The TruAge Test of Biological Aging with Ryan Smith: Rational Wellness Podcast 376

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Ryan Smith of TruDiagnostic discusses the Tru-Age Test of Biological Aging with Dr. Ben Weitz.

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Podcast Highlights

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Ryan Smith is the CEO of TruDiagnostic, who offer the TruAge test, which is the best commercially available way to measure biological aging by measuring DNA methylation.  Their website is TruDiagnostic.com.

Dr. Ben Weitz is available for Functional Nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure.  Dr. Weitz has also successfully helped many patients with managing their weight and improving their athletic performance, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111.

 

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Podcast Transcript

Dr. Weitz: Hey, this is Dr. Ben Weitz, host of the Rational Wellness Podcast. I talk to the leading health and nutrition experts and researchers in the field to bring you the latest in cutting edge health information. Subscribe to the Rational Wellness Podcast for weekly updates, and to learn more, check out my website, drweitz.com. Thanks for joining me, and let’s jump into the podcast.

Hello, Rational Wellness Podcasters! I’m very excited today to be discussing biological aging, which is one of the topics I’m very passionate about. We need to, it’s helpful to have ways to gauge our biological age as compared to our chronological age so we can find out how we’re doing in our longevity quest.  Are we on the right path? Are we aging slower? biologically than we are chronologically, which of course is the goal. And one probably the best way to do that is with methylation, biological aging tests, looking at DNA methylation, And the best commercially available way to do this is through True Diagnostics who offer the True Age Test.

And today we have Ryan Smith, the CEO of True Diagnostics to discuss biological aging and the newest variations of their tests that’s available that can help us not only to understand how good a job we’re doing with our biological aging, but perhaps with the newest version, giving us some way to figure out what sorts of diet, lifestyle, supplement, other recommendations we can make, particularly to help us improve that biological aging.  So [00:02:00] Ryan, thank you so much for joining us.

Ryan Smith:  Yeah, thanks so much for having me. I know it’s been a while since we talked about the topic and a lot’s happened.

Dr. Weitz:  Absolutely. So let’s start from the beginning. How did you start True Diagnostics and, how did you get involved in the field of DNA methylation, biological aging?

Ryan Smith: It’s a long and convoluted path. Biochemist as an undergrad, becoming a med school dropout, after finishing all the actual educational material, I got to the clinical portion of my third year and really hated it and decided to do something different.  Ended up creating a compounding pharmacy that was dealing in this sort of cash pay, preventative, integrative wellness space. And prior to that I had no idea that this existed, but I loved that there was a community focusing on preventative medicine in a true way.  It’s certainly something always easier to prevent than to treat.  And and so got really excited about that. Our pharmacy grew really rapidly. We were the fourth fastest growing company in healthcare. And then, but we always knew that we wanted to to test a lot of our products to see how they were actually to see how they were actually affecting health span and lifespan.  And that brought up this idea of these biological age clocks as surrogates to see if they were effective tools to measure this process.  I got really excited about that and I got excited about the potential applications of this biomarker, DNA methylation even beyond aging. So we basically sold that company in 2020 to start TruDiagnostic.  And now we have our four year anniversary this week and as a result we have built the largest DNA methylation database in the world and have created a lot of new algorithms to be able to read the information we find in your epigenetics. 

Dr. Weitz:  Right.  Perhaps explain what is DNA methylation and why is it a better marker for biological aging compared to other biomarkers?  I guess some people use GRIP tests. We have VO2 max. In the past, it was a telomere length test, which I guess is still available.

Ryan Smith: Yeah, definitely. The so yeah, DNA methylation generally is what we call an epigenetic modification. So these are modifications above the genome which control your gene expression.  So how much is a gene turned on and turned off? And the reason that we need this is because obviously all of our cells in our body have the same DNA, right? Our heart or our skin, our brain, the same exact DNA sequence, but they behave very differently, right? You want your heart cells to behave like heart cells and your skin cells to behave like skin cells.  And to do that, they have to express different genes. So as your cells are going for. polypotent stem cells, which can do anything to the cell type that they’re meant to be, they’re doing it by turning on and turning off genes. And one of the mechanisms for that is DNA methylation. And DNA methylation really is the off switch that we sort of think about for some genes.

And so, DNA methylation in and of itself is not good or bad. Some, there are some genes we want turned off. There’s some genes we want turned on and different I would say abilities for each cell. And so that’s really what we’re measuring though, is from whole blood at True Diagnostic, what we’re looking at is all of those patterns of gene regulation, what’s turned on, what’s turned off, and we’re interpreting that for an outcome.  And DNA methylation is probably the most frequently used biological aging tool mainly because it’s the most predictive. I think you mentioned some really great tools like VO2 max and grip strength, physiological standards that we know deteriorate with age. But generally, they’re not as predictive as some of these other clocks.  And that’s really how we judge if a clock is effective. Can it be very predictive of outcomes? So if we’re seeing, for instance, 10 year age accelerations, does that mean there were worse risks for everything in the future? Or if we’re seeing 10 years deceleration, are we seeing that risk decrease?  And that’s really what these clocks specialize in, is they’re incredibly predictive of outcomes. And so, and, they’re very precise now. So we can, measure the same sample and get the same result. And then now they also change with therapy and that’s really what we’re documenting as well.  So we can actually show that these are responding to the things we already know improve biological age. So for all those reasons, they’ve become I would say a leading method in biological age quantification, mainly because they’re highly predictive.

