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Dr. Raffaele received his B.A. in philosophy from Princeton University and his M.D. from Drexel University Medical School in 1989. He trained at The New York Hospital/Cornell University Medical Center and was formerly a clinical assistant professor of medicine at Dartmouth Medical School. Dr. Raffaele is board certified in internal... Read More
Kara Fitzgerald, ND, IFMCP, received her doctor of naturopathic medicine degree from the National University of Natural Medicine in Portland, Oregon. She completed the first Counsel on Naturopathic Medicine-accredited post-doctorate position in nutritional biochemistry and laboratory science at Metametrix Clinical Laboratory (now Genova Diagnostics) under the direction of Richard Lord,... Read More
- The basics of epigenetics and DNA methylation.
- Biological aging, healthspan, lifespan and longevity: why are these all so important?
- How do we measure BioAge? (as compared to chronological aging?)
- What we learned from our study findings about reversing it.
Joseph M. Raffaele, M.D.
So it is great to have you on, Kara. First of all, thank you very much for doing this episode of the “Telomere Summit”. And I’m really, really looking forward to being on the other side-
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
As we’ve done a podcast before. You always ask great questions, but I’m really looking forward to hearing about your new study. Tell us a little bit about your new book and everything that you’re doing in epigenetics ’cause I kind of think of you as the epigenetics and functional medicine maiden out there. So I’m really looking forward to our discussion.
Kara Fitzgerald, N.D.
Awesome. Great, yeah. It’s great to be here and to be on the other side of the microphone with you.
Joseph M. Raffaele, M.D.
You’ve been doing, you’ve been in functional medicine for a long time and doing really interesting research. And you’ve actually been on the epigenetics train before the clocks came out where, looking at the effect. That’s always been the mantra, you know. Genes load the gun. Lifestyle pulls the trigger. And we know it’s true epigenetics, that it does that. You’ve been involved in looking at the effect of diet, exercise, lifestyle, et cetera on epigenetic changes affecting other more harder markers, so to speak. But it must be exciting, it must have been exciting for you to then see this metric come out, the clocks and…
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
Why don’t we talk a little bit about, just briefly, what DNA methylation is.
Kara Fitzgerald, N.D.
Sure.
Joseph M. Raffaele, M.D.
That, Ryan Smith on, talking about that as well. But I think a little bit more detail and your perspective on it as a practicing clinician, and so its use will be great. And then we’ll talk about all the other stuff that we definitely need to get into.
Kara Fitzgerald, N.D.
Yeah, absolutely. And listen, Joe, I just wanna invite you to interrupt me if I go into an extensive, useless soliloquy. Just interrupt me before, or if it doesn’t make sense. But it is, it’s true. It’s a passion project. And it’s one that I think’s extremely important, and I do think those of us in functional medicine need to embrace epigenetics, looking at epigenetics. And now that the tools are becoming available to us, ’cause they weren’t for a long time, I think we absolutely have to be early adapters in this arena. We have, in functional medicine, been talking about neutrigenomics. We’ve been talking about diet and lifestyle influencing genetic expression, a lot of talk around that. And I, of course, it’s important. And it warrants talk, but we need to know, are we actually doing that? Are we influencing genetic expression? And that’s where the definition of epigenetics comes into play because it’s really, epigenetics is the whole field of what regulates gene expression.
So it’s getting in there and looking at the biochemistry of what genes are on and what genes are off. Most often, well, I would say, by and large, at this point in time, the best way that we can do that is by looking at DNA methylation. There are many epigenetic marks. As you know, we mapped the genome out. It’s, what, 23,000 plus genes. It was simpler and less impressive than we anticipated, and that’s when epigenetics, I think, blew up because we realized there wasn’t this really, this one gene, one disease roadmap that we had anticipated finding. And then, actually, after that, we went headlong into looking at single nucleotide polymorphisms.
And we were early adapters in functional medicine of considering those. At the time, I was in the laboratory. And we were looking at a lot of, amino acids and different proteins and organic acids and so on and so forth that would be products of these gene mutations, these SNPs. And we anticipated seeing wild changes there. So if somebody’s got MTHFR mutations or COMT, et cetera, et cetera, et cetera, we should see the end products also change. And that was kind of disappointing as well. I don’t know if you were doing that in your practice, Joe, if you were looking at SNPs and expecting to see, consistently elevated homocysteine or maybe low adrenaline, et cetera. But we weren’t, so that really wasn’t, it wasn’t as satisfying as we thought that it would be.
Joseph M. Raffaele, M.D.
Well, we shouldn’t have expected it quite as much as we did. I did as well. But if you look at the literature, the studies that supported those associations, the associations weren’t as strong.
Kara Fitzgerald, N.D.
They’re very equivocal.
Joseph M. Raffaele, M.D.
Right, exactly.
Kara Fitzgerald, N.D.
Yes.
Joseph M. Raffaele, M.D.
That-
Kara Fitzgerald, N.D.
They’re extremely equivocal, yeah. And I would say, yeah, you’re absolutely correct. And I would argue that some, well, not argue. But I would just point out that I think some of us were thinking about these things even before the larger GWAS studies came out and so forth, but absolutely. Yeah, very equivocal which means that there’s this other thing happening. There’s this other biochemical, or multiple, there’s other things that are going on that are influencing gene and then the expression of gene. And enter epigenetics, you know, really. Enter thinking about epi, above gene, genetics, the gene. So that biochemical regulation of the gene, of the DNA itself, what’s on, what’s off. And it’s all over the place.
