Healthy Biological Aging with Dr. Daniel Stickler: Rational Wellness Podcast 184

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Dr. Daniel Stickler speaks about Healthy Biological Aging with Dr. Ben Weitz.

[If you enjoy this podcast, please give us a rating and review on Apple Podcasts, so more people will find The Rational Wellness Podcast. Also check out the video version on YouTube at https://www.youtube.com/user/weitzchiro/]

Podcast Highlights

4:10 The difference between biological age and chronological age is that biological age or epigenetic age reflects the overall health of the system. We are talking about health span as compared with life span. One way to think about biological age is that lower biological age is associated with greater levels of function–physiological, physical, and cognitive.

9:50 We know that as we age, we tend to accumulate damage to our DNA. The telomere test is one way to measure damage to our DNA as a measure of biological age. Telomeres are the ends of our chromosomes that tend to shorten with age, though we are not sure if telomere length is a result of aging or a cause of aging. Another marker of aging is GlycanAge, which measures glycans that build up in your bloodstream.

12:25 Dr. Stickler said that when he is looking at markers of aging he will do DEXA scans of patients to look at lean body mass and bone density testing. EEG studies can be helpful, since certain brain wave patterns are indicative of aging. He will perform skin glycation scanning with immunofluoresence. He will also measure senescent T-cell levels to look at naive (young) vs aged T cells in the blood.

13:05 Dr. Stickler looks at functional mobility and balance. He will look at a bunch of blood metrics like albumin and uric acid levels. He also looks at hormone levels. They are trying to figure out a way to test intracellular NAD levels.

15:02 The methylation clock was first developed by Dr. Steve Horvath of UCLA and it looks at specific methylation patterns on our DNA. The Horvath Clock was developed in 2013 by looking at a constellation of epigenetic marks on the DNA that correspond to chronological or physiological age. Dr. Horvath now has the GrimAge Clock, which is an updated version, which looks at a couple of hundred methylation points on the DNA. Last September we saw the first study published that showed an epigenetic age reversal, the TRIIM Trial by Fahy, et al, which stands for the Thymus Regeneration, Immunorestoration, and Insulin Mitigation trial. [Reversal of epigenetic aging and immunosenescent trends in Humans] Gregory Fahy, Steve Horvath and the other authors showed that their intervention resulted in a reversal of aging of 2.5 years, the first time this has ever been proven. The intervention used a combination of growth hormone, DHEA, metformin, 50 milligrams of zinc, and 3000 milligrams of vitamin D.

24:32 There are a lot of products on the market now that have anti-aging benefits, including Rejuvant, which was developed by Stanford’s Buck Institute on Aging that contains calcium AKG. Also, there is NMN (nicotinamide mononucleotide), an NAD precursor, and there are also senolytics like quercetin and fisetin. Disatinib is a prescription medication that induces apoptosis in senescent cells.

45:03 Dr. Stickler does recommend resveratrol for anti-aging, though it is probably not a powerful stimulator of NAD. He recommends a multivitamin, 5000 IU vitamin D, 2 gm of fish oil, and sublingual or injections of B12.



Dr. Daniel Stickler is the co-founder and Chief Medical Officer at Apeiron ZOH, Inc. He is a physician for high-performing executives, entrepreneurs, and elite athletes. He consults with Google for wearable technology, epigenetics, and AI in healthcare. He is on the faculty of the Age Management Medical Group and is also a guest lecturer for Stanford University on Epigenetics in Clinical Practice. He is on the board of TruDiagnostic, who he is representing on this podcast today. TruDiagnostic offers the TruAge, which measures your rate of biological aging based on measuring 900,000 CpG sites on our DNA to see if they are methylated or not. Their website is TruDiagnostic.com.

Dr. Ben Weitz is available for nutrition consultations, including remote consults via video or phone, 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, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111 or go to www.drweitz.com. Phone or video consulting with Dr. Weitz is available.



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. Thank you so much for joining me again today.

Today our topic is methylation, epigenetic methylation time clocks. So this is a way to measure biological aging and so we’re going to discuss that and then some of the things that we can do to try to reverse aging. We want to know why in hell we age and what we can do about it and there have been a number of attempts to develop a method to measure biological aging as distinct from chronological aging. In other words, does our health correspond to someone younger or older than our chronological age and what can we do to slow down or even reverse aging and how can we know that our methods are working if we’re engaged in an anti-aging program? We do know that as we lead our lives, our DNA tends to get damaged and develops various types of defects and perhaps we can measure this in some way. One of the methods that has been around for awhile is measuring the length of the ends of our chromosomes, known as telomere length. Shorter telomeres corresponds to increased biological aging. Recently there’s been a lot of research devoted to developing epigenetic DNA methylation clocks, which measure the extent to which parts of our genes are methylated. Meaning are they over-methylated, under-methylated, et cetera.

