Measuring Biological Aging via Epigenetic Methylation with Ryan Smith: Rational Wellness Podcast 223

Ryan Smith speaks about Measuring Biological Aging via Epigenetic Methylation with Dr. Ben Weitz at the Functional Medicine Discussion Group meeting on August 26, 2021.

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Podcast Highlights

5:36  Epigenetic methylation.  DNA methylation is essentially inactivating of a gene transcription.  When a methyl group is placed on a particular gene, that gene typically gets turned off. This occurs especially at the CPG islands, which are the sections of our DNA when we have cytosine and guanine based pairs repeated over and over.  This process is related but separate from situations where you find out that patients have polymorphisms in the MTHFR and/or the COMT genes and who may require supplementation with methylated B vitamins like methylfolate and methyl B12.

10:30  While epigenetic methylation is used to measure aging, it is also being used for other things, including detecting cancer, including a new test known as Galleri from Grail, which is a liquid biopsy that is able to detect cancer very early, including at stage zero before it’s able to be found by any other method.  It can detect over 28 different types of cancer.

12:37  Ryan and the TruAge test are focused on using epigenetic methylation to measure biological aging. Dr. David Sinclair in his new Lifespan book talks about aging as a disease.  And to slow down and reverse aging we need to prevent cancer and other chronic diseases like heart disease and diabetes. Approximately 80% of adults in the US over age 65 have at least one chronic disease.  And if we reduce aging, then chronic disease risk will drop.  Prior to epigenetics (methylation clocks), telomere length has been validated as a way to measure biological aging, but it has low predictive capabilities. Epigenetics is both highly validated and highly predictive. The lower your biological age, the longer you are going to live.  70% of all cancers occur in people 65 and up.  For every one year you are older biologically, you increase your risk of getting cancer in the next six years by 6%.  If you are two years older biologically, you have a 12% increased risk of getting cancer in the next six years and you have 34% increased risk of dying of cancer in the next five years.  If we can reverse your biological age by seven years we can cut disease in half.  If we can slow biological aging by 20%, the US would save over $3 trillion dollars in healthcare spending.  We can also tell you how old your immune system, how many CD8 and CD4 T cells you have, how many granular sites you have. And if you reduce your aging rate, you can reduce all of these different aging phenotypes.  Aging should be treated as a disease.

44:12  Interventions to reverse aging.  While the first published intervention trial to reverse aging, the TRIIM trial (TRIIM stands for thymic rejuvenation and immunorestoration) by Dr. Fahy and others, used growth hormone, Metformin, DHEA, zinc, and vitamin D, most of the longevity researchers including Dr. Sinclair and Dr. Longo have found that lower growth hormone levels are associated with better aging.  Despite the benefits seen in this trial, the data does seem to show that higher growth hormone and IGF-1 levels are negative for longevity.  And data on Laron dwarfs show that they have a growth hormone deficiency and they tend to live longer.  Some of the recent data indicates that it may be DHEA that most consistently correlates with longevity of the three interventions in this trial.  When you look at Dr. Horvath’s original algorithm, which looks at 353 spots on the DHA over 80 of those spots are located at or near glucocorticoid receptor elements.  This means that the more cortisol you have, the more stress you have, the more it might impact your epigenetic aging and DHEA can mitigate the effects of cortisol.  Here is the TRIIM trial:  Reversal of epigenetic aging and immunosenescent trends in humans.



Ryan Smith is the co-creator and vice-president of TruDiagnostic which offers the TruAge test, which uses an epigenetic methylation clock to measure biological aging.

Dr. Ben Weitz is available for nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also specializing in Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure and also weight loss and also athletic performance, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111. Dr. Weitz is also available for video or phone consultations.


Podcast Transcript

Dr. Weitz:            Hey, this is Dr. Ben Weitz, host of the Rational Wellness Podcast. I talked 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.

Thank you for joining our functional medicine discussion group meeting tonight on epigenetic methylation in aging and disease with Ryan Smith.


I want to thank our sponsor for this evening is Integrative Therapeutics, which is one of the few high quality professional brands of nutritional supplements that we carry in our office, super high quality, very innovative. I’m just going to mention a couple of their products. They have a specialized form of curcumin called Theracurmin. There’s been a fair amount of research on it. It’s a water dispersible. And for two capsules, you get the full dosage, which makes it a lot easier and more convenient than some of the other leading forms of absorbable curcumin.

Another one of their products is a product called Heartburn Advantage, which we use a lot for gut patients. And so this is a product that includes a natural prokinetic that improves motility of the gut, and also includes deglycyrrhized licorice and zinc carnosine for soothing and healing the lining of the gut. So it’s great for patients with reflux. And we also use it for SIBO patients.


Dr. Weitz:            Tonight, our topic is epigenetic methylation in aging and disease. I’m sure most of us know what epigenetics is, which is essentially, and Ryan will give us a much more detailed explanation. It’s a set of triggers and switches that turns our genes on or genes off. Put it another way, it’s the factors that result in whether our genes are expressed or not.  Methylation can be tracked and correlated with aging. And methylation clocks are what the latest research is showing us is the best way to measure biological aging as compared to chronological aging. And this is very applicable to those in the functional medicine community who are advising our patients in diet and lifestyle programs to promote longevity.

My goals for tonight are to learn about how to test for biological aging, how to interpret such testing and how to touch on some of the latest research on interventions to promote longevity. Ryan, this is Ryan Smith, co-creator and vice-president, TruDiagnostics or for the TruAge tests. Ryan, maybe, you can give us a little bit about your background.

Ryan:                    Yeah. Absolutely. So first and foremost, thanks so much for having me. I’m excited to talk tonight. I am always excited to talk about this topic and introduce it to new people, because I think it’s always something a little bit sci-fi, something a little bit different than sort of the clinical application that they probably know about methylation right now.  I definitely have a PowerPoint. I don’t know if you’d like me to show it or not. I’m happy to, but I can’t show it at the moment–I can’t present at the moment. And so it might be good if you can allow me to share it and maybe the host, I’d be happy to do it, but yeah,… 

Dr. Weitz:            Please mute yourself…. Okay. Okay, good. I guess we should be good.

Ryan:                   Excellent. Yeah. Again, thanks for having me. My background is a little bit diverse, biochemistry undergrad. I went to medical school at the University of Kentucky. Passed step one. Did really well, but got to the clinical stuff and just hated it. So shortly thereafter, we created a compounding pharmacy that sort of specialized in peptides and proteins called Tailor Made Compounding. We had a lot of success. But as we were doing new and innovative pharmaceuticals and molecules, one of the things I always wanted to know is how is this having an effect on the long run? How is it affecting health span, life span outside of the immediate benefits you might have from a day-to-day basis?  And so I’d always been really interested in this as a diagnostic when I first heard about it, particularly because it was able to predict things like death, predict things like the age of your body. And as we know, aging is the number one risk factor for all chronic disease and death.  And so knowing that was a modifiable factor and one that we could now manage was really, really exciting to me. And so, we decided to create TruDiagnostic because I saw there was a really big need in this epigenetic methylation space for really good clinical algorithms. And so we started this company and doing commercial test in July of 2020, and we’re over a year old now. We’ve tested over 12,000 patients, have one of the largest private epigenetic databases in the world and in some of the most robust testing algorithms in the world.  And so we’re really excited to talk about everything and go through and give an introduction into methylation. And so, yeah. So just to go ahead and get started, for those of you who aren’t familiar, I would love to just quickly go through epigenetic methylation. And here’s some of the things that I want to try and go over today, right? What is it? How can you use it clinically? How does methylation relate to aging. And then, how can you use these algorithms in your current practice?

