Transcription
It was a very, very exciting moment for our biostistician, Josh Middledorf, to, you know, to tell us that compared to the control group, we had lowered biological age, as measured by that first clock, by over three years in our study subjects in eight weeks' time, with some food and supplements and meditation.
So our set of transcription factors, so these guys dictate gene expression, manipulate what proteins are being created from our DNA, and they were able to take a somatic cell and expose them to these transcription factors and bring it all the way back, reduce its age, if you will, all the way back to puripotent stem cells. So they've looked at really old skin cells, taken samples from people in their 90s, and they can wind them back, you know, to their 20s. I mean, they can just shave decades off.
In the meantime, probably rosemary, oregano, and yarrow would be really good. They're some of the highest polyphenol foods, and I eat about two tablespoons of all of them. And we're going to go really deep on things like polyphenols and what they really do in the body, reversing cells back to the way they were when they were in the womb, even, and some more research like that.
So, this is a fascinating episode. You're listening to The Human Upgrade with Dave Asprey. So you did the first study that, at least that I'm aware of, was looking at an eight-week methylation supporting supplements for longevity specifically. What did you find?
Yeah, that's right. Well, let me, um, I'll give you a little background on the study. And again, I just want to extend the opportunity to interrupt me as needed. I think the background is interesting and it's illuminating. So it was around 2013, I think, when epigenetics as a field really started to catch me through a functional medicine lens. So I'm a functional medicine clinician by training, and, you know, my first question is always, okay, here's a mechanism we're starting to tease out, incredibly complex, this is how genes are regulated. How might we think about this in terms of interventions through a functional lens? How might we alter diet, lifestyle, etc., etc., to shift epigenetics? So that was our first, that was my first entry into it. And the big thinking then, because biological age clocks were, that's not only did we not have them, but the father of this whole, you know, area of measuring biological age did not think as they came to pass that we would be able to manipulate them. So Steve Horvath is on record many times, just saying he didn't anticipate, you know, us being able to shift our biological.
Like Steve. Yeah.
Yeah. It's pretty amazing. So the area of science that was heavy at this time was in cancer. Cancer super efficiently hijacks the epigenetic machinery from us. So the tumor microenvironment will take over gene expression from us to, you know, to grow for its own nefarious end. So it will turn off tumor suppressor genes, genes that protect us from cancer. Cancer very reliably turns them off to move cancer forward, and it will turn on oncogenes. So genes that we have turned off, it will turn on. And in that way, the tumor microenvironment, the cancer spreads and grows. And it's so, I just, it's such a huge area that the sophisticated testing that we have now, like Grail and so forth, where we can do a sweep through many different cancers and identify them really early, they're using DNA methylation patterns. So there's just a lot of good science around, and it's been going for a long time. And so me, with, um, my right-hand woman in, you know, in this area of investigation, she's our, our lead nutritionist in my clinic, Ramaly Hajes. She and I started to dialogue about how we might look at this through a functional medicine lens. And we developed a diet and lifestyle intervention that was very heavy in methyl donors.
Yay. TMG and things like that.
Yeah. Yeah. Totally. Like lots of greens, eggs, liver, etc., you know, beets and so on and so forth. And then there was this other piece that was, was largely unknown at the time. And this is what we called the methylation adaptogens, but we're now we're calling them epi-epi super-super nutrients. I'm so sorry, I can't even remember what we're calling them. But back in the day, we called the methylation adaptogens. These are largely polyphenol compounds that aren't involved in the methylation cycle. They're not methyl donors.
Help it.
They help methylation happen where it should happen.
What are examples?
A classic polyphenol compound would be, um, EGCG in green tea or.
My favorites.
Yeah. It's so important. I mean, in my book, um, Younger You, we have a nutrient appendix, an e-nutrient appendix, and it's really like my favorite part of the book. You will see that there are hundreds and hundreds and hundreds of foods that contain these both the methyl donors and these adaptogens. So, we married these together, and the diet is very dense in, there's about seven to 11 cups of fruit and veg and spices and herbs that can move this needle. And so, that was arm one. And then it was, you know, it was, it was protein-dense, good fats, etc. It's a clean, healthy dietary pattern focused on these methylation manipulating compounds. And our, my interest was basically, you know, can we move the needle on gene expression? Can we move epigenetics? And, you know, we hired a clinical research center to run the study for us. It was a randomized, uh, controlled study. You know, first of its kind in the world. We included an exercise component, a meditation component. We talked about sleep hygiene. All of the things in the literature where there was some evidence, and sometimes it was pre-clinical, that showed that we could move the needle. Brought them together and put a group of healthy middle-aged men. So, we wanted to try to get.
Find a group of health.
It took us a long time. There was a rolling enrollment. It took us about a year to run this eight-week study.
Yeah. So, between 50 and 70 control group, intervention group during that time. It was 2019, the TRIM study, Greg Fay study came out showing that indeed biological age could be manipulated. So we had the measurement, we had the epigenetic data to be able to check, check the clocks, but we became very excited to see whether we had moved the needle. So we wanted to see more broadly, did we change tumor suppressor genes? Did we change, you know, all sorts? We had all sorts of questions we wanted to probe the data on. Um, but the first question we decided to answer was whether we moved the needle. And at that time, it was the Horvath multi-tissue clock that was available to us. And it was a very, very exciting moment for, um, our biostistician, Josh Middledorf, to, um, you know, to tell us that compared to the control group, we had lowered biological ages, measured by that first clock, by over three years in our study subjects in eight weeks' time.
With some food and supplements.
Yeah. Yeah.
Well, and meditation and.
Yeah. Yeah.
