Apollo Health’s Chief Science Officer Dr. Dale Bredesen and Chief Health Liaison Julie Gregory were joined by Dr. Kara Fitzgerald to discuss her recently published clinical trial that examined how epigenetic factors influence the aging process. A group of healthy middle aged men engaged in an eight week treatment program that included diet, sleep, exercise and relaxation guidance, and supplemental probiotics and phytonutrients that reversed biological age by more than three years compared to the control group that aged almost two years in the same period. Given that aging is the greatest risk factor for dementia, Dr. Fitzgerald’s study offers confirmation that the diet and lifestyle strategies very similar to those used in the protocol can influence the biological aging process and confer protection against cognitive decline.

We’ve included a complete recording of the session and a full transcript below for your convenience.

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Dr. Bredesen: Hi, everybody, I hope everyone is doing well. I hope everyone is staying safe. With the pandemic receding, the Delta variant notwithstanding, it said it really honored today to have Dr. Kara Fitzgerald with us. Welcome Kara, thank you so much for joining us.

Dr. Fitzgerald: Oh, it’s an honor to be with you, Dale and Julie.

Dr. Bredesen: And Julie, welcome.

Julie Gregory: Thank you, happy to be here.

Dr. Bredesen: And we thought it would be really interesting to talk to Dr. Fitzgerald today because she’s recently published a very exciting study. As everyone knows, there’s always been this relationship between neurodegenerative diseases, whether you’re talking about Alzheimer’s or Parkinson’s or Lewy body or frontotemporal dementia or others, and the aging process itself. And as is often pointed out, aging is the number one risk factor for Alzheimer’s disease. And so to understand what it is, what’s actually driving the process and what are the critical features that actually are increasing your risk for cognitive decline over the years is really important. And there’s great interest now. Now that we can actually begin to look at some of the biological parameters, you can really get someone’s biological age, not just their chronological age, I think it’s really exciting to look and say, okay, what happens if you do these various things and various manipulations, and what’s the optimal way and can you slow down the aging process. But the really exciting part and I’ll let Kara talk to talk to you about that. Very, very exciting what they actually saw was beyond just slowing things down. So Kara, could you give us a little background on how you got interested in this and how do you guys looking at the aging process itself?

Dr. Fitzgerald: Yes, I would love to. And Dale, I’m just giving you carte blanche interruption power. If I go into the rabbit hole too far, need to be like circled back. So, cause it’s a huge passion project for me. I mean originally, so I want to tell you, well, I’ll go back to about 2013 when I was starting to really ingest the data on epigenetics. I knew it was important for us to think about within the functional medicine model, what are we, how are interventions influencing epigenetics? And the bulk of the data is looking at cancer. We know that the tumor microenvironment really efficiently hijacks the epigenetic machinery and turns genes on and off very efficiently. And most of this is looking at DNA methylation. We know DNA, so we know that a lot of methyl groups on a promoter region of a gene will turn it off. Conversely, we can remove the methyl groups, or we can inhibit them from being laid down. And that allows a gene to be turned on. So in our world and functional medicine as you know, Dale, that we’re thinking about the methylation cycle and we’re looking at homocysteine and we tend to, I think push methylation forward. We’re concerned about insufficient methylation, generally speaking, which is reasonable because that is a part of the aging trajectory. But here, when you look at where I entered into was this cancer piece, you see both hyper and hypo methylation happening. So the next question to me as a clinician wanting to do right by my patients is, could we be overdoing it? Could I be overdoing it in a vulnerable patient? Could I be giving them too many methyl donors or. Anyway, so questions came up and with my whip smart nutrition director, Romilly Hodges, we began to realize a, we need methyl donors. We can load them up in the diet, in the food matrix, folate, B12, et cetera, always health. Well, at a minimum it’s neutral, but the dietary methyl donors by and large are healthy and preventative and important greens and polyphenols, colorful veggies, et cetera, eggs, beets, and so forth. So we built out a methyl donor rich diet that was arm one. And then arm two was our look at these extraordinary polyphenol compounds that we know and love like curcumin and green tea and resveratrol, and quercetin et cetera, again, found in many foods. And the literature on those suggest that, I mean, just to kind of cut to the chase. And a lot of this is new, a lot of it’s in vitro, some is animal. It suggests that these polyphenols influence epigenetic expression so that it’s favorable. Almost as if they’re helping direct where the methyl donor needs to go. And so that was the soul of our plan. And then we zoomed out a little bit and realized exercise, sleep, stress reduction through meditation also had an influence. So that was the genesis. And then, we leaped forward and realized, so this was the big aha for me was the recognition that aging, Alzheimer’s disease, all the chronic diseases of aging sort of share similar DNA, abberant DNA methylation patterns. It’s pretty interesting. And so it was from the genesis of reading the literature on cancer, realizing that in fact, probably this intervention was useful in a variety of chronic illness and all the illnesses of aging, as well as importantly aging itself. And so that’s where it started, and I just want to stop in.

