← Extend Podcast with Darshan Shah, MD
Extend Podcast with Darshan Shah, MD
160. Dr. Kara Fitzgerald on Biological Age, Epigenetic Clocks, and the Future of Aging Reversal
00:47:23
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- [00:03]
A
Welcome to Xtend 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 are 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. Aging has traditionally been viewed as an inevitable decline, but emerging science suggests we may have far more control over 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 Xtend, we're gonna sit down with Dr. Kara Fitzgerald. She's a naturopathic doctor and leading researcher in epigenetics. We're gonna 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 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. Kara, I can't believe you're here again. This is awesome. Thank you for coming.
- [01:52]
B
Absolutely. I love getting to hang out with you. Of course.
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A
I love hanging out with you. Of course. And thank you. So from coming up from Mexico after an injury, I know what happened.
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B
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 that I still am. But I'm. 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. And sped out and trashed my knee as. Yeah, as you know, I actually had to move our podcast time because I was, I wasn't moving that well. That knee, I had some stitches in it, but I won.
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A
You still won the race.
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B
Yeah.
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A
You're amazing.
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B
So there I was with a big bloody knee and a bloody elbow, but just really adrenaline doubt and I was telling somebody that, you know, this is like the new metabolize, right? It's funny. Like this is it. I mean, 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, 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.
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A
That's awesome. That's awesome.
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B
And there's a freedom.
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A
Yeah, yeah. So instead of menopause being this time where you're slowing down.
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B
Right.
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A
You're going stronger, harder. Right. I love that.
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B
The new menopause, 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 phenomena 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 stack 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.
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A
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?
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B
She's eight.
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A
Yeah. So, you know, I have a 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.
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B
Yes.
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A
Because I feel in my own skin right now at this age, much younger than I did even, like 10 years ago.
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B
Yes, right. 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, I've probably got a little more testosterone dancing around, or 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 combine 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.
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A
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. But if you want to age, like your grandparents age or your parents age.
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B
Yes.
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A
That's the direction you're headed in.
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B
Yes.
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A
Right. And if you shift your thought process around, maybe using some of these molecules that are naturally present in our human body anyway.
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B
Yes.
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A
Hormones, for example.
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B
Yes.
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A
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 is actually feeling incredible in your skin right now. Right.
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B
Yes.
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A
So health span is obviously very important, like time away from chronic disease.
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B
Yes.
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A
But there's so much more that can be achieved even beyond that with some of these interventions.
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B
Yes. There was a publication that just termed it peak span, you know, maintaining, you know, the, the longest peak span that you can. And, you know, why the hell not?
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A
Why not?
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B
And it, 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 foods, we didn't quite understand how horrible they were, you know, in World War II when, when I guess margarine was ushered in.
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Yeah.
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B
And, you know, and some of the really awful processing techniques were kind of introduced and Omega threes were basically exited and Omega 6s 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.
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Yes.
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And now we know that this was completely wildly shortsighted. 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. Yeah.
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A
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. 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 still.
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B
Yeah. Well, it's called the dark matter of nutrition.
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A
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 in 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.
- [09:35]
B
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 to the skin, gastrointestinal, like everything, 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, 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 it was our best guess. Cause it hadn't been demonstrated yet. 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.
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A
Yeah, 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 that we can see at my epigenetic aging score and slow down my pace of aging. And I was like, this is incredibly powerful intervention because it did not take a single pill, a single therapeutic adventures. It just took changing my diet. I did add a couple of extra supplements, but just to get a superpower of what's in the food. Absolutely.
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B
No, I think that that's absolutely correct. I mean, we know. So you've probably talked about urolithin A, one of the postbiotic compounds that comes from a compound 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 exquisitely powerful, this single molecule coming from pomegranates, et cetera, right? 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 fork full 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, and I practice this myself to be part of the conversation and part of this research journey.
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A
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.
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B
Yeah.
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A
First of all, you talk a lot about biological aging, so let's just define that for people that are new to this world. What is epigenetic aging? What is biological aging? And then we can kind of dive into the reasons we biologically age, please.
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B
Yeah. So biological age is 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, 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.
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A
And, and we have a Vizia scanner to do this.
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B
It's fun, 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. 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 mean, kind of a data hound and you are as well. So I enjoy all of this. Some of my patients are like, talk to the hand care. But they'll, you know, they'll get their, their, you know, semiannual 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 decide to do with your care provider, your physician, when we're looking at it epigenetically. So the whole biological age conversation 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. 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 we can back up on this. But we know that aging, the phenomena of aging as measured by certain epigenetic clocks, these changes are shared across species.
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A
Wow.
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B
I know.
