lifespan of these changes and so they looked first at two genetic strains. So, they had two, so I think, yeah SIR2 was one, I'm forgetting what the other one was.

Melanie Avalon: Oh, HAP4?

Morgan Levine: Yes, yeah. And they can look at the trajectory of molecular changes of these two strains over the lifespan. And they found one exhibited a lot of chromatin-related aging changes whereas the other one was more mitochondrial. And these pathways were very clear and seem to start really early. So it was almost like this deterministic thing, which based on the genes was how that yeast cell was going to age. Then eventually they actually combined them and got this third pathway as well which was really interesting. But in thinking about how this comes back to humans, I don't think there's been explicitly anything is shown. And again, I don't think it's going to be down to a single gene. But we probably each do have a propensity to age in a different way. So, some people might be more at risk of frailty or neurodegeneration with aging, whereas maybe other people are more at risk of some kind of metabolic change or developing diabetes with aging. And I think once we can eventually get a handle on personalized aging risk, I think we can actually eventually maybe even tailor prevention or treatments towards different groups of people.

Melanie Avalon: I find this so fascinating and you were talking about how in those studies they would try over-exerting certain genes, I think either the SIR2 or the HAP4, and then it would make the yeast lean towards one of the phenotypes rather than the other or that third phenotype. What really was distressing me because it was a high percent that would lean towards certain phenotype if they edited the gene, but it wasn't 100% and so I'm just haunted by, what are the other factors inn that? I just want to know.

Morgan Levine: It might be some degree of random stochasticity. So, there could be a little randomness, but then there's always a propensity towards one or the other depending on which gene you're overexpressing. And then I think in the third one, I think they overexpressed both together, I need to go back and read the study it's been a little while and found this other trajectory, but they also found I think that there are still ones that follow the other two trajectories as well. There's a little bit of randomness in which way you're going to go. So, you can think of what are those called, like, the Plinko balls, the price is right. I don't know, you dropped the ball down and it finds this way. You can bias it a little bit but, yeah, it's not a perfectly deterministic kind of feature.

Melanie Avalon: Well, actually, that ties in nicely to questions I wanted to ask surrounding your work because you talk a lot in the book about the evolution of creating your tests for measuring aging, and that whole process and the data and the algorithms that go into it and accounting for all of this information, which just seems so overwhelming to me and so the big question is, for measuring aging, so this concept of biological age versus chronological age and maybe self-explanatory and we've been saying it a lot, but chronological age would be just the literal amount of years that a person is alive and then biological involves the-- How would you define biological age?

Morgan Levine: Yeah, again I think this is a place everyone would define it slightly differently the way I define it, it's just kind of how much you've diverged from that optimal state. And you can-- we always have to put it relative to the general population. So, we're not measuring the actual age of someone's cells or systems in terms of chronological time, but we're saying, you have the profile of someone in the general population or whatever population we developed this algorithm out of that is 40 years old or 50 years old or whatever it is. And then you can compare that to someone's chronological age to say, in general, do you tend to be aging faster or slower based on what we would expect for someone with your chronological age?

Melanie Avalon: I'm super curious just because of the rampant increase of degenerative health issues and chronic disease, are clocks that are created now are substantially different rate than 50 years ago, 100 years ago, what we're comparing it to, has it changed a lot.

Morgan Levine: Yeah, that's actually a really good question and it's not something people think that much about. But yeah, if you were to create a clock using today's population, what the data actually suggests is if people today look actually slightly younger than they did, let's say in the 80s or 50s, it makes a little bit of sense why people are living longer as well, so it matches the increases in life expectancy. But the problem is that a lot of the epigenetic clocks were developed in populations from let's say the 80s or a few decades ago because we needed to actually have a long enough follow-up time to actually see mortality. So, in some ways the actual numbers people are getting are a little bit arbitrary because it's in reference to some population back from the 1980s. I always like to tell people, if you're actually measuring yourself that first measurement is not actually that big a deal and that should just be your baseline. And going forward, you should always just put it in context compared to yourself. And really the change within yourself is more important than in reference to some random population which for most of the clocks most people don't even know what population that was.

Melanie Avalon: Okay, that's fascinating. And it also kind of relates to another concept I'd never really thought about until reading your book, but you talk about how really arbitrary the concept of even disease is like we basically just have to come up with a tipping point and then we decide certain things are diseases and before that they're not diseases, but all of these processes for all of these potential diseases are all happening all the time and we just define them as a disease at a relatively arbitrary number, I don't know how the numbers are decided.

Morgan Levine: Yeah, the problem in human, we love to label things and have definitions of things but these are cultural concepts of disease. So, we've decided that once you're HbA1c or your fasting glucose reaches this magic threshold, now you suddenly have diabetes. And I guess we've done a little bit better we’re saying, "Okay, maybe there's this prediabetes stage." But we like to discretize this to say, you either have it or you don't when actually all of these things lie on some continuum and all of these diseases are actually a process. They're not necessarily a specific state, and they're constantly changing. There's a huge debate in aging of whether we should call aging a disease, but I don't like the concept of disease in general and actually think most of the diseases that we talk about are just kind of some end-stage value we've attributed to the aging process in a specific system.