Dr. Weitz:  Can you explain the history of biological methylation clocks?  I understand we’ve had the first generation clocks like the Horvath and the Hannum clock and then the second generation clocks like Grimm age and Pheno age and now we’re into the third generation. So can you explain a little bit about what this evolution in Methylation Clocks is about?

Ryan Smith: Yeah, definitely. Then, at the end of the day, it comes back to one question, which is pretty hard to define, which is what is aging, right? There are a lot of definitions for it where other people say, is it a disease or is it not? In these biological age clocks, we first wanted to

Dr. Weitz: Officially right now, it’s not considered a disease.  Yeah. Yeah correct. So there are people pushing for that so that perhaps there’ll be insurance coverage or something for somebody diagnosed or wanting to utilize therapies to promote longevity.

Ryan Smith: Yeah, definitely. And so we can have drugs approved to treat aging as a primary cause. We can’t do it right now because it doesn’t exist in the regulatory framework.  And the World Health Organization does have an ICD 11 extension code for aging to say a disease is caused by aging, but we can’t actually say that. Aging itself is a disease. And so there’s a lot of of controversy in this definition because there’s so many things that happen as we age. There’s sort of, multiple hallmarks of aging that change across our body.  But also, the things that we would even just see while looking at a person, right? They’re, the wrinkles, the gray hair, all these different things. And so aging is sort of hard to define, but in order to create a surrogate or to measure or predict the process, we really have to start with some definition.  And those definitions started in 2013 with Dr. Steve Horvath at UCLA, where he was creating just predictors of chronological age. That’s what we call those first generation clocks. So can we, by taking the methylation patterns of a blood sample, predict how old your chronological age is? And at [00:08:00] first, that wasn’t used for health.  It was used for, forensics, to date how old someone was, if they left their DNA at a crime scene, or to date refugees, to see if they were adults or minors, and therefore eligible for asylum. But then they started to notice a really big pattern, which is that those people who with this testing were younger than their chronological age, were protected from health, negative health outcomes.  And vice versa, those people who were older with this testing were at more increased risk for negative health outcomes. And so even though it was meant to be a chronological age predictor, it was sort of measuring some biological function that was predictive of outcomes. And that’s why it was so exciting.

It’s for the first time, We might’ve been able to measure the aging process molecularly that could then, tell us about outcomes. And the reason that this is important is aging is the biggest risk factor for every chronic disease and death. If you can think of a disease, aging is the biggest risk and not by a small margin.  We’re talking about 90 percent of the risk of Alzheimer’s is related to age.  Right. You can, and even things like, smoking and obesity, which we know are bad for us, pale in comparison to the relative risk that age is for most of these diseases. So age, we know this dysfunction, which happens with age, no matter how you define it is incredibly important to our health.

And so, whenever they started to see this molecular signature in 2013, it got people really excited. But ultimately it’s a little bit flawed, that definition, because we really don’t care about your chronological age, right? We know people in their eighties, who look 50 and we know people in their fifties who look 80.  That’s sort of the process we want to measure, right? We want to be able to predict what negative outcomes are going to happen. So you can maintain the most optimal function. And so the second generation clocks, instead of being trained to predict the chronological age of an individual, we’re trained to predict biological features.  So things like blood based biomarkers or in the case of probably grim age, one of the most popular algorithms it was trained to predict time until death. And time until death is a good surrogate for longevity because it’s a clearly defined outcome and, but it doesn’t take into a lot of other things.

Dr. Weitz: By the way, just stop for one second. Explain [00:10:00] what you mean when it was trained to predict time to death. We’re talking about using artificial intelligence. Is that how we’re training it? What do we mean by training it?

Ryan Smith: Yeah. So all of these algorithms have to be trained. And so generally what we’re doing is we’re taking methylation data and we’re telling an artificial intelligence system to take in this information and create a tool that can predict X that could be chronological age.  It could be how much you’ve smoked across an entire lifetime. It could be, do you have COPD or not have COPD? It could be, a wide majority. of things, but we’re training using artificial intelligence to read these patterns to predict an output. And and so that, that output again, originally was chronological age, but the, in second generation clocks, it became biological function.

So whenever these things are trained to bring time until death, what they’re really doing is looking at a group of samples that have been taken over the last 40 years and where we know where that person has passed away and then seeing if it can [00:11:00] predict. how long until a sample passes away. And and even our newest clock, Omic age that we just developed with Harvard is about 92 percent accurate within a 10 year time period of predicting death.  So we can predict death within a 10 year time period with really good accuracy, even over 75 percent within a four year time period. And so, we can get quite accurate at predicting that as an outcome.  There’s been a lot of criticism of methylation clocks that they don’t really help us predict it very accurately.

Dr. Weitz: They don’t really add much to it. There’s been a number of articles criticizing it. And you hear some of the prominent people in the health world saying there’s really no benefit. But But I think as these clocks are developing, they’re overcoming, I think, a lot of these initial criticisms.

Ryan Smith: Oh, exactly.  And I think that we do not shy away from the criticisms. I think that they’re valid. And in fact, I think [00:12:00] that we like to point them out because some of the, knowledge that we’ve gained from those clocks are no longer relevant and we need to sort of advance. And so, there, there are quite a few issues that have happened with the clocks previously.  The most I would say the biggest issue has been precision of these clocks, as I think you mentioned. If you take the same sample and then retake that same sample and perform an analysis, how close are those results? And even with the Horvath clock originally, it had a mean absolute error of right around 3.