So, one of the things that I think is awesome, but that could also be a criticism is the same thing that Dean Ornish used and saying, "Oh, look at my weird malnutrition diet, the DASH diet, but he combined with meditation and exercise and got exactly the same effects as meditation, exercise without his weird diet." Right? So, it was a confounding thing. But in the world of biohacking and functional medicine, we don't assume that it's just one thing. Is that you have to set up the whole environment as a system to support it. So you did all of that, right? Did you compare the results you got from people who just do diet and or just do exercise?
You know what? In fact, we did inadvertently because we had this healthy middle-aged male population. So our control group exercised. It was a wash.
Okay.
So we just ruled it out. Yeah.
So exercise wasn't.
Isn't that amazing? We didn't, we were not able to pull any compelling data. In fact, we just published this year a reanalysis of our original study and really identified the elements that seemed to move the needle, and they were, and they were the nutrients. And again, they were these methylation adaptogens, these polyphenol, the most dense polyphenol compounds were, um, doing the heavy lift.
It's funny, Bruce Lipton years ago wrote a book called The Biology of Belief.
Yeah.
And I was so excited to have him on the show because he opened my eyes to epigenetics.
Yes.
Sometime in the late 90s when I was running a longevity nonprofit group in Palo Alto. So that formed most of the the thinking behind my first book on fertility. It was called The Better Baby Book because I didn't want my kids to have autism the way I did, uh, because that would be bad. So I focused on methylation, methyl donors. I even wrote, take folinic acid instead of methyl folate, because it's superior, just because mechanistically it looked like it would be.
Yes.
But I came up with all this. I published in 2011, it's like epigenetics gives you the ability to have healthier babies.
Yes.
And then the next big book, obviously, Bulletproof Diet, where epigenetics was a part of it, and polyphenols are at the very center.
Yes.
Right. So here's a question for you about polyphenols.
You can drink green tea.
Yes.
And you get micro doses of EGCG and you get reasonable amounts of oxalate. So I take, I think, 800 milligrams of EGCG on a daily basis.
I would have to basically boil myself in tea to get that much.
Do we really get enough from food, or is a supplement made from a food going to be more effective?
I think that study needs to happen. I mean, what I would say is, so after we published our, I mean, even during the time we were working on our research, um, there were other dietary pattern studies coming out, you know, Mediterranean dietary patterns, and they might, you know, like the DIRECT trial, they bumped up the polyphenols, or the NEW AGE study. Like there's been, there is a growing, um, database of human, um, there's a growing body of evidence of human, um, polyphenol-dense dietary interventions really showing that we're effectively moving the needle, um, on epigenetics through a variety of measures, including the clocks. So I would suggest that, yeah, diet can definitely move the needle, but it's different. I mean, think about a very sophisticated forkful of, you know, a well-designed salad and the amount of information, the amount of polyphenolic touchpoints that are happening, you know, and repeating that multiple times per day. So, it's going to have a different impact than a, you know, single dose intervention like a green tea, you know, an EGCG supplement, or, you know, one of my favorites, urolithin A. We can, we can talk about that. It's so badass.
The first year of Urolithin A launched in the US, launched on the show.
Yeah.
Oh, did it? Oh, that's really cool. So, I would say that a sophisticated collection of polyphenolic compounds are acting on gene expression in ways that we are only beginning to touch on. It's called the dark matter of nutrition, as you know. And the technology to be able to understand the interactions, the transformations, etc., etc., is just beginning to come forward. But when you look at something very well-studied like Urolithin A, you see how profoundly impactful it is at this therapeutic dose. So I guess, what I would say to you is, you can't bypass the information from a sophisticated dietary pattern like, you know, the one that we used.
Um, it's incredibly important, you know, for physiology, for gene expression. And there is a place to layer on, you know, appropriate cocktails of higher concentration, maybe appropriately designed for bioavailability or transformation in the microbiome, etc. Like, there is a place for both of these pieces in, um, you know, really optimizing gene expression.
Over time, I've moved more towards supplements for that.
Yes.
Because something like turmeric.
Yes.
Turmeric is exceptionally high in oxalate. I know you're an oxalate guy.
Yeah, I didn't used to be. I mean, I did put oxalate in the first chapter of the Bulletproof Diet, but the more I played around with manipulating levels, the more I think oxalate is responsible for a lot of broad-spectrum inflammation in people because we know how much people can excrete. So I look at something like turmeric. If I'm going to chop it up and cook, which I certainly did, then I'm getting more than my body can excrete that day if I eat, you know, four inches of a turmeric root. But if I take curcumin, the extract of it, you're bypassing that.
Yeah, I'm bypassing that and I'm still getting the stuff.
Well, okay. So, you're concerned about oxalate elimination. But like, what, you know, what kind of problems have you associated with excessive oxalate ingestion, like moving beyond theoretical into like actual phenotypic or.
Oh, well, we can excrete about 200 milligrams per day, um, give or take. If you're one of the rare humans that has Oxalobacter formigenes in the gut, you might get to 300 a day. And so a lot of the traditional food preparation techniques that we don't use anymore, like fermenting vegetables to reduce oxalate.
So what you see is broad-spectrum connective tissue issues because you get these little microscopic crystals in your connective tissue. You see damaged lining of the arteries. You see oxalate coming out when people are doing plasmapheresis. It's actually in the, the filter bag. And you'll see 70% of kidney stones are caused by oxalate. And then the weird things are, you get little styes in your eye, it's oxalates coming out. And you see it in the brain, especially high in autistic kids.
I mean, how do you measure it? How, how.
Calcium oxalate shows up on a microscope. And it shows up if you have higher amounts of it, um, as calcium.
How did you identify it in the brain of.
In the brain individuals diagnosed.
I don't know how they did that study. I didn't do it.