Melanie Avalon: That's really interesting. Yeah, because I know David Sinclair is really big on defining aging as a disease. In a way, if you step back, it's like it sort of has to be disease because everything's a disease or it's not a disease because nothing's a disease.

Morgan Levine: Yeah, exactly.

Melanie Avalon: In a way, I have more questions about the measuring, but just a really quick tangent question. So, do we start exhibiting signs of aging the second we're born?

Morgan Levine: Yeah, a lot of people are really interested in this question of when does aging actually start and probably the person that I know that's looked into this the most is my colleague, Vadim Gladyshev who's at Harvard and he's actually tried to define what he calls this ground zero state. So, the state of having the lowest biological age, not chronological but biological age. And then from there thinking the ideas from their biological age starts increasing. And what he shows that it's actually before birth, I think he's estimated it at like eight days after conception. So yeah, it's happening pretty early and again he is using epigenetic data to define this. So, it might actually be that aging in different facets starts at different times. So, there might not be some specific time for all age changes start accumulating even at the molecular level, but at least epigenetically it seems to hit this bottom out at day eight and then start increasing from there.

Melanie Avalon: Wow, talk about it's all downhill from here. Oh, my God, that's funny. Okay, so going back to the actual measuring because I bet listeners are listening and thinking, I want to measure my biological age. So, how did you develop the system that you have for measuring biological age? What is it actually measuring?

Morgan Levine: Yeah, I've worked it on a few different kinds of systems. The one that actually started about a decade ago, you can measure or try and estimate biological age just from the normal types of lab tests that you would get done at your annual physical, so things like cholesterol and different inflammatory markers like CRP, HbA1c, or glucose and then a bunch of things to do with cell counts. And we actually developed a way that you can combine those into a single aging profiler or biological age score or we often call this your phenotypic age score, and show that that is a better predictor risk of disease or mortality risk than your chronological age. That gives you kind of a whole person systemic biological age. But actually, what my lab is more interested in are these molecular measures of biological age and usually what we use is epigenetic data. So, people may-- maybe David Sinclair, if he was on talked about the epigenetic clock. So, these are measures that use something called DNA methylation. It's not changes to your DNA sequence. So, you still ACGT, you're not changing that. But what you're changing is you have these chemical tags that can happen at specific sites throughout your genome that we call CPGs, where you have a C right next to a G. And this just changes kind of the accessibility of that part of your DNA. The interesting thing to think about is, all of the cells in your body have the exact same DNA. But clearly, they exhibit very different phenotypes. So, your skin cell does not act or look the same as your brain cells or your neurons. And what gives their phenotype is the epigenome. So, it tells the skin cell you use this part of the genome, these are the protein products that you can derive whereas your brain cell will use different parts of the genome and this is dictated by turning on or off certain parts using these epigenetic modifications. The interesting thing is that the epigenome gets dysregulated. We think dysregulated, but it definitely changes with aging and we can actually look at this profile to say, “Oh, you've had kind of this degree of drift or change that might be indicative of someone or a cell or tissue that is of some chronological age.

Melanie Avalon: Okay, wow.

Morgan Levine: All right, that was a lot.

Melanie Avalon: No, no, no, I love it. I love it. So, some questions about the tests. Actually, when I was talking to James, he was saying that they use the phenotypic age in a lot of their trials to see if what they're doing is effective. So, that was super cool. So, that first type with the nine biomarkers to clarify, what are some examples of those biomarkers of the nine?

Morgan Levine: Yeah, so for that one you have things from your CBC, so your cell blood counts, so things like what white blood cell percentage, something called red cell distribution width, which is just how wide you’re the-- how much variance there is in the width of your red blood cells. So, a bunch of these little measures, you have things that map on to, kidney function, so creatinine, alkaline phosphatase, you have liver function, and then you have fasting glucose and you have, “Oh, this is testing my actual memory,” albumins in there. I should remember all of these. Yeah, I’ve to go back and look into it exactly.

Melanie Avalon: I found one of the ones online and was taking it, but then I realized I wasn't sure I don't think I had all the data I needed to fill it out correctly because then I did it and it gave me my result and I think it basically said I was like dead. So, I was like, I don't think I've put in the right numbers.

Morgan Levine: Yeah, so that's the other thing people need to pay attention to are the units. So, the other thing is if the lab you did your tests at measuring different units than that one, you have to actually convert them or they'll give you some crazy, insane number.

Melanie Avalon: It said, "Yeah, I was like, okay, that's not correct."

Morgan Levine: That doesn't sound like it was correct. Oh, CRP is another one in their, C-reactive protein, which is--

Melanie Avalon: It needed a percent and the data I had was not in percent and I was like, I don't know how to convert this to clarify. So, for that test, is that comparing just to other people with similar biomarkers? Or is it comparing to an in between marker like a methylation status or something?

Morgan Levine: Yeah, that one is comparing to other people. So actually, it was developed using a study called the National Health and Nutrition Examination study NHANES which is supposed to be for the US nationally representative, so it should represent all different types of people within the population about the percentages that they exist in the population. And so, but the issue again, before, was that we have to use a population from the early 80s, in order to actually be able to train the test because we need mortality follow-up, we need to know who lives, how long they live. So, we need a long follow-up time. So that one is saying compared to the average United States population in the 80s, this was how old your profile looks.