9 years which is. Not helpful a lot of times, right? Because if you’re doing within a period of four years are you sure that’s technical measurement change or just because of your biological change? And ultimately we, we don’t want something that changes with the wind. We want something that is really good at predicting outcomes based on your own independent biology.

And so, so that’s been one issue that’s certainly been fixed. One other big issue is. do they respond to interventions we already know are beneficial for aging? So for instance caloric restriction is probably the most well validated therapy across animals and humans [00:13:00] to improve health span and lifespan.

But whenever we do this analysis with the epigenetic clocks, we see those first generation clocks we talked about, trained at chronological age, actually go up, which doesn’t make a lot of sense, right? And so these newer generation clocks do respond to what we would expect, But some of that first generation clock, again, is giving us bad data.

And it’s not just caloric restriction. It’s also things like senolytics, like disatinib and quercetin go up with first generation, but go down with the newer clocks. And so, that’s also been an issue. And again, you don’t want to put a tool in someone’s hands that gives you the wrong data. Otherwise you’re acting against your own self interest.

So those should have certainly been there. And then probably the last of those big issues is this idea of what do you do about it? And that’s ultimately. Yeah, the important part, right? Yeah.

Yeah. I’ve run the test a few times in the past and that was one of the big questions is, okay, so I see this rate of aging, it’s either good or bad.  And then, there’s no in, from the initial part, it’s a version of the test is really, was no way to say, [00:14:00] okay, here are some of the things you need to focus on to improve that biological aging in this particular person.

Ryan Smith: Exactly. And, that the question is, if we’re going to recommend caloric restriction to everyone, regardless of how they score, do we even need to test in the first place?  Right. It might make people more motivated, right. If you have a bad score, they might say, Hey, I need to really do these, it’s a, to have a lot of effort into this, but ultimately that’s been a huge limitation in the past as well is, you and I might be aging much differently, right.  We might have someone who smokes who has, their lungs are aging, their cardiovascular system is at risk, whereas we have someone else who maybe is a little bit overweight, doesn’t exercise, they might have more musculoskeletal aging or metabolic aging, and so this is different in every single person, and being able to identify the why we might be accelerated in aging or decelerated in aging is important because then it helps us to Set A Proper Protocol To Improve Our Health.

And previous to really I would say September of last year we didn’t have any tools which could provide that resolution. Now [00:15:00] with some of the newer clocks particularly the Omic H clock I referenced earlier as that death predictor that we developed with Harvard and then now the Symfony AH clock that we developed with Yale, those are able to provide some actual individual resolution to then tell you maybe what would be the best recommendations for treatment time.

Dr. Weitz: You mentioned senolytics and that’s one of the 12 hallmarks of aging. How well does your test correlate with those 12 hallmarks of aging?

Ryan Smith: Some of those hallmarks are hard to define as well, right? We might, some of those, for instance, like nutrient dysregulation, sensing dysregulation, or proteomic dysregulation.  Those are hard to define. And and even to have that data in match cohorts can be difficult. If we look at some of the ones that are easier, like telomere attrition, for instance, or senescence burden it can be a little bit easier. And so for instance, we see that really, although telomere length is extensively validated it’s got, over 20,000 studies on being a feature of aging, it’s really not that predictive.

It, it really only explains in a study in [00:16:00] Generation Scholarland, 2. 8 percent of the variance in aging whereas those methylation clocks are now over 60%. So as we’re comparing them, there’s some biomarkers that we would prioritize to be more important, and that would be certainly the methylation clocks over things like telomeres.

In the case of senescence is a wormhole to go down into because we’re about to publish this article with Yale that, that actually shows that even Senolytics. don’t actually change the epigenetic methylation signature of cells after they’ve received similitics.  And we’ve tried to create some surrogate predictors of that process. 

Dr. Weitz: What is, what does that mean?

Ryan Smith:  Yeah, we don’t know. But but generally we don’t think we can act with DNA methylation alone adequately capture I would say senescence signature is very well, at least at the moment.  That doesn’t mean that senescence is not impacting the methylation clocks or correlated with those clocks. They certainly are. That’s why we saw this additive inquisitin improve the epigenetic clocks, but it’s probably through a different mechanism, such as reducing the inflammation that’s oftentimes associated with senescence.  So DNA methylation I think it’s still good at predicting [00:17:00] outcomes of aging, maybe not directly good at predicting those individual features like senescence, for instance.

Dr. Weitz: Or, maybe those hallmarks of aging aren’t maybe the exact right hallmarks of aging.

Ryan Smith: Yeah, that that’s one thing too, and and with all of these things, one of the big issues is we don’t know what’s causative or correlative, right?  So we can pick up these signals that are associated with aging, but we don’t know which of those signals are causing, dysregulation versus a result of it. And so that’s something else that will be elucidated in these further years to make these clocks even more accurate and more usable.

Dr. Weitz: So now tell us about the Omic age clock that you’re using now.

Ryan Smith: Yeah. So we really have, I would say three clocks in our testing that we think are the best clocks to use. That would be the Omic age clock. As I mentioned, that one is one we developed with Harvard. And we did this with the idea that the clocks get better when you feed them more biological data.  So we’ve started with, Morgan Levine’s, first second generation clock used nine blood [00:18:00] based biomarkers. And now as the clocks have started to improve the idea is that the more information you can feed this model, the more it can pick out what’s relevant. And whenever we first started, there were nine hallmarks of aging.  Now there’s probably 15 to 19, depending on who you ask. And so one of the things we wanted to do with this cohort was measure everything. So we did, we measured in about 5,000 patients. We measured full genome. We measured the epigenomics. We did some RNA and transcriptomics. We measured, over 25, 000 proteins.

