Ep. 294 Aging Decoded: Dr. Morgan Levine on Epigenetics & Longevity

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True Age: Cutting-Edge Research to Help Turn Back the Clock

Transcript:

Cynthia Thurlow: Welcome to Everyday Wellness podcast. I’m your host, Nurse Practitioner, Cynthia Thurlow. This podcast is designed to educate, empower, and inspire you to achieve your health and wellness goals. My goal and intent, is to provide you with the best content and conversations from leaders in the health and wellness industry each week and impact over a million lives.

Today, I had the honor of connecting with Dr. Morgan Levine, who is an assistant professor of pathology at Yale University School of Medicine. 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. She is the author of the book True Age, which I had the honor of reading earlier this year. Today, we dove deep into her background, the role of biologic aging and epigenetics, the impact of lifestyle, how our cells age, the role of cellular senescent and zombie cells, why aging is considered to be a disease state, research on women in menopause, the impact of genes, especially APOE, why our number of fat cells are determined early in our lives, blue zones, fasting and hormesis, exercise and sleep all of which contribute to how we age. I hope you will enjoy this conversation as much as I did recording it.

It’s so nice to connect with you, Dr. Levine. I’ve been looking forward to interviewing you and talking about your new book.

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

Cynthia Thurlow: So, I think everyone’s backgrounds are so interesting. Did you always know that you wanted to go into research and study the complex intricacies of the aging process? When I was reading your book, I know about your parents and your background, but listeners would probably enjoy to hear a little bit about your story.

Dr. Morgan Levine: Yeah. So, I don’t think I always knew I wanted to be a scientist or go into research here. I was very worried about the aging process growing up because I had older parents, particularly my father was much older. He was in his mid-50s when I was born. So, I was always worried about his aging. And I saw aging at a very young age. And it wasn’t until probably I got to college and actually found that there is a scientific field who’s actually interested in, can you do anything about the aging process? Not necessarily that we’re going to all live forever, but can you live a healthier life for as long as possible and really postpone the onset of all these diseases? So once that became a possibility, then I was hooked in and felt like I had to work in that field and make it my mission to understand it.

Cynthia Thurlow: And it’s interesting because I think on a lot of levels, people think about anti-aging. They think it’s all this physical, this kind of phenotype, what we look like, what our hair looks like, what our skin looks like. And in your book, you’re really speaking to kind of distinguishing between chronologic versus biologic aging. And so, let’s start the conversation there specifically about the role of epigenetics. And so, this is definitely a topic that my listeners are familiarized with, but understanding that the way we lead and live our lives has a large impact on whether or not we are susceptible to certain types of diseases. Certainly, in cardiology, I saw it ran the gamut from being head to toe vasculopath, cerebrovascular disease, cardiovascular disease, peripheral vascular disease, diabetes, all of these things. But let’s talk a little bit about the differences, the distinguishing characteristics of both of those.

Dr. Morgan Levine: Yeah. So, I think when you ask someone their age or they think about, how old am I? They always think they’re chronological age. But we know you can just see from everyone around you that people age at different rates. And we don’t know exactly what’s driving aging, but at least things like epigenetics seem to potentially play a very important role in that we can actually look at someone’s epigenetic profile, and this tracks very well with age. But even among people who are the same age, it seems to be very predictive of who’s at risk for various diseases. And the reason we think that is so epigenetics can actually be very important in just setting the state of a cell. So, I almost think of it as like the operating system of a cell. Even though all your cells have the same DNA, it gives them all their different types. So, skin cells, brain cells are different because they’re epigenetics, but we know it also changes with age. So, it differentiates a young skin cell from an old skin cell or a young brain cell from an old brain cell. And so, it’s responsive to our behaviors, the environment, but also just kind of some intrinsic factors. But we think that if we could actually slow what we call epigenetic age, we would postpone the onset of different kind of chronic diseases we see rise with age.

Cynthia Thurlow: Yeah. It’s really interesting because a lot of what I speak to in my realm is hormetic stress and mitochondrial health. And this feeds directly into that understanding that a lot of the choices we make in terms of how well we sleep and do we exercise, and are we eating anti-inflammatory diet and are we eating too frequently? All can positively or negatively impact the way that we age. And I would agree with you one of the things that I got particularly good at being in the hospital was, like, looking at a patient’s chart and looking at the patient and sometimes being surprised, like, “Wow, that person looks really good for X age, or wow, that person looks 15 years older.” And having worked in the inner city and then in the suburbs, saw a wide cross section of individuals, different races, different ethnicities. And I was always humbled, like there were always the outliers. I was like, “Whatever they’re doing, I want to make sure I capitalize on.” So, when we’re talking about the aging process, you do mention in the book how do cells age, what are some of the ways that we look at this? And I know telomeres are a hot topic. I know especially with prolonged fasting, people are always interested, does this improve my telomere length? So, let’s talk a little bit about telomeres, what they are and how they’re impacted during the process of becoming chronologically older.

