Aubrey de Grey on the LEV Foundation

Author(s): Scott Douglas Jacobsen

Publication (Outlet/Website): The Good Men Project

Publication Date (yyyy/mm/dd): 2024/07/30

Dr. Aubrey de Grey is a biomedical gerontologist based in Silicon Valley, California, USA, and is the founder, President and Chief Science Officer of LEV Foundation, a biomedical research and advocacy charity focused on repairing the molecular and cellular damage of aging. He received his BA in computer science and Ph.D. in biology from the University of Cambridge. His research interests encompass the characterisation of all the types of damage that constitute mammalian aging and the design of interventions to repair and/or obviate that damage. Dr. de Grey is a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organisations. He is a highly sought-after speaker who gives frequent invited talks at scientific conferences, universities, companies in areas ranging from pharma to life insurance, and to the public.

Scott Douglas Jacobsen: So, you were started with the LEV Foundation. What is the LEV Foundation? It’s a new project.

Aubrey de Grey: Yes. LEV Foundation is a new nonprofit based in California. As you know, I’ve spent the past 20 years leading nonprofits. This is the third one. The main thing distinguishing LEV Foundation from my previous projects is that its flagship research work involves embarking on the last stage of development of the SENS portfolio.

So, of course, SENS, as I defined it 20-odd years ago, is a divide-and-conquer strategy that says, “Here are the various types of molecular and cellular damage the body does to itself throughout life.” Lots and lots and lots of them, but they can be classified into a manageable number of categories.  The key point about that classification is that it maps 1 to 1 well, 1 to many with the various ways to repair damage. This is not precisely or adequately present in the more recent restatements of this concept, such as the hallmarks of aging over the past decade.

But it’s very important to have this mapping to have these generic approaches to repairing the damage that corresponds to the various damage categories. At the Research Foundation, and indeed before that at the Foundation, I was focused on the individual categories and the individual damage repair strategies, particularly the most difficult ones, because those were not being worked on by others who had different incentive structures and were constrained more by short-termism in one way or another. That’s gone well, although there’s still plenty to do.

However, the easier ones among the categories, particularly the ones that were easy enough that I wasn’t even working on at my previous organizations, have now been taken up by others to the point where they work in mice. One can see genuine benefits when applying these interventions in middle age to mice that have already accumulated some relevant damage. Of course, if you remove a type of damage, there may be a knock-on effect on the rate of other damage types. This may result in a modest increase in health span and lifespan, which has been reported in various cases.

So, coming back to what LEV Foundation does, we are leveraging that. We are taking those techniques and applying them to the same mice simultaneously, starting in middle age, using mice that are not genetically impaired or models of accelerated aging. This is something that nobody else is doing. There are a few experiments combining orally available drugs, which are valuable, but we firmly believe that to defeat aging properly. You cannot eliminate gene therapies, cell therapies, and such, which are not orally available and must be injected.

So yes, we are doing something unique. Our first attempt started about 18 months ago with mice already 18 months old. These mice normally live for about two and a half years; a few might make it to three years if you’re lucky. That’s exactly what has happened to our control group. However, the mice who were getting all four interventions we combined were doing quite well. A third of the subjects are still alive, so we consider this experiment successful. It’s a significant success in males because we genuinely see additive effects. In females, it is not very pleasant. All the benefits we’re seeing come from one intervention, namely rapamycin, which isn’t even a damage repair intervention, but the other three are. In males, there’s no question that the other three interventions provide additional benefits over and above rapamycin. We are very happy about that, and this strongly justifies and motivates us to conduct similar experiments in the future with other interventions and the same interventions at different doses.

The difficulty, of course, is that the experiments are relatively inexpensive. This particular experiment, which we are nearing the end of, cost three and a half million dollars. There are ways we can pare that down without compromising the information gained all that much, but it will still be in that order of magnitude. So, I’m doing what I do: spending my time on stage, on camera, and the phone, trying to get people to write checks. We are hoping to kick off the next study quite soon. After all, people care about their longevity.

