209. Dr. David Barzilai: Can We Reverse Aging? Harvard's Latest Longevity Science Explained

What if aging isn't just something that happens to us—but a biological process we can actually influence? For decades, medicine has focused on treating diseases after they develop. But a growing field called geroscience is asking a much bigger question: What if we could target the underlying biology of aging itself, potentially delaying multiple age-related diseases before they begin? In this episode, I'm joined by Dr. David Barzilai, MD, PhD, MBA, longevity medicine physician, Harvard Medical School lecturer, and medical editor of Harvard's Pathways to Longevity special report, to explore the science of biological aging and what it could mean for the future of human health. We break down the 12 hallmarks of aging, why your biological age may be different from your chronological age, and how researchers are developing new ways to measure and potentially influence how quickly we age. From epigenetic age testing and telomeres to senescent cells, autophagy, rapamycin, and cellular reprogramming, we separate promising longevity science from the hype. In this episode, you'll learn: What the 12 hallmarks of aging reveal about why our bodies get older The difference between biological age and chronological age—and whether aging can be slowed How accurate biological age tests and epigenetic clocks really are Why VO2 max, muscle strength, sleep, and metabolic health are powerful indicators of longevity What telomeres reveal about cellular aging and why longer isn't always better How senescent "zombie cells" contribute to age-related inflammation What fasting, calorie restriction, and autophagy actually do inside your cells What the research says about rapamycin, senolytics, and emerging longevity treatments How cellular reprogramming and Yamanaka factors could change the future of regenerative medicine We also discuss personalized longevity testing, the limitations of today's aging biomarkers, and emerging research exploring whether scientists could one day restore more youthful function to aging cells and tissues. The most important takeaway? You don't have to wait for the next breakthrough to start improving how you age. Exercise, cardiovascular fitness, strength training, sleep, nutrition, and understanding your personal health risks remain some of the most powerful tools we have today. The future of longevity medicine is incredibly exciting. But the real opportunity is combining what we already know works with the science that's still to come. Learn more about Dr. Shah: Website:drshah.com https://drshah.com Clinic: next-health.com https://www.next-health.com/ Instagram: @darshanshahmd and @extend_podcast Learn more about Dr. David Barzilai: Website: barzilaiconsulting.com https://www.barzilaiconsulting.com/ LinkedIn: linkedin.com/in/agingdoc https://www.linkedin.com/in/agingdoc/ X (formerly Twitter): x.com/agingdoc1 https://x.com/agingdoc1 Instagram: instagram.com/agingdoc1 https://www.instagram.com/agingdoc1/ Harvard Medical School's first Special Report on longevity, Pathways to Longevity, where I served as Medical Editor: https://www.linkedin.com/posts/agingdoc_harvard-medical-school-has-just-published-ugcPost-7465326141025775616-GOnh For further reading on longevity science and its clinical application, I'm Co-Editor of Frontiers of Longevity Science, forthcoming from Springer Nature: https://www.barzilaiconsulting.com/fols Thank You to Our Sponsors! IM8: Try IM8 with a 30-day money back guarantee! Get 10% off your first order with code DRSHAH at im8health.com/drshah https://im8health.com/drshah Pendulum: Head to pendulumlife.com https://pendulumlife.com and use my code EXTEND for your first membership order!

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:03Dr. Darshan Shah?

  Welcome to Extend with me, Dr. Darshan Shah, a podcast dedicated to cutting-edge science, research, tools, and protocols designed to help you extend your health span. Having become one of the youngest doctors in the country at the age of 21, and trained and board certified at the Mayo Clinic, I've accumulated three decades of practice as a board-certified surgeon and longevity expert. Over that time, I've discovered that a mere 20% of health knowledge yields 80% of the results when it comes to your health span. We're living in a new era where we are creating a new healthcare system, no longer focused on disease management, but achieving optimal health and vitality. Join me as I interview world-renowned experts, offering you a step-by-step

• 0:41Dr. Darshan Shah?

  guide to proactively avoid disease, and most importantly, extend your health span. Welcome back. This is your host, Dr. Darshan Shah, on the podcast Extend. On today's episode, I have an absolute honor to be joined by Dr. David Bersly. He's a longevity medicine physician, one of the leading ones in the world, and a lecturer at Harvard Medical School. He's a founding faculty and trustee for the Geneva College of Longevity. Dr. Bersly is also renowned for his work in precision longevity medicine, bridging the often siloed worlds of academia, medical education, and real-world clinical care. As the medical editor for Harvard's landmark first special report on longevity, titled

• 1:25Dr. Darshan Shah?

  "Pathways to Longevity," which I highly recommend you order and read, he's going to bring an evidence-based lens to a field often cluttered with hype and snake oil. In our conversation today, we're going to dive deep into the fundamental biological drivers of aging, breaking down 12 hallmarks of aging, and how understanding these cellular mechanisms will revolutionize human health span and disease prevention. You're not going to want to miss this incredible conversation with Dr. David Bersly. Dr. Bersly, it's such an incredible pleasure to have you on the Extend podcast, and this is a true honor for me. I've been following your work very closely for a long time, both

• 2:07Dr. Darshan Shah?

  through Harvard and also through our longevity doctor community. And, you know, I really, really appreciate the work that you've done through your lens and academics at Harvard, and kind of merging the science of longevity and academia. It's, I can't wait to dive into this with you.

• 2:24Speaker 01

  Likewise. Thrilled to be here, Darshan.

• 2:26Dr. Darshan Shah?

  Yes, yes. So, Dr. Bersly, before we jump into the topic of longevity, I'd love for my audience to learn a little bit more about you and your career. Would you just give us like a 10,000-foot view there?

• 2:36Speaker 01

  10,000-foot view, but I'll fast-forward to the roles I have right now, because we should take up the podcast, how I got here. But I'm a longevity medicine physician, and what I'm known for in the field is I'm a thought leader and practitioner in longevity medicine, evidence-based best practices, and in a personalized way, which is precision longevity medicine. So, among the hats I wear, I'm a lecturer at Harvard Medical School. And something we're going to be discussing today is pathways to longevity. We'll have a link in the show notes to this big announcement, Harvard's first special report in longevity. So, I'm a medical editor for that. Also, founding faculty and trustee for the Geneva

• 3:21Speaker 01

  College of Longevity Science. And I do private longevity consulting for individuals and also for institutions, business-to-business, what's the no skin in the game, what's the real evidence, what's the real facts, and how to apply that towards one's mission.

• 3:37Dr. Darshan Shah?

  Yeah. So, it's amazing, because you kind of bring together these sometimes disparate worlds that live in silos of academia, medical education, real patient care, and bench science. So, super excited to have you on to talk about how you bring all this together into real actionable insights for people. And especially, you know, this publication that you put out, "Pathways to Longevity," can you tell us a little bit about like how that came about? Because it's really interesting, you know, traditional establishments like Harvard are usually sometimes last to kind of, you know, talk about the science of longevity medicine. Sometimes, I think academic institutions get really entrenched in the traditional

• 4:19Dr. Darshan Shah?

  kind of way of teaching medicine. And longevity medicine, I think a lot of, and I don't know if you agree with this, is sometimes looking at the same science from a different lens or vantage point. And, yeah, I'd love to kind of hear about pathways to longevity, and how that came about.

