Biological Age vs Chronological Age Test 🧬 TruDiagnostic TruAge - Interview with Ryan Smith

Aging is the biggest risk factor for all chronic disease and death, and not by a small margin. We're talking about five or six times more important than smoking status or obesity.

How you're looking on the outside actually can predict how you are on the inside, because what's going on on the face is a prediction of what's going on in your internal organs.

We do know that individuals who live in the same area get approximate levels of sun exposure, you know, are all the same ethnicity. They definitively the pace of aging is correlated to those facial appear. And if you see these pictures, sometimes you can see just how drastic some of that is. And the difference between the slowest and fasting aging members looks to be maybe 20 or 30 years of difference, even though they're the exact same chronological age.

Hello. Welcome back. So I'm super excited to have our superstar guest Ryan Smith back on again. So Ryan has been a pioneer in peptide manufacturing and peptide science, but his newest venture has been in biological age testing. So. So, Ryan, I'm so happy to have you back on the show.

Yeah, thanks for having me so quickly. It's always great to be on and as I mentioned, I love your following. They've been very vocal and responsive. So happy to on again.

Oh, yes, yes, yes. You are very popular and I want to just give everyone a overview about you again so that people are, you know, get a better, better understanding. So. So Ryan is the founder of True Diagnostic. Of course, he was a founder of TaylorMade, but Ryan basically left medical school midway and basically he went on to do bigger and better things to advance the field of medicine. So he founded TaylorMade, which had become the fourth fastest growing company in healthcare in the US and grew to $80 million within three years. So that's very impressive for somebody who just abruptly left medical school and was able to give us, you know, these incredible peptides that I'm sure helped numerous people. And. And after Ryan exited TaylorMade in 2020, he created True Diagnostic, which is a CLIA certified lab and health data company which specializes in understanding and reporting insights found through epigenetics methylation data. Since starting this company in 2020, True Diagnostic has created the largest private epigenetic database in the world with over 15,000 patients tested on their platform. And from this data set, they created many new algorithms to interpret methylation data, including algorithms to predict inflammatory markers, disease diagnosis, telomere length, aging pace, immune cell subsets, cellular replication, and more. So True Diagnostic has also led research in the field with over 30 clinical trials investigating the Best ways to reverse those markers through diet, lifestyle and prescription interventions. So currently, True Diagnostic is working with collaborators from Duke, Harvard, Yale, ucsf, Ohio State and more to uncover new insights from the methylome. So Ryan will explain everything. True Diagnostic is also the only commercial company on the market to offer second or third generation aging algorithms, which has shown to be predictive and precise, more predictive and precise than the first generation aging clocks. So, Ryan, I'm so excited to dive into these algorithms and the testing that you have helped develop. So maybe give us an idea of what got you to jump from peptide to biological age testing.

Yeah, certainly. Well, I think that it's probably a transition that I think most people will understand given our last conversation. I think that obviously I'm a big proponent of some of those peptides, but legally they're in a little bit of a weird state in terms of how you can most frequently get them, how you can use them. And we always knew that in the pharmacy. That was also one of our biggest weaknesses with all a lot of these peptides not being FDA approved. Their ability to be done in these peptide peptides and compounding pharmacies was. Was difficult sometimes, especially with all the legal loopholes. And so one of the things that we always thought would help our case to continue to always do these peptides was additional data. The best data would have been really good, I would say long term studies with placebo controlled data in the case of BPC, maybe a 10 year study on Crohn's or ulcerative colitis or some of those other gut conditions. But unfortunately we didn't have time to do that. We knew that the regulatory landscape was changing very quickly. We were looking at maybe other ways we could find biomarkers to assess their success. One thing that kept popping up, these epigenetic methylation clocks. And so as a brief history in 2013, Dr. Steve Horvath at UCLA really created for the first time ways to predict someone's age, looking at their gene expression data. So this might be an unfamiliar topic for a lot of people in terms of epigenetic methylation and what is it? But the way I usually explain it is by saying that every single cell in our body has the same DNA, right? So if you were to test the DNA from your heart or your skin or your saliva, it would be the ex same sequence. But obviously those cells behave very differently. The cells in your heart versus the cells in your skin are doing very different things. And so the way that they do those different behaviors are not by their genetics but by what genes are actually turned on and turned off. And epigenetic methylation is sort of the off switch for your genes. And so by measuring that off switch, you can get a lot of interesting data. And Dr. Horvath had done this to basically try and quantify someone's age. At first, these clocks were used for things like dating DNA. If it was left at a crime scene for forensics to see how old someone was. Many people might be familiar with an HBO series, which is going on now, where there's some age, I would say, discrepancies for a young child. It's now a really big HBO series. They're actually testing that person to see if they are and what age they actually are, if they're really young child with dwarfism or a really young child, or if they're sort of an adult who just has dwarfs. And so doing some of that validation. So some really cool tricks, but they never really ever meant to be health tools necessarily. There was really just to be quantify someone's chronological age. But whenever they started to test this in really large populations, they saw something really interesting, which is that those people who were older with this testing than their chronological age were at significantly higher risk for negative outcomes like disease and death, and vice versa. With this testing, those people that were younger than their chronological age were protected from death. Although this was meant to be a tool to measure someone's chronological age, it ended up being a measure of someone's biological age. The reason why some people might look 60 when they're 50 and other people might look 40 when they're 50 is through this process. Because aging is the biggest risk factor for all chronic disease and death. This type of tool can be really good at mitigating those risks. And so for us at TaylorMade, when we were going through these peptides, we thought it'd be great to show that some of these peptides were having age reversal related effects. Unfortunately, we never got time to study it before the FDA eventually asked that we stopped producing these products. But that was the reason I got into the space. And whenever I got in, I got very excited about all the potential applications.