Jacobsen: They tend to fear the process of dying more than death itself. With your extensive experience and connections in longevity research, what would you recommend for individuals to practice, especially those in middle-income households, to benefit from rational and enlightened self-interest? I recall you mentioning “listen to your body” in prior interviews. Beyond that, what would you suggest?

de Grey: First and foremost, listening to your body remains my main advice because people differ significantly. The subtle details of individual metabolisms vary from person to person and are crucial for optimization. Beyond general advice like not smoking, avoiding serious overweight, and maintaining a reasonably varied diet, it’s essential to find what works for you.

People often compare me with Ray Kurzweil in this context, noting that I don’t take any supplements while Ray takes 200 a day. The difference lies in our circumstances. Ray drew a lot of short straws, with a family history of cardiovascular disease and type 2 diabetes in his thirties. The difference between us is not in our thinking but in the problems we’re addressing.

I also emphasize that focusing solely on oneself could be better. Why are you concerned only about yourself? It is fashionable to care about your kids and parents. Even without considering that, people of different ages have varying probabilities of benefiting from the work people like me do. Regardless of age, there shouldn’t be any complacency or fatalism because the timeline of breakthroughs is unpredictable. People in 1900 thought powered flight was impossible, only to be proven wrong three years later. Conversely, Leonardo da Vinci’s designs for powered flight took 400 years to be realized. It can go either way, and we don’t know.

We will reach longevity escape velocity within 12 to 15 years, which means the second half of the 2030s. If we do, most people over 50 will be able to benefit, which is pretty good. But I always stress that there’s at least a 10% chance that we won’t get there for 100 years because we may hit unforeseen obstacles. So, you will benefit yourself probabilistically, no matter how old or healthy you are.

And the final thing I want to say is that the most important thing to avoid is stupid early deaths. When people ask me what I do, apart from saying I don’t take supplements, I say I don’t accept seminar invitations to dangerous countries. I wear a seatbelt even in the back seat. Things like that are quite important, too. Over and above all, the thing to do is contribute to the mission, one way or another, to the crusade, thereby hastening the arrival of the defeat of aging.

And whether that means writing me a check, interviewing me, advocating among your family, friends, and colleagues, or lobbying Congress, it could mean anything. I’m delighted that a wide and diverse community is doing all those things now. I often think back to 20 years ago when there was just me. I’m very proud of the contribution I’ve made to building that community, quite apart from the contribution I’ve made to science.

Jacobsen: What is the Alliance for Longevity Initiatives?

de Grey: The Alliance for Longevity Initiatives is one of the organizations I have seed-funded recently. It was well spent because they are a 501(c)4, which, for those who don’t know, is a bit different from a 501(c)3, which is what the LEV Foundation is. A (c)3 is a charity where you get tax advantages for donating, but it is restricted in what it can do. In particular, it is not allowed to lobby elected representatives.

Conversely, with (c)4s, you don’t get the tax benefit, or at least it works differently, but they are allowed to lobby, and that’s what the Alliance for Longevity Initiatives does. It has masterminded many things over the past few years and has more to come. One thing it did was set up a congressional caucus of a dozen congresspeople who care about aging and are in a position to influence legislation. An even more important thing they’ve done now is at the state level. They worked with the state senator in Montana to draft and push through legislation that expands the Right to Try Act.

The Right to Try Act was passed at the federal level several years ago, and it says that if you are terminally ill and you have exhausted all the options for approved treatments for whatever is wrong with you, then you are allowed to access things that are not yet approved as a last resort. Fine. But most of us would prefer not to be terminally ill in the first place. So what happened in Montana was they passed something that said that as long as the treatment in question has passed phase 1 of clinical trials, it got through the safety side but not anything to do with efficacy yet, not the expensive phases 2 and 3, you can access it in Montana however healthy you are.

You do not have to be ill. This is significant. Numerous drugs have passed Phase 1 trials but have yet to progress further. Phases 2 and 3 are still in progress or have been abandoned due to a lack of funding. Regardless, this is immensely important.

Moreover, the race is on to replicate that legislation in other states and possibly at the federal level. There was a recent setback. The senator in Montana who initiated this ran in the Republican primary for federal Congress and did not win. Consequently, he will not be able to pursue it at the federal level, but he can continue his efforts in Montana and set an example for other states. I am hopeful that this initiative will continue.

