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Find them at OneSkin.co. 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 Fahey.
I've been I've actually been pinging him to be 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, 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. You started a conversation in such a big...
powerful way. But let me give you a little bit of the background on Greg, and then we'll jump into that. And we're going to jump into so, so much more. We're going to see where he's at now since that seminal 2019 publication.
So 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. Fay designed and led the pilot trim 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 Trimex study that we'll hear about, and you have a bunch of cohorts, the A, the B, the C, and I think maybe even the D. So you've just been galloping forward. You also, though...
So we're going to get into this, but you come with this massive background in thinking about life extension. And so I want to hear what the moment, this 2019 moment was for you and how huge it just seemed like it must have been and how it's transformed you. But, you know, in 2010, you published The Future of Aging, Pathways to Human Life Extension.
I mean, this is not a new path for you. So. anyway, jump into all that and talk to me.
Thank you, Cara. That's great. Yeah, so 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. And we wanted to contact Steve Horvath because he was the guru of this whole area that we created it. But, of course, he was very busy.
So everybody in the world was sending him every sample you can imagine, trying to see what the effect of aging was, what their what their treatments were doing to aging. And he had seen it all. You know, he'd seen no effect or, you know, worsening of aging and even saw aging slowing down sometimes.
But he'd never seen reversal of aging. Well, he said, sorry to interrupt, but he was pretty clear that reversal of aging wouldn't happen. So let me just interject.
that yeah yeah so we had so i wrote to him and he didn't answer and i wrote to him again he didn't answer so our ceo bobby brooke devised this ingenious strategy to get steve's attention because steve is used to working with all these world institutions universities everything we're this dinky little startup company so we're kind of below his radar screen but bobby set up this fake organization called renaissance bio which is a seminar hosting company that with that hosted seminars at UCLA where Steve was working. So 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 so far didn't quite get through his armor yet.
So we had another one about a year later. And that time we told him in more detail what we're doing with the thymus regeneration program. And not only did he say that he would look at it, but he said he would do it.
without charging us anything for it, which was great because we had no money, right? So the rest is history. You know, 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. But we had really no idea what to expect.
We had hopes that we'd see something good, but, you know, Nobody had ever demonstrated aging reversal before, and we hoped we'd see something good, but we didn't really know what. So 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 is humans we're talking about, not some rodent or something like that. And so he ran three other clocks, and they all showed the same result. even though the clocks are based on different kinds of ways of looking at aging.
And 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 to 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 It's very interesting. The first evidence for reversing of aging in any mammal and actually any organism, as documented by these epigenetic clocks, which are the best measure that we have, was done in humans. So it's kind of the reverse of the way usually things happen.
You start off with mice, and maybe after 20 or 30 years, you get the humans. We're starting with humans, and then maybe we'll go back to mice or something to sort of confirm some of the mechanisms involved. But 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 really insisted on telling the whole story and I'm really glad that he did. We got a lot of publicity, as you mentioned. A lot. All over the place.
And I'm very pleased, actually, with the publicity we got within the scientific community. There's a little blurb on us in science, but the big one was in nature. Yeah, that's right. And they actually did a whole page on us, which is great.
And then they had another article later that talked about epigenetic aging clocks in general. And 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. And they quote Steve in there. And Steve is a hardcore scientist.
He's not going to be biased in any way. And he said, if, you know, if this doesn't work, I will tell the world. But if it does, you know, it'll be great.
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.
So we've shown aging clock reversals in 21 flavors of aging clock, including 12, which have now, 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 you have less risk of cancer. So all of this is beginning to form a self-consistent pattern that we really are onto something here. Well, I have so many questions, but concurrently, you're also demonstrating, you know, clear thymus regeneration too. Yes, that's right.
So you're tracking, yeah. It's so interesting, you know, with magnetic resonance imaging, which is what we did in the first study. The scanner, you know, can take pictures of your thymus through several cross-sections, actually more like this way.
And that means that we can get a density on that first section, a density on the second section, etc., all the way up to like five or six sections. That means we have statistical groups between different time points, even for single people. And so we can actually show statistically significant improvements in thymic structure, even in a given person.
So then when you start adding it up across other peoples and the P values go to the moon, essentially. So, yeah, we showed that we could regrow the thymus as we imagined we could, because there's 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 about the same time that we were doing our studies. And.
