This article is part of our May 2022 Healthy Aging special issue. Download the full issue here.
Natural Medicine Journal’s Editor-in-Chief, Tina Kaczor, ND, FABNO, recently had the opportunity to sit down with Kara Fitzgerald, ND, IFMCP. Fitzgerald is the coauthor of a peer-reviewed paper on antiaging epigenetic effects of a naturopathic protocol. In this interview, Fitzgerald discusses how epigenetics is involved in cellular aging, details of the protocol used in the study, and talks about where we are headed in the future.
This interview was published as a podcast in December 2021 and is being reprised here as a Q&A for our Healthy Aging special issue.
Tina Kaczor: You're the lead author of a first-of-its-kind study on a diet and lifestyle intervention that has a measurable effect on the aging process. What was so interesting about the study is that it combined the latest in assessment using DNA, epigenetics, and methylation patterns with what I would call an old-school natural medicine approach. I was excited to see you didn't use the nutraceuticals. You used basic, good, foundational medicine. How did your background lead you here?
Kara Fitzgerald: We're in a real scientific medical revolution right now. Our technologies are advancing at a breakneck pace. We're learning, though, that going back to old-school interventions is still the way we're going to get best outcomes.
I saw this when I worked at the first clinical lab to release a DNA stool analysis (ie, a PCR stool analysis) during my postdoc training. It was this amazing, stratospheric blast of technology. But the kinds of interventions that were ultimately landed on were chew your food, rest and digest, and eat a whole-food diet. The interventions got simpler and simpler.
I'm somewhat of a geeky, biochemistry-inclined naturopathic physician. I was hoping we would have pinpoint probiotic prescriptions. Not that the complexity would just be so expansive, and that we would see that a whole-foods diet ultimately changed things.
Flash forward, and we can now look at DNA methylation, which is one of the main epigenetic markers that determines whether genes are turned on or off. At the time of our study in 2017, it was only available in the research setting, but now slowly labs are making epigenetic testing more broadly available.
In our world, we talk about nutrigenomics all the time. We put a lot of attention into assuming that what we're doing is influencing genetic expression, and rightly so. So I finally started to really tussle with the epigenetic research. It was mostly in cancer, which is where the best science was coming out around 2013. So I was aware of epigenetics and that it was getting big. It really expanded after the genome was fully mapped in the early 2000s and we realized this idea of one gene driving one disease was in fact a misconception. We've got 23,000 genes. It's remarkably simple.
Epigenetics, which regulates genetic expression, controlling genes that are on or turning genes off, is as complex as DNA is simple. Mapping the genome wasn't going to provide the ticket to all the complex diseases we are facing.
One of the things that interested me was the methylation cycle. Hypermethylation on the genome—which turns a gene off when there are a lot of little methyl groups hanging out, usually in the promoter region of a gene—is going to shut that gene down. Conversely, hypomethylation also happens on different genes. Hyper- and hypo-, this tension, is happening all the time. In cancer, the tumor microenvironment can very effectively hijack our epigenetic machinery and turn genes on and off—to hyper- and hypomethylate concurrently—for its own growth process.
The big aha for me was that we could possibly be doing harm to our patients by pushing aggressive amounts of B-12 and folate, natural or otherwise. Could our interventions be negatively influencing DNA methylation? Some literature suggests it’s possible.
One of the more famous studies was the B-PROOF trial, where they gave elderly individuals with elevated homocysteine 400 mcg of folic acid and maybe 500 of B12 to try to prevent fractures. It wasn't a huge amount, but a small but significant subset of these individuals, particularly those who were older, had a statistically significant increased risk of colorectal cancer.
For me, it just shone a light on the U-curve. We know that if you don't have enough methyl donors, there are big problems, including cancer risk, but there an also be too much.
TK: How you come to develop your nutrition program?
KF: My clinic has a strong nutrition team. Our nutrition director was Romilly Hodges. She and I began to really talk about this, and I said, “Let's build out a nutrition-forward methylation program.”
There's a clear need for an abundance of methylation support. It's happening in every cell of the body, basically all of the time. So we need to support it. And we also need to perhaps be a little bit more nuanced in our approach. And that was our entry into the conversation.
We built out this methylation diet and lifestyle program to use in our clinic practice. We also used it a lot with individuals who don't tolerate B12. We had the capacity, and Romilly led the charge in building out a beautiful program that loaded up on natural folates from foods and betaine. We used lots of beets, and liver for folks who will eat liver. Liver is a multivitamin of food matrix.