Dr. Bredesen: Yeah. All right, that’s helpful. So let’s back up for one moment. So everyone knows that genetics plays a role, what your DNA sequence actually is plays a role in the aging process. As they’ve always said, if you want to live a long life, choose parents carefully. So that clearly genetics plays a role, but as you’re pointing out beyond that things that we can actually manipulate the epigenetics, the actual the methylation patterns and other acetyl patterns, and other modifications that actually tell you how you’re going to read out the genes are absolutely critical. And as you’re pointed out, most people can benefit from alterations in that from optimization basically much as we talk about with cognitive decline, optimization of these various parameters. So now what do you do with the people who may have snips in COMT, may be hyper methylators. Although they’re obviously much less common, do you identify them genetically and then treat them differently? Or how do you address those people?

Dr. Fitzgerald: So that’s a great question. Before we started, we launched our research study. We used this program in clinical practice. So we do have background in a lot of different conditions. And this program is fabulous for people who’ve got a cocktail of methylation snips, and therefore don’t respond to normal supplement protocols. That was a large and continues to be a large subset of who we know can handle this. Because probably the overall exposure to the methyl donors is less, but you’re getting it in a variety of ways. So you’re getting it through choline, you’re getting it so it’s what we call backdoor methylation. Sometimes in those sensitive people we’ll use a little creatine or maybe we’ll give them some supplemental phosphatidylcholine. So we’ve thought about that and so far we’ve done very well with the most sensitive of our patient population.

Dr. Bredesen: Great, so thank you. So you’ve given us a beautiful view now of the chemistry and the biochemistry and why this would be appropriate. Tell us a little bit then about how you actually translated that into here’s a clinical trial, what are we going to do for these people and what are we going to measure to give them, people have looked at things like mural length, and people looked at things like vascular elasticity, and of course you’re describing methylation patterns which may be the best. So tell us a little bit about how you measured biological aging, what you did, and then what the outcome was that you published.

Dr. Fitzgerald: So we designed this program, we’re using it in clinical practice. We’re thinking, our hypothesis is that we’re favorably influencing epigenetics and particularly DNA methylation. So it was our hypothesis, but it was like, we need to test this, but you can’t send a patient to quest for a DNA methylation biological age test. That will change but currently it’s in the research setting and really we were gifted. I have the deepest gratitude of an unrestricted grant through Metagenics. They paid for us to actually hire a Health Gut Institute Clinical Research Center to run our protocol and Ryan Bradley over there he heads that up was my co PI and he helped us with study design. The best tests still today, but at the time of our study design in 2017 was the Illumina epic array, which looks basically at most, it looks at most of those methyl groups on the DNA. And at that time in our study design in 2017, really the flagship and best studied biological clock was the Horvath DNA methylation age 2013 clock really considered to be the gold standard. I mean, it’s an extra, the reliability is, it’s really extraordinary. It was designed to correlate with chronological age, and it does so at about a 0.96. So that’s what we were looking at. And I just want to stop Dale, if you have any questions for me there.

Dr. Bredesen: That’s great, okay, so you’ve got a beautiful setup here. You’ve got a great way to look at functional aging, and I guess one of the obvious things people always talk about teaching to the test. So if you’re going to teach someone to learn history, if you’re just teaching to a tiny test, it’s really not changing their understanding of overall history, same for math, same for anything else. Is your sense, to me, you’ve kind of started a whole new field in one of the questions. The exciting questions that come up is when you improve, when you do something this, are you just effecting the methylation or are you truly …?

Dr. Fitzgerald: I love that question.

Dr. Bredesen: Affecting aging itself?