• 4:33Speaker 01

  So, Harvard Medical School is known for being a leader for a long time in areas that are core to longevity medicine and practice, such as optimal lifestyle best practices. I'm one of my other hats, I'm a Diplomat of the American Board of Lifestyle Medicine. That's the certification doctors have for nutrition, and exercise science, and sleep, and stress. So, that's been around for a while, but something that's new here, and I think Darshan is really representative of where we are in the science, is this is the first time we're really discussing underlying science for what's called geroscience, which is aging biology. And we're now at a point with the research, whether we're

• 5:18Speaker 01

  discussing animal models, or we're discussing insight mechanistically, or even discussing the earliest attempts to translate to human beings are happening right now under our feet, very exciting times. It's reached a critical threshold, you know, Harvard doesn't put a stamp behind, you know, marketing and hype. What it does is it waits for it, it spearheads when things reach a point where the evidence base is really there. And the other side of things is, as exciting as the science is, marketing and hype always gets ahead of whatever the science is. So, the other side of the coin is, on one hand, we're at a point where we really can discuss the science of longevity, which is going to bring

• 5:59Speaker 01

  longevity therapeutics to us. And on the second hand, we're also at the point where the hype is at a level that it's helpful for an institution that prides itself on really having a careful look at evidence to really frame this discussion, so people understand what's real, what's not, and where to put our energy. So, it came really out of that, and my own work in longevity leader on the evidence-based science applied to human beings across longevity.

• 6:30Dr. Darshan Shah?

  Yeah, and it's so true. And I think, like you said, it's kind of a, almost a historic moment, I would say, where this is not just, you know, I think for many years in the longevity science world, there was a lot of talk about, you know, the biohacking bros, and then the snake oil that's out there, and the supplements, and all these things. It just made it seem very much like this was pseudoscience, or maybe a parallel to what's going on in traditional medicine. But now, this convergence of there is real science here, and giving people, you know, to use the title of your publication, "Pathways to Longevity," is, it's a real hallmark moment, because, you know, this is real, and this is coming. And yes, there

• 7:14Dr. Darshan Shah?

  is still a lot of hype out there, to your point, a lot of marketing out there that kind of exceeds the bounds sometimes, but there's a core to this that is really powerful, I think, coming here.

• 7:25Speaker 01

  Absolutely. And I think Hallmarks might be a great place to open up the discussion. What do you think?

• 7:30Dr. Darshan Shah?

  I would love to do that. So, you know, for the people on my podcast that listen to me, I talk about this quite frequently. There was an article published back in Cell Magazine, Cell Review Magazine by Carlos Lopez Otin, I think, is, I don't know if I'm saying that correctly.

• 7:45Speaker 01

  Correct. Lopez Otin, 2013, the first one, 2023, the addition, from nine to 12 Hallmarks.

• 7:50Dr. Darshan Shah?

  Exactly. So, to me, and I think to a lot of the scientific community, this was a landmark moment where these nine, and then now 12 hallmarks of aging at a biochemical, cellular level were published. And I'd love for you to talk about like, what, before we go into each individual one, what are the hallmarks of aging? How do you define them to people that are just learning about them for the first time?

• 8:13Speaker 01

  The hallmarks of aging are the fundamental biologic drivers to aging biology. If we look at two twins, one had a hard life, one had a better life, you might expect one to live longer than the other. And often, you even see it in the way they look. People separated at birth. So, someone's chronological age is one concept, but their biologic age is another. And the faster we biologically age, not just the quicker we pass, but the greater our risk, and the sooner we get chronic disease, whether that's dementia, Alzheimer's, diabetes, heart disease, you name it. All of these are rooted in our aging biology, which is why we don't see a lot of 10-year-olds with Alzheimer's dementia, right? Unless

• 8:58Speaker 01

  they have a particular gene mutation. So, what the hallmarks are, is they explain mechanistically what's happening in our cells, and our tissues, and our molecular biology that drive aging. And why is that important? That's important because if we understand the mechanisms, we can target the mechanisms. And if we can target the mechanisms, we can do something about it. And a famous example of that is, you know, in C. elegans, a worm model, this was like in the early 1980s, Cynthia Kenyon, was at a time when longevity science was really a descriptive science. It's like, things get old, they break apart. But we always knew there was more to that. If things get old and break apart, how come it is

• 9:43Speaker 01

  that dogs age seven to 10 times faster than human beings? If arthritis is just wear and tear, how come they get arthritis when we're just kids, and they get cataracts when we're just kids, and we get it much older? So what, what at the time those thought, well, if we're going to modify this aging biology, we really need to modify, you know, thousands of genes, hundreds of thousands through this DNA, this regulatory system, the systems biology. And it's way too complex for us ever to figure out. And what Cynthia Kenyon found was that one single mutation, uh, in a, she found doubled the lifespan of a worm, which was astounding at the time, just one gene. For the first time, it became something like, oh, that's impossible. We'll never figure out the differences.

• 10:28Speaker 01

  It's just would require too complex an intervention. And that really was one of the things that moved neuroscience from a descriptive science to a trends to a, uh, applied science, how to slow biologic aging. And that's where these hallmarks of aging come in. So these mechanistic tools, if I were to define them, the way I, I framed it in, uh, Pathways to Longevity, the report I was a medical editor for, for. It's, it, something is a hallmark of aging of number one, it is associated with biologic aging, which is an exponential increased risk for the, this chronic disease or the equivalent in animal models.

• 11:10Speaker 01

  Two, it needs to be that if you worsen that hallmark of aging, that organism biologically ages faster and that organism we're hoping is us. And three, the hardest to prove, but the most important, sure, if you make something worse, maybe it'll cause damage, but let's see if we can, uh, ameliorate or make better that hallmark of aging. And I can name some examples. And if you do that, you successfully slow down its biologic age, which typically is manifested with a longer lifespan, not just average lifespan, but maximum lifespan for the species. We can double click on why that's important. And two, their health span, like these worms, they just weren't like living longer, like sickly for extra time.

• 11:54Speaker 01

  They were living healthy, wiggling around, uh, till closer till the end, which is exciting for us because we don't want to spend decades in poor health.

• 12:03Dr. Darshan Shah?

  Yeah, yeah. And I, I really, uh, would love to dive into all of these hallmarks of aging, especially as you define them, because I think what's really interesting to me and the audience is what can we do to slow some of these aging processes? But before we do that, I want to double click on this concept of maximal biological age, right? Like, so, you know, I think for humans, that is one 20. You mentioned for the, for, for dogs, it's lower, I think 18 or 19, maybe 20 years. And then there's some animals like tortoises, for example, leave to be 200 years old, right? And so what are the differences between these different organisms and why they tend to live these different lifespans or, you know, at a cellular level, age faster or slower?

• 12:46Dr. Darshan Shah?

  And is there a potential world in the future where that maximum number can be pushed out even more?