And I always like to start off with this quote, but it says” Five to 10 years from now, the health system that doesn’t use this data to help improve their medical delivery is going to be deemed archaic.” That’s how quickly that this is coming, right? This is even anticipated by some people to overtake blood testing in the next 20 years. And so this is something that if you don’t know about it yet, it will affect your clinical practice. It’ll affect your clinical practice in the next five to 10 years greatly. And that is a great thing.  And this is some of the mission and goals of us at TruDiagnostic, but we really want to improve patients’ lives by helping them make the right decision at the right time and by leveraging this new biomarker to be able to make those decisions. And so I think you gave a great explanation of what epigenetics is, right? It is every cell in your body has the exact same DNA structure, but obviously, the genes which are turned on and turned off in your skin are greatly different than the genes that are turned on and turned off in your heart.

And in the way that they do those sort of changes of turning things on or off are through these types of epigenetic modifications. For the purposes of what we’re going to talk about today, we’re really going to talk about DNA methylation. And DNA methylation is really thought to be that inactivating of a gene transcription. So usually, whenever it’s placed on a particular gene, that gene is turned off, whereas histone modifications like acetylation, on the other hand, are really turning on genes. And so we’re able to measure these things in our cells on our DNA, and then correlate them to outcomes.

And so just to give a little bit more terminology, one of the big terminology points I’ll use often are called CpGs. And these are cytosine and guanine islands where those sort of base pairs are repeated and repeated. That is actually where we’re looking for most of these methylation-related signatures. And so you might hear me talk about that quite a bit, and that’ll be a term that we use because that’s what we’re really measuring. Is methylation on or off those genes. And this is a process by which we methylate our DNA. We attach those methylate groups to cytosines in the DNA.

And to do that, we use a supplement actually that a lot of you might be familiar with, SAMe or the S-adenosylmethionine. So many people, you might be familiar with using it to help treat depression or osteoarthritis or many other things. And I think it’s also important here to separate this from a methylation that you might have already used clinically things like, for instance, MTHFR or COMT genes. It’s sort of a similar biochemical process, but how we’re sort of looking at these and addressing them are completely different.  And so I think it’s also important to say that so that the two separate processes and I think it’s important to make that distinction. And so whenever we talk about this, it’s important to know that this is a very, very new biomarker, really the first time-

Dr. Weitz:              Are those two processes similar? For example, is it the case that if you take a lot of methyl B vitamins, folate, and B12 that you can increase the methylation of the DNA?

Ryan:                     Yeah. Absolutely. They are connected. For instance, we know that some people who have polymorphisms in that MTHFR gene have actually worse biological ages because of it. And so they’re related, but the biochemical process of if you’re able to have the co-factors to methylate will affect the DNA methylation, but the DNA methylation itself is sort of the cause, the root cause I would say, of what genes are turned on and off. And therefore, what we’re expressing in our DNA.  And so they’re related, and they affect each other, but probably not the way that you’re thinking clinically where supplementation with B vitamins or 5-methylfolate or CME are going to have the same effects that you would imagine would be a good thing. And so they’re related processes, but still at the same time, very vastly different from a clinical approach.

And I think we can even sort of talk about that when we talk about some of the treatments, which were to reversing the aging process. And again, not to bury the lead, that is what we can do, is we can. Now that we have an objective way to manage this aging process, we do know ways to sort of to change it. And so before I go into the aging aspect, which is, I think, probably the most exciting, I also want to go talk about some of the other things that epigenetic methylation is used in clinically because although aging is a big part of it, it goes way beyond that.  And so many of you might be familiar with a relatively new test, just came out in the past 10 weeks, called Galleri from GRAIL who was just bought by a woman. And this is a test much like IVG [inaudible 00:10:50] if you’re familiar with those in the past. It’s called the liquid biopsy, which is able to detect a cancer at very, very early stages, even stage zero before it’s able to be found by any other method.  And this is probably the biggest growing area of sort of the commercial market, because cancer is obviously so prevalent. And you want to catch it early so that you can then treat it. And this test can detect over 28 different types of cancers with a single blood test. And so that is a very exciting development and probably one of the biggest areas of epigenetics.  In addition to that, there’s a lot of new drugs, which are being approved that treat different types of things, particularly cancer via epigenetic mechanisms where they can sort of take a drug to turn things on or off from your DNA expression. And so this is another big area as well. And again, I won’t go over it a lot today, but you’ll probably see a lot of this in the future, particularly the GRAIL Galleri test is now becoming widely popular, even though it was only released a few weeks ago.

And so those are other applications which are really, really exciting, but I just want to again stress that this is a new biomarker. Being able to actually get the information whether it’s part of your DNA is or is not methylated is a relatively new thing. Really in 2009, we only could read right around 80,000 of those markers at a time.  And there’s over 26 million for every cell in your body. Even towards 2017, we only had right around 450. Now sort of the baseline for most standard research testing is 850 to 900,000. And that is what we’re doing here. So we’re now finally able to read this data at a large scale. And that’s what sort of making all these developments so much more relevant and what will continue to sort of change medicine.  And so the real application for this epigenetic testing that I want to talk about today is biological age measurement. And many of you might be familiar with this sort of renaissance in the aging community. I always like to point this book out, Dr. David Sinclair’s Lifespan book, because in it, he sort of talks about this idea of aging as a disease and sort of bringing the light to this whole idea of treating aging before it happens.  We talk about those things like cancer. But cancer, one of the biggest risk factors for cancer is actually age. And so with those liquid biopsies, we’re trying to detect it. But if we can address age, maybe we can even prevent cancer from happening or prevent all of those age-related diseases, which is every chronic disease, diabetes, heart attack, stroke, you name. It is usually an age-related disease.  And so even though the national community is picking up on this with now the World Health Organization has added an ICD-10 extension code for age where you can sort of say that these diseases are caused by age. And even things like Alzheimer’s and hypertension weren’t even considered diseases in and of themselves at one point in time. They were considered sort of a sequelae of aging.  And so we know that aging is an important and really at TruDiagnostics, we definitely think that aging is a disease. And some of these statistics even show that 80% of adults have at least one chronic disease if they’re over 65. And you can see that the percentage of population with these chronic diseases over 65 are prevalent. And so we know this. And as I mentioned with cancer, by the time you reach 60, your risk of getting cancer doubles from when you were 50.  70% of all cancers occur in people 65 and up. And so again, aging is a disease and definitely sort of treated like it. But the good news though is that if we’re able to treat aging, we can have massive impacts on population level health.