And that was encouraging, but the HIV thymus is a different animal than a normal person's thymus. The disease does something to change people. So we didn't really have a clean baseline for comparison in literature. The only previous account for regrowing the thymus of a normal person was me regrowing my own thymus in 1996, which I finally published in 2003. And I did that on myself because nobody seemed to be interested in actually doing a human study on normal people.
And I was so frustrated. I did it on myself, 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 go forward with it.
So I'll stop and let you ask whatever questions you want to ask. Well, I've got a lot of them. And I guess the obvious is just, you know, in 1993, what was your intervention? And is it? It must be the foundation of the trim.
It was. So this is actually 1996. So I was aware that there's a problem with growth hormone. Growth hormone is great when you're young. It makes everything work better.
It keeps your body growing and your tissues turning over, renewing themselves. But if you give a growth hormone deficient, relative to youth at least, individual in their older years growth hormone then you get a negative side effect which is it raises insulin levels way up and it can even raise glucose levels up although insulin goes first and insulin is a pro-aging factor as we get older our insulin tends to go up or glucose tends to go up and we develop this whole constellation of age-related problems that are secondary to that and so I didn't want to get down that road so I had this theory So here's the paradox. Young people have tons of growth hormone. They don't have high insulin levels. They don't have high glucose levels.
So what is it that's different about a young person compared to an old person? And I thought, well, there's maybe something else that's different about young people that makes it possible for them to have a high growth hormone level without having these side effects. And that one thing might be DHEA. DHEA is another hormone that's very, 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 quote-unquote diabetogenic effect of growth hormone? And so I tried it on myself. I gave myself growth hormone for a week, measured my insulin, went up 50%.
Stayed on the same dose of growth hormone, but with DHEA on top of it, insulin went right back down to baseline. And I did that on myself so many times that I reached statistical significance just doing this experiment over and over again on myself. So...
uh my 1996 paper uh experiment which i eventually published in rejuvenation research which now rejuvenates research used this combination of growth hormone and dhea and that worked very well and i regenerated my thymus to a statistically demonstrable extent uh there's a there's a way that you can check for what would normally be called hyperplasia uh by comparing yourself to the mean of everyone else in the population, whether you change, go outside two standard deviations of the mean, which I did. So that was good, but then nothing else happened. And as I developed more and more experience, I realized that DHEA alone might not be enough to completely correct this insulin elevating effect, the growth hormone. So we added in metformin and that was a more effective treatment.
Some people are a bit more sensitive to metformin, some people a little bit more sensitive to DHEA. But in general, the two working together is the best way to go. Well, let me just, 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? And then I think you're doing 500 milligrams of metformin, but I'm curious of the sort of the range of DHEA dosing that you might be doing.
And it has, you know, we have no, you know, we use it fairly regularly, you know, for its ability to modulate insulin and, you know, just reverse some of the metabolic imbalances that are ubiquitous. I haven't seen it quite so impactful. It's interesting to me that you, you know, that you found that. So question is just on metformin. I was going to ask you this down the road.
But. you know, in some of the data in healthy humans showing it not to be, you know, the best thing necessarily, it might be actually, you know, really damaging to mitochondria. I know there's arguments back and forth that it's this hormetic effect and you want this little push on the mitochondria, but it's, you know, can also prompt kind of a, not necessarily a frank lactic acidosis, but a less efficient cellular respiration and, you know, in healthy individuals. So comment on that. and the DHEA.
Yeah, sure. So metformin 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.
So we see very few problems, if any, using metformin in combination with DHEA and growth hormone. And so it may be that the effects that have been reported with metformin as a monoagent go away. you know, in this other context.
So that's something to keep in mind always. But I don't think that 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. But generally speaking, lactic acidosis is caused more by kidney failure than by metformin. The problem with metformin in the past has always been linked to kidney failure, the combination of kidney failure and metformin, and not really to metformin by itself. And 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, they feel like exercising, they feel more, you know, they just feel good. But one or two people have felt, you know, that maybe they felt less energetic.
for a while and then it seems to go away. So the interesting thing about metformin also is that, as I'm sure your viewers know, it's been proposed as a monoagent 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. So Nir Barzilai has been trying to put together the TAME trial forever and a day. Yes.
because I know he's never succeeded. He was trying to do that before we did our trial. And so we kind of beat him to the punch to do the first human aging intervention trial.