Concurrently we also saw that exercise is associated with lowering homocysteine; it promotes balanced methylation. As do sleep and meditation. So we looked beyond just food and we looked at lifestyle components that had evidence behind them for healthy methylation.
Another big aha for me on this journey was the fact that aging is the number one risk factor for all the chronic diseases we're working with in practice. Some of the imbalances that drive aging epigenetically are the same as what's happening in cancer, cardiovascular disease, or diabetes, or stem cell exhaustion. The imbalances that are happening in stem cell exhaustion look like the tumor microenvironment.
TK: What’s your take on the term antiaging?
KF: Everybody has their own idea around aging and what antiaging is. For many people it’s Botox and whatever else you can do to make yourself look young. I'm speaking about something very, very different—biological aging. It is different than chronological aging.
TK: Yeah, it's biological aging, this is not a calendar. This is more profound than most papers out there on antiaging. So tell us more about the study you conducted.
KF: Romilly and I were thinking the whole time about whether we were actually influencing epigenetics. We put together a program that suggests yes. But we threw out all sorts of permutations of studies we might do, because measuring epigenetics at the time in practice in 2017 was not available. It's only now just barely becoming available.
I was in conversation with Brent Eck, the CEO of Metagenics, and he very graciously gave me an unrestricted grant to conduct this study. We included their probiotic and greens powder in the study, but they didn't pick those. We were allowed to do this and to manifest it ourselves, and we were in charge of design and everything.
We used the largest available DNA methylation array, which measures a good portion of the methylone, which are those marks directly on DNA. Methylation tends to become aberrant or disordered as we age. Anybody who's measuring homocysteine sees that it tends to rise and other things become imbalanced.
The study was a pilot and we needed to limit it to men since we didn’t have the resources to distinguish between pre-, peri- and post-menopausal influence. As a woman, it was difficult, but we had to make that choice.
We also wanted a healthy cohort. We weren't looking at epigenetic changes in diabetes or cardiovascular disease. We were specifically looking at whether or not we're reversing biological age. We didn't want to do that in a population that wasn't healthy.
To really push study adherence, our nutrition team volunteered their time and coached participants. Required nutrition meetings were built in. They weren’t cheerleading meetings; they were drab IRB-approved script meetings. They were not a typical encounter you would have with your patients, but adherence was very good.
We had a modest exercise prescription, the relaxation response, and some basic breathing exercises, limited to 10 to 20 minutes twice per day. We included the probiotic Lactobacillus plantarum. The reason behind the probiotic is that it may increase folate production.
We did end up significantly increasing full circulating methyl folate by 15% in our study population. And then included a greens powder.
TK: It's interesting that it worked in a healthy population, because to me that means it might have more profound effects in people with more evidence of biological aging.
KF: I think that's right, but as a counterpoint, an unwell population may require a longer intervention period. Though as a clinician I know we can turn around blood sugar, A1C, insulin in a short amount of time if you've got a motivated patient. So yes, I think unwell people might reverse aging faster and more profoundly than a healthy population. But we'll have to see what kind of a timeframe that is.
In our healthy population, we lowered total cholesterol, even though it wasn't elevated. It wasn't too low, but we brought LDL and triglycerides down.
Our diet is a little bit keto-leaning. It's got a very gentle intermittent fasting structure (not eating from 7 PM to 7 AM). And again, we have the exercise prescription. I think the burning of the triglycerides suggests a little bit of ketosis.
TK: Can you explain the tool that was used to measure biological aging on the DNA?
KF: There is a predictable change in DNA methylation patterns, starting from conception. From embryogenesis to death, predictable changes occur across the lifespan. The clock that we used is the first biological age clock, which was released in 2013. There are subsequent clocks now and we'll be looking at those. Second and even third generation clocks that track aging more closely associated with morbidity and mortality. There's aging of skin and looking at the immune system, et cetera. There are ways to track organ-specific aging, and there are all sorts of cool aging questions we can answer now with DNA methylation patterns. But the very first and most utilized clock is the Horvath 2013 DNA methylation age clock.
Horvath is a biostatistician and he created it with a massive dataset of individuals. The original clock was locked to chronological age and correlates with a 0.96-degree correlation coefficient. This one blows away any other biological age market out there. The next best at the time was telomeres, which are still used and can be useful. But the correlation coefficient is about 0.4, maybe. So this was just the most rigorous biological age assessment out there dialed in with chronological age.