Hmm. Okay. All right. So I know there are various age prediction programs. I guess. I know telomere age is one prediction and then there's methylation. Are there other type of age detection methods?

Yeah, certainly. I mean, there have been really crude measurements. I often like, oftentimes talk about in the 1920s and 30s when they were saying your biological age was how many, your chronological age was one year for every pack per day you smoked. So really crude measurement. Obviously those improved. As you mentioned, we got telomere length as one of those outputs. But telomere length is, although one of the most well known hallmarks of aging and biomarkers of aging, it's generally not that predictive of outcomes. If someone has low telomere length, it doesn't necessarily mean that we know what's actually going to happen to them. If anything, these epigenetic clocks are really what I would consider is probably the best biomarker of aging at the moment. The way that we would judge that is by how predictive they are, are of negative outcomes. So if you're accelerated in aging, does that increase your risk or does that you. Where does that put you? And these tend to be the most predictive. Just to compare to telomere length, for instance, is a good example. They just looked at a generation Scotland cohort and they said how much of the phenotypic variation in aging, so everything from disease development to the ability to move and all these different factors that associate with age, how much of that is based on telomere length? And they found that it's right around 2.3%. And then they compared some of the first generation epigenetic clocks and they found out that that was predictive of right around 28.5%. And so as we're comparing the two, the one that is much more predictive of outcomes is going to be these epigenetic methylation clocks. And now some of these newer generation clocks that are built with even more and better data are even more predictive, sometimes explaining over 50% of the difference in those phenotypes of aging. And so the clocks continue to get better.

So the new clock is that still using methylation patterns?

It is, but how they train those methylation patterns is a little bit different. And to explain that it requires maybe a little bit of background, which is that the way that they're using these things or training these things is by taking this methylation data, taking computer learning, artificial intelligence, and then taking an outcome. And they're basically saying with all of this data, can our computer system predict this outcome? The problem with that is it's really not intuitive. I think as medical professionals, most people are trained to find pathways that make a lot of sense where you might say, hey, this is being upregulated or this is being downregulated, and this is leading to X outcome due to that pathway. A lot of the peptides also are addressing certain pathways and make a Lot of intuitive sense in terms of how we think about things. But in the case of these computer learning algorithms, we don't know if it's causal or correlative, we just know that it's predicting X outcome. We don't have a lot of reason of why these things are this way. The first generation clocks, as I mentioned earlier, we're trained to predict someone's chronological age. But the problem with that is that the better that those clocks get, the closer they get to your birthday, which is something we could just ask you for. You don't need an expensive test for that, unless you're doing some of those really cool forensic things, as I mentioned earlier. But instead, those are what we call these first generation clocks. And so in order to make a better version of these clocks, what we really want to explain is why someone in their 40s might look 60, right? And why someone in their 60s might look 40. Why are some people living to 100 while other people are not? And so in order to do that, these second generation clocks started to be trained on biological phenotypes, things like blood based biomarkers, things like telomere length, things like time until death, for instance. And by training these methylation patterns with computer learning to predict those types of phenotypes, these clocks got much better. And the reason we know that they're better is because again, they're more predictive of outcomes. This makes a big difference. And then probably the best clock, at least at this point, is a third generation clock which is trained on biological phenotypes like HDL cholesterol, like gum health, like telomere length and bmi. But it's done it longitudinally on the same patients across their different aging. That's called the Dunedin PACE algorithm. It's one that we do uniquely here at True Diagnostic, which was developed at Duke in Columbia University. And that's probably the most predictive and has some really good associations, not just to death and disease, but also all these quality of life things that make life worth living, including things like facial aging.

So Is this the 50% predictive power? One?

Correct. It is excellent. It predicts everything from your grip strength to your mental processing speeds to your brain appearance on brain MRIs, and as I mentioned, even facial aging. I tell people it is. It's probably the most predictive algorithm. But if there's one algorithm you want to score really, really well on, it's that one. And that's the algorithm we've included into some of our public leaderboards. If anyone is ever Interested in competing to get the lowest age groups. We use that Dunedin Pace algorithm as sort of the gold standard.

Interesting. Do you feel? I mean, that's one thing I look at when I do stem cell therapy. And I always say, I tell people, I said, how you're looking on the outside can predict how you are on the inside. Because this, what's going on the face is a prediction of what's going on in your internal organs. So it's interesting that you guys are able to predict facial aging. How well do facial aging correlate with internal organ aging?