We know that methylation can turn on or turn off genes and there are some genes you want turned on and there are some genes you don’t want turned on. So these clocks measure whether specific locations on the DNA, known as CPG sites are methylated or not and Dr. Steve Horvath and Dr. Gregory Hannum are two of the most important researchers in this area who have each developed a different version of the methylation clock. Now, the practical application of these clocks is starting to become available for use by clinicians and for patients to measure this biological aging and True Diagnostics is a company that’s offering the True Age test, which measures your rate of biological aging based on measuring 900,000 CPG sites on our DNA to see the extent of their methylation.

Today we have Dr. Daniel Stickler joining us today and he’s the co-founder and chief medical officer at Apeiron ZOH Incorporated. He’s a physician for high performing executives, entrepreneurs, elite athletes. He’s also a consultant to Google for wearable technology, epigenetics and in healthcare. He speaks regularly and is on the faculty of the Age Management Medical Group. He’s also a guest lecturer for Stanford on epigenetics. He sits on multiple advisor boards, including the board of True Diagnostics, who I just mentioned, who he’s representing on this podcast today. So Dr. Stickler, thank you so much for joining me today.

Dr. Stickler: Thanks, Doc. A pleasure to be here and look forward to the conversation.

Dr. Weitz: Sure. So let’s start with what is the difference between chronological age and biological age?

Dr. Stickler: Well, that’s a good question, because we don’t even have a consensus that aging is a true condition. I mean, we see it and we recognize that aging occurs, but some of the more recent literature coming out from the Aging Researchers is that we really don’t have a definition of age. It’s just a … It’s a constellation of markers that we allocate to it, meaning there’s no question, we gradually deteriorate and die and there’s a question is that a programmed response? Is it a gradual breakdown of the physiologic machinery or is it a combination of the two? So it’s a vague area right now, but essentially, chronologic age is just a core marker of anything.

You see 70 year olds that function like a healthy 50-year-old and you can’t say that they’re 70 years old relative to a comparison of the average of that age group, so people have shifted more towards this biologic age. But again, that’s not something … I don’t like the actual metric of age as a metric, whether biologic or chronologic, because it’s really the health of the human system that we’re looking at. What we are gathering right now is all these biomarkers that indicate the health of the human system. I mean, it’s not pleasant to be necessarily told if you’re 70 years old, that you look good for your age. Well, what does that actually mean? You’re compared to the average of people of that age. So I tend to really kind of shift away from aging as a general statement and like to look at it as more of these are markers of the youthfulness in the system or health in the system.

Dr. Weitz: I’ve always liked to think of it in terms of function and I think the goal for myself and a lot of us is how can we have a high level of function ’til close to the end? Instead of expecting that once you hit your 40s or 50s, you just get this gradual decline in your ability to function, in your mental capacity, in your physical capacity, so that as you go through your 60s and 70s and if you’re lucky enough to get into your 80s, you can barely move. You barely have any level of function and the idea of simply living a long time doesn’t sound all that attractive if you don’t have a high level of function. In the past, we’ve talked about taking that curve where you gradually go downhill once you reach a certain point and trying to rectangularize it so you have a relatively high level of function until you get to the end. I think of biological aging as corresponding to having a higher level of function.

Dr. Stickler: Yeah and we’re seeing that. I mean, the markers that we’re gathering together, although none of them are perfect, the constellation of those markers really indicate what you’re talking about is what we refer to as health span. We want to extend health span, not only life span. People don’t have quality of life if their level of functioning is more of an invalid type of aspect or I always look at it as when I get to the point where my body can’t respond to what my brain is asking me to do. That’s a pretty broad spectrum, but it’s when it’s just basic functional aspects that get deteriorated.

Dr. Weitz: Right and in terms of function … Over the years, there have been a number of markers of physical function that seem to have a correspondence with healthier aging and there’s been grip strength. I saw a study where just being able to get up from the floor without using your hands and so it appears as though having a certain level of strength and mobility is important for healthy aging.

Dr. Stickler: Yeah, I mean, everybody’s looking for the perfect marker right now and, like I said, I think it’s going to be a constellation. I mean, in our longevity program, we call it the Rejuvenation Program, we’re looking at a bunch of metrics right now and we get varying degrees of somebody who’s really good in one area and weak in another, what does that mean? We don’t know. That’s why the more data we gather on that, and we get probably 20 or 30 markers that we use right now and we’re hoping to create kind of a health grade. Not necessarily a biologic age, but a health grade according to how you score in all these areas and it’s going to take some time and some data before we really establish what are the best markers and what grouping of markers is going to be the most telling.

Dr. Weitz: So we’re going to get into the epigenetic clock in a few minutes, but what are some of the other methods that can be used to calculate biological age right now?

Dr. Stickler: Well, like you said, the telomere testing is one.

Dr. Weitz: And what is the status of telomere testing?

Dr. Stickler: That’s a good question, because even the people in the aging industry are torn on this, because question is, is telomere shortening a result of aging such as getting gray hair or is it a cause of aging? And that question has come up recently without a good, solid answer. So telomere testing, because of such high variability in the outcomes related to other markers, it’s kind of been pushed aside a little bit. It’s an expensive test. We get it and we get it about every five years. Not frequently. And it’s not the best guide, because it takes so long to change something on that and generally you’re looking at diminishing the rate of loss on those as opposed to trying to extend them, although some of the research now is really focused on doing a genetic insertion or a plasmid that can actually add length to the telomeres versus supplements or peptides that can stimulate the telomerase themselves to add more length to it. We use another one called GlycanAge. So glycans are substances that build up in the blood over a lifetime and we’re testing this. They have pretty good data based on some preliminary studies they did.

