In this session, Greg Fahy, Co-Founder of Intervene Immune and Principal Investigator of the TRIIM and TRIIM-X clinical trials, offered a sneak peek on some preliminary data from the TRIIM-X clinical trial along with updates about its development, progress and conditions of the enrollment, as well as optimistically looking first preliminary results. Following discussion touched on possible next steps for their company, like developing a much cheaper growth hormone alternative, possibility of prolonging the lifespan of kidney transplants or reprogramming thymus with grafts to completely solve transplant rejections and autoimmune diseases.



In this session, Greg Fahy, Co-Founder of Intervene Immune and Principal Investigator of the TRIIM and TRIIM-X clinical trials, offered a sneak peek on some preliminary data from the TRIIM-X clinical trial along with updates about its development, progress and conditions of the enrollment, as well as optimistically looking first preliminary results. Following discussion touched on possible next steps for their company, like developing a much cheaper growth hormone alternative, possibility of prolonging the lifespan of kidney transplants or reprogramming thymus with grafts to completely solve transplant rejections and autoimmune diseases.


Presentation: Greg Fahy | Thymus Rejuvenation Progress Update

  • The general idea that we started with is that the thymus is very important and that it withers with age. By the time you get to 70 years, there is very little left in terms of functional thymic mass. We die because of this, we all know that mortality goes up as immune system function goes down. So we have to do something with it in order to prevent our T-cell population from getting depleted. The beauty of our approach is that it is doable right now.
  • Thymic involution can be reversed in many different ways. Growth hormone (GH) reversal has advantages at least in model animals, and seems to work across the board in different species.
  • Another reason why GH is preferable is its safety. There’s been a long clinical experience giving GH to GH deficient humans since 1996s. Side effects are known, mild and reversible, and there are also a lot of positive effects listed in the slide. Illustrated in the figures are profound effects in building up lean body mass and burning fat. Turns out that as you’re growing your muscle and burning fat, along with other organs, thymus builds back up as well.
  • There is one particular side effect I was worried about – GH induces production of insulin, which is a proaging factor. But I was able to show many years ago that it can be blocked by co-administering DHEA, which also has by itself amany anti-aging effects (it’s also called neurosteroid, since it most likely has some neuroprotective abilities like GH). Sometimes DHEA is not enough to counteract the diabetogenic effect of GH, so we also added Metformin that acts as insulin sensitizer. All the ingredients are pretty powerful but the sum of the combination is better than it’s parts.
  • TRIIM study held in Stanford university was held from 2014 to 2015 with two cohorts. The first larger one you can see on the left and the second one on the right. The aim was to regenerate the thymus with this novel drug combination of GH + DHEA + Metformin. The FDA considered that a new entity, so we had to go through IND to do the study and we did that. We published this in September of 2019th and it got a lot of attention which is a success for only an intended pilot study.
  • Turns out many interesting things came out of the study. Clear demonstration of thymus regeneration documented by disappearance of thymic fat. Naive T cell populations increased. Cancer risk factors improved (PD1, PSA), which is important because cancer is always a concern with GH. Sternal bone marrow fat decreased. CRP decreased. Insulin was partly controlled and other side effects were mild.
  • There were also some unexpected results. Evidence of hair darkening. Statistically significant improvement of eGFR (filtration rate of the kidneys) over the time of the treatment and apparently even after the end. Reduced total and CD38 Monocytes, cells that drive age-related tissue NAD depletion. NAD depletion is a great way to get aged, so that might be a reason for some of the unexpected results.
  • Which leads to the most surprising result. Highly significant and accelerating reversal of epigenetic aging in general. We measured that using 4 different epigenetic clocks, before and during the course of the treatment. From the figures you can see that the epigenetic age reversal effect was accelerating over time and it was going about 4 times faster in the last 3 months of the trial compared to the first 9 months. That means that it takes the body a while to respond and realize that it is supposed to be younger than it was.
  • The question we were left with is whether this is real or whether it was a fluke and some fault on our end. And I’ll devote a few slides to that. It has been shown in the past that thymus transplant can reverse non-immunological aspects of aging, so that’s consistent with our study. But epigenetic age reversal was not correlated with thymic regression before. When we correlated it we found out that it was not statistically significant, so I think that there are two independent effects at play that are driving epigenetic aging reversal in our volunteers.
  • Reversal of NAD depletion has been linked to many signs of global aging reversal in mice, and we confirmed that total and CD38 Monocytes were reduced in our study, so that is a second consideration why our effects are plausible.
  • Another consideration is that each one of the agents we were using have shown to oppose aging in some way, probably in a complementary way through different aging pathways. And this catabolic effect of aging is being opposed by anabolic effects of GH and DHEA, so it’s believable that it might have some profound effect on aging.
