Kara Fitzgerald, ND, IFMCP, is a Naturopathic Doctor and an Institute for Functional Medicine (IFM) Certified Practitioner in private practice in Sandy Hook, Connecticut, and faculty at the IFM. Dr. Fitzgerald completed the first CNME-accredited post-doctorate position in nutritional biochemistry and laboratory science at Metametrix (now Genova) Clinical Laboratory under the direction of Richard Lord, PhD. With the Helfgott Research Institute, Dr. Fitzgerald is actively engaged in clinical research on the DNA methylome using a diet and lifestyle intervention developed in her practice. The first publication from the study focuses on reversal of biological aging and was published in 2021.
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Robert Rountree: Please introduce yourself to our readers. As a clinician, researcher, and writer, how would you tell people who Dr. Kara Fitzgerald is? What are you doing now and how do you describe your work?
Kara Fitzgerald: I'm a naturopathic physician by training, and I heard Jeff Bland speak when I was in school, and I was immediately enamored of nutritional biochemistry and the promise of translating science into clinical application. It seemed to me a really good framework for how we might think through treating individuals. It was something that rested easy with me. I guess I just must like reason and mechanism and that kind of thing. So after I finished school, I did a postdoc in laboratory science at Metametrix, as you know, under the direction of a highly regarded nutritional biochemist, Dr. Richard Lord. I think if I didn't have that opportunity, I very well could have been back in school going for a PhD, but working with Richard was incredibly nourishing for me, and really set the trajectory of my career. So, I had this body of knowledge from naturopathic school, I was very deeply steeped in training in traditional naturopathic interventions, but then got to view it in the lens of biochemistry. So for me, having the biochemistry framework to think through Nature Cure ideas was helpful. That combination together was just very powerful for me. Working with Richard and having him have such a deep appreciation of naturopathic training, and then layering into that biochemical pathways and how we think about it, and how you can infer interventions from having some of that knowledge, was just very satisfying. It was just super—it was very satisfying for me to work at the lab, and it was also a really forward-thinking lab. Like we got to tussle with new biomarkers coming down the pike, or just new ideas in science. I mean, we were the first clinical lab to create a PCR stool test. Many iterations have followed since in the many, many years since we first did that, but just the fact that we stuck ourselves out there and figured that out, I think, is important.
Dr. Rountree: Dr. Lord was really one of the fathers of the whole field of functional medicine.
Dr. Fitzgerald: Yes. That's right. And he's an educator at heart. He was such a good teacher for me, and he really honored thinking and asking questions and chasing down mechanisms and diving into papers, spending the day in the rabbit hole of science and I don't know, it was just like a kid in a candy store for me. It shaped such a deep appreciation of science and medicine, of the possibility of what we were doing in this world of functional and integrative medicine. I am just forever deeply grateful about my time there in the lab, and this rich opportunity to grow and to think and to connect and to share ideas and to figure stuff out and try it clinically. It was an important time for me.
Dr. Rountree: Was Dr. Lord a protégé of Roger Williams
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? I suspect he was walking down that same path of biochemical individuality, etc., so those ideas would have filtered down to you. Mainstream biochemistry texts state that the same basic biological reactions occur in all of our bodies, and that's the end of the story. Whereas Dr. Williams was essentially saying, “Uniqueness in the way these reactions occur in each person is really what defines us as human beings.”
Dr. Fitzgerald: Yes, absolutely. That's exactly right. And how can we treat the individual? How can we consider what's happening biochemically with them and influence pathways? Of course, Bruce Ames, PhD, professor Emeritus of Biochemistry and Molecular Biology at the University of California, Berkeley, and former senior scientist at Children's Hospital Oakland Research Institute, figured into our conversations quite a bit, as well. We went further on that.
Dr. Rountree: Is it safe to say Metametrix Clinical Laboratory was one of the forerunners of clinical metabolomics?
Dr. Fitzgerald: Yes, absolutely, I think so. I think that's what we were doing, sort of a precursor to where we're headed. We're actually not really quite there yet. Metabolomic data isn't widely used yet, and how we interpret it, we're still wrapping our arms around and we need to move into artificial intelligence. We need to move into a new body of tools to work with all these data points that we will soon have access to. So anyway, yes, I think Metametrix was certainly one of the founding labs there.
Dr. Rountree: And is that when you wrote Case Studies in Integrative and Functional Medicine
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? Can you maybe say a little bit about that book, because I think it was a groundbreaking work. I have a thumbed copy of it.
Dr. Fitzgerald: Yes and thank you! Part of my postdoc position there was working on Laboratory Evaluations for Integrative and Functional Medicine,
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so that was the first book that we released, and again, just a great experience. And it's still a useful book. So that came out of Metametrix's laboratory, and again, it's evidence of the real commitment to education. It wasn't a moneymaker, that's for sure, but just like putting a stake in functional laboratory science. Right after that, we wanted to write a collection of case studies, and I eagerly took that on, and how do we actually use these tools, these laboratory tools? And that was published in 2011, Case Studies in Integrative and Functional Medicine.
Dr. Rountree: Is that still in press? Can people still buy it?
Dr. Fitzgerald: No, unfortunately. People can't get it. It's a shame, because it walks one through how to think through a case using a functional lens. If you join our nutrition internship program, you can actually get a copy. I have maybe a couple hundred here kicking around.
Dr. Rountree: Metametrix became part of Genova Diagnostics, just to clarify for our readers.
Dr. Fitzgerald: Yes, that's right. And Genova has decided not to print it because it needs to be updated, and that's something that I can't take on right now. There are still plenty of pearls on thinking through a functional case in this book, even as it could be updated, so if anybody is compelled to update this book, I'll certainly support you in that endeavor.
Dr. Rountree: As I'm sure you've learned, the whole process of writing a book is a massive endeavor. The editing that's involved, the fact checking, every part of it is very time-consuming, and it takes over your life.