You know, it's not always perfect, certainly, especially because, you know, facial aging has a lot of things to do with like, things like sun exposure, which might happen on our tissues of our skin, but not necessarily, you know, on our internal organs, and sun exposure to huge issue. But with the Dunedin Pace, we do know that individuals who live in the same area get approximate levels of sun exposure, are all the same ethnicity. Definitively, the pace of aging is correlated to those facial appearances. And if you see these pictures, sometimes you can see just how drastic some of that is. We have pictures of our 45 year follow up for these patients. They're all age 45. And we separate them into three images. We separate what they look like as an average, average what the 10 slowest aging members of the cohort look like and the 10 fastest aging members. And the difference between the slowest and fasting aging members looks to be maybe 20 or 30 years of difference, even though they're the exact same chronological age. And I think it's always a really good metric to show people that you can keep doing things to help fix the symptoms of aging, like Botox, like hyaluronic acid, like retinol. All of those are good tools to help improve facial appearance. But you also want to fix the underlying cause of that in the first place, which is the actual aging process. And so it certainly correlates. And I always think that's a great example.

Yeah, that's awesome. So with the methylation. So I want to, let's say a patient comes to you or comes to me and asking, okay, I want to know how well I'm aging. And I'm offering. Well, this is a great test and can be very predictive. So how would you explain this, this test for some, you know, a layperson?

Yeah, the, the best way to do it is just again, put emphasis on the importance of aging. And I think that's the, the most important thing to communicate is that a lot of people think of Aging as this maybe something that's aesthetic, right? About how I look, or something vain in terms of, you know, a vanity type of thing. But it's really not. Aging is the biggest risk factor for all chronic disease and death, and not by a small margin. We're talking about five or six times more important than smoking status or ob. You know, things that we know are really, really bad for you. And so I think that once people understand that aging itself is a problem which predisposes us to all of these negative life experiences, hopefully they'll be motivated to do something about their biggest risk factor. And so, with that being said, if you want to test that biggest risk factor, this is definitively the best way to do it. These algorithms are very new. In the case of that Dunedin Pace algorithm, it only came out in 2021. So it's not even two years old yet.

Yet.

And with that being said, it's sort of a breakthrough in science in our ability to quantify a process which previously we've only been able to do with sort of our birth dates. And so the best thing to look here is that are you advanced aging or are you decelerated aging? If you're decelerated, that's going to be protective of every negative outcome. And so that's really where you want to be. But if you're not there yet, the answer is, how do we get there? And that's the great thing about these epigenetic platforms, is that we can actually change them. We can change their with everything that we do in our lives. Medication, diets, nutrition, exercise. And so it really puts the control back into your own hands to maybe try and do whatever you can to slow your own aging.

So by focusing on the DNA, you're saying that you believe the vast majority of aging is happening on the DNA level?

Yes. Well, I should say, you know, that's epigenetic dysregulation is one of the hallmarks of aging. But with that being said, there have been really big breakthroughs recently which make us think that we might be able to restore ourselves with just by changing these epigenetic expression. One of the best examples are using actually growth factors called Yamanaka factors. This won a Nobel Prize in 2012, because what it's able to do are these growth factors are actually able to take any cell within your body and make them back into pluripotent stem cells. You could take, for instance, a biopsy of your skin and take those skin cells and keratinocytes back to pluripotent Stem cells with this reprogramming. The interesting thing about this is that they've now started to use this as age reversal treatment. Because when you use these Yamanaka factors, you can actually reset those epigenetic clocks back to zero. This actually been done in an experiment with Harvard. They did this in eyes of mice who had lost their vision due to age related blindness. What they did is they injected this into their eyes, those cells. We went back to pluripotent stem cells, and the mice actually regained their vision whenever they had been previously blind. And so these breakthroughs are happening on a weekly basis now in the aging field, and it's one of the most well invested areas of scientific development. One of the companies that is most well known for this reprogramming related investigation was just funded by Jeff Bezos for over $3.2 billion as a startup, probably one of the biggest startups of all time, all focused on this idea of reprogramming and resetting these epigenetic clocks back to zero.

Okay, so how do you use these Yamanaka factors? Are you able to ingest it or inject it? What's the global effect?

Yeah, so at the moment, there's a lot of unanswered questions on how to best do this. The way that most people have been doing it now is by doing a little bit of gene therapy, where they're using viral vectors to insert and activate these Yamanaka factors into our own genes so that we express them and then those cells which we express them in revert back to those pluripotent stem cell states. The work hasn't been done in humans yet. It's only been done in laboratory animals. But the work looks extremely promising. Some people think that we've reached this thing called the longevity escape velocity, and that is where our aging, our ability to age is actually going to be going slower than our ability to rejuvenate our age. So that we might have people even alive today that might live to 200, 250 or even more be immortal because they can continue to reset their biology.