  • We are all aware of heterochronic parabiosis, and while there is still debate about whether it is the youth factors coming from the young to the old or just a dilution to the old (probably both), GH and DHEA might be some of the youth factors at play in heterochronic parabiosis studies.
  • We also have some new evidence that hasn’t been seen before. Steve Horvath decided to go back and retrospectively look at the data from TRIIM using different measure of aging – PhenoAgePlasma. There is a component to the PhenoAge clock (which requires DNA and measurement of the methylation sites) which relies only on data available in plasma or blood. So Steve went back and recalculated this plasma aspect of PhenoAge and found out on average, just as we found with the epigenetic clocks – a 2.5 years reversal. This new method has an advantage that we can look at this in real time from blood samples, we don’t have to wait until the end of the trial. So we are doing this now with TRIIM-X.
  • But the gold standard for knowing whether this is real is replication, which is also why TRIIM-X is happening. We’re repeating and extending TRIIM in many ways, with men and women within the 40-80 age range.
  • We’re headquartered at The Lundquist Institute, where we give seminars to cohorts of people enrolling and coming in. And it gives us access to many different scanning and measurement capabilities that we also offer to our participants. CT imaging, CPET, body composition scanning, and many more.
  • This shows the course of our enrollment activity so far. In TRIIM we had 9 people, the target for TRIIM-X is around 80 people. So far we have about 23 people enrolled, 5 of them women. The enrollment is interesting and challenging experience for me because it is a very customized hands-on kind of treatment protocol.
  • Since the trial is so personalized with a lot of practical overhead with dosage and testing and reporting, we had to figure out ways how to handle that, such as a uniform schedule over the week for all participants.
  • In general, some people report feeling younger, leaner, more energetic. Some joint pains were reported, but nothing that would make them lower doses or drop out of the trial. No dropouts due to side effects. Very intelligent volunteers. Some volunteers are asking for more assays. We have many biohackers who flood us with lots of their other data, but also not so healthy people, very different ranges, so it is a learning experience to look after everybody.
  • Now I am going to show some preliminary results – keep in mind that we are only 6 months into the trial and that’s just for the first 3 people in the trial, most people are in it for less than that and we have a year to go to finish the first cohort, and we’ll have a year to go after we enroll the last cohort. So our final results are going to take years to come in, but some of the preliminary results are interesting enough to share. Some of them are expected based on TRIIM, some of them new and unexpected.
  • Expected and replicated effect on CRP – preliminary evidence seems to hold the anti-inflammatory effect. The three first time points are baseline reports before the treatment began. After the vertical dotted line are the results after the treatment began.
  • Expected and consistent with the TRIIM result – improvement in kidney function measured with eGFR.
  • Expected and consistent with the TRIIM result – prostate health measured with PSA.
  • A new result we’re seeing in the preliminary data is reduction in triglycerides. What we would expect is that triglycerides go up with the start of the treatment as fat is starting to be broken down and they would go back down again after this process is finished, so we’ll have to see for results from more people. But it is something we will be watching to see whether there are subpopulations of people that react this way in the trial.
  • Another new result is reduction in LDL-Cholesterol. Seems like an encouraging sign that we might be improving cardiovascular health at least in a subset of our population.
  • We’re finding this new effect independent of eGFR on BUN. This is intriguing because my interpretation is that it is a possible anabolic effect. You’re taking nitrogen out of the blood and putting it into tissues, you’re building up your lean body mass. BUN is a consequence of amino acid turnover and breakdown, it is a waste product of amino acid metabolism and to pull it out of the bloodstream independently of urinating it implies that it’s going into new proteins. Early, but intriguing.
  • Another finding I was very interested in is an improvement in lung function. Lung function gets worse with age, these results show the CO2 level actually going down pretty quickly with the treatment, which is a good sign. It is possible that we’re actually observing improvement of pulmonary function. That would be very exciting addition to the list of benefits of the TRIIM treatment.
  • We also had an opportunity to look at how long does the epigenetic reversal from TRIIM last. We saw with TRIIM that 6 months after the treatment in some people there was some backsliding and catching up with the chronological age. But based on the retroactively calculated PhenoAgePlasma, calculated from TRIIM patient who joined TRIIMX as well, we see net reduction in epigenetic age of 4.2 years, that is 6 years after ending TRIIM treatment. That is encouraging, and implies that the effect may actually last for a while. But it is only PhenoAgePlasma, not all the methylation clocks, and N=1, so just a preliminary analysis.
  • Based on PhenoAgePlasma which we are now doing in real time, aging reversal seems to be happening again. We are seeing the PhenoAgePlasma reversing almost instantly after the treatment which is pretty interesting, because generally people do not respond that fast, so we’re probably going to be seeing different patterns of response among different people.
  • In conclusion, things are going pretty well based on the preliminary data. Final data will take a few years to get published, but I’d rather have preliminary results like this than those that don’t.


