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I was thrilled to finally sit down with Dr. Greg Fahy, whose groundbreaking work in aging has truly reshaped our understanding of what’s possible. His 2019 TRIIM study, showing clear biological age reversal through thymus regeneration, was a game-changer. The scientific community was stunned, and rightly so—this was the first real evidence that we can turn back the clock on aging.
But Dr. Fahy isn’t stopping there. His ongoing studies hold incredible implications for the future, from potentially reversing autoimmunity to avoiding transplant rejection. Even more exciting is the possibility of creating a standardized protocol that could help other clinicians use these principles in practice. We’re on the brink of something truly revolutionary, and I’m already looking forward to having him back to hear what’s next. This conversation is a must-listen for anyone passionate about the future of longevity. ~DrKF
You Are Only As Young As Your Immune System with Dr. Greg Fahy
In this episode of New Frontiers, we dive into groundbreaking research that has the potential to change the way we approach aging and longevity. Dr. Greg Fahy shares insights from his pioneering TRIIM trials, which for the first time demonstrated age reversal in humans—an achievement that could redefine how we think about extending the human healthspan. We explore the rejuvenation of the thymus, a key organ in immune system aging, and discuss the role of IGF-1, growth hormone, and metformin in these bio age-reversing protocols. You’ll learn about the challenges and innovations in personalized dosing, the potential of AI in anti-aging medicine, and the future of hormone therapy, particularly for women. This episode is packed with actionable insights for practitioners looking to stay on the cutting edge of functional medicine and longevity science.
In this episode of New Frontiers, learn about:
- First Evidence of Age Reversal in Humans: Discover the groundbreaking findings from Dr. Greg Fahy’s 2019 publication, which demonstrated biological age reversal using epigenetic clocks.
- Thymus Regeneration and Immune Function: Learn how thymus regeneration plays a critical role in reversing immune system aging, with potential applications for longevity and healthspan extension.
- Insights from TRIIM and TRIIM-X Trials: Explore the latest results from the TRIIM and TRIIM-X trials, including the mechanisms of thymus rejuvenation and implications for future anti-aging treatments.
- Balancing Growth Hormone and Metformin: Understand the importance of optimizing growth hormone and metformin levels in age-reversal protocols, including the mitigation of insulin-related side effects.
- Impact of IGF-1 on Age Reversal: Gain insights into the role of IGF-1 as a key marker in age reversal and how individualized dosing can enhance treatment outcomes.
- Health Improvements Beyond Age Reversal: Discover the additional health benefits observed in study participants, such as improved VO2 max, reduced blood pressure, and even reversal of gray hair.
- Potential for Autoimmunity and Transplant Rejection: Explore the implications of thymus regeneration for reprogramming the immune system, with potential applications in reversing autoimmunity and preventing transplant rejection.
- Developing AI-Driven Personalized Medicine: Learn about Dr. Fahy’s efforts to create AI-driven expert systems that tailor anti-aging treatments to individual patient needs, paving the way for scalable solutions.
- Future Research and Clinical Applications: Get a glimpse into the future of anti-aging research, including ongoing studies and the development of protocols for broader clinical use.
- Cryobiology and Organ Preservation:Discover how Dr. Fahy’s expertise in cryobiology could revolutionize organ preservation for transplantation, providing time for thymus reprogramming to prevent rejection.
Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. And of course, today is no exception. I am beyond excited to be with Dr. Greg Fahy. I’ve actually been pinging him to join me on this podcast for some time, and we’re finally here. I’m thrilled to talk to him. You, of course, are likely familiar with the 2019 publication. It was really the first publication to show evidence of clear biological age reversal as measured by the epigenetic clocks. That was Greg’s work. Time stood still for me. I mean, that was such a big deal, and I want to hear what it was like for you at that momentous… You started a conversation in such a powerful way. But, let me give you a little bit of background on Greg, and then we’ll jump into that and so much more. We’re going to see where he’s at now since that seminal 2019 publication.
Dr. Kara Fitzgerald: He is a world-renowned cryobiologist. He’s also the Chief Science Officer and co-founder of Intervene Immune, a company which pioneers treatments for thymus regeneration and age-related immune system decline. Dr. Fahy designed and led the pilot TRIIM study – what I just referred to and we’ll link to that in the show notes – which was the first time showing both thymus rejuvenation and reversal of human epigenetic age. To say that you could hear a pin drop in the scientific space, I think is an understatement. It was an incredible moment for all of us paying attention. He’s now into a follow-up TRIIM-X study that we’ll hear about, and you have a bunch of cohorts: The A, B, C, and I think maybe even the D. So, you’ve just been galloping forward. We’re going to get into this, but you come with this massive background in thinking about life extension, and I want to hear what that 2019 moment was for you, how huge it seemed and how it’s transformed you.
Dr. Kara Fitzgerald: In 2010, you published The Future of Aging: Pathways to Human Life Extension. This is not a new path for you. So, let’s jump into all that and talk to me.
Dr. Greg Fahy: Thank you, Kara. That’s great. Yeah, we designed our original human study to reverse immune system aging, and we really wanted to see if it could have any effect on epigenetic aging as well, but we didn’t have that built into the original study. So we wanted to contact Steve Horvath because he was the guru of this whole area. He created it. But of course, Steve was very busy. Everybody in the world was sending him every sample you can imagine, trying to see what the effect of aging was and what their treatments were doing to aging. He had seen it all. He had seen no effect or worsening of aging, and he had even seen aging slowing down sometimes. But he’d never seen reversal of aging.
Dr. Kara Fitzgerald: And he said… Sorry to interrupt, but he was pretty clear that reversal of aging wouldn’t happen. So let me just interject that.