• 12:53Speaker 01

  So, uh, yes, so the maximum number is a species characteristic. You know, we've succeeded through conventional, uh, sort of whack a mole, treat one disease at a time. We've succeeded in increasing human lifespan. But as a result, believe it or not, the amount, the number of years we live in poor health has increased, not decreased. It's great, you know, at the, uh, you know, at the, uh, 1900, you might have, you know, you might live, you know, 40, 50, what have you. We live longer now, but now the average 65 year old, uh, well, at 65, nine out of 10 of us have at least one chronic disease and we're spending about 12 to 15 years in, in poor health.

• 13:35Speaker 01

  So the whole concept of maximum of species lifespan is we've succeeded in increasing our average lifespan in human beings by preventing premature death from things like heart disease and curing some cancer, although that's been one of the more difficult ones. By having, uh, preventative diseases such as infection addressed through immunization, uh, vaccination, antibiotics. Uh, but the, the difference between us and say a bowhead whale that lives, gosh, a Greenland shark can live 400 years of bowhead whale, like 250 plus. So it has to do with a lot of the differences we're finding is these hallmarks of aging, which we should define, but I'll give one example before I, I give, you know, some other

• 14:20Speaker 01

  like examples. So through work in comparative biogerontology, this is work out of Vera Gorbunova's lab at the University of Rochester. She asked this question, beavers are rodents. Beavers live longer than mice, laboratory lab, mice live, you know, maybe two, three or something like that. So she asked, first she asked, are there differences in hallmarks of aging between the two? And it's been found that one of the sirtuins, sirtuins being, uh, one of the, uh, in part activators around, around nutrient sensing, which is one of the hallmarks of aging, these ways we pick up our energy state and respond to energy.

• 14:59Speaker 01

  Sirt 6 is a lot more efficient for things like DNA damage repair and also repression of these transposons, which you can think of almost these virus like self-replicating segments of DNA that are more like parasitic. They like to replicate themselves. It suppresses their replication. It increases DNA damage repair and it's, uh, it's a many, many fold more efficient in a beaver than a mouse. But then she asked the more exciting question, what if we take a Sirt 6 in a beaver and put it in a mouse? I wonder what happens. I mean, they live longer and the mice lived substantially longer.

• 15:38Dr. Darshan Shah?

  Wow.

• 15:39Speaker 01

  And that's one example, genomic instability. I told you I'd give examples.

• 15:43Dr. Darshan Shah?

  Yep.

• 15:43Speaker 01

  Which relates to our, our genome. That's like the, the DNA. That is one of the hallmarks of aging, that over time, our whole, our DNA sequence, all of our cells have the same genome, the DNA sequence. It's, um, anyway, our whole, our whole genome, it's, uh, gets more and more damage over time, and that's one of the hallmarks. And, but its repair pathways is another aspect of that.

• 16:08Dr. Darshan Shah?

  Right, right. And so, yeah, you touched on genomic instability. I think, um, part and parcel of that also is part of the genome is a telomere attrition problem, right? So, um, I had the, I had the, um, pleasure of meeting, uh, Elizabeth Blackburn, who won the Nobel Prize for discovering telomerase, um, at a TED conference, um, many, many years ago. And she offered me one of the first biological age tests, which measured the length of my telomeres. And back then I was in a state of, uh, very bad health and I was really sad to see my telomeres are very short, matching the telomeres of someone almost like 15 years older than me. Now I know biological age testing has come a long way, but the concept of telomerase

• 16:50Dr. Darshan Shah?

  and, um, the ability to repair the end caps of your DNA with telomeres is also kind of part of this genomic instability piece. And, um, I'm just wondering, you know, getting into some of the more practical interventions here, are there interventions out there that can help elongate our telomeres, help us to create more genomic stability or even repair damaged genome as we age in our cells?

• 17:14Speaker 01

  Yeah, telomere instability is, is important. In fact, it's given its own hallmark and the fact that it has this relationship with DNA repair. For example, dan- damaged DNA can cause premature telomere attrition and premature telomere attrition can indirectly cause more DNA damage. So it's, think of this as a system, this network that everything is interconnected. And that's one reason in regards to your question, Darshan, like ways to ameliorate that. I, in my practice, I discuss, you know, experimental things that are coming out of labs with my, my clientele, but the foundation really is in lifestyle medicine. And this is something we've known for a long time works.

• 17:56Speaker 01

  Uh, things like, um, you know, if you're at the top 25% percentile of your, your strength versus the, the bottom, you're have about a 40% lower total mortality.

• 18:08Dr. Darshan Shah?

  Uh huh.

• 18:08Speaker 01

  If you are physically active, like your aerobic fitness, there's a big longitudinal study out of the Cleveland Clinic that showed a huge benefit, like measured cardio, uh, cardio respiratory fitness had a, people who were at the highest 2.5% compared to people who were at the bottom 25%. They were, had a whopping, uh, fivefold increased chance of survival. In other words, those who were at the bottom, uh, you know, were only, only 20% the probability of survival, uh, which by the way dwarfs, uh, like coronary heart disease, smoking, diabetes, these other, uh, metrics that they measured, which are maybe a 30 or 60% higher.

• 18:51Speaker 01

  So examples of that, such as, uh, physical fitness and lifestyle medicine, actually we're looking retrospectively, these are largely, these are, you know, one way of looking at it is that these are addressing these hallmarks of aging. So some of the most powerful things we can do for that is not a telomerase, uh, TA one, I'm not going to name specific ones, but elongating a supplement per se, the evidence for those is rather weak. And even the evidence for that, that, the, the, the testing is, is, is rather weak for telomere because it's more like, uh, variance in telomere rather than average telomere. And there's a U curve.

• 19:30Dr. Darshan Shah?

  Right.

• 19:31Speaker 01

  Uh, because if you, your telomeres are, are too short, that's not good for aging. But if they're too long, that's increased risk for cancer. There's a sweet spot and there's variability. But the bottom line is the things that where we read about in longevity science, it's a lot of the things we've known for a while is helpful and we can dig into more details. Those are the same, the same ones that make us live longer. But quick tip of the hat, Darshan, because you listed yourself. I just want to, I just want to commend you because I read about what you did. And truth be told, even the epigenetic methylation clocks are not great standalone, like, uh, tests. Uh, they're, they're fun and they're exciting when they're in the right direction, but they're, they're not very reliable at the individual level.

• 20:13Speaker 01

  They're more reliable at the population level because of test, retest issues. But what is exciting is this is what I saw when I looked at what you did, Darshan. Your body composition improved, your insulin sensitivity improved, your sleep improved, your aerobic capacity improved, your biomarkers changed, both non-traditional and traditional ones, whether you're looking at inflammation or you're looking at your home IR or your insulin resistance, all of these things moved in the right direction. And when I see that, then I know, you know, regardless of a single point, which is interesting. And, and you can see in the broad context that whatever you did, it was, it was a clear positive signal.

• 20:53Dr. Darshan Shah?

  Yes, and thank you for that, David, because like I think, you know, a couple of points there that I think should go without saying, but we always have to say it as practicing physicians is lifestyle is really 80% of this puzzle at this moment in time. And it's what we know works and has such an outsized advantage to any other kind of therapeutic thing that you can do, take a pill, get in a red light bed, whatever you might, whatever you might choose to do, right? And so, and on the lifestyle piece, what's really important, especially on the point of VO2 max, you mentioned cardiovascular fitness, strength, like grip strength,

• 21:31Dr. Darshan Shah?

  is that what you, what you do to maintain physical strength and cardiovascular fitness is a lot more valuable than what you don't do as far as like avoiding smoking, right? Avoiding smoking is very, very important, obviously, we all know that. But what's even more important, to your point, five times potentially, is doing the, doing the work, going out there into the gym, running, HIIT training, lifting those heavy weights to failure, et cetera.

