160. Dr. Kara Fitzgerald on Biological Age, Epigenetic Clocks, and the Future of Aging Reversal

Biological aging is no longer just a concept tied to time. It is something we can now measure, track, and influence through data, lifestyle, and targeted interventions that directly impact how our cells function and age. In this episode of Extend, we sit down with Dr. Kara Fitzgerald, functional medicine leader, researcher, and author, to unpack how diet and lifestyle can directly influence epigenetics and biological age. We break down the difference between chronological and biological aging, how epigenetic clocks work across organs and systems, and why aging may be driven by both environmental exposures and deeper programmed mechanisms. We also explore how polyphenols, nutrient-dense diets, and emerging interventions like Yamanaka mimetics may begin to shift the trajectory of aging at the cellular level and open new pathways for extending healthspan and peak performance. Dr. Kara Fitzgerald is a functional medicine physician, researcher, and author of Younger You, known for her pioneering clinical studies demonstrating how targeted nutrition and lifestyle interventions can reverse biological age and reshape long-term health outcomes. What We Discuss: (01:36) Aging, performance, and menopause (05:01) Healthspan vs peak span (08:39) The dark matter of nutrition (11:36) Polyphenols and urolithin A (13:12) Biological age and epigenetics (15:41) Epigenetic clocks and measurement (21:02) Exposomic aging (25:03) Programmed aging (28:20) Yamanaka factors (33:24) Yamanaka mimetics (36:29) Polyphenols and caloric restriction (40:33) Nutrition and biological age reversal Thank You to Our Sponsors: IM8: Try IM8 today with a 30-day money back guarantee. You can get 10% off your first order with code DRSHAH at https://im8health.com/discount/DRSHAH. Momentous: Head to livemomentous.com/fiber and use code DRSHAH for up to 35% off your first order. Learn more about Dr. Shah: Website: drshah.com https://www.drshah.com/ Clinic: next-health.com https://www.next-health.com/ Instagram: darshanshahmd https://www.instagram.com/darshanshahmd Learn more about Dr. Kara Fitzgerald: Website: drkarafitzgerald.com https://www.drkarafitzgerald.com/ Podcast: New Frontiers in Functional Medicine https://www.drkarafitzgerald.com/fxmed-podcast/ Webinars: webinars https://www.drkarafitzgerald.com/webinars/ Instagram: drkarafitzgerald https://www.instagram.com/drkarafitzgerald Facebook: Dr. Kara Fitzgerald https://www.facebook.com/DrKaraFitzgerald You tube: @Drkarafitzgerald https://www.youtube.com/channel/UC7jYgG7WMnqPeC4uwslqdfQ X: @kfitzgeraldnd https://x.com/kfitzgeraldnd Pubmed: Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial https://pubmed.ncbi.nlm.nih.gov/33844651/ Pubmed: Potential reversal of biological age in women following an 8-week methylation-supportive diet and lifestyle program: a case series https://pubmed.ncbi.nlm.nih.gov/36947707/ Pubmed: Dietary associations with reduced epigenetic age: a secondary data analysis of the methylation diet and lifestyle study https://pubmed.ncbi.nlm.nih.gov/40266024/

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 guide to proactively avoid disease, and most importantly, extend your health span.

• 0:49Dr. Darshan Shah?

  Aging has traditionally been viewed as an inevitable decline, but emerging science suggests we may have far more control over the process than we previously thought. From gene expression to cellular function, longevity is no longer just about extending lifespan, but optimizing how we age. In this episode of Extend, we're going to sit down with Dr. Kara Fitzgerald. She's a naturopathic doctor and leading researcher in epigenetics. We're going to explore the cutting edge of longevity science. We discuss how diet and lifestyle can influence biological age, the difference between environmental and programmed aging, and what new research reveals about the potential to slow

• 1:32Dr. Darshan Shah?

  or even reverse key aspects of aging at the cellular level. If you think aging is something you can't control, this episode will completely change how you think about longevity.

• 1:48Dr. Darshan Shah?

  Cara, I can't believe you're here again. This is awesome. Thank you for coming.

• 1:51Speaker 01

  Absolutely. I love getting to hang out with you, of course.

• 1:54Dr. Darshan Shah?

  I love hanging out with you, of course. And thank you so much for coming up from Mexico after an injury.

• 2:00Speaker 01

  I know.

• 2:01Dr. Darshan Shah?

  What happened?

• 2:03Speaker 01

  Well, I have started, as you know, I've gone back into competitive cycling. This was my first mountain bike race, so I was a road cyclist and I still am, but I've since gotten into mountain bike biking and I did my first race and was just taking a descent a little bit too intensely and sped out and trashed my knee. Yeah, as you know, I actually had to move our podcast time because I wasn't moving that well, that knee, I had some stitches in it, but I won.

• 2:31Dr. Darshan Shah?

  You still won the race.

• 2:33Speaker 01

  Yeah, because I was, so there I was with a big bloody knee and a bloody elbow, but just really adrenaline out. And I was telling somebody that, you know, this is, this is like the new menopause, right? It's funny. Like, this is, I mean, it's, it's strong and it's exciting and, you know, participating fully in life with less attachment than when, that I had when I was younger. You know, we were just talking about that. So when I was competing in university, I had all the usual anxieties and I was nervous. And now it's just like, let me get in there and, and play it, you know, and play it as, to the best of my ability. And yes, I do think winning is fun and yes, I am competitive, like in just, in that arena.

• 3:18Dr. Darshan Shah?

  That's awesome.

• 3:19Speaker 01

  Yeah, and there's the freedom.

• 3:21Dr. Darshan Shah?

  Yeah, yeah. So instead of menopause being this time where you're slowing down.

• 3:25Speaker 01

  Right.

• 3:25Dr. Darshan Shah?

  You're going stronger, harder, right? I love that, the new menopause.