Dr. Morgan Levine: Yeah. So, telomeres were– so actually this idea was discovered decades ago by someone called Leonard Hayflick. He didn’t actually discover telomeres, but the idea was that cells in a dish had a limited lifespan. They could only divide a certain number of times and then they would undergo this arrested state that we have come to know as cellular senescence. Then it was discovered years later that actually what the reason for this is that as cells divide, they’re basically losing length on these telomere regions and that once they reach this short critical point, the cells basically undergo– they have genomic instability and they kind of go [unintelligible 00:07:12] because it’s actually an evolutionary mechanism to prevent things like cancer, because the cells are dysfunctional at this stage. So, there’ve been some studies showing that telomere length declines with aging. And there are people who use it as a biomarker of aging. Actually, it’s almost been overshadowed by the epigenetic aging because that actually seems to be a better biomarker. But there’s some correlation between the two. We also see as cells divide, the epigenetic age also tends to increase. But yeah, so I don’t think we know exactly besides telomerase treatment, which actually adds back the telomere what actually can maintain telomere length, but there’s a lot of interest in this area as well.

Cynthia Thurlow: Yeah, I bet. And I think that from just my experience in talking about these things with my own patients and clients trying to explain what cellular senescence really is, and then the conversation usually lends to zombie cells and are these good or bad? And my understanding and certainly correct me if I’m wrong, is that they can be proinflammatory. So, this can be something over time that can be potentially damaging to a cell. And so, has that been your experience, obviously deep vested into the research yourself in writing a book in this area?

Dr. Morgan Levine: Yeah. So, the ability of cells to undergo senescence is a short-term benefit. It’s going to prevent that cell, if there’s something wrong with it, from being prone to becoming cancer, so tumor genic, that being said, over the long term, this isn’t a great long-term solution because these cells tend to be, as you said, very proinflammatory. So, they’re spitting out all of these proinflammatory cytokines and they’re almost immune to death, so they can’t be killed very easily. So, they’re just sitting there in your resident tissue producing out and actually probably causing nearby cells to undergo damage or be more prone to senescence or things like that. So, yeah, in the long run, they’re actually problematic and people think they might be a major driver of aging and the inflammation that we see increase with aging.

Cynthia Thurlow: So, you talk in the book a great deal about why aging is a disease state. And so, I think this is an important distinction. I think people just assume aging just happens. And so, I think it’s much more complicated nuanced than that. There’re obviously things we can be exposed to in our environment that can accelerate this process. It was interesting, I was listening to a podcast with Peter Attia talking about cardiovascular disease and talking about the role of tobacco use as a good example. I think that’s one that’s probably tangible for everyone. I think our generations, there’s probably a lot less smokers. But when I think about my grandparents, my great grandparents, everyone smoked. But let’s talk a little bit about aging as a disease state. How does that come about? Why should we shift the perspective to thinking about it as a disease as opposed to something that just randomly occurs? Because I think for many people, if you talk to them, again it goes back to the physicality, “Oh, I don’t want to get wrinkles. I notice my skin is sagging,” and I’m like, “Oh, there’s so much more that’s under the hood that’s ongoing, that’s kind of creating this process to accelerate.”

Dr. Morgan Levine: Yeah. So, most of the diseases that people are worried about getting, so heart disease, Alzheimer’s disease, diabetes, cancer, these are all diseases of aging. And aging actually ends up being the number one contributor to these diseases. Again, like you said, “It’s not about wrinkles. It’s not about how you look,” but really, it’s about driving these pathologies that people are– really you could ask anyone. No one wants to get any of these diseases. So, the idea is, if we actually were to tackle the aging process itself, we would prevent the onset probably of multiple diseases simultaneously, instead of how our current medical system is going after one at a time. So, can we cure cancer or how do we prevent heart disease? Really, the truth is to actually look at aging as its own pathology and tackle that, to try and keep people in a younger state for longer. So, I think the hard thing about when we talk about calling aging itself a disease, it can also stigmatize aging. So, this idea of, “Oh, you’re over a certain age, you now have a disease, is a problem.” But I think if we disassociate the physical or biological aging process from the chronological, basically, it would be amazing if you could be 80, being 80 is not a disease, but it’s that kind of biology that we want. If you could keep that healthier, younger for longer, then you could be 80, and it would not be “pathological” versus the opposite, which in our society it tends to be.

Cynthia Thurlow: Yeah. And it’s interesting, I had Dr. Amy Killen on in the fall and she was talking about women, specific to women and talking about menopause as an example of a disease state, and she was saying how that can sometimes be very controversial, because again, to your point, people hear that and they feel stigmatized. And she was saying, no, I want people to understand that with proper lifestyle changes, HRT, if that’s appropriate for you, etc., that doesn’t have to be your destiny. And one of the things in your book that really stood out for me specific to women was that in the research, women with older epigenetic ages tended to experience menopause earlier and surgical menopause tended to accelerate epigenetic aging. So, there are a lot of women that are middle aged that listen to this podcast, and when I read that, I was like, “Wow,” because I see a lot of thin women. Thin meaning healthy, not anorexic or body dysmorphic, thin women going into menopause earlier, like late 40s. And we know the average age here in the United States is 51, but I’m also seeing a lot of my overweight obese patients going through a little later, and so this is very telling.