Dr. Weitz: Is that like glycation? Like glycosylated hemoglobin?

Dr. Stickler: Not exactly. I mean, glycation is a component, but these are glycan products that are found in the blood and they do accumulate over time. It’s a fairly new area. We’ve just started testing with it in the last year and we see huge differences in the epigenetic age and the glycan age, but they have some pretty good data from the…

Dr. Weitz: What’s an example of a glycan product?

Dr. Stickler: I don’t know the specifics on those.

Dr. Weitz: Okay.

Dr. Stickler: I mean, there’s several hundred of them that they’re measuring.

Dr. Weitz: Okay.

Dr. Stickler: We do DEXA scans, so we look at lean body mass. We look at bone density. We do EEG studies, because there’s certain brainwave patterns that are indicative of the aging process. We do skin glycation scanning with immunofluorescence. We do senescent T-cell levels from UCLA to look at the naïve versus aged T-cells in the blood.

Dr. Weitz: So these are young versus old T-cells?

Dr. Stickler: Correct and we look at functional mobility. We look at balance. We look at stress response in the system. We look at a bunch of blood metrics, so like albumin, we look at uric acid levels. We look at hormone levels and right now, like I said, it’s just a matter of collecting as much of these as we possibly can. NAD levels, if we can figure out a good way to test intracellular NAD levels is a hot topic right now as well.

Dr. Weitz: Right. So as a step to get into the biological clocks, what is epigenetics as different from genetics for, especially for the layperson who happens to be listening in?

Dr. Stickler: The best way I can put that is that genetics is the hardware whereas epigenetics is the software. What I mean by that is that the hardware doesn’t change. It is … You only need your genetic stem one time, but epigenetics is something that controls the expressions of the genes that you have. That’s why you can have one cell that creates a neuron and another stem cell that creates a lung. This is using the exact same code, so every cell has the exact same genetic code, but the expression of that code is controlled to create the outcome. We have kind of trans-generational and generational epigenetics, which are usually the epigenetics that are written in pen on our DNA so that they’re there and it’s really tough to make any changes in that and then you have the epigenetics that are written in pencil. Those include not only the DNA methylation, but also histone methylation, which is one of the ways that we know that lifestyle, that supplementation, that medications, all of those things can actually impact and change the expression of genes and this is the area that really people focus on when it comes to the epigenetics.

Dr. Weitz: Okay. So what is the methylation clock? This epigenetic methylation clock?

Dr. Stickler: So Steve Horvath developed this methylation clock where he started looking at specific methylation patterns. So he took groupings of aged people and looked at a constellation of epigenetic marks on the DNA and what he noted is there were a bunch of these that accumulated over time that corresponded to their chronologic or physiologic age. He developed the Horvath Clock, I think back in 2013. He now has the GrimAge Clock, which is a more updated edition of it. But again, they’re only looking at a couple hundred methylation points on the DNA, so it’s rough right now, although we had the pleasure of seeing the study that came out in September of last year that showed an epigenetic age reversal. So the prevailing theory at the time, and you even hear David Sinclair had stated it prior, was that epigenetic aging is a one way linear process where you gradually accumulate these over time and it’s not a process that we have any control over, because mostly it was thought that these were the marks that were written in pen that were accumulating.

Dr. Weitz: So let me just stop you for a second. So the study you’re referring to is the TRIIM Trial by Fahy and it was published in September of 2019 and TRIM stands for Thymus Regeneration, Immunorestoration, and Insulin Mitigation trial.

Dr. Stickler: Yes and they showed a 2.5 year gain or loss of age after a one year period on this trial and they only had nine participants, but still, it was the first time that something showed that age reversal, in a sense, if we’re using this as a marker, is theoretically possible and it excited people. So a lot of the kind of world view of aging began to shift, which was dramatic. In the same month, Sinclair releases his book, so we had the perfect storm of shifting mindset, which was great. And what they used in the trial, I mean, for those of us that do age rejuvenation medicine in practice, what they did in the trial was baby steps. I mean, we have such in depth treatments right now, not only over the counter treatments, but research chemicals, peptides and prescription medications that can be used that are amazing. Even technology. I mean, we use brain stimulation technology and we’re seeing rejuvenation of aging patterns on the brain waves with that.



Dr. Weitz: This podcast episode is sponsored by Quicksilver Scientific. Quicksilver Scientific is a leading manufacturer of nutritional supplements, featuring enhanced nanoparticle delivery systems, specializing in detoxification protocols, fast acting immune formulas, and next generation longevity products. To learn more or to sign up for a professional account, visit quicksilverscientific.com. Listeners of this podcast can receive 15% off their order by using the promo code Weitz, WEITZ2020 at checkout. And I definitely utilize Quicksilver products in our office and some of their products are just absolutely amazing and there’s nothing like it on the market, so thank you to Quicksilver.



