Dr. Greg Fahy on advancing the first trial ever to reverse human ageing – Our Longevity Futures, with Chris Curwen | Ep. 2

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Over the last 150 years, our life expectancy has grown, from 40 years in 1850 to over 90 years today in some countries. This can be attributed to advances in medical science, improvements in public health, and equitable access to healthcare, especially for maternal and infant care.

What will the future hold for our world? Will we be overwhelmed by a ‘silver tsunami’ of retirees with poor health, or will we use the latest research findings to rejuvenate the elderly and extend their lifespan?

Our Longevity Futures is a show where I, Chris Curwen, speak to scientists, engineers, entrepreneurs, doctors, politicians, and community activists who are giving the world the hope that we can all live longer and better, and improve our health.

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In this captivating second episode of ‘Our Longevity Futures’ we host Dr. Greg Fahy. Dr. Fahy is a world renowned cryobiologist and is 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 discusses his personal long-term health journey, and how his former colleagues and mentors inspired his path into the field of longevity.

His pilot study, thymic rejuvenation and immunorestoration and insulin mitigation (TRIIM), was initially designed to test whether a cocktail of DHEA, metformin and growth hormone could rejuvenate the thymus. By procuring the help of Dr. Steve Horvath, the creator of the Horvath epigenetic clock, they found that drug cocktail had reversed human ageing.

Using that evidence Dr. Fahy’s company Intervene Immune, Inc. is expanding this pilot study to a Phase 2 clinical trial where he will be enrolling 85 participants between 40 and 80 years old. The clinical trial is called the Thymus Regeneration, Immunorestoration, and Insulin Mitigation Extension Trial (TRIIM-X), and will be more inclusive than the original, enrolling women, ethnic minorities, and a wider age group.

In this episode of Our Longevity Futures, Dr. Fahy discusses the groundbreaking moment they discovered the results of the TRIIM trial and whether they constitute true ageing reversal. He also delves into the details of TRIIM-X trial, changes to the protocol, going international and what success might look like.

Here are some of the highlights for my conversation with Dr. Greg Fahy:

Chris: What actually started off your interest in the longevity field and what has your journey been like to lead you to where you are now?

Greg: Well I got interested in ageing when I was in high school, actually earlier than that I was interested in aging when I was in elementary school, but in high school I read Alex Comfort’s book the process of ageing and it was fascinating. It started me thinking about what ageing is and whether it can be modified, and so that was kind of the jumping off point. I started reading papers on molecular biology when I was in the seventh grade junior high school because I wanted to sort of prepare myself to know something about ageing, and when I was an undergraduate at University of California Irvine, I actually taught a course about ageing to undergraduates there. So I’ve been interested in the field for a long time and it’s partly because I was inspired by very talented people who were investigators themselves.

Chris: You’re currently the chief science officer of Intervene Immune, could you just tell me a little bit about your work there and what you’re doing at the moment?

Greg: The main activity of Intervene Immune at the moment is to conduct the TRIIM-X trial. So some time ago we did a trial called the TRIIM trials, standing for thymus regeneration immunorestoration and insulin mitigation, and that was pretty successful. It was just one trial and we need to replicate the results and extend it to different categories of a person; such as women, older people and younger people, so that’s what we’re doing now. We have enrolled something like 15 people so far. We continue to enroll one or two cohorts every month and we’ll continue to do that until we run out of volunteers. But, our goal is to hit around somewhere around 80 to 100 people in the second trial, and that takes a lot of work, so that’s the main thing that we do.

Chris: Can you just give us a brief summary of what the thymus is and what is its function in the immune system and in the body?

Greg: Sure, so the thymus is sometimes called the master gland of the immune system. It’s located in your chest cavity, beneath your breast bone, and its job is to manufacture T-cells, which are named T-cells because they are educated in the thymus. So bone marrow precursor cells migrate through the bloodstream to the thymus and are trained to do positive and negative selection. Positive selection relates to the development of T-cells that can attack foreign antigens and defend you against antigens on organisms, and cancer cells for example, and then negative selection is the last class that the T-cell has to go to before it can graduate from the finishing school of the thymus. Negative selection involves being sure not to attack yourself as foreign and that turns out to be a very important process as well. So T-cells, once they pass both of those hurdles, are then released into the bloodstream and defend you without attacking you.