Dr. Greg Fahy: Yeah, yeah. So I wrote to him, and he didn’t answer. I wrote to him again, and he didn’t answer. So our CEO, Bobby Brooke, devised this ingenious strategy to get Steve’s attention. Steve was used to working with all these world institutions and universities, and we were this dinky startup company, so we’re kind of below his radar screen. But Bobby set up a fake organization called Renaissance Bio, which is a seminar hosting company that hosted seminars at UCLA, where Steve was working. By some strange coincidence, we happened to invite Steve Horvath to give a seminar. We also had our trial physician give a seminar, so that worked very well, but it still didn’t quite get through his armor. So we had another one about a year later, and that time we explained in more detail what we were doing with the thymus regeneration program.
Dr. Greg Fahy: Not only did he say that he would look at it, but he also offered to do it without charging us anything, which was great because we had no money. So, the rest is history. We had to send the samples out and pay for them to be analyzed, but then Steve would do all the analytical work pro bono. So, he did that and his name appears on the paper because of that seminal contribution. We really had no idea what to expect. We had hopes that we’d see something good, but nobody had ever demonstrated aging reversal before. We hoped we’d see something good, but we didn’t really know what. Steve did the first analysis using his original Horvath clock, and he was floored because the clock actually went in reverse and he had never seen that for any treatment. And this was in humans we’re talking about, not some rodent or something like that.
Dr. Greg Fahy: And so he ran three other clocks, and they all showed the same result, even though the clocks are based on different ways of looking at aging. So, the rest is history, as they say. We were very pleased, needless to say. It was almost too good to be true, but it certainly helped make the paper visible because if we had just regenerated the thymus, people might not have gotten it. But everybody understands the significance of reversing aging. So it’s very interesting that the first evidence of reversing aging in any mammal, and actually any organism, as documented by these epigenetic clocks, which are the best measurement that we have, was done in humans. It’s kind of the reverse of the way things usually happen, where you start with mice and maybe after 20 or 30 years you get to humans. We started with humans, and then maybe we’ll go back to mice or something to confirm some of the mechanisms involved. It was very exciting. We were amazed and very pleased. Bobby just wanted to focus on the epigenetic aging aspect in our paper. But I insisted on telling the whole story, and I’m very glad that we did. We got a lot of publicity, as you mentioned.
Dr. Kara Fitzgerald: A lot.
Dr. Greg Fahy: All over the place. And I’m very pleased, actually, with the publicity we got within the scientific community. There was a little blurb on us in Science, but the big one was in Nature. They actually did a whole page on us, which was great. Then they had another article later that talked about epigenetic aging clocks in general. They started off with our original study, and at the end, they came back to us and basically said that everybody’s waiting with bated breath to see whether we can reproduce it or not. They quoted Steve in there, and Steve is a hardcore scientist. He’s not going to be biased in any way. He said, “If this doesn’t work, I will tell the world. But if it does, it’ll be great.”
Dr. Greg Fahy: So, it turns out that we have reproduced the original aging clock reversals, not only with the four original aging clocks that we looked at but with 17 others. We’ve shown aging clock reversals in 21 flavors of aging clocks, including 12, which have, as of the end of last year, been linked to long-term cancer risk and morbidity and mortality risk. So if you look younger by these tests, you actually live longer and have a lower risk of cancer. All of this is beginning to form a self-consistent pattern that we really are onto something here.
Dr. Kara Fitzgerald: I have so many questions. But concurrently, you’re also demonstrating clear thymus regeneration too.
Dr. Greg Fahy: Yes, that’s right.
Dr. Kara Fitzgerald: And so you’re tracking…
Dr. Greg Fahy: It’s so interesting. With magnetic resonance imaging, which is what we did in the first study, the scanner can take pictures of your thymus through several cross-sections. And that means we can get a density on that first section, a density on the second section, etc., all the way up to 5 or 6 sections. That means we have statistical groups between different time points, even for single people.
Dr. Greg Fahy: So, we can actually show statistically significant improvements in thymic structure even in a given person. When you start adding it up across other people, the p-values essentially go to the moon. So, yeah, we showed that we could regrow the thymus as we imagined we could. There are a lot of studies in the literature, and even a few studies in humans, showing that kind of thing before, but never in normal humans. There were some studies in HIV patients that came out around the same time we were doing our studies, which was encouraging. But the HIV thymus is a different animal from the normal person’s thymus. The disease does something to change people, so we didn’t really have a clean baseline for comparison in the literature.
Dr. Greg Fahy: The only previous account of regrowing the thymus in a normal person was me regrowing my own thymus in 1996, which I finally published in 2003. I did that on myself because nobody seemed interested in actually doing a human study on normal people and I was so frustrated that I did it on myself and published it. Still, nothing happened, but mercifully, I was able to find our CEO and start a company so we could do it ourselves, because nobody else was going to move forward with it. So, I’ll stop and let you ask whatever questions you want to ask.
Dr. Kara Fitzgerald: Well, I’ve got a lot of them. And I guess the obvious one is, in 1993, what was your intervention? And is it the foundation of the TRIIM?
Dr. Greg Fahy: It was, and this was actually 1996. I was aware that there is a problem with growth hormone. Growth hormone is great when you’re young; it makes everything work better, keeps your body growing, and helps your tissues renew themselves. But if you give growth hormone to someone who is young and deficient relative to their age, you can get a negative side effect, which is that it raises insulin levels way up and can even raise glucose levels, although insulin goes up first. Insulin is a pro-aging factor. As we get older, our insulin and glucose levels tend to go up, and we develop this whole constellation of age-related problems that are secondary to that. I didn’t want to go down that road. So, I had this theory. Here’s the paradox: young people have tons of growth hormone, they don’t have high insulin levels, and they don’t have high glucose levels. So, what is it that’s different about a young person compared to an older person? I thought there might be something else different about young people that makes it possible for them to have high growth hormone levels without these side effects. And that one thing might be DHEA.