Dr. Weitz: Interestingly, as I have sort of been watching the anti-aging research, the predominant, as I see it, in my limited understanding of it, is a predominant theory maybe 15, 20 years ago is our cells die. They don’t get replaced. We lose muscle cells. Our bones degenerate. Our brain cells don’t get replaced. So a lot of the focus was on trying to stimulate growth. So things like growth hormone and testosterone and DHEA and these are really common strategies. Recently, in the last five or 10 years, the focus seems to be, at least from what I’ve seen, not some of the stuff you’re talking about necessarily, but the stuff that gets out more in the popular literature seems to be all about caloric restriction and fasting and fasting mimicking diet and things that limit damage, but don’t necessarily stimulate growth. So it’s interesting that they chose growth hormone as one of the strategies.

Dr. Stickler: One of the things they look at with hormones is you look at when the body functions optimally. What are the parameters that meet that? And growth hormone, testosterone, these are two parameters that deteriorate with age. Is this a natural process? Sure. Is it a healthy process? And most of us feel that it is not. We do note that function improves dramatically and markers of aging improve dramatically when hormones are put into healthy, youthful levels. I’m not talking about super physiologic doses in this, but in dosage levels that maintain the health. I mean, growth hormone in itself is a double edged sword. Too little is unhealthy and too much is also unhealthy. So you’ve got to keep in that Goldilocks zone of that.

When it comes to calorie restriction, recent analysis has kind of pushed back a little bit on that too. I mean, calorie restriction definitely has an impact, but calorie restriction to the point that’s required to match what they see in animal studies is pretty unpleasant state to be in. I mean, there’s no question that total calorie restriction is beneficial, but to achieve really substantial outcomes, I mean, the hunger that you would experience wouldn’t make life worth living, I don’t think, which is a big impact and now they’re actually leaning towards the chronic calorie restriction is not the best way to do it, but that you do spurts of it. So intermittent periods of it that allow the body to adjust. I mean, stress is a good thing for the body. It makes the body adapt and severe calorie restriction is a stressful event on the body.

Dr. Weitz: So for those of us who haven’t seen this study, they used the combination of growth hormone, DHEA, metformin, which is a popular drug for diabetes, because it reduces insulin resistance, but they also used 50 milligrams of zinc and 3000 milligrams of vitamin D. One of the things they showed was that there was increased stimulation of the thymus gland, which tends to degenerate with time, and that’s what they mean by immunorestoration. As your immune system weakens, you become more vulnerable to bacteria and viruses, just like older folks are dying at a higher rate from COVID-19. So keeping your immune system robust is important. We know zinc and vitamin D are crucial factors in immune function, but I haven’t heard too much talk about the potential benefits of zinc and vitamin D from this intervention study.

Dr. Stickler: Yeah and I mean, zinc and vitamin D are one of the first line interventions for COVID right now.

Dr. Weitz: Yes.

Dr. Stickler: From the consensus in the medical community.

Dr. Weitz: Yes.

Dr. Stickler: And since vitamin D is generally deficient in about 60 to 80% of a given population, it is important to supplement that and the zinc is also a double edged sword, because you can get some zinc toxicity with that.

Dr. Weitz: Sure.

Dr. Stickler: One of the things we look at is the genetics that relate to cautions with zinc and base our recommendations on that personalized approach with them. But there’s, I mean, when it comes to aging, there’s a lot of available stuff on the market right now. I mean, Rejuvant, which is calcium AKG, which was developed at Stanford’s Buck Institute on Aging, was developed by Brian Kennedy and it’s got really amazing aspects to it.

Dr. Weitz: Can you repeat that? That’s not something I’m familiar with.

Dr. Stickler: Rejuvant is the brand name of it.

Dr. Weitz: Okay.

Dr. Stickler: But calcium AKG, alpha-ketoglutarate.

Dr. Weitz: Right.

Dr. Stickler: We know deteriorates over time with aging and replacing that has, I mean, it impacts about five of the nine hallmarks of aging that need to be targeted. You have NMN, which is over the counter, and you have vitamin D, of course. You have senolytics now. I mean, supplemental senolytics. I mean, we have prescription senolytics, which take out those zombie cells that accumulate over time that the body can’t get rid of and they secrete toxins. They take up metabolic aspects of the body and when we can reduce them, we dramatically change the outcome. We use the senolytic formula that has quercetin and fisetin in it, which are two different over the counter senolytic compounds that have shown really impressive benefits. I mean, quercetin has been around forever and…

Dr. Weitz: It’s also a zinc ionophore and so we’re using that in our immune protocols these days.

Dr. Stickler: Absolutely and they found quercetin because they ran a study through a bioinformatics platform and they said, “These are the pathways we want to hit, what’s available that works on this?” And it kicked back to quercetin and dasatinib. I mean, dasatinib is a prescription, but these are two senolytic compounds that have a profound impact on aging. The key is really knowing how to take these in combinations that can create the outcome that you’re looking for.

