[Transcript] – Is This The Most Advanced Anti-Aging Analysis & Epigenetic Diagnostic Test Of The Future?

Affiliate Disclosure


From podcast: https://bengreenfieldfitness.com/podcast/self-quantification-podcasts/epigenetic-testing/

[00:00:00] Introduction

[00:01:25] Podcast Sponsors

[00:07:12] About This Podcast and Guest Introduction

[00:09:56] Biological And Chronological Age

[00:14:02] The Connection Between Stem Cells And Telomere Testing

[00:16:18] Testing Epigenetic Markers Vs. Telomere Lengths

[00:21:25] Different Types And Uses Of Epigenetic Testing

[00:28:25] How The Millions Of CpG Sites In The Body Are Tested

[00:34:42] VIP Text Club and Podcast Sponsors

[00:37:17] The Key Factors That Indicate An Acceleration Of Aging

[00:48:15] How Your Diet Affects Your Epigenetics

[00:52:26] Compounds That Slow Down Aging With Great Efficacy

[00:59:38] What Dr. Stickler And Ryan Smith Would Do If Their Biological Age Was Less Than Optimal

[01:05:37] About The Test

[01:06:59] Closing the Podcast

[01:09:42] End of Podcast

Ben:  On this episode of the Ben Greenfield Fitness Podcast.

I'd actually like to start with acceleration of aging. What are you finding out of the things that seem to really influence biological age deleteriously?

Daniel:  Your past life experiences are coded in your genes and your genes are optimized for a particular pattern that we look at for genetics.

Ryan:  Exercise, particularly aerobic exercise has more of an impact, whereas if you're younger, I think that things like sleep, closure to pollution, and exposure to environmental toxins are a little bit better.

Ben:  Health, performance, nutrition, longevity, ancestral living, biohacking, and much more. My name is Ben Greenfield. Welcome to the show.

Oh, I'm chilly. I'm cold. I had a really long weekend and I'm recording this introduction for you on a Monday, and I was a little bit tired. So, I went and just plunged my entire body, just my upper body because I was too lazy to take off my clothes and get too wet into this ice-cold tub outside my office. It's called the Morozko Forge. It stays at like 32, 33 degrees, super chilly, then a cup of coffee. I think they should have sponsored this episode because I just gave them a shout-out, but yeah, whatever.

Many of you have been asking me, possibly because podcasting is now considered to be such a cool thing to do. I was writing an article actually the other day that there's like a billion dollars in advertising and revenue now being poured into podcasting. I don't know what my count of that is, but anyways, what I can tell you is that quality audio is a must and a lot of you have asked me about how the audio quality on my show is so dialed in. Well, it's not me, I can tell you that. If it was me, you guys would be listening to a scratchy, tin foily, tin canny, complete wreck of a show. But here's the deal. My podcast editor, I wanted to tell you about him because again, I get asked so much. I figured I'd kill two birds with one stone and just tell you who this dude is. His name is James, James Newcomb. He's a former professional military musician who actually started getting into podcasting when he was stationed back in Seoul, Korea in 2014 and he founded this digital media service. And he manages like soup to nuts a ton of aspects of my podcast, all of the submission, all the different feeds, all the technical nitty-gritty when crap goes wrong, he makes all the guests sound amazing, he makes all the audio perfectly aligned or at the correct levels. He has half a decade of experience in the podcasting industry.

He is also extremely well-versed in health and fitness and nutrition, possibly because he has to listen to my voice, all my guests every single week a few times a week. So, he knows all that inside and out if you're a health and fitness person wanting to get into podcasting. He's really good at that. And he stays up to date with everything about all the new podcasting platforms, and podcasting apps, and audio and video editing programs. And he also does video. He does YouTube video production. He does video podcasts, he does copywriting, he does a lot of work on my shownotes for the podcast shownotes, he does narration for audiobooks, he does voiceovers, he does coaching and consulting for podcasters and podcast editors. If it's digital media, it can be done.

And I'm going to give you his website URL, again, because so many of you have asked me, I just figured, I would let the world know about this cat because he's amazing. Just please don't all of you go to him at once because he still has to work on my show, too. So, it's beatinpath.media, and that's his website. But here's how that's spelled, Beatin, like B-E-A-T-I-Npath.media, beatinpath.com. And Beatin is spelled with an “I”, B-E-A-T-I-Npath.media. He also told me I could just give out his phone number, so what the hell, here you go. Here's James's phone number, 757-364-8465. That could be a mistake for him to have offered to do that, but there you go, 757-364-8465. You could learn more about James, how he and his team can help take your podcast, your audiobook, your video production, or any of your other digital needs, your digital media needs to the next level. So, his name is James. Check him out. He's a real deal, baby.

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And today's episode is with a really smart pair of guys who have been studying up on so-called epigenetic aging, Dr. Dan Stickler and Ryan Smith. We're going to be talking about this true age epigenetic test. So, it's kind of fascinating. Hope you enjoy. So, that being said, enjoy.

Well, I've talked about ways to measure your age on this show before. I've talked about all these different telomere tests and briefly mentioned things like methylation clocks or Horvath clocks and really have several podcast episodes out on how we can track anything that we might be doing, say, NAD or peptides, or sauna, or sunshine, or anything else when it comes to living a longer time. But the whole field of being able to track and measure and optimize biological age is, in my opinion, a field that's kind of rife with confusion and a dizzying variety of testing methods like telomere analysis, or methylation clocks, or anything else that's popping up.

And I've recently been looking into this concept of DNA methylation testing and epigenetics, and how we can learn from that, really, what our biological age is. And I decided to interview for the show today two people who are at the cutting edge of this whole biological age testing sector to get their take on where we're at and to really educate us on how we can track in a scalable, sustainable way our biological age. So, my first guest on this show, you may have heard of before because he's been in a couple shows in the past in which we've talked on all things peptides. He's a real expert on peptides, but he also is in the biological aging sector. And his name is Ryan Smith. Ryan, what's up, man?

Ryan:  Hey, Ben. Thanks for having me.

Ben:  Yeah. No problem. And my other guest you may have heard of before because he's well-known in–I guess maybe you'd call it like the functional medicine industry, or the genetics testing industry, or the genomics analysis industry, and that's Dr. Daniel Stickler, who's the co-founder and chief medical officer at Apeiron, and he is a physician to a ton of high-performing execs and entrepreneurs. He's also an author, a speaker, a blogger, a podcaster. Dan, welcome to the show, man.

Daniel:  Thanks for having me, Ben.

Ben:  Alright, folks. Well, there's a lot of different areas where we could kick this off, but I think just to make sure that we get our terminology straight here, and Ryan and Dan, as is the case, is always a little awkward doing three people on the show and you guys deciding virtually who's going to respond to which question, but I'm going to ask it anyways and let you guys decide who's going to dive in, and that is differentiate for people biological age versus chronological age.

Daniel:  Oh, I can take that one, Ryan. I actually have a little bit of a qualm against using either one of those because what it does is it compares you against the norm of the population, which I don't necessarily agree with. So, chronologic ages is nothing other than an arbitrary number. It's a number of years since you've been born. And you can take a 70-year-old and compare them to a 50-year-old and there are norms of that in the population, but everybody's going to be very different in that regard. And we also see this in biologic age, which we're actually looking at the aging of the cells. So, it's like a clock of the cells, a chronologic clock of the cells. And you can accelerate, you can decelerate. And more recently, we've seen that there's the potential to actually reverse that clock.