We measured over 7, 000 metabolites. And then we had all of their clinical data as well. And we put all of this together in one big model to predict time until death. And so that’s what the Ohmic Age Clock is. It’s probably the clock that’s been trained on the most biological data. And and trained to predict death as an outcome.

And it’s quite good at that. It is up there with grim age as being the most predictive clocks of mortality. So if you’re really interested in mortality, specifically in living longer, this is a great clock for you. But we include some features in it, which are able even to predict your blood based biomarkers.  So we can tell you about your C reactive [00:19:00] protein or, your HbA1c or your fasting glucose, which can give us more of that resolution on what to do about it. 

Dr. Weitz: So we see that you’re talking about predicting the C reactive protein without directly measuring the C reactive protein.

Ryan Smith: Exactly. Yeah. We call those epigenetic biomarker proxies.  And in the case of C reactive protein, our predictor is actually even just a better biomarker than C reactive protein across the board. We have better hazard ratios to every disease and more significance which means

Dr. Weitz: Really? This is fascinating. So what are you seeing is you took patients, measured their C reactive protein, measured and looked at their and then found specific patterns of methylation that correlated with those biomarkers.  

Ryan Smith: Absolutely happens. Okay. Yeah, definitely. And and so this is sort of how I, for anyone who’s not watching and it is listening, you can refer to the YouTube for some of these images I’ll show really quickly, but yeah, we measured all of [00:20:00] these proteins metabolites and clinical values.

And we said, Hey, can we predict these with DNA methylation? And in the case of CRP, we certainly see this. This is data from a lithiathin birth cohort where we don’t see a trend of aging with regular CRP, but we do see a trend with aging with our DNA methylation predictor of CRP. In addition to that, we see that our predictor is more precise, meaning it’s more repeatable.

In measurements, we see associations with cognitive function we don’t see with regular CRP. We see here is brain MRIs, where we look at DNA methylation CRP versus regular CRP, and we see that our DNA methylation version is 6. 4 times more predictive of brain outcomes than regular CRP. And here you can see that sort of the effect size and significance is higher in all of these different outcomes of CRP, BMI, cardiovascular disease, diabetes, all better than even regular CRP.

So we see that and we can actually see what genes are affected in this process. So the high highest weighted gene in our algorithm comes from the SOC three gene, which is a suppressor of cytokine signaling which makes sense, right? A [00:21:00] as this gene is affected, our levels of cytokines and inflammation, it’s gonna be affected.

And so with DNA methylation, we can actually predict these other biomarkers, all with just a simple finger stick blood measurement. And we incorporate those into our models. They can tell us why we’re aging faster or why we’re aging shorter.

Dr. Weitz: Fascinating. So if I was working with a patient who has signs of cognitive dysfunction, how could I use your test and then make changes to that patient’s diet, lifestyle, et cetera, and then use that test again to see if we’re, Improving that brain function.

Ryan Smith: Yeah. I think that’s an important thing to mention is that if you have a patient who already has a disease, we know that aging is going to accelerate that disease process, but sometimes it’s not the most important thing, right? If we have someone who’s diagnosed with diabetes, we’re generally going to say, Hey, fix your HbA1c in your fasting glucose, don’t fix your aging.  Right. So a lot of times, once we [00:22:00] get to disease, this is a secondary consideration manage the disease, but for people who are looking to prevent. disease. So let’s just say someone has Alzheimer’s or a history of neurodegenerative disease in their family. We know that 90 percent of Alzheimer’s risk is age.  So this is absolutely something someone should focus on. 

Dr. Weitz: Yeah, let’s say they have one or two copies of the APOE4 gene.

Ryan Smith: Yeah, exactly. And so the idea would be that the lower that you can get your biological age, the lower your risk of developing early onset Alzheimer’s or any type of dementia. And we know that from multiple association studies.  These DNA methylation clocks, there’s now been over 2000 studies published on these DNA methylation clocks and outcomes. And generally you can find ’em connected to all outcomes. And so the idea would be that we’ll test, see where you’re at, and then make recommendations on how to improve that.

So for instance, let’s just say that you see someone come in, we give them a omic age, we tell ’em that their age is two years older than their chronological age. So they might be. 47 biologically while being 45 chronologically. They’re accelerated aging and we [00:23:00] would want to fix that. So we might recommend things to try and get that down.

Some of those things are pretty intuitive and the things that we know already work for optimal health, right? Exercise, proper diet, nutrition, reducing stress, getting the right amount of sleep, right? Those things are not. Terribly innovative, but they also work, right? And when they work, we see it reflected in reduced ages.

And then so we have that, but we can also make even, I would say, more exotic recommendations based on some of the studies we’re doing. Where hyperbaric oxygen will work, or young plasma would work, or senolytics would work, for instance and starting to make some of those recommendations as well.  So, first you get a baseline, then we will try and implement protocols to reverse that process. And then hopefully as we measure it, we see you continue to reduce that gap and become younger versus your chronological age.