So the histones, or the proteins, that the DNA is wrapped around. And that can be regulated. It can open the DNA and allow for that DNA to turn on more readily, and then there are methylation groups that will sit on different regions of the DNA and depending on how many methylation groups there are, or methyl groups there are, and where they’re located, it’s going to influence how, whether that gene is on or completely off and how strong it’s on and enable transcription factors to get in there. And then there’s other, there’s acetylation and Ubiquitination and just all sorts of little biochemical tags that can happen and regulate expression. So the best tool out there that we have, the most reliable and consistent, is looking at DNA methylation. Also, I would argue, I mean, and our knowledge is going to change, clearly.
But the enzymes involved in maintaining the methyl groups, the pattern of DNA methylation, are right there in the mix during cell division, maintaining those marks over time and through vertical and horizontal. So in daughter cell division within us but then also what we can pass onto our offspring. So there’s resilience to DNA methylation that we don’t exactly see with the others. I should also throw in RNA as well. RNA, or small RNAs can get in there and influence things too. And they’re not right in that genetic material.
But DNA methylation plays a massive role in gametogenesis and embryogenesis and then on down the line and the whole aging journey and the chronic diseases of aging, et cetera. It just, it plays a big role. And it seems to be a major player in the heritability of these patterns. And we see subsequent, in animal studies and in human studies, some of these patterns being carried for a long time. So it’s just an extraordinary opportunity for us, finally, in our practices and in the research setting to get to look at what’s happening and how we’re influencing, how environment is influencing gene expression. And I think this is where the rubber meets the road. I mean, I think it’s just extremely important.
Joseph M. Raffaele, M.D.
Yeah, so I mean, I guess, you know, the DNA would be, the hardware and the epigenetics is the software. It’s not exactly that, but it’s-
Kara Fitzgerald, N.D.
That’s good. That’s good enough, yeah.
Joseph M. Raffaele, M.D.
Malleable than the DNA. And, although, look-
Kara Fitzgerald, N.D.
Yes.
Joseph M. Raffaele, M.D.
We’re probably learning that your DNA is not just about your genes. There’s all these other, what we used to think is junk DNA but probably is not junk DNA.
Kara Fitzgerald, N.D.
Yes.
Joseph M. Raffaele, M.D.
It’s probably very important.
Kara Fitzgerald, N.D.
Correct. That’s right, absolutely.
Joseph M. Raffaele, M.D.
Regulating things as well. We’re gonna learn that as time goes on.
Kara Fitzgerald, N.D.
Yeah, well, I think that’s been shown.
Joseph M. Raffaele, M.D.
Yeah, I think that the other thing that occurs, which has occurred in almost every advance in medicine is that you have a technology that allows you to make precise measurements. Cholesterol, we needed to have the technology to measure that, same thing with DNA. Now we have the arrays, and we have the bisulfite technique that makes it, accurate and available and affordable. So now all these studies can be done and, actually, brought into clinical practice which it has been done. We’ll get into that a little bit more. But, yeah, that’s a great introduction to methylation and to these clocks that they’re using.
Kara Fitzgerald, N.D.
And let me actually, can I say something? And… Is it okay? Or do you wanna keep going?
Joseph M. Raffaele, M.D.
You can say whatever you want.
Kara Fitzgerald, N.D.
All right, thanks. Well, I just wanna, I wanna just underscore how important it is. And then we’ll flip back over to you. I just wanna, if you haven’t, have you talked about Jirtle and the agouti mice research yet? Has anybody chatted about that?
Joseph M. Raffaele, M.D.
No.
Kara Fitzgerald, N.D.
So this is extraordinary. The agouti mice are these mice who have their agouti gene always on. And when the agouti gene is on in mice, they have a very clear phenotypic pattern. They’re obese. They’re blonde, and then they’re, vulnerable to a collection of diseases because this gene is always on. And so what Randy Jirtle and his post doc showed extraordinarily is that they could give the mom, the methyl donors, a collection of methyl donors, in her diet, during pregnancy and turn off the agouti gene and the offspring were then, wild type little, you know, skinny brown mice. I mean, that he published, they published that in 2003. And they couldn’t get it published. I wanna say he submitted to maybe 16 journals, and nobody believed it. Nobody believed it, and they finally had to go to a really pretty obscure journal to get it out there. Now, currently, it’s the most cited paper in science, like, ever in science.
Joseph M. Raffaele, M.D.
Wow.
Kara Fitzgerald, N.D.
Like, not even a sub top heading of science, in science because it shows the potent influence of nutrition on DNA expression. But it also shows how malleable DNA expression is and that it can have this lasting influence on the phenotype and the fact that-
Joseph M. Raffaele, M.D.
Across generations, which-
Kara Fitzgerald, N.D.
Across, generations, that’s right. That’s exactly right, yeah. It’s absolutely extraordinary, so I think that’s a brilliant, starting point to show, hey, this is really important. And they were specifically looking at DNA methylation. So I just wanted to bring that context in in case anybody isn’t aware of it. I think most people are familiar with that research but it’s just underscores what a big deal this area is.
Joseph M. Raffaele, M.D.
Yeah, we hadn’t talked about it. And I didn’t understand what you said first when you said agouti, but that’s A-G-O-U-T-I for our listeners. But that is sort of, paradigmatic of the power of epigenetics. So I think it’s great that you brought that up. Every cell in our body has the same DNA, but obviously, we have different cells that do different things, very, very different from tiny little cells to huge neurons, huge muscle cells. And it’s just about which genes are getting expressed.