And again, it's not a great metric to use, it's a great dynamic to use. So, when I say a person's biologic age is 60 this year and next year it's 58, that's a very positive change in that age, but it's still a relative number that you're comparing to a norm. I just don't like comparing to norms. It's not as accurate as I would like. I would prefer to see people get a health score and say, “Hey, your health is 96 versus somebody else who's a 52.” But unfortunately, that's what we're using right now and that's the best way we can do it until we develop something that can truly get a more in-depth measure of them.

Ben:  Okay. And what do you guys think about telomere analysis? Because up until that point, I mean, that's what a lot of people have been talking about. And I interviewed Bill Andrews from Sierra Sciences and he talked about tests such as Life Length, the Repeat Diagnostics, or SpectraCell as being decent ways to analyze the rate at which your telomeres are shortening. And I'm wondering if you guys have a take on telomere testing.

Daniel:  Well, I've done telomere testing. I've used Life Length for the past 10 years in my clinical practice, but I've gotten more away from it because we don't know for sure whether telomere age is a cause of aging or it's a metric of aging. Like gray hair, does that really indicate that it's causing you to age? We don't know 100% on that. We suspect that it's relevant there. And right now, and I know Ryan's in the same court that we are in clinical practice that we just don't have 100% testing right now, so what we do is we get all the different potentials for determining age. And we start putting these together in a nice computer algorithm and start seeing what is truly the marker that we should be looking at or the group of markers.

Ryan:  Yeah. And if I might jump in there as well, the telomere question is actually a really, really big one, just because a majority of the people who have been involved in this space are conceptualizing this thing, the Hayflick limit, and how it affects health and disease. But there's some really, really good information about the interplay between telomere length and outcomes of physiological function or biological age. And the telomere testing and telomere link has numerous large-scale epidemiological studies, but there's only been a weak negative association with markers of biological age and life expectancy. And so, a lot of people postulate that that's because it might not have a physiological effect until the telomere length is critically shortened.

But it definitely has some implications as we talk a little bit more about how this test was created and future areas of interest in terms of stem cell, telomere length, and other things. I'd be happy to go into that a little bit later.

Ben:  Yeah. Well, I mean, you could dive into it right now while we're talking about telemeters if you want to. Go for it.

Ryan:  It's a complicated thing because, in order to get to why it's so exciting, you really have to divide this calculation of epigenetic age into intrinsic and extrinsic epigenetic age. And that becomes a very, very difficult conversation because it really all started in 2013 with two different types of clocks. Dr. Horvath, as you mentioned, has sort of been the pioneer and the leader in this field. But Dr. Greg Hannum, another biostatistician, came out with a clock at the same time. And over the course of several years, they realized that those had different powers in predicting different things.

And ultimately, they realized they were measuring sort of two separate things, both of which are incredibly important to biological age but have different outcome metrics. And it's sort of a complicated discussion, one that we can sort of talk about when we talk about some of the interventions with Dr. Fahy's TRIIM trial. But one of the things that they found is that the telomere length of stem cells is maybe one of the most exciting things and might underlie the entire biology of methylation. And so, whenever we talk about the process and what methylation is and how it happens, telomere length will come back into focus.

Ben:  But it's the telomere length on stem cells. Is there a way to actually test just the telomere length on stem cells? Because if I get a telomere test right now, I'm doing typically a finger stick blood drop, which I assume is not just testing the telomere length of stem cells.

Ryan:  Yeah. As far as I know —

Daniel:  White blood cells. I mean, that's what they're typically extracting the DNA from, and it's an indirect marker of the stem cells in that regard.

Ben:  Okay. So, they're just basically extrapolating from the telomere length on a white blood cell, what the telomere length on all the other cells in your body would be?

Daniel:  Right. And you know, I like Life Length because they do the shortest percentage. That's the reason I've always used them. As Bill Andrews said, “If you're in a room full of dynamite, do you want to know the average length of the fuses or the shortest –?”

Ben:  Right, exactly.

Daniel:  And so, that's why we've always stuck with them.

Ben:  Okay. Got it. So, how does this concept that seems to be coming up more and more these days of testing epigenetic markers compare and contrast to something like testing telomere length?

Daniel:  Well, I mean, there's a whole host of markers. I mean, this is the holy grail right now. I mean, everybody's looking for the marker that can determine our true biologic age, our true time to death, and all of this. So, one of our board members, Brian Kennedy, former CEO of the Buck Institute of Aging at Stanford, he is aggressively looking for it along with about probably 40 other labs around the world that are trying to find which markers are relevant. And right now, in our clinical practice, we're in a private clinical practice and we're doing things like epigenetic age, we're doing GlycanAge, we're doing BrainAGE by qEEG, we're doing blood markers, we're doing telomeres. So, we're gathering as much data, and that's one of the things we're working with Ryan and their company on is we gather the data. I mean, we're even looking at VO2 max changes over time and putting this all into that database so that we can have that AI algorithm that can start looking at this and seeing which are the relevant markers and how they interact with each other.

Ryan:  Definitely. To add onto that as well, taking a step back, the reason that biological age is so important is because it provides one single objective measure that is the largest risk factor for a lot of age-related diseases, dementia, osteoarthritis, metabolic disease, cardiovascular disease. All these are age-related diseases. And so, if you can define a biological marker, which is really indicative of functioning, you can test interventions against it. And that's powerful because then you can extend health span, you can extend lifespan. And using that as sort of an objective measurement technique allows you to develop the tools to really make a difference in the health span.

Ben:  Okay. So, before this podcast interview, you guys sent me over a test. I think it was called Tru–was it called TruAge or TruDiagnostics?

Ryan:  Yeah, TruAge is the test, yeah, but by TruDiagnostic.

Ben:  Okay. I did that test. I didn't get the results back yet, but how does that differ from telomere testing?

Ryan:  So, I think that the difference between telomere testing and DNA methylation testing, one of the biggest differences, how they're tied to outcome measurements, and then also, how predicted they are of actual age. Telomere testing, like I said, it doesn't really have a huge statistical significance to markers of biological age or even life expectancy. The methylation age or methylation age calculated by these methylation DNA markers is sort of the opposite. It has really, really tight correlations to, particularly aging and death, and death prediction. And so, it's a little bit, I would say more, functional. It tells a little bit more about risks to certain types of diseases, but also gives you a better overall readout of where you're at in your health.

And actually, a lot of the telomere studies have been knocked in this integrative medicine community because they can change so fluidly. And they're a little bit less reliable. Sometimes they will jump up or go down. And really, no one has any idea why. But the epigenetic aging calculators are much, much more specific. The amount of data that is used to make these tests is absolutely much more expansive looking at hundreds of thousands of copies of DNA. And as a result, you can get really, really precise measurements, which then predict risk of a lot of different things.

Ben:  Okay. So, I want to jump in here real quick because I'm a little bit confused because DNA methylation or histone modification are two ways that I know that DNA is influenced, but epigenetics is different than that. Like when you're testing epigenetics, you're not testing changes in the nucleotide sequence, right?