Melanie Avalon: You said the population in the 80s actually lived shorter than today?

Morgan Levine: Yes, most people will actually score lower than their chronological age on that test, so it actually underpredicts age.

Melanie Avalon: So even though they lived shorter, did they not have lower rates of chronic disease as well? 

Morgan Levine: It depends, some chronic diseases there were higher rates. I think we're doing better in certain cancers, mostly probably because of earlier screening or better screening. But yeah, I think the one thing that people have actually shown it's our life expectancy has increased a lot. But our health span hasn't increased quite as much. So, we're actually just keeping people alive who are sicker longer, but we actually compared biological age between that population and more current populations and we also find that people today do, at least in terms of these parameters look younger.

Melanie Avalon: Oh, we have a lower biological age now as well.

Morgan Levine: Yeah, so the average person today has lower biological age than the average person then. We've also looked at within different groups. So actually, the biggest difference tends to be older people. I forget what the age cutoff was. But I think for people in their 70s, they're even younger biologically than people in their 70s back in the 80s.

Melanie Avalon: Wow, I really wouldn't expect that. Just with all of the messaging about the obesity epidemic and metabolic syndrome it's just blowing my mind.

Morgan Levine: We did try to estimate some of the reasons for this. And I think the big one came down to smoking, so people smoked a lot more in the past than they do today. And then, obesity I think epidemic really started around that time as well. And then there's also use of medications. So, cholesterol-lowering medication or blood pressure-lowering medications that we think might actually, be helping people to some extent.

Melanie Avalon: And then that next second type of measuring that you are doing more now with the epigenetics and the methylation and all of that. So how is that tested?

Morgan Levine: Yeah, so if someone wanted to get their own tested, it's kind of feels like a genetic test. So, if anyone's done 23andMe, or ancestry, or any of these genetic tests, it's very similar where for a lot of the companies, you'll either spit in a tube or you'll do a finger prick, and do dried blood spot. And then that gets sent to a lab and then the DNA gets extracted from that and then they go through and they measure for, let's say, a million cells in that sample, the percentage of cells that are methylated or unmethylated at let's say 100 or but often 200,000 to a million sites throughout the genome. Then this gets fed into an algorithm that was developed with machine learning AI and it spits out a number.

Melanie Avalon: So, what you're comparing it to, how was that determined? Did you look at the methylation status of populations and how it correlated to their biological or chronological health.

Morgan Levine: Yeah, there are a lot of different epigenetic clocks and they're all derived slightly differently. So, some people may have heard of the Horvath clock, which is the most famous epigenetic clock, although technically not the first, even though people talk about it as the first one. And that one was, basically, Steve Horvath took tons of data from I think 52 different tissue types and measured DNA methylation on each of them, he knew the age of the person that those tissues came from and then he made an epigenetic gauge to predict that age. So, it's relative to whoever this population of people who these tissues came from. It's actually a hard one to define because it's not a specific population, but it's relative to whatever that data was. The one we developed a little bit later was actually based on that phenotypic age variable. So, the nine markers were actually trying to predict the output of that so that phenotypic age, but using methylation instead of just the nine markers. So that one still should be in reference to that 1980s US population.

Melanie Avalon: So to clarify, so you're comparing the nine markers versus the methylation, that's two separate tests where you're trying to get the same answer.

Morgan Levine: Same answer. Yeah, because the idea-- Most people who are developing these epigenetic clocks, we're always trying to predict age. So, when you develop them or what we call train epigenetic clock, you have to pick the variable that you're actually trying to be able to predict and for most people, they're going to predict chronological age because it's the easiest variable to actually get. And when you think, "Oh, I'm trying to make a measure of aging, I'll predict age." But as we've talked about, biological age and chronological age are not perfectly correlated. And we know people of the same chronological age have different health status. So that's why at least for this PhenoAge clock, we actually tried to predict this kind of physiological age that was based on the nine biomarkers and link to remaining life expectancy.

Melanie Avalon: Oh, okay. So, this is so interesting, because on the one hand if you're trying to predict chronological age, you would think, "Oh, that's more certain," because it's literally verified by the birth certificate. So, we can know if we got "Right answer." But because of what we know about biological age, it's not really that certain because any given person presumably could have a very different biological age on the inside. So in that way, the biological age is more "certain." But then it's like, how do you define biological age because it's so different for people? There's no one certain target seems to aim for.

Morgan Levine: Yeah, this is I think the hardest thing about this field is, again, this idea of what we call machine learning your ground truth. So like, you said, if your whole goal is to predict chronological age, let's say you want a forensic test, so you can say, "Oh, this blood sample came from someone who is 45." You have a verifiable ground truth, you know in your training what everyone's chronological age is, but if we're trying to predict biological age, biological age is what we call a latent variable, it's something that is not actually observable or measurable and we have to always estimate it. So, we never really know how accurately we're actually predicting this because there's no actual variable to compare against. So, we always have to come up with these other ways to validate it. And this comes back to there's a concept called kind of construct validity. So, if I think that I'm predicting biological age correctly, what should my measure be able to do? So, it should be able to predict mortality above and beyond knowing someone's chronological age, it should be able to predict disease, it should be responsive to interventions that we think are actually impacting aging, so, you have to do all these little separate tests to convince yourself you're actually doing a good job at measuring that thing that is "unmeasurable."