We, I need to do a little bit of a, we, we'll need to do a little bit of a drill down. I'm, I'm, I'm definitely pushing. I, I think it's compelling. And no, and I absolutely, calcium oxalate stones, calcium, you know, there is an oxalate arthritis for sure. But I, yeah.
I mean, on the continuum, you're over here with pulling them out. And I don't.
I've been getting more and more that way just by experimenting. And when I, I quit eating chocolate for a while and I really monitored my levels and excreted what I had. I don't have pain in my body anywhere, and I've had pain in my body my entire life.
Okay.
And like, I had, uh, the joint in my big toe rebuilt after a yoga injury. It doesn't hurt at all. But if I eat a high oxalate meal, when I walk, it hurts. And the, the crystals go there. And so, yeah, the amount of musculoskeletal tension. And the most compelling is.
Multiple studies now exist showing that calcium oxalate is directly toxic to mitochondria because it's penetrating their membrane. It's just like little bits of ground glass in the body. So I'm not saying don't eat any oxalates. I'm just saying that keep it to a dull roar. And if I want to crank up my superfoods, I just go through the list and I say, I'm going to eat the superfoods that don't have a lot of oxalate.
So, we need two cohorts. We, oxalate-sensitive, such as you. You clearly are. You've identified that you would be a gout candidate. No doubt what you're describing for sure. And then there are plenty of people such as myself who eat plenty of oxalate-dense foods and I don't have an experience of what I would describe as oxalate toxicity. I mean, yeah, you know, in the last, you know, kidney, I had a CT scan in the not-so-distant past. I don't have any, there's no evidence of stones. But it, so I think I, I think there's a continuum of sensitivity. There certainly is. And some of it's made metabolically. And Candida makes it. And, um, I would suggest just to get a good picture of of the background for this, Toxic Superfoods by Sally Fallon.
Um, and she's an, everything is oxalate person. And I don't think that's the case. Okay.
I was surprised that when I, I did, you know, high amounts of citrate and lemon juice and I just, I've got oxalate out of my body. My time as a raw vegan was not good for me because I was getting incredibly.
100%.
I would get, um, oxalate tartar on the back of my teeth. The dentist was flaking it off. And it was, it was weird. But I, I don't want to overstate the case, but I think we're understating it. And people have this weird inflammation. They can't figure it out. Sometimes.
It can be worthy. It can absolutely be worthy to do an oxalate elimination. No doubt about it. And I have seen it clinically. And I think what you're describing. Yeah. For.
So, it's just the question is like, how do I remove plant toxins and still get the benefits of.
Polyphenols.
Right? That's right. That's an absolutely reasonable and fair question.
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So for me, I do a lot of the, I get a lot of those polyphenols encapsulated. In fact, I don't eat, I, I'm a fan of liver and I take it encapsulated at this point.
Liver is gross.
It is pretty gross. So, I'm a fan of getting these, this polyphenolic information, you know, in encapsulated and isolated for sure. I do think it's going to be, you know, an endeavor that I, I'm we're excited to undertake is studying the element that we identified in our paper and just, you know, putting together a protocol to see how we move the needle using, uh, a formulation. Um, so, yeah, to your point, there's a place for that.
That's something that I think we're going to see more and more of because it's also hard to know how much polyphenols in plants. And the most abundant polyphenol in our diet is from coffee. And Danger Coffee is my new coffee company, not with Bulletproof anymore for people who haven't heard. But even there, the amount of polyphenol varies widely based on how the coffee plant is treated, how stressed it is, whether there are bugs. And so we don't, we're getting.
Yes.
I like the idea if we're going to live a long time, let's take enough polyphenols in the form of supplements to know that we're getting benefits. And let's eat a broad spectrum of stuff so that we're getting all the other things we don't know matter. But I don't want to count on the food to deliver a therapeutic dose because it doesn't have enough in it.
I think that's fair. Yeah.
And we did move the needle on bio age using a dietary pattern. And we are just doing our EWAS, our epigenome-wide association study, and we significantly moved the needle on, you know, a host of different, um, genes. We altered the, the methylation patterns on, you know, well beyond the content of the clock. So we know that diet, we know that diet moves the needle. Like, you can't discount it. And, you know, when we're thinking about like, you know, going back to our, our conversation off air on on Yamanaka. It's my belief that, um, yeah, we're going to have to go into concentrations that, you know, exceed what we can get in a diet unless you want to just eat all day.
You said my happy word, Yamanaka.
Tell me about Yamanaka factors.
So, Yamanaka factors are, you know, a set of transcription factors. So these guys, you know, dictate gene expression, um, you know, just manipulate, you know, what proteins are being created from our DNA. And Yamanaka discovered them, I guess, well, and who was his colleague who received the Nobel?
I don't remember off the top of my head. We should. I wrote about it. Google it. I've written about it too. It's easy to remember that Yamanaka was one of the guys who got the who got the Nobel. But the, I mean, the incredible thing was they put together this, um, cocktail of of four factors. And they were able to take a somatic cell, so an established cell with an identity like a muscle cell or a heart cell or whatever, and expose them to these transcription factors and bring it all the way back, reduce its age, if you will, all the way back to, uh, a pluripotent stem cell status.
Which is the holy grail for stem cells.
It's extraordinary. Yeah. It's like the starting point, you know, it's like building a baby. You start with these undefined cells and then, you know, you go on to manipulate using epigenetics to to define what that cell will become. So if you're building a baby, you're going to make a bunch of, you know, neurons and muscle cells and heart cells, etc., etc. So it was an extraordinary achievement. Of course, they both deserved the Nobel deeply. Um, these are Yamanaka factors. And.
And you can't buy Yamanaka factors, say.
Right?
But.