Kara Fitzgerald, N.D.
Yes.
Joseph M. Raffaele, M.D.
And the fact that, I always found it fascinating about how what happened to the parent prior to having the offspring that is transmitted non-genetically.
Kara Fitzgerald, N.D.
Yes.
Joseph M. Raffaele, M.D.
That is just pretty amazing as well.
Kara Fitzgerald, N.D.
It’s so fascinating, and it looks like the bulk of our DNA methylation patterns are actually wiped clean. There’s a whole DNA de-methylation family of enzymes except for about 30% and it’s probably in that, that this heritability piece is transferred from generation to generation.
Joseph M. Raffaele, M.D.
Yeah, so let’s talk about your great paper, came out and which was showed that everything that you, exactly what you said. We need to look objectively about whether or not we’re really pushing the needle here. And, in fact-
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
You showed that.
Kara Fitzgerald, N.D.
Right. Oh, my gosh. It was very, very exciting. And I always wanna just give my gratitude to Brent Eck, the CEO at Metagenics for just taking a chance. And he gave us an, they gave us an unrestricted grant so that we were actually able to answer this question. So just going back again to a lot of us saying, we’re influencing genetic expression with our various interventions. And it’s true. But to actually be able to study it. And I just, a little bit of a background, we created the, what we called, simply, the methylation diet and lifestyle years ago. We started to think about epigenetics in practice and how we might translate the science coming out.
In about 2013, a lot of the research, the strongest science, was coming out in cancer epigenetics where we see DNA methylation. The tumor micro environment takes over DNA methylation and other epigenetic processes with just this exquisite power. They just take over genetic expression. They turn off tumor suppressor genes. So they, basically, turn off our good genes that take care of us. And they turn on these pro-inflammatory, genes. Study after study shows this in any kind, any tumor type.
I mean, it’s just on and on and on. It’s very consistent. And when I really started to grasp that, the next question was, “Are we doing right by our patients? Is our approach to patient care, is our approach to thinking about methylation, and supplying methyl donors B vitamins, and folate, and butane, and so on and so forth, are we thinking about this correctly?” Because when you look at epigenetics, you’ll see that hyper and hypo methylation occur concurrently.
And so some kind of balance needs to happen and that’s what prompted us to just develop this program in practice. And then we would also have patients that didn’t respond to B vitamins or that, or a patient with severe neuropathy and peripheral neuropathy, who, any exposure to B12 just made, exacerbated the symptoms, like, any route of delivery, from topical to IV, he couldn’t handle it. And why is that? And how are we going to treat it? I mean, clearly, this person’s got macrocytic anemia and on and on. He clearly needs B12, but he can’t tolerate it. And so, for just a handful of reasons in practice at the time, we decided to create a diet program that’s packed with methyl donors and these things called, these polyphenols that we call methylation adaptogens but they’re epigenetically active.
And then we included lifestyle interventions that the literature suggested would be helpful exercise. We tracked sleep and meditation, so that, we brought into our practice years ago. And to varying extent, really all of our patients would have some element of the methylation diet and lifestyle in their treatment plan. I mean, it’s just a smart, it’s a good foundational diet that just has a lot of these methyl, these epigenetically active components layered in. But it’s low glycemic. It’s keto leaning, et cetera. It’s, it has a lot of the hallmarks of any good diet.
Joseph M. Raffaele, M.D.
Except if you’re a vegetarian, then there’s some questions to be addressed which-
Kara Fitzgerald, N.D.
Yeah, that’s right. Yeah, that’s a good question. And we should come back to that because we do- Yeah, that’s right. Yeah, it is. It does include animal protein, so we were using it in practice for quite a while. And then the next question is, we’re suggesting that we’re influencing DNA methylation. In fact, we wrote an ebook on it. And we were training professionals. Professionals were interested in this. We did at least two webinars over at the Cleveland clinic. I taught it in South Africa and Ireland and Australia. I mean, people all around the world, including here and at the Institute for Functional Medicine, it was content folks were interested in.
But are we actually influencing, the epigenetic expression? Are we changing DNA methylation? And that was when getting the grant to dive into it was absolutely extraordinary, so we took off in that. And at the time, as you said, the only clock available was the Horvath 2013 Clock. And these DNA methylation arrays were not available outside of the research setting. And so we just moved into that.
We hired the Helfgott Institute out of National University of Natural Medicine, my alma mater. And Ryan Bradley is the director over there, and he was my co-PI. And he just runs an extremely tight ship. I think we did a really good, solid study. Moshe Szyf from McGill University was our just really important guy. He’s a long-time epigeneticist, really one of the, kind of the, he’s the founder of the journal, “Epigenetics”, if that gives you a idea of his stature. And he walked us through our design and then we worked with McGill in his lab to engage in data analysis. Josh Mitteldorf, who I think that you know, is a brilliant gerontologist/biostatistician. And he did our clock analysis, through Horvath’s UCLA website. And Horvath actually helped Josh upload and initiate some of our analysis. So we just, we had a pretty incredible team working with us.
Joseph M. Raffaele, M.D.
So, yeah, so you essentially, took an eight-week diet and had some, it was men, I think, all men. And-
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
It was a placebo controlled trial. You didn’t do the interventions in the other group. But you found after eight weeks, why don’t I take the punchline away? What-?
Kara Fitzgerald, N.D.