Melanie Avalon: Kind of seems like the difference between, I feel like chronological age is trying to picking out a person from a group of people who is actually that person and then biologically age would be like the same person pretending they're all these different people and trying to pick who is the true essence of that person. It's just very vague. So, question about the testing the methylation can we intervene and change these methylation factors and if so have they done tests on rodents to change their methylation and see if it affects their chronological or their biological age?

Morgan Levine: Yeah, so there are a few ways that you can change, "The epigenetic age." And a lot of the studies, as you insinuated are done in animal models, and mostly in mice. So, the big thing that I think has been pretty robustly shown to change epigenetic age in at least a specific mouse strain is caloric restriction, which at least in that mouse strain, we know also increases life expectancies. So that kind of makes sense. And you see a pretty dramatic decrease in the epigenetic age and response. People are also looking for what other features might impact epigenetic gauge. For humans, we have to rely on population-level observational data. So, we don't have necessarily clinical trials, but we can say looking at people in the population who tend to score younger, what are their characteristics and they're not surprising. They exercise more, they eat more vegetables, they get better sleep, all kinds of normal health behaviors we think of those being good for us.

Melanie Avalon: I'm glad you brought those up because obviously topics that the audience is really interested in. But before that, so have there been actual or is there the ability or the science to because those are interventions to try to affect methylation, I guess or epigenetics and then see how that affects things. But do we have the ability to just go in and edit the methylation itself? So, we can confirm if methylation changes actually affect biological or chronological age?

Morgan Levine: Yeah, so this would be the golden perfect experiment, and actually there are technologies where you can go in and add methylation or remove methylation from specific sites. The problem is that when we look at the clocks, or we look at the aging patterns, it's not a change in methylation at one or five or 10 sites, it changes at hundreds of thousands-- It's kind of going back to that genetics thing. It's this compounding effect of large patterns of change across lots of sites. Hypothetically, you could potentially in the future figure out a way to edit that. And we also don't know well, what if you found some, “hub site," and you found like the 10 most important sites that ended at those, and there are people looking into this, but were not exactly sure whether that'll even be able to permeate and have an effect. There are things that you can do that actually indirectly affect the methylation pattern and perhaps David also talked about this. So, you can actually do what's called epigenetic reprogramming. So, if you overexpress these four factors, you actually get a change in the epigenome and this does seem to have a "rejuvenation" or age-reversal effect, so people are really interested in looking at it from this angle.

Melanie Avalon: Okay, so like that example of changing those four factors, changing those four factors where? In one place or everywhere?

Morgan Levine: Yeah, this isn't changing the epigenetics of those four factors, but it's four essentially genes that if you overexpress them in a cell, they're actually called Yamanaka factors, so people might have heard them from other things or often also people call them OSKM, the first letter of each of that factor. You can actually take even an old skin cell and if you overexpressed them for 30 days, you can convert that back into what, by all intents and purposes it looks like an embryonic stem cell. So, people have been really interested in, oh, this is completely rejuvenating the cells as well. And now instead of taking an old skin cell and making it an embryonic stem cell, can we just take an old skin cell and make it a young skin cell? So, people are looking into actually how to do that. And all of this is happening by changing the epigenome. So, it's resetting that epigenetic pattern back to an earlier state?

Melanie Avalon: Was that the work that he did in the lab with reversing glaucoma in the eye?

Morgan Levine: Yeah, so that's one example. Yeah, so David did that in terms of targeting these neural ganglion cells in the eye? And actually, we were a part of that one, where we actually, measured the epigenetic age in the cells. And then other people have also done this, either trying to do it whole body or in specific tissues as well and shown similar things.

Melanie Avalon: And when that reversion happens with the Yamanaka factors is the reverted cell identical to a cell that would be just normally at that age or can you tell the difference? Like there is any hint of its past linger?

Morgan Levine: Yeah, so you can tell the difference. And actually, we've gone back and looked at specifically the markers in the epigenetic clocks. And what we can find is very drastic reversal of a few subcategories of those markers, so specific types of epigenetic markers. But then there are also a few that seem kind of impervious to it, they do not seem to reset. So, the cells aren't fully reversed back to an original state. But the question is, is it good enough and did we actually kind of reverse the important parts? So how important are the ones that are reversed versus the ones that are not?

Melanie Avalon: And can this only occur through these methods, do any dietary lifestyle changes affect Yamanaka factors?

Morgan Levine: They don't, the one thing that does affect them is actually embryogenesis. So, this is again going back to this idea of this ground zero states. This is why you can take you’re an oocyte or egg cell from a woman, let's say she's 30, and a sperm cell from a man who's 30 and somehow combine them and get an embryo that's zero according to epigenetic clocks. So, this is something that happens naturally we think during this kind of reproduction. But you know, the question is, how do we then do it in a full adult? And it's probably not going to be through behaviors, but we do need to figure out therapeutically or pharmacologically how to do this safely and across all the different cell types in adult human’s body?