Dr. Fitzgerald: Yeah, yeah, yeah. That’s such a great question and it’s like, maybe it’s so exciting. So I want to say a couple things. One is that if you look at the guts of our diet and our program, it’s just smart. It’s smart via many different mechanisms. It’s low-glycemic, we’ve got modest inter time restricted eating, it’s a little bit keto leaning. We saw triglycerides drop by 25% in our study participants. So we know that they were likely moving into ketosis, LDL, and total cholesterol dropped also backing that up and folate. So without folate supplementation or the methylfolate, circulating methylfolate rose by 15%. So we were influencing methyl donor status.

Dr. Bredesen: Yeah, yeah.

Dr. Fitzgerald: So we know it’s just a solid workhorse diet. But the other piece Dale that I want to hear your thoughts on is, is there a programmed element to the aging journey? Why is aging the number one risk factor for all chronic disease? Why do we all go there? And if there is a programmed element, I think that there’s some suggestion that it could be in part driven by DNA methylation. And I can argue about what we see happening with DNA methylation and demethylation and gametogenesis and embryogenesis, and at different important life stages at sexual maturation, at menopause, and then aging. And when you look at methylation patterns, the aging journey is almost as the equal and opposite to what you see in the growth journey. It’s kind of remarkable. And so we we’re hedging our bets. We’re hedging our bets that optimizing DNA methylation expression with its good effect across the board is an important anti-aging tool that results in extended health span and lifespan.

Dr. Bredesen: Yeah, very interesting. And certainly there is a huge controversy in the aging field about, is it programmed, is it not programmed? The standard claim is that it is not a programmed process, but that it kind of ignores two important nuances here. Number one, what’s really programmed is longevity. You’re not going to make a mouse live to 100 years, but you might make a human live to 100 years.

Dr. Fitzgerald: That’s right.

Dr. Bredesen: So you have a setup ahead of time. There’s a genetic program that gives you a longevity. Now you can alter that just as you’ve done in your study of course. And the other thing is that as you then begin to age, as things begin to change, as Professor Bruce Ames showed there is a triage, so that you’re basically hanging on to the most important things and letting go of the less important things. So in that sense, absolutely, there’s a programmatic aspect to this process. So let’s go back to your study then for a moment and let’s talk about with the people, when you looked at your control group, what sort of aging did you see? I mean, obviously you need to validate that what you’re actually using is showing some degree of aging over the study, and then what did the treatment group actually show to them. Please get an after that to a little bit about what did you actually do to these people other than their diet. So talk a little bit about the outcomes.

Dr. Fitzgerald: I just want to affirm Bruce Ames and Linus Pauling, and of course, Jeff Bland this idea of orthomolecular medicine and giving the right amount of nutrients in the right doses to influence genetic expression. And that’s at the heart of what we were thinking about too. And I just think it’s an important concept for us in our space. So we saw it as compared to control the control group who did nothing except show up at the institute to donate blood three times through the study and fill their forms out, our participants got in the eight-week time frame 3.23 years younger. Yeah, it’s pretty, it’s extraordinary. I also wanna say that another important measure was how much younger they got in comparison to themselves at the start. And in that they got 1.96 years younger with a almost significant p-value. Our study population was small. So I think this is good. It was 0.06. So they got younger as compared to themselves at baseline. And in very importantly, as compared to control. Our control group interestingly enough, we can continue to explore this data, got an un-significant 1.27 years older, yeah.

Dr. Bredesen: Oh yeah, which made sense. So the good news is your approach certainly validated that yeah, these people are aging. The control group shows what you would expect it to show, which is that it got older.

Dr. Fitzgerald: They got older.

Dr. Bredesen: What’s interesting is that your treatment group actually got biologically younger than when they started.

Dr. Fitzgerald: Yeah they did.

Dr. Bredesen: So they can come in and say Dr. Fitzgerald can you take a little off the top here? Just to kind of move my age back a few years. Now, did they feel it, did they feel healthier? Did they feel more energetic? Did they know it?

Dr. Fitzgerald: So that’s a great question. Anecdotally they did, but according to the subjective questionnaires, a little bit of a trend towards reduction in anxiety, and I think maybe a little bit of a trend towards increased energy, not significantly. And the reason is our guys were rigorously healthy. Our study was a challenging study to recruit for because it was very involved, and we were recruiting middle-aged men who were in tip tip top shape. So, we were recruiting from gyms. We were recruiting from men who went to integrative medical clinics who were trying to maintain optimal health. So our guys were doing well. Our study population came to us healthy, So we didn’t anticipate-

Dr. Bredesen: So why did you, sorry to interrupt you? Why did you choose the healthy group as opposed to someone who perhaps wasn’t aging as well as they could.