Chris: What role does the thymus have to play in ageing?

Greg: Obviously it’s very important in the immune system and obviously the immune system is something that is affected by age because of deterioration of the thymus, right. So this gets us into a deeper question about you know: where does aging come from? What is aging? There are different schools of thought about this but the thymus is really, I think, an excellent example of my school of thought, which is that ageing is actually an active commission. It’s not an act of omission, at least not entirely, and in this case the commission is very evident because there are programs that are common to all vertebrate species and certainly to all humans that cause your thymus to start deteriorating really from birth. But primarily, it really accelerates around the time of puberty so it seems to be some kind of clock mechanism in which the thymus involutes in response to sex hormone production of puberty and then that is continued to be affected by the decline of growth hormone and probably other hormones as we get older beyond beyond puberty. So the thymus process of of deterioration is called involution and it’s this involution of the thymus that leads to long-term consequences for aging, so the T-cells that the thymus makes are long-lived, so you can do things like take somebody’s thymus out at youth and not have any effect on their immune function years afterwards and you can undergo normal age related thymic involution and still maintain a good immune system until you’re 60 years of age. But somewhere between 60 and 80 you lose about 98% of your ability to recognize foreign antigens and that obviously is not good for you, and coincident with that, we see a large increase in morbidity and mortality and then, you know, it’s just a bit of a ‘coincidence’ that people tend to die in large numbers around the time their thymus stops working. I think it may be more than just a coincidence, obviously there is a lot of other things going on, but some of those things relate to the the integrity of your immune system, for example age-related inflammation is probably associated with vascular disease and vascular disease is associated with heart disease, which is the major killer that we’re all involved in. So what would happen if we didn’t have age-related inflammation? And is age-related inflammation related to the aging of your thymus, which normally would prevent inflammation from developing? So there are a lot of questions that are yet to be answered about exactly how the thymus relates to ageing, but those are some of the superficial questions. I would also just mention circumstantially that there are studies in mouse models that show that if you take a thymus from a young mouse and transplant into an old mouse it rejuvenates aspects of brain, liver, thyroid and insulin physiology, so there may be deep connections between the ageing of the immune system, which is largely driven by atomic evolution and ageing in general.

Chris: When we think of the immune system, what we imagine is something that just fights off foreign infectious diseases coming in from outside, however, it’s more much more broad than just external infectious disease.

Greg: Yes, that’s right, for example cancer. It has been a little bit hard to prove the connection between thymus involution and increased risk of cancer, but there has been some study of the fate of people who get cancer and what their thymus is doing and what their immune system is doing at the time that they get it or don’t get it. If you look at it at that level of granularity then you find there is a very strong correlation between thymic function and the ability to resist the development of cancer. There are theories that say that we all get cancer several times in our lifespan but we never notice it because the immune system cleans up the cells as we get older. We develop things like PD-1 which inhibits the ability of the immune system to attack cancer and one of the things we saw in our trial, for example, is that by restoring immune system function the PD-1 just goes down naturally to where it was in youth. So it seems like the ageing of the time is related to a lot of other things that happen to us as we get older.

Chris: Are we yet able to grow a thymus in the lab? I know it might be quite a leap to get there but, if not, how far away are we from being able to do that?