• 3:30Speaker 01

  Well, and we have the tools, like, you know, we've got tools now to keep our bodies strong. Like, we know, we're just digging into what the phenomenon is of aging and how we turn it around, like how we reverse it, how we slow it down. I mean, I'm incredibly invested in this. I became a mom later in life, so I've got a kiddo at home who, who needs me to be as sharp and healthy and as strong as I possibly can for as long as I can. And we can do that. I think we have the technology. And just one other thing, I mean, I'm here, I'm on the advisory board of Next Health, but I'm here as a patient because you have these longevity tools that I think are incredibly important. And so they are a part of my, my life, my lifestyle.

• 4:12Speaker 01

  To come and do TPE, you know, as I'm able to and, you know, to do some stem cells and some exosomes and just to get these interventions periodically as I'm able to, because it's just, it's just worth it. And layering that on top of all the foundational stuff.

• 4:28Dr. Darshan Shah?

  Yeah. So you know, you said something very powerful there. And I think this is true for me as well. How old's your child, by the way?

• 4:33Speaker 01

  She's eight.

• 4:34Dr. Darshan Shah?

  Yeah. So, you know, I have an eight year old at home too, and a 12 year old. I'm a little older as a dad myself. And prior to getting deeply involved in this world, I would have thought I would have been an old man by the time my kid graduated high school or college, right? And now I don't feel like that at all. I feel like I'm going to approach my son's children, my kids' children, my grandchildren, with the ability to run with them and travel the world with them and do all the things.

• 5:05Speaker 01

  Yes.

• 5:06Dr. Darshan Shah?

  Because I feel in my own skin right now, at this age, much younger than I did even like 10 years ago.

• 5:12Speaker 01

  Yes.

• 5:12Dr. Darshan Shah?

  Right?

• 5:13Speaker 01

  Yes, 100%. You know, and we talk about, well, we know, of course, in the science that, you know, the leap forward in aging in women is menopause and there's, and there's a lot of anxiety and fear around it. We are talking less about the fact that with menopause comes a freedom. I mean, our, you know, the testosterone estrogen balance shifts. I've got, you know, probably got a little more testosterone dancing around. I think I've always had a sufficient quantity, but there's something that's just turned the volume down immensely on how I approach the world and I can, and I can be present in it and experience it without the kind of attachment. And actually, I'd love to hear from people who are listening to this, women who are in the transition and are finding that freedom to be. So if you can

• 5:58Speaker 01

  confine that freedom, that strength, and also it comes from experience, from life experience, and have these tools to feel fabulously, to not just feel, but we can measure it, right? And we're going to talk about that. I can see that I'm much younger than my chronological age and, and it reflects in how I feel, et cetera. So there's, there's just a experience of life right now that's awesome.

• 6:22Dr. Darshan Shah?

  Right. And you know, like when I talk about aging on a lot of stages like you do, and a lot of people say like, why do we have to do all this? Because none of this was around 20, 30 years ago. And my response to them is always, you don't have to do this.

• 6:36Speaker 01

  Yeah.

• 6:36Dr. Darshan Shah?

  But if you want to age like your grandparents age or your parents age.

• 6:40Speaker 01

  Yes.

• 6:40Dr. Darshan Shah?

  That's the direction you're headed in.

• 6:42Speaker 01

  Yes.

• 6:42Dr. Darshan Shah?

  Right? And if you shift your thought process around maybe using some of these molecules that are naturally present in our human body anyway.

• 6:51Speaker 01

  Yes.

• 6:51Dr. Darshan Shah?

  Hormones, for example.

• 6:53Speaker 01

  Yes.

• 6:53Dr. Darshan Shah?

  You could age slower and also maybe even feel better and more powerful than you did even, you know, a few years earlier. And so I think it's just like using the science to your advantage to prolong health span. And I believe it's even bigger than prolonging health span. It's actually feeling incredible in your skin right now, right?

• 7:13Speaker 01

  Yes.

• 7:14Dr. Darshan Shah?

  So health span is obviously very important, like time away from chronic disease.

• 7:18Speaker 01

  Yes.

• 7:19Dr. Darshan Shah?

  But there's so much more that can be achieved even beyond that with some of these interventions.

• 7:23Speaker 01

  Yes, there was a publication that just termed it peak span.

• 7:26Dr. Darshan Shah?

  Yes.

• 7:27Speaker 01

  You know, maintaining, you know, the longest peak span that you can. And, you know, why the hell not?

• 7:32Dr. Darshan Shah?

  Why not?

• 7:33Speaker 01

  And it's our choice. We truly sit in that decision. It's up to us. Indeed, we can look at our grandparents, we can look at our relatives now and see their quality of life and really make choices around how we want ours to be. And, you know, we didn't get, we didn't have the advantage of the level of information we have today. I mean, processed food, we didn't quite understand how horrible they were. You know, in World War II, when, when I guess margarine was ushered in.

• 8:01Dr. Darshan Shah?

  Yeah.

• 8:02Speaker 01

  And, you know, and some of the really awful processing techniques were kind of introduced and omega threes were basically exited and omega sixes were brought in and so forth. And so slowly over time, we've had this, this diminishment in our diet and, you know, and this disrespect towards nutrition and the power of nutrition, utter disrespect.

• 8:22Dr. Darshan Shah?

  Yes.

• 8:22Speaker 01

  And now we know that this was completely wildly short sighted.

• 8:27Dr. Darshan Shah?

  Yeah.

• 8:27Speaker 01

  And so we've got this new information and we can choose to use these tools in our lives to live our best and strongest life. And then on top of that, layer in indeed additional molecules and additional interventions to really kind of turn the volume up in a safe way.

• 8:42Dr. Darshan Shah?

  Yeah, you know, this disrespect, I think, also developed from a lot of just basic science research around calories and the calorie hypothesis. And food just basically became macros and calories. And that's all it was.

• 8:56Speaker 01

  Yeah.

• 8:56Dr. Darshan Shah?

  And then we forgot the power of nutrients and phytonutrients and all these other molecules in food that we don't even know what they all are.