Dr. Weitz: I looked at a PowerPoint presentation that Dr. Horvath had and one of his first slides shows a 71-year-old guy who’s an amateur body builder and he looks very good for his age, but it says on the slide that if you use clinical markers of aging such as body mass index, grip strength, blood pressure, he will probably be considered young for his age, though he is probably old according to molecular biomarkers such as the epigenetic clock. Dr. Horvath says that the message is that … This is what he says on the slide. That the message is that molecular markers will not be misled. What did he mean by that?

Dr. Stickler: Well, again, this is an area that what we’ve found, and you know, it’s funny because I found it in several of my clients, because I work with some professional athletes and their epigenetic age markers were, some of them 10 years older than their chronologic age and these were very fit, healthy people. There was a follow up study that was recently published looking at athletes and epigenetic age and they tend to be older. I know I was … I did a podcast not too long ago with Ben Greenfield and he got tested and he came out older than his chronologic…

Dr. Weitz: I saw it. I think his age is 38 and he was 43 or something.

Dr. Stickler: Yeah and so the study though that came out, some of the markers that they’re using to establish epigenetic age were methylated, which means the genes were turned down or turned off and it was interesting, because they picked out like three or four of these in particular that actually code for better health in the sense that it reduces cancer rates and heart disease. So even though the accumulation is over time, there’s benefits there. So are we truly measuring that? And that’s the issue right now, and this is what I love about True Diagnostics is they’re looking at 900,000 methylation points. How many of those do we know about? Well, maybe 5% of those that we actually have information on. So what they’re doing is not only storing this or keeping this report together, but as data accumulates, it will update that report for you so that you can contribute to it too. You provide feedback on other aspects of like lab work and your social behaviors and suddenly we can start narrowing this down. I mean, this is the age of bioinformatics and the more data we have, the more accurate we can get with what we’re doing. This epigenetic age for these athletes and these really significant exercisers, I don’t think is a reflection of their true physiologic age. So it has to be taken with an understanding of what you’re actually measuring there.

Dr. Weitz: So how does the test determine if a gene is methylated, if it’s methylated too much to a point where that J shape curve now is going the opposite direction or not methylated enough, does it take into account all that? Can it?

Dr. Stickler: You’re asking me a technical question that’s more for the biochemist, but I don’t believe it goes into specifics of the degree of methylation. Just the specific markers they’re looking at, is there a methyl group added to that marker on the DNA is the primary focus.

Dr. Weitz: Right, so interesting, in the Functional Medicine world, one of the things that we’ve been looking at for a number of years is potential for methylation based on doing genetic testing and then seeing if somebody has certain genetic markers like the methenyltetrahydrofolate reductase gene and if they’re heterozygous or homozygous for two defects, they may not be able to methylate and then we may use specific methylated, activated B vitamins to try to stimulate that methylation. But then we’re also cautious to try to make sure we don’t over-methylate, which certain genes that are over-methylated can lead to increased breast cancer risk, et cetera. So I’m wondering if there’s a way that this methylation testing could be used for feedback, say, I have a patient, they are homozygous for MTHFR and we give them methylated B vitamins. Is there a way that we can then tell are we properly methylating their genes? Are we under or over methylating them? Can we titrate the dosage? I’m wondering if there’s something like that, that is or might be available.

Dr. Stickler: Another great question, because again, we don’t have the answer to that. How does the body’s ability to methylate affect the aging methylation of the DNA? And there isn’t an answer. I mean, again, using genetics, and I run a genetics company and we test MTHFR 677 and 1298, and I have seen clients that had homozygous on both of them, which means that they have less than 25% function of the MTHFR, yet they have normal homocysteine levels and most of the time it’s because they’re consuming adequate methyl folate in the diet. And looking at these polymorphisms, which is what we’re testing in, in genetic testing right now when we’re talking about 23 and Me, when we’re talking about the Apeiron test, Ancestry, they’re looking at polymorphisms and these are not mutations. I think this has been taken to the point where it’s very misunderstood by the general public. These are variations that have inherited through your ancestry that are designed to optimize your system for the environment that you’re in. The problem is now we move around all over the world and we’re not in that ancestral environment that our genes are optimized for, so we have to make adjustments to our environment to match our genetics. This is nutrigenetics. It is basically eating for your genes as opposed to nutrigenomics, which is eating to change expressions of your genes. I really want to see this whole idea of these polymorphisms as mutations to kind of go away, because it really is … It’s putting a lot of fear into people that essentially are unnecessary. So really understanding not only the genetics, but the markers that occur with that and the lifestyle of the person that has them. I mean, I have plenty of homozygous MTHFRs that I’m just like, “You don’t need any exogenous treatments on that. You’re doing well with what you’re eating, apparently, because you don’t have the expression that is showing.”

Dr. Weitz: Right. Yeah, good. Yeah, we gauge a lot of the recommendations based on things like homocysteine levels, et cetera.

Dr. Stickler: Yeah.