Greg: This is something I have not really done my homework on. But I know that the SENS foundation has been quite interested in this. They have contracted with the Wake Forest Institute of Regenerative Medicine (WFIRM) to actually do just this, to grow things in a dish, and in theory, that may have some applications, particularly for people, who as I said before, may have had their thymus removed when they were children to treat some disease without really much attention being paid to the long-term consequences of doing that. So if you do not have a thymus that you can regrow, the only other option that you have is to make one in a lab and then transplant that. Obviously that’s a very long-term project and we are focused at Intervene Immune on what we can do right now, so we prefer to regrow the thymus that you already have that sets aside a lot of unknown questions about the fidelity of the thymus you may grow in a lab dish versus the thymus that you would that you already are relying on for for maintaining your health. It saves us from having to wait for 20 years for the FDA to approve the process, but in theory that is not a terrible approach. The only thing about it is that we have to go back again to what is driving the involution of the thymus in the first place. Ao Aubrey (de Grey) and the SENS foundation tends to think of ageing as wear-and-tear, in other words, it’s just the accumulation of damage, and so if the thymus is just damaged then you replace it with a fresh, undamaged thymus you should be good for another 60 years. But it doesn’t work that way. For example in the mouse thymus, transplant experiments I was describing before, once you transplant that thymus it works for a while, for maybe a month or so, but then it stops working and it’s not because it gets rejected. It is because it does not have the hormonal signals that it needs to keep going. So the old environment is not conducive to the maintenance of thymic function; the thymus is supposed to be involuted as we get older any time after puberty, or so your thymus is involuted and it takes a long time for that process to go to completion. But if you take a fresh laboratory grown thymus and you put it into an older person, it will be okay for a while, but then it is going to start involuting to go back to where you were before you got the transplant and the window of time in which it’s active may not be long enough for you to derive any substantial benefit from it for the long term function of your immune system. So even if you were to make thymuses in a lab and transplant them, you are still going to have to do something like what we do to support that thymus long enough for it to produce enough T-cells to make a difference for your future.

Chris: On the topic of thymus regeneration, in September 2019 you published a paper on a study in which a cocktail of three drugs: DHEA, metformin and GH (growth hormone), seemed to reverse the biological age of humans by about two and a half years. Could you give us a bit more details of this study; the original purpose of the study, the effect on the thymus, how did you take the measurement of biological age reversal?

Greg: So that is a lot of questions! But we will go through some of them. The drug cocktail is a combination of growth hormone, dhea and metformin, and the growth hormone is what regenerates the thymus, we have known that since 1986. If you continuously expose an old rat to growth hormone the incredibly deteriorated thymus, which looks nothing like a normal thymus both histologically and physically, the thymus actually shrinks down to a size that was so small that they couldn’t even weigh it. In the study it looks like a glob of fat but you can still bring that thymus back by giving the animals cells that secrete growth hormone (constitutively pituitary adenoma cells in particular), they found that when they did that not only did the thymus come back to its normal morphology, but T-cell ability to respond to foreign antigens was restored back to the level seen for a three-month-old rat. That caught my attention. Everybody else ignored it and so the the TRIIM trial was designed to see if we could do something like that in humans and what I did not know at the time is that Laura Napolitano, and a few other laboratories, were brave enough to try this to combat HIV/AIDS patients whose immune systems were being destroyed by the HIV virus and they got positive results. But my study on myself – my N=1 study – got published before any of them published their stuff and I showed in my own self-study that using growth hormone DHEA allowed me to develop statistical proof of the regeneration of the functional part of my own thymus, at least based on MRI investigations. So why DHEA plus growth hormone? Growth hormone regrows the thymus. Why do you need the DHEA? You need the DHEA because growth hormone has a side effect and you know people have linked IGF-1 and growth hormone to pro-aging processes, but there has not been that much attention to mechanisms by which that might happen, in particular to the role of insulin. One of the drawbacks to growth hormone is that it raises insulin levels and insulin is a very pro-aging factor and it may be that the drawbacks of growth from administration are largely driven by this side effect of hyperinsulinemia. I asked myself a question before I did my own self experiment: why is it that if you give growth hormone to an older person their insulin levels go up, but a young person is replete in growth hormone and has low levels of insulin? What’s the difference? I just speculated that the difference could be that young people have large amounts of DHEA in their bloodstreams as well and that may be a hidden unknown effect of DHEA is to actually block the hyperinsulinemic effect of growth hormone. So I gave myself growth hormone for a week, my insulin levels went up by about 50. I maintained the same level of growth hormone for another week but I added DHEA and my insulin levels went right back down to baseline. I did this several times over the course of about 10 years, I always got the same response and even though it’s just me, you do it enough times you can achieve statistical significance, which you know it proved that it worked at least in me. So one of the things we wanted to find out in the TRIIM trial is if it worked for other people. The answer to that, although we didn’t really dwell on it in the paper because these papers are very limited in terms of space that you have available, we did find that DHEA has similar effects in men in general. And then the last component was metformin, because in some cases the DHEA is not sufficient and so you need extra help in bringing down your insulin levels. We really like metformin because it has a lot of positive effects in addition to its ability to lower insulin levels.