Dr. Fitzgerald: Yes. I agree. It was a huge undertaking. In fact, at the lab, they didn't have an appreciation for case study writing, they did not think it held a candle to scientific writing. But it is as detailed and onerous and I really wanted to put the evidence behind what I was saying as much as I could. And there's no difference. But that came as a surprise, the length of time it took me to write this.
Dr. Rountree: You ended up in naturopathic medical school. How did you ever find out about naturopathic medicine in the first place? Is that something you'd always dreamed of doing?
Dr. Fitzgerald: Because like so many of us, I got sick, and a naturopathic doctor got me better. Jeffrey Klass, here in Connecticut, one of the longest-practicing NDs in this state, by a lot. I developed kind of a classic chronic fatigue, maybe Epstein-Barr-driven, burning the candle at both ends, and went to a bunch of MDs in conventional models and didn't really get any help. Nobody obviously knew what to do with me. And my landlady at the time worked with Jeff Klass, and she was maybe in her early 90s, or certainly her late 80s, and she was a healthy spitfire, just an amazing woman, and she referred me to him. And he got me better in a very basic, simple way. He prescribed some botanicals. I can't remember what they are. It was a combination that he put together in his office. He gave me some CoQ10 and some really simple dietary recommendations. I don't remember much else of what he did, but it was a straightforward protocol, something that a 20-something-year-old could manage to do. And I got better!
Dr. Rountree: I assume you liked the holistic thinking and problem-solving process that was involved?
Dr. Fitzgerald: Honestly, I would say that I was most appreciative of getting better, but shortly after that I got a job in the supplement section of our local health food store. And I grew up with a health-savvy mom. So I had a little bit of background. In fact, for my first job, my mom paid me to work our co-op hours; we were involved in a co-op, and we needed to do like 5 or 10 hours a month, and she would actually pay me an hourly wage to go do our volunteer time, and I would go down there, and I just remember eating loads of carob chips and things like that.
Dr. Rountree: Little did you know that would lead you to being a published author and a researcher!
Dr. Fitzgerald: Yes, that's right. I was appreciative of getting better, but concurrently I started working in the supplement section. What I remember is that was when I started to get really jazzed up about mechanisms and what things were doing. And, you know, the supplement companies would always send out a little bit of research, and it was very enticing to me. But really, a big thing was Udo Erasmus, author of Fats That Heal, Fats That Kill: The Complete Guide to Fats, Oils, Cholesterol and Human Health.
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When I started to read his work, I got very excited about fatty acid biochemistry.
Dr. Rountree: Yes. And also fatty acids.
Dr. Fitzgerald: Yes! I got into fatty acids. It's ridiculously interesting. I'm still friends with the manager of the supplement section, so many years later we're still really good buddies, and she just thinks it's absolutely hysterical how I was completely enamored of these mechanisms and just in awe because I loved biochemistry. I remember vividly not being able to read it at night; it was so interesting, it would keep me up. That's a foreshadowing!
Dr. Rountree: You were a deep knowledge diver from the beginning.
Dr. Fitzgerald: I was. I wanted to really understand the whys around things. So I think getting sick and getting better through natural medicine, being in the health food store, and all of it culminating around conventional medical school or naturopathic medical school was in the background. At that time you could talk to the presidents of the schools. I remember talking to Jim Sensenig, who was starting the University of Bridgeport, at the time the third school of naturopathic medicine, and just having access to this community to sort of parse out the pros and cons of either path. And it seemed to me that naturopathic medicine was in alignment with who I was, certainly at that time. It was a no-brainer for me to choose that. I was thinking about conventional medical school, I was thinking about a PhD in psychology and naturopathic medicine, so those were the three things that I was sitting with in my 20s. So those events culminated there. Bastyr was my first choice. It was my interview process that prompted me to jump over to National College of Natural Medicine (now called National University of Natural Medicine); I just had a really nice, kind of inspired interview there, and so I went to the sister school.
Dr. Rountree: Let's go back to when you published the book of case studies. What happened at that point in your career? I'm sure you started thinking of yourself in a different light in terms of the role you were to play as a thought leader.
Dr. Fitzgerald: I started speaking for Metametrix as soon as I landed there. I was just a newly minted physician. But with the knowledge that I gained, working with Richard and working with the labs that they were running on organic acids and the organic acid pathways and the relationships to amino acids and fatty acid biochemistry, etc., I had a body of knowledge from that time that most clinicians didn't have. So I immediately started to speak. Teaching from the get-go was a part of my journey, amazingly enough. A funny story is one of my very first breakfasts, I was talking about the Metametrix ION™ (Individual Optimal Nutrition) panel, which is all of that: organic acids, fatty acids, amino acids, and a few other things. And so I was lecturing on that and presenting some cases and so forth, and Mark Hyman, MD, physician and author of numerous books on nutrition and Functional Medicine, came in, sat right in the front, and started to ping me with really good and challenging Mark kinds of questions. And I just remember sort of—phew!—really being able to volley with him and answer him and kind of hold my own, as just, really, a newly minted doctor at that time. That was my first big deep dive into functional medicine, into the functional medicine sort of luminary crowd.
Dr. Rountree: Yes! Here's this famous doctor that is asking you tough questions, and you are answering all of them!
Dr. Fitzgerald: I hung in there.
Dr. Rountree: So you realized early on that you were destined to be an educator and that that was part of who you were professionally.
Dr. Fitzgerald: And that's how Richard positioned us, those of us in the medical education department. He would always say, “You have this very specialized body of knowledge that most of the world does not have, and therefore you need to go out and put it out there and share it and work with others.” He made that clear. It's interesting.
Dr. Rountree: It's really interesting that he had that vision. How did that evolve into you actually opening a clinical practice?
Dr. Fitzgerald: I was seeing patients through that time. I was mostly in the lab, which is where I wanted to be, but I was also with Cheryl Burnett, ND, at her clinic. She was at Progressive Medical Center, which was a large practice, actually not totally dissimilar from what I have now, with NDs and MDs and some other clinicians, nutritionists, and so forth. I did my residency there. So I was seeing patients, which I think is, obviously, essential for us, and especially at that time.