It certainly seems that we have come to that point, which is kind of scary. Yeah, there has been so many tools, including different types of stem cell therapy, I think definitely has given us a glimpse that it may be here already. Yeah, yeah. And then you can tell us with your test. Yeah. So, I mean, before the true diagnostic, I've tried a few DNA tests, you know, DNA, biological age testing. So. And there's a reason that you set up your company, right? You must have to look at. At what was going on in the biological age testing landscape. And what do you think where they were at and where were you able to do after you came on?

Yeah, that's definitely. I would say, my experience is that I was always paying attention to these epigenetic clocks. But in late 2019, something happened, which is that the first ever interventional trial on these clocks was published. And so this was called the TRMM trial, published by Greg Fay and Steve Horvath at ucla, where they use metformin, growth hormone, and DHEA in nine patients over the course of a year and a half. And when they did this, they showed that the epigenetic age of these patients was actually reversed. So they actually, on average, decreased their age by about a year and a half with that therapy.

Therapy was how long?

A year and a half.

Okay, so the therapy conducted was a year and a half, and the age was decreased by a year and a half. Have.

Correct. Correct. And that was, for me, whenever it became real, because no longer was this conjecture, but they had actually shown that they were able to reverse this. And so I think even the next day, I was in Dr. Steve Horvath's office. I just hopped on a flight and knocked on his door at UCLA and tried to learn more about the space. And when I went out there, I wasn't looking to be involved in the space. I really just wanted to. Wanted to see if someone could provide the testing for us for some clinical trials. But when I went out there, I saw that really, it wasn't commercially available, first and foremost. And the ones that were commercially available were unfortunately only measuring a really small amount of data. So they were only looking at approximately 353 locations on the genome, which might sound like a lot, but in the grand scheme of things, that's very, very small. We have over 29 million locations in each cell. And the traditional methods at that point were measuring 450,000 at a time to up to 850,000 at the time. And so I was confused on why other people weren't measuring more locations, because in my mind, the opportunity of these epigenetic methylation markers certainly was exciting for biological age, but its potential for other diagnostic ability, I think, was just being completely ignored. I was first considering this epigenetic age algorithms were really only things applied into the market. But now we have epigenetic algorithms that can do a multitude of things. We have epigenetic algorithms that can, as I mentioned, give you your immune cell subsets like flow cytometry would like a traditional lab value would we have algorithms that can predict, or I should say diagnose you with schizophrenia, which was only previously a medical diagnosis that you could do within a clinic. We have algorithms that can predict how much you've smoked across an entire lifetime, how much you're drinking in of alcohol behavior. We have algorithms that can predict when you're going to die very accurately and actually are already being used by life insurance companies to tell you how much your premium should be for life insurance. And so the ability for these epigenetic signals to tell us more about your health was really being completely ignored by any commercial company in this space. And I saw an opportunity there to maybe gather more data all together and then create new and better algorithms. And so that is what we've really tried to do here at True Diagnostic is using age and biological age as our main output, collect a lot of other information from our participants to give them better data. So even right now, we just finished a study that we've been working on for two and a half years with Harvard, where we can quantify physical function measurements like your VO2 max or your grip strength. We can give you your inflammatory markers like your C reactive protein, or your, for instance, even markers related to glucose like your HbA1c or your fasting insulin, or even just your glucose measurements. And so, you know, these are, all of this data is, can be found in just a simple finger stick blood test where we're just getting a couple drops of blood and being able to tell a lot about your life and your health status. And it's certainly my goal, hopefully to change this to where we can get so much information with one single drop of blood that it might be able to replace 60 to 70% of your traditional blood testing where we can maybe predict your risk of all disease, we can diagnose you with disease, and then we can even more than that, tell you the things that we found to best reverse or decrease those risk so that we're really doing, practicing preventive medicine.

That's really incredible that you were able to determine so many parameters. And I guess you guys have tested the accuracy. Let's just take a simple example, the hemoglobin A1C. So you're saying that your prediction is very similar to what they're going to get from a regular blood test, just from your DNA.

Yeah, exactly. So to be specific, with HbA1c, our predicted measurement versus the actual measured result is about 80% similar. Again, with just a small drop of blood, we can get so much information about an individual. And sometimes that can be scary. It can sound a little sci fi that we can predict all these different things. But at the same time, if you can consolidate so much information about your health into one simple, easy to produce diagnostic, we can start to track our health more frequently. We can start to see what lifestyle interventions are best for us. And it really issues in this new era of personalized medicine where we might find out that your response to these anti aging medications might be different than my response. And we can then, you know, have the best protocols and procedures to really find out what's working and then also just what's working best for you as an individual.

Yeah. And the fact that you can predict how many cigarettes a person have smoked or how, how much alcohol they've had, that just shows that, you know, everything you've done probably is not, doesn't go unpunished. Right. You don't, you know, it's going to leave an impact apparently on the DNA level level certainly.