• 9:07Speaker 01

  That's exactly right. Yeah, well, it's called the dark matter of nutrition.

• 9:10Dr. Darshan Shah?

  The dark matter of nutrition, right? And you've written about this in your last book. And you, basically, understanding that the dark matter of nutrition is so powerful, that can actually reverse biological aging. And that landmark study that you published and wrote about in your book, it just really, like, when I read your book, I was like, this is what food is all about. It's not just calories, it's not just macros. There's so much power in this.

• 9:34Speaker 01

  It's an extraordinarily complex collection of molecules. You know, every single forkful that we decide to put into our mouth tells our body system-wide, from the brain, you know, to the skin, gastrointestinal, like, everything, you know, what to do, how to be, how to perform, et cetera. And again, this is our choice. There's such an exquisitely complex interaction between the molecules on the fork, our saliva, the enzymes that are present, the cues that it gives the brain, the brain then cues the body and the gastrointestinal tract, you know, and it goes into what we call the cephalic, there's just the full symphony of digestion, starting with the cephalic phase, even olfactory, even smelling food. And so there's this extraordinary symphony.

• 10:18Speaker 01

  All of this information, we are just starting to unpack. All of the molecules and what they do and how they direct gene expression, we're just beginning to unpack all of that. We knew, you know, it was our best guess, because it hadn't been demonstrated yet. When we, when we started our research study back in 2018, we believed that we could design a dietary pattern that would optimize gene expression. And, you know, we hoped, it hadn't been demonstrated at the time, in so doing, it could change the rate of biological aging. We had no idea how potent. Yeah, we had no idea. So it was exciting times. And that's when you and I became friends when you reached out to me.

• 11:00Dr. Darshan Shah?

  I just had to reach out to you because you're, you know, your science that you put out there really changed my thinking. And actually helped me reverse my own biological age. So we can see my epigenetic aging score.

• 11:12Speaker 01

  Yes.

• 11:12Dr. Darshan Shah?

  And slowed down my pace of aging.

• 11:14Speaker 01

  Yes.

• 11:14Dr. Darshan Shah?

  And I was like, this is incredibly powerful intervention because it not take a single pill.

• 11:19Speaker 01

  Yes.

• 11:19Dr. Darshan Shah?

  A single therapeutic intervention, it just stuck changing my diet.

• 11:22Speaker 01

  Yes.

• 11:23Dr. Darshan Shah?

  I did add a couple of extra supplements, but just to get a superpower of what's in the food.

• 11:28Speaker 01

  Absolutely. No, I think that that's absolutely correct.

• 11:31Dr. Darshan Shah?

  Yeah.

• 11:31Speaker 01

  I mean, we know. So you've probably talked about urolithin A, one of the postbiotic compounds that comes from a compound found in pomegranate, some nuts and seeds and berries. Urolithin A is game changing in its ability to regenerate mitochondria. It changes gene expression. It slows biological age. They haven't published on that. It's it's exquisitely powerful, this single molecule coming from pomegranates, et cetera.

• 11:58Dr. Darshan Shah?

  Right.

• 11:58Speaker 01

  This single molecule. I say to people now, where there's one in this sea of dark matter, believe me, there are many, many, many, many others that we have yet to identify. Again, going back to that well-designed forkful of salad or whatever you're ingesting that's polyphenol dense into a healthy gastrointestinal microbiome, because that's where those compounds are going to be transformed. And then you're ingesting these postbiotic compounds, we call them, that are tweaking gene expression, turning the volume down on what we refer to as the hallmarks of aging, allowing us to live our best and longest life. So we're just starting to unpack it and I, and I feel deep gratitude and also commitment.

• 12:38Speaker 01

  And I practiced this myself to be part of the conversation and part of this research journey.

• 12:44Dr. Darshan Shah?

  It's so great. And, you know, I'm so excited. So for the listeners that did not hear my previous episode with you, they, you should definitely listen to get more around this topic of food affecting your epigenome and your biological aging. But I really want to take it to what you're learning now and talking about now, which is a whole other level. Which is so exciting.

• 13:03Speaker 01

  Yeah.

• 13:04Dr. Darshan Shah?

  And first of all, you know, you're you talk a lot about biological aging.

• 13:08Speaker 01

  Yes.

• 13:08Dr. Darshan Shah?

  Let's just define that for people that are new to this world.

• 13:10Speaker 01

  Yes.

• 13:11Dr. Darshan Shah?

  What is epigenetic aging? What is biological aging? And then we can kind of dive into the reasons we biologically age.

• 13:19Speaker 01

  Yes.

• 13:20Dr. Darshan Shah?

  Please.

• 13:20Speaker 01

  Yeah. So biological age is the the the the rate that you're aging at. And we're becoming more granular in how we measure it. So there's a lot of tools in Next Health where you guys are looking at, you know, VO2 max. You're looking at, you know, certain inflammatory biomarkers, et cetera, et cetera. You can cast an incredibly wide net to get an idea. You can measure, you know, you can run a clearly scan and and and look at get data from the heart. Or you can get information on brain health and brain age. We're becoming better and better and better at measuring cell types, organs. We can do skin. I mean, there's a there's a pretty cool tool. There's actually multiple cool tools around measuring skin age and.

• 14:01Dr. Darshan Shah?

  We have a Vizia scanner to do this.

• 14:03Speaker 01

  It's fun. It's easy. It's fun. It's motivating. All of this information is motivating. Our body does not, each organ system does not age, you know, in symphony, in synchrony. We age at different rates. Your vulnerable area, you know, may not be mine. I was talking to a patient yesterday that who I want to go and get a liver scan. He was in the hospital when he was a teenager with severe, severe, severe, you know, almost deadly hepatitis. And since then, liver is his vulnerable organ. It's not mine. My liver is strong, but it's his vulnerable. If you've got a history of smoking, obviously lungs need extra TLC. So we just, we need to identify those things. And we have more and more fabulous tools to do so. So we can look at biological age through a variety of lenses.