Dr. Rountree: It keeps you honest.
Dr. Fitzgerald: Yes. That's right. It does. Is there any merit to what the heck I'm talking about? So continuing to work with patients was a given for me. What happened was I realized I didn't want to stay in Atlanta long-term. I wasn't sure where I was going to end up, but I came back to Connecticut for what was supposed to be just a short stay until I sort of figured out where I would kind of set up my clinic and next steps in earnest. I'm still here, many years later. I finished the case studies book while I was here in Connecticut, so I continued to work for Metametrix, but I was doing so remotely. I continued to consult. So I had my toes in the consulting pond. Always did. So I was continuing to do education and so forth, and had a lot of fun with that. I got to travel around the world. You've been able to do the same thing and it's just so rewarding to educate, and educate elsewhere. Teaching in India was such an exciting opportunity for me. But I was seeing patients. Initially I was at a Yale-affiliated tertiary care pain center, and that was a great experience. It was short-lived. Naturopathic medicine or functional medicine is challenging to practice in a very large, bustling tertiary care pain center, where everything is just extremely structured, and visits are very short. It was hard. An hour, hour and a half, first offices needing labs, specialty diets, supplements, etc. It was challenging.
Dr. Rountree: I would imagine you were a bit of a cog in a huge wheel.
Dr. Fitzgerald: Yes. Well, I was probably a bit of a stone and not necessarily a cog. And it was a great experience for me to work with such challenging cases. Opioids inhibit magnesium absorption—everyone on them was low. Testosterone was often very low. Of course, chronic, severe constipation was a given. Sometimes just addressing the drug side effects and other obvious deficiencies—like vitamin D, fish oil—was so appreciated! I tapered a handful of willing patients off opiods using Piscidia (Jamiacan Dogwood). And there were a few undiagnosed Celiac patients in my practice—so just identifying that and pulling them off gluten was a miracle. No more pain meds, goodbye to pain management. It was a good experience. It just wasn't destined to last forever. I really didn't anticipate setting up my own clinic. I don't see myself as a businessperson. I anticipated being in the lab, doing the work that I was doing, forever. The only reason I did was because I needed to leave the pain center; there was a time when it was just clearly too oil and water. I was too much of a stone and a cog of their machine, but I had some patients that I had to take care of, and so then I had to set out my own shingle.
Dr. Rountree: Was there an opportunity to influence some of the mainstream docs that were there? Were you the only ND on staff? Did you manage to do any convincing that naturopathic medicine had a role to play in that setting?
Dr. Fitzgerald: Well, maybe for students. There were always residents rolling through, and that was probably my best opportunity to illustrate a different way. Sometimes the physicians who were co-managing patients that I saw would see that what I was doing was dramatically changing the trajectory of that particular patient. So sometimes they would see. But honestly, it just felt like their machine was so big that it was almost a burden to kind of slow it down. Our medicine is different. In that system, it's set up so that you cannot access the doctor. My patients couldn't find me. In that structure there's a large barrier. You know, callbacks don't happen, emails are not answered. The model that we practice in functional medicine is wildly different than this model.
Dr. Rountree: Absolutely.
Dr. Fitzgerald: My patients couldn't find me. It would be days before I might get a message. That doesn't happen when you're practicing functional medicine. It can't happen—the therapeutic relationships that you develop are too essential. And this would break things down, and I would lose patients to follow-up just because of the quagmire of the system. By some miracle, for a period of time I had a medical assistant—a medical assistant manages your existence in this setting. They're the face to the outside world. And I had a medical assistant who actually still works with me. She was the billing person, but she had a medical assistant background, and they didn't have an MA for me, and so they said, “Karen, you're going to be Dr. Fitzgerald's MA.” And she's actually CFO now of our clinic, so she's been with me for a long time. And I love her. She's such a bright woman, she got how to be a medical assistant in a functional medicine practice. She got it! She learned how to talk to people about an elimination diet, etc.—I remember vividly, this is a patient that I still present at the IFM Immune Module, the filaggrin mutation eczema case, but she came to me originally with polymyalgia rheumatica. She would cry buckets to my MA because the elimination diet was just such a challenge for her. And my MA figured out how to be there with her and walk her through it. She really made the practice sing. But then eventually they took her away from me and they gave me a different MA who worked in the model of the greater system, and then my practice was imploding because it didn't fit. I needed somebody who would really tend to my patients and pay attention to them and help pave their access to me and so forth, and it just didn't work within that structure. So I left and set up my own practice, and did that part-time and continued to educate and so forth. I was asked to join the Immune Module (Advanced Practice Module for Functional Immunology at the IFM) around that time.
And let me tell you an interesting little backstory. David Jones, MD, who was president of IFM, got wind that there was a case studies book in functional medicine being written by this random upstart Kara Fitzgerald. He got wind of it somehow. He had no idea who I was. “Who's writing this book on functional medicine?” And Sheila Quinn was our editor—obviously an amazing writer and medical editor who was at IFM for years and years—and was working with me and I just absolutely love her and David started to connect and meet with me. He started to mentor me during this journey. I can see in hindsight now—I think he really wanted to vet me to make sure that this was going to be a respectable book, you know, representative of functional medicine. And I absolutely loved my time with him. For quite a while we would chat weekly, and I would send him the cases, and we would chat them through, and it was just this amazing, beautiful mentorship opportunity that can happen in our world. You know? Our world is still small enough that you can have these touchpoints with people who can really guide your career. I consider myself really blessed to have had that time with him, and that direction, and that appreciation. And to get to work with Sheila. So it was from that that I was asked to join the faculty.
Dr. Rountree: And at the same time you had your own clinic, so that really fanned the flames of your involvement in the movement?