Melanie Avalon: And do you think with the future of-- and we just thinking big the future of anti-aging or even reversing aging? Do you think it will be more something like that where we are taking the existing cells and having them revert back to younger state? Or would it be something replacing the cells with just brand-new cells? Maybe I just made up a dichotomy that doesn't even exist, but options for the future?

Morgan Levine: People are thinking about this dichotomy and they can follow similar streams. So yeah, one question is, do you just do this every now and then and push yourself back a little bit in biological time? Or do we just generate better healthier organs, what we would call ex vivo cells outside the body and put them in? And actually, this technology can be used in some ways for both. So, one issue with transplants is often rejection. If you're getting, let's say, a kidney from someone else, your body might be more prone to reject that. But hypothetically, if you could in the future, I mean, not right now grow organs from the cells in your body, the nice thing is you can take a skin cell, reset it to an embryonic stem cell, and then actually, convert it to various cell types. So, people convert them to neurons or all these different types of cells. Hypothetically, in the future, you might actually be able to repopulate your body with the cells that are actually, reprogrammed ex vivo. But again, it's still little ways off. There are a lot of kinks that need to be ironed out.

Melanie Avalon: I've had Sergey Young on the show a few times and he talked about growing organs within yourself from cells. Is that sort of like the same concept?

Morgan Levine: Yeah, I think so, I think you would just do it potentially outside the body so that I think it'd be easier to monitor how it was going. Again, if you could, you still need to develop these systems actually, keep organs functioning and be able to grow them outside the body, but hypothetically.

Melanie Avalon: I was just thinking about it more and maybe I'm just so naive and don't really understand everything, but that there hasn't been some sort of genetic glitch that did cause people to age backward. Like, is that even possible? That naturally it could just happen? If the genome decided for whatever reason it wanted to age backwards? Do you think it could, like if you just wanted to?

Morgan Levine: Yeah, I'm trying to think how. I feel like it would have to be a lot of things simultaneous. It has to be at the right timing because you don't want to do anything to disturb development. So, it's this genetic thing that I say increased or over-expressed certain factors? It might actually disrupt development or change things there. But yeah, I don't know. I've never even thought about them before.

Melanie Avalon: I was thinking about Benjamin Button and I was thinking, I mean, that sounds really silly to say like why this hasn't happened, but I don't know, crazier things, maybe it seems like it happened.

Morgan Levine: I don't think you would be born old like-- like in Benjamin Button, he's [unintelligible [01:05:10] or whatever. And then like, but I don't know it would be something that could a little bit rejuvenate yourself. But, yeah, it'd have to occur at the right time as well.

Melanie Avalon: And is what you just spoke to, like the dangers of that. Is that related to-- because when they've done tests with Yamanaka factors, isn't there an issue with keeping them on too long?

Morgan Levine: Yes, yeah, that's the other thing is a lot of these things is the Goldilocks issue where you want just enough, but not too much or they become problematic. So, for the Yamanaka factors they don't just "rejuvenate a cell," but they also what we call de-differentiate a cell, so a skin cell or a fibroblast is no longer that cell type. If you keep them on long enough, they go back to these stem cell state. And you can imagine, let's say you're going to do reprogramming in your liver, you want all your liver cells actually maintain their identity. So, you want the hepatocytes to stay-- hepatocytes and Kupffer cells to stay. Kupffer cells-- but if you turn these factors on too long, you basically turn into a liver of just stem cells. And then those stem cells don't really know their identity, they can turn into all sorts of nasty identities, and you form these teratomas, which are tumors made out of kind of a hodgepodge of all these different cell types.

Melanie Avalon: Oh, wow. So, it’d sort of be like if you had a picture that was all messed up, you started erasing it to make it look better, but then if you erased it too far?

Morgan Levine: You wouldn't know, yeah, what it should. Yeah.

Melanie Avalon: Oh, wow. That's fascinating. Well, speaking of stem cells, so practical things that people do today, how do you feel about things like stem cells, or you talk in your book about young blood and blood transplants, because there's also things like rapamycin and calorie mimetics, what do you find practically seems to have the most effect and anti-aging effect?

Morgan Levine: Yeah, I mean, I think for me the only thing I would put my money behind right now are more the behavioral things, so diet, exercise, and those kinds of things, which is not exciting to people. They want this new cutting-edge technology or magic bullet, or what's the drug I can take that's going to make me live a lot longer or feel a lot younger. And there are things that people are testing out, but at least I haven't seen really good enough evidence that I would say, Yeah, that's a really great aging intervention. So, rapamycin is one that people are very interested in, there's good data around it. But I think there needs to be more data, especially in humans actually show that this will be beneficial to aging. Metformin is another one people are very interested in and this is a diabetes drug that actually has been tested a lot in humans, but in another context, so people are actually starting these clinical trials looking at aging, specifically. But those will take a decade or so to actually start getting answers on. And then the other kind of more what people might consider kind of weird science that I actually find very fascinating is this idea of kind of plasma exchange, not that I think it's anywhere near being therapeutically ready but the idea that an old animal actually can have some benefit from getting blood from a young animal. And almost the question is, are you actually diluting out problematic things in the old blood? Or is there some kind of magic factors in the young blood? I think it's probably the former and I think that's what the field is leaning towards. But yeah, it is a really fascinating concept where these circulating things, how do they actually affect, how our cells are aging, and our cells are actually responding to whether these things are present or not,

Melanie Avalon: With the dilution effect, because I think you talked in the book about how they would do tests diluting with saline compared to blood, for example. Do you know, I don't know if you remember, but was there any-- I know they saw the benefits with the saline dilution. Were there still more benefits compared with using actual blood? Or was it comparable?