So, we’re assuming that thin person is, “healthier,” but in essence, they may have these epigenetic changes that are occurring again below the surface that are driving an earlier ovarian failure or contributing to this loss of fertility and peak fertility years. Let me be clear, I think most women in their late 40s and early 50s don’t want to be thinking about being fertile. However, this was really surprising for me, because I think there’s this thought process that if you go into menopause at 47, 48, not really a big deal, and this is causing me to look very differently at my patient population, the clients that I work with.

Dr. Morgan Levine: Yeah. So, there does seem to be– because of the data we had, we couldn’t necessarily say which one was causing the other one. So, whether having an accelerated epigenetic aging would push people into early menopause or whether the early menopause would just set off this kind of acceleration of epigenetic aging, it seemed potentially like the latter might be more likely because of what we saw with the surgical menopause. So obviously, epigenetic aging is probably not causing people to undergo surgical menopause, but we did see an acceleration of aging then. And it’s interesting, women have this longevity advantage over men, but it seems to even out a little bit more after women go through menopause, so they have this benefit, but then after menopause, they catch up maybe not all the way, but a little bit to men, not in a race that you want to win though.

Cynthia Thurlow: No. And I think for a lot of women in particular, they’ve been insulin sensitive their entire lives. And then all of a sudden as they’re getting closer to the tail end of perimenopause, the 10 to 15 years preceding menopause, all of a sudden, they’re becoming a little sarcopenic, they’re not sleeping as well, they suddenly start becoming a little insulin resistant, there’re so many shifts that are going on in their bodies. Not just a hormone piece, but so many multisystem issues that are contributing to this loss of metabolic health. And I think for every woman that’s listening, this is where you have to be working with a practitioner that’s going to be able to counsel you on. Is it appropriate for you to consider hormone replacement therapy? Is this appropriate for you? If not, that certainly we can respect that. I have a lot of listeners that are, as an example, breast cancer survivors, they’re not able at this point in time to be able to take HRT. But understanding that women are protected on a lot of levels before they go into menopause and from what I have read and spoken to experts, it’s this loss of estrogen signaling that can drive a lot of these acceleration of inflammation, oxidative stress in the body.

Dr. Morgan Levine: Yeah, absolutely. And yeah, for some women it will be the right choice. It depends a lot on timing and how long you’re doing it. But yeah, I think if it’s the right situation, offset some of these changes that we see.

Cynthia Thurlow: Yeah, absolutely. And I think again, it goes back to when I finished my training a 1000 years ago. It was right when the Women’s Health Initiative was being published in 2002. And although I worked very safely in cardiology, didn’t have to have those discussions. I do recall many family members, many clinicians that were really shifting their practice based on the outcome data from Women’s Health Initiative. And I think, again, it begs the conversation with every woman that’s listening or man that’s listening, making sure you’re having that conversation with your doctor, your nurse practitioner. Now, there are specific types of genes. You mentioned a few of these in the book that we know can be implicated in longevity and also chronic disease. And I think one that’s very recognizable is APOE, apolipoprotein E. I’ve been tested for this. Let’s talk about this because I think there’s a lot of misinformation that’s out there, there’s a lot of good information that’s out there, but let’s help clear up some of the misinformation so that people will understand what it puts you at risk for.

Dr. Morgan Levine: Yeah. So, this is actually– when the Human Genome Project came about, they’re like, “We’re going to discover all these genes and be able to cure disease because we know all the genes that cause it.” There hasn’t been a ton that came out, but this one gene, so APOE is the one that has had this big effect that was found from all this data. There’re three different alleles. So, you can have APOE2, 3 or 4. And of course we have two copies, so you can have a mix of those. The one that seems the most detrimental or high risk is APOE4. So, people who have 4,4, who we call homozygous E4 have much higher risk of things like Alzheimer’s disease. I think it’s hard to estimate, but it’s about, I think they say a twelve-fold or more risk of developing Alzheimer’s.

And ironically, it actually seems to be even worse for women who are 4,4. The majority of the population are E3. So, most people are 3,3, being 3.4 increases your risk a little bit, but not nearly as much as a 4,4. And then actually there’re a few lucky people, it’s fairly rare, who are 2s, so 2,2 or 2,3 and they actually seem to have the lowest risk for everyone. So, in addition to Alzheimer’s, it also seems to be a risk factor for different cardiovascular disease. APOE is a lipid transport, so we’re not entirely sure about the exact mechanisms, but it’s something to do with lipid regulation that seems to be maybe driving risk for Alzheimer’s and cardiovascular disease as well.

Cynthia Thurlow: Now, if someone’s listening and they want to ask their internist, primary care provider for this test, do you typically just ask for the APOE? So, this is something I don’t order, which is why the impetus for the question, “Is it as simple as going to LabCorp or Quest with an order and they can just draw it and then you and the provider can have a conversation or is it more nuanced than that?”