Dr. Greg Fahy: DHEA is another hormone that’s very prevalent and abundant in youth but declines precipitously with aging, just as growth hormone does. So, I thought, what if the undiscovered effect of DHEA is to reduce the “diabetogenic” effect of growth hormone? So, I tried it on myself. I gave myself growth hormone for a week, measured my insulin, and it went up 50%. Then, I stayed on the same dose of growth hormone but added DHEA on top of it, and my insulin went right back down to baseline. I did this experiment on myself so many times that I reached statistical significance, just doing this experiment over and over again on myself. My 1996 experiment, which I eventually published in what’s now Rejuvenation Research, used this combination of growth hormone and DHEA. It worked very well, and I regenerated my thymus to a statistically demonstrable extent. There’s a way to check for what would normally be called thymic hyperplasia by comparing yourself to the mean of everyone else in the population, whether you change and go outside two standard deviations of the mean, which I did.
Dr. Greg Fahy: So that was good, but then nothing else happened. As I developed more and more experience, I realized that DHEA alone might not be enough to completely correct the insulin-elevating effect of growth hormone. So, we added in metformin and that was a more effective treatment. Some people are more sensitive to metformin, and some are more sensitive to DHEA. But in general, the two working together is the best way to go.
Dr. Kara Fitzgerald: Where do I want to go with this? I guess I want to circle back and learn about those 17 clocks. But since we’re on the intervention, do you individualize dosing of DHEA? I think you’re doing 500 mg of metformin, but I’m curious about the range of DHEA dosing you might be doing. We use it fairly regularly for its ability to modulate insulin and reverse some of the metabolic imbalances that are ubiquitous.
Dr. Kara Fitzgerald: I haven’t seen it be quite so impactful. It’s interesting to me that you found that. The question is about metformin. Some data suggests that metformin might not be ideal for healthy individuals because it could potentially damage mitochondria. I know there’s debate about whether the hormetic effect—a slight stress that benefits mitochondria—is at play here, but it can also lead to less efficient cellular respiration in healthy individuals, even if it doesn’t cause full-blown lactic acidosis. So, can you comment on that and the use of DHEA?
Dr. Greg Fahy: Yeah, sure. So, the metformin story is very interesting in multiple respects. Before I get into the meat of your question, I’ll just say that everything also depends on context. We see very few problems if any using metformin in combination with DHEA and growth hormone.
Dr. Greg Fahy: So, it may be that the effects reported with metformin as a mono agent go away in this other context so that’s something to keep in mind. I don’t think there’s any convincing evidence that metformin actually causes lactic acidosis. There was a thought about that in the past, that receded. It may have resurfaced a little bit more lately. Maybe there’s a bit more to that than was thought for a while. Generally speaking, lactic acidosis is caused more by kidney failure than metformin. The problem with metformin in the past has always been linked to the combination of kidney failure and metformin and not really to metformin by itself. There have been some reports of metformin interfering with mitochondrial function. We don’t see that. Generally speaking, the people in our trial, again the context being different, they get more energetic, they get stronger, and they feel like exercising. They just feel good.
Dr. Greg Fahy: But one or two people have felt less energetic for a while, but then it seems to go away. The other interesting thing about metformin, as I’m sure your viewers know, is that it’s been proposed as a mono agent to prove that you can intervene in aging and to be used as a tool to get the FDA to recognize aging as an indication for drug therapy. Nir Barzilai has been trying to organize the TAME Trial forever and a day, but he hasn’t succeeded yet. He was trying to do that before we did our trial, so we kind of beat him to the punch as the first human aging intervention trial. He wanted to use 1500 mg per day, which is three times what we’ve been using. And I will say, we have a control arm In our recent attempts to replicate our original TRIIM trial results, in which people do receive metformin and DHEA but not growth hormone.
Dr. Greg Fahy: And in that control branch, we just use 500 mg of metformin. I actually wanted to vary the dose because in the real trial we vary the dose, but Steve Horvath didn’t want to vary it and he was in control, so I let him have his way. And I think that probably it’s good that we kept it simple to minimize the risk of side effects. So far, we find, at least in some individuals that have non-optimal levels of insulin to start with, that it can really have a salutary effect on insulin levels, as a control matter. We don’t think it reverses aging by itself, and DHEA plus metformin doesn’t seem to reverse aging by itself either. You need the growth hormone as the third component to do that. However, it is very beneficial for glucose homeostasis.
Dr. Greg Fahy: The other thing I’ll just mention, and you probably know this and have reported this to others, is that there was a study where metformin was given to diabetics, and they actually lived longer than non-diabetics. So, there may be some downsides to metformin but on balance, it must be more beneficial than harmful. Otherwise we wouldn’t have seen that effect with the diabetics.
Dr. Kara Fitzgerald: It’s interesting that you have that pool in your control group so you’re able to explore how they’re doing at a really modest dose. I think that’s great. And yeah. I’d love to have Dr. Barzilai on the podcast, and I hope he can finally get the TAME trial launched. I’ve been paying attention to that. Is he recruiting again?
