Can We Cure Aging In The Next 12-15 Years? | Ep. 358
In a 45‑minute conversation, Dr. Jeffrey Gladden interviews renowned biogerontologist Aubrey de Grey about the current state and future trajectory of longevity research. De Grey frames aging as a societal crisis comparable to COVID‑19, arguing that a coordinated, rapid response could dramatically accelerate progress. He emphasizes a systems‑biology, divide‑and‑conquer strategy that classifies age‑related damage into seven categories (cell loss, senescent cells, hyper‑proliferative cells, mitochondrial mutations, intracellular waste, extracellular amyloid‑type waste, and extracellular matrix loss) and contrasts this with the evolving “hallmarks of aging” framework. The discussion surveys the clinical pipeline—stem‑cell replacement for Parkinson’s, senolytics, telomerase gene therapy, heterochronic bone‑marrow transplants, rapamycin, OSK/Yamanaka factor reprogramming, IL‑11 antibodies, CDK42 inhibition, oxytocin + ALK5 inhibition, and MSC‑derived exosomes—highlighting which are in trials and which remain pre‑clinical. De Grey describes past mouse combination studies (four interventions plus rapamycin) that achieved only modest lifespan extensions, leading to a new planned eight‑intervention trial aimed at “robust mouse rejuvenation” (doubling mouse lifespan). He argues that achieving this milestone will provide the data needed for human longevity escape velocity. Funding is identified as uneven, with many resources flowing to low‑hanging‑fruit approaches while harder‑to‑target damage categories remain under‑invested. De Grey advocates leveraging high‑profile influencers (e.g., Joe Rogan, Kim Kardashian, MrBeast) to mobilize public demand and push governments to relax regulatory barriers, noting that experts rarely give concrete time‑frame predictions, which hampers credibility. Finally, he shares his personal longevity regimen—avoiding unnecessary risks, extensive biomarker monitoring through Human Longevity, and targeted interventions—illustrating how high‑resolution data can guide individualized therapy. The interview ends with a call to action for listeners to stay informed and support the quest to make 100 the new 30.
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My standard slogan these days is that our goal is to make aging the new COVID. I want us to take aging as seriously as we took COVID 6 years ago. You can argue that mistakes were made here and there in terms of how this whole thing was done, but the point is humanity got its shit together. We have this new problem. We're not in favor of COVID We'd like it fixed as soon as possible, please. Multiple vaccines were developed and globally distributed in less than a year. World record fastest that that had ever been done before for any vaccine for anything was 10 years. An entire digit we've taken off the timeframe.
Hey everyone, Dr. Gladden here. I just finished a conversation with Aubrey de Grey, and we had a nice chat for about 45 minutes. Uh, he was updating me on his thoughts around longevity, some of the, uh, new technologies that are coming around, studies that he's planning to do, how he's seen the field evolve. You're gonna find this a really informative and interesting conversation, and at the end, he's gonna share the things that he's doing for his own longevity.
He went from saving hearts as a cardiologist to rewriting the entire aging playbook. Dr. Jeffrey Gladden believes 100 is the new 30, and he's got the science to back it up. This is the Gladden Longevity Podcast.
Hey, Aubrey. So great to see you again here. Gladden Longevity Podcast. Appreciate you taking the time.
Absolutely. Glad to be back.
Well, great. Bring us up to speed a little bit. As I think about the longevity space, it seems to be moving at almost an exponential, exponential rate. at this point in time, just in terms of the number of things that are being discussed, talked about, data's coming in, et cetera. I'm just curious to get your take on the field and where you see it at this point in time.
Yeah, well, I mean, I certainly agree that overall the field is moving a great deal faster than before. There's a lot more money, a lot more people that are involved. So that's all great. Certainly the conversation around the topic has improved a lot. You know, the kind of things that you and I say are no longer ridiculed. They are treated with sounds foreseeable rather than science fiction. My, you know, joy at all of that is always a bit tempered by the knowledge that the increase in interest and money and so on is extremely unevenly distributed.
Mm-hmm.
There is a huge subset of the field which remains, you know, very, very badly underfunded and for which lack of funding is undoubtedly slowing it down. And if anything, that has actually become worse in the past decade because the kind of people who were, you know, trusting people like you and me to know how to spend money and who were just basically giving it away, you know, giving it to my nonprofits, for example, are now in the position where they have the option to invest and actually make money back. Mm-hmm. And often those people, you know, just like most investors, anyone who wants to make money, they tend to want to make it tomorrow. And so there's an enormous shift in bias now towards the areas that might be described as low-hanging fruit at the expense of areas that are more difficult, but that are just as vital for getting to the real finishing line.