Daniel:  No. In the epigenetics, epigenetics is the aspect of–and methylation is a big part of that, but there are a lot of other processes that can occur, but it's in changing the way the genes are expressed. So, the genes are always going to be there. It's just some of them are turned on, some are turned off, some are turned up, and some are turned down. And there's a difference that I think we need to make here in histone modification versus CpG methylation. So, CpG methylation is methylation of nucleotides right on the DNA sequence itself. And most of these usually occur in promoter regions of genes. So, that's where the genes are turned on and off predominantly. Most lifestyle patterns have–they're hard to shift when it's a CpG methylation pattern versus a histone modification, which is very malleable to lifestyle patterns. So, differentiating the two types of methylations there I think is important.

Ben:  Okay. So, what is epigenetics testing for? Or what is epigenetics testing testing for? I guess I should say.

Ryan:  Well, there are a lot of different types of epigenetic testing, a lot of things that are associated with histone modifications. But the one that is most related to biological age is this methylation testing where they're testing whether or not these CpG sites are on your DNA, sort of in these promoter regions, are methylated or not. Usually, methylated is associated with inactivation of a particular gene in comparison to acetylation. And so, you're actually testing those methylation spots on your DNA.

Ben:  Okay. Got it. So, when you say CpG sites, I assume you're talking about that that'll be the region of the DNA where you have a cytosine nucleotide followed by a guanine nucleotide, and what you're looking at are changes in that specific region?

Ryan:  Absolutely, yeah. The CpG sites are the cytosine, and then a phosphate, and the guanine. They occur in high frequencies in certain genomic regions and they're really called CpG islands. And those areas are methylated at a very, very predictable rate, which infers that there's some underlying biology which is controlling this throughout aging.

Ben:  And so, would the rate of methylation at those sites then indicate excessive aging if that rate of methylation was accelerated and decreased rate of aging if that rate of methylation was low, or something else?

Ryan:  Yeah, absolutely. And it's not necessarily increased or decreased methylation because in some areas, increased methylation can mean that you have a higher epigenetic age. And in some other areas, an increased methylation can mean that you have a lower epigenetic age.

Ben:  Okay.

Ryan:  So, it's all about correlation to these different–where each side is correlated to chronological age. But absolutely, these are the sites that are measured to give us that reading and very, very predictable measure of biological age.

Ben:  Okay. So, someone has actually researched the type of methylation that occurs at the CpG locations and determined that the type of methylation that's occurring is going to correlate directly to your biological age?

Ryan:  Correct. And with extreme accuracy, and I know that Dr. Stickler can compare to a lot of other testing. But the typical margin of error for things like Dr. Horvath's tests are around 2.6 years, which is incredibly, incredibly accurate and it has a lot of implications in things like forensic testing where they might find someone's DNA at a crime scene and need to know how old they are. Or even, as we talked about earlier, in death prediction because if someone is 30 but has a biological age of 40, that's probably not a good sign for their overall health. And so, other companies like health insurance companies, for instance, are really interested in this metric as well because it can really help predict death, and then, therefore, they can decide how much to charge or whatever that might be. And so, it's a very, very predictive measure, especially when you compare it against all the other metrics which are available now, proteomics, metabolomics, or even telomere testing.

Ben:  Okay. Now, like I mentioned, I haven't actually seen my results from this TruAge test. I think they're coming in next week, but is this like a telomere test where it tells you, whatever, your chronological age is 40 but your biological age is 43, or chronological age is 40 but your biological age is 27, or is it more of a result that says something like, “This is when you're going to kick the can”?

Ryan:  So, at the moment, it does not predict death, and there are definitely some ethical implications as it revolves around that. So, this is basically a reading of your current cellular biological age. As Dr. Stickler said, it's a measurement of how your cells are–how old they are and how they're behaving. And in addition to that, it also talks about some of the factors which are associated with these different changes so that you can make, hopefully, some lifestyle or medicational interventions to try and live a healthier life and decrease that biological age.

Ben:  Okay. And that's because we know that epigenetics are heritable changes in gene expression. They don't alter your primary DNA sequence, but they are influenced heavily by lifestyle factors like nutrition, or smoking, or alcohol, or physical activity, or even things like relationships, meditative practice, et cetera, like these are all modifiable methylation patterns that you're testing.

Daniel:  They are modifiable. And like you said, and I like that you said that they're also heritable, and this is important because some people are born with methylation patterns that can indicate that they're older than their baseline just from the heritable aspect of it. I mean, most people don't realize that really, the most critical timeline in your life are the three months that your parents are in the preconception period right before conception. During your mother's pregnancy with you, and then the first two years of life are very critical for developing methylation patterns on these CpG islands, especially they will set the stage for the rest of your life.

Now, throughout life, you also gain and lose methylation patterns through different lifestyle factors, but we like to say that some of these methylation patterns are written in pen and some are written in pencil because the ones that are written in pen are really hard to change and erase. They're kind of fixed patterns that accumulate over time versus the ones that are written in pencil, which can change. And most people used to think that from an epigenetic age standpoint, it was a purely one-way linear process. And we've learned just with the phase study back in September, it really changed the mind of a lot of people and understanding that we can actually reverse age, the cellular aging process.

Ben:  Got it. And for people who want to get this straight, I mean, the way to think about it is the word “epi”. That comes from Greek and it means above, translated from Greek. Genetics is just the study of your DNA. And so, when we talk about epigenetics, that's the study of things that might go above and beyond just your genome, the DNA that you were born with. These are things that can be modified that go beyond just like CRISPR. Going in and trimming would be an example of how to directly modify the DNA. But we're talking about modifying things that, as the word epigenetics applies or refers to, go above and beyond just DNA, right?

Daniel:  Correct.

Ryan:  I just wanted to add a little bit. This is one of the big parts because a lot of people are scared to get their DNA sequence because they might find an APOE4 variant that predisposes them to Alzheimer's or something like that, and they don't want to work with something they can't change or know something that they can't have any effect over. And the good thing about these methylation changes is that we're sort of finding out that over 60% or around 60% is modifiable. And so, you're still controlling the majority of your genome and the expression of these things, which are linked to aging processes.

Ben:  So, the tricky part here for me is that from what I understand, there are literally millions of these CpG islands on the human genome. And so, when we're talking about testing and calculating your biological age, that seems like a hell of a lot of sites to test. How is this done? Is this done with like AI or some kind of computer algorithm? Or when you're researching, I think–I do so many tests I forget. I think it was a drop of blood. Was it drop of blood that I sent to you?

Ryan:  Yeah.

Ben:  Okay. So, when that drop of blood is received, how are you testing millions of different CpG locations?

Ryan:  Yeah. And I'll talk about this a little bit. So, our company, TruDiagnostics, in the test TruAge utilizes a microarray-based platform. And so, what we're doing is we're isolating DNA, we're doing something called the bisulfate conversion, which allows us to test where these things are methylated. And then, what we're looking at is over 900,000 different locations on the DNA using these microarray beads. And so, what we're doing is we're complexing different parts of the DNA to these beads. And whenever we look at those through sort of spectroscopy methods, we're able to see if they're methylated or if they're not.