Dr. Greg Fahy: I don’t know but I think his main problem is just getting someone to pay for the trial. Because as you know, he wants this to be a very, very, ambitious trial and it will cost a lot of money. Nobody has an enforceable patent on metformin right now, so no one is willing to pay for this. He needs to get a lot of private foundations and government support if he’s ever going to get this off the ground, but he’s literally been trying for about ten years without success, so it’s not looking particularly hopeful, at least from my perspective. He may have some possibilities I don’t know about, but it’s looking a little bit discouraging to get this going. I think what he might want to do is to simplify the trial quite a bit and tone it down to the point where he can find somebody who’s willing to pony up the money. Because any kind of trial is better than no trial. Hopefully, he’s considering that, but I don’t know for sure. If you can get him on your podcast, he’d be an engaging speaker. He’s got some definite personality and can entertain your viewers.
Dr. Kara Fitzgerald: That would be great. I’ll work on it for sure. I’d love to have him on and support him in his work. Okay, let’s circle back here and talk about these seventeen clocks. Are you working with the Clock Foundation on this?
Dr. Greg Fahy: Yes, mostly with them.
Dr. Kara Fitzgerald: All right. We’ll link to the Clock Foundation. I think that it’s available primarily to research scientists, but I think clinicians can access it as well, right?
Dr. Greg Fahy: I hope so. I’m not positive, but the purpose of the Clock Foundation is to make these clocks as available as possible. They want to make them as widely available as possible, and I think anyone who would like to incorporate them into their practice ought to contact the Clock Foundation to see if they can get something done. Because the more people that contact them, the more likely they are to find a way to accommodate you.
Dr. Kara Fitzgerald: Bobby Brooks, your partner in your research, heads it up. And I know this is Steve Horvath’s baby. This is a non-profit that he created where his clocks live.
Dr. Greg Fahy: That’s right. Bobby splits his time between Intervene Immune and the Clock Foundation. I wish I had a little bit more of his time at Intervene Immune, but the upside is he’s really a crackerjack at all of these aging clocks and he can run them for us any time we need them. There are so many flavors of these clocks. You can measure GrimAge in about five different ways. Some of these 21 clocks are redundant in that way, and some of them are unique. For example, there’s something called the skin and blood clock, which can infer how young your skin is. We’ve seen statistically significant positive results with it, along with several others.
Dr. Kara Fitzgerald: What about the mammalian clock? You must be including that. Anything interesting there?
Dr. Greg Fahy: Well, not really. It’s a bit less specific for humans.
Dr. Kara Fitzgerald: Right. It’s all mammals.
Dr. Greg Fahy: Exactly. It’s fabulous that such a clock exists and I think the fact that you can have a clock like that tells us so much about what aging is and where it comes from. You and I were talking about Josh Mittledorf earlier, to think that aging has some basis, it’s not just random events taking place. And I agree with that idea, but when you plot all of the whales and shrews and all of that on the same graph, there are some noticeable gaps between the exact aging clock result for a given species and the line that goes through all of them. So there’s definitely a correlation.
Dr. Greg Fahy: Everybody is doing pretty much the same thing, but there are wide enough variations that I would prefer to stick with the human clock for our human studies. There is something called a Human Rat clock, and it’s really good for humans and rats, so that might be a bit closer. In any case, I prefer the ones developed specifically for humans because, as I mentioned, in 12 of the clocks that we ran, there are three different flavors: the Dunedin Pace of Aging Clock, the PhenoAge clock, and the GrimAge clock. Those have been linked epidemiologically to the risk of cancer, death, and morbidity. We’ve seen all of those go in reverse, to the extent that’s possible. The Pace Of Aging clock is organized in such a way that it can only slow down. It can’t really go in reverse, but it goes basically to zero or minus 0.5 years per year, which is as low as it can go.
Dr. Kara Fitzgerald: Wow. You’ve seen that in your cohort?
Dr. Greg Fahy: Yes, that’s right. So, it’s all good.
Dr. Kara Fitzgerald: Wow. That’s extremely interesting. I’m a fan of the Pace Of Aging clock as well. Where do I want to go with this? Well, I should say, you’ve corroborated the clock changes with more standard biomarkers. You’ve corroborated the thymus regeneration with changes in T cell status, senescent burden, etc. You’re also demonstrating the physiological changes of aging. I mean, this is really so interesting. You reported VO2 max increasing 25% in your participants, which is nuts. In a small subgroup, you’re reversing gray hair and I think you fall into this. I would suggest anybody listening to this in audio hop over and take a look at Greg, because I don’t know how old you are, but I think you look a lot younger, if I’m not mistaken. I’ve seen dialogues about this before. I mean, you’re kind of living what you’re testing, but you’re validating it with a lot of different biomarkers. So anyway, let me throw that out there.
Dr. Greg Fahy: Well, thanks. We’ve seen a lot of extraordinary effects. The beauty of all these things is that they all tend to validate each other. We’ve seen hair darkening. One guy actually sent us one of his eyelashes, which he took out and photographed. It’s black at the root and white at the tip, and he saw it growing in black again so he wanted to capture that. Another guy’s body hair started growing in. His leg hair started growing much more luxuriously and black. He was about 81 by the time he noticed that and wanted to get back in the trial. We’d like to be able to recycle people back through the trial, if we can rewrite the protocol to allow that.
Dr. Greg Fahy: So, we’ve seen reductions in diastolic blood pressure and resting pulse rate. We’re seeing so many different reinforcing signs that we’re really making people healthier than they were before. And of course as we get younger, we expect to be healthier than we were before, so it’s all sort of self-consistent. We don’t find too many contradictions between these positive endpoints. This encourages us to stick with this and try to improve it as we can. We’re looking at a number of potential improvements right now.