Maybe from a lab supply house, but would, you know, I don't know that you want to be sucking down a cocktail of Yamanaka factors at this point. We could talk about risks around that. So now, as you know, they're experimenting with Yamanaka factors in cell models and animal models. There are two human trials that I'm aware of. One in skin. Um, I think one for Sinclair is doing one in in optic neuropathy. I, I mean, really right now, they're phase one in their safety trials. But they, so, so they started to experiment with using the Yamanaka factors but controlling the amount of exposure so you don't go all the way back to pluripotent stem cell.
That might not be good in it at all.
Right. That's right. Do you remember when spontaneous human combustion was really big?
Yeah. That's my visual on if you took a cocktail gray goop. Like that's my visual. So I, yeah, I don't think they're quite ready for prime time.
It must be a TV show. I know the TV writers listen to this. So someone has to make a Yamanaka factor like assassination thing that turns people into balls of pus or something. This is going to be a great show.
Okay.
Be funny. It's so funny.
Just part my way. Three years, you're going to see this.
That's so funny. So they're working on controlling it and they're exposing, you know, all sorts of different cell types and just rewinding the cell to a younger time frame. So they've looked at really old skin cells, you know, taking samples from, you know, people in their 90s, and they can wind them back, you know, to their 20s. I mean, they can just shave decades off. Um, and they're getting better and more sophisticated at controlling them. So as you know, if you, there are dangers around taking something back to a pluripotent stem cell and then and then recreating a somatic cell or beyond that you.
Create a bone cell in the middle of your eye. That's probably thing.
Right. To, yeah, there's like all sorts of mischief. But they're, you know, they're hard at work. And certainly Sinclair has shown some extraordinary, extraordinary work out of his lab, um, reversing, um, age-associated optic neuropathies using Yamanaka factors. And then they go back in and they test the neurons, and the neurons are younger.
How do you get it in? Like, like, how do you get a Yamanaka factor into your eye?
Oh my god, that's a good question. How did they actually deliver it? Yeah, I don't, you know, that's a great question. I don't know. I mean, it was a mouse model. It definitely wasn't a human model. So.
I'll be the first guy to drip some in my eye and God knows what happened, but wouldn't be the first time I was a guinea pig.
Victoria Sebastiano out of out of, uh, Stanford, their their laboratory has done some really cool work in a variety of applications. Are looking at now. I think they're moving into ovarian rejuvenation that we can talk about. And we talk about why. Yes. But they're doing, um, they're working in a skin model now and jumping the FDA hoop. So they'll be able to test, um, a topical application, uh, to reverse aging. And they're showing, and they're showing some really cool data in terms of changing. I'll tell you what, the other, what is walking hand-in-hand with that is the use of, you know, solid AI in fast-tracking identification. I mean, it is no joke what's happening. But I want to talk, I want to make a point like why I wouldn't suck down a cocktail for many reasons. But, um, Victoria, Victoria Sebastiano, who was, by the way, on my podcast, just really, really interesting, who's influenced my thinking quite a bit thinking about ovarian rejuvenation. So it seems like probably the entry point into using Yamanaka in humans will be, you know, targeting, I mean, targeting an organ or a cell type because all, you know, the, the duration of exposure to any cell type, any organ system is going to vary. It's going to be different. It has to be so highly controlled. Ovaries. And so, so the next question is, what organ is going to yield the best leverage, right? And in women, of course, it's going to be ovaries. So if we can keep hormones around longer, um, what, you know, brain health is sustained, cardiovascular health, you know, skin, GI, bone health, on and on. And obviously, if a woman wants to have a baby, if they want to maintain reproductive health, there's that opportunity as well. But in terms of a leverage point in women, it's really extraordinary to start thinking about ovarian rejuvenation.
Have you seen the experiments? These are mice, but I think they might be doing it in people, um, where they take, uh, from a young woman who's healthy, they take a small biopsy of ovarian tissue and then put in a tissue bank. And then when perimenopause starts, they reimplant it and it rejuvenates the ovaries. They get another 20 years of of no menopause.
That's absolutely extraordinary. Uh, this is something that I, I hope some companies doing right now.
Yes. Yes. Yes. Well, you know what? To that point, because probably you're dialed in on this, I was just talking to, you know, Daren Shaw, you must. Yes, of course.
He's, um, a good friend and colleague of mine. And, you know, banking stem cells in our kids or, you know, just taking a specimen to have or for me, you know, for for all of us. But I was specifically, you know, just wondering about my daughter. She's seven now, just, you know, biobanking something that she'll have access to later. And now she's only seven. So, you know, she's just, it would be a perfect time. And that's out there somewhere. So, it's something that I would like to find. And if anybody can find it, I'm sure, I'm sure that you can.
It'll happen. And, you know, cord blood and all that good.
I think the most important time is when you're probably about 23 to get, you know, your stem cells banked. And get your hormone levels because now you know the right range, at least if you're healthy. And there's such a wide range of healthy hormone levels. Some guys are actually muscular and performant at 600, and other people need 1100. And if you never knew what your healthy levels were when you're 40 or 50 and you start hitting andropause or women on perimenopause, right? Like you have to kind of guess around till you find a range that feels right. But if you just had the data, and that's like a $300 test.
Yes.
And then banking a little bit of fat that you can amplify to make stem cells. Yes. And we don't need to do bone marrow the way we used to. I've had mine tapped twice. But now you can actually take a drug that causes your marrow cells to be excreted into your blood and you can just filter them out. And once those are banked, you have them for life.
Yeah. So I do think I do think that this is important and it's where we're headed. You know, the other really cool thing is, are you familiar with BrainKey? You must be familiar. No, BrainKey. So, this is, um, it was developed in Stanford, a Stanford scientist, Owen Phillips, who was on my podcast, by the way. It was a really cool conversation. He's he's quite a badass scientist. You should talk to him.
Okay. I love it.