Jacobsen: What is the Healthspan Action Coalition?

de Grey: This is another organization that we have more than seed-funded. The Healthspan Action Coalition is a sister organization to the LEV Foundation. As its name implies, it focuses on building coalitions.

I build communities of crusaders, activists, and like-minded individuals. The Healthspan Action Coalition focuses on being much more diplomatic and politically correct and bringing together a broad array of people with diverse interests under the understanding that nearly all diseases and disabilities, even those with early onset in childhood, have aspects in common with aging. Research on aging, therefore, benefits everyone. The coalition aims to have an increasingly louder voice in the corridors of power, akin to the A4LI, but in a very different manner.

Two exceptional individuals lead it. Bernie Siegel, who 20 years ago became a prominent spokesperson for the regenerative medicine community, organized the World Stem Cell Summit for most of those years, a conference that has been a powerhouse of networking and community building. The other leader is Melissa King, who served as the executive director of the California Institute for Regenerative Medicine (CIRM) for the first eight years. Both are titans in this field and are now laser-focused on aging. The HSAC is doing an enormously important job that will become increasingly influential over the years.

These individuals must have extensive experience in being diplomatic and politically savvy, areas that take work to come to me. My strengths lie in being more outspoken, which has advantages and disadvantages.

Jacobsen: When discussing transplantation on demand, a concept advocated by the LEV Foundation, what are some potential pathways for this to become a reality? Once the technology is mastered, what are the different ways it can be implemented or requested?

de Grey: We should probably discuss this aspect further on our website. This particular area of interest is connected to one organization we have seed-funded, Kain Ice. Kain Ice is essentially a reboot of a previous company, Aragost, run by the same individual. The technology this company is pursuing is related to cryopreservation. As many people know, I have been a strong proponent of cryonics for a long time, the idea of preserving individuals at very low temperatures shortly after they have been declared legally dead in the hope that we may be able to revive them in the future. However, it has long been recognized that this technology would have enormous value in organ transplants, as currently; many people die on waiting lists because there is no available organ that is sufficiently compatible with their immune system.

The primary issue is that organs decay rapidly, necessitating immediate transplantation from donor to recipient. This urgency means that organs can only be transported over long distances with significant degradation. The goal is to extend, ideally indefinitely, the period during which an organ remains viable by storing it in liquid nitrogen. Simplistic methods of cryopreservation, however, cause substantial damage to the organ beyond any preexisting damage. This problem also applies to cryonics.

Thus, this research area aims to discover methods for cryopreserving organs or individuals with minimal damage. A significant breakthrough occurred about 30 years ago when Greg Fahy and his colleagues at 21st Century Medicine developed a technique called vitrification. Vitrification involves an intricate mixture of cryoprotectants that allows an organ to solidify without forming ice crystals, substantially reducing damage. However, this method does not eliminate damage, as cryoprotectants are somewhat toxic, and large-scale fracturing or cracking can still occur in the organs, which is detrimental to their function upon warming.

Kain Ice is focused on an innovative technology called insufflation. This technique involves pumping cold gas through the vascular system to cool the organs more rapidly, effectively addressing toxicity and fracturing issues. The gas used in this process is helium. The aim is to preserve organs to minimize damage, enabling them to be stored and transported as needed for transplantation.

Jacobsen: Regarding the original seven pathways of aging and disease involving damage to genetics, cells, and gross anatomy, which do you believe have made the most progress and still require significant research to achieve practical application?

de Grey: First, it is not a matter of one over the other. There has been substantial progress, but much work remains. Starting with stem cell research, this field addresses cell loss. A significant development in recent years is partial reprogramming in vivo, eliminating the need to transplant new stem cells outside the body. Instead, it enhances the resident cells’ stem-like properties, restoring regenerative capacity. This is crucial. Additionally, we have made enormous strides in manipulating stem cells in the laboratory before transplantation, perfecting stem cell therapies.

One example of notable progress is in treating Parkinson’s disease, a condition caused by the loss of dopaminergic neurons in the brain. This research advances significantly, providing a promising outlook for addressing aging associated with cell loss.