Dr. Morgan Levine: Yeah. I think I don’t know if they offer it, but I would imagine they would or any genetic counselor could do this. I know 23andMe actually also will tell you which alleles you have if you’re 3,3, 3,4 and report back. But again, I think if people are for 4,4, it would beneficial for them to talk to either genetic counselor or practitioner. 23andMe will give you some information, but not that much in terms of understanding what this means. And it may just be that you do have different interventions or lifestyles to try and prevent it. So, Alzheimer’s disease has no treatment right now, but there are things that people can do potentially to prevent or reduce their risk. So, things like exercise are important potentially maybe diet or depending on what your cholesterol, triglyceride levels are. So maybe some sort of lipid-lowering medication would be important if you’re a 4,4.

Cynthia Thurlow: Yeah. No, and it’s interesting the reason why I was asking, I know that my functional medicine doc has already tested me. And I am a 2,2.

Dr. Morgan Levine: Oh, wow.

Cynthia Thurlow: Yeah. I’m one of those special people. But I do know that within my family, there are a lot of heated discussions about do people want to be tested, do they not want to be tested? 23andMe I think is valuable, but you have to work with someone that can actually look at the data and know how to interpret it. I think when I first got 23andMe done, it was probably 10 years ago. And from what I understand now, they’re not giving you as much raw data as they did before. But I think, and much to your point, that working with someone that is able to give you good counseling and good information and understanding that even if you are a homozygous for APOE4, that doesn’t per se mean that you will definitely go on to develop these disorders and diseases. Now, you started speaking to some of the things that we can do. So, let’s twist this and make it kind of have a proactive bent. What are some of the things that we can do as individuals that can have a large net benefit? You do spend a good amount of time in the book talking about these things that will help slow the aging process and do it in a way that’s not focused as much on the aesthetics piece. And certainly, let me be clear, I think all of us want to take care of ourselves, but understanding that it’s on a much more substantive level inside our bodies as opposed to outside our bodies.

Dr. Morgan Levine: Yeah. I think people get upset right, when we talk [chuckles] about this because there is no quick fix. It’s not that we have a drug or I have some magical supplement that if you take this, you’re going to have slow aging. It really comes back to the things that people probably already know and maybe don’t want to hear. So regular physical activity, eating whole food, diet, getting good, not just quantity of sleep, but also making sure you have good sleep quality, stress is a major driver of aging. So obviously lots of people have stressful jobs. But there’s also some psychology about how you approach and look at stress, which actually could change how it impacts you physically and then the normal things, don’t smoke. Smoking is probably the thing if you want to age yourself fastest that you would do. And then there’s some debate on, in terms of drinking, whether moderate drinking is okay versus no drinking. I think right now the science is saying any alcohol might be detrimental. But again, it’s a balance, people can pick and choose how much different things matter and what it’s worth to them.

Cynthia Thurlow: Yeah. I think that’s a good point that for each one of us, we have to find lifestyle choices and changes that are sustainable. I think a lot of people with good intention will start intermittent fasting. They’ll try to go to bed earlier, they’ll stop smoking, they’ll start exercising. And then two weeks later they’re like, “This is too much.” [chuckles] I can’t make all these changes all at once. So, let’s start with the nutrition piece. You do speak to Mediterranean plant-based diets being beneficial. We talk about the blue zones. Maybe we can unpack what that is. I think a lot of people perhaps are familiarized with the terminology, but where in the world are these blue zones? And what is the research suggesting and sharing with us about these individuals and their lifestyle?

Dr. Morgan Levine: Yeah. So, there are a number of blue zones all over the world. These are places where you have pockets of exceptional longevity much higher than you would expect, just random chance. There’s one in the United States in Loma Linda, California. Other ones are places like Okinawa in Japan, and then Italy, and Greece. And basically, people have tried to understand what it is about these regions. And again, it’s not a randomized controlled trial where you put 100 people in each of these cities and see what happens to them. But they do tend to share some characteristics. So, people are very physically active. They do a lot of walking. They’re not sitting all day unfortunately, like a lot of people in the US are, they tend to eat very much kind of whole foods, not highly processed foods. There’s a lot of talk that they only eat vegetarian or vegan, which is not entirely true. There is some kind of meat and dairy consumption, but it’s not to the level probably seen in the United States and similar countries. And yeah, they tend to live substantially longer. And it’s not just genetics because they follow people who have left these areas and when they move to a different place, they actually tend to look more like have the longevity of the place they move to. So there does seem to be something about the community and the lifestyle that’s driving this.