• 14:48Speaker 01

  And I think it's worth it doing so as much as we can. We have wearables that can help us. On my bike, I have Garmin and my bike actually can measure my power output. And I can get VO2 data. I can get all sorts of fun. I mean, I'm a geek, as you know, I'm kind of a data hound. And you are as well. So I I enjoy all of this. Some of my patients are like, talk to the hand, Cara. But they'll, you know, they'll get their their. You know, semi-annual labs and so forth. So there's many ways that we can do it. And I think that it's good to cast a wide net as is appropriate as you, you know, decide to do with your care provider, your physician. When we're looking at it epigenetically, so the, the whole biological age conversation

• 15:30Speaker 01

  sort of began with the idea of looking at the rate of epigenetic age and epigenome being above the genome. So those are the chemical marks that change gene expression. We think now, and I can talk about this more, that aging may kind of start there. You know, if you're going to look at all of the various players in aging hierarchically, aging, the phenomena of aging that we'll tease out later, may begin here in, in the changes to gene expression. So there are a variety of clocks that look at epigenetic changes and we can get biological age from that data. The clocks are getting, you know, more and more sophisticated.

• 16:13Speaker 01

  We can look at rate of, you know, discrete organ aging using these epigenetic clocks. We can look at overall rate of aging, the pace of aging. You don't want to be aging faster than your chronological age. We can look at aging across mammals. We know that, and, and, and I'm, we can back up on this, but we know that aging, the phenomena of, of aging as measured by certain epigenetic clocks, these changes are shared across species.

• 16:41Dr. Darshan Shah?

  Wow.

• 16:42Speaker 01

  I know.

• 16:43Dr. Darshan Shah?

  Yeah, that's, that's incredible.

• 16:47Dr. 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 cellphone 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 IM8. IM8 powers that cellular Battery. It's not just another multivitamin. It's a comprehensive 92 ingredient formula designed specifically for cellular health and longevity.

• 17:31Dr. 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, IMAID actually gives you everything that you need in one scientifically formulated system. And this isn't just a theory anymore. IMAID 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.

• 18:14Dr. Darshan Shah?

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

• 18:38Dr. Darshan Shah?

  So, you know, when I look at all the measures of aging that you talked about earlier, like let's look at VO2 max or grip strength, right? So what we're doing there is this is like a physical measurement that we can take and we can compare it to other healthy individuals of our age and healthy individuals of people that are older and younger. And then we can see like where do we fit in the statistical analysis of all of this, right? So to me, that's very just is very tangible. Like, you know, you can

• 19:05Speaker 01

  Motivating.

• 19:06Dr. Darshan Shah?

  It's tangible, it's motivating, like it makes sense, right? But then this leap into what's happening at the cellular level, where we now know that all of these factors, how strong we are, how fast we can run, lead to on and offs, which is on our DNA called our epigenome, right? And then using Machine learning, AI, we can determine what switches are turned on and off per organ and see how they are aged compared to other healthy individuals. And that's how we get these epigenetic clocks first, you know, of your entire biology, but also now the resolution has increased to by organ, we can even tell these things and how fast things are aging as well.

• 19:51Dr. Darshan Shah?

  So this is really incredible information that we can now get with a simple blood test.

• 19:56Speaker 01

  It's really cool. And so going back to our original bit about, you know, my rate of organ aging is different than yours and my vulnerable organs are different than yours. And so being able to look at it at this granular level, we could really zero in, see what's going on with ourselves, with our patients, and then address accordingly and do follow up and track and make sure this. And this doesn't mean that we let go of our standard, our standard imaging and lab tests, et cetera, but we can layer that on top and just have more sophisticated data on what's happening. So for my patient with, you know, a history of hepatitis, he's getting a liver scan, of course, on top of, you know, the various epigenetic tests and on top of, of course, standard blood tests.

• 20:41Speaker 01

  But it's a, it's a different piece of information that will inform clinical decision making and it really motivates him as well.

• 20:47Dr. Darshan Shah?

  Yeah, and that's how I use it. I use it as a, number one, as a tangible tool, once again, for someone, we check it once a year on our patients. And unless there's something that we're really honed in on, like some organ that we're trying to reverse biological aging on, but we use it almost like a scorecard once a year to see how the sum total of everything that we're doing is leading to biological age change. And now that we have the, you know, that resolution of looking at organ aging, we can help us hone in, oh, wait a minute, what's going on with your heart that is, it's much older than your chronological age and older than your other organs? There's something not making sense there. We need to go looking deeper into that organ, right? And so this is kind of how we're using it right now. And I think it's really clinically useful.

• 21:32Dr. Darshan Shah?

  And, you know, the more I get my head wrapped around as a physician and seeing, you know, we see thousands of patients in next health, like this really becomes an important diagnostic and lifestyle tool for us as well. So it's really great. Now here's what's mind blowing to me. When you say that, you know, we're seeing patterns of aging at this methylation level across mammal species, right? To me, that means that there's some element of aging that is part of our evolutionary biology.

• 22:04Speaker 01

  Yes, yes.

• 22:05Dr. Darshan Shah?

  And so aging then breaks up into almost two categories. Where there's evolutionary biology aging.

• 22:10Speaker 01

  Yes.

• 22:11Dr. Darshan Shah?

  And there's kind of the damage that we do just being alive over time, right?

• 22:15Speaker 01

  That's right.

• 22:16Dr. Darshan Shah?

  Can you break that down for us a little bit?

• 22:17Speaker 01

  Yeah, that's right. So I would call it, it's so interesting to me. And I think having this division helps us again as clinicians and scientists to really think about how best to serve our patients. But there's what I would call exposomic aging. So that's the, that's the total of the exposures that you've undertaken and their influence on aging. So that can be, you know, I've got, I have a patient that comes to mind who had the, the most severe allergies in my practice. And I've seen a lot of them, of course. And one of, a piece of his origin story was that there was a superfund river in his backyard. And if I'm not taking a note on this, when he was, when he was a kid, if it's not in my chart, that this is a relevant piece of information.