Yeah. So I think it's a good point that you make. There's so many startups now in the long, quote unquote, longevity space, all of them with, you know, at least on the surface, interesting technologies and some interesting early data and some encouraging results and things like that, all of which is, you know, helping to fan the flames of the fire of people You know, getting excited about longevity. That being said, I think one of the things that you've always been a proponent of is is the basic science and the basic understanding. You know, essentially, how do we slow down this? And the way that we've evolved in our thinking, which will probably resonate with you, is we see it more as a systems biology approach than a particular thing. And so, in our practice now, with with what we're developing here, we're we're developing a systems biology approach to be able to deconstruct and understand the individual. And from that, identify what we're calling the elegant solutions to go in and bring the ecosystem back into harmony, youthful harmony, if you will, with inputs that have the greatest impact. And we're not trying to take 8,000 things or, you know, that kind of stuff. So in order to do that, however, the basic science and understanding of what's causing this and driving it becomes really critical. And, you know, you've written quite a bit in this area. You've thought about this a ton. You've done research in this area. Maybe you can outline for the audience how you see these hallmarks of aging or other factors that are actually— how they're synergizing, working together. What's actually driving all of this from your perspective?
Yeah, big question. So first of all, let me stress what I fully agree with in what you just said, and then some areas where I would give a different emphasis. So I fully agree that this is a systems thing, that the only way we can make progress here is by acknowledging that The body consists of a vast number of processes that are interlocking, that talk to each other.
That's right.
And that aging is no different, that the various types of accumulation of damage in the body at the molecular and cellular level influence the rate of accumulation of each other. So the right way to go about this, especially these days when we only have, you know, rather limited tools to postpone the health problems of late life, is to optimize those tools for the, for the individual. And of course, you and other knowledgeable physicians in this space have been very careful to emphasize how important it is to do that personalization. This is especially true, I would say, because of course, anti-aging medicine or longevity medicine or whatever we like to call it is overwhelmingly preventative. We are seeking to treat people who are not yet sick and who, you know, we don't know how soon it's going to be before they get sick, but we do things to increase that period, to increase healthspan. And of course, to increase lifespan as a kind of side effect of increasing healthspan.
That's right.
One thing I wanted to come back at you on a little bit here is the role of basic science and of understanding. Because if one were to treat the problem of aging as one that one really needed to understand well in order to be able to do anything about it, then one could not be anywhere near as optimistic as I am in terms of timeframes for how soon we might make really dramatic progress in extending healthspan and lifespan. I believe that the only reason it's possible to look at this crusade as having a good chance of success within the next couple of decades is because we are likely to be able to make a really big difference even with a very poor level of understanding. I always like to look back at what happened 200 years ago with, or 150 years ago anyway, with the early parts in the invention of modern medicine, the discovery by, you know, for example, Edward Jenner, that you could vaccinate against smallpox, you know, the discovery of the germ theory by Pasteur and such like. You know, these were people who saved the most insane number of lives. But what they were doing was they were manipulating this thing that we now call the immune system, which even today we have a really poor understanding of. And they had, of course, a tiny fraction of the understanding back then that we have today. And yet they were able to have an impact, a huge impact. So we have to ask why, and of course the answer is that the body is on our side. The body is constantly trying to not get sick and not stay sick and to keep us going. And the only reason we get health problems in late life is because the tools that the body has with which to do that, however you know extraordinary and impressive those tools may be, they are not 100% comprehensive. And there are some types of molecular and cellular damage that accumulate anyway because. The body doesn't have tools to stop that from happening. So given that the body's on our side, I feel that it is reasonable to expect that we can have a pretty big impact, a very big impact in fact, on aging without understanding it all that well. In fact, we may already understand it well enough. It may be just that we haven't really embraced the possibility that we understand it enough to the extent of using all the tools we have. And we can come back in due course to the kind of work that we're doing along those lines in at LEV Foundation. But yeah, so I mean, just a month or two ago, actually, I was on stage with Jamie Metzl. You may know him. He expressed pessimism with regard to the kind of timeframes that I talk about, you know, bringing aging under really comprehensive medical control within the next maybe 12 to 15 years from now. And the basis for his pessimism was, well, we understand very, very little about aging, you know. Maybe, you know, single-digit percent of what, of what we could understand in principle. And he and the audience were quite surprised when I fully agreed with him. But when I pointed out that the timeframes are not based on just that one number, but also on 2 other numbers, one being how much do we need to understand, and the third one being how rapidly are we increasing that understanding. And I basically, I said basically, well, it may be that actually the amount we need to understand is no more than what we already understand, and therefore we may be Quite likely to move forward. But of course it remains to be seen. We will have to do quite a few studies in order to see whether we really can use what we already understand to great effect.
Yeah, I think it's an interesting point you make. We're always working with partial information. You know, as a physician, we're always working with partial information. And yet, you know, when I was doing the interventional cardiology work, I found that when I had more information, more precise information, I could always get a better outcome for an individual if I understood the artery better, the, you know, the, environment, metabolic environment, etc. And so that kind of mindset of driving to understand what's going on is, you know, really at the heart of medical exploration. But to your point, we're always going to have partial information to some extent, maybe, maybe 50 years from now, we will have full information. The interesting thing about the body is that it has a million different or millions really of different inputs into it, but it has a limited number of responses. Right? It has a finite number of responses. And so if we're able to understand what's the status of those responses, and we can link that to maybe an input that needs to be shut off or turned on or whatever it might be, I think that kind of partial information is helpful. And then if we do understand what are the body's responses to things, right? It's inflammation, it's oxidative stress, it's decreasing mitochondrial output, you know, in the face of an infection, it's all these different responses that we, that we're familiar with, then it seems like, to your point, we We may know enough to actually make a big difference. And to that end, if, you know, what are the things that you think we understand well enough to make a big difference in now?