Dr. Weitz: Now, what about personal, personalized recommendations? So with all these things we have some guidelines, but there’s a lot of controversy.  Which is the best diet for each person? Maybe one person’s going to optimize their [00:24:00] biological aging with a vegetarian diet, and the next person’s going to optimize it with any Mediterranean diet. And maybe, is there a way that we can use this testing to say, okay, for you, the vegetarian diet’s helping you to age better?

Ryan Smith:   So, yeah so absolutely. And that’s where these newer algorithms come in. Those epigenetic biomarker proxies from omic age, for instance. So for instance, we might see someone who has really low carotenoid levels, right? Beta carotene levels. We know that beta carotene is associated with better aging across the board.  All of these epigenetic clocks. And even just in regular meta analysis studies, we can say, Hey, someone has really low beta carotene. We need to encourage their consumption of beta carotene. Leafy green vegetables and carrots, right? To increase that metabolite, which we know is going to be, reducing their biological age, reducing inflammatory markers.

So we can absolutely make some specific recommendations like that. Some that are directly related to supplements, right? So, we have, even a metabolite called uridine, which can be supplemented and sold at places like Life [00:25:00] Extension to improve those markers. And so we can certainly make those individual recommendations based on Where you’re elevated and we know that elevation should be low, right?

So if we see your HgA1C is high, or your fasting glucose is high, we know that’s not good for aging. We want to get that lower. We’ll make specific recommendations for you. The other report that we just launched last week was Symphony Age. Symphony age is one we developed with Yale. And although we don’t report on individual biomarkers like hba one C or CRP, we report on aging of different organ systems.

And that’s so that we can actually, again, make more precise recommendations to say that your overall aging might look great, but. Your brain is aging really quickly. We want to try and improve that. So let’s pay attention to the tried and true methods we know to improve brain aging. And so one of the next publications we’ll come out with that same group from Yale, and because I keep mentioning them so much, I want to give them a direct shout out, which is Albert Higgins Chan and I would say his lab, which he took over from Morgan Levine.

Many people might know Morgan Levine. As a famous aging researcher, she’s amazing as well. They’ve created a great culture in that lab and are doing some amazing research. But one of the research [00:26:00] things I also wanted to give a shout out to a PhD student, Raghav Sehgal, as well. He is also doing some work here, but we’re about to publish a paper on 50 plus longitudinal interventional trials with all of the clocks analyzed.

And we’re really excited to do it because it’s a toolkit for both patients as well as physicians on how to best improve these clocks. And so we have some really exciting data coming out there. I’ll just give you a brief picture to show you some of this analysis. But here you can see some of the different analysis that we’re doing, everything from rapamycin to, vegan or healthy vegetarian guidelines.  And we can show what clocks respond and in what direction to give you a cheat sheet. But the one thing we find out is the three best clocks. 

Dr. Weitz: And of course, I see you, you got Ozembic in there. You got semiglutide….

Ryan Smith: Yeah, definitely. And some of these come with caveats. We’re about to publish a huge semiagglutide study as well.   But but yeah the idea being is that we’ll be able to, use the same measuring sticks across trials to then tell you what is the biggest [00:27:00] potential to change your biological age in a positive way versus a negative way. And we’re really excited about that. That’s very cool.

Dr. Weitz: So, the symphony age is now available as part of your program, right?

Ryan Smith: It is, and it is. And so you’ll get with our testing now, a big report. I can just even show you really quickly what that would look like as I sort of talk to you. I know, again, most people are going to be listening so we don’t have to spend a ton of time on it. But we can give you for instance, Your omic age, that’ll tell you your age versus the population.  We’ll track those changes over time. We can even then tell you how your aging is affecting your disease risk. So are accelerated aging leading to increased disease risk of each of these outcomes? We can then tell you what to do about it. So where are you out of range and what would we want to correct?

And then what are those things that most typically correct these different biomarkers? We also give that symphony age again with the age of each organ system and track that longitudinally as well. We give the rate of aging. This is the last of those aging algorithms that I mentioned. It’s the only third generation clock trained [00:28:00] longitudinally over time.

And it’s by far the most responsive to change. So in all of the, those 50 different interventional trials, it was the one that changed the most in measuring Effective change. So we’ll do that. We’ll do your immune cell subset percentages. We’ll do, your telomere length. We’ll tell you how much you’ve smoked and drank across lifetime as well as a few other different reports.  So you get quite a bit of information. Aging is certainly what most people are using this for now, but in the future we see this actually morphing to a diagnostic that can help with all areas of health. Interesting.

Dr. Weitz: What are, so from the interventions that have been done so far you mentioned caloric restriction.  What other things do we know that seem to impact biological aging?

Ryan Smith: Yeah, I would say again a lot of the data that’s out there tells us what we already know, which is not a bad thing. I think that people might say, hey, I see that, Mediterranean diets are super helpful for aging.  That doesn’t, that’s not a huge surprise to most people, right? But the fact that we’re seeing consistency with these measurements to what we already know is actually a [00:29:00] good thing because it shows that we’re on the right track. And so a lot of the things that we know are, Avoiding bad behaviors, right?  Off the bat. And most of you know what those bad behaviors are, right? They’re going to be the smoking and drinking, the processed foods, the lack of exercise, the lack of social connection and relationships, even workplace stress. Even people who work over 40 hours a week are on average 1.5 years older with some of these algorithms than those who are not. So service off stop bad behaviors. And then replace them obviously with good behaviors, getting the right amount of sleep, right? Making sure that. You’re not eating a lot of processed foods or fatty foods.