Dr. Greg Fahy: As you mentioned, we did the original study, which is called the TRIIM Trial, which stands for Thymus Regeneration, Immuno Restoration, and Insulin Mitigation. Then the first extension is the TRIIM-XA trial, with “X” being the extension of the original trial, which includes women and older people. And then TRIIM-XB is a modification of that, which is nearing completion as we speak. For clerical reasons, some people in our organization decided to put all of the control groups into a group called TRIIM-XC, with “C” standing for control in their view and I didn’t resist them on that.
Dr. Greg Fahy: The next group will be TRIIM-XD, and there may be one or two different flavors of TRIIM-XD due to timing issues. To incorporate everything I want into TRIIM-XD, I’ll have to rewrite the study protocol. People are really eager to get in, and we’ve had to hold people back for a long time and I just feel we cannot keep people waiting forever. Some improvements will be made with the first version of TRIIM-XD, which will come online at the end of this month, and then further improvements, hopefully before the end of this year. This will complete some augmentations, possibly from TRIIM-XD2 or something like that. TRIIM-XD1 may be a small group, and then we’ll have a larger cohort. The thing is, we’re learning things all the time. The original concept of TRIIM-X was just to reproduce TRIIM, which would have been fine. However, from a moral, ethical, and scientific point of view, if I feel I can do better than what we did in TRIIM, it would be immoral and unethical for me not to, I think.
Dr. Greg Fahy: So, you have science requiring you to replicate things, and then you have medicine and humanity requiring you to go beyond that.
Dr. Kara Fitzgerald: That you move it forward.
Dr. Greg Fahy: Yeah. So, we’re trying to strike the best balance between those things.
Dr. Kara Fitzgerald: Let me just tell people again, it’s in the show notes. You can open his paper; it’s free full text so you can look at the protocol yourself. But just really quickly: It’s human growth hormone, and we should talk specifically about the type of human growth hormone and your thoughts on that and the dosing. It’s DHEA, it’s metformin, it’s vitamin D—I think it was 3000 IU in the original—and then zinc, I think 50 mg. And then you set a range for DHEA, and there’s a range for growth hormone. So, what is it now as you’ve evolved the protocol?
Dr. Greg Fahy: It’s basically the same thing. We modulated it a little bit in TRIIM-XA, and I decided in retrospect that kind of modulation was not the right way to go. So, TRIIM-XB is a pure reproduction of the original TRIIM.
Dr. Kara Fitzgerald: Okay. Can you speak to what you modulated and why you pulled back, just out of curiosity?
Dr. Greg Fahy: It’s a little difficult to discuss, but I will just say that the original TRIIM trial was only men. In TRIIM-XA, we included women, and because we included women, we had to think more deeply about sex hormones than we did in the original trial. Sex hormones can be both good and bad. They certainly can mediate thymic involution when we go through puberty. There have been some interventions where people ablate gonads or hormone production in order to regenerate the thymus, which I don’t think is a particularly popular approach so we opted not to try that. But it did suggest that maybe we should have a look at sex hormone levels, so we did some things to try to prevent them from going to extremes. I think in retrospect, that was probably the wrong approach. So I’ll just leave it at that for now. In TRIIM-XD we may actually do some further tinkering now that we’ve learned what we’ve learned in TRIIM-XA.
Dr. Greg Fahy: I’ll just leave it at that for now. In terms of communications with the scientific world, in other words publishing our results, TRIIM-XA began a story that we realized we didn’t have an ending to at the beginning. And we’re going to need to complete TRIIM-XB and TRIIM-XD in order to put it all together. I think this story will be extremely interesting and informative, but that’s about all I can say about it right now. If you want to know all the details, you’ll have to enroll in the trial.
Dr. Kara Fitzgerald: Yeah, okay. We’ll put information out. There’s no doubt in my mind that listeners will want to pursue it. I would imagine this combination, plus sex hormones… I’m curious whether women coming into TRIIM-XD who are on HRT—because you’re primarily looking at middle-aged and older participants—you’ll allow them to continue their HRT. I’m guessing that you saw hair regrowth in legs and some of the other changes you saw in men. Did any of the women start menstruating again, or did you see any of those?
Dr. Greg Fahy: Nobody has reported that to us yet, and we haven’t really gotten into a realm in which that would be expected yet. We will need to look into it in the future, but there is an issue with female sex hormones in particular. Female sex hormones reduce the IGF-1 response to growth hormone, and it’s the IGF-1 that actually regenerates the thymus. Growth hormone has some positive effects, but it’s also responsible for the hyperinsulinemia, as distinct from the IGF-1.
Dr. Greg Fahy: In women on HRT, you’re expecting to maybe double the cost of the growth hormone, because to get the same IGF-1 response, you might have to take twice as much growth hormone. Plus, you double the insulin problem we are trying to solve. Additionally, in theory, you might be increasing the risk of breast cancer because there’s this whole controversy about HRT in women after menopause. Exactly how that would couple with stimulating growth of cells with growth hormone and DHEA is unknown. At this stage of our evolution of this treatment and our knowledge, it’s best for us not to have women on HRT. None of the women in our trial so far have been on HRT. We’d like to be able to transcend that at some point in the future, but we have to take this step by step and make sure we understand what we are doing as we go along. So that’s kind of where that stands right now.
Dr. Greg Fahy: And I know that we’ve lost at least one participant who wished to remain on HRT, but I think she understood our reasoning. That’s sad, we want everybody to have everything, but one way of looking at it is giving up something for a short time in order to gain a long lasting benefit, and then perhaps go back to it if it works out that way. I’m not an expert on female HRT at this point, so I would leave that to people like you who are more expert than I am.