Cynthia Thurlow: It’s really interesting because when I was reading the book and thinking about places in the world where these individuals are found, they tend to be more physically active, they’re probably not eating a hyper-palatable, highly processed diet. They’re probably getting more sleep. They’re just genuinely seemingly taking really good care of themselves. And there was one concept in the book and I’m probably going to mangle this, the concept of hara hachi bunme, which in Japanese belly is 80% full, thinking that perhaps these are people that just intrinsically they slow down when they start to feel a little bit full. Whereas I think for a lot of us, we don’t sit down and savor meals, we’re in a rush. It’s this kind of hedonistic existence where we can get anything we want, any time of the day, delivered to our house. I mean, Uber Eats is like one of the worst inventions in the world. My teenagers get upset when I say that, but I think it’s worth mentioning. But this concept you mentioned in the book, which makes a lot of sense, I’m sure that that’s a contributor. I have friends who are from those areas in the world and they definitely are conscientious, like they don’t overeat. If they’re full, they’re done. They don’t feel a sense of obligation to finish large meals if they don’t want it. There are people that are satiated and full with a lot less food on their plate or maybe they’re more conscientious about the way that they’re actually eating.

Dr. Morgan Levine: Yeah. And I think meal times too, there is not just about sitting down and consuming large and just continually consuming throughout the day as well. I think it’s a social event and they eat to fuel their lives, but they don’t just constantly look for the next meal again and again. And they probably are what we would consider maybe very, very moderately calorically restricted. So, they’re eating probably just under their metabolic needs, but in a way that actually their bodies benefit from this and it can have this hormetic effect to actually improve their overall health.

Cynthia Thurlow: Yeah. And I think the role of hormesis, this beneficial stress and the right amount at the right time is so important and it’s a fantastic segue into talking about caloric restriction, intermittent fasting, time-restricted eating. What is the research showing us about this kind of overall prevailing concept as it pertains to the aging process?

Dr. Morgan Levine: Yeah. So caloric restriction is by far longest studied intervention in aging. It was discovered century ago and first in rodents and really did show that if you mildly restrict calories, that at least for most of them, it does give this increase in lifespan, but also seems to improve what we would consider health span. So, they’re healthier longer as well, not just living longer. [unintelligible 00:27:58] been studying a lot of other species and again, seems to have similar kind of benefits. Granted the amount of caloric restriction probably differs, so even among different mouth strains, the same level of caloric restriction can actually be beneficial for some, neutral for others, and even detrimental for others. So, there’s probably some kind of genetic tuning about how much caloric restriction one would have. And then recently people started to study this in humans. So, there are people who’ve been caloric restricting voluntarily for years and they think there’s some evidence that maybe they’re a little healthier. But then there was actual clinical trial called the CALERIE trial that they actually enrolled people and the data does suggest that when you look at different physiological markers that these people are healthier than when they started or healthier compared to the control group. But I think the hard thing is knowing how much is the right amount. And it’s not deprivation, it’s not a massive amount of caloric restriction and it’s probably for most people just the absence of overconsumption that’s going to be the most beneficial. So even if you can eat just a smidge under your normal caloric needs, it’s going to beneficial probably.

Cynthia Thurlow: Well, I find for a lot of patients, even the concept of not snacking, even if you do nothing else other than just have those three meals a day, then not snacking in between, not drinking fatty coffees and really sugary sodas and eating candy bars. I mean, just removing those things alone might be enough for a lot of people to garner benefits. And so, there’s very much this continuum of intermittent fasting. Obviously, this is something I talk a lot about on the podcast and because I’m a female and I think it’s important to distinguish that men and women need to fast differently. So, whether it’s intermittent fasting or caloric restriction or time-restricted feeding, understanding that there’s a time and a place and times in which we should do that, there’re certainly a lot of people. I think about Satchin Panda. I just literally was listening to a podcast with him this morning with Dr. Huberman and really diving into his current research. I’m like a third of the way through a three-and-a-half-hour podcast. Very depth involved, but I will get through there.

The one thing that I thought was interesting in particular to fasting and kind of a pain point for a lot of listeners is weight loss resistance. And one of the things you touch on in the context of the book and calorie restriction is talking about fat cells, so adipocytes and how a lot of this is determined a little bit by genetics, but also it’s predetermined by the time we’re an adolescent. I have all teenagers at home. So, I think about this in that context that a lot of the choices and things that we’re doing as younger people have a large net impact on. Well, how our fat cells grow or don’t grow, are they hypertrophied? Understanding that if we’re overfed and we’re continuously eating or we’re overfeeding our cells, that we’re creating a lot of inflammation, oxidative stress, toxicities. What has been your experience when you’re looking at the research specific to adipocytes and fat oxidation and fat loss for these populations of individuals when we’re looking at the aging process?