Right. Well, yeah, let me go into a few of the details on that. Because basically, you know, I agree with what you say. Certainly, the more we know, the more effective our treatments are going to be. And that's the question of the extent to which that reaches diminishing returns, whether we can get, you know, good enough with a certain amount of knowledge. But I do want to distinguish between information and understanding. Totally. You know, the information part is really important for what we were mentioning earlier about the personalization of medicine, so as to optimize our tools to work as well as possible for a given individual. But, you know, in the same way that scientists often talk about how we are— how it's important to distinguish between correlation and causation, you know, mechanistic stuff, causation, is what I would call understanding. And sometimes we don't need actually, um, you know, clear, a clear mechanistic understanding. We can get away with correlation just as long as it's reliable. Um, so what do I think? Where do I think we are at this point? Well, I mean, the great thing about, and well, the good thing and the bad thing, I guess, about the situation with aging right now is that it is so multifactorial. And of course, as it has always been the case, we Have, you know, this portfolio of different problems to fix, different types of damage to address, and some of them are easier to address than others. Way back 25 years ago when I started talking this way and thinking this way, I was really clutching at straws in many cases in terms of identifying and describing ways in which we might fix this or that type of damage. That is certainly no longer the case. There are types of damage that we are now in a position to take not only to the laboratory to work on, like model organisms like mice, but also to take to the clinic. I guess the most conspicuous examples right now are, first of all, stem cell therapies. Of course, stem cell therapies fall into a number of categories. One can use allogeneic stem cells, for example, or indeed just the extracellular vesicles that they secrete to achieve various types of rejuvenation. But the original goal of stem cell therapy was to actually replace cells, to cells hang out long-term and, you know, obviously divide and differentiate to replace cells that the body was not replacing on its own. And I would say that for sure, the most conspicuous example of that right now is Parkinson's disease, which has always been kind of the poster child for this because it's definitely caused by the loss of a particular type of neuron.
Mm-hmm.
There are now 5, if I'm not mistaken, clinical trials going on around the world using precisely stem cells for replacement of dopaminergic neurons and thus restoration of dopamine secretion. And everyone's pretty optimistic. I don't know if you know the original story of that work started 35 years ago or so in Sweden, where people tried this. Of course, back then they knew zero about how to manipulate stem cells in the laboratory in order to have them be the right kind of stem cell. So instead, what they did was they got cells out of aborted fetuses that were from vaguely the right part of the brain, but it was very vaguely. So 90 or more percent of the time, there was no benefit whatsoever.
Yeah.
But on a few cases, the few cases that did respond, the response was Extraordinary. Literally, you know, they could go off L-dopa immediately and no symptoms at all for like more than a decade. So now, of course, now that we have that technology to manipulate stem cells, we are very optimistic. The other example I would say is senolytic cells, drugs that selectively remove senescent cells. Even the early first-generation senolytics like dasatinib and quercetin, you know, are effective enough that they have now moved into clinical trials. And, you know, a lot of other more sophisticated and more specific alternatives genetics analytics are well on the way to that. So I would say, you know, we're really looking— it's looking awfully good. There are other areas that in clinical trials in a more limited way, earlier stage, you know, maybe a little more experimental. For example, one of the spinouts from my previous foundation has a clinical trial going on right now in Australia for atherosclerosis, which works— which is a treatment that involves extracting oxidized cholesterol from the arteries and thereby essentially allowing macrophages to recover their function and to reverse cholesterol transport in the way they used to be able to. It seems to be very promising. So, so we'll see how that goes. Another trial that's actually also going on in Australia, obviously Australia's a fantastic place to do early-stage clinical trials these days, is on my favorite anti-cancer therapy, which is a method that essentially rapidly kills any cell that's expressing a high level of telomerase. So of course that means 90% of human cancers. That's also going really well. So, yeah, I mean, there's plenty of good news out there. But then, there are also things that are not even working in mice yet. So, as I say, very unevenly distributed in terms of progress and in terms of enthusiasm from the people who write checks.
Yeah, exactly. Yeah, there's things going on with mitochondrial function also. I know that that's pretty interesting. People are now transplanting mitochondria, doing some other things to rejuvenate mitochondrial function. And, to your point, there seems to be an interplay. I've been impressed in the work that we've done here that rejuvenation is not really a procedure or a thing. It's actually a process.
Very good way of putting it.
Right. Yeah. That you've actually gotta prepare an individual, then you've gotta apply the therapy, and then you need to support the therapy afterwards. And many times, um, it starts with taking out the things that need to be taken out of the environment, so to speak, before you clean up the, the internal milieu and then go ahead with the other procedures. But I think if you're listening to this, if you think about optimization, longevity, itself as an ongoing process and not, oh, I'll go get a stem cell injection and then I'll be young again, right? I think, or I'm going to take senolytics and then I'll be young again. All those things actually work together and they work together in sequence and they work together in cycles as well, right? So you may do it this year, you may do it again next year. So I don't know if you want to comment on that in terms of what you're seeing out there.