So for instance, if we’re able to reverse your biological age, so the age of your body, by seven years, we would be able to cut a disease in half. 50% of the people in the world would no longer be sick. In addition to that, if biological aging could just be slowed by 20%, the US would save over $3 trillion in healthcare spending. And so what we are really trying to do is quantify the aging process, let everyone know where they’re at, so they can make the changes to reverse that aging process and improve their health and prevent all of these health outcomes. And we always say, “You can’t manage what you can’t measure.” So what we’re trying to do is give an appropriate way to measure that.  And so when it comes to aging, I also think it’s important to say why chronological age is not a very good measure. Chronological age is obviously everyone knows their chronological age. But everyone probably also knows people in their 70s who looked like they were in their 50s, and people in their 40s who looked like they’re in their 80s. People all age at different rates and that’s this phenotypic variation where depending on how well you take care of yourself, you can change the way that you age.  And so chronological age is still the biggest risk factor for chronic disease. But biological age can be even more predictive and even a bigger risk factor. And so biological age, they’ve been trying to find a way to look at this for a long time way better than chronological age.

And there’ve been a lot of different postulations for the best measurement. These are some of the criteria that American Federation for Aging Research created. But beyond that, most of you are probably familiar with what has been clinically used for the past couple of years, really the past decade, for the best measurement of biological age, which is typically telomeres. And so I won’t go into that a lot. But obviously, most of you are familiar with this, right? Those in caps on your DNA that when replicating solely gets shorter and shorter and shorter and shorter.

And when they do, that’s correlated to this aging process. And so this has sort of been the standard for a long, long time. But it’s probably not the best. And the reason being is that I always love to show this sort of summary from 2017, I should say, which compared all of the different ways to measure biological age. And telomeres, although it’s been the standard methylation related biological age testing is now becoming much more accurate and much more predictive.

One of the big problems with telomeres is that even though it is correlated to age, if you have low telomere length, it doesn’t necessarily mean you’re going to have any type of age-related outcome. It’s sorts of, as this study puts it, briefly telomere length is extensively validated, but it has low predictive capabilities. And really, what we’re trying to do with this aging is to predict the outcomes of disease.  And so telomeres have never been the best. And I always like to show this as well, where this hazard ratio, telomere really definitely has the most studies done on it. But it’s by far the least predictive if you look on this graph. It has the lowest hazard ratio, whereas epigenetics is highly predictive and highly validated, which sort of shows us it is the best way to measure age.

And so, that’s what we do. We use this biological age to give you, essentially, we test your DNA, and we give you an age, how old your body is. And this is a process which is relatively complicated. This is actually the process which we do it. We sort of collect just a few drops of blood. We can do it with just a fingerstick blood test, where then we extract the DNA. And then, we sort of look at all of the different copies at all of those CpG spots. We look at number 900,000 locations to really get an idea of is that location methylated or is it not.  And we sort of sum up all of that to get a percentage of methylation at each location in your genome. And we measure, as I mentioned, a lot of spots. And we’re getting a lot of data. This is sort of what we see at every different location that we look at over 900,000. And so what we essentially get at the top at each of those 900,000 locations is a percentage of methylation. Out of all the copies of your DNA, what was the percentage that was methylated?  So if we’re looking at, for instance, we were talking about maybe an MTHFR-related gene, we can say, “How much of those are methylated?” 80%, 20%, whatever it might be. And then, we plug it into these mathematical-derived algorithms, which are listed below. This is actually one of the first ever biological-age algorithms that came out from Dr. Steve Horvath at UCLA who’s really the worldwide expert in this.  And what did this is able to do is to take those percentages and then to turn it into something that’s clinically useful like age. And these things have been created in sort of another thing. So we’ve talked about how the bio-marker is really new. And really, we now are the first time we’re able to look at it at scale. But the other big development is computer learning and artificial intelligence, where we’re able to use these really large datasets and turn it over to computer for it to tell us these insights. And so that’s exactly how these clocks are created. We sort of train this dataset and these artificial intelligence algorithms to give us a mathematical way to predict an outcome, in this case, age.

And so just to give a little bit of history, the first of these clocks came out in 2013, really the first really accurate clocks. And the first clocks were trained to predict chronologic age. And so the first time that they were used was actually not in relationship to medicine at all. It was used in relationship to things like crime scene investigations, where they would be able to tell how old someone was at a crime scene or to date refugees and see if they were over or under 18 and therefore eligible for asylum.  And so they were used for things way before they were used clinically because the first clocks were just trained to output chronologic age, so, trying to predict your age. And as I mentioned before, chronological age is not the best metric. And honestly, it’s not great to have a test score because if you really want to know clinically how old someone is, you can usually just ask, right? So the second generation clocks, as they call them, started to train against something a little bit different, which was those age-related outcomes, all of those diseases, which are associated with age.  And as a result, they created these algorithms, which were incredibly predictive for age outcomes. And beyond that, they even train them to predict things like death. In the case of GrimAge from this graphic with Dr. Horvath where he’s actually able to predict when you might die, very, very accurately.

And so the idea is that these clocks can be trained to predict just about any outcome. If you want to train it to predict how fast you might run a mile or predict how much hair you might have in your 50s, these things can be trained for that if you have enough data. And so I’ve included some of these things for you to look at, and also the difference between those chronologically trained clocks, the first-generation and the biologically age clocks, the second generation.

But overall, I think that the one takeaway from this is that the lower age you have biologically, the better you are. You’re going to live longer. You’re going to have a better health span. And there are many classical examples of this. One of my favorites to mention is in the instance of cancer, where for every one year that you are older biologically, you would increase your risk of dying or getting cancer within the next six years by 6%.  So for someone who’s two years older, biologically, they might be 50 chronologically and 52 biologically. They’d have a six… or sorry, 12% increased risk of cancer over the course of the next three years. And then, they would have essentially a 34% increased risk of dying of cancer over the next seven years… Five years. Sorry. So again, these things have massive impacts on to our risks. And so, we really want to be able to treat this as a disease and to really measure it.

But even since then, this is a really, really fast area of growth. And so just to show you, so all of the things that we already can do now, we can do a lot more than that. So we can obviously tell you your biological age. But we can also tell you how old your immune system is. We can tell you what your immune cell subsets are, how many CD8 T cells you have, how many CD4 T cells do you have? How many granular sites you have? We can tell you your telomere length, actually, in a way that’s more accurate and more predictive than traditional telomeres length measurements. And we can tell you your instantaneous rate of aging. At this moment, how fast are you aging?  And so all of these things can be used clinically, because if you reduce the aging rate, reduce the aging process, you can reduce all of these different aging phenotypes. And that really is the power. And so that is a little bit of a history. But I also want to talk about how [crosstalk 00:23:02].

Dr. Weitz:            Are you going to go into more detail on these? And if not-

Ryan:                   Yeah.

Dr. Weitz:            Yeah. Okay, good.

Ryan:                   Absolutely. I definitely want you to know. I know that you’ve obviously had some experience, so we’d love to, obviously, for you to guide me as well. But I want to talk about sort of how it’s used clinically. What type of results do you get whenever you run this testing? And then also, what’s a good result? What’s a bad result? And what can we do about it? And so I will go into that.  This is sort of our first report. This is the first one we ever did. And this is an interesting report. And you can see on the left, it gives you your biologic age versus your chronologic age. It gives you where you stand out in the population. And this is actually a very big report. It’s over 78 pages because it provides a lot of context. One of the things that we don’t want patients to do is to get scared, right?