But he wanted to use 1500 milligrams a day, three times what you've been using. And I will say that, you know, we have a control arm in our recent attempts to replicate our original trim trial results in which people do get metformin and DHEA, but not growth hormone. And in that control branch, we do just use 500 milligrams 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 a control, so I let him have his way. So I think probably it's good that we restricted it to something simple and less likely to have any side effects.
And so far, we find... at least in some individuals who have kind of non-optimal levels of insulin to start with, that it can really have a very salutary effect on insulin levels as a control matter. We don't think that it reverses aging by itself, and the DHEA plus metformin doesn't seem to reverse aging by itself. You need the growth hormone as a third component to do that, but it it is very beneficial on your glucose homeostasis. The other thing I'll just mention, and I'm sure you know this and you probably reported this to others already too, there was a study in which metformin was given to diabetics and they actually lived longer than people who were not diabetic.
So there may be some downsides to it, but on balance, it must be better for you than harmful for you, or otherwise you wouldn't have seen that. effect with the diabetics. What's interesting that you have that pool in your control group, so you're able to kind of, you know, explore it, how they're doing at a really modest dose. I think that's great. And yeah, I would love to have Dr. Barzilai on the podcast.
And yeah, I hope he can finally launch the team. You know, I've been paying attention to that. I mean, is he recruiting again, do you know? I mean, I don't know. I think his main problem is just getting somebody to pay for the trial.
Because, as you know, he wants this to be a very, very ambitious trial and will cost a lot of money. And nobody has an enforceable patent on metformin right now, so nobody's really 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 been trying this for now 10 years and he hasn't succeeded yet. So it's not particularly hopeful, at least from the outside, you know, where I am right now.
Looking in, 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 just sort of simplify the trial quite a bit to tone it down to the point where he can find somebody who's willing to pony up the money required to do it. Because any kind of trial is better than no trial.
Yeah. So I hope that he's considering that, but I don't really know. Yeah.
If you can get him, I'm sure he would be an engaging. speaker for you yeah he's got some definite personality and he can entertain your viewers that would be great i'll i'll work on it for sure i yeah i would i'd love to have him on and and just kind of support him in in his work um okay so let me just circle back here and talk about these 17 clocks um are you working with the clock foundation is that where these clocks are okay and yeah closely with them yes All right, we'll link to the Clock Foundation. I think that it's available to, I don't know, I know that it's the Clock Foundation, research scientists are using the clocks there primarily, but I think clinicians can access it as well, right?
I hope so. I'm not positive, but the purpose of the Clock Foundation was to make these clocks as available as possible. I know they want to make them as widely available as possible. I think anyone who would like to incorporate that in their clinical practice ought to contact the Clark Foundation and see if they can get something done.
That way, because the more people that contact them, the more likely it is they'll find some way to accommodate you. And Bobby Brooks, you know, your you know, your your partner in in your research is heads. I think he heads it up. And I know this is Steve Horvath's, you know, baby, that this is a not for profit that he created where, you know, his clocks kind of live. That's right.
So Bobby does divide his time between being immune and. the clock foundation and so I wish I had a little bit more of his time in intervene immune but the upside is he's really crackerjack at all of these aging clocks and he can run them for us anytime we need them so that's that's how we're able to do actually there's so many different flavors of these clocks you can measure groom age in like five different ways so some of these 21 clocks are redundant in that way and some of them are unique so for example as For example, there's something called the skin and blood clock, which kind of sort of infers how young your skin is. And we saw positive results with that statistically significant results with that. And there's there's a variety of other ones.
What about the mammalian clock? You must be including that. Anything interesting? Not really. That's a little bit less specific for humans.
It's right. It's all mammals. Yes.