Well, I completely agree. I mean, of course, as you know, my work and my team's work in this area focuses on mice, not on humans. There we have the very interesting situation in which The crosstalk between different types of damage accumulation is very substantial. That is why we can observe, and many other groups have observed, very significant life extension in mice that you do nothing to at all until they're already in middle age. Then you do a bunch of things, and they benefit. But the point is, even if you do one thing, like for example apply a really effective senolytic, you can actually see life extension. If you apply OSK, the Yamanaka factors, to reduce Certain tissues, then again, you know, significant life extension just from one thing. The only reason that that makes any sense, the only reason that could be possible, is if removing one type of damage, if you like, relieves the pressure on the inbuilt anti-aging machinery that I was mentioning at the beginning.
Yeah, it slows down the flywheel, right? It slows down the flywheel of aging.
Yeah, yeah, yeah. So yeah, we're going to see more and more of that. I would say yes, absolutely. We need to be applying these things in parallel with each other, and of course monitoring the impact so that we know which ones to. Emphasize. The only thing that's really missing right now is the comprehensiveness of the portfolio of interventions that we have. You know, as you know, focused on the more neglected areas of this field. They're just as important as the less neglected areas and they need to catch up. And that's still a big problem.
So when you're working with the mice, I know that you're— the last time we spoke, and maybe this is still true, you were looking for additional funding to bring in to run another mouse trial that you've envisioned doing. And maybe you could bring the audience up to speed on the first mouse trial and kind of what you did there, what it showed, what the second one is going to look like. And then maybe also comment on what we were just commenting on, the fact that, you know, stacking together, layering, interdigitating, sequencing, whatever terms we want to use, different interventions can be sometimes more than additive.
Yeah, totally. So we're not even really looking for more than additive. Additive would be quite enough. So, yeah, so, so going back, so of course, the whole The strategy of addressing aging that I have propounded and pursued over the past 25 years or more is a divide-and-conquer one, where I classify the various types of damage that the body accumulates into a manageable number of categories, just 7 categories.
Why don't you rattle those 7 off, if you don't mind, for the audience?
Sure.
Yeah.
I mean, I will rattle because I've talked about those in depth on many occasions. But yeah, so loss of cells, Such as the example I gave earlier with Parkinson's disease. Accumulation of senescent cells, I mentioned that. Accumulation of cells that divide too much. So of course that mostly refers to cancer.
Mm-hmm.
Then accumulation of mitochondrial mutations, mutations in the special DNA that's inside the mitochondria. Then accumulation of waste products in the cell, such as oxidized cholesterol that I mentioned a moment ago. Then accumulation of waste products outside the cell, typically something called amyloid, which comes in various forms in different tissues. And then finally, the loss of elasticity of the extracellular matrix, this lattice of proteins that gives our tissues their physical properties. Yeah. So, um, with a divide and conquer strategy for anything, there's 2 phases. First of all, you have to develop the ways to, um, you know, the individual components, and then you have to put them together and get the overall result that you were hoping for. And in engineering, typically, you know, that second part is the easy part. If the bits work, then you can be pretty sure that the assembly is going to work. Overall, but in medicine it's not like that whatsoever because you we're seeking to manipulate a system that we have, as I mentioned earlier, a very poor understanding of, and therefore you can expect to get surprises, some of them bad surprises, at that second phase. So I've been desperate to get to that point since forever and ever. And of course, you don't necessarily have to get all the components in place in the case of medicine because of this crosstalk we mentioned earlier, and the same applies in mice. So if we get some of them working, then it's worth having a go. So what do I mean by working? What I mean is. demonstrating life extension individually. And as I say, this does happen in mice. So, come about 2022, we were in a position to do the first-ever experiment of this nature. We took 3 damage repair interventions. Firstly, telomerase gene therapy to extend the telomeres. Secondly, a senolytic. And thirdly, heterochronic bone marrow transplant. So, we gave old mice some bone marrow stem cells from young mice. Wow. And on top of that, we had a 4th intervention, which was really a positive control, namely rapamycin. So rapamycin is not a damage repair approach. It's a calorie restriction mimetic. Basically, it tricks the body into thinking it's not getting enough food when it is. And we know the thing is, the thing about calorie restriction, and therefore by extension also mimetics of calorie restriction, is that they're really effective in short-lived animals, but they really don't work worth a damn in longer-lived species. This has been for a very long time. So it's definitely not the way to go if we really want— not on its own anyway, if we want to make progress. But it's a useful, as I say, positive control for laboratory work. So all of these things had been shown to extend lifespan individually a little bit. And we thought, well, okay, what we want is to see whether we can get an additive effect, whether if we put them all together, we can get more benefit. And the great news is that that is what happened. The study ended about 18 months ago, and we indeed got an additive effect.
How big an effect did you get?
Well, I'm going to come to that in a moment. It was a bit clearer in female mice than in males, but it was clear. All right. But you asked the exact right question. How big was the effect? And that was where we were disappointed. We did not get an effect that exceeded what you can already get with rapamycin on its own, or indeed with caloric restriction on its own.