Do dogs have their special growth hormone with a different sequence?

  • Presumably they do, and it’s a key question, because I am also working with different people on dog aging intervention study, and since we don’t know how to get the dog growth hormone in any serious way, we are not thinking of running a TRIIM study on dogs right now. If anybody has ideas around that, I’d like to hear them. There have been studies when human growth hormone has been given to animals, but that will probably have side effects and is most likely not the way to go.



Do you think that Metformin and DHEA are so good that even if you don’t have an insulin problem it would be a win or is it mostly because of those anti-insulingenic features treatments?

  • I know that DHEA has effects that are in addition to its anti-insulin effects, Metformin may have as well, but Metformin was particularly developed to be anti-diabetic drug, so that’s probably it’s major feature. There is one study that indicates that DHEA can lower insulin, but in most studies it does not – it lowers it only when insulin is raised by GH. That is not a coincidence, when we’re young, we have plenty of GH and we are not diabetics, I think the reason for that is that we also have a plenty of DHEA. So by combining the two DHEA naturally and physiologically opposes this diabetogenic effect of GH. Metformin is there just as a general purpose insulin sensitizer without any built in physiology behind it.




Is IGF-1 the same across mammals?



Does GH increase insulin without increasing blood sugar?

  • It’s a matter of degree. First thing that happens is that insulin goes up. If you keep increasing the dose of GH, eventually the increase in insulin is not enough to overcome the insulin resistance that’s induced by the GH and at that point your glucose can go up as well. So both of them will go up in that case but it is a matter of dose.



With the cohort being biohackers, are you controlling for other treatments (e.g. NR, rapamycin, fasting) or letting participants continue these and tracking possible additive effects?

  • Yes, that’s an ongoing issue with a lot of people – some people are taking mass quantities of NR, NMN, Resveratrol. Constant tension between what we’re trying to do and people doing caloric restriction (CR) even though they are really skinny. With our trial, CR doesn’t really make sense because we’re trying to grow you, build you up, increase your lean body mass, give you new cells in your thymus, and that’s all inhibited by CR, which is immunosuppressive in humans. On the other hand, we don’t want to deprive people of the benefits, so we are working with people on their regimen and trying to balance this.



Do you think cycling would make more sense in this case? Cycling of autophagy, cycling of GH and CR mimetics rather than simultaneously do all of that?