Dr. Kara Fitzgerald: It’s very interesting, but there are a lot of questions down that path. I know my listeners have a lot of questions. Please post them, you guys, and I’m happy to have Rhonda, my office manager, continue to track you for the next couple of years. We’ll get him back on and ask him all of these questions. So IGF-1, what levels are you looking at, and what do you want to achieve? And does IGF-1 itself actively regenerate the thymus? IGF-1 is not just a surrogate marker of growth hormone, as most of us clinicians think that it is. It’s busy out there doing stuff.
Dr. Greg Fahy: Yes, growth hormone carries out many of its effects – not all, but many – via the IGF-1. And you are right that IGF-1 is a terrific surrogate marker for growth hormone status. Because if you try to measure growth hormone directly you’re going to get chaos. Because as you well know, growth hormone is released in pulses, mostly at night but also at certain times during the day and they’re kind of random. So, if you happen to draw blood when there’s a spike, you get one result, and if you do it between those spikes it’s a very low level. But in some magical way, the liver integrates all of those growth hormone peaks into a stable level of IGF-1 that really doesn’t change much during the day. So, we try to always measure IGF-1, and everything else, at the same time of day. But basically, IGF-1 is constant. So there’s a bit of magic in that.
Dr. Greg Fahy: One aspect of IGF-1 levels is that up to now, we’ve wanted to exclude people from the trial who didn’t have at least a certain minimum amount of IGF-1. That was based on the original HIV trials there were– It’s very vague how they described, for a variety of different results of their trial – but they said that they got their best results in people with a pretty robust level of IGF-1 to begin with. We knew from the literature that there might be a hazard to people if you increase IGF-1 by more than a certain factor. So, if you start out higher in IGF-1, then you could increase your IGF-1 more in a safe way then if you start out with a low level of IGF-1. We’ve generally restricted entry into the trial to those with a bottom of the threshold IGF-1 level, but I’m no longer positive we need to continue this way.
Dr. Greg Fahy: I’ve been testing a lady recently with IGF-1 levels that are really, really low, around 50 or 60, but that’s normal for her since she’s short. As far as I can tell, her immune system seems okay, so maybe I have to rethink that. When you get into projecting what IGF-1 level you need, it’s dependent upon multiple aspects of the biology of that individual person coming into the trial. What’s their baseline level…
Dr. Kara Fitzgerald: How healthy are they?
Dr. Greg Fahy: How healthy they are and all kinds of things. There is no single answer to that, just as there’s no one answer to what range of this or that you could use. We titrate each individual person for the doses of growth hormone, DHEA, and metformin depending on how their own personal biology responds. And we find that the titration tends to vary over time because the body is not just a lump of coal. It actually responds to things. The body adjusts itself and so we have to adjust for the adjustment as we go along.
Dr. Greg Fahy: Plus, these three things tend to interact with each other to a certain extent and we have to adjust for that. Plus, some of these things may affect some of the parameters of aging in ways that are adverse, so we have to balance all of that out too. It’s a very, very individualized thing. Actually, if you look into it, as we have since the end of last year, there are over a hundred different factors that have to be weighed before you can adjust these three medications either up or down. On top of that, you have to decide how far to adjust them up or down. So far all of this has been done by the computer known as the gray matter between my two ears, and I just can’t keep that going if we’re going to be treating hundreds or thousands or millions of people. So, we’re trying to make a “Greg in a box,” basically. We’re trying to transfer this thought process, that ability to deal with all these nuances, into an expert system and then to an AI.
Dr. Greg Fahy: We have the beginnings of an AI, of an expert system put together, and it does pretty well, but I’m still finding a few extraneous circumstances that occur at certain people, at certain times that override the fundamentals and make them make different choices. And so we’re feeding that into this expert system as it is now. But we’re hoping to finish this up before the end of the year, partly because we actually have an agreement with a clinic in the UK that wants to deploy our treatment, commercially as a medical service. So far, everything that we’ve done has been under the umbrella of a clinical trial. But in the UK, they want to offer it as a service. And that’s not going to be possible until we have the expert system making the right call virtually every time so that we can automate it to accommodate the larger number of people. And so we’re working very hard to make that happen. And hopefully that will all come together pretty soon.
Dr. Kara Fitzgerald: Can you give me numbers? I’m just being a clinician. We’re measuring growth hormone and we’re looking at insulin a lot. We’re probably looking at a lot of the variables that you’re looking at and I’m just wondering what would be an alarm number for growth hormone on either end? I know that you’re allowing for individual differences, which makes huge sense, and it also makes me wonder if the ranges that we’ve got in our heads are just for the 70 kilogram guy? Is that where we’re sort of stuck? And,so I appreciate your nuances on it and your efforts. But are there any numbers you can throw out for an audience who I know wants them?
Dr. Greg Fahy: I think the right way to address that question is to encourage any clinician who wants to explore our treatment, to get in contact with us so that we can work with you. Because there’s just really too much to try to put into a nutshell, in a presentation like this and we do have a patent on the process. So it’s something that we want to keep under our umbrella to the extent that we can.
Dr. Kara Fitzgerald: Okay.
Dr. Greg Fahy: I think that there are hazards to trying to go rogue on this. There are pitfalls or things that can go wrong quite easily. You have to be aware of a lot of things to measure that you might not be thinking of. So what we want is to deploy this treatment in a uniform way so that we can get uniform results all across the world. The best way to do that is to work directly with the clinical partners so that they can share our data with them and we can share our updates with them, and it will just work better all the way around that way.
Dr. Kara Fitzgerald: I’m assuming you’ll be doing some training. God, I’d love to go out there and just just hang out and shadow you for a while.