Chris: Was another reason behind choosing metformin because it has shown some other longevity based benefits?

Greg: it was chosen mostly because it is probably the best anti-diabetic drug that there is, but on top of that I was involved in some studies with Steve Spindler at the University of California, Riverside, in which Steve was looking at the transcriptomic signature of calorie restriction in older mice. You put an old mouse on CR (calorie restriction) and it’s physiological indices all go back to something that looks like a younger mouse and so you can track that in terms of transcriptomic changes using, at the time what we had available was these DNA microchips that could track the transcriptome without the need to do a lot of sequencing. What we found is that the signature of calorie restriction in old animals was replicated even better by metformin than by calorie restriction itself so the animals look more calories restricted on metformin than they did on calorie restriction, so that was another thing that caught my attention about it. Then of course later, Nir Barzali came along promoting metformin for this and other reasons; it has anti-cancer effects. It’s just a very good drug and one of the things that attracted us to it as well is that if you take insulin to lower your blood sugar levels you can overdo it and have your sugar levels crash and you can end up in a diabetic coma, and that essentially does not happen with metformin. It does not have a tendency to lower your sugar levels down to sub physiological values, so it was also a very safe drug and we wanted it for that reason as well. As for the (ageing reversal) results, it was almost an afterthought to actually contact Dr. Steve Horvath to get a measure of the participants biological age, and it was found through using the Horvath clock that the age of these participants had actually almost reversed by almost over two years. So how can we call this true age reversa? Let me just comment on the Horvath part of the story; I just to clarify that aspect of it because it’s kind of interesting. We did not really have any high hopes that we were going to see much in the epigenetic ageing space, but we really wanted to find out, but we did not know Steve. So Bobby contrived this seminar series that he put on through a fictitious organization called ‘Renaissance Biology’ whose purpose was to invite to Steve to give seminars at UCLA about the clock, which gave us a chance to meet him and interact with him and after a couple of years of that we told him about the trial and he said “Oh I would be happy to analyze your results”. So we got the results analyzed and he was also kind and gracious enough to do this for us without charging us for it, which was really good because we had like no money. We still had to pay a lot to get the DNA analyzed in terms of the CpG site inventory in the genome. Then armed with that, Steve was able to take that data and run the clocks for us and actually when steve first got (the sample) he ran his original Horvath DNA methylation clock first and he was kind of floored, because he actually saw a reversal of epigenetic aging in our guys (TRIIM participants). So we had nine guys aged as it happened, just based on the luck of the draw, 51 to 65 years of age we had specified 50 to 65, but we did not get any one who was 50. That’s a very small number of people and these epigenetic aging clocks have a fair amount of scatter associated with them, but we normalized everybody to themselves at baseline, so we subtracted out a lot of the noise in the in the data and what Steve was able to show was that one year after the beginning of the treatment the volunteers biological age was one and a half years less than it had been at the beginning of the treatment, even though the treatment itself had taken a year to unfold. So that meant that compared to sitting on the couch and doing nothing, which would have been a year older we were actually two and a half years younger than what would have otherwise been the case. So we first had to reverse the one year of forward time that the trial took and then on top of that another one and a half years. Steve is highly sought after in gerontology, people sent him all kinds of samples from all kinds of creatures and things and trials, and he had never seen actual ageing reversal show up before so to have this show up for the first time in a population of older guys, human beings, was pretty noteworthy. And so he had to prove to himself that it wasn’t some kind of fluke, so he just took it on himself to run three additional clocks: the phenoage clock, the Hannam clock, and the grim age clock, and they all measure aging in different ways and they were all different in the details of the response that they showed. But qualitatively they were all exactly the same and overall each individual clock showed highly significant results, in combination they showed even stronger significant results. So by nine months of treatment, on average across all of the clocks, we were younger than we were at the beginning of the trial and the significance increased significantly as we went the extra three months at the end of the trial to the 12-month point. The result persisted based on the average of all of the clocks six months after the end of the trial as well. We were still quite statistically significantly younger than we would have been if we had not been in the trial. So I do think that this points to a real global aging reversal effect, and that’s for two reasons. Number one, the Horvath clocks and these other clocks are measuring something general about ageing it’s not just related to changing immune cell populations in the bloodstream. Some of the clocks are more sensitive to that than others, but it didn’t seem to matter, they all showed the same response. Furthermore the changes in immune system function didn’t really correlate well with the changes in epigenetic aging. So, we showed improvements in the immune response, we showed improvements in the structure of the thymus, but the epigenetic aging reversal that we saw, even though it may relate in part to those immune system changes, there seems to be a dimension to the treatment that goes beyond just the immune system changes itself and it’s independent. It’s interesting to think about why that may have happened, it’s nothing that we could have really predicted in advance, but we can kind of rationalize it in various ways now that we have seen those results. The other thing I want to say about it is, is it real? Is it actual general ageing reversal? We did see other signs that can be interpreted as general aging reversal, for example, hair color coming back.