Dr. Fitzgerald: Because we really wanted, our question was to really study the fact that healthy or not, methylation changes with age. And we wanted to actually look at that question specifically, as opposed to methylation changing in diabetics or methylation changing. We know there’s been previous publications. I’m thinking of a recent Nathan Price and Lee Hood publication. They showed using their metabolic biological age measure that type two diabetics are on average six years older than their chronological age. And there’s other studies showing up to nine years older. So we already know people who have established chronic disease are aging faster. And if you turn that disease process around, you’re going to also turn around their biological age. And I think that’s exciting for you implementing the clocks in your study, and I would anticipate you’ll have some favorable findings. I’m actually really excited. So we kind of up to the bar for ourselves by omitting that an unhealthy men, very few medications were allowed in. They had to be normotensive and just on minimal supplements. So they had to be willing to do a supplement wash out. Yeah, and so these guys didn’t have high homocysteine, no high blood sugar, no high A1C, et cetera. And so we didn’t see changes there. Really the heart of our change was a repositioning of how their genes were methylated to a more favorable position.

Dr. Bredesen: Now, this also allows you now to begin to look at, okay, are there certain ones that seem to be more important? So for example, did you carry away the notion that, hey, the people who improve their triglycerides the most seem to do best are the people that improve their blood pressures the most, as you said they were normal to begin with, or people who improved. So were you able then to work with specific parameters to say these are the ones that seem to be the most associated with biological aging?

Dr. Fitzgerald: So Dale we need to dig into the literature. I don’t know if you have a couple of post-docs. I mean, not the literature into our data. We’ve got more publications to do. I can say that it, there may be some interesting. We did get snip testing. We did methylation snip testing, and there may be an interesting association with MTHFR. I don’t want to speak about it too much because we’ve got to tease it out a little more and then publish on it. And there’s one other very itty-bitty study showing that MTHFR variance might be pro aging, and you might actually be able to reverse that with methyl donors. This is not written in stone folks if you have the variant and we need to tease that out more. So we’ve got a few other papers here, what happened? So why we’re a little bit on pause with generating more analysis is that, because I had been using this in practice for so long and educating on it. In fact, the Cleveland clinic was using our program. Like we had done a few trainings with them and more broadly I was looking to write about it, just make the program available to regular people. And lo and behold, so we were getting our first paper published, COVID hit, and our proposal went out. It was kind of crazy timing, but I’m in the middle of writing a book and it’s prompted me to need to wait on further data analysis. The other piece I want to tell you that we saw that’s extraordinary is, and I think you’ll have comments on this that I want to drill into and publish on is, we used nutritionists. So the Health Gut Institute, Ryan Bradley, he said this study is so complex. And so multifactorial adherence is going be a challenge. And he said, I’m going to actually pay attention to that. I don’t know that he anticipated us getting good adherence. And I’m like, this is my one shot. I’m a clinician, I don’t have a lab. I don’t have an H grants coming in. I want this to work and we’ve got a good nutrition team here. We’ve got a great, actually a superb nutrition team. And so our study participants were required to meet with a nutritionist every week for the first month. And they could meet more than that if they wanted. And then they met as needed after that. Excuse me, just started thundering here if you heard that. But our nutrition team was a key support to adherence. They didn’t coach, they weren’t a cheerleading squad. They had a really dry script that they had to follow, very different than normal clinic practice. But I think adherence is something that I want to drill into. When we crunched the numbers, we did see that our participants hit their nutrient targets by and large. And there were a lot of vegetables in our program. We even had some liver, and we did well with that.

Dr. Bredesen: And certainly this is what Dr. Dean Ornish found with looking at cardiovascular disease. Adherence is critical to get best outcomes. And I think we’re all aware of that. We all see this when we’re talking about complex biological phenomenon, like aging and like cognitive decline and neurodegeneration. So could you then just briefly summarize the elements of your program. As I recall, there were several different pieces that you put together that’s obviously as you showed were very effective.