• 23:01Speaker 01

  As a functional medicine doctor, I've failed. So we, that's a big exposomic exposure. Or another patient who grew up in one of those, you know, dismal areas where everybody was getting random cancers in her community. And it was agriculture and there were a lot of pesticides and so forth. So this is a part of the exposome, the exposomic aging and things that I need to think about as a clinician. Our stress experience, gosh, we even know that pregnancy will, for a short time, accelerate biological age. So there's a real exposomic aging push, but then you deliver the baby, especially if you're breastfeeding, et cetera. You bounce right back surgery, that stress experience. So there's myriad ways that we can age through environmental exposures.

• 23:43Dr. Darshan Shah?

  And I would even say like being sedentary is an exposure, right?

• 23:48Speaker 01

  Yes, of course, of course. Diet.

• 23:50Dr. Darshan Shah?

  Yeah, ultra-processed food.

• 23:51Speaker 01

  Right.

• 23:52Dr. Darshan Shah?

  Sugary beverages, all of these things were exposing our biology.

• 23:56Speaker 01

  Yes, exactly.

• 23:57Dr. Darshan Shah?

  To our biology, right?

• 23:59Speaker 01

  And that will push the rate of aging forward. I call that exposomic aging. The clocks that we use, I think for today, for the most part, the clocks that you're using in practice, that I'm using in practice are picking primarily the, identifying primarily exposomic aging. And the cool thing about this is that we in functional medicine and longevity medicine accelerate at turning these things around. I mean, this is where we really are profound rock stars. And I think this is why you have, you know, probably a decade plus off your biological age for sure, as compared to your chronological age, why we really see these phenomena changing. It's very exciting. It's incredibly empowering.

• 24:44Speaker 01

  Again, we're in the driver's seat around our choices. So that's exposomic aging. And indeed, we have good tools at our fingertip and we're adding more, you know? And I have to again, give a shout out. I'm giving a lot of shout outs to you guys, but you know, I think you're doing a good job at distilling and figuring out what interventions to bring in to layer on that functional medicine protocol to really influence the rate of biological exposomic aging.

• 25:08Dr. Darshan Shah?

  Yeah. And I look at that as like, first of all, avoiding the things that will

• 25:12Speaker 01

  Yes.

• 25:12Dr. Darshan Shah?

  cause accelerated aging, but also adding

• 25:15Speaker 01

  Yes.

• 25:15Dr. Darshan Shah?

  factors that will bring you towards slower aging as well. Like you mentioned, your Lithin A.

• 25:21Speaker 01

  Yes.

• 25:21Dr. Darshan Shah?

  So, you know, that's one of my supplements stacked that I take.

• 25:24Speaker 01

  Yes.

• 25:25Dr. Darshan Shah?

  Cause we know it works.

• 25:26Speaker 01

  Yes.

• 25:26Dr. Darshan Shah?

  Timeline is a great science around it.

• 25:28Speaker 01

  EPA and D H I.

• 25:29Dr. Darshan Shah?

  Yeah.

• 25:29Speaker 01

  Vitamin D. If you're vitamin D deficient, you're aging at accelerated rate. Like period, there's multiple studies, like some of the most basic things.

• 25:38Dr. Darshan Shah?

  Right, right. Sprint training, high intensity training, there's so many things. Getting good sleep. All this stuff is gonna

• 25:44Speaker 01

  Yes.

• 25:44Dr. Darshan Shah?

  basically slow down the aging process.

• 25:47Speaker 01

  Yes.

• 25:47Dr. Darshan Shah?

  But there's only so much we can do there. That is not going to keep us alive to 160, 180 years old.

• 25:53Speaker 01

  Well, and, and it's, you know, it probably won't keep us alive to 120, which is our maximal lifespan, you know, as, as humans. Right. So this is, but we need this. We want this for peak span for health span for all of this. Yeah, of course. It's it's essential. So yeah, that's where the other, this other arm of aging that comes into play that I'm super excited to to explore as a clinician, but as as a scientist. And that is the idea that there's a programmed aging as well. Sometimes scientists refer to it as a pseudo program, programmed aging. I don't know why they tax pseudo on. I I think it's because for a long time, the party line has been that aging is just drift or something sarcastic, like basically random damage.

• 26:37Dr. Darshan Shah?

  Yeah.

• 26:38Speaker 01

  Not measurable across species, you know, that share these same patterns. It does. That seems to me so counterintuitive that we would look at aging as random damage that there wouldn't because we have a max lifespan. All species have max lifespans. Some are wildly longer. It's not like they're made of different ingredients than we are. You know, the bowhead whale isn't made of of the Greenland ice, the Greenland shark, you know, live, they live for hundreds of years. They're made of the same stuff. They just have a day of a, they have different information sort of dictating their rate and pace of aging.

• 27:12Dr. Darshan Shah?

  Yeah. And it's like, now, so I'm sorry, sorry to interrupt you, but like, now that you've said that, like, it really makes me think that you're right. Like, you know, a dog dies way before a human does, but it's not like sleeping worse, or it's not like eating more ultra processed food.

• 27:28Speaker 01

  Right.

• 27:28Dr. Darshan Shah?

  You know, it's it's a dog, right?

• 27:29Speaker 01

  Yeah.

• 27:30Dr. Darshan Shah?

  And it has a certain maximal age.

• 27:32Speaker 01

  That's right.

• 27:32Dr. Darshan Shah?

  No matter what. So there's something else going on here.