Yeah, yeah. So our big finding, we had our diet. We had an exercise component, a meditation component. And we tracked sleep. We had our nutritionists, we have a nutrition internship program here, and our nutritionists volunteered to support the participants. They actually had a very dry script. It wasn’t, they weren’t cheerleading. It was all IRB approved. But they would make sure that the participants knew what they were doing and knew what they needed to eat, et cetera. We gave them a probiotic. We gave them a greens powder, and then the control group had nothing. 20 in the control, 18 in the study group, middle-aged men, so 50 to 72.
And the reason that we chose middle age is because that’s when DNA methylation really starts to go awry with- The volume is turned up on abnormal patterns in middle-aged through older populations. We didn’t include women. This has been a huge question, because our population was too small. Our study size was too small to be able to really control for the fact that we would have pre-, peri-, and post-menopausal women. So we’ll absolutely look at women, obviously. I’m a woman. I’m interested in seeing how we respond to this. But given it was a small pilot study, we just couldn’t. So we tested them, we looked at a whole bunch of things. But one of them included the Illumina-EPIC array. And what we found, using the Horvath 2013 Clock, was that, as compared to controls, our participants reversed biological age by 3.23 years. So, yeah, extraordinary.
Joseph M. Raffaele, M.D.
Yeah.
Kara Fitzgerald, N.D.
For, it’s the first study of its kind. Kind of remarkable.
Joseph M. Raffaele, M.D.
Just to dive in, to compare to the other ones, the TRIIM trial that was a year, that only did one and a half years or so, it was a smaller study, of course. It’s hard to know what to make of that given the size of it, but it was interesting. And I think you talked about two other studies that were done, but not with- I guess since your study with clocks. But, I think, it is an extraordinary result. You know, when I was talking to Ryan Smith of True Diagnostics about epigenetics and he’s- They now have the rate of aging clock, which will be really fascinating to use. Do you still have biobank samples from this to be able to run the DNA?
Kara Fitzgerald, N.D.
We could, but we collected saliva. And I don’t know if you talked to Ryan about that. That’s just a phenomena of having started in 2017. Saliva seemed to be a good specimen. But obviously, right now, we need blood. I think we’re gonna be able to use a buckle swab at some point and that should be as reliable as blood. But, really, we could only reliably run the 2013 clock because it was trained in multiple tissue, including saliva.
Joseph M. Raffaele, M.D.
Right, yeah. That’s too bad, it would be nice if you could just run-
Kara Fitzgerald, N.D.
We just didn’t know, yeah. Yeah, it was a long time. In the world of epigenetics, it was a long time ago.
Joseph M. Raffaele, M.D.
It was. It’s just, things are accelerating so fast and that is-
Kara Fitzgerald, N.D.
We are, though. We’re in IRB, the IRB journey now. And we’re, gonna launch a larger study. People can go to my website, which is just drkarafitzgerald.com or youngeryouprogram.com. We’ll hopefully, we can list these in the show notes. And you can just sign up to get information. But we’re definitely in the middle of IRB journey, and we hope to have a rolling IRB so that we’ll just be able to research this and tweak it and really do it forever.
Joseph M. Raffaele, M.D.
Oh, yeah.
Kara Fitzgerald, N.D.
You know, layer in different interventions like TA-65. I told you before we hit record that I’m bullish on it favorably augmenting DNA methylation, so it would be fun. I just think sky’s the limit.
Joseph M. Raffaele, M.D.
It would be interesting to see whether or not TA-65 has an effect. I’m checking DNA methylation on all my patients now.
Kara Fitzgerald, N.D.
Oh, good.
Joseph M. Raffaele, M.D.
And telomere length and subsets and we have multiple interventions here as well. But there’s good reason to think, I mean- Telomere length, actually, is sort of in the epigenetics, arena ’cause it can affect telomere length, sorry, gene expression through the telomere position effect where it loops back and can affect expression as far as 10 megabases away from the end of the, megabytes megabases, sorry, away from the ends of the chromosome. So I kind of think of there’s genetics, and then there’s epigenetics. And in the middle, is what I call telogenetics, right in the middle there. It’s not coding DNA. It is DNA, but it’s not coding for proteins, but it has profound effects on the function of the cell, the phenotype of the cell, the gene expression of the cell as well. So I would be surprised if, not through that mechanism, some other mechanisms, it didn’t potentially have an effect and-
Kara Fitzgerald, N.D.
No doubt.
Joseph M. Raffaele, M.D.
I’ve talked to the company about doing that kind of a study, as you mentioned earlier.
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
It’ll be less expensive. And the clocks are pretty tight now. So the coefficient variation has gotten really tight so that you don’t really have to have a large sample size to do some interesting work. So that could be very interesting. You do much with them in your practice in terms of measuring them or?
Kara Fitzgerald, N.D.
I’m happy to hear you’re doing DNA methylation. You and I have kind of tussled a little bit on that. It’s amazing leap, but I tell you what. You’re gonna have a good body of data, so the next time you and I podcast, I wanna hear about what you’re seeing since you’re doing both of them together. I have no doubt in my mind that we’ll see that they’re closely related. And we may think about how we intervene, given patterns of imbalance in DNA methylation and biological, the bio clocks versus telomere length. We may depending on the individual, stratify. But there’s just no doubt that they’re very connected, and it’s a matter of time before we, understand that.
Joseph M. Raffaele, M.D.
Yeah, I think-
Kara Fitzgerald, N.D.
I don’t, oh, go ahead.
Joseph M. Raffaele, M.D.