Dr. Fitzgerald: Yeah, and it’ll be fun to kind of tease out what might be what, but we’re going to continue to study in this multi-variable model as you do. I think it’s essential. So we had our diet methyl donor and what we call methylation adaptogens rich. And then we had an exercise prescription, which was modest, but it was five days a week, at least 30 minutes to a perceived exertion of 60 to 80%. And it could be any exercise that the individual is interested in. Most people had no problem achieving that. We had a couple of super exercisers. Remember these guys were really healthy. We had a couple of CrossFit guys who actually had to dial it back, which is interesting. Sidebar, there is some literature, not a ton, but some that overexercising could have a pro aging effect. So we wanted to have it be relatively modest. Not that you have to stay there forever, but in our study. We had a meditation, we used Herbert Benson relaxation response, which is just a great, easy, well-studied meditation tool. And that was prescribed 10 to 20 minutes twice per day. So breathing 10 to 20 minutes. And again, great data on stress and aging like extraordinary, impactful data on stress. I think we pay a lot of lip service. I do as kind of a Type A person to stress. I think getting diving into the literature on aging and stress has really been impactful for me. Even the clock, the Horvath clock we used a full 25% of those methylation sites are glucocorticoid response elements meaning they respond to stress. I know it’s extraordinary.

Dr. Bredesen: Amazing.

Dr. Fitzgerald: Yeah, so we had that, and then we also encouraged at least seven hours of sleep a night. And we just did that by having them track it, having the nutrition team check in with them, talking to them if they needed it about sleep hygiene, scheduling things to do. So it was a suggestion and those were, oh, and we ha we used a probiotic. We use lactobacillus plantarum and that is a Metagenics product that we used. Lactobacillus plantarum as some bifido species also has some evidence on increasing folate production. So increasing microbiome produced folate. And so we had that in there and also obviously a healthy gut is essential for host epigenetic expression, via many mechanisms. And then we used a polyphenol concentrate powder and had them take two servings of that a day. And that was our study.

Dr. Bredesen: Great, and then what are the long-term, is there a followup for these people? Obviously again, another thing that this brings up is, are these people now going to net when they return to some degree of aging, you’ve already made them age backwards which is exciting, are they going to now age more slowly than other people? And what’s this follow up to this group? And I know you’ve got another study coming up, which is gonna be very exciting.

Dr. Fitzgerald: We don’t have a follow-up. Yeah, I wish that we did, I’m disappointed. We rallied for a Facebook group, you know this because you’ve been researching, you’re headed the buck institute. So you’ve been a scientist really your entire career. For me, we started a Facebook group for our participants to jump into after finished our trial, but we were crunching our data for probably a year before in writing our paper up and this lag time, we lost access to a lot of our study participants and our IRB limits us accessing them. So we would have to go back to the IRB and amended unless I had the foresight to build it in. So I’m learning a lot as a clinician and our next study will be a rolling IRB. And we’ll be looking at people at various stages through the diet. We don’t expect people to stay on it forever. We do have what we call an everyday version that’s a little bit easier. In our study we pulled people off of lagoons, which short term will limit glycemic cycling. Long-term I don’t think it’s great idea. I think lagoons are really important. So we expand on it in the everyday version, but I think we’re building out an app that will house the study program and access to testing, and it will also house the transition diet. And after that a suite of other interventions people might be interested in and as long as we can figure, keep IRB rolling, and a sub- group of the people accessing the app, want to continue to allow us to access our data, I would just love to study all the permutations you’re throwing out. I can see for myself so far so good my N of one, my biological age is almost four years younger, so yeah, my N=1.

Dr. Bredesen: Great, so I want to go to Julie for a moment here. So Kara, as you probably know, Julie founded a very exciting site, APOE 4 a number of years ago. So she deals with thousands of people who are APOE-4 positive. And obviously, that has an impact on longevity itself as has been published numerous times. And maybe before we get to Julie, do you know what percentage of your people were equally for positive?

Dr. Fitzgerald: You know what? We didn’t get APOE status, unfortunately. And we may add it, we might add it to this new just to ask them, but we’ll see. I absolutely think it’s important. And we see aberrant methylation on APOE, and it would be interesting anyway.

Dr. Bredesen: Yeah, of course they served as their own controls because you had beginning and end, so that was helpful. So Julie, could you talk a little bit about the thousands of people that you deal with on the site? Do you know, are there people who are looking at their biological age?

Julie Gregory: I think we’re all very focused on that because as you mentioned APOE-4 is inversely correlated with longevity, and it’s actually been associated with accelerated aging. So everything we do in our community is to turn back the clock and that’s why your study, Dr. Fitzgerald, is so exciting because we feel better when we do these things. And now you’re proving that we are chronologically turning back the clock, which is really exciting.