Making sure that you’re doing all the right things from a diet and nutrition perspective. When we get into the more exotic things, like the protocols, the procedures, the medications the supplements we start to see some different things that are a little bit more exciting. For instance, we’re seeing you know, good improvements with things like hyperbaric oxygen which again is probably not a surprise to a lot of people, but good to be replicated.

We’re seeing the satinib and quercetin again, similitics actually improve the biological aging over time. We’re seeing I, I would say [00:30:00] though, that the thing that jumps out to me time and time again is probably the most reliable therapy are things that inhibit mTOR. So things like caloric restriction, mTOR, this mammalian target of rapamycin is a sort of a master regulator of some of the processes in our cell.

And things that inhibit it generally have better outcomes. And so, Wrapamycin is another example of that. It specifically inhibits this enzyme and has been shown to increase lifespan in dogs by 33 percent in animal trials. recently in a rhesus monkey trial, 15%. And so I would say that, methionine restriction, caloric restriction, rapamycin derivatives, those are all play a big impact in, or one of, I think the most effective solutions we have now.

Dr. Weitz: Now you mentioned mTOR and mTOR has to do with growth and there’s kind of been two trends in longevity, Therapeutics. And one is an older trend and one is a newer trend. And the older trend was to focus on making sure that we [00:31:00] continue to regenerate our tissues. Because we know as we get older that things break down.  The cells break down, things don’t work as well, you lose muscle, you lose bone, we have sarcopenia, osteopenia etc. Brain doesn’t function as well. So We want to use things that stimulate growth and regeneration and we saw a lot of clinics using growth hormone and other hormones, testosterone other therapies that promote regeneration because as you get older, you fall you break a hip, etc.  And that’s a major cause of mortality. And in the last 10, 15 years. We’ve seen more of a trend of people talking about reducing mTOR. Let’s not have too much growth. Let’s make sure we in fact people have pointed to [00:32:00] there’s certain populations like the Laron dwarfs in Ecuador that don’t produce growth hormone.  So having less growth hormone is good. And so we have these two opposite trends, promote growth, regeneration, not lose our strength, not lose our bones, not lose our, or no, we have to reduce growth because growth is associated with cancer and we need to use things that suppress it.  And I’m sure at some point we’ll find out there’s a balance, what’s your sense of those two trends right now?

Ryan Smith: Yeah, I think there certainly is a balance, but I would say that time and time again, I think that we are more on the stop the proliferation than to encourage it. So more of the mTOR inhibition versus the growth pathways, IGF 1 and now in multiple studies, the higher the levels, generally the shorter the lifespan of the first ever animal veterinary pathway for drug approval for longevity is actually an IGF 1 blocker.  In canines. And so [00:33:00] I think that the more the data is coming I think that trying to limit proliferation or growth is generally where the data is pointing. Whereas and so things like rapamycin and mTOR inhibitors are a good way to do that. 

Dr. Weitz: On, on the other hand, the first study that showed reversal of biological aging, the Fahy trial used growth hormone and DHEA as two of its major interventions.

Ryan Smith: Yeah, but it was only in nine patients, all men and and, generally, one of the big problems with that is we know the growth hormone actually does have an effect at regenerating the thymus that immune organ that, that’s 

Dr. Weitz: Which that’s a major factor with aging.  That’s why so many older people die from severe infections is because they have Thymic involution, shrinking of the thymus gland, your immune system gets weaker.

Ryan Smith: Yeah, definitely. And, I think that metformin even if you looked at some of that interventional data, we were talking about in that trial with Yale it looks [00:34:00] good at reversing it.  So it’s hard to say which one is the main leader there, but with nine patients, it’s probably too small of a sample size to even to, to speculate. But with that being said, I think that yeah, I would go probably the mTOR inhibition over AMP kinase and some of those other activation pathways, but but I,

Dr. Weitz: it’s interesting, even some of the top researchers have said, well, yes, reduce IGF1 until you hit age 65, then it’s okay to promote more IGF1.  And this also relates to our recommendations for diet. So for example, Cool. Protein has been associated with promoting, potentially promoting, I don’t know if it’s necessarily as correlated as some people claim, but that it promotes IGF 1. And so therefore you want to have a lower protein intake, more of a vegetarian diet until you hit 65.  Then you want to have more protein because you don’t want the person to fall and break their hip and then they go [00:35:00] downhill from there.

Ryan Smith: Exactly. Frailty is one of the best surrogates we have from an FDA or governmental perspective for aging. And we know that is absolutely impacted by some things like IGF 1.

Dr. Weitz: And it’s also one of the reasons why weight training is so beneficial for aging. Because, that loss of muscle. There are people in nursing homes that can’t get out of bed simply because they’re too weak.

Ryan Smith: Exactly. Yeah. And so there are certainly, I think that’s why instead of looking for individual biomarkers, we really have to look at effective tools, right?  Tools that predict outcomes effectively. And that’s I think what we’re hoping to develop. Otherwise, you can get lost a little bit in every single biomarker that is associated with aging. That’s again, why these hallmarks of aging keep expanding. But we still are, I would say, still, So far away from having an FDA approved drug to treat that process.  And I, by the way, before we get away from this topic, the hyper function theory of aging by Mikkel Blagoslony is one that incorporates both models. I think. Oh, really? Tell me about that. Yeah, this idea that we’re optimized as evolutionarily [00:36:00] for reproduction.