But they've, so they've just moved the needle. They're using MRI technology to its full, um, or fuller capabilities by really marrying it with, um, AI that they developed, you know, painstakingly over many, many, many, many, many years, like doing his, during his postdoc and or his doctorate and postdoc with his with the group there. So they can take a highly sophisticated brain image now and, um, glean far more information from, you know, your, your mother's MRI.
Oh, because of AI.
Yes. Well.
No.
Because of AI. Yes. Because they can, as he describes it, you know, MRI is a, is a Porsche, but we drive it like it's a Ford Fusion. Seriously, we don't use it. And that's because it's mostly humans who are looking at it, and you can only look at so many images. But if you can really take, you know, thousands of images and then run it through AI, and there is, you know, there is some human involvement in there, um, you can get much more sophisticated data. So a baseline, just my point is, getting a baseline brain MRI is also a nice tool to have in your pocket for later. In fact, um, I'm a huge fan of Prenuvo because they're the first company to do AI with this. And I went to their first location. It was the only one in Vancouver and did mine years ago. And I just did it recently. And they were able to do brain volumetrics they couldn't do before, which is really.
So they're evolving it. Good.
They're evolving it. So we get better data.
Yeah.
And, um, when they came on the show, I got a call from them like six months later, and they said, Dave, that episode saved 25 lives. I said, what do you mean? And they said, "Well, of the people who came in when they saw the show, X number of them had aneurysms, like go to the hospital right now."
Wow.
And, uh, another person, um, had a three-centimeter brain tumor with no, uh, no symptoms and was able to get it removed with no problems. And she was actually an oncology nurse and didn't even know.
But it's amazing what we can do with MRI, right? We're, I mean, we're just, it's an exciting time to be in this space, both as a recipient of the evolution of these tools, but also to be able to talk about them. It is, it's pretty extraordinary.
Let's talk about Yamanaka factors.
Okay, let's get back.
You teased me ahead in the show and you said I know about Yamanaka mimetics. Okay, that sounds like something I want a pound of. So, what's a Yamanaka mimetic and how do I use it?
Well, I guess there's there's a couple, there's, there's two arms that one could think about it in. I mean, there's the published work of, you know, again, Sinclair and the various chemical cocktails he's put together that can behave as as Yamanaka factors. So he calls it chemical, I think, cellular rejuvenation. You're familiar with that work. And there are compounds that we're using now already, like alpha-ketoglutarate, fisetin, and what else? Um, sodium butyrate. And then a whole bunch of.
It makes me happy to hear these. Like, like I launched a fisetin supplement when I was at Bulletproof and, uh, sodium butyrate. Done episodes on it. So like, somehow in the longevity field, it feels like we know these things are working, but we don't know the why. And you're figuring out it might be via Yamanaka.
Via actions similar to what Yamanaka factors can do. So if you look at Yamanaka factors as being able to, you know, rejuvenate cells all the way back to a pluripotent stem cell. So if you look at this as a continuum or a walk, if you will, you know, some of these other interventions can take, well, I mean, his cocktails, I think, can pretty aggressively rejuvenate. But those aren't ready for human ingestion. They're not, it's not just sodium butyrate and alpha-ketoglutarate and fisetin. It's mixed with a whole bunch of chemicals that aren't ready for human consumption.
Got it. I would just do a shout out. You should be taking AKG and sodium butyrate, uh, for sure. And probably fisetin for fisetin, although there might be questions about that for some people. But anything else on that list?
I think, yeah, I think AKG is pretty, yeah. And and butyrate is as well.
Victoria Sebastiano's lab, where they're working with Yamanakas, um, they developed what they call an index looking at these proteins that regulate gene expression from development, you know, through age. They're called, um, PRC, polycomb repressive complex 2, specifically. And so they've created this, they've created an ability to track the changes, raw by Yamanaka factors, um, and they're able to see, uh, you know, when we look at all the hallmarks of aging, that it's the epigenetic manipulation that can then manipulate downstream the other hallmarks of aging. And there's sort of more to it than that. But they have an ability, they have a tool now, um, to be able to measure this epigenetically and identify what the Yamanakas are doing in this arena and in the cell reversal. So using this tool, they're able to begin to check other compounds to see whether or not they can move the needle on these on these polycomb repressive, uh, complexes. And therefore, uh, the suggestion would be that they're walking along with Yamanaka, not again, as far as Yamanaka, but like a gentle manipulation along the path of what what these might do.
So, if we wanted to draw a parallel, um, you go back 10 years, we couldn't tell whether a longevity intervention worked. And we came out with these biological clocks to say, are you older or younger than your biological age? And now these Yamanaka clocks, if you want to call them that, are able to say, well, is a compound turning your cells to be younger or older? So that now we can measure the efficacy of all these different ingredients or combinations, which is part of what we need to do to live way longer than we're supposed to. I think the possibility of these PRC2 clocks is that they may be more intimately touching on what I think is a programmed phenomena of aging. So there's like exposomic aging, the wear and tear of existence, exposures to toxins, stress, etc. The all of our exposomic variables.
Taxes, yeah.