Dr. Fitzgerald:  Yeah, for sure. I mean, yeah, it’ll be. I’m so excited that you’ll be bringing clock analysis into your ongoing research. Yeah, no doubt about it. One of the things we know as we age, if you look at DNA methylation is that pro-inflammatory genes get turned on. Like the genes we don’t want on are turned on and the genes that we want off are, well, excuse me, the genes we want on are turned off. It’s kind of crazy. And I think that absolutely wear and tear drives this, but I also, I guess I’m an adherent to the potential program piece, because why don’t we just spring and NF-kappa B up. Why do we hyper methylator tumor suppressor genes as we age, not just in cancer, but as we age in general, we just shut off our ability to surveil cancer. Isn’t that interesting?

Dr. Bredesen: It speaks to the idea of a programmatic aspect to the aging process itself, which is very interesting.

Dr. Fitzgerald: Yeah, I mean, why are we doing this to ourselves? Like sort of making it harder for us to recover. And I think the argument there is just as you guys know in your work is, to essentially to kind of get into the program as best you can and get a groove with it and just stay with it.

Dr. Bredesen: Yeah.

Dr. Fitzgerald: By the way, I do want to say that the handbook you created is awesome. It’s just a gold mine, I love it. We love it here.

Julie Gregory: Thank you. I’ve got a quick question. What was the mean homocysteine throughout your group?

Dr. Fitzgerald: The mean homocysteine for our group? I believe I have it in the paper. I want to say that it was 10. So it’s not a homocysteine that we would necessarily think is quite optimal, but it’s not a bad homocysteine. And we might be able to data mine and well, we could data mine and look at some outliers and kind of tease it out a little bit more.

Dr.  Bredesen: Yeah, as I said, you really have started a whole new field that people now can look at rates and they can look at the things that are associated. We now have a way, and we always talk about this with things like EMFs. There’s not a simple clinical test where you can say, aha, 30% of your cognitive decline is EMF related. And that’s been a real missing feature, unfortunately. So you’ve got now something where you can actually quantitate, you can actually say, okay, here’s what your biological aging is and here I can actually make it less, which is exciting because now you can look at, okay, what are the things that seem to do the best with this? What are the things that actually are the worst that actually get just as well with cognitive decline, you’ve got a great way to measure this, and you’ve got a great way to impact it. So congratulations, I think it’s a landmark study. I think it’s really exciting. And I look forward to the follow-ups. So we’ve got a couple of excellent questions here. So if you’ve got a minute here, let’s take a few of the questions. So Tim says, my brain biological age at 55 and 56 was 85 and 86 as stated by the neurologist. So, yeah, here’s a great example where the too much age here based on what was going on with this particular person’s genetics and epigenetics and biochemistry. And so, again, being able to impact that is huge. Louis asks, can you discuss the potential for alpha-ketoglutarate to reduce epigenetic aging?

Dr. Fitzgerald: I Think that’s compelling. So Louis, we did think about alpha-ketoglutarate. So the reason he’s asking I’m assuming is because it’s a co-factor in the 10 11 translocation enzymes, which actually participate in demethylation. So you want healthy methylation, and you also want the bad guys to be removed where you don’t want them. So you want demethylation and methylation to be happening on the genome and in as correct and robust a way as possible. Alpha-ketoglutarate is a co-factor for that family of enzymes. I think it’s an important player. I know that it’s also kind of a darling molecule with, I think Brian Kennedy is into it and I think in certainly Davidson Claire, and they’re thinking about mitochondrial health along with it. So it’s kind of a ubiquitous molecule in, and I was just talking to somebody about it yesterday. Certain amino acids will be converted into alpha-ketoglutarate. And so we’re making it in our body all of the time, but we do slow-down in our ability to make it as we age. So I think it’s an important molecule in the aging journey. It’s important for methylation and demethylations. It’s important for mitochondrial health. Will it alone reverse aging? Maybe, I think Alicia published a press release that they found sort of an anecdotal in-house study that it reversed it, am I right on that?