Dr. Fitzgerald: Yes. It did. We started a laboratory rounds in my tenure at Metametrix. And we would all challenge each other. We would bring the science forward, we would talk about biomarkers, we would have clinicians come in and present cases. There were these very lively, exciting dialogues where we would inform and challenge and keep each other thinking about the latest science, how we might translate that to laboratory biomarkers. Is there anything we want to think about measuring? And what's the clinical applicability in this? And it made me see how important community is in our field. It was essential to me to have that. And when I finished, when I was no longer at Metametrix and we no longer had our rounds, there was a gap in me. I didn't have words around it; it was like a hole in my heart. And I didn't quite know exactly why I was feeling this. I remember sharing this years ago with David Haase, MD, who's faculty at IFM now and a really brilliant functional medicine clinician.
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In that conversation with him, I realized it was this loss of community that really left me feeling empty. That's when I started our journal club, which we did for years, which you were a part of. So I created this community. Let me ask my friends if they want to meet monthly and talk about research they're thinking about, or we could present on a topic. Somebody could lead it, and we could bring in cases. Really, whatever we want to do. And don't you remember our journal club fondly?
Dr. Rountree: Yes, I do. I remember that you brought in some real luminaries, brilliant people that I'd never heard of. They would give a stellar presentation, and then you'd say, “My God, that is way out of the box, I never thought of it that way.” These were people that had been doing hard core research and publishing papers—doing amazing, innovative work for years that was often under-appreciated by the mainstream.
Dr. Fitzgerald: Yes. It was such a fulfilling experience, and it was exactly what I needed. I just needed this community, this opportunity to dialogue, to translate the science, just all of it. It was a juicy and important time in my career. It got very popular and started to become kind of unwieldy. David Jones was really excited about it. Jeff Bland was excited about it. And they announced it at a few conferences! And I didn't know what to do.
Dr. Rountree: And then suddenly it became a massive endeavor. I remember it had a large mailing list. And you had to administer all that.
Dr. Fitzgerald: I didn't know what to do. Originally, I think there were maybe four of us, and then it became huge. It was outside of what I was able to manage. Our practice, our infrastructure was really quite small at the time. But I loved doing it, and it was exactly what I needed. And so what ended up happening is that I was able to create that here. So long story long: We've got a tight, smart clinical team here. We've got our nutrition education program and smart nutritionists-in-training come. People who are interested and curious and motivated, sort of like what I've experienced across my career—we've been able to bring some of that flavor here and have our rounds meetings. So I feel really nourished in the way that I need to be as a clinician.
Dr. Rountree: This is a formal training program you have for nutritionists and/or coaches? Can you describe it?
Dr. Fitzgerald: Yes, sure. It's called Functional Nutrition Residency Program, FNRP, and it was created by Romilly Hodges and I. So Romilly, as you know, is a brilliant CNS and she's our nutrition director emeritus. She's not with us now, because she's out there in the world bringing her book to life. Her book is Immune Resilience,
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and you were one of the expert reviewers, and I'm absolutely thrilled with her direction, but I miss her. I love her. So anyway, we started this Functional Nutrition Residency Program, and we started to bring in CNS candidates. So they're in their Masters nutrition training program, and they need a certain amount of clinical hours, and we started to provide that and continue to. It's become this, because our nutrition program was started by an amazing nutritionist, the training is really highly regarded, and it's very competitive, so we end up recruiting really smart, very motivated individuals to study with us, and then they also do writing and wear a lot of different hats. They run research, little mini-research projects. I guess my point in all of this is that I think creating a community of individuals who are so passionate about this medicine is important. When I teach, I encourage people to do that: get the email, get the phone number of the colleagues around you, the people who are interesting to you, and who inspire you, and so forth, and stay in contact. It's easy for us to isolate and kind of practice in silos. But when we come together, the possibility is extraordinary.
Dr. Rountree: Create a professional network and maintain that network.
Dr. Fitzgerald: Yes. And when you have questions, rather than just scratching our heads or doing a PubMed search, take it on and do the study if you can. You know? Do it! Do the experiment. We can do this in our field. It is all possible.
Dr. Rountree: If one of our readers has an idea for something that they would like to see studied, if they have a clinical question, such as whether a dietary supplement might be effective for a particular condition—is this a research project that you are soliciting?
Dr. Fitzgerald: No, no. I'm booked. We've got IRB approval for our next-level bioage and epigenetic investigation, so I'm already in it. But that person who has that question, that reader who has that question, shouldn't simply sit on the question. Reach out to the supplement company, to their tech staff, the medical education departments of labs—they're bright, interested individuals. The good supplement companies want to answer the questions, and they want to give you the science behind it. So I would absolutely start there, and if you get a satisfactory answer, fabulous; if you don't, what's the next question, and how can you get that answered? What I would make myself available for is this: If somebody wants to sharpen an idea, I'm happy to brainstorm with them if I have a thought around it. We can be active in putting the body of evidence behind what it is that we're doing. I was just podcasting with somebody who did a retrospective case series, chart analysis of 10 different patients with cardiovascular disease. We can do that! We can do these kinds of investigations, and if we want to publish on it, publish on it. If we're overwhelmed with publishing on it and we don't want to go into the rigors of scientific writing, which is a lot of work and we don't have the bandwidth, just blog on it. Just start somewhere.
Dr. Rountree: Just write something up, and see where it goes, right?
Dr. Fitzgerald: Yes, yes.
Dr. Rountree: Since we're talking about clinical issues that come up repeatedly, this begs the question: what got you interested in the process of methylation and supplementing with methyl groups and foods rich in methyl donors? How did you get there?
Dr. Fitzgerald: My interview for the postdoc position with Richard Lord was all about homocysteine. He was really curious about the implications of low homocysteine, and we wrote a white paper about it. That was my first project. I barely knew the word when I came in. I was so excited, and also overwhelmed. We were looking at the methylation and the transsulfuration charts, and he was talking about how he thought maybe glutathione synthesis was stealing the homocysteine and that was dropping it. Anyway, that was my interview with him, and I was both daunted and just so, so, so excited. And so methylation figured into day one even before day one and my work at the lab, and we were measuring a lot of the compounds in the methylation cycle, of course, as we were measuring compounds in the transsulfuration. So it always figured into our work. And then eventually we could look at single nucleotide polymorphisms, and engaging in a sort of early multiomics type of investigation. So that was foundational to my earliest training.