And that's one thing to mention about the smoking predictors too, is that in terms of smoking, we can tell if you're a current, former or never smoker just by looking at one location on the blood. And if you've ever smoked, that methylation location will never get back to normal. And so some of these changes are irreversible, which can be a little bit scary as well. But there's so many things that are opening up in this analysis, you know, without, without getting too into the weeds. One of the things that I'm really excited about as well are these things like intergenerational exposures where we found that even the behaviors of our grandparents and great grandparents are actually manifested in our own epigenomes where we can actually see people who have markers of the, the sort of the Holocaust or the Rwandan genocide based on stress markers that are actually in their DNA. One of my favorite experiments was they've even, I would say, exposed mice to the SM of cherries and then every time they expose them to the smell of cherries, they would send an electric shock there. And even four generations later, whenever the mice were exposed to smell of cherries, they would still shake in fear. And so even things like our experiences of fear are actually ingrained epigenetically in our expression in our DNA. This is just completely new and sort of untraversed area of scientific analysis. Analysis. And, and so I, I'm really excited to see all the different applications that might come from it.

That's incredible. You could be transforming psychology oh, definitely.

And this brings up these whole ideas of nature versus nurture. You know, are. Are you programmed to be this person or is it a result of your environment? I think now we're starting to see it's more of both than we ever imagined. The interplay in your genetics and your environment.

Yeah, that's really incredible. I mean, the fact that you guys were able to predict schizophrenia. You may just have offered the first ever test for schizophrenia, because there's no. I mean, I was trained as a psychology, a psychiatrist. There was no way that we could do a test. Everything is by history. So that. That's pretty remarkable.

Yeah. And not to mention, even already, we can tell if you've had. You've ever had PTSD or if you currently have pts. And strangely enough, all of those things, ptsd, bipolar disorder, depression, all have massive impacts on your biological aging as well. Where. If you have schizophrenia or you're depressed, where you have ptsd, all of those are associated with faster biological aging. And so it brings up this whole idea of this mind body connection as well, and how even things like. I always tell people that some of my best recommendations for reversal of biological age is even stress root production, which I never was a big proponent of, but I, you know, I even. I was always one of those people doing mindfulness and, and saying, is this working? Am I doing it right? And. And never really appreciating it. But now that I can see the difference, you know, stress reduction has been one of my biggest tools to take down even my epigenetic age.

I see. Yeah. That's another thing I want to ask you about. You know, these predictive powers and these DNA changes and just how reversible are they and what have you found to be really helpful? So sounds like stress reduction can be a huge help.

Definitely, you know, surprisingly so, I think, in terms of me. But beyond that, there are a lot of other associations which unfortunately, are not too surprising. They sort of tell us what we already know, which is in a good, sometimes in a good way, it's good because it backs up. Backs up our assumptions, which means that we're on the right track and that all of that data we already know is validated. But at the same time, it can be, I would say, not the most surprising. And you're probably doing or no to do these things anyway. Things like getting the proper amount of sleep, things like being metabolically healthy and doing physical activity, all of these things have been shown to associate with better biological aging, including things like not drinking, not smoking. We know that, again, all of those are associated with better biological ages. But there are a few things that have been pretty surprising and that are pretty, I would say, unconventional in terms of our analysis. One of those things that we're about to publish on very shortly are senolytics. For those who might be listening, you don't know about this idea of senescence. These are these cells which pause. They're still alive, but they're not metabolically active. And they do this to prevent damage in the cell from proliferating a lot of the times. And whenever they sort of pause, they sort of sit there and secrete a lot of inflammation. Some people call them zombie cells, but they start this process of inflammation where they just sort of secrete inflammation. And. And it's been associated with a variety of negative diseases, including osteoarthritis, cardiovascular disease, lung fibrosis, a lot of neurodegenerative diseases. And so this is one of those hallmarks of aging. And so people have really recently started to implement strategies to clear these cells from the system. Some of those strategies, in terms of Pept, things like Foxo4DRI, or things like supplements like fisetin. But probably the most common one is a senolytic called dasatinib, which is a cancer drug that's been repurposed along with quercetin. We recently found in an analysis that dasatinib and quercetin, senolytic treatment, actually made biological age worse for almost every patient who took it. And it seemed to have a negative effect on decreasing telomere length and increasing biological age. Middle ages.

Quercetin.

Yeah, Dysatin is very popular. Yeah. And so we didn't measure quercetin by itself only with dasatinib, but we found that. And again, that. That. That was a product that people were prescribing frequently at the combining pharmacy. We had to treat these senescent cells, but it turns out that it might not be the best method. And so that was really surprising. Even fisetin as a standalone actually seemed to have some negative effects. And so that was really surprising. One of the other big studies that we're about to publish very soon with Stanford is a comparison of twins. One twin on a vegan diet, the other one on an omnivore diet. And so we looked at both. These twins were split into one group or another. Their meals were all provided for them, they were tracked, and all their calories were the same. And to be honest with you, we didn't expect to see much of a difference at all. All eight weeks is not a very long time for an intervention. But when we did the analysis, we started to see that the vegan diets in particular had much better aging outcomes than those omnivore diets, which was certainly a surprise to us. But it looks like the vegan diet has some anti aging benefits. Other studies have been done on diet types and has shown that Mediterranean diets are very, very good at anti aging and have really good data. And so we were surprised to see this, but these are some of the really non intuitive things I think that we were surprised to see.