Chris: I saw the pictures of that recently, that really is incredible.

Greg: Yeah, I mean we just had no concept that that was going to happen so we didn’t take photographs of everybody before and after. In the current trial we’re doing that part of the screening step is to have your hair photographed so we can see if we can document this again. But we saw that there’s one paper in the literature in which old women given growth hormone had an improvement in kidney function and I wasn’t aware of that paper at the time but we saw that there’s a statistically significant improvement in kidney function at least based on estimated GFR (glomerular filtration rate) over time, and that it seemed like that improvement continued to increase, in other words the kidneys continue to improve even six months after. Although we are not able to prove that ladder point statistically because we were only able to follow up on six of the guys, and the statistics are just not good enough with six people, it’s a straight line for all of the data points including out to that last point. So we’re hopeful that there may actually be an effect even after we stopped treatment and of course normally your kidneys are not just going to get better as you get older, so the implication is that there may be something else going on. There’s a few things you know like that, which led us to believe that perhaps there was a global anti-aging effect going on, and then when Steve’s clock results came in they seemed to confirm that. I’m not going to say that every aspect of aging was reversed because I can tell you right off the bat that we know of one aspect of aging that was not reversed at least not in blood cells and that’s the telomere aspect of aging. We went to a very good company and had the telomere length measured. In fact, they were very gracious; they gave me the entire distribution of telomere lengths for every individual for all of the blood samples, you see all these bell-shaped curves and they’re just all superimposed on each other for the most part. There may be tiny effects you know showing an improvement in telomere length but I wouldn’t make anything out of those results. I kind of expected the telomeres to improve for various reasons but we just didn’t see it, so you know, what do we mean by aging reversal? What is it? What does it actually consist of? Does it mean that if you have an old arthritic joint that’s killing you and you go on our treatment that that’s gonna rejuvenate and go back to where it was before? Well I’m not so sure that it will right there, may be some things that do turn into damage after a while and once things are actual damage and not just physiological patterning that’s been changed. In other words, once you go beyond signaling then you may end up with structural changes that are hard to reverse, so we don’t have any clue about that. On the other hand, there’s some interesting dimensions to even that sort of thing because one of the side effects of growth hormone is it tends to make your joints ache, and why does it do that? It’s because it’s making your cartilage grow back and it’s making your bones want to grow again your bones can’t grow because after puberty or epiphyses close and you just can’t do that so you’re setting up a contradiction between what the bone wants to do what cartilage wants to do and what is possible biologically. But I speculate in this; pure, pure speculation, we have zero evidence for this, but I speculate that may be a good thing, because it may build up your cartilage so that when you stop treatment, and you go back to ageing again, you’re starting off with better cartilage and you may actually postpone arthritis to it to an older age. So we don’t know, but that’s just one of those additional things that we look forward to exploring in more detail in the future.