But we never really turn off those developmental pathways. So we keep proliferating, we keep, sort of, growing, but the idea is that with mTOR inhibitors, you can stop or slow that process. And by slowing that process, we will lose function at a much later date. And that’s, so there’s a lot of good data to suggest this.

So for instance, rapamycin, Started earlier in life, generally has better effects than started late in life. So we’re preventing some of that degradation and signal loss versus I would say, trying to treat it once it’s already happened like we would lytics, for instance.

And so I’m a big fan of the hyper function theory of aging as well as this epigenetic information loss theory of aging. Where the instructions to ourselves on how to perform just get a little dysregulated over time whether a result or cause of disease. But yeah, I think that, those, how we manage it clinically is the end of the goal, right?

Are we using growth hormone? Are we doing nine months on mTOR inhibition and three months on, proliferative growth with, trying to improve, growth hormone levels or hormone levels or our NAD levels or whatever it might be. And so we’re trying to come to that, but through a [00:37:00] unified framework and that really means creating tools that we can use as surrogates to gauge this process.

Dr. Weitz: I suspect, even though the trend now is to reduce mTOR, that in the future we’re going to find out that this is a J shaped curve like we see with a lot of things, and having low levels of vitamin D is bad. Having, super high levels of vitamin D is probably not optimal either, and so there’s a J shaped curve where if your your promotion of growth and regeneration is too low, that’s going to be bad, and if it’s too high, that’s going to be bad too.

Ryan Smith: Yeah, definitely. And yeah, and I think we’re just now trying to answer those questions with again, something that’s reliable and reproducible. And I think that yeah we’ll get to some of that. I think in terms of where the best are, but I also want to bring up this idea of, in the future, I think probably the most exciting intervention of them all is this idea of cellular reprogramming.  It is incredibly exciting. And I think will really shift how we think about both disease as well as aging. [00:38:00] So what do we mean by cellular reprogramming? Yeah, so in, in 2012 a scientist named Yamanaka won the Nobel Prize. Oh yes. Yeah, and this is this idea that he was using proteins to take any cell and revert it back into a pluripotent stem cell.

So a cell that was a, for instance, a skin cell could go back and become anything now with that same genetic information. And in doing so, in further research, we’ve also seen that by expressing Yamanaka factors and giving them to cells, they actually epigenetically reset. So they go back to an age of a really young age for instance.

And so the idea would be, can we use those Yamanaka factors to restore function of different cells? And that’s certainly what’s happening now. They’re using Yamanaka factors to, restore vision in blind mice. They’re using Yamanaka factors to improve. Heart Failure in these animal models, it’s a way to go in and reset the instructions for a cell to its, it’s I would say like a hard restart of a computer, right?

Where you’re, going back to the factory [00:39:00] settings and starting from new where then your computer goes a little bit faster, it functions a little bit more like it should. And that’s what’s happening with those Yamanaka factors, is restoring them to the best version of themselves.

Dr. Weitz: Where, what’s the latest on the Yamanaka factors? Where are they starting to be used in humans?

Ryan Smith:  Yeah not in humans just yet. I would say the, I just got back from a trial conference in Barcelona where you’re only allowed to share unpublished data. And over the recent couple of weeks, there’ve been some major breakthroughs here.  Alatost Labs is probably the most notable company in this space. This is a company that got Steve Horvath from UCLA, got Morgan Levine from Yale. Got Yamanaka himself. So they’ve got the who’s who of scientific researchers. And they were funded by Jeff Milner with over 3 billion as a startup.  Oh, really? Yeah. That’s not the usual type of startup money going to some of these areas, but they just released some preliminary data that showed

Dr. Weitz: Horvath’s no longer at UCLA and Morgan Levine’s no longer at Yale.

Ryan Smith: Correct. They’re now with Altos, along with a host of other, Nobel prize [00:40:00] winners and other who’s who of scientists.  And so they’ve got the collection of an amazing team. And with that they just released their initial data and they showed that with a single injection, they’re improving lifespan in mice by 25 percent in over a thousand mice that have been studied. 

Dr. Weitz: A single injection of what?

Ryan Smith: Yeah. They won’t say, that’s what I’m doing, but it is based off of the Yamanaka factors. So based on some of that technology and, that’s an expensive technology, but people are now even finding small molecules that might do it, about Valproic acid is a good example of, a molecule which can cause some reprogramming and people are investigating.  What molecule? Valproic acid, which most people know, for seizure medications, right? Oh, okay. But but people are even using some of those molecules, and so there, there are ways that I think that it might become more accessible, but already it looks to be incredibly promising and the ability to regenerate, I think, as well as restore youthful information.  Fascinating. Yeah, very. It’ll be, I think, one of the biggest breakthroughs in medicine. I’ve always been [00:41:00] very skeptical of this living to 125, 150, but now with these Yamanaka factors, it looks like it’s in sight. Really? Wow. Very fascinating.

Dr. Weitz: And what do you think about the regenerative plasma therapy that’s available out there?

Ryan Smith: Yeah, I think that it’s certainly interesting. We’ve done a couple studies here. We’re about to release one with the Buck Institute and Dobry Kiprov, who’s the father of plasma apheresis. The, I think it all started with this idea that, if you take an old mouse and a young mouse and you hook their vascular systems together, so the heart of the young mouse is pumping blood to the old mouse and the heart of the old mouse is pumping blood to the young mouse.

They saw that the young mouse the older mouse regenerated, right? It got rid of gray hair and improved its muscle mass. It just looked physiologically younger, but on the other end, the younger mouse got older. It started to develop other phenotypic signatures of aging. And so it brought up this idea that maybe there’s something in our blood or plasma That is both causing age to get worse, but also maybe improving that process.