And so, you're testing many, many copies of the same DNA and you're testing 900,000 spots on them. So, the amount of data that you're generating is extensive, but it's looking at a lot of different regions. And usually, that's also an important part because the algorithms to read these things that are reporting out these biological ages actually don't use nearly as many data points as you would think. For instance, the first Horvath clock only looked at 353 different locations on the DNA. So, what happens is whenever you look at these wide genome studies, you correlate those to variables like chronological age, then you pick the things that are most highly associated with it, which gives us the ability to have these biomarker estimates which are extremely, extremely precise and accurate.

Ben:  Okay. Got it. So, when I send that blood in, you're testing a pretty large number of spots on the genome that are directly correlated with, I guess I would say expression of certain genes like, for example, your eyes are going to express different genes, and your hair. And as you age, expression gets harder to regulate, and that's where a lot of chronic disease is set in. So, you guys are looking at how good a job your DNA is doing at expressing certain factors?

Ryan:  It's mainly just a correlation between methylation sites and outcome metrics. That's really what these computer learning systems are doing is that they're using large amounts of DNA information to compare to this health information or things like chronological age. And so, by looking at such a wide variation, you can really have some really good predictive algorithms. And some of these things, for instance, if you wanted to run Dr. Horvath's original algorithm, you could only look at 353 spots on the DNA. But the test itself is different than the algorithm to look at it. The test establishes where you're at and what sites on your DNA are methylated. The algorithms are really the glasses or lenses to which you read that data and turn it into actually something useful.

Ben:  Okay. Now, there's a lot of talk right now about senescence, and especially something like immunosenescence when your immune system becomes weaker and less functional as you age. And that's often seen in a blood analysis by having a lower number of T cells, or a lower number of naive T cells and a higher number of senescent T cells. When you guys are getting this data back in, are you able to look at anything like cellular senescence?

Ryan:  Yeah, absolutely. By looking at so much of the DNA, it's all about creating new algorithms to read that. And if you can correlate, for instance, these methylation sites to senescent markers, then you can come up with new tests for senescence. And that's actually what we're doing. In addition, there's already IP out there that looks the same epigenetic methylation markers and correlates it to things like telomere length. And so, as we progress down the exploration of this at the Diagnostic, you're going to have the same measurements, these same methylation measurements to be able to report out a lot of different things. And we are working one on senescent cell burden where you can just look at the constituent of your DNA and then figure out how much of a senescent burn you had, and possibly, how much senolytic cell therapy might be able to help.

Daniel:  And that's one of the things we're working with Ryan on too is we measure, we use UCLA'S lab to do senescent and naive T cell ratios, and we're plugging that into the algorithm with Ryan for helping to get more accuracy on that testing.

Ryan:  This is also a really good point to talk about this difference between intrinsic versus extrinsic epigenetic age. As I talked about those initial two algorithms, Dr. Hannum's and Dr. Horvath, whenever they started to validate these algorithms, what they saw is that Dr. Horvath was really, really good at predicting age across all timespans, all different cellular tissues. No matter what, Dr. Horvath's was very, very accurate. But Dr. Hannum's was a little bit different, I should say, extremes of age, a little bit less predictive. And one of the reasons that happened is because as we age, the amount of senescent T cells in our body goes up, and the amount of naive T cells goes down. And the same with the plasma B cells, they also decrease.

And so, whenever we're measuring the blood, we're not just measuring DNA from one cell type. We're using a bunch of different cell types, we're using leukocytes, endothelial cells, free of circulating DNA. And so, the cells which are represented in that blood sample change as we age. And Dr. Horvath's pattern and his algorithm sort of controlled for this and didn't really–immunosenescence was not part of his algorithm. Well, it was part of Dr. Hannum's algorithm. And as a result, Dr. Horvath's is a little bit more accurate across all age groups, but Dr. Hannum's, being tied to the immune system, was a little bit more predictive of different measures like time toward death.

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So, knowing that when we look at–because I checked into some of these studies that are looking at these popular aging clocks that you're referring to, the one by Horvath and the one by Hannum, and it looks like about 40% of the determination of your aging rate is due to factors that you can't necessarily control, again, unless you were to get something like CRISPR gene editing done, like your DNA, or like how your parents lived, or what your mom did when she was pregnant with you. But that of course means, based on my rough math from sixth grade, that's about 60% that we could change, that we could affect.

Now, as you guys are getting all these tests in and you're looking at all of the different things that can affect aging, what I want to know, what's most important to me are the things that seem to most significantly affect either a decrease in the rate at which I'm aging from an epigenetic standpoint or an increase in that rate.

So, now I want to get into some of the more practical applications here. So, as you guys are getting all these tests in and running all these results, what are you finding as being the key factors that–I'd actually like to start with acceleration of aging, what are you finding are the things that seem to really influence biological age deleteriously?

Daniel:  Well, most of that is common sense, and you know this very well. It's lifestyle factors that will definitely accelerate aging such as smoking, not exercising, eating a poor diet. All of those things have been well-documented in accelerated aging in the epigenetic clocks. An interesting thing that's relevant to you, especially, is that in Horvath's original clock, people who were like really aggressive exercisers showed extreme aging. I had Ironman triathletes that would come in and they would be 10 years older by their clock age than their actual chronologic age, and it was very consistent with the people who were really heavy exercisers, and I think that they've made some corrections on the more recent clocks. Do you know about that, Ryan?

Ryan:  Definitely. In terms of its effect on exercise, I don't know that that's been validated with some of the newer clocks, but they have definitely made some changes, some of those newer clocks to be better-predicted value for across a number of things.

Ben:  Yeah. But one thing I'm curious about is we know that there's this acute response and an increase in CRP, well-known marker of inflammation, and I know that CRP is a significant explanatory biomarker of epigenetic age acceleration. But, is there a difference between something like the acute CRP that might have been present in a blood sample that was set in because someone had lifted weights the day prior and chronic inflammation and elevated CRP that might be due to other factors such as poor sleep, high alcohol intake, stress, et cetera? Like, has that been differentiated at all?

And I'm just curious because you don't see a lot of, say, ultra-endurance athletes or extreme exercisers actually dying early except for a few kind of fringe cases like bodybuilders dying of cardiomegaly or left ventricular hypertrophy, or some people dying of electrical abnormalities due to extremely excessive endurance exercise come out with mineral depletion, dehydration. I mean, I'm just curious how much you're looking at whether or not that CRP is just an acute elevation because someone had exercised a couple of days prior.

Daniel:  That's the nature of epigenetics, too. I mean, exercise is probably one of the most damaging things if you looked at it from an isolated standpoint, saying after a bout of exercise, you have some of the highest levels of free radical generation, you have muscle tears, you have microtraumas in the joints. But we know over time that that degree of intermittent stress that occurs in six months you'll change the expression of a third of your genome. I mean, 7,000 genes change expression over a six-month period of exercising on a regular basis. So, a lot of it is adaptation, and I can see what you're saying. If somebody is–if they're deconditioned and they go out and exercise, you're going to definitely see some abnormalities in that. And if you test someone right after a bout of exercise, if you're looking at blood work, you're going to see changes in that. But I don't think you're going to quite see that from an epigenetic standpoint in those early phases, it takes time for the epigenetics to really set in based on the body adapting to a new emergent trait.