• 27:36Speaker 01

  Measure it now. There's a clock that you can use to measure because there's this shared programmatic change that's happening across mammals. I mean, let me just tell you, and then we'll drill down into into that, just this side note, because I don't want to forget, but it's so crazy and interesting. They can identify now species that they just haven't been able to measure the rate of aging on. They can use this clock, you know, they haven't been able to capture them in the wild or maintain them in captivity, etc. They've also unfortunately been able to show that certain species are aging certain at an accelerated rate because of habitat changes. I'm thinking specific. Of polar bears, so they can use this tool all over the place to get this new extraordinary

• 28:17Speaker 01

  body of information. But for our purposes, it really suggests that there's a shared programmed phenomena that's happening. And so then the second question is, you know, how do we manipulate this program? And that's where it gets pretty juicy and interesting to me. I became aware and excited about this, becoming collegial with Vittorio Sebastiano, who you know, Vittorio and his team then at Stanford, now he's at Irvine, a PCR index. They created a tool to be able to measure this phenomena, this programmed phenomena. And they were also able to measure

• 28:58Speaker 01

  what, or they were also able to figure out what manipulates this. And I mean, here's my pop quiz. What do you think can change what we think is this programmed phenomena of aging? What is the one intervention that you'd be aware of that might manipulate this?

• 29:15Dr. Darshan Shah?

  Are you talking about Yamanaka factors?

• 29:16Speaker 01

  Yeah, that's right. So we, yeah. And you've talked about Yamanaka factors here, I'm sure, before.

• 29:21Dr. Darshan Shah?

  Yeah, a few times. I mean, I think, I think, I mean, this is just mind blowing that we have access to this. And I'm keeping a really close eye on retrobiosciences and how they're modifying the Yamanaka factors. So yeah, I think it'd be great for the audience to really understand who is Dr. Yamanaka and what are his factors?

• 29:41Speaker 01

  Yeah. Okay. So these are four transcription factors that when you apply them to a somatic cell type, so a cell that's already defined, not a stem cell, a cell that's already defined, an eye, heart, skin, whatever type of cell, you expose these transcription factors. Transcription factors are going to change gene expression. They will reverse that cell type to pluripotent stem cell status. So to a cell that has yet to be defined. And that's what Yamanaka did. And he won the Nobel some years ago. He's still alive, though. He's actually alive and at. Basos.

• 30:18Dr. Darshan Shah?

  Oh, no. He just joined Altos.

• 30:20Speaker 01

  Yeah, he's at Altos. So that's his original extraordinary seminal contribution to science. And since then, other players like Vittorio Sebastiano, David Sinclair, of course, at Harvard, and many, many other scientists have taken the Yamanaka factors and put stops on them so they don't reverse to this pluripotent stem cell status. There's all sorts of risks associated going back that far, you know, cancers, et cetera, et cetera. I mean, this isn't like a risk free. This is, this is actually like, you know, it's a pretty risky area, but they're looking at cell models in animal models and so forth, but figuring out how to control the rate of biological age reversal so that you're only pushing the cell or the organ or the

• 31:04Speaker 01

  animal back, you know, so far. And they've been successful. They've actually been extremely successful in starting to build out safer versions of this. Sinclair has jumped, actually Sebastiano is jumping through the FDA hoop, so he should have something starting an FDA approved trial using Yamanaka factors and his will be for skin. Sinclair already has something happening. They're looking at a age-related optic neuropathy in humans.

• 31:30Dr. Darshan Shah?

  And Retrobioscience is going into phase two in Australia right now.

• 31:33Speaker 01

  Oh, are they?

• 31:34Dr. Darshan Shah?

  Yes. And they're really pushing forward.

• 31:36Speaker 01

  Wow.

• 31:37Dr. Darshan Shah?

  I can't remember exactly what the therapeutic intervention for. I can't remember exactly, but they've, yeah, they're going to phase two, actually, I think, in Australia.

• 31:45Speaker 01

  That's pretty extraordinary.

• 31:47Dr. Darshan Shah?

  Yeah, I mean, this is, it just sounds like science fiction. If you were to tell anyone this entire story 50 years ago.

• 31:53Speaker 01

  Yeah.

• 31:54Dr. Darshan Shah?

  It's like a, you know, it's like a science fiction novel.

• 31:56Speaker 01

  Completely crazy. I know. I know. Here's the thing, though. Going back to epigenetics, biological age, programmed aging, these Yamanaka factors are doing their work at the epigenome.

• 32:07Dr. Darshan Shah?

  Right.

• 32:07Speaker 01

  That's where they're, that's where they're getting busy. And so I've had Sebastiano on my podcast and in our masterclass with you. And he says clearly, you know, when you look at the various hallmarks of aging, all the, all the variables that contribute, contribute to the aging phenomena, epigenetics really are hierarchically dominant.

• 32:26Dr. Darshan Shah?

  Right.

• 32:27Speaker 01

  You can manipulate epigenetics. You're going to change the downstream HOMARs. And that's what Yamanaka do. And that's what they do in this new clock, the PCR protein clocks that are out there now. Their Yamanakas are changing this predictable programmatic aging phenomena towards something younger. And you can measure it, you can measure it using those, using those tools. And so the question-

• 32:51Dr. Darshan Shah?

  So these clocks are new then? Are these newer clocks?

• 32:54Speaker 01

  Yeah, yeah, for sure. And they're not available clinically.

• 32:56Dr. Darshan Shah?

  Right.

• 32:56Speaker 01

  They're not, yeah.

• 32:57Dr. Darshan Shah?

  How long have they been around for?

• 32:59Speaker 01

  That's a good question. I guess whenever Sebastiano published on his, on the index, I mean, just a handful of years. You know, I mean, I'm sure they've been, obviously, but they've been tweaking and playing and aware of them in the, in the research setting for a long time. But I think the paper, the paper on the, on the index was, is just a few years old.

• 33:18Dr. Darshan Shah?

  And that's like, that just goes to show you like how recent the science is.

• 33:22Speaker 01

  Yes. And the mammalian clock just came out. And, and they're, and he's working with Horvath. Like Horvath is all over this kind of next level of, of clock investigation.

• 33:31Dr. Darshan Shah?

  Yeah, because the previous clocks were measuring more of like the exposome aging that you were talking about. So this is the programmatic aging that we're now able to measure.

• 33:40Speaker 01

  Yes.

• 33:41Dr. Darshan Shah?