Dr. Rountree: This was a long while before every other lab was running MTHFR SNP tests, and those genetic variants became a part of everyday conversation.
Dr. Fitzgerald: Yes, correct. It was before SNP testing was widely available. A couple of things happened. Two things were pivotal to me thinking about methylation more than I was in the lab or as a clinician. I think that our hypotheses around what methylation imbalances were and how we diagnosed them and how we treat them sort of got ahead of the science.
Dr. Rountree: I've seen business cards that say “Methylation Expert,” and I scratch my head and say, “How it that possible?” “Is anyone truly an expert in methylation?”
Dr. Fitzgerald: Yes. And a whole methylation cottage industry really kind of sprouted up, and as SNP testing became more widely available, patients really started coming to our practice with very strong ideas on their methylation defects, and a lot of anxiety. You know we've talked about this at IFM for so long, and I'm sort of righting the ship of what's really true here, trying to tease it out.
Dr. Rountree: And then Dr. Randy Jirtle's work gets into the mix, using Agouti mouse models, attempting to figure out what happens when we get exposed to chemicals that impair methylation and alter epigenetics.
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Dr. Fitzgerald: And not even chemicals. Genistein, from soy, changing DNA methylation. And in the Agouti mouse model, of course, it was favorable, but we can talk about the implications of that. So for me, one question was: What's going on in this field that I so cherish? I want us to be mindful about not overstating, moving beyond the science. It's absolutely appropriate to have clinical observations, and it's absolutely appropriate to observe what's happening, to see what's happening with your patients when you start an intervention. That's why I like the case studies book that I wrote and would encourage all of us to submit to the literature observation. It's essential. But we also want to try to put some evidence behind it, and certainly any studies that might validate our observations are helpful. I think that we got away from that a bit in our field. So that was one thing that made me want to talk about it.
Dr. Rountree: A lot of things were being assumed and stated as fact about what methylation means and what you should do about it, etc.
Dr. Fitzgerald: And a lot of interventions, like some pretty intense and aggressive interventions were happening, which comes to point two. Some quite aggressive interventions without a lot of sound clinical reasoning behind them were starting to happen. So point two is really concurrent to that. I started to read the literature on epigenetics. Most of the papers coming out—this was probably around 2013 or 2014 or so—were in cancer, and the main epigenetic imprint that's written about and studied is DNA methylation. There are many others, but with DNA methylation, we just have the technology to study it better, and it's actually preserved between cell division, so there's a certain resilience with DNA methylation that isn't the case with other epigenetic marks. So a lot is written on DNA methylation, in the field of epigenetics. So these cancer patient papers were really coming across my desk, coming across my inbox, and it's funny because I was a little resistant to diving into them. I knew they needed to be read, but I was also a little resistant. And was that because epigenetics is complicated? Or was it because it was going to just completely blow my career up, never to be the same again? Did I have some sort of an idea that my life was really going to change with it? Isn't that funny?
Dr. Rountree: Methylation has changed your life!
Dr. Fitzgerald: It really has. Yes. In so many of our patients. So I dove into these papers, and when you're looking at cancer, you can see that the tumor microenvironment very efficiently hijacks gene expression, takes over DNA methylation, demethylation, and other epigenetic processes. Very efficiently, completely takes it over, shuts down genes that we want on, turns on genes we want off, in this horrible nefarious way, almost, that allows the cancer to propagate and survive and grow and travel, etc.
Dr. Rountree: In other words, cancer controls epigenetics?
Dr. Fitzgerald: Cancer controls our gene expression, takes over gene expression from us, yes. Cancer controls gene expression for its own growth. And hypermethylation—so lots of methyl groups on a promoter region of the gene, that would be hyper—or hypomethylation, an absence or few, allowing the gene to be on. So a lot of methyl groups, generally speaking, turns the gene off; few methyl groups allows the gene to be turned on. And cancer does just that: turns on genes we don't want on, turns off genes we want on. And it's all via methylation and demethylation happening in DNA. So my massive question—like really, an overwhelming question, that I started a dialogue with Romilly on—was: What are we doing? Could we be harming our patients with pushing methylation, like pushing methyl donors? There's no doubt that we're capable of influencing DNA methylation with some of our supplements and interventions. I mean, Jirtle showed that in a mouse model, but we've also seen it in humans, but Jirtle showed it with astonishing clarity in his work. So that was my question, Bob: Could we be doing harm? You know: “First do no harm.” Could some of our supplements be doing harm?
Dr. Rountree: At some dose level?
Dr. Fitzgerald: Yes. At some dose level. That's correct. Or some duration. I would say high dose, long duration—which was starting to happen in this world, right? “Oh, I've gotten SNPs A, B, and C; I'm going to take this for life. I'm going to need this forever. I have to have this.” So that was my concern. And when you look at the literature, and you and I have talked about this, and I know we perhaps agree and in some ways we differ, my read on the literature was: This could be a problem. In certain conditions and at certain times, we might be negatively influencing DNA methylation patterns and perhaps be promoting things that we don't want to. And I have to qualify everything that I say here, because much of this we just don't know. But easy for me was, again, having this extraordinary team at the time—it was Romilly Hodges and I—why don't we create a diet and lifestyle program to speak to DNA methylation, to do what we think would optimize it? And I want to say, this was before anybody published human studies looking at biological age that is measured by DNA methylation. So my entry into this conversation were these two pieces looking at DNA methylation in cancer and then also looking at the conversation we were having in functional medicine.
Dr. Rountree: This predated Steve Horvath and his DNAm biological age clock?
Dr. Fitzgerald: Steve had already published his clock in 2013, but his position at that time was: No intervention is going to make a difference in a clock. That was what he believed.