I see.
And that's what we're aiming for. Many years ago, I actually specified a kind of arbitrary threshold that we want to achieve with all of this. I call it robust mouse rejuvenation. So, to put numbers on this for your audience, typical mice, healthy mice, will live about 2.5 years on average. So our treatments, as I say, we start in middle age. So we start when the mice are already 18 months old. So they've got a year to live. And my arbitrary threshold was, we want to double that. We want to take them out by a whole year, a whole 12 months more than what they would Normally live. Now, for kind of context, calorie restriction started at that kind of age will typically give you about four months. So we're seeking to treble that effect size. And rapamycin gets more or less the same—a little bit less, maybe. All right. So we did not beat the four months. What does that tell us? What does that leave us as the next step? Well, to me, it was very clear at once that what we need to do is simply throw more of the kitchen sink at the problem. In other words, see whether we can get to twelve months or even eight months by pushing a lot more things together—not just. And the thing is, back in 2022 or so, when we were first formulating this study, that was just not possible. Or rather, it was possible only if we were more relaxed about the criteria for inclusion of a particular component. It wasn't— we just didn't have enough interventions that had been shown by anybody to extend lifespan individually.
Hmm.
But during the course of our first study, that changed a lot. A whole avalanche of new studies came out. with new ways to do this and ways that were not caloristic mimetics. As I say, we kind of want to avoid those because they're not going to translate. And so now, yeah, we're almost spoilt for choice. The study that we have currently designed that's been waiting for funding is with 8 interventions. Again, not including rapamycin. We're going to use rapamycin again as a positive control in broadly the same way that we did last time.
What are the 8 interventions you're looking at?
All right. Well then, so first of all, we could, of course, reuse some of the original But, we're so spoiled for choice that we're deliberately not doing that. We're going to use new ones. Alright. So, the first one is OSK, the Yamanaka factors.
So, Yamanaka factors is epigenetic reprogramming of cells that was developed by Dr. Yamanaka and somebody else actually in Japan. I think they got the Nobel Prize in 2008 or '12 or somewhere in that ballpark.
The study was published in '06 and the Nobel Prize was 2012. That's right. Yeah. Incidentally, coming back to one of our earlier topics, The first author on that, it was just a 2-author paper for just an enormous amount of work. Completely astonishing. The first author of that, Jun Takahashi, is actually the PI on one of the Parkinson's trials that I was mentioning earlier.
Okay. This is where, just for the audience's sake, this is where the induced pluripotent stem cells showed up, where you could take a skin cell and turn it back into a stem cell by using the Yamanaka factors to make it young again, so to speak.
Yeah. So actually, you know, paradoxically, Takahashi is not using iPS cells. He's doing a genetic treatment. There's only one of these, I think, 5 trials that are going on right now that is doing an autologous approach. And that's Gene Loring's approach at Aspen Neurosciences. Anyway, back to the topic. So yeah, one of our interventions is OSK. We're using exosomes derived from MSCs. And there, actually, we still have a bunch of choice. We have not firmly decided what source we're going to use. But there's plenty of reports of really good results there. So we're definitely going to use something along those lines. Then we have a senolytic, but not the same one. We have a senolytic that we believe is a lot better than the first-generation one that we used last time. What did you use last time? We used navitoclax. Actually, not exactly navitoclax. There's a Spanish group that were able to modify navitoclax so that it's no longer toxic to platelets, which is what it normally is.
And what are you using this time?
This time we're using something that comes from an Austrian company named Rockfish Bio, and it works by a very different means. It essentially messes up arachidonic acid metabolism in a way that That senescent cells seem to be very, very sensitive to. So they've got—
Fascinating.
Yes, it is. It's fascinating. They've got really cool results. Yeah. Then we've got a few others. Of course, we've got, let's see. So people showed that you could use antibodies against an interleukin, IL-11 specifically, and that would give life extension, even if you started relatively late. Then another thing that you can inhibit, and this time with a small molecule, is something called CDK42, a cell cycle gene. There's a small molecule called Casin. that modifies that, sorry, that inhibits that.
So explain that a little bit. That's a little garbled, I think, for the audience.
I probably shouldn't try to explain the mechanisms of all of this because, as I say, all of this is published and it would be better for your audience to go to the things. But I can show you, but I have a slide in most of my talks these days which gives the PubMed IDs for all of the key studies. Okay. Just so that everybody could do that. I'll send you that slide so you can stick it in the show notes or something like that.
Beautiful. Yeah, let's do that.
And then there's various others. Oxytocin is another one that we're going to use combined with an inhibitor of something called ALK5. That again has been shown to give nice life extension. You get the idea. It's a wide variety of things that work in very different ways.
So you're combining oxytocin with what again?
Something called AI5, which is an inhibitor of a gene called ALK5. Oh, okay. And again, this has been done before. This was not our idea or anything.
And why leave off the things that are going to improve telomerase activity or some of those kinds of things?