Ben:  Yeah. I hear a lot of talk in kind of like the paleo and ancestral health and kind of like primal movement community that extreme exercising is going to shorten lifespan, and have seen some blood markers and epigenetic markers or biological age markers that seem to suggest that might be the case. But then if you look at actual epidemiological data, it seems it's very difficult to find extremely fit people who are dropping dead early, or large populations of marathoners or ultra-marathoners, or CrossFitters, or anything like that in long-term studies who are actually dying early.

Daniel:  Right.

Ben:  So, that's a tricky one. But there are some other things I think that fly under the radar. I mean, Dan, you said a lot of this stuff's obvious, and I think it is, like alcohol intake, or smoking, or sedentary lifestyle, for example. But in terms of prediction of lifespan, what about something like socioeconomic status or college education? I mean, have you guys looked at things like that?

Ryan:  Yeah. And one important thing to note is that most of the data coming out of here tend to be epidemiological data, right? Not interventional data where you do it before and after after someone, for instance, has some type of intervention like exercise. But with that being said, there's a ton of correlation between education–the higher education means you traditionally will have a lower aging rate. Beyond that, high stress or stress, particularly as a child with psychological stress or any type of abuse can severely increase your epigenetic aging rate as well. And so, there are a lot of different things that affect that. And quite a few studies now that are coming out looking at these epidemiological markers. For instance, alcohol. High alcohol intake might be negatively associated, but it's actually been found that if you have at least one drink a month, you actually can possibly affect your epigenetic aging rate.

Ben:  One drink a month? That's one precious cocktail.

Ryan:  Exactly. Well, it looks like the trend continues to once a week and once daily as well as long as you're considering just beer and wine.

Ben:  Yeah. I don't want to live forever if I can only have one drink a month, I'll put it that way. Okay. Now, in terms of sex differences, what about male versus female?

Ryan:  Yeah. Just as you would probably expect due to the fact that females have longer lifespans, females tend to age at a lower rate, and obviously again, that makes sense, but looking at these cellular markers, it is sort of confirmed across all different types of populations.

Ben:  How about ancestry when it comes to ethnicity? Have you guys been looking at any of that data? Like, do we know that African Americans might live shorter or longer versus Hispanics versus Caucasians? I mean, is there any data about that?

Daniel:  Actually, the African Americans have longer intrinsic age in general, interesting that they found.

Ben:  And that would be due to a lower–or I guess that would be a, yeah, a higher methylation age?

Daniel:  No. Their intrinsic aging is slower.

Ben:  Okay.

Daniel:  And so, it's basically their immunosenescence that we're looking at with that. So, they're actually aging much slower.

Ben:  Okay. So, African Americans have indications of a significantly younger immune system age than Caucasians, for example?

Daniel:  Right.

Ben:  That's interesting.

Ryan:  And there's actually been some really cool information with even indigenous populations as well where we see that they traditionally actually age a little bit quicker. And most likely, that's probably due to the amount of exposures they have to infectious disease agents and these chronic inflammatory loads. But even, for instance, Hispanics traditionally have a significant older extrinsic epigenetic age than Caucasians, and as a result, also some fewer naive CD4 cells. And so, there is definitely a correlation between all different types of ethnicities.

Ben:  Yeah. Obviously, right now, because we're kind of in the middle of–hoping towards the end of, but staying in the middle of this COVID pandemic and air pollution has come up multiple times during this period as being something that could predispose one to higher susceptibility to an infection. When it comes to air pollutants, I've been pretty shocked at what I've seen as far as the significant rate of aging and risk of death in response to pollution and particulates that are pretty much all around us. Have you guys seen this in the epigenetics testing you've been doing?

Ryan:  Absolutely. And in the TruAge report, we even addressed that in particular because these measurements of the air pollutant rates usually defined as these particular matter counts, but are directly associated with increased epigenetic aging.

Ben:  Yeah. I'd like to see some of these lesser-known variables that people are surrounded by, including non-native EMF, including things like the nature of the water that folks might be drinking, even things like biological versus non-biological lighting. Like, there's a lot of things in our personal environment throughout the day that can be changed. Like, it's easy to replace the light bulbs in your home or office with biological LED, get a HEPA air filter, get a water filtration system. But I would suspect that what I've seen with air pollutants as far as vastly accelerating this clock that we're talking about, I imagine we'd see some similar things. I don't know if there have been many studies done on things like water quality, or exposure to EMF, or even biological versus non-biological light. But those would be other areas I think would be super interesting to look at.

Daniel:  I'm not overly familiar with it in regards to the CpG methylations, but we've done a lot of research in environmental design. My wife's doing a lot of the work in the military with that as well. And there are huge impacts on gene expressions with a lot of the environmental pollutants, not only the air, but the light. All of that is playing a role. So, I think you're seeing a big jump in people getting into environmental design and neuroaesthetics of home and workspaces.

Ben:  Interesting. Now, it's no secret that calorie restriction and some semblance of fasting in multiple studies in yeast, fruit flies, worms, and beyond has been shown to increase biological age.

But when it comes to the nature of the diet itself, the composition of the diet itself, have certain diets, like whether it's a paleo, or a carnivore, or a vegan, or a Mediterranean, or any variant thereof been looked at as far as how it might influence in a large population the rate of epigenetic aging? Like, is there a certain diet that seems to–painting with a pretty broad brush seem to be a good idea when it comes to epigenetics, particularly?

Daniel:  I mean, you have to look at context with each individual. I mean, what's their ancestry? What are their gene expressions really? Have they, throughout their ancestral time, been optimized for certain dietary patterns? Like, you have an Inuit Eskimo who's grown up in that environment and they eat a high saturated fat diet, they're going to thrive on that. But you put them on a high-starch diet, they're going to get heart disease. And the opposite can occur with people from an ancestry where they were predominantly starch-based and not much fat.

So, you can have impacts from what your past life experiences are coated in your genes and your genes are optimized for a particular pattern that we look at for genetics. But the Mediterranean diet, not only is it more of really a universal quality diet, but aspects of the Mediterranean diet, especially with the extra virgin olive oil, the omega-3s that you get from fish, the high phytonutrient content, those all have huge epigenetic impacts. I mean, you will shift gene expressions just from the bioactive nutrients in that particular diet for sure.

Ben:  Yeah. I would tend to agree with you on that for a couple of reasons. I know that they are running that new age project right now that's looking at dietary strategies for aging, and this is a European study. And I believe they found really promising effects of the Mediterranean diet, specifically in regards to slowing the aging process in a pretty diverse array of individuals. I think that people who are Polish origin, for example, responded particularly favorably to a diet that you might say at first glance would be the diet more appropriate to someone from a more Mediterranean versus a Northern European region like that.

But then the reason I think that the Mediterranean diet–and people often ask me this. They're like, “Well, if you're just going to choose one diet, what would you choose?” And I say, “Well, it's tough.” There's, as you've just pointed out, Dan, a great deal of genetic individuality. But if I had to choose, and you sent me to a desert island with one diet, it'd be the Mediterranean diet. And it's probably just because of this whole idea that the fertile crescent was likely where the first settled agricultural communities in the Middle East and Mediterranean started and many humans blossomed out from there. And so, perhaps just from this original place where the majority of humankind must have dwelt at one time, we could say that the diet folks were accustomed to at that time and still programmed into our genes. Is that kind of a logical thought pattern?