Dr. Weitz: So what is the difference between the True Diagnostics True Age test and the Horvath clock? It’s using the Horvath clock or it’s…

Dr. Stickler: There are aspects of it in there. Also, Dr. Hannum’s and the Duke clocks that are being used. So it’s a combination of them and it’s really designed to be the largest database of epigenetic marks on the market. I mean, honestly, we can’t give you a great deal of knowledge with these reports yet. We can give you an overview of the knowledge that we’ve accumulated, but over time, as more and more people do this, we’ll be able to dive deeper and give you insights into what’s happening. The great thing is we have all these markers now and so now that we know that we’re looking at these markers, we can run it through the AI that we have that will mine this stuff and say, “Here’s all the people that are smokers. What do you see in common with them that’s not in non-smokers?” And so we can start diving into the bioinformatics, which is going to be huge for people. I mean, this is truly the next three years, we’re going to see such advances in epigenetics and I think a lot of the genetics stuff is going to fall by the wayside from that point. It’s not that we won’t need genetics, but we have to look at it as just another biomarker and the epigenetics is going to be really the top piece that we’re going to be focused on.

Dr. Weitz: So as I understand it, the Hannum clock used blood and measures methylation on white blood cell DNA, right?

Dr. Stickler: Right.

Dr. Weitz: But the Horvath clock or the newer version of the Horvath clock, uses DNA not just from white blood cells, but from other tissues.

Dr. Stickler: Mm-hmm (affirmative).

Dr. Weitz: Is that improvement? Your test basically is using the white blood cells, right?

Dr. Stickler: Right, and that’s always a question, because like I said at the beginning, every cell has different methylation. Every cell type in the body has a different methylation pattern to it, but what we’re looking at are these common denominator methylation patterns and generally you’re going to get correlation with the epigenetic markers that have been selected with like a buccal swab where we’re looking at epithelial cells from the skin or we’re looking at the blood or we’re looking at salivary accumulation. Whatever we’re looking at, the idea is that there is tissue specific methylation patterns, but then you’re also going to get universal methylation patterns that can be derived from any cell type that you get and that’s the focus of the epigenetic testing right now.

Dr. Weitz: So how can clinicians use this True Age test?

Dr. Stickler: Well, the way I use it in practice is that I will get the epigenetic age. We’ll do an intervention for a year or a series of interventions, and then we will retest. I have to say, right now, and this is being reported by several of the epigenetic companies, is that this year in particular, relative to people who got tested last year at this time, we’re seeing an acceleration of aging and what we are assuming this is relating to is the stress of this whole COVID-19 issue.

Dr. Weitz: Sure.

Dr. Stickler: It’s impacting people in ways that they don’t fully understand. I mean, the stress of anything that changes your habits in any way is a stressor on the body. We see these elevations in cortisol levels, despite the fact that we’re working with people to mitigate these, so I think that…

Dr. Weitz: People are eating worse. They’re exercising less.

Dr. Stickler: Yeah.

Dr. Weitz: I saw the CEO of Kellogg’s on TV bragging about the fact that more people are having breakfast cereal for dinner. They’re afraid to have time with other people, so they have less social connections. There’s a whole series of things along with the stress.

Dr. Stickler: Absolutely. Yep.

Dr. Weitz: So what are some of the things that negatively affect our aging? I noticed on the True Age test they mention exposure to heavy metals, pesticides and other toxins.

Dr. Stickler: Right, there’s eustressors and then there’s mal stressors. The ones that … A eustressor is good, because we have a certain kind of bandwidth that we function in and within that bandwidth, our gene expressions are set to really optimize the human body’s function within that realm. Little excursions outside that realm create stressors. Just like if you haven’t exercised in six months and you go back to exercise, suddenly you’re exceeding the body’s baseline of that comfort zone and creating a stress response. Is that a bad thing? No, that’s actually a good thing. It’s a hormetic response that the body responds and says, “Hey, this is an unfamiliar environment. I have to make adjustments to create a healthier, more resilient, anti-fragile human,” and so you get beneficial effects in that way, but there are some stressors that will take you too far out of that zone. Those can be things like heavy metals. Those can be things like smoking. Those are parameters that don’t have really an established eustress type of benefit that the body will respond in a positive way and make you more anti-fragile. It actually drops you down outside of that familiar zone and makes the system weaker.

Dr. Weitz: I notice you also mentioned adrenal cortisol dysregulation as pointing a role in biological aging. Is it in general, can you say, is it more of a lower, flattened cortisol curve or increases in cortisol that tends to correspond to worse aging?

Dr. Stickler: I mean, it’s not a … It’s that double edged sword again. Too little is not good and too much is not good. So you want to kind of keep within certain parameters with slight excursions outside of your familiar zone to create the positive response.

Dr. Weitz: Right.

Dr. Stickler: But most of the time … We do a lot of work with adrenals and we look at diurnal variations in the cortisol secretions and what we’ve found generally is we tend to blame the adrenal gland for it and the adrenal gland is nothing but the messenger. We find that when we work with stress response as far as what the perception of stress is and how the brain responds to it and how it stimulates the adrenal gland, that’s the win for the mitigation of this where we train through bio feedback mechanisms to do that. Now, using adrenal adaptogens and that, they’re nice bridging pieces for it, but really you’ve got to get to the real central aspect of what’s creating the stimulation or lack of stimulation to the adrenal itself.