Dr. Morgan Levine: Yeah. I think it’s actually an interesting place that we’ll probably be able to answer this question really well in the coming decades. Because childhood obesity was not even a thing in the generations that are now older. But for more recent generations, childhood obesity has exploded and it’s not even clear necessarily what that means for how these individuals will age, but we can imagine that it’s probably going to be detrimental. So, obesity particularly kind of central adiposity, we know, is highly pro-inflammatory and tends to be highly associated with this accelerated aging phenotype. So even if we look at things like epigenetic age or any of these aging measures, obesity is probably second only maybe just smoking, a major driver of this accelerated aging phenotype across different organ systems. So, you can measure it in blood, we’ve looked in liver, you can measure it actually in adipocytes, and it does tend to show this very accelerated aging phenotype. But yeah, it’s not clear. The both amazing and sometimes scary thing about our bodies are we are dynamic, we are responsive. So, the environment and lifestyle our bodies grow up in is going to affect how they respond and behave as we grow older. So, it can very much prime our health as we grow older. That doesn’t mean that people should think, “Well, I had an unhealthy childhood.” There’s nothing that can be done about it because, again, we’re constantly dynamic. So, there are things that you can do later in life to adopt healthier lifestyles that will beneficial and it’s not this kind of all or nothing thing, but yeah.

Cynthia Thurlow: I’m so glad you made that point because it’s interesting to me. I trained in the inner city and then obviously spent most of my time working in the suburbs. And what was interesting to me is 25 years ago, the patient populations that we’re seeing are very different than they are now. And to echo what you stated, that the degree of metabolic disease we’re seeing in younger people and children and adolescents is concerning. We’re seeing lifestyle-mediated disease states in kids. And so, they’re presenting not just with type 2 diabetes, which is a lifestyle issue. They’re having NAFLD, which is this nonalcoholic fatty liver disease, which typically you see in adults. We’re seeing kids that have got borderline chronic kidney disease, they’re having issues with their vision, they have sleep apnea, they have mobility issues because they’re carrying so much weight on their small frames and they’re still growing. And so, this is something that I think all of us should be concerned and genuinely looking into.

Like, what can we do to make things better for this younger generation? Because as I tell my kids who are both teenagers, your generation is actually the first generation that has the potential to be less healthy than my generation. And that’s something that’s hard to wrap my head around as a clinician and as a parent that we’re definitely heading in the wrong direction, but that doesn’t mean that we can’t make improvements. And if you grew up eating junk, that doesn’t mean that has to be your destiny for the rest of your life. It’s certainly hard to make those lifestyle changes, but they are absolutely worth it. And so, when I’m thinking about the things that are incredibly helpful, not just the nutrition, as you mentioned, the intermittent fasting or caloric restriction. You mentioned exercise and I think it’s important to talk about the role of exercise, especially as we’re getting older.

So being physically active is important, but understanding that the role of sarcopenia, so you don’t just lose muscle mass as you get older, lose strength, and you can actually like the strength piece. And that’s why they talk about grip strength as being a prognostic indicator for health in general. Like when you go to the gym and they want you to do those goofy tests and you’re like, “Why are you making me do this?” Grip strength is important. I think about my parents and how they’ve always been super able bodied, and now when I see them, they are sarcopenic. They are shrinking and opening a jar for them, like the things that we just really give no thought to. So, in terms of exercise, if we’re trying to prevent sarcopenia, this muscle loss with aging, what are the things that you generally look into or you think are most efficacious for helping to reverse this issue?

Dr. Morgan Levine: Yeah. Sarcopenia can be a major issue for women or actually– and for individuals with obesity. There’s sarcopenic obesity, which makes you even more prone because there’s some kind of insulin resistance that might even derive it further. But yeah, I think for women have been had less interest in weight training, but we know that weight training or any kind of weight-bearing exercises are really important both for sarcopenia and for things like osteoporosis as women get older. And I think there’s also this idea that well, as you get older and frail, exercise is maybe thought of as more dangerous, but actually they’ve shown that even the most frail and vulnerable older adults benefit from exercise. Obviously, you might want to do it under supervision if you are at risk of falls or something else similar to that, but there’s really no age in which exercise will not beneficial. And again, as you get older, it does seem like more of this kind of strength training to make sure you are slowing this decline in muscle mass and strength is really important. And cardiovascular exercise is important, I think, as well, it improves our VO2 max, which is highly predictive of a lot of different health outcomes, but particularly as people tend to see wasting in their lower extremities, especially, making sure that they’re doing some work with weights.

Cynthia Thurlow: Yeah. No, I can’t agree with you more. And it’s interesting, just as a clinician, like going about my day-to-day life and seeing women in their 40s, 50s, 60s that are just skinny, and it’s because they’ve lost a lot of their muscle mass. And if you think about muscle as this organ of longevity and you look at muscle like a fillet is young– this is terrible. I love beef, but we’re just going to use beef as the example. If you look at fillet, fillet is mostly muscle versus a ribeye, although delicious has a lot of fat distribution. And so that’s what starts to accelerate north of 40 is that we start replacing muscle with fat. And fat, as you mentioned is this kind of inflammatory organ. You mentioned sarcopenic obesity. I think a lot about how I had so many patients that couldn’t get off a bedside commode in their 50s and then you would have really frail 60, 70, 80-year-olds. I had just as many non-frail, but more often than not these very frail people that I was afraid they wouldn’t be able to get on the exam table, let alone get off. And so, we don’t want that to happen. And so, it’s interesting, my teenagers love to make fun of my husband and I, which I think is what every teenager does, but it’s interesting to listen to them and help them understand, like, your dad and I make a concerted effort to remain very active because A, we want to keep up with both of you. But number two, we don’t want to be the parents that fall and break a hip when we’re 55 years old, because I had patients like that or they’d fall at 60 and we know that breaking a hip is a poor prognostic indicator.