• 22:03Speaker 01

  There's an interesting statistic that goes exactly with, with what you said, Darshan. What's the greatest risk factor for lung cancer? The answer's not smoking. And I'm not encouraging anyone to continue and, and listen to the whole, everything I have to say because I don't want to stimulate a, a clip to, you know, things can get clipped. But basically, your greatest risk factor for lung cancer is biologic age.

• 22:29Dr. Darshan Shah?

  Yes.

• 22:29Speaker 01

  It's, that's, that's just a fact. You can, please fact check me, fact check everybody, including myself. And that's my, my gig, evidence-based best practices. And the data is constantly moving. Having said that, if I had a smoker in front of me, the very first thing I would recommend ahead of everything else is to quit smoking because that has the highest relative risk, which is why, Darshan, when individuals ask me what they should be doing, like what's the one thing everybody should be doing? The one thing everybody should be doing is risk stratifying themselves. Knowing your baseline, like, you know, something else you did is you lowered your visceral fat, you know, and that's not something you know unless you're measured. Because the reality is in a smoker, the most important first thing they can do is to quit smoking.

• 23:13Speaker 01

  And someone who is like ragged on five hours of sleep and not functioning well, their benefit is not going to be cramming in that extra workout. For someone who's totally isolated and not, you know, has no social connection. You know, the surgeon general linked or had a report where they cited, it's about the equivalent of 15 cigarettes a day to be socially isolated. And then depending on what study you read, having less social connections, it's like a 20 to 50% increased relative risk of mortality. So what I'm saying, the first thing is to get a baseline, not just to risk stratify, but so you know what areas to target most. That could be knowing your whole genome sequence.

• 23:57Speaker 01

  And it's not just traditional laboratory tests and knowing what you're doing following the guidelines. It's also testing yourself functionally, like you did, your, you know, aerobic fitness, what you can do in terms of your, your, you know, whatever metric, whatever metrics in your baseline. And once you have that baseline, you know what to target. And you can, you can also get feedback because you want to see yourself getting in a higher percentile now, not when you're older after the damage is already done. You want to be on that glide path right now to optimize your health for the long run.

• 24:30Dr. Darshan Shah?

  Yeah, no, it's such an important point. I think, you know, testing is critical because number one, it can spot a blind spot. I think like, you know, to, to your point that you, you need to know where you need to focus your attention, right? And I think people, for decades, I mean, I did this too. You think going to the gym and staying away from junk food is enough. But the reality is there's, might be something going on under the hood that you don't know about. And the testing goes well beyond just blood testing. I think it's great how ubiquitous and easy blood testing is now for people. You know, that was traditionally a very gate cat modality in, in, in Western medicine, but no, no longer. But also testing beyond that, blood pressure, your grip strength, your VO2 max, we talked about, even things like your sit to stand test.

• 25:15Dr. Darshan Shah?

  These are all tests that people can do easily at home that can point out where they need help and where they need to focus their attention. So testing is a big piece of this and it's just looking beyond just the traditional blood tests that are being done.

• 25:29Speaker 01

  A hundred percent. So know your baseline, know your weaknesses and compensate and collect information. Because something, you know, something we both focus on, Darshan, is precision medicine, right? So what, what's precision medicine? I mean, in the broader sense, all physicians are precision medicine specialists in a sense because we're not going to treat, we're not going to put a male on the same hormone replacement therapy as a female. Precision medicine's a fancy name for personalizing medicine. But of course, the best practices, you know, my, my, my focus is, you know, how can we get more and more granular data so it truly reflects you? So that reflects your family history, it reflects your genomics, it reflects your testing.

• 26:13Speaker 01

  It also reflects your preferences, it reflects what are your goals? What's important to you, what are your values? How comfortable are you with risk? You know, my, my patients and clients who are deciding to get on a certain supplement or even an off-label medication that in animal models targets some hallmarks of aging, has some promising data, they can reasonably come to different conclusions. But that's the whole thing about precision medicine. For it to be done well, it takes the right kind of information, but also takes an educated, informed patient. They need to understand the risks, they need to understand the benefits, they need to understand the unknowns because it's only after knowing these things can we truly have a kind of joint decision together?

• 26:57Speaker 01

  Because I don't believe in patronistic medicine. But I, but I want everybody to be as informed as possible. So they're truly not, you know, learning about the product from those who sell, sell, sell the product, which sometimes is unavoidable or, or part of the process. But as much as possible for them to have a sort of no skin in the games objectivity so they can decide for themselves what they're going to engage in, what they're not, that might be outside of the straight and narrow.

• 27:24Dr. Darshan Shah?

  Yeah, it's great, all great points, David.

• 27:31Dr. Darshan Shah?

  Hi, Dr. Shaw here. I want to take a minute to talk to you about cellular health. So in my clinics, I've actually seen 30-year-old people with cells that look like they're pushing retirement. And I've also seen 60-year-olds with cells that look like they're 40 years old. So what's the difference? It's really about how fast their telomeres are breaking down. Your cells you see are like phones and they have limited cell phone battery. Poor sleep, stress, processed foods, all of these things can drain that battery way faster than it should. So this is the reason why I partnered with IMA. IMA powers that cellular battery. It's not just another multivitamin. It's a comprehensive 92 ingredient formula designed specifically for cellular health and longevity.

• 28:16Dr. Darshan Shah?

  I'm talking 900 milligrams of vitamin C. That's like 20 oranges worth of DNA protection. The clinical dose of CoQ10 that you need to power your cellular engine. You also get zinc, selenium, vitamin E, alpha lipoic acid. All of these work synergistically for cellular repair and protecting your telomeres. So instead of taking a handful of pills every day and all these supplements, IMA actually gives you everything that you need in one scientifically formulated system. And this isn't just a theory anymore. IMA had partnered with Oxford University, the International Space Station, San Francisco Research Institute, and they've done studies and they've gotten this NSF certified to truly power your health.

• 28:59Dr. Darshan Shah?

  Most people are aging twice as fast as they should, unfortunately. You don't have to be one of them. Try IMA. I actually have a discount secured for you if you go to drshah.com/ima or go to imathhealth.com/discount/drsah and you can get 20% off with my discount code, Dr. Shaw. You can also find the link below.

• 29:23Dr. Darshan Shah?

  I think, you know, just to kind of go back to the hallmarks of aging, I'd love to ask, we've touched on this a little bit, but this whole world of biological age testing and epigenetics, it's kind of...

• 29:35Dr. Darshan Shah?