To be perfectly honest, the The main reason why we have made the choices we have is because we're focused on getting as much knowledge as possible per dollar and per unit time, of course. And the last study cost about $3.5 million. This study, we've got a few cost savings, but it's twice the size. So it's going to be probably $6 million. If somebody dropped $30 million on me today, then I would totally do 2 8-intervention studies in parallel, maybe 3.
Wow.
Because we can, you know, because there's enough options out there. And for that matter, because there are You know, questions about dosage.
Yeah, it seems like, it seems like there's lots of questions around that, right? Like what combination, what sequence, what dosing, what duration, what frequency. There could be many, many.
The horrifying thing is that nobody's doing it. There's billions of dollars floating around being used for just a small proportion of the things that are interesting, like Yamanaka factors or senolytics. And, you know, So much knowledge could be gained by doing, by doing this kind of work.
So is it, do you think there's any possibility to do some preliminary work now with the advent of AI and things like that in terms of like in silico kinds of conceptualization of what you're trying to get to, or?
There is, but at the end of the day, it's not a substitute for these laborious and relatively expensive studies. Because the fact is, you know, people often get this wrong, but AI does not create knowledge out of thin air. It creates insights out of data. And so you have to start somewhere. And certainly, you know, the work that has been done, including especially by Insilico Medicine, Alex Voronkov's company, has been extremely valuable and impressive, and it will continue to get better. But at the end of the day, you know, they are working towards clinical trials for particular drugs based on data that they can— especially omic data that they can analyze. My goal is to get results that the public will resonate with. Now, you know, that bears some—
So what do you mean by that? Results that the public will resonate with? What are you looking for? People can look at and intuitively understand it, or?
So not exactly, no. The ultimate thing that I'm looking for is mobilization of society in general. So my standard slogan these days is that our goal is to make aging the new COVID. I want us to be able to take aging as seriously as we took COVID 6 years ago.
Okay.
Of course, you can argue that mistakes were made here and there in terms of how this whole thing was done, but the point is humanity got its shit together and said, listen, we have this new problem. We're not in favor of COVID We'd like it fixed as soon as possible, please. And, you know, I mean, the standard example that I often point out is the sheer time frame that was involved in developing and distributing vaccines. Multiple vaccines were developed and globally distributed in less than a year. And as I'm sure you know, the world record fastest that that had ever been done before for any vaccine for anything was 10 years.
Mm-hmm.
So an entire digit was taken off the timeframe. And the way that that happened, of course, was that governments around the world just tore up all of the regulations and the institutional inertia and everything that they had written at the behest of their electorate, right? Just because they sensed that the electorate didn't want that to be a barrier this time. So we need to do the same thing again. Question is how. And, you know, my personal belief is that it's a kind of domino effect that in order to get governments to do what you want, that's the easy part. They will do whatever they think is going to get them reelected. So we have to change— we have to get the public mobilized. How do you do that? I say that the right way to do it is through the world's leading influencers, you know, Joe Rogan, Kim Kardashian, MrBeast, people like that. Now, the good news is that these people are already really interested in longevity and they don't mind people knowing it. You know, I've been on Rogan a couple of times. Sinclair's been on Rogan a few times, and so on. You know, so that's great. They're one step away from going out and doing the equivalent of Oprah saying, buy this book. All they need to do is say, right, boys and girls, you know, we seem to be at a point where we could bring aging under medical control and save a lot of lives and, you know, alleviate a vast amount of suffering. We really ought to do that as quickly as we can. And once they say it, game over. So the question is, what is stopping them from saying it today? And to my mind, that's completely clear. The thing that's stopping them from saying it is that, with the sole exception of me, the experts in the community that go on these shows are not giving actual numerical timeframe predictions of how soon they think we've got a good chance of bringing aging under control. That's really important. I've been complaining about it for 20 years that my colleagues won't do that, because the fact is, you know. My colleagues go out all the time and they're terribly breathless on camera and on stage about this or that recent breakthrough that they made. But if they don't actually, if they're unwilling, if they refuse to give any kind of timeframe prediction, then there's no credibility whatsoever. You know, everyone just thinks that they're just being breathless in order to seduce somebody or other into letting them carry on playing with their test tubes and they don't really believe it's going to get anywhere ever. So I believe that that's got to change. And here's the important thing. Governments don't give a flying fuck about mice, right? The public don't care about mice either. To be perfectly honest, the influencers don't care about mice either. But the experts do. And here's what I mean by the experts. There are probably several hundred people around the world who are perfectly entitled to describe themselves as experts on the biology of aging.
Hmm.
several hundred people, there are only literally less than a dozen of us who do all that much outreach, who actually, you know, give, for example, a general audience podcast more than once a month. You know, I do about 2 a week, right? There's literally less than a dozen of us. There's me and David Sinclair and Eric Verdin and Nir Barzilai and Brian Kennedy and Matt Kaeberlein and Andrea Meyer and Ava Bischoff, and I can't think of any others. You know, it's like insanely few. And of course we're all good friends. We know each other really well. So I feel justified in my confidence that I know what it takes for them to switch and to say, okay, boys and girls, we are in a different world suddenly as a result of this, of X breakthrough. And that would kind of give them, feel, make them feel safe in going out and doing predictions of timeframes, which might not be the same predictions as mine, but that's okay. Any prediction is far better than none. And I believe that the thing that will make that happen is reaching RMR, reaching robust mouse rejuvenation. So that's why I'm, I'm focused entirely on trying to make that happen.