The other thing about exercise that I think is so important, and you aptly address this in the book as well, is that exercise helps our brains, it helps brain health. And I think if nothing else, the most important thing to me as I get older is that I don’t lose my cognitive health. And I think this neurodegeneration that can be exacerbated by this muscle loss, this insulin resistance, this poor metabolic health, we want to remain sharp. We want to be able to contribute to society, to our families, to our loved ones and not be the person in the corner of a room who has some cognitive impairment and really can’t interact with their loved ones. And we see so much of that now.

Dr. Morgan Levine: Yeah. To me it’s like you said, one of the scariest kind of conditions of aging, you almost lose yourself, who you are, who you’ve always kind of identified as, and yeah, unfortunately there are no treatments right now, but exercise does actually seem like the biggest impact in terms of preventing neurodegeneration. Both kind of what you might think of as natural aging, so decline in cognitive functioning, but also Alzheimer’s disease and some of these more pathological declines as well. So yeah, there’s a really fascinating study by [unintelligible 00:40:12] who’s at UCSF where they took blood or plasma from exercise mice and put it in non-exercise mice and actually had cognitive benefits. So yeah, there’s some kind of magic, we don’t know necessarily what it is. They identify some proteins but not clear. Those are the critical ones, but some kind of magic response to exercise that seems beneficial across our bodies, including our brains.

Cynthia Thurlow: Yet another reason to exercise as often as you can. Let’s talk about sleep, because I think sleep is elusive for people as they start getting older, whether it’s declining levels of melatonin, sex hormones, all of which can impact sleep quality. Why are REM and deep sleep so helpful for not just our brains, but helpful for longevity, the aging process and kind of hearing it from another individual, how important sleep is for improving our metabolic health? I think all these things feed into one another, but I keep trying to bring it back to the fact that these are habits, these are lifestyle choices that have a lot of net benefit if we are doing them properly and thoughtfully.

Dr. Morgan Levine: Yeah. I think we don’t know all of the actual mechanisms of how sleep is beneficial, but it is very clear that sleep is very critical to our health. And making sure you’re having uninterrupted sleep, where you can have these longer kind of REM sleep and you’re not getting woken up and then having to go back through the sleep cycle again. In this kind of interrupted, disrupted sleep. There’s definitely a cognitive benefit that people think maybe during deep sleep, you have this washing of cerebrospinal fluid that takes all the potential toxins out and washes it. But yeah, even not to take it back to exercise, but it actually helps recovery from exercise. So as a runner, I know if I’m not sleeping well, I’m not recovering and running well the next day. So, yeah, there are all these kind of mysterious, again, like exercise mysterious benefits to sleep. And it is about getting you don’t want too much sleep, but also too little. So, there’s the sweet spot that maybe is a little bit different for everyone and maybe different for men and women as well. But the sleep quality is the critical thing that we forget about. We look at our watch and say, “Oh, I went to bed at this time and woke up at this time.” But really the question is how deep did you sleep during that time and not have to wake up and go to the bathroom or just having these kind of insomnia episodes throughout the night.

Cynthia Thurlow: Yeah. I think it’s one of those things that we take sleep for granted until it becomes a problem and then all of a sudden, like I always say, “Sleep is an art form at this stage of life.” And I do look at my Oura Ring metrics every morning, It usually confirms how I feel. So, I don’t look at it as it doesn’t destroy my mood for the day, but it will validate like “Oh, you really did have a crummy night of sleep because you were flying on an airplane or you didn’t get enough sleep, you weren’t able to get enough deep sleep.” And the thing that I find really interesting is a lot of listeners are healthcare providers or they’re EMS or people working shifts. What does the research show about the net impact of changing, kind of shifting our chronobiologic needs based on our occupational schedule? How does that impact aging? Because I used to be a night shift worker in the ER [chuckles] many years ago and I can tell you my colleagues that were 20 years older than me, they would talk about how they just never recovered. It didn’t matter how much they slept on their days off, they never felt rested, they got sick more often. So, I would imagine there’s also this interrelationship with immune function as well in terms of shifting those little biological clocks we have throughout our bodies to accommodate needing to be up when we should be asleep and vice versa.

Dr. Morgan Levine: Yes, there’ not studies necessarily with aging per se. I mean, there’s some kind of circadian studies with aging but there definitely seems to be health issues primarily kind of metabolic issues that seem to arise or inflammation from shift work or having this really disconnected from our natural circadian rhythm. I can’t remember exactly. I do talk about it in the book, but I don’t remember off the top of my head. They did do profiling of individuals who were shift workers and it was I think– I’d have to go back but yeah, definitely half of these kinds of factors that have this kind of circadian response shifted, but the other half didn’t. So, they were at this asynchronous date, which physiologically wasn’t how our bodies were meant to behave. And so, I think if it’s a short-term thing, you take a red eye or you have jet lag because you visited some other country, then it’s not as big a deal. But if you’re chronically out of circadian rhythm then there tends to be a lot of negative health benefits of that.