Dr. Weitz: Bringing up nutritional supplements, you mentioned a few already. We talked about zinc and vitamin D. You mentioned quercetin or quercetin, I’m not sure how it’s supposed to be pronounced, and that calcium supplement you mentioned. What other nutritional supplements … I think you mentioned nicotinamide riboside or…

Dr. Stickler: NMN.

Dr. Weitz: NMN, okay. You think that’s a preferred version over NR?

Dr. Stickler: Again, that’s something that we don’t have good data on.

Dr. Weitz: Okay. Okay.

Dr. Stickler: I mean, one of the biggest problems is people report doubling or tripling of NAD levels and when you see that, always question the study, because what we care about is absolute levels, not change from baseline, because somebody that’s got a 1% of where they should be and they triple that, they’re at 3%. What kind of boost is that? That’s not.

Dr. Weitz: Right. Yeah, yeah.

Dr. Stickler: So looking at the ideal way to do this, and really, I’m not a big fan of the NIDIVs. I mean, they give you a short burst, but the body gets rid of that in the next 24 hours. I think a lot of what people experience as a stress response that creates a euphoric feeling and they perceive that they’re getting benefit from it. So what most people are looking at is how do we chronically supply new NAD to the cells and so the debate is do we do intramuscular injections daily? Do we do IVs? Do we do supplementation? Should we do NR or NMN? There’s going to be some data coming out from James Clemons’ lab that I think is going to probably shift us more towards using NMN iontophoresis where we actually put a patch on, an electrical patch, that we put the NMN in to that will absorb based on electrical charges and we can do that even twice a day or a couple times a week and create the higher levels of NAD in the cells, which is really the ultimate goal in that.

Dr. Weitz: Interesting. What about resveratrol?

Dr. Stickler: Resveratrol is … I wouldn’t look at it from a standpoint of what they were initially looking at it. I mean, they were looking at it as a SIRT receptor stimulant and creating more NAD, but I think resveratrol actually has antiaging benefits. Are they from what we think we are saying? I’m not sure. I think resveratrol for somebody who is interested in age rejuvenation, and we add that to our senolytic formulation. I think that there is some benefit, we just don’t know what it is right now and I think it’s kind of minor, but we’re still looking at what’s the complete complement that can create the system? One thing that people tend to neglect is a daily multivitamin.

Dr. Weitz: Right.

Dr. Stickler: We have so many micronutrients that are deficient when we look at our nutritional intake and our nutritional needs and so I have a core that I put everybody on. It’s a foundational multivitamin, and not an excessive one. If some people are taking like six or seven multivitamins a day. I’m just like if you’re taking more than two, you’re probably taking too much. Just eat healthy, take a small dose of it. The vitamin D, and we use a 5000 IU or D3 plus K2 fish oil, so we do use fish oil and this is because of epigenetics. I mean, there’s always debates about is fish oil good for you? Is it bad for you? Different outcomes in the same week from the research. But what we do know from epigenetics and nutrigenomics is the chronic intake of fish oil really up-regulates metabolic gene activation and down-regulates pro inflammatory gene expression. So we do use fish oil, usually just two gram a day, and we also recommend B12 supplementation and either through injections or through a sublingual. Those are essentially our core, what we call foundational supplementation and then from that point on, we go into more bio-specific or more longevity focused or performance focused lines of vitamins, but we just have that foundation of we pretty much recommend for everybody as a core.

Dr. Weitz: Okay. What about specific diet? Has there been any work on … I noticed on the True Diagnostic website, Mediterranean diet was mentioned. What about Mediterranean diet versus vegan versus paleo or et cetera? Do we have a sort of…

Dr. Stickler: It again comes from [crosstalk 00:47:57].

Dr. Weitz: Depending on the person? You know?

Dr. Stickler: Yeah. I mean, it’s genetics again. When we look at gene expressions based on dietary patterns, there is no perfect human diet. I mean, if you take somebody that’s got an ancestry with [inaudible 00:48:17].

Dr. Weitz: We’re getting a weird echo.

Dr. Stickler: Yeah, there’s actually a lawnmower outside.

Dr. Weitz: Oh my gosh.

Dr. Stickler: Sorry. Yeah, didn’t expect that.

Dr. Weitz: Okay, not much you can do about that.

Dr. Stickler: Yeah. But if you have somebody with ancestry of Inuit Eskimo, their genetic polymorphisms that they’ve inherited are optimized for that environment, so a high fat diet is going to work very well for them. If you have somebody who is southeast Asian and more of a starchy diet works for them. Most of us in the United States have some kind of a core background of a Mediterranean heritage and around that, so European, Mediterranean, you’re going to find that the genes respond best to the components of the Mediterranean diet. A fish-based, high vegetable and significant intake of olive oils, we’re finding that the markers that we look at in aging, we are personally, from an anecdotal experience, finding that seems to correlate best with the outcomes.

Dr. Weitz: Yeah. So essentially as we’ve been talking about in functional medicine for a long time, you’ve got to match the right diet to the right person. What medications have been shown to slow down or reverse epigenetic aging?