Yeah. Well, it's, it's interesting perspective and good points. I tend to be very optimistic about being able to link these different procedures together. I think the studies are very important. You know, you're working in the areas that, that you elucidated early on and now have been, you know, kind of expanded further, right? In terms So the hallmarks of aging and things like that.
I should probably say something about the hallmarks since you mentioned them, because yeah, people do often misunderstand this a bit. So the hallmark, the original hallmarks paper came out in 2013. And to me, it was extremely gratifying because to a first approximation, it was a restatement of what I'd written like more than a decade earlier. But I had done the hard work and its time had come. And so people were willing to, willing to accept this divide and conquer approach, this, this classification So, you know, since that time, I have never once had to actually justify that approach to my colleagues, whereas the previous decade was quite a fight, to be honest. But here's the thing, the hallmarks do not really classify the same thing that my 7 Deadly Things classify. I was classifying types of damage that accumulate.
Yeah.
Which was to, of course, align those individual categories with particular approaches to intervention, to repairing the What the hallmarks do is they classify something that's kind of one step downstream of that. They classify the decline in this or that molecular or cellular process that arises from the accumulation of damage. So, for example, I will talk about the accumulation of waste products inside the cell, whereas the hallmarks talk about loss of proteostasis. In other words, decline in the function of protein turnover. And this actually turns out to matter. Because the classification of what happens downstream of damage is very soft. It, it, it, it, it, like, it's constantly having to change. And so it's no surprise at all that the hallmarks have had to be constantly updated. You know, first it was 9, then it was 12, then it was 14, and so on. Whereas my 7 deadly things have very much stood the test of time.
Yeah, I think, I think that's an interesting point too. The way I think about the hallmarks is that they're phenotypic expressions of aging. And then they also play together to accelerate aging.
Yeah, exactly. That's certainly true. Yeah.
However, the damage that you're referring to, what do you see as being the mechanism underlying that then?
Well, this is the beauty of the whole sense approach is that I don't really have an opinion about that and I don't need to have one. Essentially, because damage accumulation is this kind of mediator, it's kind of intermediary between being alive and being dead. In other words, you know, the network of processes of metabolism and the various pathologies that happen late in life. Because it's sitting in the middle, kind of, if we're repairing that damage, then we don't need to have much understanding of the mechanisms of how the damage is created, because we're not seeking to slow down that process. The whole of gerontology before me basically constituted that. It constituted looking at the living world, saying, well, you know, some species age more slowly than others. They kind of run more cleanly and accumulate damage more slowly. Maybe if we understand that really, really well, then we'll be able to translate that understanding into some kind of therapy. And it was all completely unsuccessful. But if you're repairing the damage, if you're intervening one step beyond that, then you can let damage accumulate at the natural rate, which means you don't need to understand how it accumulates.
Yeah, I see what you're saying. However, I can't help Quite honestly, I just can't help myself but to go want to look behind the curtain and think about things like oxidative stress and other things that are actually causing the damage.
Yeah. I don't object to understanding. But, the thing is, if you are seeking to intervene at the level of the mechanisms of damage creation, then the fundamental reason why it hasn't worked is that those mechanisms Whatever they are, and to whatever extent we actually understand them, those mechanisms are just too inextricably intertwined with the things that we need the body to do to keep us alive. Fine example here, because, you know, of course, way back in the 1950s, when Denham Harmon first suggested the free radical theory of aging, he promptly got into the lab and started giving antioxidants to mice, because antioxidants were already, you know, that was already a thing back then. They knew what antioxidants were, free radical scavengers and so on. And they made mice live a bit longer on average, but they— he couldn't extend maximum lifespan at all. And something that is very much neglected that Harmon did after that in 1972 was he was the first person to identify the possibility that mitochondrial mutations could be important in aging as a way to explain what he was seeing. However, a huge part of the explanation which came along later was the understanding that reactive oxygen species are actually— evolution has made the best of a bad job. It's got this ghastly thing called oxidative phosphorylation that creates free radicals. There's nothing that we've done about it because extracting energy from nutrients with oxygen is a very, very hairy chemical process. So, you're going to make free radicals, you're just going to live with them. And so, what's happened is that reactive oxygen species have become woven into metabolism as signaling molecules. Especially hydrogen peroxide. And that means that if you chuck in a bolus of something that scavenges hydrogen peroxide or other free radicals, then the body will not be happy about this. It will want to do something, and it will actually downregulate the enzymatic antioxidant machinery that it already has, and everything will stay the same. Essentially, metabolism laughs in your face.
Yeah.
So that was the kind of thing that led me to— I mean, because this is not new ideas, right? This is something that was generally accepted in the So this is one of the kind of ways of thinking that led me to the idea that, you know, we shouldn't be intervening in this. We shouldn't be trying to mess with metabolism. We should go one step further down the stream.