  It's not new science for people like us that we've been kind of tracking this for a while, but people are definitely hearing about this for the first time in just even the last couple of years about getting a biological age test, like what is the methylation patterns of their genome? There's turning genes on and off and comparing those to others. To your point, is this population, it might work at a population level, but individually, there's a lot of, it's fraught with errors sometimes. You know, I think, I think for me personally, I sometimes use those as like scorecards of what direction I'm going in for myself and my patient, but never do I say like, oh, your epigenetic age or your, is 30 and you're 40, so this, you know, this is, this is a real number. It's just more of just maybe there's lifestyle interventions that we need to put into place

• 30:18Dr. Darshan Shah?

  that can get you going in the right direction. What's your feedback on epigenetic age testing? And what is the current status? And do you think that there's going to be better tests available in the future?

• 30:30Speaker 01

  I'll start by saying epigenetic age tests are phenomenally exciting. And I think they're one of the, certainly one of the top five most important areas for this field to advance, both from my standpoint as a longevity medicine physician, and also from my standpoint as someone who wants to see gerotherapeutics, which is basically aging biology-based, things that in addition to lifestyle will work independently of that, or that's, that's the promise, that's the geroscience hypothesis. The geroscience hypothesis, by the way, is rather than do whack a mole medicine after the fact, after symptoms develop, after disease manifests, let's get earlier in the game to these drivers and the biology of aging.

• 31:11Speaker 01

  And by doing so, it's not just to get things earlier, when things are more effective, but you can target all of these diseases altogether. But back to your question about the biologic aging tests, you're thinking about it exactly right, because you're not looking at it as a sole measure, but you're looking at it as part of an overall picture. And you're also looking at it in terms of a trend rather than individual test. There was a, a recent study that compared some of the very best biologically methylation-based, CPG island-based, these aging clocks that are most popularly, that are popularly discussed as aging clocks. And they found like between different companies, or excuse me, between, even within the same

• 31:56Speaker 01

  company, like a nine-year difference from test to test. So even with some of the earlier work, and I was recently on a podcast with one of the pioneers for that studies, and what she did was really amazing, and it's the first of such studies, but we can never really say, well, was that a random shift up or down? So one of the caveats for these tests, okay, is, one is that they vary a lot, that's test retest reliability or technical noise. Two, if you just had a tough workout the day before, or you have a cold, which you might not even feel sick from, that can affect the test. Even delivering a baby, that can affect the test. So there are these short-term fluctuations too.

• 32:38Speaker 01

  The good news is that these are getting smaller, these are getting the, the variance or variability, or the, the equivalent of like a confidence interval analogous to it. These are getting narrower and narrower, and I do believe we're going to get to a point where these can be more and more reliable. And that's absolutely critical in two ways. Number one, we don't want to be telling people, okay, get this test, you know, 10 times over four days, and take the average of them, right? So we're combining, we're already there, they're providing some, when taken into account of the big picture, they're always already of some potential utility, but they'll be

• 33:22Speaker 01

  much more useful when we got that narrow. Another thing is the, you know, aging biology is, has some challenges in terms of this drug discovery side. We want to have something, we'll be discussing later, some examples of things in the pipeline in human beings. And to really make this work, we can't Darshan randomize people to like a 50-year trial to see who dies and who doesn't, to see what makes people live longer. So we need biomarkers. And the most effective biomarkers are those that are responsive earlier on, so we can actually have these trials, which are cost prohibitive, we just, nobody will pay for them.

• 34:03Speaker 01

  So in the future, biomarkers of aging as a clock measure, and I believe combined with everything else that we're looking at, traditional laboratory markers, functional markers like to get up and go, gate speed and so forth, strength, combining them can tell us sooner whether something is working, so we can actually get approved, a, something that targets the biology of aging to make us age more slowly, hence increase our health span, to compress our morbidity or poor health at the end of life. So we have a long and healthy life, and then a short decline at the end. That's really the best scenario.

• 34:42Dr. Darshan Shah?

  Right, absolutely. And, you know, I, I fully agree with you, like this, if this science, if we can really figure this out, the amount of discovery that we can do is massive, like testing drugs and testing, you know, alternative uses of drugs such as rapamycin, in, in understanding truly, like you can't wait for people to die in a randomized study, to your point, to see if this thing really works or not. What are some other ways that we can test? And it's through alternate biomarkers, specifically these epigenetic age tests. You know, one, one of the things that I always think about with these epigenetic age tests is that, you know, they're, they're, they're based on your blood sample, right? So they're taking your white blood cell DNA and the methylation patterns of that DNA.

• 35:27Dr. Darshan Shah?

  And to your point, that's always changing, right? Whether you were sick recently, delivered a baby, et cetera. Are there better samples that we can use that give us a better view, instead of like a blood sample using white blood cells?

• 35:38Speaker 01

  So let me, a, a quick tour through, through, through this Darshan. There's a lot we can cover in, in the, the translation and like tips for people for, for health. But there were first generation clocks that measured chronological age, that basically it was able to predict how old, how old we are. And those are, wow, we can actually pick up how old we are in those methylation patterns, and I'm happy to get into the, what that means biologically, if there's interest, but let's, let's skip to what that means. So that means you, you can look in your calendar and say how old you are. So it's like a little bit of a, so what? Well, we're really interested in someone's biologic age. Someone's biologic age is what we discussed before.

• 36:24Speaker 01

  Let, let me give you an example. If someone follows eight healthy habits, this was a VA study, then the people who followed all eight health habits compared to those who followed none, on average, they lived 24 years longer at the age of 40. That's huge, huge. There are other studies, there was like another study that if you follow five specific ones, it was like 12 to 14 years. Whatever the number is, and these are observational studies, and they're always, they're prone to confounding, but a lot of that is real. So the idea is you want to be able to tell biologically how people are aging, and that's what the second generation clocks did. Two people, same age, and it's able to predict who will die sooner. A classic example of that from Steve Horvath, the, the father of these biological aging

• 37:08Speaker 01

  clocks, Grim Age, Grim for the Grim Reaper, and it could predict, it was, you know, based on hospital mortality data and, and so forth, like who would actually die and who wouldn't, better than their, than their chronological age. That's second generation. Now there's second to third generation clocks. The third generation clocks are things like Dan Balski's, no need in pace, one of my favorite current clocks, because it's more predictive and it's more responsive than a lot of the ones out there. And it actually doesn't say, what, what is my biologic age now? Because it's like, well, that's water under the bridge. I, I want to know how fast I'm aging. I don't want to know how old, I want to know, is what I'm doing right to age more slowly? And that's the way we're, we're trying to move to make things like that more reliable,

• 37:53Speaker 01

  new, new generations of that. And that's, that's a third gen, a second to third generation clocks. And other clocks in that third generation are tissue-specific. So you mentioned that, you know, we're measuring this just in the, the, the blood. The reality is we find that there are individual aging clocks that are specific to organs. Our heart is a different ager than our lung, than our kidney, and each person has a different vulnerability. And that makes complete sense, because as I was describing earlier, the biology of aging explains why some people, in, in large part, explains why some people develop dementia sooner than others, and how some people develop heart disease sooner than others. There are biomechanical and other causes, et cetera, but a lot of it is tied to the

• 38:38Speaker 01

  hallmarks of aging, and based on the curves we see for mortality, they're the largest driver. So the idea is, if you can measure how old your heart is, how your, your kidney and so forth, we're going to have this precision medicine, back to that word again, where we have specific interventions exactly to your vulnerabilities. And the idea is prevention, we want to be proactive. So when I look at my patients, I don't want to just wait until they develop a symptom at an annual physical. I want to ask, what's optimal for you right now? Or what is, to your point, or what's your trend been? It's like, you're still doing pretty darn good, but for the last three, you've consistently, I don't want to wait till you cross some threshold.