Dr. Bredesen: Yeah, yeah, I think it’s a really good point. And so when you’re targeting things like a single bacterium, the idea of killing a bacteria with a single molecule makes all the sense in the world. It’s worked very well from penicillin to cephalosporins and on, and on. On the other hand, when you’re targeting a physiological process, I think you really do have to break down what’s actually driving this and you find limiting steps. And so there are things that are working just fine. You can enhance those. It’s not going do too much where there are other things that are not working so well. And so I do think this is part of the larger data sets and part of why we’re looking at digital health for the future and looking at larger data sets. And why, obviously when you look at methylation patterns, you’re looking at many, many different sites. It’s not just one site, let’s just fix one site and the person will be better. That’s not how life works. So I do think that that’s going to, there’s going to be more and more of that. And I think ultimately putting the optimal targeted pharmaceuticals together with the optimal targeted personalized programs is going to be very powerful.

Dr. Fitzgerald: Very powerful.

Dr. Bredesen: Yeah, and it’s unfortunate there’s been so much resistance to bringing these things together. All right, but again, you can do a tremendous amount with protocols without adding drugs that may have targets that aren’t so physiologically relevant. And then Sam asks, I’d like to see the diet plan and supplements. So I know you’ve published your paper so we can certainly put a link to where you talk about what you did to get such exciting results. And then Colette asks, how do we sign up?

Dr. Fitzgerald: Sign up, we’ve got a beta group. We’re launching our beta group in August. I mean, extraordinarily enough next month. Just hoping our IRB gets through with relatively unscathed, we’ll be launching our beta group. It’s just a 100 people. You can go to the website, Dr. Kara Fitzgerald, my name, D-R-K-A-R-A And right there on the landing page is a link you can click to get on the list. If you’re not in our beta group for whatever reason, we’re going to continue to research this. So you’ll be able to access the program and the testing and all of that stuff through our digital platform that we’re creating.

Dr. Bredesen: Great, all right. Julie, any other questions for Kara?

Julie Gregory: Yeah, I’m sorry to interrupt. Are you going to include women this time?

Dr. Fitzgerald: Oh yeah, we sure are, thank you.

Julie Gregory: Of course.

Dr. Fitzgerald: A really good question. I was pinged a lot. Like here I am a woman as a principal investigator in a study with only men.

Dr. Bredesen: What were you thinking, Kara?

Dr. Fitzgerald: I will tell you. And I want to apologize in advance to all the women, but I do have a really important reason. And that’s very simply, we were interested in that age range when we see aberrant methylation, we see negative changes to DNA methylation. So when you hit middle age, that’s when this starts going south. If we included women, remember we only had 18 people, 18 participants in 20 controls. If we included women in that, we would have had women who were premenopausal, women who are perimenopausal and women who are post-menopausal and actually teasing out with only 18 individuals that the influence of the hormonal shift, the potent hormonal shifts during that time would have been, I think it would have flattened our study. We just need larger numbers to include as complex beings.

Dr. Bredesen: Yeah, and there’s a question here from Dai who says, hi, Kara, thank you for all you’re doing and Dr. B and Julie, what would you say is the biggest anti-aging tool besides diet, exercise, meditation, avoiding stress that we can do to prevent accelerated aging? Like one to two things you can recommend. I’m female 63 and I followed zone diet for 30 years. I’m 5′ 8″ and 118 pounds too skinny. I know other factors come into play.

Dr. Fitzgerald: Wow, gosh, what would I say, God, you’re doing a great job Dai. What might I layer on to that? If you’re really interested, I’d get a good workup from a functional medicine practitioner who can really individualize your next steps. I can say that I’m excited about polyphenols. I think there’s going to be a place for sort of broad spectrum, higher dose polyphenols. You’re familiar Dale with tartare buckwheat Jeff Bland’s darling. I think that’s just a pretty cool product that we’re going to see some interesting things out of, but Dai since you’re committed, I would go cast a wide net with somebody who’s familiar and individualize a plan for you.

Dr. Bredesen: And Kara, what would you say for example, to Dai about gut health and about CGM? I think just the blips, we see so many people, there you go, so many people with cognitive change. Dropping too low at night, jumping up too high during the day and those swings, which people won’t know about and not necessarily picked up by hemoglobin A1C.

Dr. Fitzgerald: Yes, oh my gosh.

Dr. Bredesen: So by making sure that she’s pretty smooth on her glucose control.

Dr. Fitzgerald: Yeah Dai, there is just a world of cool stuff that you can investigate. I mean, I love my Oura Ring too. I’m a little bit of a data hound right now, which I hope that we are able in our next iterations or next iterations of our investigation can layer those in. In fact, Dale, I wanted to mention to you, we do the Bredesen protocol here in our practice. Ken Litwin is an MD on board with us who has his undergrad is in neurology and he’s kind of taken it on as his baby. And we layer the methylation diet and lifestyle into our Bredesen protocol. So it’ll just be nice to continue to look at that. But Dai I think the world is your oyster as far as investigations to optimize.