Talking about the biggest risk factor for all of their age, and the fact that everyone knows where they should be at, right? If someone comes back older, they oftentimes get scared. And one of the things that we try and do is add context for that value. What are some of the things that might’ve increased your score at baseline, decrease your score at baseline or up to 40% of this metric is heritable.  And so some of it is within your control, and some of it hasn’t been. And so we try and give some background to those things to change it. But what I really want to focus on today is even some of those other impacts. Clinically, my favorite aging algorithm is what I want to stress the most today, which is this probably the introduction to this. Do you need a pace of aging algorithm metric?  And so this is my favorite. It’s actually considered the third generation algorithm. So it was recently created actually even in 2021 of this year. And what this sort of reads out to you is an instantaneous rate of aging. So it takes a look at you right now and says, “How many biological years per year are you aging?” It’s like a speedometer for your aging.  And one of the reasons this is so great is because it separates what you’ve done in the past versus what you’re doing now. So for somebody who’s lived a lifestyle that might’ve been stressful or unhealthy, you can still get an idea of what behaviors you’re doing right now, and then how to change it. You and I both might take Metformin. But my response might be significantly different from yours. And this allows us to do that personalized medicine to see sort of how we’re changing.

But I also want to go into how this metric was created and how predictive it is. And so this algorithm will never, ever be replicated because of how it was created. The study to create this algorithm started in New Zealand in 1975. And it started with over a thousand three-year-old children. Sorry. And so over a thousand three-year-old children.  And the idea was that they were going to measure across the lifespans of these children their aging rates. And so Duke actually propose this. And the National Institute of Aging actually said “We’re not going to fund you because if you do detect a rate of aging, it will not be significant to these health outcomes.” However, it ended up being very, very significant. And this is just one of the ways we’d like to demonstrate it.  So as of 2019, all of these patients were now 45 years of age. So they tracked them since three to age 45. And every year, twice a year, they took all of the age-related biomarkers you can imagine. They did everything from telomeres length to MRIs of the brain, to retinal imaging scans, to dental imaging scans. They did DEXA body composition scans. They did every type of age-related metric you can imagine.

One of the other things they did was facial aging. And so these people you see on the screen, they’re all the same age. They’re chronologically all age 45. But even on the outset, how their faces look changes due to the rates of aging. You can see on the left, there’s the slowest aging members of the cohort. And on the right, the fastest aging members of the cohort. Again, all of those people are age 45. But it looks like there’s 20 years of difference between those two people, those two groups.  And in fact, there is because they’re aging at different rates. They’re biologically different ages. And so this is just one of the ways that we can sort of show it. But there’s many other ways as well. Particularly, we do believe that actually aging occurs early in life. And that leads us to all of these types of disease, disability, and frailty.

Here are some really good examples. So if you look at the bottom, the X axis, you can see that we plot the pace of aging against the scores on these testing. And as you can see, the faster that you age, the worse you perform on your balance testing. And not just balance, but also on grip strength. And this also holds up things like sarcopenia and body composition. The faster you age, the worse your body count and the worst your balance, the worst your physical performance, the worst, actually your cognitive decline, right?  So the faster you age, really the more IQ points you will lose, the slower that you’ll process that mental speed. And again, all of these things that I’m reporting on now are things that are actually quality of life metrics, health span, not just lifespan. And I think that that’s important to note as well. When we treat aging as a disease, we don’t have to think about living a long time and being super unhappy while we’re doing it.

We also get to think about how we improve our quality of life. And those things are not sort of mutually exclusive. So, if we improve our rates of aging, we improve the appearance of our base. We improve our risk for Alzheimer’s, cognitive disease, grip strength, body composition, physical function measurements. This again is just an example of the differences in facial aging appearances.  It also affects our brain, like, with things like cortical thickness and surface area. And so this is one of my favorite algorithms because it is the most predictive. And you can really take a test now. Take a test in really eight weeks after you implement some type of therapy to see if that therapy is working for you.

And so the goal with this whole algorithm is really to keep that biological aging rate, that rate of aging below one. You want to be aging less than one biological year for every chronological year, because that means you’re essentially aging in reverse, right? If for every one year that you lived, you’re going to be younger sort of biologically.  And even if you’re slightly above one, this carries heavy risk. So, for instance, even if you’re aging at a rate of 1.01 biological years per year, you would increase your risk of death in the next seven years by 56% and increase your risk of a chronic disease in the next seven years by 54%. And those are incredibly high risks. And so again, the idea is we want to treat aging before it happens and really start with a lot of these procedures.

And so a lot of those questions that might come from this is what do I do about it? And quite frankly, that’s one of the hardest questions to answer because this is such a new diagnostic. With that being said though, we’re finding out ways to reverse this process all the time. One of the ways that we know reverse this process is actually caloric restriction.  And so this is a good example of a sort of data from the calorie trial. The calorie trial had sort of two treatment groups, which was a 20% caloric restriction group who basically added a calorie deficit every day for two years. And they were on the right. And you can see their change in biological age was less than half a year, over two years compared to the group who did not do caloric restriction, who aged anywhere from really one year to over two years.  And so we know that caloric restriction is absolutely one of the things that changes this, which probably is intuitive for anyone who’s been paying some attention to things like ProLon and Fasting Mimicking Diet and caloric restriction. And so that is absolutely one of the things that we know can change. But we know a lot about these other metrics as well. And so before I go on to maybe some of the other things we can tell and the other algorithms we can learn, do you think that there’s anything else I might be missing to introduce this topic as a whole?

Dr. Weitz:            No. I mean it’s a vast topic, and there’s tons of things that… I have tons of questions. But I’m going to hold them back till I see exactly where you’re going with this.

Ryan:                   Perfect. Yeah. No. I think the biggest thing is that when you were approaching this from a clinician standpoint, you want to encourage everyone to get these metrics as low as possible. But the younger you are, the better you’re going to live, the longer you’re going to live. And so that’s sort of the idea. But the other idea is that methylation can tell you a lot more things than just your age.  One of the things it can tell you is actually telomere length. And so, via the same mechanism of DNA methylation, we can actually predict telomere length. And again, the correlation for telomeres length to age, it has an R squared value of around 0.35 at a maximum whereas the correlation for this measurement is double that with age. So it’s more highly correlated to age. But in addition to that, it’s much more predictive of outcomes. It’s better at predicting time to death. It’s better to predict time to coronary heart disease and time to congestive heart failure. So in addition to all the other reports we do, we’re actually even able to look at telomere length and predict that as well.

Dr. Weitz:            And if methylation clock is a better predictor, why do we care about telomere length?