Dr. Stickler: Well, the first one I talked about earlier was the dasatinib. That is a senolytic that’s really powerful and what we typically do is we’ll do…

Dr. Weitz: Is there another name for that? For those of us who are not familiar with it?

Dr. Stickler: Not that I’m aware of.

Dr. Weitz: Okay. Okay.

Dr. Stickler: [crosstalk 00:50:06] is, but I can’t think of it right now.

Dr. Weitz: Okay.

Dr. Stickler: That’s the generic name. D-a-s-a-t-i-n-i-b.

Dr. Weitz: Okay and what was that drug originally developed for?

Dr. Stickler: It was used as a … I can’t remember exactly, but it’s been around for many years. This was the one that they found in the bioinformatics platform that found that it limited that, but the way you use that is you typically take it for two days, like a Monday and a Tuesday for two to three weeks in a row and then you stop and then six months later you may take it again. The thing with senolytics is they tend to target specific organ types. So the skin, the liver, the fat. You will target different areas that it will reduce the senescent cells, so you want to use combinations of those. We also have rapamycin. Rapamycin is wonderful. This was developed as an adjunct for people that have had kidney transplants to suppress the immune system.

Dr. Weitz: Right.

Dr. Stickler: But we use it in lower doses and dasatinib is a [M4 00:51:25] inhibitor, which is one of the aspects that we know creates more youthful expression in the body as inhibiting M4 over time. But the other thing they found is that, when we talk about senescent cells, and I think this is the most important thing that rapamycin does, is it mitigates what are called SASPs that are secreted by senescent cells and those are the toxic elements that are secreted by these cells. So the rapamycin seems to mitigate that and you don’t do a lot of this. I mean, it’s like a once a week dose of two to three milligrams that is effective in that and you have to watch for side effects with it.

The other one is metformin. I mean, classic. Metformin is one of those ones that anybody focused on longevity, we typically work with on the metformin. It is a true M4 inhibitor. It’s one of the most potent ones that we have available to us and a lot of people will say, “Well, doesn’t inhibiting M4 limit the ability to grow muscle?” Which frailty is a hallmark of aging, but all the studies that have been done have been using metformin as an individual piece. Now, with our clients, we will use things, other things like testosterone or growth hormone, releasing hormone, and we monitor DEXA scans to see what their lean body mass is doing over time. We’re finding that the metformin is not indicative of muscle growth in that way, so we like the metformin in that regard.

You’ve also got some peptides, which don’t have a great deal of research behind them, but they’re finding that they do have significant impacts on aspects of aging. I mean, we look at things like mitochondrial rejuvenation and mitochondrial biogenesis and we have things like GW501516, which is not a peptide, but a research chemical. We have things like SS31, which is a fairly new one. We have things like MOTSC, which are peptides that have the substantial impact on mitochondria. Those are also ones called [inaudible 00:53:53] which we don’t have a great deal of data on and there’s things like [Hepatilon 00:53:57] which from the Russian researchers, they have a six and a 12 year study using Hepatilon. We have things that can rejuvenate the thymus like Thymoline or Thymosin alpha, which boosts the immune system.

Dr. Weitz: What about BPC157?

Dr. Stickler: BPC157 I really like. I love the oral form for the gut. I mean, you talk about something that heals the gut almost 100% of the time, [inaudible 00:54:27] oral BPC. Talking about working on really neuro-protection or soft tissue recoveries, BPC is wonderful for that. It accelerates the recovery for that. I don’t find that it happens very well with the oral, but the oral is awesome for the gut, for sure.

Dr. Weitz: Cool. Good. So I think that pretty much concludes my questions. Any final thoughts you want to leave us with? And then give us information about how to find out about this test as well as anybody who would like to get ahold of you?

Dr. Stickler: Yeah. The one thing I always like to emphasize is that everything starts with lifestyle, first and foremost. I mean, and that’s what I tell people, 90% of what I do in my program is lifestyle orientation and you can’t focus on the standards of just nutrition and exercise. I mean, if you’re not addressing stress, if you’re not addressing brain health, if you’re not addressing even mindset. I mean, mindset is a huge piece. Love and relationships, a huge piece. So all of these lifestyle components play together and trying to isolate them into silos and thinking you’re going to have an impact is naïve. So really working with all aspects of the way you function is really important.

Now, to get the epigenetic test and really to be part of something that’s pretty exciting, go to truediagnostics.com and you can find out how to order the test. You can order it direct, even. You don’t have to have a physician, but I recommend having a physician that can help you interpret it or a health coach that can help you interpret it. I mean, there’s probably more non-physicians that understand epigenetics better than the majority of physicians. I mean, I think physicians are moving into a world where it’s going to be sick care only and because 90% of our health is lifestyle, I think you’re going to see the functional practitioners, the coaches, all of this are going to be the go-to’s for really optimizing health and maintaining your baseline. So for anybody who wants to look into us, we have … Our website is apeironzoh.com, so it’s a-p-e-i-r-o-n-z-o-h.com. Apeiron Zoh is great for limitless life and that’s really our mission is to help create that limitless aspect of what’s possible.

Dr. Weitz: Great. Thank you, Dr. Stickler.

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