Dr. Rountree: His discoveries had a lot of impact.
Dr. Fitzgerald: Yes. That's right. And it was only 2019, in the middle of our study, that the TRIIM (Thymus Regeneration, Immunorestoration, and Insulin Mitigation Extension Trial) study was published to much fanfare, showing that these nine men were actually able to reverse biological age using growth hormone, DHEA, vitamin D, and metformin.
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So our study was already midway at that time, so we knew that there was a clock that we could look at, but let me actually back up a little bit. We created a diet and lifestyle program designed to address DNA methylation, and we sold it as an e-book, MDL: Methylation Diet and Lifestyle. In the e-book, we talked about these two ideas. So we published our Methylation Diet and Lifestyle, and our hypothesis was that we were doing something beneficial for DNA methylation. It was a methyl-donor-dense diet, lots of nutrients heavy in methyl donors. We include liver and eggs and beets and obviously tons of greens such as kale, etc.
The other really cool thing that I started to read about back then was how these polyphenols, these phytochemicals, may influence DNA methylation. And a lot of that work is in vitro, but again, we can look at some animal studies, we can look at Randy Jirtle, but even beyond Randy's work with pregnant mice, we can look at other animal studies where a lot of it is showing these phytochemicals can allow for re-expression of previously hypermethylated tumor suppressor genes. That's where the bulk of it is, in vitro and some animal studies showing that these phytochemicals can turn on previously inhibited, previously hypermethylated beneficial genes. So genes we want on, they can turn them back on. And these are all the compounds that we know and love, like EGCG (epigallocatechin gallate), curcumin, luteolin, resveratrol, quercetin, and on and on. We can see that they influence DNA methylation. It made sense to me.
Dr. Rountree: And they influence methylation without necessarily providing methyl groups, right?
Dr. Fitzgerald: That's right.
Dr. Rountree: Obviously, it's a complex nutrigenomics process. It's not just a simple matter of just taking methyl donors to increase methylation.
Dr. Fitzgerald: That's exactly right. So we're supplying the body with a lot of methyl donors in the diet, and then we were giving them what I think of as traffic directors. So: Here are these phytochemicals that may direct where the methyl donors are going to go on the epigenome. That was our hypothesis. And we added an exercise component, a meditation component, and we wanted people to get sufficient sleep. Because all of those things have evidence for potently influencing DNA methylation. There's such cool science around it all. Exercise re-expresses tumor suppressor genes. Exercise acts like a phytochemical. I just think that's really kind of cool. It's just kind of a fun way to look at it. “Eat your exercise! Exercise is a veggie.”
Dr. Rountree: “Take two exercises a day. Call me in the morning.”
Dr. Fitzgerald: That's right.
Dr. Rountree: Was this all about cancer prevention, or were you also thinking about biological age back then?
Dr. Fitzgerald: Well, I was thinking about DNA methylation more broadly and so biological age figured into this. Primarily, originally, it was cancer—that's how I entered into the conversation, but you can quickly see when you read the literature that in the aging journey our epigenome starts to look an awful lot like somebody who's very vulnerable to getting cancer. Like the aging journey turns off the genes we want on, and turns on the genes we want off. That's extraordinary.
Dr. Rountree: The older we get, the higher our cancer risk.
Dr. Fitzgerald: Exactly. Like greater than smoking for lung cancer, age. We put a lot of time into reading the science and seeing that these things could benefit DNA methylation broadly, not just pushing it forward, but balancing it. It's this balancing act with influences that have nothing to do with the methylation cycle directly. It was rather extraordinary and serendipitous, lucky, that we happened to be doing this concurrent to the revolution in biological age measurement using DNA methylation. And now the science coming out of Sinclair's lab and elsewhere showing that disordered epigenetics and disordered DNA methylation and demethylation is probably the driver of aging. We started thinking about cancer, but then you see aging itself looks like a cancer epigenome. It's just rather extraordinary.
Dr. Rountree: You started pulling a string, which led you to this totally unexpected, huge universe.
Dr. Fitzgerald: A career- and really world-deeply-changing experience for me and the people who have been supporting this work and who are interested in it. It's extraordinary. I did a podcast with a brilliant biostatistician, Josh Mitteldorf, who's a good friend of mine now. Having a podcast, I've gotten to talk to a lot of pretty amazing people, including yourself. Your podcast was actually, by the way, extremely popular. It really was. Your slides were great. People are still trying to download those slides. Not everybody gives slides, and it was so gracious of you to make those available. I got to podcast with Randy Jirtle. I got to podcast with Dr. Moshe Szyf, who's really a premier epigeneticist, one of the first. And Valter Longo. And David Sinclair. So I get to talk to these brilliant epigeneticists, biogerontologists, and I would sort of sheepishly—you know, before I hit record on our podcast—throw out that we were doing a study, or that we were starting to develop a study. I can remember talking to Moshe Szyf when I had just gotten funded. And all of them, without question, were excited, they were all interested, and it made me see that I was on to something. They were all interested. Nobody said, “Oh my God, that's a terrible idea.” Everybody said, “Keep me posted. I want to see your results” Yay! You know? Funding for diet and lifestyle interventions is just so, so, so scarce, and that was another reason why people were excited that this was happening. Moshe Szyf came on as an advisor and really helped us design and think through how we would do this, and David Sinclair was behind the scenes, cheerleading, and suggested publishing in Aging. To have a few highly respected people in that space—which was a new space to me—just kind of pushed the boat from shore, gave me additional confidence. When I podcasted with Josh Mitteldorf, a biogerontologist biostatistician, he was so excited about it, he immediately volunteered to take a train up to the clinic and to help me look at our data and just think it through. So people were very excited about it.
Dr. Rountree: Just to reiterate: At the time, what Dr. Horvath and others were saying is that we don't have any data, except perhaps from the TRIIM trial, that you can alter this epigenetic age that's essentially programmed in. The belief was that epigenetic age predicts mortality and morbidity from certain diseases, but you can't do anything about it except to measure it.