Ryan:                   It’s a very good question. And the answer is you probably don’t. But with that being said, it does capture a different part of aging than just the biological aging process we get through methylation. So, I actually just did a presentation about this before this. And one of the things I like to say is that by combining all of these things together, you can get an idea. You can actually explain more of the variance between phenotypic age. So you can sort of explain why someone might age quicker than someone else.  And so it’s an important feature. It’s still one of those hallmarks of aging. But in terms of its predictive capability, these biological age markers, these age clocks tend to be a little bit better than telomeres length completely. That’s a definitely a good question. But again, methylation can tell you just about anything you want, if you have the right data.

And so one of the things we actually look at is the immune system. So we have these things called deconvolution methods, where we essentially are able to predict the types of cells that we actually see in your testing. And so what that looks like for us on its output is we actually read these, if you can even see. I know it’s small texts. We’re actually able to tell you your percentage of lymphocytes, neutrophils, granulocytes. And also, we sort of culminate with this thing called the CD4 to CD8 ratio, which is that ratio of T-cells, which can be incredibly informative about your health status or immune health status.  And for this, you want that range to right one and four. If it’s under one, that means you might have some type of immunosuppression. So we’ve diagnosed things like HIV or chronic lymphocytic leukemia by seeing CD4 to CD8 ratios less than one. We’ve also been able to diagnose hyperreactivity events like auto-immune disease with CD4 ratios above four, which might signal a sort of a reactive immune system.

And so we can learn a lot about your immune system. And it just to sort of show you, there are many, many diseases which are associated with CD4 to CD8 ratios below one. And so that’s what we’re able to do. We’re actually able to use these sort of extrinsic gauge reports to get the age of your immune system but also sort of the overall health of your immune system. And this is obviously something that is very important as we consider COVID-19 or this pandemic where our immune response can greatly affect how much at risk we are.  And again, aging is a part of the immune process. It’s why as we get older and undergo that immunosenescence process, we have the worst immune systems, which is why older individuals are recommended for the vaccine first, because they’re at highest risk.  And so again, this is that idea, the thought process that aging affects all of our risks of all of these other diseases. And so this whole picture together, we can start to say, “How old is your body? How old is your immune system? How well is your immune system functioning?” How is your instantaneous pace of aging? And then, once we get that idea, we can sort of all compete with ourselves to get this as low as possible.

But I should also mention methylation in the case of what we already talked about it in terms of cancer diagnostics, but even beyond that, we can find out insights from low-site specific report. I mean, so this is where we look at individual areas for different disease categories. So we can actually even predict diabetes up to seven years earlier than fasting insulin and HBA-1C.  And so this can be a really early diagnostic to say, “Hey. Should I put my patient on some type of interventional treatment, something just a diet or maybe it’s Metformin, or maybe it’s a GLP-1 or an SGL2 inhibitor.” So the idea is you can even learn these things much like detecting stage zero cancer before you can detect it anywhere else. We can actually detect insulin resistance and diabetes risk before we can in any other metric. And so that’s exciting as well. We can actually-

Dr. Weitz:            Is that part of the TruAge report? Is that just-

Ryan:                   It is. Yeah. So already, we’re able to report out your risk of becoming diabetic. And really, we look at two different markers. If you’re in the risk range for both of those, then, we would highly recommend that you take some type of intervention to prevent the onset of diabetes. Unfortunately, it’s a very, very, I would say, specific test. But it’s not always the most sensitive, meaning that some people who have type-2 diabetes might read as no additional risk. But if you do read additional risk, that means you’re almost certainly likely to do that if you don’t have any other outcomes.  It’s not just diabetes. It also we can do it with obesity. And I’ll sort of fly through these because I want to spend as much time as possible sort of just discussing. But we can actually even predict if you’re likely to become obese. We can predict if you’re likely to lose weight with caloric restriction. We already talked about caloric restriction being great for the aging process. But a lot of patients also want to lose weight with it to improve their body composition. We can actually tell you if you’re going to, before you even do it. We can actually tell you how much you’ve smoked-

Dr. Weitz:            Ryan, is there an intervention if you find out that you have certain genes that are playing a role in while you’re obese? Can you either methylate or undermethylate them? Is there some way to have that happen?

Ryan:                   Unfortunately, the answer is almost certainly yes. But unfortunately, we don’t know yet. And that goes to the biggest disadvantage for this testing is that we’re not sure what interventions are going to change this yet. But we’re very, very quickly learning. There are new studies published about this every week with interventions. And so right now, we, 100%, know ways to reverse your aging. We also know ways… or I should say behaviors, which are correlated with changing those other types of reporting.  But we don’t know about particular interventions to change that risk of obesity or, I should say diabetes yet. But the idea is that they’re already great interventions to change both where your diet, exercise, nutrition, all those things and knowing that you’re at risk you can then make those changes a little bit ahead of time. But that also brings up a great idea, which is that what comes first, the behavior or the outcome?

It’s sort the chicken or the egg thing. And that’s the other great thing about the methylation marks in your DNA. It also presents a history of where you’ve been or what you’ve done your entire life. So we can actually look at, what they call, this exposome. So sort of the history of exposures that are actually found in your DNA, we can actually tell you how much you’ve smoked across your entire lifetime. We can tell you if you’re a former, never, or current smoker. We can actually do the same thing with drinking. We can tell you how much alcohol you’re currently drinking. Are you doing a moderate, mild, or a heavy amounts of alcohol?

And we can do that with more and more things as well. We can actually even predict your response to the medication. So, we can do pharmacoepigenetics. We can, for instance, predict if you’re likely to respond to Metformin from an HbA1c. Are you going to actually reduce your HbA1c or are you likely to have side effects?

In this particular study that we now have an algorithm that predicts if you’re likely to respond to Metformin, or if you’re likely to have those side effects. And for those patients who we know, I would say are, at risk, we might then not suggest Metformin. We might go to another type of intervention. And that’s just the beginning of what will happen.

And as I mentioned with the exposome as well, I wanted to mention we can actually tell you how much mold you’ve been exposed to over the course of your entire lifetime. We can tell you how much lead, mercury, arsenic, plastic, all of these environmental sort of toxins, we can actually see in your DNA. We actually just did a study on COVID-19, where now we don’t even need to take your antibodies to tell you if you’ve had COVID-19. We can see it in your methylation signals.

And so those things are all, I think, very, very exciting. And it leads to this idea of how do we change it, which is sort of found in this sort of diagram where we know all the dietary and societal things, which might increase or decrease the different types of aging processes. And I won’t go into intrinsic versus extrinsic epigenetic age. But it’s another way to even know more about your entire system.

And so these are all the things that we can develop with methylation already. Eventually, it will be one test that reads all of these different metrics. It’s probably a test that can read out your protein levels in your blood, your micronutrient levels in your blood, your hormone levels in your blood. So really, you can do almost all of the testing that you would want to do clinically with one test, if you have enough data and the correlations are tight enough.

And so that is really what we’re hoping for. But I think that the bigger picture is that although this platform is really exciting, being able to treat and quantify aging is even more exciting because you’re able to then prevent the biggest risk factor for all chronic disease and death. And that’s really what we’re trying to do. And so to work with us, it’s really easy to do again, you just order a kit from us. You take a few drops of blood from your finger. You send it back to us. And within two weeks, we give you all of these different reports. And so always happy to talk about that a little bit more. But would love to answer any questions. I know I went through that very, very quickly. And there’s a lot of information. But I’d be happy to answer any questions.