I mean, it's fabulous that that clock exists. And I think that the fact that you can have a clock like that. tells us so much about what aging is and where it comes from. And you and I were talking about Josh Middeldorf earlier, you know, 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, you know, the exact aging clock result for a given species and the... line that sort of goes through all of them so you can so there's definitely a correlation everybody's doing pretty much the same thing but there are wide enough variations that i would prefer to stick with the human clock for our for our human uh studies there there is something called i think a human rat clock uh and it's really good for humans and rats so that would be maybe a bit closer uh but uh in any case i i prefer the ones that are developed specifically for humans because as i mentioned i think uh some of these like 12 of the clocks that we ran, there are three different flavors of the pace of aging clock, the Dunedin clock, the Pheno age clock, and the Grimm age clock. And those have been linked epidemiologically to the risk of cancer and death and morbidity. So we've seen all of those go in reverse to the extent that that's possible.
The pace of aging clock is... organized in such a way it can only slow down. It can't really go in reverse, but it goes basically to zero minus 0.05 years per year, which is as low as it can go.
Wow. You've seen that in your cohort. Yeah. Yeah, that's right.
Wow. So it's all good. Wow. That's extremely interesting. I'm a fan of the pace of aging clock as well.
All right. So I just. Where do I want to go with this?
Like thinking about thymus, well, I should say also, you've, you know, corroborated the clock changes with more standard biomarkers. You've corroborated the thymus regeneration with changes in T cell status, senescent burden, etc, etc. So you're also demonstrating, I think, the physiological changes of aging too.
I mean, this is really so interesting. I mean, you reported VO2 max increasing 25% in your participants, which is nuts. You're in a small cohort or 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 Craig. Because I don't know how old you are, but I think that you look a lot younger, if I'm not mistaken. I've seen dialogues about this before.
I mean, you kind of practice, you know, you're kind of living what you're testing, but you're seeing, you're validating it with a whole different, you know, a lot of different biomarkers. So anyway, let me throw that out there. Healthcare providers have long relied on Dutch to uncover the underlying causes of hormone-related issues. offering actionable results supported by peer-reviewed research.
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Well, thanks. Yeah, we've seen a lot of extraordinary effects. The beauty of all of these things is that they all tend to validate each other.
So we've seen hair darkening. One guy actually sent us... One of his eyelashes, which he took out and photographed, and it's black at the root and white at the tip, you know, and he saw it growing in black again, so he wanted to capture that. Another guy's body hair started growing in.
His legs started growing hair much more luxuriously in black, and 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 to the trial if we can rewrite the protocol to allow that. So, you know, we've seen reductions in diastolic blood pressure and pulse rate, resting pulse rate. So 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. So. It encouraged us to stick with this and try to improve it as we can.
We're looking at a number of potential improvements right now. So as you mentioned, we did the original study, which is called the TRIM trial, which stands for Thymus Regeneration, Immunorestoration, and Insulin Mitigation. And then the first extension is the TRIM-XA trial. So X being the extension of the original trial, which we include women and older people. And then XB is a modification of that, which is nearing completion, as we talked about now.
And then for clerical reasons, some of the people in our organization decided to put all of the control groups into a group called TrimXC because C stood for control in their view. And I didn't resist them on that. So the next group will be TrimXD. And there may be one or two different flavors on TrimXD because... of timing issues.
So to incorporate everything I want to incorporate into TrimXD, I'll have to rewrite the study protocol. But 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. So there's some improvements that we'll make with the first version of TrimXD, which will come online at the end of this month, and then further improvements hopefully before the end of this year that will complete. uh some augmentations that that will come in maybe trim xd2 or something like that so trim xd1 may be a small group and then we'll have a bigger cohort so the thing is we're learning things all the time and you know the original concept of trim x was just to reproduce trim and that would have been fine but from moral ethical and scientific point of view if i feel i can do better than what we did and trim it would be immoral and unethical for me not to, I think. So you have science requiring that you replicate things and then you have medicine and humanity requiring that you go beyond.
That you move it forward. Yeah. So we're trying to strike the best balance between those things.
Well, let me just tell people, again, it's in the show notes. You can go pop his paper open. It's free, full text.
So you can look at the protocol yourself, but just really quickly, it's human growth hormone. 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. It was 3,000 IU in the original.
And then it's zinc, I think 50. 50 milligrams. And then you said a range of DHEA and there's a little bit of a, there's a range on growth hormone. So what is it now as you've evolved the protocol?
So it's the same thing. Basically, it's the same thing. We modulated it a little bit in TRIM-XA. And I decided in retrospect that that kind of modulation was not the right way to go.