The method to address this issue, specifically replacing those cells with stem cells, was demonstrated to be effective around 30 years ago, though only sporadically, as the necessary techniques to generate the correct type of cells needed to be better understood at the time. Success was, therefore, rare but remarkable when it occurred. With our advanced understanding of stem cell manipulation, efforts are being renewed. Three or four clinical trials are underway, and considerable optimism exists. Although there is still work to be done, progress is promising.

Turning to cancer, in the early days, I proposed a strategy to control cancer by inhibiting telomere elongation. This was undoubtedly the most ambitious and challenging of my proposed approaches. Many people agreed that while the rest of SENS made sense, this particular approach seemed unfeasible. I understood the skepticism and recognized the need for improvement. Enter Jerry Shay, an outstanding Dallas scientist and a leading telomere research figure. He identified a drug that kills cells attempting to elongate their telomeres rather than merely stopping telomeres from elongating. This drug essentially disrupts the telomere in conjunction with telomerase, effectively turning telomerase into a suicide gene. This drug is now in phase 2 clinical trials, and I am very hopeful about its potential. I refer to it as WILT 2.0, a more straightforward realization of my original concept.

I could continue, but the point is clear: there is progress in every area. I highlight the advancement in partial reprogramming and stem cell research. This trend is seen across all categories. Each of the seven categories now has multiple alternative approaches addressing them.

Jacobsen: What other organizations do you think do important frontline work in regenerative medicine?

de Grey: There are many now. Let’s consider the private sector for a moment. One person to whom I owe an enormous debt of gratitude for his contributions to my work over the past several years is Michael Greve from Germany. He amassed considerable wealth during the early days of the Internet in Germany and, around 2016-2017, began making substantial investments in aging research. Much of this investment took the form of donations to the SENS Research Foundation, which significantly enhanced our capabilities.

While he no longer donates due to the current economic climate, I hold no blame because he has redirected his funds into investments in start-up companies. These start-ups are among the most critical in the field. I say this not only because many of them are spin-offs from the SENS Research Foundation but also because he employs the same criteria I use to select projects: he focuses on areas grossly neglected by the rest of the world.

Among these companies are Revel Pharmaceuticals, Cyclarity, and Elastin, which are undertaking vital work and are essentially unique in their fields. This is fantastic. Additionally, extensive work is being conducted in academia, although most are tangential to the damage repair philosophy and paradigm.

It would help if you had tangential work as well. I’m happy with the increasing diversity that’s appearing out there. 

Jacobsen: There is mythos around regenerative medicine, the idea being hopeful and skeptical, even satirical to others. What about one day you take a pill, which does a lot of the core work in repairing damage and reversing or stalling aging? Is there anything on the horizon, like a single fix, that you could take orally, for instance? 

de Grey: Not a single fix. But, of course, we have to define precisely what we mean by single here. I often give examples of MMR, the measles, mumps, and rubella vaccine. Of course, it’s not a single vaccine; it’s all three vaccines that you happen to get in one injection. Similarly, you can certainly imagine a scenario in which one would have an injection of 300 things at the same time. From the recipient’s point of view, it would be a single thing, but only from that point of view.

Certainly, we can say that, by and large, things that we supply that have a large effect on aging will need to be injected rather than delivered orally simply because you can’t do gene therapies and cell therapies orally. But injections aren’t so costly. The one thing that might have a big effect and that might even be supplied orally is a good senolytic. At this point, we have several, and this is another example of an alternative approach that, back 20-odd years ago, I had never even conceived. I knew that senescent cells were accumulating and needed to be removed, but I assumed that we would have to do it with some suicide gene therapy, some approach that would directly attack the gene expression differences in senescent cells. I never considered that one might be able to find small molecules that would selectively kill such cells.