Wow. Well, you, you probably just made a lot of people very happy about the vegan diet option. I mean the diet war seems like to be a real war. There's you know, very staunch proponents of each camp and definitely there's another camp, the carnivore camp. A lot of people are placing a lot of importance on protein, on how perfect the food, you know, the animal protein is as a food group. So you just flip that on their head, you know, with this, you know.

Yeah, well, I should say it's still very early and you know, myself, I, I am, you know, I, I love my protein and trying to get increased protein intake but, but you know, I think that this is definitely preliminary data which suggests the vegan diet might be pretty better. And I should also mention that this, this, some of this data analysis was funded to Stanford for a Netflix show. There was a follow up to Game Changers if anyone is, if you might be.

Yeah, I like to Game Changers quite a bit. But there's, there's, there are definitely people who don't, don't agree with a lot of it.

Yeah, exactly. And again it's still early. It was a limited trial that only went eight weeks. A lot of our studies group was also younger, I should say in various age groups, which in that itself is not bad. But as we start to get into things like frailty with aging, as we start to lose muscle mass, some things like protein intake might be more important. And so this is definitely just one limited trial, but one that was certainly surprising and noteworthy.

Yeah. So what are some of the applications that you've seen when it comes to using this biological age testing? So one thing definitely, you probably can scare some people into action, into taking better care of themselves. Themselves. But as far as different conditions that people are dealing with, what are some of the exciting things you've seen?

Yeah, so right now it's still almost exclusively used for age diagnostics and trying to manage and mitigate that process and Sometimes I think that, you know, we get very different results from person to person based on, I would say, you know, their own lifestyle factors or what's happening, happening in terms of interventions. And so people are really finding out what's working for them. And so we've seen massive age reductions. Probably the most public and notable example are people like Brian Johnson, who many people might know about, who had age reversals. His rate of aging was 1.01 biological years per year, which is not very good for his age when he started. And now I think we are about a year or over a year later, later. And he's reversed his biological age to 0.69 biological years per year. And so he's basically gained a third of a year every year in terms of his aging, which is certainly impressive. And he's done it through trial and error and finding out what works for him to reverse some of these markers. And so I think some of those are really good case studies, actually the best case study we've ever had in terms of absolute reversal. But some people have better averages still than in their individual paces of aging. And so people are really finding out what's working for them. But I think some of the other things that are on the horizon that I think are fascinating is there already have been published methods to predict response to certain drugs, like Metformin, for instance, to find out if you are likely to have an HBA1C response, and also if you're likely to have side effects. We can actually predict side effects before you actually even start a medication or find out if another diabetic medication might be better for you. And so those are some other case studies that have, I would say, been really exciting. And again, all with the same specimen and data, so, which is one drop of blood, we can do all of these analyses for you. And that continues to grow. One of the other things that we're about to unveil on our platform is actually an aging by organ system. So we can actually tell you what organ systems are aging most in your body. Is it your skin? Is it your liver? Is it your kidneys? Is your heart, your brain, your immune system, so that you can actually focus on treatments or health in that particular area. And so we're really excited to do that as well.

Are there general speeds that are most common for different organs?

So we don't really know yet. And we're about to see some of the data we're doing on organ system aging is coming out of Yale, and so we're hopefully have it on our platform very, very shortly. And I think we'll be doing sort of a meta analysis of everything in our cohort, but also what medications might be affecting aging of different organ system. So maybe you know, metformin, is it pro aging of the GI tract for instance, or you know, is it helpful on the musculoskeletal system as we know it might prohibit sometimes some of that performance related benefits you see. So. So I think we'll start to find out those associations and as we do again, we can get better treatment recommendations to patients and quantify every patient a little bit better in terms of their own risk.

So when is the organ specific data? It's going to come out in your test?

Yeah. It should be about eight weeks. Yeah. The one I'm most excited about right now is coming out in just, I would say two or three weeks. And that's a project working on with Harvard for a long time. It's called our omic age clock. And I think it's by far the most predictive clock to date.

What does that predict?

So it's just biological age. Again, it can also predict time until death, but it tends to be about three or four times more predictive of negative outcomes than any other clock. And so we've trained it with a lot of data.

You're replacing previous clock?

We are. It's the best clock to date and so we're going to be replacing it. We never take away data on our reports. We always want people to compare apples to apples. So we'll never take away data. We'll only add data analysis and then try and tell people that why we would really focus on this clock, this clock. Clocks before this have only been based off 21 biomarkers of aging in patients. We took over 5,000 proteins, we took over 75 clinical variables, we took over 3,000 metabolites, we did full genome sequencing, we did some transcriptomics, we quantified these patients from aging just about better than has ever been done. And so we're really excited to debut that it'll be released as a preprint just. And I would say two weeks probably.

Okay, so what does that mean? Okay, I remember you mentioned that true diagnostic, the true age test test over. Was it 900,000 methylation locations? Rather, comparing to some other tests that only test for a few thousand, right?