Dr. Weitz:            Can you discuss more about the immune findings and what does that tell us? And how does that help us with our patients?

Ryan:                   Yeah, definitely. So the immune system obviously is highly connected to aging in general. But these immunity convolution methods are essentially like doing flow cytometry testing on your patients to see what percentages of cells they have and how well their immune system is functioning. And so the CD4 to CD8 ratio is just the start. But with that, you can be able to tell if your patients have sort of immunosuppresses or if they have a hyperreactive immune system.

And so what that can generally tell you is, unfortunately, you might need to do some followup testing, right? You might need to say, “Oh, hey, if we see this low CD4 to CD8 ratio, we might want to do some other follow-up testing for things that might decrease the immune response, like, cancer, like HIV, some of those other things, or if you see a hyper-reactivity, you might say, “Hey, I want to start getting some metrics on, if they’re having an auto immune response.” I might want their ANA. I might want some of those other inflammation markers to see if they’re having inflammation.

And so it’s sort of like, I would say, an overall view of how well your immune system is functioning. But we also are able to read the age of your immune system, right? Immunosenescence is a big problem and one that can be helped by taking things to activate the immune system. But we give you the age of your immune system through that extrinsic age measurement, which is able to use a sort of population level data to say where your immune system is in the course of the lifespan.

Dr. Weitz:            Do these results correlate with senescent T cells?

Ryan:                   So, great question. Absolutely great question. And the answer is yes. So, recently, there was a great paper actually published this year from Rutgers University by Dr. Herbig which was really one of the first ways that they sort of quantified senescent T cells across a lifespan. And we’re hoping that we can then create an epigenetic deconvolution method to predict senescent cells. We actually just wrote our APR’s application to the National Science Foundation a week ago. And so that is absolutely something we’re doing, is we’re helping to quantify senescent cell burden with this testing. And we think we definitely can.

Dr. Weitz:            In terms of interventions to reverse the aging process, let’s go into some of that. The first question I have is there seems to be a little bit of a dichotomy between some of research right now. On the one hand, the first intervention that was actually been shown to reverse aging was the TRIIM trial by Dr. Fahy and others. And it used an intervention of growth hormone, Metformin, DHEA, zinc, and vitamin D. And so the thing I want to focus on is the growth hormone component.  And so, the concept is that as we get older, we tend to lose function. We tend to lose muscle. We lose bone. We have less mobility, and that definitely affects quality of life and even biological aging. And that all makes sense that growth hormone would be beneficial except that everybody, including Dr. Sinclair and Dr. Longo, and a lot of the top people doing research on longevity right now are saying that you want lower growth hormone levels. And specifically, they’re looking at IGF-1 levels, which my understanding is tracks with growth hormone. And so therefore, they’re recommending lower protein levels because they say that that leads to lower cancer levels.

Ryan:                   Yeah. So, absolutely great question. And there’s, again, a lot of conflicting viewpoints here. But I will say that for years and years and years, growth hormone and IGF-1 levels have been correlated to shorter lifespans.  And so there is a good body of data on that looking at even Laron dwarfs who have this growth hormone deficiency and they tend to live longer.  And so with that being said, the first trial was looking, that Metformin growth hormone, DHEA trial, that TRIIM trial was set up. Actually, TRIIM stands for thymic rejuvenation and immunorestoration. So the whole thought process, I think there, was using some of [inaudible 00:46:41] work to rejuvenate the immune system, particularly by rejuvenating the thymus.  And they thought that they could do that through growth hormone. And so that was why they chose growth hormone as the main product. And then they started thinking, “How can we reduce the insulin side effects, the insulin resistant side effects that typically come with growth hormone?” And that’s why they included the DHEA and Metformin.

And so the idea there was that they’re going to regenerate thymus, and they absolutely did. Over the course of that one year and a half year, they were able to sort of improve that thymic fat-free fraction, improve lymphocyte to monocyte ratios. They really did enhance the immune system. And then also, they did see improvements in biological aging.  However, if you were to talk to Dr. Horvath who was also an author on that paper, he would sort of tell you now that the data show that, again, higher growth hormone, higher IGF-1 actually do correspond to lower… Or actually, the higher biological agents.  And so it is looking like the more data that we have that maybe growth hormone is not reversing the age like it should. And so actually in our own trials, we can actually see that we see something similar where growth hormone might not be a super positive effect. And so that leads us to ask questions about Metformin and growth hormone, or it’s just Metformin and DHEA. And in our studies, we actually don’t even see that big of a change with Metformin, which is unfortunate because we’re really big proponents of Metformin was really on track to be one of the first drugs approved for anti-aging benefits.

So for us not to see a change in epigenetic age is a little bit disappointing. But one of the things we do see a change and a substantial change with is DHEA. DHEA was sort of an afterthought and I think that drug cocktail. But it seems to be one of the things that’s best to reversing that epigenetic aging process in our datasets. And one of the hypothesized reasons for that is due to the impact of stress on the epigenomes or on this epigenetic aging process of Dr. Horvath’s original algorithm, 353 spots in that original algorithm.  Over 80 of those spots are located at or near glucocorticoid receptor elements, meaning that the more cortisol you have, the more stress you have, the more it might impact your epigenetic aging and DHEA can mitigate the effects of cortisol. And so out of all of those three drugs, we are actually thinking that DHEA is having the best effect. But also Greg Fahy and Intervene Immune and the Clock Foundation are actually now expanding that trial to the TRIIM-X trial, where in the first trial, they only had nine patients. And they’re hoping to, I think now, it’s expanded to 50 or a hundred.  And so hopefully with that improved dataset, we’ll be able to learn a little bit more. But it was a great question. I think the growth hormone might have given us some unfortunate results in that TRIIM trial. There may be not indicative of its overall effect on longevity.

Dr. Weitz:            Let’s see. So with respect to DHEA being beneficial for longevity because it counters cortisol, what about other methods that functional medicine practitioners use to mitigate cortisol, including lifestyle factors, focusing on sleep, breathing, a series of things? What about supplements that modulate adrenal function like phosphatidylserine and adaptogenic herbs? Would those have a similar effect as DHEA?

Ryan:                     So we don’t know. We’re not even sure that DHEA is having an effect through cortisol mitigation. We think that is. But we’re not certain. And so, unfortunately, we don’t have a lot of that data sets. Just look at people who’ve taken this testing and then essentially done these interventions and taking the test and again. In fact, they’ve only been applied interventional trials published.  Actually, to answer that question though, one of the most recent trials published was actually the work I think that you and I have already talked about by Dr. Kara Fitzgerald which actually did look at some of those adaptogens as well as a probiotic and did things like sort of mindfulness and stress management as a way to maybe even impact that change.  And although her trial was in only eight weeks of time, she was able to see improved results with a significant age-related change over the course of just eight weeks. And so that might add more data to say that stress management might be one of those things that is having an effect. I would say, in our datasets, that is a reoccurring theme, although we don’t know exactly.

Dr. Weitz:            Yeah. She actually didn’t use specific adaptogens for adrenals. She essentially used this greens type powder that contains a bunch of healthy phytonutrients.