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A
Yeah. That's incredible. Hi, Dr. Shah 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 kilometers 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 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. 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, Im8 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. 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 drshaw.comima or go to imaidhealth.com discount Dr. Shah and you can get 20% off with my discount code. Dr. Shah, you can also find the link below. 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?
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B
Yes.
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A
So what we're doing there is this is like a physical measurement.
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B
Yes.
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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 this statistical analysis of all of this? Right. So to me that's very just is very tangible. Like you know, you can motivating is tangible as motivating. Like it makes sense.
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B
Right.
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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 off switches 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 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. So this is really incredible information that we can now get with a simple blood test.
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B
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 can 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. 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. But it's a. It's a different piece of information that will inform clinical decision making, and it really motivates him as well.
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A
Yeah. And that's how I use it.
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B
Yeah.
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I use it as a number one, as a tangible tool. Once again, for someone, we. We check it once a year in our patients.
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B
Yes.
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A
And unless there's something that we're really honed in on, like some organ that we're trying 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. 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 or 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. 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. Yes. 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, Right?
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B
Yes. Yes.
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And so aging then breaks up into almost two categories where there's evolutionary biology. Aging.
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Yes.
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And there's kind of the damage that we do just being alive over time. Right?
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B
That's right.
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Can you break that down for us a little bit?
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B
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 a kid, if it's not in my chart that this is a relevant piece of information as a functional medicine doctor, I've failed. So that's a big exposomic exposure. Or another patient who grew up in one of those 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 exosome, the exosomic aging and things that I need to think about as a clinician, our stress experience.
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A
Gosh.
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B
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.
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A
And I would even say, like, being sedentary is exposure. Right, right.
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B
Yes, of course, of course. Diet.
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Yeah. Ultra processed food.
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B
Right.
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A
Sugary beverages, all of these things. We're exposing our biology to detriments to our biology.
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B
That's right. And that will push the rate of aging forward. I call that exosomic 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. So 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. It's incredibly empowering. Again, we're in the driver's seat around our choices. So that's ex bosomic 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.
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A
Yeah. And I look at that as like first of all, avoiding the things that will.
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B
Yes.
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Cause accelerated aging, but also adding.
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B
Yes.
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A
Factors that will bring you towards slower aging as well. Like you mentioned, URL of an A. Yeah. So, you know, that's one of my supplement stack that I take. I.
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B
Yes.
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A
Because we know it works.
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B
Yes.
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A
Great timeline is in. Great science around it.
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B
EPA and dha.
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A
Yeah.
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B
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.
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A
Right. Right. Sprint training, high intensity training. There's so many things. Getting good sleep, all this stuff is gonna.
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B
Yes.
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A
Basically slow down the aging process. But there's only so much we can do there that is not gonna keep us alive to 160, 180 years old.
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B
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. That's right. So this is. But we need this, we want this for peaks, 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 tack pseudo on. I. I think it's because for a long time the party line has been that aging is just drift or something stochastic. Like basically random damage.
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A
Yeah.
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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. 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.
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A
Yeah. And it's like. 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.
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B
Right.
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A
You know it's a dog, right? Yeah. And it has a certain maximal age.
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B
Right.
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No matter what. So there's something else going on here.
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B
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 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, et cetera. 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 specifically of polar bears. So they can use this tool all over the place to get this new extraordinary 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, who you know, Vittorio create and his team at, then at Stanford. Now he's at, he's at Irvine. A PCR index. They, they, they created a tool to be able to measure this phenomena, this programmed phenomena. And they were also able to measure what manip 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?
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A
Are you talking about Yamanaka factors?
- [29:17]
B
Yeah, I am.
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A
That's right.
- [29:18]
B
So we, yeah, have. And you've talked about Yamanaka factors here, I'm sure before.
- [29:22]
A
Yeah, a few times. I mean, I think, I think, I mean there's. This is just mind blowing that we have access to this and you know, I'm keeping a really close eye on retro biosciences 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.
- [29:41]
B
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 in I hearts, 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 Japan.
- [30:19]
A
Oh no, he just joined Altos.
- [30:22]
B
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 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 hoops 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.
- [31:31]
A
And retrobioscience is going into phase two in Australia right now.
- [31:34]
B
Oh, are they?
- [31:35]
A
Yes. And what really pushing forward.
- [31:37]
B
Wow.
- [31:37]
A
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.
- [31:46]
B
That's pretty extraordinary.
- [31:47]
A
Yeah, I Mean, this is. It just sounds like science fiction. If you were to tell anyone this entire story 50 years ago. Yeah, it's like a, you know, it's like a science fiction novel.