Morgan Levine: Yeah, I think in that study they didn't have three arms. So, I don't think they actually compared for like a full plasma. Yeah, I think it was saline with albumin. But yeah, the idea was that was good enough to get the effect, but it's probably a little bit of both. I would imagine there are some factors in younger blood that are going to be beneficial. The other study I love from Sausalito's group at UCSF is they actually took blood from exercise mice and gave it to non-exercising mice and it had a beneficial effect. And that's probably not just dilution, there probably is some factor in blood in response to exercise that's actually beneficial.

Melanie Avalon: What is the amount of plasma or blood required for this? If people are getting blood transfusions, is it that amount or more, less?

Morgan Levine: Yeah, I actually, don't know the answer to this. Yeah, I'd have to go back and actually look at the research. So, the interesting thing is all these studies actually came out of this paradigm called parabiosis, where it's not really exchanging blood or plasma per se, but it's actually connecting the circulatory systems of two mice. So, you would-- actually they're sewn together, it's kind of a harsh surgery but you connect like a young one to an old one, or a young one to a young one or old one to an old one and then you can compare the different groups. So, in that case actually their entire circulatory system is being shared. But yeah, in the actual exchange protocols, I don't recall the amount of plasma and I think people probably do different amounts for different studies.

Melanie Avalon: I'm just wondering, I struggle with anemia, and I had to have a blood transfusion at one point. I'm just wondering-- I wonder how old the person was that the blood that I got? Wow. And this makes you think that there's like some science behind vampires living forever if there—Is this something that you've done or would do or engage in?

Morgan Levine: Not at this point, but I am happy to watch the science unfold. And I think, to me in the future probably a better direction would be to figure out what the factors are either the problematic factors or the beneficial factors, and to actually therapeutically target them. Since we're not going to be I don't think or should be harvesting blood or plasma from young people. I don't think that go over very well in terms of PR.

Melanie Avalon: Oh, man, can you imagine being the head of that PR campaign? What about rapamycin? Have you taken rapamycin?

Morgan Levine: I have not. But that's another one too that I'm holding out hope for, I feel like of all the antiaging drugs that people are really excited about this is the one, if I was a betting person, would maybe bet on but I tend to be very cautious in terms of my buy-in into different interventions. So, I will wait for a little more data, I feel I have the luxury of being young enough right now that I might not need it immediately. So, I'll give it 10 years and then reevaluate probably.

Melanie Avalon: Okay. I've been thinking a lot about it. I'm like, "I want to try it."

Morgan Levine: I know a lot of people are, and Matt Kaeberlein, who's one of the big advocates I think makes a very compelling point, so to be determined.

Melanie Avalon: It’s on my to-do list, so the practical implementations for diet and lifestyle things. Do you practice calorie restriction, fasting, either of those?

Morgan Levine: Yeah, I've done-- I feel like my diet changes a little bit. I go in and out of different fasting regimens. I've done intermittent fasting where I do time-restricted feeding. Now, because of my workout routine I'm doing it slightly less because I feel like I need the calories at certain times a day. I have tried Valter Longo's fasting-mimicking diet, I found it very difficult, but I measured my biomarkers before and after and I did actually see an improvement. So, I do believe that it does probably have an effect. But yeah, I found it very difficult to do especially. You can't do probably any exercise during those five days, there's just not enough reserve. But exercise is one thing I think that everyone should be doing and that I try and make a point of doing almost every day if not every day.

Melanie Avalon: Quick comment on the FMD thing and you said you measure before and after, so if somebody is taking these measurements and when you checked your age, was that with your phenotypic age or was that with the methylation?

Morgan Levine: So, this is a long time ago with an earlier version of the phenotypic age, but still using those regular lab tests that you would get done at a physician's office.

Melanie Avalon: Okay, so for both of those for that type of testing and then the epigenetic testing, how fast can people see changes, and how long my interventions last? Does it oscillate pretty regularly and if it does then what does that say about the implications?

Morgan Levine: Exactly, so this is actually a really important critical point that my labs started looking at two or three years ago, where especially for the epigenetic clocks. Our question was even if you measured twice in the exact same sample, so this isn't even like a daily or monthly change in your epigenetic age, but even the exact same sample, how much variability? And what we found is actually a lot of the clocks were really bad in terms of having high variability, sometimes you'd get even a nine-year difference from the same exact sample. This is where I thought, “Oh, epigenetic clocks are over, you're not going to be able to use them for clinical trials or personal tracking.” But we actually spent a really long time trying to develop a statistical method to remove the variability and we are actually successful in doing it. And some of the consumer-based clocks use this new method, but not all of them. I would say someone's using a consumer-based clock, ask the company about their reliability. But in terms of how quickly you can see change, it'll depend a little bit on the intervention. I think things like FMD, you probably would see a change after one cycle of that because it's a pretty extreme intervention for anyone who's done it. Or if you did really long water fast, I mean your body definitely will react to that. The question is then how long is that maintained? Is it just an acute response? Actually, I did work with Valter on a study where we tested people who did three consecutive cycles of FMD, I think it was once a month for three months. And we tested them after and then we also waited, I think it was five months with them just living their normal lives, not doing the intervention, and tested again. And we found that there was a decrease in-- This time I was using the more clinical biological age measure, but also that was for the most part sustained, there was a tiny rebound. But they still did sustain a decrease in their biological age score even after they'd resumed normal life.