But we have those now. We don’t need those who are as selective as they are and to bear the most selective approach for cutting off senescent cells. The most powerful one involves the immune system and enhances it to better identify and eliminate cells through natural immune clearance. However, the point is that senescent cells have diverse consequences for the body. When Judy Campisi first considered the possibility that senescent cells might be actively toxic rather than merely inactive, it was around the same time that I was considering the idea that cells full of mutant mitochondria might be actively toxic. She and I had interesting conversations back then about this, and her focus back then was restricted to cancer. She was saying, well, some of the things these cells are secreting will be bad for neighbouring cells that may already be precancerous. The senescent cell itself is protected from further uncontrolled cell division, but the ones next door might not be, and so this might be oncogenic.

That was the thinking at that time. However, as time passed, we discovered that the SASP, or senescence-associated secretory phenotype, can have many diverse and negative effects that may contribute to various aspects of aging. Our current experiments show that it could be doing better, but that’s probably for technical reasons rather than because analytics are a bust in general. So, we need to work more on analytics.

It’s possible that orally available analytics can be improved in terms of efficacy. However, I suspect the approach will have a limit, and we will do better with the immune attack or optimization I mentioned. Yes, that’s an example. 

Jacobsen: What project do you think is your most promising outside experiment on mice? 

de Grey: Our project at the SENS Research Foundation, and of course the variations on that same theme we want to pursue, cost money, but it offers the best value for money in the field regarding the amount of information gained per dollar spent. It is inherent in the definition of any divide-and-conquer strategy, including for aging, that you have two phases. You develop the individual components, and then you put them together.

When you put them together, you find out what works, what combinations are synergistic, and which are antagonistic and cancel each other out. The absolute priority of the field ought to be conducting dozens of these large-scale experiments. We need 1,000 mice, maybe 4 or 5 different interventions combined in various subsets, and checking both healthspan and lifespan, as we are doing at the SENS Research Foundation. We perform a lot of different healthspan measures. So, yes, that’s what needs to be done.

Jacobsen: How can people get involved through time, skills, or expertise? 

de Grey: There are many ways to get involved now, and that’s very important because not everyone, only some, is financially. Some people need to decide which areas of science to enter. Not everyone is Peter Thiel. This reminds me to mention one of the other organizations I started a few years ago, which I’m extremely proud of. It has gone from strength to strength.

It’s now called the Longevity Biotech Fellowship. Originally, it was called Less Death. Every few months, they run a retreat somewhere in the world, bringing together about 50 newcomers to the field and a dozen veteran mentors. The purpose is not only to educate but also to network and form partnerships and affiliations. It’s been wildly successful.

They’ve run five retreats so far, and they’ve had an unbelievable success rate in terms of impact on people’s careers. So, whenever anyone asks how they can help, I direct them to the Longevity Biotech Fellowship. It works.

Jacobsen: What do you consider the moment when you decided that aging was the field to dedicate your life to? 

de Grey: Oh, I can pinpoint that. It wasn’t exactly a moment but a gradual realization over a year or two in the early nineties when I realized that my wife, a senior biologist nearly 20 years older than me, was not interested in aging. This was so bizarre that it took me a while to accept and believe it was true. But it wasn’t just her but all the other biologists I met through her.

But it had never crossed my mind that anybody could not think aging was the world’s most important problem and, of course, that it was a problem potentially solvable with medicine. Biologists are working on this. Yes, it’s a hard problem, so you don’t hear much about it, but I had yet to experiment with asking anybody about this. Gradually, I noticed that we should have talked about aging. I started asking questions, and after getting over the shock over a year or two, I concluded that I had to switch fields.

I have been working in artificial intelligence research for quite some time. I had convinced myself that I was good at working on hard problems, and I also knew that switching fields often worked well. People come in not encumbered by the conventional wisdom of their new field and look at a problem differently. So, I can contribute, and the rest is history.

Jacobsen: Aubrey, thank you very much again for your time today. 

de Grey: It’s my pleasure. Thank you. Thanks for having me back. You’re welcome.

Jacobsen: Thanks so much. 

De Grey: See you next time.

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In-Sight Publishing by Scott Douglas Jacobsen is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. ©Scott Douglas Jacobsen and In-Sight Publishing 2012-Present. Unauthorized use or duplication of material without express permission from Scott Douglas Jacobsen strictly prohibited, excerpts and links must use full credit to Scott Douglas Jacobsen and In-Sight Publishing with direction to the original content.