• 39:20Speaker 01

  I want to put you on the best glide path, like pilots aren't a glide path.

• 39:24Dr. Darshan Shah?

  Yes.

• 39:24Speaker 01

  From, they need, if they're off too, too far, then they, they readjust their course in the middle of it. We should be doing the same thing for medicine, rather than cross-sectional medicine once a year, did you cross the threshold? So that's the walkthrough.

• 39:39Dr. Darshan Shah?

  Yeah.

• 39:40Speaker 01

  And the other exciting thing is there we could have whole, you know, deep dives about omics. There's the transcript omics, there's proteomics, et cetera. There are things that are much more granular than epigenetic clocks, which now there are two major studies that show some of those changes, even though they're predictive of how, you know, on population level for mortality or certain disease states like phenome age. They also, they're partly noise that these methylation patterns tend to follow certain predictable patterns. So they're kind of prone to the same kind of confounding as studies are. So that's risky because that means you can uncouple an intervention that can make you

• 40:23Speaker 01

  look biologically younger, might not, might be making you biologically older. So these newer clocks will be less vulnerable to that. And that's part of including those that look at our DNA expression patterns, transcriptomics and proteomics, which is these proteins that actually come out as the end product of our DNA at the other side.

• 40:44Dr. Darshan Shah?

  Do you think the future biological age testing will include methylation testing combined with transcriptomics, combined with proteomics, and then maybe make some inference based on all of this data together? Is that kind of the future?

• 40:58Speaker 01

  I do. Just like, you know, the TAME study was as proposed by nearby's line, no relation to myself, is was a proposal to create a composite endpoint in a study of what is targeting aging biology by saying, well, time to diabetes, time to dementia, time to all these age-related diseases. That composite is powerful because you're able to look at multiple age-related conditions without even needing to call aging a disease and to see whether it's targeting aging. In a similar manner, the challenge is because we don't have these huge randomized controlled trials that are multi-decades. We need to, what I like, what I call, or what engineers call triangulation. Okay?

• 41:43Dr. Darshan Shah?

  Yeah.

• 41:43Speaker 01

  The idea is, we might not know, we might not have the gold standard perfect evidence, but if we have data mechanistically in terms of what we're measuring in our blood biomarkers, and we have data also through functional markers, through testing we do in real time, and we have other data, maybe through wearables, and other data through traditional biomarkers, we're able to create a composite together, a sort of weighted average that really becomes more and more reliable, and also more and more precise for our own biology, to tell us whether, whether something's working for us, or something is working for the biology of aging. That's going to be absolutely critical, because I don't want to, we're not going to wait now.

• 42:26Speaker 01

  We can't wait for that trial that won't happen. We need to work based on the evidence we have to optimize people's health, because if we waited for that trial, we would never benefit from everything we know right now. And AI is going to be a huge part of that, I add, and it already is.

• 42:42Dr. Darshan Shah?

  Yeah, I totally agree. It's an exciting, exciting time to be alive right now. I want to ask you, you know, we, gosh, I feel like we could talk forever. We could have a six-hour episode here, but I know, I know, I haven't blocked that much time in your calendar, so I'm gonna have to have you back. But I'd love to kind of rapidly maybe go through some of these other hallmarks of aging and get your best advice and how people should think about some of these hallmarks. And I know just from my patients, you know, they, they're, a lot of them are very knowledgeable, but they're confused about some of them. And I'd love to hear your perspective. So one of these is this whole world of senescent cells and autophagy. And how should people think about senescent cells that are living in their body as zombie cells and getting rid of them? What are your thoughts there?

• 43:27Speaker 01

  Okay, so for senescent cells, let's, so people are oriented. Senescent cells is an end state, just like apoptosis, or still death is a state, and development of cancers can connect with state. Senescence is a mostly pathologic state. It has some benefits in wound healing, and also in human development, and in cancer prevention. But senescent cells, they basically, they won't divide anymore. They ordinarily divide. They're damaged in some way. It could be DNA damage, it could be telomere attrition, just revisiting some

• 44:07Speaker 01

  of everything, and a variety of other things. And they're spewing out SASP, which is senescence associated secretory phenotype. And basically, that is like inflammatory cytokines, which can promote inflamaaging, the inflammation of aging, a chronic inflammation, which is another hallmark of aging. And it also, they're sort of contagious. You know, when we're young, these senescent cells, which have important biologic functions, which I mentioned earlier, they are, when we have something like a wound, they're used, and then they, they quickly get taken out by the immune system. They quickly disappear. But as we get older, we accumulate more of them. And we call them zombie cells, not because, some people call them zombie

• 44:50Speaker 01

  cells, some people hate that nomenclature. But the reason it's like that is, they create more zombies. The stuff they produce does local remodeling, but also converts local cells. So they start producing SASP. So we have more and more of an increase. And there's some animal models that if you give some combinations, like the satinib, but cursitin is an example, or a high dose bioflavonoid fisatine, then it's able to clear the, clear these senescent cells. So how do we clear senescent cells?

• 45:19Dr. Darshan Shah?

  Yeah.

• 45:19Speaker 01

  That's your question, because we don't want them to be at pathologic levels. So I'm not recommending everybody, it's a very nuanced discussion regarding the translational geroscience in human beings, the, the risks, the benefits, and whether it makes sense. I, you already know my school of thought. People should be able to do what they do, they just should need to make educated decisions. What I would say is, the most foolproof way for reducing these is to reduce the number of senescent cells, and also to reduce the SASP they produce, both of which are, tend to be through intense exercise or exercise. What

• 46:00Speaker 01

  we find is, and this is by the way, also true for mitochondrial health. So I would say the general lifestyle medicine principles, avoiding overweight and obesity, I'm not going, there is some interesting data for human beings, for senescent cells, I'll name this as an example. There are certain drugs that extend lifespan in animal models, that we're not sure yet whether they extend lifespan in humans by hitting the biology of aging. One of them is cannagliflozin, and I'm not saying this is what people should do, I'm just citing this as an example of something that's interesting. In, in male mice, in female mice, the dose might have been too high, and that's a long story. Cannagliflozin has been

• 46:41Speaker 01

  found to increase maximum and median lifespan. And in human beings, although they're approved for, basically for diabetes, they produce, they reduce the sodium glucose co-transporter, so we end up peeing out more glucose, we have less of a postprandial glucose excursion, we have less of a glucose spike after meals. That might be part of their mechanism. Anyway, in humans, we also find them to be renal protective, to protect our kidneys, and also have certain effects in terms of heart function. They've also been some more preliminary data in terms of mitochondrial function. But interesting enough, there's some, some data that, that's, that they might have a little bit of a senolytic effect, too.

• 47:19Dr. Darshan Shah?

  Uh huh.