So TRIM-XB is a pure reproduction of the original TRIM. Can you speak to what you modulated and why you pulled back? I'm just out of curiosity. It's a little bit difficult to discuss it, but I will just say that in TRIM, the original TRIM trial was only men. And in TRIM-XA, we included women.
And so because we included women, we had to think a little bit about sex hormones more deeply than we did in the original trial. And sex hormones are good and bad. And they... certainly can mediate thymic involution when we go through puberty.
And there have been some interventions in which people ablate gonads or ablate hormone production in order to regenerate the thymus, which I don't think is, I don't think that's a particularly popular approach to regenerate thymus. So we often not to try that, but it did suggest that, you know, that maybe we should have a look at. at sex hormone levels. And so we did some things to try to prevent those from going to extremes, you know. And I think in retrospect, probably that was the wrong thing to do.
So I'll just say that much for now. And in TRIM-XD, we may actually do some further tinkering now that we've learned what we've learned in TRIM-XA. Okay. So I'll just leave it at that for now.
But in terms of... communications with the scientific world, in other words, publishing our results. Yeah.
TrimXA began a story that we realized we didn't have an ending to at the beginning, and we're going to need to complete TrimXB and TrimXD in order to put it all together. And I think this story will be extremely interesting and informative, but that's about all I can say about it right now. Well...
If you want to know all the details, you have to enroll in the trial. Yeah, okay. And we'll put information. There's no doubt in my mind that listeners will want to pursue it.
I mean, I would imagine this combination, you know, plus sex hormones, and you could, I'm curious whether women coming into TrimXD who are on HRT, because you're primarily looking at middle aged and older, you'll allow them to continue on their HRT. But like, I'm going to guess that you saw, you know, like, you know, hairy growth on legs in men and some of the other changes you saw. I mean, some of these women must have started, you know, menstruating again.
And, you know, did you see some of those? Nobody's reported that to us yet. And we haven't really gotten into it, into a realm in which that would be expected yet.
We will have to look into that in the future. But there is an issue. with female sex hormones in particular uh female sex hormones reduce the igf-1 response to growth hormone and it's the igf-1 that actually regenerates the thymus the growth hormone has some positive effects but it's also responsible for the hyperinsulinemia as distinct from the igf-1 so uh 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're doubling the insulin problem that we're trying to solve.
Plus, in theory, you might be increasing the risk of breast cancer because there's this whole controversy about HRT in women after menopause, and exactly how that would couple with stimulating growth of cells with growth hormone and DHEA is unknown. So for the... at this stage of our evolution of this treatment and our knowledge it's best for us uh not to have women on hrt uh and so none of the women in our trials so far have been on hrt and we'd like to be able to transcend that at some point in the future but we have to take this step by step to make sure we understand what we're doing as we go along so that's where that stands right now yeah And I know we've lost at least one woman because of that.
She wanted to stay on HRT, but I think she understood our reasoning. So, you know, that's sad. You know, we want everybody to have everything, but, you know, one way of looking at it, you know, is that...
you know, give up something for a short time in order to gain a long lasting benefit and then perhaps go back if that's, if that, if it works that way, which I'm not an expert on female HRT at this point. So I would leave that to people like you are more expert than I am. It's pretty interesting.
It's just, there's a lot of questions. I mean, it's just a lot of questions down that path. I know my listeners have a lot of questions, post them, you guys, and I'll, I'm happy to have Rhonda in my office.
office manager continue to track you for the next couple of years. We'll get them back on and ask them all these questions. So IGF-1, what kind of levels are you looking at, A, and what do you want to achieve?
And B, it itself actively regenerates the hot 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.
Yeah. Growth hormone carries out many of its... effects, not all, but many of its effects 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 it's also certain times during the day, and they're kind of random. And so if you happen to draw blood when there's a spike, you get one result.
And in between those spikes, it's very low level. But 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. And so we try to always measure IGF-1 and everything else at the same time of day.
But basically, IGF-1 is a constant. So there's a bit of magic in that. So one aspect of IGF-1 levels is that up to now, we have sort of...
wanted to exclude people from the trial who didn't have at least a certain minimum amount of IGF-1. And that was because based on the original HIV trials, there were, I mean, it's very vague how they describe a variety of different results in their trial. But they said that they got their best results in people who had a pretty robust level of IGF-1 to start with.