Yeah, correct. And how many are still testing the those? We're still testing those actually. Now we're doing a little bit right around a million with some of the different changes. But again that's Only a small fraction of the 29 million in every cell. We're still only doing 1 29th of all those possible locations. But. But with that data, it's still robust enough that we can create those predictive models. And the good news is that we're doing so much data analysis for you that we might come out with algorithms in five years that can. We can then go ahead and apply to your data that you might have taken two ago, and so we might even have Updates for you 7 years from now as we, I would say, increase our knowledge of the ways to read this data. Right now, this epigenetic language is. Is present in all of our cells, but we really don't know how to read it. And that's really what we're trying to do. I often tell people we're trying to create the Rosetta Stone for these methylation data. Right. You know, the Rosetta stone allowed us to, you know, understand Egyptian hierophant hieroglyphics in ways that we had never done, because it was sort of the key. And that's really what we're trying to do with methylation is it's this language that can tell us so much about our health. We just need to learn how to read it.

Okay, so with this new clock, you're still using the same 1 million locations, and then you're having a new interpretation, Correct?

Yeah. We trained our algorithm just to be more comprehensive. You know, one of the things about aging is it's so complex. It's probably the most complex phenotype we can have have. You know, when we first started our company, there were nine hallmarks of aging. Now they're, I think, scientifically accepted over 15 different hallmarks of aging. And so aging is just so complex. It happens in a variety of different ways, and it's different among people. And so the best way to. We thought, to quantify that process is to get as much data about every single individual with the most robust testing methods. And so that's really what we tried to do with this study, is to. To get just the most information from these participants and then look at what happened to them. Did they develop disease? Did they die early? And then reuse that information to train really predictive algorithms.

Okay. So potentially, you could come out with a different biological age using this new algorithm, but you're still running the old algorithm so that people can become compare.

Yeah, definitely. You always want to compare apples to apples, but we can go back and. And change all of it, too. And just to give you an idea, Just to give you an example, the first generation clocks like the Horvath clock I mentioned, that came out in 2013, if you were one standard deviation older in that clock, it would represent a 2% increased risk and mortality. Whereas this Dunedin pace clock that came out eight years later in 2021, one standard deviation in that clock would represent a 64% increase risk of mortality. And so in terms of terms of which one you're going to prioritize, you're going to prioritize the one that's more predictive of that negative risk. And the clock that we're coming out with now tends to be about three or four times even more predictive than the Dunedin pace in terms of mortality. And so again, we're getting much better at predicting these outcomes. And as a result, we think that we're quantifying those signals of aging a little bit better.

Wow. So as far as your test, can you explain to people a little bit what they're going to get when they get this test? Because there's intrinsic and extrinsic aging, maybe you can explain a little bit.

Yeah. So that is one of the things we're getting rid of with this new omic clock, extrinsic because it's really complicated and we always want to be scientifically accurate, but sometimes that, that, that comes at the expense of being really complicated. And so this new clock is a way to take that away. But you know, some of the outputs you'll get right now with our testing is your, your omic age or your overall biological age. So how old is your body with the most predictive clock? As I mentioned, soon we'll have ages for each of your organs as well. So you can tell if one of your organs is maybe pushing your aging forward or maybe some of your organs are, are really aging really well. And so that will be coming as well. We also do that pace of aging. So at this exact moment, how fast are you aging? That is much more responsive to change. So you can test at shorter intervals. We also do your telomere length, as we talked about earlier, and our version of telomere length is actually even better than traditional telomere length because it's got double the correlation to age, and it's more predictive of almost every outcome. In addition to that, we do your fitness reports. So how, how are you aging from a fitness perspective? And we Even predict your VO2, your Max, your grip strength, your walking speed. We tell you your inflammatory markers, which tend to be more predictive of brain outcomes. So Is your inflammation causing some negative outcomes to your brain? We tell you about, for instance, how much are you smoking or how much are you drinking to see those signals in your DNA. And we even quantify things like how likely are you to lose weight with caloric restriction. Some people will cut calories and lose a lot of weight. Other people will cut calories and lose almost no weight. And we can actually predict that outcome with this type of testing. So those are just a little bit, I would say, of the many things that we report out. And that list grows almost on a weekly basis.

Wow, that's fantastic. So when a patient wants to check out their biological age, how often should they check their age?

We don't recommend it too frequently. We recommend it maybe once or twice per year. I would say most of our physicians would usually test probably twice per year every six months.

Months.

To get a good idea of what's working and to maybe shift protocols or make changes. Doing it more frequently than that might be less precise. So we might see changes go in one direction that are not real or true biological age signals. And so we don't recommend doing too frequently with every algorithm. But, you know, the test is actually very easy to perform as well. We just need a few drops of blood, as I mentioned earlier, earlier. So traditionally that's done with blood spot card methods. So you just prick your finger with a small lancet, drop a few drops on. Of blood on a card, and then ship it back to us. And this is actually what it looks like, actually. This is a sample I was taking today with my blood. And so really easy to do. And you get results in about two to three weeks.