Chris: The trial you’re running with Intervene Immune, TRIIM-X, has started recruiting for a larger phase two trial. Could you just tell me a little bit about that?

Greg: Right, so we actually enrolled our first cohort at the beginning of thanksgiving week in the United States, near the end of november. We enrolled two cohorts in December and a couple of cohorts in january. We’re still recruiting now, because of the COVID situation we had to rethink how we did these trials. In TRIIM, we had people report physically for examination by our trial physician and to get initial blood testing done and to get various scans done. So we scanned everybody for their thymic structure at baseline using MRI at Stanford and we wanted to be very consistent about that. And so we had people come back at various intervals for that, but with COVID you can’t do that sort of thing as easily. So we have two modes of entry into the trial now; one is in person as it was before, and one is just by telemedicine approaches (essentially by zoom meetings), so we have a zoom physical which you can get from our trial physician. It’s not the same, in the sense he can’t feel you to make sure that you feel right, but he can evaluate you in various ways. For example, we have a test in which you sit in a chair a firm chair with no arms and you stand up and sit down as many times as you can in 30 seconds and that’s a measure of your frailty, so if you look good by measures like that we also have a neurocognitive exam that you can do over the internet, it takes maybe 10 minutes for that to see how well you’re thinking. We’re hoping that we can actually show possibly neurocognitive improvements and maybe improvements in other things like frailty in some of our people. So these are things that can be done online, but there are things that need to be done in person so we will be scanning the thymus in some cases and we’re using the opportunity to also scan for coronary artery calcium deposition, which is related to your risk of getting you know heart attacks and so forth in the future. We also have some exercise physiology testing that we do because your ability to raise your metabolic rate in response to exercise is strongly correlated with your risk of death and if we could show favorable changes and those kinds of endpoints it would be fantastic. It has to be optional because not everybody can travel to our center in Southern California. We’re currently based at the Lundquist Institute, which is part of the harbor UCLA complex, formerly called harbor UCLA, in Southern California in Torrance, and so we have access to the scanning and exercise testing facilities, and people who are local or who wish to travel on some halves. We’ve had one volunteer fly out to us from the East Coast! Anyone who wants to show up in person can of course, you have to wear a mask and you have to be socially distanced and all of that, we respect all of that. Ideally if you can get vaccinated before you come out that’s even better. But it’s possible, so you can come out and meet us in person we get to meet with person but even if you sign up by telemedicine we meet everybody online and one of the benefits of this trial at least in TRIIM, and it seems the same is true of the current trial, is that the people that you meet are just cool people who sign up for this. They’re not your ordinary person, the people that know a lot and they’re smart and they’re interesting.

Chris: Right, it’s not just men in this trial, you’re going a bit broader with the inclusion criteria?

Greg: That’s correct, so we do have women in the trial. It took a fair amount of study to figure out how to handle women, we’re finding that women do differ from men in case you hadn’t noticed that before. We’re loving having them in the trial, we also have people in trial out to the age of 80 years old. We had one guy just squeak in recently because he was going to turn 81 in a few days and we got him enrolled just before that and we had to exclude him. But we’re also looking at people as young as 40. So far we haven’t really enrolled anybody that young yet but we have several people interested and we’ll probably be enrolling them over you know the next few months.

Chris: Are you keeping the treatment protocol exactly the same as a first trial, or are you tweaking it slightly?