Daniel:  It really is. I mean, you can modify the Mediterranean diet very well, too. I mean, the ketogenic Mediterranean diet is one of the healthiest diets from the data that I have seen. So, people who want to be more ketogenic, they can do that with the kind of a twist on that Mediterranean. So, there's a lot of variety that you can shift around within the realm of Mediterranean diet per se.

Ben:  Yeah, yeah. I'm currently–I follow some semblance of that, not really a ketogenic Mediterranean diet, more of a low-carb Mediterranean diet. I think for athletes and very active people, something like a Mediterranean diet with some carbohydrate refeeds where you're in and out of ketosis seems to be pretty supportive to activity, to endocrine function, to thyroid function, et cetera. But I tend to agree that carbohydrate mitigation in conjunction with the Mediterranean approach just seems to work so well for so many people, particularly when it comes to just decreased overall risk of mortality.

Now, we've talked about some things that could of course hold you back from an aging standpoint, things like the activities of your parents, air pollutants, environmental factors, alcohol, smoking, et cetera. But what about the things that you guys have found aside from dietary factors to increase biological age in a significant manner? We hear all sorts of anti-aging compounds being bandied about, like resveratrol and NAD, and a whole host of other things. But have you guys found in the research that you've done in putting together this test certain compounds are just kind of like hell yeses when it comes to slowing down the aging clock?

Daniel:  You can't really say anything definitively right now. I mean, metformin for sure. I don't have any doubts about the ability of metformin to really slow or reverse that clock. But the TRIIM trial with Horvath and Fahy, I mean, that was–and the interventions they used in that, I have to say they're like minor league interventions.

Ben:  That one was metformin, growth hormone, and DHEA, right?

Daniel:  Yeah. And vitamin D. I mean, they're basics, but we have–I mean, it is exploding right now in what we have available. I mean, we've got a whole host of senolytics that are either prescription or supplement-based and they're not very expensive. We even have a peptide that is senolytic. So, we're trialing a lot of these right now with like dasatinib, quercetin, fisetin, FOXO4-DRI, all of these that have the ability to substantially reduce senescent load. And you're not going to substantially have an impact on age reversal until we address really all the hallmarks of aging. I mean, from mitochondrial health to cellular sensing, to senescent cells. All of these things are going to have to be addressed at some point and we're gradually accumulating that.

I mean, I was talking on age reversal at Paleo f(x) six years ago, and I was looking back at my talk because I was supposed to talk again this year on the topic and everything I talked about in that was theoretical at that point, and now, we're actually seeing these reaching clinical practice now. So, it's really exciting to see some of these new interventions. I mean, even like Epitalon from a peptide standpoint, Cerebrolysin, all of these really cool new interventions. And they're N-of-1 people. I mean, you're not going to have the longitudinal study. We'll all be dead by the time the longitudinal studies come out and tell us whether it worked or not. So, hopefully, with epigenetic age, we can do these interventions and see in a one-year period that it's actually having that biological impact. So, I love epigenetic age as a new marker for this.

Ryan:  Exactly. And we're working together to do a lot of different research trials on interventions, doing things like NAD, doing things like thymosin alpha 1. One of the reasons they chose growth hormone in that Fahy trial was because of thymic rejuvenation and increasing the ability of the thymus and decreasing immunosenescence with age. And things like thymosin alpha 1 would make a lot of sense for that investigation as well. And one of the things I should know is that the Fahy trial, the TRIIM trial is really the only interventional trial that's been published at this point and it was sort of a proof of concept, only nine patients. But they're actually expanding that now. I think there are over 100 patients in the TRIIM-X trial and are actively recruiting patients. And so, hopefully, we'll know very, very soon a little bit more about a lot of those interventions.

Ben:  Yeah. I'm a little bit kind of on the fence about completely shutting down cellular senescence with something like dinasatib or high-dose quercetin, for example, at younger ages just because, I mean, we know that senescent cells play a crucial role in mediating tissue development in the formation of the embryo, and also tissue regeneration and wound repair later in life. It's when the so-called zombie cells of senescence accumulate with age. That's when you get a lot of inflammation and tissue dysfunction. But I think there's got to be a sweet spot at which you would want to really begin to focus on limiting cellular senescence. And so, someone sent me a bunch of dinasatib and quercetin and they said, “Oh, this is going to be the greatest anti-aging compound you could take, Ben.” Honestly, it's in my refrigerator. I haven't touched it because I have yet to be convinced that at my age at 38, I want to significantly limit cellular senescence. Do you guys have any thoughts on the sweet spot about senescence?

Daniel:  I think it's really a question of your individual context and your aging process. I mean, we're really good with clearing senescent cells when we're younger. And as we get older, we become less and less capable of doing that. I think it's a big part of the programming of aging in the DNA. And you also don't want to be overly aggressive in somebody who comes in who's 75 years old and give them a really aggressive senolytic approach because, I mean, that's going to create a lot of inflammation in the body.

So, you've got to temper that with each individual. And you also don't want to run senolytics in a continuous run. There's timing to the way we do this with age rejuvenation. I mean, you've got to basically go in and tear the system down and then build it back up. So, you come in and you hit them with the senolytics and start with the thymic rejuvenation at that point, then you start into the NAD and then potentially exosomes, growth hormone, secretagogues at that point. Right now, we're doing a lot of N-of-1s with this, but you got to use some common sense in the way you're approaching it.

But one course of dasatinib broken out over a three-week period with two days each week, then you can get a substantial 30% reduction in senescent load in many cell types with that, and that is going to be huge. I mean, our stem cells are basically poisoned by the senescent cells. And once you start depleting that load of them, those stem cells start to kick back in and the other cells start functioning well. So, senescence is a huge, huge area, but we can't attack that without looking at how do we boost NAD, how do we boost telomerase activity. You got to look at the entire picture of the individual and take that approach. But I agree with you. I mean, at 38 and your health, maybe some minor senolytics like the quercetin and the fisetin, those might be beneficial for you at this point. But hitting like the dasatinib or the FOXO4-DRI is probably not advisable at this age.

Ryan:  You can also consider it though as a way to promote quiescence or to prevent the general conversion to senescence. And so, that's where even things like rapamycin and mTOR can prevent that irreversible senescence step. And so, you can think of it more as a preventative strategy with other compounds as well as a way to, even things like these growth hormones, to create a [00:59:33] _____ ways to keep these cells from going senescent in the first place.

Ben:  Okay. Got it. Now, let's say that, and just a fun thought exercise here, that either of you guys tested, I'd love to hear each of your responses, and your results came back, and your biological age was higher than what you would like to see, and you're already eating healthy, you're avoiding excess alcohol, you're having your one cocktail a month, you're not smoking, you're taking care of relationships, lifestyle, stress, maybe have yoga or meditation practice. What are a few of either the, say, biohacks or lesser-known supplements or anything else that you might do that you would consider to be hell yeses for you armed with the knowledge that each of you guys have about how you would improve that biological age?