Oh, I was just gonna say that I think that telomere length has taken a backseat to DNA methylation as a biomarker of aging. But I think that’s largely because of the very large variation based on telomere length that we come into this world with. And so if you take the actual telomere length, it’s not gonna give you the same information as if you checked, take the rate of change.
Kara Fitzgerald, N.D.
Yes.
Joseph M. Raffaele, M.D.
It will change from one telomere length to another, that’s gonna have a negative effect on you. It gets shorter. But someone of a certain age could have a telomere length that, in years, is 15, 20 years younger than they are but still be losing telomere length at a faster rate in which case you’re gonna miss that. So we need something for telomere length like the rate of aging that they have now for DNA methylation. But I guess my point to bring that up is that, if it’s not actual telomere length, giving the telomere’s activator may have profound biological effects that aren’t necessarily even picked up in the short run with telomere length. That’s something, so we may not be using it to measure the effectiveness of it but if you have a therapy- And pretty much, just as in your study showed, I think the overlap between the things that affect methylation positively and the things that affect telomere length positively is almost 100%.
Kara Fitzgerald, N.D.
Of course. That’s right.
Joseph M. Raffaele, M.D.
Because everything that’s good for you is associated with longer or-
Kara Fitzgerald, N.D.
It’s good for you.
Joseph M. Raffaele, M.D.
Yeah. It’s good for you and your telomeres.
Kara Fitzgerald, N.D.
Yeah, that’s right.
Joseph M. Raffaele, M.D.
‘Cause telomeres are good for you.
Kara Fitzgerald, N.D.
That’s right, yeah.
Joseph M. Raffaele, M.D.
But you were saying that you do some stuff with it in your practice or-?
Kara Fitzgerald, N.D.
You know, I have to be honest and say, well, two things. One is that I’ve been in the trenches for a while now working on our study. And then, after we really wrapped up and started teasing out our results, we have more publications that we’ve gotta get on. But I was given an amazing book offer. And so I went headlong into writing the book. And then we’re building out a digital platform which will house the entire program and give people access to the biological clocks, access to the nutrition team trained in the program. And we’ll also be looking at nutrient, a whole collection of nutrient response genes that are outside of just biological clock data. And it’s just incredible but it’s very consuming. So that’s where the lion share of my attention has been these days and so I’m not seeing as many patients. However, that said, I’m a fan of TA-65. And so I think and I do think that when we hunker down and lock in, we’re going to see that not only does it influence telomere length, but it also influences the biological age clocks via DNA methylation. And then so it’s easier for me to just cut to the chase these days. And in the handful of established patients that I work with, as well as myself, I mean, I’ll prescribe it.
Joseph M. Raffaele, M.D.
Yeah, I was just actually thinking that you brought the agouti clock as the paradigm of the importance of epigenetics. And what we, Ron DePinho did essentially the same experiment with telomere length when he took his telomerase knock out mice, let them age and then gave them tamoxen which turned on the gene again for telomerase. And they reversed their aging just like that. So that’s what this two mouse models that show the power of altering telomere length and gene expression through epigenetics. So, yeah they’re areas that are very important. They both need to be worked on. And you have those two- I don’t know how cited, I’m sure it’s not the most cited ’cause yours is the most cited. But it’s a pretty well cited one, with the two mice sitting next to each other. One’s got the shiny black hair and the other one’s all gray. And his hair is falling out. And it looks like an old mouse. And they’re the same age.
Kara Fitzgerald, N.D.
That’s amazing. Yeah, that’s pretty cool.
Joseph M. Raffaele, M.D.
Kind of cool that DePinho study from back in-
Kara Fitzgerald, N.D.
Have you, just, have you followed BioViva at all? They’re actually-
Joseph M. Raffaele, M.D.
I have been following them. I can’t say I know the latest as what’s happening with them. Tell me what your take is, and I’ll tell you what mine is.
Kara Fitzgerald, N.D.
I just think it’s interesting. It might be kind of cool to have to talk to Liz Parrish and using the CRISPR. I think it’s an internasal spray, right? To turn off or to support telomerase activity. I think that they’re doing that in the animals and I think they may have just published a study. Or, at least, they’ve put some preliminary results on. I’m not following it that carefully. But I’ll see news feeds periodically.
Joseph M. Raffaele, M.D.
I’m curious. I mean, look the original work that they did with the gene therapy just didn’t seem to be convincing enough to me. If they’re doing stuff to turn on telomerase in a different way, that would be interesting. I mean, there’s other companies-
Kara Fitzgerald, N.D.
I think they’re using CRISPR technology. I think they’re kind of bullish on-
Joseph M. Raffaele, M.D.
I should take a look at that.
Kara Fitzgerald, N.D.
On CRISPR and addressing telomeres. Yeah, yeah, yeah. You should look at it for sure.
Joseph M. Raffaele, M.D.
Michael Fossel, he’s got telocite, that’s looking to use gene therapy to treat Alzheimer’s disease. So there’s, I think, there are companies that are working on that. And turning on, I use TA-65 and I think it’s effective, for sure. But it’s a moderate telomerase activator. Turning on genes to get the effect that DePinho had, from taking away 50% of the telomerase and then giving it back. If you have a therapy that can turn on 30% or more of telomerase and then get significant lengthening of your telomere, then I think you’re gonna see some big effects. And if she has technology for that that’s delivered internasally, well that would be very interesting to see.
Kara Fitzgerald, N.D.