And we knew from the literature that... There might be a hazard to people if you increase your IGF-1 by more than a certain factor. So if you start off higher in IGF-1, then you can increase your IGF-1 more safely than if you start off at a low level of IGF-1. So we have been, as a general rule, restricting the entry into the trial.
People have a sort of a bottom of the threshold IGF-1 level. But I'm not any longer positive that we have to do it that way. So I've been testing a lady recently whose IGF-1 levels are really, really low, you know, like 50 or 60. But that's normal for her because she's short.
And as far as I can tell, her immune system is okay. So maybe, you know, maybe I have to rethink that. So when you get into sort of projecting what IGF-1 level you need, it's dependent upon multiple aspects of the biology of that individual person coming to the trial what's their baseline level uh you know how healthy are they how healthy are they all kinds of things so there's no one answer to that just as there's no one answer to what range of this or that you want to use so we titrate each individual person for the doses of growth hormone dhe and metformin depending on how their own personal biology responds and We find that that titration tends to sometimes 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 to the adjustment as we go along.
Plus, these three things tend to interact with each other to a certain extent. We have to adjust for that. Plus, some of these things may affect some of the parameters of aging in ways that are adverse.
And so we have to balance all of that out, too. So it's a very, very individualized thing. So actually, if you look into it, which we've been doing since the end of last year, there's over 100 different factors that have to be weighed before you can adjust these three medications, either up or down. And then on top of that, you have to decide how far to adjust them up and down.
And so far, all of this has been done by the computer known as the gray matter between my two ears here. And I just can't keep that going if we're going to be treating hundreds or thousands of millions of people. So we're trying to make a Greg in a box. Basically, we're trying to transfer that sort of thought process.
that ability to sort of deal with all these nuances into an expert system and then into an AI. So 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, you know, as a medical service.
So, 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'll all come together pretty soon. Can you give me any, I'm wanting numbers. I'd be just being a clinician, you know, we're measuring growth hormone and looking at something. We're looking at insulin, you know, a lot.
We're probably looking at a lot of the variables that you're looking at. And I'm just like, what? what would be an alarm growth hormone on either end?
I know that you're off, you know, that you're allowing for individual differences, which makes huge sense, you know, and it, and it also makes me think that, you know, are the ranges that we've got in our heads in just like the 70 kilogram guy, you know, is that where we're sort of stuck? And, you know, I mean, so I, I appreciate your nuancing it and your efforts, but is there any, are there any numbers you can throw out for? an audience who I know wants them. Well, I mean, 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 uh keep under our umbrella to the extent that we can okay i i think that there are hazards to trying to go rogue on this uh 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 and so it's just better really so what we want is we want to deploy this treatment in a uniform way so we can get uniform results all across the world and the best way to do that is to work directly with the clinical partners so that they can share our data with them, we can share our updates with them, and it'll just work better all the way around that way. You'll be, I'm assuming you'll be doing some training. God, I'd love to go out there and just hang out and shadow you for a while.
But I, you know, we'll go ahead. We'd love to do that. We'd love to do that. We're not, we want to make sure we know what we're doing first and then we'll train you.
Yeah. 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 of TrimXD, we'll 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. Okay. We're working as hard as we can to get there, but it's very complex.
Okay. Okay. All right. Well, stay tuned, everybody.
I mean, it's pretty exciting, you know, and you've got your first trial out there and you're obviously whetting our appetite with it. with the data that you're continuing to harvest. I want to just ask you a few more questions. I, you know, you, you, you throw 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 being maybe a piece. of how we might be reversing autoimmunity and i'm going to throw in there that allergy must must follow behind that and so speak to that because that's you know that's a big deal that's a big statement yes it is it's actually an immense statement and it's universally ignored uh i'm not so 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. So 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.
So in order for the thymus to do its job, it has to preclude autoreactive T-cells developing in the body. And 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, given enough time, and it will destroy, it will inactivate all of the...
pre-existing T cells that recognize that foreign kidney as foreign, and 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 the first to allow the presented piece of tissue to survive long enough in the intended recipient to reprogram the thymus, but that's temporary. it's reversible and as the T cell population recovers, you you restore a normal level of immunity.