Melanie Avalon: Oh, wow, that's promising. Are your tests, so the methylation one is that available direct to consumer?

Morgan Levine: It's unavailable from me. So with me advocating for it, I'm not getting paid. I don't sell the tests, but it was licensed by a company called the Elysium Health. They do provide a consumer product that uses saliva to assess epigenetic age and they do use this new method that removes a lot of technical variants. And I think in some of their information online they show how reliable their measure is. But then I think since we published that paper, I would imagine other companies are starting to adopt the new method for actually calculating them, but they use different. Everyone uses a different clock.

Melanie Avalon: So, they actually at one point Elysium Basis was a sponsor on IF Podcast, are you familiar with that? Their supplement basis?

Morgan Levine: Yep. Yeah.

Melanie Avalon: Oh, yeah. How do you feel about NR/NMN?

Morgan Levine: So, I used to take Basis, I stopped not because of any problem with it. Like, it wasn't like, “Oh, something happened and that made me stop.” I wasn't keeping up with it anyway, and then stopped taking it. Again, this is another one like rapamycin where I think it has potential, but there still needs to be a few more studies till I would feel confident that taking it would probably be a benefit to me.

Melanie Avalon: I've been on-- I've been on the NR versus NMN train and debate for so long and I actually launched a supplement line last year and so I want to make an NMN. There's actually I don't know if you heard there's a new NMN, like the first FDA-approved NMN happened recently. So yeah, I'm really excited about that because there are just a lot of headaches with FDA stuff. But yeah, I'm very just very excited about everything. Speaking of what are you most excited about now, with your-- I mean there's just so much work in your book, what's the future of what you're doing right now?

Morgan Levine: Yeah, I think it's kind of twofold. So, one hand in developing these measures and developing better and better measures. Another thing that we're working towards doing a lot is actually giving people more dimensionality in their measures. Not just giving someone a single biological age, but actually understanding that different parts of our bodies are probably aging at different rates. And can we actually quantify more dimensions of our aging process and then even understand profiles of aging? So again, I think as I mentioned earlier, some people might be more prone to aging in a certain manner than others. And this might have implications for which diseases are going to be most at risk, so that's one feature and then of course constantly working on developing more "accurate measures." Again, there's this issue of how do you actually assess how accurate it is. And then the other thing that we're really excited about is coming back to this reprogramming and not necessarily using just the Yamanaka factors, but just understanding what's actually going on. So, what is this rejuvenation event? How does it occur? What drives it? How do these epigenetic changes actually map onto cell function and cell health? And then how does that actually impact whole organ and organismal health?

Melanie Avalon: The practical implementation of what you were talking about with people aging different ways? Is that something practically where people might benefit more from a dietary intervention versus sleep or stress? Or how does that practically manifest when people know the way they're aging?

Morgan Levine: Yeah, exactly. So, we think in the future, especially if there are actually aging interventions that people feel confident about, it might be that certain profiles of people benefit more or less from different interventions. So hypothetically, if you could build a big enough data set, you could actually start to predict to some degree. You might be a person that would benefit from a plant-based diet, and you might be a person that needs a little more X in your diet, or you would be someone that would benefit from a caloric restriction diet. But this would require lots and lots of data with people actually, maybe even voluntarily undergoing different interventions. And then it would almost be algorithms for Spotify or any of these kinds of other applications where they make recommendations because you look like someone else's profile that had the similar likes, so it'd be biologically you have a profile like people who tend to benefit from X, Y, or Z. But to actually train those algorithms takes lots and lots of data, but hopefully in the future that would actually be possible.

Melanie Avalon: Do you have any idea if there's any level of intuition to that? Because some people seem to intuitively want to exercise more or thrive more on exercise, some people seem to thrive more-- for me, I'm not a big-- I don't crave going to the gym, but I love fasting. And because I know some people like calorie restrictions, I feel better in that state. Do you think there's any level of intuition to this?

Morgan Levine: Yeah, I think people undervalue self-rated health, but obviously we can be a little bit overly subjective, but you can definitely feel when you're feeling better in your body, when you have more energy, of course, there's going to be some placebo effect. But I do think there's definitely intuition. And we don't know how to decode that intuition where it's coming from. But you know, our brains are really smart, and they can figure out, "Oh, when I do this, somehow, I think it feels healthier for me." Yeah, not entirely sure where the intuition comes from, but it's definitely going to be there.