Ryan:                     Absolutely. Yeah. I believe that’s a Metagenics product and I think the same with the probiotic. But, yeah, absolutely. But I think the idea was that creating sort of a diet nutrition program along with exercise, sort of a whole lifestyle program to reverse the aging process. And again, we welcome any of those new studies, which are coming out. And we have a couple that are coming out as well. One of the ones that we’re actually just finishing this week is one on some Quicksilver-related products and supplements.  We’ve also looked at things like senolytics such as dasatinib and quercetin. And so as these things start to come out over the next few weeks, we’re going to get them out and information to everyone so we can start figuring out what’s going to change these markers for the better, because again, if you change them, then you’re going to improve your health significantly.

Dr. Weitz:            Since growth hormone is potentially correlated with worse outcome, what do we know about some of the other hormones like estrogen, testosterone?

Ryan:                     Yeah, unfortunately, woefully little. And that is not probably surprising to most people because the way that we’re getting these datasets is via big institutions, things like the Framingham Heart Study, some of these big cohorts that have had samples tested 50, 60 years ago.  Unfortunately, a lot of those same data sets don’t do hormone levels. They don’t even measure them in some of these clinical investigations. And so those data sets are hard to come by. The good news is that the majority of the data sets that we’re getting, most of those people are on hormone replacement. So we’re building those data sets. But unfortunately, we don’t know much right now about estrogens, progesterones, androgens although I will say that we are starting to see an unfortunate maybe negative trend for people who have high levels of androgens particularly over the, I would say, the typical standard reference range by significant amounts. It looks to be increasing or accelerating the aging process. So bodybuilders in particular, I would say, we get some really advanced ages for those people who use significant androgens.

Dr. Weitz:            So we have hormones. What do we know about in terms of food, in terms of… I know you’ve mentioned something about a Mediterranean diet. I’m interested in a lot of times when it comes to discussions about diet and nutrition, one of the issues comes up in terms of what types of macronutrients should we be recommending in particular? And we only have three macronutrients. And so we know that sugar and carbohydrates can be correlated with diabetes and cancer.  And yet, there’s some information that especially Dr. Longo seems to talk about this a lot and Dr. Sinclair did that protein is associated with increased cancer. And saturated fat has been associated with heart disease. So what do we really know about longevity and macronutrients?

Ryan:                     Yeah. So again, as it relates to epigenetic methylation, not a lot. The majority of the research that has been done there has been done by a Stanford researcher, Dr. Lucia Aronica, who did a study called the Diet Fit Study, which compared sort of those low carb diets versus other diets. And so, I think that that data has not been fully analyzed yet. But I do think that we probably tend to see a trend in our datasets to show that the ketogenic diets are positive.  And so, I would say low calorie is definitively good. We already talked about that caloric restriction trial. Low calorie and periods of caloric restriction to then possibly increased autophagy, I think, are highly effective. But as it relates to Dr. Longo, here we’re actually doing a study with the ProLon fasting mimicking diet as well right now, to see how that works. And I think that in our initial data, what we’re seeing is that the prolonged fasting mimicking diet does indeed work or over time.  We’re seeing that caloric restriction absolutely worked. But we’re not seeing the same data, the same positive data for actually time restricted feeding. So people might like to eat between those six-hour windows. And unfortunately, we’re not seeing the same benefit unless they’re also, by doing that, doing some type of caloric constriction.

And so we don’t know a lot about the macronutrients yet. Soon, we actually think that we’ll be able to diagnose or to tell you how much of each macronutrient you’ve actually had by just looking at your methylation. But we’re not sure how it affects longevity. And so I will say that caloric restriction is the only thing we know from a diet perspective that’s great. And in the Mediterranean diet as well can reduce that aging process.  And as you might’ve saw on one of those big slides, if you’re trying to improve your aging rates, consumption of at least one drink of beer or wine per week is great along with more consumption of fish, where if we try and change the intrinsic, we would suggest at least eating poultry two or three times a week. And so I would say that, in and of itself, protein doesn’t look to be bad as long as it’s not in excess.

Dr. Weitz:            Interesting. I recently talked to Dr. Antoun from L-Nutra who works with Dr. Longo. And he said that their data shows that fasting and the fasting mimicking diet are beneficial, but that caloric restriction is not. And I’d also like to point out that Dr. Walford, who was the guy who really put caloric restriction on the map is the professor from UCLA who participated in that. What was the name of that trial where he was locked in that space in Arizona for two years?

Ryan:                   Yeah. I don’t recall the name. But I know the one that you’re referencing.

Dr. Weitz:            The Biosphere 2.  And so it turned out that they weren’t able to produce the right amount of food. And so everybody got a lot less calories. And he looked horrible when he got out, and it turns out that he actually didn’t live that long. I think he died of ALS in his later 70s. And so some people point to that as an indication that a caloric restriction might not be that beneficial obviously and N of one, it doesn’t really mean that much but-

Ryan:                   Exactly. And that’s why I love the calorie trial so much is because it’s over the course of a long period of time, two years. It’s mild calorie restriction. It’s 21%.

Dr. Weitz:            What is… 10%?

Ryan:                   20% caloric restriction. And it’s done in several thousand patients. And so it is one of the first and largest studies of its kind on caloric restriction. And I’ll throw it up here again in case it’s helpful. But again, this goes to show you over the course of 24 months the change in biological aging for caloric restriction, which again, if you’re starting here at baseline, you can see that they’re going even less than half a year, versus those who were not, who are in fast agers aging over two years and in slow agers aging a little bit less.  And so again, this is, I would say, just to start of the data analyzing that’s going to happen as a result of the calorie trial. But we do know that it slows aging and extends lifespan.

Dr. Weitz:            What do we know about exercise and its effect on biological aging?

Ryan:                   Again, woefully little. But we do know a couple of things, which is that there is probably a sweet spot which is that people who over-exercise, marathon runners, even professional athletes tend to maybe have worse biological aging. And we think that’s because they have so much reactive oxygen species. They’re sort of over-training. But we also understand that people who don’t exercise essentially then might also have the reverse. And so for most things, even as I mentioned with alcohol, there seems to be a sweet spot where some is good, but too much is bad.  You’re trying to really bind those. It can be difficult. But, again, I don’t think that that diminishes anything of the testing, particularly, even things the DunedinPoAm pace of aging allow you to do those investigations on the one person that matters for it which is you. You can take a test. You can implement some type of intervention. Let’s just say you want to try caloric restriction. And then retest to see how your pace of aging is going.  And we know that by changing that metric, you change those phenotypic outcomes. You change IQ. You change your sarcopenia risk. You change your risk for dementia or cognitive impairments. And so that we know. And so we also know that is a very precise test, which has a lot of the accuracy between samples. So even over the course of eight to 12 weeks, you can get a good idea of how it’s affecting you personally. And that’s really what I encourage everyone to do, is to start getting that information on yourself and then making the necessary changes to reverse your aging process.

Dr. Weitz:            So you can make an intervention and retest in two to three months and see a significant change potentially.