  And so now that we have a clock that actually measures this, again, probably with a blood test, we can start really advancing the science of Yamanaka anti-age reversal almost and how it's affecting our cells.

• 33:56Speaker 01

  So the next question for me would be, what are the Yamanaka memetics?

• 34:01Dr. Darshan Shah?

  Yes.

• 34:02Speaker 01

  But like, what do we have? What combination, what cocktail, what tools? Ideally, super safe, you know, maybe nutritional interventions. Probably not just a forkful of salad, but a high concentration forkful of salad, you know, that might be able to move the needle on these polycomb repressive complexes. Basically, as they're on, when we're, you know, in utero and in early infancy and development. During development, these proteins are on, they're building a human, they're doing all this evolutionary work. And then they predictably shut down.

• 34:34Dr. Darshan Shah?

  Oh.

• 34:35Speaker 01

  Yeah, it's so interesting.

• 34:36Dr. Darshan Shah?

  And these are called protein-

• 34:37Speaker 01

  Called polychome, polychome repressive complexes.

• 34:40Dr. Darshan Shah?

  And what, what are they?

• 34:42Speaker 01

  They're just, they're, they're, that's a really good question. They're like, they're, they're, you might have to pull this out. They're like sitting in the, their proteins hanging out in the histone.

• 34:52Dr. Darshan Shah?

  Oh, so they're histone based proteins, yeah.

• 34:54Speaker 01

  You, in order, so they're, they're regulating gene expression all over the place. And so these polychome repressive complexes will turn genes off predictably over time. In fact, actually, in utero, they'll keep genes from expressing and then allow them to be expressed. Like sort of, again, building a baby, the sophisticated process of growing a fetus. You know, genes, cell types, there's a whole evolution in that process. And so these PCR proteins are very actively controlling gene expression. By and large, they're on when, you know, early on in development, on through life.

• 35:38Speaker 01

  And then they predictably begin to shut off as we age. However, this is what yamanaka reverses. This is in part, some scientists argue that this is only a surrogate or a proxy for another aging phenomena. But I think that there's, there's, there's an argument to suggest that these sit at the heart of aging because they're so intimately involved in cellular regeneration, stem cell production, et cetera, et cetera, et cetera. So I think that, and I think just the, the, when you manipulate the clock using yamanaka, you can then measure the downstream hallmarks and see that those all follow suit.

• 36:20Speaker 01

  So I think we have the beginning of a hypothesis that these guys could sit more centrally to the actual aging phenomena. Maybe they're not the sole player, you know, there's other things going on. But I think it's an exciting, kind of fun, energizing target for us to begin to think about how we might be able to influence. And so, yeah, I'm hoping that that will, you know, we'll get our grant funding. We're, we're working on an NIH grant right now. And we'll be able to actually work with that team. We have done some limited investigations so far. But you need to, you can't use the, the tools that we normally use in, in the clinical setting. You have to look at the entire methyloam. You have to measure the entire genome.

• 37:05Speaker 01

  There's, there's, it, there's a broader sweep of, of investigation that has to happen in order to really understand whether we're moving the needle. But there are suggestions in the literature that polyphenols, going back to your lithin A, going back to that well-designed forkful of salad, that polyphenols have some influence on these PCR-associated genes. So, oh, and the other thing that these guys have shown too, is that profound caloric restriction will slow the rate of this PCR, the PCR aging.

• 37:37Dr. Darshan Shah?

  So, and that's probably the mechanism, one of the mechanisms by which caloric restriction works then.

• 37:42Speaker 01

  That's right. That's right. It's significant caloric restriction, like 25%

• 37:47Dr. Darshan Shah?

  Yeah.

• 37:48Speaker 01

  off in an animal model for long-term. So it's nothing that we're going to be able to do. But my question is, what will, you know, walk us in that direction?

• 37:58Dr. Darshan Shah?

  Right.

• 37:58Speaker 01

  Like, you know, a good salad isn't going to turn, you know, our cells, our cells back to stem cells. You know, um, TPE is not going to do that. I don't care how many peptides you take, you know, it's not going to have the influence of yamanaka factor, nor do you want it to.

• 38:12Dr. Darshan Shah?

  No.

• 38:13Speaker 01

  But what interventions do we have now? Or what might we build that are safe and that can walk us in that direction? And that's, you know, that's what I'm excited about right now. And that's where I want to put my attention and, you know, our, our research efforts in finding those, what we're, we're calling yamanaka mimetics.

• 38:35Dr. Darshan Shah?

  Let's take a quick break from this conversation. I want to talk to you about something that rarely gets airtime in the performance space, but you should know about it. About 95% of Americans aren't getting enough fiber. And most of them have no idea. In fact, 70% think they're already hitting their daily target. Fiber is one of those things that get written off as basic, but the science tells a very different story. Drives long-term performance and fiber is what makes gut health possible. It determines how well you absorb the nutrients from your food, how stable your energy is throughout the day, and how effectively your body controls inflammation and recovers from training. If your gut isn't functioning at a high level, everything else that you're doing, the supplements, the workout, the sleep protocols, is working at a fraction of its potential.

• 39:20Dr. Darshan Shah?

  And that's why I'm using Momentous Fiber. It's a complete three-in-one formula with soluble fiber, insoluble fiber, and prebiotic-resistant starch. Most fiber products only contain one type, which means they're only solving one part of the problem. This formula is designed to strengthen the gut, support digestion, and help stabilize blood sugar for steady, crash-free energy. Clean, minimal ingredients, no additives, and it's also independently NSF-certified for sport. It comes unflavored or even in a cinnamon flavor that's really tasty and mixes easily into a shake or even just with water. Head over to livemomentous.com/fiber and use my code DRSHAW for up to 35% off your first order.

• 40:04Dr. Darshan Shah?

  The link is in the show notes.

• 40:09Dr. Darshan Shah?

  Is there any candidates out there yet right now?