Yeah, yeah. Chase it down. Yeah, definitely. Well, it’s like looking at CRISPR for Alzheimer’s. I think CRISPR has obviously shown some- It’s extraordinary, it’s an extraordinary discovery, and MLA doses, small MLA doses study is just remarkable. But aging is a multi-genetic process. I don’t know that targeting a single gene is going to yield benefits as crisply as we see in an animal model. I mean, I’m sure it’s not. I just don’t know that it’s gonna translate so cleanly.
Joseph M. Raffaele, M.D.
I think it depends on how upstream, and I think, telomere length and telomerase activation is pretty far upstream. But, again, mice are not humans. They don’t age the same way in any stretch of the imagination.
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
Humans are much more optimized for aging than mice are because mice are in a field. They’re gonna get eaten by a hawk in about, they’re like dropping somebody into the DMZ, not the DMZ, into Hotzone in Vietnam. That’s just, we don’t have a long life expectancy there back from then. So they’re not optimized for, I think you’re right. They were probably not going to get quite the same. But think, over time, that thing may be tweaked. It’s gonna be systems biology that solves these-
Kara Fitzgerald, N.D.
Literally. Exactly.
Joseph M. Raffaele, M.D.
How they interact and the only way that we’re gonna be able to do that is if you have this massive amount of computing power, that we currently have and that’s increasing every year to be able to look at everything at the same time and try to figure out which dials to turn. I don’t wanna forget, I think my listeners would be interested, and I am also interested, to get back to this the diet that you have, I was looking through it, it has three ounces of liver in it, it has six ounces of animal protein a day. It has lots of vegetables, some fruit, and probiotics, et cetera. How did you come to that? It was through multiple ways of looking at it? Do you think that, given that it’s turning the clock back, that that tells us that there are certain things that need to be in your diet? Or what do you think?
Kara Fitzgerald, N.D.
Yeah. Well, I mean, it’s not just a diet. It’s funny. It’s kind of fun. If you talk to different experts, they’ll have an idea as to what they think is the most impactful intervention. Was it the meditation? I mean, we know meditation in, actually in anyone, you can see favorable DNA methylation changes immediately. And then, in practiced meditators, they’re biologically younger. So all of our interventions stack up to favorably influence DNA methylation. They all do, exercise, of course, balanced exercise, et cetera.
Joseph M. Raffaele, M.D.
Do you think there’s an absence of alcohol?
Kara Fitzgerald, N.D.
Yeah, yeah. That was part of the intervention. Did everybody follow what we prescribed impeccably? No, they didn’t. However, we do have adherence data. And people did really really well. And I think the difference was the fact that they had contact with our nutrition team. Otherwise, I think nutritional interventions are notoriously inadequate. But I think ours was good because we had this extra support. So I think, our diet is like the stroke of brilliance, I think, around having a smart clinical team here that’s weighted in nutrition science. Having a background myself as a naturopathic physician trained in laboratory science, where I did my post doc, and being really steeped deeply in orthomolecular thinking like Brusaints and Lioness Balling and of course, Jeff Bland is a important mentor of mine, and my mentor in the lab.
Richard Lord comes from the same lineage where you want your intervention in the- The right intervention in the right dose. And so we took that thinking and we moved away from just aggressive high-dose supplement prescription. And you can ask me why in a minute, if you want to and looked at a nutrition intervention through that lens, so right micronutrients in the right amounts. And we know that aging is globally, a hypomethylation phenomena, but then there’s these regions of hypermethylation. So at foundation, the diet is as rich in methyl donors as we could possibly make it. So it’s a very greens-forward diet, and then we’ve got beets. And then we did include three servings per week, so it’s not a daily liver ingestion, but three servings a week of liver.
And if you look at the micronutrient composition of liver, it’s this extraordinary multivitamin in a nutrient matrix, so bio availability and synergistic interactions are all there. And so we turned the volume as high as we possibly could on methyl donors in the diet. And then we also gave what was, colloquially terming methylation adaptogens. And these are, by and large, polyphenolic compounds that have data, mostly in vitro, animal, limited human data, on being able to augment the behavior of DNA methyltransferase enzymes. And so we packed it with these polyphenols that includes, and they’re polyphenols that we know, time and memorial, are effective, green tea, so EGCG and all of the components in the whole green tea-
Joseph M. Raffaele, M.D.
So you guys are actually drinking green tea?
Kara Fitzgerald, N.D.
Yeah, we wanted people to drink green tea and steep it for 10 minutes, to really get a rich complement of all of those polyphenols. Circumin, luteolin, quercetin, lutein, resveratrol.
Joseph M. Raffaele, M.D.
Those are added as supplements?
Kara Fitzgerald, N.D.
No, no, no, no supplements. But we gave them, we asked that they consume a diet that was rich in these, well, in polyphenols in general. We can’t make people eat two pounds of grapes or six onions or whatever. But we just wanted to lean on supporting them with that, with those kind of nutrients. We did give them a greens concentrate to bump that up a little bit more, so it’s not encapsulated. It’s just a greens powder. And then we gave them a probiotic, lactobacillus plantarum, that has some research on being able to increase microbial folate production. It’s got a bunch of, probiotics are good for a number of reasons. And some of them may actually help our own endogenous production of some of these nutrients via our microbiome.
We did significantly increase circulating folate without giving a vitamin, so yeah. So that was where the rubber meets the road. We had these methylation adaptogens that are polyphenols. There’s another family of enzymes called the 10-11 translocase enzymes. And these guys are active in demethylating. And, really, demethylating is important as methylating. Co-factors in those include vitamin C, Alpha-ketoglutarate, iron. And so we, it was vitamin C rich. We weren’t giving any iron. You know, middle-aged men generally don’t need any iron. Alpha-ketoglutarate, ideally.