• 47:19Speaker 01

  So the number one way you can reduce senescent cells is to follow lifestyle medicine best practices, like in, you know, the special report we're covering. But then there are other things that we're considering down the pipeline, such as the senolytics, which kill the cells, or senomorphics, which just make them spew out less, spew out less SASP.

• 47:40Dr. Darshan Shah?

  Yes.

• 47:45Dr. Darshan Shah?

  Dr. Shah here, and I want to take a quick moment to talk to you about metabolism. So you've probably already heard, unfortunately, 88% of Americans are metabolically unhealthy. And it's not because of what they're eating. It's actually a lot about what's living in your gut. I'm talking about your microbiome. This is the community of bacteria that controls everything, from how you process sugar, to your energy levels, to your mood. There's actually one specific strain in your microbiome called Akkermansia mucinophilia, that's absolutely critical for metabolic health. This is a bacteria that strengthens your gut lining. It helps you metabolize carbs more efficiently, and it increases GLP-1 production naturally.

• 48:28Dr. Darshan Shah?

  The problem is, almost everybody is completely deficient in it. And until recently, there was no way to get this. But that's why I'm really excited about joining Pendulum. They're the first company in the US to bring live Akkermansia to the market. The company was founded by PhD scientists and doctors, with the Mayo Clinic as their first investor. The metabolic daily formula that I take every single day doesn't just contain Akkermansia, it's formulated with multiple next generation strains. And these all work together to optimize your metabolism from the inside and out. So you can track every macro and calorie if you want, but if your gut microbiome is out of balance, you're going to be fighting an uphill battle. Pendulum is going to give you the tools that you need to fix your gut at

• 49:12Dr. Darshan Shah?

  its source. Try Pendulum today. Head to my link below and use the discount code. You're going to feel the difference a healthy gut microbiome can make.

• 49:26Dr. Darshan Shah?

  Do you believe in fasting or extended fasting helping to clear senescent cells?

• 49:30Speaker 01

  Fasting does more for autophagy than it does for clearing out senescent cells. And the two concepts are often confused. Of course, I mentioned that the hallmarks of aging are interconnected, so that can do some. So primarily, what, there are several things that happen. So if you're talking about prolonged fasting, like the literature from Valther Longo, for example, his FMD and the work that led up to it in animal models. If it's a prolonged fast, then you find stem cells tend to, in some organs, actually tend to get into a more quiescent state. And when you refeed, you have, you can have these progenitor cells reproduce more, which might be, stem cell exhaustion is one of the hallmarks of aging.

• 50:14Speaker 01

  And interestingly, when we're fasting itself, whether it's a prolonged fast, which is his protocol, versus a just calorically restriction, which is to be distinguished. Both cases tend to increase macroautophagy, which is another hallmark of aging, and nutrient sensing. And macroautophagy, which people colloquially call autophagy, there are these two other major types. That tends to happen a lot because in fasting, when you're eating less, there's basically what's happening is your body sent a signal that says, I'm hungry. I don't have enough basic components. Let me find some basic components. So imagine like you're in a house, and the house, like you're out of firewood.

• 51:00Speaker 01

  And you're like, crap, I'm out of firewood. I need something for the furnace. And you're saying, well, I don't want to go for any new furniture. And I'm borrowing this from Valther. I don't want to go for any new furniture. So why don't I use like the old chair that's dilapidated and partially used? Why don't I use that for firewood for kindling? So autophagy is the recycling of molecules, even, you know, potentially organelles to able to produce basic energy and also to simultaneously have these fundamental, you know, amino acids and simple sugars and so forth. So autophagy by destroying this dysfunctional old things that's sitting around, it's able to sort of clean house.

• 51:45Speaker 01

  So it's, we're basically burning trash and we're making new, clean, healthy things in a substitute.

• 51:51Dr. Darshan Shah?

  Right.

• 51:51Speaker 01

  So calorically restriction does that. And there's controversy in the human data and in the mouse data, whether prolonged fasting, whether it's every other day or it's five day regimen, seven days, what have you, whether it's doing much that the same equivalent of reducing your calories doesn't do by itself. That's its own literature. But I would say the summary, the TLDR for your listeners, is you get most of the benefit from prolonged fasting through fast, through being calorically restricted. But the more you are on the metabolic side, you know, metabolic syndrome side, the more benefit you have.

• 52:34Speaker 01

  And these prolonged fasts show some lasting effects, like it's for at least three months out. You know, your inflammatory biomarkers and some of these other hallmarks we're discussing.

• 52:46Dr. Darshan Shah?

  Right. Yeah, that's a great run through there. So thank you very much, Dr. Berzeline. You know, sadly, we're running out of time. So many more things to talk about. But I think, you know, I think your report from Harvard, Pathways to Longevity, summarizes so much in a really easy to read, what is it, like 50 pages or 40 page report that you've made?

• 53:07Speaker 01

  It's limited to 50. So it's so selective. There's so much more. Yeah, but absolutely, yes.

• 53:16Dr. Darshan Shah?

  So much more in there and it's perfectly presented to where it's not confusing and it gives people all the big wins that they can get in one report. Like you talk about, what's the best diet? What's been studied the most? You also talk about, for example, how to think about hormones and all these longevity interventions people might be hearing about, such as Kenaglofen and Rapamycin, et cetera. So I really encourage people to get a copy of that. Like you said, we're going to put the link to purchase one in our show notes. And, you know, with that, I just wanted to ask you just as a closer, you're so close to the science up there at Harvard in longevity research. Are there a couple of things you're really keeping your eye on that you feel could be game changers?

• 53:59Dr. Darshan Shah?

  And the, in what we're seeing out there, I know the science is advancing so rapidly. I love it from your, like, you know, from your view being deep in it.

• 54:07Speaker 01

  There are so many exciting things happening across all the hallmarks, whether it's your microbiota or whether it's in mitochondrial. That's, that's mitochondrial dysfunction is another hallmark. So they're, we're doing research in mitochondrial transplants to be able like to have more youthful mitochondria is one example. Then there's blood factors. We find that if you connect the circulatory system of a younger and an older mouse, that the younger mouse ages faster, but the older mice ages more slowly and they're protected. Part of that is blood, healthy blood factors. And a lot of that, probably more of that is actually removing and filtering out old blood factors. There is senescence, which we talked about.

• 54:52Speaker 01

  Unity did a trial where they tried injecting it in the knee for osteoarthritis, a senolytic to see if that could help. And while that one failed, there's a more promising systemic in other specific applications there. Let me give you one example of something, of a couple of things that are working. One of them is in the nutrient sensing pathways. I know you just had Matt Kabreline and I enjoyed watching you two there. And I concur with, with the agenda. For that, in older adults given vaccines, we tend to have less of a response. So we, our titers tend to go down and pneumonia, influenza.