And I think the preliminary data [00:42:00] looks super exciting. There are a lot of different improvements. The problem is it’s really hard to get access to, it’s a little bit expensive. And we also don’t know how often you need to do it to have all the benefits. And so I’m very hopeful about it.  I think the preliminary data looks really good, but I also don’t know how sustainable it is. I also know the FDA doesn’t like plasma. Young plasma transfers as a strategy. So I’m not sure how widely robust it will be, but it certainly looks promising. Right.

Dr. Weitz: Essentially what you do is you go in and they take albumin from a younger person and re take, replace your albumin with that, right?

Ryan Smith: Yeah. So the whole plasma generally they also will supplement with new albumin and albumin is one of those biomarkers we know, again, declines with age and the higher it is generally the better we do. Binds the majority of proteins within your blood. It’s actually the number one factor, or should I say the secondary factor in our omic age algorithm.  It’s weighted that highly. So we know albumin is certainly important and this, it brings up this hallmark of [00:43:00] aging. Proteomic dysregulation that might end up happening as well. And some people estimate that’s why saunas help improve health is by activating heat shock proteins and getting rid of non functional proteins.

So you get, get to see a lot of these same narratives and across this, but yeah, I think it’s certainly an impressive strategy and certainly merits more research. There are a lot of companies now that are basically creating synthetic versions of young plasma that might be more likely to get FDA approved.

Really? Synthetic versions? That sounds a little scary. Yeah. Well, what they basically do is they compile hundreds of thousands of plasma patients and then start to filter segments. And those segments are generally what they’re they’ll give. Alkahest is the company there that’s been doing a lot of that research.  But but yeah, so definitely I think that there are probably ingredients in that plasma that can help improve aging. We’ve just got to find out what they are and then see how we can make it more accessible. And get rid of the parts of

Dr. Weitz: it that are making aging worse, which is the damage that occurs, the old proteins that are [00:44:00] incorporated, et cetera, et cetera.

Ryan Smith: Yeah, and that’s what a lot of people now are doing. Instead of just infusing young plasma, they’re just filtering their own to get rid of some of that stuff. Plasma,

Dr. Weitz: Phoresis, yeah.

Ryan Smith: Exactly. And so we’ll have trials published on both of them coming out relatively soon. That’s,

Dr. Weitz: that’s great. You’re right on the cutting edge of all this stuff and able to offer this test to clinicians and the public.  So how do Clinicians and people watching this find out about getting the is it still called the true age test?

Ryan Smith: Yeah, it is. Yeah. The true age test is something that continually changes for us. We add algorithms as we just did with Symphony Age. We add other insights but they can, the best way to do, it’s to go to our website at true diagnostic.com.

If anyone has any scientific questions about the test, they can always reach out to me personally or our support team atRyan@truediagnostic.com or support@truediagnostic.com. We also have, just a lot of educational [00:45:00] resources. If anyone wants to learn a little bit more to go to our research page, you’ll see some of the research that we’re doing with all of these universities as well, if they want to read a little bit more about it.

Dr. Weitz: And clinicians can sign up to become to offer the tests to their patients as well.

Ryan Smith: Yes, definitely. The we actually specialize with physicians because some of this information is a little hard to interpret and you really need a really big clinical picture. And so that’s why for our main market, and we do lots of education for physicians.  If you’re new to this topic, if you’re new to the idea of DNA methylation, I mentioned that, when I was in med school, And in undergrad I had probably less than a day of epigenetic education and that’s how new and innovative some of this is. And so we do a lot of education on this topic and love to I would say get clinicians up to speed and really try and implement these in clinical practice.

Dr. Weitz: And so when they order, when the test is ordered now, is the symphony age automatically included in that?

Ryan Smith: It is. It is. And generally you get all 11 reports that we do and those reports will continue to be expanded. The next areas that we’re really going to [00:46:00] go into is personalized nutrition. So we can actually tell you the levels of, things like alpha ketoglutarate or vitamin D or your omega threes with that same data set.  And then very soon we’ll also be doing methylation risk scores for disease. So how likely are you to develop these different disease outcomes?

Dr. Weitz: So you’re not going to be measuring the level of vitamin D, you’re measuring epigenetic marks that code for vitamin D levels, right? Is that what you’re doing?  Yeah, exactly. Okay.

Ryan Smith: Yeah, so we’re just using that DNA methylation data to predict surrogates and so we really do believe that in the future we’ll be able with one single fingerprick test, be able to read those DNA methylation patterns to do probably a large majority of the clinical testing that you currently do with a single diagnostic.  And that’s really what we’re excited about. Very exciting. Thank you so much,

Dr. Weitz: Ryan. Yeah, thanks so much. Appreciate it.

 

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Thank you for making it all the way through this episode of the Rational Wellness Podcast. For those of you who enjoy listening to the Rational Wellness Podcast,  I would very much appreciate it if you could go to Apple Podcasts or Spotify and give us a five star ratings and review.  As you may know, I continue to accept a limited number of new patients per month for functional medicine. If you would like help overcoming a gut or other chronic health condition, and want to prevent chronic problems, and want to promote longevity, please call my Santa Monica Weitz Sports Chiropractic and Nutrition office.  Call us at 310 395 3111 and we can set you up for a consultation for functional medicine. And I will talk to everybody next week.