Taxes. I think that we're pretty good now in manipulating those clocks. Like we've got a lot of solid interventions that can extend, you know, quality of life, reduce our risk of developing the chronic diseases of aging, for sure. So this exposomic arena, functional medicine, I think already kicks butt, and we're, and we're moving forward with like TPE and, you know, all sorts of of new compounds that will continue to kind of push against the ravages of the experience of life. But we all age. You know, we have this, we have a built-in life expectancy. And so there's, there's another phenomena, I think, that is occurring. And that's a programmed phenomena. And I think Yamanaka is manipulating that in the way that we can. One of the ways that we may be able to test that is by looking at whether or not we're moving the needle on these polycomb repressive complexes, which, you know, basically are key in building a baby. And, you know, they're shut down over time predictably with age and death. And so if we can get in there with, um, more benign interventions and move the needle on what I think is touching on the programmed phenomenon, not the exposomic phenomena, although there's crossover, then, you know, we have the potential, potential to build, you know, we could, you know, be touching on something in more depth in the aging phenomena. Caloric restriction. So, so they showed that caloric restriction moved the needle in these clocks. And that, to my knowledge, is the only two-piece, uh, the only two interventions, Yamanaka and then pretty intense caloric restriction in an animal model has moved the needle on these polycomb, uh, repressive complex, um, data. I think so. One of the things that I'm kind of bullish on is that there is probably a collection of polyphenols because there's, there are pre-clinical data out there, that these guys may be able to do something similar with regard to this collection of proteins. So, yeah, we're terming them Yamanaka mimetics. And, you know, it's an area that I'm eager to kind of do a drill down in and explore and measure and play around and, you know, just dance in. And I'll tell you one other really interesting thing, and I know, just, I'm sorry that I'm attempting to articulate this as clearly as possible, and it's a little bit convoluted.
So you're synthesizing. It's great.
Is it? Okay. So in the pre-clinical data, we can see that polyphenolic compounds can without question help to re-express. So as we age, we predictably hypermethylate and shut these proteins down predictably. This is the aging phenomena. They're really on during development. They're on during in, in utero development, and then just predictably over time, they shut down. And so we do, you know, we can see Yamanaka turns them on. Effective anti-aging interventions turn them on. And yes, preclinical polyphenols will turn these, um, turn these babies back on. And so probably there's a cocktail, probably it's pretty aggressive. It may have a different delivery system, um, that may be able to play around with these guys.
So this is the, the future of it. And in the meantime, probably rosemary, oregano, margarm, thyme, and yarrow would be really good.
Like things that you would.
Yeah.
They're they're some of the highest polyphenol foods. And I eat about two tablespoons of all those except for yarrow, which is more common in France but has unique polyphenols for aging in it. I probably should, I just don't know how to get yarrow that tastes good.
So let me tell you a couple more things about these clocks. Um, so the Horvath multi-tissue clock, you, you probably know at this point, has been kind of poo-pooed as a first-generation clock. And now we're on to second and third generation.
Let me explain that for listeners. Um, we've had a couple episodes on DNA methylation as a way to measure your aging clock, like how old does your body versus how old does the calendar think it is? And they're looking at at least 600,000 different DNA methylation points to do this. And but there's a lot of math involved to figure out what's the right way to look at all that data. And Steve Horvath proposed the first clock that we've all used. And since then, there's probably 18 more clocks or something like that, um, that are out there. And so there's the context for this.
Yeah. And so his clock, his first clock was thought to be, you know, something you might use in for forensics. It can, you know, identify chronological age. It walks in step with chronological age. But now as we're moving towards understanding these polycomb, the polycomb collection of clocks, or as as Sebastiano calls it, an index in his case, we can see that the Horvath clock, this original clock, actually is dense with this this polycomb data, you know, may be touching on the aging phenomena more than some of the next-generation clocks that are trained against, you know, biomarkers that are associated with exposomic exposures. So anyway, this is super dense, but I think there's a full circle moment here in realizing this clock, which we thought was only useful for measuring chronological age, which basically makes it non-useful, might be touching on something, you know, rather extraordinary, rather, you know, closer to programmatic aging. And we did move the needle on that clock, and we did identify the polyphenol, um, kind of heavy lift of that. So there's a preliminary piece of data from from our research. Um, and then again, the preclinical stuff. But I want to just tell you a little bit more about these clocks because they're so badass. They're so interesting. We can, these clocks are across mammals. So we all, all mammals have this, take this polycomb repressive complex journey, you know, where they develop, you know, the baby, the fetus is developed, you know, manipulated by these guys and and, you know, turning genes on and off, and then they're slowly over time inhibited. So you can use these clocks to measure the biological age of any mammal. And we can actually, for example, now see that polar bears' age is accelerating because they're losing habitat, or they can start to identify the age of, you know, mammals that they really, that we haven't had access to to be able to track, you know, to really establish, uh, their rate of aging or their age. And so we can use these clocks across the board. And these clocks also can pick up maximum life expectancy across mammals as well. So I'm excited that we're on to something heavy duty. And my passion is, you know, and my commitment is to figure out, you know, again, using this functional medicine lens, how we might play into this. So we always in clinical practice, we'll always use these exposomic clocks. We'll always be using our full toolkit of interventions to optimize biological age as we can, to reduce our risk of developing diseases. But then the next step is to actually play around with the, you know, the underlying programmatic aging phenomena as well. And there may be some tools that we're already using that will, um, you know, that that will do that, that will help us.
That's so impressive. Um, the amount of of data there is something that no human can do, but AI can do that really, really well. So our ability to discover new associations, it's truly a golden age for longevity because of that. And you can ask these complex questions.
Yeah.
And then you can look at the real data and say, "Wow, no one ever knew that before."
And we can sort the hallmarks kind of according to, you know, is this exposomic or could this be programmatic? I mean, we can begin to look at, you know, a lot of information that we have through this lens. And, you know, Horvath, along, you know, quite a while ago, published like the intrinsic and the extrinsic aging clocks. And, um, so this has been floating around, but I don't know, I'm just.
excited to kind of, you know, play in this sandbox at least, you know, think about it and, you know, hopefully be able to engage in in some real science around it as well.