• 55:34Speaker 01

  And as we saw COVID, all these things exponentially go up as we get biologically older. And they found that a Rapamycin analog, Evrolymus, increased the titer and also improved self-reporting of upper respiratory infections. Now, that was partially reproduced in another study that used a different combination. There was a third that didn't use the same one, that it wasn't reproduced. So, but they were testing something different and they changed the endpoints. So we're very early days. So I would say, keep your, keep watching this space because this is like kind of the Wright Brothers, where the first planes are going up. Based on what we're seeing, like in Rapamycin extending lifespan, nine and 14% now, more than 30%

• 56:19Speaker 01

  is one example. But in terms of humans, in terms of humans, a nice example of something recent, Arshon, is something out of life biosciences with David Sinclair and Michael Ringel. So at the time that, that I was developing as a medical editor, Harvard's first special report in longevity, we had earlier data where epigenetic drift was a hallmark of aging. And I described in that paper how we had these earlier work where mice who are blinded, either from just age associated blindness, or they were, their optic nerve was constricted,

• 57:03Speaker 01

  or they were given glaucoma, they lost their visions. And amazingly, these mice, they're able to see again through regrowth. You could actually see regrowth of the optic nerve. Just boggles the mind. And how can you tell the mice can see? Because I was, you know, I read in detail every, that's who I am, aging doc, you know? So I read the methods, like, oh, so they're having their eyes track the ball so they could see their eyes kind of, this kind of scut, staccato. So when, when we were drafting that, that's about as far as we went and it was just going to primate models. And while it was still in press, so it didn't make its way to the report yet, but now, future edition, that now the FDA has approved based on the early data.

• 57:47Speaker 01

  Now we have in a primate model for vision restoration. And this is just the first application to vision. We're looking at a partial epigenic reprogramming being used for a variety of organ systems. Now they approved testing it in human beings. So this same therapy that's led to restoration of vision, not only is being tested in humans initially just for safety, it's something we want to test as a technology in the heart and all sorts of different places.

• 58:17Dr. Darshan Shah?

  Yeah, it's absolutely wild. I mean, something that we thought could never be fixed. Human vision blindness, other than, you know, through technological interventions like, you know, Elon Musk, Neuralink, et cetera, et cetera. The, these Yamanaka factors, what you're talking about, applying these to cells and seeing new cells grow. And what's even more incredible to me is growing the right pattern with the right connections they need to restore vision. I mean, this is just mind blowing. And this is just one example. It's not just vision, to your point. This same technology can be used throughout the body. I think in fact, vision is probably one of the more complex use cases of this.

• 58:59Dr. Darshan Shah?

  Growing new heart cells, growing new even liver cells, for example. That's an organ that can't be regenerated. When people lose their liver, the only solution is transplantation. Like these, the same technology, if it works in the eye and can work in the heart and in the liver. I mean, talk about extending lifespan. These are, these are some of the organs that, that without them we die, right? And so, so this, this could be a massive leap forward.

• 59:23Speaker 01

  And it's already been proving itself in animal models. It's not specific to organ systems. So Shinya Yamanaka won the Nobel Prize for discovering four Yamanaka factors, these transcription factors, you know, DNA to RNA, that process, that DNA expression patterns that gives each cell its identity, but also the change as we get older and it's part of biologic aging. And what they found is by using these factors, they're able to restore, you know, say, take a fibroblast or a skin cell and you're able to restore to a much younger state. And what's interesting is they also found that can make them pluripotent again. That is, you can make a specific cell that says, I'm a skin cell. And you can tell it, now I'm like a stem cell. I can form any kind of cell you want.

• 1:00:08Speaker 01

  So already for things like organ transplants, like growing some exact kind of cell you want that's in short supply, that's huge. But what's interesting is there's a technology, and this is a technology that they used, except they, they used three out of four Yamanaka cancer, Yamanaka factors, because one of the factors is associated with, with cancer. And there's a way to avoid cancer, even with that fourth one, but they wanted to play things, they wanted to be cautious in that regard. So using three out of the four, by doing partial reprogramming, instead of taking a cell and reprogramming it, say from a heart cell now, all the way down to like a stem cell. And it's like, it's not a heart cell anymore. That's not what we want in human beings, right? We want a heart cell to stay a heart cell, but we want it to be a young heart cell.

• 1:00:53Speaker 01

  We want a kidney cell to stay a kidney cell, but just to be a young one, right? So by doing it partially, what they did is they gave these factors, short term, and then they paused. Short term, and then they paused. And it's a science finding how long. And by doing so, it remembers it's supposed to be. Um, when I said heart cell earlier, I was just giving, as an example, I wasn't saying specifically that. But so the way this has proved itself in animal models, or showing itself in animal models, is partial epigenetic reprogramming they've tried in animal models, the whole organism, not just the eye. And there, there was, there's at least, uh, one major mouse model that, uh, lived healthier and longer.

• 1:01:35Speaker 01

  The lifespan extension was more modest and more up for, you know, discussion in terms of that, that finding. Uh, because you always look at how long, how long lived were the controls? But the, the health span, the better health that it had, was a, was a stronger signal. So, uh, you know, obviously we need to reach all the organs. There's a science to all that, and that's one reason they, they picked the eye first. Uh, but the idea is if it makes a mouse, uh, biologically younger in some respects, partial reversion, and it also made it healthier. Uh, this, this is, I think, a very much untapped new technology that we're just starting to test.

• 1:02:13Dr. Darshan Shah?

  Yeah, wow, it's, it's a mind blowing, mind blowing, uh, thought that this could actually be getting closer and closer to a universal intervention, um, for all cellular types. And to your point, like, you know, as we do go through more animal models and we see more universal benefits in, throughout the organism, this could be something that, you know, even, we can even use it if we don't know what's causing the aging, where, where is the aging occurring? It could just, just continually improve the age of every cell in our body and every organ. So it's just, it's just an incredible time to be alive. And, you know, I appreciate the work that you're doing because you're helping people stay healthy long enough to, to actually benefit from these interventions.

• 1:02:55Dr. Darshan Shah?

  And I think the key here is we know, we already know what we need to be doing with our day to day habits, with our lifestyle. Um, and everyone should be taking that piece of it very seriously. Because interventions will be coming down the pipeline and you just want to be there to enjoy them when they come out, right?

• 1:03:14Speaker 01

  Hundred percent. Uh, so yeah, know your data and, uh, find best practices for lifestyle right now. Follow the science, support the science, advocate for this, uh, and I could give you links to that. And I would say best practices for screening early, uh, and early, early detection. And, um, just hook yourself up with a good, with a good team and, uh, follow the literature.

• 1:03:42Dr. Darshan Shah?

  Yep, yep, exactly. Well, Dr. Merzly, this was incredibly helpful. Thank you so much for joining me. I can't wait to come out to Boston and do this again with you one of these days.

• 1:03:52Speaker 01

  I'm looking forward to that, Darshan. It was, it was really a pleasure. We were scratching the surface, but I hope it's, uh, that like science, tantalizing hypotheses, uh, a lot of fodder for further reader, for your listeners.

• 1:04:03Dr. Darshan Shah?

  Absolutely. Thank you so much.

• 1:04:07Dr. Darshan Shah?

  Thank you so much for listening to the podcast today. Please remember to subscribe if you liked this episode and give us a good review and share a link with your friends. It really helps to support all of our efforts. I also want to remind you that the information shared on this podcast is for educational purposes only and is not intended to replace professional medical advice, diagnosis, or treatment. Please consult with your healthcare provider or physician before making any decisions or taking any action based on what you hear today, especially if you have any underlying health conditions or on any medications. Your doctor knows your personal health situation the best and it's always important to seek their guidance.