But then after that, you don't need to do any immunosuppression. So I have this graph actually that was that I put together not far after 1990, maybe 1991 or so, showing, you know, in the control transplants, everybody dying after about 20 days or less and in the in the transplant. With the thymus reprogramming, everybody alive 100% after 100 days.
Humans. They did this in humans. No, this was in rats.
In animals. Okay. So 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 on like two human pediatric cardiac transplant recipients who showed fleeting, you know, 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 autoreactive T cells that are killing off the pancreas. And 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. But if we can regrow the thymus first, then it opens the door for this intervention.
Yes, to get rid of both transplant rejection and autoimmunity. So the beauty of this is that, you know, 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 also has 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's 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. So I happen to have a lab that does cryobiology research, as you kind of alluded to, and we're hoping to be able to set up a rabbit allograft kidney transplant model.
And if we can do that, we may be able to re-educate the thymus of the rabbit recipients of a given kidney so that we can like swap kidneys between rabbits. and prevent the rejection that would normally take place. And 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.
And if I think of it works in rabbits and pigs, it's gonna 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 autoimmunity in this way. So if nobody else does it, we'll do it. 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. And during that time, the intended transplant needs to be preserved and you cannot preserve a kidney or liver or whatever. for two or three months with current technology.
But my lab is able to cool a kidney to cryogenic temperatures. You can keep it forever at that temperature. So hopefully we can marry up all these technologies, regrow the thymus, bank the organ, transplant the organ. Jeez, that's so fascinating. Wow.
Isn't that interesting? Yeah. Well, and that kind of marry, that's full circle going back to the beginning of your career. So it makes a lot of sense that you, that you're thinking about all of it.
God, you know, just, I do a lot of, I work, you know, I lecture to other physicians on on allergic disease and you know the whole pathogenic mechanism of course we're like i i said sort of bullishly that i think the end potentially of allergies is inside i mean immunotherapy sublingual immunotherapy i mean retraining the immune system with with early exposures like we're just at this pretty extraordinary crossroads now you know introducing foods early etc i mean turning off autoimmunity like turning off celiac disease with early introduction but It just makes me think, too, of immunotherapy, of that being a piece of the approach to reeducating the immune system, you know, towards eliminating autoimmunity. I mean, that. Well, I mean, these things are all self-reinforcing, right?
So there's many, many treatments that are that interact here. For example, gene therapy. One of the problems with gene therapy is you reject the vehicle of the gene so you can get like one gene transplanted, but not multiple. But if you could prevent. the capsid, you know, that is carrying the gene in your body from being rejected by the body by re-educating the body to think that it's so.
Problem goes away. And with respect to immunotherapy like CAR T 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.
Well, we could go on and on. In this conversation, it's extraordinary. You know, I just, we'll have, you'll have to bring you on again.
I mean, you've been paying careful attention to not just the thymus regeneration, but dropping senescent cells, you know, and bringing and turning the volume up on like, I'm sure changing the CD4, CD8 ratio and like, are you Tregs and just the immune system in general. And you've also. thrown out, I'll do this, 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.
You know, and that most of us die, you know, from some immune-mediated problem, which makes sense to me. I mean, all the chronic diseases, I mean, if you look at the hallmarks of aging, it's all, you know, the underpinnings are right there in the immune system. But, you know, any... thoughts on that? And, you know, again, folks, we'll give you contact information to follow this, but maybe we'll leave with that for now.
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.
Yeah. 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 plop 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 that exponential curve continues. And one of the sleeping issues is 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 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 you know firing squad and we're reversing that so if we actually can impact cardiovascular disease by lowering background inflammation, then for sure that curve of how many people are dying from immune-related failure with AIDS 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, you know, very encouraged to continue in this vein and reach out and help as many people as we can as fast as possible. 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. I follow your work and I've got plenty more questions as I'm sure that I'll hear from folks. So hopefully we'll have a we'll have a part a part to one of these days.
Thanks, Greg. 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.
Yeah. Next time we'll talk a little bit about diet, nutrition, and exercise. We haven't talked about any of that yet.
We haven't talked about it. That's a whole other explored, unexplored area. And if you put those two branches of intervention together, you know, Katie, right? Yeah, absolutely.
Oh, thanks so much. Great to have you. Take care.
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