Greg: We are actually tweaking it a little bit, so we’re taking advantage of what we learned in TRIIM to accelerate the insulin mitigation aspect of it. In TRIIM we phase things in, so we started everybody with growth hormone alone and then after a week, we gave them growth hormone plus DHEA, and after another week we gave them all three medications. So we could parse out the effects of these things on men and made sure that each one of these drugs was given for a good reason that it actually had an effect. So we proved that each one of these drugs did have a good effect, so now we don’t have to do that again. Now if you’re a man you just start right off on all three, and then of course we optimize after that. But with women it was necessary to go through that same process again. So the women are getting the step-by-step procedure and we’re learning a lot from that, so that’s one way in which we’re tweaking the protocol. Hopefully at least for the men it will be an even more effective protocol because you’re not going to have unmitigated insulin exposure for that very short period of time at the beginning of the trial. There are some other things that we’re looking at as well but i’m not ready to talk about those yet, but they’re designed essentially to reduce the possibility of side effects and actually to enhance the likelihood that the treatment will be more effective in regenerating the thymus. But these are minor things from an FDA point of view, and so the FDA had no problem with us including these little extra tweaks in the protocol.

Chris: What are the primary and secondary outcome measures going to be in the TRIIM-X trial? Are they going to be primarily around thymus regeneration like they were before? or you’re going to look more broadly at the actual age reversal?

Greg: Really the most primary endpoint this time is the epigenetic aging reversal, partly because that was one of the more robust responses that we saw in TRIIM, and partly because it’s just really important that we document that effect and verify that we can reproduce that effect. So we’re going to be looking at that again, but we also want to verify that the immune cell populations improve in the right direction, and we’re also hoping to do some T-cell challenge experiments to show that the T-cells that we produce are more functional as well. So not just that we have more naive T-cells, but that when those are combined with all the other T-cells in your body, the net effect on your ability of your T-cells to respond to anagenic challenges is increased and that’s a little bit of a challenge because T-cell stimulation tests typically have incredibly noisy results, you just get data that’s all over the map. But we’re going to use the same statistical device that we used in TRIIM to filter out all the noise by normalizing each volunteer to his or her own baseline. So the beauty of this is you can take a blood sample before you start treatment and challenge the T-cells and get a response and then you can take another blood sample, which is completely independent from the first, and then do the same challenge at the end of the trial and then compare the responses over time. That allows you to subtract out the baseline without sort of giving the immune system any pre-challenge globally, which would tend to bias it in favor of increased responses. It’s not like we’re vaccinating you and then we’re challenging you with the same vaccine again. All of the challenges are done in the test tube.

Chris: What would constitute a successful trial once the trial is completed?

Greg: I would be very happy if we show in women and in older people that we can regrow the thymus because there’s no data on thymus regeneration in women, and there’s no data on thymus regeneration after the age of 65. In fact, there was no data on thymus regeneration as a function of age in humans at all up to the point we did the TRIIM trial, where we saw no difference in thymus regeneration if you were 50 or if you were 65, or say 51 or 65, but we don’t know what happens after the age of 65. We want to find that out because we want to find out if there’s going to be an age limit beyond which you can no longer benefit from this treatment. We’re hoping of course that there won’t be, or that it will be sometime after the age of 80, but we have no idea. So That’s going to be a little bit of a challenge because the number of people who are going to be scanned is not 100% of the number of people who are in the trial. So we’re going to have to have a fairly large N value so that the number of people that actually get scanned gets up to the point we’ll have enough data to analyze. But if the TRIIM trial is any indication, the thymus regeneration data are so robust that it’s possible to show statistically significant thymus regeneration in single individuals and if we can do that on even a handful of single individuals that will be breaking new ground and educating us about how far we can extend this. Of course we want to help as many people as possible, if we can show that we can benefit you even if you’re 80 that’s really, really good news. So that’s one of the things that will make the trial a success, is if we can get a bear on this point, and then of course, if we can replicate the epigenetic aging results and ideally if we can show improvements in T-cell functionality that would be really great. There are many other things we’d love to be able to do, but we’re limited by budgets and so we have to be parsimonious about what we shoot for. If we could show, for example, a reduction in frailty or an improvement you know of all things you know, and I’m not expecting this, but if we show an improvement in coronary artery calcification or in cardiac size and shape with our treatment that would be fantastic. We will just have to to see how all that turns out. But that’s all blue sky stuff so we don’t consider those kinds of endpoints primary, those are secondary endpoints and speculative right now.

Chris: Is there a possibility that TRIIM-X might go international?