Maybe they’re making some from their protein, so we were just thinking about optimizing DNA methylation with whatever we could in the diet and then layering in the lifestyle interventions that also have science behind them as favorably influencing methylation. And that’s what we created. And, yeah, it’s amazing that we, I’m absolutely thrilled that we saw what we saw. It was designed, coming from a unique background of having this orthomolecular training, lab training, and having whip smart nutritionists here. The director of our nutrition programs, Romele Hodges, worked on building out those micronutrient ratios.
Joseph M. Raffaele, M.D.
So you measured methylfolate levels.
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
Did you measure any other micronutrient levels?
Kara Fitzgerald, N.D.
Yeah, we measured a whole bunch of things. And they’re reported in the paper. We just, we highlighted what was a big deal, so folate increase, triglycerides dropped, LDL dropped, total cholesterol dropped, which just lends weight to the fact that it was keto leaning and lower glycemic.
Joseph M. Raffaele, M.D.
And a good diet.
Kara Fitzgerald, N.D.
Yeah and a good diet. Yeah, that’s right. We didn’t make a difference in Homocysteine, S-Adenosyl Methionine, S-Adenosyl Homocysteine, no difference. We looked at a-
Joseph M. Raffaele, M.D.
Maybe a power issue.
Kara Fitzgerald, N.D.
Huh?
Joseph M. Raffaele, M.D.
That may have been a power issue. I mean, depending on-
Kara Fitzgerald, N.D.
Well, they were healthy guys. They weren’t hypohomocyst anemic. They didn’t really need their homocysteine lowered so I think- But you know what it does illustrate? And, yeah, maybe when we have a lot larger population we’ll see changes. But I think it illustrates that, the methylome response, even before some of our methylation cycle actually, all of our methylatioc cycle, biomarkers respond.
Joseph M. Raffaele, M.D.
That’s a good point. That’s a really good point.
Kara Fitzgerald, N.D.
And that’s an important take home.
Joseph M. Raffaele, M.D.
It’s an important point.
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
Is it more sensitive canary coal mine, and actually, these serum levels which may not be as important.
Kara Fitzgerald, N.D.
We lean heavily on those biomarkers. They’ve been around time and memorial and we look at tweaking those and they do reflect what’s happening with DNA methylation but they’re not the end of the story. The reason that we didn’t go with supplements ’cause we could have, is because there are some studies suggesting that if you push methylation forward too much, famously is the study, they gave an older population with elevated homocysteine, they gave them folate and B12. And they ended up, when they did a secondary analysis, a large percentage of the population, a significant percentage of the population developed colorectal cancer. And they actually were challenged on the findings. They went in and re-analyzed and it was actually still there and it was even stronger and they’ve been tracking this population for a while. And that’s just not the only study to suggest that. And it goes back to Jirtle, in that first 2003 paper, those guys said, in their abstract, in the conclusion, nutrients are extremely powerful and we need to be mindful that we’re actually using them with that awareness. And that was our thinking, too. Do we need, now that we can look at the epigenome, do we need to be mindful of how heavy we hit with our various interventions?
Joseph M. Raffaele, M.D.
And that’s a really, really important take-home point. I think also, the original Horvath clock was associated with mortality and pan-tissue clock et cetera. But it’s, in the end, trained on chronological age from the beginning. The second and even third generation clocks, now you might consider, the rate of aging one, are trained on other things. So that may be think about what PhenoAge is trained on which is not on chronological ages in it but nine other markers are common markers from chemistry in a CRP and CBT. Which could be an interesting thing to do alongside the DNA methylation in a subsequent study you do. Because, in all the data sets that they look at, its highly associated with mortality and morbidity and health conditions. We have other data to show that RDW’S an important marker for mortality. And seeing those is a thing that should go along with the molecular data. Are you actually changing red cells, changing liver function, changing inflammation as a measure by CRP along with the methylone? It would be a easy and inexpensive thing to do.
Kara Fitzgerald, N.D.
Yeah. For sure. And we will.
Joseph M. Raffaele, M.D.
We started to measure that now in our where we look at the PhenoAge and track that along time longitudinally and hopefully, we’ll get some more information out of that.
Kara Fitzgerald, N.D.
That’s gonna be exciting. Yeah, you’re gonna have a bunch of information. And do let me say that we will, without question, be looking at the next generation clocks as we recruit. Yeah, we’re not gonna hang with the original Horvath clock but you could argue. So some people think it’s, the fact that we limited it to the 2013, we had no choice. We started our study before we had the advantage of the current landscape of clocks. But you could argue that maybe its a harder clock to actually nudge and so nudging it is a big deal. It depends on how you look at it. It’s not a hundred percent associated with chronological aging. There’s some wiggle room in there.
Joseph M. Raffaele, M.D.
No question about that and I think that you could argue that you’re getting closer to more intrinsic aging potentially. It’s definitely a big finding. The proliferation of clocks is nothing but a good thing.
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
I’ll be using multiple clocks for different things going forward. And even calling them clocks at a certain point doesn’t even make that much sense. So just epigenetic biomarkers, composite panels, really of changes in gene expression that its nice to have an age associated with it but the new clocks have an r squared with chronological age of 0.6 or something like that.
Kara Fitzgerald, N.D.