Dr. Fitzgerald: That's right. More reliably than chronological age. And you really can't do a lot about it. He looked at a pile of data (NHANES, WHI and elsewhere). Eating veggies, higher beta carotene, more education, etc. have limited benefit, really not a huge deal—that was his belief. But you know, he analyzed the TRIIM data, and it was mind-blowing for him, so that was 2019, that was before we published, we were just finishing our study at that time. So it's nine men, no control group, super-small study, blew up the scientific universe, blew it up. Even Nature did a writeup on it—it just stopped the world for a while. And we came out right after, in 2021. Imagine that! Where we had this diet and lifestyle study to demonstrate bioage reversal in a much shorter timeframe and with a really safe intervention. We knew behind the scenes in late 2019, just before the pandemic, that we had moved the Horvath clock significantly. It was pretty heady, to say the least.
Dr. Rountree: Can you give a really brief synopsis of the study design? And maybe we can use that to wrap up where you see all this going.
Dr. Fitzgerald: Yes. We used the diet program that we designed, heavy in methyl donors, heavy in the aforementioned phytochemicals, low glycemic, modest intermittent fasting structure, keto-leaning, so higher in fat. It's just an eight-week program. There are no grains and dairy or legumes in our eight-week program, but I do want to tell people that I think that these are—particularly beans and legumes—important nutrients, and we do want people to transition back onto them after this period, but we wanted to minimize glycemic cycling and so forth, so there's a handful of reasons we had. Anyway, that's the diet. We wanted people to sleep well. We wanted them to exercise a minimum of 30 minutes, 5 days a week. Perceived exertion: 60%–80% of max. Modest exercise: Do whatever you want. For the meditation practice we used Herbert Benson's Relaxation Response with our participants. So sleep, exercise, meditation. They took a probiotic, Lactobacillus plantarum; there's some evidence it may increase microbiome-produced folate, and we had them take a greens powder for more of those phytochemicals. So that was our program. Our participants were required to meet with our nutrition team. The nutritionists had a very sort of dry IRB-approved script, but I think that contact was very important for the success of this multimodal intervention. We had 18 participants complete, and we had 20 in our control group. And our findings were, as compared to control: the study group got 3.24 years younger using the flagship Horvath original 2013 clock.
Dr. Rountree: The participants were all compliant with your program?
Dr. Fitzgerald: We were able to get people to do it, yes. Big deal. And no doubt there are two reasons. A is having the nutrition people with them, so they had support in this throughout. But I'd say that they had a script. It had to be an IRB-approved script. So they were not coaching in the way that we do in our clinic practice. It was: “Do you have any questions?” “Are you sleeping?” “Do you need to brainstorm on where to get good-quality liver?” It was a bit dry, but I think that that was pivotal to having adherence to this otherwise difficult program. Pivotal. Ryan Bradley at Helfgott—he's my co-PI on this, he ran the study at Helfgott Institute at NUNM, at my alma mater, a great clinical research center—was paying attention to us and the success of this study because, admittedly, our program is involved.
Dr. Rountree: I'm truly impressed that people stuck with it!
Dr. Fitzgerald: Well, this is the way that I look at it, Bob: It ain't every day somebody gives me six figures and an unrestricted grant to do this. This is my chance to engage in clinical research, which was so exciting and important for me. And I really put time in to think: How are we going to have good adherence? And it was clear that we needed to have our nutrition team be there. The other piece is that I think the participants were genuinely excited to be doing a diet and lifestyle study on epigenetics. They were educated a little bit about what we were doing, and that it hadn't been done before, and I think they were interested. So that helped, as well.
Dr. Rountree: So you continued the intervention for two months, at which point you found that people got younger, or at least the biomarker of aging showed that they got younger.
Dr. Fitzgerald: Yes. That's right. The Horvath clock showed that they got younger, as compared to our control. And also the within-group comparison was impressive, as well. Their triglycerides dropped, their total cholesterol dropped. Methylfolate increased in circulation significantly. There were a handful of other changes, but they were healthy individuals from the start, so we didn't see a lot of big biochemical changes with them. We didn't anticipate that, but we saw some neat things. We didn't change that methylation. We did look at the methylation. We looked at homocysteine, SAM (s-adenosylmethionine) and SAH (s-adenosylhomocysteine), etc. We looked at the methylation cycle intermediates, and we did not significantly change those compared to control. So one of the interesting things that I wrote about in the paper was that we moved where methylation was happening on the DNA methylome.
Dr. Rountree: It was a genomic rearrangement. I bring that point out because some people think: “Oh yeah, methylation. You've either got too much or too little, and that's the whole story.” Your whole point is that it's precisely where the methyl groups are attached to the DNA that's most important.
Dr. Fitzgerald: Yes. As we age—and I don't want to get too arcane—global methylation, genetic methylation does decrease, but it becomes imbalanced, also. And so maybe, as we refine this, as we move forward on this journey, maybe we do need some supplemental methyl donors sprinkled in, in addition to diet, for some individuals—there is more to uncover. But in this first pilot study, we showed with a diet and lifestyle intervention, we rearranged methylation on the DNA methylome to a pattern arguably more favorable, as compared to controls, which is exciting.
Dr. Rountree: Very, very exciting! This study is basically opening doors in our scientific understanding of what determines health and aging. Speaking of that: As a result of this study, you wrote the book Younger You.
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What was it you were hoping to communicate to the general public about your discoveries? At the same time, how did you distill the essence of what you've learned all these years from your deep dives into biochemistry and systems biology? What are some of the core insights you want the public to understand about your work and research?