Melanie Avalon: Awesome. Well, just speaking to the smart brain piece, something else you mentioned in the book that had never occurred to me, but I was thinking about it, and really how profound it is, the ability of us to look at another human and pretty much estimate their chronological age. I mean that's pretty mind-blowing because you can't really point to one thing, but we can see somebody and we know how old they are on a chronological scale. So, I was just thinking about that.

Morgan Levine: It is pretty amazing that our brains know how to almost decode biological age at least in terms of how people look. And even carnival-like things based off this, you can go to the carnival and there's the person who will say, "Oh, guess your age and if you don't guess within some number, you win a prize or something. So yeah, our brains are really intuitive. And you can look at pictures of people and sequentially line them up and know this is when they were younger, too when they're older. So, our brains can in some ways decode all of these changes that are happening at least on the outside with us biologically as we age.

Melanie Avalon: Yes. Well, it's so fascinating. And thank you, this has been just such a fascinating conversation. I'm just so obsessed with your work and everything that you're doing and thank you, you've been so incredibly generous with your time. Oh, also, fight on, because I went to USC as well. Not nearly as cool as because you got your PhD there.

Morgan Levine: I also did my undergrad there, actually my entire family. Yeah, so I did undergrad and PhD there. My sister did her undergraduate and her master's there. My husband got his PhD there. My mother worked there. And my dad played football, so fight on, I'm a true Trojan at heart.

Melanie Avalon: Wait, what was your undergrad there?

Morgan Levine: Psychology?

Melanie Avalon: Oh, that's so cool. Wow. Did you live on campus?

Morgan Levine: I lived on campus for part of it and then I lived off campus for my last two years, so my freshman year I lived on the Row, but I wasn't in a sorority or fraternity but they had actually, I forget which fraternity it was, but they got kicked out of the house because of some drug-related undertaking. And so, they put a bunch of freshmen in one of the fraternity houses, which was a very surreal experience. But yeah, I spent my first year there.

Melanie Avalon: They made a freshman housing on the Row. That's so funny. Wow. Yeah, I lived on campus freshman year, probably wasn't there when it was called Birnkrant by the quad. I think it was a newer building.

Morgan Levine: Oh, that's a nice place.

Melanie Avalon: Yeah, right by Leavey's Library. The three following years I lived near the Row and then I was in the film fraternity, so lived at that house, so small world [chuckles]. Well, thank you again so so much. This was just amazing. And the last question, I promise that I asked every single guest on this show. And it's just because I realized more and more each day how important mindset is, so what is something that you're grateful for?

Morgan Levine: For me, I think I'm grateful for-- I actually owe this probably to my husband and I feel like he's really taught me to have more of a growth mindset. He's someone who even if he doesn't think he'll be successful at something will try it and he really likes to be out of his comfort zone. And I used to always be someone who I'd only want to work on things or do things that I knew I would be good at. But I feel like it's really taught me that you can be good at anything or learn anything even if you don't think you had the background for it if you just set your mind to it. I would say that's probably the thing I'm most grateful for.

Melanie Avalon: Oh, I love that, so unique. I love that answer. Well, thank you again, Morgan. This has been so, so amazing. I'm eagerly following all of your work. Do you think you'll be writing another book in the future?

Morgan Levine: I don't know. It was quite a bit of work. I'm glad I did it. But I also happen to do it right, I got the book deal, February 2020. So, I basically spent the pandemic writing it, which I might have a little bit of PTSD from it, but we'll see.

Melanie Avalon: You do have a daughter, right?

Morgan Levine: Yes.

Melanie Avalon: I wrote a book as well. And I haven't had a child. But I'm like, I feel like this is like giving birth to a baby. It was a lot to go through.

Morgan Levine: It was a lot. Yeah. And I had homeschooling that-- I am glad I did it. It was a nice way to put everything down. And like you said, “Yeah, it's like you're finally giving birth and actually put something together to create a whole thing.”

Melanie Avalon: Well, it's awesome. I have it in front of me right here. And it's beautiful as well. I was just looking at the cover.

Morgan Levine: I can't take credit for that.

Melanie Avalon: But it looks amazing. I like the colors a ton. So, for listeners we will put links to everything that we talked about in the show notes, which I know was a lot. And there's a full transcript there as well. What links would you like to put out there for people to best follow your work?

Morgan Levine: People can follow me on either Instagram or Twitter, I think. it's Dr. Morgan Levine on both of them or also look up I have a website for my lab. I think it's morganlevinelab.com if you guys want to see what we're up to. And actually, I recently left Yale and moved to a new company called Altos Labs, so people can also find me there.

Melanie Avalon: Oh so, I said the wrong thing at the beginning, so you're not at Yale.

Morgan Levine: I'm not but I still have affiliation there, so it's still accurate.

Melanie Avalon: Okay, what is the new company that you're at now?

Morgan Levine: It's called the Altos Labs, A-L-T-O-S. So, it's actually focusing on this reprogramming idea and understanding cell health.

Melanie Avalon: Very cool. Well, I will eagerly await all of your future findings. And again, this has been amazing and hopefully, we can connect again in the future.

Morgan Levine: Perfect. Thanks for having me, Melanie.

Melanie Avalon: Thank you, Morgan. Bye.

Morgan Levine: Bye.

[Transcript provided by SpeechDocs Podcast Transcription]