Dr. Greg Fahy: We’d love to do that. We want to make sure we know what we’re doing first and then we’ll train you. We’re still learning a few things. We’re still refining the protocols. It’s a little bit early right now. Hopefully at the end TRIIM-XD will have something that’s so good and hopefully a little bit more foolproof, that we’ll be much better equipped to have this kind of training go on and to open up more franchising opportunities. We’re working as hard as we can to get there but it’s very complex.
Dr. Kara Fitzgerald: Okay. All right. Well stay tuned everybody. I mean, it’s pretty exciting and you’ve got your first trial out there and you’re obviously whetting our appetite with the data that you’re continuing to harvest. I want to just ask you a few more questions. You threw out the idea that by regenerating the thymus gland, that we might be actually able to reprogram the immune system with that. And I don’t know whether that would require an intervention or not but you’ve talked about this potentially being a piece of how we might be reversing autoimmunity. And I’m going to throw in there that allergy must follow behind that. So speak to that because that’s a big deal. It’s a big statement.
Dr. Greg Fahy: Yes it is. It’s actually an immense statement and it’s universally ignored.
Dr. Kara Fitzgerald: I’m not ignoring it.
Dr. Greg Fahy: In 1990, there was a cover story in Science about getting rid of transplant rejection. And this is promulgated by a guy who came to our lab and gave a seminar about it and I stayed in touch with him for a little while, but it never caught on. And it requires the use of the thymus. It turns out that the thymus, of course, has two functions. It elaborates T cells that attack everything that’s not us and it kills off all the T cells that think that we are those foreign things that are not us. In order for the thymus to do its job, it has to preclude autoreactive T cells developing in the body.
Dr. Greg Fahy: It turns out that because of that, you can fake out the thymus by presenting antigens in such a way that it thinks that they are self-antigens. And if they’re self-antigens, then anything that attacks them is killed off. So, you can present the thymus with the antigens of an unrelated kidney, for example, give it enough time and it will destroy all it will inactivate all of the preexisting T cells that recognize that foreign kidney as foreign. You can now take that kidney and transplant it and the kidney is kept indefinitely with no need for immunosuppression. So you need to give a little bit of immunosuppression at first to allow the presented piece of tissue to survive long enough in the intended recipient to reprogram the thymus, but that’s temporary and it’s reversible. As the T cell population recovers, you restore a normal level of immunity, but after that, you don’t need to do any immunosuppression. I have this graph that I put together, not long after 1990, showing in the controlled transplants, everybody dying after about 20 days or less and in the transplant with the thymus reprogramming, everybody alive 100% to 100 days.
Dr. Kara Fitzgerald: Wow. Humans. They did this in humans.
Dr. Greg Fahy: No, this was in rats. That’s the problem. The trouble with humans, and I think this may be why this was never tried in humans to speak of. There was a tiny little trial that never got published in two human pediatric cardiac transplant recipients who showed fleeting positive effects, but it never got published and you can’t even find it on the internet anymore. But there’s plenty of papers on small animals showing that you can not only use this trick to avoid transplant rejection, but you can also use it to reverse established autoimmunity. So, for example, you can create autoimmune diabetes in an animal and then reverse it by reprogramming the thymus to get rid of those auto reactive T cells that are killing off the pancreas. The trouble is that most people who need to have transplants are not young people. There are some, but most people who need transplants don’t have much of a thymus left. So nobody’s really thinking about using that trick on people.
Dr. Greg Fahy: But if we can regrow the thymus first, then it opens the door to–
Dr. Kara Fitzgerald: For this intervention.
Dr. Greg Fahy: Yes.To get rid of both transplant rejection and autoimmunity. So the beauty of this is that I don’t have to be a brilliant immunologist to figure out how to solve these problems. I just have to use what nature has already given us: The thymus. The thymus already knows how to do everything we want. All you have to do is give it an opportunity. So the catch has also been that there have been trials on all these small animals and they work beautifully. And then when they try to scale it up to dogs and monkeys and pigs, you see signs that this can work, but it has never really quite worked in large animal models. So there’s still a gap that has to be filled in as to how to do the details of that procedure such that it will work in large animal models.
Dr. Greg Fahy: I happen to have a lab that does cryobiology research, as you alluded to, and we’re hoping to be able to set up a rabbit allograft kidney transplant model. If we can do that, we may be able to reeducate the thymus of the rabbit recipients of a given kidney so that we can swap kidneys between rabbits and prevent the rejection that would normally take place. A rabbit is a pretty large and advanced animal, so if we can figure out the details of that… We also have a pig colony, so we could scale it up to maybe pig kidney transplants. I think if it works in rabbits and pigs it’s going to work in people, and then we can look at clinical trials. So there’s several steps ahead of us, but nobody else seems to be interested in this. And so, as usual, it may fall on us to be the ones who actually do this. Nobody was interested in thymus regeneration, so we’re doing it. Nobody’s interested in getting rid of transplant rejection and autoimmunity in this way. So if nobody else does it, we’ll do it.
Dr. Greg Fahy: But we’re perfectly suited to do it because (A) we’re the ones who know how to regrow the thymus and (B) the best way to do this is to give the thymus a few months to reprogram itself. During that time, the intended transplant needs to be preserved and you cannot preserve a kidney or liver or whatever for 2 or 3 months with current technology. But my lab is able to cool a kidney to cryogenic temperatures and you can keep it forever at that temperature. So hopefully we can marry up all these technologies to regrow the thymus, bank the organ, transplant the organ…
Dr. Kara Fitzgerald: Geeze, that’s so fascinating. Wow.
Dr. Greg Fahy: Isn’t that interesting?
Dr. Kara Fitzgerald: Yeah. Well, and that’s full circle going back to the beginning of your career so it makes a lot of sense that you’re thinking about all of it. I lecture to other physicians on allergic disease and the whole pathogenic mechanism, and I said, sort of bullishly, that I think potentially, the end of allergies is in sight.