Ryan:                   Absolutely. And the algorithms are becoming even more accurate. We always talk about the sensitivity. Even with things like telomeres, people wouldn’t use the recommended within a period of a year. And for some of the algorithms, we definitely don’t recommend it over a period of year. But the Dunedin pace of aging in particular is very, very accurate. And so for that one, even over the course of just a few weeks, you can see a significant amount of change.

Dr. Weitz:            And what do we know about rapamycin?

Ryan:                   Yeah. So a good bit, actually. So we’ve done a rapamycin trial. And, unfortunately, we haven’t seen any changes or much changes in blood-based methylation. It’s been significant. We’re still increasing our numbers for those investigations. But we do see a change in other types of tissue, which I think is one of the other things about methylation, which is really, really important is that every cell is going to have a different methylation signature. They’re also going to have different aging rates.  If we were to test your brain, we would get much, much lower ages than if we tested your blood. And if we tested your breast tissue, we would get a much, much higher ages. So all that to say that the tissue type is important. And so for rapamycin, we don’t see changes in blood. But we do see changes in saliva. And part of the reason being is it in saliva, we have epithelial tissue that we don’t have in blood. And so we are seeing positive, beneficial changes in rapamycin. But only in saliva and not in blood, which is interesting.

Dr. Weitz:            Is biological aging correlated with mTOR?

Ryan:                   So unfortunately, we don’t have the data. I should say, as I mentioned, in some tissues, particularly liver and epithelial tissue and in skin tissue, the answer would be yes. Rapamycin as an mTOR inhibitor would then decrease the aging of all of those tissues. And so, we do know that mTOR expression levels when inhibited tend to reverse that aging process in most tissues and in most animals.  But again, that’s really the only mTOR inhibitor that’s been looked at. We’re also doing a couple transplant-related studies who have been on immunosuppressive drugs. A lot of mTOR inhibitors are, hopefully, are going to be able to use that for more data as well.

Dr. Weitz:            What do we know about nutritional supplements to promote aging?

Ryan:                   So not probably unsurprisingly, vitamin D is one that has a massive impact, particularly in overweight individuals that can reverse epigenetic age by 1.8 or 1.9 years over the course of just 16 weeks at a concentration of four to 5,000 IU per day. We’re seeing positive things with things like in NAD-related therapies. All the data still needs to be built out. We’re seeing positive things with methylation support supplements like for instance, L-methylfolate or methylcobalamin in people with certain genetic polymorphisms.  We’re seeing that polyphenols and things like ECGC or citrus bergamot, some of those flavonols can actually help as well. And so we are learning a lot more about those nutritional categories and actually about to publish too a very interesting sort of supplement trials in the near future, which I can’t speculate on now, but are very, very exciting.

Dr. Weitz:            Do we know about fish oil?

Ryan:                   So, yeah. Actually, one of, I would say, probably the best second generation algorithm, GrimAge, is the one that is able to predict death. And in that algorithm and some of those datasets, they were able to correlate higher levels of omega-3 to essentially better response or lower biological agents although in other datasets, they haven’t seen that relationship. And again, there’s been more data coming out now that says, “Maybe, it will not increase your life span.”  I think that we still don’t have enough data, particularly because there’s so much variation even between fish oil supplementation. How much bioavailability you have? How much EPA to DHEA? So unfortunately, that standardized study has not been done. But the GrimAge did report a positive association with fish oils and omega-3s.

Dr. Weitz:            What about supplements that increase NAD production?

Ryan:                   Yeah, so, as I mentioned, we were seeing positive correlations between people who are taking nicotinamide riboside, nicotinamide mononucleotide and/or doing NAD infusions. And so that’s in our dataset where we’re sort of looking at people who do versus people who don’t, which is not, again, the best study. It is informative. But it’s not the best study because probably a lot of those people who are taking NAD-related supplements are also those who were probably the most interested in their own health. So it’s a big confounding factor. But we are seeing a positive relationship between those people who were taking NAD-related supplementation and having sort of a better biological age.

Dr. Weitz:            Do we know anything about NR versus NMR? And do we know anything about dosage?

Ryan:                   Not at all. And I think the doses of NMN are sort of all over the place. And the nicotinamide riboside is a little bit more concrete. But we still don’t know anything about bioavailability. And so without some of that knowledge, it’s going to be hard for us to control and to compare the two back-to-back. And so I’m really hoping a lot of those companies like Tru Niagen and anyone doing NMN will start to get that bioavailability data.

Dr. Weitz:            What about that form of Astragalus that’s supposedly promotes longevity.

Ryan:                   So we don’t know, I should say.

Dr. Weitz:            The TA-65, I think.

Ryan:                   Yeah. TA-65, in particular, is supposed to increase telomerase and telomeres length. And we actually reached out to them for a study to see if we might be able to test their product with some of our telomeres length measurements. And I don’t think we had any interest. But we’d be interested to know as well.

Dr. Weitz:            All right. We have any other questions. Somebody was asking, do you have any special offers for a webinar participants to take the test?

Ryan:                   Unfortunately, we don’t have one now. For any of our practitioners who want to get started though we give sort of a big discount on their first orders. And so if you have any questions or would like to get started on our testing, please reach out to us directly at support@trudiagnostic.com or reach out to me atryan@trudiagnostic.com.  And we’ll hopefully get you started. And I think the best way to sort of see all the benefit is to go through it yourself. And so we’d love to have you do that. Please reach out to us and we’d love to help you.

Dr. Weitz:            And so, what is the process? Can you explain what the process is? Basically, we have the patients go online, register, and then they get sent the kit, or do you send us kits or-

Ryan:                   Yeah. So we can do either. We can drop ship it to the patient, or we can ship it to a clinic. And so if you don’t want the patients to use a finger stick blood spot test, you can collect a purple top EDTA tube from a venous puncture or you could even extract blood from another tube and put it into our tube. And so there’s a lot of ways that you can do it. It’s a really easy collection process for the patient, just takes usually about five to 10 minutes. Then, you drop it in the mail. And then, we’ll send the results back to you in right around two weeks. And so those actual, those boxes, which are kits contain everything you would need. They’re about the size of an iPhone box. So you can easily store it in your office and then give it to patients whenever they have interests.

Dr. Weitz:            Okay, great. And your website is-

Ryan:                   It’s going to be trudiagnostic.com. T-R-U Diagnostic. And again, if anyone wants to reach out to me via email, my email is ryan@trudiagnostic.com.

Dr. Weitz:            Awesome. Thank you so much, Ryan. That was awesome. A lot of very useful information. Thank you to everybody for joining, and we’ll see you next month.

Ryan:                   Thanks so much. Bye-bye.



Dr. Weitz:            Thank you, listeners, for making it all the way through this episode of the Rational Wellness Podcast. Please, take a few minutes and go to Apple podcasts and give us a five-star ratings and review. That would really help us so more people can find us in their listing of health podcasts.  I’d also like to let everybody know that I now have a few openings for new clients for nutritional consultations. If you’re interested, please call my office in Santa Monica at 310-395-3111. That’s 310-395-3111. And take one of the few openings we have now for a individual consultation for nutrition with Dr. Ben Weitz. Thank you and see you next week.


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