Right, that’s right.
Joseph M. Raffaele, M.D.
Not this other massive one but they’re telling you more important things .
Kara Fitzgerald, N.D.
At least we think they are. Time will tell but yeah.
Joseph M. Raffaele, M.D.
They’re trained on things that we think are more important.
Kara Fitzgerald, N.D.
Yeah, you’re right.
Joseph M. Raffaele, M.D.
None of my comments are taking away from the importance of the change that occurred in your study, I’m just saying-
Kara Fitzgerald, N.D.
No, I get it. Yeah, yeah.
Joseph M. Raffaele, M.D.
Interesting, yeah. You, I think, in our podcast that we did a while ago, you were the one that got me thinking about the clocks a little bit more. I’ve been the telomere guy. So now, I’ve incorporated-
Kara Fitzgerald, N.D.
I’m so happy! I’m so happy you drank the Kool Aid. Because if you’re incorporating it in your system, you’re gonna really contribute to the body of knowledge and you’re right, it’s important and it’s important we’ve got AI working on it.
Joseph M. Raffaele, M.D.
Yeah, and also would be interesting, too because we’ve talked about this in the previous podcast is how is your diet and lifestyle affecting GlycanAge? That’s a whole ‘nother interesting thing is GlycanAge is a pretty important marker. The glycosylation of the IgG that Gordon Louse looked at and highly associated with outcomes and with chronological age. So the more ways you have to look at what’s happening to us physiologically, as we age, and with certain conditions, the better. Perhaps that’s a good place to take along the conversation, always fascinating and goes by so fast with you, to a close. But I just want to let you say anything that- You have a new book coming out, you just finished 700 pages. What’s the title?
Kara Fitzgerald, N.D.
It’s a beam, it’s a beam! It’s called Younger You and it’s our journey into epigenetics and its all the details on the study. But, beyond that, just talking about epigenetics and cancer and how we got into this conversation in the first place. There’s a whole lot of really interesting angles outside of biological aging. I’ll just say one area I’m just wow’ed about in the book is this concept of biological embedding. And we’re learning that DNA methylation and epigenetics more broadly biologically embed our experience. So they’re translating our experience in life to these biochemical markers that then influence genetic expression and this is heritable as well. The bulk of the research, of course, is trauma.
You can see it in Kosovo survivors, you can see it in some of the more famous studies, like the Dutch Hunger Winter, , you can see it in Holocaust patients or survivors and their offspring. You can see it in PTSD and the heritability patterns of that. So the focus has been on trauma understandably but looking at survivors, looking at vibrant wellness, looking at the translation into biochemical patterns of living good and big and mentally powerfully clear lives. All of that is just extraordinary to me and interesting to me and new, emerging science. So we talk about that in the book. And then I also talk about big picture thoughts on aging in general and you know folks in the biohacker field maybe you’re one of them who are basically like, “let me replace an organ when it falls apart and I’m gonna live until 1000 regardless of what I eat.” There’s this interesting continuum of folks in our world and I’m obviously arguing for living your best life and eating well and et cetera, et cetera. I just touch on a lot of different areas that are interesting to me in this space.
Joseph M. Raffaele, M.D.
No, look, in terms of that, I’m not in that biohacker crew of things that can just turn the car in or turn the engine in when I need a new one. You wanna try and preserve it. And of course, the ultimate organ is the brain, that’s gonna be real difficult to just turn in. I think you’re right. I thought where we were going with that was experimentation with yourself. I think there are some people getting a little bit ahead of science.
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
Particularly with this analytics, I think is a certain degree.
Kara Fitzgerald, N.D.
Or CRISPR infusions. You know?
Joseph M. Raffaele, M.D.
Well, yeah.
Kara Fitzgerald, N.D.
Like DIY CRISPR infusions.
Joseph M. Raffaele, M.D.
I do tell patients, and I have this conversation with them, that the risk-benefit equation changes over the lifespan. So, you’re at 85 and things are really going the tube fast, I’m willing to try other things that may have a benefit on you because the downside is pretty much the same the outcome. But early on, people doing some of these things, I think is a little bit- They may not be sophisticated enough consumers of the medical literature to know what they’re getting into when they’re doing this kind of stuff.
Kara Fitzgerald, N.D.
I don’t know that the medical literature knows. I don’t think we’ve pieced all of that together yet. You know?
Joseph M. Raffaele, M.D.
Which is probably why you have to be a really sophisticated consumer because we have not pieced all that together and oftentimes there’s a lot of enthusiasm in the way in which papers are written up and so you have to be careful about it. And you’re absolutely right. In my practice, starts with lifestyle, diet, exercise take supplements, if necessary. And it goes on depending if you want to go with the foundations of it all and I’m sure there’s many other- We talk about exercise affects epigenetics et cetera.
Kara Fitzgerald, N.D.
Yeah.
Joseph M. Raffaele, M.D.
But it’s been a fascinating conversation and hopefully we’ll continue it again.
Kara Fitzgerald, N.D.
Yay! I’m sure we will. I’m sure you’ll be back on my podcast soon. Actually, I look forward to it. Especially as you crunch these new tests that you’re collecting and pop them into your machine and have some interesting stuff to report.
Joseph M. Raffaele, M.D.
Yeah, it’ll be fun.
Kara Fitzgerald, N.D.
We’ll connect.
Joseph M. Raffaele, M.D.
All right, well, thank you very much, again, Kara. And we’ll talk soon.
Kara Fitzgerald, N.D.
Okay.
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