Cynthia Thurlow: Yeah. It makes complete sense. And I know that we get messages across social media all the time from nurses and doctors and PAs and EMS workers and cops and just people who have to work, shift work and they’re trying to figure out how best to support their bodies. Now, one thing that you touched on which having trained in inner city Baltimore really rang home for me talking about economic disparities and how this impacts the aging process. And so, it is not surprising that those that are economically disadvantaged that they could have accelerated aging, the role of ACE, so adverse childhood events, can we at least kind of touch on this? Because I think it’s really relevant for people to understand that depending on where you live can have a large net impact on how accelerated versus decelerated that aging process can be.

Dr. Morgan Levine: Yeah. So, there’s really interesting data just looking at the link between the ZIP code you were born in and your life expectancy. And you can have ZIP codes that are 10 miles apart and have drastically different life expectancies. And really this comes down to these kind of social disparities and differences in socioeconomic status, both childhood socioeconomic status, so what you had growing up, but also the socioeconomic status you experienced in adulthood. And some people have looked at people who switch and go from low to high or high to low. And the early socioeconomic status does seem to set a kind of precedent, but you can also if you decline socioeconomic status later. And again, the exact mechanism of how this gets under your skin and affects your biology isn’t totally clear and it’s probably not one thing. So, some of the major hypotheses are that it’s this kind of chronic stress.

So, if you live in whether it’s areas that are less safe or you have more things like food insecurities or just all these everyday stressors that we think of, that this does really change you physiologically, it’s associated with increased inflammation and that this can drive the aging process. We also know just behaviors are very different. So lower socioeconomic areas tend to be more food deserts or have less availability of all the foods that were discussing as being beneficial and also less just availability of being able to be physically active outside. So, there are probably these kind of piling on of all these things that are affecting people and that eventually this idea that it will wear and tear on your body. And there’s something called the weathering hypothesis, which is just this idea that this constant low socioeconomic stress will weather you over time.

Cynthia Thurlow: No, it makes complete sense. And as we’re wrapping up the conversation today, I would love to get your feedback, your perspective on things like rapamycin. You know when I mentioned that we’re connecting, this question came up a lot. People are just curious, is there value in taking rapamycin? Can we talk about first what it is and what is the kind of prevailing ideas around the potential benefits it may confer?

Dr. Morgan Levine: Yeah. So, this was actually discovered on Easter Island and it was actually first used as a drug for transplant patients so to kind of prevent rejection. Then people found that actually there seems to be some pro-longevity benefits. So at least in animal models, they tend to live longer and healthier when they’re on rapamycin. And so, people have been very interested in this as a potential therapeutic for aging to slow the aging process. There isn’t great data in humans yet on whether this is beneficial. I would say of all of the potential drugs and/or supplements people are looking at is probably the one I’m most optimistic about. At the same time, just I’m personally not taking it. So, I feel like, “I’d rather wait for the data to see.” They are doing more studies now in companion animals, so in dogs, to see if it actually shows beneficial effects in them. And people are starting clinical trials in humans. So, I would say to people, if you don’t feel the need to take it immediately, wait five to 10 years and I think we’ll actually have a much better idea on potential benefits of it.

Cynthia Thurlow: No, that’s really helpful. And lastly, senolytics which are drugs that actually target these zombie cells and create apoptosis. Thoughts on these? Are we at a point where we’re using these on humans, or is it again, we’re still really looking at animal-based models for how these can impact the aging process.

Dr. Morgan Levine: Yeah. So, people are looking at senolytics in human clinical trials, but they’re mostly in the context of fairly debilitating diseases. So, this is not something that people are looking at in otherwise healthy individuals as a preventative for aging. And I think even people who work in the field of senolytics would not recommend people take these voluntarily. So, yeah, there are some trials in people with idiopathic pulmonary fibrosis or osteoarthritis. So far, the data has been mixed on whether you get a benefit, but I think, again, over time, we’ll know, but whether this is something that you would take as a more preventative prophylactic is not. Right now, I would say nothing beats the lifestyle interventions, so yeah.

Cynthia Thurlow: I love that. It’s a great way to end our conversation. Dr. Levine, please let my listeners know where to get your book, which I really enjoyed reading, how to connect with you on social media or learn more about your research.

Dr. Morgan Levine: Yeah. So, you can pick up True Age at probably most, try your brick-and-mortar first. Otherwise, you can also get it on Amazon or any kind of major bookstores. You can follow me, I’m on Twitter, I think, @DrMorganLevine and Instagram as well and yeah.

Cynthia Thurlow: Thank you so much. It’s been such a great conversation.

Dr. Morgan Levine: Thank you so much for having me.

Cynthia Thurlow: If you love this podcast episode, please leave a rating and review, subscribe and tell a friend.