Wow. Okay. Amazing. All right, so any. Any last bits of wisdom that you've learned from helping with age reverse? One thing I realized is that things are rapidly changing. The satinib that, that you were talking about and quercetin, I think just back maybe six months ago, it was still recommended as something that can help reverse aging. And now we're looking at different kind of data. So things are rapidly shifting.

Yeah, definitely things are shifting. Now that we have these better tools. Tools, our understanding is changing. And so these things are certainly moving quickly. And I would say if there is one thing to sort of take away from this, I hope that people will really start thinking of age as something they can have an impact on, something they can prevent, and a process that, if they prevent or treat, can have improvements in their health span and their lifespan. And so I hope that that's one big takeaway. I hope the other Big takeaway is that epigenetic methylation as a platform, technology, Technology will impact every area of medicine. It'll be used in cancer diagnostics already. It's people might be familiar with the grail or gallery test. That's where they're looking at the same DNA methylation markers we're looking at, but they're looking at it for cell free DNA versus the ones that we find in blood. So if you're going to your doctor for cancer diagnosis or even cancer progression, or to detect diabetes or heart disease, these things are going to be done with methylation in the very near future. And so this is going to be a process that people should probably become aware of.

Yeah, amazing. Yeah. Cancer diagnosis, if you are able to predict from the methylation patterns, that would be incredible. And especially knowing that cancer cells have DNA changes, it should be very relevant test.

Yeah. And it's already out there on the market where you can detect cancer at stage zero before it can be found in any other method, just through taking some plasma and doing a methylation analysis. One of the great things about plasma is that it includes cell free DNA. And so the idea is that the DNA that's found in that cell free DNA is from cells that are lysing and oftentimes they lyse because of rapid proliferation. And so what happens is cancer cells start to develop, they start to break. And as they break, that DNA is found in your blood and that can be isolated and then also you can find out what tissue it's from to detect cancer really, really early, before any other method. And so that's one of the, probably the biggest, breakthroughs in DNA methylation technology. We're not doing a lot of it, but we are working with some other companies to make it available on our platform probably in the fall of this year.

Okay. And then I think, you know, before we end the session, I want to ask you some of the best known tricks for age reversal as far as you know that that's backed up by some of the data. So you mentioned the human growth hormone metformin DHEA combo. So anything else that you've seen that's pretty exciting because there's so many biohacking methods out there. Maybe some of the ones that you have looked at that actually have shown good results.

Yeah, definitely. There's a couple things I recommend for everyone. It is certainly things like caloric restriction, which is been widely proven. Also I'm a big fan of rapamycin as well. I think as we talked about, both those have a similar mechanism in that they inhibit mtor. And so I think those are certainly great in the case of some other supplements or nutritional things that almost always have a positive effect. Things like DHEA supplementation, as we sort of already talked about. Also vitamin D in multiple studies has shown improvements in biological aging. Again, I think if you're not doing caloric restriction, the Mediterranean diets or vegan diets, as we've already talked about, tend to have really good effects. Stress reduction, again, has a major impact. And I think those things almost work for everyone. If you're not doing those things, I certainly recommend doing it. Outside of that. The other things we already know, things like exercising regularly, but maybe not too much. Actually, we've also found that some of our professionals, athletes and Olympians, tend to have worse aging due to all of the stress they're putting their body under. And so maybe some, but not an excessive amount. And so I say those are the tried and true tricks for everyone. But we're starting to get into very specific recommendations and some things that are a little bit less intuitive. Some really interesting things on the pop, I would say on the horizon, as I've already mentioned, are things like the cellular reprogramming with those shamans factors. But also I would say young plasma, plasma from younger individuals tends to have some pretty beneficial effects with this testing as well.

Okay. Haven't looked into stem cells yet or you have?

We haven't. We've done two small studies of 10 people with STEM cells and in one trial we got excellent results. The other trial we got terrible results. So it seems to be that the type of stem cell matters. Currently we're doing some fun work actually with, with Dana Farber Cancer Institute with some stem cell work where we're taking stem cells and reprogramming them with valproic acid and then reinfusing them. And so there was some exciting work there, but still too early to say, I think on stem cells at the moment.

Yeah, wonderful. Amazing. Thank you for all the great tips. And where can people get this test?

The information that we can actually deliver through a physician is much more robust than what we can do in a direct to fashion. And in direct consumer fashion, we're really only allowed to report on aging because aging itself is not considered a disease yet. I think, I think it certainly will be in the future. So I always recommend going through a physician if you can. However, we do offer direct consumer testing on our website at trudiagnostic. It's not nearly as robust as some of the things we were talking about. But still includes a lot of those age related metrics. And so if anyone has any questions, they can always email me directly at Ryan and True Diagnostic. I'm happy to send them more information.

Fantastic. Thank you so much. Ryan. Thank you for enlightening us with all these new information in medicine and all the breakthrough that you are involved in. So thank you for your contribution.

Thanks. I appreciate you having me again.

Yeah. It's always fabulous conversation with you and love having you as a guest. So thank you again.