• 40:11Speaker 01

  Well, interestingly enough, Sinclair has already published on this. You are probably aware it was really popular for a little while. He was talking about a chemical cocktail that could behave like Yamanaka factors. Most of those chemicals are not appropriate for human consumption. They're not safe. But there's also for scolin, like there's some botanical compounds in there. Alpha-ketoglutarate was one of them. So it's not like alpha-ketoglutarate is a standalone, even though I think there's reason. I think it's something worth considering. But alpha-ketoglutarate plus other compounds in a cocktail behaved similarly to Yamanaka factors in an animal model. So he's already published. He and his team, they've already published on it.

• 40:56Speaker 01

  We're wondering again about polyphenols. And again, there's preliminary research, cell studies, animal studies suggesting that polyphenol compounds, things like green tea, curcumin, et cetera. Might have some influence on those polychrome proteins. The other thing that's kind of cool is that, you know, we talk, we talk, we talk about clocks now in generations. So we've got the Horvath first gen, and then we've got the second gen and third gens, which we use in our practices. It turns out those first gen clocks that we were like, ah, they're not that cool. They're just measuring chronological age. Basically, they're in step with chronological age. Interventions can't really manipulate them. The reason that they're mostly more closely aligned with chronological age and less manipulatable

• 41:39Speaker 01

  is because they are dense with these polychrome proteins. So in fact, there's a reason to keep those clocks in the mix. Isn't that wild?

• 41:51Dr. Darshan Shah?

  Interesting. That's wild.

• 41:52Speaker 01

  Yeah. So don't, you know, don't say, oh, they're first generation. Push them out. Don't say that at all.

• 41:57Dr. Darshan Shah?

  They're measuring something different.

• 41:58Speaker 01

  They're measuring something different and they, they may be measuring something that is touching a little bit more on this programmatic aging phenomenon.

• 42:07Dr. Darshan Shah?

  Wow.

• 42:08Speaker 01

  And so, you know, we did move that first generation clock with our intervention. You know, again, I just, I want to be very careful in making any claims. I don't want to say that our intervention is going to, you know, move the, the, the polychrome associated genes or act or is a yamanaka mimetic. But I do wonder whether some elements of the dietary pattern. When we re-examined our dietary pattern and we published this in 2025, we saw that it were, it was the foods, the intervention that moved the needle on that first generation Horvath clock, Horvath clock the most were the most dense polyphenol compounds.

• 42:49Speaker 01

  And I can't underscore enough how potent these players are. They're so, they're really beyond our wildest dreams. And right now we can look at Urolithin A. We can look at Urolithin A and its ability to increase VO2 max in sedentary adults.

• 43:07Dr. Darshan Shah?

  It's crazy.

• 43:07Speaker 01

  In four months' time, by about a decade. I mean, it's nuts. I think it increases by 10%. It can increase muscle mass in sedentary adults. This is player coming. From pomegranate. And I'm telling you, it's just one compound. And when you mix these together and you get synergistic interactions, et cetera, et cetera. I think the sky is the limit with the potential power of polyphenols. And we can see in our intervention and other interventions, other dietary pattern interventions corroborate the power of polyphenols on moving the needle in epigenetics. So the question for me now is, yes, we use the dietary pattern, but now how do we layer on a more potent cocktail on top of that? I mean, ideally, we'll get to study the dietary

• 43:50Speaker 01

  pattern, dietary pattern plus polyphenol cocktail pattern, and then polyphenol cocktails as standalone. But we have an idea from our last year's publication on, you know, what seemed to do the heavy lift? And, you know, can we play around with that and turn the volume up and, and, you know, and really pay attention to the data that we, that we obtained?

• 44:08Dr. Darshan Shah?

  And I love it.

• 44:09Speaker 01

  Yeah. So that's, yeah.

• 44:11Dr. Darshan Shah?

  I'm excited. I'm so excited that you're doing this research. I'm so excited that you are talking about it with me on the podcast. And I just can't wait to see what comes next with this. And hopefully there's a part two of Younger You, which is actually

• 44:25Speaker 01

  There should be. We've talked about, we've talked about it. Yeah.

• 44:29Dr. Darshan Shah?

  Yeah, well, it sounds like another big study's coming out and you're going to be writing about it, hopefully.

• 44:33Speaker 01

  I really want to walk in this direction. I'm super, super excited about it. You know, just touching, touching on programmed aging. And that is like, if we're going to be able to, if we're going to be able to push up against, you know, lifespan, or if we're even more important for me, anyway, if we're going to be able to ensure the longest health span.

• 44:56Dr. Darshan Shah?

  Yes.

• 44:56Speaker 01

  You know, it's these tools that we're going to be leaning into.

• 44:59Dr. Darshan Shah?

  Absolutely. Well, Dr. Fitzgerald, thank you so much for updating us on what's going on with you. And where can people read more about you and find more information from you?

• 45:09Speaker 01

  Yeah, just come over to the website. It's drkarafergill.com. Easy peasy.

• 45:14Dr. Darshan Shah?

  Awesome. Thank you so much, Kara.

• 45:15Speaker 01

  Yeah, great to see you.

• 45:20Dr. Darshan Shah?

  Here are my top five takeaways from this episode of Dr. Kara Fitzgerald. Number one, the goal is no longer just lifespan, it's peak span. Longevity isn't just about living longer, it's about maintaining strength, cognition, and performance for as many years as possible. Number two, there are two types of aging. Exposomic aging comes from lifestyle and environment, while programmed aging is built into our biology. Both play a role in how we age. Number three, food is genetic information, not just fuel. Phytonutrients act as signals to our genes, influencing processes like inflammation, repair, and mitochondrial function.

• 46:04Dr. Darshan Shah?

  Number four, cellular reprogramming is the future of longevity. Research on yamanaka factors is exploring how cells can be reset to a more youthful state, opening the door to potential age reversal therapies. And number five, testing is becoming more precise and personalized. Advanced tools like epigenetic clocks can now measure biological age of specific organs, allowing for more targeted interventions.

• 46:33Dr. 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.