Dr. Fitzgerald: That we are driving the genetic car. We're driving the car, whether you want to be or not. So it's great—I think in the -omics era, there's great promise, there's great excitement. We, in functional medicine, are being validated now like never before for the interventions that we use. The science is backing up what we've been doing in practice forever, for time immemorial. And I think the take-home from my study and others is that our choices directly influence gene expression significantly more so than the genes themselves. And that's what I mean when I say we're driving the genetic car. Our choices influence gene expression potently. So this is an extraordinary possibility, but it's also a great responsibility. And I want us to take that responsibility. So we can't say, “My mom was sick, my parents were sick, my grandparents were sick, they died early, so screw it, I can eat whatever I want.” Or we can make that choice. But it would be a false choice. Or: “My parents and grandparents lived well for long; therefore, I'll do whatever. I'm going to live well. I've got good genetics.” Influence from genes themselves is markedly less than, I think, from our epigenes, from our epigenomes, from our direct choices. So great promise and great possibility, validation for what we've known for a long time. In fact, Tina Kaczor, a very highly regarded naturopathic physician, interviewed me and she's like: “Jeez, Kara, this is like the Nature Cure Diet.” I thought that was kind of cool. I mean, certainly early Nature Cure docs were using organ meats and so forth. At least some of them.
Dr. Rountree: Hippocrates had a point?
Dr. Fitzgerald: Yes, Hippocrates had a really good point. Let me tell you something extraordinary. I know we keep going on. But just looking at the statistics in our country we are biologically aging faster than we should be. On average, over 50% of Americans will, for the last 16 years of their lives, have two diagnoses, and likely be on multiple medications. We don't have healthspan in this country. We might have lifespan, but maybe it's in skilled nursing care, maybe it's in the hospital. All of our hard-earned dollars will go towards our medical care to sort of keep us propped up in a poor quality of life. I think the promise of using biological age and interventions that can reverse it can directly counter what we have now in this country and other countries.
Dr. Rountree: People are living longer, but they're not living healthier. That's kind of the bottom line.
Dr. Fitzgerald: That is the bottom line. And I like to underscore that with some of the data, like those statistics, because they're brutal. None of us are sitting here thinking: “I'm going to spend the last 16 years of my life really sick. And my family members are going to have to care for me,” or “All of my hard-earned money that will go to my daughter Isabella is going to go towards my skilled nursing care, where I'll be propped up on a pillow.” We need to change the conversation urgently, in how we're looking at aging and what we're doing about it.
Dr. Rountree: We're finally getting the data to outline how to do that. Your team is helping us gather the evidence that says: “Here's a proof of principle that following these guidelines will make a difference.”
Dr. Fitzgerald: Yes. Yes. And Jeff Bezos just started Altos Laboratory, where they've recruited the best biogerontologists the globe over, and his best billionaire buddies dumped billions of dollars into cracking the aging nut. It's extraordinary. So I'm absolutely grateful to be part of the conversation. It's very exciting to have this finding and to be able to turn my career towards teasing it out, understanding it. We have some preliminary findings that look good, kind of back up what we saw in our first study, and I look forward to pulling more and more. But I know that we'll refine it, we'll grow it, we'll layer in other interventions. I have no doubt that some of the supplements that we prescribe are beneficial, and let's look and see what those are doing. Is rapamycin something appropriate for us to consider? Are some of the other interventions, maybe metformin? I talk about it in the book, there are caveats there, but we're at a pretty revolutionary place right now.
Dr. Rountree: So what does the future hold for Dr. Kara Fitzgerald? Where do you see yourself going? More research? Do you think you will continue along the same line of researching biological age, or are there other burning questions you want to investigate?
Dr. Fitzgerald: Good question. Yes. I want to continue to research biological age. We are. We have IRB approval. We have an app called 3YY, Three Years Younger. I don't love that name, but there it is. It doesn't roll off the tongue at all. But in the app, we have an IRB-approved arm, so we can continue to gather data of people participating in the program. I want to individualize it and refine it, and just take that along the journey. So yes. The bio-age question is definitely continuing for me. The other piece, though, that I'm very interested in teasing out are the nutrient-responsive genes, and what kind of interventions make a difference there. In my book I created a table looking at the different tumor-suppressor genes and the nutrients that turn them back on. You can have a hypermethylated BRCA gene, and it's going to behave like you have a BRCA mutation. So I want to study that. We significantly changed, in our study population, promoter methylation. We turned a lot of genes on in our study population, as compared to our control. So what are those genes? What's the relevance? And that's the next publication for me. Here's another question that's interesting: the hypermethylation of oxytocin receptors, there are all sorts of genes associated with PTSD and depression and life stress, and we know some of the methylation patterns. Can we change those, with a commitment to lifestyle and meditation practices, etc.? I just think it would be cool to kind of dance in that a little bit more, and I touch on it in the book, but I would like to study it.
Dr. Rountree: Wow. It sounds like getting involved in this research project has just really lit you up. You're really on fire about moving the needle, showing the convergence between natural medicine and solid scientific evidence.
Dr. Fitzgerald: Yes! And it is an interesting convergence of my original training. It wasn't a big jump. I am deeply, deeply grateful to have gotten funding. Back in the day, when we had just come up with this, we were scratching our heads, like, “Well, we think this shift might be genetics. We think this might influence DNA methylation.” Of course, how are you going to tell? You can't send somebody to Quest Diagnostics. So to actually be able to study it in the research setting, in a rigorous, controlled clinical study, I'm over the moon about that, and will just forever be grateful for that experience, and I'm excited to keep walking in that direction.
Dr. Rountree: Awesome, it's been great to spend all this time talking with you! If people want to get in touch with you or follow your work, I know you have a website. Is that the best place to find you? What about your podcast?
Dr. Fitzgerald: Yes. That's it. The hub of the blog and podcast, and my team here at the clinic, and all the amazing things are just right at drkarafitzgerald.com. You can find the book and the apps at drkarafitzgerald.com, or you could go to https://youngeryouprogram.com.▪
To Contact Dr. Kara Fitzgerald, ND, IFMCP
Kara Fitzgerald, ND, IFMCP
Naturopathic Doctor, Private Practice, Sandy Hook, Connecticut, USA
Faculty, Institute for Functional Medicine
E-mail:
kf@drkarafitzgerald.com