  • Yes, definitely, you really don’t want to do CR and TRIIM-X simultaneously. It does not make sense. CR is good, but thymuses are good too. Cycling regimens makes more sense, you should want to use your time in TRIIM to maximize your TRIIM benefits. If you take your body out of CR for a year, you are not going to age by more than a year, but you are actually going in reverse with TRIIM. CR slows aging, TRIIM reverses it.



If 4x weekly dosing causes some degree of GH resistance, how might the protocol be adapted to once-a-week or twice-a-month GH dosing with regard to the combination protocol? In other words, do you think that metformin and DHEA might be best given on a different schedule than the intermittent GH? Speculations?

  • The real question is whether to give Metformin and DHEA when you don’t take GH? Most likely yes, I don’t see any good reason not to. There are some hazards but they are the same whether you’re taking GH or not. So we ask people to take them simultaneously, mainly to make it as easy and cost efficient as possible. Some people are taking these things more frequently and some not, and based on that we’re beginning to reconstruct some information on which way most people should go, but we’re still in the process of figuring that out. But your point is well taken that we’re using Metformin and DHEA for specific reason in our protocol and that is to block diabetogenic effects of GH, but they have independent benefits as well so it makes sense to take them other times as well. We’re gonna have a lot more information about that later.



Will investors support clinical trials on drugs that are off patent? Why or why not? Your Stanford colleague Susan Athey (economist) has done work on this issue.

  • Two major ways to address that issue. The first is to create new pharmaceuticals and the second to create workarounds that do not need the high-cost items. We work on both of those, we do a fair amount of work to find alternatives to GH which is the expensive part of our cocktail. So far we are not satisfied with the results and therefore are not ready to go down that path yet. But there is another way and that is to make the growth hormone ourselves. It might be off-patent but every time you make a new variation you have to go through the FDA approval process. And GH is not perfect, there are certain features and ways to improve GH without changing the molecule itself – just changing the stabilizing solution that GH is in for example – that would allow a new patent, which would reduce cost by ~5x and be superior to now available GH. If we can do that, we will own that version and we will have a massive advantage over potential competitors and to our treatment clients. So that could unlock the door to get the treatment to tens of millions of people, because it will be much much much more affordable. That’s a major thing of interest for us, it helps that I am a cryobiologist preserving proteins in my dayjob, and I have some ideas. But we don’t have that much money in the bank to do it fast, but we are working on it and are in talks with a few people. So that’s the future of our company.



Are you looking for investors right now?

  • Yes, but it is sometimes problematic because of the IP. We’re growing our company by organic growth, even though this is a trial, we’re allowed to make a small margin for each person on the trial to have our administrative needs covered and we’re actually demonstrating that there is a market for this product despite the high cost. So we have a way forward with organic growth that would eventually lead to these new products I was discussing.


Does growth hormone stimulate growth of some features like nose or ears (that grow with age), and cartilages everywhere, and if yes isn’t it a concern as this therapy would likely need to be taken permanently or semi permanently? Is it something you measure in the trial?

  • Time will tell on that, but we haven’t really noticed anything like that. Interesting thing is that even though all of the evidence shows that we are reversing aging, so far people are not looking facially much younger even when they get epigenetically younger. So we may get there, we have ideas, but so far we didn’t notice getting noses, ears, hair worse or anything like that.



Are you gathering daily facial pictures? It is interesting for aging, but even more for what was asked in the previous question.

  • We have taken a lot of photographs of people and hair at baseline, yes. And we will continue to do so throughout the trial.



You mentioned eGFR going up, implicating improvement in renal function. Would this protocol be appropriate and compatible for someone with a kidney transplant – and immunosuppressed – to extend transplant life? If you could extend transplant life for a year, you could get a financial benefit out of Medicare, so potentially a financing opportunity?