Dr. Bredesen: Yeah, and then Emanuel says, do you have to be a US resident to sign up?

Dr. Fitzgerald: For the beta launch, unfortunately you do. So while we get our ducks in a row for test shipping and supplement shipping and we refine the app, you do have to be here, but in January, the book will come out as well as the full launch. And that will be international. I want everybody to have access to it.

Dr. Bredesen: Yeah great, and then Louis is asking. So thanks for addressing the question regarding rapamycin. Sarah Lemus has failed to affect the methylation clock and marmosets according to a recent pre-print from Horvath. All right, thank you, Louis. And then Cosy is asking what we hear at every talk now, everything always has to have a discussion of psychedelics. So we’re always talking about micro dosing and of course, Michael Pollen has really brought out with how to change your mind. Something that everyone’s thinking about. And there are more and more studies on, do these have impacts potentially positively for people who are at risk for cognitive decline? So Christie’s role for psychedelics in reversing neurological aging.

Dr. Fitzgerald: Yeah, that’s so interesting. Louis, I want to say that this suggests our original point. I’m not sure about marmoset physiology. There’s probably some unique components to it, but it has to be a multi-factorial approach I think if for best outcome. Single intervention studies are, I don’t think that they wed with anti-aging medicine as well as perhaps some of the gerontologists would like, I mean, don’t you think?

Dr. Bredesen: Yeah, I think that’s a good point. Monica says I’m 51, and life has been a medical mess. I think I have been to just about every ologist that exists, answers are all over the place I don’t do well with meds, only met him on his armor thyroid. Now my gastroenterologist thinks I might have brachycardia, my pulse was all over to the point of blackout. So Monica some of what you’re describing sounds a bit like people who have autonomic dysfunction and there are clearly specific diseases such as MSA, multiple system atrophy and others that impact this. And so yes, you need to see hopefully a good internist who is very familiar with autonomic function and the autonomic nervous system and responses.

Dr. Fitzgerald: Yes.

Dr. Bredesen: So Dai is talking about tartary buckwheat. Yes, I know Jeffrey Bland and his group have been very excited about this. And let’s see. So she’s mentioning, Di says that her father’s 97, has no MCI or anything. He’s a college athlete and takes a lot of garlic. So great, yeah, that’s another critical piece. So just as a final word then, what do you recommend for vascular health? Because that’s such a big impact on aging and of course, on cognitive decline.

Dr. Fitzgerald: Yeah, that’s a good question. That’s a great question. So we didn’t specifically, we had healthy guys in our study, so we didn’t specifically answer that, but we do a full functional approach here in clinic. We do a broad laboratory investigation. I mean, it’s not dissimilar from what you’re doing. We use cardiovascular specific supplements. I will say that our Artero is something that I’m kind of excited about. I don’t know if you’ve looked in. Yeah, so stay tuned for that coming out. I’ll give a little bit of a shout out there, but we’ve certainly used our MDL protocol on plenty of our cardiovascular patients. And it’s always a good foundational starting point.

Dr. Bredesen: Yeah, I think a lot of the studies in the past have suffered from the fact that there’s this floor effect. You had one medicine, you just don’t see much, but now that everyone’s looking more at physiological parameters, and you mentioned the wearables, which are going to help so much and help collect data to understand what’s critical. Now that we’ve actually got things that actually impact these various processes, now we can see adding or subtracting one thing. Now we’re in a dynamic range with many of these parameters. I think it makes a huge difference.

Dr. Fitzgerald: It’s exciting.

Dr. Bredesen: This is fantastic. Thank you so much, Dr. Fitzgerald. Great to see you very excited.

Dr. Fitzgerald: You too.

Dr. Bredesen: About your study.

Dr. Fitzgerald: Thank you.

Dr. Bredesen: Look forward to the next study. And of course, look forward to including your approach as you and I have discussed in our upcoming study as well. I think it would be very helpful to see whether people are aging forward or backward, and what impacts that. Thank you very much, Julie for questions and comments as always, and everyone stays safe, thanks again.

Dr. Fitzgerald: Ciao.Dr. Bredesen: We’re going to sign off. Thanks, bye-bye.

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