Daniel:  I can tell you from personal experience. I mean, when I was 39 years old, I did a telomere test from Life Length and I was 10 years older by biologic age than my chronologic age. And I was a general and vascular surgeon at that time. I slept very little. I ate pizza and drank Mountain Dew all day long. I was not overweight because my exercise masked my unhealthiness. But that was an eye-opener for me and I completely shifted. I started really getting on a regular sleep schedule. I quit surgery for many reasons, but health was a big one. I started meditating, I started exercising regularly, eating a healthy diet, but I think sleep is probably one of the biggest things that we see in our clinical practice that people are–they're undervaluing the benefits that sleep can give them from so many angles of aging. It is a high priority for sure.

Ben:  Okay. So, that's not necessarily uncommon knowledge, but let's dive in just a little bit more to that. Is there anything that you do for sleep that you think more people should know about, who don't know about it?

Daniel:  Well, the biggest thing is I get on a regular sleep schedule. So, I'm in bed around 9:30, 9:15 and 9:30 every night. I wake up without an alarm clock every morning between 5:00 and 5:15. And I keep to that schedule as aggressively as I can. And when I'm off that schedule, I monitor, I wear wearable devices all the time. I've got a WHOOP on one arm and a garment on the other, and I track all of this, and I watch what happens. And I think this is an important thing for people to get is start learning interoception, understanding the body, and the wearables can help teach you that process and learning. You have a glass of alcohol. I have one glass of wine and my stress level goes through the roof for about eight hours for my HRV tanking, and that's okay to have periodically. I mean, stress is not a bad thing periodically, but if I'm having that glass every night, it's certainly going to have a health impact on me. I take things like metformin for aging. For the calorie restriction, I intermittently fast, but I don't tend to calorie restrict, but the metformin will tell my body that I'm basically calorie restricting, which is nice. So, there's hacks around that as well.

Ben:  Yeah. It just goes to show you, too, the level of individual variation on this because I tend to have a drink most nights of biodynamic organic wine or like a really nice cocktail, like a really high-quality bourbon or rye or gin with a splash of bitters and some lemon juice. I actually, just now while we're talking, I pulled up my Oura sleep scores and Tuesday was the only night this week on which I did not drink and I've got sleep scores of 90, 89, 67, 88, 92, and 85. And the one night on which the sleep score was low was the night I did not have a drink. And part of that could also be the fact drinks have carbohydrates. Carbohydrates can assist with serotonin production, enhance relaxation, and perhaps help to fill some glycogen reserves to a certain extent. And so, part of it could be that as well, but for me personally, in my own internal testing, a glass of wine or a cocktail at night actually seems to help out quite a bit.

But I think one really important thing that you highlighted, Dan, was this idea that you don't go to bed at, let's say, 11:00 p.m. every weekday and get up at 4:00 a.m. and then catch up on the weekends. Like regular sleep cycles, in my opinion, are underemphasized and super, super important. Now, how about you, Ryan, anything you would do if you got back with a low biological age that you just think would be a non-negotiable for you?

Ryan:  Yeah. I think that there are two considerations for there, and unfortunately, I don't have some secret intervention that's not well-known. I wish I did, but I think that one of the things to consider is where you're at, and particularly, what your age is because what the data shows is that your age, your chronological age is really correlated to how much of a difference you can make in these therapies. The one thing about this Fahy trial that was so exciting is they reduced the epigenetic aging rate by around 2.5 years, which is a pretty crazy statistic. It would look like toward the end; they were accelerating to even more age effects and even going up at a higher interval. And so, the reason that that's important is because, for older individuals, I think that exercise, particularly aerobic exercise has more of an impact. Whereas if you're younger, I think that things like sleep, closure to pollution, exposure to environmental toxins are a little bit better. So, I think it greatly depends. The intervention depends on your age, but ultimately, I think that if you're not doing the intuitive things in one area, that should be your focus.

Ben:  Mm-hmm. Yeah, yeah. Well, when it comes to this actual test, again, it's pretty simple really. You guys sent the kit to my house. I put the blood drop in the collection tube, which I think has some EDTA in it to prevent coagulation, and then shipped it back. I'm still waiting on results. I think it'll be about a week out when I get them. I will probably get them by the time I publish this podcast. So, for those of you listening in, what I can do is put my actual sample results into the shownotes if you guys want to see what a sample report looks like. I'm going to put the shownotes at BenGreenfieldFitness.com/trudiagnostic. It's spelled with just a “U”, T-R-U Diagnostic.

And then, if you want to get this test yourself, it's pretty simple. You go to the website; you order the test. I'll put a link in the shownotes. Ryan and Dan are giving us a $50 off code on your TruAge kit. It's just BEN50 if you go to BenGreenfieldFitness.com/trudiagnostics. You can use code BEN50 to get your test. Or actually, it's TruDiagnostic, not TruDiagnostics. And then, what is it, guys? It's about three weeks to get the results, from what I understand, right?

Ryan:  Yeah. By the time the test is published, it should be around three weeks to get the results. And they tend to be relatively comprehensive. It's a big report, but we'll address all the things we talked about.

Ben:  Okay. Alright, cool. Well, fellas, anything else you want to throw in when it comes to the status of these methylation clocks, the status of age testing, or anything else that while you're here you want to share with folks that's something you want to get off your chest? Or you can just go out of cocktail, it's up to you.

Daniel:  I would just want to emphasize that don't get hung up on the absolute value that you get back on that. It's more about the dynamic over time. And we're going to get more accurate over time as more and more samples are brought in and we compare this to other markers, but if you come back in two years over your current age, it's not something for somebody to get all worried about and start panicking about something. What you want to see is what's happening with that age dynamically over time. A year from now, you repeat that. And this is why I like epigenetic age over telomeres. I mean, you got to wait five years really to get really actionable outcomes from telomere testing. With epigenetic age, I mean, we've done some six months apart with looking at interventions and seeing how it's creating a dynamic change in that. And even at six months, we're seeing effects of lifestyle patterns that are shifting the rate of aging in the epigenetic aging.

Ben:  Wow. It's impressive. Well, and you're right. I mean, these are all modifiable factors and we know that there are gin chugging, cigarette smoking grandmas in Sardinia who are living impressively long times. And, so we don't necessarily want to think ourselves into via placebo effect accelerated aging or just identify ourselves with a higher biological age. But I consider any of these tests to simply be a method of equipping and armoring yourself with the knowledge that you need to make really, really good decisions about the diet you're going to follow, supplements you're going to take, modifications you can make, et cetera. So, I think that's where the value really lies.

Alright, folks. Well, that's what we got for you. And again, the shownotes are at BenGreenfieldFitness.com/trudiagnostic. If you want to get a test, you can get 50 bucks off with code BEN50. And Ryan and Dan, thanks so much for coming on the show and sharing this stuff with these guys. And I'm pretty excited to get my results back and thumb through them and learn about how much I actually can drink and whether I need to take NAD or resveratrol or inject peptides or any of these other things that we can do to live a longer time so we can make maximum impact on this planet with the life that we've been given. So, thanks for coming on, fellas.

Daniel:  Thank you.

Ryan:  Yeah. Thanks for having us.