When you look at some of the nutritional recommendations, the ones that always kind of drive me nuts, eat a rainbow, right? Eat every color of food every day. And I think historically we didn't do that because there plants don't grow in winter, right? So you generally eat whatever colors in front of you and it changes based on the time of year. So there's some sort of circadian seasonal matching here that we haven't really done that much work on, but we know seasonal eating can change. And then there's a lot of plants you can eat that provide calories, but they may not be that good for you in the long term. So the old school just, you know, eat one of everything better than not eating one of everything. But we're getting to the point where we can say for your biology.
Yeah.
You should eat these 25 polyphenol things or take a pill with that and it's going to have the most benefit,
right?
And that just is so much data, but we're getting there.
Yeah.
And we do have anecdotal data that some polyphenols are better than others. My friends from Vineia were just on talking about red grape polyphenols and how they've been able to get 100 times more of them with cell culturing to do that. So we're even getting the ability to manufacture like superhuman levels of polyphenols that have in that case a direct effect on nitric oxide signaling in the body and blood flow and things. So all we need to do now is come up with the right recipe and it may be personalized.
Yeah, that's right. the right recipe as well as you know that I could see us perhaps manipulating delivery you know I mean there's some pretty badass science out you know looking at sort of like you know nano
polyphenolic structures like shutting down cancer stem cell production and I think you know the take-home is that polyphenols are no joke
but to your and there's thousands of them and they interact synergistically they interact with our microbiome they interact with you know, digestive juices. Um, some of them are absorbed and and used intact. Some of them are completely transformed. You know, we need different quantities for different actions. Some of them I to your point, we I think we want highdose concentrates like uriththna. I mean, the data on eurolithna is just
super impressive.
But that is just one player in a sea of, you know, many, many, many compounds that we just really have have yet to unpack. I'm a fan of Himalayan tartery buckwheat and the you know the work that that Dr. Jeff Bland and Austin Dr. Austin pulmontor are doing and I think you know there's something about the collection of polyphenols in that compound and I appreciate their commitment to the science as well.
There's good evidence for that. Yeah.
I bought a bunch of it and started cooking with it. Buckwheat is one of the highest oxalate grains after a week of it. I got all I got all the joint pain. I was like damn.
So it's like I can have a sprinkling of it for the polyphenols. But give me a Himalayan tarty buckwheat polyphenol extract and I'm all over.
That's right. Yeah. That's right. That makes sense. So, it's it is exciting, but you know, I would say we, you know, let's consume these, you know, do the well-designed fork full of salad, get that information. It's interesting to me, you know, eating along with the seasons. Yeah. There's going to be times when we're eating mostly like protein, you know, when plants aren't really aren't flourishing or maybe protein plus apples or something like that.
Is a carnivore diet bad for you?
You know, that's funny. That's a that's funny. I I think it's fabulously effective short term for some individuals. Fabulously effective. There are people who are who are at it long term. I think a lot of long-term carnivore diet folks will probably cash crash and burn. And most of them do.
Yeah. There. But short term, if you really want to shut down a lot of damaging physiological processes, you can do that, you know, remarkably effectively.
It's like the world's best elimination diet. Just eliminate everything that might be a problem.
Right. Right.
Okay. So, we we're aligned on that. And I I tested out a long-term carnivore diet before we called it that. I was stress testing the bulletproof diet before I published it. And I went on only meat and butter for months.
Mhm.
And I felt amazing. I got leaner than I'd ever been. This is magic. Yes.
But then I tracked my sleep. Yes.
And suddenly I started waking up, you know, 10 12 times a night without knowing it. And I needed more sleep. and things just weren't right. And this often times happens,
right? And I think I gave myself leaky gut. In fact, I got an egg allergy from doing that, which was unfortunate. Just
you know, if you have nothing to feed the lining of your gut,
sure,
those acromancia will dig right through and give you leaky gut.
And plus, I have a history of autoimmunity. I'm probably higher risk, etc. But yes,
I I tell lots of people, go carnivore for two to four weeks and see how you feel. And they come back and go,
my life has changed. It's like, great. Now, find out which of the foods you were eating was causing the problem, right?
And I'm going to bet first on lectins and second on oxalate, but it could be many other things like histamine or mold or whatever. But I'm glad that you're you're sort of talking about that. So, if you're on a long-term carnivore,
it's great. I just have pancakes on Saturday and keep doing it. You'll probably be much better off. That cyclical ketosis seems to work better if people
What about the InWit, though? You know, they did pretty well back in the day on a pretty like whale blubber diet.
They they they did, but it wasn't just whale. is also very high uh omega-3. So, they're getting EPA and PHA at at incredible levels. Like Nick Norwitz, who's been on the show, did a sardine diet.
Yes, that's right.
You know, you you'll see some really interesting things that happen. Yeah.
So, they also had a lot of polyphenols in their diet,
berries and so forth.
Yeah. And they dried them and they had a whole thing where they would mash the whale blubber up with basically with herbs. Yeah.
And so even some of the French paradox maybe not the obvious French paradox is why don't Americans just eat like French people with lots of butter and then not get all the health problems. But anyway, the the thing that the French do though is they use a lot more herbs than Americans do and it's the polyphenols. I think that's a big part of the of the question. We're looking at macros when we should be looking at polyphenols.
Yeah. I mean, I think I mean, I think we should be looking at the whole gamut, but indeed. Yeah, indeed. This whole area, you know, this whole sort of so-called dark matter of nutrition. I mean, there's just a ridiculous amount of information.
Are you into flavones as well as polyphenols?
I mean, I I think that they're important. I have less command of what they're doing, although I would imagine that that it's shared and they all and they track together.
Yeah, they're very similar. They they hang out together and they have similar effects biologically. Yes.