Well, it's an interesting point. Putting on my engineering hat, I always kind of feel like metabolism can always be kind of fine-tuned, right? Kind of like getting your car to run better.
Well, I mean, actually, no. I mean, I use cars as an analogy all the time, as you know. Yes, let's look at rust. You know, I mean, rust happens. It happens faster in some cars than others, but that's a function of how the car was built and designed. If you want to maintain a car to last longer than how it was built and designed to last, then you don't need to understand the chemistry of rusting. All you need to do is scrape off the rust and get rid of it every so often so that there's never enough rust to make the doors fall off. Right.
Well, yes. Or you could use, you know, something that would protect the door from rust developing in the first place.
Right. Well, that's right. That's how you would build the thing, you know, if you were building the car from scratch.
If we were bringing it de novo. Yeah. What you're saying is we don't have the option to build it de novo. Yeah. It's really an interesting interplay of prevention and repair, right? Because we do know that there are choices we can make that accelerate damage, right? And decrease repair. And so, yeah, quite interesting.
And that's where today's medicine comes in. You know, the area that you're the expert in and I'm not. You know, what we can do today can somewhat optimize what people have. You know, everyone's got their own weak links. I've got the variant of MTHFR that gives you high homocysteine, things like that. And optimizing for those things with tools that exist today, you know, that, that example, of course, is a particularly easy one because methylcobalamin just does it, right? It just fixes the problem. You know, I'm all over that. But of course, we all know that there are— that there's a limit to how much we can do that way. What we really want is something that works far better than anything that works today, however optimized it may be.
I wonder, with this repair model that you're working with, if you go back to the mice, if intermittently treating them with Muse cells or Muse cells and exosomes and some peptides, you know, kind of a nice combination, maybe start with some senolytics and then, you know, kind of clean the system to some extent, put in these things. It seems to me that just like taking care of a car is an ongoing process, it seems like maintaining youthfulness is a process of returning to youthfulness and then maintaining it. And so there's going to be maintenance, right?
Yeah, absolutely. Periodic is the word. Absolutely. Right. Then of course it's slightly more than that because the reason I, well, the thing that led me to come up with this concept of longevity escape velocity was the understanding that at first, When we get treatments that are only fairly comprehensive, but not 100%, it won't really matter how often we apply them. There will still be the let's call it the difficult damage, the damage that the therapies just don't repair, which progressively accumulates and eventually on its own, however however frequently we are repairing the easy damage, we're going to end up having enough damage to make us sick and eventually to kill us. So the whole LEV idea revolves around the recognition that. If we can get maybe 20 years of additional healthy life for people with version 1.0 of this portfolio, this panel, that will be enough time for the researchers to, you know, to hack away at the difficult damage and to shift some of it into the easy category, the category that can be repaired, such that when someone comes in 20 years later and they need to be re-rejuvenated, we can actually do it and give them another 20 years.
Sure.
Now, this of course leads to the rather paradoxical conclusion that we have a pretty good chance of reaching longevity escape velocity for humans fairly soon. But it'll be touch and go whether we ever reach it for cats and dogs. And we definitely will never reach it for mice. Because repairing most of the damage just doesn't buy enough time to figure out what to do next.
Interesting. That's interesting. So I'm curious about a couple things here. One is, what year were you born?
1963.
'63. Okay. And what are you doing for yourself at this point in time with regards to your own longevity program?
I'm doing 2 big things. First of all, avoiding dying of anything stupid. One thing I've said for quite a long time when people ask me that question is I don't accept seminar invitations to dangerous countries. Yeah. Things like that. But the other thing is I get checked up really, really well, partly because of who I am. I've been able to access for free treatments that are really high-end for the past 20-odd years to measure various aspects of my biological age. You know, the usual things, measuring 150 different things in your blood and, you know, cognitive and physical things and, you know, DEXA and CT scans and MRIs. I now get that from Human Longevity, which is a fantastic organization, one of the very best who do this kind of thing. And yeah, I mean, it's really important. It's, it's like, if you, this is one thing that I believe is the number one thing that Bryan Johnson has brought to the table in the, in the few years that he's been so prominent. is he's so strong on measurements. Obviously, he spends $2 million a year on his own. I mean, he has an MRI machine in his house.
Right.
But the point is, even if you've only got $2,000 a year to spend, you can still use it very effectively to give yourself more knowledge about what your weak links are and what kind of things that are available today you can do about those things. And most people, let's face it, will probably only be able to gain you know, a year or 2 at most relative to just living the way their mother told them to and not smoking and not getting seriously overweight and so on. But some people can go more than that because they've got serious weak links that can be addressed. And also some people refuse to live the way their mother told them to anyway. And so, you know.
Sure. Yeah, no, I get that. Well, cool. Well, Aubrey, it's been a pleasure chatting with you. Uh, appreciate coming back on. Yeah, always, always good stuff. I'm sure our paths will cross again, but thank you so much for taking the time.
Totally. How do we live young for a lifetime? How do we make 100 the new 30? The answers are out there, and we're bringing them to you every episode. Make sure you're subscribed. Check out more episodes right here and follow us on social media so you never miss a breakthrough. Thanks for listening.