Ben:  Alright, folks. I'm Ben Greenfield along with Dan Stickler, Ryan Smith signing out from BenGreenfieldFitness.com. Have an amazing week.

Well, thanks for listening to today's show. You can grab all the shownotes, the resources, pretty much everything that I mentioned over at BenGreenfieldFitness.com, along with plenty of other goodies from me, including the highly helpful “Ben Recommends” page, which is a list of pretty much everything that I've ever recommended for hormone, sleep, digestion, fat loss, performance, and plenty more. Please, also, know that all the links, all the promo codes, that I mentioned during this and every episode, helped to make this podcast happen and to generate income that enables me to keep bringing you this content every single week. When you listen in, be sure to use the links in the shownotes, use the promo codes that I generate, because that helps to float this thing and keep it coming to you each and every week.



The ability to track, measure, and optimize your biological age is a field rife with confusion and a dizzying variety of testing methods such as telomere analysis and methylation clocks, transcriptomic-based, proteomic-based, and metabolomic-based predictors, and composite biomarkers.

But a new biological age test developed by a company called TruDiagnostic claims that it will change how we measure health and ultimately, how we can improve it using epigenetic testing.

In this episode, my guests from Tru Diagnostic, Ryan Smith and Dr. Daniel L. Stickler, talk about why this new development in epigenetics testing promises to be so revolutionary.

Ryan Smith is part of the team that developed the biological age test and worked to bring it to market. Dr. Stickler, co-founder and chief medical officer at Apeiron ZOH, Inc., is a physician to high-performing executives and entrepreneurs who want to upgrade their current state and is also an author, speaker, blogger, and podcaster.

During this discussion, you'll discover:

-The difference between biological and chronological age…10:15

  • Chronological age is simply the time since you've been born (70 years old)
  • Biological age is similar to a “clock” of the cells; can be accelerated or reversed due to one's lifestyle
  • Problematic to use either metric because they are measured against norms such as the general population
  • A “health score” is preferable
  • BGF podcast with Dr. Bill Andrewson telomere analysis
  • Life Lengthtelomere testing
  • Unclear whether telomere aging is a cause or a metric of aging in general

-The connection between stem cells and telomere testing…14:05

  • Intrinsic vs. extrinsic epigenetic age
  • Began in 2013 with two different epigenetic “clocks”:
    • Steve Horvath
    • Greg Hannum
  • Telomere length of stem cells is a key metric in the methylation process
  • Currently no way to measure the length of only stem cell telomeres

-The difference between testing epigenetic markers vs. telomere lengths…16:20

  • The holy grail of current anti-aging research is finding the relevant markers: brain, telomeres, epigenetics, etc.
    • Epigenetic age, glycan age, brain age by quantitative electroencephalogram (qEEG), blood markers, telomeres…
  • Brian Kennedyis leading the charge
  • Biological age provides a single objective measure to predict a large number of age-related diseases: dementia, osteoarthritis, cardiovascular disease, etc.
  • TruAge Epigenetic Test Kitprovided by TruDiagnostic (use code BEN50 to save $50)
  • Big difference is how they're tied to outcome measurements, how predictive they are of actual age
  • Telomere testing doesn't have statistical significance to markers of biological age or life expectancy, can change so fluidly, can jump up or down and no one really knows why
  • DNA methylation testing is more accurate, more functional, more about risks to other types of diseases, overall readout of where you are at in your health
  • Epigenetic testing does not track changes in the nucleotide sequence, genes are always there, some are turned on, turned off, turned up, turned down
  • It's the aspect of changing the way in which genes are expressed

-Different types and uses of epigenetic testing…21:25

  • Methylation testing is the one closest to biological age
  • CpG sites (cytosine, guanine nucleotide) are methylated at a predictable rate
  • Accelerated methylation of DNA is indicative of a high rate of aging
  • Horvath testing is accurate; typical margin of error is ~2.6 years, which is very good
  • Crime investigators, health insurance companies use this data for their investigations
  • TruAgetest is a reading of cellular and biological age, does not predict death
  • Epigenetics are “heritable” changes in gene expression (heavily influenced by lifestyle factors, not genetic history)
  • The most important time in a person's life is the lifestyle of their parents 3 months before conception thru the first 2 years of life
  • Some methylation patterns are written in “pen”(really hard to change fixed patterns), and some are in “pencil,” which can change
    • Cellular aging process can really be reversed
    • Around 60% is modifiable
  • “Epi” comes from Greek language and means “above”

-How the millions of CpG sites in the body are tested…28:25

  • TruAge test utilizes a microarray-based platform, isolating DNA, doing bisulfate conversion which allows testing methylation sites
  • Testing many copies of the same DNA, with over 900,000 CpG sites
  • The test determines what site on the DNA is methylated; different from the algorithm used to look at it
  • Cellular senescence; looking at DNA is all about creating new algorithms to read DNA; correlating methylation sites to senescent markers, coming up with new tests for senescence
    • Looking at methylation markers and correlating it to telomere length
    • Look at constituent DNA and figure out how much is the senescent cell burden
  • Intrinsic vs. extrinsic epigenetic age;
    • Horvath's algorithm is really good at predicting cellular age at all different time spans, different tissues
    • Hannum's is a little bit less predictive
    • As we age, amount of senescent T cells in the body goes up, amount of naive T cells go down

-The key factors that indicate an acceleration of aging…38:20

  • What accelerates aging:
    • Lifestyle factors: smoking, poor diet, not exercising, etc.
    • Very aggressive exercisers show extreme aging
  • Negative effects of lifestyle won't show up epigenetically right away
  • Socioeconomic status, education levels can affect epigenetics tremendously
  • Stress levels, particularly as a child
  • One drink per day (beer or wine) can positively affect epigenetic rate
  • Females age at a slower rate than men
  • African Americans tend to age slower than other ethnicities
  • Environmental factors: air pollutantsnon-native EMFwaterbiological lighting

-How your diet affects your epigenetics…48:15

  • Depends on the individual's ancestry and genetic history
  • Mediterranean diet tends to favor epigenetics
    • It's the diet of the first humans, so it's in more people's history

-Compounds that slow down aging with great efficacy…52:30

  • Metformin
  • TRIM Trial(Metformin, DHEA, growth hormone, vitamin D)
  • TruDiagnostichas a whole host of senolytic compounds on the horizon
  • Things that were theoretical a short while ago are reaching clinical practice today
  • The “sweet spot” of cellular senescence is dependent on an individual's age, lifestyle, genetic history, etc.
  • Stem cells are poisoned by senescent cells
  • Quercetin
  • Fisetin
  • Rapamycin
  • mTOR

-What Dr. Stickler and Ryan Smith would do if their biological age was less than optimal…59:45

  • Meditation
  • Regular exercise
  • Sleep tips
  • Understand how your chronological age will affect your testing
  • Repeating telomere testing – wait around 5 years to get an actionable outcome
  • Repeating epigenetic age testing – after 6 months, effects lifestyle pattern shift are seen

-And much more!

Resources from this episode:

– Ben's TrueAge Results:

TruDiagnostic TruAge Epigenetic Test Kit (use code BEN50 to save $50)

– BGF podcasts:

– Supplements:

– Gear:

Other resources:

Episode sponsors:

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