And some of them are profound. U my favorite one is not in plants it's synthetic but it's dihydroxy flavone
and this is so small like a lot of polyphenols it can cross the bloodb brain barrier
interesting
and it directly attaches to the BDNF receptor which causes neuroplasticity and young brains can learn more easily and so these flavones are having direct activation of receptors just the same way that biological humanmade compounds would or made inside our bio our body compounds would. So there's this whole realm and we're talking about all these sexy peptides which I know you and I are fans of but looking at these you know good oldfashioned oregano I might
100%. I mean I and and you know the soy derived isopones and you know you can get them elsewhere
they're they're badass. I mean when you look at the in vitro data around reexpressing like a hyperthylated um broa gene you know they're potent players
um
so yeah you know isoplones or fivones in in that arena you know just important interventions again who uh we're just touching on our ability to understand what they're doing and this guy this one sounds interesting it's new to me it's interesting
leave it to me to find the weird stuff
yes
cara you also have a unique ability to find the weird stuff. You've been even on this this path and it's really fascinating. And thanks for sharing what's going on in the world of polyphenols and methylation and for doing real longevity research on food because you've proven beyond a shadow of a doubt that at least in middle-aged healthy men, you can get three years of improvement on your biological clocks just in 8 weeks of eating the right foods. Yeah, we did publish a collection of of of case reports in women. So, we showed we showed we showed the same thing in women.
Great.
Yes. Yeah. So, yeah. And and onward, we want to refine it and keep going. Humans. Yeah.
Why did you choose to only study men in the first one? That seems kind of sexist.
Super sexist. Super sexist. Because middle-aged women, we were concerned about the fact that there would be challenges with regard to where they are in their hormonal journey. So,
you sound like a 1970s white doctor. Cara, I'm offended right now.
No, we our cohort our cohort was was small enough so we would have um premenopausal women, permenopausal women, and postmenopausal women in a small group. And that would be a compounding variable.
Oh, 100%. And just to be really fair, there's huge amounts of research on men and women in all these different fields. And much more so in the last 20 years than there was before. Um, but some people say, you know, biohacking's just for men. 58% of biohackers are women and have been since I started the biohacking movement. Like women are great biohackers because of that change that your bodies go through. And it's actually very reasonable to say that I don't want to study for if you're looking for a broad effect, I don't want to study women in parmenopause unless I'm working on parameopausal symptoms because you can't get a cohort because every month things are different until they stabilize. But maybe hormone replacement therapy if you have them all on properly managed hormones, you could do it.
Yes. Yes. Yes. Well, you know, we ended up studying we I mean women are the primary group who are interested in our dietary pattern and we and we went on to do you know groups through the clinic like nationally internationally um and you know primarily primarily they were women and so we got to just track their data. Many of them came to us already using our dietary pattern for a long time and they started biologically just really young you know we use the pace of aging now as our measure. So just you know well less than um
the dun
less than one. Yeah we use the dune and pace and f just responding fabulously and in the publication they actually sort of outperformed the men as far as their bio age reversal but they we used we used a different specimen and you know the testing parameters were slightly different we used although we used the same clock but you know they did they're great they did they just absolutely responded to it um and do respond to it profoundly. Do you find that women who go on these protocols around methylation and on nutrition when they enter parameopause that they have less symptoms?
Absolutely. Exactly.
100%. Yes. Yes. Yes. Yes. Yeah. The symptoms of the transition period are as can be as much about you know what's going on in the exposome.
Yeah. It's not supposed to hurt to go through
parmenopause. That's right. That's right. And there's plenty of sort of less evolved areas of the world that don't experience the same, you know, drama that we do.
And it it's an area that that needs well, it has a lot of research right now, but it needs even more. Yes.
And I I feel like
a doctor like you, a functional medicine doctor who's educated on all these things. You can take a woman who's having a really strong parameopausal reaction and with the right labs and the right prescriptions, um, usually hormones and some other things, you can stabilize it and take away 90% of the suffering. It's just that most people don't know we can do that. So, we have this thing that's going on. And I'm incredibly stoked that they just made hormone replacement therapy the standard of care for women after 23 years of just punishing women because of a press release. Yeah.
So, I'm hopeful that that becomes a population that we can study because we've got parmenopause stabilized and it's just a normal thing.
Yeah. We've got, you know, a ways to go as far as having, you know, really paying attention to women. Um, but yeah, it's huge. It's really, really, really huge. The other thing just for because I'm on your show is looking at fibroids. Like, we still don't really get fibroids. Almost every woman has uterine fibroids and we don't know why. Nor do we really get how to address them adequately. And yeah, um it's it's a it's a massive miss in my opinion. Just a massive miss.
I've worked with a few friends who have them on biohacking them and it is really tough,
very challenging
and it's different than regular tissue fibrosis, which I think I know how to punch that in the face. You can stop fibroic tissue unless it's caused by hormones and that's a dark art right now. So, we got to fix that
for sure. And actually there was just a publication out attaching it to increased risk of cardiovascular disease with which completely makes sense because it's really inflammatory driven but you know the narrative around them is that they're benign and don't worry about them unless you're anemic etc etc but you know they're problem players and they shouldn't be there. Absolutely. And we should really really drill down and understand what it's all about and we we just haven't done uh we haven't done it.
We'll get there. I'm sure there's somebody working on it. We'll we'll find out who they are and get them on the show.
Cool. Good. Well, and thank you for coming and spending some time with me and going deep on this. And your work is fascinating and you're you're doing real longevity in combination with the lifestyle stuff that's part of biohacking, part of functional health. So, you're providing the science that makes it so it's impossible for big food companies to sell us garbage and tells us it's healthy for us. So, thank you.
Thanks for having me on. It was it was a lot of fun.
Dr. carafitchell.com.
Yep.
Dr. Right. Okay, guys. Check her out. And if you are a functional practitioner, I know that we have lots listening. Um, you should listen to her show. It's pretty cool. It's very doctory, but it's cool. Thanks.
See you next time on the Human Upgrade podcast.