  • All kinds of ways how these things can intersect. Considering the cost of TRIIM-X for all the protocol and monitoring which is like 18k a year – pretty expensive for most people – but transplants are like 500k a year, plus dialysis a year which is more than 18k a year, so if we could marry these together, the cost aspect becomes negligible. So that’s one aspect of it. Another aspect is that GH seems to benefit kidney function, so if your transplant is not up to speed, we may even compensate for that deficiency. Then there are two competing approaches that have to be factored in. The first is that there might be some tension between regenerating thymus and immunosuppressants – it might accelerate transplant rejection, which would obviously be a problem. The other consideration would be the “thymic magic” aspect – the thymus has two jobs, manufactures cells to destroy enemies, and manufactures cells that do not destroy self (thymus). The second aspect is really interesting, because if you have a decent amount of thymus, you could re-engineer thymus to accept any graft and accept it. This has been shown in any animal model of transplant there is, and it always worked, including in large animals. And it seems like something that could be doable in humans, based on what we saw in TRIIM. We saw we are able to regenerate the thymus, that means there is some place to do this engineering work on, it involves a minor surgical procedure to introduce the right antigens into the thymus, but once you do that, you give it a few months and your transplant rejection should be eliminated for life. You can go off immunosuppression for the rest of your life and keep that kidney as if it was from your identical twin, which means it will last for 25 years instead of 5-10 years. And it gets better then that, because you could use the same process and technology to cure all autoimmune diseases by reprogramming the thymus and deleting the cells that are attacking yourself. This has also been tried and proved in all animal models, but haven’t been tried in humans. This is another multi billion opportunity. Somebody needs to do this and we’re gonna do it if nobody does. I run this company called 21st Century Medicine during the day where we have a lab with pigs where we can test this with little overhead and cost.



Do you have an investment number for those investor individuals among us?

  • We’re looking for at least $1M, but of course $5 or $10 would be great.



We all want this to work, I just wanna make sure that we’re not biased in how we interpret the data. Do you feel good that these preliminary results are representative of overall performance as opposed to something that you (unconsciously) cherry-picked?

  • At the end of the day you have to analyze the data. I am aware of the potential bias, but I am not aware of it right now. I’ve been very impressed with the leukocyte / monocyte ratio result in TRIIM. Partly because of the story it tells between what we’re doing and NAD. That if we increase the leukocyte / monocyte ratio by reducing CD38 positive monocytes, then we should increase tissue stores of NAD and we should rejuvenate the body and get the results that we are seeing. We have highly statistically significant results about this. There is this bizarre aspect of it though, that you don’t see this ratio with ordinary techniques and normal instrumentation, we see it only with these ultra sophisticated techniques that are used at Stanford – I am still trying to figure out how is it actually possible, we need to look into that. And by the way as far as the epigenetic aging reversal is concerned, tests and calculations are done by Steve Horvath, and he is the last person to be biased in this respect. As far as the preliminary results go, I showed you the favorable and didn’t show the not as favorable, but we’re so early in the trial that we’ll have to see with more data. What I’ve shown has basis in other results, so I think that it is right. But again, we’re less than 6 months in the trial, we’ve got probably another year and half to go before we have all the data in, a very limited amount of people, so take it as really very preliminary. I am not seeing any red lights, more of favorable things, globally.



Is there a structure that allows the trial to be self-funding? So anyone who wants to join the trial can join, pay for all the infrastructure costs and you deliver the therapy?

  • Yes, TRIIM-X is that kind of study. Everybody in the trial is paying their own way – this leads to very committed volunteers. We are able to make a little bit of margin to keep us alive as a company. It’s all allowed and approved by the FDA and IRP. The beauty of this mechanism of funding is that we don’t have a limit of the people in the study as long as we can deliver it, up to some administrative point. At some point later we’ll have to turn it into something else than a study, however that is a long way ahead of us. But this mechanism functions so far. Actually that’s another thing for investors to participate in, people don’t want to pay for being controls, so that is something we could use the money for as well.



What can this group help you with?

  • Tell your friends that TRIIM-X is open for enrollment, we keep the things going by enrolling more people. It’s our only source of income and knowledge. So anyone who is interested in the trial and is able to invest $18k into it – which is pretty steep I know, we’re working on it – will be appreciated.
  • Tell your investment friends about TRIIM-X as well, just in case they might be interested in some of the things we’ve talked about, be it the GH alternative or the bioengineering and thymus reprogramming aspect.


Seminar summary by Bolek Kerous.