Dr. Kara Fitzgerald: I mean, sublingual immunotherapy, retraining the immune system with early exposures… We’re just at this pretty extraordinary crossroads now. Introducing foods early, etc.. turning off autoimmunity, turning off celiac disease with early introduction. But it just makes me think of immunotherapy as being a piece of the approach to re-educating the immune system towards eliminating autoimmunity.
Dr. Greg Fahy: These things are all self-reinforcing, right? There’s many, many treatments that interact here. For example, one of the problems with gene therapy is you reject the vehicle of the gene, so you can get one gene transplanted but not multiple. But if you could prevent the capsid that is carrying the gene in your body from being rejected by the body, by re-educating the body to think that it is self, the problem goes away. With respect to immunotherapy, like CAR T cell therapy and things like that, Car-T therapy is as good as the T cells you have in your body to stimulate. So if we manufacture more T cells by regenerating the thymus, that’s going to improve too. So all of these things help each other out I think.
Dr. Kara Fitzgerald: Well, we could go on and on in this conversation. It’s extraordinary. We’ll have to bring you on again. You’ve been paying careful attention to not just the thymus regeneration, but dropping senescent cells and changing the CD4, CD8 ratio and T-regs, and the immune system in general. Maybe I’ll end with this. You’ve thrown out this provocative idea that by 50, a third of us die as a consequence of thymic involution. That’s pretty provocative. And that most of us die from some immune mediated problem, which makes sense to me. I mean, if you look at the hallmarks of aging, the underpinnings are right there in the immune system. Any thoughts on that? And again folks, we’ll give you contact information to follow this, but maybe we’ll leave with that for now.
Dr. Greg Fahy: Yeah. So I think that that curve that you referred to — and I can tell you’ve been paying attention, so thank you very much — So I was able to use CDC statistics and plot the fraction of all deaths that seem to be related to immune system incompetence versus age. And it goes up exponentially and I’m only able to plot the curve out to about the age of 50. And as you say, at that point, about 30% of all deaths are caused by immune related failures. But I think that exponential curve continues. And one of the sleeping issues is that most of us actually die of cardiovascular disease, but a lot of that is mediated by atherosclerosis, and a lot of that is caused by background low-grade inflammation.
Dr. Greg Fahy: And our trial seems to reverse that, at least based on what we’ve been able to measure so far. Because that low grade background inflammation may be coming in large part from autoimmune disorders, because the thymus is losing its ability to tell self and non-self. And so you’re actually executing yourself slowly by this immune firing squad and we’re reversing that. If we can actually impact cardiovascular disease by lowering background inflammation then for sure that curve of how many people are dying from immune related failure with age is going to continue up to greater and greater ages. And we’ve noticed that immune collapse takes place between 60 and 80, which is when everybody starts to die. And I think it’s not a coincidence. So I think we’re on to something important and I think that we’re very encouraged to continue in this vein and reach out and help as many people as we can as fast as possible.
Dr. Kara Fitzgerald: Well, I really appreciate the fact that you made time to join me today. I look forward to hopefully meeting you in person one day. Yeah, I do follow your work and I’ve got plenty more questions, as I’m sure that I’ll hear from folks. Hopefully we’ll have a part two one of these days. Thanks Greg.
Dr. Greg Fahy: It was my pleasure and I appreciate everything that you do as well. You do innovative work and you publish your results and I think that’s very important. So kudos to you as well.
Dr. Kara Fitzgerald: Yeah. Next time we’ll talk a little bit about diet, nutrition and exercise. We haven’t talked about any of that yet.
Dr. Greg Fahy: We haven’t talked about it. That’s a whole other unexplored area. And if you put those two branches of intervention together, you know–
Dr. Kara Fitzgerald: You’re right. Yeah, absolutely. Oh, thanks so much. Great to have you.
Dr. Greg Fahy: Take care.
Dr. Kara Fitzgerald: Bye bye.
Dr. Greg Fahy: Bye bye.
Dr. Greg Fahy received his Ph.D. in Pharmacology and Cryobiology from the Medical College of Georgia in 1977. A world-renowned cryobiologist, Dr. Fahy is the chief science officer and co-founder of Intervene Immune, where he leads groundbreaking research on thymus regeneration and combating age-related immune decline. He designed and led the TRIIM trial, the first to demonstrate both thymus rejuvenation and the reversal of human epigenetic age. His work has been pivotal in advancing aging research, resulting in successful follow-up trials like TRIIM-XA, and further planned studies aimed at refining and expanding these innovative treatments.
Email: fahy@interveneimmune.com
Seminal Study: Reversal of epigenetic aging and immunosenescent trends in humans
TRIIM-X Trial: Thymus Regeneration, Immunorestoration, and Insulin Mitigation Extension Trial
The Future of Aging: Pathways to Human Life Extension
Science: TRIIM trial to target thymus
Nature: First hint that body’s ‘biological age’ can be reversed
Research and Resources from Intervene Immune
Study: Apparent induction of partial thymic regeneration in a normal human subject: a case report
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Blog: New and Notable Studies Using Epigenetic Biological Age Clocks
Podcast: Decoding Aging: The Science Of Cellular Rejuvenation With Dr. Vittorio Sebastiano
Podcast: AI, Digital Twins, and the Future of Personalized Medicine Interventions with Dr. Nathan Price
DrKF Clinic: Patient consults with DrKF physicians including Younger You Concierge
Better Broths and Healing Tonics book
Interview: Past, Present, and Future of “Biological Aging” with Dr. Fitzgerald
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