- [31:56]
B
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. 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, when you look at the various hallmarks of aging, all the variables that contribute to the aging phenomena, epigenetics really are hierarchically dominant. So if you can manipulate epigenetics, you're going to change the downstream hallmarks. 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, they're. 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, these clocks are
- [32:52]
A
new, then are these newer clocks?
- [32:54]
B
Yeah, yeah, for sure. And they're not available clinically, right? They're not, yeah.
- [32:58]
A
How long have they been around for?
- [32:59]
B
That's a good question. I guess whenever Sebastiano published on the index, I mean, just a handful of years. I mean, I'm sure they've been, obviously they've been tweaking and playing and aware of them in the research setting for a long time, but I think the paper on the index is just a
- [33:18]
A
few years old, and that just goes to show you how recent the science is.
- [33:22]
B
Yes. And the mammalian clock just came out, and he's working with Horvath. Like Horvath is all over this kind of next level of clock investigation.
- [33:32]
A
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.
- [33:41]
B
Yes.
- [33:41]
A
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 age reversal almost into how it's affecting our cells.
- [33:56]
B
So the next question for me would be, what are the Yamanaka mimetics?
- [34:02]
A
Yes.
- [34:03]
B
Like what do we have? What combination, what cocktail, what tools? Ideally super safe, you know, maybe nutritional interventions, probably not just a fork full of salad, but a high concentration for 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. That. Yes.
- [34:36]
A
And these are called protein polycomb.
- [34:39]
B
Polycomb repressive complexes.
- [34:41]
A
And what are they?
- [34:42]
B
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, There are proteins hanging out in the histone.
- [34:52]
A
Oh, so they're histone based proteins.
- [34:54]
B
Yeah, in order. So they're regulating gene expression all over the place. And so these polycomb 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, 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 is a, 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, the, when you manipulate the clock using Yamanaka, you can then measure the downstream hallmarks and see that those all follow suit. 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 how we might be able to influence. And so I'm hoping that that will, you know, we'll get our grant funding. 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 methylome, you have to measure the entire genome there's, there's, 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 urolithin 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.
- [37:38]
A
So, and that's probably the mechanism, one of the mechanism by which caloric restriction works then.
- [37:43]
B
That's right. That's right. It's significant caloric restriction like 25% 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? Like, you know, a good salad isn't going to turn, you know, our snails, ourselves back to stem cells. You know, 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. 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 research efforts and finding those what we're calling Yamanaka Mimetics.
- [38:35]
A
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. Gut health 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. 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. The link is in the show notes. Is there any candidates out there yet right now for.
- [40:12]
B
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. And, and, but there's also forskolin, 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, 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, his team is, are, have. They've already published on it. 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 polycomb proteins. The other thing that's kind of cool is that, you know, we call, we talk, we talk about clocks now in generation. 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 is because they are dense with these polygon proteins. So in fact, there's a reason to keep those clocks in the mix. Isn't that wild? Don't, you know, don't say, oh, they're first generation. Push them out. Don't say that at all.
- [41:57]
A
They're Measuring something different.
- [41:59]
B
They're measuring something different. And they may be measuring something that is touching a little bit more on this programmatic aging phenomena.
- [42:08]
A
Wow.
- [42:08]
B
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 polycomb 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. The most, were the most dense polyphenol compounds. 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, you know, in four months time by about a decade. I mean, it's nuts. I think it increased it by 10%. It can increase muscle mass in sedentary adults. This 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, and ideally we'll get to study the dietary pattern. Dietary pattern plus polyphenol cocktail pattern. And then polyphenol cocktail is a 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. And I love it. I love it. So that's.
- [44:11]
A
Yeah, 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. This. And hopefully there's a part two of younger you, which is actually there should be.
- [44:27]
B
We've talked about, We've talked about it. Yeah.
- [44:29]
A
Right. Yeah. Well, it sounds like another big study is coming out and you're going to be writing about it, hopefully.
- [44:33]
B
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.
- [44:56]
A
Yes.
- [44:57]
B
You know, it's these tools that we're going to be leaning into.
- [45:00]
A
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?
- [45:10]
B
Yeah, just come over to the website. It's drkarafitzgerald.com Easy peasy.
- [45:14]
A
Awesome. Thank you so much, Kara.
- [45:15]
B
Yeah, great to see you.
- [45:21]
A
Here are my top five takeaways from this episode of Dr. Kara Fitzgerald. Number one, the goal is no longer just lifespan, its 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. Exosomic 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. 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. Thank you so much for listening to the podcast today. Please remember to subscribe if you like this episode and give us a good review and share a link with your friends. It really helps us 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 is always important to seek their guidance.