Greg: Yeah, it’s difficult, there’s two major problems. One is that we have to analyze your blood, and that means we have to have access to your blood in a reasonable time frame. So if you’re living in Antarctica or something it’s going to take so much time for us to get your blood, we’re not going to be able to keep it alive during the transport back to our labs. So we need to be able to work with people who have access to the blood lab that we have a national account with, which is Quest. Anyone in the United States, generally speaking, has access to a local Quest, the diagnostics lab, and so they can be enrolled, they can be tested and we can get blood results done in a timely fashion, if you’re in the United States. When you get over into Europe it starts getting more difficult but we still think it could be stretched using courier delivery i.e. fedex delivery that sort of thing, but the best and we’re working on that we have some links into Germany to establish partnerships with local blood testing labs there. So we can get at least some of the tests done in Germany, and then many of the other tests can be done on frozen cells. If the cells can be frozen and shipped to us frozen, then we can bank them, then thaw them out and run those assays later on that would also solve the distance problem.
But of the overseas opportunities that we see coming online, the first is in the UK. There is a nice institute in the UK that’s quite interested in exploring our treatment and we’re working with them to make that available sometime hopefully in the next few months. We’ll have to see how that works out. Naturally in real life everything always takes 10 times longer than you expected but there are certainly possibilities of offering the treatment in the UK in the foreseeable future.

Chris: I’ve just got one final question: what is one aspect of longevity or the ageing field at the moment most excites you?

Greg: One of the great things about this field right now is that there’s so many exciting things that are taking place right now. I have a little bit of trepidation about naming a few of my favorites because I may undervalue some of the other ones which are great as well. But I’m really excited about epigenetic reprogramming, unfortunately that has a way to go before we’re going to be able to apply that to people I’m afraid. I like what Liz Parrish is doing with gene therapy. There’s an effort being made now to map out something I’ve dubbed the senesome, which is the total population of mRNA transcripts changes that bring about the aging process that we see, and if we could trace how that happens we could begin to find out what changes upstream that we could block to prevent the downstream changes that manifest themselves as ageing. That effort has not quite gotten funded yet but there’s a wonderful paper out of Wyss-Corey’s lab that came out last year that’s making a big contribution toward that, at least with mice, but we need studies like that in people too.
I like simple things, like Irina Conboy’s ability to reset aging by removing some of the old age factors that are probably driving it. You just take your blood, take out half of your old plasma, throw it away, and replace it with saline solution basically, and suddenly a lot of aspects of ageing are reset to the youthful value, which again speaks to what ageing is and where it comes from. Whether it’s wear-and-tear, or whether it’s actually an active commission, as I think that it is, I think that experiment illustrates. Related to that there’s Harold Katcher’s epigenetic rejuvenation study in rats in which he showed radical changes using a young plasma fraction and actually I’m working with Harold’s group right now to see if we can replicate his rat results in dogs. I have access to a dog colony and there’s some old dogs in the colony we’re going to see if we can rejuvenate those dogs starting perhaps next month or something like that, so we’ll see how that goes. So there’s just a lot of things going on.
I know George Church is into wonderful things. David Sinclair, you know the story of NAD that he started back in 2013 is so exciting and so sweeping in its implications there’s bound to be all kinds of exciting things that come out of that. In the end these things are all related to each other in some way or the other. It’s like the old myth of the elephant, we can see a tusk over here and a tail over here and a leg over here, we still don’t see the entire elephant. We’re beginning to form that picture and that’s very exciting in and of itself, so I’m just bursting with excitement about what’s happening at ageing. But we have to live long enough for all of that promise to come to fruition so that’s why I like my treatment even I’m not allowed to choose it, because it will maybe help us live a little bit longer so we can have a better chance of benefiting from all of these other things that are coming down the pipeline.

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At Gowing Life, we want to say another massive thank you to Dr. Greg Fahy for giving us the time to have such an in depth discussion about all aspects of his work. We were thrilled to find out the result of the TRIIM trial, and can not wait to hear the progress that TRIIM-X makes. To keep up to date with any of the updates from the trial please be sure to visit the Intervene Immune website.

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