One of the big questions we set out to answer was whether we could improve the biological aging patterns in our population. Being a naturopath and working with Romilly on orthomolecular nutrition, we wanted to see how we could massage the DNA methylone for optimal expression.
One of the revolutions in thinking that I've experienced on this journey is that all of the massive timestamped movements we go through as human beings are regulated in significant part with changes to methylation, DNA methylation. This is both adding methylation, but subtracting demethylation too. In fact are 2 families of enzymes that are involved in here—DNA methyltransferase enzymes, and then a family of enzymes called Ten-eleven translocation enzymes that take methyl groups off.
Over time these really influence the course of our life. There is probably a program to the aging journey that may be dictated by changes to DNA methylation. I think that's where some of the science is really headed now. So if we put attention on optimizing DNA methylation, yes, we saw improvement in the standard biomarkers of our participants. But we also saw improvement in their DNA methylation patterns.
So our proposal is that changing and optimizing DNA methylation patterns as it relates to biological aging isn't just changing the surrogate marker of biological aging, it actually is changing biological aging.
TK: And the worst case is, you're eating a healthy diet. You wake up feeling good, your joint pain goes away. Best case is you feel good longer.
KF: Well, and you live longer, you've got a longer health span. And we're actually influencing sort of a pre-programmed clock. If aging is a pre-programmed event and there's some evidence that it is, and some evidence that at least a chunk of that role is played by changes to DNA methylation, then it looks like what we're doing could be massaging that favorably. When you think about things with an orthomolecular model, why wouldn't we be able to do that, right? Why wouldn't we be able to influence with the sweet spot of nutrients to ingest?
TK: Was there a calorie count that these participants had to adhere to?
KF: No. The cool thing about this program is you can layer it into whatever intervention you want. We've used it in clinical practice with FODMAP, or with people with allergies, or with cancer. We really want to massage methylation in a balanced, healthy way. We use this all of the time, but we might turn up the volume with ketosis or turn down the volume on caloric intake. But if we had done caloric restriction and we'd achieved these findings, we wouldn't be able to lean on our intervention, it would've been clear.
TK: You recently published a book. Can you tell us a bit about that?
KF: The book is called Younger You: Reduce Your Bio Age and Live Longer, Better. In it, I walk through this program with more nuance. I give more specific protein requirements for body size and age. I've also interpreted it for pregnancy. And I go into how to transition to other foods, since this not necessarily a forever diet.
TK: I really appreciate your being at the forefront of combining the functional medicine and naturopathic medicine with integrity. Thank you for taking the time to share your research with us.
KF: That means a lot. And right back at you. You’re blazing amazing trails as well.
[Sidebar] The Study Intervention
- 3 servings of liver
- 5-10 eggs
2 cups dark leafy greens
2 cups cruciferous vegetables
3 additional cups colorful vegetables
1-2 medium beets
4 tablespoons pumpkin seeds
4 tablespoons sunflower seeds
1+ servings of methylation adaptogens like berries, garlic, and some herbs
6 ounces animal protein
2 servings low-glycemic fruit
- Stay hydrated
- Don’t eat between 7 PM and 7 AM,
- Include healthy oils in the diet
- Avoid sugar, candy, dairy, grains, legumes, and beans
- Minimize plastic food containers
- Supplement exercise
- Sleep 7 hours
- Manage stress through breathing exercise
About the Expert
Kara Fitzgerald, ND, IFMCP
Kara Fitzgerald, ND, IFMCP, is the first-ever recipient of the 2018 Emerging Leadership Award from the Personalized Lifestyle Medicine Institute in recognition of her work on DNA methylation. Receiving her doctorate in naturopathic medicine from the National University of Natural Medicine, she lectures globally on functional medicine, is on the faculty at the Institute for Functional Medicine (IFM), and is an IFM Certified Practitioner with a clinical practice in Newtown, Connecticut. She runs a Functional Medicine Clinic Immersion program for professionals and hosts the podcast New Frontiers in Functional Medicine. Fitzgerald is also actively engaged in clinical research on the DNA methylome using a diet and lifestyle intervention developed in her practice. Her first study was published in the journal Aging. A consumer book, Younger You, and an application-based program, 3YY, based on the study are scheduled for release January 2022. She lives with her daughter in Connecticut.